In this learning activity, we will review the findings of the study which compared the use of remimazolam to propofol in an elderly patient cohort, with a view to reducing the risk associated with anaesthesia.

 

In Context

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Elderly patients, who represent an increasing proportion of the surgical population, are particularly vulnerable to perioperative complications, especially hypotension. Post-induction and intra-operative hypotension in this population have been linked to poor outcomes, including increased mortality.^1,2

Propofol, one of the most frequently used intravenous anaesthetics, is commonly employed to induce and maintain general anaesthesia due to its rapid onset and smooth recovery. However, propofol has known side effects which are particularly concerning in older adults. 

In particular, the dose-dependent hypotension caused by propofol is associated with a reduction in systemic vascular resistance and myocardial depression. To avoid these impacts in elderly patients, the recommended dose is only 50-70% of the dose needed for younger patients: 1–1.5 mg/kg in older patients vs 2–2.5 mg/kg in younger adults. Research, however, has shown that this dosage guideline is not well recognised, resulting in increased complications in these patients.³ 

Of additional concern is that various studies have shown that post-induction hypotension related to propofol is associated with increased mortality, prompting some experts to recommend avoiding propofol induction in elderly patients, particularly those with baseline low blood pressure.^2,4 

Remimazolam, a short-acting benzodiazepine, has gained attention for its efficacy in delivery of anaesthesia and procedural sedation in elderly patients. It acts on the gamma-aminobutyric acid A (GABA-A) receptors in the brain enhancing the inhibitory neurotransmission within the central nervous system, leading to sedation, muscle relaxation, and anxiolysis, which are key components of anaesthesia. But what sets remimazolam apart from other benzodiazepines is its unique metabolism. Unlike most intravenous sedatives, which are metabolised by the liver, remimazolam is hydrolysed by the enzyme carboxylesterase 1, which is found in various tissues, including the liver and plasma. 

This enzyme-dependent metabolism results in a rapid conversion to inactive metabolites, leading to a shorter duration of action compared to other benzodiazepines, reducing the likelihood of prolonged sedation or residual effects, which are common concerns with other anaesthetics in elderly patients. A meta-analysis conducted by Hung & Illias et al found that remimazolam has shown promising results, with improved haemodynamic profiles and a reduced incidence of side effects, such as hypotension and bradycardia, compared to traditional anaesthetics like propofol.⁴ Furthermore, it has a significantly lower risk of causing respiratory depression or apnoea, making it safer in comparison to other sedatives. 

Another notable advantage of remimazolam is the availability of a specific antagonist—flumazenil— which can reverse its effects in case of overdose, adding an extra layer of safety for patients undergoing anaesthesia or sedation procedures. ^2,4,5

This unique combination of rapid onset, short duration, minimal side effects and an effective antagonist positions remimazolam as a potential alternative to propofol, particularly in vulnerable populations such as the elderly, where managing perioperative haemodynamics is critical.⁴

However, prior to the 2024 study by Morares & Vito et al no meta-analysis had compared these two drugs in terms of their efficacy and safety for elderly patients undergoing general anaesthesia, making this an important area for further investigation. 

 

 

Study Purposes

In this clinical review, we summarise the findings of Morares & Vito et al.'s systematic review and meta-analysis, which compared the efficacy and safety of propofol and remimazolam for general anaesthesia in elderly surgical patients during the peri-operative period.

 

 
Study Methodology

The following methodology was recorded

Eligibility criteria
 

Trial sequential analysis (TSA) was performed to estimate the required information size and assess the risk of type I and II errors. 

Four hundred forty-four studies met the original requirement, 33 of which underwent full study review. 

Eleven trials were included in the study, reflecting a total of 947 patients. Table 1 below details the 11 studies for reference throughout the remainder of this review.


Table 1: Baseline characteristics of included studies.
 

