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Trial registered on ANZCTR

Registration number
Ethics application status
Date submitted
Date registered
Date last updated
Date data sharing statement initially provided
Type of registration
Prospectively registered

Titles & IDs
Public title
Interactions between central and peripheral respiration's control cells in humans with high blood pressure.

Scientific title
Chemoreflex testing to assess interactions between central and peripheral chemoreflexes in human hypertension.
Secondary ID [1] 299777 0
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypertension 314878 0
Condition category
Condition code
Respiratory 313228 313228 0 0
Normal development and function of the respiratory system
Cardiovascular 313229 313229 0 0

Study type
Description of intervention(s) / exposure
This is a non-therapeutic mechanistic physiological study.

All the following measurements and tests described will be conducted by a trained human physiologist staff member.

At an initial visit to the laboratory, written informed consent will be obtained from participants who will then undergo screening and familiarization. Anthropometric (height, weight, hip-to-waist ratio), demographic, clinical history information will be obtained, and health questionnaires and 7-day physical activity recall data will be collected.

Participants will then attend a single experimental session lasting ~3 hours, including set-up time. Experimental sessions will be scheduled ~2-7 days after the initial familiarisation / screening visit, as appropriate. However, premenopausal women will be studied during the first five days of their menstrual cycle (early follicular phase) or during the placebo/no-hormone phase of oral contraceptive use, as appropriate.

At the experimental session, participants will be asked to lie in a semi-recumbent position on a medical examination couch and to remain in that position throughout the session. Bilateral internal carotid and vertebral artery blood flow will be measured using duplex Doppler ultrasound. This ultrasound examination is similar to scan done for pregnant women, but a large artery is examined. This is a simple and safe procedure and involves a probe being put on the patients’ skin over the region of interest with the help of a ‘water jelly’.

Participants will then be instrumented for continuous monitoring of BP, heart rate (HR), respiration, brachial artery blood flow and sympathetic nerve activity. More specifically, brachial BP will be measured with a clinically validated automated sphygmomanometer (Omron), using a cuff wrapped around the upper arm. In addition, beat-to-beat BP will be measured using finger photoplethysmography, using a small lightweight cuff wrapped around the finger. Heart rate will be measured using standard electrocardiogram involving the placement of several sticky patch electrodes on the collarbones and chest (standard 3 lead ECG). For breathing monitoring, participants will wear a mouthpiece/noseclip or oronasal mask (Hans Rudolph) and chest movements will be monitored with a belt placed around the thorax. Sympathetic nerve activity will be measured using the microneurgraphy technique. This involves the insertion of a small, sterile wire (unipolar tungsten microelectrodes, tip measuring 1-5 um) near the fibular head on the outside of the leg, to obtain a multiunit recording of postganglionic muscle sympathetic nerve activity from the peroneal nerve.

After a resting baseline of 20 min (last 5 min used for analysis), chemoreflex testing will be undertaken. Chemoreflex testing will involve five tests. Each test lasts 5 min and is separated by 15 min rest period. Each participant will receive all five tests in a randomised order. Each test involve the breathing of a different gas mixture, while the participant wears a mouthpiece/noseclip or oronasal mask. The five tests are: 1) hypercapnic hyperoxia (to evaluate central chemoreflex stimulation with diminished peripheral chemoreflex stimulation, using a gas concentration of: 7% CO2, 50% O2 and 43% N2); 2) isocapnic hypoxia (to evaluate peripheral chemoreflex stimulation, using a gas concentration of: 10% O2 and 90% N2); 3) hypercapnic hypoxia (to evaluate combined central and peripheral chemoreflex stimulation, using a gas concentration of: 7% CO2, 10% O2 and 83% N2); 4) isocapnic hyperoxia (to evaluate potential central effects of hyperoxia, using a gas concentration of: 50% O2 and 50% N2); and 5) hypocapnic hyperoxia (to evaluate central chemoreflex tonicity, using a gas concentration of: 50% O2 and 50% N2 which will be conducted with a rebreathing test).
Intervention code [1] 315849 0
Early detection / Screening
Comparator / control treatment
The "control" treatment are protocols 4) and 5) described above (i.e., isocapnic hyperoxia test and hypocapnic hyperoxia test) for intra-individual comparison. Also, the normotensive controls will be consider as "controls" for the inter-individual comparison.
Control group

Primary outcome [1] 321725 0
Muscle sympathetic nerve activity as assessed by microneurography.

