pCO2 Oscillations During Exercise: Relation to Cerebral Blood Flow and to Cognitive Dysfunction in COPD

Chronic Obstructive Pulmonary Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02660437
• Other study ID #: RESPIRE2-8465
• Status: Completed
• Phase: N/A
• Start date: March 2016
• Est. completion date: July 2018

Study information

• Verified date: February 2019
• Source: Klinikum Berchtesgadener Land der Schön-Kliniken
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 91
• Est. completion date: July 2018
• Est. primary completion date: March 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Chronic Obstructive Pulmonary Disease
• Cognitive Dysfunction
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Other:
• Pulmonary Rehabilitation program
Patients will attend a comprehensive 3-week PR program (12sessions/ 60min·day) including high intensive interval exercise equivalent to 100% of peak work rate (WRpeak) with 30sec work periods interspersed with 30sec rest periods for 30min and light resistance training (3muscle groups/ 4sets each/10repetitions; ~30min).

Locations

Country	Name	City	State
Germany	Klinikum Berchtesgadener Land der Schön-Kliniken	Schonau am Konigssee

Sponsors (2)

Lead Sponsor	Collaborator
Klinikum Berchtesgadener Land der Schön-Kliniken	European Respiratory Society

Country where clinical trial is conducted

Germany, 

References & Publications (8)

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. — View 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). pii: e12163. doi: 10.14814/phy2.12163. Print 2014 Sep 1. — View 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. — View 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. Erratum in: Arch Neurol 1999 Jun;56(6):760. — View 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. — View Citation

