Digestive Endoscopy 2021; 33: 21–53 doi: 10.1111/den.

13882

Guidelines

Guidelines for sedation in gastroenterological endoscopy

(second edition)
Takuji Gotoda,1 Takuji Akamatsu,1 Seiichiro Abe,1 Masaaki Shimatani,1
Yousuke Nakai,1 Waku Hatta,1 Naoki Hosoe,1 Yoshimasa Miura,1 Ryoji Miyahara,1
Daisuke Yamaguchi,1 Naohisa Yoshida,1 Yosuke Kawaguchi,2 Shinsaku Fukuda,1
Hajime Isomoto,1 Atsushi Irisawa,1 Yasushi Iwao,1 Toshio Uraoka,1 Miyuki Yokota,2
Takeo Nakayama,3 Kazuma Fujimoto1 and Haruhiro Inoue1
1
Japanese Gastroenterological Endoscopy Society, Tokyo, 2Japanese Society of Anesthesiologists, Hyogo and
3
Department of Health Informatics, Kyoto University School of Public Health, Kyoto, Japan

Sedation in gastroenterological endoscopy has become an
important medical option in routine clinical care. Here, the
Japan Gastroenterological Endoscopy Society and the Japanese
Society of Anesthesiologists together provide the revised
“Guidelines for sedation in gastroenterological endoscopy” as
a second edition to address on-site clinical questions and issues
raised for safe examination and treatment using sedated
endoscopy. Twenty clinical questions were determined and
the strength of recommendation and evidence quality
(strength) were expressed according to the “MINDS Manual
for Guideline Development 2017.” We were able to release up-
to-date statements related to clinical questions and current
issues relevant to sedation in gastroenterological endoscopy
(henceforth, “endoscopy”). There are few reports from Japan in
this field (e.g., meta-analyses), and many aspects have been
based only on a specialist consensus. In the current scenario,
benzodiazepine drugs primarily used for sedation during
gastroenterological endoscopy are not approved by national
health insurance in Japan, and investigations regarding
expense-related disadvantages have not been conducted.
Furthermore, including the perspective of beneficiaries (i.e.,
patients and citizens) during the creation of clinical guidelines
should be considered. These guidelines are standardized based
on up-to-date evidence quality (strength) and supports on-site
clinical decision-making by patients and medical staff. There-
fore, these guidelines need to be flexible with regard to the
wishes, age, complications, and social conditions of the patient,
as well as the conditions of the facility and discretion of the
physician.
Key words: gastroenterological endoscopy, patient
monitoring, pre-sedative assessment, sedation, training

methods, and (vi) importance of recovery-period care. The

CREATION OF GUIDELINES RELATED TO
SEDATION DURING ENDOSCOPIC
EXAMINATION (SECOND EDITION)
HE FIRST EDITION 1 of the “Guidelines for sedation
T in gastroenterological endoscopy” was issued in 2013.
The American Society of Anesthesiologists (ASA) revised
the “Practice guidelines for sedation and analgesia by non-
anesthesiologists” in 2002.2 These guidelines emphasized (i)
pre-operation patient assessment, (ii) patient monitoring,
(iii) security and training of the individual in charge of
sedation, (iv) emergency material preparation and drug
administration, (v) general principles for drug administration
second edition of the “Guidelines for sedation in gastroen-
terological endoscopy” continues to apply the content of the
first edition while addressing on-site clinical questions
(CQs) and issues raised by a newly formed committee based
on the “Practice guidelines for sedation and analgesia by
non-anesthesiologists.” Moreover, CQs were determined,
and new evidence was collected. Accordingly, we were
mindful of creating evidence-based medicine (EBM) guide-
lines according to the “MINDS Manual for Guideline
Development 2017”,3 which in turn is based on the EBM
Medical Information Network Distribution System
(MINDS) of the Japan Council for Quality Health Care.

Corresponding: Takuji Gotoda, Division of Gastroenterology and

AIM OF THE GUIDELINES
Hepatology, Department of Medicine, Nihon University School of
Medicine, 1-6 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8309,
Japan. Email: takujigotoda@yahoo.co.jp
T HE OBJECTIVE OF creating these guidelines was to
provide current evidence regarding the assurance of
Received 18 September 2020; accepted 21 October 2020.

© 2020 Japan Gastroenterological Endoscopy Society 21

22 T. Gotoda et al.
safety and efficacy in sedative usage, as well as the selection
of appropriate sedatives.
TASK FORCE MEMBERS AND CONSULTANTS
E LEVEN GASTROINTESTINAL ENDOSCOPISTS
were commissioned as task force members of the Japan
Gastroenterological Endoscopy Society (JGES) committee
for creating the guidelines, with a single anesthesiologist as
an external committee member. Furthermore, five gastroin-
testinal endoscopists and a single anesthesiologist were
assigned as assessment consultants, and a single specialist in
charge of guideline creation was included as an external
assessment consultant (Table 1).
BASIC PRINCIPLES FOR GUIDELINE CREATION
T HESE GUIDELINES HAVE been created according to
the “MINDS Manual for Guideline Development
2017,” showing the strength of recommendation and
evidence quality (strength; Table 2). References with high
up-to-date evidence quality (strength) and specialist con-
sensus were integrated to determine the strength of recom-
mendation in each category. However, although assessments
of a given evidence quality (strength) were conducted, there
were also some sections where social demands such as the
current state of Japanese affairs and medical insurance
regulations needed to be considered. In other words, the
basic principles were determined based on the (i) creation of
clinical principles that emphasize the entire body of
evidence based on systematic reviews and (ii) strength of
recommendation, which may not necessarily correlate with
evidence quality (strength). The content of these guidelines
was created with the objective of supporting on-site clinical
decision-making, and their relevance will be realized
through its use in routine clinical care. The content of these
guidelines should not serve as the justification for medical
lawsuits. As such, the medical staff in charge takes
responsibility for the results of clinical actions that occur
in practice.
Furthermore, clinical content and social demands can
change substantially when considering constant changes in
the social landscape and medical fee revisions; therefore, the
content of these guidelines should be revised within a few
years.
GUIDELINE CREATION PROCEDURE AND
METHODS
A TASK FORCE for guidelines related to sedation
during endoscopic examination was set up based on
© 2020 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; 33: 21–53
the JGES guideline committee, and the guidelines were
created with the participation of the Japanese Society of
Anesthesiologists as well. First, a key clinical issue
addressed by the clinical guidelines was whether improved
examination/treatment success rate and elimination of pain
or anxiety can be achieved with the “benefits” of sedative
usage. Furthermore, the possibility of increased adverse
events due to sedative usage was considered as an outcome.
Disadvantages such as financial burdens were not included
in assessments in the creation of these guidelines. The
reason for this is because in Japan, dexmedetomidine
hydrochloride is the only sedative among those used in
endoscopy that can be reimbursed, while no other sedatives
are covered by national health insurance in Japan. Further-
more, there were regional differences in the assessment
conditions of the sedatives used, and it was difficult to
conduct a unified assessment.
Based on this context, the task force members included
contributions to preventing adverse outcomes through
on-site regulations or education for sedative usage con-
sidering key clinical issues, collecting a total of 83 CQs,
which show PICO (P, patients/problem/population; I,
interventions; C, comparisons/controls/comparators; O,
outcomes).
Investigations were conducted twice on the content of
these CQs from the viewpoint of usage conditions in current
clinics, and 20 CQs were ultimately created following
further revision (Table 3).
Systematic reference searches from PubMed, Cochrane
Library databases, and Japan Medical Abstract Society were
conducted for each CQ, wherein keywords were extracted,
and a search equation was determined for the period from
1990 to 2019 (search dates: June 9–12, 2019). Manual
searches were also used for insufficient references. The
searched references were assessed, and the necessary
references were used, after which a statement and analysis
were created for each CQ. The task force members and
assessment consultants then assigned strength of recom-
mendation of the statement and evidence level of the
references in each of their assigned disciplines according to
the “MINDS clinical guideline creation manual 2017”. The
created statement and analysis were used to create the CQ-
format guidelines, and the statement plans were decided
with unregistered independent voting among the task force
members and the assessment consultants (17 members in
total) according to the modified Delphi method.4 The
modified Delphi method involves the selection of a single
number along a nine-step scale (1–3, disagree; 4–6,
dissatisfied; 7–9, agree), and statements with a median
value of 7 or higher were used (Table 4). The statement or
strength of recommendation was revised after sufficient
Digestive Endoscopy 2021; 33: 21–53 Sedation for GI endoscopy 23

Table 1 Members of the committee for guidelines for sedation in gastroenterological endoscopy (second edition)

Japan Gastroenterological Endoscopy Society guideline committee

Director Haruhiro INOUE (Gastroenterological Clinic, Digestive Diseases Center, Showa University Koto Toyosu
Hospital)
Special counsel Hisao TAJIRI (Department of Innovative Interventional Endoscopy Research, Jikei University School of
Medicine)
Director in charge Kazuma FUJIMOTO (Department of Internal Medicine, Faculty of Medicine, International University of
Health and Welfare)
Chairperson Kazuma FUJIMOTO (Department of Internal Medicine, Faculty of Medicine, International University of
Health and Welfare)
Members of the task force for guidelines related to sedation during endoscopic examination
Guideline creation Takuji GOTODA (Division of Gastroenterology and Hepatology, Department of Medicine, Nihon
chairperson University School of Medicine)
Guideline creation Takuji AKAMATSU (Department of Gastroenterology and Hepatology, Japanese Red Cross Society,
members Wakayama Medical Center)
Seiichiro ABE (Endoscopy Division, National Cancer Center Hospital)
Masaaki SHIMATANI (The Third Department of Internal Medicine, Division of Gastroenterology and
Hepatology, Kansai Medical University)
Yousuke NAKAI (Department of Endoscopy and Endoscopic Surgery, The University of Tokyo
Hospital)
Waku HATTA (Division of Gastroenterology, Tohoku University Graduate School of Medicine)
Naoki HOSOE (Center for Diagnostic and Therapeutic Endoscopy, Keio University Hospital)
Yoshimasa MIURA (Department of Medicine, Division of Gastroenterology, Jichi Medical University)
Ryoji MIYAHARA (International Medical Center, Fujita Health University Hospital)
Daisuke YAMAGUCHI (Department of Gastroenterology, National Hospital Organization, Ureshino
Medical Center)
Naohisa YOSHIDA (Department of Gastroenterology, Graduate School of Medical Science, Kyoto
Prefectural University of Medicine)
External guideline Yosuke KAWAGUCHI (Department of Anesthesia and Intensive Care, National Cancer Center
creation member Hospital)
Assessment consultant Shinsaku FUKUDA (Hirosaki University Hospital)
chairperson
Assessment consultant Hajime ISOMOTO (Division of Medicine and Clinical Science, Tottori University Hospital)
members Atsushi IRISAWA (Department of Gastroenterology, Dokkyo Medical University)
Yasushi IWAO (Center for Preventative Medicine, Keio University Hospital)
Toshio URAOKA (Department of Gastroenterology and Hepatology, Gunma University Graduate
School of Medicine)
Miyuki YOKOTA (Department of Anesthesiology/Pain Service, Cancer Institute Hospital of JFCR)
External assessment Takeo NAKAYAMA (Department of Health Informatics, School of Public Health, Kyoto University
consultant Graduate School of Medicine)

discussion and repeated until it reached the agreement

standard in cases where the assessment had a value of 6 or
lower. The complete guideline plan was assessed by the
assessment consultants and an external assessment consul-
tant, revised, and then released to the Society committee
members. The guidelines were then completed following
the receipt of public comments and discussions on the
results.
The guideline creation group also took on the responsi-
bilities of the systematic review team in the creation of these
guidelines.
ITEMS TO BE INCORPORATED FOLLOWING
GUIDELINE PUBLICATION (REMAINING
ISSUES)
T HAS ALSO been specified in the “MINDS Manual for
I Guideline Development 2017” that the anticipated role of
clinical guidelines is in proposing clinical, educational,
research, and medical strategies. Themes for which evidence
from Japan has been shown to be insufficient through the
creation of these guidelines have been set as high-priority
research issues.

