Differential Effects of Glycopyrrolate on Heart Rate and Heart Rate Variability in Patients with Varying Baseline Heart Rates

Differential Effects of Glycopyrrolate on Heart Rate and Heart Rate Variability in Patients with Varying Baseline Heart Rates | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Differential Effects of Glycopyrrolate on Heart Rate and Heart Rate Variability in Patients with Varying Baseline Heart Rates Zhuan Zhang, Xinqi Zhang, Jiajia Yin, Shantian Feng, Wei Zhou, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7112431/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To evaluate the effects of glycopyrrolate on heart rate (HR) and heart rate variability (HRV) in patients with different baseline HR levels during general anesthesia. Methods A total of 46 patients aged 18–65 years undergoing elective non-laparoscopic surgery under general anesthesia were divided into Group L with basal HR 40–60 bpm and Group H with basal HR 60–100 bpm. All patients received an intravenous dose of glycopyrrolate (0.006mg/kg). HR, mean arterial pressure (MAP), and HRV parameters were recorded before anesthesia induction (T0), at baseline (T1), and 30 minutes after glycopyrrolate administration (T2). The absolute (∆HR) and relative (∆HR%) increases in HR from T1 to T2 were also calculated. Results Group L showed significantly lower HR values at T1 and T2 compared to Group H ( p < 0.01), while both ∆HR and ∆HR% were significantly higher ( p < 0.01). In both groups, HR increased significantly at T2 compared to T1 ( p < 0.01). LF and HF values were significantly reduced at T1 and T2 compared to T0 ( p < 0.01), with further reductions at T2 relative to T1. The LF/HF ratio increased significantly at T2 ( p < 0.01), suggesting altered autonomic tone. Conclusion Glycopyrrolate produces a greater HR increase in patients with lower baseline HR and alters HRV by decreasing parasympathetic activity and increasing the LF/HF ratio. These findings suggest that glycopyrrolate may help stabilize autonomic function during general anesthesia, particularly in patients with bradycardia. Trial registration ClinicalTrials.gov NCT06237478, registered on 2 February 2024. Retrospectively registered. Glycopyrrolate Baseline heart rate Heart rate variability Autonomic nervous system Parasympathetic activity General anesthesia Figures Figure 1 Figure 2 Background The autonomic nervous system (ANS), comprising the sympathetic and parasympathetic branches, plays a fundamental role in regulating cardiovascular stability and maintaining physiological homeostasis. During anesthesia and surgical procedures, external stimuli and anesthetic agents can disrupt autonomic balance, sometimes resulting in exaggerated parasympathetic activity. This overactivation, especially of the cardiac vagal branch, may cause bradycardia or even transient cardiac arrest. Such vagal responses are particularly concerning in procedures like endotracheal intubation, laryngoscopy, and anorectal surgery, where abrupt changes in ANS tone may occur. Glycopyrrolate is a long-acting, quaternary ammonium anticholinergic agent that [ 1 ]. Clinically, it is widely used to reduce airway secretions, mitigate vagal reflexes, and prevent bradyarrhythmias during the perioperative period[ 2 ]. Its relatively poor penetration of the blood-brain barrier minimizes central nervous system effects, while its preferential activity on M1 and M3 receptors contributes to bronchodilation and secretion suppression[ 3 ]. Although glycopyrrolate has a weaker chronotropic effect compared to atropine, it offers greater cardiovascular stability. However, its effect on heart rate (HR) and heart rate variability (HRV) may vary depending on the baseline autonomic tone of individual patients -a factor often overlooked in prior research. Heart rate is modulated by both sympathetic and parasympathetic influences, but at rest, vagal tone is the dominant regulator. Patients with lower resting HR often exhibit higher baseline parasympathetic activity, while those with higher HRs tend to have reduced vagal influence[ 4 ]. It remains unclear whether the heart rate response to glycopyrrolate differs according to baseline HR, particularly under general anesthesia. Furthermore, the autonomic modulation reflected by HRV in this context is not well characterized. This study aimed to investigate the effects of glycopyrrolate on HR and HRV in patients with different baseline HRs during general anesthesia. We hypothesized that due to higher baseline parasympathetic tone, patients with lower baseline HR would show a stronger chronotropic response and greater shifts in HRV following glycopyrrolate administration during general anesthesia. Methods We hypothesized that glycopyrrolate would induce a more significant heart rate (HR) increase and more pronounced alterations in heart rate variability (HRV) parameters in patients with lower baseline HR (40–60 bpm) than in those with higher baseline HR (60–100 bpm), due to greater parasympathetic tone in the former group. Participants Patients, gender not restricted, undergoing elective general anesthesia surgery from March 2024 to June 2024 were included. Inclusion criteria were: age between 18 and 65 years, body mass index (BMI) of 18–30 kg/m 2 , American Society of Anesthesiologists (ASA) status of class I-II, an expected operation time ˃1 h, and undergoing orthopedic or urological surgery. Exclusion criteria were allergy to glycopyrrolate, laparoscopic surgery, liver or kidney dysfunction, pre-existing bradycardia, concomitant glaucoma, and refusal to participate. The elimination criteria consisted of unstable hemodynamics or severe bradycardia (HR 100 bpm) at 10 min after the start of surgery, use of vasoactive drugs or other medications significantly affecting HR due to severe blood pressure or HR abnormalities, administration of other anticholinergic drugs, interference with the collection of HRV electrocardiogram signals. Patients were stratified into two groups according to baseline HR measured 10 minutes after the start of surgery (T1), based on literature-supported autonomic tone ranges in adults[ 5 ]: Group L (Low HR): 40–60 bpm;Group H (High HR): 60–100 bpm. HRV Monitoring Upon entering the operating room, all patients received continuous monitoring including ECG, blood pressure, SpO₂, and depth of anesthesia (Ai index). HRV data were collected using the Conview YY-106 anesthetic depth monitor (Zhejiang Puke Medical Technology Co. Ltd., China) with a sampling frequency of 500 Hz and time-domain data window of 5 minutes. Frequency-domain HRV analysis was performed using the embedded algorithm validated in prior literature, and categorized as follows: Low frequency (LF): 0.04–0.15 Hz; High frequency (HF): 0.15–0.4 Hz; LF/HF ratio: Index of sympathovagal balance. Data were exported and analyzed using the manufacturer’s proprietary software (Conview HRV Analysis Suite v2.1), which follows Task Force standards for HRV interpretation. Anesthesia protocol None of the patients received preoperative medication. An intravenous line was established on patients’ non-dominant hand for fluid infusion and drug delivery. General anesthesia induction was performed by intravenous injection of midazolam 0.5 mg/kg, propofol 1–2 mg/kg, sufentanil 0.2–0.4 µg/kg, and rocuronium bromide 0.6 mg/kg. After muscle relaxation, endotracheal intubation was performed for mechanical ventilation. Respiratory parameters were adjusted to maintain an oxygen concentration of 60%, tidal volume of 6–8 ml/kg, ventilation frequency of 10–12 times/min, and an inspiratory-expiratory ratio of 1:2, with the end-tidal CO 2 pressure (P ET CO 2 ) maintained between 35-45mmHg. Maintenance of general anesthesia involved continuous intravenous infusion of propofol at 4-8mg·kg − 1 ·h − 1 and remifentanil at 0.1–0.5µg·kg − 1 ·min − 1 . Sufentanil was additionally administered before surgery beginning to a total dose of 0.6µg/kg. Rocuronium bromide was intermittently injected to maintain moderate muscle relaxation. Treatment After basal HR, mean arterial pressure (MAP), and HRV frequency domain analysis parameters were recorded at T1 in both groups, glycopyrrolate 0.006 mg/kg was injected intravenously. Propofol and remifentanil infusions were ceased at the end of surgery. Patients were extubated when they had awoken and restored adequate muscle strength after surgery. Then the patients were transferred to the post-anesthesia care unit (PACU). The fluctuations of mean arterial pressure (MAP) and heart rate (HR) were maintained within ± 20% of the basal values by adjusting the anesthetics with Ai index between 40–60 during surgery. If HR dropped below 40 bpm or severe hypotension occurred (a decrease in MAP exceeding 20% of baseline), atropine or ephedrine was administered, and the case was eliminated from the study. Measurements The demographics, including age, gender, height, weight, and ASA classification, was recorded. Dosage of anesthetics, type of surgery, surgery duration, and anesthesia duration were documented. The increase in HR at 30 min after the administration of glycopyrrolate (T2) compared to T1 was calculated and considered as the maximum increase of HR, the ∆HR (∆HR = [HR at T2] - [HR at T1]). The maximum increase ratio of HR (∆HR% = ∆HR / [HR at T1]) were also calculated and recorded. HR, MAP and the HRV frequency indexes were recorded before induction of general anesthesia (T0), and at T1 and T2. HRV frequency indexes include low frequency power (LF, 0.04–0.15 Hz), high frequency power (HF, 0.15–0.4 Hz), and LF/HF. Glycopyrrolate-related adverse reactions were recorded, including allergic reactions, tachycardia, and delayed emergence from anesthesia, etc. Sample Size Calculation Sample size was calculated using PASS 15.0 (NCSS LLc., USA). The ∆HR was chosen as the main outcome indicator. Based on the results of our preliminary experiment, the ∆HR was (15.4 ± 2.51) bpm in Group L and (13.0 ± 2.12) bpm in Group