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

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.

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).

Figure 1

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).

Table 1

Table 1. Description of included studies.

Table 2

Table 2. Description of included studies.

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).

Table 3

Table 3. Reported clinical outcomes of included studies.

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.

Figure 2

Figure 2. 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.

Figure 3

Figure 3. 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.

Table 4

Table 4. Results from pairwise meta-analyses and network meta-analyses on mechanical ventilation.

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).

Figure 4

Figure 4. 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.

Table 5

Table 5. Subgroup analyses for the duration of mechanical ventilation in different populations.

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.

Table 6

Table 6. Result of GRADE for primary outcome.

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

Footnotes

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

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

3. ^www.chictr.org

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