© 2020 Japan Gastroenterological Endoscopy Society

24 T. Gotoda et al.
Table 2 Strength of recommendation and evidence quality
(strength)
Strength of recommendation
1: Strongly recommended
2: Weakly recommended (proposed)
None: No clear recommendations can be made, or the
strength of recommendation cannot be determined
Evidence quality (strength)
A: Based on strong grounds
B: Based on moderate grounds
C: Based on weak grounds
D: Based on very weak grounds
Furthermore, most of the drugs used in endoscopy are not
eligible for insurance approval. In other words, these drugs are
just widely used in general clinics as well-known options.
Regional differences interfere with whether the sedatives used
are inspected, and it is unclear who shoulders the responsibility
when adverse events occur as a result of the sedative. This was
also made clear with the creation of these guidelines, but the
use of these drugs cannot be avoided since the disadvantages to
the patient during endoscopy treatment without sedatives or
general anesthesia are too high, and comparison trials between
sedative use and non-use are not available.
In Japan, even if sedative use is shown to be a “benefit” for
the patient (i.e., beneficiary), this is disadvantageous to the
medical provider (i.e., facility, endoscopist), and the patient
will be held responsible for the financial burden or for serious
incidents. These guidelines are for endoscopy, a general
medical procedure, and all Japanese citizens become bene-
ficiaries. Even with regard to expenses, it is unlikely that this
would require vast expenses that affect the national budget of
Japan. The “individual and social aspects to be gained and its
considerations,” and the consideration of medical regulation
and policy decisions (e.g., medical insurance regulations)
from the perspective of safety in sedative use are issues that
should be addressed in the future.
The present guidelines are designed for medical providers
who have the opportunity to conduct examinations and
treatment using endoscopy. However, it is extremely
important to reflect the patient and citizen perspective
(Patients and Public Involvement) in addition to that of the
medical staff when creating the clinical guidelines. The need
for patient/citizen participation for creating the guidelines
has also been clearly stated in the “MINDS Manual for
Guideline Development 2017”,3 but the incorporation of the
guideline subject group’s values and hopes to the extent
possible is thought to be an issue to be addressed in the next
revision. This requires preparation for patient participation,
including education and training. The Society will also need
to provide a program that brings about patient/citizen
© 2020 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; 33: 21–53
participation like that of the National Institute for Health
and Care Excellence in the U.K. and support participation in
the creation of such clinical guidelines.
SUBJECTS AND GUIDELINE USERS
T HE SUBJECTS OF these guidelines are patients who
undergo investigation and treatment using endoscopy.
Children are excluded from the subjects of these guidelines.
The users of these guidelines include clinical physicians
who conduct endoscopy and all medical staff involved in
endoscopy. The guidelines are standardized based on current
evidence and support on-site clinical decision-making
between the patient and medical staff. As such, these
guidelines need to be flexible with regard to the wishes, age,
complications, and social conditions of the individual
patient, as well as the conditions at the facility and the
discretionary powers of the physician.
CONFLICT OF INTEREST
E ACH OF THE task force members of the guideline
creation and assessment committee declared the fol-
lowing content with regard to conflict of interest.
Takuji GOTODA (lecturer’s fee: Fujifilm), Seiichiro ABE
(lecturer’s fee: Boston Scientific Japan; research expenses/
scholarship: Olympus, Fujifilm), Naoki HOSOE (research
expenses/scholarship: Olympus), Yoshimasa MIURA (en-
dowed lecture: Fujifilm Medical), Hajime ISOMOTO
(lecturer’s fee: Takeda Pharmaceutical Company, Daiichi
Sankyo Company; scholarship contributions: Otsuka Phar-
maceutical, Eli Lilly Japan), Atsushi IRISAWA (scholarship
contributions: Takeda Pharmaceutical Company, EA
Pharma, AbbVie), Kazuma FUJIMOTO (lecturer’s fees:
Tsumura & Co., EA Pharma, AstraZeneca, Daiichi Sankyo;
scholarship contributions: AstraZeneca, Daiichi Sankyo,
Astellas Pharma, Takeda Pharmaceutical Company, EA
Pharma, Asahi Kasei Medical), Haruhiro INOUE (patent
fees: Olympus; lecturer’s fees: Olympus, Takeda Pharma-
ceutical Company; scholarship contributions: Olympus,
Boston Scientific Japan, Takeda Pharmaceutical Company).
Takuji GOTODA and Hajime ISOMOTO are Deputy
Editors‐in‐Chiefs of Digestive Endoscopy, and Yousuke
NAKAI, Atsushi IRISAWA and Naohisa YOSHIDA are
Associate Editors of Digestive Endoscopy.
FUNDING INFORMATION
E XPENSES RELATED TO the creation of these guide-
lines were covered by the JGES, and no funds were
provided from other businesses.
 Table 3 List of clinical questions and statements
CQ Clinical question
No.
CQ1 Are pre-sedative assessments recommended for
suitable and safe sedation?
CQ2 Are sedated endoscopy examinations safe for
patients with complications (e.g., COPD, heart
disease, chronic renal failure, hepatic cirrhosis,
psychotropic drug administration, myasthenia
gravis), seniors, and pregnant patients?
CQ3 What constitutes suitable monitoring during
sedation?
CQ4 Is a monitoring supervisor necessary when
conducting sedated endoscopy?
CQ5 How should monitoring release during sedated
endoscopy be ascertained?
CQ6 Is sedation training for endoscopists and
endoscopy staff recommended?
CQ7 What are suitable sedation methods during
emergency endoscopy?
CQ8 Do sedatives contribute to transoral endoscopy?
CQ9 Do sedatives contribute to transanal endoscopy?
CQ10 What is a suitable benzodiazepine drug for
transoral endoscopy examinations?
CQ11 What is a suitable benzodiazepine drug for
transanal endoscopy examinations?
CQ12 What is a suitable benzodiazepine drug when
undergoing transoral endoscopy treatment?
CQ13 What is a suitable benzodiazepine drug when
undergoing transanal endoscopy treatment?
© 2020 Japan Gastroenterological Endoscopy Society
Statement Strength of Evidence
recommendation quality
(strength)
Clinical history and physical status (PS) assessments prior to sedation are 1 C
recommended for utilizing the suitable depth of sedation and preventing
adverse events
Sedated endoscopy examinations can be safely conducted if sufficient pre- 2 D
operation assessments are conducted, including consultations with
anesthesiology departments and other clinical departments, and a sedative
suitable for the underlying disease is selected
Digestive Endoscopy 2021; 33: 21–53
Suitable monitoring during sedation constitutes continuous monitoring of a 1 B
patient’s consciousness level, respiratory dynamics, and circulatory
dynamics
A single monitoring supervisor should be present for minimal or moderate 2 D
sedation, and more than one monitoring supervisor should be present for
high-risk endoscopy
Monitoring release (discharge) standards have not been established, but this 2 D
should be determined upon assessment of the patient’s consciousness level,
respiratory dynamics, and circulatory dynamics
Sedation training should be proposed to endoscopists and endoscopy staff 2 D
who provide sedation
Secure monitoring should be conducted, and antagonist sedatives or those 2 D
with a short half-life should be used under an environment where emergency
treatment can be conducted
Sedatives improve the receptivity and satisfaction of transoral endoscopy 2 A
and contribute to improved examination/treatment performance
Sedatives reduce anxiety and pain during transanal endoscopy and 2 C
contribute to increased satisfaction and improved examination/treatment
performance
Among midazolam, diazepam, and flunitrazepam, midazolam usage is 2 C
proposed for its sedative effects and patient satisfaction
Among midazolam, diazepam, and flunitrazepam, midazolam usage is 2 C
proposed for its sedative effects and patient satisfaction
There is no evidence related to benzodiazepine drug selection, and no None D
suitable drugs have been established
There is no evidence related to benzodiazepine drug selection, and no None D
suitable drugs have been established
Sedation for GI endoscopy
25
 Table 3 (Continued)
CQ Clinical question
No.
CQ14 What should be done when a suitable depth of
sedation cannot be obtained even when more
than the recommended amount of
benzodiazepine drug is administered during
sedated endoscopy?
CQ15 Is the use of analgesics in addition to sedatives
effective during transoral endoscopy?
CQ16 Is the use of analgesics in addition to sedatives
effective during transanal endoscopy?
CQ17 What is the efficacy of propofol in endoscopy?
© 2020 Japan Gastroenterological Endoscopy Society
CQ18 Can propofol be used by non-anesthesiologists
in an endoscopy facility?
CQ19 Is dexmedetomidine hydrochloride effective in
sedation during endoscopy treatment with long
sedation times?
CQ20 Is antagonist use recommended for
sedation/pain relief cases?
26
Statement Strength of Evidence
recommendation quality
(strength)
The addition of analgesics (e.g., pethidine hydrochloride, pentazocine) should 2 D
be considered when using only benzodiazepine drugs. Patients suspected of
T. Gotoda et al.
disinhibition should be administered antagonists, and the procedure should
be conducted while awake or the examination/treatment should be extended
The use of analgesics in addition to sedatives is effective for ERCP. There are 2 B
cases with other endoscopies where the use of analgesics in addition to
sedatives is effective
There are cases where the use of analgesics in addition to sedatives is 2 C
effective in transanal endoscopy
Adverse outcomes do not increase if propofol is used under suitable 2 A
monitoring conditions, and it has the advantages of short duration of
recovery/confinement, low interruption rate of long-term surgical
procedures, and high physician/nurse/patient satisfaction
Propofol may be used by physicians who have undergone training (e.g., with 2 A
airway maintenance) only if sufficient care is given to the depth of sedation
and is administered to ASA-PS I or II patients
Dexmedetomidine hydrochloride is effective in sedation during endoscopy 1 B
treatment with long sedation times
Flumazenil and naloxone hydrochloride are recommended as antagonists for 2 B
respiratory suppression induced by benzodiazepine drugs and opioid
analgesics, respectively
Digestive Endoscopy 2021; 33: 21–53
Digestive Endoscopy 2021; 33: 21–53
Table 4 Extent of consent based on the modified Delphi
method
1–3 Disagree
4–6 Dissatisfied
7–9 Agree
REFERENCES
1 Obara K, Haruma K, Irisawa A et al. Guidelines for sedation in
gastroenterological endoscopy. Dig Endosc 2015; 27: 435–49.
2 American Society of Anesthesiologists Task Force on Sedation
and Analgesia by Non-Anesthesiologists. Practice guidelines
for sedation and analgesia by non-anesthesiologists. Anesthe-
silogy 2002; 96: 1004–17.
3 https://minds.jcqhc.or.jp/english/english.php. Accessed 6
March 2020.
4 Fink A, Kosecoff J, Chassin M et al. Consensus methods:
Characteristics and guidelines for use. Am J Public Health
1984; 74: 979–83.
CQS AND STATEMENTS
CQ 1: Are pre-sedative assessments
recommended for suitable and safe
sedation?
x reviews/clinical guidelines, 40 were clinical trials, 99 were
Statement 1:
Clinical history and physical status (PS) assessments
prior to sedation are recommended for utilizing the
appropriate level of sedation and preventing adverse
events.
Assessment based on the modified Delphi method:
median, 9; minimum, 5; maximum, 9
Strength of recommendation: 1, Evidence quality
(strength): C
Textual explanation
Suitable sedation requires the determination of the target
level of sedation for the planned procedure, as well as the
patient’s PS, clinical history, and pre-existing medical
conditions, which are thought to be correlated with
sedation-related adverse events.1,2 Parameters similar to
those shown in the American Society for Gastrointestinal
Endoscopy (ASGE)3 and the ASA4 and to be assessed in
advance are shown in Table 5. Assessments of vital signs,
Sedation for GI endoscopy 27
auscultation of the heart and lungs, baseline consciousness
level, and the airway are similarly recommended for
physical findings. The modified Mallampati score5,6 is often
used for airway assessment (Table 6). Previous reports have
indicated the efficacy of the ASA pre-procedure assessment
classification “ASA physical status (PS) classification”
(Table 7) for PS assessment. Anesthesiologist consultations
are recommended for patients with an ASA-PS classification
of IV and above according to ASGE3 and ASA4 guidelines
and ASA-PS classification of III and above according to the
European Society of Anaesthesiology (ESA) guidelines,7
given their higher risk of adverse events. Other risk factors
for sedation-related adverse events in the ESA guidelines7
include patients with cardiovascular diseases, obstructive
sleep apnea, obesity, renal failure, liver failure, and old age.
The ASGE requires careful administration of sedation in
elderly patients but does not provide a clear definition for
elderly patients. ESA guidelines7 state that anesthesiologist
consultations are recommended for patients over the age of
70 due to their higher risk of sedation-related adverse
events.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search using the keywords “endoscopy”
and “sedation” and (“training” or “assessment”) yielded 177
articles, of which 22 were meta-analyses/systematic
miscellaneous clinical research/epidemiological research,
and 16 were controlled trials. Manual searching added
seven articles, and screening results yielded seven related
references, including two clinical guidelines.
Table 5 Items for pre-sedative assessments
Clinical history
Presence of serious cardiopulmonary conditions
A history of stridor, snoring, sleep apnea
Drug allergies
Prior sedation- or anesthesia-related adverse reactions
Current medications
History of smoking and alcohol consumption
Pregnancy/lactation
Time and contents of the last oral intake
Physical examinations
Physical status (PS) assessment (ASA-PS classification)
Vital signs
Auscultation of the heart and lungs
Baseline consciousness level
Airway assessment
© 2020 Japan Gastroenterological Endoscopy Society
28 T. Gotoda et al.
REFERENCES
1 Sharma VK, Nguyen CC, Crowell MD et al. A national study
of cardiopulmonary unplanned events after GI endoscopy.
Gastrointest Endosc 2007; 66: 27–34.
2 Enestvedt BK, Eisen GM, Holub J et al. Is the American
Society of Anesthesiologists classification useful in risk
stratification for endoscopic procedures? Gastrointest Endosc
2013; 77: 464–71.
3 ASGE Standards of Practice Committee, Early DS, Lightdale
JR et al. Guidelines for sedation and anesthesia in GI
endoscopy. Gastrointest Endosc 2018; 87: 327–37.
4 Practice guidelines for moderate procedural sedation and
analgesia 2018. A report by the American Society of
Anesthesiologists Task Force on Moderate Procedural Seda-
tion and Analgesia, the American Association of Oral and
Maxillofacial Surgeons, American College of Radiology,
American Dental Association, American Society of Dentist
Anesthesiologists, and Society of Interventional Radiology.
Anesthesiology 2018; 128: 437–79.
5 Mallampati SR, Gatt SP, Gugino LD et al. A clinical sign to
predict difficult tracheal intubation: A prospective study. Can
Anaesth Soc J 1985; 32: 429–34.
6 American Association for Study of Liver Diseases, American
College of Gastroenterology, American Gastroenterological
Association Institute et al. Multisociety sedation curriculum for
gastrointestinal endoscopy. Gastrointest Endosc 2012; 76: e1–25.
7 Hinkelbein J, Lamperti M, Akeson J et al. European Society of
Anaesthesiology and European Board of Anaesthesiology
guidelines for procedural sedation and analgesia in adults. Eur
J Anaesthesiol 2018; 35: 6–24.
CQ 2: Are sedated endoscopy examinations
safe for patients with complications (e.g.,
COPD, heart disease, chronic renal failure,
hepatic cirrhosis, psychotropic drug
administration, myasthenia gravis), seniors,
and pregnant patients?
Statement 2:
Sedated endoscopy examinations can be safely conducted
if sufficient pre-operation assessments are conducted,
including consultations with anesthesiology departments
and other clinical departments, and a sedative that is
chosen while considering the underlying disease.
Assessment based on the modified Delphi method:
median, 9; minimum, 7; maximum, 9
Strength of recommendation: 2, Evidence quality
(strength): D
© 2020 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; 33: 21–53
Textual explanation
Care must be taken with regard to patient safety (e.g.,
organ load, interactions with internally administered drugs)
when conducting sedated endoscopy on seniors with
several underlying diseases or younger patients with
complications. Performing long-term and invasive endo-
scopy under general anesthesia has been reported to reduce
the adverse incident rate compared to examination under
sedation1, and this should be considered as a selection
option.
The 2018 revised ASA guidelines2 recommend (i)
confirmation of medical records (e.g., primary organ
abnormalities, obesity, sleep apnea syndrome, anatomical
airway abnormalities, congenital abnormalities, respiratory
diseases, allergies, history of sedation, surgical history, drug
administration dose, etc.), (ii) physical finding assessments,
and (iii) confirmation of other examination results. Patients
with an ASA-PS classification of IV (serious life-threatening
systemic disease present)3 (Table 7) or complications of
obstructive pulmonary disease, ischemic heart disease, and
congestive heart failure should consult beforehand with an
anesthesiologist or the respective specialists.4,5 The safety of
sedated endoscopy varies widely depending on the patient’s
PS or severity of comorbid diseases. Thus, it is essential that
pre-procedural assessments (including consultations with
anesthesiologists or other specialists) be sufficiently con-
ducted, the sedative be chosen considering the underlying
disease, and suitable monitoring be performed during and
after the procedure.
COPD and sleep apnea syndrome. Endoscopic examina-
tions in patients with severe chronic respiratory insuffi-
ciency can have fatal results if accompanied by aspiration
pneumonia or CO2 narcosis. Avoiding over-sedation,
which results in decreased respiration rate, is also impor-
tant with regard to sedative usage.5 CO2 narcosis in
particular can occur if the PaO2 is too high during type 2
respiratory failure (hypoxemia with hypercapnia), and the
oxygen saturation (SpO2) should be maintained at 88–
92%.6
Moderate sedation has been determined to not increase
the risk of sleep apnea syndrome-related adverse events, but
deep sedation can induce hypoxemia or hypotension, and
suitable management from an anesthesiologist is required.2
Heart disease. Prior assessments of cardiac function are
recommended for highly invasive examinations or proce-
dures requiring long durations on patients with ischemic
Digestive Endoscopy 2021; 33: 21–53 Sedation for GI endoscopy 29

Table 6 Modified Mallampati score for airway assessment
Class I Full visibility of the tonsils, uvula, and soft palate
Class II Visibility of the hard and soft palate, upper portion of
the tonsils, and uvula
Class The soft and hard palate and base of the uvula are
III visible
Class Only the hard palate is visible
IV
heart disease, as they can cause anginal attacks or heart
failure.2
Chronic renal failure. Reports have indicated that patients
with renal function lower than GFR 60 mL/min/1.73 m2 are
at higher-than-normal risk of hypoxemia or respiratory
insufficiency. Therefore, short-acting and liver-metabolizing
drugs (e.g., propofol) are recommended.7
Liver cirrhosis. Benzodiazepine drugs, which are often used
for sedation, have variable durations of action depending on
the drug type, but since they are deactivated through
glucuronic acid conjugation, decreased liver function influ-
ences the liver metabolism of the sedative and increases the
frequency of adverse events.8,9 Short-acting drugs (e.g.,
midazolam) can be considered, but care must be taken
against the prolonged half-life of these drugs.2 Furthermore,
deep sedation is a risk factor for the onset of hepatic
encephalopathy; thus, moderate sedation is recommended.10
Psychotropic drug administration. The necessary sedative
dose during endoscopic examination increases when benzo-
diazepine drugs, opioid analgesics, or psychotropic drugs are
regularly used, and patient satisfaction also decreases.11,12
Myasthenia gravis. Myasthenia gravis is an autoimmune
disease that disrupts synapse transmission at the neuromus-
cular junction. Assessments of the voluntary and respiratory
muscles are conducted in order to safely conduct sedated
endoscopic examinations. For respiratory muscle examina-
tion, sedated endoscopy is not recommended under condi-
tions where negative expiratory pressure and forced vital
capacity are used in lung function examinations and spare
respiratory functions are virtually non-existent.13 Benzodi-
azepine drugs like midazolam and diazepam have muscle
relaxation effects and are contraindicated due to their
tendency to exacerbate symptoms. Reports have indicated
the efficacy of propofol due to its short-acting effects, which
do not influence the neuromuscular junction.13
Seniors. Prior assessments should be conducted for seniors,
because age-related functional decreases in the heart, lungs,
kidney, liver, endocrine system, and nerves increase the risk
of sedation-related adverse events.14,15
Closer attention should be paid to hypotension, hypoxemia,
arrhythmia, and pulmonary aspiration in seniors than in
younger patients.16–18 Furthermore, seniors are known to
have a higher sensitivity to sedatives like midazolam, and the
appropriate dose for them is lower than that for younger
patients.19,23 It is therefore important to avoid overdosing and
to conduct management during and after surgery carefully;
reduced post-procedural onset of hypoxemia during rest can
be expected by selecting a short-acting drug.24
Pregnant patients. Sedative use should be prolonged if
possible, given its effects on the fetus (e.g., hypoxemia,
hypotension, teratogenesis). Elective administration is rec-
ommended in the second trimester (14–27 weeks). With
regard to sedative safety assessments on pregnant women,
anesthesiologist-administered propofol and midazolam have
been classified as category B (relatively safe) and D,
respectively, by the U.S. Food and Drug Administration.
Diazepam is not recommended due to reports indicating its
correlations to infants being born with a cleft palate.25
Breast-feeding after sedation is not recommended, con-
sidering reports indicating the transfer of sedatives through
breast milk (e.g., midazolam breast milk/blood plasma ratio,
0.15) and variable half-life of drugs between adults and

Table 7 American Society of Anesthesiologists physical status classification (ASA-PS classification; adapted from the ASA website)

Class Patient status

I The patient is normal and healthy

II The patient has mild systemic disease that does not limit activities
III The patient has moderate or severe systemic disease that does not limit activities
IV The patient has severe systemic disease that is a constant threat to life
V The patient is morbid and is at a substantial risk of death within 24 h
E Emergency status: in addition to the underlying ASA status, any patient undergoing an emergency procedure is indicated by
suffix “E”

