Impact of ageing on sevoflurane’s hypnotic potency and induction kinetics during wash-in period: A prospective observational study

Abstract

Background and Aims:

The age-dependent decline in sevoflurane’s minimum alveolar concentration is well established. However, the relationship between ageing and its hypnotic potency at the effect-site concentration (Ceff) remains unclear. This study aimed to evaluate the impact of ageing on sevoflurane’s hypnotic potency and induction kinetics during the wash-in period.

Methods:

This prospective observational study enroled 83 female patients stratified by age into four decades: 30–39, 40–49, 50–59, and 60–69 years. Anaesthesia was induced using 5% sevoflurane in a non-rebreathing manner. We continuously recorded bispectral index (BIS) values and end-tidal sevoflurane concentrations during the 4 min wash-in period, with Ceff values calculated through pharmacokinetic modelling. Subsequently, the end-tidal concentration was maintained at 1.5% for 20 min (10 min equilibration + 10 min stabilisation) at 2 L/min to achieve a cerebral steady-state, and the final stabilised BIS value was calculated. One-way ANOVA with Bonferroni post-hoc correction or Kruskal-Wallis test was used to compare continuous variables. Pearson’s Chi-square test was used to compare categorical variables, with the significant difference set at P < 0.05.

Results:

During the wash-in period, the 60–69-year group exhibited a prolonged time from awakening to BIS 50 compared to younger cohorts (P < 0.05 or < 0.01). Ceff values exhibited progressively delayed kinetics with increasing age, but Ceff values of sevoflurane at BIS 50 were not different across the four age groups (P > 0.05). At a steady state of 1.5% sevoflurane anaesthesia, the intergroup analysis revealed no significant variations in BIS values.

Conclusion:

The hypnotic potency of sevoflurane is preserved among female patients aged 30–69 years despite delayed induction kinetics in older individuals.

INTRODUCTION

Sevoflurane, one of the most widely used volatile anaesthetics in clinical practice, requires monitoring its minimum alveolar concentration (MAC) to guide depth management during anaesthesia. MAC serves as a well-established metric for assessing the analgesic potency of volatile anaesthetics[1] and exhibits an inverse correlation with ageing.[2] However, recent studies have reported conflicting evidence regarding the association between MAC and its hypnotic efficacy in aged populations.[3,4,5,6] Although end-tidal concentration (C_ET) is routinely monitored during sevoflurane anaesthesia,[7] the effect-site concentration (Ceff) provides more reliable guidance for the dose titration, particularly during dynamic phases such as wash-in or wash-out periods. Despite these insights, the relationship between sevoflurane’s hypnotic potency and its Ceff across different age groups remains unclear.

Based on clinical observations, we hypothesised that elderly patients might require a lower Ceff of sevoflurane to achieve equivalent hypnotic depth. To test this hypothesis, we recruited female patients aged 30–69 years scheduled for elective breast surgery. The primary objective of this study was the time from awakening to a bispectral index (BIS) value of 50 during the wash-in period. The secondary objectives were the correlation between BIS value and sevoflurane Ceff, Ceff value when BIS value was down to 50 during the wash-in period, and the final stabilised BIS values at steady-state of 1.5% sevoflurane anaesthesia.

METHODS

This prospective observational study was approved by the Ethics Committee of Chongqing University Cancer Hospital (vide approval number: CZLS2022109-A, dated 8 April 2022) and was registered at www.chictr.org.cn (Clinical Trial Registration Number: ChiCTR2200061569). This study was conducted at the surgical centre of Chongqing University Cancer Hospital from 18 October 2022 to 8 June 2023. The written informed consent was obtained for participation in this study and the use of the patient data from all participants for research and educational purposes. This study was carried out according to the principles of the Declaration of Helsinki (2013) and Good Clinical Practice guidelines.

