Anger and anxiety in patients with primary aldosteronism treated with amiloride hydrochloride or spironolactone or adrenalectomy

ANGER AND ANXIETY IN PATIENTS WITH PRIMARY ALDOSTERONISM TREATED WITH AMILORIDE HYDROCHLORIDE OR SPIRONOLACTONE OR ADRENALECTOMY.. Abstract Background In Primary Aldosteronism PAL exce

ANGER AND ANXIETY IN PATIENTS WITH PRIMARY ALDOSTERONISM TREATED WITH AMILORIDE HYDROCHLORIDE OR SPIRONOLACTONE OR

ADRENALECTOMY

Robin Sherill Armstrong RN, Dip App Sci (Nsg Edn), BHSc.(Nsg)

Institute of Health and Biomedical Innovation

School of Public Health Queensland University of Technology

Thesis for Master of Applied Science (Research) 2007

Abstract

Background

In Primary Aldosteronism (PAL) excessive amounts of aldosterone cause sodium

and water retention and, in many individuals, this leads to moderate to severely high blood pressure Although the chemistry and physiology are increasingly well

understood, including the outcomes of treatment on physical health, there has been

no systematic study of the psychological dimension of PAL Anecdotally, patients exhibit symptoms such as angry outbursts, irritability, anxiety and defensiveness, and partners of these patients sometimes mention poor anger control and brittle or

unpredictable moods This thesis reports a systematic study of anger and anxiety among patients undergoing treatment for PAL

Eighty-three patients were recruited over an 11-month period to a prospective, post design study to determine if treatment was associated with change in

pre-psychological state

Method

Participants completed the State-Trait Anger Expression Inventory (STAXI-2), State-Trait Anxiety Inventory (STAI) and Psychosocial Adjustment to Illness Scale (PAIS) questionnaires Adrenal Vein Sampling confirmed overproduction of

aldosterone in one or both adrenal glands Patients with Aldosterone Producing Adenoma (APA) were offered adrenalectomy As per usual treatment protocols, patients with Bilateral Adrenal Hyperplasia (BAH) were prescribed spironolactone or amiloride depending predominantly on severity of blood pressure and potassium

levels Post-test questionnaires were completed after 6-8 months Analysis was by mixed design (between-within subjects) ANOVA

Participant numbers in the adrenalectomy group fell far short of expectations

Fourteen past patients who had undergone unilateral adrenalectomy completed a retrospective semi-structured questionnaire This qualitative data was analysed to identify themes similar to quantitative data

Results

At baseline, ‘non-completers’ (ie those who did not complete the post-test; n=19),

were significantly more angry than ‘completers’ (n=50) in State Anger (p< 01), Trait Anger (p< 05) and Anger Expression Index (p< 001) Trait Anxiety was also higher (p< 05), as was Psychological Distress (p< 05)

Among those who participated at both interviews, there was small but statistically

significant adverse treatment effect with higher scores for State Anger (p< 05), and

Feeling Angry (p< 05) However for Trait Anger (p< 01), and 2 of its 3 sub-scales Angry Temperament (p< 05) and Angry Reaction (p< 01) there was a slight to moderate decrease in negative affect with treatment Psychological Distress scores also improved (p< 05) Across all ANOVAs, there were no significant interaction effects, suggesting that any treatment effect was equivalent for the two drugs

Qualitatively collected data elucidated participants’ changes in approach to life and relationships since adrenalectomy Themes that emerged in the data included

improved ability to cope with external stress, better control of emotions, more

relaxed relationships and attitude to work, and a greater vitality and quality of life

Generally the comments were consistent with the drug treatments; there was

noticeable benefit, including perceived better anger control and less anxiety

Conclusions

Positive psychological effects of treatment observed in the two drug groups were triangulated with data from a qualitative study The combined evidence suggests that when excess circulating aldosterone is reduced (adrenalectomy), or blocked

(spironolactone), or aldosterone’s salt and water retaining effects are minimised (amiloride), then nervous irritability and its subsequent psycho-behavioural

manifestations are reduced The effect however is slight and the conclusions are weakened by an apparent attrition bias, and the absence of a control group

Implications for further research are discussed

Table of Contents

Chapter 1: Introduction and Literature Review 12

Chapter 4: Qualitative inquiry into the effects of adrenalectomy (Study 2)

Patient perceptions of behavioural, emotional, physical

And lifestyle change, 6-24 months post-adrenalectomy for aldosterone producing adenoma: A qualitative study

Chapter 5: Conclusion The combined quantitative and

Appendix 1: Psychometric Analysis - modified STAI – Form Y 96

Appendix 2: Qualitative Study questionnaire 112

List of Tables and Figures

Chapter 2: Method (Study 1)

Table 2.1: Descriptive characteristics of participants in spironolactone and

amiloride groups at baseline _30 Table 2.2: Concomittant medication use by participants in spironolactone and

amiloride groups at baseline 32 Table 2.3: Scale and sub-scale definitions taken from STAXI-2 Professional

Manual (Spielberger, 1996). _ 35

Chapter 3: Results (Study 1)