© 2020 Japan Gastroenterological Endoscopy Society

30 T. Gotoda et al.
children (e.g., midazolam half-life in adults, approximately
1.9 h; in children, 6.5–23 h), with a particularly large
number of reports indicating adverse outcomes in infants
within 2 months of birth.26 Sedatives with a short half-life
need to be selected when breast-feeding after awakening
from sedation, but the discharge amount is thought to
accumulate up to 87.8% even with midazolam up to 24 h
after drug administration. Safety measures such as infant
monitoring are necessary even after awakening since the
drug type used for sedation and the metabolic functions of
the mother and infant all influence the infant.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search including the keywords (“en-
doscopy” or “digestive system”) and (“sedation” or “anes-
thesia” or “analgesia”) and (“elderly” or “cirrhosis” or
“pulmonary” or “cardiac” or “renal disease” or “high risk”
or “pregnancy”) yielded 404 articles, of which 18 were
meta-analyses/systematic reviews/clinical guidelines, 96
were clinical trials, 273 were miscellaneous clinical
research/epidemiological research, and 17 were controlled
trials. After manual searching added 21 articles (including
four clinical guidelines), screening results yielded 26 related
references, including four randomized controlled trials
(RCTs) and four clinical guidelines.
REFERENCES
1 Smith ZL, Mullady DK, Lang GD et al. A randomized
controlled trial evaluating general endotracheal anesthesia
versus monitored anesthesia care and the incidence of
sedation-related adverse events during ERCP in high-risk
patients. Gastrointest Endosc 2019; 89: 855–62.
2 Practice guidelines for moderate procedural sedation and
analgesia 2018. A report by the American Society of
Anesthesiologists Task Force on Moderate Procedural Seda-
tion and Analgesia, the American Association of Oral and
Maxillofacial Surgeons, American College of Radiology,
American Dental Association, American Society of Dentist
Anesthesiologists, and Society of Interventional Radiology.
Anesthesiology 2018; 128: 437–79.
3 Hinkelbein J, Lamperti M, Akeson J et al. European Society of
Anaesthesiology and European Board of Anaesthesiology
guidelines for procedural sedation and analgesia in adults. Eur
J Anaesthesiol 2018; 35: 6–24.
4 ASGE Standards of Practice Committee, Early DS, Lightdale
JR et al. Guidelines for sedation and anesthesia in GI
endoscopy. Gastrointest Endosc 2018; 87: 327–37.
5 American Society of Anesthesiologists Task Force on Sedation
and Analgesia by Non-Anesthesiologists. Practice guidelines
for sedation and analgesia by non-anesthesiologists. Anesthe-
silogy 2002; 96: 1004–17.
© 2020 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; 33: 21–53
6 Hirose S, Sato T, Yamaguchi T et al. Endoscopy for high-risk
patients with serious comorbidities. Endoscopia Dig 2018; 30:
831–7. (Article in Japanese with English summary).
7 Lee SM, Kim GH, Lee JJ et al. Does propofol and alfentanil-
induced sedation cause periodic apnoea in chronic renal failure
patients? Int J Clin Pract 2010; 64: 1–5.
8 Jensen DM. Endoscopic screening for varices in cirrhosis:
Findings, implications, and outcomes. Gastroenterology 2002;
122: 1620–30.
9 Thuluvath PJ. Toward safer sedation in patients with cirrhosis:
Have we done enough? Gastrointest Endosc 2009; 70: 269–71.
10 Mao W, Wei XQ, Tao J et al. The safety of combined sedation
with propofol plus fentanyl for endoscopy screening and
endoscopic variceal ligation in cirrhotic patients. J Dig Dis
2014; 15: 124–30.
11 Papachristou GI, Gleeson FC, Papachristou DJ et al. Endo-
scopist administered sedation during ERCP: Impact of chronic
narcotic/benzodiazepine use and predictive risk of reversal
agent utilization. Am J Gastroenterol 2007; 102: 738–43.
12 Pe~na LR, Mardini HE, Nickl NJ. Development of an
instrument to assess and predict satisfaction and poor tolerance
among patients undergoing endoscopic procedures. Dig Dis
Sci 2005; 50: 1860–71.
13 Abel M, Eisenkraft JB. Anesthetic implications of myasthenia
gravis. Mt Sinai J Med 2002; 69: 31–7.
14 Ekstein M, Gavish D, Ezri T et al. Monitored anaesthesia care
in the elderly: Guidelines and recommendations. Drugs Aging
2008; 25: 477–500.
15 Travis A, Pievsky D, Saltzman J. Endoscopy in the elderly.
Am J Gastroenterol 2012; 107: 1495–501.
16 Fritz E, Kirchgatterer A, Hubner D et al. ERCP is safe and
effective in patients 80 years of age and older compared with
younger patients. Gastrointest Endosc 2006; 64: 899–905.
17 Katsinelos P, Kountouras J, Chatzimavroudis G et al. Outpa-
tient therapeutic endoscopic retrograde cholangiopancreatog-
raphy is safe in patients aged 80 years and older. Endoscopy
2011; 43: 128–33.
18 Salminen P, Gr€ onroos JM. Anesthesiologist assistance in
endoscopic retrograde cholangiopancreatography procedures
in the elderly: Is it worthwhile? J Laparoendosc Adv Surg
Tech A 2011; 21: 517–9.
19 Liu LL. Conscious sedation in the elderly. In: Wiener-Kronish
JP, Gropper MA (eds). Conscious Sedation. Philadelphia, PA:
Hanley & Belfus, 2001; 105–17.
20 Schnider TW, Minto CF, Shafer SL et al. The influence of age
on propofol pharmacodynamics. Anesthesiology 1999; 90:
1502–16.
21 Bell GD, Spickett GP, Reeve PA et al. Intravenous midazolam
for upper gastrointestinal endoscopy: a study of 800 consec-
utive cases relating dose to age and sex of patient. Br J Clin
Pharmacol 1987; 23: 241–3.
22 Christe C, Janssens JP, Armenian B et al. Midazolam sedation
for upper gastrointestinal endoscopy in older persons: a
randomized, double-blind, placebo-controlled study. J Am
Geriatr Soc 2000; 48: 1398–403.
Digestive Endoscopy 2021; 33: 21–53
23 Heuss LT, Schnieper P, Drewe J et al. Conscious sedation with
propofol in elderly patients: a prospective evaluation. Aliment
Pharmacol Ther 2003; 17: 1493–501.
24 Riphaus A, Stergiou N, Wehrmann T. Sedation with propofol
for routine ERCP in high-risk octogenarians: a randomized,
controlled study. Am J Gastroenterol 2005; 100: 1957–63.
25 ASGE Standard of Practice Committee, Shergill AK, Ben-
Menachem T et al. Guidelines for endoscopy in pregnant and
lactating women. Gastrointest Endosc 2012; 76: 18–24.
26 Dalal PG, Bosak J, Berlin C. Safety of the breast-feeding
infant after maternal anesthesia. Pediatr Anesth 2014; 24:
359–71.
CQ 3: What constitutes suitable monitoring
during sedation?
Statement 3:
Suitable monitoring during sedation constitutes contin-
uous monitoring of a patient’s consciousness level,
respiratory dynamics, and circulatory dynamics.
Assessment based on the modified Delphi method:
median, 9; minimum, 7; maximum, 9
Strength of recommendation: 1, Evidence quality
(strength): B
Textual explanation
Moderate sedation (conscious sedation) is primarily recom-
mended for sedation conducted for the purposes of endo-
scopic examination and treatment,1 and deep sedation may
be necessary depending on the sedation type, treatment
difficulty, treatment duration, and patient conditions2
(Table 8).
Visual examinations and suitable/continuous observations
of respiratory/circulatory dynamics are important with
regard to patient monitoring.3 The frequency of adverse
events is somewhat variable depending on the drug used for
sedation and the depth of sedation, but the basic parameter
needed for monitoring include the consciousness level, pulse
rate, blood pressure, and degree of SpO2.2,4
The ASA Clinical Outcomes Research Initiative database
showed that cardiopulmonary events during endoscopy were
the most important fatal adverse events.5 Suitable patient
monitoring, particularly that of respiratory and circulatory
dynamics, is needed for sedated endoscopy in an endoscopy
facility.
With regard to both moderate and deep sedation, the
physician in charge of the anesthetic needs to begin
Sedation for GI endoscopy 31
assessment of the patient’s consciousness level and vital
signs at the very least prior to anesthesia and must regularly
and continuously conduct this at least every 5 min once
securing the blood vessels, administering the sedative, and
conducting endoscopy until the examination/treatment is
completed and the patient awakens.4 The physician in
charge of the anesthetic can perform short-term treatments
for moderate sedation, but should be focused on continuous
monitoring for deep sedation.1,6
With regard to respiratory system monitoring, direct
monitoring of respiratory status is extremely important, and
auscultation/respiratory rate measurements should also be
conducted as needed. Furthermore, a pulse oximeter is an
important respiration monitor since it can accurately digitize
hypoxemia.7 The ASGE recommends the use of a pulse
oximeter in all endoscopy treatments,4 being particularly
essential during sedated endoscopy. Oxygen administration
should be considered under moderate sedation to prevent
hypoxemia, and it is essential under deep sedation.
Capnography measures the gaseous carbonic acid con-
centration during expiration and has been shown to detect
insufficient ventilation and hypoxemia at an early stage,8,9
but the relationship between temporary hypoxemia and
serious cardiopulmonary events during sedated endoscopy
has not been clarified.10 A report has indicated that
capnography was not able to reduce hypoxemia incidence
during upper and lower endoscopic examinations on healthy
individuals under mild sedation,11 while an RCT reported
that capnography-based monitoring was able to significantly
reduce hypoxemia during lower gastrointestinal endoscopic
examinations with deep sedation.12 Therefore, capnography-
based monitoring should be used during deep sedation.
With regard to the circulatory system, it is important to
monitor arrhythmia and measure blood pressure under deep
sedation,1,13 and both ASA and ASGE guidelines particu-
larly recommend continuous electrocardiogram-based mon-
itoring for patients with serious cardiovascular diseases or
arrhythmia and cases where endoscopy extends over long
periods of time.1,3 Monitoring with higher-accuracy devices,
including blood pressure monitors and electrocardiography
devices, is recommended for sedated endoscopy conducted
in high-risk patients.
In addition, Bispectral index monitoring and brainwave
monitors, both of which measure and objectively quantify
brainwaves, have been used for deep sedation during
endoscopy treatment primarily using propofol. This has
been shown to minimize the risk of over-sedation during
endoscopy treatment14,15 and to reduce the administered
dose of propofol.16,17
Safer sedated endoscopy should be pursued through the
combination of visual examination of the patient,
© 2020 Japan Gastroenterological Endoscopy Society
32 T. Gotoda et al.
Table 8 American Society of Anesthesiologists (ASA) sedation/anesthesia classification
Minimal Moderate sedation/analgesia;
sedation = anxiolysis conscious sedation
Responsiveness Normal response to Purposeful response to verbal
verbal stimulation or tactile stimulation
Airway Unaffected No intervention required
Spontaneous Unaffected Adequate
ventilation
Cardiovascular Unaffected Usually maintained
function
appropriate monitoring of consciousness level and respira-
tory/circulatory dynamics, and the use of various monitoring
devices.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search using the keywords “monitor-
ing”[TIAB] AND “sedation”[TIAB] AND (“Endoscopy,
Digestive System”[MeSH Terms]) AND (English[LA] OR
Japanese[LA]) AND “humans”[MeSH Terms]) yielded 365
articles, of which 43 were meta-analyses/systematic reviews/
clinical guidelines, 164 were clinical trials, 104 were
miscellaneous clinical research/epidemiological research,
one was a Cochrane review, and 16 were controlled trials.
Manual searching added seven articles (including three
clinical guidelines), and screening results yielded 17 related
references, including six RCTs and five clinical guidelines.
REFERENCES
1 American Society of Anesthesiologists Task Force on Sedation
and Analgesia by Non-Anesthesiologists. Practice guidelines
for sedation and analgesia by non-anesthesiologists. Anesthe-
silogy 2002; 96: 1004–17.
2 ASGE Ensuring Safety, in the Gastrointestinal Endoscopy Unit
Task Force, Calderwood AH, Chapman FJ et al. Guidelines for
safety in the gastrointestinal endoscopy unit. Gastrointest
Endosc 2014; 79: 363–72.
3 Standards of Practice Committee of the American Society for
Gastrointestinal Endoscopy, Lichtenstein DR, Jagannath S
et al. Sedation and anesthesia in GI endoscopy. Gastrointest
Endosc 2008; 68: 815–26.
4 ASGE Standards of Practice Committee, Early DS, Lightdale
JR et al. Guidelines for sedation and anesthesia in GI
endoscopy. Gastrointest Endosc 2018; 87: 327–37.
5 Metzner J, Posner KL, Domino KB. The risk and safety of
anesthesia at remote locations: The US closed claims analysis.
Curr Opin Anaesthesiol 2009; 22: 502–8.
6 American Association for Study of Liver Diseases, American
College of Gastroenterology, American Gastroenterological
© 2020 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; 33: 21–53
Deep sedation/analgesia General anesthesia
Purposeful response after Unarousable even
repeated or painful stimulation with painful stimulus
Intervention may be required Intervention often
required
May be inadequate Frequently
inadequate
Usually maintained May be impaired
Association Institute et al. Multisociety sedation curriculum for
gastrointestinal endoscopy. Gastrointest Endosc 2012; 76: e1–
25.
7 Cohen LB, Delegge MH, Aisenberg J et al. AGA Institute
review of endoscopic sedation. Gastroenterology 2007; 133:
675–701.
8 Lightdale JR, Goldmann DA, Feldman HA et al. Microstream
capnography improves patient monitoring during moderate
sedation: a randomized, controlled trial. Pediatrics 2006; 117:
e1170-8.
9 Qadeer MA, Vargo JJ, Dumot JA et al. Capnographic
monitoring of respiratory activity improves safety of sedation
for endoscopic cholangiopancreatography and ultrasonogra-
phy. Gastroenterology 2009; 136: 1568–76.
10 Vargo JJ 2nd. Sedation-related complications in gastrointestinal
endoscopy. Gastrointest Endosc Clin N Am 2015; 25: 147–58.
11 Mehta PP, Kochhar G, Albeldawi M et al. Capnographic
monitoring in routine EGD and colonoscopy with moderate
sedation: a prospective, randomized, controlled trial. Am J
Gastroenterol 2016; 111: 395–404.
12 Friedrich-Rust M, Welte M, Welte C et al. Capnographic
monitoring of propofol-based sedation during colonoscopy.
Endoscopy 2014; 46: 236–44.
13 Maurer WG, Walsh M, Viazis N. Basic requirements for
monitoring sedated patients: Blood pressure, pulse oximetry,
and EKG. Digestion 2010; 82: 87–9.
14 Imagawa A, Fujiki S, Kawahara Y et al. Satisfaction with
bispectral index monitoring of propofol-mediated sedation
during endoscopic submucosal dissection: a prospective,
randomized study. Endoscopy 2008; 40: 905–9.
15 Paspatis GA, Chainaki I, Manolaraki MM et al. Efficacy of
bispectral index monitoring as an adjunct to propofol deep
sedation for ERCP: a randomized controlled trial. Endoscopy
2009; 41: 1046–51.
16 Gotoda T, Okada H, Hori K et al. Propofol sedation with a
target-controlled infusion pump and bispectral index monitor-
ing system in elderly patients during a complex upper
endoscopy procedure. Gastrointest Endosc 2016; 83: 756–64.
17 Park SW, Lee H, Ahn H. Bispectral index versus standard
monitoring in sedation for endoscopic procedures: a system-
atic review and meta-analysis. Dig Dis Sci 2016; 61: 814–24.
Digestive Endoscopy 2021; 33: 21–53
CQ 4: Is a monitoring supervisor necessary
when conducting sedated endoscopy?
Statement 4:
A single monitoring supervisor should be present for
minimal or moderate sedation, and more than one
monitoring supervisor should be present for challenging
endoscopy.
Assessment based on the modified Delphi method:
median, 8.5; minimum, 5; maximum 9
Strength of recommendation: 2, Evidence quality
(strength): D
Textual explanation
Thereareextremelyfewopportunities foranesthesiologists tobe
present during non-intubated endoscopy in Japan relative to the
case in western countries, and the monitoring individual is either
a physician or a nurse. Observational research reportedthe safety
ofmoderate todeepsedationusingpropofoladministeredbyone
endoscopist and one monitoring individual (nurse),1–3 but there
isnoclearevidenceshowingthatthesafetyofsedatedendoscopy
increases with the presence of a monitoring supervisor. How-
ever, various international guidelines recommend that a single
monitoring individual, who can concurrently be responsible for
short-duration duties such as biopsy or polypectomy assistance,
be assigned for endoscopy under minimal or moderate sedation,
and more than one monitoring supervisor be present for
challenging endoscopy.4–7 These limitations do not apply for
patients with complications that fall in the category of ASA-PS
classification III and above (Table 7). In such cases, an
endoscopist and monitoring supervisor should be assigned as
upper-level physicians as needed, anesthesiologists should be
consulted, and the sedation method should be discussed.8 The
monitoring supervisor should use pulse oximetry and electro-
cardiography and continue monitoring the course during the
procedure, as well as duringtransfer fromtheendoscopy room to
the hospital ward.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search using the keywords (“en-
doscopy” or “digestive system”) and (“sedation” or “anal-
gesia”) and (“nurse” or “assistant” or anesthesiologist) and
(“monitoring”) yielded 124 articles, of which 24 were meta-
analyses/systematic reviews/clinical guidelines, 37 were
clinical trials, 59 were miscellaneous clinical research/
epidemiological research, and four were controlled trials.
Sedation for GI endoscopy 33
After manual searching added five articles (including three
clinical guidelines), screening results yielded eight related
references, including four clinical guidelines.
REFERENCES
1 Cohen LB, Dubovsky AN, Aisenberg J et al. Propofol for
endoscopic sedation: a protocol for safe and effective admin-
istration by the gastroenterologist. Gastrointest Endosc 2003;
58: 725–32.
2 Kulling D, Orlandi M, Inauen W. Propofol sedation during
endoscopic procedures: How much staff and monitoring are
necessary? Gastrointest Endosc 2007; 66: 443–9.
3 Yusoff IF, Raymond G, Sahai AV. Endoscopist administered
propofol for upper-GI EUS is safe and effective: a prospective
study in 500 patients. Gastrointest Endosc 2004; 60: 356–60.
4 ASGE Standards of Practice Committee, Jain R, Ikenberry SO
et al. Minimum staffing requirements for the performance of
GI endoscopy. Gastrointest Endosc 2010; 72: 469–70.
5 ASGE Standards of Practice Committee, Early DS, Lightdale
JR et al. Guidelines for sedation and anesthesia in GI
endoscopy. Gastrointest Endosc 2018; 87: 327–37.
6 Cohen LB, Delegge MH, Aisenberg J et al. AGA Institute review
of endoscopic sedation. Gastroenterology 2007; 133: 675–701.
7 Cohen LB, Ladas SD, Vargo JJ et al. Sedation in digestive
endoscopy: The Athens international position statements.
Aliment Pharmacol Ther 2010; 32: 425–42.
8 Standards of Practice Committee of the American Society for
Gastrointestinal Endoscopy, Lichtenstein DR, Jagannath S
et al. Sedation and anesthesia in GI endoscopy. Gastrointest
Endosc 2008; 68: 815–26.
CQ 5: How should monitoring release during
sedated endoscopy be ascertained?
Statement 5:
Monitoring release (discharge) standards have not been
established, but this should be determined upon assess-
ment of the patient’s consciousness level, respiratory
dynamics, and circulatory dynamics.
Assessment based on the modified Delphi method:
median, 8; minimum, 7; maximum, 9
Strength of recommendation: 2, Evidence quality
(strength): D
Textual explanation
The observer’s assessment of alertness/sedation (OAA/S)
scale1 and the Ramsay sedation score2 are used to assess
© 2020 Japan Gastroenterological Endoscopy Society
34 T. Gotoda et al. Digestive Endoscopy 2021; 33: 21–53

