Journal of Herbal Medicine 21 (2020) 100326

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Journal of Herbal Medicine

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

Research paper

The effects of Citrus aurantium aroma on anxiety and fatigue in patients with T
acute myocardial infarction: A two-center, randomized, controlled trial
Razieh Shirzadegana, Mohammad Gholamib,*, Shirin Hasanvandc, Afsaneh Beiranvanda
a
School of Nursing& Midwifery, Lorestan University of Medical Sciences, Khorramabad, Iran
b
Social Determinants of Health Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
c
School of Nursing & Midwifery, Lorestan University of Medical Sciences, Khorramabad, Iran

A R T I C LE I N FO A B S T R A C T

Keywords: Objectives: Anxiety and fatigue affect the clinical course and quality of life in patients with Acute Myocardial
Acute myocardial infarction Infarction (AMI). Complementary therapies are recommended for managing these symptoms. The present study
Anxiety was conducted to evaluate the effects of Citrus aurantium aroma on anxiety and fatigue in patients with AMI
Fatigue admitted to coronary care units.
Citrus aurantium
Design: In this triple-blind, randomized, controlled, clinical trial, 80 patients with AMI were allocated to a Citrus
Aromatherapy
aurantium group and a placebo group (n = 40 per group) through stratified randomized blocks. From their
Cardiac care unit
second day of hospitalization and for two consecutive days, the subjects in the experimental and control groups
inhaled three drops of Citrus aurantium essential oil or the placebo using absorbable patches connected to the
inside of oxygen masks for 20 min. Anxiety and fatigue were measured in the patients using the Spielberger
State-Trait Anxiety Inventory (STAI) and the Multidimensional Fatigue Inventory (MFI-20) 30 min before and 15
and 30 min after the interventions.
Results: There was a statistically significant difference between the Citrus aurantium and placebo groups con-
cerning the mean changes in their anxiety and fatigue scores (P < 0.001Citrus aurantium essential oil reduced
anxiety and fatigue on all the four measurement occasions after the intervention compared to before.
Conclusion: Aromatherapy with Citrus aurantium can be used as part of holistic care for managing the symptoms
of AMI by nurses.

1. Introduction
Acute Myocardial Infarction (AMI), which may be the by-product of
an industrial life, is one of the main causes of mortality in human so-
cieties that requires emergency treatment (Mosa Farkhani et al., 2014).
One in every 25 people dies of AMI in the first two years after hospital
discharge (Khosravi and Ebrahimi, 2008). After AMI, patients experi-
ence multiple physical and mental problems, such as cardiac dys-
rhythmias, decreased cardiac output, depression (Najafi et al., 2014),
reduced self-esteem, fatigue and anxiety (Shokri et al., 2013). The in-
cidence of anxiety and fatigue symptoms is common after AMI (Jeff
et al., 2008). According to a review of the literature, 50 % of patients
with AMI suffer from anxiety (Nematollahi et al., 2017) and 35 % from
fatigue (Akbari et al., 2008).
Anxiety is a multifactorial phenomenon in hospitalized patients
with AMI that is associated with separation from the family, an un-
familiar environment, fear of strangers (Aisagbonhi et al., 2011), fear of
the disease or another heart attack (Nematollahi et al., 2017), en-
vironmental stimuli, frequent care measures (Yeon Cho et al., 2013),
sleep disorders, pain and discomfort (Babaei et al., 2011), lack of
awareness about diagnostic and therapeutic procedures, treatment ex-
penses, concerns about self-care and the ability to return to work, and
the risk of death (Devon et al., 2011). By its contribution to the release
of catecholamine, anxiety results in impaired cardiac function, in-
creased blood pressure and heart rate, dysrhythmia, pain aggravation,
ischemia and heart failure. Anxiety is also associated with an increase
in the need for mechanical ventilation and hospital stay and thereby
reduces the quality of life and may even cause death (Huffman et al.,
2008; Nematollahi et al., 2017; Ulvik et al., 2008). A study by Watkins
et al. showed that anxiety increases the risk of mortality after discharge
in cardiac patients (Watkins et al., 2013).
Fatigue is another discomforting and irritating symptom of AMI and
the most common prodromal and acute symptom of this disease. In one
study, 70 % of the patients experienced marked symptoms two days

⁎
Corresponding author.
E-mail addresses: Mohammad13565@yahoo.com, gholami.m@lums.ac.ir (M. Gholami).

