A feasibility study to ascertain the impact of a novel gravity induced

exercise intervention for individuals with Postural Tachycardia

Syndrome and establish where the intervention may fit in the

multifaceted management of the condition.

Student: Robert Andrew BallantineStudent Number: 120007600

Supervisors: Professor Julia Newton and Victoria Strassheim

Degree Programme: MSc Medical Sciences1

Academic Year: 2015-2016Word Count: 6835

1 Abstract:Background: Postural Tachycardia Syndrome (PoTS) is commonly underpinned by a dysfunctional Autonomic Nervous System (ANS). A reduction in gravitational exposure in this population has been shown to both instigate and perpetuate the condition. By conducting 8 exercises in the presence of gravity, this novel intervention aimed to alleviate the debilitating orthostatic symptoms that characterise the condition. Methods: 7 patients with PoTS completed this novel exercise intervention run once a month over a 5 month period. The first patient was part of a pilot study and completed the intervention individually, whereas it was delivered in a class format for the remaining 6. Patients attempted to complete as many asymptomatic repetitions as possible of 8 progressively more difficult exercises that aimed to directly challenge and therefore improve their dysfunctional ANS, the root of their orthostatic symptoms. Objective and subjective measures were used to assess progression throughout the intervention. Results: The intervention had a high rate of compliance, with no drop outs over its duration. In 3 out of the 7 patients, there was an improvement in cumulative monthly repetitions completed, combined orthostatic symptoms, fatigue impact score and measures of general health. For the other 4 patients, results often fluctuated on a month per month basis. Even for these patients though, the intervention did reinforce pacing. Functional activity levels were shown to increase in two cases by 13% and 37%. Conclusion: Overall, this novel intervention had a variable effect on the 7 patients involved, however for those that did improve, the impact it had was momentous. The patients’ background medical and behavioural stability were determined to be key components in their progress. Further studies should focus on ascertaining the most efficacious target group for the application of this intervention.

2 Acknowledgements:I would like to thank my two supervisors Professor Julia Newton and Victoria Strassheim for their kind and unending support and guidance throughout this project. In addition to this, they have allowed me to take on other ventures alongside my dissertation and gain both extremely valuable and rewarding clinical experience with patients. I thank them for entrusting me with this responsibility. I would also like to thank all of the individuals who have

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participated in the exercise intervention. Their willingness and commitment to it whilst still juggling all of their other responsibilities is incredibly motivating. Finally, I would like to thank the members of staff at the CRESTA clinic, where the intervention took place, for their tireless hard work.

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3 Contents:1 Abstract:.........................................................................................................22 Acknowledgements:........................................................................................23 Contents:.........................................................................................................34 List of Figures:................................................................................................55 List of Tables:.................................................................................................56 List of Abbreviations:......................................................................................57 Introduction:...................................................................................................7

7.1 The Physiological Response to Standing:.................................................87.2 Postural Tachycardia Syndrome (PoTS):..................................................9

7.2.1 Subtypes of PoTS:................................................................................107.2.2 Current Management and Treatment of PoTS:...................................11

7.3 Exercise as an Intervention for Individuals with PoTS:..........................117.3.1 Rationale and Development of the Novel Gravity Induced Exercise Intervention:.................................................................................................12

7.4 Outline of this study:..............................................................................138 Hypothesis and Aims:...................................................................................139 Materials and Methods:................................................................................13

9.1 CRESTA fatigue clinic:...........................................................................139.2 Inclusion Criteria for the Intervention:..................................................149.3 Tests and Questionnaires used:..............................................................149.4 Delivery and Tailoring of the Exercise Intervention:.............................159.5 Wider Purpose of the Study:...................................................................17

10 Results:.........................................................................................................1710.1 Patient Characteristics:..........................................................................1710.2 Cumulative Monthly Repetitions:...........................................................1910.3 Compliance with the Intervention:.........................................................2010.4 Effect of the Intervention on Orthostatic Symptoms:.............................2110.5 : Effect of the intervention on General Health Measures:......................22

10.5.1 Fatigue Impact Scale (FIS) Score:...................................................2210.5.2 Combined Health Today and Likert Scale Scores:...........................2310.5.3 Functional Activity Levels:...............................................................25

11 Discussion:....................................................................................................2811.1 Why did some patients improve with the intervention?.........................2811.2 Why did other patients not improve with the intervention?...................29

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11.3 What is the future for the intervention and where may it fit in the multifaceted management of the condition?....................................................3011.4 How did this intervention meet the aims of this study?.........................32

12 Advantages and Limitations:........................................................................3313 Conclusions and Further Work:....................................................................3314 References:...................................................................................................3415 Appendices:...................................................................................................36

15.1 Appendix 1:.............................................................................................3615.2 Appendix 2:.............................................................................................38

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4 List of Figures: Figure 1 – Role of the Sympathetic and Parasympathetic branches of the ANS.Figure 2 – Cardiac parameter changes upon standing. Figure 3 – Criteria needed for PoTS diagnosis. Figure 4 – Subtypes of PoTS.Figure 5 – PoTS Treatment and Management Options. Figure 6 – Hydrostatic Column and Pooling Areas Location. Figure 7 – Specialist gym facility at the CRESTA clinic.Figure 8 - Exercise 1 of the intervention. Figure 9 - Exercise 2 of the intervention. Figure 10 – Exercise 3 of the intervention. Figure 11 – Exercise 4 of the intervention. Figure 12 - Exercise 5 of the intervention.Figure 13 - Exercise 6 of the intervention. Figure 14 – Exercise 7 of the intervention. Figure 15 – Monthly cumulative repetitions graph. Figure 16 – Monthly combined orthostatic symptoms graph. Figure 17 – Fatigue Impact Scale progression graph. Figure 18 – Combined monthly Health Today and Likert Scale graph. Figure 19 – Activity Logs Patient 1. Figure 20 – Activity Logs Patient 6. Figure 21 – Exercise Adaptation Curve. Figure 22 – Overtraining Curve.Figure 23 – N=1 StudyFigure 24 – RCT Study. Figure 25 - Foci of Modifications for PoTS patients.

5 List of Tables:Table 1 – Questionnaires used in this study. Table 2 - Patient characteristics. Table 3 – Monthly cumulative repetitions. Table 4 – Monthly intervention attendance. Table 5 - Monthly Orthostatic Symptoms. Table 6 – Monthly Fatigue Impact Scale score. Table 7 – Monthly combined Health Today and Likert Scale scores. Table 8 – Overall changes in Objective and Subjective measures.

