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AIIHPC REPORT
THE ROLE OF CONNECTED HEALTH IN THE DIAGNOSIS
OF AUTONOMIC DYSFUNCTION IN CANCER
CLINICAL FELLOW:
Dr Brenda O’Connor1,2
SUPERVISOR:
Professor Declan Walsh1,2,3
AFFILIATIONS:
1. Our Lady’s Hospice & Care Services
2. School of Medicine & Medical Science, University College Dublin
3. School of Medicine, Trinity College Dublin
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LAY SUMMARY
The Autonomic Nervous System regulates the “automatic” functions of the body such
as blood pressure, heart rate, breathing, stomach function, temperature regulation
and bladder function. When this system becomes unbalanced, it affects many body
functions and can cause a variety of symptoms. These include tiredness, reduced
appetite, weight loss, nausea, blackouts and falls.
Limited studies suggest that autonomic nervous system disturbance is common in
advanced cancer. This disorder remains poorly understood. Causes may include
both the cancer itself and chemotherapy. Assessment is complex, can only be
undertaken in hospital and does not represent real life activities. Admission for this
type of investigation is not desirable in seriously ill cancer patients. Modern, mobile
medical devices may provide the solution.
This study investigates if mobile medical technology can effectively measure
autonomic dysfunction in cancer. Participants wear 4 small medical devices for
approximately 75 minutes. These record blood pressure, heart rate, temperature
and sweat production both at rest and during a series of activities. The devices
transmit wirelessly to a central computer for analysis.
The study is comprised of three stages:
Study A: Pilot study with healthy volunteers
Study B: Early stage cancer patients at St. Vincent’s Hospitals
Study C: Advanced cancer patients at Our Lady’s Hospice & Care
Services
The acceptability of this device for participants, both practical and psychological
is explored. On pilot end, a review of the study will take place. Where possible,
adjustments will be made for any challenges encountered before patient
recruitment.
It is hoped that this study will determine which one of these devices is most
effective in measuring autonomic nervous system disturbance.
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BACKGROUND
Cancer
Cancer is a high prevalence, high impact disorder that impairs function, mobility and
social interaction. People with cancer experience multiple, fluctuating symptoms that
are complex to measure and difficult to record.1 If the underlying cause of these
symptoms can be characterised, quality of life can be enhanced through more
targeted treatment strategies.1 Dysfunction of the autonomic nervous system is a
common disorder in cancer.
Autonomic Nervous System
The autonomic nervous system (ANS) is an involuntary nervous system which
innervates every organ in the body.2 The ANS regulates important bodily functions
which include blood pressure, heart rate, thermoregulation, respiration,
gastrointestinal, bladder and sexual function.2 Limited studies report ANS
dysfunction in 50-80% of advanced cancer patients.3-7
Autonomic Nervous System Dysfunction
Autonomic dysfunction predisposes patients to a number of symptoms which include
fatigue, reduced appetite, weight loss, shortness of breath, blackouts, falls, and even
sudden death.8 Autonomic dysfunction is an important prognostic indicator in
cancer.6-8 Postulated causes include decreased physical activity, medications,
chemotherapy, and paraneoplastic processes.6-8
The pathophysiology of autonomic dysfunction remains poorly understood. Ewing’s
protocol has become the gold standard objective assessment of autonomic
dysfunction.7,9,10 This protocol measure sympathetic and parasympathetic activity by
analysing end organ responses to a series of physiological stressors. The
assessment takes approximately 30 minutes. This assessment is cumbersome,
challenging and can only be carried out in a clinical setting. Inpatient admission for
this investigation is not desirable in seriously ill patients with advanced cancer and
acts as a barrier to adequate treatment of this disorder. Further studies on autonomic
dysfunction must address novel methods to provide a reliable proxy for current
standardised tests. Advances in wireless medical technology may provide the
solution.
Connected Health and Autonomic Dysfunction
Autonomic dysfunction remains under-researched, poorly understood and thus
under-diagnosed. New low-cost, low-power wearable sensors for long-term
measurement of cardiovascular, gastrointestinal and thermoregulatory functions
could revolutionise autonomic dysfunction management. To date, these devices
have not been applied in a clinical setting in cancer. Simplified investigations could
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negate the need for inpatient care. Larger populations could be studied in real life
settings.
