Content uploaded by Oana Roxana Ciobotaru
Author content
All content in this area was uploaded by Oana Roxana Ciobotaru on Apr 01, 2019
Content may be subject to copyright.
REV.CHIM.(Bucharest)♦70♦No. 3 ♦2019 http://www.revistadechimie.ro 843
Dexamethasone - Chemical Structure and Mechanisms
of Action in Prophylaxis of Postoperative Side Effects
OANA ROXANA CIOBOTARU1,7, MARY-NICOLETA LUPU2,8*, LAURA REBEGEA1,9, OCTAVIAN CATALIN CIOBOTARU2,7,
OANA MONICA DUCA3, ALIN LAURENTIU TATU4, CARINA DOINA VOINESCU1,7, GABRIELA STOLERIU5*,
KAMEL EARAR6, MAGDALENA MIULESCU4,8
1Dunarea de Jos University of Galati, Faculty of Medicine and Pharmacy, Clinical Departament, 35 Al. I. Cuza Str.., 800010, Galati,
Romania
2Dunarea de Jos University of Galati, Faculty of Medicine and Pharmacy, Departament of Surgery, 35 Al. I. Cuza Str., 800010, Galati,
Romania
3General Hospital Railways, 5-7 Alexandru Moruzzi Str., 800223, Galati, Romania
4Dunarea de Jos University of Galati, Faculty of Medicine and Pharmacy, Research Center in the Field of Medical and Pharmaceutical
Sciences, Pharmacology Sciences Department, 35 Al. I. Cuza Str., 800010, Galati, Romania
5Dunarea de Jos University of Galati, Faculty of Medicine and Pharmacy, Department of Pharmaceutical Sciences, 35 Al. I. Cuza
Str., 800010, Galati, Romania
6Dunarea de Jos University of Galati, Faculty of Medicine and Pharmacy, Department of Dental Medicine, 35 Al. I. Cuza Str.,
800010, Galati, Romania
7Research Center in the Health Status of the Population in Correlation with Risk Factors, Faculty of Medicine and Pharmacy, 35
Al. I. Cuza Str., 800010, Galati, Romania
8Research Center in the Functional Cardiorespiratory and Neuromotor Exploration, Faculty of Medicine and Pharmacy, 35 Al. I.
Cuza Str., 800010, Galati, Romania
9Research Center in the minimally invasive surgery, Faculty of Medicine and Pharmacy, 35 Al. I. Cuza Str., 800010, Galati,
Romania
Dexamethasone is a synthetic glucocorticoid used for its anti-inflammatory and analgesic effect. In addition
to these therapeutic indications, it is also recommended for nausea and vomiting treatment which may
occur during the postoperative period, with impact on postoperative evolution, regarding the evolution of
wound healing and length of stay (LOS), with a reflection on the costs of hospital admission. Therefore, their
prevention is very important for both patients’ comfort and a good recovery.
Keywords: synthetic glucocorticoid, disodium salt, nuclear steroid receptors anti-inflammatory, postoperative
side effects, prevention
The increased prevalence in nausea and vomiting
(PONV) represent a stress factor for the patient who had
undergone surgery, and also a negative factor for
postoperative recovery process.
In recent years there have been published many studies
and articles which attempted to draw out some
multimodal strategies in order to prevent PONV, mainly
based on risk factors identification, and also an optimal
multimodal treatment with antiemetics.[1]
Recently, in 2014 the Society for Ambulatory
Anesthesiology published an article which lists the main
trigger factors of PONV, including the female gender, non-
smokers, patients with antecedents of PONV and the
postoperative administration of opioids, and also
recommendations regarding their pharmacological
management [2].
Antiemetics represent the main method to combat and
prevent PONV such as: corticosteroids (Dexamethasone),
butyrophenones, serotonergic antagonists, phenothiazines
and gastrointestinal prokinetics (Metoclopramide).
Dexamethasone is an adrenocortical steroid which has
an anti-inflammatory effect with prophylactic properties,
which was highly proven in several publications with a
great impact regarding medical statistics. The
recommended dose for a prophylactic treatment is an IV
dose of 4-5 mg in the immediate postinductionperiod [2].
