Understanding how long COVID-19 impacts breathing, heart rate, and blood pressure control
| ISRCTN | ISRCTN58994514 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN58994514 |
| IRAS number | 296727 |
| Secondary identifying numbers | IRAS 296727 |
- Submission date
- 17/11/2021
- Registration date
- 27/01/2022
- Last edited
- 27/03/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English summary of protocol
Background and study aims
Around 4 million individuals have tested positive for COVID-19 in the UK up to February 2021. Those who have recovered from the acute effects of COVID-19 often describe ongoing symptoms including decreased exercise tolerance, fatigue, chest pain, and dizziness, typical of an emerging syndrome known as ‘Post-COVID-19 Syndrome’. ‘Post COVID-19 Syndrome’ is emerging as a prevalent syndrome, encompassing a plethora of debilitating symptoms (including breathlessness, chest pain, palpitation, and orthostatic intolerance) which can last for weeks or more following mild to moderate illness. There is increasing evidence pointing to an ongoing, multi-system disorder involving the brain and dysfunctional neural control systems following COVID-19 infection. The carotid body, a small organ in the carotid arteries, monitors oxygen levels in the blood and keeps tight control over breathing, heart rate, and blood pressure. This organ has a high distribution of angiotensin-converting enzyme, the enzyme by which coronavirus enters cells. The carotid body is also sensitive to inflammation, which is triggered by local infection. It is possible this inflammation drives symptoms such as breathlessness, inappropriate increases in heart rate, and dizziness. The aim of this study is to investigate the longer-term effects of COVID-19 on breathing and cardiovascular (heart) functions in men and women.
Who can participate?
Patients aged 18-80 years old with previous COVID-19 infection with symptoms less than 4 weeks in duration or with a formal diagnosis of Post-COVID-19
Syndrome, without major illness
What does the study involve?
The study involves one telephone consultation and two visits to the Clinical Research Facility (CRF), Bristol. The duration of the first CRF visit will be up to 3 hours, and the second CRF visit will be up to 2 hours and 15 minutes. During the telephone consultation, the researchers will ask screening questions with regards to any recent positive test results for, or symptoms of, COVID-19, recent travel outside the UK, and whether participants have been in contact with someone who has recently tested positive for COVID-19. The first part of the visit involves screening. This is where the researchers go through the participants' medical history and complete some screening tests to make sure they are safely able to take part in the study. The researchers will also carry out an assessment of the nerve signals that control the dilatation of the blood vessels using a technique called microneurography whilst carrying out hand-grip exercises. Office blood pressure will be measured twice on each arm with an automated blood pressure cuff, followed by two further readings from the arm with higher blood pressure, two minutes apart. An average of the final two readings will be used. Ambulatory blood pressure monitoring will be used to measure blood pressure over 24 hours. Participants will be issued an ambulatory blood pressure monitor after the screening visit. Participants will be asked to keep a blood pressure diary to record waking/sleeping times, which will be used to calculate daytime ambulatory blood pressure. Activities completed during blood pressure readings will also be noted. 12-lead electrocardiography (ECG) will be performed to exclude obvious cardiovascular disease (assessed by a Doctor). A urine pregnancy test will be performed for premenopausal women.
The researchers will take a blood sample to test for levels of inflammation and catecholamine hormones. Microneurography is a technique used to measure the activity of the nerves that control blood pressure (the sympathetic nerves). The researchers use two small electrodes, similar to acupuncture needles. One is inserted into a nerve in the lower leg called the peroneal nerve. The other is placed into the surface of the skin nearby the nerve and acts as a reference. It may take up to an hour to position the electrodes correctly. The researchers will record sympathetic nerve activity at rest and whilst performing some handgrip exercise. Handgrip exercise involves squeezing a hand-held device at 40% of maximal voluntary contraction (the contraction generated with maximum effort). To work out 40%, participants first squeeze the device with maximum effort three times. The handgrip procedure will show how the changes in nerve activity and blood flow to the arm seen during exercise differ between men and women, younger and older people, and people with high or normal blood pressure. The researchers will measure the blood flowing to the arm using an ultrasound probe (see below). Throughout the study, heart rate is recorded using three ECG stickers. Blood pressure will be measured by a small cuff that inflates around the end of a finger. Breathing will be monitored by a belt placed around the chest (at the diaphragm). The researchers will measure the ability of receptors in the carotid artery to adapt to changes in oxygen levels and blood flow (chemoreflex testing). Throughout the test, they will monitor heart rate and rhythm, oxygen levels, and blood pressure. Participants will initially breathe room air then switch to pure pharmaceutical grade nitrogen gas for 10-45 seconds. This will be repeated around 5-8 times to achieve short-lived falls in oxygen level and assess how the body increases its breathing rate to compensate. Some of the study procedures (ECG, blood pressure monitoring, urine sample testing, and blood sample testing) could identify abnormal results. If abnormal results are found in ECG or urine participants may be unable to take part in the rest of the study. Participants will be informed of any abnormalities in urine or ECG during the study visit. 24-hour blood pressure monitoring and testing of the blood sample take place after the study visit. If abnormal results are found in the blood pressure or blood sample, participants will be informed. However, the testing of blood samples will take place at the end of the study. Therefore, the researchers may not know the results of this test for 2-3 years after participating. The researchers will also inform the participant's GP of any abnormal results if they have given permission for this.