Study	Country	Patients n Remi vs Pro	Patient Age in Yrs Remi vs Pro	ASA Status	Surgery	Flumazenil	Induction Dose Remi vs Pro	Maintenance Dose Remi vs Pro
1. Zhang et al	China	30 vs. 29	74.3±10.6 vs. 75.0±9.9 a	II - III	Hip arthroplasty	Yes	0.2 to 0.4 mg kg–1 vs. 1.5 to 2 mg kg–1	0.3 to 0.5 mg kg–1 h–1 vs. 4 to 8 mg kg–1 h–1
2. Yang et al.	China	147 vs. 153	68 65 to 71) vs. 68 (65 to 71) b	II - III	Mixed orthopaedics	No	0.2 to 0.3 mg kg–1 vs. 1 to 1.5 mg kg–1	According to BIS
3. Duan et al.	China	30 vs. 30	67.8 ± 3.2 vs. 68.7 ± 2.9 a	II - III	Hip arthroplasty	No	0.2 to 0.4 mg kg–1 vs. 1.5 to 2 mg kg–1	0.3 to 0.5 mg kg–1 h–1 vs. 4 to 8 mg kg–1 h–1
4. Kuang et al.	China	42 vs. 42	65.4 ± 3.9 vs. 65.2 ± 4.4 a	II - III	Lobectomy	No	0.3 mg kg–1 vs. 2 mg kg–1	0.6 to 1.2 mg kg–1 h–1 vs. 2 to 10 mg kg–1 h–1
5. So et al.	South Korea	42 vs. 39	74.5 (70 to 78.3) vs. 76 (70 to 81) b	II - III	Cholecystectomy	Yes	6 mg kg–1 vs. 1 to 1.5 mg kg–1	1 to 2 mg kg–1 h–1 vs. 100 μg kg–1 ml–1
6. Toyota et al.	Japan	20 vs. 19	80 (79 to 83) vs. 81 (79 to 82) b	II - III	Spine	Yes	12 mg kg–1 h–1 vs. 3 μg ml–1	According to BIS
7. Jeon et al.	South Korea	60 vs. 62	70.9 ± 4.3 vs. 71.5 ± 4.3 a	II - III	Cholecystectomy TURBT	Yes	6 mg kg–1 h–1 vs. 4 μg ml–1	1 - 2 mg kg–1 h–1 vs. 2.5 - 4 μg mL–1
8. He et al.	China	28 vs. 29	70.3 ± 4.1 vs. 70.8 ± 3.5 a	II - III	Mixed Transurethral	No	6 mg kg–1 h–1 vs. 60 mg kg–1 h–1	0.5 - 2 mg kg–1 h–1 vs. 4 to 10 mg kg–1 h–1
9. Kim et al.	South Korea	23 vs. 22	73 (65 to 86) vs. 68 (65 to 82) b	II - II	Mixed	No	6 mg kg–1 h–1 vs. 4 μg ml–1	0.8 to 1.2 mg kg–1 h–1 vs. 2.5 to 3 μg ml–1
10. Xu et al.	China	30 vs. 30	69.9 ± 4.3 vs. 68.6 ± 3.3 a	II - II	Lower limbs	No	0.2 mg kg–1 vs. 1.5 mg kg–1	-
11. Gao et al.	China	20 vs. 20	67.2 ± 4.4 vs. 67.2 ± 4.4 a	II - III	Carotid endarterectomy	No	0.3 mg kg–1 vs. 1.5 to 2 mg kg–1	-

Source:Pereira, E. M., Moraes, V. R., et al. (2024). Remimazolam vs. propofol for general anaesthesia in elderly patients: a meta-analysis with trial sequential analysis. European journal of anaesthesiology

ASA, American Society of Anesthesiology; BIS, bispectral index; Pro, propofol; Remi, remimazolam; TURBT, transurethral resection of bladder tumour.
aMean ± standard deviation. bMedian (interquartile range
 

 

Key Study Findings
 

Remimazolam was used in four hundred seventy-two patients (49.8%) and 475 (50.2%) of these patients received propofol. 