H. A two-sided test with α = 0.05 and a test efficacy of 90% was performed to include at least 21 patients in each group. A minimum of 27 patients were recruited in each group considering the possibility of loss to follow-up or consent withdrawal. Statistical analysis Statistical analysis was conducted using SPSS 26.0 (IBM, Chicago, IL, USA). The Shapiro-Wilk test was applied to assess the normality of continuous data. Normally distributed variables were expressed as mean ± standard deviation and compared using independent samples t-tests for between group comparisons and repeated measures analysis of variance (ANOVA) for within group comparisons across time points. Non-normally distributed variables were presented as median (interquartile range) and analyzed using the Mann-Whitney U test for between group comparisons and the Wilcoxon signed-rank test or Friedman test for within group comparisons, as appropriate. Categorical variables were presented as frequencies and percentages and compared using the Chi-square test or Fisher’s exact test. A two-tailed P-value of < 0.05 was considered statistically significant. Results Patient Characteristics Twenty-seven patients were initially enrolled in each group. In Group L, 3 patients received vasopressor drugs during surgery, and 1 patient received anticholinergic medication, resulting in a total of 23 patients included. In Group H, 2 patients received vasopressor drugs during surgery, 1 patient received anticholinergic medication, and 1 patient experienced interference with HRV electrocardiogram signal collection due to intraoperative surgical position changes. Consequently, Group H also included a total of 23 patients. There were no statistically significant differences in the demographics in terms of gender, age, body mass index (BMI), and ASA classification, and in the intraoperative parameters in terms of surgery duration, anesthesia duration, intraoperative anesthesia drug dosage, and type of surgery between the two groups (all p > 0.05; Table 1 ) . Table 1 Baseline characteristics and intraoperative parameters of the two study groups Group L Group H p Gender (M/F) 14/9 15/8 0.76 Age (yr) 50.7 ± 11.2 51.5 ± 10.7 0.82 BMI (kg/m 2 ) 23.5 ± 1.6 24.1 ± 1.9 0.29 ASA classification (Ⅰ/Ⅱ) 17/6 18/5 0.73 Surgery duration (min) 85.2 ± 13.7 84.3 ± 9.3 0.80 Anesthesia duration (min) 99.1 ± 14.1 98.5 ± 10.1 0.86 Dosage of propofol (mg) 552.6 ± 115.3 552.9 ± 97.7 0.99 Dosage of sulfentanyl (µg) 33.3 ± 4.3 33.6 ± 3.9 0.85 Dosage of remifentanil (mg) 1.08 ± 0.19 1.11 ± 0.19 0.60 Type of surgery (Orthopaedic / Urology) 12/11 10/13 0.56 Data are expressed as mean ± standard deviation or number. BMI: body mass index; ASA: American Society of Anesthesiologists Heart Rate Changes HR was significantly lower in Group L both at T1 and T2 than Group H ( p < 0.001 for both). While compared with Group H, ∆HR and the ∆HR% were significantly higher in Group L ( p < 0.001 for both; Table 2 ). Compared with T0, HR was significantly decreased at T1 in both groups ( p < 0.001 for both). In comparison with T0, Group L showed a significant decrease ( p < 0.001), while Group H exhibited a significant increase ( p < 0.001) in HR at T2. Compared with T1, there was a significant increase in HR at T2 in both groups ( p < 0.001 for both; Table 3 ). Figure 1 illustrates the temporal changes in heart rate in both groups. Mean Arterial Pressure (MAP) There were no statistically significant differences in MAP at each time point between the two groups (T0: p = 0.91, T1: p = 0.47, T2: p = 0.36, respectively). Compared with T0, MAP was significantly decreased at T1 and T2 in both groups (Group L: T1: p < 0.001, T2: p = 0.003; Group H: T1: p < 0.001, T2: p < 0.001). Compared with T1, there were no statistically significant differences in MAP at T2 in both groups ( p = 0.90 for Group L, and p = 1.00 for Group H; Table 3 ). Table 2 Comparison of ∆HR and ∆HR% between groups Group L Group H p ∆HR (bpm) 16.04 ± 2.16 12.78 ± 3.10 < 0.001 The ∆HR% 0.30 ± 0.05 0.19 ± 0.05 < 0.001 Data are expressed as mean ± standard deviation. ∆HR = [HR at T2] - [HR at T1]; The ∆HR% = ∆HR / [HR at T1] Table 3 Heart rate and mean arterial pressure at different time points Indicators Time point Group L Group H p HR (bpm) T0 75.17 ± 2.48 76.57 ± 5.01 0.24 T1 54.26 ± 3.08 68.65 ± 3.55 < 0.001 T2 70.30 ± 2.96 81.43 ± 3.44 < 0.001 P T0−1 < 0.001 < 0.001 P T0−2 < 0.001 < 0.001 P T1−2 < 0.001 < 0.001 MAP (mmHg) T0 96.74 ± 5.54 96.43 ± 11.17 0.91 T1 87.52 ± 10.32 85.13 ± 11.66 0.47 T2 88.61 ± 10.82 85.52 ± 11.98 0.36 P T0−1 < 0.001 < 0.001 P T0−2 0.003 < 0.001 P T1−2 0.90 1.00 Data are expressed as mean ± standard deviation. T0: before induction of general anesthesia; T1: 10 min after the start of surgery; T2: 30 min after the administration of glycopyrrolate. P T0−1 for comparison between T1 and T0; P T0−2 for comparison between T2 and T0; P T1−2 for comparison between T2 and T1. Heart Rate Variability Parameters Low-frequency power (LF) and high-frequency power (HF) decreased significantly from T0 to T1 and T2 in both groups ( p < 0.001). Compared to T1, LF and HF further decreased at T2 (Group L: p < 0.001; Group H: LF: p = 0.002, HF: p < 0.001). There were no significant between-group differences in LF or HF at any time point.The LF/HF ratio significantly decreased from T0 to T1 and subsequently increased at T2 in both groups ( p < 0.01), suggesting a shift in autonomic tone (Table 4 ). Figure 2 illustrates the changes in frequency-domain HRV parameters (LF, HF, and LF/HF) over time, highlighting a pronounced decrease in HF and increase in LF/HF following glycopyrrolate administration. Table 4 Frequency-domain HRV indices (LF, HF, LF/HF) in both groups at each time point Indicators Time point Group L Group H p LF (ms 2 , ± s ) T0 1646.55 ± 803.05 2108.65 ± 1739.86 0.25 T1 378.26 ± 175.74 335.11 ± 183.19 0.42 T2 227.11 ± 140.17 210.20 ± 147.63 0.69 P T0−1 < 0.001 < 0.001 P T0−2 < 0.001 < 0.001 P T1−2 < 0.001 0.002 HF (ms 2 , ± s ) T0 616.67 ± 292.10 745.19 ± 503.90 0.30 T1 196.65 ± 104.85 179.13 ± 103.52 0.57 T2 75.49 ± 55.04 65.45 ± 43.23 0.49 P T0−1 < 0.001 < 0.001 P T0−2 < 0.001 < 0.001 P T1−2 < 0.001 < 0.001 LF/HF [M ( P 25 , P 75 )] T0 2.62 (1.94, 3.63) 3.15 (1.82, 3.92) 0.82 T1 1.97 (1.54, 2.54) 1.78 (1.54, 2.26) 0.50 T2 3.32 (2.06, 4.01) 2.87 (2.45, 3.99) 0.98 P T0−1 0.004 0.002 P T0−2 0.08 0.15 P T1−2 < 0.001 < 0.001 Data are expressed as mean ± standard deviation for LF and HF, and as M ( P 25 , P 75 ) for LF/HF. T0: before induction of general anesthesia; T1: 10 min after the start of surgery; T2: 30 min after the administration of glycopyrrolate. P T0−1 for comparison between T1 and T0; P T0−2 for comparison between T2 and T0; P T1−2 for comparison between T2 and T1. Adverse Events No adverse reactions related to glycopyrrolate administration were observed in either group, including allergic reactions, tachycardia, and delayed emergence from anesthesia, occurred. Discussion This study demonstrates that glycopyrrolate administration during general anesthesia results in a significantly greater heart rate (HR) increase in patients with lower baseline HRs (40–60 bpm) compared to those with higher baseline HRs (60–100 bpm). Additionally, frequency domain heart rate variability (HRV) parameters showed reduced high frequency power (HF) and increased LF/HF ratio after glycopyrrolate injection, indicating a shift in autonomic balance. Our findings are consistent with those of Hattori et al.[ 6 ], who observed significant reductions in HF and elevation in LF/HF during general anesthesia, indicative of vagal suppression. Similarly, Valentini and Parati emphasized that glycopyrrolate produced a modest HR increase compared to atropine, suggesting baseline autonomic tone might explain interindividual differences in response[ 7 ]. Glycopyrrolate is a long-acting quaternary ammonium anticholinergic agent that can reduce parasympathetic nervous system activity and promote a balanced autonomic nervous system (ANS) function by antagonizing muscarinic receptors, with potent and sustained peripheral anticholinergic effect. Glycopyrrolate can reduce secretion from salivary glands, bronchus, and pharynx, dilate bronchus, and relieve bronchospasm by antagonizing M3 and M1 receptors. It can also prevent and attenuate vagal reflexes in the heart and prevent bradycardia by antagonizing M2 receptors. Glycopyrrolate exhibits stronger affinity for M3 and M1 receptors than M2 receptors. In comparison with atropine, it demonstrates a stronger reduction in secretions and bronchodilation, with a weaker tendency to cause tachycardia[ 8 ], indicating superior cardiovascular stability[ 9 ]. However, the effects of glycopyrrolate on HR in different basal HR levels has not been determined. The ANS, comprising the sympathetic nervous system and the parasympathetic nervous system, is a crucial regulatory system in maintaining the homeostasis of the human nervous system[ 10 ]. Dysfunction in the ANS can increase the incidence of adverse reactions in patients during perioperative period. Certain anesthesia procedures, such as the insertion of a laryngoscope, endotracheal intubation, endotracheal suction, as well as specific surgical procedures like exposing the glottis through suspension laryngoscopy, cervical dilation during artificial abortion surgery, and anal dilatation during internal hemorrhoidectomy, may induce abnormal ANS activity, leading to overactivity of the vagus nerve. Overactivity of the cardiac vagal branch may lead to extreme cardiac slowing or even 10–15 s or longer cardiac arrest. This condition may or may not be accompanied by sympathetic withdrawal, adding to the loss of pressure in the systemic circulation. The ANS plays a role in regulating HR[ 11 ]. The body has an intrinsic HR, that is, the basal firing rate of pacemaker cells. In the resting situation, HR is mainly under vagal influence, with the sympathetic nervous system playing only a partial regulatory role. On