sedation/analgesia levels. The Aldrete score,3 postanesthetic The databases used for this reference extraction were
discharge scoring system (PADSS),4 and the modified post- PubMed, Cochrane Library database, and Japan Medical
anesthesia discharge scoring system (MPADSS)5 are scores Abstract Society. A search using the keywords (“en-
often used as standards for monitoring release (discharge) in doscopy”) and (“sedation”) and (recovery assessment)
endoscopy. Table 9 shows the Aldrete score, which yielded 148 articles, of which nine were meta-analyses/
comprises five parameters (respiration, SpO2, consciousness systematic reviews/clinical guidelines, 88 were clinical
level, circulation, activity), and where discharge standards trials, 49 were miscellaneous clinical research/epidemiolog-
are satisfied with a score of 9 or higher. These standards are ical research, and two were controlled trials. After manual
used when assessing the recovery time from sedation in searching added six articles (including RCTs), screening
RCTs assessing sedative efficacy. The efficacy of these results yielded seven related references.
scores has only been verified with a relatively small number
of prospective trials.6 As such, further investigations are REFERENCES
needed to assess the efficacy of these scores.
Willey et al.7 used the Aldrete score to assess the 1 Chernik DA, Gillings D, Laine H et al. Validity and reliability
of the observer’s assessment of alertness/sedation scale: Study
discharge standards of 31 patients who underwent sedated
with intravenous midazolam. J Clin Psychopharmacol 1990;
upper gastrointestinal endoscopy during outpatient care.
10: 244–51.
Results showed that of the patients whose discharge 2 Ramsay MA, Savege TM, Simpson BR et al. Controlled
standards were satisfied, 60–70% showed a recovery of sedation with alphaxalone-alphadolone. Br Med J 1974; 2:
psychomotor function. 656–9.
Based on the above findings, it must be stated that 3 Aldrete JA, Kroulik D. A postanesthetic recovery score.
monitoring release (discharge) standards following sedated Anesth Analg 1970; 49: 924–34.
endoscopy have not been established, but monitoring release 4 Chung F, Chan VW, Ong D. A post-anesthetic discharge
should be determined by assessing the patient’s conscious- scoring system for home readiness after ambulatory surgery. J
ness level, respiration dynamics, SpO2, circulation, and Clin Anesth 1995; 7: 500–6.
activity (motor function), and assessments at the time of 5 Chung F. Discharge criteria–a new trend. Can J Anaesth 1995;
42: 1056–8.
determination should be written in clinical records.
Table 9 Aldrete score 6 Amornyotin S, Chalayonnavin W, Kongphlay S. Recovery
pattern and home-readiness after ambulatory gastrointestinal
Parameter Standard Points endoscopy. J Med Assoc Thai 2007; 90: 2352–8.
Respiration Able to breathe deeply and cough 2 7 Willey J, Vargo JJ, Connor JT et al. Quantitative assessment of
Dyspnea or shallow breathing 1 psychomotor recovery after sedation and analgesia for outpa-
Apnea 0 tient EGD. Gastrointest Endosc 2002; 56: 810–6.
Oxygen Maintains >92% on room air 2
saturation Needs O2 inhalation to maintain O2 1
CQ 6: Is sedation training for endoscopists
(SpO2) saturation ≧90%
SpO2 <90% (with supplemental 0
and endoscopy staff recommended?
oxygen administered) Statement 6:
Consciousness Fully awake 2
level Arousable upon calling 1
Not responding 0
Circulation Blood pressure 20 mmHg 2 Sedation training is recommended for endoscopists and
(relative to pre-operation standard endoscopy staff who perform sedation.
value) Assessment based on the modified Delphi method:
Blood pressure 20–50 mmHg 1 median, 7.5; minimum, 5; maximum, 9
(relative to the pre-procedural
Strength of recommendation: 2, Evidence quality
standard value)
(strength): D
Blood pressure 50 mmHg 0
(relative to the pre-procedural
standard value)
Activity Able to move the four extremities 2
Able to move two extremities 1 Textual explanation
Cannot move the four extremities 0 To provide safe and appropriate endoscopic sedation,
Discharge standards satisfied if score is 9 or above. knowledge of the level of sedation appropriate for each