Table 3.1: Comparison at baseline of mean State Anger and Mean State Anxiety scores of participants who subsequentlydid complete (completers) and did not

complete (non-completers) the post-test questionnaire 42 Table 3.2: Comparison at baseline of mean Trait Anger and mean Trait Anxiety scores of participants who subsequently did complete (completers) and did not

complete (non-completers) the post-test questionnaire 43 Table 3.3: Comparison at baseline of mean Anger Expression and mean Anger control scores of participants who subsequently did complete (completers) and did not complete (non-completers) the post test questionnaire _44 Table 3.4: Comparison of mean PAIS baseline scores for participants who did or did not complete the post-test questionnaire _45 Table 3.5: Comparison of treatment groups spironolactone and amiloride at

baseline. _46 Table 3.6: Variables significantly differing by gender at baseline _47 Table 3.7: Post-test differences in scores that were significantly different at baseline, grouped by gender and treatment group _47 Table 3.8: Mixed between-within analysis of variance (ANOVA) State Anger and State Anxiety. _49 Figure 3.1: Change in mean State Anger scores from pre-test to post-test. 49 Figure 3.2: Change in mean Feeling Angry scores from pre-test to post-test _50 Table 3.9: Mixed between-within analysis of variance (ANOVA) Trait Anger, Anger Expression, Anger Control and Trait Anxiety _ 51 Figure 3.3: Change in mean Trait Anger scores pre-test to post-test. 52

Figure 3.4: Change in mean Angry Temperament scores pre-test to post-test. _52 Figure 3.5: Change in mean Angry reaction scores pre-test to post-test. _ 53 Table 3.10: Mixed between-within analysis of variance (ANOVA) Psychosocial Adjustment to Illness Scale (PAIS) _53 Figure 3.6: Change in mean (PAIS) Psychological Distress scores pre-test to

post-test 55 Table 3.11: Mixed between-within analysis of variance (ANOVA) Serum Potassium and Systolic Blood Pressure. _56

Chapter 4 : Qualitative enquiry into the effects of adrenalectomy

Table 4.1: Participant perceptions of their ability to cope with external stress. 73 Table 4.2: Participant perceptions of their improved emotional control 75 Table 4.3: Participant perceptions of positive changes in their spouse/partner,

family and social relationships, and work. _76 Table 4.4: Participant perceptions of improvement in their vitality and quality of life. _78 Table 4.5: Participant perceptions of most important physical change _ 79 Table 4.6: Participant blood pressure and medications. 80

Appendix 1:Psychometric analysis of State-Trait Anxiety Inventory (STAI)

Table 1.1: Pre-test State Anxiety modified 8-item form 97 Table 1.2: Pre-test Trait Anxiety modified 8-item form 98 Table 1.3: Post-test State Anxiety modified 8-item form _ 98 Table 1.4: Post-test Trait Anxiety modified 8-item form _ 99 Table 1.5: Pre-test State Anxiety – same 8 items used in modified version from participants who completed the 20-item form-Y. 100 Table 1.6: Pre-test State Anxiety – 20-item form-Y. _ 101 Table 1.7: Pre-test Trait Anxiety – same 8 items used in modified version from participants who completed the 20-item form-Y. 102 Table 1.8: Pre-test Trait Anxiety –20-item form-Y 103 Table 1.9: Post-test State Anxiety – same 8 items used in modified version from participants who completed the 20-item form-Y. 104 Table 1.10: Post-test State Anxiety – 20-item form-Y. _105

Table 1.11: Post-test Trait Anxiety – same 8 items used in modified version from participants who completed the 20-item form-Y. 106 Table 1.12: Post-test Trait Anxiety – 20-item form-Y. _107 Table 1.13: Correlation of 8-item modified scale total score with PAIS (vii)

Psychological Distress score and correlation of 20-item version with PAIS (vii) Psychological distress score 108 Figure 1.1: Total score correlation of pre-test State Anxiety 1-8 with matched

PAIS (vii) item Psychological Distress. 109 Figure 1.2: Total score correlation of pre-test Trait Anxiety 1-8 with matched

PAIS (vii) item Psychological Distress. 110 Figure 1.3: Total score correlation of post-test State Anxiety 1-8 with matched PAIS (vii) item Psychological Distress. 111 Figure 1.4: Total score correlation of post-test Trait Anxiety 1-8 with matched PAIS (vii) item Psychological Distress. 112

Statement of Original Authorship

“The work contained in this thesis has not been submitted for a degree or diploma at any other higher education institution To the best of my knowledge and belief, this thesis contains no material previously

published or written by another person except where due reference is made.”

Robin S Armstrong RN, Dip App Sci (Nsg Edn) BHSc (Nursing)

Acknowledgements

Thankyou to Dr Diana Battistutta for making me think that I could do the study and being there for my seminar presentation Thanks to Professor Michael Dunne for taking on my supervision though I am sure there were many times he wished he hadn’t Thanks for your patience and guidance and for hanging in through the ups and downs Many thanks also to Professor Ross Young for his unyielding optimism and assistance over and above the call of duty Thanks to Mr Simon Kitto for

guidance in constructing the qualitative questionnaire Also acknowledged is the psychological support for the underlying idea of the study given by Dr Nik Nikwan (cardiologist) and thanks to Dr Michael Stowasser (physician) for early guidance in the design assistance with recruitment

Thankyou to the many patients who shared their feelings with me over the 14 years that I worked in Hypertension, and particularly those who participated in both of the studies Greatly acknowledged is the assistance of the Queensland Hypertension Association for financial help in purchase of the study questionnaires

Thanks to Robyn Huttenmeister who didn’t mind my breaking the 5am peace of the Brisbane river when I needed to talk about things that would have been most

uninteresting, and for her kind encouragement

Finally and mostly, I would like to thank my husband Greg and children Ebony and Imogen who believed in me, let me have the computer, and let me get on with it

Anger and anxiety in patients with primary aldosteronism treated with amiloride hydrochloride, spironolactone or adrenalectomy

Chapter 1: Introduction and literature review

The aim of this study was to examine anger, anxiety and quality of life in individuals living with a form of sodium-dependent hypertension known as primary

aldosteronism (PAL) and to examine the effects of three current treatment modalities for that condition

