Sedation with propofol during ERCP: is the combination with esketamine more effective and safer than with alfentanil? Study protocol for a randomized controlled trial
Eberl et al. Trials
Sedation with propofol during ERCP: is the combination with esketamine more effective and safer than with alfentanil? Study protocol for a randomized controlled trial
Susanne Eberl 0
Lena Koers 0
Jeanin E. van Hooft 2
Edwin de Jong 1
Thomas Schneider 1
Markus W. Hollmann 0
Benedikt Preckel 0
0 Department of Anesthesiology, Academic Medical Centre, University of Amsterdam , Meibergdreef 9, Amsterdam 1100 DD , The Netherlands
1 Department of Anesthesiology, Tjongerschans Ziekenhuis , Thialfweg 44, 8441 PW Heerenveen , The Netherlands
2 Department of Gastroenterology & Hepatology, Academic Medical Centre, University of Amsterdam , Meibergdreef 9, Amsterdam 1100 DD , The Netherlands
Background: Endoscopic retrograde cholangiopancreatography (ERCP) is a gastrointestinal procedure that requires a relatively motionless patient during the intervention. Deep sedation by intravenous propofol combined with an opioid has recently become the preferred sedation technique. However, when high doses of propofol are used, side effects, namely respiratory depression, may occur. Esketamine has hypnotic, analgesic, and sympathomimetic effects. Our assumption is that a combination of propofol with esketamine reduces the dosage of individual drugs, thereby minimizing sedation side effects while keeping the same satisfaction level of patients and endoscopists. Methods/design: The study will be performed as a randomized controlled multicenter trial. Patients undergoing ERCP, ≥ 18 years old, with American Society of Anesthesiologists (ASA) classification I-III will be randomized after written informed consent to group K (propofol/esketamine) or to group A (propofol/alfentanil). The primary outcome, reflecting effectiveness of sedation, is the total dose of propofol. Secondary outcome parameters are patients' and endoscopists' satisfaction with the procedure and the number of sedation-related pulmonary and cardiovascular events. Data on sedation-related events are collected by recording of oxygen saturation (SpO2), respiratory rate (RR), end-tidal CO2 (etCO2), heart rate (HR), arrhythmias (electrocardiogram (ECG)), and non-invasive blood pressure (NIBP) measurements. Satisfaction parameters are collected by means of questionnaires before and after the procedure and on the following day. Discussion: Esketamine is known for its effective anesthetic and analgesic effects maintaining spontaneous breathing and airway reflexes. Due to an increase in sympathetic tone, hypotension and cardiac depression is less common. Unfortunately esketamine is also known for its psychotomimetic effects. We aim to demonstrate that the combination of esketamine with propofol for sedation in patients subjected to ERCP interventions is nevertheless superior to a combination of propofol with an opioid. Trial registration: Nederland's Trial Register, NTR5486. Registered on 17 September 2015.
Procedural sedation; Propofol; ERCP; Esketamine
Endoscopic retrograde cholangiopancreatography
(ERCP) is a complicated, often painful gastrointestinal
procedure. It is used for diagnostic purposes in biliary
and pancreatic disease and also for therapeutic
interventions such as sphincterotomy, gallstone extraction, and
biliary and pancreatic duct stenting. Because any
movement of the patient could importantly affect success of
the ERCP, procedures are usually performed under deep
sedation or even general anesthesia with the patients in
the semi-prone or prone position [
]. Over the last
decade the combination of propofol and an opioid has
become the preferred sedative regime during ERCP in
many countries, despite known side effects.
Esketamine, the s-enantiomer of ketamine - is not only
a well-known sedative, but also has strong analgesic
properties. Furthermore, its sympathomimetic qualities
can counteract the hemodynamic depression of propofol
and so reduce the risk of cardiovascular and respiratory
depression during sedation. A potential problem of
esketamine could be its psychotomimetic effects, such as
visual disturbances, vertigo, or nausea that could
compromise patient satisfaction. There is still little
evidence of an improved safety profile of a combination
of propofol/esketamine and it is still open to discussion
whether esketamine psychomimetic effects play a
significant role in outpatient treatment.
Aim of the study
We hypothesize that procedural sedation with propofol
and esketamine reduces the dosage of individual drugs,
thereby minimizing sedation side effects while keeping
the same satisfaction level of patients and endoscopists.
To test this hypothesis we compare two groups. Group
K receives propofol/esketamine sedation; group A
receives propofol/alfentanil sedation during ERCP. Both
groups receive standard deep sedation with propofol
target controlled infusion (TCI) provided by specialized
sedation anesthesia nurses.
