Hindawi

Anesthesiology Research and Practice

Volume 2022, Article ID 5061803, 10 pages
https://doi.org/10.1155/2022/5061803

Research Article
A Randomized Controlled Trial for Prevention of Postspinal
Anesthesia Shivering in Gynecological Surgeries: Mirtazapine
vs. Dexamethasone

Ibrahim M. Esmat ,1 Ahmed M. Elsayed ,1 Hazem M. El-Hariri ,2

and Tarek M. Ashoor 1
1
Department of Anesthesia and Intensive Care, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
2
Community Medicine Department, National Research Centre, Cairo, Egypt

Correspondence should be addressed to Ibrahim M. Esmat; [email protected]

Received 22 October 2021; Accepted 28 January 2022; Published 9 March 2022

Academic Editor: Basavana B. Goudra

Copyright © 2022 Ibrahim M. Esmat et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Background. The frequency of shivering regarding regional anesthesia is 55%. Newer effective and tolerable options for postspinal
anesthesia shivering (PSAS) prophylaxis are necessary to improve patients’ quality of care. This research assessed the impact of
preemptive mirtazapine versus preemptive dexamethasone to decrease frequency and severity of PSAS in gynecological pro-
cedures. Methods. 300 patients booked for gynecological procedures under spinal anesthesia (SA) were randomly apportioned
into three groups (100 each) to get one preemptive dose of 30 mg mirtazapine tablet (M group), 8 mg dexamethasone diluted in
100 ml of saline infusion (D group) or placebo (C group) two hours before surgery. Incidence of clinically significant PSAS was the
primary outcome. Core temperature, shivering score, hemodynamics changes, adverse events, and patient satisfaction score were
documented as secondary outcomes. Results. Compared with C group, mirtazapine and dexamethasone decreased incidence of
clinically significant shivering (74% vs. 16% and 31%, respectively; P < 0.001). M and D groups had less hypotensive episodes
during 5–25 min after intrathecal injection (P < 0.001). 90 min after SA, tympanic temperatures were lower than baseline values in
the three groups (P < 0.001). Pruritus, nausea, and vomiting were more often in C group (P < 0.001), whereas sedation was more
frequent in M group (P < 0.001). C group had the lowest satisfaction scores (P < 0.001). Conclusion. Prophylactic administration
of mirtazapine or dexamethasone attenuated shivering with minimal hazards in patients scheduled for gynecological surgeries
under spinal anesthesia with priority to mirtazapine. The trial is registered with NCT03675555.

1. Introduction involved in the pathogenesis of postspinal anesthesia shiv-

ering (PSAS) including intraoperative heat loss and en-
Spinal anesthesia (SA) is commonly practiced in gyneco- dogenous pyrogens. PSAS exerts metabolic effects and
logical surgeries. SA has many advantages, e.g., less intra- hemodynamic impacts including increased oxygen con-
operative bleeding, less risk of venous thromboembolism, sumption, excess carbon dioxide production, high cate-
and better pain relief. Complications may happen, e.g., cholamine levels in plasma, and increased cardiac output [2].
hypotension, postdural puncture headache (PDPH), and Patients may feel uncomfortable about the PSAS which may
shivering [1]. The frequency of shivering regarding regional interfere with ECG monitoring, measurements of blood
anesthesia is 55% [2]. pressure, and readings of O2 saturation [4]. Women vary
SA influences temperature regulation through promo- from men in their more prominent subcutaneous fat layer
tion of heat loss by vasodilation leading to trunk hypo- and poor exercise capacity resulting in different thermal
thermia and shivering [3, 4]. Several mechanisms are reactions to external and internal heat loss during rest and
2 Anesthesiology Research and Practice