Aldosterone, a hormone produced by the adrenal glands, acts via specific receptors located in cells within the kidney, colon and sweat glands to cause these tissues to retain sodium rather than to excrete it into the urine, faeces and sweat In primary aldosteronism (PAL), the adrenal glands secrete excessive amounts of aldosterone, resulting in sodium and water retention that is excessive to the body’s needs and this typically leads to hypertension Studies over the last 15 years have suggested that excessive production of aldosterone, in addition to causing hypertension, may have adverse consequences on the cardiovascular system that are independent of its effect

on blood pressure These include autonomic imbalance (Barr & Struthers, 1994) and electrolyte abnormalities contributing to altered cardiac function and problems of cardiac rhythm (Struthers, 2002), and cardiovascular remodelling and fibrosis

(Weber & Brilla, 1991) Studies conducted by Brilla and Weber (1992) on rats administered large doses of exogenous aldosterone, demonstrated that the presence

of sodium was required for development of myocardial remodelling and fibrosis in the aldosterone treated animals

Within the brain, aldosterone is thought to act on neurones in centres responsible for receiving and integrating information on electrolyte, fluid and cardiovascular status,

to bring about alterations in central sympathetic nervous system output Sanchez, 1997) Zhang et al (2002) demonstrated that in Sprague Dawley rats with ischaemia induced heart failure, the renin angiotensin aldosterone system (RAAS) drives paraventricular nucleus neuronal activity, “likely increasing sympathetic drive and volume accumulation” As well, Huang et al (a, 2005) showed that intracerebral infusion of aldosterone into Dahl salt-sensitive rats induced sympathetic

(Gomez-hyperactivity and hypertension Huang and Leenen (b, 2005) in a separate study on Wistar rats post-myocardial infarction found that blockade of mineralocorticoid receptors (aldosterone receptor sites) and sodium channels prevented sympathetic hyper-reactivity These studies suggest a relationship between aldosterone, sodium and sympathetic nervous system hyperactivity

It is not certain if there are any psychological effects resulting from the action of aldosterone on receptors in the brain However, there are reasonable grounds to expect this may be the case For example, it is known that aldosterone levels are raised in the luteal (premenstrual) phase of the menstrual cycle (O’Brien et al, 1980) Many of the affective and somatic symptoms stated in the American College of Gynaecologist’s diagnostic criteria for pre-menstrual tension (PMS) (ACOG, 2000 in Rapkin, 2003) overlap with those observed by this investigator and by patients seen over many years These symptoms include depression, angry outbursts, irritability, anxiety, social withdrawal, headache and abdominal bloating Raised aldosterone and salt and water retention are phenomena common to PMS and PAL

The aetiology of premenstrual syndrome is unknown and the pathophysiology is likely to be complex (Breckwoldt & Keck, 2002) There has been a plethora of pharmacologic and non-pharmacologic treatments proposed over the past few

decades and some of these (low sodium diet, Vitamin B6) have been aimed at

minimising sodium and water retention in this phase of the menstrual cycle (Rapkin, 2003)

Halbreich (2003) lists the aldosterone antagonist spironolactone as an effective treatment for PMS In the same article however it is stated that data are conflicting and spironolactone may be effective mostly for bloatedness and fluid related

symptoms Burnet and colleagues (1991) in their double blind, placebo controlled, randomised crossover study failed to find a significant difference in somatic or neuropsychiatric symptoms of women with PMS assessed on or off spironolactone However, other authors have found spironolactone (an aldosterone blocker) to have a broad effectiveness in the treatment of PMS Significant improvement in negative mood symptoms was demonstrated by O’Brien et al (1979) in a double blind

crossover trial over four menstrual cycles in 28 women with premenstrual syndrome (PMS) They found that spironolactone reduced weight and relieved psychological symptoms in more than 80% of the symptomatic group Wang et al (1995) included

35 women with PMS in a double blind placebo controlled crossover trial They found that spironolactone not only reduced somatic symptom scores for breast tenderness, feeling of swelling, and food cravings (p < 001), but also significantly (p < 001) decreased negative mood symptom scores for irritability and depression

Furthering the plausibility of a connection between aldosterone, sodium and water retention and mood symptoms is more recent work in PMS and menopause with

drospirenone, a mineralocorticoid receptor antagonist and derivative of

spironolactone Drospirenone blocks, or at least reduces, aldosterone effects on the renin angiotensin system allowing increased sodium and water excretion which can result in weight and blood pressure reduction Drospirenone also appears to control PMS (Ylikorkala, 2005)

Successful treatment of PMS and menopause is also achieved by use of drospirenone

in combination with oestrogen (Oelkers, 2004) According to Foidart (2005), the improvements in negative affect and feelings of wellbeing attributable to

drospirenone are likely to improve treatment compliance in women suffering from PMS and menopausal symptoms

In the last decade, a number of studies have demonstrated behavioural changes in

“sodium sensitive” individuals challenged with sodium loading versus a placebo A sodium (salt) sensitive person can be described as one whose blood pressure rises after a period of oral or parenteral sodium loading A salt resistant person however has no change in blood pressure with the same period and amount of sodium loading Deter et al (1997) recruited 16 “salt-sensitive”and 16 “salt-resistant” healthy,

normotensive (blood pressure within normal range) participants and measured their response to mental stress They found an increased level of irritation, a greater rise in blood pressure and pulse wave velocity, higher levels of anxiety and lower levels of anger control in “salt-sensitive” individuals Bucholz et al (1999) administered several standardised psychological questionnaires to the same cohort and found an increased level of emotional irritation in the same “salt-sensitive” group Deter et al (1997) suggest from the results of their study assessing psychological reactivity in

“salt-sensitive” normotensive subjects, that psychophysiological traits may play a role in the development of “salt-sensitive” hypertension