Valdueza JM, Balzer JO, Villringer A, Vogl TJ, Kutter R, Einhäupl 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Airflow limitation (Forced Expiratory Pressure in 1 Second [FEV1, %predicted])	Measurement of Forced Expiratory Pressure in 1 Second (FEV1, %predicted).	Day 1-4
Other	Exercise capacity (peak Work Rate, [WRpeak watts])	Measurement of exercise capacity by a cardiopulmonary exercise test (CPET) on cycle ergometer using an incremental protocol to the limit of tolerance (peak Work Rate, watts)) for establishing the work rate corresponding to 75% of peak (maximum working capacity) according to the international guidelines.	Day 1-6
Other	Blood Gas Analyses (Arterial oxygen partial pressure [PaO2, mmHg])	Measurement of arterial oxygen partial pressure (PaO2, mmHg) in blood samples.	Day 1-6
Other	Blood Gas Analyses (Arterial carbon-dioxide partial pressure [PaCO2, mmHg])	Measurement of arterial carbon-dioxide partial pressure (PaCO2, mmHg) in blood samples.	Day 1-6
Other	Brain Derived Neurotrophic Factor (BDNF serum levels, ng/mL).	Measurement of serum levels of Brain Derived Neurotrophic Factor (BDNF, ng/mL) in blood samples.	Day 1-8
Other	Psychological condition/ Psychological data (Hospital Anxiety and Depression Scale [HADS, scores])	Psychological factors will be assessed by the use of the Hospital Anxiety and Depression Scale (HADS).	Day 5-8
Other	Psychological condition/ Psychological data (COPD Assessment Test [CAT, scores])	Psychological factors will be assessed by the use of the COPD Assessment Test (CAT).	Day 5-8
Other	Psychological condition/ Psychological data (St. George Respiratory Questionnaire [SGRQ, scores])	Psychological factors will be assessed by the use of the St. George Respiratory Questionnaire (SGRQ).	Day 5-8
Other	Perception of Dyspnoea (Medical Research Council dyspnoea scale, [MRC scores])	Perception of dyspnoea will be assessed by the use of the Medical Research Council (MRC) dyspnoea scale.	Day 5-8
Primary	Carbon-dioxide partial pressure oscillations (?pCO2, mmHg)	Changes in transcutaneous pCO2 (?pCO2, mmHg from baseline values) during Cycle-Endurance Test (CET) at 75% of peak Work Rate (WRpeak). The pCO2 oscillations will be transcutaneous monitored and continuously recorded by the use of "SenTec" Digital Monitoring System (pre/post measurements): 1st measurement during a CET prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement during a CET at the end of PR program (post-PR).	Day 4-21
Secondary	Cognitive Dysfunction (yes/no)	Screening of Cognitive Dysfunction according to Petersen's criteria: Consistent memory complaints preferably corroborated by a close-informant.; Objective characterization of specific deficits in memory and/or other cognitive domains, as indicated by a poor performance on MoCA (<26 points), MMSE (<25 points), ACE-R (<88 points) and TICS (<33 points).; Preserved ability to perform activities of daily living (ADLs), or minimal impairment if considering instrumental ADLs.; Normal global cognitive function.; Absence of dementia (Clinical Dementia Rating Scale (CDR =1 point)).	Day 1-3
Secondary	Cognitive Impairment (Standardized Mini-Mental State Examination [SMMSE, scores])	Evaluation of Cognitive Impairment (CI) by the use of clinical instrument of the Standardized Mini-Mental State Examination (SMMSE, scores); 1st measurement prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement at the end of PR program (post-PR).	Day 1-21
Secondary	Cognitive Impairment (Addenbrooke's Cognitive Examination [ACE-R])	Evaluation of Cognitive Impairment (CI) by the use of clinical instrument of the Addenbrooke's Cognitive Examination (ACE-R scores); 1st measurement prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement at the end of PR program (post-PR).	Day 1-21
Secondary	Cognitive Impairment (Montreal-Cognitive Assessment [MoCA, scores])	Evaluation of Cognitive Impairment (CI) by the use of clinical instrument of the Montreal-Cognitive Assessment (MoCa scores); 1st measurement prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement at the end of PR program (post-PR).	Day 1-21
Secondary	Cognitive Impairment (Telephone Interview for Cognitive Status [TICS])	Evaluation of Cognitive Impairment (CI) by the use of clinical instrument of the Telephone Interview for Cognitive Status (TICS scores); 1st measurement prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement at the end of PR program (post-PR).	Day 1-21
Secondary	Cognitive Performance (Stroop test [reaction-time, seconds])	Assessment of cognitive performance (Stroop test - reaction-time, seconds) before and immediately after Cycle-Endurance Test (CET) at 75% of WRpeak. Cognitive performance will be measured by the use of Stroop-test (pre/post measurements): 1st measurement during a CET prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement during a CET at the end of PR program (post-PR).	Day 4-21
Secondary	Cerebral Blood Flow Velocity (CBFv, cm/sec)	Measurement of Cerebral Blood Flow velocity (CBFv, cm/sec) as surrogate of Cerebral Blood Flow (CBF) before and immediately after Cycle-Endurance Test (CET) at 75% of WRpeak. Cerebral Blood Flow velocity (CBFv) will be measured by the use of transcranial Doppler ultrasonography (pre/post measurements): 1st measurement during a CET prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement during a CET at the end of PR program (post-PR).	Day 4-21
Secondary	Frontal cortex cerebrovascular oxygen saturation (Tissue Oxygen Saturation [TOI, %])	Measurement Tissue Oxygen Saturation (TOI, %) as an index of frontal cortex cerebrovascular oxygen saturation during Cycle-Endurance Test (CET) at 75% of WRpeak. Tissue oxygen saturation (TOI, %) will be continuously measured by the use of Near-Infrared Spectroscopy (NIRS-method; pre/post measurement): 1st measurement during a CET prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement during a CET at the end of PR program (post-PR).	Day 4-21
Secondary	Frontal cortex cerebrovascular oxygen saturation (Changes in Deoxygenated Haemoglobin [?HHb, µM/cm])	Measurement of the changes in Deoxygenated Haemoglobin (?HHb) in micrometer per centimeter (µM/cm) as an index of frontal cortex cerebrovascular oxygen saturation during Cycle-Endurance Test (CET) at 75% of WRpeak. Changes in Deoxygenated Haemoglobin (?HHb, µM/cm) will be continuously measured by the use of Near-Infrared Spectroscopy (NIRS-method; pre/post measurement): 1st measurement during a CET prior to the participation in a 3-week (12 sessions) Pulmonary Rehabilitation program (pre-PR); 2nd measurement during a CET at the end of PR program (post-PR).	Day 4-21

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