Short-Acting Sedative Agents During Endoscopic Retrograde Cholangiopancreatography: A Review of Clinical Effectiveness and Guidelines

Kwakye Peprah; Melissa Severn; Charlotte Wells; Anusree Subramonian

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Short-Acting Sedative Agents During Endoscopic Retrograde Cholangiopancreatography: A Review of Clinical Effectiveness and Guidelines

CADTH Rapid Response Report: Summary with Critical Appraisal

Kwakye Peprah, Melissa Severn, Charlotte Wells, and Anusree Subramonian.

Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2020 Aug 17.

Abbreviations

ASA: American Society of Anesthesiologists
BIS: Bi-Spectral index scale
bpm: beats per minute
CI: confidence interval
DK: dexmedetomidine–ketamine
DR: dexmedetomidine–remifentanil
ERCP: endoscopic retrograde cholangiopancreatography
IQR: interquartile range
ITT: intent-to-treat
MAP: mean arterial pressure
ME: midazolam–etomidate
MF: midazolam–fentanyl
MK: midazolam–ketamine
MM: midazolam–meperidine
MP: midazolam–propofol
MPt: midazolam–pethidine
MR: midazolam–remifentanil
PA: propofol–alfentanil
PE: propofol–esketamine
PF: propofol–fentanyl
PK: propofol–ketamine
PM: propofol–meperidine
PR: propofol–remifentanil
RCT: randomized controlled trial
RSS: Ramsey Sedation Scale
SD: standard deviation
SRS: Steward Recovery Score

Context and Policy Issues

Endoscopic retrograde cholangiopancreatography (ERCP) is essential in the diagnosis and treatment of pancreaticobiliary pathologies.¹ The procedure time ranges from 30 to 60 minutes, and it is commonly performed in endoscopy suites away from the operating room.² ERCP is a minimally invasive technique and has fewer complications, generally shorter hospitalization times, and lower medical costs compared to traditional surgery, particularly in sick and elderly patients suffering from hepatobiliary tract disorders.¹ The procedure may be performed under general anesthesia to keep patients stable³ or with moderate to deep levels of sedation and analgesia to minimize patient discomfort during the procedure.² However, potential complications involving respiratory and cardiovascular conditions, which may be related to the level of sedation,⁴ may occur during the operation. Essential factors to consider concerning the level of sedation for ERCP procedure include patient tolerance, the presence of comorbidities, the endoscopist’s comfort and ease of the procedure, staff, equipment, and anesthesia support available in the endoscopy suite.² Benzodiazepine, opiates, and propofol in different combinations are commonly administered to provide conscious or deep sedation for patients undergoing ERCP.⁵ It has been reported that one-third to one-half of patients undergoing ERCP under conscious sedation experience discomfort and pain.⁶ Thus, there is a need for a sedation method or regimen that offers efficacy and has an excellent safety profile regarding sedation-related side effects.

This report aims to identify and summarize evidence on the clinical effectiveness of short-acting sedative agents for conscious sedation during ERCP. An additional objective is to synthesize evidence-based guidelines for moderate procedural sedation during ERCP.

Research Questions

What is the clinical effectiveness of short-acting sedative agents during endoscopic retrograde cholangiopancreatography?
What are the evidence-based guidelines for moderate procedural sedation during endoscopic retrograde cholangiopancreatography?

Key Findings

Thirteen randomized controlled trials and one retrospective cohort study provided information regarding the clinical effectiveness of short-acting sedative agents during endoscopic retrograde cholangiopancreatography. The studies covered a wide range of short-acting sedatives, including propofol alone, etomidate alone, and remifentanil alone. Others were propofol-based combinations (i.e., propofol–alfentanil, propofol–esketamine, propofol–fentanyl, propofol–ketamine, propofol–meperidine, midazolam–propofol, and propofol–remifentanil), midazolam-based combinations (i.e., midazolam–etomidate, midazolam–fentanyl, midazolam–ketamine, midazolam–meperidine, midazolam–pethidine, and midazolam–remifentanil), and dexmedetomidine-based combinations (dexmedetomidine–ketamine and dexmedetomidine–remifentanil).

Therefore, although 14 studies were included in this report, they were spread over several unique intervention-comparator pairs. In effect, there was a limited quantity of evidence for each comparison. Also, doses of sedative agents used tended to vary from study to study, so that even where drugs appeared to be the same in two or more studies, they usually differed in doses. Other sources of limitations included inadequate determination of sample sizes to ensure that studies were adequately powered to determine differences in treatment effects between competing groups, the use of unvalidated methods to assess satisfaction with sedation and pain during the ERCP procedure, lack of adequate blinding in some randomized trials, and the use of data from different historical periods in the retrospective cohort study. Although each of the agents investigated in the included studies demonstrated some effectiveness, given the limitations discussed here and elsewhere in the report, a definitive conclusion could not be drawn about the optimal choice of short-acting sedative agents during ERCP due to the qualitative and quantitative limitations of the evidence that was available for this report.

No relevant evidence-based guidelines were identified for moderate procedural sedation during endoscopic retrograde cholangiopancreatography.

Methods

Literature Search Methods

A limited literature search was conducted by an information specialist on key resources, including Medline via Ovid, the Cochrane Library, the University of York Centre for Reviews and Dissemination (CRD) databases, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy was comprised of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were endoscopic retrograde cholangiopancreatography and sedation. No filters were applied to limit the retrieval by study type. The search was also limited to English language documents published between Jan 1, 2015, and Jul 16, 2020.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed, and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1

Selection Criteria.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1; they were duplicate publications or were published before 2015. A systematic review⁷ in which outcomes of interest were presented only in ranked form was not included since rankings can be misleading.

Critical Appraisal of Individual Studies

The included publications were critically appraised by one reviewer using the Downs and Black checklist⁸ for randomized and non-randomized studies. Summary scores were not calculated for the included studies; instead, the strengths and limitations of each included publication were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 340 citations were identified in the literature search. Following the screening of titles and abstracts, 324 citations were excluded, and 16 potentially relevant reports from the electronic search were retrieved for full-text review. Two potentially relevant publications were retrieved from the grey literature search for full-text review. Of these potentially relevant articles, four papers were excluded for various reasons, and 14 publications met the inclusion criteria and were included in this report. These comprised 13 randomized controlled trials (RCTs)¹^–³^,⁵^,⁶^,⁹^–¹⁶ and one retrospective cohort study.¹⁷ Appendix 1 presents the PRISMA¹⁸ flowchart of the study selection.

Summary of Study Characteristics

Additional details regarding the characteristics of included publications are provided in Appendix 2.

Study Design

Thirteen RCTs¹^–³^,⁵^,⁶^,⁹^–¹⁶ and one retrospective cohort study¹⁷ published between 2015 and 2020 were included in this report. One trial³ used a noninferiority design for assessing the primary outcome. Seven of the trials were double-blind studies,³^,⁵^,¹⁰^–¹³^,¹⁶ one was single-blind with only investigators blinded. In contrast, four had partial blinding, where the patients and some research staff were blinded to the allocation of study groups, but the endoscopist¹⁵ or sedation practitioners²^,⁶^,⁹ were not blinded. The retrospective cohort study¹⁷ was based on data from patients who had ERCP in 2016 and 2018 at a single hospital.