average, it is much lower than the “intrinsic HR”[ 12 ]. In normal individuals, the HR is approximately 72 bpm, and the intrinsic HR is around 105 bpm[ 13 ]. This indicates that, at rest, HR is primarily regulated by the parasympathetic nervous system. It may be implied that increases or decreases of vagal activity will have a major impact on decelerating or accelerating HR. When HR is slow, the parasympathetic nervous system predominates in HR regulation; whereas when HR is fast, the role of the parasympathetic nervous system in HR regulation is relatively weaker compared to when HR is slow[ 14 ]. The greater ∆HR and ∆HR% observed in Group L can be attributed to the underlying autonomic tone at baseline. In healthy individuals, resting HR is primarily under parasympathetic control, while intrinsic HR, determined by sinoatrial pacemaker activity, is substantially higher (around 105 bpm). When glycopyrrolate, a muscarinic receptor antagonist, is administered, it reduces vagal inhibition of the sinoatrial node, leading to HR acceleration. This effect is more pronounced in patients with dominant parasympathetic influence. Therefore, Group L patients experienced a stronger chronotropic response due to greater vagal blockade. Furthermore, the reduction in HF reflects decreased vagal modulation, while the elevated LF/HF suggests a relative sympathetic predominance. Glycopyrrolate’s antagonism of M2 receptors on the sinoatrial node diminishes parasympathetic tone, unmasking latent sympathetic influence. This shift was more evident in Group L, aligning with their stronger basal vagal tone. Combining the results of the preliminary experiment with the pharmacokinetics of glycopyrrolate, the fastest HR occurs approximately 30 min after peripheral intravenous injection of glycopyrrolate. Hence, in this study, we observed the changes of HR at this time point of T2 and considered it as the highest HR after glycopyrrolate administration. Heart rate variability (HRV) is a measurement of the fluctuation of time between each heartbeat and reflects the function of the ANS[ 15 ]. HRV reflects the function of the ANS as well as the balance between the sympathetic and parasympathetic nervous systems[ 16 ]. Temporal analysis methods are greatly affected by the non-stationarity of HRV[ 17 ]. In anesthesia-related research, frequency domain analysis is commonly employed for short-term studies, typically utilizing 5 min of HRV electrocardiogram data for analysis. HF reflects parasympathetic nervous system activity[ 18 ]. The results of HRV frequency domain indices in this study indicate that compared with T0, HF values were significantly decreased at T1. It may be associated with the inhibitory effect of anesthetic drugs on the parasympathetic nervous system[ 19 ]. Mechanical ventilation and controlled respiration, may weaken the regulatory ability of the parasympathetic nervous system, potentially leading to a decrease in HF as well[ 20 ]. Compared with T1, HF values were significantly decreased at T2. The primary reason may be glycopyrrolate acting as an anticholinergic drug, selectively antagonizing M receptors and reducing parasympathetic nervous system activity. Additionally, it might also be partly related to the effects of anesthetic drugs and mechanical ventilation. LF reflects sympathetic nervous system activity. In this study, compared with T0, LF values were significantly decreased at T1 and T2 in both groups, with more decrease at T2 than T1. It may be associated with the inhibitory effect of anesthetic drugs on the sympathetic nervous system[ 21 ]. This study also observed a significant increase in LF/HF values at T2 compared with T1 in both groups. The value of LF/HF reflects the balance between the sympathetic and parasympathetic nervous systems. The parasympathetic nervous system has an inhibitory effect on sympathetic nervous system activity, acting as a natural β-adrenergic blocker, attributed to a reduction in release of norepinephrine and a decrease in cAMP induced by cholinergic[ 22 ]. When the anticholinergic drug glycopyrrolate is used, parasympathetic nerve activity is significantly decreased, which weakens the inhibitory effect of parasympathetic nerve on sympathetic nerve and increases the sympathetic nerve activity relatively. Although both LF and HF values decreased, the reduction in LF was less pronounced than HF, thus leading to an increase in LF/HF. The strength of this study is that we, for the first time, investigated the effect of glycopyrrolate on HR in patients with different basal HR. Clinically, our results suggest that glycopyrrolate may provide hemodynamic benefits by enhancing HR in patients prone to intraoperative bradycardia. Compared to atropine, glycopyrrolate offers a more gradual HR increase with less risk of excessive tachycardia, making it a safer choice for autonomic modulation during anesthesia[ 8 ]. Paech et al. demonstrated similar cardiovascular stability with glycopyrrolate when used for reversal of neuromuscular blockade, supporting its utility in surgical settings[ 23 ]. However, certain limitations still exist. First, older adults inherently have lower intrinsic HR[ 24 ] and poorer parasympathetic nervous system regulatory capacity[ 25 ], so this study only included patients aged 18 to 65 years old. The impact of glycopyrrolate on patients in other age groups warrants further investigation. Second, this study did not assess hematological indicators such as catecholamines, which could reflect changes in ANS activity. Additionally, since orthopedic or urological non-laparoscopic surgery require the use of an electric scalpel less than other types of surgery, which has less disturbance on the collection of HRV signal, this study only included patients undergoing orthopedic or urological non-laparoscopic surgery. Pneumoperitoneum can lead to increased intra-abdominal pressure, which can affect HRV[ 26 ]. Due to the exclusion of laparoscopic procedures, the external validity of our findings may be limited, especially in surgeries involving high intra-abdominal pressure. The effect of glycopyrrolate on HR and HRV in patients undergoing other types of surgery or laparoscopic procedures needs further study. Third, we did not evaluate biochemical markers such as plasma catecholamines to directly quantify sympathetic activation. Lastly, although HRV analysis provides a non-invasive window into autonomic regulation, the use of short-term, frequency-domain metrics alone may not fully capture dynamic autonomic interactions. Combining these with time-domain or nonlinear HRV analysis in future studies may provide more comprehensive insights. In summary, glycopyrrolate administration during general anesthesia results in differential HR and HRV responses based on baseline autonomic tone. Patients with lower resting HRs experience greater chronotropic effects and more marked vagal inhibition. These findings highlight the importance of individualized autonomic assessment when selecting perioperative anticholinergic therapy. Conclusions Glycopyrrolate elicits stronger chronotropic and autonomic effects in patients with lower baseline HR. Baseline autonomic tone should guide perioperative anticholinergic use to optimize hemodynamic stability. Declarations Consent for publication Not applicable. Conflicts of Interest All the authors declare that they have no conflicts of interest. Ethics approval and consent to participate This prospective, controlled study was approved by the Institutional Research Ethics Committee of the Affiliated Hospital of Yangzhou University, Yangzhou, China (2023-YKL03-019). The trial was registered with https://www.clinicaltrials.gov (NCT06237478) and was conducted in accordance with the Declaration of Helsinki and the principles of the International Conference on Harmonization Good Clinical Practice Guideline. All study participants provided written informed consent. Funding This work was supported by Key project of Beijing Medical Award Foundation (YXJL-2021-0307-0632); Social Development General Project of Jiangsu Provincial Science and Technology Plan (BE2023749); and General Project of Jiangsu Province Traditional Chinese Medicine Technology Development (MS2022151). Author Contribution NL and ZZ conceived and designed the research; NL, JY, LZ, and ST collected data and conducted the research; XZ, WZ, and MW analyzed the data; NL, SF, and JY interpreted the data; NL wrote the initial draft; NL and ZZ revised the manuscript. All authors read and approved the final version of the manuscript. Acknowledgement The authors sincerely thank all the surgical and nursing staff of the Affiliated Hospital of Yangzhou University for their patience and enthusiastic support of this research. Data Availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. References Tashkin DP, Gross NJ. Inhaled glycopyrrolate for the treatment of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2018;13:1873–88. Yun Y, Cao D, Zhang X, Ouyang W, Min S, Lv J, Li L, Huang F. 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Nat Commun. 2017;8:14155. Paech C, Wagner F, Strehlow V, Gebauer RA. Drug-Induced Loss of Preexcitation in Pediatric Patients with WPW Pattern During Electrophysiologic Study. Pediatr Cardiol. 2019;40(1):194–7. Campbell CL, Cadar D, McMunn A, Zaninotto P. Operationalization of Intrinsic Capacity in Older People and Its Association With Subsequent Disability, Hospital Admission and Mortality: Results From The English Longitudinal Study of Ageing. J Gerontol Biol Sci Med Sci. 2023;78(4):698–703. Yeh CH, Chen CY, Kuo YE, Chen CW, Kuo TBJ, Kuo KL, Chen HM, Huang HY, Chern CM, Yang CCH. Role of the autonomic nervous system in young, middle-aged, and older individuals with essential hypertension and sleep-related changes in neurocardiac regulation. Sci Rep. 2023;13(1):22623. Tian F, Sun X, Yu Y, Zhang N, Hong T, Liang L, Yao B, Song L, Pei C, Wang Y, Lu W, Qu Q, Guo J, Zhang T, He X. Comparison of low-pressure and standard-pressure pneumoperitoneum laparoscopic cholecystectomy in patients with cardiopulmonary comorbidities: a double blinded randomized clinical trial. BMC Surg. 2024;24(1):348. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7112431","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":535489818,"identity":"c7533138-5ae6-43e5-b9c1-e60c59dbb79e","order_by":0,"name":"Zhuan Zhang","email":"","orcid":"","institution":"the Affiliated Hospital of Yangzhou University, Yangzhou University","correspondingAuthor":false,"prefix":"","firstName":"Zhuan","middleName":"","lastName":"Zhang","suffix":""},{"id":535489821,"identity":"2c1a3362-5035-44db-902d-b38f64868b8f","order_by":1,"name":"Xinqi Zhang","email":"","orcid":"","institution":"Xinjiang Medical 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1","display":"","copyAsset":false,"role":"figure","size":54453,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7112431/v1/a6336a973e9602dc8b379d60.png"},{"id":94622564,"identity":"2feb9267-8b3d-4e76-8d93-ffa7846f15ec","added_by":"auto","created_at":"2025-10-29 04:18:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":78894,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7112431/v1/fc3f70796b1100b71ca38cd2.png"},{"id":96709022,"identity":"a3cf20a9-2c2f-418c-aa82-e702f69a69eb","added_by":"auto","created_at":"2025-11-25 10:07:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1053683,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7112431/v1/7edbd90a-8074-4349-bf5a-7c328ec6bbcf.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Differential Effects of Glycopyrrolate on Heart Rate and Heart Rate Variability in Patients with Varying Baseline Heart Rates","fulltext":[{"header":"Background","content":"\u003cp\u003eThe autonomic nervous system (ANS), comprising the sympathetic and parasympathetic branches, plays a fundamental role in regulating cardiovascular stability and maintaining physiological homeostasis. During anesthesia and surgical procedures, external stimuli and anesthetic agents can disrupt autonomic balance, sometimes resulting in exaggerated parasympathetic activity. This overactivation, especially of the cardiac vagal branch, may cause bradycardia or even transient cardiac arrest. Such vagal responses are particularly concerning in procedures like endotracheal intubation, laryngoscopy, and anorectal surgery, where abrupt changes in ANS tone may occur.\u003c/p\u003e\u003cp\u003eGlycopyrrolate is a long-acting, quaternary ammonium anticholinergic agent that [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Clinically, it is widely used to reduce airway secretions, mitigate vagal reflexes, and prevent bradyarrhythmias during the perioperative period[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Its relatively poor penetration of the blood-brain barrier minimizes central nervous system effects, while its preferential activity on M1 and M3 receptors contributes to bronchodilation and secretion suppression[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Although glycopyrrolate has a weaker chronotropic effect compared to atropine, it offers greater cardiovascular stability. However, its effect on heart rate (HR) and heart rate variability (HRV) may vary depending on the baseline autonomic tone of individual patients -a factor often overlooked in prior research.\u003c/p\u003e\u003cp\u003eHeart rate is modulated by both sympathetic and parasympathetic influences, but at rest, vagal tone is the dominant regulator. Patients with lower resting HR often exhibit higher baseline parasympathetic activity, while those with higher HRs tend to have reduced vagal influence[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. It remains unclear whether the heart rate response to glycopyrrolate differs according to baseline HR, particularly under general anesthesia. Furthermore, the autonomic modulation reflected by HRV in this context is not well characterized. \u003cb\u003eThis study aimed to investigate the effects of glycopyrrolate on HR and HRV in patients with different baseline HRs during general anesthesia.\u003c/b\u003e We hypothesized that due to higher baseline parasympathetic tone, patients with lower baseline HR would show a stronger chronotropic response and greater shifts in HRV following glycopyrrolate administration during general anesthesia.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe hypothesized that glycopyrrolate would induce a more significant heart rate (HR) increase and more pronounced alterations in heart rate variability (HRV) parameters in patients with lower baseline HR (40\u0026ndash;60 bpm) than in those with higher baseline HR (60\u0026ndash;100 bpm), due to greater parasympathetic tone in the former group.\u003c/p\u003e\u003cp\u003e\u003cb\u003eParticipants\u003c/b\u003e\u003c/p\u003e\u003cp\u003ePatients, gender not restricted, undergoing elective general anesthesia surgery from March 2024 to June 2024 were included. Inclusion criteria were: age between 18 and 65 years, body mass index (BMI) of 18\u0026ndash;30 kg/m\u003csup\u003e2\u003c/sup\u003e, American Society of Anesthesiologists (ASA) status of class I-II, an expected operation time ˃1 h, and undergoing orthopedic or urological surgery. Exclusion criteria were allergy to glycopyrrolate, laparoscopic surgery, liver or kidney dysfunction, pre-existing bradycardia, concomitant glaucoma, and refusal to participate. The elimination criteria consisted of unstable hemodynamics or severe bradycardia (HR\u0026thinsp;\u0026lt;\u0026thinsp;40 bpm) or tachycardia (HR\u0026thinsp;\u0026gt;\u0026thinsp;100 bpm) at 10 min after the start of surgery, use of vasoactive drugs or other medications significantly affecting HR due to severe blood pressure or HR abnormalities, administration of other anticholinergic drugs, interference with the collection of HRV electrocardiogram signals.\u003c/p\u003e\u003cp\u003ePatients were stratified into two groups according to baseline HR measured 10 minutes after the start of surgery (T1), based on literature-supported autonomic tone ranges in adults[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]: Group L (Low HR): 40\u0026ndash;60 bpm;Group H (High HR): 60\u0026ndash;100 bpm.\u003c/p\u003e\u003cp\u003e\u003cb\u003eHRV Monitoring\u003c/b\u003e\u003c/p\u003e\u003cp\u003eUpon entering the operating room, all patients received continuous monitoring including ECG, blood pressure, SpO₂, and depth of anesthesia (Ai index). HRV data were collected using the Conview YY-106 anesthetic depth monitor (Zhejiang Puke Medical Technology Co. Ltd., China) with a sampling frequency of 500 Hz and time-domain data window of 5 minutes. Frequency-domain HRV analysis was performed using the embedded algorithm validated in prior literature, and categorized as follows: Low frequency (LF): 0.04\u0026ndash;0.15 Hz; High frequency (HF): 0.15\u0026ndash;0.4 Hz; LF/HF ratio: Index of sympathovagal balance.\u003c/p\u003e\u003cp\u003eData were exported and analyzed using the manufacturer\u0026rsquo;s proprietary software (Conview HRV Analysis Suite v2.1), which follows Task Force standards for HRV interpretation.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAnesthesia protocol\u003c/b\u003e\u003c/p\u003e\u003cp\u003eNone of the patients received preoperative medication. An intravenous line was established on patients\u0026rsquo; non-dominant hand for fluid infusion and drug delivery. General anesthesia induction was performed by intravenous injection of midazolam 0.5 mg/kg, propofol 1\u0026ndash;2 mg/kg, sufentanil 0.2\u0026ndash;0.4 \u0026micro;g/kg, and rocuronium bromide 0.6 mg/kg. After muscle relaxation, endotracheal intubation was performed for mechanical ventilation. Respiratory parameters were adjusted to maintain an oxygen concentration of 60%, tidal volume of 6\u0026ndash;8 ml/kg, ventilation frequency of 10\u0026ndash;12 times/min, and an inspiratory-expiratory ratio of 1:2, with the end-tidal CO\u003csub\u003e2\u003c/sub\u003e pressure (P\u003csub\u003eET\u003c/sub\u003eCO\u003csub\u003e2\u003c/sub\u003e) maintained between 35-45mmHg. Maintenance of general anesthesia involved continuous intravenous infusion of propofol at 4-8mg\u0026middot;kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u0026middot;h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and remifentanil at 0.1\u0026ndash;0.5\u0026micro;g\u0026middot;kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u0026middot;min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. Sufentanil was additionally administered before surgery beginning to a total dose of 0.6\u0026micro;g/kg. Rocuronium bromide was intermittently injected to maintain moderate muscle relaxation.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTreatment\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAfter basal HR, mean arterial pressure (MAP), and HRV frequency domain analysis parameters were recorded at T1 in both groups, glycopyrrolate 0.006 mg/kg was injected intravenously. Propofol and remifentanil infusions were ceased at the end of surgery. Patients were extubated when they had awoken and restored adequate muscle strength after surgery. Then the patients were transferred to the post-anesthesia care unit (PACU).\u003c/p\u003e\u003cp\u003eThe fluctuations of mean arterial pressure (MAP) and heart rate (HR) were maintained within \u0026plusmn;\u0026thinsp;20% of the basal values by adjusting the anesthetics with Ai index between 40\u0026ndash;60 during surgery. If HR dropped below 40 bpm or severe hypotension occurred (a decrease in MAP exceeding 20% of baseline), atropine or ephedrine was administered, and the case was eliminated from the study.