The chemical formula (fig. 1) of dexamethasone is 9-
fluoro-11 β, 17-dihydroxy-16α-methyl-21- (phosphonooxy)
pregna-1, 4-diene-3, 20-dione disodium salt [3].
* email: lupumarynicoleta@yahoo.com; stoleriugabriela@yahoo.com All authors had an equal contribution to this work.
It is a synthetic glucocorticoid which exerts its agonist
action by linking itself to specific nuclear steroid receptors.
Fig. 1. Chemical formula
of dexamethasone [3]
Dexamethasone is a synthetic glucocorticoid, formerly
used for its anti-inflammatory and antialgic effect [4].
In 1958, Taub synthetized the
first
β
-substituted cortical
steroid derivatives
and obtained 16β - methylprednisolone
acetate, considered to be, at that time, the most potent
steroidal anti-inflammatory agents [5,6].
So 16β - methylprednisolone acetate is dehydrated to
the 9,11 dehydro – derivative which will be converted in
9α bromo - 11β hydrin derivative, which will determine
the epoxide ring closure.
The formation of dexamethasone is made secondary
to a
ring-opening reaction with hydrogen fluoride in THF
(tetrahydrofuran)
[7] (fig. 2).
Currently, dexamethasone is administered per os,
intravenous, intramuscular, ophthalmic substances or
dermatological preparations, in shock treatment or
anaphylactoid reactions, exacerbations in multiple sclerosis
http://www.revistadechimie.ro REV.CHIM.(Bucharest)♦70♦ No. 3 ♦2019
844
(MSR) or cerebral edema, especially in paraneoplastic type,
and also in postoperative nausea and vomiting prevention.
It can also be administered during pregnancy, aiming to
increase fetal surfactant production in patients with
preterm delivery risk [8].
It has proven effective also in the administration by
nebulization in both bronchospasm remission, and
prophylactic in pain prevention (sore throat) secondary to
extubation - removal of the orotracheal tube (OTT) at the
end of the surgical procedure. [9]
The doses used vary depending on the purpose of the
administration.
Dexamethasone is metabolized by the cytochrome
P450 (CYP) 3A4 within the liver [10,11].
Its elimination occurs via renal excretion. It has a
biological half-life of 3 h.
Experimental part
Material and method
We conducted a clinical trial on 1121 patients who
underwent traditional or laparoscopic cholecystectomy
and all the patients received general anesthesia with
orotracheal intubation.
Patients with the following associated pathologies were
excluded:
-neoplasia
-segmental intestinal resection
-migraine syndrome
There were two study groups: one consisted of 59.8% of
patients medicated with dexamethasoneand a witness
group containing patients who did not receive the
corticosteroid.The witness group took part in a retrospective
cohort study and the study group consisted of patients in
whom cholecystectomy was indicated, and who did not
match the excluding criteria during 5 months.
Study design
The study fulfils the medical, ethical and deontological
criteria, according to the Romanian legislation, and
approved by the Faculty of Medicine and Pharmacy Ethic
Comissionof Dunarea de Jos University of Galati [12].
Aneshtesia
The induction of anesthesia was made with Fentanyl
(1-3µg/kg), Propofol (1-2.5mg/kg) and Atracurium (0.5 mg/
kg) and it was maintained with boluses of Fentanyl (2µg/
kg) andAtracurium (0.1 mg/kg).
Atropine (0.014mg/kg) and Neostigmine (0.04mg/kg)
were used for the reversal of the motor block and
awakening.The doses were used according to the
indications presented in Morgan and Mikhail’s Clinical
Anesthesiology [13].
Right before the induction, the study group was
medicated with Dexamethasone, a 2 mL ampoule, 4mg/
mL (Rompharm, Romania).
Statistical analysis
The statistical analysis was made using the software
named IBM SPSS Statistics, version 21 (SPSS Inc. Chicago,
IL)Regarding the analysis for the numeric scalar values,
we used the correlation coefficient, also referred to as
Pearson’s coefficient (r) which shows us that, whether or
not there is a relationship between two values, and also a
correlation coefficient. If the calculated probability (p-value)
is less than the significance level (α=0.05), both values
are accepted, as they are correlated. If p >α = 0.05,we
decide that the two variables are not correlated. The
Pearson (r) coefficientcan take a range of valuesbetween
+1 and-1. When the coefficient reaches +1 or -1, the
correlation coefficient takes a higher value, whether it is in
the same direction (+) or in the opposite one (-).The more
the coefficient reaches 0, the less the correlation between
the two series of variations. If r=0, there is no correlation.
