Perioperative adverse events attributed to α2-adrenoceptor agonists in patients not at risk of cardiovascular events: systematic review and meta-analysis

British Journal of Anaesthesia, xxx (xxx): xxx (xxxx) doi: 10.1016/j.bja.2019.07.029 Advance Access Publication Date: xxx Review Article

REVIEW ARTICLE

Perioperative adverse events attributed to a2-adrenoceptor agonists in patients not at risk of cardiovascular events: systematic review and meta-analysis Migena Demiri1, Tiago Antunes1, Dominique Fletcher1,2,3 and Valeria Martinez1,2,3,*
sie, Ho ^ pital Raymond-Poincare
de Garches, Assistance Publique Ho ^ pitaux de Paris, Paris, Service d’anesthe
et de la Recherche Me
dicale, U-987, Ho ^ pital Ambroise Pare
, F-92100 France and France, 2Institut National de la Sante 3
Versailles Saint-Quentin, F-78035, Versailles, France Universite 1

*Corresponding author. E-mail: [email protected]

Abstract Background: Several systematic reviews have reported the benefits of perioperative a2-adrenoceptor agonist use for various conditions, but safety evidence is poorly documented. Methods: We performed a systematic review focusing on adverse events. We searched the MEDLINE, Embase, LILACS, Cochrane, and Clinical Trials Register databases for RCTs comparing the effects of a2-adrenoceptor agonists and placebo during non-cardiovascular surgery under general anaesthesia, for any indication, in patients not at risk of cardiovascular events. The primary outcome was the incidence of severe adverse events during or after a2-adrenoceptor agonist administration. The secondary endpoints were other adverse events. A meta-analysis was carried out on the combined data. Evidence quality was rated by the Grading of Recommendations Assessment, Development and Evaluation method. Results: We included 56 studies (4868 patients). Our review, based on moderate-quality evidence, revealed that hypotension occurred frequently during the preoperative and postoperative periods, for both clonidine and dexmedetomidine. Bradycardia was reported only with dexmedetomidine. In contrast, dexmedetomidine seemed to protect against intraoperative hypertension and tachycardia. Subgroup analysis suggested that the risk of hypotension and bradycardia persisted after cessation of treatment. Interestingly, intraoperative hypotension and postoperative bradycardia were not observed with a bolus dosage of dexmedetomidine less than 0.5 mg kg
1 or with continuous administration alone. Conclusions: The pooled data for the incidence of adverse events associated with the use of a2-adrenoceptor agonists in various perioperative contexts provided high-confidence evidence for a risk of hypotension and bradycardia, and protective effects against hypertension and tachycardia. Protocol registration: CRD42017071583. Keywords: adverse effect; a2a-adrenoceptor agonist; clonidine; dexmedetomidine; meta-analysis; systematic review

Editor’s key points  The risk/benefit balance of the perioperative use of a2adrenoceptor agonists is not well known.  This systematic review and meta-analysis summarises evidence from RCTs that included almost 5000 subjects.

 a2-adrenoceptor agonists appear to increase the incidence of hypotension. Dexmedetomidine appears to protect against intraoperative hypertension and tachycardia.

Editorial decision: 27 December 2018; Accepted: 26 July 2019 © 2019 Published by Elsevier Ltd on behalf of British Journal of Anaesthesia. For Permissions, please email: [email protected]

1

2

-

Demiri et al.

Clonidine and dexmedetomidine are centrally acting a2a2adrenoceptor agonists acting on presynaptic adrenoceptors in the vasomotor centre in the brainstem. The activation of these receptors stimulates a negative feedback loop, decreasing sympathetic activity and the central regulation of vasoconstrictor tone.1 a2-adrenoceptor agonists interact with the pain regulation system,2 exert antinociceptive effects by decreasing the perioperative catecholamine release,3,4 and inhibit the activation of microglia and signal-regulated kinase in the spinal dorsal horn after a nerve injury.5 As a result, these agonists can be used to decrease the demand for intraoperative anaesthetics and to reduce postoperative pain. Martinez and colleagues6 showed, in a network metaanalysis, that a2-adrenoceptor agonists were useful for reducing morphine consumption after a major surgery. The analysis revealed that these agonists had morphine-sparing and pain-relieving effects similar to those of non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors.6 a2-adrenoceptor agonists appeared to be the most beneficial non-opioid analgesics for morphine sparing and reducing opioid side-effects.6 These findings are novel, compared with the most recent meta-analyses of clonidine and dexmedetomidine reporting decreases in morphine consumption, pain, nausea, and vomiting relative to placebo.7e10 However, the paucity of severe adverse-effect data did not allow the assessment of efficacyesafety balance.6 This aspect must be addressed before a prescription can be recommended, and is particularly important given the increasing perioperative use of a2-adrenoceptor agonists because of their various benefits. Several systematic reviews have reported these drugs to be beneficial for a number of conditions other than postoperative pain, including the prevention of postoperative delirium,11 cognitive dysfunction,12 cardiac complications,13 postoperative nausea and vomiting,14 and postoperative shivering.15 However, there is far too little evidence concerning safety to draw any conclusions from these systematic reviews. Therefore, we gathered all the available evidence concerning safety from studies assessing the benefits of the two a2adrenoceptor agonists in current use (clonidine and dexmedetomidine) for various conditions during the perioperative period. We then performed a systematic review to provide an updated meta-analysis of adverse events attributable to a2adrenoceptor agonists used in the perioperative period in patients undergoing a major non-cardiovascular surgery.

Methods Data sources and search strategy The study was registered at the International Prospective Register of Systematic Reviews (CRD42017071583). This systematic review of RCTs was performed in accordance with the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the current recommendations of the Cochrane Collaboration.16,17 We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and LILACS databases for reports of RCTs included from the inception of each database to July 2018 in English, French, or Spanish using the terms ‘Surgical Procedures Operative’ OR ‘surgery’ and ‘clonidine’ or ‘dexmedetomidine’ or ‘a2-adrenoceptor agonist’. The search equation is available in Supplementary material 1. We identified randomised trials with the highly sensitive search strategy of the Cochrane

Collaboration.18 We also searched the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects for previous relevant systematic reviews. We searched the annual conference proceedings of the ASA and the European Society of Anaesthesiology from 2012 to 2018, by hand. We searched https://clinicaltrials.gov/and the WHO International Clinical Trials Registry Platform for completed trials. The reference lists of the identified published review articles on the perioperative use of a2-adrenoceptor agonists were also searched for eligible clinical trials, as were the reference lists of the studies they included.

Study selection We included all RCTs, including adults undergoing major surgery except cardiovascular surgery. Cardiovascular surgeries are defined as all operations for repairing structural defects of the cardiovascular system, including cardiac and vascular surgeries. We included only interventions performed under general anaesthesia. We excluded RCTs that selected patients at risk of cardiovascular events. The intervention of interest was the administration of a2-adrenoceptor agonist (dexmedetomidine or clonidine) before, during, or after surgery, at any dose or frequency. The drugs could be administered orally or intravenously. We accepted the use of a2adrenoceptor agonists for any indication, but we excluded trials set in periods other than the perioperative period, including, in particular, those focusing on the use of these drugs to prevent withdrawal syndrome, or for sedation in intensive care. We accepted all existing analgesic drugs or placebo as comparators. Two pairs of authors independently screened titles, abstracts, and full manuscripts according to the selection criteria. Any disagreement was discussed with a third author until a consensus was reached.