https://doi.org/10.1016/j.hermed.2019.100326
Received 25 September 2018; Received in revised form 23 May 2019; Accepted 16 December 2019
Available online 23 December 2019
2210-8033/ © 2019 Elsevier GmbH. All rights reserved.
R. Shirzadegan, et al.
before the onset of AMI (Brink and Alsen, 2014; Moghadam et al.,
2008), and according to other evidence, some experienced symptoms
two to 16 weeks (Brink and Alsen, 2014) and some two to three years
(Hugh, 2016) before the incident, and the symptom continued until
their hospital admission (Fennessy et al., 2010).
As an adaptive response to stressors, fatigue reduces the ability to
adapt to stressors and therefore turns into exhaustion if remaining
persistent (Alsen and Eriksson, 2015). Fatigue is linked to disorders
such as poor cardiac function, daily sleepiness, comorbid diseases, an-
emia, low social support and depression (Barton Crane et al., 2016).
Relieving the acute symptoms of patients suffering from AMI should
be a priority of nurses in intensive care units. A reduction in anxiety in
patients admitted to Cardiac Care Units (CCUs) requires independent
interventions on the part of nurses with the goal of enhancing the pa-
tients’ quality of life (Haeng Hura et al., 2014; Yeon Cho et al., 2013).
Anxiety and fatigue may be ameliorated to some extent by medic-
inal interventions, but previous research has shown links between
pharmacological interventions aimed at reducing anxiety and fatigue,
including mild tranquilizers, benzodiazepines, anxiolytics and (Babar
et al., 2015) anti-fatigue drugs, and complications such as drowsiness,
confusion, agitation, asthenia and depression (Shirzadegan et al.,
2017).
Given the mechanism whereby anxiety and fatigue operates and the
role of inflammatory agents in cases where the patient’s adherence to
medications is far from satisfactory, researchers have proposed re-
laxation techniques to help curb the production of inflammatory agents
(Babaei et al., 2011; Bagheri nasami et al., 2011; Devon et al., 2011;
Shirzadegan et al., 2017). Aromatherapy with medicinal herbs is one of
these recommended complementary therapies (Yeon Cho et al., 2013;
Nematollahi et al., 2017).
Aromatherapy with Citrus aurantium as a sedative and soporific herb
has been practiced in Iranian traditional medicine (Fink et al., 2010;
Nematollahi et al., 2017) and is considered beneficial in the traditional
treatment of depression, stress colic, stress dyspepsia, colitis and skin
conditions (Alsen and Brink, 2016; Babar et al., 2015;
Fredriksson‐Larsson et al., 2015; Najafi et al., 2010). The chemical
composition of C. aurantium is responsible for its health-promoting ef-
fects and includes vitamins, minerals, phenolic compounds and terpe-
noids. Among the diverse chemical components of C. aurantium, fla-
vonoids have been recognized as an important phenolic compound due
to their physiological and pharmacological role and health benefits
(Khan et al., 2017; Nabavi et al., 2018; Marya et al., 2018). Citrus
aurantium has terpene (Alsen and Brink, 2016) and also anti-fatigue
properties in addition to an agreeable aroma (Akhlaghi et al., 2011).
Zeighami et al., 2014 & Fink et al., 2010 reported the effectiveness of
this fruit in augmenting sleep quality among patients with cardiovas-
cular conditions in the CCU. Aromatherapy is, however, not widely
known to have major positive therapeutic properties. In a study by
Mohseni on patients with AMI, aromatherapy with mint essence failed
to have any positive impact on the patients’ vital signs and cardiac
arrhythmias (Mohsenifard et al., 2015). The controversies surrounding
aromatherapy may be due to the current paucity of scientific evidence
vis-à-vis its efficacy and safety (Haeng Hur et al., 2014).
Considering the substantial evidence demonstrating the increasing
prevalence of AMI and the presence of anxiety and fatigue in its pa-
tients, and also the many side-effects of pharmacotherapy
(Fredriksson‐Larsson et al., 2015) the present multicenter, randomized,
controlled trial was conducted to investigate the effects of Citrus aur-
antium aroma on anxiety and fatigue among patients with AMI. Ar-
omatherapy was chosen from the available non-pharmaceutical mod-
alities due to its user-friendliness for nurses, acceptability by patients
and inexpensiveness. To the best of the researchers’ knowledge, the
present study is the first of its kind to examine the efficacy of Citrus
aurantium in relieving anxiety and fatigue in patients suffering from
AMI.
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Journal of Herbal Medicine 21 (2020) 100326
2. Objectives
This article presents some of the results of a larger randomized
clinical trial conducted on the effects of Citrus aurantium on anxiety and
fatigue in patients with AMI hospitalized in CCUs.
3. Methods
3.1. Study design
This triple-blind, randomized, clinical trial was conducted in two
groups.
3.2. Participants
Eighty patients with AMI were randomly and sequentially selected
from December 2016 to May 2017 and allocated to the experimental
and placebo groups using stratified random sampling with a block de-
sign to ensure their homogeneity in terms of age and gender.
3.3. The inclusion criteria
The inclusion criteria consisted of age between 18 and 60 years,
definitive diagnosis of AMI by a specialist based on the electro-
cardiography, no history of allergic rhinitis, eczema or known re-
spiratory disorders such as asthma or chronic obstructive pulmonary
disease, no uncontrolled medical/chronic disorders, orientation to time,
place and self, no known mental illness, no cardiopulmonary re-
suscitation upon entering the emergency room, no history of head
trauma or seizures, no smell and taste disorders, no drug addiction, no
disease disrupting sleep, such as migraine, rheumatoid arthritis and
nocturnal respiratory disorders, stable vital signs, no pain reported
during the interview and while filling out the questionnaire, no allergy
to the used aromas, not using benzodiazepines, analgesics or anxiolytics
for at least ten hours prior to the intervention, no history of using other
complementary and alternative therapies at least one week before the
intervention, obtaining a score above 20 on the Spielberger State-Trait
Anxiety Inventory (STAI) and a score of 20–100 on the
Multidimensional Fatigue Inventory (MFI-20).
3.4. The exclusion criteria
The exclusion criteria consisted of unwillingness to continue parti-
cipation in the study, decreased consciousness level during the inter-
vention, cardiac shock, cardiopulmonary arrest or MI during the in-
tervention, cardiac dysrhythmia, cardiogenic shock, ventricular
fibrillation, using benzodiazepines, analgesics or anxiolytics, allergic-
respiratory problems such as dysrhythmia and hemodynamic in-
stability.
3.5. Blinding
The researcher who collected the data before and after ar-
omatherapy and the patients were blind to the group allocations. The
aroma vial was covered with a black strip and the type of aroma was
unknown to the healthcare provider. The treatment (aromatherapy)
and evaluations were performed by a specialist cardiac nurse. The ex-
perimental and control groups received aromatherapy at different times
and locations. The researcher who entered the data into the software
and analyzed it was also blind to the group allocations.
3.6. Randomization
The patients were randomly assigned to an experimental group
(n = 40) receiving C. aurantium aroma and a control group (n = 40)
