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Efficacy of dexmedetomidine on postoperative shivering: a meta-analysis of clinical trials

  • Zhen-Xiu Liu
  • Feng-Ying Xu
  • Xiao Liang
  • Miao Zhou
  • Liang Wu
  • Jing-Ru Wu
  • Jian-Hua XiaEmail author
  • Zui ZouEmail author
Review Article/Brief Review

Abstract

Purpose

Shivering is a frequent complication in the postoperative period. The aim of the current meta-analysis was to assess the efficacy of dexmedetomidine on postoperative shivering.

Methods

Two researchers independently searched PubMed, EMBASE™ and the Cochrane Central Register of Controlled Trials for controlled clinical trials. The meta-analysis was performed by Review Manager.

Results

Thirty-nine trials with 2,478 patients were included in this meta-analysis. Dexmedetomidine reduced postoperative shivering compared with placebo (risk ratio [RR] = 0.26; 95% confidence interval [CI]: 0.20 to 0.34), with a minimum effective dose of 0.5 µg·kg−1 (RR = 0.36; 95% CI: 0.21 to 0.60). The anti-shivering effect can be achieved both intravenously and epidurally when administered within two hours prior to the end of surgery. The efficacy of dexmedetomidine was similar to widely used anti-shivering agents, such as fentanyl, meperidine, tramadol, clonidine and so on; however, dexmedetomidine may increase the incidence of sedation, hypotension, bradycardia and dry mouth.

Conclusions

The present meta-analysis indicates that dexmedetomidine shows superiority over placebo, but not over other anti-shivering agents. Therefore, considering its high price and potential adverse events, dexmedetomidine may not be appropriate solely for the purpose of the prevention of postoperative shivering.

Keywords

Clonidine Tramadol Dexmedetomidine Meperidine Cochrane Central Register 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Efficacité de la dexmédétomidine pour contrôler les frissons postopératoires: une méta-analyse d’études cliniques

Résumé

Objectif

Les frissons sont une complication fréquente en période postopératoire. L’objectif de cette méta-analyse était d’évaluer l’efficacité de la dexmédétomidine pour contrôler les frissons postopératoires.

Méthode

Deux chercheurs ont analysé de façon indépendante les bases de données PubMed, EMBASE™ et le registre central d’études contrôlées Cochrane (Cochrane Central Register of Controlled Trials) pour en extraire les études cliniques contrôlées pertinentes. La méta-analyse a été réalisée avec Review Manager.

Résultats

Trente-neuf études comportant un total de 2478 patients ont été incluses dans cette méta-analyse. La dexmédétomidine a réduit les frissons postopératoires par rapport au placebo (risque relatif [RR] = 0,26; intervalle de confiance [IC] 95 % : 0,20 à 0,34), avec une dose efficace minimum de 0,5 µg·kg−1 (RR = 0,36; IC 95 % : 0,21 à 0,60). L’effet anti-frissons peut être obtenu par voie intraveineuse et péridurale lorsque l’agent est administré dans les deux heures précédant la fin de la chirurgie. L’efficacité de la dexmédétomidine était semblable à celle d’agents anti-frissons fréquemment utilisés tels que le fentanyl, la mépéridine, le tramadol et la clonidine; toutefois, la dexmédétomidine pourrait augmenter l’incidence de sédation, d’hypotension, de bradycardie et de sécheresse buccale.

Conclusion

Cette méta-analyse indique que la dexmédétomidine démontre une supériorité par rapport au placebo, mais pas par rapport à d’autres agents anti-frissons. Par conséquent, au vu de son prix élevé et de ses effets secondaires néfastes potentiels, la dexmédétomidine peut ne pas être appropriée si le seul but est de prévenir les frissons postopératoires.