6 List of Abbreviations: OI – Orthostatic Intolerance ANS – Autonomic Nervous System SV – Stroke VolumeBP – Blood Pressure CO – Cardiac Output

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TPR- Total Peripheral Resistance HR – Heart RateSNS – Sympathetic Nervous System BPM – Beats Per Minute PoTS – Postural Tachycardia Syndrome CFS/ME – Chronic Fatigue Syndrome/Myalgic Encephalitis CRESTA – Clinics for Research and Themed Assessment OGS – Orthostatic Grading ScaleOH A/S – Orthostatic Hypotension Activity/SymptomFIS – Fatigue Impact Scale DNA – Did Not Attend RCT – Randomised Control Trial

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7 Introduction: According to the World Health Organisation, chronic diseases will underpin the most significant cause of disability by 2020. Accompanying symptoms faced by the individuals affected, such as fatigue and stress, will be the greatest challenge to future healthcare provision (1). Symptoms of Orthostatic Intolerance (OI) have been found in up to 9 out of 10 people with chronic illnesses (2). Individuals with OI experience symptoms when they stand up such as light headedness, palpitations and dizziness that are alleviated when they lie down (3). These symptoms are collectively referred to as orthostatic symptoms and they are often a by-product of a dysfunctional Autonomic Nervous System (ANS) (4). The ANS is integral to involuntary responses in the human body and is technically subdivided into sympathetic, parasympathetic and enteric branches. The sympathetic and parasympathetic branches effectively antagonise each other, with the sympathetic branch modulating the ‘fight or flight’ response and the parasympathetic branch coordinating the ‘rest and digest’ response, as shown in figure 1. The ANS in its entirety underpins the regulation of homeostatic processes and key bodily functions such as heart rate and blood pressure, digestion and the stress response (5).

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Figure 1: Comparing the effect of the sympathetic and parasympathetic branches of the Autonomic Nervous System on the human body.

7.1The Physiological Response to Standing: The physical act of standing is a stress on the human body. When an individual stands, 500ml – 1000ml of blood accumulates in their lower abdomen, buttocks and legs as a result of gravity. Most of the blood shift occurs in the veins due to their high compliance. This redistribution of blood leads to a reduction of intrathoracic blood volume to the heart. As a result of the Frank - Starling mechanism, Stroke Volume (SV) can decline by approximately 30-40% (6). Intricate compensatory mechanisms maintain blood pressure at a fairly constant level despite this drop in SV. The interrelationships of key cardiovascular parameters is detailed below.

Blood Pressure (BP) = Cardiac Output (CO) x Total Peripheral Resistance (TPR)CO = Heart Rate (HR) x SVTherefore: BP = HR x SV x TPR

As there is a fall in SV upon standing, HR and TPR increase to counteract this and help to maintain BP. Mechanisms in place include a surge in Sympathetic Nervous System (SNS) stimulation of the heart, increasing its rate by 15-20 beats per minute (bpm), and augmented peripheral SNS stimulation, leading to arteriolar vasoconstriction and increased TPR (6). These changing cardiovascular parameters are shown graphically in figure 2. Additionally, the medulla oblongata in the brain incites vasoconstriction of smooth muscles within arterioles, in particular those in the brain, to increase blood pressure against the force of gravity. This aims to alleviate symptoms associated with cerebral hypoperfusion such as dizziness, lightheadedness and fainting (7). Orthostatic stabilisation is maintained within <1 minute in a healthy person (8).

Figure 2: – Changes in various cardiovascular parameters from supine (lying flat) to standing.

Figure adapted from Smith J et al (9).

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7.2Postural Tachycardia Syndrome (PoTS):Postural Tachycardia Syndrome (PoTS) is an example of an orthostatic condition that is commonly underpinned by a dysfunctional ANS. It is five times more common in women than men (10) and can present in all age groups. Its current prevalence in the UK is unknown. PoTS is a group of heterogeneous disorders that manifest themselves in a similar way clinically (11). Individuals with PoTS often have a low blood volume (12) and their dysfunctional ANS can lead to impaired peripheral vasoconstriction. Upon standing these two factors combine to produce a significantly reduced venous return to the heart, leading to excessive tachycardia to counteract this.Obtaining a diagnosis of PoTS is often a fairly protracted process, due to both the lack of awareness of the disorder and the battery of tests needed to rule out other conditions affecting the ANS (13). The criteria for acquiring a diagnosis of PoTS are displayed in figure 3.

Figure 3: Criteria needed for PoTS diagnosis. Figure adapted from Raj S (14).

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Other orthostatic symptoms such as dizziness, headaches and syncope present in this population, as well as customary symptoms of visual problems, gut problems and high levels of fatigue (15). The nature and often multiple combinations of these symptoms can be extremely debilitating, with approximately 25% of those with PoTS unable to work (16). Certain triggers have been reported to accentuate these symptoms, such as excess heat, dehydration and overly strenuous exercise (17).

7.2.1 Subtypes of PoTS:

The modified blood flow physiology in those with PoTS has led to the subtyping of patients depending on their altered blood flow and level of arterial resistance (18), as outlined below:

High Blood Flow PoTS - This group has a high level of blood flow with decreased resting peripheral resistance. This is due to deficient ANS modulated noradrenaline release in their lower limbs and therefore attenuated postural vasoconstriction. They have normal limb capacitance.

Low Blood Flow PoTS - This group has a low level of blood flow as a result of high arterial resistance, high venous pressure and low limb capacitance. A dysfunctional ANS modulated response is reported to be present in the internal organs and lower limbs of these patients.

Normal Blood Flow PoTS - This group has normal blood flow with normal arterial resistance and normal venous pressure. Evidence suggests increased pooling in their internal organs and pelvic regional circulations.

PoTS can also be dichotomised into primary or secondary forms (19). Primary PoTS is idiopathic and is not associated with other diseases. It can either be acquired developmentally, follow a febrile illness, pregnancy or surgery, or be considered hyperadrenergic, which is of genetic origin with a slower onset period. Secondary forms of PoTS occur in association with a known disease or disorder, for example Joint Hypermobility Syndrome, Primary Sjorgens Syndrome or Diabetes Mellitus. Finally, the deconditioning process following prolonged bed rest can both lead to PoTS and perpetuate the condition further, as explained later on. The various subtypes of PoTS are shown in figure 4.

Figure 4: Subtypes of PoTS.

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Figure adapted from Conner et al (20).

7.2.2 Current Management and Treatment of PoTS:

Due to the complexity of the condition, management and treatment of PoTS is often multifaceted and bespoke to each patient. It may be dictated to an extent by their specific PoTS subtype, or for those with secondary forms, their underlying condition. Figure 5 shows the different treatment and management strategies avaliable for PoTS.

Figure 5: Flowchart displaying the plethora of treatment and management options available for individuals with PoTS. Figure adapted from an article by Grubb (21).