Data extraction and assessment of the risk of bias We developed a data-extraction form and tested it on five of the studies included. The form was then refined according to the results obtained. Pairs of reviewers independently extracted data from each study. Disagreements were resolved by a consensus with a third author. We extracted information about the trial setting (country), participants (age, sex, and weight), the trial itself (first author, number of arms in the study, and country), participants (age, ASA physical status, characteristics of the population, and number of patients randomised and analysed), the experimental intervention (timing of administration, duration, and doses used), and exclusion criteria. Two independent reviewers assessed the quality of the trial methodology with the Cochrane risk-of-bias tool, with any discrepancies resolved by a consensus.19

Outcome measures The primary outcome was the proportion of patients reporting serious adverse events (SAEs) during the perioperative period (intraoperatively and during the first 72 h after surgery). A serious adverse event (SAE) in human drug trials is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires inpatient hospitalisation or causes prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, may have caused a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage. We

Iden fica on

a2-adrenoceptor agonist adverse effects in major surgeries - 3

Literature search: databases PubMed/Embase/Cochrane/LILACS Date of last search: July 31, 2018

Other sources: registries, meetings, and previous systematic reviews

Six studies were identified

3902 studies were screened

Selec on

Remaining records after duplicates removed (n=1741)

Remaining records after screening by title (n=1004)

Two studies assessed for inclusion

Remaining records after screening by abstract (n=320)

Studies excluded on basis of full text (n=264):

Eligibility

-

Inclusion

-

Study design (n=74) Duplicated studies (n=17) Two abstracts not published, with no response from the authors Absence of adverse effects reported (n=75) Only continuous data for haemodynamic impact; no incidence available (n=71) No match with our criteria of outcomes definition (10) Other languages (5)

Remaining records after full-text articles assessed (n=56)

56 studies included in the quantitative analysis Clonidine, n=16 Dexmedetomidine, n=40

Fig 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart detailing retrieved, excluded, assessed, and included trials.

expected that the total number of SAEs reported to be small. We therefore analysed specific adverse effects corresponding to the Food and Drug Administration definition of an SAEs. A panel of experts independently predetermined which adverse effects frequently reported with a2-adrenoceptor agonists in previous studies corresponded to SAEs. After a discussion to resolve any conflicts/disagreements, we classified the following adverse effects as SAEs: haemodynamic instability, arrhythmia or bradycardia, syncope, and myocardial infarction. We have considered haemodynamic instability as an SAE when drug administration was required to correct it (atropine for bradycardia, vasoactive drug for hypotension or

hypertension, and beta blockers for tachycardia). The secondary outcomes were the proportion of patients reporting other frequent adverse events, but not SAEs. We extracted the incidence of adverse events, as defined by the authors.

Data synthesis and analysis For the proportion of patients with SAEs, the treatment effect was assessed as the risk ratio (RR), with 95% confidence intervals (CIs), for dichotomous data. To aid clinicians in their interpretation of effect sizes, we computed the number needed to treat for an additional harmful outcome (NNTH) from the results of a meta-analysis of each significant RR. We

4

-

Demiri et al.

expected there to be heterogeneity, and we therefore used the DerSimonian and Laird random effects meta-analysis modules. We assessed statistical heterogeneity by visual inspection of graphs and the use of the I2 statistics, which describes the proportion of variability in effect estimates because of heterogeneity rather than sampling error. We interpreted the value of the I2 statistics according to the following thresholds: 0e40% (heterogeneity probably not important), 30e60% (may represent moderate heterogeneity), 50e90% (may represent substantial heterogeneity), and 75e100% (considerable heterogeneity).20 We also performed a subgroup analysis to explore heterogeneity in estimation of the effect of intensity. We investigated whether the occurrence of an adverse effect was significantly related to the dose delivered, or to the mode and time of administration. Based on the doses currently used and the median bolus doses reported in previous reviews,8,9 the thresholds for high doses were set at 5 mg kg
1 for clonidine and 0.5 mg kg
1 for dexmedetomidine. We also assessed the mode of administration (bolus or continuous perfusion) and the timing of administration (preoperative, intraoperative, and postoperative periods).

Rating of evidence quality The quality of evidence for each outcome was rated according to the Grading of Recommendations Assessment, Development and Evaluation working group system,21 for five points: risk of bias, inconsistency, indirectness, imprecision, and publication bias. Each point was rated independently by two authors, with a discussion to reach a consensus if necessary.

Results Characteristics of trials and patients For the 2805 reports identified as potentially eligible in databases, we examined 276 full-text articles and selected 56 studies. Sixteen concerned clonidine and 40 dexmedetomidine, and 4868 patients, in total, were included in these studies (Fig. 1). Table 1 presents the characteristics of the selected trials (a detailed description in Supplementary material 2). The most frequently reported exclusion criteria were, in descending order of frequency: cardiac or respiratory disease (41%), psychological disorders (38%), cardiac conduction disorder (28.8%), hypo- or hypertension (18%), bradycardia (13.6%), and pregnancy and breastfeeding (10.2%). a2-adrenoceptor agonist treatment was initiated intraoperatively in most studies (39/ 56), but before operation in 11/56 studies and after operation in 6/56 studies. Treatment was administered intravenously in 94.6% (53/56) and orally in 5.4% (3/56) of the studies. In 41% (22/ 56) RCTs, the use of a bolus followed by a continuous administration was assessed. In 41% (23/56) RCTs, the use of a bolus alone was assessed, and 16% (9/56) of studies assessed continuous administration alone. The median bolus dose of clonidine was 3 mg kg
1 (range: 1e6 mg kg
1), and the median continuous dose was 0.3 mg kg
1 h
1. The median bolus dose of dexmedetomidine was 1 mg kg
1 (range: 0.1e2 mg kg
1), and the median continuous dose was 0.5 mg kg
1 h
1. The overall risk of bias was low for 12/56 (21%) trials, high for 11/56 trials (20%), and unclear for 33/56 (59%). In the 11 trials with a high risk of bias, this bias resulted principally from the consideration of incomplete outcome data or the selective reporting of data (Fig. 2).

Serious adverse events None of the included studies reported the SAEV outcome. Only two studies, totalling 156 patients, investigated myocardial ischaemia.22,23 One study reported that oral clonidine reduces myocardial ischaemia.23 In both studies, the episode of myocardial ischaemia was defined by the magnitude of ST segment depression. A depression of at least 1 mm, occurring 60 ms after the junction point and persisting for 3 min or more, was specified in one of the two studies.23 No troponin measurements were used. No event was observed in the other study, in which dexmedetomidine was used.22 Cardiac rhythm disorders were reported in two studies, including 283 patients,24,25 with only one patient in the placebo group presenting arrhythmia.24

Hypotension Clonidine Undesirable hypotension (requiring the administration of a drug to correct it) was reported in 12 studies.22,23,26e36 The pooled analysis revealed that the incidence of intraoperative hypotension was significantly higher with clonidine than with placebo, with an RR of 1.85 (1; 2.65).22,23,26e36 The quality of evidence was low (Table 2). The analyses of subgroups defined in terms of dose and type of administration revealed no differences between subgroups (Table 3). No significant difference was observed for postoperative hypotension.37,38

Dexmedetomidine Undesirable hypotension (requiring the administration of a drug to correct it) was reported in 23 studies.24,25,30,39e60 The pooled analysis revealed that the incidence of intraoperative hypotension was significantly higher with dexmedetomidine

Table 1 Characteristics of included trials. Data are numbers (percentages) unless otherwise indicated. ENT, eye, nose, and throat. Characteristics of the studies Publication year, median (range) 2013 (1991e2018) Single-centre trials 56 (100) Trial size, median no. of patients (range) 67 (28e300) Population characteristics ASA physical status 1e2 57 (96) Type of surgery Abdominal 12 (21) Gynaecological 14 (25) Orthopaedic 7 (12.5) ENT 5 (8) Neurosurgery 4 (6) Thoracic 5 (8) Mixed 9 (16) Objective of the study Prevention of pain 23 (41) Haemodynamic stability 4 (7) Reduction of shivering 6 (11) Sedative effect 3 (5) Recovery 3 (5) Cough reduction 2 (3) Immunomodulator/ 2 (3.6) prevention of inflammation Others 5 (7) Mixed indication 8 (12.3)

a2-adrenoceptor agonist adverse effects in major surgeries - 5 than with placebo, with an RR of 1.89 (1.1; 3.25).25,30,49,50,52e60 The quality of evidence was low to moderate (Table 2). The subgroup analysis showed a higher RR of hypotension for bolus doses alone, with an RR of 3.28 (1.42; 7.64), and for dose above 0.5 mg kg
1, with an RR of 2.38 (1.2; 4.7). The risk of postoperative hypotension was reported in the group with intraoperative administration.24,39e51 (Table 3).

