Front. Med. Frontiers in Medicine Front. Med. 2296-858X Frontiers Media S.A. 10.3389/fmed.2024.1370481 Medicine Systematic Review ICU patients receiving remifentanil do not experience reduced duration of mechanical ventilation: a systematic review of randomized controlled trials and network meta-analyses based on Bayesian theories Lu Fangjie 2 † Qin Sirun 3 † Liu Chang 4 † Chen Xunxun 5 * Dai Zhaoqiu 6 * Li Cong 1 * 1Department of Critical Care Medicine, Southern University of Science and Technology Yantian Hospital, Shenzhen, Guangzhou Province, China 2Department of Critical Care Medicine, Changshu Hospital Affiliated to Nanjing University of Traditional Chinese Medicine, Changshu, Jiangsu, China 3Department of Cardiovascular Medicine, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China 4Department of Emergency Center, Affiliated Huaian Hospital of Xuzhou Medical University, Huaian, China 5Center for Tuberculosis Control of Guangdong Province, Guangzhou, China 6Department of Traditional Chinese Medicine, Changshu Hospital Affiliated to Nanjing University of Traditional Chinese Medicine, Changshu, Jiangsu, China

Edited by: Abele Donati, Marche Polytechnic University, Italy

Reviewed by: Neha Gupta, University of Oklahoma Health Sciences Center, United States

Yiying Zhang, Massachusetts General Hospital and Harvard Medical School, United States

 *Correspondence: Xunxun Chen, grace_chen514@163.com Zhaoqiu Dai, 517711828@qq.com Cong Li, congcongli2020@163.com

†These authors have contributed equally to this work and share first authorship

 07 08 2024 2024 11 1370481 28 01 2024 24 07 2024 Copyright © 2024 Lu, Qin, Liu, Chen, Dai and Li. 2024 Lu, Qin, Liu, Chen, Dai and Li

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 Background

The purpose of this network meta-analysis (NMA) was to evaluate the efficacy of intravenous opioid μ-receptor analgesics in shortening the duration of mechanical ventilation (MV) in ICU patients.

 Methods

Randomized controlled trials comparing the efficacy of remifentanil, sufentanil, morphine, and fentanyl on the duration of MV in ICU patients were searched in Embase, Cochrane, Pubmed, and Web of Science electronic databases. The primary outcome was MV duration. The Bayesian random-effects framework was used to evaluate relative efficacy.

 Results

In total 20 studies were included in this NMA involving 3,442 patients. Remifentanil was not associated with a reduction in the duration of MV compared with fentanyl (mean difference (MD) -0.16; 95% credible interval (CrI): −4.75 ~ 5.63) and morphine (MD 3.84; 95% CrI: −0.29 ~ 10.68). The secondary outcomes showed that, compared with remifentanil, sufentanil can prolong the duration of extubation. No regimen significantly shortened the ICU length of stay and improved the ICU mortality, efficacy, safety, and drug-related adverse events.

 Conclusion

Among these analgesics, remifentanil did not appear to be associated with a reduction in MV duration. Clinicians should carefully titrate the analgesia of MV patients to prevent a potentially prolonged duration of MV due to excessive or inadequate analgesic therapy.

 Systematic Review Registration

https://www.crd.york.ac.uk/prospero/, CRD42021232604.

 critical illness mechanical ventilation analgesics opioid remifentanil network meta-analysis section-at-acceptance Intensive Care Medicine and Anesthesiology Highlights

Question: Is remifentanil more effective than other intravenous opioid analgesics at reducing mechanical ventilation duration in ICU patients?

Findings: Compared to other intravenous analgesics that target the μ-receptor opioid, Remifentanil did not show any decrease in the length of mechanical ventilation.

Meaning: To prevent excessive or inadequate analgesia prolonging the duration of mechanical ventilation, clinicians are advised to carefully titrate analgesia.

Introduction Description of the intervention

Intensive care unit (ICU) patients on invasive mechanical ventilation (MV) experience pain, especially in patients requiring long-term MV (1–4). These unpleasant sensory experiences may prevent MV weaning (5). Therefore, preemptive analgesic therapy should be administered to ICU patients on MV to alleviate pain (5–7).

Intravenous (IV) opioid μ-receptor analgesics, such as morphine, fentanyl, and sufentanil, are considered first-line drugs for the treatment of nonneuropathic pain (5, 7, 8). However, they have long half-lives and are easily redistributed and accumulated. Even when administered at doses normally used for several days, they are associated with increased respiratory depression and prolonged duration of MV (5, 9–17). Hence, the use of fentanyl, sufentanil, and morphine should be restricted to mechanically ventilated patients requiring long-term analgesia (4, 7, 18).

Remifentanil is a potent selective μ-opioid receptor that is rapidly metabolized by non-specific esterases into inactive metabolites (19, 20). As a result, regardless of the dose and duration of infusion, its onset and offset are very rapid and its context-sensitive half-life is extremely short (19–21). Therefore, remifentanil can be easily titrated and administered for prolonged periods, with a lower risk of respiratory depression (5, 10, 22). It seems to make remifentanil more ideal for ventilated ICU patients.

 Controversy of the intervention

The advantages of remifentanil in reducing the duration of MV in ICU patients have been debated. Randomized controlled trials (RCTs) have examined that the MV duration for remifentanil-based analgesia was significantly shorter than that for morphine-based, fentanyl-based, and sufentanil-based analgesia in postsurgical patients and patients undergoing MV for up to 10 days (23–26). Similarly, remifentanil reduced MV duration in these patients when compared with other opioid μ-receptor analgesics, according to two meta-analyses (27, 28). Even so, opioids administered intravenously at similar pain intensity endpoints seem to exhibit similar MV durations (5). Analgesia with remifentanil had a similar duration of MV as that with fentanyl or morphine when used in postsurgical and non-surgical mechanically ventilated patients and NICU patients undergoing MV for up to 5 days (29–31). In addition, a meta-analysis including 1,067 critically ill patients showed that remifentanil was not associated with a significantly shorter duration of MV than other opioids (32). Moreover, the majority of RCTs have even shown an increased risk of hypotension and bradycardia (25, 33).

