Received: 19 June 2019 Accepted: 28 July 2019

DOI: 10.1111/iwj.13191

ORIGINAL ARTICLE

Effectiveness and safety of olive oil preparation for topical

use in pressure ulcer prevention: Multicentre, controlled,
randomised, and double-blinded clinical trial

Antonio Díaz-Valenzuela1,2 | Francisco P. García-Fernández3,4 |

PedroJ. Carmona Fernández1,5 | M. Jesús Valle Cañete1 | Pedro L. Pancorbo-Hidalgo2,4

1
Agencia Sanitaria Alto Guadalquivir, Hospital Puente Genil, Puente Genil, Córdoba, Spain
2
Universidad de Jaén, Nursing Department, Jaén, Andalusia, Spain
3
Complejo Hospitalario de Jaén. Care Strategy Unit, Jaén, Spain
4
Spanish National Pressure Ulcer Advisory Group GNEAUPP, Spain
5
Universidad de Córdoba, Nursing Department, Andalusia, Spain

Correspondence
Antonio Díaz-Valenzuela, MSc, PhD,
Hospital Alta Resolución de Puente Genil,
C/Miguel Quintero Merino S/N. Puente
Genil. C.P: 14500, Córdoba, Andalusia,
Spain.
Email: antonioxdixva@gmail.com
Funding information
Fundación Progreso y Salud, Consejería de
Salud de la Junta de Andalucía (Spain),
Grant/Award Number: PI-0772-2010
Abstract
This non-inferiority, multicentre, randomised, controlled, and double-blinded clini-
cal trial compared the therapeutic effectiveness of the topical application of an olive
oil solution with that of a hyperoxygenated fatty acid compound for the prevention
of pressure ulcers in at-risk nursing home residents. The study population com-
prised 571 residents of 23 nursing homes with pressure ulcer risk, randomly
assigned to a hyperoxygenated fatty acid group (n = 288) or olive oil solution
group (n = 283). Both solutions were applied on at-risk skin areas every 12 hours
for 30 days or until pressure ulcer onset. The main outcome variable was the pres-
sure ulcer incidence. The absolute risk difference was estimated (with 95% CI)
using Kaplan-Meier survival and Cox regression curves. The groups did not signifi-
cantly differ in any study variable at baseline. The pressure ulcer incidence was
4.18% in the olive oil group vs 6.57% in the control group, with an incidence differ-
ence of −2.39% (95% CI = −6.40 to 1.56%), which is within the pre-established
non-inferiority margin of ±7%, thus supporting the study hypothesis. We present
the first evidence of the effectiveness and safety of the topical application of olive
oil to prevent pressure ulcers in the institutionalised elderly.

KEYWORDS
hyperoxygenated fatty acids, non-inferiority clinical trial, olive oil, pressure ulcers, skin care

1 | INTRODUCTION quality of life of sufferers,1 the socio-occupational repercus-

sions on carers, and their elevated resource consumption,
Pressure ulcers (PUs) constitute an important problem for besides PU-related law suits.2 A high PU prevalence has
health systems, given their negative impact on the health and been described in hospitals in the United States—ranging

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Int Wound J. 2019;1–9. wileyonlinelibrary.com/journal/iwj 1

