Brain, Behavior, and Immunity 26 (2012) 212–217

Contents lists available at ScienceDirect

Brain, Behavior, and Immunity

journal homepage: www.elsevier.com/locate/ybrbi

A brief relaxation intervention reduces stress and improves surgical wound

healing response: A randomised trial q
Elizabeth Broadbent a,⇑, Arman Kahokehr b, Roger J. Booth a, Janine Thomas c, John A. Windsor b,
Christina M. Buchanan d, Benjamin R.L. Wheeler b, Tarik Sammour b, Andrew G. Hill b
a
Department of Psychological Medicine, The University of Auckland, New Zealand
b
Department of Surgery, The University of Auckland, New Zealand
c
Inner Zest Ltd., Auckland, New Zealand
d
Maurice Wilkins Centre for Molecular Biodiscovery, Department of Molecular Medicine and Pathology, The University of Auckland, New Zealand

a r t i c l e i n f o a b s t r a c t

Article history: Psychological stress has been shown to impair wound healing, but experimental research in surgical
Received 9 March 2011 patients is lacking. This study investigated whether a brief psychological intervention could reduce stress
Received in revised form 21 June 2011 and improve wound healing in surgical patients. This randomised controlled trial was conducted at a sur-
Accepted 24 June 2011
gical centre. Inclusion criteria were English-speaking patients over 18 years booked to undergo elective
Available online 28 June 2011
laparoscopic cholecystectomy; exclusion criteria were cancellation of surgery, medical complications,
and refusal of consent. Seventy five patients were randomised and 15 patients were excluded; 60 patients
Keywords:
completed the study (15 male, 45 female). Participants were randomised to receive standard care or stan-
Surgery
Wound healing
dard care plus a 45-min psychological intervention that included relaxation and guided imagery with
Relaxation take-home relaxation CDs for listening to for 3 days before and 7 days after surgery. In both groups ePTFE
Intervention tubes were inserted during surgery and removed at 7 days after surgery and analysed for hydroxyproline
Stress as a measure of collagen deposition and wound healing. Change in perceived stress from before surgery to
Hydroxyproline 7-day follow-up was assessed using questionnaires. Intervention group patients showed a reduction in
ePTFE perceived stress compared with the control group, controlling for age. Patients in the intervention group
had higher hydroxyproline deposition in the wound than did control group patients (difference in means
0.35, 95% CI 0.66–0.03; t(43) = 2.23, p = 0.03). Changes in perceived stress were not associated with
hydroxyproline deposition. A brief relaxation intervention prior to surgery can reduce stress and improve
the wound healing response in surgical patients. The intervention may have particular clinical application
for those at risk of poor healing following surgery.
Ó 2011 Elsevier Inc. All rights reserved.

1. Introduction
A systematic review has shown that psychological stress im-
pairs wound healing across a variety of laboratory and clinical set-
tings (Walburn et al., 2009). Dermal punch biopsy wounds heal
more slowly in women caring for relatives with Alzheimer’s dis-
ease than in matched control subjects, and mucosal punch biopsy
wounds heal more slowly in students during exams than during
vacation time (Kiecolt-Glaser et al., 1995; Marucha et al., 1998).
Diabetic foot ulcers heal more slowly in depressed patients, and
surgical wounds show impaired healing in patients with higher
stress levels in the month prior to surgery (Broadbent et al.,
q
Please see Brief commentary by Kavita Vedhara on page 210 of this issue.
⇑ Corresponding author. Address: Department of Psychological Medicine, Faculty
of Medical and Health Sciences, The University of Auckland, Private Bag 92109,
Auckland 1142, New Zealand. Fax: +64 9 3737013.
E-mail address: e.broadbent@auckland.ac.nz (E. Broadbent).
2003; Cole-King and Harding, 2001; Monami et al., 2008; Vedhara
et al., 2010). Higher cortisol levels may play a role in the relation-
ship between stress and slower healing by down-regulating the
immune system (Ebrecht et al., 2004). Local inflammatory cells,
and pro-inflammatory cytokines including interleukin-1, have
been shown to be lower in the wounds of highly stressed individ-
uals (Glaser et al., 1999).
This evidence points to the potential for psychological interven-
tions to improve wound healing. A recent study has shown that
emotional disclosure improves the healing of punch biopsy
wounds in healthy males, although no changes in depression or
stress were achieved (Weinman et al., 2008). Psychological inter-
ventions may be particularly applicable for surgical patients,
where poor wound healing can have serious consequences (Galat
et al., 2009). Meta-analysis has shown psychological preparation
for medical procedures can reduce distress, pain, and length of hos-
pital stay (Devine, 1992). In terms of physiological indices, relaxa-
tion and guided imagery have improved anxiety, and reduced
urinary cortisol and wound erythema amongst cholecystectomy

