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FOT-BOS: Respiratory Impedance and Obliterative Bronchiolitis

Sponsor
IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy (Other)
Overall Status
Completed
CT.gov ID
NCT01255449
Collaborator
(none)
26
Enrollment
1
Location
1
Arm
18
Duration (Months)
1.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of the present study will be to test the hypothesis that changes in within-breath total respiratory input impedance (Zrs) may provide an early evidence of obliterative bronchiolitis after allogeneic hematopoietic stem cell transplantation (HSCT). Before and after HSCT, Zrs will be measured by a modified forced oscillation technique (FOT) during spontaneous breathing both at baseline and 30 min after albuterol inhalation . Such technique may be particularly sensitive to small changes in lung mechanics observed in the early stages of peripheral airflow obstruction.

Condition or Disease Intervention/Treatment Phase
N/A

Detailed Description

1.0 INTRODUCTION

  • Shortly after the introduction of allogeneic HSCT in clinical practice, it was recognized that standard pulmonary function tests (PFTs) are sensitive enough to detect HSCT-related respiratory complications [PMID: 2661259; PIMD: 8823260]. Accordingly, the finding of a progressive obstructive abnormality of new onset was considered as the functional hallmark of obliterative bronchiolitis (OB) [PMID: 16338616; PMID: 19896545]. As a result, routinely performed spirometry has been proposed as a non-invasive tool to monitor the risk of OB in HSCT population [PMID: 17470622]. Yet, due to a peripheral airway involvement in OB, the sensitivity of conventional PFTs for early detection of OB is low [PMID: 2298060]. For instance, it does not exceed 75% in lung-transplanted population as the decrease of forced expiratory volume in 1 s (FEV1) may occur at a stage when the process is already irreversible and potentially life-threatening [PMID: 9246138].

2.0 EXPERIMENTAL HYPOTHESIS

  • Because the branching pattern of the bronchial tree results in an increasingly large number of small airways with a luminal diameter of less than 2 mm in peripheral generations, these airways contribute little to total pulmonary resistance [PMID: 5442364; PMID: 651978]. Intuitively, a large proportion of small airways may be damaged or obliterated without impairing any of the conventional PFTs. In this regard, a previous study [PMID: 12186817] pointed out that indexes of ventilation distribution may provide an early evidence of OB after lung transplantation. In particular, some authors [PMID: 12186817] have found that tests of ventilation distribution invariably deteriorated about 1 yr before a 20% decrease in FEV1 was apparent. Previous studies [PMID: 970731; PMID: 507525] showed that total respiratory input impedance (Zrs), measured by a forced oscillation technique (FOT) during spontaneous breathing, may be particularly sensitive to small changes in lung mechanics observed in the early stages of smoking-related airflow obstruction. Subsequently, it was developed a modified FOT to identify within-breath differences in Zrs, with values of Zrs representing the sum of respiratory system resistance (Rrs) and reactance (Xrs), the latter being the imaginary part of the former [PMID: 14979497; PMID: 19164347]. This method allows the assessment of more breaths and adds a potential quantitative evaluation of instantaneous inspiratory and expiratory Rrs and Xrs before and after external interventions such as a deep inspiration, bronchodilator drugs, etc. Although these effects can be identified when within-breath analysis is performed [PMID: 14979497], most published reports of oscillatory mechanics on chronic obstructive pulmonary disease (COPD) only report total respiratory cycle data [PMID: 1519830; PMID: 10489847].

3.0 STUDY RATIONALE

  • The aim of the present study will be to test the hypotheses that:

  1. post-HSCT changes in within-breath Rrs and Xrs may provide an earlier evidence of OB than standard PFTs. Indeed, the obliteration of terminal bronchioles, observed in up to 48% of OB patients following HSCT [PMID: 17470622], could make the real part of Zrs abnormally high [PMID: 5653219] and ventilation more heterogeneous;

  2. post-HSCT changes of airway responsiveness to acute bronchoactive interventions such as a deep inspiration to total lung capacity and/or a bronchodilator drug (i.e., albuterol) may be detected by our modified FOT. We speculate that these changes may represent an early sign of OB. Although a previous study from our group failed to find an increase in airway responsiveness after HSCT without pulmonary complications [PMID: 18684842], we have recently shown that airway smooth muscle tone may play an active role in the airflow obstruction of OB [PMID: 20724742].