exercise [5]. Nonpharmacological interventions (e.g., warm All selected patients underwent routine preoperative
fluids infusion and forced-air warming devices) provide medical check, preoperative and postoperative hemoglobin
inadequate control of central hypothermia and hence the concentration analysis, 6 h preoperative fast for solid food,
need for drugs for both treatment and prophylaxis of and 2 h preoperative fast for clear fluids.
shivering [6]. Newer effective and tolerable options for PSAS
prophylaxis are necessary to improve patients’ quality of
2.2. Randomization and Blinding. Patients were randomized
care.
into 3 groups (100 each) in a 1 : 1 : 1 allocation ratio in ac-
The antagonism of the serotonergic system was found to
cordance with shivering prevention protocol using com-
lower hypothalamic temperature set threshold, therefore
puter-generated random numbers concealed in sealed
reducing metabolic cold defense and suggesting a role in
opaque envelopes, and a nurse randomly chose the envelope
postoperative shivering control [7]. Mirtazapine is a nor-
to determine the assigned group [16]. Patients were allocated
adrenergic and a serotonergic antidepressant (NaSSA).
to mirtazapine (M) group, dexamethasone (D) group, or
Mirtazapine antagonises central α2-auto- and hetero-adre-
control (C) group and obtained shivering prophylaxis
noreceptors enhancing release of both noradrenergic and 5-
protocol 2 h before surgery. In M group, patients obtained
HT1A-mediated serotonergic neurotransmission [8].
30 mg mirtazapine tablet with sips of water and an identical-
Moreover, mirtazapine has anxiolytic, antinausea, and an-
looking placebo 100 ml 0.9% sodium chloride (normal saline
tiemetic effects due to blocking of 5-HT2 and 5-HT3 re-
[NS]) intravenous infusion (IVI) over 15 minutes. In D
ceptors [9]. In addition, mirtazapine has an antinociceptive
group, patients obtained 8 mg/2 ml dexamethasone ampoule
effect [8] and decreases incidence of PDPH after SA [10].
mixed with 100 ml 0.9% NS IVI over 15 minutes and an
Mirtazapine is promptly absorbed and its peak plasma
identical-looking placebo tablet, whereas in C group patients
concentration (C-max) is available within 1 to 2.1 h [11].
obtained an identical-looking placebo tablet and solution.
Dexamethasone diminished the frequency of shivering
Intervention drugs, including mirtazapine and dexa-
following open-heart surgeries. Anti-inflammatory prop-
erties of dexamethasone allow reduction of temperature ®
methasone, were in the form of Remeron tablets manu-
factured by Organon NV/Netherlands and Dexamethasone
gradient between tympanic and skin temperatures [12].
Preoperative 8 mg intravenous (IV) dexamethasone im- ®
Sodium Phosphate 8 mg/2 ml, ampoules, MUP Egypt. The
hospital pharmacy was responsible for preparation of the
proved quality of recovery in patients scheduled for lapa-
study drugs which were delivered to ward nurses to be given
roscopic cholecystectomy in comparison to placebo-treated
to patients. Follow-up notes were documented by anesthesia
patients [13–15]. IV dexamethasone may cause burning
residents. Patients, ward nurses, gynecologists, and anes-
perineal sensation in 50–70% of awake patients [13].
thesia residents were blinded to the patient’s group as-
This research assessed the impact of preemptive mir-
signment [16].
tazapine versus preemptive dexamethasone to decrease the
incidence and severity of PSAS in gynecological procedures.
2.3. Study Protocol. The research team applied the same
anesthetic management and the same quality of care to all
2. Methods patients involved in this study. Before commencing SA, no
premedication was given, standard monitoring was estab-
2.1. Study Population. This study was conducted between lished including tympanic membrane (core) temperature
March and August, 2018, after approval of the local ethical (T), and each patient received 10 ml/kg IV Ringer’s lactate
committee (FMASU R 47/2018) on 300 women, aged 18–60 preload. Core temperature was measured by Braun
years and ASA I or II scheduled for elective gynecological
surgeries under SA. This study was registered at ClinicalTrials. ®
ThermoScan IRT 4020 ear thermometer [17]. Operating
room temperature was provided in a range of 23–25°C and
gov (NCT03675555) and followed the regulations and 60 to 70% relative humidity. Hypothermia was developed if
amendments of the Helsinki Declaration-2013. Every patient the core temperature dropped below 36.5°C.
who chose to participate in this research signed a consent. Intrathecal block was performed at L3-4 or L4-5 in-
Exclusion criteria were diabetes mellitus, thyroid dis- terspace through the midline approach with patient in sitting
ease, cardiopulmonary disease, bleeding tendencies, neu- position using a 25-gauge Quincke spinal needle. The at-
rologic disease, psychological disorders, liver dysfunction, tending anesthesiologist injected 2.5–3.5 ml (12.5–17.5 mg)
a body mass index (BMI) >35 kg/m2, body temperature of 0.5% hyperbaric bupivacaine to reach the desired surgical
<36.5°C or >38.0°C, history of substance abuse, treatment level taking into consideration patient’s height and weight.
with sedative hypnotic agents, medications altering ther- By the end of SA technique, the patient lied supine, an
moregulation, vasodilators, allergy to the study medica- oxygen face mask was applied at a rate of 5 L/min, covered
tions, and contraindications to SA. Patients were also ruled with a standard single blanket and did not receive any active
out if they refused to participate in clinical research, re- perioperative warming.
quired blood transfusion during procedure, or had oper- Pinprick test was used to assess the peak sensory level,
ation time >120 min. If patients did not achieve satisfactory time to reach this level (min), and time to two-segment
bilateral sensory block level or Bromage score 3 motor regression (min) after the intrathecal bupivacaine admin-
blockade, they received general anesthesia and were ex- istration (starting point of this research). Anesthesia resi-
cluded from this research. dents reported success of SA if a bilateral T4-T8 sensory
Anesthesiology Research and Practice 3