Country of Origin

Four RCTs were conducted in China,¹^,⁵^,⁶^,¹⁶ while two were conducted in Iran,¹²^,¹³ two in South Korea,³^,¹¹ and one each in Egypt,¹⁰ India,² Netherlands,⁹ Turkey,¹⁴ and the United Kingdom.¹⁵ The retrospective cohort study¹⁷ was conducted in Turkey.

Patient Population

All the studies¹^–³^,⁵^,⁶^,⁹^–¹⁷ included in this report were conducted in adults (i.e., 18 years or older) who underwent ERCP procedure. In one RCT,¹¹ eligibility to participate was limited to patients who were over 80 years old. Also, the retrospective cohort study¹⁷ enrolled only patients who were at least 85 years old. According to the authors, inclusion criteria were restricted to patients belonging to the American Society of Anesthesiologists (ASA) Physical Status Classifications Class I to II,³^,¹¹^–¹³ Class I to III,¹^,²^,⁹^,¹⁴^–¹⁶ Class III to IV,¹⁷ and Class I to IV.⁶^,¹⁰ One study⁵ did not report the ASA classification of the participants. The ASA classification system defines patients’ medical co-morbidities conditions before anesthesia. It ranks them in a range from ASA I to ASA VI, where ASA I refers to a regular a healthy patient, and ASA VI describes a patient who has been declared brain dead.¹⁹ Patients in the ASA Classes of II, III, IV, and V, are those with mild systemic disease, severe systemic disease, severe systemic disease that is a constant threat to life, and a moribund patient who is not expected to survive without the operation, respectively.¹⁹ Twelve RCTs¹^–³^,⁵^,⁶^,¹⁰^–¹⁶ and the retrospective cohort study¹⁷ were conducted at single hospital settings, whereas one RCT⁹ was conducted in two hospitals.

Interventions and Comparators

Eleven of the studies²^,³^,⁶^,⁹^–¹⁴^,¹⁶^,¹⁷ included in this report evaluated interventions involving propofol-based sedation protocols. The sedation effectiveness of a combination of propofol with fentanyl (PF) was investigated in six RCTs,²^,⁶^,¹¹^–¹⁴ where it was compared with combinations of midazolam plus fentanyl (MF),¹¹ propofol plus ketamine (PK),¹²^,¹³ dexmedetomidine plus ketamine (DK),² propofol plus meperidine (PM),⁶ propofol plus remifentanil,¹⁴ or propofol alone.¹⁴ Propofol alone was also an intervention in two other RCTs,¹⁰^,¹⁶ in which it was compared with a combination of PK,¹⁰ or etomidate alone.¹⁶ Other comparisons involving propofol-based sedation were propofol plus alfentanil (PA) versus propofol plus esketamine (PE) in one RCT,⁹ midazolam plus propofol (MP) versus midazolam plus etomidate (ME) in another RCT,³ and PK versus midazolam plus meperidine (MM) in one retrospective cohort study.¹⁷

The remaining three studies¹^,⁵^,¹⁵ compared midazolam-based sedation with other interventions. One RCT,¹ compared a combination of midazolam plus remifentanil (MR) with dexmedetomidine plus remifentanil (DR), one RCT⁵ compared MM with remifentanil alone, and one RCT¹⁵ compared midazolam plus pethidine (MPt) with midazolam plus ketamine (MK).

The doses of the individual drugs varied across the studies. Further details are available in Table 2.

Outcomes

Sedation effectiveness or quality was measured directly using Ramsey Sedation Scale (RSS),¹^,¹²^–¹⁴ or Bi-Spectral index scale (BIS).¹⁰ The RSS is a validated scale used to evaluate the depth of sedation with scores ranging from 1 to 6, where patients with a score of 1 are described as awake, agitated or restless, or both; and those with a score of 6 are asleep or have no response to a glabellar tap or loud auditory stimulus.¹^,¹³ The BIS assesses the depth of anesthesia on a scale of 0 to 100, using a numerical derivative from brain electrical activity. Zero on the scale represents a state of no detectable brain electrical activity, and 100 represents a state of complete wakefulness. Values below 60 correspond to deep sedation.¹⁰ Indirect assessments of sedation effectiveness were performed using surrogates such as the time to achieve sedation,¹⁷ the total dose (in milligrams) of sedation medication,¹^,⁹^,¹²^,¹⁴ doses of medication used to restore sedation (sedation rescue),¹^,¹³^,¹⁷ and pain during the procedure.¹^,⁵^,¹⁰^,¹¹^,¹⁵ One RCT¹⁵ assessed pain on a 0 to 4 scale, where zero meant no pain and 4 represented very severe pain. Two RCTs¹⁰^,¹¹ reported using a visual analogue scale to assess pain without providing any details about the scales. Two RCTs¹^,⁵ and Zhang et al.⁵ did not specify how pain assessments were performed.

Other outcomes of interest included time to recovery,¹^–³^,⁶^,⁹^–¹¹^,¹³^,¹⁵^,¹⁷ satisfaction with sedation (as rated by patients,¹^,³^,⁵^,⁹^–¹¹^,¹³^,¹⁵^,¹⁶ and endoscopists¹^–³^,⁵^,⁹^–¹¹^,¹³ or gastroenterologist¹⁴^,¹⁶), overall hemodynamic stability,¹²^–¹⁴ overall cardiovascular adverse events,¹^,¹¹ mean arterial pressure (MAP),¹^,¹³^,¹⁶ hypotension,²^,⁵^,⁶^,⁹^–¹¹^,¹⁶^,¹⁷ bradycardia,²^,⁵^,⁶^,⁹^–¹¹^,¹⁶^,¹⁷ heart rate,¹^,¹³^,¹⁶ respiratory rate,¹^,⁵^,¹³ oxygen desaturation,⁶^,⁹^–¹¹^,¹³^,¹⁷ respiratory depression,¹^,²^,⁵ apnea,⁵^,¹²^,¹³^,¹⁶^,¹⁷ hypoxia,¹¹ nausea and/or vomiting,¹^,²^,⁵^,⁹^,¹⁰^,¹³^,¹⁵^,¹⁶ hypersalivation,¹⁰ and agitation.¹⁰

Eight of the ten studies that reported time to recovery findings defined the outcome based on as time to achieve modified Aldrete score ≥ 9.²^,³^,⁶^,⁹^,¹¹^,¹³^,¹⁶^,¹⁷ The Aldrete scale is a validated tool with five domains to evaluate recovery after anesthesia.²⁰ Each domain is rated from 0 to 2 points, with higher scores indicating a greater likelihood of recovery without the need for observation. Ratings of 7 and below indicate a need for continuous observation.²⁰ One study each assessed time to recovery using BIS (as previously defined) score ≥ 90,¹⁰ or Steward Recovery Score (SRS) of 6.¹ The SRS is a scoring system with three domains for recording post-anesthetic recovery, each rated from 0 to 2 for a total score range of 0 of 6. A score of 0 indicates an unresponsive, immobile patient whose airway requires maintenance, and a score of 10 denotes a fully recovered patient.²¹

Summary of Critical Appraisal

Additional details regarding the strengths and limitations of included publications are provided in Appendix 3.