Bradycardia Clonidine Undesirable bradycardia (requiring the administration of a drug to correct it) was reported in 11 studies. The pooled analysis revealed no significant difference between clonidine and placebo22,26e31,33e35,37,38 (Table 2). No differences between subgroups were identified in the subgroup analyses by dose or type of administration (Table 3).

Dexmedetomidine Undesirable bradycardia (requiring the administration of a drug to correct it) was reported in 25 studies.25,30,39e42,45,47,49,50,53,54,56,57,59e71 The pooled analysis revealed that the incidences of intraoperative and postoperative bradycardia were significantly higher with dexmedetomidine than with placebo, with RRs of 2.68 (1.78; 4.05)25,30,49,50,53,54,56,57,59e69 and 2.44 (1.71; 3.48),39e42,45,47,49,50,65,70,71 respectively. The quality of evidence was moderate to strong (Table 2). The subgroup analysis showed that there was a risk of intraoperative bradycardia, whatever the dose used, and the mode and time of administration (Table 3).

Hypertension Clonidine Undesirable hypertension (requiring the administration of a drug for its correction) was reported in four studies.27,29,30,72 No difference was found for both preoperative and postoperative hypertension.

Dexmedetomidine Undesirable hypertension (requiring the administration of a drug to correct it) was reported in 13 studies.24,25,30,41,46,50,55e57,71,73e75 The pooled analysis revealed that the incidence of intraoperative hypertension was significantly lower with dexmedetomidine than with placebo, with an RR of 0.12 (0.09; 0.18)25,30,55e57,73,74 The quality of evidence was moderate (Table 2). No difference was found for postoperative hypertension.24,41,46,50,71

Tachycardia Clonidine Too few data were available to assess this aspect.22

Dexmedetomidine

Fig 2. Risk-of-bias summary: review of authors’ judgements about each risk-of-bias item for each included study.

Undesirable tachycardia (requiring the administration of a drug to correct it) was reported in eight studies.24,25,46,55e57,71,74 The pooled analysis revealed that the incidence of intraoperative tachycardia was significantly lower with dexmedetomidine than with placebo, with an RR of 0.41 (0.26;

6

Demiri et al.

Table 2 Summary of findings of pairwise meta-analyses and the level of evidence. CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development and Evaluation; NNTH, number needed to treat for an additional harmful outcome calculated only for statistically significant results; RR, risk ratio. The level of evidence was assessed by the GRADE method. 4444 (High quality): we are very confident that the true effect is close to the estimated effect. 4442 (Moderate quality): we are moderately confident in the effect estimate; the true effect is likely to be close to the estimated effect, but there is a possibility that it is substantially different. 4422 (Low quality): our confidence in the effect estimate is limited; the true effect may be substantially different from the estimated effect. 4222 (Very low quality): we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimated effect. *Downgraded for imprecision: optimal information size not reached. yDowngraded for insufficient data quality. zDowngraded for inconsistency (I2>50%). Outcomes

Intraoperative hypotension Postoperative hypotension Intraoperative bradycardia Postoperative bradycardia Cardiac rhythm disorder Myocardial infarction Intraoperative hypertension Postoperative hypertension Intraoperative tachycardia Postoperative tachycardia Respiratory depression Laryngospasm Cough Drowsiness Dizziness Itch Headache Myalgia Agitation Dryness of mucous membranes

Dexmedetomidine

Clonidine

Studies Patients RR (95% CI)

Heterogeneity, NNTH I2 (%)

GRADE

Studies Patients RR (95% CI)

Heterogeneity, NNTH GRADE I2 (%)

13 14 16 13 2 1

1004 1161 1272 843 283 80

1.89 1.76 2.68 2.44 0.33 d

(1.1; 3.25) (0.95; 3.29) (1.78; 4.05) (1.71; 3.48) (0.01; 8.01)

0 33 17 15 d d

18 (7; 166) d 10 (5; 22) 8 (5, 17) d d

4442* 4422*y 4444 4442* d d

13 2 10 2 1 1

1264 140 866 140 44 64

1.855 (1; 2.6) 2.4 (0.13; 44) 1.22 (0.89; 2.24) d d d

0 d 0 d d d

d d d d d d

6 5 5 3 18 1 4 8 7 12 2 1 4 3

450 521 410 407 1175 50 350 628 478 915 130 80 249 333

0.12 0.61 0.41 0.35 0.59 d 0.37 1.39 0.89 0.64 0.43 1.00 0.34 2.43

(0.18; (0.32; (0.26; (0.13; (0.22;

0.09) 1.17) 0.65) 0.93) 1.59)

(0.23; (0.85; (0.61; (0.45; (0.12; (0.15; (0.20; (1.29;

0.61) 2.28) 1.30) 0.92) 1.58) 6.76) 0.59) 4.55)

0 20 60 0 43 d 5 74 0 0 0 d 0 78

7 (6; 8) d 7 (6; 12) 25 (19; 238) d d 5 (4; 9) d d 20 (13; 93) d d 21 (13; 26) 10 (2; 25)

4442* 4422yz 4442z 4442z 4422yz d 4222z 4422*z 4442* 4442* 4442* d 4442* 4422*z

4 1 1 0 6 0 1 1 1 0 0 0 0 1

327 187 64 0 576 0 300 60 50 0 0 0 0 80

0.17 (0.02; 1.33) d d d 0.68 (0.21; 2.18) d 0.45 (0.30; 0.67) 6.67 (2.21; 20.09) d d d d d 7.0 (0.37; 131.2)

0 d d d d d d d d d d d d d

d 4422*z d d d d d d d 4422*z d 4 (3; 7) 4422*z 3 (1; 7) 4222*z d d d d d d d d d d d 4222*yz

4422* 4222*y 4442* d d d

Table 3 Subgroup analyses for clonidine and dexmedetomidine. For each drug, a subgroup analysis was performed based on doses (the thresholds for high doses were set at 5 mg kg
1 for clonidine and 0.5 mg kg
1 for dexmedetomidine), mode of administration (bolus alone, bolus followed by continuous administration, and continuous administration alone), and administration time (preoperative, intraoperative, and postoperative periods). The data shown are the number of trials (number of patients). RR, risk ratio [95% confidence interval]. In bold, significant effect size. Adverse effects Bolus dose

Postoperative hypotension

Administration time relative to surgery

<5 mg kg¡1

≥5 mg kg¡1

Bolus

Bolusþ continuous i.v.