block to pinprick test within 15 min of intrathecal drug β � 0.80 [23] and calculating with PASS 11th release [24].
administration happened and they also documented time to The research team allocated 100 cases for each study group
rescue analgesia (min). Motor block was evaluated by using to account for possible attrition and to detect possible ad-
modified Bromage score [18] to determine time to reach verse effects.
maximum motor block (Bromage score 3) (min) and du-
ration of motor block (min).
Hemodynamics of patients including heart rate (HR), 3.2. Data Analysis. The gathered data were managed and
mean arterial pressure (MAP), peripheral arterial oxygen analyzed using IBM SPSS statistics (Statistical Package for
saturation (SPO2%) and T were documented before intra- Social Sciences) program 22.0th release, IBM Corp., Chicago,
thecal injection (baseline) and thereafter at 2 and every 5 min USA, 2013. Quantitative data were described as mean ± SD
till the first 30 minutes after SA and then at 10-minutes (standard deviation) and then were compared using
intervals till 90 min after SA (ending point of the study). ANOVA test and repeated measures analysis of variance
Shivering severity was assessed by a scale of 4 grades 0; (RMANOVA) if normally distributed. If data were not
no shivering, 1; mild shivering, 2; moderate shivering, 3; normally distributed, median and 1st & 3rd interquartile
severe shivering [19]. Two anesthesia residents, unaware of range were used for description and Kruskal Wallis test for
the study intervention allocation, documented the grades of comparison. While in conditions of qualitative data, number
shivering till 90 min after the subarachnoid block. If the and percentage were used for description and each of chi
shivering grade developed to equal or more than 2 (clinically square test and Fisher’s exact test for comparisons
significant PSAS) after 15 min from the completion of SA, depending on expected number size. Rates were compared
the preventive protocol for PSAS was considered inefficient using Log rank test. P- value <0.050 was set as a significance
and 25 mg IV meperidine was administered. Onset of cut point. Bonferroni test was used for post hoc
shivering, response rate, and shivering recurrence were also comparisons.
reported. Response rate is the complete suspension of
shivering activity within 10 min after the first dose of me- 4. Results
peridine. Satisfaction of patients with shivering prevention
protocol was evaluated with seven-point Likert rating scale Among the 326 female patients who were screened for el-
[20]. igibility, 300 patients were properly enrolled and subjected
The research team documented any adverse events to statistical analysis. A consort flow chart is presented in
including hypotension (MAP <20% from prespinal Figure 1. There were no statistically significant differences in
values), bradycardia (HR <50 beats/min), respiratory demographics or confounders between the 3 groups
depression (respiratory rate ≤8/min or oxygen saturation (Table 1).
≤92%), pruritus, nausea, vomiting, headache, and dry More patients in M and C groups reached the peak
mouth. Hypotension was treated with 250 ml crystalloid sensory level in a significantly long period of time compared
infusion and/or incremental dose of 6 mg IV ephedrine. If to D group (P < 0.001) (Table 1) with no significant dif-
a patient complained of hypotension and nausea at the ference between M and C groups. D group patients had a
same time, an incremental dose of 6 mg IV ephedrine was significantly more time for two-segment regression and a
given. 0.01 mg/kg IV atropine was administered if bra- significantly more time for rescue analgesia in comparison to
dycardia occurred. Patients with nausea (>10 min) and/or M and C groups with significant differences between M and
vomiting (≥2 episodes) were treated with 10 mg IV C groups (P < 0.001, P < 0.001, respectively) (Table 1). There
metoclopramide. Pruritus was managed with 2 mg IV were no significant differences between groups as regards the
®
clemastine (Tavegyl ). Sedation was evaluated every
15 min over 90 min after SA and was assessed with a scale
peak sensory level, the time to reach maximum motor block,
and the duration of motor block (P � 0.389, P � 0.062,
of four points as per Filos et al. [21]. The research team P � 0.065, respectively) (Table 1).
members collected blood samples from all patients pre- Alterations of heart rate were comparable between the
operatively and one week after surgery to compare liver three groups till 90 min after SA (P > 0.05) (Figure 2). More
enzymes level (SGPT). cases in M and D groups exhibited higher MBP values till
The incidence of clinically significant PSAS occurring 25 min after SA in comparison to C group (P < 0.001) with
during the first 90 min after SA was considered as a primary comparable efficacy between M and D groups (Figure 3).
outcome. Secondary outcomes included evaluation of core Alterations of SpO2 (%) were comparable between the three
temperature, shivering profile, satisfaction of patients with groups till 90 min after SA (P > 0.05).
shivering prophylaxis protocol, and adverse events. Core temperature values 90 min after SA were signifi-
cantly decreased in the three groups in comparison to
3. Statistical Analysis baseline values (P < 0.001) (Figure 4) without significant
difference when compared to each other (P > 0.05).
3.1. Power of the Study. Based on earlier research, a sample In C group, the incidence of shivering was higher
size of 19 cases in every group was required to keep a whereas the onset of shivering was lower than the other two
statistical significance when the expected incidences among groups with significant differences between M and D groups
the three groups were as follows: group C (33.3%), group P (P < 0.001, P < 0.001, respectively) (Table 2) (Figures 5 and
(0.0%), and group D (0.0%) [22] with adjusting α � 0.017, 6). The incidence of clinically significant shivering was
4 Anesthesiology Research and Practice