2 DÍAZ-VALENZUELA ET AL.
from 6.3 to 17% 3,4 and Europe (18.3%5 and a prevalence of
12.3–13.5% was reported by an international survey of acute
hospitals.6 PU prevalence in Spanish hospitals was found to
be 8.24% in 20097 and 7.87% in 2013.8 Reported PU preva-
lence in nursing home residents has ranged from 9% in Ire-
land9 to 10% in Japan,10 11% in the United States,11 13.4%
in Spain,8 and 16.9% in Jordan.12
PU treatment costs vary among countries but generally
represent a considerable burden for health systems. They
have been estimated at £1.4 to £2.1 million (€1.74-2.61 mil-
lion) per year in the United Kingdom,13 with costs per case
ranging from £1214 (€1510) for category I ulcers to £14 108
(€17 551) for those in category IV.14 The cost per hos-
pitalised patient was reported to range from $7276 to
$10 054 (€5550-€7674). In the United States,15 while the
total annual cost to the Spanish health system was estimated
at €461 million, with costs per case ranging from €58.3 for
category I PUs to €4868 for those in category IV.16
Current clinical practice guidelines for PU prevention
include the assessment and care of skin.17-20 Dry skin is con-
sidered a significant independent risk factor for PU onset,17
while smooth skin is more resistant to external pressures.
Recommended skincare measures include the topical appli-
cation of emollients/hydrating products (skin moisturisers),
hyperoxygenated fatty acids (HOFAs), or silicon creams.19
The benefits of the topical administration of essential
fatty acids for preventing and treating different skin lesions
are well documented. It has been found to improve skin
hydration and elasticity and to prevent skin breakage in the
cases of nutritional deficiency.21 The most widely used
essential fatty acids are HOFAs, which have been reported
to increase blood microcirculation, enhance epidermal cell
renewal, repair skin trophicity, improve skin hydration,
avoid skin dryness, protect against friction,22,23 and increase
transcutaneous oxygen pressure.24
The first studies with hyperoxygenated fatty acids were
carried out in France in 1987 and are observational descrip-
tive studies.25 In 1998, Colin et al revealed that the transcu-
taneous oxygen pressure values decreased significantly
when the patient applied pressure to the sacral area before
the test product was applied, whereas no difference in oxy-
gen pressure values was noted after application of the test
product.26 The hyperoxygenated fatty acids began as legally
produced and commercialised products in 1995, in Spain
they were first used in 1996 for pressure ulcer prevention.27
In 2001, Gallart et al demonstrated in their experimental
study that the incidence of pressure sores was lower in the
group receiving preventive treatment with HOFAs, thereby
indicating that this therapy may be useful in the prevention
of the development of pressure ulcers in hospitalised
patients.28 Although there were not many clinical studies
until 2009, the HOFAs could be an effective preventive
Key Messages
• clinical guidelines describe skincare as a basic
pressure ulcer prevention measure in the elderly
• application of a hyperoxygenated fatty acid solu-
tion on at-risk skin areas is an effective pressure
ulcer prevention treatment
• the study goal was to test whether a new topical
olive oil preparation is as effective as hyper-
oxygenated fatty acid solution for preventing
pressure ulcers in nursing home residents
• pressure ulcer incidence was not higher in resi-
dents treated with olive oil preparation than in
those treated with hyperoxygenated fatty acids,
indicating that the two products are equally effec-
tive for pressure ulcer prevention
• topical olive oil preparation can be considered as
a useful and effective option for preventing pres-
sure ulcers in the elderly
measure in treatment of pressure ulcers.29 As of 2009, there
is an increase in experimental studies with HOFAs in pre-
vention of pressure ulcers with higher quality evidence,
which suggests that it is adequate to support a particular rec-
ommendation in hospital protocols, clinical protocols, and
clinical practice guidelines in the prevention of the pressure
ulcers and the care of skin perilesional. 30,31
Various types of oils have been used for skincare in
patients,32 including olive oil, which is rich in essential fatty
acids such as oleic and linoleic acids, phytosterols, and squa-
lene. These molecules endow olive oil with exceptional
skincare properties, improving hydration and exerting a pro-
tective, emollient, and regenerating action.33 Experimental
studies have demonstrated that olive oil exerts beneficial
effects on the skin34 and promotes ulcer healing.35-37 Never-
theless, there has been no research on the efficacy of topical
olive oil application for PU prevention.
The application of HOFAs is recommended in Spanish
clinical practice guidelines for PU prevention38,39; therefore,
it would be ethically unacceptable to study a control group
receiving no treatment or placebo. We designed a non-
inferiority study with active control40 to test our hypothesis
that the incidence of PUs would not be higher among resi-
dents when topically treated with an olive oil solution than
among those treated with HOFAs, establishing a non-