4.0 STUDY DESIGN

  • Before and at regular intervals (2-4 wk onward) after HSCT, patients will attend our laboratory and perform all PFTs measurements in the same order. Firstly, the patient will breathe spontaneously through the modified FOT system for 5 min and then, without disconnecting from the apparatus, perform an inspiratory capacity maneuver and soon after resume spontaneous breathing for the next 2 min. Subsequently, spirometry, transmural total body plethysmography and CO diffusing capacity of the lung (standard PFTs) will be taken in triplicate. Thirty minutes after inhaling four separate doses of 100 μg of albuterol, the modified FOT measurements and standard PFTs will be repeated anew.

Study Design

Study Type:
Interventional
Actual Enrollment :
26 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Diagnostic
Official Title:
Predictive Value of Within-breath Respiratory Input Impedance in the Early Diagnosis of Obliterative Bronchiolitis After Allogeneic Hematopoietic Stem Cell Transplantation
Study Start Date :
Dec 1, 2010
Actual Primary Completion Date :
Mar 1, 2012
Actual Study Completion Date :
Jun 1, 2012

Arms and Interventions

Arm Intervention/Treatment
Experimental: albuterol

Twenty-six consecutive patients undergoing allogeneic HSCT for hematological malignancies were studied. All patients were in stable clinical conditions at the time of study. All patients received a myeloablative conditioning regimen either including or not including total body irradiation. Spirometry, lung volumes, FOT and lung CT scan were obtained before the start of conditioning treatment and, approximately, two months after HSCT. On each study day, all the above measurements were taken before and 30 min after inhaling four consecutive albuterol doses, of 100 mcg each, through a valved-holding chamber. DLco was measured only after bronchodilator inhalation.

Drug: albuterol
400 mcg by inhalation
Other Names:
  • Broncovaleas pressurized solution

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Airway Distensibility With Lung Inflation After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) [2 weeks before and 2 months after HSCT]

      We studied 26 subjects, 2 weeks before and 2 months after HSCT. Within-breath respiratory system conductance (Grs) at 5, 11 and 19 Hz was measured by forced oscillation technique (FOT) at functional residual capacity (FRC) and total lung capacity (TLC)

    Secondary Outcome Measures

    1. Post-HSCT Changes in Lung Tissue Density [Before and 2 months after HSCT]

      Changes in lung tissue density were measured by quantitative computed tomography(CT) scan 2 weeks before and 2 months after HSCT

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • consecutive, clinically-stable, outpatients undergoing allogeneic HSCT (sourcing from bone marrow) for hematological malignancies

    • values of standard PFTs within normal range before HSCT

    • good collaboration during the maneuvers

    Exclusion Criteria:

    • patients showing any spirometric and/or volumetric abnormality before HSCT

    • poor collaboration and/or coordination during the maneuvers

    • any clinically-significant respiratory disease (bronchial asthma, COPD, cystic fibrosis, etc.) before HSCT

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 U.O. Medicina Preventiva e del Lavoro, Laboratorio di Fisiopatologia Respiratoria, IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro Genova Italy 16132

    Sponsors and Collaborators

    • IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

    Investigators

    • Principal Investigator: Giovanni Barisione, MD, IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Giovanni Barisione, MD, IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
    ClinicalTrials.gov Identifier:
    NCT01255449
    Other Study ID Numbers:
    • FOT-BOS-01
    First Posted:
    Dec 7, 2010
    Last Update Posted:
    Jan 31, 2013
    Last Verified:
    Dec 1, 2012
    Keywords provided by Giovanni Barisione, MD, IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
    Forced oscillation technique
    Respiratory input impedance
    Allogeneic hematopoietic stem cell transplantation
    Obliterative bronchiolitis
    Additional relevant MeSH terms:
    Bronchiolitis
    Bronchiolitis Obliterans
    Albuterol

