View PDF - Diabetic Foot Journal

article
Impact of psychological stress on wound
healing for patients with diabetic foot ulcers
Hussam Eddine Saleh Itani, Nashat Ali Gandoura, Tauqeer Ahmed,
Rima Mazen Ahmad
Diabetic foot ulcers are complex, chronic wounds that will often have a
delayed healing trajectory. In the past the focus of treatment has been on the
pathophysiology of DFUs. This article argues that there should be a greater
focus on the impact of psychological stress when treating patients with DFUs.
The authors show, through a review of the literature, that although acute levels
of stress can have a positive effect on wound healing, long-term stress can
delay wound healing in chronic wounds by raising levels of glucocorticoid and
causing a down-regulation effect on the inflammatory response. The authors
suggest that stress levels should be considered when planning treatment for
patients with DFUs and that there should be more research into this area.
A
Authors
Dr Hussam Eddine Saleh Itani,
Wound Care Consultant and
Educator, Dubai, UAE; Dr Nashat
Ali Gandoura is Consultant
General and Diabetic Foot
Surgeon at, King Fahad Hospial in
Jeddah, KSA; Dr Tauqeer Ahmed
Malik is a Senior Registrar G
Surgery, Diabetic Foot Surgeon
and Wound Care at the King Fahad
Armed Forces Hospital Jeddah,
KSA; Rima Mazen Ahmad is
Department Supervisor at Derma
Clinic in Riyadh, KSA
18
diabetic foot ulcer (DFU) is a complication
of diabetes and represents a significant
medical, social and psychological risk
to patients, as well as an economic burden to
healthcare systems[1]. In his review Boulton[2],
described the multifactorial aetiology of a DFU as
the complication of uncontrolled hyperglycemia
damaging the peripheral nerves and blood vessels.
Bolton also stressed that this damage causes pain,
tingling and loss of feeling that can easily allow
injuries to go unnoticed, risking infection and
ulceration.
As with all chronic wounds, the healing process
for a DFU is governed by physiological and
psychological factors[3]. Physiological factors include
poor circulation, neuropathy, immune suppression,
systemic diseases, aging and repeated trauma[4].
Psychological and behavioural factors range from
psychological stress, mood swings, and changes
in sleep patterns[5]. These factors contribute to the
stagnation of wounds in the inflammatory phase
thus preventing these wounds from healing, and
leading to further complications[6] such as pain,
infection, malodour and leakage as well as an
increased risk of amputation[7].
Complications can also boost the stress response
that might be observed as an alteration in mood[8]
and a disturbance in patients’ daily routine which
has a negative impact on their quality of life[9].
The knowledge about the pathogenesis of DFU as
well as treatment and prevention has improved in the
past decade[10]. Nevertheless, there needs to be more
research into the influence of psychological stress
on the healing outcome of patients with DFU[11].
When planning clinical treatment protocols, not
much attention is given to psychological factors
despite the growing evidence provided about the
impact of psychological stress on wound healing[12].
The main objective of this paper is to assess the
relationship between psychological stress and the
healing of DFUs.
Definition of stress
Stress occurs when individuals perceive that
environmental strains exceed their adaptive
capabilities resulting in behavioural and physiological
changes[13]. According to Webster-Marketon and
Glaser[14], the degree and duration of perceived
environmental strains determine the level of stress
response to a given event. Different forms of stress
such as acute, chronic, psychological, or physical have
different effects on the release of neuroendocrine
hormones and immune functions[15].
Impact of stress on human health
Animal and human studies have demonstrated
that stress increases the amount of neuroendocrine
hormones released through two main pathways [16].
The Diabetic Foot Journal Middle East Vol 1 No 1 2015
Impact of psychological stress on wound healing for patients with diabetic foot ulcers
The hypothalamic-pituitary-adrenal (HPA)
axis causes the release of glucocorticoids, while
the sympathetic-adrenal-medullary (SAM) axis
results in the release of catecholamine [16].
Existing research indicates that the release
of glucocorticoid hormones, predominantly
cortisol, causes the suppression of the
inflammatory response, the modification of the
cytokines profile, and the elevation of blood
glucose levels [17]. Catecholamine release causes
the secretion of epinephrine and norepinephrine
that results in alterations of the immune cell
function and elevation in blood glucose level[18].