receiving a placebo. Computer-generated numbers were used to
R. Shirzadegan, et al.
randomize the patients. An independent person not involved in the
study performed the computer randomization.
3.7. Clinical intervention
The C. aurantium distillated water used in this study was produced
by Adonis Gol Darou Co. in Iran. The essences consisted of pure oil
diluted with 10 % primrose oil to a final concentration of 100 % and
analyzed using Cooper Chromatography J. C. The constituents of C.
aurantium are Limonene, Myrcene, Camphene, Pinene, Ocimene and
Cymene.
The hemodynamically-stable subjects in the experimental group
(n = 40) received C. aurantium aroma on the second and third days of
their CCU stay and the aromatherapy continued until the third and
fourth days of their stay. The subjects in the placebo group (n = 40)
received sunflower oil 12 %. The olfactory nerve in the experimental
group was checked before the intervention by placing a dark glass
container with rosewater essential oil under the subjects’ nostrils and
asking them to report the aroma, and they were excluded from the
study if unable to perform this task.
In the experimental group, a trained nurse poured three drops of C.
aurantium essential oil on absorbable patches connected to the inside of
the patients’ oxygen masks and they were asked to inhale the aroma for
20 min. Aromatherapy was performed for 20 min twice daily (10–11
AM and 6–7 PM) on two consecutive days, the timing and manner of the
administration of the aroma were based on the results of previous
studies (Shirzadegan et al., 2017). For the patients in the placebo group,
three drops of sunflower oil were poured on absorbable patches con-
nected to the inside of their oxygen masks twice daily (10–11 AM and
6–7 PM) on two consecutive days, and the patients were asked to inhale
the aroma for 20 min. Over the course of the study, symptoms such as
dyspnea, chest pain, dysrhythmia and changes in vital signs were
checked by the researcher using daily notes. None of the patients
manifested these symptoms during the study period. The levels of an-
xiety and fatigue were evaluated in the patients 30 min before and then
15 and 30 min after the intervention using two relevant questionnaires
by a researcher blind to the group allocations (Fig. 1).
3.8. Measurements
The data collection tools consisted of a demographic information
form, the STAI and the MFI-20.
3.8.1. Demographic data
The demographic questionnaire contained items on age, gender,
education, place of residence, marital status, history of MI in first-de-
gree relatives, use of prescribed tranquilizers, smoking and known
underlying diseases.
3.8.2. Anxiety
The STAI was used to measure anxiety. This questionnaire consists
of 20 items scored on a 4-point Likert scale (1= almost never to 4=
almost always). Items 1, 2, 5, 8, 10, 11, 15, 16, 19 and 20 are reverse-
scored. The total score ranges from 20 to 80, with scores 21–39 de-
noting mild anxiety, 40–59 moderate anxiety and 60–80 severe anxiety.
The score of 20 indicates the absence of anxiety and higher scores re-
present higher anxiety levels (Hugh, 2016). In Iran, the reliability of the
STAI was estimated at 0.93 (Cronbach’s alpha) for the state anxiety
subscale and its concurrent validity was confirmed by clinical inter-
views and comparisons with a number of other anxiety scales (Fink
et al., 2010). In the present study, the test-retest reliability of this in-
strument was 0.84. The face and content validities of the questionnaire
were evaluated by ten faculty members of universities of medical sci-
ences and the questionnaire was used only after the application of their
comments.
3
Journal of Herbal Medicine 21 (2020) 100326
3.8.3. Fatigue
The intensity of fatigue was measured with the MFI-20, which is a
questionnaire for the examination of fatigue in five dimensions: (1) The
individual’s general fatigue or general performance during the day; (2)
Physical fatigue, which entails a physical sensation directly linked to
fatigue; (3) Mental fatigue, which denotes the presence of cognitive
symptoms in the individual; (4) Reduced activity as a result of fatigue;
and (5) Diminished motivation, which signifies a reduction in or the
absence of motivation to start any activity. Each dimension consists of
four items that are answered based on a 5-point Likert scale from “Yes,
completely true” to “No, completely untrue”. Each dimension is scored
from 1 to 5, and the scoring is reversed in some dimensions. The total
score for each dimension ranges from 4 to 20, and the total fatigue score
ranges from 20–100 and is calculated by adding up the scores of all the
dimensions. A higher score implies a higher fatigue level (Alsen and
Brink, 2016; Alsen and Eriksson, 2015; Fredriksson‐Larsson et al.,
2015). The MFI-20 was translated into Persian by Najafi Mehri et al.,
2010 and its content validity was qualitatively verified. The reliability
of the MFI-20 was examined using the internal consistency method and
was approved with a Cronbach’s alpha of 0.89 (Najafi Mehri et al.,
2010). In the present study, the reliability of this questionnaire was
determined through the test-retest method with a correlation coeffi-
cient of 0.92. The qualitative face and content validities of the MFI-20
were determined through its distribution among ten faculty members of
medical universities and the questionnaire was used only after the ap-
plication of their comments.
3.8.4. Depression
Depression was considered a confounding variable in this study. The
patients’ depression scores were measured using the Beck Depression
Inventory (BDI) concurrently with the collection of the baseline data.
The BDI encompasses 21 items, each with four statements describing a
mood in the respondent and scored from 0 to 3 based on a Likert scale.
The score obtained on the BDI ranges from 1 to 40. A score of 1–10 is
considered normal, while a score of 11–16 denotes minimal depression,
17–20 a need for psychological consultation, 21–30 moderate depres-
sion, 31–40 severe depression and above 40 excessive depression
(Najafi et al., 2018; Gary et al., 2018).
3.9. Research data analysis and evaluation techniques
The data was analyzed in SPSS-20 and descriptive statistics were
used to describe the data in the groups, including central tendency,
measures, dispersion indices and frequency distributions. The χ2 test
was applied to compare the groups with regard to the qualitative
variables, and the Kolmogorov-Smirnov test was employed to in-
vestigate the normality of the continuous variables. After the normality
assumption was confirmed, the ANOVA was used to compare the mean
of the two groups. Considering the internal correlation between the two
dependent variables anxiety and fatigue, the multivariate repeated
measures ANOVA was used to compare the changes in the anxiety and
fatigue scores by taking age and the depression score as the covariates.
The results were reported at a significance level of 5 %.
3.10. Sample size calculation
Sample size was calculated based on type one (α) and type two
errors (β) as 0.05 and 0.20 (power = 80 %) respectively. Based on the
previous study (Najafi et al., 2014) considering 7.1 as standard devia-
tion (SD) and 9.1 as the difference in mean or effect size (d) of anxiety
level, the main outcome.
3.11. Ethical considerations
The protocol of the study was approved by the Ethics Committee of
Lorestan University of Medical Sciences in accordance with the
R. Shirzadegan, et al. Journal of Herbal Medicine 21 (2020) 100326