Shivering is a physiological response of the body for heat preservation through peripheral vasoconstriction and involuntary skeletal muscle contractions.1 Despite the benefits from reducing heat loss, shivering increases the patients’ oxygen consumption, carbon dioxide production, and energy expenditure,2 and it may cause severe adverse effects during the recovery from general anesthesia, especially in patients with impaired cardiac and pulmonary reserves. Moreover, for awake patients, shivering is an uncomfortable experience, sometimes even worse than surgical pain.3 Effective prevention and treatment of shivering has become an essential step in increasing postoperative comfort and reducing shivering-related complications. Currently used anti-shivering agents are restricted by their side effects. For example, meperidine may induce nausea, vomiting, and respiratory depression,4 and patients receiving ketamine5 frequently experience hypertension and tachycardia.

Dexmedetomidine is a potent and highly selective α2-adrenoceptor agonist with sympatholytic, sedative, amnestic,6 and analgesic7 properties. Clinical researchers have already studied the administration of dexmedetomidine to prevent shivering. Nevertheless, controversy about the effectiveness of dexmedetomidine for the prevention of shivering is still ongoing, with different results reported in associated literature. In our view, a quantitative analysis on a consolidation of the related data was needed, and therefore, we conducted the present meta-analysis in order to assess the relative merits regarding the anti-shivering effect of dexmedetomidine.

Methods

This meta-analysis of controlled trials evaluates the effect of intraoperative dexmedetomidine on postoperative shivering and was performed according to the recommendations of the PRISMA statement.

Search strategy

Two authors (L.Z.X and X.F.Y.) systematically searched PubMed, EMBASE™ and the Cochrane Central Register of Controlled Trials (CENTRAL). The search strategy comprised the following key words: (dexmedetomidine) and (shivering, shiver, tremor, shaking, or anti-shivering) and (postoperative, operation, surgery, anesthesia, or anaesthesia). The literature search was updated on August 30, 2014 with no language limitation. The reference lists of the reviews, original reports, and case reports (retrieved through the electronic searches) were checked to identify studies that had not yet been included in the computerized databases.

Study selection and data retrieval

The study selection criteria were pre-established. Inclusion criteria included: (1) controlled clinical trials; (2) intraoperative administration of dexmedetomidine; and (3) the reported presence or absence of shivering. Exclusion criteria included: (1) abstracts only; (2) patients with severe cerebrovascular disease or other contradictions for dexmedetomidine; (3) duplications; (4) missing data; and (5) incorrect statistical analysis performed in the report. The data retrieval included: name of the first author, publication year, funding, interventions, patients and operations, type of anesthesia, length of surgery, number of shivering cases and total patients, randomization, blinding, allocation concealment, withdrawal, body temperature, and side effects such as nausea, vomiting, and hypotension. Two authors (L.Z.X. and X.F.Y.) independently assessed the articles for compliance with the inclusion/exclusion criteria. Any disagreement during the process of meta-analysis was resolved by discussion among all authors.

Qualitative assessment

Two authors (L.X. and Z.M.) independently evaluated the quality of the trials according to the guidelines recommended by the Cochrane Collaboration.8 Six categories were evaluated, with the first three considered as “key domains” (randomization and sequence generation, allocation concealment, blinding method, incomplete outcome data, selective outcome reporting, and other sources of bias). Each category was summarized into three levels: low risk, unclear risk, and high risk. The risk of bias of a particular study was assessed in relation to the three key domains: LOW (low risk of bias for all key domains); UNCLEAR (unclear risk of bias for one or more key domains); and HIGH (high risk of bias for one or more key domains).

Statistical analysis

The effect of dexmedetomidine on postoperative shivering compared with placebo or other anti-shivering drugs was estimated by calculating the pooled risk ratio (RR) and its 95% confidence intervals (CI) of the incidence of shivering. The overall effect was determined by a Z-test. All reported P values are two sided. A fixed effects model was used when I2 ≤ 50%, otherwise a random effects model was adopted. Sensitivity analysis was performed to test the robustness of the results by re-analyzing the data after excluding the high-risk studies. Subgroup analyses were based on the types of anesthesia, the doses and routes administered, and the A-E interval (defined as the time interval from the last administration to the end of the operation. Two-hour duration was used as the cut-off point, because the half-life of dexmedetomidine is about two hours).9 Begg’s test was conducted to assess potential publication bias. Statistical analysis was performed with Review Manager (RevMan version 5.3; Cochrane Collaboration, Oxford, UK) and Stata® version 12.0 (Stata Corp, College Station, TX, USA).