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMeasurements\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe demographics, including age, gender, height, weight, and ASA classification, was recorded. Dosage of anesthetics, type of surgery, surgery duration, and anesthesia duration were documented. The increase in HR at 30 min after the administration of glycopyrrolate (T2) compared to T1 was calculated and considered as the maximum increase of HR, the ∆HR (∆HR = [HR at T2] - [HR at T1]). The maximum increase ratio of HR (∆HR% = ∆HR / [HR at T1]) were also calculated and recorded. HR, MAP and the HRV frequency indexes were recorded before induction of general anesthesia (T0), and at T1 and T2. HRV frequency indexes include low frequency power (LF, 0.04\u0026ndash;0.15 Hz), high frequency power (HF, 0.15\u0026ndash;0.4 Hz), and LF/HF. Glycopyrrolate-related adverse reactions were recorded, including allergic reactions, tachycardia, and delayed emergence from anesthesia, etc.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSample Size Calculation\u003c/b\u003e\u003c/p\u003e\u003cp\u003eSample size was calculated using PASS 15.0 (NCSS LLc., USA). The ∆HR was chosen as the main outcome indicator. Based on the results of our preliminary experiment, the ∆HR was (15.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.51) bpm in Group L and (13.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.12) bpm in Group H. A two-sided test with α\u0026thinsp;=\u0026thinsp;0.05 and a test efficacy of 90% was performed to include at least 21 patients in each group. A minimum of 27 patients were recruited in each group considering the possibility of loss to follow-up or consent withdrawal.\u003c/p\u003e\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eStatistical analysis was conducted using SPSS 26.0 (IBM, Chicago, IL, USA). The Shapiro-Wilk test was applied to assess the normality of continuous data. Normally distributed variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation and compared using independent samples t-tests for between group comparisons and repeated measures analysis of variance (ANOVA) for within group comparisons across time points. Non-normally distributed variables were presented as median (interquartile range) and analyzed using the Mann-Whitney U test for between group comparisons and the Wilcoxon signed-rank test or Friedman test for within group comparisons, as appropriate. Categorical variables were presented as frequencies and percentages and compared using the Chi-square test or Fisher\u0026rsquo;s exact test. A two-tailed P-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwenty-seven patients were initially enrolled in each group. In Group L, 3 patients received vasopressor drugs during surgery, and 1 patient received anticholinergic medication, resulting in a total of 23 patients included. In Group H, 2 patients received vasopressor drugs during surgery, 1 patient received anticholinergic medication, and 1 patient experienced interference with HRV electrocardiogram signal collection due to intraoperative surgical position changes. Consequently, Group H also included a total of 23 patients.\u003c/p\u003e\n\u003cp\u003eThere were no statistically significant differences in the demographics in terms of gender, age, body mass index (BMI), and ASA classification, and in the intraoperative parameters in terms of surgery duration, anesthesia duration, intraoperative anesthesia drug dosage, and type of surgery between the two groups (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05; Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline characteristics and intraoperative parameters of the two study groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup L\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup H\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGender (M/F)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14/9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (yr)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50.7\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eASA classification (Ⅰ/Ⅱ)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17/6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSurgery duration (min)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e85.2\u0026thinsp;\u0026plusmn;\u0026thinsp;13.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84.3\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnesthesia duration (min)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e99.1\u0026thinsp;\u0026plusmn;\u0026thinsp;14.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e98.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDosage of propofol (mg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e552.6\u0026thinsp;\u0026plusmn;\u0026thinsp;115.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e552.9\u0026thinsp;\u0026plusmn;\u0026thinsp;97.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDosage of sulfentanyl (\u0026micro;g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDosage of remifentanil (mg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eType of surgery (Orthopaedic / Urology)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12/11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10/13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eData are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or number.\u003c/p\u003e\n \u003cp\u003eBMI: body mass index; ASA: American Society of Anesthesiologists\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eHeart Rate Changes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHR was significantly lower in Group L both at T1 and T2 than Group H (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both). While compared with Group H, ∆HR and the ∆HR% were significantly higher in Group L (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both; Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Compared with T0, HR was significantly decreased at T1 in both groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both). In comparison with T0, Group L showed a significant decrease (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), while Group H exhibited a significant increase (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in HR at T2. Compared with T1, there was a significant increase in HR at T2 in both groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both; Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Figure 1 illustrates the temporal changes in heart rate in both groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMean Arterial Pressure (MAP)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were no statistically significant differences in MAP at each time point between the two groups (T0: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.91, T1: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.47, T2: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.36, respectively). Compared with T0, MAP was significantly decreased at T1 and T2 in both groups (Group L: T1: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, T2: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003; Group H: T1: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, T2: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Compared with T1, there were no statistically significant differences in MAP at T2 in both groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.90 for Group L, and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.00 for Group H; Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eComparison of ∆HR and ∆HR% between groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup L\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup H\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e∆HR (bpm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.04\u0026thinsp;\u0026plusmn;\u0026thinsp;2.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.78\u0026thinsp;\u0026plusmn;\u0026thinsp;3.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eThe ∆HR%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eData are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation.\u003c/p\u003e\n \u003cp\u003e∆HR = [HR at T2] - [HR at T1]; The ∆HR% = ∆HR / [HR at T1]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eHeart rate and mean arterial pressure at different time points\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIndicators\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTime point\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup L\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup H\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHR (bpm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75.17\u0026thinsp;\u0026plusmn;\u0026thinsp;2.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76.57\u0026thinsp;\u0026plusmn;\u0026thinsp;5.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54.26\u0026thinsp;\u0026plusmn;\u0026thinsp;3.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68.65\u0026thinsp;\u0026plusmn;\u0026thinsp;3.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70.30\u0026thinsp;\u0026plusmn;\u0026thinsp;2.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81.43\u0026thinsp;\u0026plusmn;\u0026thinsp;3.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csub\u003eT0\u0026minus;1\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csub\u003eT0\u0026minus;2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csub\u003eT1\u0026minus;2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMAP (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96.74\u0026thinsp;\u0026plusmn;\u0026thinsp;5.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96.43\u0026thinsp;\u0026plusmn;\u0026thinsp;11.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87.52\u0026thinsp;\u0026plusmn;\u0026thinsp;10.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e85.13\u0026thinsp;\u0026plusmn;\u0026thinsp;11.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88.61\u0026thinsp;\u0026plusmn;\u0026thinsp;10.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e85.52\u0026thinsp;\u0026plusmn;\u0026thinsp;11.