Fig. 1. CONSORT diagram of the study.

Declaration of Helsinki (LUMS.REC.1395.160) and the project was re- Table 1

gistered at the Iranian Registry of Clinical Trials The demographic and basic information by group.
(IRCT2017011824080N10). Written informed consent was obtained Variable Citrus aurantium Placebo P-value
from all the subjects prior to beginning the study. (n = 40) (n = 40)
Mean ± SD Mean ± SD
N (%) N (%)
4. Results
Education
Illiterate 26 (65 %) 21 (52.5 %) 0.71
4.1. The baseline characteristics and homogeneity of the two groups High school diploma 11 (27.5 %) 13 (32.5 %)
Above diploma 3 (7.5 %) 6(15 %)
In this triple-blind, randomized, clinical trial, 80 patients with AMI Place of Residence
Urban 23 (57.5 %) 25 (62.5 %) 0.34
were randomly assigned to two groups. Given the sampling method
Rural 17 (42.5 %) 15 (37.5 %)
(stratified block design), the subjects were allocated to the two groups Known Concurrent Diseases
with equal numbers of female (n = 20) and male (n = 20) patients in Yes 12 (30 %) 25 (65 %) 0.75
each group. The mean age of the patients was 49.95 ± 11.58 years in No 28 (70 %) 15 (35 %)
the group receiving Citrus aurantium aromatherapy and 49.25 ± 12.50 Family History of
Myocardial Infarction
years in the group receiving the sunflower oil aromatherapy. The in- Yes 14 (35 %) 18 (45 %) 0.56
tervention and control groups were not significantly different in terms No 26 (65 %) 22 (55 %)
of age (P = 0.7). The 2 groups were similar vis-à-vis family history of Tranquilizer Use
MI, known concurrent diseases, tranquilizer use, education and place of Yes 12 (30 %) 15 (37.5 %) 0.50
No 28 (70 %) 25 (62 %)
residence (P > 0.05); (Table 1). The mean depression score was
Smoking
8.40 ± 5.93 in the subjects undergoing C. aurantium aromatherapy Yes 6 (15 %) 7 (17.5 %) 0.94
and 9.82 ± 7.03 in those receiving the placebo. The differences be- No 34 (85 %) 33 (82.5 %)
tween the intervention and control groups with regard to the depression
score were not statistically significant (P = 0.517).
The multivariate analysis showed that the effect of time was sta- individually.
tistically significant (P < 0.001). In other words, the changes in at
least one of the two variables (i.e. anxiety and fatigue) were significant 4.2. Effects of aromatherapy on anxiety
over time. The single-variable analysis was also used to examine the
status of each of these two variables and the results were presented At all the four time points in the present study (the morning and

4
R. Shirzadegan, et al. Journal of Herbal Medicine 21 (2020) 100326

Table 2 Table 3
A comparison of the mean and standard deviation of the anxiety scores between A comparison of the mean and standard deviation of the fatigue scores between
the two groups before and after the intervention on the different measurement the two groups before and after the intervention on the different measurement
occasions. occasions.
Intervention Time Citrus aurantium Placebo (n = 40) P-value Intervention Time Citrus aurantium Placebo (n = 40) P-value
(n = 40) (n = 40)
Mean ± SD Mean ± SD Mean ± SD Mean ± SD

Morning of the First Day Morning of the First Day

Before the intervention 61.37 ± 6.86 59.52 ± 7.47 0.253 Before the intervention 77.12 ± 22.86 71.13 ± 8.69 0.072
After the intervention 23.52 ± 3.28 57.27 ± 6.58 < 0.001 After the intervention 26.4 ± 17.85 71.13 ± 32.42 < 0.001
P-value < 0.001 < 0.001 P-value < 0.001 < 0.001
Evening of the First Day Evening of the First Day
Before the intervention 60.42 ± 6.29 58.17 ± 7.15 0.139 Before the intervention 78.12 ± 50.23 73.14 ± 22.59 0.113
After the intervention 25.02 ± 4.16 72.12 ± 14.31 < 0.001 After the intervention 25.4 ± 20.16 72.14 ± 12.31 < 0.001
P-value < 0.001 < 0.001 P-value < 0.001 < 0.001
Morning of the Second Day Morning of the Second Day
Before the intervention 59.35 ± 6.99 58.3 ± 6.73 0.496 Before the intervention 77.12 ± 47.69 73.14 ± 22.06 0.160
After the intervention 22.65 ± 3.68 56.2 ± 6.46 < 0.001 After the intervention 25.4 ± 67.85 71.13 ± 25.34 < 0.001
P-value < 0.001 < 0.001 P-value < 0.001 < 0.001
Evening of the Second Day Evening of the Second Day
Before the intervention 57.07 ± 6.34 56.55 ± 7.8 0.742 Before the intervention 74.12 ± 5.93 72.15 ± 87.19 0.608
After the intervention 22.3 ± 3.29 54.72 ± 6.06 < 0.001 After the intervention 24.4 ± 15.75 71.14 ± 35.25 < 0.001
P-value < 0.001 < 0.001 P-value < 0.001 < 0.001

Table 4
A comparison of the mean and standard deviation of the total fatigue score in
the five dimensions before and after the intervention between the two groups.
Intervention Time Citrus aurantium Placebo (n = 40) P-value
(n = 40)
Mean ± SD Mean ± SD