    Study Results

    Participant Flow

    Recruitment Details The recruitment started on 10-Nov-2010 and finished on 15-feb-2012. The recruitment was performed at Pulmonary Function Tests Laboratory of IRCCS AOU San Martino.
    Pre-assignment Detail All patients were in stable clinical conditions and none had a history of significant respiratory disease.
    Arm/Group Title Albuterol
    Arm/Group Description On each study day, all lung function measurements were taken before and 30 min after inhaling four consecutive albuterol doses of 100 mcg each, through a valved-holding chamber. Lung diffusing capacity for carbon monoxide was measured only after bronchodilator inhalation.
    Period Title: Overall Study
    STARTED 26
    COMPLETED 26
    NOT COMPLETED 0

    Baseline Characteristics

    Arm/Group Title Albuterol
    Arm/Group Description All recruited subjects underwent an acute bronchodilation with albuterol following baseline pulmonary function measurements.
    Overall Participants 26
    Age (Count of Participants)
    <=18 years
    2
    7.7%
    Between 18 and 65 years
    24
    92.3%
    >=65 years
    0
    0%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    37
    (14)
    Sex: Female, Male (Count of Participants)
    Female
    9
    34.6%
    Male
    17
    65.4%
    Region of Enrollment (participants) [Number]
    Italy
    26
    100%

    Outcome Measures

    1. Primary Outcome
    Title Airway Distensibility With Lung Inflation After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
    Description We studied 26 subjects, 2 weeks before and 2 months after HSCT. Within-breath respiratory system conductance (Grs) at 5, 11 and 19 Hz was measured by forced oscillation technique (FOT) at functional residual capacity (FRC) and total lung capacity (TLC)
    Time Frame 2 weeks before and 2 months after HSCT

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Airway Distensibility With Lung Inflation After HSCT
    Arm/Group Description Changes in airway conductance at 5 Hz (Grs5) were related to changes in lung volume (DeltaGrs5/DeltaVL) to estimate airway distensibility
    Measure Participants 26
    Mean (Standard Deviation) [1/cmH2O*s]
    0.07
    (0.10)
    2. Secondary Outcome
    Title Post-HSCT Changes in Lung Tissue Density
    Description Changes in lung tissue density were measured by quantitative computed tomography(CT) scan 2 weeks before and 2 months after HSCT
    Time Frame Before and 2 months after HSCT

    Outcome Measure Data

    Analysis Population Description
    CT scans, in a format suitable for software analysis, were available in 8 patients only
    Arm/Group Title Post-HSCT Changes in Lung Tissue Density
    Arm/Group Description In eight out of 26 patients, a quantitative CT scan analysis was conducted to measure changes in lung tissue density
    Measure Participants 8
    Mean (Standard Deviation) [g/mL]
    0.03
    (0.02)

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Albuterol
    Arm/Group Description All subjects underwent an acute bronchodilation with albuterol by inhaling four consecutive doses (100 mcg each)of the drug through a valved-holding chamber
    All Cause Mortality
    Albuterol
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    Albuterol
    Affected / at Risk (%) # Events
    Total 0/26 (0%)
    Other (Not Including Serious) Adverse Events
    Albuterol
    Affected / at Risk (%) # Events
    Total 0/26 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Giovanni Barisione
    Organization IRCCS Azienda Ospedaliera Universitaria San Martino IST - Genova, Italy
    Phone +39010555 ext 3367
    Email giovanni.barisione@hsanmartino.it
    Responsible Party:
    Giovanni Barisione, MD, IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
    ClinicalTrials.gov Identifier:
    NCT01255449
    Other Study ID Numbers:
    • FOT-BOS-01
    First Posted:
    Dec 7, 2010
    Last Update Posted:
    Jan 31, 2013
    Last Verified:
    Dec 1, 2012