Asian Journal of Anesthesiology 57(3): 66-84, Sep.

2019
DOI:10.6859/aja.201909_57(3).0002
Review Article

Pharmacological Approach for the Prevention of

Postoperative Shivering: A Systematic Review of
Prospective Randomized Controlled Trials
Paraskevi K. Matsota, Iosifina K. Koliantzaki, Georgia G. Kostopanagiotou
2nd Department of Anesthesiology, School of Medicine, National and Kapodistrian University of Athens, “Attikon” University Hospital,
Athens, Greece

Shivering is a common postoperative complication that occurs after both general and regional anesthesia
even in the cases when hypothermia during surgery has been averted. Patients describe it as a highly
unpleasant experience, while clinicians are concerned due to its adverse effects such as increased oxygen
consumption. In this article, we present a summary of the pathophysiological mechanisms involved in
postoperative shivering (POS), risk factors, and inadvertent effects. The major objective of this article was to
review the existing literature on the efficiency of various drug interventions as a prophylactic measure against
POS. Since α2-adrenergic, opioid, anticholinergic, and serotonergic pathways are thought to play a role in the
pathogenesis of POS, a wide variety of drugs has been investigated in this regard. Although the methodological
diversity of the study designs and regimens does not support drawing definite conclusions, there is evidence
indicating a beneficial effect of dexmedetomidine, ketamine, tramadol, meperidine, dexamethasone, nefopam,
granisetron, and ondansetron in the prevention of POS. The purpose of this review is to provide a thorough
insight on various drug options and to serve as an aid for clinicians for careful analysis of the advantages and
disadvantages of each regimen to decide which regimen will be ideally suited for the medical profile of each
patient.
Keywords: drugs, preventing, postoperative shivering

Introduction always seem to correlate with the incidence of shiv-

Postoperative shivering (POS) is defined as read-
ily detectable fasciculations affecting muscle groups,
usually appearing early in the postoperative period.1
Its prevalence ranges between 5–65% after general
anesthesia and 33–66% after regional anesthesia.2
Pathophysiology
Shivering is the body’s response to augment heat
production commonly perceived as a symptom of hy-
pothermia, although core body temperature does not
ering after anesthesia. Thus, non-thermoregulatory
shivering is believed to be caused by special factors
related to surgery, such as stress or pain.3-5
Risk Factors
Risk factors that predispose the patient to hy-
pothermia and shivering include young age,6 male
gender,7 low body weight, or poor nutritional status,8
prolonged preoperative fasting,9 an American Society
of Anesthesiologists (ASA) risk class higher than I,10
combined general-regional anesthesia and the extent

Received: 29 May 2019; Received in revised form 7 June 2019; Accepted: 2 July 2019.
Corresponding Author: Paraskevi K. Matsota, MD, PhD, 2nd Department of Anesthesiology, School of Medicine, National and Kapodistrian
University of Athens, “Attikon” University Hospital, Rimini 1 Str, Chaidari, Postal Code 12462, Athens, Greece. E-mail: matsota@yahoo.gr

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 Drugs Used to Prevent Postoperative Shivering

of induced sympathetic blockade,8,10 administration of Exclusion Criteria

premedication, volatile anesthetics, and muscle relax-
We did not include data from retrospective anal-
ants.11
yses or studies without randomization, to avoid any
Furthermore, the type and duration of surgery
potential bias. Also, data from abstracts, case reports,
are the surgery-related risk factors for the develop-
nonsurgical settings, cardiac surgery or any other type
ment of hypothermia. Endoprosthesis and long-lasting
of surgery using induced hypothermia, guidelines, or
abdominal surgery bear a high risk of consequential
from experimental studies using volunteers or animals
hypothermia. 6 Likewise, intraoperative use of un-
were excluded.
warmed irrigation fluids,12 transfusion of cold red
blood cells and the low temperature of the operating
room (OR)13 predispose the patient to hypothermia. Results
Trials Included
Adverse Effects
Of the 244 articles identified initially, only 38
Patients describe shivering as a highly disturbing
met the selection criteria for this review and were in-
experience. However, the foremost concern of clini-
cluded in the analysis. The flow diagram is illustrated
cians lies in the fact that shivering can increase oxy-
in Fig. 1.
gen consumption dramatically, by up to 700% in cases
From the 38 included studies, 24 studies had
of severe shivering.14 This imposes significant stress
been performed on patients undergoing surgery under
on patients, particularly those with burdened cardio-
general anesthesia and 1 under conscious sedation
respiratory reserve. Furthermore, shivering increases
(Table 1),19–43 and 13 on patients receiving regional
intraocular15 and intracranial pressure.16 Hypothermia,
anesthesia (Table 2). 44–56 Information on patients,
which may be the underlying cause of shivering, is
type of surgery, investigated drugs (doses, routes, and
associated with a number of adverse events,17,18 but
timing of the administration), power of the study and
discussion on these extends beyond the scope of this
study findings are presented in these Tables.
review.
Since α2-adrenergic, opioid, anticholinergic, and
Several studies investigating the precautionary
serotonergic pathways are thought to contribute to
measures for shivering have been conducted. This re-
the pathogenesis of POS, a wide variety of drugs has
view aims to investigate the existing literature regard-
been investigated regarding their efficacy in its pre-
ing the efficacy of various drugs used to prevent POS.
vention. The route of administration for all the drugs
mentioned in this review is mainly intravenous unless
Methods stated otherwise.
Identification of Trials α2-Adrenergic Agonists
Published trials (till the September of 2018)
The efficacy of α2-adrenergic agonists in the
investigating the pharmacological options for the
prevention of POS has been extensively investigated.
prevention of POS were identified by conducting a
Dexmedetomidine, with an α1/α2 ratio of 1:1,620,
search on PubMed and Scopus databases, using the
is a highly selective and potent drug of this class, as
keywords “preventing postoperative shivering” and
opposed to clonidine, which is a partial agonist with
“preventing shivering after anesthesia.”
an α1/α2 ratio of 1:220.57 Due to the selectivity of
dexmedetomidine, it is preferred over clonidine in the
Inclusion Criteria
majority of relevant trials.
We considered solely prospective randomized
clinical trials written in English. The investigated General Anesthesia—Τable 1
drugs had been administered prophylactically at any Our review revealed that clonidine, adminis-
time between just before the induction of anesthesia tered either as oral premedication (0.2 mg) 25 or as
till the end of surgery, as a single dose or by infusion, an intravenous bolus dose (2 mcg/kg) at the end of
through any parenteral or enteral route. surgery, 20 effectively prevents POS after general
anesthesia. Dexmedetomidine (1 mcg/kg) appears