This study investigates the feasibility and user interface of prototype wireless
technology in the measurement of ANS dysfunction in cancer. Parasympathetic and
sympathetic autonomic function is assessed by cardiovascular and thermoregulatory
responses to physiological stressors:
a. Parasympathetic function: Cardiovascular (heart rate variability)
b. Sympathetic function: Cardiovascular (blood pressure variability) and
thermoregulatory (sweat production and core temperature alteration)
OBJECTIVES
Primary
1. Conduct a feasibility study to examine if wireless technology can objectively
measure autonomic dysfunction in cancer
a. Cardiovascular Autonomic Function:
i. Electrocardiography (ECG)
ii. Blood Pressure (BP) Monitor
iii. Stroke Volume Sensor
b. Thermoregulatory Function
i. Core Temperature Monitor
ii. Galvanic Skin Response (GSR) Sensor
2. Determine the wireless device user interface with:
a. Volunteer
b. Patient
c. Researcher
Secondary
1. Assess the prevalence of autonomic dysfunction in participants with:
a. Non-metastatic cancer
b. Metastatic cancer
2. Correlate subjective symptom reports with objective device results
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METHODS
Study Design
This is a prospective observational feasibility study. Autonomic function is analysed
in three populations:
Study A: Pilot with healthy volunteers (physicians and nurses in clinical practice)
Study B: Non-metastatic cancer patients pre-chemotherapy
Study C: Metastatic cancer patients
Participant Selection
Participants in Study A are healthy staff volunteers at Our Lady’s Hospice & Care
Services (OLH&CS). Study B participants will be recruited in the Oncology Day
wards at St Vincent’s Hospital Group. Study C participants will be recruited from the
out-patient palliative care services at OLH&CS.
Patients are recruited if they have a loco-regional or metastatic solid tumour
diagnosis, are aged ≥18 years, have an Eastern Cooperative Oncology Group
(ECOG) performance status of ≤ 2, can lie supine with 1 supporting pillow and can
stand /mobilise unaided.
Exclusion criteria are: established diagnosis of diabetes mellitus, dementia or
delirium, a clinical diagnosis of dehydration, the presence of a pacemaker or an
Implantable Cardiac Defibrillator (ICD), an abnormal resting electrocardiograph
(ECG), oxygen saturation of less than 90% on room air, the need for continuous
oxygen use, or a life expectancy of <7 days.
Research Approval
Ethical approval was granted by St Vincent’s Healthcare Group Ethics and Medical
Research Committee. Approval to conduct research at St Vincent’s Hospital Group
was also granted by the Medical Board and the Data Manager.
Approval to enrol staff and patients was granted by OLH&CS Education and
Research Committee.
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Study Devices
This study is undertaken with our technology collaborators Tyndall National Institute
(TNI) in Cork. Several collaborative meetings were held with the chief project
engineer to discuss the features of the technology. The existing technology needed
adjustment to maximise comfort and utility for the advanced cancer population. TNI
conducted further research to develop the most suitable design. Alterations to the
research protocol were required based on their device refinement. Prototype
technology has since been reviewed by the researcher and feedback given to
technology partners for further adjustment.
Four wireless devices have been developed to measure the multifaceted
components of cardiovascular (cardiac output, heart rate and blood pressure
variability) and thermoregulatory (core temperature and sweat production) autonomic
function. These devices are applied to the participant for the study duration:
1. Thoracic Sensor Belt: Measures electrocardiography (ECG), core temperature
and cardiac output
2. Wrist Band: Galvanic Skin Response (GSR) sensor measures sweat
production
3. Arm Device: Wireless blood pressure (BP) monitor
4. Ankle Sensor: Wireless inertial measurement unit to correlate measurements
with activity
Each device relays encrypted data via Bluetooth to a central pre-programmed base
station positioned within 10 metres of the participant. Please see appendix 1 for a
detailed description.
A number of unforeseen challenges resulted in full technology development and
deployment being delayed by several months. These include TNI resource
constraints (personnel), and technological challenges related to device
interoperability. A key component of this technology is the need for each device to
communicate with all other devices and the central base station. Final design testing
is in progress and it is hoped that recruitment will begin in December 2014.
Data Collection
An initial interview establishes demographic details, current medications,
caffeine/nicotine intake and the participant’s autonomic symptom profile.
Objective autonomic function tests are conducted using a modified Ewing’s protocol
suitable for cancer patients.4,7,10
Modified Ewing’s Classification System of Autonomic Dysfunction10
The presence or absence of autonomic dysfunction is detected by an assessment
protocol which measures end organ responses to physiological stressors. SV and
GSR are continuously recorded throughout the test period. ECG and blood pressure
are monitored during parasympathetic and sympathetic tests:
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PARASYMPATHETIC
1. Heart Rate Response to Deep Breathing (Normal Value ≥15 beats/min)
Maximum and minimum heart rate during the first 3 successive breathing
cycles is calculated from the shortest and longest R-R interval. The mean of
the differences between the maximum and minimum R-R intervals during the
three successive cycles is calculated.