All the studies¹^–³^,⁵^,⁶^,¹⁰^–¹⁷ included in this report stated their objectives clearly and outlined the inclusion and exclusion criteria. Seven of the RCTs had a double-blind design,³^,⁵^,¹⁰^–¹³^,¹⁶ and six were single or partial blind RCTs. Thus, there was a potential risk for bias in the single or partial blind RCTs due to an uneven approach to sedation rescue and other maneuvers, as a result of knowledge of the sedative intervention to which patients were assigned.¹^,²^,⁶^,⁹^,¹⁴^,¹⁵ One RCT³ had a noninferiority design with a prespecified margin of 10%, which was appropriately applied in the interpretation of the results. However, the rationale for choosing that margin level was not provided. Investigators in nine RCTs¹^–³^,⁶^,⁹^,¹⁰^,¹²^,¹³^,¹⁶ conducted sample size calculations beforehand to determine the number of patients that will adequately power the studies to detect relevant differences in effect between the competing treatment study groups. Sample size calculations were not performed in four RCTs⁵^,¹¹^,¹⁴^,¹⁵ and one retrospective cohort study.¹⁷ However, even in the studies that performed sample size calculations, they were based on primary outcomes and not the secondary and other outcomes. Thus, in comparisons where statistically significant differences in treatment effects in secondary outcomes were not observed, it was unclear whether a larger sample size could have resulted in different results.

All the studies listed the relevant characteristic of the study participants in tabular form. The baseline demographic characteristics, procedure time, and indications for ERCP were similar across the treatment groups, without statistically significant differences in eight RCTs.¹^–³^,⁶^,¹⁰^–¹⁵ In two RCTs,⁵^,⁹ some baseline characteristics (age,⁵^,⁹ sex,⁹ and cardiovascular disease⁹) appeared dissimilar between the treatment groups. However, P-values were not reported. Therefore, one could not tell whether the differences were statistically significant. Patients in the two treatment groups of the retrospective cohort study¹⁷ underwent the ERCP procedure in two different periods (midazolam-meperidine group in 2016 and propofol-ketamine group in 2018). Thus, there is a potential for significant differences in the delivery of healthcare over time that could bias outcomes. For example, the duration of the procedure differed significantly between the treatment groups.

The interventions and comparator in all the studies¹^–³^,⁵^,⁶^,¹⁰^–¹⁷ were described in detail, including doses, mode of administration, and co-administered medications. However, in reporting the doses of drugs used for sedation rescue, one RCT¹ provided data about only one out of at least three drugs that were used for that purpose. The omission to include information about the other rescue medications suggested a risk of bias due to selective reporting. The outcomes measures in all the studies¹^–³^,⁵^,⁶^,¹⁰^–¹⁷ appeared relevant, and they were well-defined. However, for studies that evaluated satisfaction with sedation¹^–³^,⁵^,⁶^,⁹^–¹¹^,¹³^,¹⁵^,¹⁶ and pain during the ERCP procedure,¹^,⁵^,¹⁰^,¹¹^,¹⁵ it was unclear if the assessment method had been validated for that purpose. All the studies used appropriate statistical methods to analyze the study outcomes, and they reported the main findings well. In eight RCTs, ³^,⁵^,¹⁰^–¹³^,¹⁵^,¹⁶ the analyses were based on the intention-to-treat (ITT) population involving data from all the patients who were randomized in their original group to which they were assigned. However, five RCTs excluded some patients from analysis for various reasons such as, not receiving allocated intervention,⁹ not undergoing the ERCP procedure,⁹ failure of intubation,¹ duodenal perforation,¹ severe respiratory depression,¹ missing data,²^,⁶ procedure termination,² and a drop in their oxygen saturation levels during the procedure.¹⁴ In four RCTs,⁵^,¹⁰^,¹²^,¹⁴ the authors did not acknowledge limitations or consider any in the discussion of results and conclusions of their studies.

Authors of 13 of the included studies declared no conflict of interest. In contrast, no statement on potential conflict of interest or sources of funding was provided in one RCT.¹⁰ Other sources of uncertainty included restricting the study population to low-risk patients, ³^,⁹^,¹¹^–¹³ enrollment of only patients of particular geographic origin,⁶^,¹⁶ and limiting eligibility to patients over eighty¹¹ or eighty-five years old.¹⁷ These limitations potentially restricted the generalizability of the findings to other patients. All studies¹^–³^,⁵^,⁶^,¹⁰^–¹⁷ included in this report were conducted outside of Canada. Thus, the generalizability of the reported outcomes in the Canadian context is unknown.

Summary of Findings

Appendix 4 presents the main study findings and the authors’ conclusions.

Clinical Effectiveness of Short-acting Sedative Agents During Endoscopic Retrograde Cholangiopancreatography

Effectiveness of the sedative or sedation quality

Nine RCTs¹^,⁵^,⁹^–¹⁵ and one retrospective cohort study¹⁷ reported on the comparative sedation effectiveness of various short-acting sedative agents for ERCP.

Ramsey Sedation Scale as a measure of sedation

Lu et al.¹ reported that dexmedetomidine–remifentanil (DK) combination provided a significantly higher depth of sedation than midazolam–remifentanil (MR) combination (P < 0.05). Bahrami Gorji et al.¹³ determined that the sedation quality of a propofol–ketamine (PK) combination was statistically significantly better than a propofol-fentanyl (PF) combination at assessments four minutes (P = 0.037) and 15 minutes (P = 0.035) after the start of sedation, but not at other times (0, 2, 6, 8, 10, 20 minutes) of assessment (P > 0.05). However, Akhondzadeh et al.¹² found no significant difference in the quality of sedation between PF and PK combinations (P = 0.68). Similarly, Haytural et al.¹⁴ found no statistically significant difference in the level of sedation between PF versus propofol–remifentanil combination (PR) versus propofol alone (P > 0.0033; by Bonferroni corrections, where P < 0.0033 was the accepted level statistical significant).

Time to Achieve Sedation

In the retrospective cohort study by Ebru and Resul,¹⁷ the mean (standard deviation [SD]) time to achieve the targeted sedation score of RSS ≥ 4 was statistically significantly longer in the MM conventional group than the PK group (5.41 [0.49] minutes versus 3.21 [0.41] minutes, respectively; P < 0.001).

