The effects of hypercapnia on cerebral blood flow velocity and arterial blood pressure in
healthy subjects lead to an increase in orthostatic tolerance, peak HR and time to peak
HR compared with normocapnic orthostatism. The CO2 effects on heart rate and orthostatic
tolerance were observed in a small group of POTS patients with orthostatic hypocapnia,
after supplying CO2 to correct hypocapnia. It is unclear, however, whether this
intervention will also work for the broader POTS population. This might constitute an
attractive option of therapy for POTS patients.
The investigator's hypothesis is that increasing end-tidal CO2 (ETCO2) will reduce
orthostatic tachycardia and orthostatic symptoms in patients with POTS. The secondary
hypothesis is that blood pressure will be better maintained during increased ETCO2 via
improved cardiac output.
INTERVENTION The RespirAct™ system (Thornhill Research Inc., Toronto, Canada) is a
computer-controlled gas blender providing CO2, O2 and nitrogen for a subject to inhale
while breathing for the purpose of controlling the concentrations of the respective blood
gases. The RespirAct™ records inspired and exhaled gas concentrations, which can be
recalled, analyzed and graphed. Data is collected breath-by-breath including end-tidal O2
and CO2, the length of inspiration and expiration for the breath, the respiration rate
and the tidal volume per breath. The system has been Health Canada approved and utilized
in several publications in healthy individuals and clinical populations. Subjects will be
fitted with a face mask which will be connected to a tube supplied with gas from
RespirAct™ system
Primary Analysis The primary analysis will compare the magnitude of ΔHR from supine to
HUTT during hypercapnia compared to HUTT with no intervention (HUTT 3 and 4 vs 1). The
comparison will use a paired t-test (or a Wilcoxon Signed-Rank test if the data are
non-normally distributed).
Secondary Analysis The secondary analysis will compare the VOSS Symptom Rating at the end
of each 8 min HUTT, comparing each HUTT run.
Sample Size Calculation Since this is a pilot study, there are few preliminary data about
the effect of hypercapnia on orthostatic symptoms in POTS adults. A clinically meaningful
reduction in orthostatic tachycardia of 10 bpm would be clinically significant. It is
estimated a standard deviation of about 15 bpm for our sample. With the aforementioned
assumptions for a paired test of continuous data and a 0.05 two-sided significance level,
a sample size of 20 POTS patients would allow for 80% power to detect this difference. To
account for study withdrawal and dropout the investigators intend to enroll 26 POTS
patients in total
Adverse Event (or Unanticipated Problem) Reporting Any adverse events of a serious nature
will be reviewed immediately with the principal investigator. Serious adverse events will
be reported in writing to the CHREB within 10 days of the PI's notification of the event.
All study adverse events will be summarized once a year, during the annual review
reporting, for the CHREB. The research coordinator will be responsible for tracking
adverse events in this study.
The adverse event will be described with the following information: description of the
event, outcome of the event, how long it lasted, whether the event required treatment or
intervention, and the outcome.
The definition of events is as follows:
Mild - transient and mild in nature, with no treatment necessary. Moderate - some
intervention and treatment necessary, but the participant completely recovers. Severe -
an event that results in hospitalization, disability, death or is life-threatening.
Data & Safety Monitor There will be no external Data & Safety monitor for this study.
PRIVACY and CONFIDENTIALITY ISSUES
Protected Health Information will be used in this study. The investigators will comply
with the patient privacy guidelines of the University of Calgary and applicable
provincial and federal rules.
The research team is comprised of experienced research nurses and research assistants who
are aware of the importance of confidentiality of health information. Paper research
records will be stored in a locked office. Digital records will be stored on
password-protected University of Calgary computers/servers and in the University of
Calgary Clinical Research Unit REDCap Database.
Every effort will be made to publish and present the data from this study. At no time
will any participant be identified in any such publication
Information about participants will be handled as confidentially as possible, but there
is always the potential for an unintended breach of privacy.
Data Management Plan:
All data will be stored under an assigned participant code for data storage and a
master list linking the code to the participant name and other identifiers will be
kept on the encrypted restricted access drive at the University of Calgary.
All data collected before, during, and after the study, including identifiable data,
will always be kept on password protected computers on an encrypted restricted
access drive at the University of Calgary or in the case of paper records, locked in
a secure file cabinet in a locked room. Only the researchers will have access to
these.