The study is designed as a prospective, randomized,
controlled, multicenter trial and reported following the
Standard Protocol Items: Recommendations for
Interventional Trials (SPIRIT) statement [
]. The sponsor of
this trial is the Department of Anesthesiology of the
Academic Medical Center (AMC) in Amsterdam. The
sponsor is responsible for the collection, management,
analysis, and interpretation of data; writing of the report;
and the decision to submit the report for publication.
The study is supported by institutional funding.
Additional file 1 shows the SPIRIT checklist that we
followed in this report.
Number of patients needed
Alfentanil reduces the required hypnotic dose of
propofol by 20–50% at fairly low doses according to the
]. A 15% reduction in propofol requirement when
using esketamine instead of alfentanil would reflect a
total dose reduction of propofol by up to 65%, which is
not only a statistically significant but also a clinically
The sample size calculation is based on
retrospectively obtained observational data from previous
ERCPs, collected in our hospital sedation database.
The primary endpoint is the difference in the dose of
propofol used. The mean dosage of propofol during
ERCP was 580 mg, with a standard deviation of
190 mg. We will need to study 76 subjects in each
group, given power of 0.80 and type I error of 0.05, to
reduce propofol requirement by about 15%.
Considering a dropout rate of 10%, the estimated sample size
will be 83 patients per group, thus a total of 166
patients will be randomized.
The study takes place at two centers: the Department
of Gastroenterology and Hepatology in the AMC of
the University of Amsterdam and the Department of
Gastroenterology and Hepatology in the Tjongerschans
ziekenhuis, Heerenveen, The Netherlands - beginning
December 2015 to January 2018. Eligible patients for
participation in this clinical trial are those planned to
undergo elective ERCP under deep propofol sedation,
aged above 18 years, and American Society of
Anesthesiologists (ASA) classification I–III, who give written
Patients are excluded if the following criteria in the
patients’ medical history are applicable:
Age range < 18 years
ASA classification IV or V
Allergic reaction to planned medication
History of unregulated or malignant hypertension
Significant ischemic heart disease
History of psychological problems or psychiatric
Use of drugs that affect the central nervous system
Increased intracranial pressure
The schedule of enrollment, intervention, and
assessment is reported according to the SPIRIT statement
The number of excluded patients and the reasons for
their exclusion will be reported according to the SPIRIT
Patients’ medical history and their current state of health
are screened on paper during standard anesthetic
preassessment before the scheduled sedation. The
investigator uses the anesthetic pre-assessment form to screen
patients for inclusion and exclusion criteria. Patients
meeting inclusion criteria are contacted by phone to
verify criteria and asked for their willingness to participate
in this study. Further information is sent by mail if they
agree to participate. Final inclusion occurs after written
informed consent is provided on the day of the
If patients decline to take part in the study, they are
sedated according to the AMC standards with propofol
and alfentanil. The investigator or physician performing
the examination can decide to withdraw a subject from
the study for urgent medical reasons (allergic reactions
or acute health problems).
Patients are randomized online in both centers after
signing informed consent using the ALEA software
program provided by the Clinical Research Unit (CRU)
of the AMC for centralized randomization in clinical
trials. Patients are allocated to a treatment arm after the
anesthetic nurse has entered patient details and absence
of exclusion criteria in the ALEA program.
The study is performed as a single-blinded study.
Because of safety reasons the anesthetic nurse is not be
blinded to the treatment arm and will therefore perform
the randomization in the ALEA program. The patient,
endoscopist, and investigator are blinded to the allocated
Patient data are collected on case report forms (CRFs)
in each center. Data processing will take place in the
AMC using the Castor database and will be performed
by the investigator or study coordinator. The CRU also
will independently monitor both locations of this
multicenter trial (AMC and Tjongerschans ziekenhuis) three
times using duplicated measurements documented in
the hospital data management systems with complete
access to all databases.
All patients are fasted at least 6 hours before ERCP.
Antibiotic prophylaxis is given according to hospital
standards. As a standard procedure, diclofenac 100 mg
is administered rectally immediately before the
procedure to reduce post ERCP pancreatitis [
sedation is performed by anesthesia nurses trained in
the standards of care for procedural sedation and
analgesia (PSA) according to the Dutch national
guidelines. An anesthesiologist is available for liaison,
supervision and emergency help. Insufflation of the duodenum
during ERCP is with CO2 instead of air, to reduce
periprocedural pain and abdominal distension.