11 (1147); RR¼1.57 (0.92; 2.70); I2¼0% 9 (777); RR¼1.46 (0.81; 2.62); I2¼38% NA

6 (406); RR¼5.00 (0.9; 28); I2¼0% 6 (258); RR¼1.2 (0.45; 3); I2¼0% NA

9 (928); RR¼1.44 (0.84; 2.50); I2¼0% 9 (646); RR¼1.23 (0.73; 2.07); I2¼18% NA

4 (319); RR¼5.00 NA (0.90; 27.91); I2¼0% 4 (327); RR¼7 NA (0.4; 12.5); I2¼NA NA NA

7 (295); RR¼4.9 (0.6; 40); I2¼0% 7 (472); RR¼6.3 (1.1; 34); I2¼0% NA

8 (1017); RR¼1.43 3 (269); RR¼6 (0.83; 2.46); I2¼0% (0.75; 47.74); I2¼0% 8 (735); RR¼1; 23 3 (269); RR¼7.00 (0.73; 2.07); I2¼18% (0.39; 125.44); I2¼0% NA NA

NA

NA

NA

NA

NA

NA

Continuous Preoperative i.v. only

NA

10 (660); RR¼2.38 6 (720); RR¼3.28 5 (324); RR¼1.04 1 (100); NA 3 (330); RR¼1.47 (1.2; 4.7); I2¼0% (1.42; 7.64); I2¼0% (0.69; 1.58); I2¼0% (0.5; 4.3); I2¼0% 3 (330); RR¼9.01 12 (778); RR¼2.92 9 (612); RR¼1.7 9 (800); RR¼4.26 1 (100); NA (1.71; 47.62); I2¼0% (1.5; 3.8); I2¼9% (1.05; 2.7); I2¼28% (2; 9); I2¼0% 5 (356); RR¼1.82 6 (433); RR¼3.1 2 (100); RR¼11.00 9 (622); RR¼1.89 4 (258); (0.81; 4.07); I2¼0% (2; 4.8); I2¼40% (3.19; 37.88); I2¼3% (1.22; 2.93); I2¼0% RR¼2.2 (0.78; 5.6); I2¼0% 4 (258); RR¼2.2 8 (573); RR¼1.8 5 (310); RR¼2.5 6 (437); RR¼1.69 2 (211); (0.87; 5.62); I2¼0% (0.7; 4.7); I2¼56% (0.5; 12.7); I2¼72% (0.75; 3.62); I2¼0% RR¼1.6 (0.5e5); I2¼0%

Intraoperative

Postoperative

NA

2 (100); 11 12 (945); RR¼1.31 NA (0.64; 188); I2¼NA (0.89; 1.94); I2¼0% 3 (170); RR¼7.9 14 (858); RR¼1.9 NA (1.14; 54); I2¼0% (1.25; 2.98); I2¼0% 4 (414); RR¼2 10 (672); RR¼2.09 2 (0.68; 6); I2¼50% (1.4; 4.3); I2¼0% (129); RR¼16 (2.2; 117.8); I2¼18% 2 (130); RR¼0.63 (0.09; 4.58); I2¼40%

5 (589); RR¼1.62 9 (587); RR¼3 (0.6e4.2); I2¼0% (1.68; 5.35); I2¼0%

a2-adrenoceptor agonist adverse effects in major surgeries - 7

Clonidine Intraoperative hypotension Intraoperative bradycardia Postoperative bradycardia Postoperative hypotension Dexmedetomidine Intraoperative hypotension Intraoperative bradycardia Postoperative bradycardia

Mode of administration

8

-

Demiri et al.

0.65).25,55e57,74 The quality of evidence was low (Table 2). No difference was found for postoperative tachycardia.24,46,71

Other adverse events Clonidine Few other adverse events were reported for clonidine. Clonidine had no significant effect on respiratory depression, with an RR of 0.68 (0.21; 2.18),26,27,32,36,38,76 but was associated with a significantly lower incidence of cough, with an RR of 0.45 (0.30; 0.67).32 The only study that evaluated drowsiness reported a greater incidence of drowsiness with clonidine.23 Other adverse events were rarely reported, with dizziness reported in two studies38,77 and dryness of the mucous membranes with no significant repercussions in one study78 (Table 2).

Dexmedetomidine Drowsiness, agitation, respiratory depression, dizziness, and dryness of the mucous membranes were reported in eight, four, three, seven, and three studies, respectively. Dexmedetomidine did not increase the risk of drowsiness, with an RR of 1.39 (0.85; 2.28),39,42,43,45,55,61,79,80 but it was associated with a significantly lower risk of agitation (RR¼0.34 [0.20; 0.59]),43,44,66,81 with no significant effect on respiratory depression (RR¼0.59 [0.22; 1.59]).39,41,44,49e52,55,59,63,64,69,70,73,82e84 Dexmedetomidine did not increase the risk of dizziness (RR¼0.89 [0.61; 1.30])59,61,70,82,83; it decreased the risk of itching (RR¼0.64 [0.45; 0.92])24,41,45,62e64,69,70,73,82,83; and it increased the occurrence of mucous dryness, with an RR of 2.43 (1.29; 4.55).24,59,79 Other side-effects, such as laryngospasm, headache, and myalgia, were reported in only one85 or two studies,59,79 and dexmedetomidine had no significant effect on the likelihood of these effects (Table 2).

Discussion Description of the adverse events associated with a2adrenoceptor agonists This systematic review summarises the available evidence concerning the adverse effects of a2-adrenoceptor agonist use in the perioperative period in non-cardiovascular surgery. The quality of evidence is higher for dexmedetomidine than for clonidine. Our review, based on evidence of moderate quality, showed a high incidence of intraoperative hypotension for both drugs. Preoperative and postoperative bradycardia were frequently reported with dexmedetomidine, but were not reported with clonidine. Dexmedetomidine was found to have a protective effect against intraoperative hypertension and tachycardia. Our subgroup analyses showed that the risk of bradycardia and hypotension persisted even after the cessation of dexmedetomidine treatment. Our results also suggest that the use of low doses of dexmedetomidine (<0.5 mg kg
1) may reduce the risk of intraoperative hypotension and postoperative bradycardia. Isolated dexmedetomidine bolus has a negative impact for intraoperative bradycardia and hypotension. The available evidence for clonidine does not support a similar impact on the incidence of side-effects.

Strengths and weaknesses of our methodology Our study has several strengths. First, we conducted a rigorous and extensive literature search on the adverse effects of a2adrenoceptor agonist use in the perioperative period, and it is rare in the literature to have a quantitative analysis focused on adverse events. Second, by extending our research to different uses of a2a-adrenoceptor agonists, we were able to increase considerably the amount of information available. For respiratory depression and intraoperative bradycardia with dexmedetomidine, the minimum optimal information size was reached, increasing the confidence level for our results. Third, we calculated from RR ‘the number needed to harm’ for greater clarity for clinicians. Fourth, our systematic review was associated with a rating of evidence quality, providing transparency in the presentation of the evidence available and information about the extent to which we can have confidence in our effect estimates. Finally, we extracted the exclusion criteria from each study, making it possible for clinicians to appreciate the direct evidence and possible differences between the population included in this metaanalysis and their populations of interest. Our data were mostly obtained from a population of patients without cardiovascular and respiratory diseases undergoing a major surgery (excluding cardiovascular surgery). The main weakness of our review is the lack of evaluation of benefit/RR. We chose not to evaluate the incidence of benefit in the studies selected, as these aspects have already been evaluated in several metaanalyses, including a larger number of studies in each specific domain of interest.7,9,11,13,15,86,87