0889-1591/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.bbi.2011.06.014
 E. Broadbent et al. / Brain, Behavior, and Immunity 26 (2012) 212–217
patients, but the effect on physiological indices of wound healing
has not been assessed (Holden-Lund, 1988).
Wound healing proceeds as a cascade with the later stages
involving the deposition of collagen, which restores strength and
function to damaged tissue (Hunt and Hopf, 1997). The ePTFE mod-
el measures collagen synthesis as an index of healing through the
assessment of hydroxyproline deposited in high porosity tubing
(Goodson and Hunt, 1982). Hydroxyproline is an amino acid that
gives stability to the triple helix structure of collagen (Prockop
et al., 1979), and has been used as a marker of collagen synthesis,
and therefore a marker of the proliferative phase of wound healing.
Hydroxyproline levels have also been shown to correlate with the
tensile strength of wounds, which is of clinical relevance (Wicke
et al., 1995). Reduced hydroxyproline deposition occurs with corti-
costeroid therapy (Wicke et al., 1995), which provides further basis
for suggesting that psychological stress and stress hormones might
impair wound healing. The ePTFE method has been used previ-
ously in surgical studies to investigate the influence of anaemia
(Jensen et al., 1986), pre-operative illness (Goodson et al., 1987),
recent food intake (Windsor et al., 1988), and tissue oxygenation
(Jonsson et al., 1991) on wound healing. It has also been used to
test the effectiveness of peri-operative interventions on wound
healing. For example, immunonutrition has been shown to in-
crease levels of hydroxyproline in surgical patients (Farreras
et al., 2005; Williams et al., 2002).
This study aimed to investigate whether a psychological inter-
vention to reduce stress could improve the deposition of hydroxy-
proline in surgical wounds. Elective laparoscopic cholecystectomy
patients were selected because the operation is common, of mod-
erate magnitude, and the acute phase response is short lived and
well characterised. The psychological intervention was based on
the study by Holden-Lund (1988). We hypothesised that patients
who received the psychological intervention would demonstrate
higher concentrations of hydroxyproline at the wound site than
would the control group.
2. Methods
Ethical approval was obtained from the Northern X ethics com-
mittee. The trial was registered at clinicaltrials.gov NCT00633737.
2.1. Sample characteristics and setting
Inclusion criteria were patients over the age of 18, able to read
and write English, and undergoing elective laparoscopic cholecys-
tectomy at Manukau Surgical Centre, South Auckland, New Zea-
land, between April 2008 and May 2010. Laparoscopic
cholecystectomy is the preferred treatment for gallstone disease,
where the gallbladder is removed through laparoscopic techniques
(Soper et al., 1992). It involves the insertion of 4 ports through 4
wounds, all one centimetre or less in length.
2.2. Procedure
Eligible patients were informed about the study and invited to
participate by the surgical research fellow. If patients agreed to
take part in the study they were met by a health psychologist at
least 3 days prior to their surgery (range 3–132 days), gave written
informed consent and completed a pre-operative questionnaire.
While 80% of participants had their surgery within 28 days of com-
pleting the first questionnaire, 20% of participants had their sur-
gery delayed due to changes in hospital scheduling. Following
informed consent, patients were randomised by the health
psychologist, and received standard care or the intervention plus
standard care. All patients completed further questionnaires at
213
the 7-day follow-up. During surgery, two ePTFE tubes were
implanted in the wound site and patients returned for a 7-day
follow-up where the tubes were removed by a surgeon blind to
group allocation.
2.3. Trial design
This was a parallel group randomised controlled study with a
1:1 allocation. Participants were randomised using a random se-
quence generator and allocation was sealed in consecutively num-
bered envelopes by EB. The surgeons and surgical research fellows
conducting the surgical procedure and follow-up assessments, as
well as the laboratory technician performing the hydroxyproline
tests, were all blind to group allocation. Patients were asked not
to reveal their group allocation.
2.4. The intervention
Patients individually met with a health psychologist for 45 min.
They were informed that stress could influence surgical outcomes