An early study linking sodium and sympathetic nervous system stimulation by

Rankin et al (1981) demonstrated an increased blood pressure response to

noradrenaline infusion in normotensive (normal blood pressure) human subjects who

had been sodium loaded for 5 days This raised the possibility that sodium loading alters sympathetic nervous system function, and possibly other aspects of neural activity Hunyor and Henderson (1996) cite studies in which hypertension was not evoked in dogs and rats in response to shock stress until a high sodium diet was given to the rats or saline infused into the dogs, again illustrating a link between increased blood pressure and sympathetic nervous system only after sodium was added Conversely, Skrabal et al (1984) demonstrated reduced cardiovascular response to noradrenaline infusion and mental arithmetic by maintaining

normotensives (individuals with normal blood pressure) on low sodium, high

potassium diet for 4 weeks This illustrated that the reverse could be induced and it was thought by Scrabal and colleagues (1984) that there may be a link between noradrenergic activity and salt sensitivity

Light et al (1983) also found that psychological stress induced sodium and water

retention in men who had one or two parents with hypertension or, had borderline hypertension (determined by the mean of 8 systolic seated blood pressure readings during a one hour rest period being 140 mmHg or greater) Deter et al (1997) also cite studies on humans, baboons, dogs and rats that suggest that behavioural stress has an antinatriuretic (sodium retaining) effect In this study we are exploring the

concept that if we have a sodium and water loaded state as there is in PAL, could this

be the cause of the irritability described earlier in PAL patients or is it the direct action of aldosterone on the brain

The association between hypertension, anger and anxiety has been the subject of debate over many decades (van der Ploeg, 1985, Pickering, 1993) Crane (1981) in her dissertation on “The role of anger, hostility and aggression in essential

hypertension” cites reports of case studies from as early as 1939 in which the

aggressive, hostile impulses of hypertensive patients typically appeared in

connection with anxiety Williams et al (2003) reviewed the association between psychosocial risk factors and cardiovascular disease and suggested that not all

components of the now devalued concept of the global Type A behaviour pattern should be discounted They stated that hostility was the component most associated with coronary heart disease risk Williams et al (2003) also cited Yan and colleagues (2003) who studied hostility and time urgency/impatience (TUI), both components of the Type A behaviour pattern This prospective study of 3308 black and white young adults (the CARDIA study) found that TUI and hostility were associated with a two-fold increase in the incidence of hypertension in young adults (matched for age, sex, ethnicity and education) over a 15 year period

The evidence that overactivity of the sympathetic nervous system plays a role in early stage development of hypertension is extensive (Pickering, 1997) However not all individuals with hypertension are angry or anxious or pressured and not all

individuals who are angry, anxious or pressured have hypertension It may be that hypertension (because of common nervous system pathways) occurs in parallel with the psychological symptoms due to sodium and water retention common to both

Hunyor and Henderson (1996) suggested that it may be only in subsets of individuals with hypertension that bio-behavioural factors play a significant role The concept that aldosterone excess may be associated with psychological function remains largely unexplored Aldosterone may act either directly via receptors in the brain, indirectly through sodium and water retention or may simply effect alterations in nervous system activity

Rationale for this study

Patients who have hypertension associated with primary aldosteronism appear to exhibit more anger, irritability and emotionality than do patients with hypertension

from other causes The experience of ward nurses who care for these patients,

patients’ family members and the patients themselves have frequently concurred with this observation During blood pressure self-measurement and life-style

modifications teaching sessions that include discussion of issues such as dietary salt reduction, weight loss, exercise and stress management; many patients indicated that they have a low threshold for stress and anxiety

Conversely, file notations and comments from (some) patients and (some) family members of patients, who have had surgical removal of an adrenal gland for

aldosterone-producing adenoma (APA) suggest a comparative calmness after

surgery The need to find evidence for this clinical impression was the initial

motivation for this study Does aldosterone either directly or indirectly through salt and water retention, have a role in heightening the experience of psychological symptoms of persons suffering from this condition?

The establishment of a retained sodium and water environment (as seen in PAL due

to excessive production of aldosterone through mechanisms other than stress), may promote a heightened nervous system responsiveness or nervous irritability that manifests as anger, anxiety and increased emotional irritability Alternatively,

aldosterone may have an effect on the brain and nervous system independent of the role in sodium and water retention

The primary physiological outcome of each of the treatment modes for primary aldosteronism is increased sodium and water excretion Adrenalectomy for

aldosterone producing adenoma (Discussed in Chapter 4) reduces excess levels of circulating aldosterone hence less sodium and water is retained Spironolactone acts

by blocking aldosterone receptors thus preventing aldosterone action, again less sodium and water is retained Amiloride (not known to block the aldosterone

receptor) prevents reabsorption of sodium and water by inhibiting sodium channels

in the distal renal tubules (and other aldosterone responsive tissues) that have been stimulated by aldosterone (Oberleithner et al, 2004)

By comparing the effect of amiloride with that of other treatment modalities, this project has the potential to differentiate the role of sodium retention alone from that

of other putative effects of aldosterone excess

Evolution of the quantitative study.

