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Brazilian Journal of Anesthesiology xxxx;000(xxx): 1−24

SYSTEMATIC REVIEW

Effects of dexmedetomidine in non-operating room

anesthesia in adults: a systematic review with meta-
analysis

nimo Fonseca
Francisca Jero a
, Leonardo Ferreira b,
*, Ana Lídia Rouxinol-Dias b,c,d
,
Joana Moura~o a,b

a
Faculty of Medicine of the University of Porto, Porto, Portugal
b
~o Joa
Sa ~o University Hospital Center, Department of Anesthesiology, Porto, Portugal
c
Faculty of Medicine of the University of Porto, Department of Community Medicine, Information and Decision in Health, MEDCIDS,
Porto, Portugal
d
Faculty of Medicine of the University of Porto, Center for Health Technology and Services Research, CINTESIS, Porto, Portugal

Received 7 April 2021; accepted 5 December 2021

Available online xxx

KEYWORDS Abstract
Anesthesiology; Background: Dexmedetomidine (DEX) is an a2-adrenergic receptor agonist used for its sedative,
Conscious sedation; analgesic, and anxiolytic effects. Non-Operating Room Anesthesia (NORA) is a modality of anes-
Dexmedetomidine; thesia that can be done under general anesthesia or procedural sedation or/and analgesia. In
Hypnotics and this particular setting, a level-2 sedation, such as the one provided by DEX, is beneficial. We
sedatives; aimed to study the effects and safety of DEX in the different NORA settings in the adult
Patient safety population.
Methods: A systematic review with meta-analysis of randomized controlled trials was con-
ducted. Interventions using DEX only or DEX associated with other sedative agents, in adults
(18 years old or more), were included. Procedures outside the NORA setting and/or without
a control group without DEX were excluded. MEDLINE, ClinicalTrials.gov, Scopus, LILACS,
and SciELO were searched. The primary outcome was time until full recovery. Secondary
outcomes included hemodynamic and respiratory complications and other adverse events,
among others.
Results: A total of 97 studies were included with a total of 6,706 participants. The meta-analysis
demonstrated that DEX had a higher time until full recovery (95% CI = [0.34, 3.13] minutes, a higher
incidence of hypotension (OR = 1.95 [1.25, 3.05], p = 0.003, I2 = 39%) and bradycardia (OR = 3.60
[2.29, 5.67], p < 0.00001, I2 = 0%), and a lower incidence of desaturation (OR = 0.40 [0.25, 0.66],
p = 0.0003, I2 = 60%).

* Corresponding author.
E-mail: [email protected] (L. Ferreira).

https://doi.org/10.1016/j.bjane.2021.12.002
0104-0014/© 2021 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: F.J. Fonseca, L. Ferreira, A.L. Rouxinol-Dias et al., Effects of dexmedetomidine in non-
operating room anesthesia in adults: a systematic review with meta-analysis, Brazilian Journal of Anesthesiology (2021),
https://doi.org/10.1016/j.bjane.2021.12.002
JID: BJANE
ARTICLE IN PRESS [mSP6P;January 29, 2022;9:59]
F.J. Fonseca, L. Ferreira, A.L. Rouxinol-Dias et al.

Conclusion: DEX in NORA procedures in adults was associated with a lower incidence of amnesia
and respiratory effects but had a long time to recovery and more hemodynamic complications.
© 2021 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/
4.0/).

Introduction Items for Systematic Review and Meta-Analysis Protocols)

guidance.8 Under the guidelines, our systematic review pro-
Dexmedetomidine (DEX) is an a2-Adrenergic Receptor (a2-AR) tocol was registered in the International Prospective Regis-
agonist used for its sedative, analgesic, and anxiolytic effects.1 ter of Systematic Reviews (PROSPERO) on the 22nd of
It is a relatively new drug, having been approved by the Food October 2020 (registration number CRD42020215880). This
and Drug Administration (FDA) in 1999 for use in short-term systematic review was written following the PRISMA
sedation and analgesia (< 24 hours) in the Intensive Care Unit Statement.9
(ICU).1 It provides a unique type of sedation, “arousable seda-
tion”, in which patients appear to be sleepy but are easily Eligibility criteria
aroused, cooperative, and communicative when stimulated,
resembling natural sleep.1 Furthermore, in the ICU setting, it We included papers that studied patients with 18 years of
is associated with reduced anesthetic requirements and pres- age or older. Only Randomized Controlled Trials (RCTs),
ervation of respiratory function, offering hemodynamic stabil- regardless of their population size, were included. Of inter-
ity with a reduced dose of vasopressor in septic shock est were interventions using DEX only or DEX associated with
patients,2 hence facilitating early weaning from the ventilator other sedative agents, comparing with the use of another
and thereby reducing overall ICU stay costs.1,3 pharmacological sedative strategy (without DEX).
Non-Operating Room Anesthesia (NORA) is an upcoming
and challenging modality of anesthesia in remote locations Search strategy
within the hospital that requires expertise and skill.4 In this
particular backdrop, level 2 sedation is beneficial because it The full queries applied to the different information sources
allows the patient to follow commands during the procedure and results are presented in Appendix I. Search was con-
while maintaining airway function and reflexes.4 The partic- ducted on MEDLINE (through Pubmed), ClinicalTrials.gov,
ular goals of sedation are patient safety and welfare, mini- Scopus, LILACS (through Virtual Health Library Regional Por-
mizing discomfort and pain, controlling anxiety, minimizing tal), and SciELO for all available literature on the subject
psychological trauma, maximizing the potential of antero- until October 12, 2021. The bibliographies of relevant sys-
grade amnesia, controlling movement for safer completion tematic reviews were studied to identify any studies missed
of the procedure, and rapid recovery of the patient to a by our literature search. Articles written in all languages
state of safe discharge from medical supervision.4 were searched.
In NORA sedation, there is a paucity of literature describing
the efficacy and safety of DEX, alone and in combination, both Data collection and assessment
in children and in adults.5 A recent review reported DEX as a
promising alternative to midazolam for use in procedural seda- Two reviewers independently read all titles and abstracts
tion in adults, providing more comfort during the procedure and selected the studies to include in the review according
for the patient and clinician.6 Therefore, further embracing to the eligibility criteria. Then, the full article was obtained
investigation is warranted to better understand the effects and read in its integrity by the two authors, and it was
and safety of DEX, alone or in combination, in the different decided if it met the inclusion criteria. Uncertainty and dis-
NORA settings, especially in the adult population.7 For chil- agreement were resolved by discussion between the
dren, there is already a recent systematic review reporting sig- reviewers. Reviewers were blind to the journal titles and
nificant benefits of DEX in NORA sedation. But for the adult institutions. The data extraction from the selected studies
population, a preliminary search of PROSPERO, MEDLINE, the was independent and in duplicate to avoid errors and reduce
Cochrane Database of Systematic Reviews, and the JBI Data- biases. Any remaining discrepancies were resolved by a third
base of Systematic Reviews and Implementation Reports was author.
conducted and no current or underway systematic reviews on The following outcomes were evaluated in this review:
the topic were identified. Therefore, we developed a system- recovery time (primary outcome), sedation level, pain and
atic review to evaluate and report time until recovery and side discomfort, patient and physician satisfaction, hemody-
effects of DEX only or DEX associated with other sedative namic complications (hypotension and hypertension, brady-
agents in NORA settings for adults’ procedures in comparison cardia, and tachycardia), respiratory depression and other
to other sedatives. respiratory complications, and nausea or vomiting.
Literature search results were uploaded to EndNote Vx9
(Clarivate Analytics, PA, USA), a reference management
Methods software that facilitates the collection, duplicate exclusion,
and analysis of research materials and collaboration
The protocol of this systematic review and meta-analysis between researchers during the selection process. For
was written following the PRISMA-P (Preferred Reporting screening, a database was built using Microsoft Excel

2
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Brazilian Journal of Anesthesiology xxxx;000(xxx): 1−24

V16.42/2020 (Microsoft Corporation, USA). For data collec- Included trials

tion, synthesis, and analysis, data were extracted to Rev-
Man 5.1 (Review Manager 5.1) V5.4 (Copenhagen: The The 97 RCTs studies included involved a total
Nordic Cochrane Centre, Cochrane). of 6,706 participants and 6,853 procedures. This difference
is due to Nooh et al.,15 Shetty et al.,16 and Hiwarkar et al.,17
where each subject participated in two procedure sessions
Risk of bias in individual studies and received both interventions. We summarized the char-
acteristics of the included studies in Table 1.
The risk of bias for each study was evaluated by the collec- The studies included were from 2004 onward, 21 from
tion of information, using the Cochrane Risk of Bias Tool,10 before 2013 and 75 from 2013 onward. Twenty-three studies
by 2 review authors independently. The inter-rater agree- were conducted in India, 16,17,86,48,51,20,90,28,61,64−66,30,21,
ment was measured. All studies were retained indepen- 106,107,84,71,108,32,82,78,68
sixteen in China,41,87,88,59,23−25,89,81,
dently of their risk of bias. 36,109,69,110,111,95,103
thirteen in Turkey,38,96,98,40,43,44,19,99,
52,55,56,104,22
nine in Japan,49,27,54,63,77,67,33,35,100 seven in the
Certainty assessment Republic of Korea,73,42,53,80,57,58,92 five in the USA,18,74,105,29,34
four in each of the following countries: Iran 72,39,83,101 and
Certainty assessment was performed using GRADEpro GDT Saudi Arabia,15,97,46,70 and two in each of the following coun-
software to prepare the “Summary of findings” tables (GRA- tries: Egypt 85,75 and Singapore. 26,37 For other countries, only
DEpro Guideline Development Tool [Software]. McMaster one study was reported.
University, 2020 developed by Evidence Prime, Inc.). All The age of participants ranged from 18 to 99 years. Four
decisions to down- or up-grade the certainty of studies is studies included patients with an American Society of Anes-
reported as footnotes. thesiologists (ASA) physical status of I only,15−17,33 and six-
teen studies did not report the patients’ ASA physical
status.90,21,106,88,40,49,27,54,77,67,80,83,76,91
Statistical analysis Most of the studies used standard monitorization with
non-invasive Blood Pressure (BP), Electrocardiogram (ECG),
If the studies were sufficiently homogeneous, we conducted pulse oximetry, and capnography.4 Depth of sedation was
a meta-analysis using a random-effects approach, with a 5% evaluated with Bispectral Index (BIS), Ramsay Sedation
significance level. For dichotomous variables, we deter- Score (RSS), or Observer Assessment of Alertness/Sedation
mined the Odds Ratio (OR) with a 95% Confidence Interval Scale (OAA/S) in the majority of the studies, although five
(95% CI). As for continuous variables, we determined the used the Richmond Agitation Sedation Scale
mean with a 95% CI. Heterogeneity was evaluated by using I2 (RASS),61,27,54,77,62 and seven used another sedation
and Cochran’s Q test. Values of I2 greater than 50% were con- score.108,43,19,22,80,91,60
sidered as indicative of substantial heterogeneity,11 and
investigated by subgroup analysis (setting and comparator/ Risk of Bias and GRADE assessment
control intervention).
Twenty-five trials were judged to be low risk of bias in all
domains.86,90,64,66,107,78,68,41,87,23−25,81,36,69,103,58,92,105,29,85,
Publication bias evaluation 37,62,47,93
Forty trials had unclear risk of bias,15,16,51,
20,28,30,21,106,84,108,32,82,89,109,110,95,96,40,19,52,56,22,49,27,54,
The outcome reporting and small study biases were assessed 72,39,83,70,60,45,50,79,102,94
with the help of Funnel plots and Egger’s Test.12 The domains judged to have the
highest risk of bias were both blinding of participants and
personnel (performance bias) as well as incomplete outcome
data (attrition bias) (Fig. 1 and Appendix 4). GRADE assess-
Results ment is described in Table 2.