What are the possible benefits and risks of participating?
The results of this study will be of immediate benefit to the NHS by identifying a new mechanism that contributes to ongoing symptoms when recovering from COVID-19. Understanding what drives some of the symptoms in Post-COVID-19 Syndrome will help guide future treatments for COVID-19. Further work could include testing the efficacy of exercise interventions and breathing control techniques in these populations. Further benefits to patients include increasing confidence that exercising is safe when recovering from COVID-19 and that it has beneficial effects, as well as raising awareness of the benefits of early monitoring of oxygen levels in people who have COVID-19 to determine whether low oxygen levels are more likely in people with an altered sense of taste or smell.
During the study, a Research Nurse or Doctor will take a blood sample, which will be tested for levels of inflammation and catecholamine levels. Participants may experience mild discomfort and/or mild swelling at the site. Microneurography sometimes causes numbness or tingling (paraesthesia) in the lower leg for 3-7 days after the procedure is completed. However, this is reported to occur in less than 10% of cases. To minimise the risk of infection, the researchers use sterile, single-use electrodes and a ‘no-touch’ technique after they have sterilised the skin. There are no known risks associated with handgrip exercise or the use of ultrasound to measure either blood flow to the arm (vascular ultrasound) or blood pumped by the heart (echocardiography). Repeated blood pressure measurements may lead to mild discomfort and numbness in the arm or finger. There are no known risks associated with monitoring heart rate or breathing. During the chemoreflex testing breathing nitrogen can cause some short-lived dizziness or light-headedness. The nitrogen can be immediately switched off and clears from the breathing circuit in seconds. Oxygen saturation levels return to normal quickly after the nitrogen is switched off, and supplemental oxygen can be given if needed.
Where is the study run from?
Clinical Research Facility, Bristol (UK)
When is the study starting and how long is it expected to run for?
March 2021 to March 2023
Who is funding the study?
1. The University of Bristol (UK)
2. Above & Beyond (UK)
3. Elizabeth Blackwell Institute (UK)
Who is the main contact?
Dr Ahmed El-Medany
Ahmed.El-Medany@bristol.ac.uk
Contact information
Scientific
Bristol Heart Institute
Bristol Royal Infirmary
University Hospitals Bristol and Weston NHS Foundation Trust
Upper Maudlin Street
Bristol
BS2 8HW
United Kingdom
| Phone | +44 (0)1173426572 |
|---|---|
| angus.nightingale@bristol.ac.uk |
Public
School of Physiology, Pharmacology & Neuroscience
Faculty of Biomedical Sciences
University of Bristol
Bristol
BS8 1TD
United Kingdom
 ORCID ID |
0000-0003-4419-6693 |
|---|---|
| Phone | +44 (0)1173311971 |
| Ahmed.El-Medany@bristol.ac.uk |
Public
School of Physiology, Pharmacology & Neuroscience
Faculty of Biomedical Sciences
University of Bristol
Bristol
BS8 1TD
United Kingdom
| Phone | +44 (0)1173311971 |
|---|---|
| Emma.Hart@bristol.ac.uk |
Study information
| Study design | Single-center observational longitudinal case-control study |
|---|---|
| Primary study design | Observational |
| Secondary study design | Case-control study |
| Study setting(s) | Hospital |
| Study type | Quality of life |
| Participant information sheet | 40687 PIS V2 09Sept2021.pdf |
| Scientific title | Assessment of chemoreflex control of respiratory and cardiovascular systems in Post-COVID-19 syndrome |
| Study acronym | ARC C-19 |
| Study objectives | Post COVID-19 syndrome is emerging as a prevalent syndrome, encompassing a plethora of debilitating symptoms (including breathlessness, chest pain, palpitation, and orthostatic intolerance) which can last for weeks or more following mild to moderate illness. Whilst this is partially due to direct lung injury, increasing evidence points to an ongoing, multi-system disorder involving the brain and the carotid body. The carotid body, a small organ in the carotid arteries, monitors oxygen levels in the blood and keeps tight control over breathing, heart rate, and blood pressure. This organ has a high distribution of angiotensin-converting enzyme 2, the enzyme by which coronavirus enters cells. The carotid body is also sensitive to inflammation, which is triggered by local infection. It is possible this inflammation drives symptoms such as breathlessness, inappropriate increases in heart rate, and dizziness. The aim of this study is to investigate the longer-term effects of COVID-19 on autonomic and peripheral chemoreflex control of respiratory and cardiovascular systems. This will be achieved by recruiting patients from two populations both of whom have had acute COVID-19: Firstly, a group with Post-COVID-19 Syndrome and secondly a matched control group with COVID-19 symptoms lasting no longer than 4 weeks as per NICE guidelines. The researchers will assess carotid body chemosensitivity at rest and during submaximal exercise. They will also assess autonomic function at rest and during exercise. These data will provide an insight into whether the carotid body is involved in post-COVID-19 syndrome and whether it is linked to autonomic dysfunction. The carotid body could be targeted to help treat post-COVID-19 syndrome. |