 Importance of study

No network meta-analysis (NMA) has evaluated the efficacy of intravenous opioid μ-receptor analgesics in shortening the duration of MV in ICU patients. In view of the uncertainty surrounding sufentanil, fentanyl, morphine, and remifentanil’s efficacy in shortening the duration of MV, we designed this systematic review and NMA to evaluate and rank their effectiveness in reducing MV duration among ICU patients. In addition, the efficacy of these drugs on clinically important outcomes and drug-related adverse events (AEs) was also investigated.

 Methods Approval

This article complies with the PRISMA statement (34). The registration number of PROSPERO was CRD 42021232604.

 Eligibility criteria Types of studies, participants, and interventions

In this NMA, we included only full-text published RCTs that involved 16-year-old ICU patients undergoing invasive MV via endotracheal intubation. Studies comparing two or more of the four therapies were included (remifentanil, sufentanil, fentanyl, and morphine).

 Types of outcome measures

As a primary outcome, the duration of MV was evaluated. Secondary outcomes included extubation duration, ICU mortality, ICU length of stay (LOS), safety, drug-related bradycardia, drug-related hypotension, and drug-related bradycardia.

 Exclusion criteria

Studies with controlled before-and-after comparisons, interrupted time series studies, and controlled clinical trials were excluded from our analysis. A study without reporting outcome variables, or a study with duplicate publications, was excluded from the study.

 Search strategy Electronic searches

Electronic medical databases including PubMed, Embase, Web of Science, and Cochrane were systematically searched for clinical trials published from 1 January 1991 to 31 December 2023. No language restrictions were applied. Each database used specific search terms, and the search strategy details (Supplementary File 1) were developed as proposed by Cochrane (35). We searched relevant literature using the following MeSH terms and their entry terms: ‘Critical Care’ OR ‘Critical Illness’ OR ‘Intensive Care Units’ OR ‘Coronary Care Units’ OR ‘Respiratory Care Units’ OR ‘Postoperative Care’ OR ‘Burn Units’ AND ‘Respiration, Artificial’ OR ‘Ventilators, Mechanical’ OR ‘Liquid Ventilation’ OR ‘active Ventilatory Support’ OR ‘Continuous Positive Airway Pressure’ OR ‘Intermittent Positive-Pressure Breathing’ OR ‘Positive-Pressure Respiration’ OR ‘High-Frequency Ventilation’ OR ‘Airway Extubation’ OR ‘Intubation, Intratracheal’ AND ‘Analgesics, Opioid’ OR ‘Analgesics’ OR ‘Remifentanil’ OR ‘Sufentanil’ OR ‘Fentanyl’ OR ‘Morphine’.

 Searching other resources

Our search for relevant gray literature was conducted via Google Scholar. We also searched the following registers for complete trials (latest search 31 December 2023): ISRCTN,1 World Health Organization International Clinical Trials Registry Platform (ICTRP),2 Chinese Clinical Trial Register,3 and ClinicalTrials.gov.

 Data collection and analysis Study selection

Abstracts and titles of selected articles were independently reviewed by four reviewers. Thereafter, they carefully read the full text and decided to include studies. When there were any discrepancies between the reviewers, it was necessary to discuss them with the fifth reviewer and make a decision after consensus.

 Definition of interventions and outcomes

All study drugs included in this study were IV opioid μ-receptor analgesics. The duration of MV was defined as the time from administration of the study drug after the patients were randomized into groups until the time of actual extubation. The extubation duration was defined as the time from the patient meeting the extubation criteria to the actual extubation. Safety was defined as the occurrence of drug-related AE. Drug-related AE included drug-related hypotension, drug-related bradycardia, and drug-related bradypnea. If AE was not specified as drug-related, it was presumed to be related. In the definition of drug-related hypotension, mean arterial pressure was multiplied by 50 millimeters of mercury. In the definition of drug-related bradycardia, the heart rate was multiplied by 50 beats per minute. In the definition of drug-related bradypnea, the respiratory rate was multiplied by 12 breaths per minute. The criteria for the MV model, weaning from MV, and extubation are shown in Supplementary File 2.

 Data extraction

The Cochrane Handbook was used to collect all the data. Using the data from the study, five investigators extracted details of the study (language, published year, author, institutions, and funding), participant information (gender and age range), intervention information (drug, duration, and route of administration), results (MV duration and secondary outcomes), and methodological design (randomization, blinding, and allocation concealment) from each study. When there were any discrepancies between the reviewers, it was necessary to discuss and make a decision after consensus with the sixth reviewer.

 Risk of bias assessment

Using the Cochrane Collaboration ROB (risk of bias) tool, we assessed the methodological quality of the study (35). Every study evaluated ROB in seven domains, categorizing it as high, unclear, or low. Low ROB studies were defined as three or less as unclear risk and none as high risk. Moderate ROB studies were defined as none rated as high risk but four or more were rated as unclear risk, or one was rated as high risk. All other studies have identified higher ROB studies.

 Measures of treatment effect Data synthesis

Continuous and dichotomous variables were analyzed using mean difference (MD) and odds ratio (OR), respectively. An NMA with random effects was used to estimate effect sizes using MDs or ORs with a 95% credible interval (CrI). Continuous and dichotomous outcomes were used for normal and binomial likelihoods, respectively. Model convergence was satisfactory when the potential scale reduction factor approached 1.0 (36). The treatments were evaluated and ranked according to the surface area under the cumulative ranking curve (SUCRA) (37).

 Assessment of heterogeneity

Statistically significant heterogeneity was I2 greater than 50%, and we discussed the sources of heterogeneity (38–40).

 Assessment of inconsistency

Node splitting and design-by-treatment tests were used to assess inconsistencies (39, 41). A p-value less than 0.05 was considered an inconsistency between the indirect and direct comparisons.

 Assessment of transitivity

In order to test the transitivity assumption of NMA, the distribution of clinical variables was compared (37, 42).

 Subgroup analysis

Subgroup analyses for the primary outcome were evaluated using population, duration of analgesia, and quality of the study. The patients were divided into postoperative critical and general critical groups. The duration of analgesia was divided into the short-term (≤72 h) and long-term (>72 h).

 Sensitivity analysis

Sensitivity analysis was evaluated through studies quality and studies without publication bias datasets.

 Quality assessment

GRADE was used to assess the certainty of evidence contributing to the network estimates (high, moderate, low, or very low) (43). Additionally, the comparison-adjusted funnel plots were used to assess publication bias (44, 45).