Description of studies Outcomes

After systematically searching five electronic databases, we Time until full recovery
obtained studies according to the search strategy as follows: Overall, 41 studies evaluated time until full recovery as out-
MEDLINE (n = 1,874), ClinicalTrials.gov (n = 64), Scopus comes, although there was not a consistent definition of
(n = 205), LILACS (n = 104), and SciELO (n = 103). Among recovery. Of the studies, 46.3% used Aldrete's scoring system
these articles, 232 studies were excluded because they were (the full description of the outcome’s definition can be found
duplicates. A total of 1,946 studies were excluded because in Appendix III). A meta-analysis was computed to evaluate
they did not meet the inclusion criteria after reviewing their this outcome (just for RCTs considering Aldrete or modified
titles and abstracts. Cohen’s kappa of agreement between Aldrete > 9) (Fig. 2). Overall, there was a tendency for a
the two authors was 67%, fair to a good agreement.13 The mean higher time until full recovery of 1.73 minutes (95% CI
remaining 172 studies were considered relevant, and [0.34, 3.13] minutes). There was severe heterogeneity
reviewers carefully screened the full articles. The study (I2 = 96%), not fully explained by subgroup analysis (test for
selection process is outlined through the PRISMA (Preferred subgroup differences: Chi2 = 10.41, df = 3 (p = 0.02),
Reporting Items for Systematic Reviews) 14 diagram in I2 = 71.2%), nor control group (test for subgroup differences:
Appendix II. Chi2 = 33.11, df = 5 (p < 0.00001), I2 = 84.9%) (Appendix IV).

3
 Table 1 Studies’ characteristics.
NORA setting Study Country Age (yr) Male (%) Sample ASA Type of procedure Monitorization Intervention/comparator Timing of DEX Main outcome Other outcomes
size physical injection
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status

Not specified (n = 1) Candiotti USA NR NR 326 1, 2, 3, 4 Not specified Vital signs and 1: 0.5 μg.kg−1 DEX for 10 min + Before and dur- Percentage of Total amount of rescue MDZ,
18
OAA/S score 0.6 μg.kg−1.h−1 (initial rate) ing the patients not time from onset of study drug
infusion DEX procedure requiring MDZ infusion to the first dose of res-
2: 1 μg.kg−1 DEX for 10 min + for rescue cue MDZ, percentage of patients
0.6 μg.kg−1.h−1 (initial rate) sedation who converted to alternative
infusion DEX sedative and/or anesthetic ther-
3: Normal saline apy, recovery time, time until
discharge, the total amount of
fentanyl, incidence of adverse
events and complications,
hemodynamic stability, and
patient and physician
satisfaction.
Burn unit procedure Gündüz 19 Turkey (19–65) 67.8 90 1, 2, 3 Dressing changes HR, SBP, DBP, 1: 1 μg.kg−1 iv DEX for 10 min + Before the No clear Hemodynamic effects, analgesic
−1
(n = 4) MAP, SpO2 and 1 mg.kg iv ketamine procedure definition effect, and sedation score.
urine output 2: 0.05 mg.kg−1 iv MDZ for
−1
(bladder 10 min + 1 mg.kg iv ketamine
catheter) 3: iv normal saline for 10 min +
1 mg.kg−1 iv ketamine
Kundra 20 India NR 28.3 60 1, 2 Dressing changes BP, SpO2, HR 1: 4 μg.kg−1 oral DEX Before the No clear Analgesic efficacy, pain, seda-
and RSS 2: 5 mg.kg−1 oral ketamine procedure definition tion score and adverse events
and complications.
Ravipati 21 India (18–60) 23.3 60 NR Dressing change and NIBP, ECG, pulse 1: 1 μg.kg−1 IM DEX + 0.5 mg.kg−1 1h before No clear Total drug consumption and
−1
debridement oximeter and iv bolus ketamine + 1 mg.kg iv induction definition recovery time
−1 −1
RSS bolus propofol + 1 mg.kg .h iv
infusion ketamine + 100 μg.kg−1.

4
min−1 iv infusion propofol
2: 0.5 mg.kg−1 iv bolus ketamine
+ 1 mg.kg−1 iv bolus propofol + 1
mg.kg−1.h−1 iv infusion ketamine
+ 100 μg.kg−1.min−1 iv infusion
propofol
Zor 22 Turkey (19–54) 83.3 24 2, 3 Dressing change HR, non-inva- 1: 1 mg.kg−1 IM tramadol + 1 mg. 15 min before No clear Pain, sedation score, adverse
sive SBP, SpO2 kg−1 IM DEX HCl + 2 mg.kg−1 IM the procedure definition events and complications and
and RR ketamine patient satisfaction.
2: 2 mg.kg−1 IM ketamine
3: 1 mg.kg−1 IM tramadol +
ARTICLE IN PRESS

0.05 mg.kg−1 IM MDZ HCl+ 2 mg.

kg−1 IM ketamine
F.J. Fonseca, L. Ferreira, A.L. Rouxinol-Dias et al.

Dental procedure (n = Cheung 23 China (18–50) 30 60 1, 2 Unilateral third molar HR, BP, RR, SpO2 1: 1 μg.kg−1 infusion DEX for 10 Before the Patient Pain, relaxation during the oper-
19) surgery and RSS min procedure satisfaction ation, amnesia, surgical condi-
2: 5 mg infusion MDZ for 10 min tions, physician satisfaction and
adverse events and
complications.
24 −1
Cheung China (18–50) 41.0 105 1, 2 Bilateral third molar HR, BP, RR and 1: 1 μg.kg iv infusion DEX for Before and at No clear Recovery profile, pain, BP, HR,
(1) surgery SpO2 and RSS 10 min + infiltration normal the end of the definition SpO2, RSS, postoperative anal-
saline procedure gesic consumption and adverse
2: iv infusion normal saline + events and complications.
1 μg.mL−1 infiltration DEX
3: iv infusion normal saline +
infiltration normal saline
Cheung 25 China (18–50) 45 60 1, 2 Unilateral third molar HR, BP, RR and 1: 1 μg.kg−1 intranasal DEX 45 min before Postoperative Sedation score and psychomotor
(2) surgery SpO2, BIS and 2: intranasal normal saline the procedure pain relief function.
OAA/S score
26 −1 −1
Fan Singapore NR 70 60 1, 2 Not specified NIBP, ECG, pulse 1: 0.1 μg.kg .min infusion DEX Before and dur- Efficacy (seda- NR
oximeter, BIS + 0.2 μg.kg−1.h−1 infusion DEX ing the tion score, anx-
and OAA/S 2: 0.005 mg.kg−1.min−1 infusion procedure iolysis, analge-
score MDZ + 0.01 mg.kg−1.h−1 infusion sic effects,
MDZ operating condi-
[mSP6P;January 29, 2022;9:59]

tions, and
patient satisfac-
tion) and safety.
 Table 1 (Continued)
NORA setting Study Country Age (yr) Male (%) Sample ASA Type of procedure Monitorization Intervention/comparator Timing of DEX Main outcome Other outcomes
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size physical injection

status

Hiwarkar India (18–60) NR 20 1 Surgical removal of bilater- SpO2, HR, BP 1: 1.5 μg.kg−1 intranasal DEX 10 min before No clear Efficacy
17
ally impacted mandibular and modified 2: 0.2 mg.kg−1 intranasal MDZ procedure definition
third molars OAA/S
Kawaai 27 Japan NR 35 40 NR Dental implant surgery BP, HR, ECG, 1: 0.05 mg.kg−1 iv bolus butor- During the No clear Amnesic action, recovery profile
SpO2 and RASS phanol + 0.05 mg.kg−1 iv bolus procedure definition and sedation comfort.
−1 −1
MDZ + 0.56 (±0.14) μg.kg .h
infusion DEX
2: 0.05 mg.kg−1 iv bolus butor-
phanol + 0.05 mg.kg−1 iv bolus
MDZ + 2.3 mg.kg−1.h−1 infusion
propofol
Mishra 28 India (18–65) 76.7 60 1, 2 Multiple days care oral and SBP, DBP, HR, 1: 1 μg.kg−1 bolus DEX for 10 min Before and dur- No clear Respiratory and hemodynamic
maxillofacial surgical RR, SpO2 and + 0.5 μg.kg−1.h−1 DEX ing the definition effects, adverse events and
−1
procedures BIS 2: 0.08 mg.kg bolus MDZ for procedure complications, amnesia, dis-
10 min + 0.05 mg.kg−1.h−1MDZ charge score, patient relaxation
and patient satisfaction.
29 −1 −1
Nolan USA (18–35) 33.3 144 1,2 Surgical removal of third NIBP, ECG, pulse 1: 0.03 mg.kg MDZ + 1 μg.kg Before and dur- Respiratory Pain, cooperation score, time to
molar oximetry and infusion DEX for 10 min + 0.5 μg. ing the events requiring ambulation, time to discharge,
capnography kg−1.h−1 infusion DEX procedure intervention amnesia, patient satisfaction,
2: 0.03 mg.kg−1 MDZ + 0.8 μg. operating conditions score and
−1 −1
kg fentanyl + 125 mg.kg . hemodynamic stability.
−1
min infusion propofol ± 0.1 mg.
kg−1 boluses propofol, as needed
Nooh 15 Saudi (20–28) 56 18 1 Surgical removal of the NIBP, ECG, pulse 1: 1.5 μg.kg−1 intranasal atom- 30 min before No clear Preoperative anxiety, reaction
Arabia third molar oximeter, modi- ized DEX the procedure definition to the anesthetic injection,
fied OAA/S 2: intranasal water pain, sedation score, vital signs,