| Ethics approval(s) | Approved 05/10/2021, Hampshire Research Ethics Committee (2 The Square, Temple Quay, Temple Quay House, BS1 6PN, UK; hampshireb.rec@hra.nhs.uk), ref: 21/SC/0260 |
| Health condition(s) or problem(s) studied | Post-COVID-19 syndrome |
| Intervention | The researchers will measure the hypoxic ventilatory response at rest and during moderate dynamic exercise. They will measure sympathetic nerve activity via microneurography, which is a direct measure of the sympathetic nerve activity at 1) rest and 2) during isometric handgrip exercise. They will measure C-reactive protein (CRP) and Interleukin-6 (IL-6) at rest and following peak exercise. They will examine whether this correlates with the increase in sympathetic nerve activity measured. |
| Intervention type | Not Specified |
| Primary outcome measure | 1. Level of muscle sympathetic nerve activity at rest is measured using microneurography at baseline 2. Level of MSNA during exercise is measured using microneurography following 6-12 minutes of ramped bike exercise tolerance testing 3. Hypoxic ventilatory response at rest will be calculated using spirometry, and ear oxygen saturation monitoring at baseline 4. Hypoxic ventilatory response during exercise will be calculated using spirometry, and ear oxygen saturation monitoring following 2 minutes of cycle ergometry at 30-40% VO2 peak and inhalation of medical grade nitrogen gas for 10-45 seconds 5. Change in the inflammatory biomarker IL-6 from rest to peak exercise will be measured using venous blood sampling at baseline and following 6-12 minutes of ramped exercise bike testing |
| Secondary outcome measures | 1. Spontaneous sympathetic baroreflex sensitivity will be measured using microneurography at baseline and following 6-12 minutes of ramped bike exercise tolerance testing 2. Spontaneous parasympathetic baroreflex sensitivity will be measured using 3-lead electrocardiogram (ECG) recording at baseline 3. 24-hour ambulatory blood pressure and office blood pressure will be measured using a 24-hour blood pressure cuff and office blood pressure cuff, respectively, continuously and at baseline, respectively 4. Beat-to-beat blood pressure variability at rest will be measured using a beat-to-beat finger blood pressure recording at baseline 5. Change in blood pressure (BP) in response to handgrip exercise will be measured using an office blood pressure cuff following 2 minutes of handgrip exercise 6. Sympathetic-respiratory coupling at rest will be measured using microneurography and a respiratory belt at baseline 7. Maximal oxygen uptake (VO2 peak) will be measured using a 12-lead ECG and spirometry following 3 minutes of pre-exercise baseline rest 8. Ventilatory efficiency (VE/VCO2) slope will be calculated from minute ventilation (VE) measurements at rest and VCO2 measurements following 2 minutes of ramped bike exercise tolerance testing 9. Rating of perceived exertion will be measured using the Borg scale after 6-12 minutes of ramped bike exercise tolerance testing 10. Change in heart rate from peak exercise to recovery will be measured using 3-lead ECG recording within the first 2 mins of stopping exercise 11. Blood pressure response to hypoxia at rest will be measured using an office blood pressure cuff at baseline 12. Blood pressure response to hypoxia during exercise will be measured using an automated brachial arm blood pressure cuff throughout cycle ergometry 13. Heart rate response to hypoxia at rest will be measured using 12-lead ECG monitoring at baseline 14. Heart rate response to hypoxia during exercise 12-lead ECG monitoring throughout 6-12 minutes of cycle ergometry and following inhalation of medical grade nitrogen gas for 10-45 seconds 15. Capillary blood lactate at rest will be measured using a capillary blood sample at baseline 16. Capillary blood lactate at end of moderate exercise will be measured using a capillary blood sample following 2 minutes of ramped exercise bike testing, and at the end of the cycle ergometry intermittent hypoxia protocol at around 33 minutes 17. Change in other inflammatory biomarkers, including C-reactive protein (CRP) from rest to peak exercise will be measured using venous blood sampling at baseline and following 6-12 minutes of ramped exercise bike testing 18. Change in catecholamines from rest to peak exercise will be measured using venous blood sampling at baseline and following 6-12 minutes of ramped exercise bike testing |