The impact of these hormones affects health in
many ways and can precipitate illnesses such as
cardiovascular diseases, osteoporosis, arthritis,
diabetes, certain types of cancer and also a delay
in wound healing [19].
Two meta-analyses have been conducted to
determine the relationship between stress and
healthy human immunity[20, 21]. The first
synthesised findings from 38 studies[20] and the
second synthesised findings from 75 studies[21].
Both reviews included the study of speech tasks as
acute laboratory stressors and medical examinations
as short-term naturalistic stressors while long-term
naturalistic stressors included divorce, bereavement,
care-giving, and unemployment. Both meta-analyses
concluded that consistent and prolonged stress
resulted in an increase in circulating neutrophils
and monocytes, a reduction in natural killer cell
activity, and decreased lymphocyte proliferation
and antibody production which resulted in delayed
wound healing.
Research by Dhabhar[22] on the body’s response
to acute stress, found a positive impact of shortterm stressors in activating the body’s physiological
fight system that helps humans and animals to
cope with challenges like fear, anger and other lifethreatening burdens. In relation to acute wound
healing, Dhabhar’s work showed an increase in
leukocyte trafficking and cytokine gene expression
at the wound site to manage foreign bodies and
microorganisms in response to acute wound
injuries.
These findings makes it clear that human and
animal response to short-term stress can have
a therapeutic benefit, while prolonged stressful
stimuli can lead to an imbalance in the body’s
system that might contribute to the development of
various diseases through different mechanisms[23].
The Diabetic Foot Journal Middle East Vol 1 No 1 2015
Impact of stress on the physiology of
wound healing
In their meta-analysis, Herbert and Cohen[20] verified
that perceived stress is directly associated with cellular
and humoral immune deficiency, which has an
impact on wound healing. Perceived stress is linked
to wound healing through various routes involving
increase in negative mood, alteration in immune
function, prolonged inflammatory process[24], and
changing behaviour such as inadequate sleeping
patterns[25].
The physiological factor is revealed by the
increase in glucocorticoid level that suppresses
the wound healing processes[26]. Glucocorticoid
has a down-regulation effect on the inflammatory
response and leads to the modification of cytokine
profiles, mainly interleukin-1 (IL-1), IL-6, IL-8
and tumour necrosis factor[18]. These cytokines play
a critical role in the inflammatory and granulation
phases of the wound healing stages[6].
Stalled wounds possess decreased growth
factors and increased pro-inflammatory cytokines
which lead to excessive matrix metalloproteinase
activation[6]. This outcome results in the breakdown
of extracellular matrix molecules and growth
factors, and inhibits the proliferation of fibroblasts
and keratinocytes thus preventing the wound from
healing[6].
“The impact of these
hormones affects
health in many ways
and can precipitate
illnesses such as
cardiovascular
diseases, osteoporosis,
arthritis, diabetes,
certain types of cancer
and also a delay in
wound healing.”
Stress and wound healing: gaps in the
literature
In the past decade, the interest in understanding the
relationship between psychological stress and wound
healing has increased tremendously. This has led to
rapid growth in the amount of qualitative research
done in this area[28]. Qualitative research helps to
understand human behaviour to build up the gap
between scientific evidence and clinical practice[29].
However, the subjective methodologies used to
assess and interpret the collected data from such
studies might hinder the accuracy of the outcome[30].
Sandelowski stressed that qualitative research is
designed to study small groups thus the outcomes
may not be accurate enough to generate statistical
data. The triangulation of research methods, which
combines qualitative and quantitative approaches,
could help to fill in the gaps between the two
methods and might help to obtain more reliable
research outcomes[31].
A search of the literature indicates that studies
addressing psychological stress and wound
19
A
Mrticle
eeting Report
healing have mainly concentrated on acute wound
models[32]. Acute and chronic wounds do not have
the same healing trajectory, thus the impact of
stress on chronic wound healing will be different[33].
Future research should focus on the biological
and behavioural factors mediating the association
between psychological stress and healing of chronic
wounds with different aetiologies[5].
