Shimizu T, Kanazawa T, Yoshida T, Sakura T, Shimizu K, Iwasaki T, Morimatsu H.J Cardiothorac Vasc Anesth. 2024 Dec;38(12):3118-3126. doi: 10.1053/j.jvca.2024.08.038. Epub 2024 Sep 5.PMID: 39332984
Take-home points
- What is already known:
- Remimazolam is an ultra-short-acting benzodiazepine with the benefits of a classic benzodiazepine coupled with very rapid onset and quick emergence profile while maintaining reversibility with flumazenil.
- Little data is available on the hemodynamic effects of this novel drug when used in pediatric patients, especially in those with congenital heart disease.
- What this study adds:
- A remimazolam-based general anesthetic in pediatric patients with congenital heart disease undergoing cardiac catheterization appears feasible.
- Hypotension is common, occurring in almost half of the patients, in both remimazolam and sevoflurane groups.
Commentary by Dr Ahmed Zaghw, Dr Destiny Chau (Arkansas, USA)
Children undergoing cardiac catheterization frequently require general anesthesia to facilitate the procedure. General anesthesia is associated with hypotension, which can be significant in certain patient populations (Lin 2015). Anesthesia-induced hypotension is dependent on the agent and the doses utilized. When anesthetic doses are reduced to mitigate the hypotension under general anesthesia, patients risk experiencing recall and intraoperative awareness while paralyzed, which could lead to post-traumatic stress disorder. Remimazolam besylate is a novel ultra-short-acting benzodiazepine that was approved by the United States Food and Drug Administration (FDA) in 2020 for procedural sedation in adults. Preliminary adult reports indicate that it may provide improved hemodynamic stability compared to propofol (Chu 2024), although its overall hemodynamic effects in patients with heart disease are unclear.
Briefly, remimazolam besylate (“remimazolam” from now on) has the benefits of a classic benzodiazepine coupled with a very rapid onset, and quick emergence profile while maintaining reversibility with flumazenil. This medication has also been approved for sedation, or sedation and general anesthesia in several countries including Japan, South Korea, and European countries. A tosylate form of remimazolam received approval for procedural sedation in China. Like midazolam, remimazolam targets γ-aminobutyric acid A (GABAA) receptor activity and it is rapidly hydrolyzed by carboxylesterase-1 to a pharmacologically inactive metabolite (CNS 7054). (Kim 2022) Metabolism occurs primarily in the liver, with little or no blood metabolism, which differs from remifentanil’s metabolism by tissue and blood esterases. Remimazolam is predominantly excreted in the urine. It has been reported that remimazolam’s context-sensitive half time is like that of propofol. (Masui 2024) The reported terminal half-life is 0.75 h; it has low oral (2%), and nasal (50%) bioavailability. (Kim 2022, Masui 2024) Of note, nasal administration has been associated with severe nasal pain. Regarding tolerance, remimazolam tolerance has been reported in long-term benzodiazepine users; also, acute tolerance during infusion has been reported, possibly due to the accumulation of its metabolite CNS7054 which may compete with GABAa receptors without an effect. Hepatic dysfunction may prolong remimazolam effects, while renal impairment may be associated with acute tolerance during infusion. Flumazenil administration can reverse overdose, however, the potential for re-sedation can occur if the flumazenil dose is inadequate. Additionally, it has been noted that current processed EEG indices may not be accurate indicators of its hypnotic effects. (Masui 2024) Remimazolam in adults is typically administered at a rate of 6 to 12 mg/kg/h infusion or 0.1-0.2 mg/kg bolus for induction of anesthesia and 1–2 mg/kg/ h for maintenance of general anesthesia. (Kim 2022)
Since its FDA approval, reports of its use in the pediatric population have been increasing. Scoping reviews of the pediatric literature are reporting preliminary safety and efficacy for sedation in multiple settings including children with genetic abnormalities (Pieri 2024, Kuklin 2024). There are very few reports of its use in pediatric patients with congenital heart disease (CHD).
The authors of this recent study aimed to compare the incidence of hypotension associated with remimazolam versus sevoflurane general anesthesia for cardiac catheterization in pediatric patients with CHD. This retrospective single-center study reviewed the medical records of 400 children and included for analysis 309 children under 15 years of age who underwent cardiac catheterization under general anesthesia between March 1, 2021, and December 31, 2022. Of these patients, 28 patients received remimazolam. They were propensity-matched to 28 patients who received sevoflurane.