2. Heart Rate Response to Valsalva Manoeuvre (Normal Value ≥ 1.21)
Participants are requested to blow into a mouthpiece at a pressure of
40mmHg for 15 seconds. This is repeated 3 times and the best/maximum
response is used for analysis. A minimum of 30mmHg for 12 seconds is
required for inclusion. The heart rate normally increases during the
manoeuvre followed by a rebound bradycardia after release. Heart rate
response is calculated as the ratio of the maximum R-R interval shortly after
to the minimum R-R during the manoeuvre.
3. Heart Rate Response to Standing (Normal Value ≥1.04)
Participants are requested to stand quickly from the supine position. Normally
an immediate increase in heart rate occurs, maximal at around the 15th beat,
followed by a relative bradycardia, maximal around the 30th beat. Heart rate
response is measured as the ratio of the maximum R-R interval at the 30th
beat, to the minimum R-R interval at the 15th beat.
SYMPATHETIC
4. Blood Pressure Response to Standing (Normal: Systolic drop ≤10mmHg)
This assessment takes place simultaneously with the Heart Rate Response to
Standing. BP on the left arm is measured after the patient has been lying
supine for 5 minutes. On standing from the supine position, BP is measured
every 1 minute to a total of 5 minutes. The difference in systolic and diastolic
blood pressures is taken as the measure of postural blood pressure change.
On completion of these assessments, a questionnaire examines the acceptability of
wireless device use in participants.
Data Analysis
1. Ewing’s existing classification system will be used to categorise autonomic
function
i.
Normal: All tests normal or one borderline
ii.
Early dysfunction: One of three heart rate tests abnormal or two
borderline
iii.
Definite dysfunction: Two or more heart rate tests abnormal
iv.
Severe dysfunction: Two or more heart rate tests abnormal plus one
BP test abnormal
v.
Atypical pattern: Any other combination of abnormal tests
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TEST
NORMAL
BORDERLINE
ABNORMAL
Heart Rate Response
Valsalva
Manoeuvre
Deep Breathing
≥1.21
≤1.20
≥15 beats/min
11-14 beats/ min
≤10 beats/ min
Standing
≥1.04
1.01-1.03
≤1.00
11-29mm Hg
≤30mm Hg
Blood Pressure Response
Standing
≥ 10mm Hg
2. Data in metastatic and non-metastatic cancer patients is compared to that of
healthy volunteers
3. Objective autonomic function results are correlated with subjective symptom
reports
4. The acceptability of wireless monitor use in participants is assessed
i.
Practical
ii.
Psychosocial
FINDINGS
Due to the significant delays outlined above, this study is yet to be completed.
Results will be submitted as soon as they are available.
IMPLICATIONS FOR PRACTICE
This research is diagnostic in nature. Study outcomes will define effective sensor
streams to measure autonomic dysfunction in this population with a view to replacing
existing cumbersome measures.
We will gain further insight into modern non-invasive techniques to screen for and
monitor cancer related autonomic dysfunction. Effective technology will facilitate
the investigation of predisposing factors or associated symptom profiles. This will
enable targeted treatment and close supervision of effect.
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PLANS FOR DISSEMINATION/OUTPUT FROM STUDY
Research outcomes will be disseminated to the academic community through
presentation at national and international conferences, and publication in peer
reviewed palliative medicine and oncology journals. Results will be disseminated
locally at OLH&CS Palliative Medicine Grand Rounds.
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REFERENCES
1. Fainsinger R, Nekolaichuk C, Lawlor PG, Neumann C, Hanson J, Vigano A. A
mulicenter study of the revised Edmonton Staging System for classifying pain
in advanced cancer patients. J Pain Symptom Manage. 2005;29:224-37
2. Gabella G. Autonomic Nervous System. eLS: John Wiley & Sons, Ltd; 2001
3. Bruera E, Chadwick S, Fox R, Hanson J, MacDonald N. Study of
cardiovascular autonomic insufficiency in patients with advanced cancer.
