Farmaci inalatori e dispnea nell asma e nella BPCO. Federico Lavorini

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1 Farmaci inalatori e dispnea nell asma e nella BPCO Federico Lavorini Dept. Experimental and Clinical Medicine Careggi University Hospital Florence - Italy

2 Presenter Disclosures F.L. has received in the last 3 years fees for lectures, advisory boards and reimbursements for attending meetings from the following pharma companies: - AstraZeneca, - Boehringer Ingelheim, - CIPLA, - Chiesi, - TEVA. The content of this talk represents the personal opinion of the presenter and does not necessarily represent the views or policy of the A.O.U. Careggi.

3 Am J Respir Crit Care Med 2012; 185(4): A subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. Corollary: The experience of dyspnea derives from interactions among multiple physiological, psychological, social and environmental factors, and may induce secondary physiological and behavioral responses.

4 A neurobiologic model of dyspnea in COPD Red arrows represent neural inputs reaching the somatosensory cortex and contribute to dyspnea Mahler DA and O Donnell DE (eds). Dyspnea, mechanisms, measurement and management 2014, CRC press.

5 Domains of Dyspnea Measurement (ATS 2012) Domain Definition Measurement Sensoryperceptual experience Affective distress Symptom impact or burden Measures of what breathing feels like «What does your breathing feel like and how bad is it?» Measures of how distressing breathing feels «How distressing or unpleasant is your breathing?» Measures of how dyspnea affects functional ability or health status «How does breathing affect your functional ability?» Single-item intensity ratings (e.g., Borg scale, VAS) Descriptors of specific sensations/clusters of related sensations Single-item ratings of severity of distress or unpleasantness Multi-item scales of emotional responses such as anxiety Ratings of disability or activity limitation (e.g., MRC dyspnea scale) Ratings of functional ability Scales of quality of life, health status Parshall MB, et al; ATS Committee. Am J Respir Crit Care Med 2012; 185:

6 Dyspnea Intensity: Sensory-Perceptual Domain

7 Exertional dyspnea in mild COPD is associated with the combined deleterious effects of higher ventilatory demand and abnormal dynamic ventilatory mechanics.

8 Lung Volume (% predicted TLC) Operating Lung Volumes during Exercise 120 Control (n=21) COPD (n=21) TLC 100 IC IRV VT EELV Rest Iso-V E Peak Rest Iso-V E Peak (78 L/min) (68 L/min)

9 Dyspnea (Borg Scale) Dyspnea Intensity with Increasing COPD Severity very severe Normal COPD (FEV 1 quartile): IV (worst) III II I (mildest) Ventilation (L/min) O Donnell DE, et al. Chest 2011.

10 Reduced chemosensitivity to hypoxia and blunted perception of dyspnea may predispose asthma patients to fatal attacks.

11 Dyspnea Quality: Sensory-Perceptual Domain

12 Dyspnea Intensity- Work rate Relationships Quality of Dyspnea during Exercise Breathing discomfort (Borg scale) maximal very, very severe very severe severe somewhat severe moderate slight very slight none COPD Health Work rate (% predicted maximum) Increased Work/Effort Unsatisfied Inspiration Inspiratory Difficulty Heavy Shallow Rapid Tight Chest Expiratory Difficulty * Selection frequency (% of group) p<0.05 vs Health * * * Health COPD O Donnell DE, et al. AJRCCM 1997;155:

13 Qualitative Descriptors of Exertional Dyspnea Increased Work/Effort Unsatisfied Inspiration Inspiratory Difficulty Heavy Normal COPD ILD * * * * Shallow Rapid * * Tight Chest Expiratory Difficulty *p<0.05 vs. Normal Selection Frequency (% of subjects) Selection Frequency (% of subjects) Selection Frequency (% of subjects) O Donnell DE, et al. J Appl Physiol 1998.

14 QUALITIES OF DYSPNEA Work/effort Arise through cortical motor command Tightness Stimulation of airway receptors Hunger for air Imbalance when ventilation increases ATS Statement. Am J Respir Crit Care Med 2012

15 Am J Respir Crit Care Med 2012; 185(4): many advances in the understanding of dyspnea mechanisms., but not yet translated into improved therapies. The field is plagued by studies involving small numbers of patients in what are often poorly controlled trials..there are still no drugs for which relief of dyspnea is an approved indication; rather, drugs are approved for the treatment of diseases in which dyspnea is a prominent symptom.

16 A neurobiologic model of dyspnea in COPD Anxyolitics Opiates Oxygen Furosemide Bronchodilators Heliox ICS

17 39 publications reviewed; only 17/39 with high strength of research design. Although limited literature examining the efficacy of nebulized medications for the treatment of dyspnea does exist, the results of these publications vary. Whereas some authors acknowledge that nebulized medications are effective for treating dyspnea, others have found widely inconsistent results or have cautioned against its use.