| Overall study start date | 01/03/2021 |
| Completion date | 31/03/2023 |
Eligibility
| Participant type(s) | Mixed |
|---|---|
| Age group | Mixed |
| Lower age limit | 18 Years |
| Upper age limit | 80 Years |
| Sex | Both |
| Target number of participants | 54 |
| Total final enrolment | 28 |
| Key inclusion criteria | All participants: Aged 18-80 years Post-COVID-19 Syndrome participants: As per NICE guidelines https://www.nice.org.uk/guidance/ng188 Age and sex-matched controls@ 1. Positive SARS-CoV-2 antibody test before vaccination, or a positive COVID-19 PCR antigen swab test 2. Asymptomatic or symptoms <4 weeks after COVID-19 infection |
| Key exclusion criteria | All participants: 1. Body mass index ≥35 kg/m² 2. Pregnancy/breastfeeding women 3. Ongoing requirement of oxygen therapy 4. Taking antihypertensive, nitrate, steroid or immunosuppressant medication or medication 5. Major illness e.g., cancer, inflammatory disease (including vasculitis) or receiving palliative care 6. History of organ transplantation or are candidates for organ transplantation at the time of screening 7. History of Chronic Fatigue Syndrome prior to COVID-19 infection 8. Diagnosed cardiovascular disease (including current non-benign arrhythmia, chronic heart failure) 9. History of major psychiatric disorder including bipolar disorders, schizophrenia, schizoaffective disorder, major depression. 10. Diagnosis of structural lung disease (such as COPD or pulmonary fibrosis) 11. Diagnosed renal disease 12. Congenital or acquired neurological conditions (including dementia), language disorders, repeated or chronic pain conditions (excluding menstrual pain and minor sporadic headaches) 13. Diabetes Mellitus 14. Symptoms of febrile illness 2 weeks before experiment 15. Excessive alcohol consumption (>28 units/week) or use of illicit drugs 16. History of smoking within 2 months 17. Inability to understand instructions given in English 18. Surgery under general anaesthesia within 3 months 19. History of stroke 20. Heart transplant 21. Coronary revascularisation 22. Haemodialysis or peritoneal dialysis 23. Participating in another study for an investigational medicinal product Controls: Symptoms lasting >4 weeks following acute, confirmed, COVID-19 infection |
| Date of first enrolment | 01/11/2021 |
| Date of final enrolment | 28/02/2023 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Bristol
BS2 8HW
United Kingdom
Bristol
BS2 8DX
United Kingdom
Sponsor information
University/education
Research & Enterprise Division (RED)
1 Cathedral Square
Bristol
BS1 5DD
England
United Kingdom
| Phone | +44 (0)1173940177 |
|---|---|
| research-governance@bristol.ac.uk | |
| Website | http://bristol.ac.uk |
"ROR" |
https://ror.org/0524sp257 |
Funders
Funder type
Charity
No information available
No information available
Results and Publications
| Intention to publish date | 01/06/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from the chief investigators, Dr Angus Nightingale (Angus.Nightingale@bristol.ac.uk). Personal data will be stored for 15 years at the University of Bristol in electronic and hard copy. Access will be controlled by Dr Angus Nightingale who will continue to act as custodian. Dr Angus Nightingale will have control of and act as custodian of the data on behalf of the University of Bristol and University Hospitals Bristol NHS Foundation Trust. All source documents will be retained for a period of fifteen years following the end of the study. Where trial-related information is documented in the medical records, those records will be identified by a ‘Do not destroy before dd/mm/yyyy’ label where the date is 15 years after the last patient last visit. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version 2 | 09/09/2021 | 15/12/2021 | No | Yes |
| Protocol file | version 1 | 06/07/2021 | 15/12/2021 | No | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Results article | 19/02/2024 | 27/03/2024 | Yes | No |
Additional files
Editorial Notes
27/03/2024: Publication reference added.
16/03/2023: The following changes were made to the trial record:
1. The overall end date was changed from 01/05/2023 to 01/06/2023.
2. The total final enrolment was added.
12/12/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/11/2022 to 28/02/2023.
2. The overall trial end date was changed from 31/12/2022 to 31/03/2023.
3. The intention to publish date was changed from 01/03/2023 to 01/05/2023.
15/12/2021: Trial's existence confirmed by University of Bristol.