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7.3Exercise as an Intervention for Individuals with PoTS:

In figure 5, exercise is listed as a physiological therapy for PoTS. This is evidenced by research showing the beneficial role of exercise as a symptomatic management strategy for PoTS (22-24). Current exercise interventions used for those with PoTS normally fall under the umbrella of Graded Exercise Therapy, with certain types aiming to improve aerobic capacity, and others, such as resistance training, improving the skeletal pump mechanism (25). A consideration of these current interventions is that they may work by improving the compensatory mechanisms in place for a dysfunctional ANS rather than targeting the defective ANS itself. The exercise intervention used in this study specifically targets areas of ANS regulation, as explained in the following section.

7.3.1 Rationale and Development of the Novel Gravity Induced Exercise Intervention:

Individuals with PoTS understandably avoid the stimulus of gravity, as it is their exposure to it that causes their orthostatic symptoms. However, a prolonged period of time in a low gravity or microgravity environment can have a detrimental effect on the human body, as demonstrated in studies conducted on astronauts (26-28). This detrimental effect is partly attributable to a reduction in the functional capacity of certain bodily systems that have evolved to operate in spite of gravity. The conjunctive action of the ANS and Cardiovascular System upon standing, as explained in section 7.1, is an example of this. The decline in functional capacity of these systems is due to their reduced challenge of gravity; they effectively ‘decondition’ against it in the same way that unchallenged muscles degrade (29). This attenuates the compensatory mechanisms in place to deal with further prospective gravitational exposure, leading to greater orthostatic symptoms and a continuation of this vicious cycle.

This intervention aimed to stop this vicious cycle by specifically challenging the cause of the debilitating orthostatic symptoms seen in those with PoTS, their dysfunctional ANS. The relationship between the ANS and CV system was specifically targeted, as improving their association, by challenging them in the presence of gravity, would help deliver blood to the correct areas, especially the brain, leading to a consequential decline in symptoms and enhancement of function. Firstly, the ANS modulated hydrostatic column, which maintains adequate blood flow between the heart and the brain, was challenged by exercises that involved relocating the head in relation to the heart. Secondly, pooling areas were addressed by exercises that involved moving the head and heart in relation to the ground. Figure 6 highlights the key targets of the intervention. Research by Antonutto and Di Prampero (30) underpinned these concepts.

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7.4Outline of this study:Seven individuals with PoTS undertook this intervention. One was a pilot patient who completed the intervention individually. This allowed for a refinement of the protocol in place and to ensure that patients would be able to participate. Subsequently, a further six completed the intervention in a specifically run group exercise class. The intervention took place once a month and was run over a 5 month period.

8 Hypothesis and Aims:The hypothesis for this study was that a novel gravity induced exercise intervention conducted once a month over a 5 month period will have a positive impact on the symptoms of a small group of individuals with PoTS.

There were four main aims of this study:

To determine whether a group of patients would comply with the intervention, as demonstrated by their attendance throughout its duration.

To determine the efficacy of the intervention on the improvement of orthostatic symptoms, its intended target.

To determine whether there was an improvement in measures of general health as a result of the intervention.

To determine the future direction of this intervention and its potential role as a management strategy of PoTS.

9 Materials and Methods:

9.1CRESTA fatigue clinic:

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Figure 6 – The location of the Hydrostatic Column and Pooling Areas, both key targets of the intervention.

Table 1 - Plethora of questionnaires completed by the study participants.

The intervention occurred in the specialist gym facility (see figure 7) at the Clinics for Research and Themed Assessment (CRESTA) fatigue clinic in Newcastle upon Tyne (31).

9.2Inclusion Criteria for the Intervention:

All patients must have been diagnosed with PoTS, as determined by the diagnostic criteria evident in figure 3. Due to the timing of the intervention, a Monday morning at 10am, the patients involved were often those who were able to offset external factors such as childcare and work commitments.

9.3Tests and Questionnaires used:

Upon arrival at the clinic, all individuals complete an active stand test. An active stand test can diagnose PoTS and give a general indication of the functioning of the ANS and CV system. For those who participated in the intervention, a battery of questionnaires was completed every month, evaluating different aspects of their condition, as shown in table 1. To ascertain whether there were changes in activity levels within the 5 month duration of the intervention, patients were asked to fill out an activity log at the start, middle and its conclusion. A selection of the questionnaires used and an example of an activity log is shown in Appendix 1.

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Figure 7 – A photograph showing the specialist gym facility at the CRESTA clinic, the location of the intervention.

9.4Delivery and Tailoring of the Exercise Intervention:

An active stand test was completed by every patient before the commencement of the intervention, at its midpoint and at its conclusion. The 1 hour intervention periodically began with the completion of the aforementioned questionnaires and an unstructured discussion between the specialist physiotherapist who ran the intervention and the patients about their health over the previous weeks. Following this, the PoTS patients completed as many asymptomatic repetitions as possible of each exercise. Depending on the severity of their symptoms, patients often only accomplished very low repetitions or even missed out certain exercises. Adequate rest periods were ensured by consistent dialogue between the patients and specialist physiotherapist, in addition to those in the group exercise class always completing each exercise in the same consecutive order. The 8 exercises conducted in the intervention, shown below in figures 8-14, were designed to become progressively more challenging throughout. Exercise 8 does not have a figure as it entails getting up from the floor in any fashion possible, an individualised process. Following the 8 exercises, the PoTS patients all completed 10 minutes of meditation to conclude the intervention. They were then given a copy of how many repetitions they had completed, feedback questionnaires and on specific occasions a weekly activity log to fill in.

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Questionnaire Name Function Directionality Validated in this

population?Orthostatic Grading Scale

(OGS)Symptoms of OI. Lower Score =

ImprovedYes

Orthostatic Hypotension Activity/Symptom

assessment (OH A/S)

Severity of OI symptoms and how these symptoms affect activity.

Lower Score = Improved

No

EQ-5D-5L Simple, standardised and generic measure of health status for clinical

and economic appraisal.

Lower Score = Improved

Yes

Health Today Value of 0 -100 to evaluate patient’s health today.

Higher Score = Improved

Yes

Fatigue Impact Scale (FIS) Impact fatigue has on patient’s everyday life.

Lower Score = Improved

Yes

Likert Function Assessment of patient’s perspective on their condition.

Higher Score = Improved

No

Intervention Feedback Individualised feedback of the exercise intervention.

N/A No

A monthly interval was chosen between each juncture of the intervention to allow for adequate recovery, as directly challenging the multifaceted ANS can have profound effects on the rest of the body and its homeostatic processes (32).

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Figure 8 – Exercise 1 of the intervention: Modified sit up.

Figure 12 – Exercise 5 of the intervention: Sit to stand from a chair.

