Efficacy and safety of alfentanil plus propofol versus propofol only in painless gastrointestinal endoscopy: A meta-analysis

Background:

To systematically evaluate the efficacy and safety of alfentanil plus propofol versus propofol only for painless gastrointestinal endoscopy.

Methods:

The Cochrane Library, PubMed, Embase, China Biology Medicine, CNKI, WanFang, and VIP databases were searched to identify randomized controlled trials on alfentanil combined with propofol versus propofol only for painless gastrointestinal endoscopy from the inception of the database to August 2022. The Rev Man 5.4 software was used for statistical analyses.

Results:

Thirteen randomized controlled trials involving 1762 patients were identified as eligible for this study. The meta-analysis showed that compared with propofol, alfentanil combined with propofol had a more stable mean arterial pressure [mean difference (MD) = 5.38, 95% confidence interval (CI): 1.97–8.80; P = .002], heart rate (MD = 3.78, 95% CI: 1.30–6.26; P = .003) and pulse oxygen saturation (MD = 1.90, 95% CI: 0.93–2.78; P = .0001); a lower propofol dose (standard mean difference = −2.82, 95% CI: −3.70 to −1.94; P < .00001), lower awakening time (MD = −3.23, 95% CI: −4.01 to −2.45; P < .00001) and lower directional force recovery time (MD = −3.62, 95% CI: −4.22 to −3.03; P < .00001); a lower incidence of nausea and vomiting (relative risk [RR] = 0.32, 95% CI: 0.14–0.71; P = .005), body movement (RR = 0.27, 95% CI: 0.13–0.54; P = .0002), hypotension (RR = 0.23, 95% CI: 0.12–0.46; P < .0001), respiratory depression (RR = 0.37, 95% CI: 0.15–0.89; P = .03) and cough reflex (RR = 0.33, 95% CI: 0.12–0.89; P = .03).

Conclusion:

This meta-study found that current evidence indicates that alfentanil plus propofol is better than propofol alone for painless gastrointestinal endoscopy and is associated with a lower incidence of adverse reactions. Due to the limited quality and quantity of the included studies, more high-quality studies are needed to validate these above conclusions.

1. Introduction

Gastrointestinal endoscopy is widely used to diagnose and treat digestive tract diseases. However, patients might experience obvious discomforts, such as nausea, vomiting and throat bleeding, during the procedure, which could lead to anxiety and poor patient compliance, thereby affecting the outcomes of the procedure.^[1,2]

With the introduction and promotion of the concept of comfortable medical treatment, painless gastrointestinal endoscopy has been popularized because it could ease patients discomforts by using appropriate sedative and anesthetic drugs and shorten the time to leave the hospital after the procedure, thereby decreasing the potential impact on their daily work on the same day and return to their routine lifestyle habits by the next day.^[3] Propofol is a short-acting intravenous anesthetic widely used in gastroenteroscopic anesthesia due to its strong controllability and good respiratory and circulatory system control when used alone but at the expense of using a larger dosage to achieve these effects.^[4] Comparatively, alfentanil acts on μ-opioid receptors. It is an ultra-short-acting opioid analgesic drug with quick onset and little impact on the cardiovascular system.

Previous studies showed that alfentanil could significantly reduce adverse reactions and propofol dosage when used in combination with propofol.^[5,6] However, despite several clinical trials on this topic, some of the results were contrasting, urging the need for a meta-analysis to perform much in-depth analysis. The purpose of this study was to compare the efficacy and safety of alfentanil combined with propofol versus propofol only in painless gastrointestinal endoscopy through a meta-analysis to provide a reference for clinical practice and potential drug selection.

2. Materials and methods

This meta-analysis was conducted according to the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines^[7] and the Cochrane Handbook for Systematic Reviews of Interventions.^[8] All analyses were based on previously published studies; thus, no ethical approval and patient consent were required.