Psychological stress and diabetic
foot ulcers
The risk of developing a DFU has increased among
patients with diabetes in North America, where
prevalence rates might exceed 20% and the rate of
recurrence is also high. This increase has made the
burden of DFU a major focus for the International
Diabetes Federation[2].
The management of patients with DFUs requires
long-term intensive care that might exceed five
months[2]. Such an extended period is associated
with high cost and burden for patients, healthcare
providers and healthcare systems[34]. Long-term
management and ulcer complications such as
loss of mobility, pain, infection, and malodour
create physiological stressors[35]. Social isolation
and fear of amputation lead to the development
of psychological stressors[36]. These stressors might
lead to increased psychological stress among
patients with DFU[8].
Although few studies have been done on the
impact of stress on chronic wounds, particularly
in DFU, more extensive work has been undertaken
on biopsy and surgical wounds to provide
evidence on the relationship between stress and
wound healing[16]. The available literature shows
strong evidence relating to the psychological and
physiological effect of stress on wound healing[33].
Kiecolt-Glaser et al[37] were among the first
to carry out a qualitative study to investigate
the consequence of long-term psychological stress
caused by caring for a relative with dementia on
wound healing. Participants included 13 healthy
female carers and 13 controls. The subjects were
inflicted with a 3.5 mm punch biopsy wound on
the forearm. Hydrogen peroxide foaming and
photography were used to assess wound healing.
Complete healing was indicated by the absence of
foaming upon application of hydrogen peroxide.
The Perceived Stress Scale (PSS)[13] was used to
20
assess the subjects’ psychological stress. PSS is one
of the most widely used psychological questionnaire
for measuring how stressful life situations are
perceived. The questions are used to identify and
measure the degree to which situations in one’s
life are appraised as stressful. Kiecolt-Glaser et al
reported higher stress levels among carers and a
delay in wound healing by an average of nine days
compared with the control group.
In a similar study by Marucha et al[38], the impact
of short naturalistic stressors on the healing rate
of hard palate punched wounds was examined.
Participants included 11 dental students inflicted
with punch wounds where the first wound
was induced during the summer holiday and
the second was given three days before taking
exams. Daily assessments of the wounds using
hydrogen peroxide foaming and photography were
conducted. Complete healing was reported there
was no foaming at the biopsy site. At the time of
each wounding, psychological stress was assessed
using PSS[13] and blood samples were collected to
screen for the level of IL-1 in the blood.
The study revealed a delay in the wound healing
rate and a decrease in IL-1 in the blood collected
during the examination period compared with the
results collected during the summer vacation. While
both studies provided statistically significant results,
the number of researchers and their experience
in assessing wound healing was not clarified in
the methodology[5]. Moreover, both used hydrogen
peroxide to evaluate wound healing and this may
have given false results since hydrogen peroxide has
the ability to damage non-epithelialised tissue and
delay wound healing[39]. Furthermore, negative health
behaviour such as smoking[40], alcohol consumption,
altered sleeping pattern[41], and nutrition[42] are further
putative factors caused by psychological stress that
were not considered and might have contributed
to the wound healing delay[15]. Finally, the lack of
accuracy of surface photography to evaluate deep
tissue healing process compared with high resolution
ultrasound[43] and the small population used in both
studies might throw doubt on the results[5].
A similar prospective longitudinal study
was conducted by Ebrecht et al[39]. The authors
investigated the relationship between perceived stress
and cutaneous wound healing in 24 healthy nonsmoking males. Each participant was inflicted with
The Diabetic
Foot Journal
The Diabetic
Foot Journal
MiddleVolume
East VolX1No
No X1 20XX
2015
Impact of psychological stress on wound healing for patients with diabetic
foot R
ulcers
Meeting
eport
a 4 mm punch biopsy wound on the dominant
arm and examined by high-resolution ultrasound
scanning to assess healing progress at day 7, 14 and 21
post biopsy. Ebrecht and his team assessed perceived
stress and health behaviour using both PSS[13] and
the General Health Questionnaire[44]. Assessment of
cortisol levels was conducted using saliva collected
upon waking, two weeks before and two weeks after
inflicting the wounds. The results demonstrated
negative correlations between wound healing speed
and both perceived stress and an increase in cortisol
level, while a positive relationship was found between
wound healing speed and optimism.