Figure 9 – Exercise 2 of the intervention: Movement of head to the ground.

Figure 10 – Exercise 3 of the intervention: Full upper body raise from a position of hands and knees.

Figure 11 – Exercise 4 of the intervention: Sitting arms raise.

Figure 13 – Exercise 6 of the intervention: Standing arms raise.

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Figure 14 – Exercise 7 of the intervention: Standing incremental roll down, taking arms down to the floor.

9.5Wider Purpose of the Study: This study was run as a service development, aiming to enhance the current clinical service delivered at the CRESTA clinic. The use of quality and service improvement tools are frequently applied in health care settings to improve the quality, efficiency and productivity of the patient care provided (33).

By gaining clinical observer status, I was able to observe the intervention taking place at the CRESTA clinic and interact with a wide range of patients and their families.

10 Results:

10.1 Patient Characteristics:

A broad demographic of patients participated in the intervention. This is attributed to the heterogeneous nature of the condition in its aetiology, affliction and presentation. Table 2 briefly describes the characteristics of each patient. The relative stability of the patient’s home and work background can hugely impact on their symptoms and progression, hence the reason for it being displayed in table 2. Patient 1 is the pilot patient who conducted the intervention individually, whereas patients 2 – 7 participated in the exercise class.

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Patient ID Age Gender Condition (s) Home Background

Work Background

1 44 Female PoTS, Chronic Fatigue Syndrome/Myalgic Encephalitis (CFS/ME)

Lives at home with parents. Bedbound for 10-15 years. Stable.

Unable to work due to severity of symptoms.

2 40 Male PoTS, Psoriatic Arthritis

2 young children, wife is pregnant with another child. Unstable.

Worked as joiner. Unable to currently work due to fatigue.

3 27 Female PoTS Lives with Partner. Stable.

Completing PhD, extremely demanding. Fluctuating stability.

4 29 Male PoTS Lives with parents. Stable

Works full time, manages work well. Stable.

5 27 Female PoTS, Joint Hypermobility Sydrome, Irritable Bowel Syndrome. Very prevalent tachycardia.

Lives with partner. Stable.

Works full time, unsympathetic employer. 1 hour commute. Unstable.

6 35 Female PoTS, CFS/ME. Vitamin D deficiency.

Lives with parents. Stable.

Fatigue too severe to accommodate employment.

7 54 Female PoTS, Arrhythmia, Fibromyalgia, Connective Tissue disorder. Underactive Thyroid. Recovered from breast cancer.

Lives with partner and two grown up sons. Fairly stable.

Retired nurse. Fatigue too severe to accommodate employment.

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Table 2 – Patient characteristics.

10.2 Cumulative Monthly Repetitions:

The objective measure of the number of completed repetitions of each exercise every month was important to assess as it was indicative of progress throughout the intervention. A cumulative value of completed repetitions for all 8 exercises each month was calculated for each patient. This is shown both in table 3 and graphically in figure 15. For reference, DNA = Did Not Attend.

There were some months where patients could not participate in the intervention, however for all individuals there was data from at least three months to assess. There was an increase in the number of completed cumulative repetitions from the first month to the end of the study in patients 1, 4 and 6. According to the specialist physiotherapist who ran the intervention, patient 1

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1 2 3 4 5 6 70

10

20

30

40

50

60

70

Monthly Cumulative Repetitions completed

Month 1 Month 2 Month 3 Month 4Month 5

Patient ID

Cum

ulati

ve R

epeti

ons

Table 3 – Monthly cumulative repetitions of all 8 exercises completed by the patients. Figure 15 – A graph to show the monthly cumulative repetitions of all 8 exercises completed by the patients. Cumulative Repetitions per Month

Month 1 Month 2 Month 3 Month 4 Month 5Patient ID1 30 56 60 40 402 27 23 11 DNA 133 26 DNA 8 23 164 DNA 32 35 37 DNA5 20 22 26 29 46 21 23 28 28 07 18 DNA 23 9 16

initially pushed herself too hard each month, hence the high number of repetitions. She subsequently reduced her repetitions, helping her symptoms stabilise and functional activity increase. Patients 4 and 6 started with lower repetitions and made fairly steady progress in the number of repetitions that they completed over the 5 months. This was also the case for patient 5 except for her final month. The cumulative repetitions for patients 2, 3 and 7 fluctuated fairly prominently over the 5 months and a general improvement was not seen.

10.3 Compliance with the Intervention:

The level of patient compliance towards an intervention was indicative of their feelings towards it. The completion rate of exercise interventions in studies concerning PoTS is often fairly low as the intervention can precipitate detrimental symptoms for the patient. Table 4 documents the monthly attendance of all the patients completing the intervention.

Intervention Compliance per MonthMonth 1 Month 2 Month 3 Month 4 Month 5

Patient ID1 2 DNA

3 DNA 4 DNA DNA5

6 7 DNA

No one dropped out of the study over its 5-month duration. This high level of compliance indicates that the patients felt the intervention aided them in some way, notwithstanding the symptoms it may have provoked. The DNA rate was 14%, with mitigating circumstances for a lack of attendance on occasion, such as holidays, work or family commitments.

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Table 4 – Monthly attendance for all patients.

10.4 Effect of the Intervention on Orthostatic Symptoms:

The intended target of this intervention was to alleviate the debilitating orthostatic symptoms that characterise PoTS. If successful, this intervention would indicate that specifically challenging the ANS is a potential treatment and management strategy for the condition. The monthly results of the OGS and OH A/S questionnaires, described in section 9.3, have been combined to produce one single integer to determine the patients’ orthostatic symptoms. This is shown both in table 5 and graphically in figure 16.

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Table 5 – Monthly combined orthostatic symptoms of the patients.

Figure 16 – A graphical representation of the patients’ monthly combined orthostatic symptoms.

Combined Orthostatic Symptoms Month 1 Month 2 Month 3 Month 4 Month 5

Patient ID1 50 53 52 50 352 79 79 80 DNA 913 71 98 72 78 754 DNA 60 51 43 DNA5 73 77 71 75 756 48 47 47 47 DNA7 80 64 83 78 94

There are contrasting results evident from both table 5 and figure 16. The orthostatic symptoms of patients 1, 4 and 6 decrease from the initial measurement in month 1, albeit in a different manner. Patient 1’s orthostatic symptoms show an initial increase before a fairly steep decline at the end of the intervention; patient 4’s shows a steady decline throughout; patient 6’s stay very steady, with just a slight decline measured. The orthostatic symptoms of patients 2, 3, 5 and 7 increase from the initial measurement in month 1, again though in different fashions. There is little perturbation in the orthostatic symptoms of patients 2,3 and 5 throughout the intervention except for one noteworthy fluctuation seen in patient 2 and 3, occurring in different months. Patient 7 had fairly fluctuating orthostatic symptoms throughout the intervention.