Timepoint [1] 321725 0
: Assessed at multiple timepoints during a single experimental session: hypercapnic hyperoxia (primary timepoint), isocapnic hypoxia, hypercapnic hypoxia, isocapnic hyperoxia and hypocapnic hyperoxia
Secondary outcome [1] 376012 0
Blood pressure as assessed by finger photoplethysmography.
Timepoint [1] 376012 0
Assessed at multiple timepoints during a single experimental session: hypercapnic hyperoxia, isocapnic hypoxia, hypercapnic hypoxia, isocapnic hyperoxia and hypocapnic hyperoxia

Key inclusion criteria
- Patients with essential hypertension (Stage 2, treated controlled or uncontrolled; office SBP greater than 140 mmHg or DBP greater than 90 mmHg);
- Normotensive controls (office SBP less than 120 mmHg and DBP less than 80 mmHg);
- BMI less than 35 kg.m2.
Minimum age
18 Years
Maximum age
No limit
Both males and females
Can healthy volunteers participate?
Key exclusion criteria
• Significant arrhythmias (e.g., atrial fibrillation, previous VT / significant ventricular ectopy)
• Significant valvular heart disease
• Previous coronary artery bypass surgery
• Primary angioplasty for acute ST elevation
• Myocardial infarction
• Severe left ventricular dysfunction
• Recent (< 3 months) ischemic stroke
• Current smoker
• Body mass index < 18 kg/m2.
• Current pregnancy
• Users of recreational drugs
• Abusers of alcohol
• Inability to fully or appropriately provide consent (e.g., language issue, reading capability)
• Underlying medical conditions, which in the opinion of the Investigator place the participant at unacceptably high risk for participating in the study.
Chronic and systemic illness including:
• Severe respiratory disease (e.g., chronic obstructive pulmonary disease);
• Severe, uncontrolled type II diabetes;
• Current active treatment for cancer
• Connective tissue or inflammatory disease
• Neurological disease
• Infection or pyrexial illness
• Uncontrolled thyroid disorders
• Renal impairment (e.g., chronic kidney disease with creatinine clearance <29 ml/min)

Study design
Purpose of the study
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

Intervention assignment
Other design features
Both groups (hypertensive and normotensive subjects) will receive all 5 gas inhalation protocols in random order during the study.
Not Applicable
Type of endpoint(s)
Statistical methods / analysis
For the assessment of normality and homogeneity of distribution of each variable will be performed using the Kolmogorov-Smirnov and Levene’s tests, respectively. Chi-square (X2) test will be used to analyse categorical data. Comparisons between groups and between trials will performed repeated measures ANOVA with appropriate post hoc tests.

Recruitment status
Not yet recruiting
Date of first participant enrolment
Date of last participant enrolment
Date of last data collection
Sample size
Accrual to date
Recruitment outside Australia
Country [1] 21936 0
New Zealand
State/province [1] 21936 0

Funding & Sponsors
Funding source category [1] 304076 0
Name [1] 304076 0
Auckland Medical Research Foundation
Address [1] 304076 0
PO Box 110139, Auckland Hospital, Auckland 1148
Country [1] 304076 0
New Zealand
Primary sponsor type
University of Auckland
Private Bag 92019
Auckland 1142
New Zealand
Secondary sponsor category [1] 304273 0
Name [1] 304273 0
Address [1] 304273 0
Country [1] 304273 0

Ethics approval
Ethics application status
Ethics committee name [1] 304568 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 304568 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Ethics committee country [1] 304568 0
New Zealand
Date submitted for ethics approval [1] 304568 0
Approval date [1] 304568 0
Ethics approval number [1] 304568 0

Brief summary
A better understanding of the mechanisms regulating blood pressure in hypertensive patients is required once at least one in three people have hypertension in New Zealand. Given that the peripheral chemoreceptors are sensitised in hypertension and that they excite central chemoreceptors, we hypothesise that the central chemoreflex is also sensitised in hypertension. We will test for the first time the interaction between peripheral and central chemoreflexes on the regulation of vasomotor sympathetic activity and BP in hypertensive patients.
Trial website
Trial related presentations / publications
Public notes

Principal investigator
Name 97414 0
A/Prof James P Fisher
Address 97414 0
Faculty of Medical and Health Sciences
Department of Physiology
University of Auckland
85 Park Road
Auckland 1023
Country 97414 0
New Zealand
Phone 97414 0
Fax 97414 0
Email 97414 0
Contact person for public queries
Name 97415 0
A/Prof James P Fisher
Address 97415 0
Faculty of Medical and Health Sciences
Department of Physiology
University of Auckland
85 Park Road
Auckland 1023
Country 97415 0
New Zealand
Phone 97415 0
Fax 97415 0
Email 97415 0
Contact person for scientific queries
Name 97416 0
A/Prof James P Fisher
Address 97416 0
Faculty of Medical and Health Sciences
Department of Physiology
University of Auckland
85 Park Road
Auckland 1023
Country 97416 0
New Zealand
Phone 97416 0
Fax 97416 0
Email 97416 0

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results