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csub\u003eT0\u0026minus;1\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csub\u003eT0\u0026minus;2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csub\u003eT1\u0026minus;2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003eData are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation.\u003c/p\u003e\n \u003cp\u003eT0: before induction of general anesthesia; T1: 10 min after the start of surgery; T2: 30 min after the administration of glycopyrrolate. \u003cem\u003eP\u003c/em\u003e\u003csub\u003eT0\u0026minus;1\u003c/sub\u003e for comparison between T1 and T0; \u003cem\u003eP\u003c/em\u003e\u003csub\u003eT0\u0026minus;2\u003c/sub\u003e for comparison between T2 and T0; \u003cem\u003eP\u003c/em\u003e\u003csub\u003eT1\u0026minus;2\u003c/sub\u003e for comparison between T2 and T1.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eHeart Rate Variability Parameters\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLow-frequency power (LF) and high-frequency power (HF) decreased significantly from T0 to T1 and T2 in both groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Compared to T1, LF and HF further decreased at T2 (Group L: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Group H: LF: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002, HF: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). There were no significant between-group differences in LF or HF at any time point.The LF/HF ratio significantly decreased from T0 to T1 and subsequently increased at T2 in both groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), suggesting a shift in autonomic tone (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Figure 2 illustrates the changes in frequency-domain HRV parameters (LF, HF, and LF/HF) over time, highlighting a pronounced decrease in HF and increase in LF/HF following glycopyrrolate administration.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab4\" border=\"1\" class=\"fr-table-selection-hover\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eFrequency-domain HRV indices (LF, HF, LF/HF) in both groups at each time point\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIndicators\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTime point\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup L\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup H\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLF (ms\u003csup\u003e2\u003c/sup\u003e, \u003cem\u003e\u0026plusmn; s\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1646.55\u0026thinsp;\u0026plusmn;\u0026thinsp;803.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2108.65\u0026thinsp;\u0026plusmn;\u0026thinsp;1739.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e378.26\u0026thinsp;\u0026plusmn;\u0026thinsp;175.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e335.11\u0026thinsp;\u0026plusmn;\u0026thinsp;183.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e227.11\u0026thinsp;\u0026plusmn;\u0026thinsp;140.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e210.20\u0026thinsp;\u0026plusmn;\u0026thinsp;147.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csub\u003eT0\u0026minus;1\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csub\u003eT0\u0026minus;2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csub\u003eT1\u0026minus;2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHF (ms\u003csup\u003e2\u003c/sup\u003e, \u003cem\u003e\u0026plusmn; s\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e616.67\u0026thinsp;\u0026plusmn;\u0026thinsp;292.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e745.19\u0026thinsp;\u0026plusmn;\u0026thinsp;503.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e196.65\u0026thinsp;\u0026plusmn;\u0026thinsp;104.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e179.13\u0026thinsp;\u0026plusmn;\u0026thinsp;103.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75.49\u0026thinsp;\u0026plusmn;\u0026thinsp;55.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65.45\u0026thinsp;\u0026plusmn;\u0026thinsp;43.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csub\u003eT0\u0026minus;1\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csub\u003eT0\u0026minus;2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csub\u003eT1\u0026minus;2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLF/HF [M (\u003cem\u003eP\u003c/em\u003e\u003csub\u003e25\u003c/sub\u003e, \u003cem\u003eP\u003c/em\u003e\u003csub\u003e75\u003c/sub\u003e)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.62 (1.94, 3.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.15 (1.82, 3.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.97 (1.54, 2.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.78 (1.54, 2.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.32 (2.06, 4.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.87 (2.45, 3.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csub\u003eT0\u0026minus;1\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csub\u003eT0\u0026minus;2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csub\u003eT1\u0026minus;2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003eData are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation for LF and HF, and as M (\u003cem\u003eP\u003c/em\u003e\u003csub\u003e25\u003c/sub\u003e, \u003cem\u003eP\u003c/em\u003e\u003csub\u003e75\u003c/sub\u003e) for LF/HF.\u003c/p\u003e\n \u003cp\u003eT0: before induction of general anesthesia; T1: 10 min after the start of surgery; T2: 30 min after the administration of glycopyrrolate. \u003cem\u003eP\u003c/em\u003e\u003csub\u003eT0\u0026minus;1\u003c/sub\u003e for comparison between T1 and T0; \u003cem\u003eP\u003c/em\u003e\u003csub\u003eT0\u0026minus;2\u003c/sub\u003e for comparison between T2 and T0; \u003cem\u003eP\u003c/em\u003e\u003csub\u003eT1\u0026minus;2\u003c/sub\u003e for comparison between T2 and T1.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse Events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo adverse reactions related to glycopyrrolate administration were observed in either group, including allergic reactions, tachycardia, and delayed emergence from anesthesia, occurred.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study demonstrates that glycopyrrolate administration during general anesthesia results in a significantly greater heart rate (HR) increase in patients with lower baseline HRs (40\u0026ndash;60 bpm) compared to those with higher baseline HRs (60\u0026ndash;100 bpm). Additionally, frequency domain heart rate variability (HRV) parameters showed reduced high frequency power (HF) and increased LF/HF ratio after glycopyrrolate injection, indicating a shift in autonomic balance.\u003c/p\u003e\u003cp\u003eOur findings are consistent with those of Hattori et al.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], who observed significant reductions in HF and elevation in LF/HF during general anesthesia, indicative of vagal suppression. Similarly, Valentini and Parati emphasized that glycopyrrolate produced a modest HR increase compared to atropine, suggesting baseline autonomic tone might explain interindividual differences in response[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eGlycopyrrolate is a long-acting quaternary ammonium anticholinergic agent that can reduce parasympathetic nervous system activity and promote a balanced autonomic nervous system (ANS) function by antagonizing muscarinic receptors, with potent and sustained peripheral anticholinergic effect. Glycopyrrolate can reduce secretion from salivary glands, bronchus, and pharynx, dilate bronchus, and relieve bronchospasm by antagonizing M3 and M1 receptors. It can also prevent and attenuate vagal reflexes in the heart and prevent bradycardia by antagonizing M2 receptors. Glycopyrrolate exhibits stronger affinity for M3 and M1 receptors than M2 receptors. In comparison with atropine, it demonstrates a stronger reduction in secretions and bronchodilation, with a weaker tendency to cause tachycardia[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], indicating superior cardiovascular stability[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, the effects of glycopyrrolate on HR in different basal HR levels has not been determined.\u003c/p\u003e\u003cp\u003eThe ANS, comprising the sympathetic nervous system and the parasympathetic nervous system, is a crucial regulatory system in maintaining the homeostasis of the human nervous system[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Dysfunction in the ANS can increase the incidence of adverse reactions in patients during perioperative period. Certain anesthesia procedures, such as the insertion of a laryngoscope, endotracheal intubation, endotracheal suction, as well as specific surgical procedures like exposing the glottis through suspension laryngoscopy, cervical dilation during artificial abortion surgery, and anal dilatation during internal hemorrhoidectomy, may induce abnormal ANS activity, leading to overactivity of the vagus nerve. Overactivity of the cardiac vagal branch may lead to extreme cardiac slowing or even 10\u0026ndash;15 s or longer cardiac arrest. This condition may or may not be accompanied by sympathetic withdrawal, adding to the loss of pressure in the systemic circulation.