To conclude, an overall improvement in combined orthostatic symptoms was seen in 3 out of 7 of the patients, 43%.

10.5 : Effect of the intervention on General Health Measures:

Another way to evaluate the impact of the intervention was to determine whether there was any progression in measures of general health during its 5 month duration. If shown to have a positive impact on general health, then this would provide added weight for its use as an interventional strategy for PoTS.

10.5.1 Fatigue Impact Scale (FIS) Score:

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1 2 3 4 5 6 70

20

40

60

80

100

120

Combined Monthly Orthostatic Symptom Trends

Month 1 Month 2 Month 3 Month 4 Month 5

Patient ID

Com

bine

d O

rtho

stati

c Sym

ptom

s

Firstly, the influence of the intervention on the 7 patients’ level of fatigue was evaluated. A decline in their fatigue as a result of the intervention would be a definite positive as this symptom can be extremely debilitating for those with PoTS and the root of a plethora of issues. The patients’ level of fatigue was assessed by their monthly FIS scores, as shown in table 6 and graphically in figure 17.

Similar to the orthostatic symptoms discussed in section 10.4, there was a variable effect of the intervention on the patients’ level of fatigue. An improvement in the measure was seen in patients 1, 4 and 6, meaning that

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1 2 3 4 5 6 70

20

40

60

80

100

120

140

160

FIS score progressionMonth 1 Month 2 Month 3Month 4 Month 5

Patient ID

FIS

Scor

e

Table 6 – Monthly FIS scores.

Figure 17 – A graphical representation of patients’ FIS score progression.

FIS scoreMonth 1 Month 2 Month 3 Month 4 Month 5

Patient ID

1 79 70 71 65 602 117 109 114 DNA 1263 91 118 103 114 1024 DNA 75 66 60 DNA5 115 128 120 132 1326 107 108 107 104 DNA7 129 111 113 122 141

Table 7 – Monthly combined Health Today and Likert Scale results for all patients who competed this intervention other than Patient 1.

fatigue had less of an impact on them as the intervention went on. For patients 2,3,5 and 7, FIS increased over the duration of the intervention. Patients 3 and 7 had larger fluctuations in their FIS than patients 2 and 5.

10.5.2 Combined Health Today and Likert Scale Scores:

Secondly, the impact of the intervention on both the patients’ evaluation of their current health and also their perspective of their condition was assessed by combining the monthly results of their Health Today and Likert Scale questionnaires. A positive change in these parameters, even without changes in symptoms, would be a reflection of the effect of the intervention on the mental state of the individual, which can play a significant role in their ability to adapt and recover from the condition. This is shown in table 7 and graphically in figure 18. The Likert Scale was not used as an outcome measure in the pilot study, therefore there are no results for patient 1.

Combined Monthly Health Today and Likert Scale scores

Month 1 Month 2 Month 3 Month 4 Month 5Patient ID1 N/A N/A N/A N/A N/A2 109.1 126.8 124.6 DNA 126.93 186.1 161 170.3 228.6 196.94 DNA 175.6 135.1 196.9 DNA5 105.1 63.7 77 74.2 75.16 128.5 129.9 132.7 117.4 DNA7 75.9 150.9 100.3 85.6 46

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Figure 19 – A representation of the activity levels of patient 1 at baseline and at the end of the intervention.

1 2 3 4 5 6 70

50

100

150

200

250

Combined Monthly Health Today and Likert Scale Score Trends

Month 1 Month 2Month 3 Month 4Month 5

Primary ID

Com

bine

d He

alth

Tod

ay a

nd Li

kert

Sco

res

An improvement in the combined Health Today and Likert Scale results was seen in patients 2, 3 and 4 from their first month to the conclusion of the study. These values did often fluctuate, understandably though as the nature of the condition dictates that people have good days and bad days. The greatest change was seen in patient 4, whose final combined score was 11% higher than his initial score.

For patients 5, 6 and 7 there was an overall decline in combined Health Today and Likert Scale results from their first month to the conclusion of the study. The trends followed similar patterns to what has been seen previously for these patients, with patient 6 showing little perturbation in these values apart from a slight dip in her final month of attendance and patient 7 having substantial fluctuation throughout. Patient 5 showed the greatest decline in combined score, 29%. However, it is important to note that following quite a steep decline from month 1 and 2, patient 5’s score did stabilise and was on a slight upward trend at the commencement of the study.

10.5.3 Functional Activity Levels:

The final measure of general health assessed was the activity diaries filled in by the patients. Not all of the patients filled them in and for the results to be worthwhile presenting at least two were needed so that a ‘before’ and ‘after’ can be established. In the activity diaries presented below, time asleep is coloured in red, sedentary activity (e.g. time on the sofa) is in yellow and functional activity (e.g. exercise, cooking) is in green.

Patient 1’s activity diaries are shown below in figure 19. On the left hand side is her baseline activity levels, whereas the right hand side depicts her activity levels at the end of the intervention.

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Figure 18 – A graphical representation of patients’ Monthly combined Health Today and Likert Scale scores.

Figure 20 – A representation of the activity levels of patient 6 at baseline and at the end of the intervention.

A cumulative increase in patient 1’s functional activity and also an extended duration of this functional activity is evident. At baseline, she spent 41 hours of her week completing functional activity as opposed to 47 hours at the end of the intervention. The nature of what she could now do also changed. By the end of the intervention patient 1 had begun driving lessons for the first time, a fairly energy intensive process. Moreover, when she visited the clinic for a follow up appointment three months after she had finished the intervention, she declared that she had passed her driving test, a fantastic achievement and indicative of a much greater ability to complete functional activities.

It is also of interest to look at the activity diaries of patient 6, who has CFS/ME and is unable to work due to her fatigue, similar to patient 1. Patient 6’s activity diaries are displayed below in figure 20, in an identical format as before.

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From these activity logs it is clear that patient 6’s baseline functional activity levels were low but did increase by the commencement of the intervention. At baseline she spent 31 hours of her week completing functional activity whereas at the end of the intervention she spent 49 hours of her week completing functional activity, a 37% increase. For an individual who has had CFS/ME and PoTS for 20 years, this is momentous.

The EQ-5D-5L scores were not analysed in the results section as this generic measure is similar to that of the Health Today questionnaire. These results can be found in Appendix 2 if required.

An overall round up of the objective and subjective measures evaluated in section 10.5 for each patient are displayed in table 8.

ID Behaviour Stability

Medical Stability

Cumulative Monthly Reps

Combined Orthostatic Symptoms

Combined Health Today and Likert Score

FIS score Activity Levels

1 Good understanding of conditions. Stable

Stable Initial increase, then decline.