The primary outcome was the incidence of hypotension during the case. The definition of hypotension was a time-averaged area under the line (AUL) greater than 1 mmHg. The AUL is the area in which the systolic arterial pressure fell below the threshold, which was 80% of the systolic non-invasive blood pressure (NIBP) before anesthesia induction (pre-sNIBP), from the start of anesthesia to the end of the procedure. The secondary outcomes included systolic arterial pressure (sAP) and mean arterial pressure (mAP) from the start of anesthesia to the end of the procedure, the ratio of median sAP / pre-sNIBP, fentanyl dose, Psi value, and the rate of using vasopressor agents.
All study patients had a peripheral intravenous catheter placed prior to induction of anesthesia. Patients in the remimazolam group received a continuous remimazolam infusion at 12 mg/kg/hour for anesthesia induction while patients in the sevoflurane group were given propofol (1-4 mg/kg), thiopental (2-5 mg/ kg), or midazolam (0.5-2 mg/kg) as needed for anesthesia induction. After loss of consciousness, 2 to 5 mcg/kg fentanyl and 1 mg/kg rocuronium were administered for tracheal intubation. An arterial line was then placed. For maintenance of anesthesia, those in the remimazolam group, had remimazolam titrated as guided by electroencephalography (EEG) to maintain beta waves while accounting for blood pressure. For patients in the sevoflurane group, sevoflurane doses were guided based on end-tidal sevoflurane concentration, processed EEG, and blood pressure.
The results showed that hypotension was found in 39.3% (n=11) in the remimazolam group versus 46.4% (n = 13) in the sevoflurane group, (p = 0.79). As secondary outcomes, median sAP/pre-sNIBP was 91.4 vs 83.2 (p = 0.03); mean sAP was 89.4 mmHg versus 80.1 mmHg (p= 0.004), and mean mAP was 65.7 mmHg versus 59.6 mmHg (p= 0.006), in the remimazolam and sevoflurane groups, respectively. Vasopressor agent use was 28.6% vs 25.0% in the remimazolam and sevoflurane groups respectively (p = 1.0). In the non-hypotensive cohorts, the remimazolam group has a statistically significant higher systolic pressure versus the sevoflurane group, mean sAP/pre-SBP was 100.5% versus 91.1% (p = 0.01), respectively. However, in the hypotensive cohorts, the remimazolam group has a non-statistically significant higher systolic pressure compared with the sevoflurane group, 77.4 % versus 74.2 (p = 0.31), respectively. In the non-hypotensive cohorts, the remimazolam group has a statistically significant higher systolic pressure versus sevoflurane group; mean sAP/pre-SBP was 100.5% versus 91.1% (p = 0.01), respectively. However, in the hypotensive cohorts, the remimazolam group has a non-statistically significant higher systolic pressure compared with the sevoflurane group, 77.4 % versus 74.2 (p = 0.31), respectively. The subgroup analysis in the remimazolam cohort showed that the remimazolam dose was not correlating with the incidence of hypotension or the vasopressin usage, as the remimazolam dose in the vasopressin arm was lower than the non-vasopressin arm, 0.8 versus 3.16 mg/kg/hour, respectively. This hemodynamic profile of remimazolam was equivalent to sevoflurane under specific clinical settings, i.e., the use of invasive arterial pressure, advanced neurological monitoring, and EEG-based anesthetic protocol. The results agree with the results of a small cohort study of 26 patients at the Nationwide Children’s Hospital that remimazolam used for procedural sedation or as an adjunct to general anesthesia did not cause significant adverse hemodynamics. (Gillis 2024)
There are several major limitations to this retrospective review study. The study was not powered to test hemodynamic differences for remimazolam versus sevoflurane. The convenience sample was too small for multivariate analysis. Although the propensity matching was done to create more comparable patient groups, there were significant confounding variables, including the lack of a protocolized anesthetic plan for hypotension and anesthetic titration which highlights inter-provider practice variabilities as uncontrolled variables. Based on these findings, future studies should be prospective, properly designed and adequately powered to demonstrate the real and potential benefits of remimazolam. Replication of this study in adults and children with a history of congenital heart disease undergoing cardiac catheterization or procedural sedation would provide additional information of relevance to pediatric cardiac anesthesiologists.