© 2020 Japan Gastroenterological Endoscopy Society

Digestive Endoscopy 2021; 33: 21–53
endoscopic procedure, as well as the management of
sedation-related adverse events (even though they have a
low frequency), is required. Sedation training should
involve basic knowledge on pre-sedative assessment, the
level of sedation appropriate for endoscopic procedures,
sedative drug/monitoring, recovery care and discharge, and
sedative antagonists, as well as basic life support (BLS) and
advanced cardiovascular life support (ACLS) certifications
to provide emergency management of cardiopulmonary
events. The training curriculum for sedation for endoscopic
procedures has been published by the Multisociety Sedation
Curriculum for Gastrointestinal Endoscopy (MSCGE)1 and
the European Society of Gastrointestinal Endoscopy/Euro-
pean Society of Gastroenterology and Endoscopy Nurses
and Associates (ESGE/ESGENA).2 There is some variation
in the content of the two documents, but each curriculum
includes BLS or ACLS as an item for the training
curriculum to manage adverse events during sedation. Some
research has shown the improvement of sedation-related
knowledge through the use of training curricula,3 but to
date, no reports have demonstrated that these resulted in
improvement in sedation safety or efficacy itself. However,
considering safety aspects such as the management of
adverse events, endoscopists or endoscopy staff who
provide sedation are recommended to undergo training.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search using the keywords “endoscopy”
and “sedation” and (“preoperative care” or “preprocedural
assessment” or “risk assessment” or “patient evaluation”)
yielded 65 articles, of which eight were meta-analyses/
systematic reviews/clinical guidelines, five were clinical
trials, 40 were miscellaneous clinical research/epidemiolog-
ical research, and 12 were controlled trials. After manual
searching added three articles, screening results yielded
three related references, including verification research.
REFERENCES
1 American Association for Study of Liver Diseases, American
College of Gastroenterology, American Gastroenterological
Association Institute et al. Multisociety sedation curriculum
for gastrointestinal endoscopy. Gastrointest Endosc 2012; 76:
e1–25.
2 Dumonceau JM, Riphaus A, Beilenhoff U et al. European
curriculum for sedation training in gastrointestinal endoscopy:
Position statement of the European Society of Gastrointestinal
Endoscopy (ESGE) and European Society of Gastroenterology
and Endoscopy Nurses and Associates (ESGENA). Endoscopy
2013; 45: 496–504.
3 Jensen JT, Savran MM, Møller AM et al. Development and
validation of a theoretical test in non-anaesthesiologist-
Sedation for GI endoscopy 35
administered propofol sedation for gastrointestinal endoscopy.
Scand J Gastroenterol. 2016; 51: 872–9.
CQ 7: What are suitable sedation methods
during emergency endoscopy?
Statement 7:
Secure monitoring should be conducted, and antagonist
sedatives or those with a short half-life should be used
under an environment where emergency treatment can be
conducted.
Assessment based on the modified Delphi method:
median, 8; minimum, 7; maximum, 9
Strength of recommendation: 2, Evidence quality
(strength): D
Textual explanation
Sedation is thought to be effective for conducting safe and
secure emergency treatment if vital signs are stable, partic-
ularly when the patient is in an agitated or anxious state,1 but
sedation may not be effective depending on the patient’s PS
or extent of symptoms.2 Sedation control or monitoring by
anesthesiologists, emergency physicians, or intensive treat-
ment physicians is particularly recommended for emergency
endoscopy similar to that conducted under intubation.
When performing sedation, it is desirable to secure blood
vessels and to confirm oxygen saturation, blood pressure,
heart rate, respiration rate, etc., with a biological monitor to
ensure safety.3,4 It is also important that the sedation
supervisor name, supervisory nurse name, sedative name,
administered dose, administration route, administered dose
of oxygen, etc., all be recorded.
Recently, endoscopy treatment using CO2 supply insuf-
flation under sedation has been widely performed, but this
poses a risk of CO2 accumulation; hence, capnography-
based monitoring and non-invasive continuous transcuta-
neous CO2 partial pressure monitors have been considered
useful for early-stage detection of hypercapnia.5,6
Commonly used drugs include diazepam, midazolam, and
flunitrazepam for sedatives with antagonists, and pethidine
hydrochloride and pentazocine for analgesics. The adminis-
tered dose should be carefully determined by considering the
clinical conditions, including the patient’s PS, age, weight,
type of treatment, and the predicted treatment duration.
Recently, it has been reported that drugs such as propofol
have an equivalent or greater effect and safety than sedation
© 2020 Japan Gastroenterological Endoscopy Society
36 T. Gotoda et al.
caused by small doses of benzodiazepine drugs,6–15 and that
safe endoscopy treatment with minimal respiratory suppression
or rough body movements can be conducted with dexmedeto-
midine hydrochloride sedation,16,17 and these drugs may be
effective for emergency endoscopy as well. However, care
must be taken with regard to bradycardia arrhythmia or
respiratory suppression/hypotension caused by dexmedeto-
midine hydrochloride or propofol, respectively. Accordingly,
monitoring supervisors need to be present to conduct suitable
monitoring and circulatory dynamics management, and seda-
tion should be conducted while rapidly ensuring airway
maintenance and conducting airway intubation.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search using the keywords (“emergency
endoscopy” or “urgent endoscopy”) and (“appropriate
sedation” or “analgesia” or “anesthesia”) and “safety” and
(“utility” or “availability”) yielded 271 articles, of which 18
were meta-analyses/systematic reviews/clinical guidelines,
83 were clinical trials, 116 were miscellaneous clinical
research/epidemiological research, two were Cochrane
reviews, and 52 were controlled trials. After manual
searching added 17 articles (including six RCTs relating to
adverse outcomes), screening results yielded 19 related
references, including six RCTs and one clinical guideline.
REFERENCES
1 Waye JD. Intubation and sedation in patients who have
emergency upper GI endoscopy for GI bleeding. Gastrointest
Endosc 2000; 51: 768–71.
2 Duch P, Haahr C, Møller MH et al. Anaesthesia care for
emergency endoscopy for peptic ulcer bleeding. A nationwide
population-based cohort study. Scand J Gastroenterol 2016;
51: 1000–6.
3 Berg JC, Miller R, Burkhalter E. Clinical value of pulse
oximetry during routine diagnostic and therapeutic endoscopic
procedure. Endoscopy 1991; 23: 328–30.
4 Iber FL, Sutberry M, Gupta R et al. Evaluation of complica-
tions during and after conscious sedation for endoscopy using
pulse oximetry. Gastrointest Endosc 1993; 39: 620–5.
5 Jopling MW, Qiu J, Capnography sensor use is associated with
reduction of adverse outcomes during gastrointestinal endo-
scopic procedures with sedation administration. BMC Anes-
thesiol 2017; 17: 157.
6 Miyoshi H, Shimatani M, Kato K et al. Transcutaneous
monitoring of partial pressure of carbon dioxide during
endoscopic retrograde cholangiopancreatography using a
double-balloon endoscope with carbon dioxide insufflation
under conscious sedation. Dig Endosc 2014; 26: 436–41.
7 Krugliak P, Ziff B, Rusabrov Y et al. Propofol versus
midazolam for conscious sedation guided by processed EEG
during endoscopic retrograde cholangiopancreatography: a
© 2020 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; 33: 21–53
prospective, randomized, double-blind study. Endoscopy
2000; 32: 677–82.
8 Vargo JJ, Zuccaro G Jr, Dumot JA et al. Gastroenterologist-
administered propofol versus meperidine and midazolam for
advanced upper endoscopy: a prospective, randomized trial.
Gastroenterol 2002; 123: 8–16.
9 Tohda G, Higashi S, Sakumoto H et al. Efficacy and safety of
nurse-administered propofol sedation during emergency upper
endoscopy for gastrointestinal bleeding: a prospective study.
Endoscopy 2006; 38: 684–9.
10 Imagawa A, Fujiki S, Kawahara Y et al. Satisfaction with
bispectral index monitoring of propofol-mediated sedation
during endoscopic submucosal dissection: a prospective,
randomized study. Endoscopy 2008; 40: 905–9.
11 Paspatis GA, Manolaraki MM, Vardas E et al. Deep sedation
for endoscopic retrograde cholangiopancreatography: Intra-
venous propofol alone versus intravenous propofol with oral
midazolam premedication. Endoscopy 2008; 40: 308–13.
12 Thanvi BR, Munshi SK, Vijayakumar N et al. Acceptability of
oesophagogastroduodenoscopy without intravenous sedation:
Patients’ versus endoscopist’s perception with special refer-
ence to older patients. Postgrad Med J 2003; 79: 650–1.
13 Horiuchi A, Nakayama Y, Tanaka N et al. Propofol sedation
for endoscopic procedures in patients 90 years of age and
older. Digestion 2008; 78: 20–3.
14 Schilling D, Rosenbaum A, Schweizer S et al. Sedation with
propofol for interventional endoscopy by trained nurses in
high-risk octogenarians: a prospective, randomized, controlled
study. Endoscopy 2009; 41: 295–8.
15 Aviv JE. Effects of aging on sensitivity of the pharyngeal and
supraglottic areas. Am J Med 1997; 103: 74S–S76.
16 Yin S, Hong J, Sha T et al. Efficacy and tolerability of
sufentanil, dexmedetomidine, or ketamine added to propofol-
based sedation for gastrointestinal endoscopy in elderly
patients: A prospective, randomized, controlled trial. Clin
Ther 2019; 41: 1864–77.
17 Chang ET, Certal V, Song SA et al. Dexmedetomidine versus
propofol during drug-induced sleep endoscopy and sedation: a
systematic review. Sleep Breath 2017; 21: 727–35.
CQ 8: Do sedatives contribute to transoral
endoscopy?
Statement 8:
Sedatives improve the receptivity and satisfaction of
transoral endoscopy and contribute to improved exam-
ination/treatment performance.
Assessment based on the modified Delphi method:
median, 9; minimum, 8; maximum, 9
Strength of recommendation: 2, Evidence quality
(strength): A
Digestive Endoscopy 2021; 33: 21–53
Textual explanation
Adverse events like hypoxemia or hypotension can occur
during sedation; therefore, maintaining observations and the
depth of sedation is important when conducting transoral
sedated endoscopic examination and treatment, and further
care must be taken for adverse outcomes when sedating
seniors or patients with numerous comorbid disorders.
Many reports have indicated the efficacy of sedation
during transoral endoscopic examinations from the perspec-
tive of the patient, and meta-analyses have shown that
endoscopic examination under transoral sedation results in
decreased discomfort/anxiety, improved patient satisfaction,
and increased requests for re-examination.1
Sedation is effective from the perspective of the endo-
scopist as well, and RCTs have shown improved endo-
scopist satisfaction in upper gastrointestinal endoscopic
examinations.2 In contrast, there have been no trials
comparing the use of sedatives during transoral endoscopy
treatment, but this was thought to be because long-duration
transoral endoscopy treatment is usually conducted under
sedation. Western guidelines state that sedation is effective
in improving endoscopy diagnosis quality and achieving the
goals of treatment.3,4
The frequency with which sedation is used for transoral
endoscopic examination is expected to increase in the future
due to the increase in global awareness of sedation concepts.
However, generalized conclusions cannot be made since
decisions on whether to use sedation are influenced by
differences in the sociocultural backgrounds of countries
and regions, patient expectations, cost effectiveness, and
facility conditions. The medical staff should sufficiently
explain the efficacy and adverse events associated with
sedation prior to endoscopy, allow the patient to decide
whether to use sedation after considering clinical safety, and
respect this decision.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search using the keywords (“en-
doscopy” or “endoscopic” or “esophagogastroduo-
denoscopy” or “enteroscopy”) and (“routine” or
“diagnosis” or “therapy” or “therapeutics”) and (“sedation”
or “anesthesia” or “analgesia”) and (“quality” or “efficacy”
or “time” or “acceptance” or “tolerance” or “satisfaction” or
“pain” or “detection” or “complication”) yielded 664
articles, of which 65 were meta-analyses/systematic
reviews/clinical guidelines, 268 were clinical trials, 281
were miscellaneous clinical research/epidemiological
research, and 50 were controlled trials. After manual
searching added two national studies relating to adverse
Sedation for GI endoscopy 37
outcomes, screening results yielded six related references,
including one systematic review and two clinical guidelines.
REFERENCES
1 McQuaid KR, Laine L. A systematic review and meta-analysis
of randomized, controlled trials of moderate sedation for
routine endoscopic procedures. Gastrointest Endosc 2008; 67:
910–23.
2 Kashiwagi K, Hosoe N, Takahashi K et al. Prospective,
randomized, placebo-controlled trial evaluating the efficacy
and safety of propofol sedation by anesthesiologists and
gastroenterologist-led teams using computer-assisted person-
alized sedation during upper and lower gastrointestinal
endoscopy. Dig Endosc 2016; 28: 657–64.
3 Cohen LB, Ladas SD, Vargo JJ et al. Sedation in digestive
endoscopy: The Athens international position statements.
Aliment Pharmacol Ther 2010; 32: 425–42.
4 Cohen LB, Delegge MH, Aisenberg J et al. AGA Institute
review of endoscopic sedation. Gastroenterology 2007; 133:
675–701.
CQ 9: Do sedatives contribute to transanal
endoscopy?
Statement 9:
Sedatives reduce anxiety and pain during transanal
endoscopy, contribute to increased satisfaction, and
contribute to improved examination/treatment perfor-
mance.
Assessment based on the modified Delphi method:
median, 7; minimum, 5; maximum, 9
Strength of recommendation: 2, Evidence quality
(strength): C
Textual explanation
From the perspective of the patient, sedation has been
shown to decrease the pain and anxiety associated with
transanal endoscopy, increase patient satisfaction, and
increase requests for re-examination.1,2 Sedation is partic-
ularly effective in women, younger patients, patients with
lower body mass indices, patients with a history of surgery
for gynecological diseases, and patients with high anxiety
prior to medical procedures.3–5 Meanwhile, some patients
were satisfied without sedation during transanal endoscopic
examinations. Sedative use should be based according to the
© 2020 Japan Gastroenterological Endoscopy Society
38 T. Gotoda et al.
patient’s decision, but there are regions or facilities where
sedation cannot always be safely administered. With regard
to adverse events, it is important to maintain suitable
observations and an appropriate depth of sedation since the
frequency of hypoxemia and hypotension increases with
sedation. Recent reports have indicated that the incidence of
adverse outcomes like aspiration pneumonia increased
during transanal endoscopic examinations under general
anesthesia or anesthetic assistance compared to other
examinations under sedation,7,8 and care should be taken
on this aspect.
From the perspective of the endoscopist, sedation
increases endoscopist satisfaction during transanal endo-
scopy.2,9 Western guidelines also indicate that sedation is
effective in improving diagnosis quality and achieving
treatment objectives,10,11 and that the cecal intubation rate
during transanal endoscopic examination is particularly
better in women.12 Meanwhile, sedation has been shown to
not improve intubation difficulties, reduce the cecal intuba-
tion time, or improve polyp discovery rates during exam-
ination.12,13
The frequency with which sedation will be used in transanal
endoscopy is expected to continue increasing in the future.
Regional and facility-based conditions need to be considered
in sedation use, but medical staff should investigate adjust-
ments based on sedation efficacy and adverse outcomes and
sufficiently respect the decision of patients with regard to
sedation use after considering clinical safety.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search using the keywords (“colono-
scopy” or “enteroscopy”) and (“routine” or “diagnosis” or
“therapy” or “therapeutics”) and (“sedation” or “anesthesia”
or “analgesia”) and (“quality” or “efficacy” or “time” or
“acceptance” or “tolerance” or “satisfaction” or “pain” or
“detection” or “complication”) yielded 514 articles, of
which 32 were meta-analyses/systematic reviews/clinical
guidelines, 163 were clinical trials, 196 were miscellaneous
clinical research/epidemiological research, and 123 were
controlled trials. After manual searching added six articles
(including two national reports relating to adverse out-
comes), screening results yielded 15 related references,
including three RCTs and one clinical guideline.
REFERENCES
1 Baudet JS, Aguirre-Jaime A. The sedation increases the
acceptance of repeat colonoscopies. Eur J Gastroenterol
Hepatol 2012; 24: 775–80.
2 Kinugasa H, Higashi R, Miyahara K et al. Dexmedetomidine
for conscious sedation with colorectal endoscopic submucosal
© 2020 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; 33: 21–53
dissection: a prospective double-blind randomized controlled
study. Clin Transl Gastroenterol 2018; 9: e167.
3 Takahashi Y, Tanaka H, Kinjo M et al. Sedation-free
colonoscopy. Dis Colon Rectum 2005; 48: 855–9.
4 Park DI, Kim HJ, Park JH et al. Factors affecting abdominal
pain during colonoscopy. Eur J Gastroenterol Hepatol 2007;
19: 695–9.
5 Eckardt AJ, Swales C, Bhattacharya K et al. Open access
colonoscopy in the training setting: Which factors affect
patient satisfaction and pain? Endoscopy 2008; 40: 98–105.
6 Paggi S, Radaelli F, Amato A et al. Unsedated colonoscopy:
An option for some but not for all. Gastrointest Endosc 2012;
75: 392–8.
7 Wernli KJ, Brenner AT, Rutter CM et al. Risks associated with
anesthesia services during colonoscopy. Gastroenterology
2016; 150: 888–94.
8 Bielawska B, Hookey LC, Sutradhar R et al. Anesthesia
assistance in outpatient colonoscopy and risk of aspiration
pneumonia, bowel perforation, and splenic injury. Gastroen-
terology 2018; 154: 77–85.e3.
9 Kashiwagi K, Hosoe N, Takahashi K et al. Prospective,
randomized, placebo-controlled trial evaluating the efficacy
and safety of propofol sedation by anesthesiologists and
gastroenterologist-led teams using computer-assisted person-
alized sedation during upper and lower gastrointestinal
endoscopy. Dig Endosc 2016; 28: 657–64.
10 Cohen LB, Ladas SD, Vargo JJ et al. Sedation in digestive
endoscopy: The Athens international position statements.
Aliment Pharmacol Ther 2010; 32: 425–42.
11 Cohen LB, Delegge MH, Aisenberg J et al. AGA Institute
review of endoscopic sedation. Gastroenterology 2007; 133:
675–701.
12 Bannert C, Reinhart K, Dunkler D et al. Sedation in screening
colonoscopy: Impact on quality indicators and complications.
Am J Gastroenterol 2012; 107: 1837–48.
13 Ristikankare M, Hartikainen J, Heikkinen M et al. Is routinely
given conscious sedation of benefit during colonoscopy?
Gastrointest Endosc 1999; 49: 566–72.
CQ 10: What is a suitable benzodiazepine
drug for transoral endoscopy?
Statement 10:
Among midazolam, diazepam, and flunitrazepam, mida-
zolam is proposed for its sedative effects and patient
satisfaction.
Assessment based on the modified Delphi method:
median, 8; minimum, 6; maximum, 9
Strength of recommendation: 2, Evidence quality
(strength): C
Digestive Endoscopy 2021; 33: 21–53
Textual explanation
Intravenously administered benzodiazepine drugs that can
be used for transoral endoscopy in Japan include midazolam
(Dormicumâ), diazepam (Cercineâ, Horizonâ), and fluni-
trazepam (Sileceâ, Rohypnolâ).1 Among four RCTs com-
paring patients sedated with benzodiazepine drugs and those
who were not sedated during upper gastrointestinal endo-
scopy, two RCTs compared patients who were not sedated,
those sedated with midazolam, and those sedated with
diazepam2,3; one RCT compared patients who were not
sedated and those sedated with midazolam4; and one RCT
compared patients who were not sedated and those sedated
with flunitrazepam.5 Midazolam was shown to be effective
in improving patient satisfaction, inducing amnesia effects
under the examination procedure, decreasing phlebitis, and
decreasing difficulties for the operator in endoscope inser-
tion or examination relative to diazepam.2,3 Meanwhile, the
rate of requests for the same sedative during re-examination
was somewhat higher with midazolam, and amnesia effects
under examination were significantly higher for midazo-
lam.4 A report has also indicated that low oxygen doses are
ideal since midazolam administration results in a lower
SpO2 compared to that with non-sedation or diazepam
use.5,6 Meanwhile, a meta-analysis on midazolam showed
that only its amnesia effects under examination were
significantly different when compared to diazepam, and no
significant differences were observed for procedure anxiety,
discomfort, and pain.7 A side effect of benzodiazepine drugs
is restlessness, but the same report indicated that there were
no differences for non-cooperativeness for the examination
procedure between the two drugs.
Randomized controlled trials in Japan that used fluni-
trazepam showed that patient satisfaction improved relative
to a placebo for both low (0.25 mg) and normal (0.50 mg)
flunitrazepam dose groups. The low-dose group also showed
no respiratory suppression with an SpO2 below 90%.8
Reports also indicated that amnesia effects under examina-
tion were significantly higher in the normal dose group.
The ASGE, Spanish Endoscopy Society (SEED), and
German Society for Digestive and Metabolic Diseases
(DGVS) guidelines all indicated that diazepam and mida-
zolam can be ordinarily used as a benzodiazepine drug, but
rapid expression of effects, low phlebitis, short duration of
expression of effects, and high amnesia effects under
examination with midazolam sedation have been raised as
differences between the two drugs.9–11