In contrast to the previous studies, Ebrecht et
al[39] attempted to control imputed variables such
as negative health behaviour that might have a
direct impact on elevating stress level[45]. They also
limited their recruitment to men to minimise the
possibility of cortisol level difference between male
and female participants[46]. Finally they used highresolution ultrasound scanning to accurately assess
healing activity in deep tissue wounds[43]. Despite
the relevant result, the small sample size, young age
and low comorbidity of the subjects, and short-term
monitoring of the negative health behaviour might
have an impact on the validity of the findings and
the ability to generalise the outcome[5].
Studies have showed that patients experiencing
psychological stress due to the presence of a chronic
wound might develop depression[47]. Depression
caused by psychological stress has an indirect impact
on the delay in wound healing processes by affecting
the patient’s behaviour and quality of life[48].
Cole-King and Harding[49] were among the first to
examine the inter-relationship between depression
and chronic wound healing in 53 males and females
with chronic leg ulcers. A five point Likert scale[50]
was used to rate wound healing and the Hospital
Anxiety and Depression Scale (HADS)[51] was used
to measure depression and anxiety. Wound and
psychological assessments were measured with both
researcher and participants blinded to the results
of other procedures. Cole-King and Harding[49]
reported a statistically significant result showing a
direct relation between higher HADS scores and a
delay in ulcer healing.
Despite the complexity in studying chronic
wounds, Cole-King and Harding used relatively
large size samples compared with similar studies
The
Diabetic Foot
Foot Journal
Journal Middle
VolumeEast
X No
The Diabetic
VolX 120XX
No 1 2015
and they also used validated psychological and
wound assessment methods. They also managed
to find a statistically significant relationship
between psychological factors and wound
healing. Nevertheless, physical complications and
limitations[33] , circulatory, hormonal and immunity
alterations due to venous disease and diabetes[16] are
factors that might have been relevant to the delay in
healing that were not considered in this study.
“Cole-King and
Harding were among
the first to examine
the inter-relationship
between depression
and chronic wound
healing in 53 males
and females with
chronic leg ulcers.”
Clinical relevance
Although the multidisciplinary team approach
became a common practice in managing DFU,
more attention is still given to the pathophysiology
of disease[52]. The negative impact of psychological
stress on wound healing that has been demonstrated
in the studies discussed should urge the practitioners
to give equal attention to the physiological and
psychological aspects of wound healing when
considering treatment plans[32]. The statistically
significant results of psychological stress assessment
tools like PSS[13] could be used in clinical practice
to evaluate the psychological status of patients with
DFUs, and to determine the scope of support to
reduce their stress.
Early detection of patients’ perception, concern
and reaction to their disease means that practitioners
could provide effective management to prevent and
treat DFU and minimise stress[35].
Conclusion
The worldwide incidence of DFU and its
complications is increasing despite the
improvement in prevention and treatment
strategies[2]. Practitioners tend to give less focus
to psychological stress within their management
protocols. The past decade has witnessed a
significant increase in research indicating the
negative impact of psychological stress on wound
healing. Studies have recruited healthy and
health-compromised individuals to understand
the mechanism of stress in slowing the healing
rate of acute and chronic wounds using different
stress and wound assessment tools. Concordant
findings from these studies have revealed a direct
correlation between psychological stress and
alteration in glucocorticoid, catecholamine levels
and cytokines function. A continuous increase
in cortisol and catecholamine levels can have an
21
article
M
eeting
Report
“The past decade
has witnessed a
significant increase
in research indicating
the negative impact of
psychological stress on
wound healing.”
impact on the immune and cellular response,
downgrading pro-inflammatory cytokines
and increasing blood glucose level, which
would impair wound healing.