inferiority (delta) margin of 7%.
The study objectives were as follows: (a) to compare the
effectiveness of the topical application of olive oil vs
DÍAZ-VALENZUELA ET AL.
HOFAs to prevent PUs in elderly residents at risk and (b) to
compare the safety (adverse effects) of the two treatments.
2 | METHODS
A non-inferiority, multicentre, randomised, controlled,
double-blinded clinical trial was conducted. The study popu-
lation was recruited from among nursing home residents at
risk of PU onset (Braden Scale score <14 points) in the
province of Cordoba (southern Spain). Exclusion criteria
were as follows: the presence of PUs (any category), non-
healed skin lesion, or active vascular disease, or expected
failure to complete the follow-up study (eg, due to very poor
health status or planned transfer to another centre).
Estimation of the sample size for a non-inferiority trial
was based on data from previous studies on HOFA's use in
PU prevention.41,42 Considering a PU frequency in nursing
homes of 13%,8 the noninferiority (delta) margin was
established at 7%. For a power of 80% and an alpha error of
5%, 267 subjects were required per treatment group, and this
number was increased by 5% to cover losses to the follow-
up, yielding a planned total sample size of 560.
Systematic and consecutive sampling was conducted
between January 2011 and October 2014 in 23 participating
nursing homes, including all residents who met the eligibil-
ity criteria and agreed to participate. The nursing homes
were chosen that were comparable in terms of patients cared
for and the consistency of education and training of the staff.
Participants were randomly assigned (1:1) to the olive oil or
HOFA group using a list of random numbers generated
using the Epidat 3.1 software.
2.1 | Intervention
An extra-virgin olive oil solution (Oleicopiel, Potosi-10,
Orcera, Jaen, Spain) or HOFA solution (Mepentol, Bama-
Geve, Barcelona, Spain) was applied to PU-risk areas in the
respective groups in addition to usual care procedures. To
ensure consistent dosing and spreading of agent, the attend-
ing nurses applied two sprays to each risk area every
12 hours (at morning wash and after evening meal), using an
atomiser and their fingers to gently spread the product with-
out rubbing, following published recommendations.41 One
spray delivers 0.2 mL. Each product was packed by a phar-
maceutical company not otherwise involved in the study in
identical packages with no external identification except for
a code number, which was only revealed at the end of the
study period in each home. The study was double-blinded,
and the residents, the nurses applying the treatment, and the
researchers who collected the data did not know which of
the two products was used.
3
2.2 | Variables
The main outcome variable was the onset of any category of
PU, with category I being non-blanchable erythema.17 PU
diagnosis was conducted as recommended using both finger
and transparent disk methods.43
Treatment safety was defined by the absence of local
adverse effects (eg, rash, itching, stinging, or pain). Data
were also gathered on demographic characteristics, risk fac-
tors, other prevention methods, resident's usual position (sea-
ted, in bed, or mobile), localisation of risk areas, the
presence of incontinence, nutritional intake, and time inter-
val before any PU onset.
2.3 | Data gathering method
Each study participant was treated and followed up for
30 days or until PU onset, if sooner. In a first visit to each
home, two researchers (ADV, MJVC) conducted skin
assessments and evaluated the PU risk using the Braden
scale (baseline values). The same researchers repeated the
skin assessments every 7 days. The skin condition of the res-
idents was also evaluated twice daily by attending nurses
before administering the treatment. All the areas of skin at
risk were looked at and any skin tears in the data gathering
form were recorded.
2.4 | Ethical aspects
The study was approved by the Ethics and Clinical Trial
Committee of the “Alto Guadalquivir” Health Agency in
July 2010 and was conducted in accordance with the Decla-
ration of Helsinki and Spanish legislation on biomedical
research. The patients and/or their relatives signed informed
consent before the study.
2.5 | Data analysis
Absolute frequencies and percentages were calculated for cate-
gorical variables and means with SD for quantitative variables.
The baseline characteristics of the two groups were compared
using the Student's t test for continuous variables and the chi-
square test for categorical variables. The incidence and the inci-
dence density per 1000 at-risk resident-days were calculated.
Kaplan-Meier and Cox regression curves were constructed for
survival analysis in each group. The absolute risk reduction
and relative risk were also estimated. SPSS 16 was used for the
statistical analysis; P < .05 was considered significant.
The non-inferiority hypothesis was tested by establishing
the incidence difference between the groups, calculating the
95% confidence interval (CI) with the Newcombe method to
estimate the intervals for the difference between independent
proportions.44,45 In order to accept or reject the hypothesis,
4 DÍAZ-VALENZUELA ET AL.