General Fatigue
Before the intervention 14.80 ± 3.16 13.73 ± 3.81
After the intervention 4.80 ± 0.87 13.55 ± 3.63 < 0.001
P-value < 0.001 < 0.001
Physical Fatigue
Before the intervention 16.48 ± 2.93 15.72 ± 3.37
After the intervention 4.81 ± 0.85 15.36 ± 3.26 < 0.001
P-value < 0.001 < 0.001
Mental Fatigue
Before the intervention 13.92 ± 3.42 13.15 ± 3.33
After the intervention 4.32 ± 0.75 13.1 ± 3.31 < 0.001
P-value < 0.001 < 0.001
Reduced Activity
Before the intervention 15.85 ± 2.54 15.27 ± 2.93
After the intervention 5.91 ± 1.99 15.02 ± 2.63 < 0.001
P-value < 0.001 < 0.001
Fig. 2. A comparison of the mean changes in anxiety scores in the two groups Reduced Motivation
on the eight measurement occasions. Before the intervention 15.75 ± 2.56 14.90 ± 2.97
After the intervention 5.38 ± 1.45 14.55 ± 2.85 < 0.001
P-value < 0.001 < 0.001
evening of the first and second days after the intervention), ar-
omatherapy with C. aurantium lowered the mean anxiety score sig-
nificantly in the intervention group compared to the placebo group (P < 0.001). As shown in Tables 3 and 4, C. aurantium aroma lowered
(P < 0.001). The differences between the two groups failed to reach both the mean scores of each dimension of fatigue and the mean total
statistical significance at these four time points before the intervention score of fatigue significantly in the different intervention stages
(P > 0.05). The results revealed that the changes in the anxiety score (P < 0.001). The interaction between group and time (time×group)
were significant over time (on the eight measurement occasions) in the was also statistically significant (P < 0.001). Tables 3 and 4 and Fig. 3
group receiving aromatherapy with C. aurantium (P < 0.001). These demonstrate that the changes in the mean score of fatigue were sig-
changes also reached statistical significance in the placebo group, nificantly different between the two groups. In the C. aurantium group,
which, according to Table 2, may have been due to the momentary in comparison with the control group, there was a significant drop in
elevation in anxiety on the evening of the first post-intervention day. the mean fatigue score after each intervention (P < 0.001). Before the
Regarding the effect of time in the between-group comparisons, how- intervention, however, there were no significant differences between
ever, there was a significant difference between the two groups in terms the intervention and control groups in terms of the mean scores of each
of the mean changes, as demonstrated in Fig. 2. dimension of fatigue separately or the mean total score of the five di-
mensions (P > 0.05). The reduction in the mean score of physical fa-
4.3. Effects of aromatherapy on fatigue tigue was more significant than that of the other dimensions following
the intervention in the subjects receiving C. aurantium aromatherapy.
The repeated measures ANOVA was used for examining the changes
in the fatigue score. Regarding the significance of the effect of time, the
changes in the mean scores of each dimension of fatigue and the mean
total score of the five dimensions were significant over time