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 Matsota et al.
Fig. 1. Flow diagram.
to be as efficacious against POS as meperidine (0.5
mg/kg),19,22,24 but is inferior to tramadol (1 mg/kg),20
when administered at the end of surgery. In contrast,
Alvarez Corredor reported that 0.4 mg/kg meperidine
performed better than 1 mcg/kg dexmedetomidine.19
However, one must also consider that 70% of the
patients in the dexmedetomidine group reported se-
vere postoperative pain, while most of the patients in
the other groups reported mild to no pain. Since the
presence of postoperative pain can facilitate non-ther-
moregulatory tremors,4 coupled with the fact that the
mean duration of anesthesia and surgery, volume of
intraoperative IV fluids and blood loss were greater
in the dexmedetomidine group, the result may be
considerably biased against dexmedetomidine. Kim
68 Asian Journal of Anesthesiology 57(3) 2019
麻醉學雜誌57(3)-02 Paraskevi Matsota.indd 68
et al. compared three different dosages of dexmedeto-
midine (0.50, 0.75, and 1.00 mcg/kg) to placebo and
found that dexmedetomidine at 0.75 or 1.00 mcg/kg
is an effective prophylactic measure against shivering
when administered 30 min before the completion of
surgery.21 Furthermore, dexmedetomidine infusion
has been successfully used in a placebo-controlled
study.23 Sedation, prolonged extubation time, and a
tendency of lower mean arterial pressure and heart
rate, all of which are dose-dependent adverse effects,
were observed in most of the aforementioned studies,
without compromising the outcomes of anesthesia.
Regional Anesthesia—Table 2
Only two published studies have investigated
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 Table 1. Randomized controlled trials investigating drugs to prevent postoperative shivering in patients who received general anesthesia

Title Intervention Study population Type of surgery/anesthesia Conclusion Power

Alvarez 1. Dexmedetomidine 1.00 mcg/kg iv 160 patients, Both elective and emergency Meperidine was the most 80%
Corredor19 2. Meperidine 0.40 mg/kg iv ASA I–II, 18–70 surgery lasted more than effective drug in preventing

麻醉學雜誌57(3)-02 Paraskevi Matsota.indd 69

3. Ketamine 0.50 mg/kg iv years 1 h, including open and POS, while 70% of patients in
4. Placebo (0.9% saline solution) iv laparoscopic procedures. the group of dexmedetomidine
All drugs were given 20 min before skin suture. General anesthesia. reported severe pain (p <
0.01).
Sahi et al.20 1. Clonidine 2 μg/kg iv 120 patients, ASA LPC. General anesthesia. Tramadol was the most NM
2. Tramadol 1 mg/kg iv I–II, adults effective drug, although all
3. Dexmedetomidine 1 mcg/kg iv three drugs were more effective
4. Placebo (0.9% saline solution) iv than placebo in preventing
All drugs were given at the beginning of wound POS.
closure.
Kim et al.21 1. Dexmedetomidine 0.50 mcg/kg iv 132 patients, Elective laparoscopic total Higher doses of 80%
2. Dexmedetomidine 0.75 mcg/kg iv ASA I–II, 18–60 hysterectomy. General dexmedetomidine (0.75 mcg/
3. Dexmedetomidine 1.00 mcg/kg iv years, female anesthesia kg and 1.00 mcg/kg) were
4. Placebo (0.9% saline solution) iv effective in preventing POS.
All drugs were given 30 min before the
anticipated completion of surgery.
Bicer et al.22 1. Dexmedetomidine 1.00 mcg/kg iv 120 patients Elective abdominal or Both drugs were equally NM
2. Meperidine 0.50 mg/kg iv ASA I-II, 18–50 orthopedic surgery of about effective in preventing POS.
3. Placebo (0.9% saline solution) iv years 1–3 h duration. General
All drugs were given at the time of wound anesthesia
closure.
Karaman et al.23 1. Dexmedetomidine iv as a loading of 1.00 mcg/ 60 patients, Elective gynecologic Dexmedetomidine was NM
kg for 10 min followed by a maintenance ASA I–II, laparoscopy. General effective in preventing POS.
infusion of 0.50 mcg/kg/h 20–50 years, anesthesia
2. Placebo iv (0.9% saline solution given at a female
similar mode)
The loading dose was given just after
endotracheal intubation. The infusion was
stopped at the beginning of the closure of the
fascia.

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 Table 1. Randomized controlled trials investigating drugs to prevent postoperative shivering in patients who received general anesthesia (continued)

Title Intervention Study population Type of surgery/anesthesia Conclusion Power

24
Aldehayat 1. Dexmedetomidine 1.00 mcg/kg iv 70 patients, ASA The type of surgery was Dexmedetomidine was NM
2. Placebo iv (0.9% saline solution) –II patients, not mentioned. General effective in preventing POS.
Matsota et al.