Remimazolam was given for both induction and maintenance of general anaesthesia in nine studies and Flumazenil was used in four trials,^1,5,6,7

The overall risk of bias was classified as 'some concerns' in four studies - 1,4,5,10  -  and 'low' in the remaining seven studies.

The certainty of the evidence for the primary outcome of hypotension was considered high. 

It should be noted that although the risk of bias assessment indicates that the overall quality of included studies was reasonable, the GRADE assessment showed a considerably low certainty of the evidence for some outcomes, such as anaesthetic depth and emergence agitation, primarily due to the high heterogeneity, a limited number of studies and wide.  

 

Haemodynamics

Injection Pain
Remimazolam was associated with a significantly lower risk of injection pain (risk ratio 0.04, 95% CI 0.01 to 0.16, P < 0.001, I2 = 0%) across three studies (185 patients)^8-10

Recovery Period

Emergence Time
No significant differences were found in emergence time (mean difference -0.11 min, 95% CI -1.05 to 0.83, P = 0.82, I2 = 77%) across six studies (324 patients)^1,3,5,6,9,11

Extubation Time
No significant differences were observed in extubation time (mean difference 0.40 min, 95% CI -0.92 to 1.73, P = 0.55, I2 = 89%) in seven studies (706 patients) ^{1-3, 5-7, 9}

Emergence Agitation
There was no significant difference in the incidence of emergence agitation (risk ratio 0.64, 95% CI 0.17 to 2.42, P = 0.51, I2 = 70%) across three studies (419 patients) ^1-3

Heterogeneity and sensitivity analysis
 

For the primary outcome of hypotension, the sensitivity analysis showed that the exclusion of any study would not change the effect size, and the heterogeneity is mostly attributed to one study.¹⁰ Likewise, the analysis was consistent for the time to LOC, injection pain, HR, emergence time and extubation time.

The removal of one particular study in the assessment of anaesthetic depth ⁸ MAP⁵ and emergence agitation² would also change the pooled effect size.  

With regards to bradycardia, the removal of four studies - 4,5,9,10 - makes the results statistically insignificant.
 

Trial Sequential Analysis (TSA)

 TSA showed sufficient evidence to conclude that remimazolam affects hypotension with high index of confidence.

There is some evidence of an effect on heart rate, but more data is required to confirm with a higher degree of confidence. Further studies are needed to draw definitive conclusions on the impacts on bradycardia, anaesthetic depth, and MAP

Other outcomes (Time to Loss of Consciousness (LOC), Injection Pain, Emergence Time, Extubation Time, Emergence Agitation) could not be assessed using TSA because there was too little data available.
 

In Conclusion

The use of remimazolam in elderly patients, compared with propofol, demonstrated a significant reduction in the incidence of hypotension and bradycardia, making it a promising alternative for general anaesthesia.
Despite a longer time to loss of consciousness (LOC) and higher BIS values, remimazolam did not show any significant differences in recovery characteristics compared to propofol.

This suggests that, while it may take slightly longer for patients to reach LOC, remimazolam is well-tolerated and maintains comparable recovery outcomes.

Given its reduced risk of hypotension and bradycardia—both critical concerns in elderly patients—the researchers conclude that remimazolam may be considered an effective and safer option for general anaesthesia in this population.

 

A Summary of Key Findings
 

1. Compared with propofol, remimazolam decreased the risk of hypotension and bradycardia in the elderly

2. Time to loss of consciousness was higher with remimazolam with a higher bispectral index.

3. No differences in the anaesthetic recovery characteristics were found between the two drugs

4. On the basis of these findings, the researchers conclude that remimazolam may offer an effective and safer option for general anaesthesia in the elderly.

