Introduction
Gastroscopy is the gold standard evaluation modality for upper gastrointestinal tract diseases [
1]. However, gastroscopy without any anesthesia causes discomfort in patients. Gastroscopy after the administration of general anesthesia by the anesthesiologist improved the patient’s comfort and satisfaction, decreased stress response and the occurrence of adverse reactions, and elevated security [
2,
3].
Currently, one of the most widely used sedative agents is propofol [
4]—a short-acting anesthetic commonly used in clinical settings. It has the advantages of rapid onset of action and recovery and no obvious accumulation after long-term infusion. It is widely used in anesthesia induction, anesthesia maintenance of various surgeries, and painless endoscopy. Nonetheless, it has been reported that propofol can cause respiratory and cardiovascular depression, hypoxia, and injection site pain [
5].
Remimazolam is a new short-acting benzodiazepine that acts as a γ-aminobutyric acid subtype A (GABA-A) receptor agonist [
6]. Its properties include rapid onset, a short duration of sedation, and full recovery. Remimazolam is characterized by a metabolism mechanism independent of liver and kidney function and is rapidly metabolized to inactive compounds by tissue esterases [
7]. A phase III trial involving adult patients showed that remimazolam has a lower incidence of hypotension than propofol [
8]. Additionally, the pharmacological effects of remimazolam can be quickly reversed by the specific antagonist flumazenil, which provides a relatively safer profile.
Studies have found that remimazolam has a sedative effect similar to that of propofol. They have similar success rates of sedation and depth of sedation [
9,
10] but remimazolam has a lower incidence of respiratory and circulatory inhibition. However, the induction time, incidence of postoperative nausea and vomiting(PONV), and other outcomes have diametrically opposite results. Considering the different sedation needs and anesthetic concerns of different endoscopic examinations, we only included studies on the use of remimazolam in gastroscopy, while focusing on outcome indicators of airway protection, such as respiratory depression, hypoxemia, and coughing, to explore the differences in the effects between remimazolam and propofol.
Discussion
Sedation and anesthesia in gastroscopy have become an indispensable medical treatment, which can not only give patients a comfortable medical experience, but also facilitate the operator to perform the examinations, and improve safety by inhibiting unexpected body movements or coughing reactions [
47]. However, different anesthetics may bring different sedative effects and adverse reactions, such as hemodynamic instability, respiratory depression, and so on [
48].
This study has shown that the incidence of hypotension and bradycardia in the remimazolam group was significantly lower than that in the propofol group. Although hypotension had high heterogeneity and publication bias, the results after sensitivity analysis or the trim and filling method remained stable. Dogan’s research has found that contrary to the compensatory increase in the sympathetic dominance of propofol, remimazolam has not changed the balance between sympathetic and parasympathetic activities, reducing the fluctuation in the circulatory system [
49]. Studies have shown that remimazolam mechanism that regulates the bradykinin B
1 receptor and autophagy to relieve the pain [
50], which may benefit circulation stability.
The incidence of respiratory depression and hypoxemia also favored remimazolam with a higher evidence grade. Research on the mechanism of respiratory inhibition of propofol by Jiang showed that propofol may bind to β
3, which mediates respiratory depression and loss of consciousness [
51], whereas the four receptor subtypes to which remimazolam binds are associated the β
2 subunit [
7], which may explain the incidence of less respiratory function inhibition during the application of remimazolam; however, the differences between different GABA subtypes need more in-depth research.
This meta-analysis showed that the incidence of injection site pain during gastroscopy can be reduced when using remimazolam. The results were stable despite having high heterogeneity. Similar findings have been reported in relevant studies outside this study [
52]. The incidence of injection site pain induced with propofol has been reported to be > 66% [
53]. Lidocaine, as an effective adjuvant known to inhibit injection site pain [
54], still results in injection site pain in 30% of patients [
55] and even the hardest part of the anesthesia process for some patients [
56]. Pain by injection may be linked to the stimulation of lipid components in the compatibility of propofol on blood vessels. The difference is that remimazolam is water-soluble; therefore, it has less tissue stimulation and less incidence of pain by injection.
This study showed no statistically significant difference between propofol and remimazolam in the incidence of PONV, and both had an incidence of less than 20%, which is lower than the 25%-50% incidence reported in the literature [
57]. Using opioid analgesics in gastroscopy is a risk factor for early PONV. In this study, in order to minimize differences due to opioids, we excluded trials with different opioid analgesics or different doses between the two groups. Most of the studies that were included used alfentanil and sufentanil. However, the effect of different opioids on the incidence of PONV needs to be further investigated. Although a previously published meta-analysis has shown that midazolam reduces the incidence of PONV compared to placebo [
58], but the mechanism of action is unclear. Propofol has been widely demonstrated to be effective in reducing the incidence of PONV [
59] but is not evident during subhypnotic infusion [
60]. Compared with general anesthesia surgery, gastroscopy examination is shorter and fewer anesthetic drugs are injected during anesthetic sedation, which may weaken the inhibitory effect of propofol on PONV. This may explain why this meta-analysis showed that remimazolam is similar to propofol in terms of incidence of nausea and vomiting after gastroscopy, which is similar to the previously published meta-analysis results of midazolam [
61], but further research is needed to determine whether remimazolam has the same effect as propofol in reducing PONV.
Cough and body movement did not show a difference between the two groups in this study, as there are many factors that can influence this, such as dose, age, criteria, analgesic medication, and even operator technique. Using both cough and body movement as criteria and outcome indicators may add bias to the experimental design. The spectral edge frequency (SEF) can be closer to the depth of sedation of remimazolam than the bispectral index and MOAA/S [
62,
63]. The application of the SEF in gastroscopic sedation may bring higher evidence for cough and body movement.
For the time-related outcomes, only the induction time was slightly slower in remimazolam group than propofol, but the SMD between the two groups was not sufficient to produce a clinically significant difference. Heterogeneity was high for all three outcomes, but no potential confounding factors were identified that might be related to the method of outcome measurement.
This study confirms that remimazolam has advantages over propofol in terms of cardiopulmonary depression and injection site pain, as well as a lower risk of abuse [
64] compared to the potentially addictive properties of propofol [
65]. However, as a member of the benzodiazepine class, it is important to consider the potential risk of postoperative cognitive impairment. While there are few studies on the postoperative cognitive impairment induced by remimazolam, it should be advisable to continue vigilance and conduct further research.
This study also had some limitations. First, most of the included studies had possible bias and were rated as moderate in the overall assessment section, leading to some bias and possible heterogeneity and ultimately to a lower level of evidence. Second, all studies, regardless of where they were published, were conducted in China and lacked data from other countries and regions, which may result in findings that are not generalizable. Third, there was publication bias for the hypotension and recovery outcome. Improving the level of evidence for these two outcomes requires more rigorous, large-sample study support.
In conclusion, compared with propofol, remimazolam can be safely used for gastroscopic sedation and reduce the incidence of respiratory depression, hypoxemia, bradycardia, injection pain, and dizziness, and doesn't increase the incidence of nausea and vomiting, or cough. Remimazolam had a slightly longer induction time than propofol, but there was no difference in recovery or discharge time.
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