Total doses of sedation agents as a surrogate measure of the quality of sedation

Eberl et al.⁹ reported that patients sedated with a Propofol–Esketamine (PE) combination group received significantly less propofol than those sedated with a Propofol–Alfentanil (PA) combination (8.3 mg/kg/hour versus 10.5 mg/kg/hour; P<0.001). Haytural et al.¹⁴ found that the total dose of propofol administered was statistically significantly higher in the propofol alone group than in the PR group (375 mg versus 150 mg; P < 0.05) or the PF (375 mg versus 245 mg; P < 0.001). They also reported that the total propofol dose administered was statistically significantly higher in the PF group than in the PR group (245 mg versus 150 mg; P < 0.05). However, Akhondzadeh et al.¹² found no significant difference in the total dose of propofol used for sedation between the PF and PK groups (P = 0.36).

Doses of Sedation Rescue as Surrogate

Lu et al.¹ reported that six patients (5.6%) sedated with DK and five patients (5.8%) sedated with MR required additional doses of sedative medication to sustain sedation at the desirable level. They found that the additional dosage of midazolam to maintain sedation was statistically significantly higher in the MR group than the DR group (P < 0.001). It is worth noting that the comparison was limited to midazolam. However, according to the authors, drugs used for rescue sedation during the procedure included midazolam, propofol, and remifentanil.¹ Bahrami Gorji et al.¹³ found no statistically significant difference between the PF and PK regarding the need for rescue medication to sustain sedation. The mean (SD) doses of propofol used for rescue were 30.95 (47.77) mg with PF versus 41.00 (64.71) mg with PK (P = 0.45). In the retrospective cohort study by Ebru and Resul,¹⁷ the mean (SD) dose of propofol used as the rescue was statistically significantly higher in the group of patients sedated with midazolam–meperidine (MM) combination than those sedated with PK group (12.15 [0.56] mg versus 10.32 [0.62] mg, respectively; P < 0.001)

Pain During Procedure

In the RCT by Lu et al.,¹ two patients (1.9%) sedated with DK reported a painful procedure compared with six patients (6.9%) sedated with MR. The difference was statistically significant (P = 0.001). Zhang et al.⁵ reported that five patients (15.2%) in the MM conventional group experienced pain during the procedure versus three patients (9.1%) each in the remifentanil alone or MR groups. The difference was not statistically significant (P > 0.05 in each comparison). Sayed et al.,¹⁰ Han et al.,¹¹ and Narayanan et al.¹⁵ also found no significant difference between propofol alone versus PK, PF versus midazolam–fentanyl (MF), and MP versus MK, respectively, regarding pain during the procedure (P > 0.05 in each study). It should be noted that only Narayanan et al.¹⁵ provided details about the measuring scale for pain (0 to 4 scale, where zero = no pain and 4 = very severe pain). Even so, it was unknown if the scale was validated. Sayed et al.¹⁰ and Han et al.¹¹ reported using a visual analogue scale to assess pain without providing any details about the scales. Lu et al. ¹ and Zhang et al. ⁵ did not specify how pain assessments were performed.

Time to recovery

Ten RCTs¹^–³^,⁶^,⁹^–¹¹^,¹³^,¹⁵^,¹⁶ and one retrospective cohort study¹⁷ reported time to recovery outcomes for various comparisons between short-acting sedative agents.

The RCT by Sayed et al.¹⁰ found that the mean (SD) time to time to recovery was statistically significantly shorter with propofol alone than PK (7.23 [0.92] versus 13.95 [2.19] minutes, respectively; P = 0.00). The RCT by Han et al.¹¹ reported that the mean (SD) times to recovery were significantly shorter with PF sedation than with MF (14.11 [4.46] versus 17.91 [6.29] minutes, respectively; P < 0.001). In the RCT by Goyal et al.,² the mean (SD) time to recovery was statistically significantly shorter in the PF group than the DK group (5 [5] versus 10 [5] minutes, respectively; P < 0.001) Similarly, the retrospective cohort study by Ebru and Resul¹⁷ found that the mean (SD) time to recovery (RSS ≥ 4) was statistically significantly longer in the MM conventional group than the PK group (5.41 [0.49] minutes versus 3.21 [0.41] minutes, respectively; P < 0.001)

However, in three RCTs by Bahrami Gorji et al.,¹³ Lu et al.,¹ Park et al.,³ and Song et al.¹⁶ there was no significant difference in the mean (SD) time to recovery between the PF versus PK, DR versus MR, etomidate alone versus propofol alone (P> 0.05 in all comparisons). Also, three RCTs by Eberl, et al.,⁹ Narayanan et al.,¹⁵ and Shin et al.⁶ did not find a statistically significant difference in the median (interquartile range [IQR]) time to recovery between PA versus PE, MP versus MK, and Propofol–Meperidine (PM) versus PF combinations, respectively (P> 0.05 in all comparisons).

Satisfaction with sedation

Twelve RCTs reported satisfaction with sedation outcomes as rated by patients¹^,³^,⁵^,⁹^–¹¹^,¹³^,¹⁵^,¹⁶ and endoscopists,¹^–³^,⁵^,⁹^–¹¹^,¹³ or gastroenterologists¹⁴^,¹⁶

Sayed et al.¹⁰ reported that the overall patients’ satisfaction with sedation was statistically significantly higher with propofol alone than with PK combination (P =0.008). Similarly, Lu et al. ¹ found that patients’ satisfaction was significantly higher in the DR group than the MR group (P = 0.001). Zhang et al.⁵ also found that the mean (SD) endoscopists’ satisfaction score was generally high in all treatment groups; however, significantly higher with remifentanil alone than both MM (96.2 [4.7] versus 93.5 (5.8), respectively; P< 0.05), and RM (96.2 [4.7] versus 94.9 [5.2], respectively; P< 0.05). However, the difference in the endoscopists’ satisfaction score between MM versus RM was not statistically significant

In the other studies, patients in each group had high satisfaction ratings with sedation without statistically significant differences between the treatment groups. In the RCT by Eberl et al.,⁹ the median (IQR) patients’ satisfaction was not statistically significantly different between PA and PE groups (P=0.812), and there was no significant difference between the groups regarding patients’ willingness to recommend the sedation regimen (P=0.33). Likewise, the median (IQR) patients’ satisfaction scores in the RCTs by Shin et al.⁶ and Song et al.¹⁶ were not statistically significantly different between PM versus PF and etomidate alone versus propofol alone, respectively (P≥0.419). In the RCTs by Han et al.,¹¹ Bahrami Gorji et al.,¹³ Zhang et al.,⁵ and Narayanan et al.,¹⁵ there were no statistically significant differences in the mean (SD) scores for patients’ satisfaction with sedation between MF versus PF, PF versus PK, remifentanil alone versus MR, and MP versus MK, respectively (P≥0.646). The RCT by Park et al.³ found no statistically significant difference between the ME versus MP groups regarding the percentage of patients who were satisfied with sedation (93.8% versus 96.8%, respectively; P = 1.000)

Furthermore, in all the RCTs that reported endoscopist satisfaction, the ratings were similarly high across treatment groups in each study and showed no statistically significant differences. Eberl, et al.⁹ and Shin et al.⁶ found no statistically significant differences in the median (IQR) endoscopist satisfaction scores between PA versus PE and PF versus PM, respectively (P≥0.199). Similarly, Sayed et al.,¹⁰ Park et al.,³ and Goyal et al.,² reported that the percentage endoscopists’ satisfaction with sedation was not statistically significantly different between propofol alone versus PK, ME versus MP, and PF versus DK, respectively (P ≥ 0.113). Haytural et al.¹⁴ also reported that the percentage satisfaction with sedation rating of the attending gastroenterologist was not statistically significantly different between PF versus PR (the p-value was not reported). Likewise, Lu et al.,¹ Han et al.,¹¹ Bahrami Gorji et al.,¹³ and Zhang et al.⁵ reported that the mean (SD) endoscopists’ satisfaction scores were not statistically significantly different between the DR versus MR, MF versus PF, and PK versus PF, respectively (P ≥ 0.317). Also, Song et al.¹⁶ found that the mean (SD) gastroenterologists’ satisfaction score was the same for etomidate alone versus propofol alone (P = 1.000).