 Statistical software

R software, Stata, and Review Manager were used for analysis.

 Results Results of the search

Over 12,048 articles were identified, of which 153 in full-text were potentially eligible for inclusion. In total, 20 RCTs involving 3,442 patients were identified (Figure 1).

Flow diagram of included studies.

 Description of included studies

A total of 20 studies have been published in 12 countries between 1997 and 2023 (25, 29–31, 33, 46–60). There were 14 English articles, 3 Chinese articles, and 1 each in Turkish, French, and Tunisian. A total of nine (45%) trials recruited patients from Asia, seven (35%) trials recruited patients from Europe, two (10%) trials recruited patients from America, and each (5%) trial recruited patients from Oceania and Africa. Study samples ranged from 19 to 681 participants, with an average of 69 (standard deviation [SD] = 84). Participants were 55 years old (SD = 17 years), and 59% were men. Participants in one study (5%) were randomly assigned to three groups, and six (30%) were conducted at different research centers. In total, 14 (70%) studies were double-blind. The most critical patients were postoperative in the ICU, followed by those with brain trauma alone, severe multiple traumas, sepsis, and septic shock. Ten studies involved remifentanil versus fentanyl, 6 studies involved remifentanil versus morphine, and 1 study involved remifentanil versus sufentanil. There were three other studies involving fentanyl and morphine and two studies involving sufentanil versus morphine. Despite this, there have been no studies examining the interactions between sufentanil and morphine. The dose of opioids varied among studies; remifentanil, 0.05–1.0 ug/kg•min; fentanyl, 0.015–2.0 ug/kg•min; morphine, 0.75–2 ug/kg•min; sufentanil, 0.002–0.005 ug/kg•min (Tables 1, 2).

Description of included studies.

ID Author Year Country Participants Design N Mean age (SD) Male (%) Weight (kg) Height (cm) Evaluation Analgesia/Sedation score Study drug
1 Yamush 1997 America MV patients in ICU after surgery MC/DB 72 43.4 (14.9) 26 NR NR NR NR Remifentanil
78 44.4 (17.2) 40 NR NR NR NR Morphine
2 Chinachoti 2002 Thailand MV patients in ICU with normal renal function or mild renal impairment MC/DB 74 58.8 (14) 30 71.4 (16) 167.3 (8.6) SAPS II 25.8 (9.6) PI/ SAS1.9 (1.1)/3.5 (1.1) Remifentanil
78 59.9 (14.2) 35 71.0 (17.8) 167.2 (8.7) SAPS II 25.6 (8.5) PI/ SAS1.6 (1.1)/3.4 (1.1) Morphine
3 Dahaba 2004 Austria MV patients in ICU after orthopedic and general surgery SC/DB 20 58 (19) 60 69 (17) NR SAPS II 24 (7) NR Remifentanil
20 54 (20) 50 76 (16) NR SAPS II 22 (4) NR Morphine
4 Karabinis 2004 Greece MV patients in NICU MC/OP 84 46.8 (16.3) 52 76.5 (12.2) 171.1 (9.1) GCS 8.4 (2.7) PI/ SAS2.1 (1.1)/3.7 (1.5) Remifentanil
37 49.6 (16.9) 65 76.5 (12.6) 170.9 (7.4) GCS 8.8 (2.9) PI/ SAS2.1 (1.0)/3.6 (1.2) Fentanyl
40 47.3 (20.0) 63 75.2 (12.2) 170.9 (8.5) GCS 8.6 (2.5) PI/ SAS2.1 (1.0)/3.7 (1.5) Morphine
5 Muellejans 2004 Germany MV patients in ICU MC/DB 77 61.5 (13.4) 71 77.2 (12.7) 170.4 (9.1) SAPS II 28.2 (8.8) PI/ SAS1.4/3.2 Remifentanil
75 58.7 (13.9) 69 74.8 (13.9) 169.6 (9.6) SAPS II 27.7 (8.8) PI/ SAS1.5/3.5 Fentanyl
6 Akinci 2005 Turkey MV patients in ICU after surgery SC/DB 22 32 (15) 64 NR NR APACHE II 13 (7) BPS/SAS5/5 Remifentanil
22 44 (16) 55 NR NR APACHE II 16 (6.75) BPS/SAS5/5 Fentanyl
7 Baillard 2005 France MV patients in ICU SC/ DB 21 59 (19) 80 66 (12) NR NR NR Remifentanil
20 58 (19) 68 70 (12) NR NR NR Sufentanil
8 Amor 2007 Tunisie MV patients in ICU with normal renal function or mild renal impairment SC/DB 9 58 (20) 67 76 (15) 171 (87) APACHE II 21 (7) NR Remifentanil
10 57 (20) 70 77 (15) 170 (89) APACHE II 20 (7) NR Fentanyl
9 Carrer 2007 Italy MV patients in ICU after major surgery SC/DB 50 69 (9) 56 75 (15) NR SAPS II 26.1 (7.2) NR Remifentanil
50 69 (10) 51 71 (17) NR SAPS II 26.3 (9.5) NR Morphine
10 Spies 2010 Germany MV patients in ICU MC/DB 28 64 (15) 71 BMI 27 (5) APACHE II 24 (8) NR Remifentanil
32 63 (12) 84 BMI 26 (4) APACHE II 26 (9) NR Fentanyl
11 Cevik 2011 Turkey MV patients in ICU SC/OP 16 50.63 (25.24) 44 65.94 (11.89) NR APACHE II 9.56 (3.83) NR Remifentanil
16 51.88 (20.77) 63 70.06 (15.12) NR APACHE II 11.94 (6.4) NR Fentanyl
12 Oliver 2011 America MV patients in ICU after cardiopulmonary bypass SC/DB 38 62 (4) 66 83 (5.25) 173 (3.5) NR NR Fentanyl
41 63 (4.75) 61 82 (8.25) 175 (4.25) NR NR Morphine
13 Liu 2013 China MV patients in ICU after tumor operation SC 30 66.8 (7.8) 33 67.2 (10.8) NR APACHE II 21.0 (4.9) NR Remifentanil
30 64.3 (9.3) 27 68.3 (10.9) NR APACHE II 20.2 (3.8) NR Fentanyl
14 Lee 2014 Korea MV patients in ICU MC/OP 49 6 6 (14.5) 67 60.6 (13.4) 162.1 (9.4) APACHE II 23.4 (8.7) NR Remifentanil
47 66 (15.2) 55 58.1 (10.2) 160.7 (8.9) APACHE II 21.4 (7.8) NR Morphine
15 Yang 2014 China MV patients in ICU MC/DB 282 53.6 (19.4) 66 66.6 (10.4) NR APACHE II 23.1 (8.7) FPS/RS 7.1/1.6 Sufentanil
262 54.6 (20.0) 66 65.3 (11.5) NR APACHE II 22.9 (7.5) NR Fentanyl
16 Yue 2016 China MV patients in ICU after major surgery SC/OP 300 58.3 (10.4) 56 60.2 (5.8) NR NR Sufentanil
300 59.1 (15.1) 55 59.8 (11.3) NR NR Fentanyl
17 Liu 2017 China MV patients in ICU after surgery SC/DB 35 66.11 (11.94) 60 65.29 (17.54) NR APACHE II 19.2 (4.19) BPS/CPOT4 (0.74)/3 (1.48) Remifentanil
35 62 (9.96) 49 67.66 (9.95) NR APACHE II 20.20 (5.04) BPS/CPOT4 (0.74)/4 (0.74) Fentanyl
18 Casamento 2021 Australia MV patients in ICU MC/OP 344 56.9 (17.9) 63 84.6 (22.4) NR APACHE II 16.6 (6.7) NR Fentanyl
337 58.5 (19.9) 62 82.4 (18.5) NR APACHE II 17.7 (7.4) NR Morphine
19 Doi 2023 Japan MV patients in ICU MC/DB 98 68.5 (10.9) 75 BMI 21.54 (3.69) NR BPS 3.6 (1.1) Remifentanil
98 65.9 (13.2) 80 BMI 22.41 (3.86) NR BPS 3.5 (1.1) Fentanyl
20 Li 2023 China MV patients in ICU MC/DB 69 59.3 (16.3) 61 66.4 (16.3) 166.3 (8.5) APACHE II 12.5 (5.56) CPOT/RASS0.4 (0.74)/−1.4 (1.11) Remifentanil
68 59.4 (18.2) 72 64.1 (12.6) 165.0 (7.4) APACHE II 13.0 (6.67) CPOT/RASS0.4 (0.74)/−0.3 (0.74) Fentanyl