5
score and BIS adverse events and complica-
tions and total analgesic
consumption.
Dental procedure (n = Rasheed 30 India (20–50) 46 50 1, 2 Not specified NIBP, ECG, pulse 1: 1 μg.kg−1 iv DEX for 2 min + NR No clear Duration of procedure, induc-
−1
19) oximeter and 0.5 mg.kg iv ketamine definition tion-incision time, hemody-
−1
OAA/S score 2: 0.05 mg.kg iv MDZ for 2 min namic effects, duration of
+ 0.5 mg.kg−1 iv ketamine analgesia, mean a total extra
dose of ketamine and patient
and physician satisfaction.
31 −1 −1
Salazar Venezuela (18–30) 38.6 44 1, 2 Surgical removal of the RR, SBP, DBP, 1: 0.2 μg.kg .h iv infusion DEX Before and dur- Patient behav- Sedation score, time until seda-
−1 −1
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third molar MAP, SpO2, ECG, 2: 0.1 mg.kg .min iv infusion ing the ior (pain or dis- tion, patient response, hemody-
HR and RSS propofol procedure comfort) during namic and respiratory effects,
the procedure need for additional anesthetic,
recovery time, need for rescue
Alfentanil and adverse events
Brazilian Journal of Anesthesiology xxxx;000(xxx): 1−24

and complications.
Shetty 16 India (18–35) NR 15 1 Surgical removal of the NIBP, pulse 1: 1.5 LG kg−1 intranasal atom- 30 min before No clear Sedation score and pain.
third molar oximeter and ized DEX the procedure definition
modified OAA/S 2: Intranasal normal saline
score
Sivasubra- India (18–40) NR 30 1, 2 Minor oral surgery HR, SBP, DBP, 1: 1 μg.kg−1.h−1 infusion DEX for Before and dur- No clear Vital signs, sedation score, pain,
mani 32 (1) ECG, SpO2 and 10 min + 0.5 μg.h−1 infusion DEX ing the definition cognitive judgment, amnesia,
RR 2: 0.05 mg.kg−1 infusion MDZ + procedure patient ambulatory status and
0.5 μg.h−1 infusion MDZ surgical wound and output.
−1 −1
Sivasubra- India (18–40) NR 60 1, 2 Minor oral surgery HR, ECG, pulse 1: 1 μg.kg .h iv infusion DEX Before and dur- No clear RSS and bite force.
mani 32 (2) oximeter, SpO2, for 10 min + 0.5 μg.h−1 infusion ing the definition
BP, RR and RSS DEX procedure
2: 0.05 mg.kg−1 iv infusion MDZ
for 10 min + infusion normal
saline
Taniyama Japan NR 21.4 14 1 Minor oral surgery BP, HR, SpO2, 1: 6 mg.kg−1.h−1 iv DEX hydro- Before and dur- No clear Amnesia, comfort, sedation
33
Mackenzie's chloride for 10 min + 0.4 μg. ing the definition score and hemodynamic and
−1 −1
sedation assess- kg .h infusion DEX hydrochlo- procedure respiratory effects.
[mSP6P;January 29, 2022;9:59]

ment score and ride

BIS 2: 20 mg iv lidocaine
 Table 1 (Continued)
NORA setting Study Country Age (yr) Male (%) Sample ASA Type of procedure Monitorization Intervention/comparator Timing of DEX Main outcome Other outcomes
size physical injection
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status

hydrochloride + 0.5 mg.kg−1

bolus propofol + 4 mg.kg−1.h−1
infusion propofol
Taylor 34 USA (32–74) 42 12 1, 2 Maxillary and mandibular NIBP, ECG, pulse 1: 4 mg.kg−1.h−1 infusion DEX + Before and dur- Anesthesia NR
arch extractions with asso- oximetry, cap- 2 mg iv MDZ + 50 mg iv fentanyl ing the proce- times, vital
ciated dentoalveolar pre- nography, RR 2: 2 mg iv MDZ + 50 mg iv fenta- dure, until signs and the
prosthetic surgery nyl + infusion normal saline 15 min to the patient subjec-
end of the tive experience
procedure
Togawa 35 Japan (20–80) 93.2 88 1, 2 Minor oral surgery NIBP, ECG, HR, 1: 0.02 mg.kg−1 MDZ + 3 μg.kg−1. Before and dur- Unexpected Responsiveness, mouth opening
−1
SpO2 and BIS h infusion DEX for 10 min + 0.2– ing the patient time, cough, snoring, total and
−1 −1
0.7 μg.kg .h infusion DEX procedure movement rescue dose of MDZ, patient and
2: 0.02 mg.kg−1 MDZ + 1.0 μg. physician satisfaction, amnesia,
mL−1 target plasma concentra- recovery profile, hemodynamic
tion propofol (up titrated until and respiratory effects, operat-
desired sedation level) ing time and sedation time.
36 −1
Wang China NR 61.7 60 1,2 Dental implant surgery NIBP, ECG, pulse 1: 1.0 μg.kg DEX for 10 min + Before and dur- Hemodynamic Duration of surgery, the dosage
oximeter and 0.2–0.7 μg.kg−1. h−1 infusion DEX ing the stability of local anesthesia, vital signs,
−1
OAA/S score 2: 0.05 mg.kg MDZ + 0.04– procedure sedation score, pain, physician
0.2 mg.kg−1.h−1 infusion MDZ and patient satisfaction and
recovery time.
Dental procedure (n = Yu 37 Singapore (19–60) 61.7 60 1, 2 Unilateral impacted teeth SBP, HR, SpO2 1: 0.5 μg.kg−1 DEX and 1μg.kg−1 Immediately No clear Vital signs, sedation score, pain,
19) extraction and OAA/S fentanyl for 10 min + 0.5 μg. before and dur- definition preoperative anxiety, patient
−1 −1
kg .h infusion DEX ing the and physician satisfaction and
2: 0.05 mg.kg−1 MDZ and 1 μg. procedure total time for analgesic effect.
−1
kg fentanyl for 10 min +
−1 −1

6
0.05 mg.kg .h infusion MDZ
Gastroenterologic Akarsu 38 Turkey (18–80) NR 121 1, 2 Colonoscopy NIBP, ECG, pulse 1: 0.2 μg kg−1 h−1 DEX NR No clear The total dose of propofol used,
procedure (n = oximetry and 2: 0.1 μg.kg−1 intranasal sufen- definition total sedation time, patient and
39) BIS tanil; physician satisfaction, sedation
3: 0.4 mg.kg−1 iv meperidine + score, recovery time, total cost
−1
1 mg.kg bolus propofol + 0.5– and adverse events and
3 mg.kg−1.h−1 infusion propofol complications.
−1
4: 0.4 mg.kg iv meperidine +
0.03 mg.kg−1 iv midazolam + 0.5–
3 mg.kg−1.h−1 infusion propofol
Amri 39 Iran (20–70) 52.5 80 1, 2 Colonoscopy NIBP, ECG and 1: 1 μ.kg−1 bolus DEX + 0.5 μ kg−1 Until 10 min No clear The analgesic effect, hemody-
ARTICLE IN PRESS

pulse oximetry h−1 infusion DEX before and dur- definition namic stability, duration of colo-
−1
2: 0.5 μ.kg fentanyl + infusion ing the noscopy, patient and physician
F.J. Fonseca, L. Ferreira, A.L. Rouxinol-Dias et al.

normal saline procedure satisfaction and adverse events

and complications.
40 −1
Bavullu Turkey NR NR 40 NR Percutaneous treatment of NIBP, ECG, end- 1: 1 μg.kg bolus DEX for 10 min Before and dur- No clear Need for additional doses of pro-
hepatic hydatid cyst tidal CO2, SpO2, + 0.2 μg.kg−1.h−1 infusion DEX ing the definition pofol infusion and sedation
BIS and modi- 2: 0.07 mg.kg−1 iv bolus MDZ + procedure score.
fied OAA/S 0.01 mg.kg−1.h−1 infusion MDZ
score
Cheung 41 China (18–60) NR 50 1, 2, 3 Upper gastrointestinal HR, BP, SpO2, RR 1: 0.015 mL.kg−1 intranasal undi- 1h before the Total consump- Sedation scores, recovery pro-
endoscopy and OAA/S luted DEX procedure tion of PCS file, vital signs, adverse events
−1
score 2: 0.015 mL.kg intranasal propofol and complications and patient
placebo satisfaction.
Cho 42 Republic NR 85.9 66 1, 2 Drug-induced sleep NIBP, ECG, pulse 1: 1.0 μg.kg−1 bolus DEX for NR Incidence of Incidence of cough reflex, hemo-
of Korea endoscopy oximetry, end- 10 min + 0.2 μg.kg−1.h−1 (initial oxygen dynamic stability, time until suf-
tidal CO2, BIS rate) infusion DEX + 1.5 ng.mL−1 desaturation ficient sedation, sedation score
and OAA/S Ce infusion remifentanyl and adverse events and
−1
score 2: 1.0 μg.mL propofol + infu- complications.
sion normal saline
3: 1.0 μg.mL−1 propofol + 1.5 ng.
mL−1 Ce remifentanyl
Demiraran Turkey (18–60) NR 50 1, 2 Upper gastrointestinal HR, MAP, SpO2 1: 1 μg.kg−1 iv infusion DEX for Before and dur- No clear Respiratory and hemodynamic
43
[mSP6P;January 29, 2022;9:59]

endoscopy and RR 10 min + 0.2 μg.kg−1.h−1 infusion ing the definition effects, patient and physician
DEX procedure satisfaction, adverse events and
2: 0.07 mg.kg−1 (max 5 mg) iv complications, analgesic effect
MDZ and sedation score.
 Table 1 (Continued)
NORA setting Study Country Age (yr) Male (%) Sample ASA Type of procedure Monitorization Intervention/comparator Timing of DEX Main outcome Other outcomes
JID: BJANE

size physical injection

status

Dere 44 Turkey (20–80) NR 60 1, 2 Colonoscopy NIBP, ECG, pulse 1: 1 mg.kg−1 iv infusion DEX for Before and dur- No clear Hemodynamic effects, sedation
oximetry and 10 min + 1 mg.kg−1 iv fentanyl + ing the definition score, pain, satisfaction score
RSS 0.5 mg.kg−1.h−1 infusion DEX procedure and recovery score.
2: 0.05 mg.kg−1 iv MDZ + 1 mg.
kg−1 iv fentanyl + 0.1 mL.kg−1.
h−1 infusion normal saline
45
Eberl The NR 80.6 63 1, 2, 3 Endoscopic esophageal NIBP, ECG, 1: 1 mg.kg−1 (if > 65yr, 0.5 mg Before and dur- Patient and phy- Safety of sedation (hemody-
Nether- procedures SpO2, HR, end- kg−1) iv bolus DEX for 10 min + ing the sician namic and respiratory effects).
−1 −1 −1
lands tidal CO2, NICO, 0.7 mg.kg h infusion DEX procedure satisfaction
stroke volume, 2: 2.0 mg mL−1 (targeted plasma
systemic vascu- concentration) propofol
lar resistance
and OAA/S
score
Gastroenterologic Eldesuky Saudi (18–60) 58 50 1, 2 ERCP HR, MAP and 1: 1 μg.kg−1 iv DEX for 10 min + Before and dur- No clear Respiratory and hemodynamic
46
procedure (n = Arabia SpO2 0.5 μg.kg−1.h−1 infusion DEX ing the definition effects, sedation score, pain,
−1
39) 2: 1 mg.kg ketofol for 10 min + procedure recovery time, patient and phy-
50 μg.kg−1.min−1 ketofol sician satisfaction and adverse
events and complications.
Elkalla 47 Egypt (18–50) 61.7 60 1, 2, 3 Drug-induced sleep NIBP, ECG, pulse 1: 1 μg.kg−1 iv DEX for 10 min + Before and dur- Incidence of Hemodynamic effects, time to
endoscopy oximeter and 0.3 μg.kg−1.h−1 infusion DEX ing the oxygen achieve sufficient sedation
RSS 2: 0.7 mg.kg−1 iv propofol for procedure desaturation level, recovery time, patient
10 min + 0.5 mg.kg−1.h−1 infusion and physician satisfaction and
propofol adverse events and
3: 1 mg.kg−1 ketofol (2 mg.mL−1 complications.
propofol + 2 mg mL−1 ketamine)

7
for 10 min + 50 μg.kg−1.h−1 infu-
sion ketofol
Goyal 48 India (18–75) 71.1 90 1, 2, 3 ERCP Noninvasive 1: 0.5 μg.kg−1 DEX and 1 mg.kg−1 Before and dur- Efficacy and NR
MAP, ECG, SpO2, ketamine in 2 divided boluses of ing the safety.
HR and imped- each drug, alternately, for procedure
ance 30 seconds + 0.5 mg.kg−1.h−1
pneumography infusion DEX + 1–2 mg.kg−1.h−1
ketamine
2: 1 μg.kg−1 fentanyl + 1 mg.kg−1
bolus propofol + 2–4 mg.kg−1.h−1
ARTICLE IN PRESS

infusion propofol
Hashiguchi Japan (38–54) 100 100 NR Upper gastrointestinal NIBP, HR, SpO2, 1: 6.0 μg.kg−1.h−1 infusion DEX Before and dur- No clear Sedative properties, safety pro-
49
endoscopy RSS, mSAS and for 10 min + 0.6 μg.kg−1.h−1 infu- ing the definition file, respiratory and hemody-
GRS sion DEX procedure namic effects, characteristics of
2: 0.05 iv infusion MDZ for 1 min scope insertion and patient per-
Brazilian Journal of Anesthesiology xxxx;000(xxx): 1−24

3: Not sedated ception of the procedure.