Overall Hemodynamic Stability Cardiovascular Events

Four RCTs¹^,³^,¹¹^–¹⁴^,¹⁶ reported on overall hemodynamic stability and cardiovascular events during sedation with short-acting sedative agents for ERCP.

Park et al.³ identified overall respiratory events in 10 patients (15.6%) in the etomidate group versus 16 patients (25.4%) in the propofol group after sedation. The difference was not statistically significant (P = 0.172). Thus, with a rate difference of −9.8% (97.5% confidence interval [CI], −□ to 4.2%), they concluded that etomidate was non-inferior to propofol in terms of overall respiratory events since the upper bound of the CI was within the prespecified noninferiority margin of 10%. They also reported the rate of adverse respiratory events requiring airway intervention was significantly less in the etomidate group than in the propofol group (9.4% versus 22.2%, respectively; P = 0.047). Park et al.³ also found that the overall incidence of cardiovascular events was 43 (67.2%) in the etomidate group compared with 32 (50.8%) in the propofol group. The difference was not statistically significant (P = 0.060). Likewise, Han et al.¹¹ did not find a statistically significant difference in the overall cardiopulmonary event during sedation with MF or PF (P = 0.812).

In the RCT by Lu et al.,¹ the mean (SD) of mean arterial pressure (MAP) decreased from 104 (18) mmHg at baseline to 91 (10) mmHg at the end of the operation in the DR group compared with a decrease from 102 (16) mmHg to 99 (13) mmHg for the MR group. The difference between the two groups was statistically significant (P = 0.001). Also, the mean (SD) heart rate values decreased to from 87 (19) beats per minute (bpm) to 84 (14) bpm in the DR group, whereas in the MR group the heart rate increased from 83 (15) bpm at baseline to 98 (14) bpm. The difference between the two groups was statistically significant (P = 0.008).¹ Similarly, Song et al.¹⁶ found that the mean (SD) drop from baseline in MAP during the ERCP procedure was statistically significantly less with etomidate than propofol (−8.4 [7.8]% versus −14.4% [9.4]%, respectively; P = 0.002). However, the mean (SD) percent change from baseline heart rate was not statistically significantly different between etomidate and propofol (P = 0.874).

The RCTs by Akhondzadeh et al.,¹² Bahrami Gorji et al.,¹³ and Haytural et al.¹⁴ found no statistically significant differences between the PF versus PK, PF versus PK, and PF versus PR versus propofol alone, respectively, regarding the overall MAP,¹³^,¹⁴ systolic blood pressure,¹²^,¹⁴ diastolic blood pressure,¹²^,¹⁴ respiratory rate,¹³ and heart rate¹²^,¹³ during and after the procedure (P > 0.05 in all comparisons).

Hypotension

Seven RCTs²^,⁵^,⁶^,⁹^–¹¹^,¹⁶ and one retrospective cohort study¹⁷ provided comparative outcomes on hypotension during sedation with various sedative agents.

In the RCT by Goyal et al.,² hypotension was identified in eight patients (19%) in the PF group, whereas there was no incident of hypotension among patients in the DK group. The difference was statistically significant (95% CI 0.07 to 0.31; Fisher exact test). Eberl, et al.,⁹ Sayed et al.,¹⁰ Han et al.,¹¹ Zhang et al.,⁵ Shin et al.⁶ and Song et al.,¹⁶ did not observe a statistically significant difference in the incidence of hypotension between PA versus PE, propofol alone versus PK, PF versus MF, MM versus remifentanil alone versus RM, PF versus PM, and etomidate alone versus propofol alone, respectively (P ≥ 0.10). Similarly, the retrospective cohort study by Ebru and Resul,¹⁷ found no statistically significant difference between the MM and PK groups in the number of patients who had hypotension during the procedure (P = 0.300)

Bradycardia

Seven RCTs²^,⁵^,⁶^,⁹^–¹¹^,¹⁶ and one retrospective cohort study¹⁷ provided comparative outcomes on bradycardia during sedation with various sedative agents

In the RCT by Goyal et al.,² two patients (4.7%) in the PF group had bradycardia, whereas there was no incident of bradycardia among patients in the DK group. The difference was statistically significant (95% CI 0.0 to 0.31; Fisher exact test). Similarly, the retrospective cohort study by Ebru and Resul,¹⁷ the number of patients in whom bradycardia was identified during the procedure was statistically significantly more in the MM group than the PK group (17 [22.7%] versus 2 [2.7%], respectively; P < 0.05). Eberl et al.,⁹ Sayed et al.,¹⁰ Han et al.,¹¹ Zhang et al.,⁵ Shin et al.⁶ and Song et al.,¹⁶ did not observe a statistically significant difference in the incidence of hypotension between PA versus PE, propofol alone versus PK, PF versus MF, MM versus remifentanil alone versus RM, PF versus PM, and etomidate alone versus propofol alone, respectively (P ≥ 0.08 in all comparisons).

Oxygen desaturation

Six RCTs¹^,³^,⁶^,⁹^,¹⁰^,¹⁶ and one retrospective cohort study¹⁷ reported comparative findings on oxygen desaturation during sedation with various sedative agents.

In the RCT by Lu et al.,¹ desaturation occurred 19 patients (22%) in the MR group compared with none in the DR group. The difference was statistically significant (P = 0.001). However, in the RCTs by Eberl et al.,⁹ Sayed et al.,¹⁰ Park et al.,³ Shin et al.,⁶ and Song et al.,¹⁶ as well as the retrospective cohort study by Ebru and Resul,¹⁷ there was no statistically significant difference in desaturation between PA versus PE, propofol alone versus PK, ME versus PM, PF versus PM, etomidate alone versus propofol alone, and MM versus PK groups, respectively (P ≥ 0.172 in all comparisons).

Respiratory depression

Two RCTs⁹^,¹⁰ reported findings on respiratory depression, during sedation with short-acting sedative agents for ERCP.