Patients are asked to complete a questionnaire before
the procedure to assess baseline pain, drowsiness,
nausea, perception, and mood using a visual analog scale
(VAS) (0 = 100). Baseline assessments of the Modified
Observer’s Assessment of Alertness/Sedation Scale
(MOAA/S), the Aldrete recovery score and
measurements of heart rate (HR), non-invasive blood pressure
(NIBP), respiratory rate (RR), and oxygen saturation
(SpO2) are recorded.
After placement of an intravenous line, an infusion of
500 ml NaCl 0.9% is started at the rate of 250 ml/h.
Five minutes before insertion of the endoscope,
glycopyrrolate 0.2 mg, and lidocaine 50 mg are administered
intravenously. Then patients are asked to place
themselves into the prone or semi-prone position. From the
start of sedation till the end of the endoscopic
procedure, 2 L/min of oxygen are administered by nasal
cannula, and HR, SpO2, RR, electrocardiogram (ECG),
NIBP, end-tidal carbon dioxide (etCO2) and sedation level
measured by the MOAAS/S are collected at 5-minute
intervals. An independent, blinded observer collects
Both groups are sedated by a propofol TCI system
(Propofol 1% MCT Fresenius). TCI means a weight
preprogrammed system using the Marsh pharmacokinetic
model to attain a specific estimated propofol plasma
target level [
]. We start propofol TCI in both groups with
a targeted plasma level of 1.5 μg/ml. Reaching this
plasma level, group K is treated with esketamine
(Ketanest S, Pfizer) 150 μg/kg and group A is treated
with alfentanil (Rapifen, Janssen-Cilag) 2.0 μg/kg. After
2 min propofol TCI is stepped up - if needed - to a
maximum targeted plasma level of 2.5 μg/ml.
Before starting the endoscopic procedure, patients are
assessed for their level of sedation using the MOAA/S
scale yielding at a score <2. The modified form of the
MOAA/S scale uses not only the responsiveness
component of the original scale (awake (5) - unresponsive (1))
but is extended with assessment of painful stimuli. As
reaction to painful stimuli are still possible at anesthetic levels
that block reactions to verbal commands, prodding, or
shaking they can be used to assess deeper sedation levels.
If MOAA/S is > 2, e.g. the patient is too responsive to
tolerate the procedure; additional sedation is provided with
TCI increments of 0.5 μg/ml plasma target level. These
very small steps are performed in order to avoid deep
sedation. For every step up of propofol TCI, additional
esketamine 50 μg/kg or alfentanil 1 μg/kg is added. Maximum
dosage is 500 μg/kg ketamine or 7.5 μg/kg alfentanil.
Total dosage of propofol, alfentanil, and esketamine and
the time of the total procedure and length of time between
the end of the procedure (removing the scope) till
reaching an MOAAS score > 4 and the declaration that the
patient is ready for transport to the recovery unit, is noted.
At arrival in the recovery room, monitoring is
limited to SpO2, RR, ECG, and NIBP only. Recovery from
anesthesia and the return of psychotomotoric fitness is
assessed using the modified Aldrete score at arrival
and 15, 30, 45, and 60 min later. This score describes
the patient’s motoric activity, mechanical respiratory
function, oxygen saturation, blood pressure, and
consciousness and is designed to assess patient recovery
after sedation. The total score is 10 [
]. During the
time in the recovery room patients have to complete
the identical questionnaire they completed at baseline,
on pain, drowsiness, nausea, perception, and mood,
using a VAS (0 = 100). Following daily standards,
postprocedural pain is indicated as VAS > 40 and is treated
with 2 mg morphine intravenously; nausea indicated
by a VAS > 40 will be treated with 4 mg ondansetron
Patients have to stay for at least 1 h in the recovery
room. “Ready for discharge” is declared when an
Aldrete score ≥ 9 or similar to the pre-procedural score
is reached. The patient must be wide awake without
suffering from side effects (e.g. nausea, dizziness), with
stable hemodynamic signs, and able to ambulate
without assistance. A follow-up telephone call will take
place on the next day after the procedure.
Definition of primary endpoint
The primary endpoint of the study - reflecting the
effectiveness of coadministration of propofol and esketamine
is the total dose of propofol used.
Assessment of primary endpoint
We will record the total amount of propofol, esketamine,
alfentanil, and all other drugs administered.
Definition of secondary endpoints
Secondary endpoints focus on the satisfaction of
patients and endoscopists with sedation and side effects,
and on hemodynamic stability and safety, which is
reflected in the number of respiratory and
Assessment of secondary endpoint
Pain, sedation level, and side effects such as nausea and
psychotomimetic effects are recorded on questionnaires
that patients have to fill in before and after the
procedure. To assess post-procedural satisfaction patients are
contacted the day after the procedure by telephone. In
addition, endoscopists’ experiences with sedation are
recorded on a questionnaire after the procedure.