Comparison with other reviews Previous meta-analyses have explored side events, but pooled insufficient data for any firm conclusions to be drawn. Our meta-analysis was justified, as it included more than 2500 more patients than the largest previously published metaanalysis covering the perioperative period.7,11,13 This corresponds to 75% more patients than the previous largest study. Thirteen of the 16 published systematic reviews on a2adrenoceptor agonist (either clonidine or dexmedetomidine) use in the perioperative period explored cardiovascular effects. The maximum number of RCTs pooled was 16 for hypotension and 15 for bradycardia in the most recent systematic review exploring the prevention of cardiac complications in patients undergoing surgery.13 Our systematic review included twice as many RCTs, and explored the effects of clonidine and dexmedetomidine separately. Our results are consistent with the results of some previous systematic reviews analysing the adverse effects of a2adrenoceptor agonists. Only one previous review provided the NNTH for per- and post-haemodynamic effects.7 That review, published 6 yr ago, provided more information for clonidine and similar results for dexmedetomidine. However, our NNTH were higher and more accurate with a smaller CI. Several other systematic reviews have already reported hypotension in patients on dexmedetomidine9,88,89 or clonidine.7,89 Bradycardia has been reported in patients on dexmedetomidine in several systematic reviews,7,15,88,90 but it remains unclear whether clonidine has a similar effect. Our finding of a lack of reports of bradycardia in patients on clonidine is consistent with the findings of other recent systematic reviews,7,86 but all these results contrast with the findings of a large prospective study, including more than 4000

a2-adrenoceptor agonist adverse effects in major surgeries - 9 patients at risk of perioperative cardiovascular events. This study reported not only a clinically significant increase in the incidence of hypotension, but also increases in the incidence of bradycardia and non-fatal arrest.91 This discrepancy may be attributable to the inclusion of more vulnerable patients in this study than in our meta-analysis, but also to the more accurate measurement of myocardial infarction based on the measurement of troponin. Contrary to the findings of systematic reviews exploring a2adrenoceptor agonist use in cardiovascular surgery,13,89 morbidity, myocardial infarction, stroke, and cardiac arrest are either very infrequent or not reported at all in patients undergoing non-cardiovascular surgery.7,11,15 Furthermore, trials evaluating these serious outcomes have mostly focused on a selected population with a diagnosis of risk factors for coronary artery disease, such as the POISE.91 Concerning myocardial infarction, not only is this rarely reported, but when it is, it is rarely detected with an appropriate troponin measurement, as recommended during the perioperative period. This is a major weakness in the available data for a population that would not appear to be at risk of cardiovascular events. In contrast to the low number of SAEs reported in RCTs, some case reports described cardiac arrest during the intraoperative period after dexmedetomidine infusion.92e95 In these cases, patients had a prior cardiovascular system abnormality,93,94 or were taking chronotropic and negative inotropic drugs simultaneously.95 In two cases, the procedure was performed under spinal anaesthesia promoting the activity of the parasympathetic system.93,94

Effect of dose and mode of administration In our systematic review, we analysed the intra- and postoperative cardiovascular events separately. Only one previous systematic review used this approach.7 Our study included two items of information not available in this previous study. First, we have twice the amount of data available for the intraoperative period, and these data suggest that dexmedetomidine is significantly associated with both intraoperative hypotension and bradycardia, whereas only postoperative events were reported in the previous review. Second, our analysis of subgroups for the timing of administration revealed that postoperative cardiovascular events were reported even if dexmedetomidine administration ceased before wound closure. These results are not surprising, considering the long half-lives of both drugs, which are 20 h for clonidine and 2.5 h for dexmedetomidine.96 Our results also suggest that cardiovascular effects may be prevented by the choice of administration strategy. Indeed, although the quality of the available evidence is lower, no intraoperative hypotension or postoperative bradycardia was reported for dexmedetomidine boluses of less than 0.5 mg kg
1, or for continuous administration without a bolus injection. These results confirm what only one trial has explicitly reported to date higher rates of bradycardia and hypotension in groups receiving a bolus of dexmedetomidine 0.75 or 1.0 mg kg
1 than in the group receiving a bolus of 0.5 mg kg
1.53 The subgroup analyses reported that isolated dexmedetomidine bolus has a negative haemodynamic impact, and clearly questioned the use of bolus during anaesthesia. No such effect of dose or mode of administration was detected for clonidine.

Protective effect of a2-adrenoceptor agonists Our systematic review also highlighted lower rates of certain adverse effects, such as tachycardia and hypertension, during the use of dexmedetomidine. This protective effect against the cardiovascular symptoms of sympathetic stimulation has been described in other reviews86,88,89; most included trials conducted in patients undergoing cardiac or vascular surgery.13,89 Our study confirmed these findings for surgeries, in which there is no haemodynamic instability, but too few data were available to demonstrate a decrease in mortality and myocardial ischaemia with a2-adrenoceptor agonists similar to that reported for patients undergoing cardiovascular surgery.13,89 We indirectly compared the protective effect against tachycardia and hypertension, and the frequency of adverse events, such as bradycardia and hypotension, with the number needed to treat. We found that, for the treatment of any one patient with dexmedetomidine, the chances of preventing hypertension or tachycardia before operation were higher than that of causing bradycardia or hypotension in this population not at risk of cardiovascular events.

Other effects As expected, no respiratory depression was observed with dexmedetomidine or clonidine, and the incidence of cough seemed to be lower. Interestingly, our results did not report an increase of postoperative drowsiness with dexmedetomidine. It was not possible to draw the same conclusion for clonidine because of a lack of evidence. The timing of measurements, the method of measurement with mainly the Ramsay scale, and the reduction of morphine consumption in the preoperative and postoperative periods could explain this result. A substantial decrease in agitation was reported with dexmedetomidine; this point has already been well studied in children.97 Dryness of the mucous membrane is a well-known effect of dexmedetomidine that may be desirable in cases of fibreoptic-guided intubation in conscious patients.

Research implications Our systematic review highlighted both the poor reporting and lack of standardisation of adverse-event reporting in RCTs. During the screening phase, 29% of trials were excluded because of a lack of adverse-event evaluation. Furthermore, no SAEs were reported in any of the trials. It is essential to report SAEs in trials, whatever condition is evaluated. It is also important to standardise the definition of each adverse effect and use the more accurate markers. Considering the paucity of myocardial infarctions reported in our review compared with the high rate of infarction diagnosed if troponin was measured, we may question how the accuracy of the tools used to define myocardial infarction could affect the conclusions of the reviews. Future research evaluating the benefits of perioperative a2adrenoceptor agonist use in patients with diverse conditions is required to explore the impact of dose and administration more accurately.

Clinical implications The lack of evidence and the weak confidence in this evidence for clonidine allow us to provide clinical recommendations only for dexmedetomidine. The use of low doses of dexmedetomidine, the avoidance of boluses, and the use of

10

-

Demiri et al.

continuous administration reduce the risks of hypotension and bradycardia. Because of the risk of postoperative bradycardia, patients receiving dexmedetomidine should undergo haemodynamic monitoring for a prolonged period after treatment cessation. The use of dexmedetomidine is potentially valuable for avoiding peaks of hypertension and tachycardia during a major surgery under general anaesthesia. In our study that focused on patients not at risk of a cardiovascular event, it appears that one patient suffers of hypotension for every 18 people treated, and one patient avoids a hypertension for every seven people treated. This information seems important for the clinician who can personalise a treatment depending on the surgical context.

Authors’ contributions Protocol development: VM, MD Search strategy development: VM, MD Study search/procurement: TA Selection of studies: MD, TA, VM (arbiter) Data extraction: MD, TA Data analyses: VM, MD Interpretation of analyses: VM, MD, DF Final review: all authors Updating of final review: VM, DF

Declarations of interest The authors declare that they have no conflicts of interest.

Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.bja.2019.07.029.

References 1. Muzi M, Goff DR, Kampine JP, Roerig DL, Ebert TJ. Clonidine reduces sympathetic activity but maintains baroreflex responses in normotensive humans. Anesthesiology 1992; 77: 864e71 2. Pertovaara A. The noradrenergic pain regulation system: a potential target for pain therapy. Eur J Pharmacol 2013; 716: 2e7 3. Gil DW, Cheevers CV, Kedzie KM, et al. Alpha-1-adrenergic receptor agonist activity of clinical alpha-adrenergic receptor agonists interferes with alpha-2-mediated analgesia. Anesthesiology 2009; 110: 401e7 4. Maze M, Tranquilli W. Alpha-2 adrenoceptor agonists: defining the role in clinical anesthesia. Anesthesiology 1991; 74: 581e605 5. Liu L, Ji F, Liang J, He H, Fu Y, Cao M. Inhibition by dexmedetomidine of the activation of spinal dorsal horn glias and the intracellular ERK signaling pathway induced by nerve injury. Brain Res 2012; 1427: 1e9 6. Martinez V, Beloeil H, Marret E, Fletcher D, Ravaud P, Trinquart L. Non-opioid analgesics in adults after major surgery: systematic review with network meta-analysis of randomized trials. Br J Anaesth 2017; 118: 22e31 7. Blaudszun G, Lysakowski C, Elia N, Tramer MR. Effect of perioperative systemic alpha2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials. Anesthesiology 2012; 116: 1312e22

8. Jessen Lundorf L, Korvenius Nedergaard H, Moller AM. Perioperative dexmedetomidine for acute pain after abdominal surgery in adults. Cochrane Database Syst Rev 2016; 2: Cd010358 9. Schnabel A, Meyer-Friessem CH, Reichl SU, Zahn PK, Pogatzki-Zahn EM. Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A metaanalysis of randomized controlled trials. Pain 2013; 154: 1140e9 10. Fletcher D, Martinez V. How can we prevent opioid induced hyperalgesia in surgical patients? Br J Anaesth 2016; 116: 447e9 11. Duan X, Coburn M, Rossaint R, Sanders RD, Waesberghe JV, Kowark A. Efficacy of perioperative dexmedetomidine on postoperative delirium: systematic review and meta-analysis with trial sequential analysis of randomised controlled trials. Br J Anaesth 2018; 121: 384e97 12. Zhou C, Zhu Y, Liu Z, Ruan L. Effect of dexmedetomidine on postoperative cognitive dysfunction in elderly patients after general anaesthesia: a meta-analysis. J Int Med Res 2016; 44: 1182e90 13. Duncan D, Sankar A, Beattie WS, Wijeysundera DN. Alpha-2 adrenergic agonists for the prevention of cardiac complications among adults undergoing surgery. Cochrane Database Syst Rev 2018; 3: CD004126 14. Jin S, Liang DD, Chen C, Zhang M, Wang J. Dexmedetomidine prevent postoperative nausea and vomiting on patients during general anesthesia: a PRISMA-compliant meta analysis of randomized controlled trials. Medicine (Baltimore) 2017; 96, e5770 15. Lewis SR, Nicholson A, Smith AF, Alderson P. Alpha-2 adrenergic agonists for the prevention of shivering following general anaesthesia. Cochrane Database Syst Rev 2015; 8: CD011107 16. Higgins J, Green S. Guide to the contents of a Cochrane protocol and review (updated March 2011). The Cochrane Collaboration. In: Cochrane handbook for systematic reviews of interventions, version 5.1.0; 2011. Available from: http:// handbook-5-1.cochrane.org/. [Accessed 25 September 2019] 17. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and metaanalyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339: b2700 18. Lefebvre C, Manheimer E, Glanville J. Searching for studies (updated March 2011). The Cochrane Collaboration. In: Cochrane handbook for systematic reviews of interventions, version 5.1.0; 2011. Available from: http://handbook-5-1. cochrane.org/. [Accessed 25 September 2019] 19. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928 20. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539e58 21. Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 3. rating the quality of evidence. J Clin Epidemiol 2011; 64: 401e6 22. Montazeri K, Kashefi P, Honarmand A, Safavi M, Hirmanpour A. Attenuation of the pressor response to direct laryngoscopy and tracheal Intubation: oral clonidine vs. oral gabapentin premedication. J Res Med Sci 2011; 16: S377e86

a2-adrenoceptor agonist adverse effects in major surgeries - 11 23. Yin YC, Chow LH, Tsao CM, et al. Oral clonidine reduces myocardial ischemia in patients with coronary artery disease undergoing noncardiac surgery. Acta Anaesthesiol Sin 2002; 40: 197e203 24. Gao Y, Deng X, Yuan H, et al. Patient-controlled intravenous analgesia with combination of dexmedetomidine and sufentanil on patients after abdominal operation: a prospective, randomized, controlled, blinded, multicenter clinical study. Clin J Pain 2018; 34: 155e61 25. Xu L, Hu Z, Shen J, McQuillan PM. Does dexmedetomidine have a cardiac protective effect during non-cardiac surgery? A randomised controlled trial. Clin Exp Pharmacol Physiol 2014; 41: 879e83 26. Bernard JM, Bourreli B, Hommeril JL, Pinaud M. Effects of oral clonidine premedication and postoperative i.v. infusion on haemodynamic and adrenergic responses during recovery from anaesthesia. Acta Anaesthesiol Scand 1991; 35: 54e9 27. De Kock MF, Pichon G, Scholtes JL. Intraoperative clonidine enhances postoperative morphine patient-controlled analgesia. Can J Anaesth 1992; 39: 537e44 28. El-Kerdawy HM, Zalingen EE, Bovill JG. The influence of the alpha2-adrenoceptor agonist, clonidine, on the EEG and on the MAC of isoflurane. Eur J Anaesthesiol 2000; 17: 105e10 29. Fehr SB, Zalunardo MP, Seifert B, et al. Clonidine decreases propofol requirements during anaesthesia: effect on bispectral index. Br J Anaesth 2001; 86: 627e32 30. Hazra R, Manjunatha SMD, Manuar B, Basu R, Chakraborty S. Comparison of the effects of intravenously administered dexmedetomidine with clonidine on hemodynamic responses during laparoscopic cholecystectomy. Anaesth Pain Intensive Care 2014; 18: 25e30 31. Hommeril JL, Bernard JM, Passuti N, Pinaud M, Souron R. [Effects of intravenous clonidine on postoperative shivering]. Ann Fr Anesth Reanim 1991; 10: 554e8 32. Horng HC, Wong CS, Hsiao KN, et al. Pre-medication with intravenous clonidine suppresses fentanyl-induced cough. Acta Anaesthesiol Scand 2007; 51: 862e5 33. Reena A, Vikram A. Comparative evaluation of clonidine and magnesium sulfate infusions upon intraoperative hemodynamics and anesthetic consumption, and postoperative recovery profile in lumbar spine surgery: a prospective, randomized, placebo controlled, doubleblind study. Acta Anaesth Belg 2017; 68: 31e8 34. Samantaray A, Rao MH, Chandra A. The effect on postoperative pain of intravenous clonidine given before induction of anaesthesia. Indian J Anaesth 2012; 56: 359e64 35. Vanderstappen I, Vandermeersch E, Vanacker B, Mattheussen M, Herijgers P, Van Aken H. The effect of prophylactic clonidine on postoperative shivering. A large prospective double-blind study. Anaesthesia 1996; 51: 351e5 36. Chattopadhyay S, Goswami S, Rudra A. Efficacy of prophylactic clonidine in preventing postanesthetic shivering in laparoscopic-assisted vaginal hysterectomy. J South Asian Feder Obst Gynae 2013; 5: 120e3 37. Marinangeli F, Ciccozzi A, Donatelli F, et al. Clonidine for treatment of postoperative pain: a dose-finding study. Eur J Pain 2002; 6: 35e42 38. Striebel WH, Koenigs DI, Kramer JA. Intravenous clonidine fails to reduce postoperative meperidine requirements. J Clin Anesth 1993; 5: 221e5 39. Bindu B, Pasupuleti S, Gowd UP, Gorre V, Murthy RR, Laxmi MB. A double blind, randomized, controlled trial to