From the above, midazolam is weakly recommended as
the optimal benzodiazepine drug for transoral endoscopy
owing to the large amount of evidence in its favor, its
sedation effects, and patient satisfaction. However, the drug
Sedation for GI endoscopy 39
to be used should be determined after considering the fact
that regional or facility-based conditions may result in
differences in the drugs that can be used.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search using the keywords (“benzodi-
azepines”[MeSH Terms] AND (“endoscopy, digestive sys-
tem”[MeSH Terms]) AND English[All Fields] AND
(“humans”[MeSH Terms] AND (“diagnosis”[MeSH
Terms]) yielded 190 articles, of which 17 were meta-
analyses/systematic reviews/clinical guidelines, 95 were
clinical trials, 73 were miscellaneous clinical research/
epidemiological research, and five were controlled trials.
Manual searching added six articles (including three RCTs),
and screening results yielded 11 related references, includ-
ing two clinical guidelines.
REFERENCES
1 Obara K, Haruma K, Irisawa A et al. Guidelines for sedation
in gastroenterological endoscopy. Dig Endosc 2015; 27: 435–
49.
2 Lee MG, Hanna W, Harding H. Sedation for upper gastroin-
testinal endoscopy: A comparative study of midazolam and
diazepam. Gastrointest Endosc 1989; 35: 82–4.
3 Patterson KW, Noonan N, Kirkham R et al. Hypoxemia during
outpatient gastrointestinal endoscopy: The effects of sedation
and supplemental oxygen. J Clin Anesth 1995; 7: 136–40.
4 Bell GD, Morden A, Coady T et al. A comparison of diazepam
and midazolam as endoscopy premedication assessing changes
in ventilation and oxygen saturation. Br J Clin Pharmacol
1988; 26: 595–600.
5 Hennessy MJ, Kirkby KC, Montgomery IM. Comparison of
the amnestic effects of midazolam and diazepam. Psychophar-
macology 1991; 103: 545–50.
6 Bardhan KD, Morris P, Taylor PC et al. Intravenous sedation
for upper gastrointestinal endoscopy: Diazepam versus mida-
zolam. Br Med J (Clin Res Ed) 1984; 288: 1046.
7 Conway A, Rolley J, Sutherland JR. Midazolam for sedation
before procedures. Cochrane Database Syst Rev 2016:
CD009491.
8 Yoshizawa T, Miwa H, Kojima T et al. Low-dose
flunitrazepam for conscious sedation for EGD: a randomized
double-blind placebo-controlled study. Gastrointest Endosc
2003; 58: 523–30.
9 ASGE Standards of Practice Committee, Early DS, Lightdale
JR et al. Guidelines for sedation and anesthesia in GI
endoscopy. Gastrointest Endosc 2018; 87: 327–37.
10 Igea F, Casellas JA, Gonzalez-Huix F et al. Sedation for
gastrointestinal endoscopy. Endoscopy 2014; 46: 720–31.
11 Riphaus A, Wehrmann T, Hausmann J et al. Update S3-
guideline: "sedation for gastrointestinal endoscopy" 2014
(AWMF-register-no. 021/014). Z Gastroenterol 2016; 54:
58–95.
© 2020 Japan Gastroenterological Endoscopy Society
40 T. Gotoda et al.
CQ 11: What is a suitable benzodiazepine
drug for transanal endoscopy?
Statement 11:
Among midazolam, diazepam, and flunitrazepam, mida-
zolam is proposed for its sedative effects and patient
satisfaction.
Assessment based on the modified Delphi method:
median, 8; minimum, 6; maximum 9
Strength of recommendation: 2, Evidence quality
(strength): C
Textual explanation
Intravenously administered benzodiazepine drugs that can
be used for transanal endoscopy in Japan include midazolam
(Dormicumâ), diazepam (Cercineâ, Horizonâ), and fluni-
trazepam (Sileceâ, Rohypnolâ).1 Three RCTs using intra-
venously administered benzodiazepine drugs related to
transanal endoscopy have been conducted, and RCTs that
compared midazolam and placebos showed no differences
in patient pain/discomfort or difficulty/examination time
perceived by the endoscopist between the midazolam group
and placebo group.2 However, the same research indicated
that the administered dose of midazolam was adjusted
between 0.03 and 0.05 mg/kg according to age (e.g.,
2.4 mg/body if patient was 60 years old and 60 kg) and
that the administered dose was somewhat small. Meanwhile,
two RCTs compared midazolam and diazepam, where one
RCT showed that the two drugs had similar results with
regard to sedation extent, tolerance of the examination
procedure, and recovery rate, but that midazolam had
significantly higher amnesia effects under examination.3
Midazolam is thought to be recommended somewhat more
often in transanal endoscopic examinations for this reason.
Furthermore, other RCTs investigated adverse events in the
venous system due to the two drugs, which showed that
diazepam caused a significantly higher frequency of
phlebitis, particularly pain in the injection area (35% vs.
7%), relative to midazolam, and accordingly, midazolam has
been more strongly recommended for these reasons.4
American Society for Gastrointestinal Endoscopy, SEED,
and DGVS guidelines all indicated that diazepam and
midazolam can be ordinarily used as a benzodiazepine drug,
but rapid expression of effects, low phlebitis, short duration
of expression of effects, and high amnesia effects under
examination with midazolam sedation have been raised as
© 2020 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; 33: 21–53
differences between the two drugs.5–7 Meanwhile, although
there have been numerous studies in the West on the
combined use of benzodiazepine drugs with analgesics in
colonoscopy examinations, there has been little research on
benzodiazepine drugs alone, with a limited body of evidence
for this. Actual Japanese endoscopists have also indicated
that benzodiazepine drug use by itself can result in severe
pain in the patient; thus, the combined use of analgesics like
pethidine hydrochloride and pentazocine is not uncommon.
From the above, midazolam is weakly recommended as
the optimal benzodiazepine drug for transanal endoscopy
due to its sedation effects and patient satisfaction. However,
the drug to be used should be determined after considering
the fact that regional or facility-based conditions may result
in differences in the drugs that can be used.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search using the keywords (“benzodi-
azepines”[MeSH Terms] AND (“colonoscopy”[MeSH
Terms] AND English[All Fields] AND (“humans”[MeSH
Terms] AND (“diagnosis”[MeSH Terms]) yielded 143
articles, of which nine were meta-analyses/systematic
reviews/clinical guidelines, 77 were clinical trials, 55 were
miscellaneous clinical research/epidemiological research,
and two were controlled trials. After manual searching
added seven articles (including three RCTs and four
clinical guidelines), screening results yielded seven related
references, including three RCTs and four clinical guide-
lines.
REFERENCES
1 Obara K, Haruma K, Irisawa A et al. Guidelines for sedation in
gastroenterological endoscopy. Dig Endosc 2015; 27: 435–49.
2 Ristikankare M, Hartikainen J, Heikkinen M et al. Is routinely
given conscious sedation of benefit during colonoscopy?
Gastrointest Endosc 1999; 49: 566–72.
3 Macken E, Gevers AM, Hendrickx A et al. Midazolam versus
diazepam in lipid emulsion as conscious sedation for
colonoscopy with or without reversal of sedation with
flumazenil. Gastrointest Endosc 1998; 47: 57–61.
4 Carrougher JG, Kadakia S, Shaffer RT et al. Venous compli-
cations of midazolam versus diazepam. Gastrointest Endosc
1993; 39: 396–9.
5 ASGE Standards of Practice Committee, Early DS, Lightdale
JR et al. Guidelines for sedation and anesthesia in GI
endoscopy. Gastrointest Endosc 2018; 87: 327–37.
6 Igea F, Casellas JA, Gonzalez-Huix F et al. Sedation for
gastrointestinal endoscopy. Endoscopy 2014; 46: 720–31.
7 Riphaus A, Wehrmann T, Hausmann J et al. Update S3-
guideline: "sedation for gastrointestinal endoscopy" 2014
(AWMF-register-no. 021/014). Z Gastroenterol 2016; 54:
58–95.
Digestive Endoscopy 2021; 33: 21–53
CQ 12: What is a suitable benzodiazepine
drug when undergoing transoral endoscopy
treatment?
Statement 12:
There is no evidence related to benzodiazepine drug
selection.
Assessment based on the modified Delphi method:
median, 8; minimum, 7; maximum 9
Strength of recommendation: none, Evidence qual-
ity (strength): D
Textual explanation
Transoral endoscopy treatments include EMR/ESD, endo-
scopic balloon dilation (EBD), gastrointestinal stenting,
endoscopic gastrostomy, endoscopic retrograde cholan-
giopancreatography (ERCP), endoscopic ultrasonography
(EUS; including EUS with fine-needle aspiration; FNA),
interventional EUS, and transoral enteroscopy. The extent of
pain, required time, and procedural difficulty of transoral
endoscopy treatment vary according to each procedure.
Internationally, transoral endoscopy treatment is primarily
managed under intravenous anesthesia combined with
analgesics like propofol or fentanyl and administered by
anesthesiologists, or general anesthesia with tracheal intu-
bation, with the latter particularly recommended in patients
with a high risk of pulmonary aspiration, such as in cases of
upper gastrointestinal hemorrhaging or gastric content
retention.1,2
Intravenously administered benzodiazepine drugs are
widely used in Japan for transoral endoscopy treatment,
and drugs like midazolam, diazepam, and flunitrazepam can
be selected for these purposes. However, none of these
drugs have received approval for insured use in sedation
during endoscopy, and at present, these drugs are used
without insurance coverage.3 Sedation using benzodiazepine
drugs or analgesics like pethidine hydrochloride singly is
often performed for short-duration and relatively painless
endoscopy treatment. Meanwhile, moderate or deep sedation
is needed to safely and securely conduct long-duration
transoral endoscopy treatments like ESD, and benzodi-
azepine drugs together with analgesics are widely used.
Among benzodiazepine drugs, midazolam has been widely
used internationally for moderate sedation during gastroin-
testinal endoscopic examinations.1,2 A prospective trial of
endoscopy sedation with around 4–5 mg of midazolam and
Sedation for GI endoscopy 41
70–100 mg of pethidine hydrochloride indicated that the
onset of deep sedation (see Table 7) accompanying respi-
ratory suppression was up to 85% in ERCP. Alongside EUS,
ERCP has been reported to be an independent risk factor for
deep sedation, and careful observations and monitoring are
needed.4
With regard to transoral endoscopic examination, mida-
zolam efficacy (e.g., amnesia effects under examination and
reduction of phlebitis) has been reported to be superior to
that of diazepam.5–7 However, there have not been any
reports up until now that directly compared benzodiazepine
drugs in sedation during transoral endoscopy treatment.
There is no clear evidence related to the selection of
benzodiazepine drugs during transoral endoscopy treatment,
and no suitable drugs have been established.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search using the keywords (therapeutic
endoscopy OR endoscopic treatment OR endoscopic ther-
apy) and benzodiazepine and (randomized OR controlled
OR meta OR guideline) and esophagogastroduodenoscopy
yielded 128 articles, of which 17 were meta-analyses/
systematic reviews/clinical guidelines, 29 were clinical
trials, 71 were miscellaneous clinical research/epidemiolog-
ical research, and 11 were controlled trials. After manual
searching added seven articles (including four clinical
guidelines), screening results yielded seven related refer-
ences, including three RCTs and three clinical guidelines.
REFERENCES
1 Igea F, Casellas JA, Gonzalez-Huix F et al. Sedation for
gastrointestinal endoscopy. Endoscopy 2014; 46: 720–31.
2 ASGE Standards of Practice Committee, Early DS, Lightdale
JR et al. Guidelines for sedation and anesthesia in GI
endoscopy. Gastrointest Endosc 2018; 87: 327–37.
3 Obara K, Haruma K, Irisawa A et al. Guidelines for sedation
in gastroenterological endoscopy. Dig Endosc 2015; 27: 435–
49.
4 Patel S, Vargo JJ, Khandwala F et al. Deep sedation occurs
frequently during elective endoscopy with meperidine and
midazolam. Am J Gastroenterol 2005; 100: 2689–95.
5 Bianchi Porro G, Baroni S, Parente F et al. Midazolam versus
diazepam as premedication for upper gastrointestinal endo-
scopy: a randomized, double-blind, crossover study. Gastroin-
test Endosc 1988; 34: 252–4.
6 Cole SG, Brozinsky S, Isenberg JI. Midazolam, a new more
potent benzodiazepine, compared with diazepam: a random-
ized, double-blind study of preendoscopic sedatives. Gas-
trointest Endosc 1983; 29: 219–22.
7 Lee MG, Hanna W, Harding H. Sedation for upper gastroin-
testinal endoscopy: a comparative study of midazolam and
diazepam. Gastrointest Endosc 1989; 35: 82–4.
© 2020 Japan Gastroenterological Endoscopy Society
42 T. Gotoda et al.
CQ 13: What is a suitable benzodiazepine
drug when undergoing transanal endoscopy
treatment?
Statement 13:
There is no evidence related to benzodiazepine drug
selection.
Assessment based on the modified Delphi method:
median, 8; minimum, 7; maximum, 9
Strength of recommendation: none, Evidence qual-
ity (strength): D
Textual explanation
Transanal endoscopy treatments include colon EMR/ESD,
transanal enteroscopy, and colonic stenting. The extent of
pain, required time, and procedural difficulty or transanal
endoscopy treatment vary according to each procedure and
treatment. Transanal endoscopy treatment is less painful
than transoral endoscopy treatment. Furthermore, position
changes are sometimes required during treatment for
colorectal EMR/ESD. As such, mild to moderate sedation
is sufficient for transanal endoscopy treatment, and non-
sedation is also possible depending on the type of treatment.
However, internationally, transanal endoscopy treatment is
primarily managed under intravenous anesthesia combined
with analgesics like propofol or fentanyl and administered
by anesthesiologists, or under general anesthesia with
tracheal intubation.1,2
Among transanal endoscopy treatment types, short-dura-
tion and low-difficulty treatment can be conducted with or
without sedation, using either benzodiazepine drugs or
analgesics like pethidine hydrochloride singly. However,
challenging and long-duration endoscopy treatment requires
benzodiazepine drugs + analgesics to safely yet securely
conduct treatment. Intravenous benzodiazepine drugs are
widely used for transanal endoscopy treatment in Japan, and
drugs like midazolam, diazepam, and flunitrazepam can be
selected for these purposes.3 However, none of these drugs
have received approval for insured use in sedation during
endoscopy, and the current state is such that these drugs are
used without insurance coverage. Midazolam is widely used
for moderate sedation during gastrointestinal endoscopic
examination in the West.1,2 With regard to transanal
endoscopic examination, midazolam efficacy (e.g., amnesia
effects under examination and reduction of phlebitis) has
been reported to be superior to that of diazepam.4,5 However,
© 2020 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; 33: 21–53
thus far, there have been no reports directly comparing
benzodiazepine drugs during transanal endoscopic treatment.
There is no clear evidence related to the selection of
benzodiazepine drugs during transanal endoscopy treatment,
and no suitable drugs have been established.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search using the keywords (“therapeutic
endoscopy” OR “endoscopic treatment” OR “endoscopic
therapy”) and “benzodiazepine” and (“randomized” OR
“controlled” OR “meta” OR “guideline”) and “colono-
scopy” yielded 147 articles, of which 16 were meta-
analyses/systematic reviews/clinical guidelines, 30 were
clinical trials, 41 were miscellaneous clinical research/
epidemiological research, and 60 were controlled trials.
After manual searching added four articles (including three
clinical guidelines), screening results yielded five related
references, including two RCTs and three clinical guide-
lines.
REFERENCES
1 Igea F, Casellas JA, Gonzalez-Huix F et al. Sedation for
gastrointestinal endoscopy. Endoscopy 2014; 46: 720–31.
2 ASGE Standards of Practice Committee, Early DS, Lightdale
JR et al. Guidelines for sedation and anesthesia in GI
endoscopy. Gastrointest Endosc 2018; 87: 327–37.
3 Obara K, Haruma K, Irisawa A et al. Guidelines for sedation
in gastroenterological endoscopy. Dig Endosc 2015; 27: 435–
49.
4 Macken E, Gevers AM, Hendrickx A et al. Midazolam versus
diazepam in lipid emulsion as conscious sedation for
colonoscopy with or without reversal of sedation with
flumazenil. Gastrointest Endosc 1998; 47: 57–61.
5 Zakko SF, Seifert HA, Gross JB. A comparison of midazolam
and diazepam for conscious sedation during colonoscopy in a
prospective double-blind study. Gastrointest Endosc 1999; 49:
684–9.
CQ 14: What should be done when a suitable
depth of sedation cannot be obtained even
when more than the recommended amount
of benzodiazepine drugs is administered
during sedated endoscopy?
Statement 14:
The addition of analgesics (e.g., pethidine hydrochloride,
pentazocine) should be considered when only using
benzodiazepine drugs. Patients suspected of disinhibition
Digestive Endoscopy 2021; 33: 21–53
should be administered antagonists, and the procedure
should be conducted while awake or the examination/
treatment should be extended.
Assessment based on the modified Delphi method:
median, 8; minimum, 7; maximum, 9
Strength of recommendation: 2, Evidence quality
(strength): D
Textual explanation
It is standard practice overseas for anesthesiologists or nurse
anesthetists to conduct sedation control during invasive
endoscopy. However, currently in Japan, there is little
treatment compensation for independently ensuring human
resources for conducting these procedures, and that the only
drug covered by insurance is dexmedetomidine hydrochlo-
ride, thus making these procedures difficult.
Most sedation problems are caused by insufficient
measures against discomfort/pain during endoscopic exam-
ination/treatment. Many reference investigations that com-
pared sole use of benzodiazepine versus benzodiazepine
with analgesics like pethidine hydrochloride or pentazocine
showed that the combined analgesic use was effective.1–3
However, sedative and analgesic overdosing can cause
upper airway obstruction and respiratory suppression,
warranting intermittent monitoring of respiratory conditions
before and after additional drug administration.
Besides analgesics, reports have indicated that combining
droperidol with midazolam/pethidine hydrochloride
improves sedation quality in upper endoscopic examina-
tion/treatment.4,5 However, side effects related to the
circulatory system (e.g., QT extension) have been found,
and droperidol use for sedation in Japan is not standard
practice, with its usage being difficult even when drug
conditions are ideal. There are no other references for drugs
that can be recommended for simultaneous use with
benzodiazepine drugs.
Benzodiazepine drug-based sedation should be sus-
pended, and antagonists should be promptly used when
disinhibition occurs.6 The possibility of continuing the
examination/treatment should be investigated while the
patient is awake, and temporarily suspending the procedure
and postponing it to another date might be safer if a separate
sedation method needs to be conducted.
Sedatives that should be investigated as substitutes to
benzodiazepine drugs include dexmedetomidine hydrochlo-
ride and propofol. First, dexmedetomidine hydrochloride
additionally includes the additional insurance-covered use of
“sedation during non-intubated surgery and treatment under
Sedation for GI endoscopy 43
local anesthesia” and also induces minimal respiratory
suppression. Its use during endoscopy examinations is
thought to be difficult due to the high cost of the drug and its
need for continuous administration.
Next, propofol use needs to be carefully selected since it
is not covered by insurance. As a general rule, the drug
should be continuously administered, because single admin-
istrations are thought to easily induce unstable sedation
conditions. In either case, the combined use of benzodi-
azepine drugs and other sedatives might increase the risk of
over-sedation-related adverse events, and the reversal of
benzodiazepine drugs using flumazenil should consistently
be considered. Patients in whom sedation is difficult
(particularly those who have circulatory or respiratory
complications) should also consider consulting with anes-
thesiologists for appropriate selection of the drugs to be used
in sedation and decide whether to undergo general anesthe-
sia with intubation.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search using the keywords (“en-
doscopy” or “endoscopic”) and “benzodiazepine” and
“insufficient sedation” and ( “disinhibition” or “paradoxical
reaction” or “paradoxical effect”) yielded 92 articles, of
which 10 were meta-analyses/systematic reviews/clinical
guidelines, 26 were clinical trials, 51 were miscellaneous
clinical research/epidemiological research, and five were
controlled trials. Screening results yielded six related
references, including four RCTs.
REFERENCES
1 Terui T, Inomata M. Administration of additional analgesics
can decrease the incidence of paradoxical reactions in patients
under benzodiazepine-induced sedation during endoscopic
transpapillary procedures: Prospective randomized controlled
trial. Dig Endosc 2013; 25: 53–9.
2 Y€uksel O, Parlak E, K€okl€
u S et al. Conscious sedation during
endoscopic retrograde cholangiopancreatography: Midazolam
or midazolam plus meperidine? Eur J Gastroenterol Hepatol
2007; 19: 1002–6.
3 Dzeletovic I, Harrison ME, Crowell MD et al. Impact of
fentanyl in lieu of meperidine on endoscopy unit efficiency: a
prospective comparative study in patients undergoing EGD.
Gastrointest Endosc 2013; 77: 883–7.
4 Cohen J, Haber GB, Dorais JA et al. A randomized, double-
blind study of the use of droperidol for conscious sedation
during therapeutic endoscopy in difficult to sedate patients.
Gastrointest Endosc 2000; 51: 546–51.
5 Barthel JS, Marshall JB, King PD et al. The effect of
droperidol on objective markers of patient cooperation and
vital signs during esophagogastroduodenoscopy: a
© 2020 Japan Gastroenterological Endoscopy Society
44 T. Gotoda et al.
randomized, double-blind, placebo-controlled, prospective
investigation. Gastrointest Endosc 1995; 42: 45–50.