Results

Study selection

As shown in the flow diagram (Fig. 1), the search of PubMed, EMBASE, CENTRAL, and the reference lists yielded 237 articles. Initially, 166 trials were discarded because they were not controlled trials according to the titles, and after reviewing the abstracts, an additional 21 trials were excluded as they were not relevant to our study. We could not retrieve the full texts of three10-12 of the remaining 50 papers despite attempting electronic retrieval interlibrary loan or contacting the authors. After carefully reading 47 papers, we excluded eight with no related endpoints. Finally, 39 trials3,9,13-49 met the selection criteria and were included in the meta-analysis.
Fig. 1

Flow diagram of the inclusion and exclusion process

Study characteristic

Twenty-two of the included studies explored the efficacy of intraoperative dexmedetomidine compared with placebo.3,9,13-32 Other control agents included fentanyl,33-36 remifentanyl,37,38 meperidine,15 midazolam,39-41 propofol,43,44 ketamine,45,46 tramadol,24,47 clonidine,42 propacetamol,48 and buprenorphine49 (Table 1). Twenty studies reported the side effects, including sedation,4,13,22,28,31 nausea,9,14,20,22,23,27,29,30 vomiting,14,22,23 bradycardia,17,20,23,26-28,30-32 hypotension20,23,26-28,30,32 and dry mouth.14,22,23 Only eight of the included articles clearly mentioned the funding status, five of which3,21,22,35,37 were supported by an institutional foundation, and three studies23,44,47 declared no financial support.
Table 1

Characteristics of the included trials

Study

Year

patients

Type of anesthesia

Time

Comparisons

Total

Event

Mean or median of surgery time (min.)

Mean temperature of the end of surgery (°C)

Funding

Aldehayat13

2011

adults

GA

E

dexmedetomidine 1.0 µg·kg−1 iv

35

4

152

-

-

placebo iv

35

16

140

-

 

Bajwa14

2012

adults

GA

M

dexmedetomidine 1.0 µg·kg−1 iv

40

2

59

36.4

 

placebo iv

40

17

58

36.2

 

Bicer15

2006

adults

GA

E

dexmedetomidine 1.0 µg·kg−1 iv

40

6

115

35.7

-

meperidine 0.5 mg·kg−1 iv

40

4

102

35.8

 

placebo iv

40

22

98

35.8

 

Elvan16

2008

adults

GA

L+M

dexmedetomidine iv

40

7

78

35.8

-

placebo iv

40

21

82

36

 

Gao17

2012

adults

GA

L+M

dexmedetomidine iv

24

0

-

-

-

no treatment

24

6

-

-

 

Jalonen18

1997

adults

GA

L+M

dexmedetomidine iv

40

13

180

-

-

placebo iv

40

23

185

-

 

Karaman3

2013

adults

GA

L+M

dexmedetomidine iv

30

3

62

35.3

placebo iv

30

14

66

35.3

 

Kim19

2013

adults

GA

E

dexmedetomidine 0.5 µg·kg−1 iv

30

12

111

35.7

-

dexmedetomidine 0.75 µg·kg−1 iv

30

4

106

35.8

 

dexmedetomidine 1.0 µg·kg−1 iv

30

5

105

35.9

 

placebo iv

30

19

109

36

 

Lee20

2013

adults

GA

L+M

dexmedetomidine iv

28

2

141

36.1

-

placebo iv

29

17

141.6

36.1

 

Li21

2011

adults

GA

P

dexmedetomidine 0.5 µg·kg−1 iv

40

0

-

-

placebo iv

40

12

-

-

 

Wu22

2013

adults

GA

P

dexmedetomidine 1.0 µg·kg−1 iv

40

3

96

-

placebo iv

40

15

92

-

 

Yildiz23

2006

adults

GA

P

dexmedetomidine 1.0 µg·kg−1 iv

25

2

59

-

No

placebo iv

25

2

61

-

 