The initial design of the study was to be a comparison of anger, anxiety and quality

of life outcomes of 3 treatment modalities for primary aldosteronism; spironolactone, amiloride and adrenalectomy Spironolactone, an aldosterone antagonist, inhibits the

action of aldosterone by blocking its receptor (Delyani et al, 2001) Amiloride

antagonises the sodium retaining effects of aldosterone by inhibiting the sodium channels that are normally activated in response to the binding of aldosterone to the receptor (Haddy & Pamnani, 1987) Adrenalectomy for aldosterone producing

adenoma (APA) reduces excess levels of circulating aldosterone hence less sodium and water is retained, blood pressure is mostly (60% by 12 months) returned to normal and potassium loss is minimised (Stowasser & Gordon, 2004) Recent

clinical loads and advice from consulting physicians suggested that one third of patients with PAL were candidates for adrenalectomy (Stowasser et al, 2001) and thus about 30 patients could be expected in each group

Unfortunately the recruitment of adrenalectomy patients did not proceed as planned and there were insufficient adrenalectomy patients to be followed over 6 months in parallel with the other treatment modes Recruitment to the spironolactone and amiloride groups was quite successful Seventeen were medicated with

spironolactone and 33 participants were medicated with amiloride, but over that time, only 5 participants were diagnosed with unilateral aldosterone producing adenoma (APA) and were thus potential recruits to the adrenalectomy group This drop in numbers was unexpected and only one of these five participants went on to have an adrenalectomy during the period of the study The remaining four participants with APA chose either to delay their surgery because of social reasons or they chose alternative treatment options This unexpected reduction in participant numbers necessitated an alternative method of collecting appropriate data from patients who had undergone this method of treatment It was not possible to collect prospective data hence a retrospective design was developed to gather qualitative information

from patients who had undergone adrenalectomy for APA in the preceding 6-24 months Full Ethics Committee approval was obtained for this additional study both from the University Human Research Ethics Committee and the Ethics Committee of the hospital where the study was conducted

The assistance of the Director of the Hypertension Unit was sought to provide contact details of potential participants for this study A semi-structured

questionnaire was developed to explore anger, anxiety and quality of life, including psycho-social and behavioural changes participants had noticed in the 6-24 months since their adrenalectomy A retrospective qualitative sub-study (reported in Chapter 4) was conducted to obtain data thematically comparable to that quantitatively

measured in the amiloride and spironolactone groups reported below

Objectives

1 To compare differences in participant’s experience of anger and anxiety as

effected by two current medical treatment modalities for primary

aldosteronism (Chapter 3)

2 To examine the impact on quality of life by utilising the Psychosocial

Adjustment to Illness Scale (PAIS) to measure participant’s responses before and after 6-8 months of treatment with amiloride hydrochloride and before and after 6-8 months treatment with spironolactone (Study 1, Chapter 3)

3 To examine patient perceptions of changes following adrenalectomy in order

to triangulate results and confirm quantitative findings with qualitative data

(Study 2, Chapter 4)

Chapter 2: Method (Study 1)

Rationale for this study

The principal investigator worked for many years within a specialist hypertension investigation unit Her clinical impression is that patients who have hypertension associated with primary aldosteronism exhibit more anger, irritability and

emotionality than do patients with hypertension from other causes An early thought was that the males were exhibiting behaviour similar to that of premenstrual

syndrome Ward nurses’ experiences supported these observations and their

descriptions of patients’ behaviour included ‘hard to handle’, ‘quick to rise’,

‘intense’, ‘emotional’ and ‘short fuse’

When discussing their condition with the investigator, many patients used words and

phrases such as ‘impatient’, ‘fly off the handle’, ‘I get angry over nothing’, ‘my

brothers and sisters hate it’, and speak also of ’overwhelming anxiety with no due cause’ and ‘feeling like I’m going to burst with anxiety … couldn’t explain why it was happening or what it was that was happening … very weepy all the time… felt angry with everyone at times’ File notations and comments from (some) patients

and family members of patients who have had an adrenalectomy (surgical removal of

an adrenal gland) for aldosterone-producing adenoma (APA) suggest a comparative calmness after surgery The need to find evidence for this clinical impression was the initial motivation for this study

The establishment of a retained sodium and water environment (as seen in PAL due

to excessive production of aldosterone through mechanisms other than stress), may

manifests as anger, anxiety and increased emotional irritability Alternatively,

aldosterone may have an effect on the brain and nervous system independent of the role in sodium and water retention The primary physiological outcome of each of the treatment modes for primary aldosteronism is increased sodium and water

excretion Adrenalectomy for aldosterone producing adenoma reduces excess levels

of circulating aldosterone hence less sodium and water is retained Spironolactone acts by blocking aldosterone receptors thus preventing aldosterone action, again less sodium and water is retained Amiloride prevents reabsorption of sodium and water

by inhibiting sodium channels in the distal renal tubules (and other aldosterone responsive tissues) that have been stimulated by aldosterone (Oberleithner et al, 2004) By comparing the effect of amiloride with that of other treatment modalities, this project has the potential to differentiate the role of sodium retention alone from that of other putative effects of aldosterone excess

There is indirect evidence to support the hypothesis that adrenalectomy reduces anger and anxiety The proposed mechanisms include (1) reduced circulating

aldosterone resulting in increased excretion of excess sodium and water, or (2) reduced circulating aldosterone resulting in stimulation of brain aldosterone

receptors It is also hypothesised that in participants taking spironolactone,

improvement in anger and anxiety scores may be due to (1) blocking the

salt-retaining action of aldosterone thus promoting excretion of sodium and water or (2) blocking other putative effects of aldosterone, including possible direct effects on the brain Improvement in anger and anxiety scores in the group treated with amiloride which promotes sodium and water excretion (but is not known to block the

aldosterone receptor), may indicate that a salty intra or extracellular environment is

the means by which aldosterone excess promotes anger, anxiety and irritability This study examines outcomes from three different treatments with three distinct

mechanisms of action to see if the outcomes illuminate the nature of the

bio-behavioural interaction between aldosteronism and psychological state

Change in anger, anxiety and quality of life scores will not differ by treatment

modality (amiloride or spironolactone) for PAL

Design

A pre-test – post-test quasi experimental design is used to measure change in state –

trait anger, state – trait anxiety and quality of life in a cohort of patients with PAL

who are undergoing one of two treatment modalities for this condition Hypothesis testing is two-tailed