Assessed for eligibility

n=326

Excluded (n= 26)

Not meeting
Enrollment inclusion criteria
(n=17)
Declined to
participate (n= 9)

Randomization
n=300

M group (n=100) D group (n=100) C group (n=100)

Received allocated intervention Received allocated Received allocated
(n=100) intervention (n=100) intervention (n=100)
Allocation
Did not receive allocated Did not receive allocated Did not receive allocated
intervention (n=0) intervention (n=0) intervention (n=0)

Lost to follow-up (n=0) Lost to follow-up (n=0) Lost to follow-up (n=0) Follow-up

Analysis of data Analysis of data Analysis of data

Analysis
n=100 n=100 n=100

Figure 1: Consort flow chart.

higher in C group (74.0%) in comparison to M group groups (P < 0.001, P < 0.001, P < 0.001, P < 0.001, respec-
(16.0%) and D group (31.0%) with significant differences tively) (Table 3). In M group, sedation scores and incidence
between M and D groups (P < 0.001) (Table 2) (Figure 6). In of dry mouth were higher than the other two groups
C group, the mean dose of meperidine was higher whereas (P < 0.001, P < 0.001, respectively) (Table 3) with no sta-
the response rate after single dose of meperidine was lower tistically significant differences between D and C groups.
than the other two groups with significant differences be- More patients in M and D groups were satisfied with
tween M and D groups (P < 0.001, P � 0.002, respectively) shivering prophylaxis protocol in comparison to C group
(Table 2). The recurrence of shivering was recorded in 9/31 (P < 0.001) (Table 3) with comparable efficacy between M
(29.0%) patients of D group and in 33/74 (44.6%) patients of and D groups.
C group; on the contrary, no recurrence of shivering was
documented in M group (P � 0.002) (Table 2).
5. Discussion
In C group, incidence of postspinal anesthesia (PSA)
hypotensive episodes, the administered ephedrine, and the The research team had found that the use of a one pre-
need for ephedrine to treat hypotension were more frequent emptive dose of mirtazapine versus a one preemptive dose of
than the other two groups with comparable efficacy between dexamethasone efficiently decreased the incidence and se-
M and D groups (P < 0.001, P < 0.001, P < 0.001 respec- verity of PSAS in comparison to placebo controls in gy-
tively) (Table 3). Incidences of pruritus, nausea, vomiting, necological procedures under SA. In addition, incidence of
and use of rescue antiemetic were higher in C group than the hypotensive episodes, pruritus, nausea, and vomiting were
other two groups with comparable efficacy between M and D lower in M and D groups in comparison to C group.
Anesthesiology Research and Practice 5