Initial increase before steep decline.

N/A Steady decline.

Increased levels of functional activity.

2 Pushes through relentlessly. ‘Boom and Bust’ mentality. Unstable.

Low Blood cell counts. Comorbidities. Unstable

Fluctuating – exercises help reinforce pacing.

Increased from initial measure, little fluctuation.

Small improvement, remained steady throughout.

Declined. Did not complete.

3 ‘Boom and Bust’ High work pressures. Not fully stable but

Fairly stable. Reps stabilising. More with less recovery period.

Increased from initial measure, little

Improvement from initial measure.

Fluctuates slightly, higher than

Relatively high levels of functional

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improving. fluctuation. initial score.

activity.

4 Stable behaviour traits. Manages routine well.

Stable. Constant increase in reps.

Steady decline throughout intervention.

Improvement from initial measure.

Declined incrementally month by month.

High levels of functional activity.

5 Unstable behaviour often down to work pressures.

Lots of comorbidities, unstable.

Incremental improvement until final month.

Very steady overall, slightly higher at end than initial measure.

Declined then stabilised, at lower level than initial score.

Increased from initial value, remains high.

Did not complete.

6 Stable behaviour, manages and understands condition well.

Stable, fairly reliant on Midodrine.

Incremental increase month on month.

Stay very steady, slight decline at end of the intervention.

Incremental improvement before drop in last month.

Remained high but has been stable.

37% increase in functional activity.

7 Fairly stable, understands condition well.

Lots of comorbidities, unstable.

Fluctuating, depends on other illnesses.

Fluctuated throughout.

Fluctuating levels, dropped to lower than initial value.

Fluctuating, remains high.

Manages activity fairly well.

11 Discussion:

It is evident from the results section that this intervention had a variable impact on the group of individuals with PoTS regarding improvements in their symptoms and general measures of health. This section will portray possible reasons for this and describe the broader trends generated from this study.

11.1 Why did some patients improve with the intervention?

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Table 8 – Individualised overall changes in objective and subjective measures over the course of the intervention.

Figure 21 – Exercise Adaptation Curve displaying the Supercompensation process.

Patients 1, 4 and 6 showed a general improvement in the majority of objective and subjective measures assessed, such as FIS score and combined orthostatic symptoms following the 5 month intervention. A potential reason for this improvement was their relative behavioural and medical stability, as is evident in table 8. Following each monthly juncture of the extremely demanding intervention, this relative stability enabled the patients’ bodies to rest and put in place the correct infrastructure to effectively recuperate. Examples of important processes occurring in this rest period include an increase in neutrophils, lymphocytes and white blood cells to mediate waste products, cellular damage and inflammation respectively (34). With an adequate and fairly undisrupted rest period following a specific challenge such as this one, the respective patients’ fitness levels increased to surpass their baseline level in anticipation of their next challenge; a process known as supercompensation (35).

The supercompensation process is displayed in an Exercise Adaptation Curve shown in figure 21. It must be noted that there is not a ‘one size fits all’ curve due to the many components of the biological regeneration process (35).

11.2 Why did other patients not improve with the intervention?

Conversely, patients 2,3,5 and 7 did not show general improvements in the majority of objective and subjective measures assessed. All of these individuals displayed instability either behaviourally or medically to differing degrees. An example of a trait of unstable behaviour present in this group of patients was for them to relentlessly push themselves through their symptoms and then crash severely afterwards, the so called ‘Boom and Bust’ phenotype. Achieving

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behavioural stability can be extremely challenging as there are often factors to consider beyond a patient’s control, such as the flexibility of their employer or family responsibilities. However, without this stability, patients are constantly challenging themselves without the space or time to fully rest and recuperate. Consequently, their fitness levels never quite reach their baseline or surpass it before being challenged again, creating a negative trend and leading to the phenomenon of overtraining. Figure 22 documents an example of an overtraining curve.

A second possible reason for the indifferent impact of this intervention for these patients could be their medical instability. None of the patients in the study had their PoTS subtyped so the pathology of their condition was unknown, however patients 2,5 and 7 displayed high levels of comorbidities to which their PoTS may be secondary. It is essential that an individual’s underlying condition is managed in conjunction with their PoTS. Evidence from this study would suggest that stabilising comorbities is essential before pursuing this demanding intervention if it is to have a positive impact.

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Figure 22 – Overtraining Curve

Despite a lack of broad improvements in the objective and subjective measures assessed, evidence would suggest that this intervention helped individuals understand and reinforce pacing. Pacing is an important management tool in all conditions with fatigue as a prominent symptom (36). For example this was evident with patient 3, who pushed herself far beyond her asymptomatic range in her first month and required 11 days to get back to normal afterwards. Subsequently, she reduced her repetitions, leading to small corresponding improvements towards the end of the intervention in measures such as her level of functional activity and combined Health Today and Likert Scale scores. Additionally, patient 5 had seen an incremental improvement in her cumulative monthly repetitions (see figure 15) until the last month of the intervention. During the two weeks prior to the final class, her employment workload had increased. Consequently she stopped her exercises very early on in this class to manage her symptoms and activity levels, another example of pacing.

11.3 What is the future for the intervention and where may it fit in the multifaceted management of the condition?

As this was a novel intervention, it is important to look at ways it could be developed to have a greater impact on patients. The reinforcement of pacing and peer support it provided demonstrated the positives of running interventions such as this one in a group environment. Although the greatest overall positive change in many of the outcome measures was made by patient 1, the pilot patient who completed the intervention individually, it is probably the high level of background stability that she had both medically and behaviourally that enabled her to make this progress. In addition to this, it is more cost effective to treat six patients in an hour rather than one.

The necessity of medical and behavioural stability for a patient to make progress as a result of this intervention is the significant communication from this study and would help to shape further research.

A series of ‘N=1 studies’ of stable PoTS patients could be conducted to ensure that it was definitely this intervention that was having an effect (37). An N=1 study involves deriving many preliminary outcome measures over a period of time before adding an intervention whilst changing nothing else, to indicate the actual role of the intervention. This is depicted in figure 23.

A Randomised Controlled Trial (RCT) is known to be the most rigorous method to determine whether there is a relationship between the outcome and the intervention (38). Subjects are randomly assigned to one group receiving the intervention and another receiving an alternative or control treatment and are followed up over time. Based on the results from this intervention, there is too much variability in patient response to the outcome and disparity in the patient group to elicit the use of an RCT. There may be scope for an RCT following other studies, such as those previously described. A depiction of an RCT is displayed in figure 24.

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Figure 23 – Graphic to depict N=1 Study.

It would also be of interest to subtype participating patients in future studies more stringently either into Primary or Secondary PoTS or by their altered blood flow physiology, as described in section 7.2.2, to determine whether this affected the efficacy of the intervention in any way.