2.1. Literature search and selection criteria

The Cochrane Library, PubMed, Embase, China Biology Medicin, CNKI, WanFang, and VIP databases were systematically searched from inception till August 2022 using the following keywords: “Alfentanil” AND “Propofol” AND “Painless gastrointestinal endoscopy” (OR “gastrointestinal endoscopy” OR “gastroscopy” OR “colonoscopy”). The reference lists of the retrieved studies and relevant reviews were also hand-searched to extend the potential of including additional eligible studies. This above process was performed repeatedly until no further article was identified.

The inclusion criteria for this meta-analysis were: an randomized controlled trials (RCT) study design, the investigated patients underwent gastrointestinal endoscopy, and intervention treatments were alfentanil plus propofol versus propofol.

2.2. Data extraction and outcome measures

The following information was extracted from eligible RCTs: authors information, the number of patients investigated, the detailed methodology for each group etc. The data were independently retrieved by 2 investigators, and discrepancies were resolved by mutual consensus. When needed, the corresponding author of an eligible study was contacted to obtain missing or incomplete data. The primary outcomes of this study were cyclic indicators, propofol dose, awakening time and directional force recovery time. Secondary outcomes included the incidence of nausea, vomiting, body movement, hypotension, respiratory depression, and cough reflex.

2.3. Quality assessment in individual studies

Two reviewers independently read and evaluated the methodological validity of all eligible studies using the Cochrane Handbook v5.1.0 (https://www.cochranelibrary.com/central/doi/10.1002/central/CN-00871375/full?highlightAbstract=cochran%7Ccochrane%7Chandbook). Any discrepancies were resolved through joint discussion, and when necessary, a third researcher assisted in the decision-making.^[8] The following information was evaluated: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting and other biases, and each of them was graded as “high risk of bias”, “uncertain risk of bias or “low risk of bias”.^[9]

2.4. Statistical analysis

All statistical analyses were performed using the Review Manager Version 5.4 (The Cochrane Collaboration, Software Update, Oxford, UK).^[10] The standard mean differences or mean differences (MDs) with 95% confidence intervals (CIs) for continuous outcomes (i.e., mean arterial pressure, heart rate, pulse oxygen saturation, propofol dose, awakening time, and directional force recovery time) and relative risk (RR) with 95% CIs for dichotomous outcomes (i.e., the incidence of nausea and vomiting, body movement, hypotension, respiratory depression, and cough reflex) were used to estimate the pooled effects. Heterogeneity was quantified with the I²statistic, and an I² value > 50% indicated significant heterogeneity. If there was no statistical heterogeneity among the research results (P ≥ .05, I²≤50%), the fixed effect model was used for meta-analysis. When statistical heterogeneity was present among the research results (P < .05, I² > 50%), we further investigated the source of the heterogeneity. After excluding the influence of obvious clinical heterogeneity, the random effect model was used for the meta-analysis.^[11] Sensitivity analysis was performed to detect the influence of a single study on the overall estimate by omitting 1 study in turn when necessary.^[12] Publication bias was evaluated by drawing funnel charts. P < .05 in 2-tailed tests was considered statistically significant. All statistical analyses were performed with Review Manager Version 5.4 (The Cochrane Collaboration, Software Update, Oxford, UK).^[10]

3. Results

3.1. Study identification and selection

Figure 1 shows the flowchart of the meta-analysis search strategy and selection process. Initially, 3289 studies were identified, but after excluding duplicates (n = 1023) and those that did not match the inclusion criteria, 13 RCTs were found eligible for this meta-analysis.^[13–25]

Figure 1.

Flow diagram of the searching, selection and analysis process.

Table 1 shows the characteristics of the 13 eligible RCTs. They were published between 2013 and 2022. The sample size varied from 40 to 400 patients, with a total of 1762 patients. Figure 2 shows the results of the bias risk assessment.

Table 1.

Characteristics of the 13 RCTs for this meta-analysis.