6 Tae CH, Kang KJ, Min BH et al. Paradoxical reaction to
midazolam in patients undergoing endoscopy under sedation:
Incidence, risk factors and the effect of flumazenil. Dig Liver
Dis 2014; 46: 710–5.
CQ 15: Is the use of analgesics in addition to
sedatives effective during transoral
endoscopy?
Statement 15:
The use of analgesics in addition to sedatives is effective
for ERCP. There are cases with other types of endoscopy
where the use of analgesics in addition to sedatives is
effective.
Assessment based on the modified Delphi method:
median, 8; minimum, 5; maximum, 9
Strength of recommendation: 2, Evidence quality
(strength): B
Textual explanation
1. Highly invasive transoral endoscopy: ERCP, esophageal
dilation, esophago-gastro-duodenal ESD, gastrostomy,
transoral enteroscopy, interventional EUS, enteroscopic
ERCP, etc.
a Controlled trials between sedatives and seda-
tives + analgesicsFour RCTs have been reported for
controlled trials between sedatives and seda-
tives + analgesics in ERCP,1–4 with one comparing
midazolam and midazolam + pethidine hydrochlo-
ride,1 one comparing midazolam and midazo-
lam + pentazocine,2 and two comparing propofol
and propofol + fentanyl.3,4 The success rate and depth
of sedation were equivalent in both groups,1–4 and
adverse outcomes related to the circulatory system1,3,4
and respiratory system1–4 were also equivalent in both
groups. Pain was lower in the combined drug
group,1,3,4 and patient satisfaction was either equiva-
lent1464 or higher in the combined drug group.1
Operator satisfaction was also either equivalent3,4 or
higher in the combined drug group.1,2 Combined use
© 2020 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; 33: 21–53
with analgesics was effective in ERCP due to less pain
in the combined drug group, higher possibility of
patient and operator satisfaction, and minimal costs.
Meanwhile, many RCT participants were under the
age of 80 and had an ASA-PS classification of II or
below (Table 77); thus, careful measures are required
for patients with extremely advanced age or those with
an ASA-PS classification of III or higher.There are no
controlled trials between sedatives and seda-
tives + analgesics that focus on examination/treatment
other than ERCP. Combined use with analgesics in
addition to sedatives is an option for endoscopies
involving high levels of pain or discomfort or which
are long in duration.
b Controlled trials between different analgesics
An RCT that compared different analgesics under
conditions where sedatives + analgesics were used,
specifically propofol + pethidine hydrochloride and
propofol + fentanyl, has been conducted.5 The success
rate, required time, duration of recovery room stay,
cardiopulmonary system-related adverse events, patient
satisfaction, and operator satisfaction were all equiv-
alent. The administered dose of propofol was low in
the combined propofol + fentanyl group. From the
perspective of administered doses of propofol, fentanyl
is potentially thought to be safer. There are no
controlled trials comparing pentazocine with other
drugs.
2. Moderately invasive transoral endoscopy: esophagogas-
tric EMR, esophageal stenting, esophagogastric varicose
vein treatment, gastrointestinal hemostasis, cauteriza-
tion, EUS-FNA, etc.
There have been no controlled trials comparing sedatives
and sedatives + analgesics for these procedures. Short-
duration and minimally painful examination/treatment can
be conducted with only sedatives, but combined use with
analgesics is also an option.
3. Minimally invasive transoral endoscopy: upper endo-
scopy examinations (including biopsy), diagnostic
EUS.
a Controlled trials between sedatives and seda-
tives + analgesics.
There have been five RCTs that compared sedatives
and sedatives + analgesics for upper endoscopy
examination,6–10 with three comparing midazolam
and midazolam + pethidine hydrochloride,6–8 one
comparing midazolam and midazolam + fentanyl,9
and one comparing midazolam and midazolam + nal-
buphine.10 No RCTs have used propofol as a sedative
Digestive Endoscopy 2021; 33: 21–53
or pentazocine as an analgesic. The success rate,
cardiopulmonary adverse events, and patient satisfac-
tion were all equivalent in both groups.6–10 Many
reports have indicated that operator satisfaction was
higher with the combined drug group.6,7,9,10 In many
cases, upper endoscopy examinations could be con-
ducted with only sedatives, but combined use with
analgesics was an option as well due to its possibility
of increasing operator satisfaction and its minimal
cost. Meanwhile, many RCT participants were below
the age of 80 and had an ASA-PS classification of II
or below; hence, careful measures are needed for
patients with extremely advanced age or those with an
ASA-PS classification of III or higher.There have
been no controlled trials that compared sedatives and
sedatives + analgesics for diagnostic EUS. In many
cases, these can be conducted with only sedatives, but
EUS-specific scopes have a large diameter and can be
somewhat painful; therefore, combined use with an
analgesic is also an option.
b Controlled trials between analgesics
Three trials compared analgesics under conditions
where sedatives + analgesics were used for upper
endoscopy examination.11–13 Two of these11,12 were
small-scale RCTs that compared midazo-
lam + pethidine hydrochloride and midazolam + fen-
tanyl. The examination time, patient satisfaction, and
adverse event rates were equivalent in both groups for
both trials. One of these13 was not an RCT but instead
a relatively large-scale, prospective observational
study with 1963 patients, which compared midazo-
lam + pethidine hydrochloride and midazolam + fen-
tanyl. Success rate and operator satisfaction were
equivalent, but the time from the start of sedation
introduction and discharge from the recovery room
was significantly shorter in the fentanyl group
(79.8 min. vs. 69.7 min, P < 0.001), with time from
the start of sedation to the start of examination and
duration of recovery room stay both being particularly
shorter. Based on these findings, pethidine hydrochlo-
ride and fentanyl are both thought to have an
equivalent success rate, safety (i.e., lower rate of
adverse events), patient satisfaction, and operator
satisfaction. The examination facility turnaround rate
may be higher with fentanyl. There have been no
trials comparing pentazocine with other drugs.The
databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan
Medical Abstract Society. A search using the key-
words (“endoscopy” or “endoscopic” or “ERCP” or
“EMR” or “ESD” or “EUS” or “endoscopic therapy”)
Sedation for GI endoscopy 45
and (“sedation” or “anesthesia” or “benzodiazepine”
or “midazolam” or “propofol” or “dexmedetomidine”)
and (“analgesia” or “opioid” or “opiate” or “narcotic”)
and (“meta-analysis” or “randomized controlled” or
“RCT”) not (“colonoscopy”) yielded 424 articles, of
which 41 were meta-analyses/systematic reviews/clin-
ical guidelines, 182 were clinical trials, 189 were
miscellaneous clinical research/epidemiological
research, and 12 were controlled trials. Screening
results yielded 13 related references, including 12
RCTs.
REFERENCES
1 Y€uksel O, Parlak E, K€okl€
u S et al. Conscious sedation during
endoscopic retrograde cholangiopancreatography: Midazolam
or midazolam plus meperidine? Eur J Gastroenterol Hepatol
2007; 19: 1002–6.
2 Terui T, Inomata M. Administration of additional analgesics
can decrease the incidence of paradoxical reactions in patients
under benzodiazepine-induced sedation during endoscopic
transpapillary procedures: Prospective randomized controlled
trial. Dig Endosc 2013; 25: 53–9.
3 Haytural C, Aydinli B, Demir B et al. Comparison of propofol,
propofol-remifentanil, and propofol-fentanyl administrations
with each other used for the sedation of patients to undergo
ERCP. Biomed Res Int 2015; 2015: 465465.
4 Fassoulaki A, Iatrelli I, Vezakis A et al. Deep sedation for
endoscopic cholangiopancreatography with or without pre or
intraprocedural opioids: A double-blind randomised controlled
trial. Eur J Anaesthesiol 2015; 32: 602–8.
5 Shin S, Oh TG, Chung MJ et al. Conventional versus
analgesia-oriented combination sedation on recovery profiles
and satisfaction after ERCP: A randomized trial. PLoS One
2015; 10: e0138422.
6 Diab FH, King PD, Barthel JS et al. Efficacy and safety of
combined meperidine and midazolam for EGD sedation com-
pared with midazolam alone. Am J Gastroenterol 1996; 91:
1120–5.
7 LaLuna L, Allen ML, DiMarino AJ Jr. The comparison of
midazolam and topical lidocaine spray versus the combination
of midazolam, meperidine and topical lidocaine spray to sedate
patients for upper endoscopy. Gastrointest Endosc 2001; 53:
289–93.
8 Ozel AM, Onc€ u K, Yazgan Y et al. Comparison of the effects
of intravenous midazolam alone and in combination with
meperidine on hemodynamic and respiratory responses and on
patient compliance during upper gastrointestinal endoscopy: a
randomized, double-blind trial. Turk J Gastroenterol 2008; 19:
8–13.
9 Barriga J, Sachdev MS, Royall L et al. Sedation for upper
endoscopy: Comparison of midazolam versus fentanyl plus
midazolam. South Med J 2008; 101: 362–6.
© 2020 Japan Gastroenterological Endoscopy Society
46 T. Gotoda et al.
10 Chin KW, Tan PK, Chin MK. Sedation for gastroscopy: A
comparison between midazolam and midazolam with nal-
buphine. Ann Acad Med Singapore 1994; 23: 330–2.
11 Chokhavatia S, Nguyen L, Williams R et al. Sedation and
analgesia for gastrointestinal endoscopy. Am J Gastroenterol
1993; 88: 393–6.
12 Robertson DJ, Jacobs DP, Mackenzie TA et al. Clinical trial: a
randomized, study comparing meperidine (pethidine) and
fentanyl in adult gastrointestinal endoscopy. Aliment Pharma-
col Ther 2009; 29: 817–23.
13 Dzeletovic I, Harrison ME, Crowell MD et al. Impact of
fentanyl in lieu of meperidine on endoscopy unit efficiency: a
prospective comparative study in patients undergoing EGD.
Gastrointest Endosc 2013; 77: 883–7.
CQ 16: Is the use of analgesics in addition to
sedatives effective during transanal
endoscopy?
Statement 16:
There are cases where the use of analgesics in addition to
sedatives is effective in transanal endoscopy.
Assessment based on the modified Delphi method:
median, 8; minimum, 7; maximum, 9
Strength of recommendation: 2, Evidence quality
(strength): C
Textual explanation
1. Highly invasive transanal endoscopy: colon ESD, colonic
stenting, EBD, enteroscopy (including treatment),
etc.There have been no trials comparing the use of
sedatives only and sedatives + analgesics for these pro-
cedures. Combined use of analgesics and sedatives is an
option for endoscopies causing high levels of pain or
discomfort or that are long in duration.
2. Moderately invasive transanal endoscopy: colon EMR,
gastrointestinal hemostasis, cauterization, etc.No trials
have compared the use of sedatives only and seda-
tives + analgesics for these procedures. Endoscopy treat-
ment that is short in duration and causes relatively little
pain can be conducted with only sedatives, but combined
use with analgesics is also an option.
3. Minimally invasive transanal endoscopy: colonoscopy
examinations (including biopsy, polypectomy), colon
EUS (including FNA)
© 2020 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; 33: 21–53
a Controlled trials between sedatives and seda-
tives + analgesicsSeven RCTs have compared seda-
tives and sedatives + analgesics for colonoscopy
examination,1–7 with two comparing midazolam and
midazolam + pethidine hydrochloride,1,2 one compar-
ing midazolam and midazolam + fentanyl,3 one com-
paring diazepam and diazepam + pethidine
hydrochloride,4 one comparing propofol and propo-
fol + pethidine hydrochloride,5 and two comparing
propofol and propofol + fentanyl.6,7 There have been
no trials using pentazocine as an analgesic. The success
rate and patient satisfaction were equivalent in both
groups.1–7 Many reports indicated that the rate of
adverse events related to the circulatory system was
equivalent in both groups,1–3,5,6 whereas those related
to the respiratory system were either equivalent in both
groups2,3,5,6 or lower in the combined drug group.1,7
Operator satisfaction was equivalent in both
groups1,4,6,7 or higher in the combined drug group.3,5
The administered dose of sedatives was either equiv-
alent4 or lower in the combined drug group,5–7 and the
duration of recovery room stay was either equivalent2
or shorter in the combined drug group.5,6 There are
many cases where colonoscopy examinations could be
conducted with only sedatives, but combined use with
analgesics is an option due to the increased frequency
of pain, potentially higher operator satisfaction, higher
examination facility turnaround rate, and minimal
costs. Meanwhile, many RCT participants were below
the age of 80 and had an ASA-PS classification of II or
below (Table 77), necessitating careful measures for
patients with extremely advanced age or those with an
ASA-PS classification of III or higher.
There have been no controlled trials comparing the use
of sedatives only and sedatives + analgesics for colon
EUS (including FNA). There might be cases where
endoscopic examination can be conducted with only
sedatives, but combined use with analgesics is also an
option.
b Controlled trials between analgesicsThree trials had
pethidine hydrochloride and fentanyl comparison arms
under conditions where sedatives + analgesics were
used for colonoscopy examinations.8–10 There have
been no trials comparing pentazocine with other drugs.
Some trials have compared analgesics that are not in
standard use in colonoscopy examinations in Japan,
e.g., sufentanil,11,12 alfentanil,13–17 remifentanil,18,19
ketamine,13,20 nalbuphine,11 paracetamol,21 and tra-
madol.19,22 In three RCTs that compared midazo-
lam + pethidine hydrochloride and
midazolam + fentanyl,8–10 safety and operator
Digestive Endoscopy 2021; 33: 21–53
satisfaction were equivalent between the two groups.
Patient pain was reported as either equivalent in both
groups8,10 or lower in the pethidine hydrochloride
group.9 The duration of recovery room stay was shorter
in the fentanyl group for all studies. Based on these
findings, safety, patient satisfaction, and operator
satisfaction are thought to be virtually equivalent for
pethidine hydrochloride and fentanyl. The examina-
tion facility turnaround rate might be higher with the
administration of fentanyl.The databases used for this
reference extraction were PubMed, Cochrane Library
database, and Japan Medical Abstract Society. A
search using the keywords (“endoscopy” or “colono-
scopy” or “endoscopic” or “EMR” or “ESD” or “EUS”
or “endoscopic therapy”) and (“sedation” or “anesthe-
sia” or “benzodiazepine” or “midazolam” or “propo-
fol” or “dexmedetomidine”) and (“analgesia” or
“opioid” or “opiate” or “narcotic”) and (“meta-analy-
sis” or “randomized controlled” or “RCT”) not
(“ERCP”) yielded 468 articles, of which 33 were
meta-analyses/systematic reviews/clinical guidelines,
221 were clinical trials, 186 were miscellaneous
clinical research/epidemiological research, and 28
were controlled trials. Screening results yielded 22
related references.
REFERENCES
1 Froehlich F, Thorens J, Schwizer W et al. Sedation and
analgesia for colonoscopy: Patient tolerance, pain, and
cardiorespiratory parameters. Gastrointest Endosc 1997; 45:
1–9.
2 Cinar K, Yakut M, Ozden A. Sedation with midazolam versus
midazolam plus meperidine for routine colonoscopy: a
prospective, randomized, controlled study. Turk J Gastroen-
terol 2009; 20: 271–5.
3 Wang F, Shen SR, Xiao DH et al. Sedation, analgesia, and
cardiorespiratory function in colonoscopy using midazolam
combined with fentanyl or propofol. Int J Colorectal Dis 2011;
26: 703–8.
4 Rembacken BJ, Axon AT. The role of pethidine in sedation for
colonoscopy. Endoscopy 1995; 27: 244–7.
5 Hsieh YH, Chou AL, Lai YY et al. Propofol alone versus
propofol in combination with meperidine for sedation during
colonoscopy. J Clin Gastroenterol 2009; 43: 753–7.
6 VanNatta ME, Rex DK. Propofol alone titrated to deep
sedation versus propofol in combination with opioids and/or
benzodiazepines and titrated to moderate sedation for colono-
scopy. Am J Gastroenterol 2006; 101: 2209–17.
7 Doganay G, Ekmekcßi P, Kazbek BK et al. Effects of alfentanil
or fentanyl added to propofol for sedation in colonoscopy on
Sedation for GI endoscopy 47
cognitive functions: Randomized controlled trial. Turk J
Gastroenterol 2017; 28: 453–9.
8 Chokhavatia S, Nguyen L, Williams R et al. Sedation and
analgesia for gastrointestinal endoscopy. Am J Gastroenterol
1993; 88: 393–6.
9 Robertson DJ, Jacobs DP, Mackenzie TA et al. Clinical trial: a
randomized, study comparing meperidine (pethidine) and
fentanyl in adult gastrointestinal endoscopy. Aliment Pharma-
col Ther 2009; 29: 817–23.
10 Hayee B, Dunn J, Loganayagam A et al. Midazolam with
meperidine or fentanyl for colonoscopy: Results of a random-
ized trial. Gastrointest Endosc 2009; 69: 681–7.
11 Deng C, Wang X, Zhu Q. Comparison of nalbuphine and
sufentanil for colonoscopy: A randomized controlled trial.
PLoS One 2017; 12: e0188901.
12 Akarsu Ayazo glu T, Polat E, Bolat C et al. Comparison of
propofol-based sedation regimens administered during colo-
noscopy. Rev Med Chil 2013; 141: 477–85.
€
13 T€urk HS ß , Aydogmusß M, Unsal O et al. Ketamine versus
alfentanil combined with propofol for sedation in colonoscopy
procedures: a randomized prospective study. Turk J Gastroen-
terol 2014; 25: 644–9.
14 T€urk HSß , Aydo €
gmusß M, Unsal O et al. Sedation-analgesia in
elective colonoscopy: Propofol-fentanyl versus propofol-
alfentanil. Braz J Anesthesiol 2013; 63: 352–7.
15 Ho WM, Yen CM, Lan CH et al. Comparison between the
recovery time of alfentanil and fentanyl in balanced propofol
sedation for gastrointestinal and colonoscopy: a prospective,
randomized study. BMC Gastroenterol 2012; 12: 164.
16 Usta B, T€ urkay C, Muslu B et al. Patient-controlled analgesia
and sedation with alfentanyl versus fentanyl for colonoscopy:
A randomized double blind study. J Clin Gastroenterol 2011;
45: e72–e75.
17 Holloway AM, Logan DA. Pain relief for outpatient colono-
scopy: a comparison of alfentanil with fentanyl. Anaesth
Intensive Care 1990; 18: 210–3.
18 Fanti L, Agostoni M, Gemma M et al. Remifentanil vs.
meperidine for patient-controlled analgesia during colono-
scopy: A randomized double-blind trial. Am J Gastroenterol
2009; 104: 1119–24.
19 Arici G, Kayacan N, Dincer D et al. Remifentanil/midazolam
versus tramadol/midazolam use for colonoscopy. Hepatogas-
troenterology 2003; 50(Suppl 2): cclxxxiii-vi.
20 Khajavi M, Emami A, Etezadi F et al. Conscious sedation and
analgesia in colonoscopy: Ketamine/propofol combination has
superior patient satisfaction versus fentanyl/propofol. Anesth
Pain Med 2013; 3: 208–13.
21 Ahmadi A, Amri P, Shokri J et al. Comparison of the analgesic
effect of intravenous paracetamol/midazolam and fentanyl in
preparation of patients for colonoscopy: A double blind
randomized clinical trial. Caspian J Intern Med 2015; 6: 87–
92.
22 Hirsh I, Vaissler A, Chernin J et al. Fentanyl or tramadol, with
midazolam, for outpatient colonoscopy: Analgesia, sedation,
and safety. Dig Dis Sci 2006; 51: 1946–51.
© 2020 Japan Gastroenterological Endoscopy Society
48 T. Gotoda et al.
CQ 17: What is the efficacy of propofol in
endoscopy?
Statement 17:
The use of propofol under suitable monitoring conditions
does not increase adverse events and has a short duration
of recovery/confinement, low interruption rate of long-
term surgical procedures, and high physician/nurse/pa-
tient satisfaction.
Assessment based on the modified Delphi method:
median, 9; minimum, 7; maximum, 9
Strength of recommendation: 2, Evidence quality
(strength): A
Textual explanation
Over 20 years have passed since the initial use of propofol in
Japan, and it has seen widespread use in closed-circuit
anesthesia. The high arousal quality is a distinct characteristic
of propofol, and this is said to be a reason for its use in
endoscopic examinations in some facilities. However, the
“Guidelines for sedation in gastroenterological endoscopy”
(first edition) have minimal discussions on propofol, and it is not
in common use in endoscopy sedation in Japan due to insurance
coverage and safety issues. Thus, we state up front that reports
relating to propofol use in Japanese subjects is limited.
Meanwhile, there have been many RCTs and meta-analyses
related to propofol-based sedation in endoscopy. Many of these
reports are from overseas, and there are an extremely limited
number of reports related to upper endoscopy examination. CQ
17 in these guidelines primarily focuses on reports that
compared propofol with existing sedatives and analgesics.
We did not include RCTs and meta-analyses that investigated
additional effects (i.e., propofol vs. propofol + other drugs).
Note that “existing sedatives/analgesics” here refers to benzo-
diazepine drugs (midazolam, diazepam, etc.) and opioid
analgesics (remifentanil, pethidine hydrochloride, etc.).
A meta-analysis that compared propofol and existing
sedatives in the three broad groups of upper endoscopy
examinations, colonoscopy examinations, and ERCP/EUS
reported that propofol significantly reduced adverse events
like hypotension and hypoxemia in colonoscopy examination
but had no differences in upper endoscopy examination and
ERCP/EUS.1 This was thought to be due to differences in the
intubation route. A recent meta-analysis limited to colono-
scopy examinations2 showed that time to sedation, recovery
time, time to ambulation, and discharge time were all
© 2020 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; 33: 21–53
significantly reduced, and that there was no increase in the
adverse event rate. A meta-analysis of six RCTs regarding
ERCP3 showed no significant differences in hypotension and
hypoxemia frequency and significant reductions in recovery
time. There has also been a recent meta-analysis relating to
advanced endoscopy (e.g., ERCP, EUS, DBE). This meta-
analysis of nine RCTs4 showed no differences in hypoxemia,
hypotension, and operation time but showed significant
decreases in recovery time. A meta-analysis on ESD that
analyzed three RCTs from Japan reported that propofol
significantly reduced the rate of restlessness (defined as body