Figure 24 – Graphic to depict an RCT. Figure adapted from Kendall, J (38)

In reality, it was impossible to fully establish from one 5 month long study involving 7 patients where this intervention may fit in the complex management of PoTS. Nonetheless, the results from this study have provided an indication of this.

Patients with a relatively stable medical and behavioural background and who have the resources available to rest and recover adequately may choose to incorporate the exercises conducted in this intervention into the treatment and management of their condition. For example they may complete the exercises at the start of the week and complete light lower body resistance exercises at the end of the week to improve their skeletal pump mechanism.

For the PoTS patients that have a background of behavioural and/or medical instability, an intervention that modifies their environment to accommodate their functional limitations, as discussed by Utsun et al (39), may be more applicable. This would help them to reach a stable baseline from which to progress. As prolonged gravitational exposure is the main stimulus of PoTS patients, this is challenging; however adjustments can be made, typically at home. This could include using a perching stool when washing up, resting for 10 minutes every hour or incorporating meditation into their everyday routines to reduce their SNS activity. Figure 25 depicts where possible modifications can be made for PoTS patients, with relevant examples.

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A major advantage of patient treatment occurring at the CRESTA clinic is that its interdisciplinary nature allows for the use of a holistic approach such as this to improve an individual’s circumstances.

11.4 How did this intervention meet the aims of this study?

The first aim of this study was to determine whether PoTS patients would comply with this demanding intervention run over a 5 month period. The compliance rate was high, with no patients dropping out and a DNA rate of only 14%. This indicated that the intervention was generally well received and that interventions conducted only once a month can retain patients if delivered correctly.

The second aim of this study was to evaluate the efficacy of the intervention on patients’ orthostatic symptoms. The subjective measurements of orthostatic symptoms were combined into one value, with improvements seen in three out of the seven patients (43%) following the intervention. For the other four patients, these values fluctuated quite broadly. A possible reason for this fairly low efficacy is that it may take a longer a period of time than 5 months for changes in orthostatic symptoms to come to the fore and be recognised by the patient.

The third aim of the study was to ascertain whether participation in the intervention led to an improvement in measures of patients’ general health. FIS improved in 43% of patients, combined Health Today and Likert Scale results improved in 50% of the patients assessed and for two of the patients, functional activity levels increased 13% and 37%. These improvements indicate the

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Figure 25 – Foci of Modifications for PoTS patients

benefits an intervention such as this one can have over a short period of time and why it is necessary to keep pursuing research in this area.

Finally, the fourth aim of this study was to look at the potential future role of the intervention and its applicability in the treatment and management of the condition. This study displayed promising results for 3 out of the 7 patients who had a relatively high background behavioural and medical stability. This would indicate that the intervention should be targeted to this subgroup of the patient population, who may choose to incorporate the specific exercises involved into the management of their condition alongside other physiological or pharmacological therapies such as those displayed in figure 5.

12 Advantages and Limitations:The first advantage of this intervention was its high compliance rate, with no patients dropping out. This is notable as other studies documenting exercise interventions for PoTS have had high dropout rates (22, 40). Secondly, the intervention was fairly simple in its delivery, requiring only a mat and a chair to perform the exercises. An adjunct to this however is the need for a physiotherapist to run the intervention with the requisite specialist knowledge and patient trust. A final advantage is that meaningful improvements were made, especially in terms of functional activity levels, for 3 out of the 7 patients.

This study and the nature of the intervention does have some limitations. Firstly, there was difficulty in ascertaining all of the subjective measures from each individual every month. Reducing the amount of paperwork involved or making it electronic would help. Secondly, the OH A/S questionnaires and Likert Scale questionnaires were not validated in this population, so the results may not be fully applicable. Thirdly, the information derived from the active stand tests could not be accessed properly and therefore it was impossible to determine whether there were any changes in measures of ANS function such as maximum HR upon standing and Baroreceptor Efficiency Index. A further limitation of this study is the lack of follow up results. Finally, as touched upon throughout, the high level of variability between each patient in terms of their background both medically, behaviourally, at work and at home meant that many factors were uncontrolled during the study. This variability will always be a factor in studies involving patients, however stricter inclusion criteria would alleviate it somewhat.

13 Conclusions and Further Work:This study documents the impact of a novel gravity induced exercise intervention delivered over a 5 month period for 7 patients with PoTS. The intervention was generally positively received, as documented by individual feedback and high compliance levels. Broadly speaking, orthostatic symptoms and measures of general health improved in 3 out of the 7 patients. Further studies using a greater selection of objective measures, stricter inclusion

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criteria, follow up data and lasting for a longer duration would be useful. Finally, greater comprehension of microgravity physiology in those with PoTS would help to develop the intervention itself, improving its impact.

14 References:

1. Alwan, A. (2011) Global status report on noncommunicable diseases 2010, World Health Organization

2. Frith, J., Ng, W.-F., Day, C. P., Payne, B., Sheerin, N., Gorman, G., Jones, D., and Newton, J. L. (2014) Orthostatic intolerance is common in chronic disease--a clinical cohort study. International journal of cardiology 174, 861

3. Robertson, D. (1999) The epidemic of orthostatic tachycardia and orthostatic intolerance. The American journal of the medical sciences 317, 75-77

4. Raj, S. R. (2006) The postural tachycardia syndrome (POTS): pathophysiology, diagnosis & management. Indian pacing and electrophysiology journal 6, 84

5. Carnethon, M. R., and Craft, L. L. (2008) Autonomic regulation of the association between exercise and diabetes. Exercise and sport sciences reviews 36, 12-18

6. Kanani, M., and Elliott, M. (2004) Applied surgical physiology vivas, Cambridge University Press

7. Bio 236 Lab Cardiovascular Physiology, Available at: http://people.fmarion.edu/tbarbeau/236%20Lab%20Cardiology%20EKG%20&%20Posture.pdf last accessed: 04/08/2016

8. Kanjwal, Y., Kosinski, D., and Grubb, B. P. (2003) The Postural Orthostatic Tachycardia Syndrome. Pacing and Clinical Electrophysiology 26, 1747-1757

9. Smith, J. J., Bush, J. E., Wiedmeier, V. T., and Tristani, F. E. (1970) Application of impedance cardiography to study of postural stress. Journal of applied physiology 29, 133-137

10. Low, P. A., Sandroni, P., Joyner, M., and Shen, W. K. (2009) Postural tachycardia syndrome (POTS). Journal of cardiovascular electrophysiology 20, 352-358