Studies	Total cases	AP group (no. of patients)	P group (no. of patients)	Observations
Cui Jie2021	80	40	40	④⑤⑦⑧⑨⑩
Chu Shuangping2022	200	100	100	①②③④⑤⑥⑦⑧⑩
Yu Huifang2022	186	93	93	④⑤⑧⑨⑪
Zhang Ning2021	60	30	30	④⑤⑥⑧
Zhuo Yifen2021	240	120	120	①②③④⑤⑥
Zhang Yonghua2021	80	40	40	①②③④⑤⑥⑦⑧⑪
Xu Handa2021	400	200	200	④⑤⑥⑧
Wang Beibei2022	80	40	40	①②③④⑤⑥⑦⑪
Shuai Xunjun2013	40	20	20	②③④⑤⑥⑦⑧
Xie Zhiqiang2021	80	40	40	①②③④⑥⑦⑧⑩
Ou Yangfeng2021	96	48	48	⑤⑥
He Xiuwen2021	86	43	43	①②③⑤⑥⑦⑧⑩
Liu Shengan2021	134	68	66	④⑤⑧⑨⑪

①: Mean arterial pressure; ②:heart rate; ③:pulse oxygen saturation; ④:propofol dose; ⑤:awakening time; ⑥:directional force recovery time; ⑦:nausea and vomiting; ⑧:body movement; ⑨:hypotension; ⑩:respiratory depression; ⑪:cough reflex.

RCTs = randomized controlled trials.

Figure 2.

Risk of bias assessment among the 13 RCTs included in this meta-analysis. RCTs = randomized controlled trials.

3.2. Primary outcomes: Cyclic indicators, propofol dose and awakening time

The pooled estimate of the included RCTs suggested that compared with propofol, alfentanil combined with propofol had a more stable mean arterial pressure (MD = 5.38, 95% CI: 1.97–8.80; P = .002;Fig. 3), heart rate (MD = 3.78, 95% CI: 1.30–6.26; P = .003; Fig. 4) and pulse oxygen saturation (MD = 1.90, 95% CI: 0.93–2.78; P = .0001; Fig. 5), but the results showed significant heterogeneity of I²=91% (P < .00001), I²=80% (P < .0001) and I²=97% (P < .00001), respectively. The combined regimen was associated with lower propofol dose (standard mean difference = −2.82, 95% CI: −3.70 to −1.94; P < .00001; Fig. 6), lower awakening time (MD = −3.23, 95% CI: −4.01 to −2.45; P < .00001; Fig. 7) and lower directional force recovery time (MD = −3.62, 95% CI: −4.22 to −3.03; P < .00001; Fig. 8), which also demonstrated significant heterogeneity of I²=98% (P < .00001), I²=98% (P < .00001) and I² = 94% (P < .00001).

Figure 3.

Forest plot for the meta-analysis of mean arterial pressure.

Figure 4.

Forest plot for the meta-analysis of heart rate.

Figure 5.

Forest plot for the meta-analysis of pulse oxygen saturation.

Figure 6.

Forest plot for the meta-analysis of propofol dose.

Figure 7.

Forest plot for the meta-analysis of awakening time.

Figure 8.

Forest plot for the meta-analysis of directional force recovery time.

3.3. Sensitivity analysis

Considering that significant heterogeneity was observed for the primary outcomes, sensitivity analysis was performed by omitting 1 study in each turn to detect the source of heterogeneity. However, despite this, there was still significant heterogeneity in the results of the primary outcomes.

3.4. Secondary outcomes

Secondary outcome analyses showed that alfentanil combined with propofol was associated with a lower incidence of nausea and vomiting (RR = 0.32, 95% CI: 0.14–0.71; P = .005; Fig. 9) (no obvious heterogeneity, I² = 0%; P = 0.96), body movement (RR = 0.27, 95% CI: 0.13–0.54; P = .0002; Fig. 10) (significant heterogeneity, I² = 55%; P = .02), hypotension (RR = 0.23, 95% CI: 0.12–0.46; P < .0001; Fig. 11) (no obvious heterogeneity, I² = 0%; P = .99), respiratory depression (RR = 0.37, 95% CI: 0.15–0.89; P = .03; Fig. 12) (no obvious heterogeneity, I² = 0%; P = .97) and cough reflex (RR = 0.33, 95% CI: 0.12–0.89; P = .03; Fig. 13) (no obvious heterogeneity, I²=0%; P = .54) in patients undergoing gastrointestinal endoscopy.