APACHE II, acute physiology and chronic health evaluation; BMI, body mass index; BPS, behavioral pain scale; CPOT, critical care pain observation tool; DB, double-blind; GCS, Glasgow coma scale; MC, multi-center; MV, mechanical ventilation; NICU, neurological intensive care unit; NR, not reported; OP, open study; PI, pain intensity score; RASS, Richmond agitation-sedation scale; RCT, randomized controlled trials; SC, single-center; SD, mean deviations; SAPS II, simplified acute physiology score; SAS, sedation agitation score.

Description of included studies.

ID Author Participants Post-surgical patients (%) Details of study drug Supplement analgesic/sedative Aim Outcomes
1 Yamush MV patients in ICU after surgery 100 Remifentanil: 0.025 ug/kg/min No supplement analgesic/sedative PI≤1 Duration of extubation, ICU LOS, and bradypnea
100 Morphine: 2 mg bolus (every 5 min)
2 Chinachoti Post-surgical and medical ICU patients requiring MV for 12–72 h 98.6 Remifentanil: 0.15–1 ug/kg/min Two groups were given midazolam 0.03–0.2 mg/kg/h when the dose of the study drug reached the midazolam “trigger dose” PI≤2 and SAS = 4 Duration of MV, duration of extubation, ICU mortality, efficacy, safety, and bradypnea
98.7 Morphine: 0.75–5 ug/kg/minWith bolus 10ug/kg (over 60s)
3 Dahaba MV patients in ICU after orthopedic and general surgery 100 Remifentanil: 0.15–0.2 ug/kg/min Two groups were given midazolam a 30 ug/kg bolus and 0.5 ug/kg/min when the dose of the study drug reached the midazolam “trigger dose.” Increased 0.125 ug/kg/min accompanied with a bolus of 15 ug/kg or decreased by 0.125 ug/kg/min PI≤2 and SAS = 4 Duration of MV, duration of extubation, ICU LOS, ICU mortality, efficacy, safety, and hypotension
98.7 Morphine: 0.75–5 ug/kg/minWith bolus 25 ug/kg (over 60s)
4 Karabinis MV patients in NICU 37 Remifentanil: 0.15-1ug/kg/min From the first day to the third day, the three groups were given propofol a 0.5 mg/kg bolus, and 0.5 ug/kg/h when the dose of the study drug reached the propofol “trigger dose.” Starting on the fourth day, all patients changed to midazolam infusion (0.01–0.5 mg/kg bolus and 0.03–0.3 ug/kg/h) PI≤2 and SAS < 4 Duration of MV, duration of extubation, ICU LOS, ICU mortality, efficacy, safety, and bradycardia
49 Fentanyl: follow the clinical practice routines of each investigating site
25 Morphine: follow the clinical practice routines of each investigating site
5 Muellejans MV patients in ICU 92 Remifentanil: 0.15–0.2 ug/kg/min Two groups were given propofol a 0.5 mg/kg bolus and 0.5 ug/kg/h when the dose of the study drug reached the propofol “trigger dose.” Increased 0.125 mg/kg/h accompanied with a bolus of 0.25 mg /kg or decreased by 0.125 mg/kg/h PI≤2 and SAS = 4 Duration of MV, duration of extubation, ICU LOS, efficacy, safety, hypotension, and bradycardia
95 Fentanyl: 1 ug/kg bolus and 1.5–2 ug/kg/h
6 Akinci MV patients in ICU after surgery 100 Remifentanil: 0.1 ug/kg/min Morphine as rescue treatment for two groups BPS = 3 andSAS = 3 Duration of extubation, hypotension, and bradypnea
100 Fentanyl: 0.025 ug/kg/min
7 Baillard MV patients in ICU 29 Remifentanil: 0.17 ug/kg/min Two groups were given midazolam 0.1 mg/kg/h RS 2–4 Duration of extubation, ICU LOS, ICU mortality, and efficacy
20 Sufentanil: 0.002 ug/kg/min
8 Amor MV patients in ICU with normal renal function or mild renal impairment 0 Remifentanil: 6 ug/kg/h, titrated up by increment of 100 ug/h Two groups were given midazolam 0.1 mg/kg/h RS 3–4 Duration of MV, duration of extubation, and ICU LOS
0 Fentanyl: 1.5 ug/kg/h, titrated up with an increment of 25 ug/h
9 Carrer MV patients in ICU after major surgery 100 Remifentanil:0.1 ug/kg/minstepwise variations by ±25% and boluses allowed (0.025 μg/kg in 30 s) Two groups were given morphine 0.24 mg/kg/h while in patients aged 75 years 0.12 μg/kg/min RS 2–3 and NRS < 3 Duration of MV, ICU LOS, ICU mortality, safety, hypotension, bradycardia, and bradypnea