All drugs were given 20 min before the end of 18–68 years anesthesia anticipated to last

麻醉學雜誌57(3)-02 Paraskevi Matsota.indd 70

the surgery. 2 to 3 h.
Mohammadi and 1. Clonidine 0.20 mg orally 80 patients, ASA Elective abdominal surgery. Clonidine was effective in 85%
Seyedi25 2. Placebo (0.9% saline solution) I–II, General anesthesia. preventing POS.
All drugs were given 30 min before induction of older than 18
anesthesia. years
Petskul et al.26 1. Ketamine 0.25 mg/kg iv 183 patients, ASA Orthopedic surgery. General Ketamine failed to prevent 80%
2. Placebo iv (0.9% saline solution) I–II, anesthesia. POS.
All drugs were given 20 min before the 18–65 years

70 Asian Journal of Anesthesiology 57(3) 2019

completion of surgery.
Norouzi et al.27 1. Ketamine 0.125 mg/Kg iv 120 patients, ASA Elective orthopedic surgery. Higher doses of Ketamine NM
2. Ketamine 0.250 mg/Kg iv I–II, 18–65 years General anesthesia (0.25 mg/kg, 0.5mg/kg) were
3. Ketamine 0.500 mg/Kg iv effective in preventing POS
4. Placebo iv (0.9% saline solution)
All drugs were given 20 min before completion
of surgery
Dal et al.28 1. Pethidine 20.0 mg iv 90 patients, ASA General anesthesia for Both drugs were equally NM
2. Ketamine 0.5 mg kg/kg iv I–II, 18–65 years surgery lasting 60–180 min. effective in preventing POS.
3. Placebo iv (0.9% saline solution)
All drugs were given 20 min before completion
of surgery.
Zavareh et al.29 1. Pethidine 0.5 mg/kg iv 135 patients, ASA Elective surgery. Pethidine was more effective NM
2. Ketamine 0.5 mg/kg iv I–II, 18–70 years General anesthesia than the other two drugs in
3. Dexamethasone 0.6 mg/kg iv preventing POS.
All drugs were given 30 min before the
anticipated completion of surgery.

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 Table 1. Randomized controlled trials investigating drugs to prevent postoperative shivering in patients who received general anesthesia (continued)

Title Intervention Study population Type of surgery/anesthesia Conclusion Power

Köse et al.30 1. Meperidine 20.00 mg iv 150 patients, ASA General anesthesia for an Meperidine 20 mg and NM
2. Ketamine 0.10 mg/kg iv I–II, 18–65 years anticipated duration of ketamine 0.5 mg/kg were

麻醉學雜誌57(3)-02 Paraskevi Matsota.indd 71

3. Ketamine 0.25 iv 60–180 min effective in preventing POS.
4. Ketamine 0.50 mg/kg iv
5. Placebo iv (0.9% saline solution)
All drugs were given 20 min before completion
of surgery.
Dar et al.31 1. Pethidine 20.0 mg iv 90 patients, ASA General anesthesia for an Investigated drugs were 93%
2. Ketamine 0.5 mg/kg iv I–II, 18–70 years anticipated duration of equally effective in
3. Placebo iv (0.9% saline solution) 120–180 min preventing POS.
All drugs were given 20 min before the end of
surgery.
Ogawa et al.32 1. Remifentanil 29 patients, ASA Laparotomy or laparoscopic Remifentanil + Ketamine NM
2. Remifentanil ＋ ketamine 0.5 mg/kg iv I–II, 20–80 years gastrointestinal and were effective in preventing
Infusions were started immediately after gynecological surgery lasted POS.
anesthesia induction, the flow rate was set at more than 2 h. General
5.0 mcg/kg/min by continuous iv infusion, and anesthesia
they were discontinued
Approximately 15 min before completion of
surgery.
Yousuf et al.33 1. Propofol groups 124 patients, ASA Orthopedic, gynecological, Tramadol in a dose of 1 80%
a. Tramadol 1 mg/kg iv I–II, 18–60 years and general surgical mg/kg with propofol as an
b. Placebo iv (0.9% saline solution) procedures with duration induction agent was more
2. Thiopentone groups of 60–240 min. General effective in preventing POS.
a. Tramadol 1 mg/kg iv anesthesia
b. Placebo iv (0.9% saline solution)
All drugs were given 15 min before wound
closure.

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 Table 1. Randomized controlled trials investigating drugs to prevent postoperative shivering in patients who received general anesthesia (continued)

Title Intervention Study population Type of surgery/anesthesia Conclusion Power

34
Mohta et al. 1. Tramadol 1.0 mg/kg iv 165 patients, ASA Elective abdominal surgery All three doses of tramadol 80%
2. Tramadol 2.0 mg/kg iv I–II, adults performed under general were effective and
Matsota et al.

3. Tramadol 3.0 mg/kg iv anesthesia with expected comparable to meperidine in

麻醉學雜誌57(3)-02 Paraskevi Matsota.indd 72

4. Pethidine 0.5 mg/kg iv duration > 1 h and expected preventing POS.
5. Placebo iv (0.9% saline solution) VAS score ≥ 5 cm.
All drugs were given at the time of wound
closure.
Heid et al.35 1. Tramadol 2.0 mg/kg iv 60 patients, ASA Lumbar disc surgery under Tramadol 2 mg/kg was more 80%
2. Placebo iv (0.9% saline solution) I–III, 18–75 years remifentanil-based general effective in preventing POS.
All drugs were given 45–30 min before skin anesthesia.
closure.