and relaxation could help reduce stress. The psychologist in-
structed the participants in deep breathing techniques and read a
script that included deep breathing, progressive muscle relaxation,
and guided imagery about the body being relaxed and prepared for
surgery. Patients were provided with a 20-min recording of the
script on a CD to take home and listen to each day prior to surgery,
with quiet background music. The psychologist helped the patient
plan a time in their day to listen to the CD, and telephoned them
the next day to see how they were doing with the exercises. The
CD contained a second recording of a similar script for patients
to listen to each day after surgery for 7 days; the guided imagery
focused on the body healing after surgery.
2.5. ePTFE tube implantation
All patients underwent a standard elective four-port laparo-
scopic cholecystectomy under general anaesthesia. At the end of
the procedure prior to closure of the skin wounds, two 20 cm ePTFE
tubes (High porosity PTFE tubing, International Polymer Engineer-
ing, Tempe, Az, USA) with an internal diameter of 1.2 mm and a
0.6 mm wall thickness and 90–120 lm pore size, were inserted
in the subcutaneous layer of the abdominal wall using a guiding
laparoscopic instrument. Each end was brought out through the
right-sided abdominal port site (5 mm) wounds to the skin. The
ends of the ePTFE tubes were trimmed and sutured to the skin to
avoid accidental removal. A standard sterile dressing was applied.
All patients were seen at a 7-day follow-up at the clinic by a surgi-
cal research fellow and the ePTFE tubes were removed under local
anaesthetic. The subcutaneous portion was measured and sent to
the laboratory in a sterile container to be stored at 80 °C prior
to testing.
2.6. Measures
2.6.1. Hydroxyproline assessment
The ePTFE tubes were trimmed to a length of 5 cm and sub-
merged in 1 ml 6 M HCl in a 10 ml screw-cap Pyrex glass tube (Ki-
max) to breakdown the embedded protein into composite amino
acids by hydrolysis at 105 °C for 16 h (Contherm Series 5 digital
oven). The samples were then freeze-dried for 24 h (Glass dessica-
tor attached to a Thermo RVT4104 refrigerated vapour trap and a
Thermo DC120A chemical trap). Once dry, 1 ml of milli Q water
and 45 ll of 5 M NaOH was added to each tube and vortex mixed
for hydroxyproline analysis. Acetate–citrate buffer, oxidant solu-
tion and Erlich’s reagent were prepared for the hydroxyproline as-
say according to established methods (Chiariello et al., 1986). To
214 E. Broadbent et al. / Brain, Behavior, and Immunity 26 (2012) 212–217
the contents of the hydrolysis tube was added 1 ml of isopropyl
alcohol (Merck Emsure 99.8% pure), the tubes mixed and centri-
fuged 5 min at 2000g before duplicate samples of 120 ll of solution
were transferred into 2 ml microcentrifuge tubes (Beckman Coul-
ter). To the 120 ll of sample was added 280 ll of acetate–citrate
buffer and 100 ll of oxidant solution. Tubes were incubated for
5 min at room temperature before the addition of 1.3 ml of Erlich’s
reagent and an incubation for a further 30 min in a 60 °C water
bath. Absorbance was measured at 558 nm (Hitachi U-1800 spec-
trophotometer), and concentrations were determined by compar-
ing against a curve generated from hydroxyproline (Sigma
#56250) in a concentration range from 1.5 to 100 lg ml 1.
Because deposition can vary along the length of tube due to
proximity to vessels in the wound, two measurements were per-
formed on each of the two ePTFE implants from each patient and
the average of all four measures computed. The first four partici-
pants’ wound tubes were used to set up the assay at the beginning
of the study prior to analysis of the remaining samples and
Fig. 1. Consort diagram of participants.
therefore results from those patients could not be included in the
analyses.
2.6.2. Questionnaires
The pre-operative and 7-day follow-up the questionnaires in-
cluded the four-item Perceived Stress Scale (PSS) (Cohen et al.,
1983). Patients were asked how many times they had listened to
the CD before and after surgery. Post-surgical fatigue was also as-
sessed and is reported elsewhere (Kahokehr et al., submitted for
publication).
2.7. Statistical analysis
Analyses were conducted using PASW Statistics18 computer
software. Data were checked for normality and transformed when
distributions were non-normal. A between-groups t-test analysis
was conducted to determine whether there was a difference in
hydroxyproline between the intervention and control groups.
 E. Broadbent et al. / Brain, Behavior, and Immunity 26 (2012) 212–217 215