Regarding the analysis of the nominal variables, we
calculated the values for the correlation coefficients at a
nominal levelö, C and V, and also the probabilities associated
with these values. If p < 0.05, we can state that there is a
correlation betweenthe variables.
We calculated the values for the correlation coefficients
τb, Kendall’s coefficient, γ(Gamma) and Somer’s
coefficient of correlation (d), for the ordinal variables, and
also the probabilities associated to these values. If the
associated probabilities of these coefficients arep < 0.05,
we must admit that there is a correlation between the
variables in the analysis.
The Mann-Whitney Utest is used in order to test the
difference between independent groups for which the
dependent variable is expressed in ordinal values, or when
a parametric statistical test can not be made.
The χ2 test analyses the association between two
variables.
Results and discussions
Among the administrations of dexamethasone, the
most interesting one is its usage in postoperative nausea
and vomiting prevention, being known that these
manifestations are more disturbing for patients undergoing
surgical procedures, than postoperative pain itself.
Postoperative nausea and vomiting are complications
which may occur in 20-40% of patients undergoing surgical
procedures [2,14,15]. This type of complications affect
postoperative evolution by the risk of dehydration which
may occur, bleeding or belated wound healing, all of these
determining prolonged hospitalization.
Out of the total number of 1121 patients, 82.2 % were
women and 17.8% were men, between 24 and 85 years
old. We divided the patients into subgroups, depending on
the gender, BMI’s value, age, surgical technique, using
dexamethasone for prophylaxis of PONVand the PONV’s
incidence (table 1).
Fig. 2. Synthesis reaction of dexamethasone from 16β - methylprednisolone acetate, to the 9,11 dehydro -derivative, and in the end to
dexamethasone [5]
REV.CHIM.(Bucharest)♦70♦No. 3 ♦2019 http://www.revistadechimie.ro 845
The group of patients was analysed taking into account
the PONV’s incidence, depending on the patients’ age and
it was noticed that out of the total number of cases which
reported PONV, 58,82% were less than 50 years old and
for those under or over 50 years old, 41.18%, but this was
not statistically relevant (p = 0.064 >α = 0.05).
The sex of the patient is one of the risk factors in PONV,
proposed by Aphel in creating a risk scale of PONV [16].
Moreover, it was thought that the main reason why the
female gender is frequently associated with postoperative
nausea and vomiting is the hormonal variation, mostly the
estrogen, to which many women are exposed during the
immediate postoperative period [17].
Regarding the sex and the incidence of the PONV, among
the studied group, it was noticed that all the patients who
reported PONV were females.
Statistically, the values of the correlation coefficients
for a nominalj level, C and V, and also the probabilities
associated to these values were following: ϕ= -0.209, C
= 0.205 and V = 0.209, p = 0.035 <α= 0.05.
By analysing these values, we can conclude that there
is a correlation between the postoperative nausea and the
patient’s sex but the correlation is a weak one.
Many articles share different views regarding the
influence of the BMI in PONV, also several research papers
suggest that a lower BMI value was associated with a higher
incidence in PONV but there are also many clinical trials
which disprove this correlation [18].
Regarding the patients distributed depending on the BMI
and PONV, there was no significant statistical correlation
for our research. By applying the Mann-Whitney and
Wilcoxon tests we obtained: p = 0.586 >α= 0.05 (the
significance level) which means that there is no connection
between between the presence of postoperative nausea
and BMI.
Due to complex pathogenesis, which represents the
main cause of the PONV syndrome, the prophilaxis must
be quickly initiated, before the occurrence of PONV.
Considering the presented thesis, in 54.90 % of cases
the prophylaxis for PONV was made by intraoperative
administration, postinduction of 4-8 mg IV of Dexa-
methasone. By analyzing this subgroup, we noticed a
decrease in the PONV incidence, in comparison with the
subgroup where no antiemetic prophylaxis was initiated.