With the increased understanding of the
significance of stress in wound healing, more
research is required to study the correlation
between psychological stress and wound
healing in chronic wounds and DFU. n
27. Velnar T, Bailey T, Smrkolj V. The wound healing process: an
overview of the cellular and molecular mechanisms. J Int Med
Res 2009; 37: 1528–42
28.Campbell R, Pound P, Pope C et al. Evaluating metaethnography: a synthesis of qualitative research on lay
experiences of diabetes and diabetes care. Soc Sci Med 2003;
56(4): 671–84
29. Green J, Britten N. Qualitative research and evidence based
medicine. BMJ 1998; 316(7139): 1230–2
30.Sandelowski M. Combining qualitative and quantitative
sampling, data collection, and analysis techniques in mixedmethod studies. Res Nurs Health 2000; 23(3): 246–55
2. Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The
global burden of diabetic foot disease. Lancet 2005; 366(9498):
1719–24
31. Mingers J. Combining IS research methods: towards a pluralist
methodology. Information Systems Res 2001; 12(3): 240–59
4. Snyder RJ. Treatment of non-healing ulcers with Allografts. Clin
Dermatol 2005; 23(4): 388–95
5. Walburn J, Vedhara K, Hankins M et al. Psychological stress
and wound healing in humans: A systematic review and metaanalysis. J Psychosom Res 2009; 67(3): 253–71
6. Christian LM, Graham JE, Padgett DA et al. Stress and wound
healing. Neuroimmunomodulation 2006; 13(5): 337–46
7. McEwen LN, Ylitalo KR, Herman WH, Wrobel JS. Prevalence
and risk factors for diabetes-related foot complications in
Translating Research Into Action for Diabetes (TRIAD). J
Diabetes Complications 2013; 27(6): 588–92
32. Gouin JP, Kiecolt-Glaser JK. The impact of psychological stress
on wound healing: methods and mechanisms. Immunol Allergy
Clin North Am 2011; 31(1): 81–93
33.Solowiej K, Mason V, Upton D. Review of the relationship
between stress and wound healing: part 1. J Wound Care 2009;
18(9): 357–66
34.Apelqvist, J, Larsson, J. What is the most effective way to
reduce incidence of amputation in the diabetic foot Diabetes/
Metabolism Research and Reviews 2000; 16(S1): S75–83
35. Vileikyte L. Diabetic foot ulcers: a quality of life issue. Diabet
Metab Res Rev 2001; 17(4): 246–9
36.Brod M. Quality of life issues in patients with diabetes and
lower extremity ulcers: patients and care givers. Qual Life Res
1998; 7(4): 365–72
8. Carrington AL1, Mawdsley SK, Morley M et al. Psychological
status of diabetic people with or without lower limb disability.
Diabetes Res Clin Pract 1996; 32(1–2): 19–25
37. Kiecolt-Glaser JK, Marucha PT, Malarkey WB et al. Slowing of
wound healing by psychological stress. Lancet 1995; 346(346):
1194–6
9. Nabuurs-Franssen MH, Huijberts MS, Nieuwenhuijzen
Kruseman AC et al. Health-related quality of life of diabetic
foot ulcer patients and their caregivers. Diabetologia 2013;
48(9): 1906–10
38. Marucha PT, Kiecolt-Glaser JK, Favagehi M. Mucosal wound
healing is impaired by examination stress. Psychosom Med
1998; 60(3): 362–5
10. Jeffcoate WJ, Harding KG Diabetic foot ulcers. Lancet 2003;
361(9368): 1545–51
39.Ebrecht M, Hextall J, Kirtley LG et al. Perceived stress and
cortisol levels predict speed of wound healing in healthy male
adults. Psychoneuroendocrinology 2004; 29(6): 798–809
11. Vileikyte L, Rubin R, Leventhal H. Psychological aspects of
diabetic neuropathic foot complications: an overview. Diabetes
Metab Res Rev 2004; 20(S1): S13–8
40.Silverstein P. Smoking and wound healing. Am J Med 1992;
93(1): S22–4
12. Monami M, Longo R, Desideri CM et al. The diabetic person
beyond a foot ulcer: healing, recurrence, and depressive
symptoms. J Am Podiatr Med Assoc 2008; 98(2): 130–6
13.Cohen S, Kamarck T, Mermelstein R. A global measure of