100 Morphine:0.48ug/kg/minstepwise variations by ±25%, and boluses allowed (0.1 mg/kg in 30 s)
10 Spies MV patients in ICU 92 Remifentanil: 0.1–0.4 ug/kg/min (IBW) Two groups were given morphine for rescue pain and were given midazolam 0.01–0.18 mg/kg/h, propofol 4 mg/kg/h for sedation VAS ≤3 and/orBPS ≤6 Duration of MV and ICU LOS
97 Fentanyl: 0.02–0.08 ug/kg/min (IBW)
11 Cevik MV patients in ICU 88 Remifentanil:0.05 ug/kg/min (initial dose)Increased 0.05 ug/kg/min Two groups were given midazolam at an initial dose of 0.03 mg/kg/h RS ≤3 Duration of MV, ICU LOS, safety, hypotension, and bradycardia
88 Fentanyl:0.015 ug/kg/min (initial dose)Increased 0.01 ug/kg/min
12 Oliver MV patients in ICU after cardiopulmonary bypass 100 Fentanyl: 0.5 ug/kg/h Two groups were given propofol 25 ug/kg/min VAS ≤3 and RS >3 Duration of extubation and ICU LOS
100 Morphine boluses
13 Liu MV patients in ICU after tumor operation 100 Remifentanil:0.05–0.1 ug/kg/min Two groups were given propofol 0.5 mg/kg/h when the dose of the study drug reached the propofol “trigger dose” FPS ≤ 2RS 2–3 Duration of MV, ICU LOS, safety, hypotension, bradycardia, and bradypnea
100 Fentanyl: 0.5–1 ug/kg/h and 0.7–1.5 ug/kg bolus when necessary
14 Lee MV patients in ICU 9 Remifentanil: 0.1–0.2 ug/kg/min Midazolam as rescue treatment for two groups NR Duration of extubation
12 Morphine: 0.8–35 mg/h
15 Yang MV patients in ICU 0 Sufentanil:≤0.3 ug/kg/h Two groups were given midazolam when the dose of the study drug reached the midazolam “trigger dose” FPS ≤ 2 orRS = 3 Safety, hypotension, bradycardia, and bradypnea
0 Fentanyl: ≤2 g/kg/h
16 Yue MV patients in ICU after major surgery 100 Sufentanil: 5 ug/h Two groups were given propofol 1 mg/kg bolus as rescue treatment Prince-Henry 0–1RASS -1 ~ 0 Safety, hypotension, bradycardia, and bradypnea
100 Fentanyl: 50 ug/h
17 Liu MV patients in ICU after surgery 100 Remifentanil: 1 ug/kg/h Three groups were given midazolam infusion (0.05 mg/kg bolus and 0.02–0.1 ug/kg/h) RASS-3 ~ −1 Duration of MV, duration of extubation, and ICU LOS
100 Fentanyl: 50 ug/h
18 Casamento MV patients in ICU 35.8 NR NR -2 ≤ RASS≤1 Duration of MV, ICU LOS, ICU, and mortality
34.4 NR
19 Doi MV patients in ICU 100 Remifentanil: 1.5 ug/kg/h (Initial dose)Increased 1.5 ug/kg/h Fentanyl was administered as a rescue analgesic BPS ≤ 5 or NRS ≤ 3 Duration of MV, duration of extubation, ICU mortality, efficacy, safety, hypotension, and bradypnea
100 Fentanyl: 0.1 ug/kg/h (Initial dose)Increased 0.1 ug/kg/h
20 Li MV patients in ICU 70 Remifentanil: 1.5 ug/kg/h (Initial dose)Increased 1.5 ug/kg/h Two groups were given propofol 0.5 mg/kg/h when the dose of the study drug reached the propofol “trigger dose” CPOT≤2−2 ≤ RASS≤1 Duration of MV, duration of extubation, ICU LOS, ICU mortality, efficacy, safety, hypotension, and bradycardia
70 Fentanyl: 1 ug/kg bolus and 0.25 ug/kg/h (Initial dose)Increased 0.25 ug/kg/h

BPS, behavioral pain scale; CPOT, critical care pain observation tool; FPS, facial pain scale; GCS, Glasgow coma scale; IBW, ideal body weight; MV, mechanical ventilation; NR, not reported; NRS, numerical rate score; PI, pain intensity score; RASS, Richmond agitation sedation scale; RS, Ramsey scale; SAS, sedation agitation score; VAS, visual analog scale.

A total of 13 studies reported the duration of MV, 13 studies reported the duration of extubation, 14 reported ICU LOS, and 8 reported ICU mortality. In total, 7 studies reported efficacy, 11 reported safety, 10 reported drug-related hypotension, 8 reported drug-related bradycardia, and 8 reported drug-related bradypnea (Table 3).

Reported clinical outcomes of included studies.