5
R. Shirzadegan, et al.
Fig. 3. A comparison of the mean changes in the fatigue score between the two
groups on the eight measurement occasions.
5. Discussion
The present study was designed to determine the effect of ar-
omatherapy with Citrus aurantium on anxiety and fatigue in patients
with AMI. The results showed that aromatherapy with C. aurantium
essential oil decreases anxiety in patients with AMI. This finding is
consistent with the results obtained by Moslemi et al., and other find-
ings of recent studies indicating that C. aurantium affects the central
nervous system activity (Moslemi et al., 2019; Heydari et al., 2018).
Sedative and anti-anxiety effects of this plant have been shown in
previous studies. These effects are likely due to 5-HT1A-receptors in-
volvement (Costa et al., 2013). Citrus aurantium L. essential oil exhibits
anxiolytic-like activity mediated by 5-HT1A-receptors and reduces
cholesterol after repeated oral treatment). A previous study concluded
that aromatherapy with C. aurantium extract could be as effective as
diazepam in reducing preoperative anxiety (Akhlaghi et al., 2011).
Although further evidence is required to arrive at a firm conclusion on
the efficacy of aromatherapy in alleviating anxiety, research indicates
that aromas can stimulate the olfactory nerve cells and the lymphatic
system and trigger the release of neurotransmitters such as Endorphin,
Enkephalin, Serotonin and Noradrenaline (Ebrahimi Hoshyar et al.,
2015).
Some researchers have reported that aromatherapy with C. aur-
antium extract alone can enhance sleep quality (Zeighami et al., 2014)
and when used in combination with lavender and German chamomile,
this extract can also reduce anxiety in patients with acute coronary
syndrome (Nematollahi et al., 2017; Najafi et al., 2014). Chu et al.
concluded that aromatherapy was more effective with C. aurantium
extract than lavender and German chamomile in ameliorating anxiety
in CCU patients (Yeon Cho et al., 2013). The findings of the discussed
studies can be explained by noting that the flavonoids isolated from the
extract of C. aurantium, such as limonene and myrcene, possess sedative
and anti-anxiety properties (Mahmoodi et al., 2005; Pultrini Ade et al.,
2006). Moreover, a few studies have reported no effectiveness for C.
aurantium in alleviating anxiety; this inconsistency could be due to the
inadequate diffusion of the essence in the studies due to their type of
application and ventilation system (Holm and Fitzmaurice, 2008). The
current study also contrasts Watson et al.’s (2019) findings of Lemon
Balm aromatherapy to be less beneficial than placebo in reducing agi-
tation or irritability in patients with dementia (Watson et al., 2019).
This difference in essential oil effect between the groups may be at-
tributed to placebo effects. Induction of deep and slow breathing by
placebo may be one mechanism by which it reduces stress, anxiety and
6
Journal of Herbal Medicine 21 (2020) 100326
pain (Masaoka et al., 2013).
These findings suggest that the concentration of the essence applied,
and the frequency of aromatherapy can have some bearing on the effect
of Citrus aurantium on anxiety. In the present study, aromatherapy with
the extract of C. aurantium was found to reduce the level or severity of
fatigue in the patients. These results are in line with the results obtained
by Bahraini et al. and Kim et al., who reported that aromatherapy
massage was capable of decreasing fatigue in women suffering from
multiple sclerosis and in middle-aged women as well. It is not clear,
however, whether the reduction in the level of fatigue was attributable
to the synergy between aromatherapy and massage or the effect of ar-
omatherapy alone. Overall, it appears that the application of aromatic
essential oils can lead to further decline in fatigue by augmenting the
physiological and psychological effects of massage therapy.
Farahani reported that aromatherapy with lavender oil and
Damascene rose oil was effective in reducing fatigue in emergency
department nurses. In tune with that finding (Farahani et al., 2017),
Sakamoto et al. also showed that the aromatic oil of lavender decreased
fatigue in male students and attributed the clinical effects of this aro-
matic oil to the suppression of the sympathetic system, mood en-
hancement and stress reduction (Sakamoto et al., 2005).
In contrast to the present findings, Bagheri et al. reported that ar-
omatherapy with the essential oil of lavender did not reduce fatigue in
hemodialysis patients (Bagheri-Nesami et al., 2016). The discrepancy
between the present findings and Bagheri’s results may be due to the
higher immuno-inflammatory activity in hemodialysis patients and the
fact that fatigue can be a result of the build-up of oxidative stress in the
cell mitochondria. Undoubtedly, fatigue is a multifactorial phenomenon
and its management should take into consideration other factors, such
as BMI and sleep quality. It is also worth noting that aromatic oils can
inhibit the γ-aminobutyric acid (GABA) pathways and suppress the
neurotransmitters, which makes them a good candidate for inducing
sleepiness and alleviating fatigue (Fismer and Karen, 2012).
6. Limitations and suggestions
A major limitation of the present study is its short duration due to
the clinical conditions of CCU patients and their quick transfer to post-
CCU. Future studies are recommended to examine the long-term effects
of aromatherapy by noting the unique conditions of each patient.
Another limitation is that the subjects were not transferred from the
CCU to a more appropriate environment where they could receive
emotional comfort from their therapists and relatives. Future studies
are recommended to implement appropriate measures to address this
shortcoming.
One other limitation is that the characteristic scent of the inter-
vention could affect blinding. In addition, the present findings could
have been further confirmed if other clinical outcomes had also been
measured in the AMI patients, such as chest pain, vital signs, physio-
logical indices and depression, or if fatigue had been assessed in pa-
tients suffering from other cardiac diseases, such as heart failure.
Given the paucity of information in the existing literature on the