Goyal et al. ² reported that respiratory depression was not identified in any patients sedated with DK compared with five patients (11.9%) who had respiratory depression following sedation with PF. The difference was statistically significant (95% CI, 0.02 to 0.22; Fisher exact test). Similarly, Zhang et al.⁵ found that the number of patients who experienced respiratory depression was statistically significantly lower with remifentanil alone than with MM (11 [33%] versus 3 [9.1%]; P< 0.05) or RM group (10 [20.3%] versus 3 [9.1%]; P< 0.05).

Apnea and Hypoxia

Five RCTs⁵^,¹¹^–¹³^,¹⁶ and one retrospective cohort study¹⁷ provided outcomes on apnea,⁵^,¹²^,¹³^,¹⁶^,¹⁷ and hypoxia¹¹ during sedation with various short-acting sedative agents for ERCP.

Akhondzadeh et al.¹² reported that statistically significantly more patients sedated with PF experienced apnea compared with those who were sedated with PK (31 [63%] versus 16 [32.7%], respectively; P < 0.05). However, Bahrami Gorji et al.,¹³ did not observe a statistically significant difference in the number of patients who had apnea following sedation with PF or PK (7 [16.7%] versus 1 [3.3%], respectively; P = 0.128). In the RCT by Zhang et al.,⁵ no patients sedated with remifentanil alone experienced apnea. In contrast, apnea was identified in one patient (3.0%) in the MM group and four patients (12.1%) in the RM groups. The difference was statistically significant only when comparing the remifentanil alone with RM groups (P< 0.05). Similarly, the retrospective cohort study by Ebru and Resul¹⁷ found that the number of patients who had apnea during the procedure was statistically significantly more in the MM group than the PK group (22 [29.3%] versus 3 [4.0%], respectively; P < 0.05). There was no incidence of apnea following sedation with either etomidate alone or propofol alone in the RCT by Song et al..¹⁶ The RCT by Han et al.¹¹ found no statistically significant difference in the number of patients in whom hypoxia occurred while sedated with PF or MF (P = 0.779).

Nausea, Vomiting, or Hypersalivation

Seven RCTs¹^,²^,⁵^,¹⁰^,¹³^,¹⁵^,¹⁶ reported on the incidence of nausea or vomiting and hypersalivation¹⁰ following the use of various short-acting sedative agents for ERCP.

In the RCT by Lu et al.,¹ nausea and vomiting occurred in statistically significantly more patients sedated with DR than patients sedated with MR (7 [6.5%] versus 2 [2.3%], respectively; P = 0.001). Zhang et al.⁵ reported that nausea or vomiting occurred in two patients (6.1%) sedated with MM compared with seven patients (21.2%) who received remifentanil alone, and nine patients (27.3%) who received RM. The difference was statistically significant only when comparing MM versus RM (P< 0.05). Sayed et al.,¹⁰ Bahrami Gorji et al.,¹³ Goyal et al.,² Narayanan et al.,¹⁵ Song et al.¹⁶ found no statistically significant difference in the incidence of nausea or vomiting between propofol alone versus PK, PF versus PK, PF versus DK, MP versus MK and etomidate alone versus propofol alone, respectively (P ≥ 0.239 for in all cases). Sayed et al.¹⁰ also reported that the incidence of hypersalivation following sedation was not statistically significantly different between propofol alone versus PK (P = 0.246).

Agitation

In the RCT by Sayed et al.,¹⁰ the number of patients who exhibited agitation after sedation was not statistically significantly different between PK versus propofol alone (P = 0.239).

Evidence-based guidelines for moderate procedural sedation during endoscopic retrograde cholangiopancreatography

No relevant evidence-based guidelines regarding the use of ondansetron for palliative patients were identified; therefore, no summary can be provided.

Limitations

Although 14 studies were included in this report, they were spread over several unique intervention-comparator pairs. In effect, there was a limited quantity of evidence for each comparison. Also, doses of sedative agents used tended to vary from study to study, so that even where drugs appeared to be the same in two or more studies, they usually differed in doses. In that sense, it was challenging to assign effects to drug protocols with no standardized doses. Moreover, there were studies that enrolled unique populations such as only Asians⁶^,¹⁶ or patients over eighty¹¹ or eighty-five years old,¹⁷ which prevented comparisons across studies. For some outcomes, including but not limited to time to recovery and satisfaction with sedation, the difference in score between groups seemed numerically small yet they were statistically significant in some cases. Thus, in the absence of a defined minimally clinically important difference, the clinical relevance of the differences between the groups were unknown.

Furthermore, all the studies included in this report¹^–³^,⁵^,⁶^,⁹^–¹⁷ were conducted outside Canada. Therefore, the generalizability of the findings to the Canadian context is unclear, given the potential for differences in practice patterns, including differences in drug availability or use in practice, that might impact the interpretation of the results or the resources used to achieve them.

Conclusions and Implications for Decision or Policy Making

Thirteen RCTs¹^–³^,⁵^,⁶^,⁹^–¹⁶ and one retrospective cohort study¹⁷ were identified regarding the clinical effectiveness of short-acting sedative agents during ERCP. No relevant evidence-based guidelines were identified for moderate procedural sedation during ERCP.

There was a total of eight RCT involving sedation with propofol alone or in combination with other drugs such as alfentanil, esketamine, fentanyl, ketamine, midazolam, meperidine, and remifentanil. Apart from a combination of propofol and midazolam (MP), six other midazolam-based sedative agents were investigated in which midazolam was combined with etomidate, fentanyl, ketamine, meperidine, pethidine, or remifentanil. Other drugs that were investigated were dexmedetomidine–ketamine (DK) combination dexmedetomidine–remifentanil (DR) combination, etomidate alone, and remifentanil alone.

In assessing the comparative effectiveness of sedation using propofol as a standalone short-acting sedative for ERCP, evidence from one RCT¹⁰ indicated no significant difference between propofol alone and a propofol–ketamine (PK) combination in terms of pain during the procedure. Based on the total doses of propofol used during ERCP procedures, evidence from one RCT¹⁴ suggested that the effectiveness of propofol alone was significantly less effective compared to propofol–fentanyl (PF) or propofol–remifentanil (PR) combination. Regarding the sedation effectiveness of propofol–alfentanil (PA) and propofol–esketamine (PE), evidence from one RCT⁹ indicated that PE was significantly more effective than PA as a short-acting sedative for ERCP, as assessed by the total dose of propofol used during the procedure for ERCP. Evidence from one RCT¹³ suggested that the sedation quality, as measured by RSS, may be significantly better with a PK than with PF at some points (four minutes and 15 minutes) during the ERCP procedure. However, in the same RCT,¹³ there was no evidence of a significant difference in sedation effectiveness between PF and PK in terms of additional doses of propofol used to sustain sedation during the procedure. Likewise, evidence from another RCT¹² indicated no significant difference in the quality of sedation between the PF and PK as measured by RSS or the total dose of propofol used for sedation. Evidence from one RCT¹¹ showed no significant difference between PF versus a midazolam–fentanyl (MF) combination in pain during sedation. Another RCT³ found no evidence between PF versus PR regarding the effectiveness of sedation using the RSS.¹⁴ For sedation effectiveness in terms of time to achieve RSS sedation, evidence from one retrospective cohort study¹⁷ showed that PK was significantly more effective than a midazolam–meperidine (MM). In that study, the dose of propofol used as the rescue was significantly higher with MM.