Female patients aged 30–69 years scheduled for elective breast surgery were enroled in this study. All participants provided written informed consent to participate in the study before inclusion. The inclusion criteria were American Society of Anesthesiologists (ASA) physical status I-II and planned general anaesthesia with laryngeal mask airway (LMA) insertion. Exclusion criteria included pre-existing comorbidities, including asthma, arrhythmia, psychiatric disorders, neurological diseases, ischemic heart disease, or cardiac dysfunction; long-term medications including hypnotics, antidepressants, or beta-blockers; and receipt of adjuvant chemotherapy within 30 days preceding surgery.

The study protocol is summarised in Figure 1. Participants received no premedication upon entering the operating room. All patients were maintained at normothermia using a forced-air warming system (Bair Hugger^TM, 3M HealthCare, St Paul, Minnesota, USA). Standard monitoring included five-lead electrocardiography, pulse oximetry, blood pressure, heart rate (HR), and core body temperature via an anaesthesia monitor (BeneView T5, Mindray Bio-Medical Electronics Co. Ltd., Shenzhen, China). Continuous non-invasive haemodynamic monitoring was achieved using a CNAP® Monitor (V.5.2.14, CNSystemsMedizintechnik AG, Graz, Austria) with dual finger cuffs, which provided beat-to-beat recordings of mean arterial blood pressure (MAP) and cardiac output (CO). An oscillometric blood pressure cuff was applied for periodic device calibration.

Figure 1.

Study protocol during the sevoflurane wash-in period. BIS = bispectral index; LMA = laryngeal mask airway; OR = operation room; MVV = minute ventilation volume

A BIS-Quatro^TM sensor (Covidien LLC, Singapore) was positioned on the forehead and connected to a BIS monitor (A-2000, Version 3.34, Covidien LLC, Singapore), with electrode impedance below 5 kΩ and a 15-s smoothing window. A peripheral venous catheter was placed on the dorsum of the non-surgical hand for continuous Ringer’s solution infusion (10 mL/kg/h). Baseline haemodynamic parameters (MAP, HR, and CO) and BIS values were recorded before anaesthesia. BIS values were derived from six measurements at 10 s intervals over 1 min.

General anaesthesia was induced via a face mask using sevoflurane (AbbVie Co., Shanghai, China) in oxygen. The vaporiser concentration was set to 5% with a fresh gas flow of 10–15 L/min, ensuring the fresh gas flow exceeded individual minute ventilation volume (MVV) as quantified by the anaesthesia machine (EX-65 Pro, Mindray Bio-Medical Electronics Co. Ltd., Shenzhen, China). Inspired and C_ET of sevoflurane and carbon dioxide (CO₂) were measured breath-by-breath using a multigas analyser (Anaesthesia Gas Module, Mindray Bio-Medical Electronics Co. Ltd., Shenzhen, China). End-tidal CO₂ was maintained at 35–40 mmHg throughout the procedure. Assisted ventilation was administered via face mask before LMA insertion. All parameters (MAP, HR, CO, MVV, inspired/end-tidal sevoflurane, and CO₂) were recorded continuously throughout the procedure.

Vecuronium (0.15 mg/kg) was administered intravenously to achieve neuromuscular blockade, followed by an LMA insertion. The mechanical ventilation was initiated with a 7 mL/kg tidal volume, and the respiratory rate was adjusted to 12–18 breaths per minute (bpm) to maintain end-tidal CO₂ within 35–40 mmHg. The fresh gas flow was reduced to 2 L/min, and the dial flow setting of the vaporiser was reduced and adjusted to maintain the end-tidal sevoflurane concentration of 1.5% for 10 min, followed by an additional 10 min equilibration period to ensure steady-state diffusion into cerebral tissue. The final stabilised BIS value was calculated as the average of six consecutive measurements recorded at 10 s intervals over 1 min at this steady state of sevoflurane anaesthesia. During the induction phase, phenylephrine was administered intravenously if MAP decreased by >20% from baseline or fell below 65 mmHg. Atropine was administered intravenously if HR dropped to below 50 bpm. No opioids were used throughout the study procedure.