Jalowiecki Poland (18–60) 42.2 64 1, 2 Colonoscopy HR, MAP, SpO2, 1: 1 μg.kg−1 iv infusion DEX for Before and dur- No clear Respiratory and hemodynamic
50
RR and OAA/S 15 min + 0.2 μg.kg−1.h−1 infusion ing the definition effects, analgesia/sedation
score DEX procedure score, adverse events and com-
−1
2: 1 mg.kg iv meperidine + plications and patient readiness
0.05 mg.kg−1 iv MDZ for home discharge.
3: Not sedated, but were given
0.1–0.2 mg iv fentanyl in
response to pain
Gastroenterologic Karanth 51 India (25–60) 66.7 60 1, 2 Colonoscopy NIBP, ECG, pulse 1: 1 μg.kg−1 iv DEX for 10 min + Before and dur- No clear Efficacy
procedure (n = oximeter and 0.2–0.8 μg.kg−1.h−1 infusion DEX ing the definition
−1
39) modified OAA/S 2: 2–3 mg.kg iv propofol for 10 procedure
score min iv + 25–100 μ.kg−1.min−1
infusion propofol
Kilic 52 Turkey (18–80) 62 50 1, 2 ERCP Noninvasive 1: 1 μg.kg−1.h−1 bolus DEX + 0.2– Before and dur- Respiratory, Patient degree of comfort and
SBP, DBP and 0.7 μg.kg−1.h−1 infusion DEX ing the hemodynamic, usefulness of the drug to
MAP, HR, SpO2, 2: 0.04 mg.kg−1 iv bolus MDZ + procedure sedative and surgeons.
RR and RSS
[mSP6P;January 29, 2022;9:59]
 Table 1 (Continued)
JID: BJANE

NORA setting Study Country Age (yr) Male (%) Sample ASA Type of procedure Monitorization Intervention/comparator Timing of DEX Main outcome Other outcomes
size physical injection
status

0.5 mg bolus MDZ until RSS score cognitive

3–4 effects
53 −1
Kim Republic NR 69.5 60 1, 2, 3 Endoscopic submucosal SpO2, SBP and 1: 0.5 μg.kg iv bolus DEX for 5 min before No clear Efficacy (ease of advancing the
of Korea dissection DBP, ECG, HR 5 min + 0.3–0.7 μg.kg−1.h−1 infu- the procedure definition scope, gastric motility and
and modified sion DEX patient and physician satisfac-
OAA/S score 2: 0.5 mg.kg−1 bolus propofol + tion) and patient safety (respira-
30 μg.kg−1.min−1 infusion tory and hemodynamic effects,
propofol adverse events and complica-
tions and the total amount of
sedative drug and remifentanil
used).
Kinugasa Japan (18–90) 51.3 80 NR Endoscopic submucosal BP, SpO2, HR, 1: 6.0 μg.kg−1.h−1 infusion DEX Before and dur- Patient Patient pain level, physician sat-
54
dissection BIS and RASS for 5 min + 0.4 μg.kg−1.h−1 infu- ing the satisfaction isfaction, objective patient pain
sion DEX procedure level viewed from the physi-
2: 6.0 μg.kg−1.h−1 infusion pla- cian's perspective, patient
−1 −1
cebo for 5 min + 0.4 μg.kg .h movement, the difficulty of the
infusion placebo procedure, rate of patient
response, rate of en bloc, rate of
R0 resection, resection time,
resected tumor size, the total
amount of analgesic used, rate
of adverse events and
complications.
55 −1
Koruk Turkey (20–78) 45 40 1, 2, 3 ERCP MAP, SpO2, HR, 1: 1 μg.kg iv DEX for 10 min + Before the Recovery time Respiratory and hemodynamic
−1
RR and BIS 1–1.5 mg.kg bolus propofol + procedure effects.

8
20 mg intermittent bolus propo-
fol until desired sedation level
2: 0.05 mg.kg−1 iv MDZ for 10
min + 1–1.5 mg.kg−1 bolus propo-
fol + 20 mg intermittent bolus
propofol until desired sedation
level
Kuyru- Turkey (18–50) NR 40 1, 2 Drug-induced sleep MAP, RR, SpO2, 1: 1 μg.kg−1 iv DEX for 10 min + Before and dur- No clear The sedative effect, hemody-
kluyıldız 56 endoscopy HR, RSS and BIS 0.3 μg.kg−1.h−1 infusion DEX (up ing the definition namic and respiratory effects
titrated by 0.1 μg.kg−1.h−1 every procedure and patient and physician
ARTICLE IN PRESS

5 min until desired sedation satisfaction.

level – max 0.6 μg.kg−1.h−1)
−1
2: 0.7 mg.kg iv propofol for
F.J. Fonseca, L. Ferreira, A.L. Rouxinol-Dias et al.

10 min + 0.5 mg.kg−1.h−1 infusion

propofol (up titrated by 0.1 mg.
kg−1.h−1 every 5 min until
desired sedation level)
Lee 57 Republic (20–80) 58.2 116 1, 2, 3 ERCP MAP, RR, SpO2, 1: 1 μg.kg−1.h−1 iv infusion DEX 15 min before Sedation score Total procedure time, time until
of Korea RSS and BIS 2: normal saline insertion of the and require- discharge, pain, patient satis-
scope ment for addi- faction, BIS score and adverse
tional sedative events and complications.
(MDZ) or anal-
gesic
(meperidine)
Gastroenterologic Lee 58 Republic (20–80) 85 80 1, 2 Endoscopic submucosal BP, ECG, pulse 1: 1 μg.kg−1 iv bolus DEX for Before and dur- Suitability of Safety, patient and physician
procedure (n = of Korea dissection oximetry, HR, 10 min + 0.4 μg.kg−1.h−1 infusion ing the drugs for satisfaction, total procedure
39) RR and modified DEX procedure sedation time, complete resection rate,
−1 −1
OAA/S score 2: 0.1 mL.kg .h normal saline additional MDZ used, frequency
for 10 min + 0.05 mg.kg−1 (max of body movements, rapidity of
5 mg) iv MDZ recovery and adverse events and
complications.
Lu 59 China (18–85) 52.6 208 1, 2, 3 ERCP
[mSP6P;January 29, 2022;9:59]
 Table 1 (Continued)
NORA setting Study Country Age (yr) Male (%) Sample ASA Type of procedure Monitorization Intervention/comparator Timing of DEX Main outcome Other outcomes
JID: BJANE

size physical injection

status

Noninvasive 1: 1 μg.kg−1 bolus (if > 65 yr, Before the Efficacy and Respiratory and hemodynamic
SBP, DBP and 0.5 μg.kg−1) DEX for 10 min + procedure safety effects, sedation score, recov-
MAP, HR, RR, 0.05–0.2 μg.kg−1.min−1 infusion ery score and adverse events
SpO2 and RSS remifentanyl and complications.
2: 0.05 mg.kg−1 MDZ (titrated
slowly with 1 mg.mL−1 diluted
formula) + 0.05–0.2 μg.kg−1.
min−1 infusion remifentanyl
Mazanikov Finland (34–65) 84 50 1, 2, 3 ERCP HR, ECG, RR, 1: 1 μg.kg−1 infusion DEX for Before and dur- Propofol Sedation score, sedation success
60
end-tidal CO2, 10 min + 0.7 μg.kg−1.h−1 iv infu- ing the consumption rate, adverse events and compli-
SpO2, modified sion DEX procedure cations, vital signs, pain, recov-
OAA/S score 2: Normal saline + 300 mL h−1 ery time and patient and
and Gillham Ringer acetate physician satisfaction.
score
−1
Mukhopa- India NR 44 45 1, 2, 3 ERCP BP, HR, ECG, 1: 1 μg.kg infusion DEX for 7– Before and dur- No clear Sedation score, efficacy and
dhyay 61 RR, SpO2, RSS 10 min + 0.2–0.5 μg.kg−1.h−1 ing the proce- definition adverse events and
and RASS infusion DEX for ≥ 30 min + dure, but an complications.
0.5 mg iv MDZ + 6 mg iv pentazo- attempt was
cine + 25 mg iv ketamine + made to stop
0.75−1 mg.kg−1 iv propofol + 10– the infusion 15–
20 mg iv propofol as top up 20 min before
−1 −1
2: 1 mg iv MDZ + 0.75 mg.kg the end of the
iv propofol + 10–20 mg iv propo- procedure
fol as top up
3: 0.5 mg iv MDZ + 6 mg iv pen-
tazocine + 25 mg iv ketamine +

9
0.75–1 mg.kg−1 iv propofol + 10–
20 mg iv propofol as top up
62
Muller Brazil (20–78) 26.9 26 1,2,3 ERCP BP, HR, RR, end- 1: 1.0 μg.kg−1 bolus DEX for Before and dur- Sedation score Vital signs.
tidal CO2, SpO2 10 min + 0.7 μg.kg−1.h−1 iv DEX ing the and require-
and RASS until desired sedation level procedure ment of addi-
2: 1.5 μg.mL−1 Ce infusion pro- tional sedative
pofol (titrated by 0.2 μg.mL−1 or analgesic
until desired sedation level)
Gastroenterologic Nonaka 63 Japan (52–86) 81.03 58 1, 2 Gastric endoscopic submu- ECG, BP, pulse 1: 6 μg.kg−1.h−1 infusion DEX for Before and dur- Physician Effectiveness and safety.
procedure (n = cosal dissection oximetry, cap- 10 min + 20 mg iv bolus propofol ing the satisfaction
ARTICLE IN PRESS