efficacy of aromatherapy with Citrus aurantium extract in alleviating
anxiety and fatigue among patients with AMI, future studies are re-
commended to examine the biochemical mechanisms of effect of this
plant in relation to anxiety and fatigue.
7. Conclusion
Aromatherapy with the essential oil of Citrus aurantium is an easy,
inexpensive and harmless method that reduces anxiety among patients
with AMI. Considering this credible evidence and given the significant
role of nurses in the emotional support of patients with AMI in CCUs,
cardiac care nurses are recommended to employ the potentials of ar-
omatherapy to decrease anxiety among their patients.
R. Shirzadegan, et al.
Authorship contribution
R, S. has contributed to study design, data collection, data analysis,
drafting the manuscript writing, and dritical revisions of dinal manu-
script. M, G. has contribute to study design, data collection, study de-
sign, data analysis, study supervision, drafting the manuscript writing,
and critical revisions of final manuscript. S, H and A, B interpreted data.
Ethical considerations
The protocol of the present study was approved by the Ethics
Committee of Lorestan University of Medical Sciences in accordance
with the Declaration of Helsinki (LUMS.REC.1395.160) and recorded in
the Iranian Registry of Clinical Trials (IRCT2017011824080N10).
Written informed consent forms were obtained from all the subjects.
Funding/Support
This research was funded by Lorestan University of Medical
Sciences as part of an M.Sc. thesis.
Declaration of Competing Interest
No authors on this manuscript have any conflicts of interest.
Acknowledgments
We wish to express our gratitude to the Vice Chancellor of Research
of Lorestan University of Medical Sciences for funding this study and
also the CCU personnel and patients of Shahid Madani Hospital and
Shahid Rahimi Hospital of Khorramabad and the CEO of the pharma-
ceutical group Adonis Gol Darou Co.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.hermed.2019.100326.
References
Aisagbonhi, O., Rai, M., Ryzhov, S., Atria, N., Feoktistov, I., Hatzopoulos, A.K., 2011.
Experimental myocardial infarction triggers canonical Wntsignaling and endothelial-
to-mesenchymal transition. Dis ModelMech. 4 (4), 469–483.
Akbari, M., Mohammad Zadeh, M.H., Rajabpour, M., Azimpour, A., 2008. Factors asso-
ciated with knowledge and practice of patients with acute myocardial infarction in
the face of clinical symptoms leading to hospitalization in Hospitals in Urmia. Nurs.
Midwifery 7 (2), 72–80.
Akhlaghi, M., Shabanian, G.H., Rafieian-Kopaei, M., Parvin, N., Saadat, M., Akhlaghi, M.,
2011. Citrus aurantium blossom and preoperative anxiety. Rev. Bras. Anestesiol. 61
(6), 702–706.
Alsen, P., Brink, E., 2016. Fatigue after myocardial infarction a two - year follow-up
study. J. Clin. Nurs. 22, 1647–1652.
Alsen, P., Eriksson, M., 2015. Illness perceptions of fatigue and the association with sense
of coherence and stress in patients one year after myocardial infarction. J. Clin. Nurs.
29, 526–533.
Babaei, M., Kermanshahi, S.M.K., Alhani, F., 2011. Influence of discharge planning on
anxiety levels in patients with myocardial infarction. Koomesh 12 (3), 272–278.
Babar, A., Al-Wabel, N.A., Shams, S., Ahamad, A., Alam Khan, S.H., Anwar, F., 2015.
Essential oils used in aromatherapy: a systemic review. Asian Pac. J. Trop. Biomed. 5
(8), 601–611.
Bagheri-Nesami, M., Shorofi, S.A., Nikkhah, A., Espahbodi, F., Sadat Ghaderi, F., 2016.
The effects of aromatherapy with lavender essential oil on fatigue levels in haemo-
dialysis patients: a randomized clinical trial. Complement. Ther. Clin. Pract. 22,
33–37.
Bagheri nasami, M., Zargar, N., Gholipoor baradari, A., 2011. The effect of reflexology on
pain and fatigue in patients undergo Coronary artery bypass surgery. JMUMS 22 (9),
56–62.
Barton Crane, P., Efird, T., Mae Abel, W., 2016. Fatigue in older adults postmyocardial
infarction. Front. Public Health 4 (55), 1–7.
Brink, E., Alsen, P., 2014. Fatigue or depression after myocardial infarction - how to
promote health and recovery. J. Clin. Nurs. 11–30.
Cho, M., Sil Min, E., Hur, M., Soo Lee, M., 2013. Effects of aromatherapy on the anxiety,
vital signs, and sleep quality of percutaneous coronary intervention patients in
7
Journal of Herbal Medicine 21 (2020) 100326
intensive care units. Evid. Based Complement. Altern. Med. 2013.
Costa, A.P., Vieira, C., Bohner, L.O., Silva, C.F., Santos, E.C., De Lima, T.C., Lino-de-
Oliveira, C., 2013. A proposal for refining the forced swim test in Swiss mice. Prog.
Neuropsychopharmacol. Biol. Psychiatry 1 (45), 150–155.
Devon, H.A., Catherine, J., Amy, L., Moshe, S., 2011. Symptoms across the continuum of
acute coronary syndromes: differences between women and men. Am. J. Crit. Care 17
(1), 14–24.
Ebrahimi Hoshyar, A., Rezai, H.H., Jahani, Y., Kazemi, M., Monfared, S., 2015.
Comparison of two methods of aromatherapy with lavender essence and
Transcutaneous Electrical Nerve Stimulation (TENS) on cesarean postoperative pain.
Iran JObstet Gynecol Infertil 18 (146), 6–12.
Farahani, P., Hekmatpou, D., Khonsari, A.H., Harorani, M., Lotfi, A., 2017. Effect of in-
halation aromatherapy with lavender and rose damascene essential oil on the fatigue
of emergency nurses. Pharm. Lett. 9 (5), 94–102.
Fennessy, M.F.A., Eckhardt, A., Jones, J., Kruse, D., VanderZwan, K., et al., 2010. Gender
differences in fatigue associated with acute myocardial infarction. J. Cardiopulm.
Rehabil. Prev. 30 (4), 224–230.
Fink, A., Fink, A., Fennessy, M., Jones, J., Kruse, D., VanderZwan, K., et al., 2010.
Psychometric properties of three instruments to measure fatigue with myocardial
infarction. West. J. Nurs. Res. 32 (7), 967–983.
Fismer, K.L., Karen, P., 2012. Lavender and sleep: a systematic review of the evidence.
Eur. J. Integr. Med. 4 (4), 436–447.
Fredriksson‐Larsson, U., Alsén, P., Karlson, B.W., Brink, E., 2015. Fatigue two months
after myocardial infarction and its relationships with other concurrent symptoms,
sleep quality and coping strategies. J. Clin. Nurs. 24 (15–16), 2192–2200.
Gary, F.A., Yarandi, H., Evans, E., Still, C., 2018. Beck Depression Inventory-II: factor
analyses with three groups of midlife women of African descent in the Midwest, the