Evidence from three RCTs²^,¹⁰^,¹¹ and one retrospective cohort study¹⁷ showed that the time to recovery was significantly shorter with propofol alone than PK,¹⁰ PF than MF,¹¹ PF than DK,² and PK than MM.¹⁷ Evidence from seven RCTs indicated no significant difference in time to recovery between PF versus PK,¹³ DR versus MR,¹ ME versus MP,³ etomidate alone versus propofol alone,¹⁶ PA versus PE,⁹ MPt versus MK,¹⁵ and PF versus PM.⁶

For satisfaction with sedation, evidence from three RCTs¹^,¹⁰ suggested that patients were significantly more satisfied with propofol alone than PK¹⁰ and with DR than MR.¹ Evidence from one RCT showed that endoscopists were significantly more pleased with sedation with remifentanil alone than MM. For all other comparisons, there was no significant difference in patients’ or endoscopists’/gastroenterologists’ satisfaction with one sedative agent over the others.

For overall hemodynamic stability and cardiovascular events, evidence from one RCT indicated that ME was not inferior to MP in terms of the overall respiratory events, and adverse respiratory events requiring airway intervention were significantly less with ME than MP. However, there was no evidence that one sedative agent (ME or MP) was associated with significantly lower overall cardiovascular events in patients who underwent ERCP. Evidence from two RCTs indicated that the MAP decreased markedly more during the ERCP procedure with DR than MR, and with etomidate alone than propofol alone. Comparisons of PF versus PK,¹²^,¹³ and PF versus PR versus propofol alone did not show evidence of a significant difference between the sedative agents in MAP,¹³^,¹⁴ systolic blood pressure,¹²^,¹⁴ diastolic blood pressure,¹²^,¹⁴ respiratory rate,¹³ and heart rate¹²^,¹³ during the procedure.

Concerning hypotension, evidence from one RCT² indicated that sedation with DK was associated with significantly less hypotension than sedation with PF. In other comparisons six RCTs⁵^,⁶^,⁹^–¹¹^,¹⁶ and one retrospective cohort study¹⁷ found no evidence of a significant difference in the incidence of hypotension between PA versus PE,⁹ propofol alone versus PK,¹⁰ PF versus MF,¹¹ MM versus remifentanil alone versus RM,⁵ PM versus PF,⁶ etomidate alone versus propofol alone,¹⁶ and MM versus PK.¹⁷

Regarding bradycardia, evidence from one RCT² and one retrospective cohort study¹⁷ suggested a significantly higher incidence of bradycardia following sedation with PF than DK² or MM than PK.¹⁷ In other comparisons, evidence from six RCTs⁵^,⁶^,⁹^–¹¹^,¹⁶ did not indicate a statistically significant difference in the incidence of hypotension between PA versus PE,⁹ propofol alone versus PK,¹⁰ PF versus MF,¹¹ MM versus remifentanil alone versus RM,⁵ MP versus PF,⁶ and etomidate alone versus propofol alone¹⁶

Evidence from one RCT¹ indicated that the incidence of oxygen desaturation was significantly higher following sedation with MR than sedation with DR. In other comparisons, evidence from five RCTs,³^,⁶^,⁹^,¹⁰^,¹⁶ and one retrospective cohort study¹⁷ suggested no significant difference in the incidence of desaturation following sedation with PA versus PE,⁹ propofol alone versus PK,¹⁰ ME versus MP,³ MP versus PF,⁶ etomidate alone versus propofol alone¹⁶ and MM versus PK.¹⁷

Evidence from two RCTs²^,⁵ indicated that respiratory depression during sedation occurred significantly more frequently with PF than DK² and MM than remifentanil alone.⁵ Similarly, evidence from two RCT⁵^,¹² and one retrospective cohort study¹⁷ showed that the incidence of apnea was significantly higher with PF than PK,¹² MM than remifentanil alone,⁵ and MM than PK.¹⁷ In other comparisons, evidence from four RCTs⁵^,¹¹^,¹³^,¹⁶ did not show a significant difference in the incidence of apnea between PF versus MF¹¹ PF versus PK,¹³ MM versus RM,⁵ and etomidate alone versus propofol alone.¹⁶

Two RCTs⁵^,¹ had evidence suggesting that the incidence of nausea and vomiting was significantly higher sedation with DR than MR,¹ and with RM than MM.⁵ In other comparisons, evidence from six RCTs²^,⁵^,¹⁰^,¹³^,¹⁵^,¹⁶ indicated that the incidence of nausea and vomiting was not significantly different following sedation with propofol alone versus PK,¹⁰ PF versus PK,¹³ PF versus DK,² MP versus MK,¹⁵ and etomidate alone versus propofol alone.¹⁶ Evidence from one RCT¹⁰ suggested no significant difference between propofol alone versus PK regarding the incidence of hypersalivation or agitation following sedation.

In addition to the limitations discussed under the critical appraisal section, it is essential to note that although 14 studies were included in this report, they were spread over several unique intervention-comparator pairs. In effect, there was a limited quantity of evidence for each comparison. Also, doses of sedative agents used tended to vary from study to study, so that even where drugs appeared to be the same in two or more studies, they usually differed in doses. Therefore, although each of the agents investigated in the included studies demonstrated some effectiveness, a definitive conclusion could not be drawn about the optical agent or agents for short-term sedation during ERCP due to the limitations in the quality and quantity of evidence available for this report. There is a need for more rigorous studies comparing standardized doses of particular short-acting sedative agents in a large population with a wide diversity of patients. The analysis in such a study should consider stratification for essential subgroups such as high-risk and low-risk patients as well as those in different age brackets.