Before ERCP, after the procedure and arrival on the
recovery unit, and on the following day patients are asked to
complete questions on pain levels, drowsiness, nausea,
perception, and mood using VAS scales (0 = 100). Pain
intensity will be assessed by using a 100-mm VAS scale, with
0 = no pain and 100 = worst possible pain. Nausea will be
measured by a VAS scale, with 0 = none and 100 =
vomiting. Perceptual change will be assessed in five categories
(i.e., body, surroundings, time, reality, colors, and sounds)
by using a VAS scale anchored by “normal” at one end
and “extremely” at the other end. Mood states are ranked
between 0 and 100 in five categories: anxious/composed,
hostile/agreeable, depressed/elated, tired/energetic, and
confused/clearheaded) (modified from Mortero et al. [
The day after the procedure patients are contacted by
telephone to assess post-procedural satisfaction. The
patient is asked the same questions from part one and two
of the patient questionnaire. Patients are also be
interviewed about their total satisfaction with the procedure,
about their physical activity level using a 5-point rating
scale: 1 = chair bound; 2 = minimal (i.e. can go to the
bathroom); 3 = moderate (i.e. can go around the house
and garden); 4 = almost normal; and 5 = normal, and
they are asked if they would recommend this sedation
regime to one of their friends. Endoscopists have to fill
in questionnaires on their estimation of pain, sedation,
ease of performance, and satisfaction with the
Pulmonary and cardiovascular vital signs are
electronically recorded throughout the procedure and include
SpO2 measured by pulse oximetry, etCO2, RR, HR,
arrhythmias, and NIBP. Sedation-related pulmonary and
cardiovascular incidents are defined according to the
International Sedation Task Force of the World Society
of Intravenous Anaesthesia (SIVA) consensus statement
for standardized definitions and terminology for
sedation-related adverse events [
incidents are defined as oxygen desaturation (SpO2 75–90%)
for < 60 s, severe (SpO2 < 75% at any time) or prolonged
(SpO2 < 90% for >60 s) oxygen desaturation, apnea,
prolonged apnea (>60 s), airway obstruction with need for
airway interventions: facemask ventilation, guedel,
nasopharyngeal airway, and endotracheal tube.
Cardiovascular incidents are defined as bradycardia*, tachycardia*,
hypotension*, hypertension* (*as a change >25% from
baseline and/or necessitating an intervention),
cardiovascular collapse and arrest. In addition, the use of atropine,
ephedrine or phenylephrine intravenously to treat
hypotension or bradycardia is noted.
Statistical analyses will be performed using SPSS
statistics. All data will be checked for normal distribution
using the Kolmogorov test. For normally distributed
data, continuous variables will be analyzed using the
independent Student’s t test and the variables will be
presented as mean ± standard deviation (SD).
Nonnormally distributed data will be compared using the
Mann-Whitney U test where appropriate, and data will
be presented as the median and interquartile range
(IQR). For categorical variables, cross-tabulation and the
Pearson chi-squared test will be applied and variables
will be allegorized as number and/or percentage of the
total. To compare the continuous measurements of HR,
NIPD, and SpO2 between the groups, the area under the
curve (AUC) for each value will be calculated over the
different measurement time points during the procedure. A
p value <0.05 will be considered statistically significant.
Confidence intervals will be reported where appropriate.
This trial is conducted in accordance with the protocol
and in compliance with the moral, ethical, and scientific
principles governing clinical research as set out in the
Declaration of Helsinki (1989) and Good Clinical Practice
(GCP). It is registered in the Nederland’s Trial Register
(NTR5486) (registration date 17 September 2015). A
centralized ethics committee (the Medical Ethics Committee
of the AMC, Amsterdam, The Netherlands (NL)) has
approved this study for both participating centers: the AMC,
Amsterdam and the Tjongerschans ziekenhuis,
Heerenveen, The Netherlands. The National Authority, the Central
Committee on Research Involving Human Subjects
(CCMO), performed a marginal review and there were no
objections to perform this study (NL53999.018.15 BI).
In recent years, the combination of propofol with an
opioid for sedation has replaced the conventionally used
combination with benzodiazepines, and became the
standard for analgo-sedation during ERCP, with the advantage
of improved titration of sedation, shorter recovery time,
and better patient tolerance and satisfaction. However, a
possible consequence of high-dose propofol sedation is
that it may result in progression from deep sedation to
general anesthesia. Cote et al. showed that hypoxemia
occurred in 12.8% of 799 patients sedated for endoscopic
procedures with propofol applied by trained anesthesia
]. Minimizing these risks is therefore an
important goal to make sedation procedures safer. A possible
approach is to reduce the propofol dosage using a
combination with other substances.
