Nitric Oxyde Concentration in Chronic Obstructive Pulmonary Disease Patients - SANOB Study
Nitric Oxyde Concentration in Chronic Obstructive Pulmonary Disease Patients - SANOB Study
-  Among many other causes, Bronchial obstruction in Chronic Obstructive Pulmonary Disease
 (COPD) is also caused by inflammation of peripheral airways walls.

 -  Neutrophils and other inflammatory mediators like Interleukin-6 (IL6), Interleukin-8
 (IL8), Interleukin-1 alpha (IL-1 alpha),Interleukin-1beta (IL-1 beta), Tumor Necrosis
 Factor alfa (TNF-alfa), Reactive Oxygen Species (ROS), Leukotriene B4 (LTB4), Nitric
 Oxyde (NO) are implicated in the inflammation.

 -  NO is produced in response to physical and chemical stress on bronchial epithelium and
 plays a critical role in small airways remodelling

 -  Exhaled NO concentration is usually used to monitor bronchial inflammation

 -  The relationship between stretch and strain of small airways and bronchial inflammation
 is not well understood.

 -  The investigators hypothesis is that cyclic opening and closure of peripheral obstructed
 airways through the consequent stretching and strain acting on them can provoke an
 inflammatory response which can be monitored by exhaled NO.

 -  The pharmacological effects of bronchodilators may play a role on bronchial inflammation
 by reducing the stretching stress on bronchiolar walls thus reducing the production of
 NO in exhalate

 -  Data about these physiopathological aspects is missing in literature.
Bronchial inflammation in COPD represents one of the main causes of not fully reversible
 obstruction and airflow limitation. The main inflammatory cells involved are represented by
 the neutrophils, while some inflammatory mediators like Interleukin-6 (IL6), Interleukin-8
 (IL8), Interleukin-1 alpha (IL1alpha), Interleukin-1 beta (IL1beta), Tumor Necrosis Factor
 alfa (TNFalfa), Reactive Oxygen Species (ROS), Leukotriene B4 (LTB4) and Nitric Oxide (NO)
 provoke the disruption of the elastic alveolar bonds that support the small airways, thus
 invalidating their physical and mechanical characteristics. During tidal volume respiration,
 in such patients, the chronically obstructed small airways are subjected, the investigators
 suppose, to one of the following effects:

 -  a total closure of the smaller bronchioli causing atelectasis

 -  a cyclic opening and closure of the airways thus provoking friction and strain stress
 and an inflammatory response of mechanical origin.

 The Fraction of Exhaled Nitric Oxyde (FeNO) concentration is largely used in clinical
 practice as a marker to monitor the lung inflammatory status. Formoterol and Salmeterol are
 two of the most used Long Acting Beta 2 Agonists (LABA) for inhaled therapy of COPD,
 representing the basis of the bronchodilator therapy in this disease.

 The purpose of the study is to evaluate the possible mechanical origin of the bronchial
 inflammation and then the capacity of inhaled LABA in acute conditions to modify the trend of
 production of NO by reducing stretching and strain forces. Thus the possible decline of
 exhaled NO concentration will be used as an index of the small airways inflammatory state
 occurring after inhaled therapy.

 To do this the investigators will measure the exhaled NO concentration in COPD patients with
 moderate to severe obstruction, that is a Forced Expiratory Volume less than 70% of predicted
 value (FEV1<70%pred). The evaluation will be done in four different moments:

 1. at baseline, after 72 hours of pharmacological washout conditions

 2. at 30 minutes after the assumption of inhaled therapy (Salmeterol 50 mcg or Formoterol
 12 mcg in double blind conditions)

 3. at 60 minutes after step 2

 4. at 180 minutes after step 2 Together with NO concentration, also the Respiratory
 Frequency and Tidal Volume will be registered during each evaluation.

 All the subjects will be inpatients accessing a respiratory rehabilitation unit or
 outpatients of the ambulatory service. After every NO measure, a functional respiratory
 assessment will be made (spirometry, plethysmography, Carbon Monoxide (CO) diffusion lung
 test, Single Breath N2 washout test), together with an arterial blood gas analysis.

 At every step a dyspnoea assessment will be made by Visual Analogic Scale, while Modified
 Medical Research Council (mMRC) scale will be assessed at the beginning of the test.

 Every patient will repeat the four step assessment after 72 hours, while a double blind
 pharmacological crossover will be performed, thus creating a controlled study in witch every
 patients, at the end of the study, will take Salmeterol and Formoterol in a randomized way.

 For the study duration all the patients will perform a pharmacological washout (living the
 short acting inhaled Beta 2 agonists as rescue medication)
Inclusion criteria:

 -  Signature of informed consent

 -  COPD patients with age raging from 50 to 85 years old

 -  Patients with at least a history of COPD of one year

 -  COPD patients clinically stable in the last three months

 -  COPD subjects with FEV1 (Forced Expiratory Volume in 1st second)<70% of predicted
 value

 -  FEV1/FVC (Forced Expiratory Volume in 1st second/Forced Vital Capacity) <88% (males)
 or <89% (females) of LLN (Low Levels of Normality)

 -  COPD former or active smokers with at least a smoking history of 20 pack year

 Exclusion Criteria:

 -  Acute Bronchial Exacerbation at recruitment

 -  Fertile women with age between 18 and 50 years old or with active period

 -  Pregnancy

 -  Subjects enrolled in other clinical trials or that have taken part in one of them in
 the month preceding the enrollment.

 -  FEV1/FVC more than 70% of predicted value in basal conditions

 -  FEV1 more than 70% of predicted value in basal conditions

 -  Known deficit of alpha 1 antitrypsin

 -  Subjects that underwent a Lung Volume Reduction Surgery (LVRS)

 -  Subjects with known positivity to Human Immunodeficiency Virus (HIV)

 -  Misuse of alcool or drugs

 -  Lack of compliance in performing respiratory tests

 -  Subjects not capable to follow the study prescriptions because of psychic disorders or
 language problems.

 -  Long Term Oxygen Therapy with flows > 6 litres per minute (l/min) at rest