Out of the total number of patients who were medicated
with Dexamethasone, only 10% reported PONV, by
statistically analyzing this statementwe noticed that the
value obtained at the χ2 test was 4.928 and the probability
associated to this value is: p = 0.026 <α = 0.05, and this
result proves that there is a relationship (correlation)
between the administration of Dexamethasone and the
presence of postoperative nausea.
At a nominal level, the values of the ϕ correlation
coefficients, C and V, and also the probabilities associated
to these obtained values are:ϕ= 0.221, C = 0.216 si V =
0.221 and the associated probabilities are: p = < 0.026
<α= 0.05.
By analyzing these values we can admit that there is a
correlation between the administration of dexamethasone
and the presence of postoperative nausea and vomiting .
The mechanism of PONV
The mechanism of postanesthetic nausea and vomiting
is not completely understood.
The area of the brain involved in this mechanism is
located in the solitary nucleus (nucleus tractus solitarius -
NTS), receiving information from chemoreceptors via
neurons which belong to area postrema. Neuro-
transmission from NTS
travels
to the hypothalamus, the
ventral medulla, and also to a central pattern generator
Table 1
DESCRIPTIVE STATISTICS
*PONV= Postoperatory Nausea and Vomiting;
BMI= Body Index Mass;
http://www.revistadechimie.ro REV.CHIM.(Bucharest)♦70♦ No. 3 ♦2019
846
(CPG), which represents the area where emesis behavior
is coordinated [4].
Trigger areas of the chemoreceptors contain many
dopaminergic, serotonin 5-hydroxytryptamine type 3 (5-
HT3), opioids and neurokinin 1 receptors [19-21].
A great number of neurokinin-1, 5-HT3, acetylcholine,
histamine, enkephalin, and glucocorticoids receptors are
also found in the NTS, where afferent pathways of the vagus
nerve, from the abdominal viscera, are being projected.
[22, 23]
The most emetogenic substances used during general
anesthesia are volatile anesthetics, nitrous oxide and
opioids.
Halogenated inhalational anesthetics have an emetic
effect which is directly proportional to the duration of their
usage. The stimulation of chemoreceptors depends on the
plasmatic concentration of the anesthetics, resulting in
stimulation of the NTS and enzyme production [24].
There have been incriminated various mechanisms by
which opioids determine the occurrence of PONV:
-paralytic ileus (delayed gastric emptying)
-higher vestibular sensitivity
-direct effect on the trigger area of the chemoreceptors
[25].
The action mechanism of dexamethasone in PONV
prevention
The action mechanism of dexamethasone aiming to
prevent PONV is not completely known.
The antiemetic effect may be the consequence of:
-the anti-inflammatory effect of membrane stabilization
[25];
-the inhibition of pro-inflammatory mediators: C-reactive
protein, tumor necrosis factor (TNF), interleukins [26];
-the inhibition in production of inflammatory autacoids;
autacoids are represented by eicosanoids (derived from
membrane lipids, such as PG-type (prostaglandins),
prostacyclin, leukotrienes, thromboxane) histamines,
somatomedins [27], serotonin-neurotransmitter involved
in the occurrence of emesis [28]. Dexamethasone
determines tryptophan depletion, which is a precursor for
serotonin synthesis. [29] This way, stimulation of
serotoninergic receptors decreases;
-inhibition in the release of endomorphins.
Dexamethasone dose usages, according to the studies, in
PONV prevention
Literature data report that two preoperative IV doses of
dexamethasone were studied in PONV prevention: a low
dose (4 - 5 mg) and a high dose (8 - 10 mg).
Several studied have been conducted, taking into
consideration multiple factors: The Apfel Score (patient
risk factors in the occurrence of PONV), type and duration
of the surgical procedure, type of the anesthetics,
dexamethasone dosage, dexamethasone efficiency, in
single administration or in combination with other
antiemetics.
Patient risk factors for PONV (The Apfel Score) [30]:
-female gender
-nonsmoking status
-age < 50 years
-antecedent motion sickness
-postoperative analgesia with opioids.