72 Asian Journal of Anesthesiology 57(3) 2019

Angral et al.36 1. Laparoscopic 80 patients, ASA Laparoscopic or open Tramadol 1.0 mg/kg was 80%
a. Tramadol 1.0 mg/kg iv I–II cholecystectomy General effective in preventing POS
b. Placebo iv (0.9% saline solution) anesthesia following both open and
2. Open laparoscopic surgery.
a. Tramadol 1.0 mg/kg iv
b. Placebo iv (0.9% saline solution)
All drugs were given at the time of wound
closure.
Sajedi et al.37 1. Tramadol 1.0 mg/kg iv 132 patients, ASA Elective orthopedic surgery. All drugs were equally NM
2. Granisetron 40.0 mcg/kg iv I–II, 18 65 years General anesthesia effective in preventing POS.
3. Meperidine 0.4 mg/kg iv
4. Placebo iv (0.9% saline solution)
All drugs were given at the end of surgery.
Abdollahi et 1. Meperidine 0.4 mg/kg iv 90 patients, ASA OPCABG under general Ondansetron 8.0 mg NM
al.38 2. Ondansetron 8.0 mg iv I III anesthesia. was more effective than
3. Placebo iv (0.9% saline solution) meperidine in preventing
All drugs were given 15 min before the end of POS.
surgery.

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 Table 1. Randomized controlled trials investigating drugs to prevent postoperative shivering in patients who received general anesthesia (continued)

Title Intervention Study population Type of surgery/anesthesia Conclusion Power

Bhukal et al.39 1. Meperidine 0.3 mg/kg iv 60 patients, ASA Laparoscopic gynecological Pre-induction meperidine was 85%
2. Meperidine 0.5 mg/kg iv I–II, 25–35 years, procedures. General not effective in preventing

麻醉學雜誌57(3)-02 Paraskevi Matsota.indd 73

3. Placebo iv (0.9% saline solution) female anesthesia POS.
All drugs were given just before induction of
general anesthesia.
Iqbal et al.40 1. Meperidine 25.0 mg iv 90 patients, ASA Laparoscopic surgery. Both drugs were equally 80%
2. Granisetron 40.0 mcg/kg iv I–II, 20–60 years General anesthesia effective in preventing POS.
3. Placebo iv (0.9% saline solution)
All drugs were given before induction of
anesthesia.
Parsa et al.41 1. Buprenorphine 3.0 mcg/kg iv 60 patients, ASA Elective cesarean section. Meperidine 0.5 mg/kg was NM
2. Meperidine 0.5 mg/kg iv I–II, 18–40 years General anesthesia more effective in preventing
All drugs were given 30 min before the end of POS.
surgery.
Entezariasl and 1. Dexamethasone 0.1 mg/kg iv 120 patients, ASA Orthopedic, and ENT Although both drugs were 80%
Isazadehfar42 2. Meperidine 25.0 mg iv I–II, adults surgeries (mean duration 60 effective, dexamethasone was
3. Placebo iv (0.9% saline solution) min). General anesthesia superior in preventing POS.
All drugs were given after induction of
anesthesia.
Bilotta et al.43 1. Nefopam 15.0 mg/kg 101 patients, Elective or emergency Both interventions NM
2. Clonidine 3.0 mcg/kg ASA I–III, interventional neuroradiology significantly lowered the rate
3. Placebo iv (0.9% saline solution) adults with conscious sedation and severity of shivering.
All drugs were given 15 min before the However, nefopam was more
procedure. effective than clonidine.
iv: intravenously; ASA: American Society of Anesthesiologists; POS: postoperative shivering; LPC: laparoscopic cholecystectomy; NM: not mentioned; VAS: Visual Analogue Scale; OPCABG: off-
pump coronary artery bypass grafting; ENT: ear-nose-throat.

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 Table 2. Randomized controlled trials investigating drugs to prevent postoperative shivering in patients who received regional anesthesia

Title Intervention Study population Type of surgery/anesthesia Conclusion Power

44
Bozgeyik et al. 1. Tramadol 100.0 mg iv 90 patients, ASA Elective arthroscopic surgery Both drugs were equally NM
2. Dexmedetomidine 0.5 mcg/kg iv I–II, 18–60 years under spinal anesthesia effective in preventing POS.
Matsota et al.

All drugs were given after spinal block.

麻醉學雜誌57(3)-02 Paraskevi Matsota.indd 74

Usta et al.45 1. Dexmedetomidine 1 mcg/kg iv over a 10-min 60 patients, ASA Elective minor surgical Dexmedetomidine was more 80%
period followed by an infusion of 0.4 mg/kg/h I–II, 18–50 years operations under spinal effective than placebo in
2. Placebo iv (0.9% saline solution) anesthesia preventing POS.
Administration began after intrathecal injection
and infusions were stopped at the completion of
skin closure.
Kose et al.46 1. Ketamine 0.25 mg/kg iv 90 parturient, Cesarean delivery under Ketamine at both doses was 80%
2. Ketamine 0.50 mg/kg iv ASA I–II, 18–45 spinal anesthesia effective in preventing POS.

74 Asian Journal of Anesthesiology 57(3) 2019

3. Placebo iv (0.9% saline solution) years
All drugs were given after intrathecal injection.
Sagir et al.47 1. Ketamine 0.50 mg/kg iv 160 patients, Urological surgery under Ketamine alone at the dose 80%
2. Granisetron 3.00 mg iv ASA I–II, 18–65 spinal anesthesia of 0.50 mg/kg was the most
3. Ketamine 0.25 mg/kg + Granisetron 1.50 mg years effective regimen in preventing
iv POS.
4. Placebo iv (0.9% saline solution)
All drugs were given after intrathecal injection.
Lakhe et al.48 1. Ondansetron 4.00 mg iv 120 patients, ASA Elective general, All drugs were equally NM
2. Ketamine 0.25 mg/kg iv I–II, 18–65 years gynecological and orthopedic effective in preventing POS.
3. Tramadol 0.50 mg/kg iv surgery under spinal
4. Placebo iv (0.9% saline solution) anesthesia
All drugs were given after intrathecal injection.
Solhpour et al.49 1. Meperidine 0.40 mg/kg iv 200 patients ASA Orthopedic and urologic Meperidine 0.20 mg/kg plus NM
2. Ketamine 0.25 mg/kg plus midazolam 37.5 I–II, 20–60 years surgery under spinal dexamethasone 0.10 mg/kg
mcg/kg iv anesthesia was the most effective regimen
3. Meperidine 0.20 mg/kg plus dexamethasone in preventing POS.
0.10 mg/kg iv
4. Placebo iv (0.9% saline solution)
All drugs were given immediately after
intrathecal injection.

