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Acute Bronchodilation and Bronchial Inflammation: Nitric Oxyde Concentration in Chronic Obstructive Pulmonary Disease Patients. Stretching of Airways and Nitric Oxide in Bronchodilation, SANOB Study

Phase 4
45 Years
90 Years
Not Enrolling
Chronic Obstructive Pulmonary Disease (COPD)

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Trial Information

Acute Bronchodilation and Bronchial Inflammation: Nitric Oxyde Concentration in Chronic Obstructive Pulmonary Disease Patients. Stretching of Airways and Nitric Oxide in Bronchodilation, SANOB Study

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

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

- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Basic Science

Outcome Measure:

Change in exhaled Nitric Oxide concentration after Long acting Beta 2 Agonist assumption

Outcome Description:

The evaluation of exhaled Nitric Oxide concentration will be performed following the schedule below: at baseline (T0), after 72 hours of inhalatory therapy washout 30 minutes (T1) after the assumption of a inhaled bronchodilator (Salmeterol 50 mcg or Formoterol 12 mcg) 60 minutes after T0 (T2) 180 minutes after T0 (T3) every patient will repeat the same four steps in two different days after 72 hours of pharmacological washout, crossing over in blind conditions the bronchodilator taken the previous study day. The measurements of Exhaled NO will be performed by Medi-Soft Exp'air FeNo concentration sampling device, Sorinnes (Dinant) Belgium. At every step, will be performed 3 measurements at different flows (50 ml/sec, 100 ml/sec, 150 ml/sec and 350 ml/sec), for a total of 12 valid measurements for each step. Alveolar NO and Bronchial Wall NO concentrations will be taken in consideration.

Outcome Time Frame:

- At baseline, after 30 minutes of LABA assumption, after 60 minutes of LABA assumption, after 180 minutes of LABA assumption

Safety Issue:


Principal Investigator

Pierachille santus, Md, PhD

Investigator Role:

Study Director

Investigator Affiliation:

Università degli Studi di Milano-Pneumologia Riabilitativa-Fondazione Salvatore Maugeri-MILANO


Italy: Ethics Committee

Study ID:




Start Date:

May 2013

Completion Date:

December 2013

Related Keywords:

  • Chronic Obstructive Pulmonary Disease (COPD)
  • COPD
  • bronchial inflammation
  • NO concentration
  • small airways
  • LABA
  • Small Airways Stretching
  • Stretch and strain of small airways in COPD
  • Acute LABA effect on NO production
  • Pulmonary desufflation
  • Inflammation
  • Lung Diseases
  • Respiration Disorders
  • Pulmonary Disease, Chronic Obstructive
  • Lung Diseases, Obstructive