Sample

Process of Recruitment

The clinical coordinator role in the Hypertension Unit included liaising and

providing information regarding Fludrocortisone Suppression Test (FST) procedures Information regarding upcoming bookings for FSTs was thus readily accessible to

the principal investigator Patients were informed about the study by phone and it was explained that participation was voluntary Those agreeing by phone were invited to participate on day one of the admission for FST Patients reaching this stage of their diagnostic work-up have had at least two abnormal (high) aldosterone-renin ratios (ARR) This pathological finding is an early indicator of PAL As well, each patient reaching this stage has been screened for all other known causes of hypertension

The Fludrocortisone Suppression Test (FST) is a definitive diagnostic test for PAL (Stowasser et al, 2001) Patients are administered a synthetic form of aldosterone (fludrocortisone) over a four day period Fludrocortisone normally suppresses normal adrenal production of aldosterone Other factors that affect aldosterone production such as potassium, sodium and posture are controlled according to a strict test

protocol As well, the potential for stimulating adrenocorticotrophic hormone

(ACTH) is monitored by serum cortisol estimation at the same time as aldosterone, renin and potassium samples are collected A positive FST is one in which

aldosterone continues to be produced autonomously despite complete suppression of renin Renin stimulates aldosterone’s normal chronic regulator, Angiotensin II

(Stowasser et al, 2001)

Sampling Strategy and Size

Based on figures from the previous two years there were approximately 40-60

admissions yearly to the Hypertension Unit for FST This study aimed to recruit

90-100 participants over 2 years Discussions with physicians indicated that in past years, excess aldosterone production in approximately one third of patients

(Stowasser et al, 2001) lateralised to one gland only, most commonly due to

aldosterone producing adenoma (APA)

Estimates of the occurrence of aldosterone producing adenoma (APA) were based not only on physicians’ judgements and recent clinical workloads, but also were consistent with the literature International figures (Mulatero et al, 2004) provide mixed results, as many patients do not undergo adrenal vein sampling (AVS) The absence of this diagnostic procedure precludes diagnosis of APAs that are not

detectable on Computer Axial Tomography (CT) scan These figures from the last decade in four international centres suggest that the percentage of the primary

aldosterone (PAL) population that had APA confirmed by AVS to be; Torino, Italy – 30% or 18.9 per year, Rochester Minnesota – 28% or 34 patients in 1999, Brisbane, Australia – 29.6% or 17 per year, Singapore, Republic of Singapore – 50% or 12.6 per year, and Santiago, Chile – 9.1% or 2 per year (at this centre AVS was not

performed on any patients) On this basis, it was expected that the patient recruitment

in Brisbane at that time would include about 30% of PAL patients where surgery was appropriate This did not occur, and the clinical staff did not have a clear explanation

of why there was such a dramatic shift

These patients would if surgically suitable, be offered adrenalectomy The remaining two-thirds of patients would most commonly have bilateral adrenal hyperplasia and thus be pharmacologically treated Approximately one-third would receive amiloride and one-third would receive spironolactone

Eighty-five eligible persons were admitted for the fludrocortisone suppression test and invited to participate in the study, two declined and 83 participants completed the pre-test phase over an 11- month period Thirteen participants were excluded for not meeting protocol requirements leaving 70 participants remaining An additional five participants indicated that they were currently too busy or wanted to opt for medical treatment leaving a potential cohort of 65 however, fourteen participants did not respond to an invitation or reminder phone call or letter leaving 51 participants in the final sample Thirty-three participants were medicated with amiloride and 17 medicated with spironolactone

One participant only, underwent adrenalectomy for APA (Five participants were actually diagnosed with APA but 4 chose other treatment options) This paucity of participants in the adrenalectomy treatment group necessitated the development of the retrospective qualitative study described in Chapter 4

Inclusion criteria

Participants were included if they had at least two, raised aldosterone-renin ratios and progressed to a positive fludrocortisone suppression test to definitively diagnose PAL The aldosterone renin ratio is accepted internationally as a valid means of successfully diagnosing Primary Aldosteronism (Brown et al 1996, Lim et al, 2002) The use of this ratio is reported to have increased the detection of this condition from 1% to 12% of hypertensive patients (Mulatero et al 2004) In this study all

participants had had other secondary causes of hypertension excluded and ARR performed under conditions recommended for accuracy These conditions preclude

known factors that can cause false positives or false negatives in the ARR (Stowasser

& Gordon, 2004)

Participants were required to have an adequate understanding of English and

cognitive ability to understand and complete the questionnaires and provide informed consent was also necessary

Exclusion criteria

Patients suffering from the rare hybrid gene Familial Hyperaldosteronism Type 1 (FH-I) are identified genetically This glucocorticoid-remediable form of PAL is treated with dexamethasone (Stowasser et al, 2001); the sub-group is rare and not included in the study Patients found not to have PAL by way of negative FST are also excluded from the study One of the 83 pre-test participants had negative FST

not wish to proceed to adrenal vein sampling, or chose no treatment or usual hypertensive treatment Two were subsequently treated with spironolactone and twelve with amiloride hydrochloride

anti-Characteristics of the sample

The mean age of participants in each group is similar but gender is significantly different across groups Thirteen males and 4 females comprised the spironolactone group whereas in the amiloride group there were 26 females and 7 males There was

no gender specific reason for this as treatment is prescribed according to severity of blood pressure and evidence of potassium wasting Other significant differences between the groups were in the biological variables (Table 2.1) Systolic Blood Pressure (SBP) (p< 05) and Serum Potassium (Se K+) (p< 001)