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

study the effect of dexmedetomidine on hemodynamic and recovery responses during tracheal extubation. J Anaesthesiol Clin Pharmacol 2013; 29: 162e7 Cheng M, Shi J, Gao T, et al. The addition of dexmedetomidine to analgesia for patients after abdominal operations: a prospective randomized clinical trial. World J Surg 2017; 41: 39e46 Dong CS, Zhang J, Lu Q, et al. Effect of dexmedetomidine combined with sufentanil for post-thoracotomy intravenous analgesia: a randomized, controlled clinical study. BMC Anesthesiol 2017; 17: 33 Elvan EG, Oc B, Uzun S, Karabulut E, Coskun F, Aypar U. Dexmedetomidine and postoperative shivering in patients undergoing elective abdominal hysterectomy. Eur J Anaesthesiol 2008; 25: 357e64 Ham SY, Kim JE, Park C, Shin MJ, Shim YH. Dexmedetomidine does not reduce emergence agitation in adults following orthognathic surgery. Acta Anaesthesiol Scand 2014; 58: 955e60 Kwon SY, Joo JD, Cheon GY, Oh HS, In JH. Effects of dexmedetomidine infusion on the recovery profiles of patients undergoing transurethral resection. J Korean Med Sci 2016; 31: 125e30 Lin TF, Yeh YC, Lin FS, et al. Effect of combining dexmedetomidine and morphine for intravenous patientcontrolled analgesia. Br J Anaesth 2009; 102: 117e22 Liu C, Zhang Y, She S, Xu L, Ruan X. A randomised controlled trial of dexmedetomidine for suspension laryngoscopy. Anaesthesia 2013; 68: 60e6 Wang Y, Xu X, Liu H, Ji F. Effects of dexmedetomidine on patients undergoing radical gastrectomy. J Surg Res 2015; 194: 147e53 Zhang B, Wang G, Liu X, Wang TL, Chi P. The opioidsparing effect of perioperative dexmedetomidine combined with oxycodone infusion during open hepatectomy: a randomized controlled trial. Front Pharmacol 2017; 8: 940 Lawrence CJ, De Lange S. Effects of a single pre-operative dexmedetomidine dose on isoflurane requirements and peri-operative haemodynamic stability. Anaesthesia 1997; 52: 736e44 Tanskanen PE, Kytta JV, Randell TT, Aantaa RE. Dexmedetomidine as an anaesthetic adjuvant in patients undergoing intracranial tumour surgery: a double-blind, randomized and placebo-controlled study. Br J Anaesth 2006; 97: 658e65 Yang XH, Bai Q, Lv MM, Fu HG, Dong TL, Zhou Z. Effect of dexmedetomidine on immune function of patients undergoing radical mastectomy: a double blind and placebo control study. Eur Rev Med Pharmacol Sci 2017; 21: 1112e6 Chang J, Wang X, Xin D, Sun Q, Jiang M, Ma J. Intraoperative and postoperative infusion of dexmedetomidine combined with butorphanol for intravenous patientcontrolled analgesia after radical mastectomy: a doubleblind, randomized clinical trial. Int J Clin Exp Med 2017; 10: 2505e13 Kim YS, Kim YI, Seo KH, Kang HR. Optimal dose of prophylactic dexmedetomidine for preventing postoperative shivering. Int J Med Sci 2013; 10: 1327e32 Lee SH, Lee CY, Lee JG, Kim N, Lee HM, Oh YJ. Intraoperative dexmedetomidine improves the quality of recovery and postoperative pulmonary function in patients undergoing video-assisted thoracoscopic surgery: a CONSORT-prospective, randomized, controlled trial. Medicine (Baltimore) 2016; 95, e2854

12

-

Demiri et al.

55. Luthra A, Prabhakar H, Rath GP. Alleviating stress response to tracheal extubation in neurosurgical patients: a comparative study of two infusion doses of dexmedetomidine. J Neurosci Rural Pract 2017; 8: S49e56 56. Seo KH, Kim YI, Kim YS. Optimal dose of dexmedetomidine for attenuating cardiovascular response during emergence in patients undergoing total laparoscopic hysterectomy. J Int Med Res 2014; 42: 1139e49 57. Soliman RN, Hassan AR, Rashwan AM, Omar AM. Prospective, randomized study to assess the role of dexmedetomidine in patients with supratentorial tumors undergoing craniotomy under general anaesthesia. Middle East J Anaesthesiol 2011; 21: 325e34 58. Sun S, Huang SQ. Effects of pretreatment with a small dose of dexmedetomidine on sufentanil-induced cough during anesthetic induction. J Anesth 2013; 27: 25e8 59. Yildiz M, Tavlan A, Tuncer S, Reisli R, Yosunkaya A, Otelcioglu S. Effect of dexmedetomidine on haemodynamic responses to laryngoscopy and intubation: perioperative haemodynamics and anaesthetic requirements. Drugs R D 2006; 7: 43e52 60. Karaman S, Gunusen I, Ceylan M, et al. Dexmedetomidine infusion prevents postoperative shivering in patients undergoing gynecologic laparoscopic surgery. Turk J Med Sci 2013; 43: 232e7 61. Chang J, Wang X, Xin D, Sun Q, Jiang M, Ma J. Intraoperative and postoperative infusion of dexmedetomidine combined with butorphanol for intravenous patientcontrolled analgesia after radical mastectomy: a doubleblind, randomized clinical trial. Int J Clin Exp Med 2017; 10: 2505e13 62. Cicek M, Yucel A, Gedik E, Sagir O, Kadir But B, Ozcan Ersoy M. The effects of intra-operative low-dose dexmedetomidine infusion on postoperative pain in patients undergoing septorhinoplasty. Pain Clinic 2006; 18: 395e402 63. Fan W, Xue H, Sun Y, et al. Dexmedetomidine improves postoperative patient-controlled analgesia following radical mastectomy. Front Pharmacol 2017; 8: 250 64. Shi C, Jin J, Pan Q, et al. Intraoperative use of dexmedetomidine promotes postoperative sleep and recovery following radical mastectomy under general anesthesia. Oncotarget 2017; 8: 79397e403 65. Sun S, Huang SQ, Wagner D, et al. Effects of pretreatment with a small dose of dexmedetomidine on sufentanilinduced cough during anesthetic induction. J Anesth 2013; 27: 25e8 66. Zhao D, Hu Z. Effect of dexmedetomidine hydrochloride combined with limb remote ischemic preconditioning on quality of recovery from anesthesia in patients undergoing thoracoscopic lobectomy. Int J Clin Exp Med 2018; 11: 891e7 67. Zhou H, Lu J, Shen Y, Kang S, Zong Y. Effects of dexmedetomidine on CD42a(þ)/CD14(þ), HLADR(þ)/CD14(þ) and inflammatory cytokine levels in patients undergoing multilevel spinal fusion. Clin Neurol Neurosurg 2017; 160: 54e8 68. Shin HW, Yoo HN, Kim DH, Lee H, Shin HJ, Lee HW. Preanesthetic dexmedetomidine 1 mg/kg single infusion is a simple, easy, and economic adjuvant for general anesthesia. Korean J Anesthesiol 2013; 65: 114e20 69. Zhao JN, Kong M, Qi B, Ge DJ. Comparison of the morphine-sparing effect of intraoperative dexmedetomidine with and without loading dose following general anesthesia in multiple-fracture patients: a prospective,