Figure 9.

Forest plot for the meta-analysis of the incidence of nausea and vomiting.

Figure 10.

Forest plot for the meta-analysis of the incidence of body movement.

Figure 11.

Forest plot for the meta-analysis of the incidence of hypotension.

Figure 12.

Forest plot for the meta-analysis of the incidence of respiratory depression.

Figure 13.

Forest plot for the meta-analysis of the incidence of cough reflex.

4. Discussion

Presently, no studies have performed a meta-analysis on the efficacy and safety of alfentanil plus propofol versus propofol in painless gastrointestinal endoscopy. The results showed that the alfentanil plus propofol group was significantly superior to propofol in maintaining circulatory stability, and the propofol dose is less, the awakening time and directional force recovery time is shorter, with the patients using the combined regimen experiencing lower rates of adverse reactions such as nausea and vomiting, body movement, hypotension, respiratory depression and cough reflex.

Propofol is a short-acting intravenous anesthetic of alkyl acids, which can enhance γ-aminobutyric acid (γ-aminobutyric acid), which reacts with type A receptor, opens chloride channels to allow an inflow of chloride ions flow, hyperpolarize cells, inhibit the transmission of excitement and produce sedative and hypnotic effects.^[26] It exerts inhibitory effects on the circulatory system, which can decrease blood pressure, myocardial blood perfusion, oxygen consumption and peripheral vascular resistance.^[27–29] Propofol anesthesia induction has a long onset time and no analgesic effect. During the examination process, it is susceptible to additional dosage due to factors such as body movement, resulting in excessive dosage. As the dosage of propofol increases, the incidence of side effects such as cardiovascular suppression, respiratory suppression, injection pain, and delayed awakening also increases.^[30–32]When propofol is used to induce anesthesia, involuntary muscle movements and muscle rigidity might occur, especially in light-state anesthesia. These adverse events made clinicians more cautious about propofol use and challenged the perioperative period’s management.^[33,34]

Alfentanil is a short-acting and strong analgesic drug that mainly acts on μ-opioid receptors with around 1/4 the potency and 1/3 the duration of action of fentanyl. The metabolism of alfentanil is fast, the effect is obvious, the maintenance time is short, the elimination is quick, and its effects on the cardiovascular system are small. Alfentanil has a low incidence of respiratory depression and has significant advantages in combination with propofol anesthesia during outpatient examinations and short surgeries.^[35,36]Alfentanil and propofol have a synergistic effect, which can improve the anesthesia effect, reduce the dosage of both drugs, and minimize the side effects of the drug.^[37–39]Additionally, it was reported that when combined with propofol, alfentanil could significantly reduce the rates of adverse reactions and the dose of propofol needed to achieve satisfactory anesthetic effects.^[40,41] Further, it was reported that alfentanil supplementation could reduce the injection pain related to propofol administration.^[42]

Painless gastrointestinal endoscopy allows patients to complete the examination painlessly under anesthesia, creating safe and effective examination conditions, especially for patients unwilling to undergo gastroscopy, which is conducive to the popularization of gastrointestinal endoscopy. The implementation of painless gastrointestinal endoscopy was also shown to effectively reduce the adverse reactions of non-painless endoscopy and significantly improve the operating environment and quality of gastrointestinal endoscopy.^[43]

In all the RCTs included in this meta-analysis, we found that the propofol dose in the combined group was lower than in the propofol only group, with the circulation indicators of the combined group being more stable. The results also showed that the combination of alfentanil and propofol not only improved the overall anesthesia outcomes and endoscopy quality but also reduced the rates of adverse events. Altogether, this combined regimen seems clinically reliable and effective, with good clinical and practical significance.

Author contributions

Conceptualization: Huan Yang.

Data curation: Huan Yang.

Formal analysis: Huan Yang.

Methodology: Huan Yang.

Software: Huan Yang, Xiaoling Shi.

Supervision: Xiaoling Shi, Longqiu Yang.

Validation: Xiaoling Shi.

Writing – original draft: Huan Yang.

Writing – review & editing: Jinping Li, Longqiu Yang.