Therefore, in 2004, Apffel et al. organized six batches of
study to which he administered preoperative IV
dexamethasone 4 mg, odansetrone 4 mg, droperidol l.25
mg, each of those reported to a batch to which he used the
placebo effect. He noticed that all 3 active drugs, in analyzed
doses, had similar efficiency in PONV [31].
Buck et al. have proven the efficiency of dexamethasone
administration in preoperative IV dose of 8 mg and 10 mg,
in plastic surgery, a study published in 2006 [32,33].
Sistla et al. analyze the effect of dexamethasone in
preoperative IV dose of 8 mg in patients who underwent
laparoscopic cholecystectomy, where they notice
reduction in the necessity of postoperative administration
of antiemetics (0.56 mg vs. 2.24 mg; P=0.02) [34].
Karanicolas et al., using literature data reported between
1966 and 2007, and 4 bibliographic databases (Web of
Science, Embase, Medline, The Cochrane Central Register
of Controlled Trials) noticed that the efficiency of the
antiemetic effect of dexamethasone gets better by using
higher doses (16 mg), compared with its lower doses (2-5
mg) [35].
In 2013, a study conducted by De Oliveira et al,
contradicts Karanicolas’s study and shows that there were
no different results regarding PONV in doses of 4 - 5 mg,
compared with the usage of 8 -16 mg [36].
Nevertheless, recent studies evaluated the efficiency of
dexamethasone administered in a dose of 8 mg, noticing
clear efficiency in PONV prevention, compared with the
placebo effect [37,38].
Adverse effects of dexamethasone administration
Due to its anti-inflammatory and immunosuppressant
effect, dexamethasone is used in dermatology, oncology,
surgery, rheumatology, endocrinology, pneumology,
ophthalmology etc. [39-44]. Being a broad-spectrum drug,
adverse effects have been known for a long time. They
depend on the root of administration, especially on its
duration [42, 45, 46].
In PONV prevention, it was pursued the potential
occurrence of dizziness and headache.
Studies have shown that dexamethasone administered
in PONV prevention did not determine adverse effects,
whether higher doses, of 8-10 mg or those of 4-5 mg, were
administered [35, 36].
Contraindications of dexamethasone administration
The two most important contraindications of
dexamethasone administration are [37]:
-Hypersensitivity to dexamethasone
-Fungal infections
Conclusions
Studies have shown the efficiency of IV dexamethasone
in PONV, and the most commonly used dose is 4 mg.
However, there were no reports on dexamethasone-related
adverse effects, whether higher doses, of 8 - 10 mg or
those of 4 - 5 mg, were administered. Even for these doses,
and also for single administration, the contraindications
for dexamethasone administration shall be maintained.
The analysis of our studies group has proven the fact
that the indicence of PONV was frequent in female patients,
young patients who were less than 50 years old and also in
cases of laparoscopic cholecystectomy.GanMoreover, we
noticed a decrease in the PONV frequence for the subgroup
in which patients were medicated with Dexamethasone
as a prophylactic method for PONV.
Positive statistical correlations were made between the
presence of PONV and the female gender, and also
between prophylactic administration of Dexamethasone,
according to the existing protocols and the incidence of
PONV.
REV.CHIM.(Bucharest)♦70♦No. 3 ♦2019 http://www.revistadechimie.ro 847
References
1.SAEEDA, I., JAIN, P.N., Indian J. Anaesth, 48, no. 4, 2004, p. 253.
2.GAN, T.J., DIEMUNSCH, P., HABIB, A.S., KOVAC, A., KRANKE, P.,
MEYER, T.A., Anesth Analg, 118, no. 1, 2014, p. 85.
3.VENKATA SAIRAM, K., THEJASWINI, J.C., PRUDHVI RAJU, M.V.,
CHANDAN, R.S., GURUPADAYYA, B.M., MRUTHUNJAYA, K., World
Journal of Pharmaceutical Research, 4, no. 2, 2015, p. 1148.
4.HORNBY, P.J., Am. J. Med., 111, Suppl.8A, 2001, p. 106S.
5.TAUB, D., HOFFSOMMER, R.D., SLATES, H.L., LWENDLER, N.L.,
Journal of the American Chemical Society, 80, no. 16, 1958, p. 4435.