ANCOVA was conducted to assess changes in perceived stress be-

tween the intervention and control groups, controlling for initial
values (Vickers and Altman, 2001); in three cases missing baseline
PSS values were replaced with the sample mean so the analysis
contained 60 participants.

2.8. Power analysis

Previous work indicated that patients undergoing surgery of

moderate magnitude had mean hydroxyproline deposition of
0.45 lg/cm tubing by post-operative day 7, SD = 0.16 (Goodson
and Hunt, 1982). In the current study, 26 patients per group would
allow detection of a between-groups difference of approximately
half a standard deviation in hydroxyproline, using 80% power
and significance of 0.05. Recruitment ended after complete data
was collected for this sample size for both groups. Fig. 2. Change in perceived stress scores (PSS4) from before the intervention to 7-
day follow-up between groups (mean, SD).

3. Results

3.1. Comparison of groups at baseline

A participant flow diagram is included in Fig. 1. The control and

intervention groups did not differ in regards mean age, gender,
body mass index, time to surgery, or mean perceived stress at
baseline (see Table 1).

3.2. Intervention group compliance with CD listening

Twenty-five of the 30 patients reported listening to the CD prior

to surgery at least twice and up to 11 times (5 did not answer the
question). Three patients reported not having listened to the CD
after surgery, five did not answer, the remaining 22 reported lis-
Fig. 3. There was a significant difference between the intervention and control
tening between one and 15 times. Patients with higher pre-surgical
groups in mean hydroxyproline per centimetre of ePTFE tubing (transformed using
stress reported listening to the CD more often prior to surgery natural log). Each dot represents a patient, and the line represents the mean with
(Spearman’s q = 0.40, p = 0.04). Because there was variability in standard deviation bars.
the number of days to surgery, a ratio was calculated by dividing
the number of times the patient listened to the CD prior to surgery Fig. 2). Within the intervention group, listening to the CD more
by the number of days prior to surgery that the CD was given, often was associated with greater stress reduction, r = 0.45,
which varied between 0.03 and 1.57. Neither this ratio nor the p = 0.026.
number of days prior to surgery were associated with either stress
or hydroxyproline levels. 3.4. Effects of the intervention on hydroxyproline deposition