The primary outcome was the time from awakening to a BIS value of 50 during the wash-in period of sevoflurane, which was defined as the duration from the vaporiser initiation to the achievement of BIS 50. The secondary outcomes included the Concentration-Time Curve of end-tidal or effect-site sevoflurane, the BIS-Ceff correlation, and Ceff values when BIS dropped to 50 during the wash-in period and BIS values at steady-state of 1.5% sevoflurane anaesthesia. The C_ET of sevoflurane was recorded, and Ceff of sevoflurane was calculated at the 30, 60, 90, 120, 150, 180, 210 s and 240 s after the vaporiser initiation during the sevoflurane wash-in;

Based on our preliminary results, the mean time taken to BIS value of 50 from awakening was 124.7 [standard deviation (SD): 43.2] s, 148.5 (SD: 27.5) s, 103.8 (SD: 14.5) s, and 153.8 (SD: 21.5) s in the 30–39, 40–49, 50–59, and 60–69 age groups, respectively (each group, n = 5, data not published). A minimum of 19 subjects per group was required to detect a 10% difference in the time interval from awakening to a BIS value of 50. Accounting for a potential 10% dropout rate, 21 subjects per group were recruited.

During the 4 min wash-in period, the Ceff of sevoflurane for each subject was calculated using the C_ET of sevoflurane at each time point and the equilibration half-life (t1/2 ke0). C_ET was assumed to be equivalent to the central compartment concentration, with the following differential equation governing Ceff dynamics: dCeff(t)/dt = ke0[C_ET(t)-Ceff(t)].[8] As the equilibration rate constant (ke0) decreases with age, it was calculated using the validated formula: ke0 = 0.383 [1 − 0.0084 (age − 33.5)].[9] Patients whose BIS value failed to decrease below 50 by the end of the 4 min induction period were excluded from subsequent analysis. Scatter plots with locally weighted smoothing curves were generated to illustrate the relationship between BIS values and sevoflurane Ceff values during the 4 min wash-in phase for each cohort.

All analyses were conducted in Stata 16 (StataCorp, College Station, TX, USA). Mean (SD) and median [interquartile range (IQR)] were used to describe continuous variables, and numbers (percentages) were used to describe categorical data. The Shapiro-Wilk test was used to test the normality of the data. One-way ANOVA with Bonferroni post-hoc correction was used to compare normally distributed continuous variables (body temperature and CO). Kruskal-Wallis test was used to compare non-normally distributed variables (age, BMI, MAP, HR, BIS value, the time from awakening to a BIS 50 and Ceff value when BIS was down to 50 during the wash-in period, and BIS value at steady-state of sevoflurane anaesthesia). Pearson’s Chi-square test was used to compare categorical variables (ASA classification). A two-sided P value of < 0.05 was considered statistically significant.

RESULTS

Of the 116 patients screened for eligibility, 84 met the inclusion criteria and were enroled in this study. One participant withdrew, yielding a final analytical cohort of 83 subjects across four groups. The screening flowchart and enrolment process are detailed in Figure 2. Baseline demographic and clinical characteristics showed homogeneity across all groups, except age and baseline MAP values [Table 1].

Figure 2.

Flowchart of subjects screening and allocation

Table 1.

Characteristics of participants

	Age 30–39 group (n=21)	Age 40–49 group (n=21)	Age 50–59 group (n=21)	Age 60–69 group (n=21)	P
Age (years)	34 (33–36)	45 (41–47)	53 (51–58)	63 (61–66)	<0.001
BMI (Kg/m2)	22.1 (20.4–26.7)	25.3 (22.5–26.2)	24.5 (23.2–27.1)	26 (22.9–27.9)	0.302
ASA physical status					0.226
I/II	21	19	18	17
III/IV	0	2	3	4
T (°C)	36.4 (0.3)	36.3 (0.3)	36.4 (0.3)	36.3 (0.3)	0.942
Baseline value
MAP (mmHg)	90 (76–93)	98 (84–100)	99 (89–110)	108 (105–118)	<0.001
HR (bpm)	80 (66–90)	78 (66–87)	73 (71–80)	76 (73–81)	0.68
CO (L/min)	5.9 (1.0)	5.6 (1.0)	5.0 (0.7)	5.5 (1.0)	0.197
BIS	97 (95–98)	97 (94–97)	95 (92–97)	97 (96–98)	0.183