18 Comprehensive Approach to Management of Dyspnea in Advanced COPD Marciniuk DD, et al; CTS Committee. Can Respir J 2011; 18:

19 Stepwise Approach to Therapy Dyspnea (Borg Scale) very severe severe somewhat severe moderate slight very slight nothing at all Endurance exercise time (min) O Donnell DE. Med Sci Sports Exerc 2001;33:S647-S655.

20 Bronchodilators Bronchodilators improve different physiological correlates associated with dyspnea in COPD patients; Both LABAs and LAMAs improve lung hyperinflation at rest and during exercise and enhance exercise endurance; Medications from both bronchodilator classes have demonstrated significant improvements in dyspnea, related to exercise and daily activities compared with placebo. Parshall MB, et al; ATS Committee. Am J Respir Crit Care Med 2012; 185:

21 Lung Volume (%pred TLC) Improvements in Respiratory Mechanics during Exercise in Response to Tiotropium Tidal Pes / V T (cmh 2 0/L) Pre-dose IC Post-dose normal Pleural Pressure (cmh 2 0) VO 2 (% predicted max) Bronchodilator therapy was associated with a consistent reduction in operating lung volumes with improved effort-displacement ratios. Adapted from O Donnell DE, et al. J Appl Physiol 2006;101:

22 Improvements in dyspnea with bronchodilators in COPD Constant work rate cycle exercise Daily activities : Minimal clinically important difference

23 Most patients were at least moderately symptomatic based on BDI score

24 All patients TDI Responders (<1 Unit) IND/GLY provides significant benefits compared with tiotropium or SFC in patients with COPD who are experiencing dyspnea.

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26 TDI: UMEC/VIL vs. UMEC Chest 2015, online

27 TDI: UMEC/VIL vs. VIL Chest 2015, online

28 Brit J Clin Pharmacol 2004 = 200 g salbutamol VHC = 400 g salbutamol VHC = 200 g salbutamol DPI = 400 g salbutamol DPI X = Placebo Lung function variables display lower variability and higher sensitivity to bronchodilation than dyspnea intensity (VAS score).

29 11 studies involving patients treated with either ICS or oral steroids; Some studies showing improved perception and other studies showing worsened perception of dyspnea after corticosteroid; Firm conclusions cannot be derived from the currently available data.

30 The total breath-holding time and the period of no respiratory sensation after furosemide inhalation were remarkably longer than those after placebo inhalation. These findings indicate that inhaled furosemide alleviates dyspneic sensation during breath-holding.

31 Aims: to investigate the effect of inhaled high (80 mg) doses furosemide on dyspnea intensity («breath disconfort» on a VAS) in healthy subjects. Dyspnea was induced by varying inspired PCO 2 while restricting minute ventilation. Furosemide deposition was optimised by controlling inspiratory flow ( ml/s) and Vt (15%VC) Conclusions: Neither wellcontrolled aerosol delivery, nor doubling the furosemide dose increase the proportion of responders.

32 Am J Respir Crit Care Med 2012; 185(4): Scientific respiratory societies advocate that oral and pareteral opiods be dosed and titrated for relief of refractory dispnea.

33 GINA guideline lacks specific guidance on treatment of refractory dyspnea in asthma.

34 «Opiodis modulate the perception of dyspnea by decreasing respiratory drive (and associate corollary discharge), altering central perception and/or decreasing anxiety»

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37 Methods: healthy (fit) men with chest wall strapping (CWS) decreasing vital capacity by 20%; nebulized Fentanyl (FC 250 μg) or Placebo (PLA); constant work rate cycle exercise (85% of maximal incremental work rate). Conclusions: the results do not support a role for intrapulmonary opioids in the neuromodulation of dyspnea in health nor do they provide a rationale for nebulized fentanyl for treating dyspnea due to mild, restrictive pulmonary disorders.

38 Effects of Oxygen and Bronchodilators on Exercise BD: bronchodilators; PL: placebo; RA: room air. By combining the benefits of BD (reduced hyperinflation) and O 2 (reduced ventilatory drive), additive effects on dyspnea are observed in normoxic COPD patients.

39 Key Messages Dyspnea is a complex multi-dimensional symptom; No unique afferent source of dyspnea; Evaluation of dyspnea in the sensory, affective and impact domains is suggested; Increase dyspnea intensity during activity in COPD is, in part, related to increased sense of effort (increased motor drive and central corollary discharge); Interventions that relieve dyspnea intensity in COPD reduce central drive, improve respiratory mechanics/ muscle function and enhance neuromechanical coupling.

40 Key Messages (cont.) Literature review found mixed evidence regarding the use of nebulised medication for dyspnea relief; Differences in the Methods of inhalation, nebuliser systems, drugs properties, and patients characteristics may account for the discrepancies; Larger and long-term clinical trials are needed to assess which disease population may benefit most from nebulised drugs; In the meantime, the use of nebulised medications may be recommended if the advantages outweight the disadvantages.

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