Cancer Treat Rep. 1986;70:1383-7
4. Walsh D, Nelson K. Autonomic nervous system dysfunction in advanced
cancer. Support Care Cancer. 2002;10:523-8
5. Strasser F, Palmer JL, Schover LR, Yusuf SW, Pisters K, Vassilopoulou-Sellin
R, et al. The impact of hypogonadism and autonomic dysfunction on fatigue,
emotional function, and sexual desire in male patients with advanced cancer:
a pilot study. Cancer. 2006 Dec 15;107(12):2949-57
6. Fadul N, Strasser F, Palmer JL, Yusuf SW, Guo Y, Li Z, et al. The association
between autonomic dysfunction and survival in male patients with advanced
cancer: a preliminary report. J Pain Symptom Manage. 2010 Feb;39(2):28390
7. Stone CA, Kenny RA, Nolan B, Lawlor PG. Autonomic dysfunction in patients
with advanced cancer; prevalence, clinical correlates and challenges in
assessment. BMC palliative care. 2012;11:3
8. Chiang JK, Koo M, Kuo TB, Fu CH. Association between cardiovascular
autonomic functions and time to death in patients with terminal hepatocellular
carcinoma. J Pain Symptom Manage. 2010 Apr;39(4):673-9
9. Guo Y, Palmer JL, Strasser F, Yusuf SW, Bruera E. Heart rate variability as a
measure of autonomic dysfunction in men with advanced cancer. European
journal of cancer care. 2013 Apr 30.
10. Ewing DJ, Martyn DN, Young RJ et al. The value of cardiovascular autonomic
function tests: 10 years experience in diabetes. Diabetes Care. 1985; 8(5):
491-498
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APPENDIX 1: DEVICES
General Description
 4 separate devices will be simultaneously applied to the study participant
 Each device will relay encrypted data via Bluetooth to a central preprogrammed base station placed within a 10 metre range (See Figure 1)
 Devices are research prototypes, custom developed for this study
Figure 1
Device No 1: Thoracic Device
EQUIVITALTM SENSOR BELT (Figure 2)
 An appropriately sized belt will be applied around the chest circumference
 This device is comprised of:
a. Continuous Electrocardiograph (ECG) sensor
b. Core temperature sensor
c. Wireless inertial monitor (allows cardiovascular and thermoregulatory
data to be correlated with activity)
CARDIAC OUTPUT SENSOR
 Sensor will be applied to the above EquivitalTM belt
 The device works on the principle of biological electrical impedance
 A small current is passed through the measurement tissue volume
 Monitoring electrodes measure the voltage developed across the tissue
volume
 The sensor measures cardiac output under a variety of conditions: lying down;
sitting; standing up; post exercise
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Figure 2
Device No 2: Wireless Blood Pressure Cuff
BLOOD PRESSURE MONITOR
 A wireless blood pressure cuff will be applied to the left upper arm
Dimensions 14.5 x 5.8 x 3 cm. Cuff circumference 22-42cm (Figure 3)
 Two activation systems are in place to activate the blood pressure monitor
i.
Pre-programmed activation: cuff will automatically inflate at a frequency
set by the researcher
ii.
Manual activation system: researcher can manually inflate the device
using an activation key on the base station
Figure 3
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Device No 3: Galvanic Skin Response Sensor




A galvanic skin response (GSR) sensor will be applied to the left wrist to
measure sweat production on the palmar surface (Figure 4)
This device communicates with the thoracic EquivitalTM sensor belt
Galvanic skin resistance refers to the recorded electrical resistance between
two electrodes, placed an inch apart, when a weak current is steadily passed
over the surface of the skin between them
Sweat contains water and electrolytes which increase electrical conductivity
and lower the electrical resistance of the skin
Figure 4
Device No 4: Wireless Inertial Measurement Unit
 A wireless inertial unit (5 x3.5 x1.5 cm) will be placed on the left ankle using
an ankle strap around the circumference (Figure 5)
 In combination with the thoracic wireless inertial unit, activity levels will be
measured in 6 degrees of freedom using an accelerometer and gyroscope
Figure 5
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AIIHPC CLINICAL RESEARCH FELLOWSHIP: COST BREAKDOWN
Brenda O’Connor
Total Scholarship Amount: €10,000
Budget Used to Date: €8,339
 Overall cost of custom development of study devices for by Tyndall National Institute
(including VAT): €41,697
 This cost breakdown was for:
1. Personnel
2. Consumables
3. Overheads
4. Travel/Subsistence


Science Foundation Ireland provided 80% of funding through a successful application
to their National Access Programme: €33,358
The budget from the clinical research fellowship was used for the remaining 20% of
the cost of technology development: €8,339
Plans for Remaining Budget: €1,661
 Study Laptop with Software: €600
 Dissemination of Study Results (National/International Conferences):
1. 5th International Seminar of the European Palliative Care Research Centre
and EAPC Research Network, Leeds, 2015
a. Conference Registration
b. Travel
c. Accommodation
th
2. 9 World Congress of the EAPC, Dublin, 2016
a. Conference Registration
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