the lower limit of 95% CI was compared with the pre-
established delta margin of ±7%, which is sufficiently strict
according to published recommendations.46
Per-protocol analysis was carried out to test the hypothe-
sis, only including data for patients who completed treatment
and were not lost to the follow-up, because this is a more
robust approach against possible biases in non-inferiority
clinical trials. Intention-to-treat analysis was also conducted
(including all enrolled residents regardless of study comple-
tion) in order to examine the equivalence of the results of
the two analyses, as recommended by the Committee for
Proprietary Medicinal Products (CPMP) for this type of
study.46 An intermediate analysis (continuation trial) was
performed after the treatment and follow-up of around half
of the planned number of participants. Study design and
reporting followed the recommendations of the CONSORT
2010 guidelines.47
3 | RESULTS
The study sample included 571 people from 23 nursing
homes in the Cordoba province (southern Spain). There
were 34 cases lost to the follow-up; therefore, complete data
were gathered for 537 residents (274 in the HOFA group
and 263 in olive oil group) (Figure 1).
3.1 | Sample characteristics
Table 1 lists the baseline characteristics of residents in the
two groups. Participants were typically elderly patients,
mainly females, confined to armchair or bed, with a high
risk of developing PU and suffering from mixed inconti-
nence. No significant differences were found between the
groups in any study variables at baseline.
3.2 | PU incidence
A total of 29 patients developed PUs during follow-up, that
is, a global incidence of 5.4% (95% CI 3.79-7.65%). In the
olive oil group, 11 residents developed PUs (all category I),
with an incidence of 4.18% (95% CI 2.35-7.33%), 6 (55%)
of the PUs were on sacrum, 4 (36%) were on heel, and
1 (9%) was on gluteus. In the HOFA group, 18 residents
developed PUs (all category I), an incidence of 6.57% (95%
CI 4.20-10.14%): 11 (61%) of the PUs were on sacrum,
6 (33%) on heel, and 1 (6%) on malleolus.