Bozgeyik24

2014

adults

SA

P

tramadol 100 mg iv

30

3

45

36.44

-

dexmedetomidine 0.5 µg·kg−1 iv

30

1

44

36.33

 

placebo iv

30

6

42

36.58

 

Coskuner25

2007

adults

EA

L+M

dexmedetomidine iv

30

0

81

-

-

placebo iv

30

4

86

-

 

Dinesh26

2014

adults

SA

L+M

dexmedetomidine iv

50

0

-

-

-

placebo iv

50

5

-

-

 

Gupta27

2011

adults

SA

I

dexmedetomidine SA 5 µg

30

0

-

-

-

placebo SA

30

1

-

-

 

Hanoura28

2014

adults

SA

I

dexmedetomidine EA 1.0 µg·kg−1

25

1

49

-

-

placebo EA

25

8

48

-

 

Jain29

2012

adults

SA

I

dexmedetomidine EA 2.0 µg·kg−1

30

1

81

-

-

placebo EA

30

8

79

-

 

Salgado30

2008

adults

EA

I

dexmedetomidine EA 1.0 µg·kg−1

20

3

213

-

-

placebo EA

20

2

208

-

 

Tekin9

2007

adults

SA

L+M

dexmedetomidine iv

30

0

71

-

-

placebo iv

30

5

73

-

 

Usta31

2011

adults

SA

L+M

dexmedetomidine iv

30

3

65

36

-

placebo iv

30

17

68

36.2

 

Yektas32

2014

adults

SA

I

dexmedetomidine SA 2 µg

20

4

-

-

-

dexmedetomidine SA 4 µg

20

5

-

-

 

placebo SA

20

2

-

-

 

Aksu33

2009

adults

GA

E

dexmedetomidine 0.5 µg·kg−1 iv

20

0

175

-

-

fentanyl 1.0 µg·kg−1 iv

20

1

179

-

 

Bajwa34

2011

adults

EA

I

dexmedetomidine EA 1.0 µg·kg−1

50

1

-

-

-

fentanyl EA 1.0 µg·kg−1

50

2

-

-

 

Techanivate35

2012

adults

GA

I

dexmedetomidine 0.5 µg·kg−1 iv

20

1

35

-

fentanyl 0.5 µg·kg−1 iv

20

2

35

-

 

Turgut36

2008

adults

GA

L+M

dexmedetomidine iv

25

6

216

-

-

fentanyl iv

25

11

229

-

 

Jung37

2011

adults

GA

L+M

dexmedetomidine iv

25

3

98

-

 

remifentanil iv

25

0

97

-

Turgut38

2009

adults

GA

L+M

dexmedetomidine iv

25

7

216

-

-

remifentanil iv

25

13

229

-

 

Erkola39

1994

adults

GA

P

dexmedetomidine 2.5 µg·kg−1 im

60

6

-

-

-

midazolam 0.08 µg·kg−1 im

61

31

-

-

 

Koruk40

2010

children

GA

I

dexmedetomidine iv

21

0

16.1

-

-

midazolam iv

25

4

17

-

 

Sheta41

2014

children

GA

P

dexmedetomidine IN 1.0 µg·kg−1

36

9

112

-

-

midazolam IN 0.2 µg·kg−1

36

3

108

-

 

Bajwa42

2011

adults

EA

I

dexmedetomidine EA 1.5 µg·kg−1

25

2

96

-

-

clonidine EA 2.0 µg·kg−1

25

1

100

-

 

Tosun43

2006

children

GA

L+M

dexmedetomidine iv

22

0

40

-

-

propofol iv

22

1

45

-

 

Mousa44

2013

adults

GA

L+M

dexmedetomidine iv

20

3

216

-

No

propofol iv

20

9

214

-

 

Koruk45

2010

children

GA

I

dexmedetomidine 1.0 µg·kg−1 iv

9

1

57

-

-

ketamine 0.5 mg·kg−1 iv

9

0

48

-

 