Table 2.1: Descriptive characteristics of participants in spironolactone and amiloride groups at baseline

Concomittant Medication

There are many medications taken concomitantly by patients in both treatment groups and as medications may often affect mood and behaviour all medications being taken by participants at baseline have been documented in Table 2.2

Anxiolytic / antidepressant use was much the same between groups

Table 2.2: Concomittant medication use by participants in spironolactone and amiloride groups

at baseline (Medications were classified according to National Health Survey Users’ Guide

Appendix 6 – Classification of type of medication 4363.0.55.001)

6 Potassium replacement supplements 1 5.9 - -

19 Vitamins / minerals/ other hormones 3 17.6 6 18.2

22 ACE Inhibitors / AII receptor antagonists 2 11.8 - -

(trandolapril / irbesartan)

23 Non-potassium sparing diuretics - - - -

24 Non Steroidal Anti-inflammatory Drugs - - 1 3.0

(Mobic)

Measurement

The State-Trait Anger eXpression Inventory – 2nd Edition (Spielberger, 1996) is a

57 item self-report questionnaire that provides concise measures of the experience, expression and control of anger and takes 10-15 minutes to complete Table 2.3 (Spielberger, 1996) defines the nature of the information measured by each scale and sub-scale Also provided are the number of items in and the possible range of scores obtainable for each

The STAXI was first published in 1979 and has generated valid norm-referenced data in adolescent, college student, and adult samples along with general medical and surgical patient, male and female groups Deffenbacher and colleagues (1990) used the STAXI in a pre-post design with a 5 week and 12 month follow-up to measure the effectiveness of an anger reduction program in 29 college students Hains (1992) used the STAXI in a randomised, controlled pre-post design to measure the

effectiveness of two cognitive behavioural interventions to help adolescent boys cope with stress and other negative emotional arousal The STAXI-2 has been successfully used in anger testing in cardiac disease and hypertension (Spielberger, 1996)

Whilst we found no normative data on such a definitively diagnosed sub-group of hypertensives (hypertension due to PAL, mean age 55.90 in current sample), other researchers have used STAXI (an earlier version of STAXI-2) to investigate the relationship of anger type manifestations in ‘essential’ (cause not found)

hypertensive’ populations Jula et al (1999) used STAXI in a Finnish study to

demonstrate a lack of correlation of anger expression with high blood pressure in 237 newly diagnosed hypertensives and 147 normotensive controls The mean age of participants in their study was 10 years younger and participants were all newly

diagnosed, untreated hypertensives The researchers found no difference in Trait Anger scores between the hypertensives and age / gender matched controls Mann and Gerber (2000) used STAXI in a study on 22 hypertensive patients to measure psychological characteristics and responses to anti-hypertensive drug

State-therapy Interestingly they found that Anger-out scores were positively correlated with a diuretic (hydrochlorothiazide) induced fall in blood pressure

Crane (1981) used a very early version of the STAXI called State-Trait Personality Inventory (STPI), to compare levels of State and Trait anger and anxiety in a

population of 88 US Veterans Administration patients diagnosed with essential hypertension The control group of 47 general medical patients had no history of hypertension or heart disease but differed significantly (p < 001) from the

hypertensive group in their time on active duty and marital status (p < 05) Crane found that hypertensive patients scored significantly higher on State and Trait anger scales, Angry Reaction sub-scale and State and Trait Anxiety

The differing participant groups, different levels of development of the scales used in the published literature and different numbers of items used in each version to

measure State-Trait anger and its sub-sets, make difficult the establishment of

normative data for hypertensive patients and those with hypertension due to PAL

Table 2.3: Scale and sub-scale definitions taken from STAXI-2 Professional

Manual (Spielberger, 1996)

Scale/Subscale Items Range Description

State Anger 15 15–60 Measures the intensity of angry feelings and the

(S-Ang) extent to which a person feels like expressing

anger at a particular time

Feeling Angry 5 5–20 Measures the intensity of the angry feelings the

(S-Ang/F) person is currently experiencing

Feel Like Expressing 5 5-20 Measures the intensity of current feelings

Anger Verbally related to the verbal expression of anger

(S-Ang/V)

Feel like Expressing 5 5-20 Measures the intensity of current feelings

Anger Physically related to the physical expression of anger

(S-Ang/P)

Trait Anger 10 10-40 Measures how often angry feelings are

(T-Ang) experienced over time

Angry Temperament 4 4-16 Measures the disposition to experience anger

Angry Reaction 4 4-16 Measures the frequency that angry feelings are

(T-Ang/R) experienced in situations that involve frustration

and/or negative evaluations

Anger Expression-Out 8 8-32 Measures how often angry feelings are

(AX_O) expressed in verbally or physically aggressive

behaviour

Anger Expression-In 8 8-32 Measures how often angry feelings are (AX-I) experienced but not expressed (suppressed)

Anger Control –Out 8 8-32 Measures how often the person controls the

(AC-O) outward expression of angry feelings

Anger Control –In 8 8-32 Measures how often a person attempts to

(AC-I) to control angry feelings by calming down or

cooling off

Anger Expression 32 0-96 Provides a general index of anger expression

(AX-Index) and AC-I items

The State-Trait Anxiety Inventory – STAI – Form Y (Spielberger et al 1983) consists

of two, twenty item self-report scales designed to measure anxiety proneness (trait),

as well as the current level of tension and apprehension (state) and takes 15- 20

minutes to complete The STAI has been used extensively in research on anxiety in cardiovascular disease Lane and colleagues (2002) used this scale to study 288 patients in the UK for the prevalence and persistence of anxiety after myocardial infarction