Residents assessed for elegibilty

(n= 707)

Excluded: 136
Reasons: (Do not fit

Refuse= 14)

Randomized (n= 571)

Allocated to Olive Oil group (n= 283) Allocated to HOFA group (n= 288)

Lost to folow-up Lost to follow-up

Adverse effect: 0 Adverse effect: 1
Data record lost: 0 Data record lost: 1
Withdrawn: 2 Withdrawn: 1
Death: 8 Death: 3
Move to other centre: 4 Move to other centre: 4
Product bottle lost: 3 Product bottle lost: 2
Worsening.: 3 Worsening.: 2

Analized (per protocol) (n= 263) Analized (per protcol) (n= 274)
FIGURE 1 Study flow chart
DÍAZ-VALENZUELA ET AL. 5

TABLE 1 Characteristics of the nursing home residents

Olive oil group N = 283 HOFA group N = 288 Test and significance
Age (years) average (SD) 84.37 (8.15) 83.1 (8.99) t = 1.757; P = .079
Braden Scale score average (SD) 12.05 (1.43) 12.06 (1.33) t = −0.143; P = .88
Gender
Male 53 (18.7%) 120 (41.7%) Chi2 = 3.637
Female 230 (81.3%) 168 (58.3%) P = 0.057
Pressure ulcer risk
Medium (Braden <14 >12) 116 (41%) 120 (41.7%) Chi2 = 0.027;
High (Braden <12) 167 (59%) 168 (58.3%) P = 0.869
Incontinence
Urinary 26 (9.2%) 33 (11.5%) Chi2 = 0.795;
Urinary and faecal 257 (90.8%) 255 (88.5%) P = 0.373
Position
Bedridden 25 (8.8%) 21 (7.3%) Chi2 = 0.458;
Bed and chair/wheelchair 258 (91.2% 267 (92.7%) P = 0.498
Regular repositioning in bed
Yes 142 (50.2%) 135 (46.9%) Chi2 = 0.623;
No 141 (49.8%) 153 (53.1%) P = 0.430
Local pressure relief device
Yes 107 (37.8%) 121 (42%) Chi2 = 1.052;
No 176 (62.2%) 167 (58%) P = 0.305
Pressure relief mattresses
Yes 137 (48.4%) 125 (43.4%) Chi2 = 1.441;
No 146 (51.6%) 163 (56.6%) P = 0.230
Nutritional supplementation
Yes 37 (13.1%) 27 (9.4%) Chi2 = 1.963;
No 246 (86.9%) 261 (90.6%) P = 0.161
Previously HOFA treated
Yes 35 (12.4%) 34 (11.8%) Chi2 = 0.042;
No 248 (87.6%) 254 (88.2%) P = 0.837

Abbreviation: HOFA, hyperoxygenated fatty acids.

TABLE 2 Pressure ulcers incidence in nursing homes residents treated with topical olive oil or with hyperoxygenated fatty acids

PU incidence
Olive oil PU/totala HOFA PU/total difference (95% CI) ARR (95% CI) RR 4 (95% CI)
Per-protocol analysis 11/263 18/274 2.39% (−1.56 to 6.40%) −0.024 (−2.45 to 2.40) 0.64 (0.30 to 1.32)
Intention-to-treat 11/283 18/288 2.36% (−1.34 to 6.18%) −0.024 (−2.39 to 2.38) 0.62 (0.29 to 1.29)
analysis

Abbreviations: ARR, absolute risk reduction; HOFA, hyperoxygenated fatty acids; RR, relative risk.
a
Residents with pressure ulcers/total number of treated residents.