References

1.: Lu Z, Li W, Chen H, Qian Y. Efficacy of a Dexmedetomidine-Remifentanil Combination Compared with a Midazolam-Remifentanil Combination for Conscious Sedation During Therapeutic Endoscopic Retrograde Cholangio-Pancreatography: A Prospective, Randomized, Single-Blinded Preliminary Trial. Dig Dis Sci. 2018;63(6):1633–1640. [PubMed: 29594976]
2.: Goyal R, Hasnain S, Mittal S, Shreevastava S. A randomized, controlled trial to compare the efficacy and safety profile of a dexmedetomidine-ketamine combination with a propofol-fentanyl combination for ERCP. Gastrointest Endosc. 2016;83(5):928–933. [PubMed: 26364968]
3.: Park CH, Park SW, Hyun B, et al. Efficacy and safety of etomidate-based sedation compared with propofol-based sedation during ERCP in low-risk patients: a double-blind, randomized, noninferiority trial. Gastrointest Endosc. 2018;87(1):174–184. [PubMed: 28610897]
4.: Chainaki IG, Manolaraki MM, Paspatis GA. Deep sedation for endoscopic retrograde cholangiopacreatography. World J Gastrointest Endosc. 2011;3(2):34–39. [PMC free article: PMC3055942] [PubMed: 21403815]
5.: Zhang J, Huang Y, Li Z, Li J, Liu K, Li C. Sedation and use of analgesics in endoscopic retrograde cholangiopancreatography: a double-blind comparison study of meperidine/midazolam, remifentanil/midazolam, and remifentanil alone. Int J Clin Pharmacol Ther. 2016;54(11):872–879. [PubMed: 27569734]
6.: 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(9):e0138422. [PMC free article: PMC4581832] [PubMed: 26402319]
7.: Li S, Sheng G, Teng Y, Sun M. Systematic review of anaesthetic medication for ERCP based on a network meta-analysis. Int J Surg. 2018;51:56–62. [PubMed: 29367034]
8.: Downs S, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;152(6):377–384. [PMC free article: PMC1756728] [PubMed: 9764259]
9.: Eberl S, Koers L, van Hooft J, et al. The effectiveness of a low-dose esketamine versus an alfentanil adjunct to propofol sedation during endoscopic retrograde cholangiopancreatography: A randomised controlled multicentre trial. Eur J Anaesthesiol. 2020;37(5):394–401. [PubMed: 31860599]
10.: Sayed E. Propofol vs. Ketofol for Endoscopic Retrograde Cholangiopancreatography (ERCP) Bi-Spectral Index (BIS) Guided Sedation: A Randomized Clinical Trial. J Anesth Clin Res. 2019;10(8).
11.: 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(3):369–376. [PubMed: 28181706]
12.: Akhondzadeh R, Ghomeishi A, Nesioonpour S, Nourizade S. A comparison between the effects of propofol-fentanyl with propofol-ketamine for sedation in patients undergoing endoscopic retrograde cholangiopancreatography outside the operating room. Biomedical J. 2016;39(2):145–149. [PMC free article: PMC6138805] [PubMed: 27372170]
13.: Bahrami Gorji F, Amri P, Shokri J, Alereza H, Bijani A. Sedative and Analgesic Effects of Propofol-Fentanyl Versus Propofol-Ketamine During Endoscopic Retrograde Cholangiopancreatography: A Double-Blind Randomized Clinical Trial. Anesth. 2016;6(5):e39835. [PMC free article: PMC5106556] [PubMed: 27853681]
14.: 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. [PMC free article: PMC4631853] [PubMed: 26576424]
15.: Narayanan S, Shannon A, Nandalan S, Jaitly V, Greer S. Alternative sedation for the higher risk endoscopy: a randomized controlled trial of ketamine use in endoscopic retrograde cholangiopancreatography. Scand J Gastroenterol. 2015;50(10):1293–1303. [PubMed: 26061267]
16.: Song JC, Lu ZJ, Jiao YF, et al. Etomidate Anesthesia during ERCP Caused More Stable Haemodynamic Responses Compared with Propofol: A Randomized Clinical Trial. Int J Med Sci. 2015;12(7):559–565. [PMC free article: PMC4502060] [PubMed: 26180512]
17.: Ebru TK, Resul K. Comparison of ketamine-propofol mixture (ketofol) and midazolam-meperidine in endoscopic retrograde cholangiopancretography (ERCP) for oldest old patients. Ther Clin Risk Manag. 2019;15:755–763. [PMC free article: PMC6592063] [PubMed: 31417263]
18.: Liberati A AD, Tetzlaff J, et al. . The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1–e34. [PubMed: 19631507]
19.: American Society of Anesthesiologists. ASA Physical Status Classification System. 2019; https://www.asahq.org/standards-and-guidelines/asa-physical-status-classification-system. Accessed 2020 Aug 12.
20.: MDApp. Aldrete Score. 2017; https://www.mdapp.co/aldrete-score-calculator-147/. Accessed 2020 Aug 7.
21.: Steward DJ. A simplified scoring systemt for the post-operative recovery room. Canad Anaesth Soc J. 1975;22(1):111–113. https://link.springer.com/content/pdf/10.1007%2FBF03004827.pdf. Accessed 2020 Aug 7. [PubMed: 1109700]

Appendix 1. Selection of Included Studies

Appendix 2. Characteristics of Included Publications

Table 2. Characteristics of Included Primary Clinical Studies

Appendix 3. Critical Appraisal of Included Publications

Table 3. Strengths and Limitations of Clinical Studies Using the Downs and Black checklist

Appendix 4. Main Study Findings and Authors’ Conclusions

Table 4. Summary of Findings of Included Primary Clinical Studies

About the Series

CADTH Rapid Response Report: Summary with Critical Appraisal

ISSN: 1922-8147

Version: 1.0

Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.

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Short-Acting Sedative Agents During Endoscopic Retrograde Cholangiopancreatography: A Review of Clinical Effectiveness and Guidelines. Ottawa: CADTH; 2020 Aug. (CADTH rapid response report: summary with critical appraisal).

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Peprah K, Severn M, Wells C, et al. Short-Acting Sedative Agents During Endoscopic Retrograde Cholangiopancreatography: A Review of Clinical Effectiveness and Guidelines [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2020 Aug 17.
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Context and Policy Issues
Research Questions
Key Findings
Methods
Summary of Evidence
Conclusions and Implications for Decision or Policy Making
References
Selection of Included Studies
Characteristics of Included Publications
Critical Appraisal of Included Publications
Main Study Findings and Authors’ Conclusions

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Short-Acting Sedative Agents During Endoscopic Retrograde Cholangiopancreatography: A Review of Clinical Effectiveness and Guidelines

Abbreviations

Context and Policy Issues

Research Questions

Key Findings

Methods

Literature Search Methods

Selection Criteria and Methods

Table 1

Exclusion Criteria

Critical Appraisal of Individual Studies

Summary of Evidence

Quantity of Research Available

Summary of Study Characteristics

Study Design

Country of Origin

Patient Population

Interventions and Comparators

Outcomes

Summary of Critical Appraisal

Summary of Findings

Clinical Effectiveness of Short-acting Sedative Agents During Endoscopic Retrograde Cholangiopancreatography

Effectiveness of the sedative or sedation quality

Ramsey Sedation Scale as a measure of sedation

Time to Achieve Sedation

Total doses of sedation agents as a surrogate measure of the quality of sedation

Doses of Sedation Rescue as Surrogate

Pain During Procedure

Time to recovery

Satisfaction with sedation

Overall Hemodynamic Stability Cardiovascular Events

Hypotension

Bradycardia

Oxygen desaturation

Respiratory depression

Apnea and Hypoxia

Nausea, Vomiting, or Hypersalivation

Agitation

Evidence-based guidelines for moderate procedural sedation during endoscopic retrograde cholangiopancreatography

Limitations

Conclusions and Implications for Decision or Policy Making

References

Appendix 1. Selection of Included Studies

Appendix 2. Characteristics of Included Publications

Appendix 3. Critical Appraisal of Included Publications

Appendix 4. Main Study Findings and Authors’ Conclusions

About the Series

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