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 Table 2. Randomized controlled trials investigating drugs to prevent postoperative shivering in patients who received regional anesthesia (continued)

Title Intervention Study population Type of surgery/anesthesia Conclusion Power

Savafi et al.50 1. Ondansetron 8.00 mg iv 90 patients, Lower extremity orthopedic Investigated drugs were equally NM
2. Ketamine 0.25 mg/kg plus midazolam 37.50 ASA I–II, 18–65 surgery under spinal effective in preventing POS.

麻醉學雜誌57(3)-02 Paraskevi Matsota.indd 75

μg/kg iv
3. Placebo iv (0.9% saline solution)
All drugs were given immediately after spinal
block.
Shakya et al.51 1. Ketamine 0.25 mg/kg iv
2. Ondansetron 4.00 mg iv
3. Placebo iv (0.9% saline solution)
All drugs were given just after the intrathecal
injection.
Honarmand and 1. Ketamine 0.50 mg/kg iv
Safavi52 2. Midazolam 75.00 mcg/kg iv
3. Ketamine 0.25 mg/kg + midazolam 37.50 mcg/
kg iv
4. Placebo iv (0.9% saline solution)
All drugs were given just after intrathecal
injection.
Xue et al.53 1. Epidural ketamine 0.5 mg/kg
2. Epidural placebo (0.9% saline solution)
All drugs were given right after epidural catheter years
placement.
years anesthesia
120 patients, ASA Lower abdominal surgery Ketamine was more effective NM
I–II under spinal anesthesia than ondansetron in preventing
POS.
120 patients, ASA Orthopedic surgery under The combination of ketamine NM
I–II, 18–60 years spinal anesthesia plus midazolam was more
effective in preventing POS
than monotherapy with each
drug alone.
60 patients, Elective cesarean section Epidural ketamine was more 90%
ASA I–II, 22–41 under CSE effective than placebo in
preventing POS.

Misiran and 1. Midazolam 0.02 mg/kg plus ketamine 0.25 mg/ 90 patients, Emergency lower limb Both regimens of midazolam 80%
Aziz54 kg iv ASA I–II, surgery, combined with ketamine
2. Midazolam 0.04 mg/kg plus ketamine 18–60 years spinal anesthesia were equally effective in
0.25 mg/kg iv preventing POS.
3. Placebo iv (0.9% saline solution)
All drugs were given after administration
of spinal anesthesia.

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 Table 2. Randomized controlled trials investigating drugs to prevent postoperative shivering in patients who received regional anesthesia (continued)

Title Intervention Study population Type of surgery/anesthesia Conclusion Power

55
Hong et al. 1. Electroacupuncture 90 patients, ASA Elective urological surgery Both interventions were NM
2. Nefopam 0.15 mg/kg iv I–II, 20–65 years under spinal anesthesia equally effective in
Matsota et al.

3. Placebo iv (0.9% saline solution) preventing POS.

麻醉學雜誌57(3)-02 Paraskevi Matsota.indd 76

All interventions were given 30 min before
anesthesia.
Bilotta et al.56 1. Nefopan 0.15 mg/kg iv 90 patients, ASA Lower limb Both interventions were 90%
2. Tramadol 0.50 mg/kg I–II, 45–48 years orthopedic surgery under effective but nefopam was
3. Placebo iv (0.9% saline solution) (age mean) either epidural or spinal even more effective than
All drugs were given immediately before anesthesia tramadol in preventing POS.
neuraxial anesthesia.
iv: intravenously; ASA: American Society of Anesthesiologists; POS: postoperative shivering; NM: not mentioned; CSE: combined spinal epidural.