movements forcing discontinuation of treatment) and signif-
icantly increased the rate of being fully awake 1 h after ESD.5
The definition of hypoxemia and hypotension varied in each
RCT, but the studies reported no significant differences for
these as well. There has also been an RCT from Japan related
to esophageal ESD, which reported difficulty with sedation
due to disturbance issues caused by conventional sedatives.6
This study reported higher hypotension frequency in the
propofol group but no significant differences in hypoxemia or
bradycardia in either group. The study reported discontinu-
ation due to a poor response to sedation in 37.9% of patients in
the midazolam-only group, but there was no case of
discontinuation in the propofol group.
An RCT conducted on seniors over the age of 80 has been
reported with regard to the efficacy of propofol in seniors in
the field of therapeutic ERCP.7 The recovery time was
significantly shorter with propofol, but no differences
between the two groups were seen in the rate of adverse
events (hypotension, hypoxemia, bradycardia, tachycardia)
and endoscopist/nurse satisfaction, and it was concluded that
midazolam-based sedation can also be used for seniors.
From the findings shown above, the advantages of
propofol when compared to existing sedatives/analgesics
are as follows: (i) shorter recovery time and discharge time
with propofol; (ii) increased patient/nurse/physician satis-
faction with propofol, although there are no differences
among seniors; and (iii) minimal suspension time during
long-duration procedures like ESD. However, it is recom-
mended that this be used by those who have sufficient
training with airway maintenance, and this also applies to
CQ 18. Whether propofol-based sedation can be safely
conducted by non-anesthesiologists in an endoscopy facility
cannot be determined at present under Japanese on-site
clinics and education regulations, as well as with the current
state of medical regulations and measures.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search using the keywords “propo-
fol”[MeSH Terms] and “endoscopy”, “digestive sys-
tem”[MeSH Terms] and (“diagnosis”[MeSH Terms] OR
Digestive Endoscopy 2021; 33: 21–53
“therapeutics”[MeSH Terms] OR “therapy”[MeSH Terms])
and “human”[MeSH Terms] and (English[LA] OR Japanese
[LA]) and (“outcome and process assessment”[MeSH Terms]
OR “safety”[MeSH Terms]) yielded 538 articles, of which 68
were meta-analyses/systematic reviews/clinical guidelines,
187 were clinical trials, 141 were miscellaneous clinical
research/epidemiological research, and 142 were controlled
trials. Screening results yielded seven related references,
including one RCT and five meta-analyses.
REFERENCES
1 Qadeer MA, Vargo JJ, Khandwala F et al. Propofol versus
traditional sedative agents for gastrointestinal endoscopy: a
meta-analysis. Clin Gastroenterol Hepatol 2005; 3: 1049–56.
2 Zhang W, Zhu Z, Zheng Y. Effect and safety of propofol for
sedation during colonoscopy: A meta-analysis. J Clin Anesth
2018; 51: 10–8.
3 Bo LL, Bai Y, Bian JJ et al. Propofol vs traditional sedative
agents for endoscopic retrograde cholangiopancreatography: A
meta-analysis. World J Gastroenterol 2011; 17: 3538–43.
4 Sethi S, Wadhwa V, Thaker A et al. Propofol versus traditional
sedative agents for advanced endoscopic procedures: A meta-
analysis. Dig Endosc 2014; 26: 515–24.
5 Nishizawa T, Suzuki H, Matsuzaki J et al. Propofol versus
traditional sedative agents for endoscopic submucosal dissec-
tion. Dig Endosc 2014; 26: 701–6.
6 Ominami M, Nagami Y, Shiba M et al. Comparison of
propofol with midazolam in endoscopic submucosal dissection
for esophageal squamous cell carcinoma: a randomized
controlled trial. J Gastroenterol 2018; 53: 397–406.
7 Han SJ, Lee TH, Park SH et al. Efficacy of midazolam- versus
propofol-based sedations by non-anesthesiologists during
therapeutic endoscopic retrograde cholangiopancreatography
in patients aged over 80 years. Dig Endosc 2017; 29: 369–76.
CQ 18: Can propofol be used by non-
anesthesiologists in an endoscopy facility?
Statement 18:
Propofol may be used by physicians who have under-
gone training (e.g., with airway maintenance) only if
sufficient care is given to depth of sedation and the drug
is administered to ASA-PS I or II patients.
Assessment based on the modified Delphi method:
median, 8; minimum, 5; maximum, 9
Strength of recommendation: 2, Evidence quality
(strength): A
Sedation for GI endoscopy 49
Textual explanation
This CQ was created from reports that compared sedation
conducted by either anesthesiologists or non-anesthesiolo-
gists. A joint statement has been issued by the American
Association for the Study of Liver Disease, American
College of Gastroenterology, American Gastroenterological
Association, and ASGE regarding propofol management by
non-anesthesiologists,1 wherein propofol sedation by non-
anesthesiologists was referred to as non-anesthesiologist
administration of propofol (NAAP), and terms like non-
anesthesia provider-administered propofol, nurse-adminis-
tered propofol sedation (NAPS) were treated as synonymous
with NAAP.
One meta-analysis compared propofol administration by
either endoscopists or anesthesiologists only during screen-
ing upper endoscopy/colonoscopy. A majority of the
subjects in most of the reports were low-risk patients with
an ASA-PS classification of either I or II (Table 7). The
endoscopist-administered propofol group had significantly
higher frequency of bradycardia but showed no increase in
the frequency of airway maintenance treatment or hypoten-
sion. Propofol doses administered by endoscopists were
significantly lower, and the frequency of memory of the
examination was shown to be significantly higher in the
endoscopist-administered propofol group.2
A meta-analysis of 16 NAAP and 10 anesthesia provider-
administered propofol (AAP) RCTs has been reported with
regard to advanced endoscopy procedures. The frequency of
hypoxemia was equivalent in both groups, but the percent-
age of patients requiring airway maintenance treatment was
higher in AAP compared to NAAP. However, the admin-
istered dose of propofol was reported to be higher in the
AAP than in the NAAP group, which was similar to the
results in the previously mentioned meta-analysis, and it was
reported that both patient and endoscopist satisfaction were
higher in the AAP group.3
A sub-group analysis in a meta-analysis compared the
frequency of cardiopulmonary adverse events between
propofol and existing sedatives and analyzed gastroenterol-
ogist-administered anesthesia, endoscopy nurse-administered
anesthesia under the guidance of a gastrointestinal endo-
scopist, and anesthesiologist/ICU physician-administered
anesthesia. The study reported that there were no differences
in the frequency of cardiopulmonary adverse events between
these various forms of anesthesia administration.4
Several RCTs are introduced here since the use of various
supporting devices for the safe administration of propofol
(which has a narrow treatment range) by non-anesthesiolo-
gists is thought to be important. A double-blind RCT
© 2020 Japan Gastroenterological Endoscopy Society
50 T. Gotoda et al.
comparing propofol-based sedation with NAAP that used a
target-controlled infusion (TCI) pump and midazolam-based
sedation during colonoscopy and upper endoscopy examina-
tion has been reported.5 The propofol group in the colono-
scopy examination had a significantly shorter hospital
discharge time and a significantly higher physician/patient
satisfaction. The propofol group in upper endoscopy exam-
ination had significantly higher patient/physician satisfaction
but showed no significant differences in hospital discharge
time, and the propofol sedation group was reported to request
the same sedative for their next session. These results suggest
that there are differences in propofol- based sedation with
NAAP that uses a TCI pump, depending on transoral or
transanal intubation. There is also an RCT that investigated
the efficacy of capnography. There was no difference in
decreased SpO2 when the groups with or without capnogra-
phy in ERCP were compared, but the detection rate of apnea
lasting longer than 15 s was significantly higher in the
capnography group (64.5% vs. 6.0%, P < 0.001).6
Based on the above findings, (i) propofol management by
either non-anesthesiologists or anesthesiologists is equiva-
lent for patients with an ASA-PS classification of I or II, and
(ii) the administered dose of propofol is larger with
anesthesiologists, but this is superior for deep sedation.
Propofol management by anesthesiologists is particularly
recommended for patients with an ASA-PS classification of
III or higher.
This reference extraction used the search results shown in
CQ 17. Following the screening of 538 articles, seven
related references were used, including two RCTs, two
clinical guidelines, and three meta-analyses.
REFERENCES
1 Vargo JJ, Cohen LB, Rex DK et al. Position statement:
Nonanesthesiologist administration of propofol for GI endo-
scopy. Gastroenterology 2009; 137: 2161–7.
2 Daza JF, Tan CM, Fielding RJ et al. Propofol administration
by endoscopists versus anesthesiologists in gastrointestinal
endoscopy: A systematic review and meta-analysis of patient
safety outcomes. Can J Surg 2018; 61: 226–36.
3 Goudra BG, Singh PM, Gouda G. Safety of non-anesthesia
provider-administered propofol (NAAP) sedation in advanced
gastrointestinal endoscopic procedures: Comparative meta-
analysis of pooled results. Dig Dis Sci 2015; 60: 2612–27.
Erratum in: Dig Dis Sci 2015; 60: 3151.
4 Wadhwa V, Issa D, Garg S et al. Similar risk of cardiopulmonary
adverse events between propofol and traditional anesthesia for
gastrointestinal endoscopy: A systematic review and meta-
analysis. Clin Gastroenterol Hepatol 2017; 15: 194–206.
5 Fanti L, Gemma M, Agostoni M et al. Target Controlled
Infusion for non-anaesthesiologist propofol sedation during
© 2020 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; 33: 21–53
gastrointestinal endoscopy: The first double blind randomized
controlled trial. Dig Liver Dis 2015; 47: 566–71.
6 Klare P, Reiter J, Meining A et al. Capnographic monitoring of
midazolam and propofol sedation during ERCP: a randomized
controlled study (EndoBreath Study). Endoscopy 2016; 48: 42–
50.
CQ 19: Is dexmedetomidine hydrochloride
effective in sedation during endoscopy
treatment with long sedation times?
Statement 19:
Dexmedetomidine hydrochloride is effective in sedation
during endoscopy treatment with long sedation times.
Assessment based on the modified Delphi method:
median, 8; minimum, 7; maximum, 9
Strength of recommendation: 1, Evidence quality
(strength): B
Textual explanation
There are numerous procedures for endoscopy treatment,
and the necessity of sedation varies according to the
endoscopy treatment type since the treatment time also
varies according to the frequency of pain and the difficulty
of treatment. Short-duration endoscopy treatments such as
colonic polypectomy can be conducted without sedation.
Meanwhile, esophageal and gastric ESD and ERCP are
painful procedures, warranting sedation to safely and
securely conduct treatment. Moderate sedation is the
standard sedation level, but general anesthesia is also an
option when the patient needs to be immobilized and stable
for long periods of time during treatment.
Dexmedetomidine hydrochloride is an a2 adrenaline
receptor agonist and expresses its sedative effects by acting
on the locus coeruleus and spinal cord of the pons.1–3 Unlike
GABA agonists (e.g., midazolam), dexmedetomidine
hydrochloride has virtually no respiratory suppression and
has sedative, analgesic, and sympathetic nerve suppression
effects.4
The use of this drug for sedation during non-intubated
treatment under local anesthesia in Japan is covered by
insurance. It is clearly stated that physicians who are trained
in patient management during non-intubated sedation are to
accurately understand the pharmacological effects of this
drug and to carefully and continuously manage the patient’s
sedation level and physical status. It also clearly states that
Digestive Endoscopy 2021; 33: 21–53
physicians are to be prepared to conduct airway mainte-
nance, oxygen inhalation, artificial respiration, and circula-
tion management.
A meta-analysis of dexmedetomidine hydrochloride and
midazolam in endoscopy1 showed that the percentage of body
movement that resulted in the suspension of treatment was
significantly lower in the dexmedetomidine hydrochloride
group relative to the midazolam group. The Ramsay sedation
score was significantly higher in the dexmedetomidine group
compared to the midazolam group. There were no significant
differences in the frequency of adverse events like hypox-
emia, hypotension, and bradycardia between the two groups.
There were also no significant differences in the onset of body
movement during upper endoscopy and colonoscopy exam-
ination, but body movement was suppressed with dexmedeto-
midine hydrochloride during endoscopy treatment, which
required longer periods of time (e.g., ESD, ERCP).
Comparisons between dexmedetomidine hydrochloride,
midazolam, and propofol groups in gastric ESD showed that
the dexmedetomidine hydrochloride group had significantly
lower body movement, treatment time, and additional
administered doses of midazolam.5 There were no patients
whose examination was suspended due to respiratory
suppression in the dexmedetomidine hydrochloride group.
Reports indicated that the combined use of dexmedeto-
midine hydrochloride with sedatives/analgesics reduced the
additional administration and total administered dose of
sedatives, as well as the frequency of SpO2 decrease.6–8
Based on these reports, dexmedetomidine hydrochloride
was shown to have superior sedation effects during
endoscopy (particularly with ESD and ERCP, which
requires over 30 min for the procedure) without increasing
respiratory suppression.
However, there are a number of drawbacks to dexmedeto-
midine hydrochloride. Side effects influencing circulatory
dynamics (e.g., bradycardia, hypotension) can occur due to
sympathetic nerve blocking effects,9 and dexmedetomidine
hydrochloride-administered groups were shown to have a
higher frequency of hypotension and bradycardia during
ERCP and esophageal/gastric ESD; hence, sufficient care
must be given to circulatory dynamics during drug admin-
istration.2,10,11 The administration method is also somewhat
complicated, requiring a 10 min initial loading period;
furthermore, single drug administration can destabilize
circulatory dynamics,12 and it has a higher cost than other
drugs.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search using the keywords “dexmedeto-
midine”[MeSH Terms] AND “sedation”[TIAB] AND “en-
doscopy”[MeSH Terms] NOT “bronchoscopy”[MeSH
Sedation for GI endoscopy 51
Terms] NOT “laparoscopy”[MeSH Terms] NOT “ureteros-
copy”[MeSH Terms] AND (English[LA] OR Japanese[LA])
AND “humans”[MeSH Terms] yielded 126 articles, of which
12 were meta-analyses/systematic reviews/clinical guideli-
nes, 56 were clinical trials, 20 were miscellaneous clinical
research/epidemiological research, and 38 were controlled
trials. After manual searching added four articles (including
two RCTs), screening results yielded 14 related references,
including six RCTs and one meta-analysis.
REFERENCES
1 Nishizawa T, Suzuki H, Sagara S et al. Dexmedetomidine
versus midazolam for gastrointestinal endoscopy: A meta-
analysis. Dig Endosc 2015; 27: 8–15.
2 Hashiguchi K, Matsunaga H, Higuchi H et al. Dexmedeto-
midine for sedation during upper gastrointestinal endoscopy.
Dig Endosc 2008; 20: 178–83.
3 Hayashi Y, Guo TZ, Maze M. Desensitization to the behav-
ioral effects of alpha 2-adrenergic agonists in rats. Anesthe-
siology 1995; 82: 954–62.
4 Riker RR, Shehabi Y, Bokesch PM et al. Dexmedetomidine vs
midazolam for sedation of critically ill patients : a randomized
trial. JAMA 2009; 301: 489–99.
5 Takimoto K, Ueda T, Shimamoto F et al. Sedation with
dexmedetomidine hydrochloride during endoscopic submu-
cosal dissection of gastric cancer. Dig Endosc 2011; 23: 176–
81.
6 Lee BS, Ryu J, Lee SH et al. Midazolam with meperidine and
dexmedetomidine vs. midazolam with meperidine for sedation
during ERCP: Prospective, randomized, double-blinded trial.
Endoscopy 2014; 46: 291–8.
7 Sethi P, Mohammed S, Bhatia PK et al. Dexmedetomidine
versus midazolam for conscious sedation in endoscopic
retrograde cholangiopancreatography: An open-label ran-
domised controlled trial. Indian J Anaesth 2014; 58: 18–24.
8 Lu Z, Li W, Chen H et al. Efficacy of a dexmedetomidine-
remifentanil combination compared with a midazolam-rmifen-
tanil combination for conscious sedation during therapeutic
endoscopic retrograde colangio-pancreatography: A prospec-
tive, randomized, single-blinded preliminary trial. Dig Dis Sci
2018; 63: 1633–40.
9 Venn RM, Grounds RM. Comparison between dexmedeto-
midine and propofol for sedation in the intensive care unit:
Patient and clinician perceptions. Br J Anaesth 2001; 87: 684–
90.
10 Nonaka T, Inamori M, Miyashita T et al. Feasibility of deep
sedation with a combination of propofol and dexmedeto-
midine hydrochloride for esophageal endoscopic submucosal
dissection. Dig Endosc 2016; 28: 145–51.
11 Nonaka T, Inamori M, Miyashita T et al. Can sedation using a
combination of propofol and dexmedetomidine enhance the
satisfaction of the endoscopist in endoscopic submucosal
dissection?Endosc Int Open 2018; 6: E3–10.
© 2020 Japan Gastroenterological Endoscopy Society
52 T. Gotoda et al.
12 Muller S, Borowics SM, Fortis EA et al. Clinical efficacy of
dexmedetomidine alone is less than propofol for conscious
sedation during ERCP. Gastrointest Endosc 2008; 67: 651–9.
CQ 20: Is the use of antagonists
recommended for sedation/pain relief cases?
Statement 20:
The use of flumazenil and naloxone hydrochloride is
recommended as antagonists for respiratory suppression
induced by benzodiazepine drugs and opioid analgesics,
respectively.
Assessment based on the modified Delphi method:
median, 8; minimum, 5; maximum, 9
Strength of recommendation: 2, Evidence quality
(strength): B
Textual explanation
Flumazenil is a benzodiazepine antagonist and is effective
in avoiding respiratory suppression induced by benzodi-
azepine drugs under emergency situations and the early
confirmation of PS during patient arousal. Antagonist
effects against respiratory suppression induced by mida-
zolam are expressed in 120 s of intravenous injections of
flumazenil, immediately reducing and eliminating respira-
tory suppression.1–3 However, flumazenil has a short
duration of action due to its prompt metabolism in the
liver, necessitating re-sedation.
When flumazenil or a placebo was administered in 50
patients who underwent upper endoscopy examinations
under midazolam-based sedation, significant improvements
in memory, psychomotor functions, and regulatory functions
were seen in the flumazenil-administered patients 5 min
after its administration, but no differences were seen
between the two groups during re-assessments after
3.5 h.4 When flumazenil or a placebo was administered
10 min after the end of upper GI endoscopy examination,
the duration of recovery room stay was significantly shorter
in the flumazenil-administered group, but there were no
significant differences in other factors (satisfaction, treat-
ment memory, psychological status, discomfort on the day
of the procedure and the following day, all based on the
pain/visual analog scale (VAS)) between the two groups.5
Flumazenil has been shown to have stronger antagonistic
effects against benzodiazepine-based sedation and amnesia
rather than against respiratory suppression,6 and reports
© 2020 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2021; 33: 21–53
have indicated flumazenil administration to be effective in
greatly reducing patient observation time following exam-
ination.7 As regards the timing of flumazenil administration,
trials comparing two groups where the drug was adminis-
tered immediately after or 15 min after endoscopy showed
that the latter group had higher patient satisfaction.8 This
suggests that flumazenil administration was effective not
only in the prompt elimination of respiratory suppression
but also in the prompt recovery from sedation or amnesia.
Issues relating to flumazenil use involve the possibility of
requiring re-sedation due to flumazenil having a shorter
duration of action than that of midazolam1–3 and patients
sometimes having convulsive or anxiety attacks (for those
who take anti-anxiety medication) due to flumazenil
administration.3
Naloxone hydrochloride is an opioid receptor antagonist,
which is metabolized in the liver into naloxone-3-glu-
curonide, and it can diminish or eliminate sedation,
respiratory suppression, delayed gastric discharge, papilla
sphincter muscle contraction, and analgesic effects by
expressing its opioid receptor antagonist effects.9 Issues
relating to naloxone hydrochloride use involve eliciting
acute withdrawal syndrome in opioid-dependent patients
and inducing hypertension, tachycardia, ventricular fibrilla-
tion, pulmonary edemas, hyperventilation, nausea, vomiting,
and convulsions, and naloxone hydrochloride itself can
induce respiratory suppression and sedation.9 Arbitrary use
of naloxone hydrochloride is not recommended since its
adverse effects can be potentially life-threatening.
The databases used for this reference extraction were
PubMed, Cochrane Library database, and Japan Medical
Abstract Society. A search using the keywords (“en-
doscopy” or “digestive system”) and (“sedation” or “anal-
gesia”) and (“antagonist” or “reversal agent” or “flumazenil”
or “naloxone”) and (“usefulness” or “utility” or “availabil-
ity”) yielded 132 articles, of which nine were meta-analyses/
systematic reviews/clinical guidelines, 59 were clinical
trials, 52 were miscellaneous clinical research/epidemiolog-
ical research, and 12 were controlled trials. After manual
searching added three articles (including RCTs), screening
results yielded nine related references, including seven
RCTs and one meta-analysis.
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© 2020 Japan Gastroenterological Endoscopy Society