\u003c/p\u003e\u003cp\u003eThe ANS plays a role in regulating HR[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The body has an intrinsic HR, that is, the basal firing rate of pacemaker cells. In the resting situation, HR is mainly under vagal influence, with the sympathetic nervous system playing only a partial regulatory role. On average, it is much lower than the \u0026ldquo;intrinsic HR\u0026rdquo;[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In normal individuals, the HR is approximately 72 bpm, and the intrinsic HR is around 105 bpm[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This indicates that, at rest, HR is primarily regulated by the parasympathetic nervous system. It may be implied that increases or decreases of vagal activity will have a major impact on decelerating or accelerating HR. When HR is slow, the parasympathetic nervous system predominates in HR regulation; whereas when HR is fast, the role of the parasympathetic nervous system in HR regulation is relatively weaker compared to when HR is slow[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe greater ∆HR and ∆HR% observed in Group L can be attributed to the underlying autonomic tone at baseline. In healthy individuals, resting HR is primarily under parasympathetic control, while intrinsic HR, determined by sinoatrial pacemaker activity, is substantially higher (around 105 bpm). When glycopyrrolate, a muscarinic receptor antagonist, is administered, it reduces vagal inhibition of the sinoatrial node, leading to HR acceleration. This effect is more pronounced in patients with dominant parasympathetic influence. Therefore, Group L patients experienced a stronger chronotropic response due to greater vagal blockade.\u003c/p\u003e\u003cp\u003eFurthermore, the reduction in HF reflects decreased vagal modulation, while the elevated LF/HF suggests a relative sympathetic predominance. Glycopyrrolate\u0026rsquo;s antagonism of M2 receptors on the sinoatrial node diminishes parasympathetic tone, unmasking latent sympathetic influence. This shift was more evident in Group L, aligning with their stronger basal vagal tone.\u003c/p\u003e\u003cp\u003eCombining the results of the preliminary experiment with the pharmacokinetics of glycopyrrolate, the fastest HR occurs approximately 30 min after peripheral intravenous injection of glycopyrrolate. Hence, in this study, we observed the changes of HR at this time point of T2 and considered it as the highest HR after glycopyrrolate administration.\u003c/p\u003e\u003cp\u003eHeart rate variability (HRV) is a measurement of the fluctuation of time between each heartbeat and reflects the function of the ANS[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. HRV reflects the function of the ANS as well as the balance between the sympathetic and parasympathetic nervous systems[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Temporal analysis methods are greatly affected by the non-stationarity of HRV[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In anesthesia-related research, frequency domain analysis is commonly employed for short-term studies, typically utilizing 5 min of HRV electrocardiogram data for analysis. HF reflects parasympathetic nervous system activity[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The results of HRV frequency domain indices in this study indicate that compared with T0, HF values were significantly decreased at T1. It may be associated with the inhibitory effect of anesthetic drugs on the parasympathetic nervous system[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Mechanical ventilation and controlled respiration, may weaken the regulatory ability of the parasympathetic nervous system, potentially leading to a decrease in HF as well[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Compared with T1, HF values were significantly decreased at T2. The primary reason may be glycopyrrolate acting as an anticholinergic drug, selectively antagonizing M receptors and reducing parasympathetic nervous system activity. Additionally, it might also be partly related to the effects of anesthetic drugs and mechanical ventilation. LF reflects sympathetic nervous system activity. In this study, compared with T0, LF values were significantly decreased at T1 and T2 in both groups, with more decrease at T2 than T1. It may be associated with the inhibitory effect of anesthetic drugs on the sympathetic nervous system[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis study also observed a significant increase in LF/HF values at T2 compared with T1 in both groups. The value of LF/HF reflects the balance between the sympathetic and parasympathetic nervous systems. The parasympathetic nervous system has an inhibitory effect on sympathetic nervous system activity, acting as a natural β-adrenergic blocker, attributed to a reduction in release of norepinephrine and a decrease in cAMP induced by cholinergic[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. When the anticholinergic drug glycopyrrolate is used, parasympathetic nerve activity is significantly decreased, which weakens the inhibitory effect of parasympathetic nerve on sympathetic nerve and increases the sympathetic nerve activity relatively. Although both LF and HF values decreased, the reduction in LF was less pronounced than HF, thus leading to an increase in LF/HF.\u003c/p\u003e\u003cp\u003eThe strength of this study is that we, for the first time, investigated the effect of glycopyrrolate on HR in patients with different basal HR. Clinically, our results suggest that glycopyrrolate may provide hemodynamic benefits by enhancing HR in patients prone to intraoperative bradycardia. Compared to atropine, glycopyrrolate offers a more gradual HR increase with less risk of excessive tachycardia, making it a safer choice for autonomic modulation during anesthesia[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Paech et al. demonstrated similar cardiovascular stability with glycopyrrolate when used for reversal of neuromuscular blockade, supporting its utility in surgical settings[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHowever, certain limitations still exist. First, older adults inherently have lower intrinsic HR[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] and poorer parasympathetic nervous system regulatory capacity[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], so this study only included patients aged 18 to 65 years old. The impact of glycopyrrolate on patients in other age groups warrants further investigation. Second, this study did not assess hematological indicators such as catecholamines, which could reflect changes in ANS activity. Additionally, since orthopedic or urological non-laparoscopic surgery require the use of an electric scalpel less than other types of surgery, which has less disturbance on the collection of HRV signal, this study only included patients undergoing orthopedic or urological non-laparoscopic surgery. Pneumoperitoneum can lead to increased intra-abdominal pressure, which can affect HRV[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Due to the exclusion of laparoscopic procedures, the external validity of our findings may be limited, especially in surgeries involving high intra-abdominal pressure. The effect of glycopyrrolate on HR and HRV in patients undergoing other types of surgery or laparoscopic procedures needs further study. Third, we did not evaluate biochemical markers such as plasma catecholamines to directly quantify sympathetic activation. Lastly, although HRV analysis provides a non-invasive window into autonomic regulation, the use of short-term, frequency-domain metrics alone may not fully capture dynamic autonomic interactions. Combining these with time-domain or nonlinear HRV analysis in future studies may provide more comprehensive insights.\u003c/p\u003e\u003cp\u003eIn summary, glycopyrrolate administration during general anesthesia results in differential HR and HRV responses based on baseline autonomic tone. Patients with lower resting HRs experience greater chronotropic effects and more marked vagal inhibition. These findings highlight the importance of individualized autonomic assessment when selecting perioperative anticholinergic therapy.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eGlycopyrrolate elicits stronger chronotropic and autonomic effects in patients with lower baseline HR. Baseline autonomic tone should guide perioperative anticholinergic use to optimize hemodynamic stability.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eConsent for publication\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003cp\u003eAll the authors declare that they have no conflicts of interest.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cp\u003e This prospective, controlled study was approved by the Institutional Research Ethics Committee of the Affiliated Hospital of Yangzhou University, Yangzhou, China (2023-YKL03-019). The trial was registered with \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.clinicaltrials.gov\u003c/span\u003e\u003cspan address=\"https://www.clinicaltrials.gov\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (NCT06237478) and was conducted in accordance with the Declaration of Helsinki and the principles of the International Conference on Harmonization Good Clinical Practice Guideline. All study participants provided written informed consent.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis work was supported by Key project of Beijing Medical Award Foundation (YXJL-2021-0307-0632); Social Development General Project of Jiangsu Provincial Science and Technology Plan (BE2023749); and General Project of Jiangsu Province Traditional Chinese Medicine Technology Development (MS2022151).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eNL and ZZ conceived and designed the research; NL, JY, LZ, and ST collected data and conducted the research; XZ, WZ, and MW analyzed the data; NL, SF, and JY interpreted the data; NL wrote the initial draft; NL and ZZ revised the manuscript. All authors read and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors sincerely thank all the surgical and nursing staff of the Affiliated Hospital of Yangzhou University for their patience and enthusiastic support of this research.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTashkin DP, Gross NJ. Inhaled glycopyrrolate for the treatment of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2018;13:1873\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYun Y, Cao D, Zhang X, Ouyang W, Min S, Lv J, Li L, Huang F. Glycopyrrolate versus atropine for preventing bradycardia induced by neostigmine injection after general anesthesia surgery: a randomized open, parallel-controlled multicenter clinical trial. Am J Transl Res. 2021;13(11):12996\u0026ndash;3002.