Chest
Volume 147, Issue 1, January 2015, Pages 232-241
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Recent Advances in Chest Medicine
Recent Advances in Dyspnea

https://doi.org/10.1378/chest.14-0800Get rights and content

Dyspnea is the most prevalent symptom among patients with cardiac and respiratory diseases. It is an independent predictor of mortality in patients with heart disease, COPD, and the elderly. Studies using naloxone to block opioid-receptor signaling demonstrate that endogenous opioids modulate dyspnea in patients with COPD. Neuroimaging studies support a cortical-limbic network for dyspnea perception. A 2012 American Thoracic Society statement recommended that dyspnea be considered across three different constructs: sensory (intensity), affective (distress), and impact on daily activities. The 2013 GOLD (Global Initiative for Chronic Obstructive Lung Disease) executive summary recommended a treatment paradigm for patients with COPD based on the modified Medical Research Council dyspnea score. The intensity and quality of dyspnea during exercise in patients with COPD is influenced by the time to onset of critical mechanical volume constraints that are ultimately dictated by the magnitude of resting inspiratory capacity. Long-acting bronchodilators, either singly or in combination, provide sustained bronchodilation and lung deflation that contribute to relief of dyspnea in those with COPD. Opioid medications reduce breathing discomfort by decreasing respiratory drive (and associated corollary discharge), altering central perception, and/or decreasing anxiety. For individuals suffering from refractory dyspnea, a low dose of an opioid is recommended initially, and then titrated to achieve the lowest effective dose based on patient ratings. Acupuncture, bronchoscopic volume reduction, and noninvasive open ventilation are experimental approaches shown to ameliorate dyspnea in patients with COPD, but require confirmatory evidence before clinical use.

Section snippets

Clinical Impact

Among 2, 258 patients with severe COPD (postbronchodilator FEV1 < 50% predicted), breathlessness was most problematic upon awakening in the morning.1 A majority of these patients reported daily and/or weekly variability in their breathing difficulty. Treatment with one long-acting bronchodilator was associated with less variability during the day.1 Women generally report more breathlessness than men.2 Pregnancy and menopause are important life events in women that are often associated with

Neurobiology of Dyspnea

A neurobiologic model that involves the respiratory and nervous systems has been used to describe our understanding of the perception of dyspnea18, 19, 20 (Fig 1). The respiratory system is modulated continuously by excitatory and inhibitory neuropeptides that act from sensory neurons to central networks.19 Endogenous opioids are inhibitory neuropeptides that affect respiratory rhythm and nociception. Studies have demonstrated that these substances modulate breathlessness in patients with COPD.

Exercise Testing to Investigate Dyspnea

Controversy has existed concerning the optimal exercise modality (treadmill vs cycle ergometer) to evaluate the intensity of dyspnea in the laboratory. Recent studies have confirmed that when the increase in work rate is matched between these two modalities, dyspnea ratings are similar for any level of ventilation.27, 28 Thus, either modality can be used as a stimulus to assess dyspnea.

The rise in dyspnea intensity during exercise in COPD is more closely linked to the decrease in dynamic

Measurement of Dyspnea

In a 2012 update, the American Thoracic Society proposed that dyspnea be considered across three different constructs: sensory, affective, and symptom impact or burden (Table 1).20 Generally, the intensity (sensory) and distress (affective) are considered in response to a specific stimulus, such as an exercise test or RLB, whereas the impact of dyspnea on an individual's daily activities may be considered in patient care or in a clinical trial.

Most instruments currently used to quantify

Dyspnea to Categorize Disease Severity

The GOLD (Global Initiative for Chronic Obstructive Lung Disease) committee recommended that symptom scores be used as one dimension to categorize the severity of COPD.37 Scores of 0-1 and 2-4 on the modified Medical Research Council (mMRC) scale differentiated those with less and more dyspnea, respectively.37 In a 2014 update, the GOLD committee revised this recommendation and prioritized that a comprehensive symptom assessment be used, including the COPD Assessment Tool and the Clinical COPD

Dyspnea as a Treatment Outcome

As breathing difficulty is the primary reason that most patients with cardiorespiratory disease seek medical care, it is reasonable to expect that relief of dyspnea would be a major treatment goal. The GOLD committee has recommended a treatment paradigm based on the severity of breathlessness on the mMRC scale.37 For example, different therapies are recommended for those patients with less dyspnea (mMRC = 0-1) and those with more dyspnea (mMRC = 2-4). The Canadian40 and Spanish41 COPD

Inhaled Medications in COPD

Bronchodilators reduce airway smooth muscle tone, improve airflow, and deflate the overinflated lung. Both classes of bronchodilators (as single agents) have consistently increased the resting IC in patients with COPD by an average of about 200 mL, or about 15%, from baseline. The improvement in IC is more pronounced in patients with resting lung hyperinflation. Changes of this magnitude have generally been associated with improvements in dyspnea and exercise endurance time.32

Randomized

Therapies in Idiopathic Pulmonary Fibrosis

Swigris and Fairclough68 proposed the use of the baseline and transition dyspnea indexes and the UCSD SOBQ to quantify patient-reported dyspnea in clinical trials involving patients with idiopathic pulmonary fibrosis (IPF). In two prospective studies involving patients with IPF, there was no beneficial treatment effect for dyspnea ratings on the TDI between bosentan and placebo over 1 year.69, 70 In a phase 3 trial in patients with IPF, King and colleagues71 reported no significant difference

Pulmonary Rehabilitation

Wadell and colleagues72 reported clinically meaningful improvements in the affective dimension (breathing-related anxiety) and symptom impact (TDI) of dyspneaafter 8 weeks of pulmonary rehabilitation compared with usual care in patients with COPD. They did not report clinically meaningful improvements in the sensory (intensity) domain.

Opioids

Opioids modulate the perception of dyspnea by decreasing respiratory drive (and associated corollary discharge), altering central perception, and/or decreasing anxiety.73 Fear of overdosing and the development of respiratory depression have historically limited the use of opioids for relieving dyspnea in clinical practice. However, recent statements by the American College of Chest Physicians (CHEST),74 the Canadian Thoracic Society,75 and the American Thoracic Society20 advocate that oral and

Novel Investigational Therapies

Novel treatments have been proposed for relief of dyspnea.84 Although each is based on a scientific rationale, supporting evidence from randomized clinical trials for these novel therapies is minimal and/or inconsistent. Consequently, these therapies are considered investigational at the present time.

Conclusions

Recent advances have expanded our understanding of the neurobiology of dyspnea. Laboratory investigations have demonstrated the role of endogenous opioids in modulating the perception of dyspnea in patients with COPD. Neuroimaging techniques have identified brain activity in the cortical-limbic network in healthy subjects when breathing discomfort/difficulty is provoked by a specific respiratory stimulus. Awareness of the different constructs of dyspnea has been a major advance that can be

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Mahler serves as a consultant to Boehringer Ingelheim GmbH, Forest Laboratories Inc, GlaxoSmithKline plc, Novartis AG, and Sunovion and serves on advisory boards of Forest Laboratories Inc, GlaxoSmithKline Plc, Merck & Co Inc, Novartis AG, Pearl Therapeutics Inc, and Sunovion Pharmaceuticals Inc. The Clinical Trials Office at Dartmouth-Hitchcock Medical Center has received grant

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