3.3. Effects of the intervention on perceived stress There were no infections at the ePTFE sites. Hydroxyproline
deposition was not significantly associated with age or BMI or days
Age was related to reduction in stress r = 0.26, p = 0.048, with to surgery, and did not significantly differ by gender (p > 0.05). An
older age related to greater stress reduction. There was no gender independent t-test with Welch’s correction for unequal variance
difference in perceived stress (p > 0.05). There was greater reduc- showed hydroxyproline in lg per cm was higher in the interven-
tion in perceived stress in the intervention group compared with tion group (mean 22.35 lg/cm, SD 17.84) than the control group
the control group from pre-intervention to 7-day follow-up, con- (mean 13.56 lg/cm, SD 6.04) which was significantly different,
trolling for baseline stress and age, F(3, 56) = 4.09, p = 0.048, ad- (t(31) = 2.44, p = 0.02 with a mean difference of 8.80, 95% CI
justed difference between means 1.50, 95% CI 0.02–2.97, (see 1.43–16.16). This difference was maintained when a natural log
transformation was used to normalise the hydroxyproline data
Table 1
(control group mean 2.51, SD 0.43; intervention group mean
Demographic variables in the control and intervention groups.
2.86, SD 0.68; t(43) = 2.23, p = 0.03). Levene’s test indicated un-
Control Intervention Test statistic Significance equal variances so the degrees of freedom were adjusted from 54
Age (years) 50.5 52.1 (18.0) t(58) = 0.38 ns to 43. The difference in means was 0.35 (95% CI 0.66–0.03) and
(15.5) the effect size, Cohen’s d = 0.60 (see Fig. 3). Pre-operative stress,
Gender 9:21 6:24 v2 = 0.80 ns post-operative stress, and change in stress, were not associated
(male:female)
Body mass index 31.41 28.74 (6.99) t(56) = 1.30 ns
with hydroxyproline (p > 0.05).
(8.61)
Perceived stress- 7.57 7.85 (3.77) t(58) = 0.31 ns 4. Discussion
baseline (3.20)
Days, baseline to 20 (27) 15 (15) Z= 0.72 ns
surgery A brief pre-operative psychological intervention decreased
stress and increased hydroxyproline deposition in the wounds of
ns = non-significant.
laparoscopic cholecystectomy patients at a 7-day follow-up
216 E. Broadbent et al. / Brain, Behavior, and Immunity 26 (2012) 212–217
relative to a control group. However, changes in perceived stress
were not significantly correlated with hydroxyproline deposition.
This novel finding extends previous research into the effects of
psychological interventions on post-surgical pain, distress, compli-
cations, and length of stay (Devine, 1992).
The results are in line with previous experimental work on the
effects of psychological interventions on wound healing in a labo-
ratory setting (Weinman et al., 2008). The study extends our
knowledge of how psychological interventions may affect healing
to the stage of collagen synthesis, as previous work has been lim-
ited to subjective evaluation by ultrasound of the wound (Wein-
man et al., 2008) or visual inspection of wound erythema
(Holden-Lund, 1988).
Previous research has shown that levels of hydroxyproline
deposition depend on the type of wound and the site. For example,
hydroxyproline deposition has been shown to be higher in the sur-
gical wound in the groin of hernia patients (4.12 lg/cm) compared
to an experimental standard wound in the upper arm (3.17 lg/cm)
(Jorgensen et al., 2001), so it is difficult to compare results across
studies with different wound types. With that caveat, other re-
search has shown patients undergoing surgery for gastric cancer
who received immunonutrition had higher hydroxyproline levels
(59.7 nmol/cm, range 5–201.8) and fewer wound complications
than a control group (28 nmol/cm, range 5.8–89.6), when the tubes
were placed in the deltoid area (Farreras et al., 2005). Like our
study, there was much greater variability in the intervention group
than the control group, which suggests some patients had a greater
response to the intervention than others. There was a difference of
23 nmol/cm in hydroxyproline between patients with and without
wound healing complications. These results support the clinical
relevance of the observed effect in our study.
This research supports previous proposed models of psycholog-
ical influences on surgical recovery (Kiecolt-Glaser et al., 1998). It
has been shown that patients have elevated anxiety well before
admission and for at least 5 or 6 days following surgery, so psycho-
logical interventions may have potential application both before
and after surgery (Johnston, 1980). The intervention in this study
was designed so that patients could perform relaxation during
pre-operative and post-operative periods. The session with the
psychologist was delivered before surgery, but the use of recorded
instructions allowed patients to repeat the relaxation sessions as
often as required both before and after surgery.
The intervention included deep breathing, muscle relaxation,