39) nography and repeated until desired sedation procedure

modified OAA/S level + 0.5 μg.kg−1.h−1 infusion
−1 −1
scale DEX + 2 mg.kg .h infusion pro-
pofol
2: 20 mg iv bolus propofol
Brazilian Journal of Anesthesiology xxxx;000(xxx): 1−24

repeated until desired sedation

level + 2 mg.kg−1.h−1 infusion
propofol
64
Padiyara India (18–65) 87 60 1, 2 Drug-induced sleep NIBP, ECG, pulse 1: 1 μg.kg−1 bolus DEX for 10 min NR Airway obstruc- Airway obstruction (at velum,
endoscopy oximetry and + 0.5–1.0 μg.kg−1.h−1 infusion tion pattern at oropharyngeal lateral wall, and
BIS DEX titrated until desired seda- tongue base epiglottis), hemodynamic and
tion level level respiratory effects, time until
2: 50-150 μg.kg−1.min−1 infusion sufficient sedation, recovery
propofol titrated until desired time and adverse events and
sedation level complications.
Pushkarna India (40-80) 53.3 60 2, 3 ERCP HR, MAP and 1: 1 μg.kg−1 iv DEX for 10 min + NR Requirement of Recovery characteristics and
65 −1 −1
SpO2 0.5 μg.kg .h infusion DEX propofol and patient and physician
2: 0.05 mg.kg−1 iv bolus MDZ for patient and satisfaction.
10 min + infusion normal saline physician
comfort.
Ramkiran India (18–75) 57.3 75 1, 2,3 ERCP NIBP, ECG, pulse 1: 1 μg.kg−1 bolus DEX + 0.5 μg. After patient Total propofol Recovery profile and hemody-
66
oximeter and kg−1.h−1 infusion DEX positioning and consumption namic profile.
−1
BIS 2: 0.25 mg.kg bolus ketamine +
[mSP6P;January 29, 2022;9:59]
 Table 1 (Continued)
NORA setting Study Country Age (yr) Male (%) Sample ASA Type of procedure Monitorization Intervention/comparator Timing of DEX Main outcome Other outcomes
JID: BJANE

size physical injection

status

infusion 5 μg. kg−1 min−1 infusion during the

ketamine procedure
3: Bolus normal saline + infusion
normal saline
Takimoto Japan (47–80) 47 90 NR Endoscopic submucosal BP, HR, SpO2, 1: 3 μg kg−1 h−1 iv DEX for 5 min + Before and dur- No clear BP, HR, SpO2, ECG, body move-
67
dissection ECG and RSS 0.4 μg kg−1 h−1 iv DEX ing the definition ment, additional doses of mida-
2: 5 mg iv propofol + 3 mg. kg−1. procedure zolam and sedation score.
h−1 iv propofol
3: 0.1 mg.kg−1 MDZ
Trivedi 68 India (18–40) 35.6 90 1, 2 Short surgical procedures NIBP, ECG and 1: 0.5 μg.kg−1 DEX in 10 mL nor- Before the No clear Delirium, hemodynamic stability
HR mal saline for 10 min + 2 mg.kg−1 procedure definition and pain.
ketamine
2: 0.05 mg.kg−1 MDZ in 10 mL
normal saline for 10 min + 2 mg.
kg−1 ketamine
3: 10 mL normal saline for
10 min + 2 mg.kg−1 ketamine
Wu (2014) China (20–60) 55 60 1, 2 Upper gastrointestinal NIBP, ECG, pulse 1: 0.3 mg.kg−1 bolus DEX and 10 min before No clear Time to full sedation, recovery
endoscopy oximetry and 1 mg.kg−1 iv infusion fentanyl procedure definition time, adverse events and com-
RSS citrate for 10 min + 0.2–0.3 mg. plications, patient satisfaction,
−1 −1
kg .h infusion DEX until sedation score and pain.
desired sedation level
2: 0.05 mg.kg−1 iv bolus MDZ and
1 mg.kg−1 iv infusion fentanyl
citrate for 10 min + 0.01 mg.kg−1
bolus MDZ every 2–5 min until

10
desired sedation level
69
Gastroenterologic Wu China (18–65) 40 70 1, 2 Esophago- NIBP, ECG, pulse 1: 1 μg.kg−1 DEX + 0.5 μg.kg−1. Immediately No clear Hemodynamics and respiratory
procedure (n = gastroduodenoscopy oximetry, RR h−1 infusion DEX until desired before the definition effects, sedation score, recov-
39) sedation level procedure ery profile, adverse events and
2: 0.6 mg.kg−1 bolus propofol + complications and patient and
10–20 mg doses propofol until physician satisfaction.
desired sedation level
−1
Yin (2019) China (60–80) 44.2 120 1, 2, 3 Gastrointestinal endoscopy NIBP, ECG, pulse 1: 0.4 μg.kg infusion DEX for Before the Hemodynamic Sedation score, total propofol
oximetry, end- 5 min + 1 mg.kg−1 infusion pro- procedure and respiratory consumption, recovery time,
−1 −1
tidal CO2 and pofol for 30s + 3–5 mg.kg .h stability adverse events and complica-
ARTICLE IN PRESS

RSS infusion propofol tions and the use of additional

2: 0.1 μg.kg−1 infusion sufentanil medications.
F.J. Fonseca, L. Ferreira, A.L. Rouxinol-Dias et al.

for 5 min + 1 mg.kg−1 infusion

−1
propofol for 30s + 3–5 mg.kg .
h−1 infusion propofol
3: 0.4 mg.mL−1 infusion keta-
mine for 5 min + 1 mg.kg−1 infu-
sion propofol for 30s + 3–5 mg.
kg−1.h−1 infusion propofol
4: Normal saline + 1 mg.kg−1
infusion propofol for 30s + 3–
5 mg.kg−1.h−1 infusion propofol
Gynecology proce- Elnabtity Saudi (25–38) 0 52 1, 2 In vitro fertilization BP monitor, 1: 1 μg.kg−1 iv DEX for 10 min + Before and dur- Pain relief and NR
70
dure (n = 2) Arabia ECG, pulse 0.5 μg.kg−1.h−1 infusion DEX ing the patient
−1
oximeter and 2: 0.06 mg.kg iv MDZ for procedure satisfaction
RSS 10 min + 0.5 mg incremental
doses MDZ
Sethi 71 India (18–60) NR 50 1, 2 Dilatation and curettage HR, SBP, DBP, 1: 1 μg.kg−1 iv DEX for 10 min + NR Hemodynamic Recovery profile and patient and
MAP, RR, SpO2 0.5 μg.kg−1.h−1 infusion DEX and respiratory physician satisfaction and
−1
and RSS 2: 1.5 mg.kg iv bolus propofol effects adverse events and
for 10–15 min complications.
Iran (18–70) NR 68 2, 3, 4
[mSP6P;January 29, 2022;9:59]
 Table 1 (Continued)
NORA setting Study Country Age (yr) Male (%) Sample ASA Type of procedure Monitorization Intervention/comparator Timing of DEX Main outcome Other outcomes
JID: BJANE

size physical injection

status

Hemodynamic lab Alizade- Transoesophageal NIBP, ECG, pulse 1: 1 μg.kg−1 infusion DEX for 10 Before and dur- No clear Sedation scores, hemodynamic
procedure (n = hasl 72 echocardiography oximetry, BIS min + 0.1–0.5 μg.kg−1.h−1 DEX ing the definition stability, recovery time and
−1
13) and RSS 2: 0.1 mg.kg propofol + 25– procedure total procedure time.
−1 −1
75 μg.kg .min propofol
Hemodynamic lab Cho 73 Republic (20–70) NR 90 1, 2 AF catheter ablation NIBP, ECG, SpO2 1: 1.0 mg.kg−1 bolus DEX for 10 Before and dur- Sedation score Incidence of adverse events and
procedure (n = of Korea and RR min + 0.2–0.7 mg.kg−1.h−1 infu- ing the complications, pain score and
13) sion DEX + 1.2–2.4 mg.kg−1.h−1 procedure patient and physician
infusion remifentanyl satisfaction.
−1
2: 0.02–0.05 mg.kg bolus MDZ +
−1 −1
3.6–7.2 mg.kg .h infusion
remifentanyl
74 −1
Cooper USA (18–65) NR 22 1, 2, 3, 4 Transoesophageal NIBP, ECG, pulse 1: 1 μg.kg DEX for 15 min + Before and dur- Adequacy of NR
echocardiography oximetry, HR, 0.2 μg.kg−1.h−1 infusion DEX ing the sedation and
RR and RSS 2: Normal saline for 15 min + procedure patient
infusion normal saline satisfaction
Khalil 75 Egypt NR 66 50 3, 4 Transcatheter aortic valve Invasive BP, 1: 1 μg.kg−1 DEX + 0.5 μg.kg−1. NR No clear Pain, patient and physician sat-
−1
implantation ECG, pulse h iv infusion DEX definition isfaction, sedation score and
−1
oximetry, cap- 2: 0.5 mg.kg bolus propofol + adverse events and
−1 −1
nography, RRS 30–50 μg.kg .min infusion complications.
and BIS propofol
Pra- Thailand NR 29.4 34 NR Electrophysiology study HR, BP, SpO2 1: 0.5 μg.kg−1 infusion DEX for NR RR Sedation score and hemody-
chanpa- and modified 10 min + 0.4 μg.kg−1.h−1 infusion namic and respiratory effects.
nich 76 OAA/S score DEX
−1
2: 1 mg.kg propofol for 10 min
+ 3 mg.kg−1.h−1 propofol
77
Sairaku Japan (18–75) 80 88 NR Atrial fibrillation ablation NIBP, SpO2, HR 1: 1.0 μg.kg−1 DEX for 10 min + At the time of Respiratory dis- Movement index, adverse events

11
and RASS 0.2 μg.kg−1.h−1 infusion DEX the turbance index and complications and sedation
2: 1.25 mg.kg−1 bólus iv thiamy- venipuncture score.
lal every 15 min
Sruthi 78 India (18–60) 44 50 NR Transesophageal NIBP, ECG, HR, 1: 10 μg.mL−1 infusion DEX Before and dur- Time until Hemodynamic effects need for
echocardiography pulse oximetry, 2: 3.2 mg ketamine and 9.5 mg. ing the desired rescue sedation, adverse events
−1
end-tidal CO2 mL propofol infusion procedure sedation and complications, patient and
and RSS physician satisfaction, analgesic
effect, total drug dose, total
procedure time, and total recov-
ery time.
ARTICLE IN PRESS

Loh 79 Malaysia (18–70) 53.3 30 1, 2 MRI NIBP, ECG, pulse 1: 1 μg.kg−1 bolus DEX for 10 min Before and dur- Efficacy of Patient satisfaction, image qual-
oximetry, HR + 0.2 μg.kg−1.h−1 infusion DEX ing the sedation ity and safety profile.
−1 −1
and RSS (up titrated by 0.1 μg.kg .h ) procedure
until desired sedation level
Brazilian Journal of Anesthesiology xxxx;000(xxx): 1−24

2: 1.5 μg.kg−1 propofol (up

titrated by 0.1 μg.kg−1) until
desired sedation level
Invasive radiology Kim 80 Republic (30–50) 0 56 NR Uterine artery NIBP, SpO2 and 1: 0.2 μg.kg−1.h−1 infusion DEX 30 min before Efficacy of dex- Pain and sedation score.
procedure (n = of Korea embolization HR for 30 min + 0.4 μg.kg−1.h−1 infu- and during the medetomidine
1) sion DEX for 6h procedure in reduction of
2: Infusion normal saline fentanyl con-
sumption and
adverse events
and
complications.
Neuroradiologic pro- Ren 81 China (40–75) 52.3 109 1, 2, 3 Aneurysm embolization NIBP, ECG, pulse 1: 0.5 μg.kg−1 infusion DEX for NR Total consump- Recovery time, pain, consump-
cedure (n = 3) SpO2, tempera- 10 min + 0.2 μg.kg−1.h−1 infusion tion of nimodi- tion of dexmedetomidine and
ture and BIS DEX pine during the sufentanil, patient and physician
2: 0.5 μg.kg−1 infusion DEX for first 48 h after satisfaction, neurological exami-
−1 −1
10 min + 0.4 μg.kg .h infusion the procedure nation, comfort, adverse events
DEX and complications, sedation
3: Infusion normal saline score, the incidence of
[mSP6P;January 29, 2022;9:59]
 Table 1 (Continued)
JID: BJANE