Shanreai46

2012

adults

GA

L+M

dexmedetomidine iv

30

1

-

-

 

ketamine iv

30

0

-

-

 

Mittal47

2014

adults

SA

E

dexmedetomidine 0.5 µg·kg−1 iv

25

1

-

-

No

tramadol 0.5 mg·kg−1 iv

25

2

-

-

 

Gome-Vazquez48

2007

adults

EA

L+M

dexmedetomidine iv

15

0

55

-

-

propacetamol iv

15

4

50

-

 

Gupta49

2014

adults

SA

I

dexmedetomidine SA 5 µg

30

5

95

-

-

buprenorphine SA 60 µg

30

2

92

-

 

GA = general anesthesia; SA = spinal anesthesia; EA = epidural anesthesia; IM = intramuscular; IN = intranasal; P = preoperative; I = induction; E = end; L + M = loading and maintenance

➀The institutional and/or departmental sources

➁ Natural Science Foundation of Heilongjiang Province (D200857)

➂ Natural Science Foundation of Guangdong Province (2010Y05)

➃ Ratchadapisek Sompoch Fund of Chulalongkorn University, Bangkok, Thailand (RA 57/53)

⑤ 2010 Research Fund from the Research Institute of Medical Science, St Vincent’s Hospital, Suwon, Republic of Korea

The methodological quality of the included studies

Thirty3,13,14,16,19-21,23,24,26-33,35-38,40-44,46-49 of the 39 included trials provided a detailed description of randomization. Odd/even admission number was used in the process of randomization in three trials.9,25,45 Twenty-nine trials3,9,13,14,16,19,21,23,27-31,33-38,41-44,47-49 reported allocation concealment, and 27 studies39,13,14,16,19,24,25,27-35,37-42,44,47-49 were double-blinded. No incomplete outcomes (attrition bias)8 were reported in the 39 included trials, and all studies reported every endpoint mentioned in the Methods section (reporting bias).8 however, some bias8 may exist in of the two trials,27,32 as the length of surgery was not clear. An overview of the risk of bias is summarized in Fig. 2.
Fig. 2

Summary of the risk of bias of the included studies

Results of the meta-analysis

Dexmedetomidine versus placebo

Twenty-two trials3,9,13-32 including 1,415 patients investigated the anti-shivering efficacy of dexmedetomidine compared with placebo. The incidence of postoperative shivering in the dexmedetomidine group was significantly lower than in the placebo group (34.2% vs 8.6%, respectively; pooled RR = 0.26; 95% CI: 0.20 to 0.34) (Fig. 3). Begg’s test suggested no significant publication bias (P = 0.128) in this comparison between dexmedetomidine and placebo.
Fig. 3

Results of subgroup analysis of the incidence of postoperative shivering by anesthesia types

Furthermore, dexmedetomidine can significantly reduce postoperative nausea and vomiting (PONV) compared with placebo (data not shown). Nevertheless, compared with placebo, dexmedetomidine increased the probability of sedation (pooled RR of five trials: 2.94; 95% CI: 2.18 to 3.98), bradycardia (pooled RR of nine trials: 2.39; 95% CI: 1.54 to 3.72), hypotension (pooled RR of seven trials: 1.35; 95% CI: 1.04 to 1.75), and dry mouth (pooled RR of three trials: 7.33; 95% CI: 2.28 to 23.58) (Table 2).
Table 2

Incidence of various side effects of dexmedetomidine vs placebo

Side effects

Number of studies

Number shivering/total number of patients

RR (95%CI)

References

Dexmedetomidine

Placebo

Sedation

5

104/170

35/170

2.94 (2.18 to 3.98)

13,14,22,28,31

Bradycardia

9

52/252

21/253

2.39 (1.54 to 3.72)

17,20,23,26-28,30-32

Hypotension

7

70/198

52/199

1.35 (1.04 to 1.75)

20,23,26-28,30,32

Dry mouth

3

21/105

2/105

7.33 (2.28 to 23.58)

14,22,23

CI = confidence interval; RR = risk ratio

Subgroup analyses were carried out to evaluate the factors that affected postoperative shivering.