76 Asian Journal of Anesthesiology 57(3) 2019

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the use of dexmedetomidine in the setting of regional
anesthesia. The low dose of dexmedetomidine (0.5
mcg/kg), which did not seem to offer significant re-
lief against POS after general anesthesia,21 was found
to be similarly effective in preventing POS as 100
mg tramadol, in patients under spinal anesthesia, 44
although it was associated with a higher level of se-
dation. A possible explanation for this discrepancy
may be the fact that under general anesthesia, there is
a greater suppression of the sympathetic nervous sys-
tem activity compared to spinal blockade reaching the
T8–10 dermatome. Also, continuous infusion of dex-
medetomidine was found to be effective in preventing
POS resulting from spinal anesthesia.45 In this case,
patients are also sedated, but in cases of regional an-
esthesia, sedation is many times desirable for patients’
comfort.
N-Methyl-D-Aspartate Receptor Antagonists
Research has revealed that N-methyl-D-aspartate
(NMDA) receptor antagonists interfere with thermo-
regulation at various locations within the central ner-
vous system.28
General Anesthesia—Table 1
Ketamine, a non-competitive NMDA receptor
antagonist, administered 20 min before the com-
pletion of surgery has been investigated at different
dosages in the prevention of POS after general anes-
thesia. Ketamine (0.100 mg/kg or 0.125 mg/kg) does
not appear to offer any advantage in the prevention of
POS.27,30 Norouzi et al. demonstrated that high doses
of ketamine (0.25 mg/kg or 0.50 mg/kg) had similar
efficacy in preventing shivering, but the higher dose
of ketamine was correlated with an increase in hal-
lucinations and delay in extubation.27 Petskul et al.
disagree with this finding, as the dose of 0.25 mg/kg
ketamine used in their study failed to prevent POS.26
However, in the aforementioned study, the reported
overall incidence of shivering was possibly too low to
detect a statistically significant difference.
The efficacy of late administration of ketamine
in patients under general anesthesia has also been
compared with meperidine, with conflicting results.
Ketamine at a dose of 0.5 mg/kg performed better
than placebo, but was not as effective as meperidine at
doses of 0.4 mg/kg19 or 0.5 mg/kg.29 On the contrary,
three studies concluded that 0.5 mg/kg ketamine is
麻醉學雜誌57(3)-02 Paraskevi Matsota.indd 77
Drugs Used to Prevent Postoperative Shivering
as effective as 30 mg meperidine in preventing POS,
without significant side effects.28,30,31 This inconsisten-
cy might be attributed to the lower dose of meperidine
employed in the previous studies.
Ogawa conducted a study to investigate whether
shivering associated with remifentanil-based anesthe-
sia could be prevented by the concomitant use of low-
dose ketamine infusion, reaching favorable results.32
However, the low number of patients recruited reduc-
es the credibility of the conclusion.
Regional Anesthesia—Table 2
Two studies on adults undergoing elective sur-
gery demonstrated that 0.25 mg/kg ketamine was
more effective than placebo in the prevention of POS
after spinal anesthesia.48,51 Kose et al. also studied
the effects of ketamine on parturients undergoing
cesarean section and showed that the prophylactic
IV administration of 0.25 mg/kg ketamine was as
effective as 0.5 mg/kg ketamine in the prevention of
shivering.46 The drug was administered immediately
after intrathecal injection and did not exhibit serious
maternal or neonatal adverse effects. Xue et al. re-
vealed that prophylactic epidural administration of 0.5
mg/kg ketamine reduced the incidence and severity
of shivering in patients undergoing cesarean section
under combined spinal-epidural anesthesia.53
The combination of ketamine with midazolam
has also been investigated using the rationale that
vasoconstriction induced by ketamine is opposed by
the effect of midazolam, which impedes tonic thermo-
regulatory vasoconstriction.58 The study by Savafi et
al. yielded positive results regarding the combination
of 0.25 mg/kg ketamine plus 37.5 mcg/kg midazolam,
for the prevention of POS after spinal anesthesia.50
Another study confirmed this finding and even found
the aforementioned combination of ketamine plus
midazolam to be more effective than monotherapy
using either 0.5 mg/kg ketamine or 75.0 mcg/kg mid-
azolam.52 The same combination was also tested in
another study, wherein although it was effective in the
prevention of POS, it was found to be inferior to the
combination of 0.2 mg/kg meperidine plus 0.1 mg/kg
dexamethasone in doing so.49
Misiran and Aziz compared the combination
of 0.25 mg/kg ketamine with two different doses of
midazolam (0.02 mg/kg vs. 0.04 mg/kg), and con-
cluded that the two regimens were equally effective.54
One peculiarity of this study was that the test group