South, and the US Virgin Islands. Issues Ment. Health Nurs. 39 (3), 233–243.
Haeng Hura, M., Ah Songa, J., Lee, J., Soo Leec, M., 2014. Aromatherapy for stress re-
duction in healthy adults: a systematic review and meta-analysis of randomized
clinical trials. Elsevier Ireland Ltd 79 (1), 362–369.
Holm, L., Fitzmaurice, L., 2008. Emergencydepartment waiting room stress:can music or
aromat herapy improveanxiety scores? Pediatricemergency Care 12 (24), 836–838.
Huffman, J.C., Smith, F.A., Blais, M.A., Januzzi, J.L., Fricchione, G.L., 2008. Anxiety,
independent of depressivesymptoms, is associated with inhospital cardiac compli-
cations afteracute myocardial infarction. J. Psychosomatic Res. 65 (6), 557–563.
Hugh, J.N., 2016. Fatigue as a prodromal symptom of myocardial infarct the cardiac
rehabilitation centre hants. United Kingdom 22 (1), 109–311.
Heydari, N., Abootaleb, M., Jamali Moghadam, N., Akbarzadeh, M., 2018. Investigation
of the effect of aromatherapy with Citrus aurantium blossom essential oil on pre-
menstrual syndrome in university students: a clinical trial study. Complement. Ther.
Clin. Pract. 32.
Jeff, C., Huffmana, C., Felicia, A., Smitha, C., Mark, A., Blaisa, C., et al., 2008. Anxiety,
independent of de -pressive symptoms, is associated with in-hospital cardiac com-
plications after acute myocardial infarction. J. Psychosom. Res. 65, 557–563.
Khosravi, A., Ebrahimi, H., 2008. To study the possible one-year survival and its risk
factors in patients with acute myocardial infarction. Knowledge Health Univ. Med.
Sci. Health Serv. 3 (1), 1–7.
Khan, H., Nabavi, A., Sureda, et al., 2017. Therapeutic potential of songorine, a di-
terpenoid alkaloid of the genus Aconitum. Eur. J. Med. Chem. 2017.
Mahmoodi, M., Shamsi Meimandi, M., Foroumadi, A.R., Raftari, S., Asadi Shekari, M.,
2005. Antidepressant effect of sour orange flowers extract on lipopolysaccharide.
Kerman Univ of Med Sci 4 (12), 44–51.
Moghadam, H.R., Kazemi, T., Besharati, F., 2008. Effect of Prodromal symptoms in pa-
tients with myocardial infarction. Iran. J. Epidemiol. 4 (2), 1–5.
Mohsenifard, M., Rezaei, K., Alisaeidy, A., Ghorbanpour, M., Moslemi, A., 2015. The
effect of Peppermint aromas on vital signs and cardiac dysrhythmias in patients with
acute myocardial infarction. J. - Complementary Med. Res. 4 (3), 876–889.
Mosa Farkhani, E., Baneshi, M.R., Zolala, F., 2014. Survival rate and its related factors in
patients with acute myocardial infarction. Med. J. Mashhad Univ. Med. Sci. 57 (4),
636–646.
Marya, H., Khan, S., Nabavi, M., Habtemariam, S., 2018. Anti-diabetic potential of pep-
tides: future prospects as therapeutic agents. Life Sci. 193 (153–158), 2018.
Masaoka, Y., Takayama, M., Yajima, H., Kawase, A., Takakura, N., Homma, I., 2013.
Analgesia Is Enhanced by Providing Information regarding Good Outcomes
Associated with an Odor: Placebo Effects in Aromatherapy? Evid. Based Complement.
Altern. Med ID 921802.
Moslemi, F., Alijaniha, F., Naseri, M., Kazemnejad, A., Charkhkar, M., Heidari, M.R.,
2019. Citrus aurantium aroma for anxiety in patients with acute coronary syndrome:
a double-blind placebo-controlled trial. J. Altern. Complement. Med. 25 (8),
833–839.
Najafi, S., Pashandi, S.H., Mahmoudi, H., Ebadi, A., Ghaneie, M., 2010. The relationship
of fatigue with spirometry parameters in veterans with respiratory disorders. Iran. J.
War Public Health 8 (2), 29–35.
Najafi, Z., Taghadosi, M., Sharifi, K., Farrokhian, A., Gary, F.A., Yarandi, H., Evans, E.,
Still, C., 2018. Beck Depression Inventory-II: factor analyses with three groups of
midlife women of African descent in the Midwest, the South, and the US Virgin
Islands. Issues Ment. Health Nurs. 39 (3), 233–243.
Najafi, Z., Taghadosi, M., Sharifi, K.H., Farrokhian, A., Tagharrobi, Z., 2014. The effects of
inhalation aromatherapy on anxiety in patients with myocardial infarction: a ran-
domized clinical trial. Iran. Red Crescent Med. J. 16 (8), 1–7.
Nematollahi, M., Bazeli, J., Moghaddam, M., Aalami, H., 2017. Effect of aromatherapy on
anxiety in patients with acute coronary syndrome hospitalized in cardiac care unit.
Bali Med. J. 6 (2), 331–336.
Nabavi, S., Khan, H., D’Onofrio, G., et al., 2018. Apigenin as neuroprotective agent: of
mice and men. Pharmacol. Res. 128 (359–365), 2018.
R. Shirzadegan, et al.
Pultrini Ade, M., Galindo, L., Costa, M., 2006. Effects ofthe essential oil from Citrus
aurantium L. In experimental anxiety models in mice. Life Sci. 78 (15), 1720–1725.
Sakamoto, R., Minoura, K., Usui, A., Ishizuka, Y., Kanba, S., 2005. Effectiveness of aroma
on work efficiency: lavender aroma during recesses prevents deterioration of work
performance. Chem. Senses 30 (8), 683–691.
Shirzadegan, R., Gholami, M., Hasanvand, S.H., Birjandi, M., Beiranvand, A., 2017.
Effects of geranium aroma on anxiety among patients with acute myocardial in-
farction: a triple-blind randomized clinical trial. Complement. Ther. Clin. Pract. 29,
201–206.
Shokri, H., Hekmatpou, D., Ebrahimi Fakhar, H.R., Niazi, A., Azadi, M., Taghizadeh, M.,
2013. Effect of Ducrosia Anethifolia (Barilax) on anxiety after acute myocardial in-
farction. Arak Med. Univ. J. (AMUJ) 16 (76), 28–34.
Ulvik, B., Bjelland, I., Hanestad, B.R., Omenaas, E., Wentzel-Larsen, T., Nygård, O., 2008.
Journal of Herbal Medicine 21 (2020) 100326
Comparison of the Short Form 36 and the Hospital Anxiety and Depression Scale
measuring emotional distress in patients admitted for elective coronary angiography.
Heart Lung: J. Acute Crit. Care 37 (4), 286–295.
Watkins, L., Gary, G., Sherwood, A., Blumenthal, J., Davidson, J., Connor, C.H., et al.,
2013. Association of anxiety and depression with all-cause mortality in individuals
with coronary heart disease. J. Am. Heart Assoc. 2 (1), 1–10.
Watson, K., Hatcher, D., Good, A., 2019. A randomised controlled trial of Lavender
(Lavandula angustifolia) and Lemon Balm (Melissa officinalis) essential oils for the
treatment of agitated behaviour in older people with and without dementia.
Complement. Ther. Med. 42, 366–373.
Zeighami, R., Mohamadi hariry, F., Jalilolghadr, S.H., Alipour heidari, M., 2014.
Investigating the effect of “Citrus aurantium” aroma on sleep quality of patients
hospitalized in the coronary care unit (CCU). J. – Res. Cam 4 (1), 720–732.