Types of anesthesia

Dexmedetomidine significantly reduced the incidence of shivering in general anesthesia (pooled RR of 12 trials:3,13-23 0.26; 95% CI: 0.20 to 0.34) and regional anesthesia (pooled RR of ten trials:9,24-32 0.27; 95% CI: 0.16 to 0.45) (Fig. 3). The most common dexmedetomidine dosage was 1.0 µg·kg–1, so we chose this group in one trial.1

The A-E interval
The incidence of shivering in groups with an A-E interval less than two hours was reduced by dexmedetomidine (pooled RR of 18 trials: 0.24; 95% CI: 0.19 to 0.32) compared with placebo (Fig. 4); however, only one trial30 was conducted with an A-E interval more than two hours in which no statistical difference in the incidence of shivering could be found between dexmedetomidine and placebo (P = 0.64).
Fig. 4

Results of subgroup analysis of the incidence of postoperative shivering by the A-E intervals (defined as the time interval from the last administration to the end of the operation)

Dose of dexmedetomidine
Subgroup analysis suggested a beneficial effect of a single-dose bolus of 0.5 µg·kg−1 dexmedetomidine compared with placebo (pooled RR of three trials: 0.36; 95% CI: 0.21 to 0.60). A sensitivity analysis to remove a high-risk study21 (high risk of bias for one or more key domains, refer to Methods section) showed a similar result favouring dexmedetomidine (pooled RR = 0.52; 95% CI: 0.31 to 0.87) and decreased heterogeneity (I2 from 73% to 42%). One trial19 presented that 0.75 µg·kg−1 dexmedetomidine reduced the incidence of shivering with a reported P value of 0.002. A subgroup of dexmedetomidine 1.0 µg·kg−1 also reduced the incidence of shivering (pooled RR of six trials: 0.24; 95% CI: 0.16 to 0.37) (Fig. 5).
Fig. 5

Results of subgroup analysis of the incidence of postoperative shivering by doses of intravenous dexmedetomidine

Routes of administration
Dexmedetomidine injected intravenously (pooled RR of 17 trials: 0.24; 95% CI: 0.18 to 0.31) or into the epidural space (pooled RR of three trials: 0.28; 95% CI: 0.11 to 0.72) lowered the incidence of shivering; however, two trials evaluating dexmedetomidine injected into the subarachnoid space showed no difference compared with placebo (pooled RR = 1.57; 95% CI: 0.45 to 5.54) (Fig. 6). Sensitivity analysis was performed excluding the article30 with an A-E interval more than two hours (no difference from placebo) to minimize heterogeneity. A similar result favouring dexmedetomidine was found (pooled RR = 0.13; 95% CI: 0.03 to 0.52) with almost no heterogeneity across studies (I2 = 0%).
Fig. 6

Results of subgroup analysis of the incidence of postoperative shivering by routes of dexmedetomidine administration

Dexmedetomidine vs other anti-shivering agents

Nineteen studies,15,24,33-45,47-49 involving 1,063 patients, compared the efficacy of dexmedetomidine with other drugs on postoperative shivering. No significant difference could be found between dexmedetomidine and other agents, including fentanyl, remifentanyl, meperidine, midazolam, ketamine, tramadol, clonidine, buprenorphine, or propacetamol, except propofol (pooled RR = 0.33; 95% CI: 0.11 to 0.98) (Table 3). Nevertheless, one of the articles comparing dexmedetomidine with propofol was assessed and had a high risk of bias. Therefore, the superiority of dexmedetomidine over propofol was not reliably assessed.
Table 3

Incidence of postoperative shivering with dexmedetomidine compared with other anti-shivering drugs

Drugs

Number of studies

Number shivering/total number of patients

RR (95%CI)

References

Dexmedetomidine

Control

Fentanyl

4

8/115

16/115

0.52 (0.25 to 1.07)

33-36

Remifentanyl

2

10/50

14/50

0.93 (0.19 to 4.64)

37,38

Meperidine

1

6/40

4/40

1.50 (0.46 to 4.91)