NORA setting Study Country Age (yr) Male (%) Sample ASA Type of procedure Monitorization Intervention/comparator Timing of DEX Main outcome Other outcomes
size physical injection
status

symptomatic cerebral vaso-

spasm during 7 days after the
procedure, Glasgow Outcome
Score at 3 months and incidence
of cerebral infarction 30 days
after the procedure.
Sriganesh India NR 45 60 NR Cerebral angiography NIBP, ECG, pulse 1: 1 μg.kg−1 DEX for 10 min + Before and dur- Incidence of Onset and recovery times,
82 −1 −1
oximetry, cap- 0.5 μg.kg .h infusion DEX ing the adverse respira- movement during the procedure
−1
nography and 2: 1.5 mg.kg bolus propofol + procedure tory events and additional sedative needed
RSS 1.5 mg.kg−1.h−1 infusion to complete the procedure.
propofol
Orthopedic proce- Masoumi Iran (18–70) 86.7 60 NR Reduction of anterior dislo- NR 1: 1 μg.kg−1 iv bolus DEX + NR No clear Pain and onset time of sedation.
83
dure (n = 1) cation of the glenohumeral 0.2 μg.kg−1.h−1 DEX for 10 min definition
−1
joint 2: 0.05 mg.kg iv MDZ and 1 μg.
kg−1 MDZ-fentanyl for
10 minutes
Psychiatric unit pro- Sannakki India (18–50) 63 30 1, 2 Electroconvulsive therapy NIBP, ECG, pulse 1: 1 μg.kg−1 DEX for 10 min NR No clear Vital signs, duration of the
84
cedure (n = 1) oximetry, RR, 2: Normal saline definition motor seizure and recovery
pneumatic tour- profile.
niquet to assess
motor seizures
and RASS
Upper airway proce- El Mourad Egypt (18–60) 70 80 1, 2, 3 Laryngeal mass biopsy NIBP, ECG, pulse 1: 4 μg.mL−1 iv bolus DEX for NR Time to reach Intubation time and the number
85
dure (n = 11) oximetry and 10 min + 0.5 μg.kg−1.h−1 infusion sufficient seda- of intubation trials, the number
RSS DEX + 4 mg.mL−1 infusion propo- tion level of patients in need of rescue

12
fol (same rate as DEX) propofol, patient discomfort,
2: 0.125 mL.kg−1 Ketofol (4 mg. patient tolerance to the proce-
mL−1 propofol + 2 mg.mL−1 keta- dure, cough score, vital signs,
mine) for 10 min + 0.125 mL. adverse events and complica-
−1 −1
kg .h infusion Ketofol (4 mg tions and patient and physician
mL−1 propofol and 2 mg.mL−1 satisfaction.
ketamine) + infusion normal
saline (same rate as ketofol)
Gonep- India (18–70) 77.2 57 1, 2, 3 Flexible bronchoscopy NIBP, ECG, pulse 1: 1 μg.kg−1 infusion DEX + bolus 10 min before A composite NR
pana-var oximeter, HR, normal saline and during the score for best
86 −1
ARTICLE IN PRESS

RR and RSS 2: 0.02 mg.kg bolus MDZ + procedure patient toler-

infusion normal saline ance and
improved fiber-
F.J. Fonseca, L. Ferreira, A.L. Rouxinol-Dias et al.

scopist comfort
without
compromising
patient safety
Gu 87 China NR 58.3 63 1, 2 Flexible bronchoscopy NIBP, ECG, SpO2 1: 0.6 μg.kg−1 nebulized DEX + During the Incidence of Rate of glottis closure, complete
and BIS 10 mL nebulized 2% lidocaine procedure moderate to jaw relaxation and limb move-
−1
2: 0.6 μg.kg iv DEX + 10 mL severe coughing ment, recovery time and dos-
nebulized 2% lidocaine ages of vasoconstrictors and
3: 10 mL nebulized 2% lidocaine atropine.
Liao 88 China NR 62.2 226 NR Flexible bronchoscopy NIBP, ECG, SpO2 1: 1 μg.kg−1 infusion DEX for Before and dur- Mean lowest Respiratory and hemodynamic
and RSS 10 min + 0.5 μg.kg−1.h−1 infusion ing the SpO2 effects, patient tolerance of
DEX procedure procedure and cough scores.
2: 2 mg MDZ ± 1 mg iv boluses
MDZ (as needed)
Ma 89 China NR NR 60 1, 2 Radiofrequency volume tis- Noninvasive 1: 1.0 μg.kg−1 infusion DEX for Before and dur- No clear Sedation score, analgesic
sue reduction MAP, HR, ECG, 10 min + 0.7 μg.kg−1.h−1 iv DEX ing the definition effects, pain, patient tolerabil-
pulse oximeter, until desired sedation level procedure ity and satisfaction, airway
end-tidal CO2, 2: 1.5 μg.mL−1 Ce infusion pro- obstruction score, consumption
RSS and BIS pofol (titrated by 0.2 μg.ml−1) of study drugs, final propofol Ce,
until desired sedation level adverse events and
[mSP6P;January 29, 2022;9:59]
 Table 1 (Continued)
JID: BJANE

NORA setting Study Country Age (yr) Male (%) Sample ASA Type of procedure Monitorization Intervention/comparator Timing of DEX Main outcome Other outcomes
size physical injection
status

complications and need for atro-

pine, esmolol, adrenaline or
requirement for supplemental
analgesia.
Upper airway proce- Magazine India (18–65) 61.1 54 NR Flexible bronchoscopy NIBP, HR, RR, 1: 0.5 μg.kg−1 infusion DEX for 10 Before the Composite score Pain, respiratory and hemody-
90
dure (n = 11) SpO2 and RSS min + normal saline procedure (sedation, respi- namic effects, number of doses
2: Normal saline + 0.035 mg kg−1 ratory response, of rescue MDZ, duration of the
MDZ calmness, facial procedure, total lignocaine
tension and used, cough, ease of the proce-
physical dure and postprocedural patient
movement) response.
Riachy 91 Lebanon (18–70) 52.5 162 NR Flexible bronchoscopy BP, HR, RR, 1: 0.5 μg.kg−1 iv infusion DEX + 5 min before No clear Bronchoscopy feasibility, seda-
SpO2, ECG and 2 mL iv infusion normal saline procedure definition tion score, tolerance to the pro-
end-tidal CO2 2: iv infusion normal saline + cedure and adverse events and
10 μg.kg−1 iv infusion alfentanil complications.
3: iv infusion normal saline +
2 mL iv infusion normal saline
Ryu 92 Republic (18–70) 66.7 72 1, 2, 3 Flexible bronchoscopy NIBP, ECG, pulse 1: 0.5 mg.kg−1 infusion propofol NR Incidence of Hemodynamic effects, cough
of Korea oximetry and + 0.05 mL.kg−1 bolus DEX (4 μg. oxygen desatu- score, patient and physician sat-
modified OAA/S mL−1) + 0.1–0.5 mL.kg−1.h−1 infu- ration and oxy- isfaction, requirements for oral
score sion DEX (4 μg.mL−1) gen saturation cavity suction and instillation of
2: 0.5 mg.kg−1 infusion propofol trend topical anesthesia, adverse
+ 0.05 ml.kg−1 bolus remifen- events and complications, seda-
tanyl (10 μg.ml−1) + 0.1–0.5 ml. tion score, recovery time, the
−1 −1
kg .h infusion remifentanyl experience of the physician,

13
(10 μg.ml−1) bronchoscope diameters and
procedure type.
St-Pierre Canada (18–75) NR 60 1, 2, 3 Endobronchial Ultrasound- NIBP, ECG, pulse 1: 0.4 μg.kg−1 iv bolus DEX for During the Number of Vocal cords movement, the total
93
Guided Transbronchial oximetry, RR 10 min + 0.5–1.0 μg.kg−1.h−1 procedure major respira- dose of endotracheal lidocaine,
Needle Aspiration and OAA/S infusion DEX tory adverse sedation score, pain, amnesia,
2: 0.5 μg.kg−1 iv bolus remifen- events per patient and physician satisfac-
tanyl for 10 min + 0.05–0.25 μg. patient tion, discharge conditions,
−1 −1
kg min infusion remifentanyl cumulative doses of vasopres-
sors administered and adverse
events and complications.
ARTICLE IN PRESS

Wu 94 (1) Taiwan NR 38.8 80 1, 2, 3 Flexible bronchoscopy NIBP, ECG, HR, 1: 0.7 μg.kg−1 bolus DEX for Before and dur- Safety profile Recovery profile, physician and
SpO2, capnogra- 10 min + 0.07 μg.kg−1.h−1 infu- ing the patient satisfaction and post-
phy and abdom- sion DEX procedure procedural events.
inal wall and 2: 1 mg bolus MDZ ± 1 mg bolus
Brazilian Journal of Anesthesiology xxxx;000(xxx): 1−24

chest excursions MDZ repeated until desired

sedation level
95
Yuan China (20–75) 49 100 1, 2, 3 Flexible Bronchoscopy NIBP, ECG and 1: 1 μg.kg−1 bolus DEX for 12 min NR Mean SpO2 and Cough, discomfort, willingness
SpO2 and modi- + 0.5 μg.kg−1.h−1 infusion DEX hemodynamic to repeat procedure, sedation
fied OAA/S 2: 2–4 μg.mL−1 Ce infusion effects score, duration of procedure and
score propofol recovery time.
Urologic procedure (n Akça 96 Turkey (18–75) NR 75 1, 2 Cystoscopy NIBP, ECG, pulse 1: 1 μg.kg−1 DEX 5 min before No clear CRBD, patient satisfaction and
−1
= 9) oximetry and 2: 250 μg.kg iv ketamine the end of the definition postoperative pain, sedation
RSS 3: normal saline procedure score and adverse events and
complications.
Alhashemi Saudi (18–60) NR 60 1, 2 ESWL NIBP, ECG, pulse 1: 1 μg.kg−1 iv DEX for 10 min + Before and dur- Patient's pain Vital parameters, sedation
97
Arabia oximetry, AAI 0.5 μg.kg−1.h−1 infusion DEX + ing the (VAS scale) scores, recovery score (TDT),
and OAA/S 2 mg.hr−1 infusion morphine + procedure patient and physician satisfac-
score 2 mg PCA morphine (1 every tion, the total dose of analgesic
5 min) used, number of PCA demand,
2: 1.5 mg.kg−1 iv tramadol pre- number of shockwaves deliv-
−1
mixed with 30 μg.kg MDZ for ered, shockwave intensity and
10 min + infusion normal saline + recovery time.
[mSP6P;January 29, 2022;9:59]
 Table 1 (Continued)
JID: BJANE

NORA setting Study Country Age (yr) Male (%) Sample ASA Type of procedure Monitorization Intervention/comparator Timing of DEX Main outcome Other outcomes
size physical injection
status