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePoe E, Bosley R, Steele R, Chesnut C. Trigeminocardiac Reflex: A Review and Key Implications to Dermatologic Surgery. Dermatol Surg. 2023;49(7):654\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArmstrong R, Wheen P, Brandon L, Maree A, Kenny RA. Heart rate: control mechanisms, pathophysiology and assessment of the neurocardiac system in health and disease. QJM. 2022;115(12):806\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBufo MR, Guidotti M, De Faria C, Mofid Y, Bonnet-Brilhault F, Wardak C. Aguillon-Hernandez, Autonomic tone in children and adults: Pupillary, electrodermal and cardiac activity at rest. Int J Psychophysiol. 2022;180:68\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHattori K, Asamoto M, Otsuji M, Ito N, Kasahara S, Hashimoto Y, Yamada Y. Quantitative evaluation of stress in Japanese anesthesiology residents based on heart rate variability and psychological testing. J Clin Monit Comput. 2020;34(2):371\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBatista LD, Valentini Neto J, Grande de Franca NA, Lima Ribeiro SM, Fisberg RM. Body composition affects the accuracy of predictive equations to estimate resting energy expenditure in older adults: An exploratory study. Clin Nutr ESPEN. 2023;53:80\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang Y, Ren L, Li Y, Zhou Y, Yang J. The effect of glycopyrrolate vs. atropine in combination with neostigmine on cardiovascular system for reversal of residual neuromuscular blockade in the elderly: a randomized controlled trial. BMC Anesthesiol. 2024;24(1):123.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDeshar R, Subedi A, Pokharel K, Sah BP, Prasad JN. Effect of glycopyrrolate on vasopressor requirements for non-elective cesarean section under spinal anesthesia: a randomized, double-blind, placebo-controlled trial. BMC Anesthesiol. 2022;22(1):327.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBillet B, Goudman L, Rigoard P, Billot M, Roulaud M, Verstraete S, Nagels W, Moens M. Effect of neuromodulation for chronic pain on the autonomic nervous system: a systematic review. BJA Open. 2024;11:100305.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBaker JR, Hira R, Uppal J, Raj SR. Clinical Assessment of the Autonomic Nervous System. Card Electrophysiol Clin. 2024;16(3):239\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePan WT, Ji MH, Ma D, Yang JJ. Effect of perioperative autonomic nervous system imbalance on surgical outcomes: a systematic literature review. Br J Anaesth, 2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLefaucheur JP, Delon-Martin C, Hodaj H. Functional coupling between chronic pain and the autonomic nervous system revealed by neuromodulation techniques. Comment on 'Effect of neuromodulation for chronic pain on the autonomic nervous system: a systematic review' (BJA Open 2024; 11: 100305). BJA Open, 2025. 14: p. 100393.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMaki KA, Goodyke MP, Rasmussen K, Bronas UG. An Integrative Literature Review of Heart Rate Variability Measures to Determine Autonomic Nervous System Responsiveness Using Pharmacological Manipulation. J Cardiovasc Nurs. 2024;39(1):58\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAli H, Brooks C, Tzeng YC, Crane J, Beasley R, Gibson P, Pattemore P, Stanley T, Pearce N, Douwes J. Heart rate variability as a marker of autonomic nervous system activity in young people with eosinophilic and non-eosinophilic asthma. J Asthma. 2023;60(3):534\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGoodyke MP, Hershberger PE, Bronas UG, Dunn SL. Perceived Social Support and Heart Rate Variability: An Integrative Review. West J Nurs Res. 2022;44(11):1057\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSagnard A, Guenancia C, Mouhat B, Maza M, Fichot M, Moreau D, Garnier F, Lorgis L, Cottin Y, Zeller M. Involvement of Autonomic Nervous System in New-Onset Atrial Fibrillation during Acute Myocardial Infarction. J Clin Med, 2020. 9(5).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHafez OA, Chang RB. Regulation of Cardiac Function by the Autonomic Nervous System. Physiol (Bethesda). 2025;40(3):0.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDeschaumes C, Devoize L, Sudrat Y, Pereira B, Dallel R, Duale C. The role of the sympathetic component of the autonomic nervous system on pain before and after third molar extraction- an observational cohort study. BMC Anesthesiol. 2025;25(1):117.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ede Jesus P, Zangirolami-Raimundo J, Miranda JA, Sorpreso ICE, Raimundo RD. Autonomic heart rate modulation in patients with coronavirus disease 2019 in mechanical ventilation. Rev Assoc Med Bras (1992), 2023. 69(1): pp. 181\u0026ndash;185.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu X, Rabin PL, Yuan Y, Kumar A, Vasallo P 3rd, Wong J, Mitscher GA, Everett TH, Chen PS, editors. Effects of anesthetic and sedative agents on sympathetic nerve activity. Heart Rhythm, 2019. 16(12): pp. 1875\u0026ndash;1882.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJungen C, Scherschel K, Eickholt C, Kuklik P, Klatt N, Bork N, Salzbrunn T, Alken F, Angendohr S, Klene C, Mester J, Klocker N, Veldkamp MW, Schumacher U, Willems S, Nikolaev VO, Meyer C. Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias. Nat Commun. 2017;8:14155.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePaech C, Wagner F, Strehlow V, Gebauer RA. Drug-Induced Loss of Preexcitation in Pediatric Patients with WPW Pattern During Electrophysiologic Study. Pediatr Cardiol. 2019;40(1):194\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCampbell CL, Cadar D, McMunn A, Zaninotto P. Operationalization of Intrinsic Capacity in Older People and Its Association With Subsequent Disability, Hospital Admission and Mortality: Results From The English Longitudinal Study of Ageing. J Gerontol Biol Sci Med Sci. 2023;78(4):698\u0026ndash;703.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYeh CH, Chen CY, Kuo YE, Chen CW, Kuo TBJ, Kuo KL, Chen HM, Huang HY, Chern CM, Yang CCH. Role of the autonomic nervous system in young, middle-aged, and older individuals with essential hypertension and sleep-related changes in neurocardiac regulation. Sci Rep. 2023;13(1):22623.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTian F, Sun X, Yu Y, Zhang N, Hong T, Liang L, Yao B, Song L, Pei C, Wang Y, Lu W, Qu Q, Guo J, Zhang T, He X. Comparison of low-pressure and standard-pressure pneumoperitoneum laparoscopic cholecystectomy in patients with cardiopulmonary comorbidities: a double blinded randomized clinical trial. BMC Surg. 2024;24(1):348.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Glycopyrrolate, Baseline heart rate, Heart rate variability, Autonomic nervous system, Parasympathetic activity, General anesthesia","lastPublishedDoi":"10.21203/rs.3.rs-7112431/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7112431/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eTo evaluate the effects of glycopyrrolate on heart rate (HR) and heart rate variability (HRV) in patients with different baseline HR levels during general anesthesia.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA total of 46 patients aged 18\u0026ndash;65 years undergoing elective non-laparoscopic surgery under general anesthesia were divided into Group L with basal HR 40\u0026ndash;60 bpm and Group H with basal HR 60\u0026ndash;100 bpm. All patients received an intravenous dose of glycopyrrolate (0.006mg/kg). HR, mean arterial pressure (MAP), and HRV parameters were recorded before anesthesia induction (T0), at baseline (T1), and 30 minutes after glycopyrrolate administration (T2). The absolute (∆HR) and relative (∆HR%) increases in HR from T1 to T2 were also calculated.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eGroup L showed significantly lower HR values at T1 and T2 compared to Group H (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), while both ∆HR and ∆HR% were significantly higher (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). In both groups, HR increased significantly at T2 compared to T1 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). LF and HF values were significantly reduced at T1 and T2 compared to T0 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), with further reductions at T2 relative to T1. The LF/HF ratio increased significantly at T2 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), suggesting altered autonomic tone.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eGlycopyrrolate produces a greater HR increase in patients with lower baseline HR and alters HRV by decreasing parasympathetic activity and increasing the LF/HF ratio. These findings suggest that glycopyrrolate may help stabilize autonomic function during general anesthesia, particularly in patients with bradycardia.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e\u003cp\u003eClinicalTrials.gov NCT06237478, registered on 2 February 2024. Retrospectively registered.\u003c/p\u003e","manuscriptTitle":"Differential Effects of Glycopyrrolate on Heart Rate and Heart Rate Variability in Patients with Varying Baseline Heart Rates","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-29 04:02:04","doi":"10.21203/rs.3.rs-7112431/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6cf00c43-4fb2-4f77-930e-6e6fd8a0dc02","owner":[],"postedDate":"October 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-24T10:24:04+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-29 04:02:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7112431","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7112431","identity":"rs-7112431","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}