Asian Journal of Anesthesiology 57(3) 2019 77
2019/12/19 下午 01:46:05
 Matsota et al.
consisted of emergency cases, some of which were
trauma cases that were resuscitated in the emergency
department prior to surgery. Thus, the pathophysiolo-
gy of these patients is distinctive, due to which the re-
sults of this study cannot be compared with the results
of other studies.
A different regimen consisting of ketamine and
granisetron (a serotonin 5-HT3 receptor antagonist)
has been studied by Sagir et al., who observed that 0.5
mg/kg ketamine was more effective than the combi-
nation of a lower dose of ketamine (0.25 mg/kg) plus
1.5 mg granisetron, in the prevention of shivering as-
sociated with regional anesthesia.47
Opioids and Tramadol
It is hypothesized that the anti-shivering effect of
opioids is associated with their μ-receptor agonist ac-
tivity.59,60 It seems more probable that the anti-shiver-
ing action of meperidine involves its μ- and κ-receptor
agonist activity, in addition to its α2-adrenoreceptor
agonist properties and anticholinergic properties.14
The fact that the anti-shivering effect of meperidine is
inhibited by high-dose naloxone but not by low-dose
naloxone indicates that both μ- and κ-receptors play a
major role.61
General Anesthesia—Table 1
Most published studies on this topic have inves-
tigated the prophylactic effect of meperidine admin-
istered at the end of surgery. As mentioned before,
meperidine at a dose of 20 mg, administered 20 min
before the completion of surgery, is as effective as 0.5
mg/kg ketamine in preventing POS,28,30,31 while higher
doses of meperidine (0.4 mg/kg and 0.5 mg/kg) ap-
peared to perform better than 0.5 mg/kg ketamine.19,29
The highest dose of meperidine (0.5 mg/kg) was ob-
served to be as effective as dexmedetomidine 1 mcg/
kg.22 Abdollahi et al. compared 0.4 mg/kg meperidine
with 8 mg ondansetron in patients undergoing off-
pump coronary artery bypass graft who, after the end
of surgery, were transferred to intensive care unit
(ICU) and remained intubated.38 The shivering scores
recorded at the time of ICU admission were in favor
of 0.4 mg/kg meperidine and 8 mg ondansetron, com-
pared to placebo.
Three other studies had tested the prophylactic
administration of meperidine given before or right
after the induction of anesthesia. 39,40,42 Entezariasl
78 Asian Journal of Anesthesiology 57(3) 2019
麻醉學雜誌57(3)-02 Paraskevi Matsota.indd 78
and Isazadehfar compared the efficacy of 25 mg me-
peridine with 0.1 mg/kg dexamethasone, both given
immediately after the induction of anesthesia. The
researchers observed that the incidence of POS was
10% in the dexamethasone group, 37.5% in the me-
peridine group, and 47.5% in the control group.42 The
findings of Iqbal et al. also support the prophylactic
administration of meperidine before the induction of
anesthesia.40 In contrast, Bhukal et al. have disputed
the pre-induction efficacy of meperidine.39 This incon-
sistency may be attributed to the fact that they studied
only female patients, and intravenous fluids adminis-
tered were heated to 37°C.39
The study by Parsa et al. is unique in that it com-
pared the efficacy of buprenorphine to meperidine in
a group of parturients undergoing cesarean section
under general anesthesia.41 The researchers valued bu-
prenorphine for being a partial μ-receptor agonist and
a betaine derivative that is attached to κ- and σ-recep-
tors, and observed that although both drugs decreased
postoperative pain equally, meperidine performed
better as an anti-shivering agent.41
Tramadol acts centrally on μ-opioid receptors,
inhibits the reuptake of 5-hydroxytryptamine and
norepinephrine, and facilitates the release of 5-hy-
droxytryptamine. In 2017, a meta-analysis by Li et al.
showed that tramadol was an effective cure against
POS by significantly reducing the severity of shiv-
ering and the need for a rescue agent.62 No adverse
events were associated with its use, even when doses
as high as 3 mg/kg were employed. In any case, au-
thors of this meta-analysis recommended the dose of
1 mg/kg, in order to avoid the possibility of adverse
effects.
Mohta et al. compared different doses of trama-
dol (1, 2, and 3 mg/kg) for their anti-shivering and
analgesic effects.34 Tramadol at a dose of 2 mg/kg,
administered at the time of wound closure, appeared
to have the best anti-shivering and analgesic effect,
without any undesirable adverse effects. It is worth
noting that all patients received prophylaxis for post-
operative nausea and vomiting (PONV) using 10 mg
metoclopramide. The three groups of tramadol were
found to be as efficient as 0.5 mg/kg meperidine in
terms of POS prevention. Findings of few studies
confirm that 1 mg/kg tramadol administered at the
end of surgery prevents POS after general anesthesia33
and is equally effective to 0.4 mg/kg meperidine.37
2019/12/19 下午 01:46:05