PU incidence density was 1.40 per 1000 at-risk inferiority margin of 7% in either of the analyses, thus
resident-days in the olive oil group vs 2.22 per 1000 at- supporting the study hypothesis. In addition, the ARR and
risk resident-days in the HOFA group. Data in Table 2 RR values obtained support the absence of differences
show that the incidence difference did not exceed the non- between the products.
6 DÍAZ-VALENZUELA ET AL.
FIGURE 2 Kaplan-Meyer survival analysis
3.3 | Survival analysis
Figure 2 depicts the Kaplan-Meier survival curves for each
group, considering the time interval before PU onset (sur-
vival) of each resident. No differences in survival were
found between the groups (Mantel-Cox log-rank test 1.512;
df = 1; P = 0.21).
3.4 | Adverse effects
No adverse effects were observed in the olive oil group. One
adverse effect was recorded (skin rash and itching) in the
HOFA group, which disappeared after cessation of the
treatment.
4 | DISCUSSI ON
In this study, in elderly nursing home residents at risk of PU
development, the topical application of an olive oil prepara-
tion proved to be at least as effective as the application of a
HOFA solution for PU prevention, supporting the initial
non-inferiority hypothesis. The absolute PU incidence differ-
ence (with 95% CI) between the olive oil and HOFA groups
was within the equivalence margin of ±7% and did not differ
according to the data analysis approach (per-protocol or
intention-to-treat analysis). This margin is sufficiently strict
to guarantee true product equivalence and is closer than the
15% margin established by Candela-Zamora et al in their
comparison of two different HOFA products.23 Our final
results corroborate the preliminary data obtained in the
intermediate analysis.48 They are also in agreement with the
findings of another Spanish research group, who found that
an olive oil product and HOFA product were equally effec-
tive to prevent PUs in 831 at-risk patients receiving home
care in the province of Malaga.49
This study did not include a placebo group on ethical
grounds (see Introduction), but the findings can be indirectly
compared with the results for placebo groups in previous
studies of HOFA products. The PU incidence of 4.18% in
our olive oil group was lower than the incidence of 17.37%
in the placebo group studied by Torra i Bou et al42 and that
of 35% in the group studied by Gallart et al48 and was even
below the lower 95% CI limit of 27% in the latter study.
Although these comparisons are indirect, they suggest that
application of the olive oil solution may be more effective
for PU prevention in comparison to placebo or non-active
products.
The present results demonstrate that the therapeutic
safety profile of topical treatment with olive oil is equivalent
to that of HOFA treatments. No adverse effects were
observed in our olive oil group, similar to findings of other
studies on the topical application of olive oil on healthy
skin49 and diabetic foot ulcers.36,37 Olive oil can therefore
be considered a safe product for topical application.
The mechanisms underlying the protective effect of vir-
gin olive oil against PU development are not fully under-
stood, but they may involve an anti-inflammatory action and
a positive effect on local blood flow. Recent studies identi-
fied various compounds with anti-inflammatory activity in
olive oil, including polyphenols and oleocanthal.50-52
In Spain, HOFAs are more frequently applied as a PU
preventive measure in hospitals (42.9%) than in nursing
homes (18.2%), where other products are widely used. These
include moisturising lotions, creams, and different types of
oil whose effectiveness has not been verified.53 In fact, only
12.3% of the present at-risk residents had been treated with
HOFAs before the study. The availability of a spray-
delivered extra-virgin olive oil preparation as another
evidence-supported option may therefore contribute to
expanding the application of PU preventive measures in
these centres.
The topical application of the olive oil preparation pro-
vides optimal hydration and elasticity of the skin, preventing
skin peeling or skin tears in people at risk. It has protective,
restorative and regenerating actions while providing elastic-
ity, thus maintaining the integrity and tone the skin.
5 | LIMITATIONS
It proved necessary to include numerous nursing homes to
reach the estimated sample size, but care was taken to mini-
mise variability through the rigorous application of the same
DÍAZ-VALENZUELA ET AL.
standard protocol at all centres, which received regular visits
by the research team. Moreover, the statistical power of our
study allowed conclusive results to obtained, unlike in some
similar studies.23
6 | CONCLUSI ON S
This olive oil preparation is not less effective than HOFAs
as a topical preventive treatment against pressure ulcers in
at-risk residents of nursing homes and is not associated with
any adverse effects. It offers a safe and effective therapeutic
option for PU prevention.
C ON F L I C T O F IN T E RE S T
No conflict of interest has been declared by the authors.
ACKNOWLEDGEMENTS
We are grateful to the nursing homes and nursing staff
involved and to all participating residents and relatives,
without whose help this study would not have been possible.
O R C ID
Antonio Díaz-Valenzuela https://orcid.org/0000-0002-
5878-2274
Pedro L. Pancorbo-Hidalgo https://orcid.org/0000-0002-
0092-6095
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How to cite this article: Díaz-Valenzuela A, García-
Fernández FP, Carmona Fernández P, Valle
Cañete MJ, Pancorbo-Hidalgo PL. Effectiveness and
safety of olive oil preparation for topical use in
pressure ulcer prevention: Multicentre, controlled,
randomised, and double-blinded clinical trial. Int
Wound J. 2019;1–9. https://doi.org/10.1111/iwj.
13191