Esketamine offers the advantages of minimizing
sedation side effects, making optimal use of the concept of
synergy while being an analgesic at the same time. Despite
its effective anesthetic and analgesic effects, spontaneous
breathing and airway reflexes are maintained and
hypotension is less common due to an increase in
sympathetic tone. Varadarajulu et al. [
] demonstrated that the
use of ketamine in patients who were difficult to sedate
during ERCP resulted in better quality of sedation and
analgesia. They observed shorter recovery times compared
with opiate and benzodiazepine sedation. However, they
concluded that it is necessary to conduct further
randomized trials. Wehrmann et al. [
] recommended the
combination of propofol with ketamine because of its analgesic
properties without cardiorespiratory depressant effects.
Mortero et al. [
] found that the combination of
propofol with small doses of ketamine during
monitored anesthesia for surgical interventions reduced
hypoventilation caused by propofol, induced a stable
positive spirit, and provided earlier recovery of
perception in comparison to propofol alone.
The most widespread doubts about esketamine,
however, correspond to its mind-altering effects in cognition.
It can produce psychotomimetic effects that may be
associated with symptoms similar to dissociative states of
]. On the other hand, Nakao et al. [
that propofol used in clinical relevant dosages suppresses
these effects via the activation of GABA receptors.
Unfortunately, there are only a few studies with only
limited significance investigating the effectiveness of a
propofol/esketamine regime with emphasis on the
aforementioned safety aspects during ERCP and the
eventually psychotomimetic effects such as visual disturbances,
vertigo, or nausea that could compromise patient
satisfaction and recovery after discharge home.
A limitation of our study could be that we based
sample size calculation on the reduction of the total
dosage of propofol. Probably, acute respiratory or
hemodynamic adverse events would have been a more
appropriate primary outcome. However, much
largerscale studies would have been necessary to address this
outcome. Alongside this we defined cardiorespiratory
events according to the SIVA consensus statement for
standardized definitions and terminology for
sedationrelated adverse events. However, their clinical impact
cannot be determined when a sedation specialist
provides adequate rescue maneuvers during such events.
The aim of our trial is to show that the synergy of
esketamine and propofol reduces the dosage of
individual drugs, thereby providing a better safety and
satisfaction profile than the combination with an
opioid during ERCP.
The first patient was included on 8 December 2015. We
expect to finalize the study in December 2017.
Additional file 1: SPIRIT checklist. (DOC 121 kb)
AMC: Academic Medical Centre; ASA: American Society of Anesthesiologists;
AUC: Area under the curve; CCMO: Central Committee on Research Involving
Human Subjects; CRU: Clinical Research Unit; ECG: Electrocardiogram;
ERCP: Endoscopic retrograde cholangiopancreatography; EtCO2: End-tidal
CO2; GCP: Good Clinical Practice; HR: Heart rate; IQR: Interquartile range;
MOAA/S: Modified Observer’s Assessment of Alertness/Sedation Scale;
NIBP: Non-invasive blood pressure; NRS: Numeric rating score;
NTR: Nederland’s Trial Register; SD: Standard deviation; SIVA: Society of
Intravenous Anaesthesia; SO2: Oxygen saturation; SPIRIT: Standard Protocol
Items: Recommendations for Interventional Trials; TCI: Target controlled
infusion; VAS: Visual analog scale
This study does not have any financial support from the manufacturer or
other sources. It is supported by institutional funding of the Department of
anesthesiology of the AMC.
Availability of data and materials
SE is responsible for drafting the manuscript. SE, BP, JEvH, and LK are
responsible for the study design. SE, LK, BP, JEvH, EdJ, TS, and MWH are
responsible for revising the manuscript. All authors have read and approved the
Ethics approval and consent to participate
This trial is conducted in accordance with the protocol and in compliance
with the moral, ethical, and scientific principles governing clinical research as
set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP).
It is registered in the Nederland’s Trial Register (NTR5486) (registration date:
17.11.2015). A centralized ethics committee (the Medical Ethics Committee of
the Academic Medical Centre, Amsterdam, The Netherlands (NL)) has
approved this study for both participating centers: the Academic Medical
Center, Amsterdam and the Tjongerschans ziekenhuis, Heerenveen, The
Netherlands. The National Authority, the Central Committee on Research
Involving Human Subjects (CCMO), performed a marginal review and there
were no objections to perform this study (NL53999.018.15).
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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