15

Midazolam

3

15/120

13/121

1.10 (0.29 to 4.17)

39-41

Propofol

2

3/42

10/42

0.33 (0.11 to 0.98)

43,44

Ketamine

2

2/39

0/39

3.00 (0.33 to 27.23)

45,46

Tramadol

2

2/55

5/55

0.40 (0.08 to 2.01)

24,47

Clonidine

1

1/25

2/25

0.50 (0.05 to 5.17)

42

Buprenorphine

1

5/30

2/30

2.5 (0.53 to 11.89)

49

Propacetamol

1

0/15

4/15

0.11 (0.01 to 1.90)

48

CI = confidence interval; RR = risk ratio.

Our systematic review showed that dexmedetomidine not only has an anti-shivering effect, but it may also increase hemodynamic stability during a sudden increase in stress (e.g., intubation, skin incision, extubation), provide a deeper level of sedation, decrease PONV, and prolong postoperative analgesia compared with different agents (Table 4). Of importance, however, recovery and orientation time (patients’ response to questions regarding time, place, and person) after tracheal extubation was prolonged with dexmedetomidine when compared with certain other agents (Table 4).
Table 4

Incidence of various side effects of dexmedetomidine vs other anti-shivering drugs (P < 0.05)

Drugs

Hemodynamics*

Sedation

Nausea and vomiting

Postoperative analgesia and consumption of analgesic

Recovery time

Orientation time

Heart rate

Fentanyl

Unstable33,36

Lower34

Higher34

Shorter and more34-36

No difference33,35

-

-

Remifentanyl

Unstable37

Lower38

-

Shorter and more38

-

-

-

Meperidine

-

Lower15

-

-

-

Shorter15

-

Midazolam

Unstable39

Lower41

Higher40

-

Longer40

-

-

Propofol

-

-

-

-

Shorter43

-

-

Ketamine

Unstable45

-

-

-

Longer45 , 46

-

Quicker45 , 46

Tramadol

-

Lower24

Higher47

-

-

-

-

Clonidine

-

Lower42

-

-

-

-

-

Buprenorphine

-

-

-

Shorter and more49

-

-

-

Propacetamol

-

Lower48

-

-

-

-

-

*Hemodynamics were recorded when patients experienced tracheal intubation, skin incision, tracheal extubation, or other sudden increase in stress

Discussion

Postoperative shivering frequently causes uncomfortable feelings and is complicated by such complications as tachycardia, hypertension, and cardiac ischemia, which can lead to severe consequences. There is still an urgent need to find an effective way to prevent or control postoperative shivering.

The present meta-analysis was undertaken to evaluate the efficacy of dexmedetomidine in the prevention of postoperative shivering. The main findings are as follows: (1) Dexmedetomidine shows superiority over placebo in the prevention of postoperative shivering, but not over other anti-shivering agents. (2) The beneficial effect can be achieved through both intravenous and epidural injection. Nevertheless, the time interval between the last administration and the end of surgery should be less than two hours, which is about the half-life of dexmedetomidine. (3) While a 1.0 µg·kg−1 bolus dose is the most commonly used in the published articles, a 0.5 µg·kg−1 bolus infusion can still have a preventive effect. (4) Physicians should be cautious about the side effects of dexmedetomidine, such as sedation, bradycardia, hypotension, and dry mouth.

The anti-shivering effect of dexmedetomidine may be mediated primarily by the α2b-drenoceptor, in the hypothalamus. Dexmedetomidine suppresses the spontaneous firing rate of neurons, decreases the central thermosensitivity,14 and finally reduces the vasoconstriction and shivering thresholds.50

Several elements for the clinical use of dexmedetomidine should be considered. Kim et al. 19 recommended the minimum effective dose of 0.75 µg·kg−1 for adults. Furthermore, Bozgeyik et al.24 did not find any difference between 0.5 µg·kg−1 dexmedetomidine and placebo; however, this investigation was hampered by a relatively small sample size (30 patients per group). Based on the data of relevant trials, we found that 0.5 µg·kg−1 dexmedetomidine was sufficiently effective to prevent postoperative shivering. Our finding that epidural dexmedetomidine, not spinal, is an available option for anti-shivering might cause confusion, since subarachnoid administration has always been considered a faster and more effective approach compared with the epidural route. We speculate that the injected dose may be responsible. Spinal administration of 4-5 µg of dexmedetomidine compared with epidural administration of 1.0 µg·kg−1 may not be enough to activate the receptors inhibiting shivering.28