Furthermore, 1 mg/kg tramadol is more efficient than
α2-agonists.20 Notably, the higher dose of 2 mg/kg
was even found to be effective in remifentanil-iso-
flurane-based general anesthesia, which is associated
with a particularly high incidence of POS.35
Angral et al. studied the usage of 1 mg/kg tra-
madol, administered at the time of wound closure,
in open and laparoscopic cholecystectomy. 36 The
incidence of POS was similarly low in the treat-
ment groups, but significantly higher in the control
groups.36
Regional Anesthesia—Table 2
Even though meperidine is highly valued as an
anti-shivering agent, our search revealed only one
study that had employed meperidine as anti-shivering
prophylaxis for regional anesthesia. According to this
study, a combination of 0.2 mg/kg meperidine plus
0.1 mg/kg dexamethasone was more effective than
0.4 mg/kg meperidine alone or combination of 0.25
mg/kg ketamine plus 37.5 mcg/kg midazolam, in the
prevention of shivering resulting from spinal anesthe-
sia.49
Tramadol at doses of 0.5 mg/kg has been found
to be as effective in preventing POS as 0.5 mg/kg me-
peridine, with negligible side effects.48 Bozgeyik et al.
claim that 100 mg tramadol acts as effectively as 0.5
mcg/kg dexmedetomidine.44
Serotonin 5-HT3 Receptor Antagonists
The mechanism of action of serotonin 5-HT3 re-
ceptor antagonists could be related to the inhibition of
serotonin reuptake on the preoptic anterior hypotha-
lamic region. The 5-HT3 receptors may also influence
both heat production and heat loss pathways.
General Anesthesia—Table 1
Iqbal et al. have shown that the prophylactic
use of 40 mcg/kg granisetron is as effective as 25
mg meperidine in preventing POS.40 It is worth men-
tioning that this dose was found to be even equally
effective to a higher dose of meperidine (0.4 mg/kg)
or to tramadol (1 mg/kg) without prolonging the time
of emergence from anesthesia or affecting the respira-
tory or cardiovascular system.37 Likewise, Abdollahi
et al. have compared the efficacy of ondansetron (8
mg) to meperidine (0.4 mg/kg) on a population more
prone to cardiovascular side effects, and observed no
significant difference in the incidence of side effects
麻醉學雜誌57(3)-02 Paraskevi Matsota.indd 79
Drugs Used to Prevent Postoperative Shivering
such as bradycardia, convulsion, rash, and myoclonus
between groups.38
Regional Anesthesia—Table 2
Serotonin 5-HT3 receptor antagonists have been
studied for the prophylaxis of POS-related to regional
anesthesia and compared to various regimens. Sagir
et al. commented that 3 mg granisetron alone or a
combination of 0.25 mg/kg ketamine plus 1.5 mg
granisetron were inferior to 0.5 mg/kg ketamine in
preventing shivering related to regional anesthesia.47
Savafi et al. reported that although 8 mg ondansetron
was effective in controlling POS, a combination of
0.25 mg/kg ketamine plus 37.5 mcg/kg midazolam
performed better.50 Ondansetron at a lower dose (4
mg) still appears to be effective but is inferior to
0.25 mg/kg ketamine.51 On the contrary, Lakhe et al.
showed that 4 mg ondansetron is as effective as 0.25
mg/kg ketamine or 0.5 mg/kg tramadol.48
Dexamethasone
The available data on dexamethasone efficacy
are rare. It has been proposed that dexamethasone de-
creases the gradient between core and skin tempera-
ture and inhibits the release of vasoconstrictors and
pyrogenic cytokines released during surgery, through
its action on the immune system.63
General Anesthesia—Table 1
As mentioned earlier, Entezariasl and Isazade-
hfar showed that dexamethasone surpassed meperi-
dine’s efficacy in preventing POS, when administered
after induction of anesthesia.42
Regional Anesthesia—Table 2
Solhpour et al. observed that the combination of
meperidine and dexamethasone is superior to meperi-
dine alone, in preventing POS in patients subjected to
spinal anesthesia.49
Nefopam
Nefopam is a non-opioid, non-steroidal, central-
ly acting analgesic drug that increases the activity of
serotonin, norepinephrine, and dopamine. Further-
more, it acts on the sodium and calcium channels,
inhibiting the release of glutamate64 and it seems to
have a promising role in the prevention of POS.
Conscious Sedation—Table 1
Asian Journal of Anesthesiology 57(3) 2019 79
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 Matsota et al.
We opted for including in our review a random-
ized control trial that compared the efficacy of nefopam
and clonidine on patients undergoing interventional
neuroradiological procedures under conscious sedation
with midazolam infusion. In such cases, prevention
of shivering is essential, as any movement can cause
technical difficulties or even complications, such as
vessel perforation.43 Authors concluded that although
both drugs are effective in preventing POS, nefopam is
more potent than clonidine. In addition, patients receiv-
ing nefopam were more hemodynamically stable than
patients in clonidine and placebo groups.
Regional Anesthesia—Table 2
According to Hong et al., 0.15 mg/kg nefopam
was efficient in preventing POS after spinal anesthe-
sia, but nausea and injection pain were observed.55
Nefopam even surpassed tramadol’s efficacy in lower-
ing the rate and severity of intraoperative shivering in
patients undergoing neuraxial anesthesia for orthope-
dic surgery, according to Bilotta et al.56 However, the
dose of tramadol (0.5 mg/kg) studied was possible too
low to evaluate its full effect in preventing shivering.
Conclusion
Although the published studies on this topic are
greatly heterogeneous in factors such as temperature
of the OR, type and duration of surgery, anesthetic
drugs used, intraoperative fluid replacement, use of
active warming measures, as well as the scales used to
evaluate shivering, there is evidence that some drugs
can effectively prevent POS. However, dose-response
studies are required to determine the most appropriate
dosing regimen of each drug for the optimal preven-
tion of POS. Studies of cost-effectiveness are also
essential.
Regarding α2-agonists, intravenous dexmedeto-
midine was found to be promising. It appears to have
a dose-dependent preventive effect on patients sub-
jected to general anesthesia. Notably, meperidine and
tramadol surpass its efficacy in most studies, and the
expected side effects associated with α2-agonists, in-
cluding bradycardia, sedation in the immediate post-
operative period, and prolonged extubation time, are
observed. Although limited data are available regard-
ing regional anesthesia, it appears that the continuous
infusion of dexmedetomidine, or even the low dose of
0.5 mcg/kg, is effective in preventing POS.
80 Asian Journal of Anesthesiology 57(3) 2019
麻醉學雜誌57(3)-02 Paraskevi Matsota.indd 80
Regarding NMDA antagonists, 0.25 mg/kg ket-
amine has questionable efficacy in preventing POS af-
ter general anesthesia, while lower doses do not seem
to confer any advantage at all. Ketamine at a dose of
0.5 mg/kg performs better than placebo and possibly,
is even equally effective to meperidine. Despite the
number of studies concerning regional anesthesia, the
diverse regimens used in each study makes it infeasi-
ble to draw safe conclusions. In general, the rationale
for the use of ketamine in the setting of POS is that
it could serve as an alternative drug for patients with
bradycardia, hypotension, respiratory depression, nau-
sea, vomiting, or allergic reactions to pethidine. Still,
adverse effects (hallucination, nystagmus, sedation,
etc.) should always be borne in mind.
As far as opioids are concerned, 0.4–0.5 mg/kg
meperidine is effective in the prevention of POS after
general anesthesia, when administered at the end of
surgery, and possibly, even when administered at the
beginning. It appears to be effective in patients with
different ASA classifications and undergoing different
procedures. There are not enough data available to
comment on the efficacy of meperidine after regional
anesthesia.
As for tramadol, the dose of 1–2 mg/kg appeared
to be effective as anti-shivering prophylaxis after
general anesthesia, without adverse effects includ-
ing PONV. However, most of the studies involved
patients that had been administered metoclopramide
in advance. Tramadol was found to be effective as a
preventive measure for shivering under regional anes-
thesia, but the ideal dose is not established yet.
Additionally, the use of serotonin 5-HT3 recep-
tor antagonists, such as ondansetron or granisetron,
seems promising as a preventive measure against
POS. The main advantage of this class of drugs is
that they prevent PONV and do not prolong the emer-
gence time from anesthesia or significantly affect the
respiratory or cardiovascular system.
Finally, as for dexamethasone, data are limited
on reaching definite conclusions. On the contrary, ne-
fopam seems to play an important role in the preven-
tion of POS, since it has been found to surpass trama-
dol and clonidine’s efficacy and to possess a favorable
hemodynamic profile.
In conclusion, even though an association be-
tween the occurrence of shivering and an increase
in cardiac morbidity has not yet been established,
POS should be avoided because it raises the oxygen
2019/12/19 下午 01:46:05

demand. Consequently, as with all other preventive
measures, the prophylactic administration of the
aforementioned drugs should also be considered in
patients at a high risk of developing POS. However,
clinicians should carefully weigh the advantages of
preventing shivering against the risk of inadvertent
drug reactions. Thus, a personalized approach should
be applied and the regimen best suited to the medical
profile of each patient should be selected. In this re-
gard, this review contributes to a rational framework
for daily clinical practice.
Conflicts of Interest
None.
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