6.TOADER, E., BAHRIN, L.G., JONES, P.G., HOPF, H., SARBU, L.G.,
STOLERIU, G., REV. CHIM. (Bucharest), 67, no. 8, 2016, p. 1520.
7.LEDNICER, D. Strategies for organic drug synthesis and design.
Steroids; Part 2: Compounds related to progesterone, cortisone and
cholesterol, Second Edition Ed A John Wiley& Sons, Inc., 2009, p.179.
8.ELSNOSY, E., SHAABAN, O.M., ABBAS, A.M., G ABER, H.H., DARWISH,
A., Middle East Fertility Society Journal, 22, 2017, p. 13.
9.SALAMA, A.K., EL-BADAWY, A.M., Ain-Shams Journal of
Anesthesiology, 9, 2016, p. 104.
10.TEO, Y.L., SAETAEW, M., CHANTHAWONG, S., YAP, Y.S., CHAN, E.C.,
HO, H.K., CHAN, A., Breast Cancer Res Treat, 133, no. 2, 2012, p. 703.
11.FILIP-CIUBOTARU, F., MANCIUC, C., STOLERIU, G., FOIA, L., Rev
Med Chir Soc Med Nat Iasi, 120, no. 1, 2016, p. 29.
12.ROGOZEA, L., PURCARU, D., LEASU, F., NEMET, C., Rom J
MorpholEmbryol, 55, no, 2S, 2014, p. 719.
13.BUTTERWORTH, J.F., MACKEY, D.C., WASNICK, J.D., Morgan &
Mikhail’s Clinical Anesthesiology, Ed McGraw Hill, 2013.
14.HORN, C.C., WALLISCH, W.J., HOMANICS, G.E., WILLIAMS, J.P.,
Eur J Pharmacol. 722, no. 1, 2014, p. 55.
15.PHILLIPS, C., BROOKES, C.D., RICH, J., ARBON, J., TURVEY, T.A.,
Int J Oral Maxillofac Surg, 44, no. 6, 2015, p. 745.
16.APFEL, C.C., LAARA, E., KOIVURANTA, M., GREIM, C.A., ROEWER,
N., Anesthesiology, 91, no. 3, 1999, p. 693.
17.VAHABI, S., ABASZADEH, A., YARI, F., YOUSEFI, N., Korean J
Anesthesiol, 68, no. 6, 2015, p. 581.
18.CHOI, D.H., SANG K.O., J., AHN, H.J., KIM, J.A., J Korean Med Sci.,
20, no. 5, 2005, p. 811.
19.BRANISTEANU, D.E., IANOSI, S.L., DIMITRIU, A., STOLERIU, G.,
OANÃ, A., BRANISTEANU, D.C., Experimental and Therapeutic
Medicine, 15, 2018, p. 785.
20.KIZILCIK, N., BILGEN, S., MENDA, F., TURE H., AYDIN B., KASPAR,
E.C., KONER, O., Aesth Plast Surg, 41, 2017, p. 204.
21.NISSAR, A.D., ANDREW, P.R., Chem. Rev., 109, no. 7, 2009, p. 3158.
22.LESLIE, R.A., SHAH, Y., THEJOMAYEN, M., MURPHY, K.M.,
ROBERTSON, H.A., Canadian Journal of Physiology and Pharmacology,
68, no. 2, 1990, p. 279.
23.BALAN, G., PELIN, A.M., MACOVEI, L.A., CONDRATOVICI, A.P.,
CONDRATOVICI, C.P., BUSILA, C., Rev. Chim. (Bucharest), 68, no. 3,
2017, p. 603.
24.APFEL, C.C., KRANKE, P., KATZ, M.H., GOEPFERT, C., PAPENFUSS,
T., RAUCH, S., HEINECK, R., GREIM, C.A., ROEWER, N., British Journal
of Anaesthesia, 88, no. 5, 2002, p. 659.
25.COLUZZI, F., ROCCO, A., MANDATORI, I., MATTIA, C., Current
Pharmaceutical Design, 18, 2012, p. 6043.