ID Study drug Duration of MV (hours) Duration of extubation (hours) ICU LOS (days) ICU Mortality (n/N) Efficacy (%/hours) Safety (n/N) Hypotension (n/N) Bradycardia (n/N) Bradypnea (n/N)
1 Remifentanil NR 0.10 (0.10) 0.11 (0.11) NR NR NR NR NR 10/72
Morphine NR 0.14 (0.20) 0.10 (0.11) NR NR NR NR NR 5/78
2 Remifentanil 17.20 (10.51) 1.50 (1.90) NR 2/106 94.5 (24.28) 23/106 NR NR 4/106
Morphine 16.90 (8.65) 2.50 (4.00) NR 1/83 93.9 (23.88) 13/83 NR NR 10/83
3 Remifentanil 14.38 (2.85) 0.28 (0.10) 1.46 (0.19) 0/20 78.3 (6.2) 8/20 1/20 NR NR
Morphine 19.32 (3.46) 1.22 (0.12) 2.54 (0.39) 0/20 66.5 (8.5) 6/20 0/20 NR NR
4 Remifentanil 25.83 (24.56) 1.0 (24.30) 2.85 (1.77) 4/84 95.6 (21.25) 21/84 NR 1/84 NR
Fentanyl 24.76 (14.05) 0.68 (1.40) 2.79 (1.41) 0/37 98.1 (3.25) 3/37 NR 0/37 NR
Morphine 38.97 (26.65) 1.93 (24.05) 3.61 (1.69) 2/40 99.0 (25) 4/40 NR 0/40 NR
5 Remifentanil 14.7 (19.61) 1.00 (5.25) 1.70 (1.68) NR 89.5 (13.7) 26/115 19/115 2/115 NR
Fentanyl 15.3 (18.79) 1.10 (1.125) 1.65 (1.69) NR 89.3 (16.88) 14/81 8/81 3/81 NR
6 Remifentanil NR 0.10 (3.23) NR NR NR NR 10/22 NR 3/22
Fentanyl NR 0.10 (7.05) NR NR NR NR 11/22 NR 10/22
7 Remifentanil NR 22 (30.37) 26.00 (27.41) 12/21 89.0 (46.13) NR NR NR NR
Sufentanil NR 96 (70.37) 19.00 (17.04) 12/20 89.0 (44.87) NR NR NR NR
8 Remifentanil 132 (79) 24.67 (16.34) 15.00 (13.00) NR NR NR NR NR NR
Fentanyl 129 (66) 48 (21.33) 17.00 (11.00) NR NR NR NR NR NR
9 Remifentanil 17 (6) NR 2.30 (2.30) 1/50 NR 9/50 0/50 0/50 1/50
Morphine 18 (4) NR 2.30 (2.50) 1/50 NR 6/50 0/50 0/50 8/50
10 Remifentanil 136 (218.6) NR 23.00 (34.83) NR NR NR NR NR NR
Fentanyl 162 (255.4) NR 26.00 (34.83) NR NR NR NR NR NR
11 Remifentanil 45.75 (74.71) NR 8.70 (9.96) NR NR 7/16 5/16 2/16 NR
Fentanyl 45.75 (47.13) NR 9.88 (6.66) NR NR 5/16 5/16 0/16 NR
12 Fentanyl NR 4.67 (0.50) 0.97 (0.33) NR NR NR NR NR NR
Morphine NR 4.73 (0.54) 0.96 (0.02) NR NR NR NR NR NR
13 Remifentanil 73.6 (26.7) NR 5.25 (1.55) NR NR 13/30 8/30 3/30 0/30
Fentanyl 94.9 (37.3) NR 6.28 (2.12) NR NR 5/30 2/30 1/30 0/30
14 Remifentanil NR 90 (89) NR NR NR NR NR NR NR
Morphine NR 144 (176) NR NR NR NR NR NR NR
15 Sufentanil NR NR NR NR NR 34/282 9/282 6/282 12/282
Fentanyl NR NR NR NR NR 39/262 18/262 5/262 15/262
16 Sufentanil NR NR NR NR NR 11/300 0/300 0/300 11/300
Fentanyl NR NR NR NR NR 21/300 0/300 0/300 21/300
17 Remifentanil 102 (65.93) 12 (17.22) 6.00 (3.70) NR NR NR NR NR NR
Fentanyl 126 (139.3) 18 (37.78) 7.00 (6.01) NR NR NR NR NR NR
18 Fentanyl 61.84 (79.23) NR 4.38 (4.37) 34/344 NR NR NR NR NR
Morphine 72.74 (88.90) NR 4.96 (4.67) 46/337 NR NR NR NR NR
19 Remifentanil 7.03 (11.99) 1.68 (4.31) NR 0/92 99.16 (2.60) 12/92 3/92 NR 2/92
Fentanyl 6.88 (12.95) 1.17 (2.68) NR 0/90 98.50 (3.44) 15/90 3/90 NR 0/90
20 Remifentanil 26.11 (21.33) 0.94 (0.72) 2.45 (1.17) 1/69 98.75 (2.13) 24/69 47/69 14/69 NR
Fentanyl 25.34 (20.22) 1.20 (1.27) 2.29 (0.68) 1/68 98.50 (2.76) 22/68 47/68 11/68 NR

Continuous variables are represented by means and standard deviations.LOS, Length of stay; MV, mechanical ventilation; NR, not reported.

 ROB in included studies

In summary (Figure 2), 17 (85%) of the 20 trials were rated as having low ROB, and 3 (20%) as having moderate ROB.

Risk of bias.

 Effects of interventions Primary outcome (duration of MV)

An analysis of 13 studies, including 1860 patients, was conducted to determine the duration of MV. There were 9, 4, and 2 trial arms involving direct comparisons of remifentanil and fentanyl, remifentanil and morphine, and morphine and fentanyl, respectively. None of the studies on sufentanil were included. All the Bayesian parameters converged well. Figure 3 displays a network of eligible comparisons for the MV duration.

Network plot of all intervention comparisons for the duration of mechanical ventilation. The node size corresponds to the total number of participants in this study’s treatments. The comparable treatments are linked with a line. The colors and thickness of the line correspond to the quality and standard error of trials that study this comparison, respectively. Low risk of bias is green, moderate risk of bias is yellow.

The results of the NMA are shown in Table 4 for the duration of MV. Compared with remifentanil, when fentanyl and morphine were administered to analgesia, the duration of MV was not significantly prolonged (MD -0.16; 95% CrI: −4.75 to 5.63) and (MD 3.84; −0.29 to 10.68), respectively. The differences between the three opioids were not significant. The SUCRA results showed that the best possible interventions for achieving the shortest duration of MV were remifentanil (46.0%), fentanyl (52.2%), and morphine (1.8%) (Supplementary Figure S8.1). However, we cannot conclude from the above results that fentanyl is the best regimen to shorten the duration of MV among the three opioids.