Despite its analgesic, sedative, antiemetic, and anti-shivering properties, dexmedetomidine increased the risk of these side effects. Somnolence, one of the most dangerous complications, although rare, has been reported resulting from an overdose of dexmedetomidine.51 Moreover, the price of dexmedetomidine is considerably higher than other drugs. Consequently, we do not recommend the use of dexmedetomidine solely for the purpose of preventing postoperative shivering.

A previous meta-analysis1 suggested an inferior role of dexmedetomidine compared with some “more efficacious agents” like meperidine, tramadol and nefopam. Nevertheless, the results of the analysis are inconclusive, as there were only two trials involving dexmedetomidine with just 160 patients, and there was no direct comparison between dexmedetomidine and the other agents. In contrast, we included 39 articles, adopted a wide range of clinically relevant outcome variables, and focused on direct comparison in order to reach a solid conclusion.

This is a novel meta-analysis regarding the use of dexmedetomidine for anti-shivering and an evaluation of the factors that might influence its effectiveness. Most of the included trials were well designed and reported with low risk of bias. Moreover, we compared dexmedetomidine directly with other anti-shivering agents and excluded studies with a high risk of bias through sensitivity analysis. All of these strategies enhanced the reliability of our conclusion. Nevertheless, this meta-analysis has several limitations. First, only eight trials3,21-23,35,37,44,47 reported the source of their funding; and therefore, we did not know whether the other trials were supported by industry, which could make the design prone to show the drug in its best light. Second, body temperature was detected by various techniques throughout the literature and we failed to include this as an evaluation item.

In conclusion, the present meta-analysis indicated that the administration of dexmedetomidine may prevent the incidence of postoperative shivering, although there was no difference compared with other anti-shivering drugs, such as fentanyl, meperidine, tramadol, and clonidine. Our results provided evidence to extend the clinical value of dexmedetomidine beyond its routine usage for sedation and analgesia. Nevertheless, due to its relatively high price and potential side effects, we do not recommend that anesthesiologists or perioperative medical staff use dexmedetomidine solely for the purpose of preventing postoperative shivering.

Notes

Declaration of conflict of interest

The authors declare no financial interests relating to patents or shareholdings in corporations involved in the medical market.

Funding

The study was supported by the Shanghai Chen-Guang program (10CG40), Shanghai Health Bureau (XYQ2011022), National Natural Science Foundation of China (30772092), and Natural Science Foundation of Shanghai (14ZR1413700).

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Copyright information

© Canadian Anesthesiologists' Society 2015

Authors and Affiliations

  • Zhen-Xiu Liu
    • 1
    • 2
    • 3
  • Feng-Ying Xu
    • 4
  • Xiao Liang
    • 5
  • Miao Zhou
    • 1
    • 2
  • Liang Wu
    • 1
    • 2
  • Jing-Ru Wu
    • 1
    • 2
  • Jian-Hua Xia
    • 3
    Email author
  • Zui Zou
    • 1
    • 2
    • 4
    Email author
  1. 1.Jiangsu Province Key Laboratory of AnesthesiologyXuzhou Medical CollegeXuzhouPeople’s Republic of China
  2. 2.Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application TechnologyXuzhou Medical CollegeXuzhouPeople’s Republic of China
  3. 3.Department of AnesthesiologyNo. 411 Hospital of PLAShanghaiPeople’s Republic of China
  4. 4.Department of Anesthesiology, Changzheng HospitalSecond Military Medical UniversityShanghaiPeople’s Republic of China
  5. 5.Department of AnesthesiologyAffiliated People’s Hospital of Jiangsu UniversityZhenjiangPeople’s Republic of China

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