Table 1: Patients’ demographics and perioperative data.

Items M group (n � 100) D group (n � 100) C group (n � 100) P value
^
Age (year) 44.3 ± 7.9 44.8 ± 7.4 42.8 ± 7.2 0.140
BMI (kg/m2) 30.4 ± 1.5 30.5 ± 1.6 30.2 ± 1.7 ^
0.288
#
ASA (I/II) 26/74 27/73 29/71 0.889
^
Dose of bupivacaine (mg) 14.9 ± 1.9 15.1 ± 1.9 15.4 ± 2.1 0.199
^
Operation time (min) 113.9 ± 14.4 113.6 ± 13.6 112.5 ± 13.7 0.761
Types of operations; n, %
(i) Total abdominal hysterectomy (TAH) 14 (14%) 13 (13%) 12 (12%)
(ii) TAH + BSO 40 (40%) 41 (41%) 39 (39%)
#
(iii) Vaginal hysterectomy (VH) 9 (9%) 10 (10%) 8 (8%) 0.998
(iv) VH + PFR 27 (27%) 26 (26%) 28 (28%)
(v) Vesicovaginal fistula repair 10 (10%) 10 (10%) 13 (13%)
^
Preoperative Hb (g/dl) 11.5 ± 0.4 11.5 ± 0.4 11.6 ± 0.4 0.141
^
Postoperative Hb (g/dl) 9.3 ± 0.5 9.3 ± 0.4 9.4 ± 0.4 0.342
^
Total IV fluids used (ml) 2035.0 ± 111.4 2007.0 ± 117.4 2023.0 ± 116.2 0.227
Characteristics of neuraxial anesthesia techniques
§
Peak sensory level T5 (T4–T8) T6 (T4–T8) T6 (T4–T8) 0.389
^
Time to peak sensory level (min) 6.5 ± 0.6a 4.6 ± 0.6b 6.7 ± 0.6a <0.001∗
^
Time to two-segment regression (min) 63.2 ± 1.7a 77.1 ± 1.4b 69.3 ± 1.2c <0.001∗
^
Time to reach maximum motor block (min) 9.2 ± 0.4 9.1 ± 0.5 9.2 ± 0.4 0.062
^
Duration of motor block (min) 135.2 ± 2.4 135.9 ± 2.2 135.4 ± 2.3 0.065
^
Time to rescue analgesia (min) 173.9 ± 4.1a 321.3 ± 4.8 b 215.8 ± 4.4c <0.001∗
Data were presented as median (range), mean (SD), numbers, and percent. ^ANOVA test, #chi square test, and §Kruskal Wallis test. Labels (a, b, c) denote
homogenous groups depending on post hoc Bonferroni test. ∗ Statistically significant. TAH + BSO: total abdominal hysterectomy with a bilateral salpingo-
oophorectomy. PFR: pelvic floor repair. M group: mirtazapine group; D group: dexamethasone group; C group: control group.

100
95
90
Heart rate (beats/min)

85 *
80
75
70
65
60
55
50
Pre-spinal

2 min

5 min

10 min

15 min

20 min

25 min

30 min

40 min

50 min

60 min

70 min

80 min

90 min

M Group
D Group
C Group
Figure 2: Heart rate (beats/min) changes over 90 minutes among the studied groups.