20 mg.h−1 infusion tramadol +

20 mg PCA tramadol (1 every
5 min)
98
Urologic procedure (n Arpaci Turkey (20–70) NR 40 1, 2 Cystoscopy NIBP, ECG, pulse 1: 0.2–0.7 μg.kg−1.h−1 infusion During the No clear Total procedure time, adverse
= 9) oximetry, VNS, DEX procedure definition events and complications and
−1 −1
OAA/S score, 2: 0.05–0.15 μg.kg .h infusion type of treatment.
and BIS MDZ
Kaygusuz Turkey (18–60) 47.5 46 1, 2 ESWL RR, HR, nonin- 1: 6 μg.kg−1.h−1 iv infusion DEX Before and dur- Improved Respiratory and hemodynamic
99
vasive MAP, for 10 min + 0.2 μg.kg−1.h−1 infu- ing the analgesia effects, pain, patient satisfac-
SpO2 and modi- sion DEX procedure tion and adverse events and
−1 −1
fied OAA/S 2: 6 mg.kg .h iv infusion pro- complications.
score pofol for 10 min + 2.4 mg.kg−1.
−1
h infusion propofol
Kumakura Japan NR 80.6 36 1, 2, 3 TUR of Bladder NIBP, ECG, pulse 1: 4 μg.kg−1.h−1 iv DEX for 10 min 20 min after spi- Regional cere- SpO2, MAP and HR.
100
oximeter, tem- + 0.4 μg.kg−1.h−1 infusion DEX nal anesthesia bral tissue oxy-
perature, 2: 2 μg.mL−1 target-controlled gen saturation
regional cere- infusion propofol
bral tissue oxy-
gen saturation
and BIS.
Modir 101 Iran (18–65) 51.7 60 1, 2 Cystoscopy MAP, HR, RR, 1: 0.5 mg.kg−1 ketamine + 1 μg. Before the Efficacy of seda- Sedation score, recovery score,
SpO2 and RSS kg−1 DEX procedure tion and physician satisfaction and
2: 0.5 mg.kg−1 ketamine +2 μg. analgesia adverse events and
kg−1 fentanyl complications.
Shariffud- Malaysia (18–65) 78.3 60 1, 2 Ureteroscopy and ureteric NIBP, ECG, pulse 1: 0.5 μg.kg−1 iv DEX Before general Minimum alveo- Postoperative pain, periopera-

14
din 102 stenting oximetry, HR 2: Normal saline anesthesia lar tive analgesia requirements,
and BIS concentration adverse events and complica-
tions and recovery profile.
103 −1 −1
Tan China (60–85) 100 96 1, 2, 3 TUR of Prostate MAP, ECG, HR, 1: 6 μg.kg .h iv DEX for 10 min 10 min after spi- Postoperative NR
pulse oximeter + 1.2 μg kg−1 h−1 iv infusion DEX nal injection sleep quality
and BIS 2: 0.225 mg.kg−1.h−1 iv MDZ for
10 min + 0.045 mg.kg−1.h−1 iv
infusion MDZ
3: Normal saline
Zeyneloglu Turkey (18–80) 52 50 1, 2 ESWL NIBP, HR, RR, 1: 1.0 μg.kg−1 bolus DEX for 10 5 min before Recovery time Pain, sedation score, procedure
104
ARTICLE IN PRESS

SpO2 and OAA/S min + 0.2 μg.kg−1.h−1 infusion and during the characteristics, number of
DEX procedure shocks delivered and maximal
2: 0.05 mg.kg−1 iv MDZ and 1 mg. voltage, patient satisfaction and
F.J. Fonseca, L. Ferreira, A.L. Rouxinol-Dias et al.

kg−1 iv fentanyl for 10 min + effectiveness and safety.

infusion normal saline
Huncke 105 USA NR NR 55 1, 2, 3, 4 Not specified BP, HR, RR, SpO2 1: 1 μg.kg−1 DEX + 0.6 mg.kg−1. 10 min before Efficacy (per- Total doses of MDZ required for
and OAA/S h−1 infusion DEX and during the centage of rescue sedation and the total
−1 −1
score 2: 0.5 μg.kg DEX + 0.6 mg.kg . procedure patients not dose of fentanyl required to
h−1 infusion DEX requiring MDZ) treat pain.
3: Normal saline + infusion nor-
mal saline
Saman- India (18–65) 77.8 54 NR Central venous catheter SpO2, RR, SBP, 1: 1 μg.kg−1 infusion DEX for Before the Discomfort and Sedation score, SpO2 and hemo-
taray 106 insertion HR and modified 10 min procedure pain dynamic and respiratory effects.
OAA/S score 2: Infusion normal saline
−1
Vascular procedure (n Saman- India (18–65) 56.7 60 1, 2 Central venous catheter HR, SBP, RR, 1: 1 μg kg infusion DEX for Before the No clear Discomfort, pain, sedation score
= 5) taray 107 insertion SpO2 and modi- 10 min procedure definition and adverse events and
−1
fied OAA/S 2: 1 μg.kg infusion fentanyl for complications.
score 10 min
3: Infusion normal saline
Wu 94 (2) China (40–75) 52.5 80 2, 3 Carotid artery stenting BP, HR, RR and 1: 1 μg.kg−1 DEX + 0.5 μg.kg−1 15 minutes No clear Cognitive function, vital signs,
SpO2 and RSS bolus infusion DEX for 15 min + before and dur- definition sedation score and anxiety
−1 −1
0.6 μg.kg .h infusion DEX ing the score.
2: 0.6 μg.kg−1.h−1 normal saline procedure
[mSP6P;January 29, 2022;9:59]
 JID: BJANE
Table 2 DEX compared to comparator in NORA.

Outcomes N° of paripants Certainty of the Relative effect (95% CI) Anticipated absolute effects
(studies) follow up evidence (GRADE) Risk with Risk difference
comparator with DEX
Time until full 2052 (32 RCTs) ⨁⨁^
x^x Lowa − MD 1.73 minutes higher (0.34 higher to 3.13
recovery higher)
Hypotension 2274 (33 RCTs) ⨁⨁⨁⨁ Highd OR 1.89 (1.43 to 2.48) 78 per 1000 60 more per 1000
(30 more to 95
more)
Bradycardia 1521 (21 RCTs) ⨁⨁⨁⨁ Highd OR 3.60 (2.29 to 5.67) 128 per 1000 218 more per 1000
(124 more to 327

Brazilian Journal of Anesthesiology xxxx;000(xxx): 1−24

more)
Desaturation 1394 (16 RCTs) ⨁⨁⨁^
x Moderated OR 0.44 (0.21 to 0.91) 87 per 1000 47 fewer per 1000
(67 fewer to 7

ARTICLE IN PRESS
fewer)
Nausea 1643 (25 RCTs) ⨁⨁⨁^
x Moderatec OR 1.06 (0.72 to 1.56) 84 per 1000 5 more per 1000
(22 fewer to 41
more)
Pain/Discomfort (52 RCTs) ⨁^
x^x^
x Very lowb,c 42.6% studies reported better control
42.6% studies reported similar control
7.7% reported insufficient control of pain/discomfort with DEX
15

Amnesia and (9 RCTs) ⨁^

x^x^
x Very lowb,c 55.6% found no difference
awareness of 44.4% studies reported inferior amnesic effects
the procedure
Physician (35 RCTs) ⨁^
x^x^
x Very lowb,c 42.8% studies reported higher physician satisfaction
satisfaction 42.8% studies reported no differences
10.9% studies reported lower satisfaction
Patient (48 RCTs) ⨁^
x^x^
x Very lowb,c 33.3% studies reported higher patient satisfaction
satisfaction 58.3% studies reported similar patient satisfaction
8.3% studies reported lower patient satisfaction
Grade of conscious (75 RCTs) ⨁⨁^
x^x Lowb 34.7% studies reported better sedation profile
sedation 28.0% studies reported similar sedation profile
24.0% studies reported lower sedation profile
*The risk in the intervention group (and its 95% Confidence Interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI, Confi-

[mSP6P;January 29, 2022;9:59]

dence Interval; MD, Mean difference; OR, Odds Ratio; GRADE Working Group grades of evidence; High certainty, We are very confident that the true effect lies close to that of the estimate of
the effect; Moderate certainty, We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substan-
tially different; Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect; Very low certainty: We have
very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
Explanations:
a
There was severe heterogeneity (I2 = 96%), not fully explained by subgroup analysis.
b
Heterogeneity in the reporting style.
c
Some imprecision exists: Few events and wide confidence intervals.
d
Some heterogeneity in the reporting style.
JID: BJANE
ARTICLE IN PRESS [mSP6P;January 29, 2022;9:59]
F.J. Fonseca, L. Ferreira, A.L. Rouxinol-Dias et al.

Figure 1 Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included
studies.

92
Pain/Discomfort did not report the scale applied. Due to this heterogeneity
Overall, 52 studies evaluated pain or discomfort as out- in the reporting style, no metanalysis was performed for this
comes: 27 studies evaluated pain or discomfort during the outcome.
procedure, 9 during recovery time, and 16 during both peri- Most of the studies reported a statistically significant
ods. The full description of pain definition and measurement higher physician satisfaction with DEX (n = 15; 42.8%), when
can be found in Appendix III. The pain outcome measure compared to the control group, 61,65,30,71,36,98,43,52,
63,73,58,18,97,37,94
most frequently used in the 52 eligible studies was the VAS or did not report any statistically significant
score (0 no pain − 10 worst pain). difference between both groups (n = 15; 42.8%).23,81,69,38,44,
56,104,54,35,53,29,72,39,75,47
Regarding the analgesic properties of DEX, 42.6% studies A few studies (n = 6; 10.9%)
reported better pain/discomfort control with reported a statistically significant higher physician satisfac-
DEX.16,51,106,107,68,24,89,36,43,44,99,22,54,73,80,57,105,39,83,101, tion in favor of the control group.30,78,92,46,85,45
97,70,102
42.6% studies reported similar analgesic effects with
DEX, when compared with other drugs 15,90,108,78,23,25,81, Patient satisfaction
109,95,96,19,52,27,33,35,92,46,85,75,37,93,31,50
; and 7.7% reported In total, 48 studies evaluated patient satisfaction as an out-
insufficient analgesia with DEX.20,65,104,60 come. The scales used were very different and included, for
Reporting of pain outcomes were mostly presented as example, VAS score 10 cm,61,89,69,54,35,57,58,29,75,26 a
repeated measures during procedure time, either presented questionnaire,109,74,34,45 a 7-point Likert scale 30,56,97,70,60 or
as graphic evolution of pain score or in tables for different a satisfaction score (4 = excellent, 3 = good, 2 = fair, and
time sets. Due to this heterogeneity in the reporting style, 1 = bad),65,71,46,47,94 among others. Candiotti et al. 18
no metanalysis was performed for this outcome 112. applied the Iowa Satisfaction with Anesthesia Scale. Akarsu
et al.,38 Amri et al. 39 Mishra et al. 28 and Ren et al. 81 did
Amnesia and awareness of the procedure not report the scale applied. Due to this heterogeneity in
The ability to produce amnesia of the procedure was evalu- the reporting style, no metanalysis was performed for this
ated in 9 studies, using different methods of measurement outcome.
and different reporting styles, therefore, no metanalysis Most of the studies did not report any statistically signifi-
was performed for this outcome (Appendix III). cant difference in patient satisfaction between the groups
Amnesic effects were inferior in DEX groups in 44.4% of studied (n = 28; 58.3%).61,78,41,23,25,81,36,38,96,43,56,
studies.28,108,23,35 However, in Togawa et al. 35, this differ- 35,73,53,58,92,74,29,39,85,75,26,37,60,47,93,79,94
However,
ence was not statistically significant. The other studies 33.3% (n = 16) reported a statistically significant higher
(55.6%) found no difference in amnesic effects. It is impor- patient satisfaction with DEX, when compared with the con-
tant to note that midazolam was used in both the DEX group trol group,28,65,30,71,89,109,98,44,52,22,54,57,18,34,97,70 and
and the control group in 2 of these studies, 27,29 while St- 8.3% (n = 4) studies reported a statistically significant higher
Pierre et al. 93 compared DEX to remifentanil. Taniyama patient satisfaction in favor of the control group.69,104,46,45
et al. 33 did not evaluate intraoperative recalling, and
Hiwarkar et al. 17 did not perform statistical analyses. Grade of conscious sedation
Of the included studies, 75 evaluated the grade of sedation
Physician satisfaction acquired during the procedure. The method used for access-
Overall, 35 studies evaluated physician satisfaction as an ing adequate sedation was not consistent and the different
outcome. Every study used a different method to evaluate methods used can be found in summary in Appendix III.
this outcome, for example, a VAS scale (0 being most unsat- Overall, the majority of the studies (62.6%) reported
isfactory and 100 being most satisfactory),61,63 NRS scale either a better sedation profile with DEX groups, with higher
score (0 being least satisfied and 10 being most satisfied) achievement of the desired level of sedation for the proce-
23,36
or a satisfaction score (4 = excellent, 3 = good, 2 = fair, dure (n = 26) 15,86,107,32,82,41,23,36,109,38,96,19,99,54,77,67,
and 1 = bad), 65,71,46,47,94 among others. Akarsu et al.,38 Can- 35,73,80,57,58,92,101,70,37,60
; or no difference at all when com-
diotti et al. 18 Mazanikov et al.,60 Ren et al. 81 and Ryu et al. pared to the control groups (n = 21).48,51,28,61,24,69,111,95,43,

16
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ARTICLE IN PRESS [mSP6P;January 29, 2022;9:59]
Brazilian Journal of Anesthesiology xxxx;000(xxx): 1−24

Figure 2 Forest plot of comparison: Time until recovery by control.