11. Grubb, B. P. (2008) Postural tachycardia syndrome. Circulation 117, 2814-2817

12. Stewart, J. M., Glover, J. L., and Medow, M. S. (2006) Increased plasma angiotensin II in postural tachycardia syndrome (POTS) is related to reduced blood flow and blood volume. Clinical Science 110, 255-263

13. UK, P. Postural Tachycardia Syndrome Available at: http://www.potsuk.org/UserFiles/File/Booklet_Final_Dec_14.pdf last accessed: 04/08/2016

14. Raj, S. R. (2013) Postural tachycardia syndrome (POTS). Circulation 127, 2336-2342

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15. Low, P. A., Opfer-Gehrking, T. L., Textor, S. C., Benarroch, E. E., Shen, W.-K., Schondorf, R., Suarez, G. A., and Rummans, T. A. (1995) Postural tachycardia syndrome (POTS). Neurology 45, S19-25

16. Benrud-Larson, L. M., Dewar, M. S., Sandroni, P., Rummans, T. A., Haythornthwaite, J. A., and Low, P. A. (2002) Quality of life in patients with postural tachycardia syndrome. In Mayo Clinic Proceedings Vol. 77 pp. 531-537, Elsevier

17. Patient Info Postural Tachycardia Syndrome Available at: http://patient.info/health/postural-tachycardia-syndrome-pots-leaflet last accessed: 09/08/2016

18. Spence, V., and Stewart, J. (2004) Standing up for ME. Biologist 51, 65-70

19. Grubb, B. P., Kanjwal, Y., and Kosinski, D. J. (2006) The Postural Tachycardia Syndrome: A Concise Guide to Diagnosis and Management. Journal of Cardiovascular Electrophysiology 17, 1-5

20. Conner, R., Sheikh, M., and Grubb, B. (2012) Postural orthostatic tachycardia syndrome (POTS): Evaluation and management. British Journal of Medical Practitioners 5, a540

21. Overcoming: Life with a Chronic Illness (2010) PoTS Treatment Overview: Chart from Dr. Blair Grubb, M.D Available at: https://hopealways.wordpress.com/2010/02/19/pots-treatment-overview-chart-from-dr-blair-grubb-m-d/ last accessed: 05/08/2016

22. Shibata, S., Fu, Q., Bivens, T. B., Hastings, J. L., Wang, W., and Levine, B. D. (2012) Short‐term exercise training improves the cardiovascular response to exercise in the postural orthostatic tachycardia syndrome. The Journal of physiology 590, 3495-3505

23. Fu, Q., and Levine, B. D. (2015) Exercise in the postural orthostatic tachycardia syndrome. Autonomic Neuroscience 188, 86-89

24. Galbreath, M. M., Shibata, S., VanGundy, T. B., Okazaki, K., Fu, Q., and Levine, B. D. (2011) Effects of exercise training on arterial-cardiac baroreflex function in POTS. Clinical Autonomic Research 21, 73-80

25. Benarroch, E. E. (2012) Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. In Mayo Clinic Proceedings Vol. 87 pp. 1214-1225, Elsevier

26. Fitts, R. H., Riley, D. R., and Widrick, J. J. (2000) Physiology of a microgravity environment invited review: microgravity and skeletal muscle. Journal of Applied Physiology 89, 823-839

27. Blaber, E., Marçal, H., and Burns, B. P. (2010) Bioastronautics: the influence of microgravity on astronaut health. Astrobiology 10, 463-473

28. Aubert, A. E., Beckers, F., and Verheyden, B. (2005) Cardiovascular function and basics of physiology in microgravity. Acta Cardiol 60, 129-151

29. Stewart, J. M. (2009) Chronic fatigue syndrome: comments on deconditioning, blood volume and resulting cardiac function. Clinical Science 118, 121-123

30. Antonutto, G., and Di Prampero, P. E. (2003) Cardiovascular deconditioning in microgravity: some possible countermeasures. European journal of applied physiology 90, 283-291

31. Hackett, K. L., Lambson, R. L., Strassheim, V., Gotts, Z., Deary, V., and Newton, J. L. (2015) A concept mapping study evaluating the UK's first NHS generic fatigue clinic. Health Expectations

32. Tarazi, R. C. (1983) Pathophysiology of essential hypertension: Role of the autonomic nervous system. The American journal of medicine 75, 2-8

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33. Improvement, N. H. S. (2011) First steps towards quality improvement: a simple guide to improving services. Department of Health UK

34. Bessa, A. L., Oliveira, V. N., Agostini, G. G., Oliveira, R. J. S., Oliveira, A. C. S., White, G. E., Wells, G. D., Teixeira, D. N. S., and Espindola, F. S. (2016) Exercise Intensity and Recovery: Biomarkers of Injury, Inflammation, and Oxidative Stress. The Journal of Strength & Conditioning Research 30, 311-319

35. Gambetta, V. (2007) Athletic development: The art & science of functional sports conditioning, New World Library

36. Shepherd, C. (2001) Pacing and exercise in chronic fatigue syndrome. Physiotherapy 87, 395-396

37. Lillie, E. O., Patay, B., Diamant, J., Issell, B., Topol, E. J., and Schork, N. J. (2011) The n-of-1 clinical trial: the ultimate strategy for individualizing medicine? Personalized medicine 8, 161-173

38. Kendall, J. (2003) Designing a research project: randomised controlled trials and their principles. Emergency medicine journal: EMJ 20, 164

39. Üstün, T. B., Chatterji, S., Bickenbach, J., Kostanjsek, N., and Schneider, M. (2003) The International Classification of Functioning, Disability and Health: a new tool for understanding disability and health. Disability and rehabilitation 25, 565-571

40. Fu, Q., VanGundy, T. B., Galbreath, M. M., Shibata, S., Jain, M., Hastings, J. L., Bhella, P. S., and Levine, B. D. (2010) Cardiac origins of the postural orthostatic tachycardia syndrome. Journal of the American College of Cardiology 55, 2858-2868

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15 Appendices:

15.1 Appendix 1:

Appendix 1 shows a photographic image of a selection of the questionnaires used as part of the intervention, in addition to the activity log used.

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1) OH Activity Scale 2) OH Symptom Assessment

3) EQ-5D-5L Questionnaire

4) Health Today Questionnaire

15.2 Appendix 2:

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5) Part of the Fatigue Impact Scale

6) Likert Scale Questionnaire

7) Intervention Feedback Questionnaire

8) Example of a completed Activity Diary

Below is a table of the monthly EQ-5D-5L scores for each individual who completed the intervention.

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EQ-5D-5L Month 1 Month 2 Month 3 Month 4 Month 5

Patient ID1 11 12 10 10 102 17 11 12 DNA 123 4 6 7 5 54 DNA 3 2 4 DNA5 6 12 13 10 126 5 5 5 6 DNA7 10 7 10 9 12