Continuous data are expressed as mean (SD) or median (IQR), One-way ANOVA with Bonferroni post hoc correction or Kruskal-Wallis test was used for comparison. Categorical data are expressed as numbers, and Pearson’s Chi-square test was used for comparison. BMI=body mass index; ASA=American Society of Anesthesiology; MAP=mean blood pressure; HR=heart rate; CO=cardiac output; BIS=bispectral index; SD=standard deviation; IQR=interquartile range; bpm=beats per minute

BIS values were plotted for each subject throughout the 4 min study period [Figure 3a-d]. The median time from awakening to reaching a BIS value of 50 were 110 (IQR: 100–120) s, 110 (IQR: 105–140) s, 120 (IQR: 110–140) s, and 160 (IQR: 120–170) s in the 30–39, 40–49, 50–59, and 60–69 age groups, respectively, which was significantly longer in the 60–69 age group than in the other three (P < 0.05 or P < 0.001) [Figure 3e]. Although the 40–49 and 50–59 age groups exhibited slightly prolonged times compared with the 30–39 age group, these differences were not statistically significant [Figure 3e].

Figure 3.

Changes in BIS value during the wash-in period. (a-d) BIS-time curves for the 30–39, 40–49, 50–59, and 60–69 age groups, respectively. (e) Intergroup comparison of the time from awakening to the BIS value of 50. BIS = bispectral index

The absolute values of C_ET and Ceff of sevoflurane during the wash-in period are presented in Figure 4. Ceff values exhibited progressively delayed kinetics with increasing age, but there was no significant difference in Ceff between different age groups.

Figure 4.

End-tidal concentration (C_ET) and effect-site concentration (Ceff) change during the sevoflurane wash-in. Sev = sevoflurane

Scatter plots with nonlinear regression curves were constructed to investigate the relationship between BIS values and Ceff of sevoflurane. The fitted curves exhibited a slight rightward shift with advancing age [Figure 5a]. Statistical analysis revealed no significant differences in Ceff of sevoflurane at BIS 50 across the four age groups (P > 0.05) [Figure 5b].

Figure 5.

Relationship between BIS values and effect-site concentration (Ceff). (a) Fitted curves of BIS values versus Ceff. (b) Ceff values at the BIS value of 50 across groups (no significant differences observed). C_ET = End-tidal concentration; Ceff = effect-site concentration; Sev = sevoflurane; BIS = bispectral index

Under cerebral haemodynamic equilibrium conditions with stabilised end-tidal sevoflurane concentration (1.5%), the median BIS values were 45.0 (IQR: 44–46), 45.0 (IQR: 43–46), 46.4 (IQR: 45–48), and 47.5 (IQR: 46–50) in the 30–39, 40–49, 50–59, and 60–69 age groups, respectively. The intergroup analysis revealed no significant variations despite marginally elevated values observed in the 60–69-year age group [Figure 6].

Figure 6.

BIS values at steady-state of 1.5% sevoflurane across groups (no significant differences observed). BIS = bispectral index

DISCUSSION

In this pharmacological investigation utilising BIS monitoring, we systematically analysed the relationship between sevoflurane’s hypnotic effect and its Ceff in female surgical patients and found that the 60–69 year group exhibited a significantly prolonged time from awakening to a BIS 50, and Ceff values of sevoflurane at BIS 50 were not different across all age groups during the wash-in period; the intergroup analysis revealed no significant variations of BIS values at steady-state of 1.5% sevoflurane anaesthesia.

