Clinical trial NCT02660437: pCO2 Oscillations During Exercise: Relation to Cerebral Blood Flow and to Cognitive Dysfunction in COPD
Official title: Carbon Dioxide Partial Pressure Oscillations During Exercise: Relation to Cerebral Blood Flow Regulation and and to the Prevalence of Cognitive Dysfunction in COPD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: COPD
Carbon dioxide partial pressure (pCO2)
Cerebral blood flow (CBF)
Cognitive dysfunction
Mild/Moderate Cognitive Impairment (MCI)
Pulmonary Rehabilitation (PR)
Standardized Mini Mental State Examination (SMMSE)
Addenbrooke's Cognitive Examination (ACE-R)
Montreal Cognitive Assessment (MoCA)
Telephone Interview for Cognitive Status (TICS)
Stroop test (Reaction Time)
Lead sponsor: Schön Klinik Berchtesgadener Land
Sponsor class: OTHER
Collaborators: name: European Respiratory Society
First posted: 2016-01-21
Enrollment: 91
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: Investigators wish to identify a relationship between substantial changes in carbon dioxide partial-pressure (pCO2), which frequently occur during the transitions from rest to exercise (ΔpCO2 \>4 millimeters of mercury \[mmHg\] from baseline), and the prevalence of cognitive dysfunction in COPD. In particular, it is anticipated to investigate the vascular effect of pCO2 oscillations in the regulation of cerebral blood flow (CBF) during exercise and its impact on cognitive function in Chronic Obstructive Pulmonary Disease (COPD). Furthermore, this study aims to examine whether major pCO2 oscillations have prognostic value in cognitive deterioration at 6, 12, and 18-month follow-up. In addition, the acute effect of 3-week pulmonary rehabilitation (PR) on cognitive function will be explored. The evaluation of cognitive function will be performed by the use of Standardized Mini Mental State Examination (SMMSE), Addenbrooke's Cognitive Examination (ACE-R), Montreal Cognitive Assessment (MoCA), and Telephone Interview for Cognitive Status (TICS) assessing several cognitive domains (cognitive scores) whereas Stroop test \[color reading interference\] will be used for measuring cognitive performance (Reaction-Time).

Detailed description: Cerebral Blood Flow (CBF) regulation is crucial for the adequate oxygen supply to the brain and the sustenance of cerebrovascular reserve capacity. A fundamental physiologic regulator of CBF is the carbon dioxide partial pressure (pCO2), which determines the dilatation or contraction of cerebral vasculature. CBF regulation response has been found to be strongly dependent upon pCO2 but much less so upon changes in arterial oxygen saturation. CBF is highly sensitive to pCO2 changes which cause pronounced-vasodilatation in increased pCO2 (CBF augmentation) or vasoconstriction in decreased pCO2 levels (CBF diminution). During cerebral activation and increased metabolism, cerebral arterioles dilate contributing to increase CBF but this process is often challenged during exercise and has a potential impact on cognitive function. CBF is linked to cognitive function while serum level of Brain Derived Neurotrophic Factor (BDNF) has been shown as a critical driving force behind neural plasticity with a potential utility as a biomarker of cognitive decline.

Investigators assume that major pCO2 oscillations during exercise (ΔpCO2 \>4 millimeters of mercury \[mmHg\] from baseline) as a reflection of the abnormality in ventilatory efficiency/drive, lead to overall and local disturbances of cerebral blood flow (CBF) and thus can be associated to increased prevalence of cognitive dysfunction in patients with Chronic Obstructive Pulmonary Disease (COPD). Moreover, investigators hypothesize that patients with major pCO2 oscillations during exercise may develop worse cognitive impairment in several cognitive domains and greater cognitive decline compared to "isocapnic" patients at 6, 12, and 18-month follow-up. Inpatient PR may benefit cognitive function by improving breathing (diminishing pCO2 oscillations), therefore improving CBF, and by increasing cerebral neural activation through exercise.

With regard to cognitive dysfunction, which is associated to increased all-cause mortality and disability, investigators wish:

(A) to detect a relationship between major pCO2 oscillations during exercise and increased prevalence of cognitive dysfunction in COPD; (B) to investigate the impact of different pCO2 transitory-patterns (1. pCO2: decline/ hypocapnic, 2. steady/ isocapnic, 3. increase/ hypercapnic) on CBF regulation and cognitive function; (C) to examine whether major pCO2 oscillations can be a determinant of greater cognitive deterioration in several cognitive domains at 6, 12, and18-month follow-up and (D) to explore the acute effect of 3-week PR on pCO2 oscillations and CBF in respect to cognitive function in COPD patients with cognitive impairment.

The evaluation of cognitive function will be performed by the use of Standardized Mini Mental State Examination (SMMSE), Addenbrooke's Cognitive Examination (ACE-R), Montreal Cognitive Assessment (MoCA) and Telephone Interview for Cognitive Status (TICS) assessing several cognitive domains (cognitive scores) whereas Stroop test will be used for measuring cognitive performance (Reaction-Time).