and guided imagery, and it is not clear whether one of the compo-
nents was more effective than the others on wound healing. When
introducing the intervention, patients were informed that stress
could affect wound healing and that relaxation could help reduce
stress (this was not told to the control group). This may have cre-
ated an expectancy that the relaxation could improve wound heal-
ing, which may have influenced healing rather than the relaxation
per se.
The lack of an association between change in stress and
hydroxyproline deposition suggests that the effects of the inter-
vention are not simply due to stress reduction. Similarly, stress
reduction did not mediate the effects of emotional disclosure on
wound healing in Weinman et al.’s study (2008), and reduction
in anxiety was not reported to be associated with wound erythema
in Holden-Lund’s surgical study (1988). Other potential mediators
could include affective, cognitive or perceptual changes resulting
from the intervention. A potential mediator not examined in this
study is positive mood. Relaxation has been shown to increase po-
sitive mood states in a student sample (Jain et al., 2007). With re-
gards studies of wound healing, positive affect was not associated
with cytokine levels in blister wounds (Glaser et al., 1999), but trait
positive affect has been shown to buffer the effects of stress on skin
barrier recovery (Robles et al., 2009). Positive affect may also act as
a moderator. A review of the effects of guided imagery, hypnosis
and relaxation on immunity and health suggests that an activated
personality type, which encompasses positive affect and behav-
ioural activity, may be a factor in response to such interventions
(Gruzelier, 2002). Patients with this personality type may have re-
sponded to the relaxation intervention more than others in this
study. Inspection of Fig. 3 suggests that the eight individuals with
the highest levels of hydroxyproline deposition may have particu-
larly benefitted from the intervention, however these individuals
did not systematically differ from the others on stress or any other
variables measured in this study. These findings encourage further
research into the mediators and moderators of relaxation interven-
tions on wound healing.
The research has several strengths and limitations. The require-
ment that the intervention be delivered at least 3 days prior to sur-
gery meant that acute cholecystectomy patients could not be
included. However, previous research has suggested that acute
pre-operative illness may affect hydroxyproline deposition (Good-
son et al., 1987) so limiting the inclusion criteria to non-acute sur-
gery may have helped to control for this potential confound. The
timing of the intervention could be investigated in future research,
with an aim to optimise the practicality of its administration. The
public hospital setting increased the generalisability of the results,
however, it reduced the researchers’ control over the experimental
conditions. For example, some operations were delayed due to
anaesthetist shortages and some patients were lost to the study
due to rescheduling to other hospitals in order to cut waiting lists.
The study was limited by its relatively small sample size; a larger
sample would be required to allow the detection of differences in
wound infection rates.
This research has shown that the effects of psychological inter-
ventions on wound healing in surgery patients can be investigated
using the ePTFE model to assess hydroxyproline deposition, an
objective standardised measure. Previous research in this area
has been criticised for tending to rely on subjective outcome mea-
sures of healing (Walburn et al., 2009). Implications for future re-
search are that this method can offer an objective measure of
healing for psychology studies with surgery patients.
The clinical implications of this work are that brief relaxation
interventions may be beneficial for improving wound healing in
surgical patients. They may be particularly applicable to those
who are at high risk of poor wound healing, with no apparent po-
tential harms, although more research is needed to investigate
whether patients with various degrees of wound healing impair-
ment respond differently to intervention. Future research could
investigate the effects of similar interventions on wound healing
in patients undergoing major surgery, such as bowel resection, so-
lid-organ transplantation and coronary artery bypass grafting.
5. Funding
This study was funded by the Health Research Council of New
Zealand, grant 07/259. The funding source had no role in the study
design, conduction, analysis or publication of results. The research-
ers were independent of the funding source.
Acknowledgments
The authors would like to thank Iris Fontanilla, Natasha Lucas,
Emily Gorman, and Heidi Koschwanez for their assistance in this
study.
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