Volatile anaesthetics agents exhibited an age-progressive MAC reduction of 6.47% per decade.[2] Contemporary pharmacodynamic research documented age-dependent BIS elevation patterns, persisting even under normalised age-adjusted MAC dosing protocols for sevoflurane.[4,5] Moreover, equi-MAC concentrations across different inhalational agents generate distinct cerebral electrophysiological response profiles but the same antinociceptive properties.[6,10,11,12] This collective evidence substantiates the MAC functional definition as the C_ET required to prevent somatic movement in 50% of subjects in response to surgical stimulation, rather than serving as an index of cerebral electrical activity suppression.

In clinical practice, intravenous anaesthetic agent titration commonly utilises plasma and effect-site pharmacokinetic targets.[13] Monitoring the Ceff poses methodological challenges for an inhalation anaesthetic agent such as sevoflurane. In our study, we implemented the standard formula: dCeff(t) = ke0[Cet(t)-Ceff(t)], to model Ceff of sevoflurane incorporating Cet and ke0. We implemented a high-flow non-rebreathing method, achieving alveolar plateau stabilisation within 30 s, which is not routinely used in clinical practice. The ke0 of sevoflurane was decreased with ageing.[9] We incorporated validated age-dependent ke0adjustments to accommodate known geriatric pharmacokinetic alterations; thus, the calculated Ceff based on the standard equation in our study was dependent on age but not Cet.

In our study, the 4 min wash-in period was long enough for BIS to decline from awakening to a value below 50, which indicated a sufficient anaesthetic depth.[14] From our study, Ceff values were not different between groups when BIS values were down to 50 during the wash-in period, and BIS values were not different between groups at a steady state of sevoflurane. It can be said that sevoflurane could induce analogous hypnotic responses across ages between 30 and 69 years. It has been confirmed that neuromuscular blockade decreases BIS values in awake volunteers.[15] Thus, neuromuscular blocking agents were not administered during the wash-in period in this study, leaving electromyography (EMG) activity only influenced by sevoflurane. The calculation of Ceff in this study was based on the assumption that C_ET equals central compartment concentration, while a reported discrepancy existed between end-tidal and arterial values.[16] Thus, we recorded the BIS values at a steady state of 1.5% sevoflurane anaesthesia to verify the results during the wash-in period, and BIS values were different between groups, which indicated that the hypnotic potency of sevoflurane was preserved despite chronological ageing of female patients. Neuromuscular blocking agents were used for LMA insertion and mechanical ventilation after a wash-in period, and steady-state sevoflurane anaesthesia was achieved in this study, as it was reported that the BIS value was independent of EMG activity under steady-state sevoflurane anaesthesia, unlike the results from awake volunteers.[17]

Several limitations should be acknowledged in this study. First, BIS values were assessed only under resting conditions without surgical stimulation. Second, our study population was restricted to female patients aged 30–69 years. One recent animal study revealed that male mice were more sensitive to sevoflurane than female ones, which was mediated by oestrogen receptor 2.[18] This indicated that the results might not generalise to male patients. In our study, patients with pre-existing comorbidities and long-term medications were excluded to minimise the effect of cofounders on BIS value monitoring, but these are common in real-world older populations, which limits the applicability to typical surgical patients. Third, while ke0 was individualised for each subject, these values were derived from published equations rather than being empirically determined from clinical data.

CONCLUSION

The hypnotic potency of sevoflurane is preserved among female patients aged 30–69 years despite delayed induction kinetics in older individuals. These results support the validity of applying uniform sevoflurane concentration to achieve analogous hypnosis within this demographic.

Conflicts of interest

There are no conflicts of interest.

Author contributions

HLL, QYP, YJY: Study conception and design. YJY, YMF: Data collection, Data analysis. QYP: Drafting of the manuscript. HLL: Manuscript review. All authors were involved in editing and approval of the mansucript.

Study data availability

De-identified data may be requested with reasonable justification from the authors (email to the corresponding author) and shall be shared after approval per the authors’ institution’s policy.

Disclosure of use of artificial intelligence (AI)-assistive or generative tools

The AI tools or language models (LLM) have not been utilised in the manuscript, except that software has been used for grammar corrections and references.

Declaration of use of permitted tools

Nil.

Presentation at conferences/CMEs and abstract publication

None.

Funding Statement

Nil.