Both physical and therapeutic strategies have been used Maximal effects of the three mechanisms of SA causing
to diminish loss of tympanic temperature for prevention of core hypothermia occur at the 1st 30–60 min after the
PSAS. In addition, the use of forced-air warming devices and subarachnoid block necessitating patients’ monitoring, ac-
meperidine to maintain tympanic temperatures of patients tively warming and antishivering treatment. So, the research
at ≥36.5°C is also recommended by the ASA guidelines [25]. team chose the 1st 90 minutes after SA as a time frame for
Nonetheless, potential side effects of meperidine were this study [3]. In addition, an anecdotally endorsed dose for
previously described [26]. So, the investigators conducted oral mirtazapine is a single administration of 30 mg tablet
this study to possibly seek medications with insignificant [10, 27] taken 2 hours prior to surgery [27], whereas the
adverse effects to substitute the utilization of IV meperidine selected protocol for dexamethasone administration was
for management of PSAS. based on earlier research [13] and adhered to optimal dose
6 Anesthesiology Research and Practice

100
95

Mean arterial blood pressure

90
85
80

(mmHg)
75
70
65
60 *
* * * *
55
50 Pre-spinal

2 min

5 min

10 min

15 min

20 min

25 min

30 min

40 min

50 min

60 min

70 min

80 min

90 min
M Group
D Group
C Group
Figure 3: Mean arterial blood pressure (mm·Hg) changes over 90 minutes among the studied groups. ∗ Statistically significant.

37.2
Core (Tympanic membrabe)

37.0
temperature(°C)

36.8

36.6

36.4

36.2

36.0 * * *
Pre-spinal 90 min after

M Group
D Group
C Group
Figure 4: Variations in core temperature (°C) after 90 minutes of subarachnoid block in comparison to the prespinal (baseline) values.
∗
Statistically significant.

Table 2: Incidence, grades, and treatment of postspinal anesthesia shivering among the studied groups.
Time points M group (n � 100) D group (n � 100) C group (n � 100) P value
#
Incidence of shivering; n, % 41 (41%) a 62 (62%) b 91 (91%) c <0.001∗
Grade; n, %
(i) 0 59 (59%) a 38 (38%) b 9 (9%) c
(ii) I 25(25%) a 31 (31%) a 17 (17%) a #
<0.001∗
(iii) II 10 (10%) a 19 (19%) a 43 (43%) b
(iv) III 6 (6%) a 12 (12%) a 31 (31%) b
#
Patients with clinically significant shivering (Grade ≥2); n, % 16 (16%) a 31 (31%) b 74 (74%) c <0.001∗
^
Onset of shivering (min) 51.3 ± 5.2 a 32.8 ± 3.5 b 16.0 ± 5.4 c <0.001∗
^
Dose of meperidine (mg) 25.1 ± 1.2 a 31.3 ± 4.7b 36.1 ± 3.5 c <0.001∗
st #
Response rate after administration of 1 dose of meperidine; n, % 16 (100%) a 22 (71%) b 41 (55.4%) b 0.002∗
#
Recurrence; n, % 0 (0.0%) a 9 (29%) b 33 (44.6%) b 0.002∗
Data were presented as numbers and percent. #Chi square test and ^ANOVA test. Labels (a, b, c) denote homogenous groups depending on post hoc
Bonferroni test. ∗ Statistically significant. M group: mirtazapine group; D group: dexamethasone group; C group: control group.
Anesthesiology Research and Practice 7

1.0

Proportion of patients not in shivering

0.8

0.6

(Grade 0)
0.4

Log rank test,

0.2 P-value <0.001

0.0
0 20 40 60 80 100
Study period (minutes)

Group-M Group-M-censored
Group-D Group-D-censored
Group-C Group-C-censored
Figure 5: Proportions of patients not in shivering (Grade 0) represented on the Kaplan Meier plot.

100
90
80 74.0%
70
59.0%
60
% 50 43.0%
38.0%
40
31.0% 31.0% 31.0%
30 25.0%
17.0% 19.0%
20 16.0%
10.0% 12.0%
9.0%
10 6.0%

0
Grade 0 Grade 1 Grade 2 Grade 3 Grade 2+3

M Group (N=100)
D Group (N=100)
C Group (N=100)
Figure 6: Patients’ percentages of different grades of shivering after 90 minutes of subarachnoid block.