Results from pairwise meta-analyses and network meta-analyses on mechanical ventilation.

Fentanyl 13.14 (2.54, 23.17) −0.95 (−6.23, 3.14)
−4.09 (−11.38, 1.94) Morphine −2.60 (−7.72, 1.41)
−0.16 (−4.76, 5.65) 3.85 (−0.26, 10.74) Remifentanil

Data are the MDs (95% CrI) in the column-defining treatment compared with the row-defining treatment. With treatment as the boundary, the lower left part of the table is the result of network meta-analyses, and the upper right part of the table is the result of pairwise meta-analyses. For network meta-analyses, MDs lower than 0 favor the column-defining treatment: e.g., column 1 vs. row 3 in the lower left part of the table (Fentanyl vs. Remifentanil) is the result of network meta-analyses (MDs − 0.16 95% CrI -4.76 to 5.65). For pairwise meta-analyses, MDs higher than 0 favor the row-defining treatment: e.g., column 3 vs. row 1 in the upper right part of the table (Remifentanil vs. Fentanyl) is the result of pairwise meta-analyses (MDs − 0.95 95% CrI -6.23 to 3.14). MDs, mean differences; CrI, credible interval.

 Secondary outcomes

Figure 4 presents the results of secondary outcomes. Compared with remifentanil, sufentanil can prolong the duration of extubation (MD 80.42; 95% CrI 18.31–127.36). No regimen significantly improved ICU LOS, efficacy, safety, and other secondary outcomes. The SUCRA ranking curve showed that remifentanil ranked first for shortening the extubation duration and reducing the occurrence of drug-related bradypnea. Fentanyl ranked first for ICU mortality. Moreover, morphine ranked first for efficacy, reducing the occurrence of drug-related hypotension and bradycardia. Furthermore, sufentanil ranked first for ICU-LOS and safety (Supplementary File 8).

Forest plot for each active intervention versus remifentanil on secondary outcomes estimates are presented as MD (mean difference) or odds ratios (OR) and 95% CrI. OR < 1 favor the treatment. MD < 0 favor the treatment. CrI, credible interval; LOS, Length of stay.

 Direct meta-analysis

A pairwise analysis of the duration of MV is presented in Table 4.

Heterogeneity, inconsistency, and transitivity

In terms of MV duration (I2 = 68.70%) and ICU LOS (I2 = 99.87%), there was moderate-to-high global heterogeneity (Supplementary File 4).

No global inconsistency was observed in any of the outcomes (Supplementary Table S4.2). When the node-splitting model was compared indirectly and directly, there was no evidence of inconsistency.

Most comparisons had similar mean ages in the assessment of transitivity (Supplementary File 5).

 Subgroup analyses and sensitivity analyses for the duration of MV

Compared with remifentanil, when morphine was administered as analgesia, the duration of MV was significantly prolonged (MD 12.53; 95% CrI: 2.34 to 22.59). The three opioids had similar effects on shortening the duration of MV in each subgroup of patients, regardless of their patient population, duration of analgesia, and study quality (Table 5). In addition, heterogeneity and consistency were not statistically significant among the subgroups.

Subgroup analyses for the duration of mechanical ventilation in different populations.

Treatment Overall patients Postoperative ICU patients Mixed ICU patients Analgesia is greater than 72 h Analgesia is less than 72 h High quality studies only
MDs (95% CrI) Rank MDs (95% CrI) Rank MDs (95% CrI) Rank MDs (95% CrI) Rank MDs (95% CrI) Rank MDs (95% CrI) Rank
Fentanyl −0.16 (−4.75, 5.63) 1 5.44 (−5.37, 23.44) 3 −0.27 (−6.39, 5.78) 1 8.41 (−9.80, 30.97) 2 −1.68 (−8.17, 4.90) 1 −0.62 (−5.62, 4.09) 1
Morphine 3.84 (−0.29, 10.68) 3 1.91 (−9.96, 13.62) 2 12.53 (2.34, 22.59) 3 19.34 (−17.40, 61.27)- 3 3.22 (−1.19, 9.66) 3 2.48 (−1.47, 7.19) 3
Remifentanil Reference 2 Reference 1 Reference 2 Reference 1 Reference 2 Reference 2
Number of studies 13 8 5 6 7 11
Participants 1860 710 1,150 1,086 774 1,666

Bold values are compared with remifentanil, when morphine was administeredas analgesia, the duration of MV was significantly prolonged.

The sensitivity analysis did not change substantially (Supplementary File 9).

 GRADE assessments

Except for the extubation duration, no publication bias was found (Supplementary File 6). The degree of certainty about shortening MV time was variable (Supplementary Table S7.1). For comparisons involving fentanyl, morphine, and remifentanil, it was low, whereas, for comparisons involving morphine and remifentanil, it was very low. The GRADE of ranking of treatment was very low. The GRADE was raised to at least moderate when subgroup analysis was performed. Table 6 and Supplementary File 7 presents details of GRADE.

Result of GRADE for primary outcome.

Nature of the evidence Study limitations Imprecision Inconsistency Indirectness Publication bias Confidence Downgrading due to
A vs. B Mixed estimated No downgrade Downgrade because point estimate <1.0 but upper limit >1.25 Downgrade because pair heterogeneity I2 = 81.2% No downgrade No downgrade LOW Imprecision Inconsistency
A vs. C Mixed estimated No downgrade Downgrade because point estimate >1.0 but lower limit<0.80 No downgrade No downgrade Downgrade because publication bias LOW Imprecision Publication bias
B vs. C Mixed estimated Downgrade because >70% contribution from moderate ROB comparisons Downgrade because point estimate >1.0 but lower limit<0.80 Downgrade because pair heterogeneity I2 = 85.1% No downgrade Downgrade because publication bias VERY LOW Study limitations ImprecisionInconsistencyPublication bias
Ranking of treatments No downgrade Downgrade because similar distributions of ranks Downgrade because global heterogeneity I2 = 67.70% No downgrade Downgrade because publication bias VERY LOW ImprecisionInconsistencyPublication bias

A, Fentanyl; B, Morphine; C, Remifentanil.