perceived stress. J Health Soc Behav 1983; 24(4): 385–96
41.Baum A, Posluszny DM. Health psychology: mapping
biobehavioral contributions to health and illness. Ann Rev
Psychol 2003; 50(1): 137–63
42. Edmonds J. Nutrition and wound healing: putting theory into
practice. Br J Community Nurs 2007; 12(12): S31–4
14. Webster-Marketon JI, Glazer R. Stress hormones and immune
function. Cell Immunol 2008; 252(1–2): 16–26
43. Dyson M, Moodley S, Verjee L et al. Wound healing assessment
using 20MHz ultrasound and photography. Skin Res Technol
2003; 9(2): 116–21
15.Lucas VS. 2011. Psychological stress and wound healing in
humans: what we know. Wounds 22(4): 76–83
44.Goldberg D. General Health Questionnaire (GHQ-12). NFER
Nelson, 1992
16.Vileikyte L. Stress and wound healing. Clin Dermatol 2007;
25(1): 49–55
45. DeLongis A1, Folkman S, Lazarus RS. The impact of Daily Stress
on Health and Mood: Psychological and Social Resources as
Mediators. J Pers Soc Psychol 1988; 54(3): 486–95
17. Sapolsky RM. Physiological stress in ecology: lessons from
biomedical research. Endocrine Reviews 2000; 21(1): 55–89
18.Miller DB, O’Callaghan P. Neuroendocrine aspects of the
response to stress. Metabolism 2002; 51(6): 5–10
19.Irwin MR. Human psychoneuroimmunology: 20 Years of
discovery. Brain Behav Immun 2008; 22(2): 129–39
20. Herbert TB, Cohen S. Stress and immunity in humans: a metaanalytic review. Psychosom Med 1993; 55(4): 364–79
21. Zorrilla EP, Luborsky L, McKay JR et al. The relationship of
depression and stressors to immunological assays: a metaanalytic review. Brain Behav Immun 2001; 15(3): 199–226
22. Dhabhar FS. Stress, leukocyte trafficking, and the augmentation
of skin immune function. Ann NY Acad Sci 992(1): 205–17
23.Glaser R, Kiecolt-Glaser JK. Stress-induced immune
dysfunction: implications for health. Nat Rev Immunol 2005;
5(3): 243–51
24. Kiecolt-Glaser JK, Page GG, Marucha PT et al. Psychological
influences on surgical recovery: perspectives from
psychoneuroimmunology. Am Psychol 1998; 53(11): 1209–18
26.Gupta A, Jain GK, Raghubir R. A time course study for the
development of an immunocompromised wound model, using
hydrocortisone. J Pharmacol Toxicol Methods 1999; 41(4):
183–7
1. Leung PC. Diabetic foot ulcers — a comprehensive review.
Surgeon 2007; 5(4): 219–31
3. Baker SR, Stacey MC, Jopp-McKay AG et al. Aetiology of
chronic leg ulcers. Eur J Vasc Surg 1992; 6(3): 245–51
22
25.Graham JE, Streitel KL 2014. Sleep quality and acute pain
severity among young adults with and without chronic pain:
the role of bio-behavioural factors. J Behav Med 2014; 33(5):
335–45
46.Kirschbaum C, Wüst S, Hellhammer D. Consistent sex
differences in cortisol responses to psychological stress.
Psychosom Med 1992; 54(6): 648–57
47. de Rooij SR, Schene AH, Phillips DI, Roseboom TJ. Depression
and anxiety: associations with biological and perceived stress
reactivity to a psychological stress protocol in a middle-aged
population. Psychoneuroendocrinology 2010; 35(6): 866–77
48. Franks PJ, Oldroyd M, Bosanquet N et al. Community leg ulcer
clinics: effect on quality of life. Phlebology 1994; 9: 83–6
49. Cole-King A, Harding KG. Psychological factors and delayed
healing in chronic wounds. Psychosom Med 2001; 63(2):
216–20
50. Norman, G. Likert scales, levels of measurement and the “laws”
of statistics. Adv Health Sci Educ 15(5): 625–32
51. Zigmond AS, Snaith RP The hospital anxiety and depression
scale. Acta Psychiatr Scand 1983; 67(6): 361–70
52.Driver VR, Fabbi M, Lavery LA, Gibbons G. The costs of
diabetic foot: the economic case for the limb salvage team. J
Vasc Surg 2010; 52(3): 17S–22S
The Diabetic
The Diabetic
Foot Journal
Foot Journal
MiddleVolume
East VolX1No
NoX1 20XX
2015