[12–15] for prevention of postoperative nausea and vomiting acts on mixed receptors and strongly and selectively binds to
after laparoscopic cholecystectomy (LC) [15]. the 5-HT3 receptors with decreased or no affinity for other 5-
Patients’ demographic characteristics and patients’ HT receptors. Moreover, mirtazapine may affect pain
perioperative data of the three groups were comparable modulation of the spinal cord through antagonism of 5-HT3
(Table 1). The investigators of this research reported that M receptors [28, 29]. Moreover, results of this study matched
group had a significantly faster regression times by two with previous studies assessing the advantages of dexa-
segments and a significantly shorter duration of analgesia methasone whether IV [3, 15, 30] or intrathecally [26] in
than placebo-treated patients. The investigators suggested an reducing the time to the highest dermatome block level and
explanation to these findings by the similarity between increasing both the regression times by two segments and
mirtazapine and granisetron, contrary to ondansetron, that the duration of analgesia.
8 Anesthesiology Research and Practice

Table 3: Side effects, administered treatments, and patient satisfaction score.

Time points M group (n � 100) D group (n � 100) C group (n � 100) P value
#
Bradycardia; n,% 6 (6%) 8 (8%) 7 (7%) 0.858
#
Hypotension; n,% 6 (6%) a 8 (8%) a 25 (25%) b <0.001∗
#
Need for ephedrine; n, % 27 (27%) a 32 (32%) a 78 (78%) b <0.001∗
^
Ephedrine dose (mg) 10.3 ± 3.1 a 13.5 ± 4 a 21.4 ± 6.9 b <0.001∗
#
Pruritus; n, % 2 (2%) a 10 (10%) a 24 (24%) b <0.001∗
#
Nausea; n, % 4 (4%) a 5 (5%) a 28 (28%) b <0.001∗
#
Vomiting; n, % 2 (2%) a 3 (3%) a 17 (17%) b <0.001∗
#
Rescue antiemetic; n, % 3 (3%) a 4 (4%) a 22 (22%) b <0.001∗
Sedation; n, %
(i) I 7 (7%) a 100 (100%) b 100 (100%)b
(ii) II 85 (85%) 0 (0) 0 (0) #
<0.001∗
(iii) III 8 (8%) 0 (0) 0 (0)
(iv) IV 0 (0) 0 (0) 0 (0)
#
Headache; n, % 6 (6%) 4 (4%) 5 (5%) 0.810
#
Dry mouth; n, % 22 (22%) a 8 (8%) b 10 (10%) b 0.007∗
⌂
Elevated liver enzymes; n, % 3 (3%) 1 (1%) 1 (1%) 0.625
§
Patient satisfaction score 5.0 (5-6) a 5.0 (4–6) a 2.0 (2-3) b <0.001∗
Data were presented as median (range), mean (SD), numbers, and percent. #Chi square test,^ANOVA test, §Kruskal Wallis test, and ⌂Fisher’s exact test. Labels
(a, b, c) denote homogenous groups depending on post hoc Bonferroni test. ∗ Statistically significant. M group: mirtazapine group; D group: dexamethasone
group; C group: control group.