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

randomized, controlled clinical trial. Medicine (Baltimore) 2016; 95, e4576 Ge DJ, Qi B, Tang G, Li JY. Intraoperative dexmedetomidine promotes postoperative analgesia and recovery in patients after abdominal colectomy: a CONSORTprospective, randomized, controlled clinical trial. Medicine (Baltimore) 2015; 94: e1727 Zhang YS, Jin LJ, Zhou X, Liu Y, Li Y, Wen LY. Effect of dexmedetomidine on stress reactions and cellular immune function of patients in perioperative period following radial resection for rectal carcinoma. J Biol Regul Homeost Agents 2018; 32: 139e45 Bernard JM, Hommeril JL, Passuti N, Pinaud M. Postoperative analgesia by intravenous clonidine. Anesthesiology 1991; 75: 577e82 Abdelmageed WM, Elquesny KM, Shabana RI, Abushama HM, Nassar AM. Analgesic properties of a dexmedetomidine infusion after uvulopalatopharyngoplasty in patients with obstructive sleep apnea. Saudi J Anaesth 2011; 5: 150e6 Liu HL, Qian YN, Saravana Babu M, et al. [Effects of dexmedetomidine on perioperative inflammatory response in patients undergoing valve replacement]. A comparative study in the post-operative spine surgeries: epidural ropivacaine with dexmedetomidine and ropivacaine with clonidine for post-operative analgesia. Zhongguo Ying Yong Sheng Li Xue Za Zhi 2013; 29: 316e7 Han Y, Han L, Dong M, et al. Comparison of a loading dose of dexmedetomidine combined with propofol or sevoflurane for hemodynamic changes during anesthesia maintenance: a prospective, randomized, double-blind, controlled clinical trial. BMC Anesth 2018; 18: 12 Mirhosseini H, Avazbakhsh MH, Hosseini Amiri M, Entezari A, Bidaki R. Effect of oral clonidine on shoulder tip pain and hemodynamic response after laparoscopic cholecystectomy: a randomized double blind study. Anesth Pain Med 2017; 7, e61669 Mohammadi S, Seyedi M. Comparing oral gabapentin versus clonidine as premedication on early postoperative pain and vomiting after general anesthesia. Int J Pharmacol 2008: 1e4 NCT01548209. Effects of a dexmedetomidine on quality of recovery 40 and postoperative nausea and vomiting in breast cancer surgery. Available from: https://clinicaltrials. gov/ct2/show/NCT01548209. [Accessed 25 Sep 2019] Bajwa SJ, Gupta S, Kaur J, Singh A, Parmar S. Reduction in the incidence of shivering with perioperative dexmedetomidine: a randomized prospective study. J Anaesthesiol Clin Pharmacol 2012; 28: 86e91 Das R, Das RK, Sahoo S, Nanda S. Role of dexmedetomidine as an anaesthetic adjuvant in breast cancer surgery as a day-care procedure: a randomised controlled study. Indian J Anaesth 2018; 62: 182e7 Yang X, Li Z, Gao C, Liu R. Effect of dexmedetomidine on preventing agitation and delirium after microvascular free flap surgery: a randomized, double-blind, control study. J Oral Maxillofac Surg 2015; 73: 1065e72 Ge DJ, Qi B, Tang G, Li JY. Intraoperative dexmedetomidine promotes postoperative analgesia and recovery in patients after abdominal hysterectomy: a double-blind, randomized clinical trial. Sci Rep 2016; 6: 21514 Fan W, Yang H, Sun Y, et al. Comparison of the propostoperative analgesia of intraoperative dexmedetomidine with and without loading dose following general

a2-adrenoceptor agonist adverse effects in major surgeries - 13

84.

85.

86.

87.

88.

89.

anesthesia: a prospective, randomized, controlled clinical trial. Medicine (Baltimore) 2017; 96, e6106 Bindu B, Bindra A, Kaushal A, Prabhakar H, Chaturvedi A. Neuroprotective role of dexmedetomidine in epilepsy surgery: a preliminary study. Available from: http:// cochranelibrary-wiley.com/o/cochrane/clcentral/articles/ 360/CN-01605360/frame.html. [Accessed 25 Sep 2019] Yun Y, Wang J, Tang RR, Yin XR, Zhou H, Pei L, et al. Effects of an intraoperative dexmedetomidine bolus on the postoperative blood pressure and pain subsequent to craniotomy for supratentorial tumors. J Neurosurg Anesthesiol 2017; 29: 211e8 Nishina K, Mikawa K, Uesugi T, et al. Efficacy of clonidine for prevention of perioperative myocardial ischemia: a critical appraisal and meta-analysis of the literature. Anesthesiology 2002; 96: 323e9 Wang X, Liu N, Chen J, Xu Z, Wang F, Ding C. Effect of intravenous dexmedetomidine during general anesthesia on acute postoperative pain in adults: a systematic review and meta-analysis of randomized controlled trials. Clin J Pain 2018; 34: 1180e91 Biccard BM, Goga S, de Beurs J. Dexmedetomidine and cardiac protection for non-cardiac surgery: a metaanalysis of randomised controlled trials. Anaesthesia 2008; 63: 4e14 Wijeysundera DN, Bender JS, Beattie WS. Alpha-2 adrenergic agonists for the prevention of cardiac complications among patients undergoing surgery. Cochrane Database Syst Rev 2009; 7: CD004126

90. Schnabel A, Reichl SU, Weibel S, et al. Efficacy and safety of dexmedetomidine in peripheral nerve blocks: a metaanalysis and trial sequential analysis. Eur J Anaesthesiol 2018; 35: 745e58 91. Devereaux PJ, Sessler DI, Leslie K, et al. Clonidine in patients undergoing noncardiac surgery. N Engl J Med 2014; 370: 1504e13 92. Aikaterini A, Ioannis D, Dimitrios G, Konstantinos S, Vasilios G, George P. Bradycardia leading to asystole following dexmedetomidine infusion during cataract surgery: dexmedetomidine-induced asystole for cataract surgery. Case Rep Anesthesiol 2018; 2018: 2896032 93. Yeoh C, Fischer G, Tollinche L. Arrest under anesthesiadwhat was the culprit? A case report. EC Anaesth 2018; 4: 372e5 94. Kim BJ, Kim BI, Byun SH, Kim E, Sung SY, Jung JY. Cardiac arrest in a patient with anterior fascicular block after administration of dexmedetomidine with spinal anesthesia: a case report. Medicine (Baltimore) 2016; 95: e5278 95. Bharati S, Pal A, Biswas C, Biswas R. Incidence of cardiac arrest increases with the indiscriminate use of dexmedetomidine: a case series and review of published case reports. Acta Anaesthesiol Taiwan 2011; 49: 165e7 96. Giovannitti Jr JA, Thoms SM, Crawford JJ. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth Prog 2015; 62: 31e9 97. Ni J, Wei J, Yao Y, Jiang X, Luo L, Luo D. Effect of dexmedetomidine on preventing postoperative agitation in children: a meta-analysis. PLoS One 2015; 10, e0128450 Handling editor: J.G. Hardman