Eligibility criteria: Inclusion Criteria:

* Patients with Chronic Obstructive Pulmonary Disease (COPD) in Global Initiative on Obstructive Lung Disease (GOLD) stages II to IV
* COPD patients with mild to moderate cognitive impairment (MCI-group: n=100) and without cognitive impairment (Control-group: n=60)
* Normotensive (Blood Pressure range: 101-143/62-91 millimeters of mercury \[mmHg\])

Exclusion Criteria:

* Resting partial pressure of oxygen in arterial blood (paO2) \<55 millimeters of mercury \[mmHg\]
* Resting partial pressure of carbon dioxide in arterial blood (paCO2) \>45 millimeters of mercury \[mmHg\]
* last exacerbation ≤4weeks
* severe cognitive impairment/dementia
* other neuropsychiatric symptoms

Primary outcomes:
measure: Carbon-dioxide partial pressure oscillations (ΔpCO2, mmHg)
timeFrame: Day 4-21
Secondary outcomes:
measure: Cognitive Dysfunction (yes/no)
timeFrame: Day 1-3
measure: Cognitive Impairment (Standardized Mini-Mental State Examination [SMMSE, scores])
timeFrame: Day 1-21
measure: Cognitive Impairment (Addenbrooke's Cognitive Examination [ACE-R])
timeFrame: Day 1-21
measure: Cognitive Impairment (Montreal-Cognitive Assessment [MoCA, scores])
timeFrame: Day 1-21
measure: Cognitive Impairment (Telephone Interview for Cognitive Status [TICS])
timeFrame: Day 1-21
measure: Cognitive Performance (Stroop test [reaction-time, seconds])
timeFrame: Day 4-21
measure: Cerebral Blood Flow Velocity (CBFv, cm/sec)
timeFrame: Day 4-21
measure: Frontal cortex cerebrovascular oxygen saturation (Tissue Oxygen Saturation [TOI, %])
timeFrame: Day 4-21
measure: Frontal cortex cerebrovascular oxygen saturation (Changes in Deoxygenated Haemoglobin [ΔHHb, μM/cm])
timeFrame: Day 4-21
Other outcomes:
measure: Airflow limitation (Forced Expiratory Pressure in 1 Second [FEV1, %predicted])
timeFrame: Day 1-4
measure: Exercise capacity (peak Work Rate, [WRpeak watts])
timeFrame: Day 1-6
measure: Blood Gas Analyses (Arterial oxygen partial pressure [PaO2, mmHg])
timeFrame: Day 1-6
measure: Blood Gas Analyses (Arterial carbon-dioxide partial pressure [PaCO2, mmHg])
timeFrame: Day 1-6
measure: Brain Derived Neurotrophic Factor (BDNF serum levels, ng/mL).
timeFrame: Day 1-8
measure: Psychological condition/ Psychological data (Hospital Anxiety and Depression Scale [HADS, scores])
timeFrame: Day 5-8
measure: Psychological condition/ Psychological data (COPD Assessment Test [CAT, scores])
timeFrame: Day 5-8
measure: Psychological condition/ Psychological data (St. George Respiratory Questionnaire [SGRQ, scores])
timeFrame: Day 5-8
measure: Perception of Dyspnoea (Medical Research Council dyspnoea scale, [MRC scores])
timeFrame: Day 5-8
Locations:
city: Schonau am Konigssee
country: Germany
facility: Klinikum Berchtesgadener Land der Schön-Kliniken
Study officials:
affiliation: Schön Klinik Berchtesgadener Land
name: Klaus Kenn, Prof. med.
role: STUDY_CHAIR
References:
citation: Payne SJ, Mohammad J, Tisdall MM, Tachtsidis I. Effects of arterial blood gas levels on cerebral blood flow and oxygen transport. Biomed Opt Express. 2011 Mar 25;2(4):966-79. doi: 10.1364/BOE.2.000979.
citation: Ogoh S, Tsukamoto H, Hirasawa A, Hasegawa H, Hirose N, Hashimoto T. The effect of changes in cerebral blood flow on cognitive function during exercise. Physiol Rep. 2014 Sep 28;2(9):e12163. doi: 10.14814/phy2.12163. Print 2014 Sep 1.
citation: Shimada H, Makizako H, Doi T, Yoshida D, Tsutsumimoto K, Anan Y, Uemura K, Lee S, Park H, Suzuki T. A large, cross-sectional observational study of serum BDNF, cognitive function, and mild cognitive impairment in the elderly. Front Aging Neurosci. 2014 Apr 15;6:69. doi: 10.3389/fnagi.2014.00069. eCollection 2014.
citation: Ito H, Ibaraki M, Kanno I, Fukuda H, Miura S. Changes in the arterial fraction of human cerebral blood volume during hypercapnia and hypocapnia measured by positron emission tomography. J Cereb Blood Flow Metab. 2005 Jul;25(7):852-7. doi: 10.1038/sj.jcbfm.9600076.
citation: Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999 Mar;56(3):303-8. doi: 10.1001/archneur.56.3.303.
citation: Van der Elst W, Van Boxtel MP, Van Breukelen GJ, Jolles J. The Stroop color-word test: influence of age, sex, and education; and normative data for a large sample across the adult age range. Assessment. 2006 Mar;13(1):62-79. doi: 10.1177/1073191105283427.
citation: Valdueza JM, Balzer JO, Villringer A, Vogl TJ, Kutter R, Einhaupl KM. Changes in blood flow velocity and diameter of the middle cerebral artery during hyperventilation: assessment with MR and transcranial Doppler sonography. AJNR Am J Neuroradiol. 1997 Nov-Dec;18(10):1929-34.
citation: Vogiatzis I, Louvaris Z, Habazettl H, Andrianopoulos V, Wagner H, Roussos C, Wagner PD, Zakynthinos S. Cerebral cortex oxygen delivery and exercise limitation in patients with COPD. Eur Respir J. 2013 Feb;41(2):295-301. doi: 10.1183/09031936.00016312. Epub 2012 May 3.