 

Original Studies

1. Zhang, J., Wang, X., Zhang, Q. et al. Application effects of remimazolam and propofol on elderly patients undergoing hip replacement. BMC Anesthesiol 22, 118 (2022). https://doi.org/10.1186/s12871-022-01641-5

2.Yang, J. J., Lei, L., Qiu, D., Chen, S., Xing, L. K., Zhao, J. W., Mao, Y. Y., & Yang, J. J. (2023). Effect of Remimazolam on Postoperative Delirium in Older Adult Patients Undergoing Orthopedic Surgery: A Prospective Randomized Controlled Clinical Trial. Drug design, development and therapy, 17, 143–153. https://doi.org/10.2147/DDDT.S392569

3. Duan, J., Ju, X., Wang, X., Liu, N., Xu, S., & Wang, S. (2023). Effects of Remimazolam and Propofol on Emergence Agitation in Elderly Patients Undergoing Hip Replacement: A Clinical, Randomized, Controlled Study. Drug design, development and therapy, 17, 2669–2678. https://doi.org/10.2147/DDDT.S419146

4. Kuang, Q., Zhong, N., Ye, C., Zhu, X., & Wei, F. (2023). Propofol Versus Remimazolam on Cognitive Function, Hemodynamics, and Oxygenation During One-Lung Ventilation in Older Patients Undergoing Pulmonary Lobectomy: A Randomized Controlled Trial. Journal of cardiothoracic and vascular anesthesia, 37(10), 1996–2005. https://doi.org/10.1053/j.jvca.2023.06.027

5. So, K. Y., Park, J., & Kim, S. H. (2023). Safety and efficacy of remimazolam for general anesthesia in elderly patients undergoing laparoscopic cholecystectomy: a randomized controlled trial. Frontiers in medicine, 10, 1265860. https://doi.org/10.3389/fmed.2023.1265860

6. Toyota, Y., Kondo, T., Oshita, K., Haraki, T., Narasaki, S., Kido, K., Kamiya, S., Nakamura, R., Saeki, N., Horikawa, Y. T., & Tsutsumi, Y. M. (2023). Remimazolam-based anesthesia with flumazenil allows faster emergence than propofol-based anesthesia in older patients undergoing spinal surgery: A randomized controlled trial. Medicine ,102(46), e36081. https://doi.org/10.1097/MD.0000000000036081

7. Jeon, Y. G., Kim, S., Park, J. H., Lee, J., Song, S. A., Lim, H. K., & Song, S. W. (2023). Incidence of intraoperative hypotension in older patients undergoing total intravenous anesthesia by remimazolam versus propofol: A randomized controlled trial. Medicine, 102(49), e36440. https://doi.org/10.1097/MD.0000000000036440

8. He, M., Gong, C., Chen, Y., Chen, R., & Qian, Y. (2023). Effect of remimazolam vs. propofol on hemodynamics during general anesthesia induction in elderly patients: Single-center, randomized controlled trial. Journal of biomedical research, 38(1), 66–75. https://doi.org/10.7555/JBR.37.20230110

9. Kim, T. K., Kwak, H. J., Jung, W. S., Choi, G. B., Park, S. Y., & Kim, J. Y. (2023). Effects of Remimazolam Anesthesia with Two Induction Doses on Hemodynamics and Recovery Profile in Older Patients: Comparison with Propofol Anesthesia. Journal of clinical medicine, 12(16), 5285. https://doi.org/10.3390/jcm12165285

10.Xu, Q., Wu, J., Shan, W., Duan, G., & Lan, H. (2023). Effects of remimazolam combined with sufentanil on hemodynamics during anesthetic induction in elderly patients with mild hypertension undergoing orthopedic surgery of the lower limbs: a randomized controlled trial. BMC anesthesiology, 23(1), 311. https://doi.org/10.1186/s12871-023-02249-z

11. Gao, J., Yang, C., Ji, Q., & Li, J. (2023). Effect of remimazolam versus propofol for the induction of general anesthesia on cerebral blood flow and oxygen saturation in elderly patients undergoing carotid endarterectomy. BMC anesthesiology, 23(1), 153. https://doi.org/10.1186/s12871-023-02095-z

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Publication Information

Published:12  March  2025
Catalogue Number: MAICPD002
Category: Anaesthetics
Sub-Category: Gerontology
Fact-Checked: 12 March 2025
 

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