 Discussion Main results summary

This study was conducted to investigate the effect of analgesic regimens using remifentanil, morphine, and fentanyl on the duration of MV. It was concluded that remifentanil did not significantly shorten the duration of MV in mechanically ventilated patients compared to morphine or fentanyl. This finding was supported by sensitivity and subgroup analyses. In addition, the SUCRA ranking curve indicated that fentanyl ranked first among the three opioids for shortening the duration of MV, but the difference was not statistically significant.

 Applicability of evidence

Remifentanil did not reduce the duration of MV, which is consistent with the previous conclusion that all opioids administered intravenously appear to exhibit a similar duration of MV when titrated to similar pain intensity endpoints (5). However, the pharmacokinetics of remifentanil is not similar to those of morphine and fentanyl. The results were interpreted carefully for the following reasons: First, elimination independent of renal function seems to make remifentanil more effective in patients with renal impairment (20). Amor and Chinachoti’s study focused on patients with mild renal impairment, although not suggested remifentanil can shorten the duration of MV, they indicated remifentanil was associated with shorter the duration of weaning (47, 50). In Chinachoti et al.’s study, it should be noted that twice the amount of midazolam in the morphine group may have reduced morphine-related side effects (47). Second, a prolonged infusion did little to affect the context-sensitive half-life of remifentanil. Remifentanil shortened the duration of MV by at least 24 h when analgesia was > 5 days (29, 33, 57). Although the difference was not statistically significant, it is important to avoid ventilator-associated pneumonia, improve ICU outcomes, and reduce costs (23, 61). This suggests that remifentanil is the most suitable treatment for mechanically ventilated patients undergoing long-term analgesia (28). Third, as a result of remifentanil’s rapid onset and offset action, it permitted a significantly quicker and more predictable awakening when it came to performing neurological assessment (31). Thus, although the reduced duration between remifentanil and either of the comparator opioids was less than 1 h, remifentanil may be more meaningful for these patients (31, 62). Fourth, the agents and sedation protocols used differed between studies. Seven studies used midazolam as an adjuvant sedative, and the other three used propofol as an adjuvant sedative. It was more difficult to estimate the effect of opioids when sedatives and analgesics were combined. Finally, heterogeneity and publication bias were the main reasons for the reduction in the GRADE scores. Therefore, these factors weaken the inference drawn from the current findings. Larger, well-powered, and more definitive clinical trials based on different populations are urgently needed to avoid such biases.

 Analysis of secondary outcomes

In terms of extubation duration, sufentanil showed a prolonged effect compared with remifentanil. However, these findings were inconclusive. We need to note that the CrI was too wide because this result was only determined in one study that enrolled 41 patients on MV and was stopped after an interim analysis (48). Therefore, caution should be exercised when interpreting the impact of sufentanil, and it is imperative to conduct future large RCTs to validate these clinical results. Neither of the four opioid medications significantly differed in ICU-LOS, ICU mortality, efficacy, safety, or drug-related adverse events. It can be interpreted for two reasons. First, all available IV opioids were equally effective when titrated to similar pain intensity end points (5). Second, the frequent reassessment of pain and careful titration of analgesic interventions were helpful in preventing negative sequelae due to excessive or inadequate analgesic therapy (63).

 Strengths of this NMA

This study has several strengths. First, this is the first NMA to assess the effectiveness of IV opioid μ-receptor analgesics to shorten the duration of MV in mechanically ventilated patients. Second, it was the most updated evaluation of IV opioid μ-receptor analgesics for patients on MV. A structured search strategy retrieved all identified studies. Third, several relevant clinical outcomes were examined in a heterogeneous population. Fourth, we focused on the co-interventions of sedatives and included only studies that employed the same strategies for sedation. Finally, this study focused on a wide range of clinical outcomes.

 Limitations of this NMA

There are still several limitations in drawing strong treatment inferences. First, several studies did not provide accurate study criteria, such as mode of MV, weaning, and extubation. It is difficult to make these definitions consistent. In addition, the varying opioid doses, sedative types, length of administration, and consumption in different studies weakened any possible recommendations and conclusions. Second, because of the inconsistency in adjuvant sedatives, fewer eligible studies were included and subgroup analyses could not be performed. Therefore, we downgraded the GRADE score. Third, many comparisons had low-level evidence. Mainly because of a wide 95% CrI, possibly implying a small number of studies. Finally, European and Asian countries accounted for 80% of all studies.

 Conclusion

This study provides evidence that remifentanil, compared with fentanyl and morphine, does not shorten the duration of MV in ICU patients. Clinicians should carefully titrate the analgesia of mechanically ventilated patients to prevent a potentially prolonged duration of MV. As such, based on current data, no final recommendations or conclusions can be made. Further large-scale multicenter RCTs according to the characteristics of different populations, especially organ failure patients and long-term analgesic patients, are needed to clarify the most appropriate analgesics, dosages, duration of infusion, and strategies of analgesia.

 Data availability statement

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

 Author contributions

FL: Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – original draft. SQ: Data curation, Formal analysis, Investigation, Methodology, Writing – review & editing. ChL: Data curation, Formal analysis, Investigation, Writing – review & editing. XC: Data curation, Investigation, Project administration, Writing – review & editing. ZD: Data curation, Formal analysis, Investigation, Project administration, Writing – review & editing. CoL: Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Writing – review & editing, Writing – original draft.

 Funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was funded by the Key Research and Development project of Xuzhou (KC22238). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

 Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2024.1370481/full#supplementary-material

1http://www.controlled-trials.com/isrctn/

2http://www.who.int/ictrp/en/

3www.chictr.org

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Adverse events

 APACHE II

Acute Physiology and Chronic Health Evaluation II

 CrI

Credible interval

 DB

Double-blind

 GCS

Glasgow coma scale

 GRADE

Grades of Recommendation, Assessment, Development and Evaluation

 ICU

Intensive care unit

 LOS

Length of stay

 MC

Multicenter

 MD

Mean difference

 MV

Mechanical ventilation

 NMA

Network meta-analysis

 NR

Not reported

 OP

Open study

 OR

Odds ratio

 PRISMA

Preferred Reporting Items for Systematic Review and Meta-analysis

 PROSPERO

Prospective register of systematic reviews

 RCTs

Randomized controlled trial studies

 SAPS

Simplified acute physiology score

 SB

Single-blind

 SC

Single-center

 SD

Standard deviation

 SUCRA

Surface under the cumulative ranking curve