26.TOLVER, M.A., STRANDFELT, P., BRYLD, E.B., ROSENBERG, J.,
BISGAARD, T., British Journal of Surgery, 99, 2012, p. 1374.
27.TULBURE, D., DROC, G., Anestezie Terapie Intensiva, Ed
Universitara Carol Davila, Bucuresti, 2009, p. 134.
28.CHUA, C.C, HSING, C.H., SHIEH, J.P., CHIEN, C.C., HO, C.M., WANG
J.J., European Journal of Pharmacology, 722, 2014, p. 48.
29.RICHARD, D.M., DAWES, M.A., MATHIAS, C.W., ACHESON, A.,
KAPTURCZAK, N.H., DOUGHERTY, D.M., Int J Tryptophan Res, 2,
2009, p. 45.
30.WEILBACH, C., RAHE-MEYER, N., RAYMONDOS, K., WEISSIG, A.,
SCHEINICHEN, D., PIEPENBROCK, S., Acta Anaesth. Belg, 57, 2006, p.
361.
31.APFEL, C.C., KORTTILA, K., ABDALLA, M., KERGER, H., TURAN,
A., VEDDER, I., ZERNAK, C., DANNER, K., JOKELA, R., POCOCK, S.J.,
TRENKLER, S., KREDEL, M., BIEDLER, A., SESSLER, D.I., ROEWER,
N., N Engl J Med, 350, no. 24, 2004, p. 2441.
32.BUCK, D.W., MUSTOE, T.A., KIM, J.Y.S., Semin Plast Surg, 20, no. 4,
2006, p. 249.
33.TATU, A.L., CIOBOTARU, O.R., MIULESCU, M., DUMITRIU BUZIA,
O., ELISEI, A.M., MARDARE, N., DIACONU, C., ROBU, S., NWABUDIKE,
L.C., Rev. Chim.(Bucharest), 69, no.8, 2018, p. 2110.
34.SISTLA, S., RAJESH, R., SADASIVAN, J., KUNDRA, P., SISTLA , S., Surg
Laparosc Endosc Percutan Tech, 19, no. 6, 2009, p. 506.
35.KARANICOLAS, P.J., SMITH, S.E., KANBUR, B., DAVIES, E., GUYATT,
G.H., Ann Surg, 248, 2008, p. 751.
36.DE OLIVEIRA, G.S.JR, CASTRO-ALVES, L.J., AHMAD, S., KENDALL,
M.C., MCCARTHY, R.J., Anesth Analg, 116, no. 1, 2013, p. 58.
37.DREAMS Trial Collaborators, BMJ 357, 2017, j1455.
38.PARTHASARATHY, P., BABU, K., RAGHAVENDRA RAO, R.S.,
RAGHURAM, S., Anesth Essays Res, 12, 2018, p. 313.
39.BUMBACEA, R.S., POPA, L.G., ORZAN, O.A., VOICULESCU, V.M.,
GIURCANEANU, C., Acta Endocrinologica, X, no. 4, 2014, p. 595.
40.REBEGEA, L., NECHITA, A., SERBAN, C., DIACONU, C., MACOVEI,
L.A., DRAGANESCU, M., FIRESCU, D.,Rev. Chim.(Bucharest), 69, no.
10, 2018, p. 2833.
41.REBEGEA, L., STEFAN, AM., FIRESCU, D., MIRON, D., ROMILA, A.,
Acta Medica Mediterranea, 34, 2018, p. 1265.
42.***Dexamethasone.https://www.drugs.com/pro/dexa-methasone.
html.
43.BLOOM, S.L., SHEFFIELD, J.S., MCINTIRE, D.D., LEVENO, K.J.,
Obstet Gynecol, 97, no. 4, 2001, p. 485.
44.GRIGOROVICI, A., CHERCIU, M.S., POPESCU, C.M., CIOBANU
APOSTOL, D.G., PREDA, C., CÃLIN, A., AELENE, P., Farmacia, 65, no.
1, 2017, p. 29.
45.TATU, A.L., CLATICI, V., J Am Acad Dermatol, 72, no. 5, spp. 1, 2015,
AB91.
46.TATU, A.L., Acta Endo (Buc), 12, 2016, p. 232.
Manuscript received: 4.07.2018