The STAI has also been used successfully in pre-post treatment studies Linden and colleagues (2001) in a randomised, controlled trial, used the STAI to assess an individualised stress management program in 60 primary hypertensive patients Systolic blood pressure reduction in this study correlated positively with reductions

in psychological stress Wilk and Turkoski (2001) in a small randomised, controlled pilot study measured the effects of progressive muscle relaxation on anxiety in 14 patients enrolled in a cardiac rehabilitation program, using the STAI Reduction in anxiety correlated well with reduction in heart rate In another pre-post design using the STAI, Khatri and colleagues (2001) demonstrated that hypothermia during coronary artery bypass surgery was associated with increased incidence of anxiety and depression at 6 weeks and 6 months after surgery

In the current study, a modified version of the STAI – Form Y was used Eight items measured trait anxiety and eight items measured state anxiety Item analysis and basic psychometric data indicated a high comparability to the 20-item version (Form-Y) STAI scores in the modified version were also compared to anxiety scores in the PAIS-SR Psychological distress section and again found to be comparable

(Appendix 1)

The Psychosocial Adjustment to Illness Scale – Self Report – PAIS-SR (Derogatis &

Lopez, 1983) is a 46 item multi-dimensional assessment of psychological and social adjustment of medical patients to their illness in a self-report format The scale addresses seven domains of health care orientation, vocational environment,

domestic environment, sexual relationships, extended family relationships, social environment and psychological distress

The PAIS-SR has been extensively used to assess adjustment to illness in chronic medical conditions (Streisand et al, 1999) Such studies include patients having haemodialysis (DeNour, 1982), diabetics with lower limb disability (Carrington et al, 1996), psychosocial adjustment of patients with HIV infection (Morer et al 1998), patients with prostate cancer (Lilleby et al, 1999) and patients with chronic psoriasis (Adams et al, 2001)

Two further studies have used the PAIS-SR in a prospective pre-post design as in this study in primary aldosteronism Langeluddecke and colleagues (1989) measured change in psychological and psychosocial impairment before and 6 months after by-pass graft surgery Geevarghese et al (1998) administered the PAIS-SR to 100 liver transplant patients 6 months and then yearly for 5 years post-transplantation The validity of the PAIS-SR is supported by strong correlations with other adjustment measures commonly used in the assessment of adults with chronic physical

conditions (Rodrigue et al, 2000)

Procedures

Phase 1 – Pre-test For those patients who agreed to participate in the study,

Participant Information, Informed Consent, STAXI-2, STAI-Form Y (modified version) and PAIS-SR forms were given on the 1st day of admission for FST This ensured that all baseline data were collected at a similar time in the diagnostic

process Each participant’s set of forms was given a three-digit code for

identification

Biological data included blood pressure measurements, weight, basal day FST serum aldosterone-renin and ratio and biochemical profile A brief medical history was obtained from the hospital file in order to identify other medical conditions and concomitant medications which may impact on anger and anxiety scores

After FST results confirmed a diagnosis of PAL (usually 1 week later), participants were contacted to book an admission for Adrenal Vein Sampling (AVS) to

differentiate between unilateral and bilateral adrenal gland over-production of

aldosterone

Prescription of treatment regimes determining treatment groups

Adrenal Vein Sampling is performed under skilled radiological guidance via a

Femoral Vein puncture A fine catheter is progressed through to the very small Adrenal Vein from which 2-3 samples of adrenal outflow blood are collected for measurement of aldosterone and cortisol A higher level of cortisol (also produced by the adrenal cortex) than in the simultaneously collected peripheral sample, helps to ensure that the sample is from the adrenal vein This procedure differentiates

between unilateral over-production, usually aldosterone producing adenoma, and bilateral overproduction, usually bilateral adrenal hyperplasia, (Daunt, 2005)

Comparison of adrenal and peripheral venous serum aldosterone and cortisol levels,

is the most reliable means of determining whether autonomous excessive aldosterone production is confined to one gland or is occurring in both glands (Stowasser et al, 2001) Unilateral over-production (usually found in approximately one third of patients) gives the patient the choice of surgery (unilateral adrenalectomy of the over-producing gland) in their treatment options When excess aldosterone

production does not lateralise to one side on AVS, or the patient is unfit or not ready for surgery or prefers pharmacological treatment; specific drugs, spironolactone and amiloride are used (Stowasser et al, 2001)

Phase 2 – Treatment

Following detailed discussion with the participant, the decision regarding treatment

is made by the physician This decision though independent of the study, determined the treatment group of the participant in the study Time of initiation of treatment was the date of commencement of amiloride or spironolactone as determined by the clinic visit when the drug was prescribed Information regarding concomitant

medications was collected and participants were asked to contact the study

coordinator if there was any change in treatment during the 6-8 month treatment period so that Phase 3 post-test could be carried out before commencing the new drug In this study two participants forgot to inform the study coordinator prior to commencement of the alternative treatment These participants were subsequently withdrawn from the study

Phase 3 – Post-test

Six to eight months after commencement of Phase 2, participants were interviewed

by phone or in person in order to update information such as change in medications, average home blood pressures and current weight Recent pathology results were collected from hospital files and follow-up STAXI, STAI and PAIS forms were posted or completed on site

determines difference in the effects of spironolactone or amiloride on the above variables over time An interaction effect indicates whether the change in scores over time is different for the 2 groups (Pallant, 2005)

Gender differences at baseline were analysed using an Independent samples T-Test Changes over time were analysed using the Paired Samples T-Test

Participants who did not return post-test surveys (non-completers), were compared at baseline with the group who did respond (completers) An independent samples T-Test was used to identify significant differences between these two groups