Commentary
This study informs the use of this new drug on pediatric patients with CHD, as overall data on remimazolam in pediatric patients is currently very limited. The study confirmed that hypotension under general anesthesia is common, finding that it occurred in about half of the study patients. This study did not find differences in the rate of hypotension whether using remimazolam or sevoflurane for maintenance of anesthesia, although it was not powered to detect this difference. The definition of hypotension used by the authors incorporates the threshold of 20% below the pre-induction noninvasive blood pressure into a time-averaged variable. Although this definition uses the same patient as its reference point, it has the pitfall in that it uses one point BP measurement which may not be an accurate reflection of a patient’s baseline BP. Additionally, the finding that the stand-alone systolic and the mean arterial pressures under general anesthesia were higher in the remimazolam group must be cautiously interpreted, as the study sample included patients of different ages and weights, e.g. mean of 6 years with a standard deviation of 5 years, so these patients could range from 1 year to 11 years of age at one standard deviation; thus, each age group has an associated range of normal blood pressures. The subgroup analysis of those with and without vasopressor use in each arm is shadowed by the very small sample size; thus, the results and conclusions are mainly speculative. It is known that benzodiazepines, when added as an adjuvant to other agents for general anesthesia, can significantly drop systemic vascular resistance and blood pressure in patients with prior compensated hemodynamics. It is unclear how much of the reduction in blood pressure occurred from the presence of sizable doses of fentanyl used at induction (median of 5.9 and 4.7 mcg/kg in remimazolam and sevoflurane groups, respectively) and the uncontrolled variables of premedication, use of midazolam at induction by 28% in the sevoflurane group, as well as unprotocolized titration of remimazolam or sevoflurane. Interestingly, flumazenil was used in 4 patients, citing potentially as a reversal for respiratory depression. Of note, processed EEG (beta waves and PSi) were utilized in 100% of the remimazolam group vs 70% in the sevoflurane group to guide titration. The authors mentioned that no patients were diagnosed with recall, although this was not specifically studied. Caution must be applied as preliminary data suggest that current processed EEG indices may not be accurate indicators of its hypnotic effects.
This article provides insight into the feasibility of using remimazolam for general anesthesia in pediatric patients with CHD. As more data comes forth, the role and safety profile of remimazolam in pediatric patients with CHD will be better defined. Building upon prior experience with other benzodiazepines, and extrapolating from the use of fentanyl and remifentanil, we are cautiously optimistic of the addition of this medication to our anesthetic toolkit for our patients.
References:
- Shimizu T, Kanazawa T, Yoshida T, Sakura T, Shimizu K, Iwasaki T, Morimatsu H. A Retrospective Comparative Study of the Frequency of Hypotension in Pediatric Cardiac Catheterization under General Anesthesia: Remimazolam versus Sevoflurane. J Cardiothorac Vasc Anesth. 2024 Dec;38(12):3118-3126. doi: 10.1053/j.jvca.2024.08.038. Epub 2024 Sep 5. PMID: 39332984.
- Lin CH, Desai S, Nicolas R, et al. Sedation and anesthesia in pediatric and congenital cardiac catheterization: A prospective multicenter experience. Pediatr Cardiol 2015;36:1363–75. https://doi.org/10.1007/s00246-015-1167-8.
- BYFAVO (remimazolam). Accessed 4 January 2025 athttps://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212295s000lbl.pdf
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- Hosokawa M, Takahashi Y, Ueno T, Oe K, Masui K. Remimazolam anesthesia in pediatric patients undergoing cardiac catheterization for congenital heart disease: a retrospective observational study. J Anesth. 2024 Dec;38(6):796-805. doi: 10.1007/s00540-024-03395-5. Epub 2024 Aug 17. PMID: 39153037.
- Gillis H, McKee C, Chenault K, et al. Preliminary experience with remimazolam for procedural sedation and as an adjunct to general anesthesia during diagnostic and interventional cardiac procedures. Cardiol Res 2024;15:12–7. https://doi.org/10.14740/cr1595