Results of this study revealed that the incidence of hy- dexamethasone and spinal meperidine for reducing the
potensive episodes after SA during the study period was shivering threshold in comparison to control group in
lower in M group due to the 5-HT3 blocking properties of transurethral prostatectomy under SA [26]. Moreover, our
mirtazapine as displayed by other 5-HT3 receptor antago- results were supported by prior studies regarding high doses
nists [29, 31]. Furthermore, a previous study reported about of meperidine used to manage PSAS in placebo controls in
possible mechanisms of dexamethasone in attenuation of comparison to intervention groups [22, 36].
PSA hypotension [16]. Terkawi et al., in contrast to our The results of Abdel-Ghaffar et al. and Chen et al. were in
results, reported that ondansetron premedication did not concordance with our recent findings concerning the lower
attenuate hemodynamic changes after SA; did not reduce the percentage of pruritus, nausea episodes, and vomiting ep-
amount of vasopressor use; and did not decrease the inci- isodes in M group and they attributed the antipruritic and
dence of pruritus, nausea, and vomiting [32]. antiemetic efficacy due to 5-HT3 receptor blockers prop-
SA-induced vasodilation in the lower half of body will erties of mirtazapine [27, 36]. In addition, 5-HT3 antago-
lead to loss of thermoregulation and core hypothermia nists, like ondansetron, and granisetron have been utilized to
whereas vasoconstriction and shivering will be confined to forestall the neuraxial opioid-induced pruritus. Further-
the upper half of the body to augment tympanic temperature more, mirtazapine has strong antihistamine effect, exerts its
[3]. The research team reported a higher incidence of antipruritic effect through activating the k-opioid system,
clinically significant shivering in placebo-treated patients in and reduces the perception of pruritus through action on the
spite of significant differences between basal and 90 minutes cerebral cortex [37]. In spite of the antiemetic and anti-
after SA tympanic temperature measurements in the three inflammatory properties of dexamethasone, it lacks an an-
groups following high level of the subarachnoid block tipruritic effect [38]. However, earlier research showed re-
[33, 34]. This might be explained by mirtazapine-induced duced severity of pruritus in dexamethasone-treated patients
serotonin uptake inhibition in the preoptic anterior hypo- compared to placebo-treated patients which reinforced
thalamic part which controls heat production and loss [34]. outcomes of this study [39]. Furthermore, the high per-
In addition, anti-inflammatory properties of dexamethasone centage of pruritus, nausea, and vomiting in C group cases
allow reduction of temperature gradient between tympanic may be due to increased utilization of meperidine [26]. In
and skin temperatures [12]. Similar to the current study, addition, the research team recorded increased utilization of
Shen et al. [35] and a plethora of studies [34, 36] documented ephedrine in C group cases which might explain probability
that prophylactic 5-HT3 receptor antagonists were efficient of systemic hypersensitivity reactions [40].
for decreasing the occurrence of perioperative shivering Chen et al. recorded that premedication with mirtaza-
(POS) in patients after SA. In addition, Kelsaka et al. also pine reduced preoperative anxiety in patients undergoing
reported no significant difference in the incidence of shiv- gynecological operations [27]. Those results were consistent
ering between ondansetron and meperidine groups in or- with this study that affirmed the sedative response of mir-
thopedic surgeries under SA [34]. Additionally, previous tazapine as proved by higher Ramsay sedation scores.
studies revealed that dexamethasone decreased post- Moreover, use of dexamethasone improves mood and it
anesthetic shivering [12, 15]. Over and above, earlier clinical could also lead to a greater feeling of well-being due to
study had documented equal efficacy of spinal primary central nervous system impact of steroids [15]. For
Anesthesiology Research and Practice 9

the aforementioned merits of mirtazapine and dexameth- Consent

asone, this might justify high satisfaction scores in mirta-
zapine and dexamethasone groups in comparison to Written consent was obtained from each patient who par-
placebo-treated patients. ticipated in this research.
This clinical trial suffered distinct limits. To begin
with, this research needed warmed IV fluids. At our Conflicts of Interest
institution, the utilization of warmed IV fluids is held for
emergency procedures and for all lengthy procedures. The authors declare that they have no conflicts of interest.
Nevertheless, the research team trusted that the utili-
zation of mirtazapine and dexamethasone in this clinical Authors’ Contributions
trial furnished an easy, demonstrated adequacy as an-
IM E formulated the research design and database searching,
tiemetic, less side effects, and more economical for
performed the clinical study, and wrote the primary and final
prevention of PSAS in countries with low financial re-
manuscript. AM E performed the clinical study, database
sources. Second, the consequences of this study did
searching, and drafted the manuscript. HM E analyzed the
exclude endoscopic urosurgical procedures and invasive
data and drew graphs and tables. TM A performed the
procedures interconnected with increased blood loss. In
clinical study and database searching and final manuscript
spite of that, the investigators proved that mirtazapine
editing.
and dexamethasone diminished the impact of high levels
of intrathecal block which reduced the tympanic tem-
perature threshold for shivering [33, 34]. Furthermore,
Acknowledgments
mirtazapine and dexamethasone showed the favorable The investigators are thankful to the anesthesia residents and
feedback to stay away from the techniques used to escape the operating theatre staff for their valuable help in data
the PSA hypotension (e.g., volume loading or vaso- collection. Support was provided from Ain-Shams Uni-
pressor use) which might augment the risk of hyper- versity Hospital resources.
volemia as well as myocardial ischemia [16]. Third, this
clinical trial was completed at a single center. Even so, References
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