52,55,53,74,105,72,97,46,26,76,93,102
Twenty four percent of stud- especially in terms of Blood Pressure (BP) and Heart Rate
ies reported DEX regimens as either insufficient for adequate (HR) alterations. However, the definitions of hypotension
sedation during the procedure or as having a higher demand (n = 53 studies), hypertension (n = 8 studies), bradycardia
16,20,64,106,59,89,110,40,44,56,104,
for rescue medication (n = 47 studies) and tachycardia (n = 8 studies) varied among
22,42,18,85,91,31,45
; 13.3% studies did not compare the grade of studies.
sedation between different regimens.17,90,108,88,27,33,62,50,79 Regarding hypotension, definitions used varied from
Reporting of the grade of conscious sedation is generally alterations in the Mean Arterial Pressure (MAP) or Systolic BP
presented as repeated measures during procedure time, (SBP) to define this outcome, although the cut-off varied. A
with different methods of evaluation, leading to heteroge- meta-analysis was computed for RCTwith comparable defini-
neity in the evaluation method and the characteristics of tions (including subgroup analysis for different settings),
the outcome (repeated measures). As such, no metanalysis shown in
was performed for this outcome. Fig. 3 (see also Appendix V). Dexmedetomidine sedation
was associated with a significantly higher incidence of hypo-
Hemodynamic complications and adverse events tension than the other sedatives (OR = 1.95 [1.25, 3.05],
The hemodynamic stability of the patient during the NORA p = 0.003, I2 = 39%), and there were significant differences in
procedure was one of the most reported outcomes, the effect of DEX between subgroups (p = 0.02).

17
JID: BJANE
ARTICLE IN PRESS [mSP6P;January 29, 2022;9:59]
F.J. Fonseca, L. Ferreira, A.L. Rouxinol-Dias et al.

Figure 3 Forest plot of RCTs reporting hypotension with subgroup analysis by setting.

Concerning changes in HR, bradycardia was generally [2.29, 5.67], p < 0.00001, I2 = 0%), independently of the def-
defined by HR cut-offs, differing from absolute changes to inition used for bradycardia.
relative ones in relation to baseline (further details in Overall, tachycardia and hypertension did not occur dur-
Appendix III), except for Khalil et al., that defined bradycar- ing the procedure. When they did, the difference between
dia as the need for synchronized cardioversion or defibrilla- the study groups was not statistically significant.111,95,2,92
tion, use of cardiopulmonary resuscitation and emergency
extracorporeal circulation.
A meta-analysis was computed for RCTs considering bra- Respiratory complications and adverse events
dycardia from HR < 40 to HR < 60 bpm, or < 20%−25% from Reporting the involvement of the respiratory system was one
baseline, shown in Figure 4 (see also Appendix V). Dexmede- of the major outcomes studied, however, there was not a
tomidine sedation was associated with a significantly higher consistent definition for respiratory depression. A total
incidence of bradycardia than in control groups (OR = 3.60 of 13.4% of studies did not define respiratory depression but

18
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Brazilian Journal of Anesthesiology xxxx;000(xxx): 1−24

Figure 4 Forest plot of comparison of RCT reporting bradycardia incidences (defining bradycardia as HR < 40 to HR < 60 bpm, or <
20%−25% from baseline).

reported major respiratory events, such as desaturation, There are insufficient data to determine a conclusion on
coughing, bradypnea, apnea, and aspiration pneumonia. DEX dose and method of administration for NORA. Most of
A meta-analysis of the studies that reported desatura- the studies used a strategy of an intravenous (IV) bolus
tion < 90% or < 92% (either as an outcome itself or as an indi- of 0.4 to 1 mg.kg 1 followed by continuous perfusion of 0.1
cator of respiratory depression with respective data −0.5 mg.kg 1.h 1. As reported in this review, DEX is often
exclusive to desaturation incidence) was computed. Signifi- associated with bradycardia, as a consequence of its central
cant lower incidence of desaturation was found (OR = 0.40 sympathetic blockage, an effect that is more evident with
[0.25, 0.66], p = 0.0003), but with heterogeneity between continuous infusions (compared to single boluses).7 There is
studies (I2 = 60%), not completely explained by setting (p- also a concern about the higher risk of hypotension with
value for subgroup differences = 0.26, I2 = 23.4%), nor com- DEX. However, this can be suppressed by a slower rate of
parator (p-value for subgroup differences = 0.65, I2 = 0%; intravenous infusion or intranasal administration of DEX,
with only the placebo and propofol control group achieving achieving the same adequate plasma levels without the
I2 < 50%) (Fig. 5 and Appendix V). Five studies reported inci- prejudicial high peak plasma level.6,15−17,41,24 More studies
dence and severity of coughing, using different tools for are needed comparing the type of DEX administration (IV
measurement.90,109,111,95,85 boluses alone or followed by infusion vs. intranasal) and
additive effect with ketamine (considering the merge of sed-
ative and analgesic effects and the different directions in
Nausea
hemodynamic effects, keeping the beneficial respiratory
A post hoc analysis of 26 RCT reporting the incidence of nau-
safety profile).
sea, as an adverse outcome, was performed. Overall, no dif-
In this review, we intended to carry out an extended anal-
ferences were found in the incidence of nausea with DEX,
ysis and description of the existing evidence on the effects
compared to control groups (OR = 1.06 [0.72, 1.56], I2 = 3%).
of DEX on sedation in NORA for adults, therefore, many dif-
ferent settings of NORA were considered: burn unit, dental,
gastrointestinal, gynecological, hemodynamic lab, invasive
Discussion radiology, neuroradiology, orthopedical, psychiatric unit,
urological, vascular, and upper airway procedure setting.
Our results support the evidence that DEX produces effec- This scope allowed for a transversal perspective to different
tive sedative, analgesic, and hypnotic effects, without respi- configurations and different sedation protocols (compara-
ratory depression.6,7 These characteristics enhance patient's tive drugs) that can be communicated in NORA.
and physician’s satisfaction with DEX.6 Kinugasa et al. 54 Despite bringing a holistic and global view, it also
reported also an interaction of the use of DEX with the diffi- involved greater complexity in the analysis and review of
culty of the procedure in the correlation between physi- results, considering that different configurations mean dif-
cians, especially when considering gastroenterology ferent stimuli and different levels of desirable sedation.
endoscopic procedures, with increased endoscopist satisfac- Added to this complexity, considerable heterogeneity was
tion with DEX in higher difficulty cases compared to the pla- noted, with at least 15 different domains being used as pri-
cebo group, but with similar endoscopist satisfaction mary and secondary outcome measures in the included stud-
between groups in lower difficulty procedures. ies. The most frequent efficacy outcomes reported were

19
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F.J. Fonseca, L. Ferreira, A.L. Rouxinol-Dias et al.

Figure 5 Forest plot of comparison: Desaturation by the comparator.

sedation level (evaluated in 82 studies) and the most fre- nausea, and time until full recovery could be considered for
quent adverse outcomes reported were hemodynamic meta-analysis. Of these outcomes, high certainty of the evi-
adverse reactions − hypotension (evaluated in 61 studies) dence was found for a higher incidence of hypotension
and bradycardia (evaluated in 53 studies). There was also (OR = 1.89) and bradycardia (OR = 3.60) with DEX, moderate
variation in outcome definition and measurement as certainty of the evidence for lower desaturation incidence
reported in III. Heterogeneity was explored with subgroup and nausea and, time until full recovery was found to
analysis for setting and comparator/control intervention. A be 1.73 minutes longer with DEX but with low certainty due
significant difference was found for control intervention sub- to severe inconsistency and suspected publication bias.
group analysis in time to recovery (although all subgroups Newman et al. 113 reported a safe discharge time after pro-
presented significant heterogeneity) and a tendency was cedural sedation of 30 minutes. An increase of time-to-dis-
found for the same analysis in hypotension incidence (com- charge of 1.73 would only increase discharge time by
parison with placebo and midazolam had low heterogeneity, about 6%.
with the first presenting significant lower incidence of hypo- Almost 10 years ago, the World SIVA International Seda-
tension). We also found significant differences among set- tion Task Force proposed standardized definitions and termi-
tings for the same outcomes. In time to recovery, all settings nology for adverse events during procedural sedation, to
presented significant heterogeneity, but no heterogeneity increase comparability of outcomes not only in monitoring
was found in hypotension incidence for airway procedure, clinical practice but also as a research tool. Although the
dental procedures, hemodynamic lab, invasive radiology, world SIVA adverse sedation event-reporting tool is being
and vascular procedures settings, with a significant increase applied in clinical practice across the globe,114 none of the
of hypotension incidence found in dental procedures and included studies used this tool. New standards for definitions
hemodynamic lab settings. and use of outcome measures for clinical effectiveness
Overall, the included studies were at low risk of bias. The research in procedural sedation are therefore needed.
highest risk bias was found for participant and staff blinding Exploring specific efficacy and safety in different proce-
(performance bias) as well as incomplete outcome data. dures might be of interest in the future, allowing for tar-
Considering the high heterogeneity found from the outcomes geted procedure recommendations. Further research is
reviewed, only hypotension, bradycardia, desaturation, warranted to include the use of DEX in the following

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ARTICLE IN PRESS [mSP6P;January 29, 2022;9:59]
Brazilian Journal of Anesthesiology xxxx;000(xxx): 1−24

procedures not evaluated in this review: labor, intubation Conflicts of interest

and awake fibroscopy, endoscopic sinus surgery, chronic and
postoperative pain, orthopedic surgery (especially in the The authors declare no conflicts of interest.
elderly), and awake neurosurgery.
This was an extensive systematic review exploring time
until recovery and side effects of DEX only or DEX associated
with other sedatives, in several different NORA settings for Supplementary materials
adults' procedures, in comparison to other sedative pharma-
cological strategies, intending to summarize existing evi- Supplementary material associated with this article can be
dence generalizable to different usual procedural sedation found, in the online version, at doi:10.1016/j.
and analgesia practices. Although it is advantageous to have bjane.2021.12.002.
such a comprehensive summary of the existing evidence of
the use of DEX in NORA, this diversity of contexts and com-
parators is a synthesis challenge. In addition to this diversity,
the heterogeneity in the definition and reporting of out- References
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