Changes in Autonomic Nervous Activity and Blood Pressure After Anesthesia Induction: Remimazolam Versus Propofol

Effects of Changes in Autonomic Nervous Activity on Changes in Blood Pressure After Anesthesia Induction: Remimazolam Versus Propofol

The goal of this clinical trial is to compare the effects of changes in autonomic nervous activity on changes in blood pressure after anesthesia induction between propofol and remimazolam in patients undergoing low-risk surgery. The main questions it aims to answer are:

• Does remimazolam shift sympathovagal balance toward parasympathetic predominance less than propofol?
• Does the less shift in sympathovagal balance toward parasympathetic predominance attenuate the reduction in blood pressure? Participants will be administered either propofol or remimazolam for anesthesia induction, after which the autonomic nervous activity and blood pressure will be measured.

Researchers will compare the propofol and remimazolam groups to see if remimazolam causes less shift in sympathovagal balance toward parasympathetic predominance and subsequently attenuates the reduction in blood pressure.

Study Overview

• Status: Completed
• Conditions: General Anesthetics
• Intervention / Treatment: Drug: Anesthesia induction with propofol; Drug: Anesthesia induction with remimazolam

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Phase 3

Contacts and Locations

Study Locations

• Korea, Republic of
  • Daegu, Korea, Republic of, 42472
    • Daegu Catholic University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 58 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age between 20 and 60 years
• American Society of Anesthesiologists physical status of 1
• Elective low-risk surgery requiring general anesthesia, the duration of which is shorter than 2 hours and 30 minutes (e.g., Laparoscopic cholecystectomy, Functional endoscopic sinus surgery, etc.)
• Body mass index less than 30 kg/m2

Exclusion Criteria:

• Arrhythmias or cardiac conduction disorders
• Disease or medical conditions affecting autonomic nervous activity (hypertension, diabetes mellitus, ischemic heart disease, congestive heart failure, cerebrovascular accident, chronic kidney disease, thyroid dysfunction, etc.)
• Valvular heart disease
• Use of medications affecting autonomic nervous activity or cardiac conduction (e.g., beta blocker)
• Limited mouth opening, limited head and upper neck extension, history of obstructive sleep apnea, or Modified Mallampati class 3 or 4
• Serum electrolyte abnormalities
• Severe hypovolemia
• Psychiatric diseases

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Propofol group; Receives propofol for anesthesia induction	Drug: Anesthesia induction with propofol; After a 10-minute-long acclimation, general anesthesia is induced with 2% propofol at the effect-site concentration of 4 μg/ml based on the Marsh Pharmacokinetic model. The effect-site concentration was maintained at 4 μg/ml until the trachea was intubated. Five minutes after the anesthesia induction, remifentanil was administered at the effect-site concentration of 4 ng/ml based on the Minto pharmacokinetic model until the trachea was intubated. With the initiation of remifentanil infusion, 1 mg/kg of rocuronium was administered following the calibration of the neuromuscular monitoring device. With the train-of-four count of 0, the trachea was intubated. Then, the effect-site concentrations of propofol and remifentanil were decreased to 3 μg/ml and 0 ng/ml, respectively, until the surgical incision was made.
Experimental: Remimazolam group; Receives remimazolam for anesthesia induction	Drug: Anesthesia induction with remimazolam; After a 10-minute-long acclimation, general anesthesia is induced with a 2-minute-long infusion of remimazolam at a rate of 12 mg/kg/hr, after which the infusion rate was reduced to 1 mg/kg/hr and was maintained until the surgical incision was made. Five minutes after the anesthesia induction, remifentanil was administered at the effect-site concentration of 4 ng/ml based on the Minto pharmacokinetic model until the trachea was intubated. With the initiation of remifentanil infusion, 1 mg/kg of rocuronium was administered following the calibration of the neuromuscular monitoring device. With the train-of-four count of 0, the trachea was intubated. Then, the effect-site concentration of remifentanil was decreased to 0 ng/ml until the surgical incision was made.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in low-to-high frequency power ratio (LF/HF) of heart rate variability (HRV) between 5-minute-pre-anesthesia and 5-minute-post-anesthesia induction	Low-frequency power (LF) and high-frequency power (HF) of heart rate variability (HRV) were calculated with the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. LF/HF represents the sympathovagal balance.	Between 5 minutes before and after anesthesia induction

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Low-frequency power (LF) of heart rate variability (HRV) during 5 minutes before anesthesia induction	Low-frequency power (LF) of heart rate variability (HRV) were calculated by integrating power spectra between 0.04 and 0.15 Hz, which were obtained from the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. LF represents the combined sympathetic and parasympathetic modulation of heart rate via baroreceptor reflexes, but is mainly modulated by sympathetic nervous activity.	5 minutes before anesthesia induction
Low-frequency power (LF) of heart rate variability (HRV) during 5 minutes after anesthesia induction	Low-frequency power (LF) of heart rate variability (HRV) were calculated by integrating power spectra between 0.04 and 0.15 Hz, which were obtained from the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. LF represents the combined sympathetic and parasympathetic modulation of heart rate via baroreceptor reflexes, but is mainly modulated by sympathetic nervous activity.	5 minutes after anesthesia induction
Low-frequency power (LF) of heart rate variability (HRV) during 5 minutes after endotracheal intubation	Low-frequency power (LF) of heart rate variability (HRV) were calculated by integrating power spectra between 0.04 and 0.15 Hz, which were obtained from the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. LF represents the combined sympathetic and parasympathetic modulation of heart rate via baroreceptor reflexes, but is mainly modulated by sympathetic nervous activity.	5 minutes after endotracheal intubation
Low-frequency power (LF) of heart rate variability (HRV) during 5 minutes before surgical incision	Low-frequency power (LF) of heart rate variability (HRV) were calculated by integrating power spectra between 0.04 and 0.15 Hz, which were obtained from the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. LF represents the combined sympathetic and parasympathetic modulation of heart rate via baroreceptor reflexes, but is mainly modulated by sympathetic nervous activity.	5 minutes before surgical incision
High-frequency power (HF) of heart rate variability (HRV) during 5 minutes before anesthesia induction	High-frequency power (HF) of heart rate variability (HRV) were calculated by integrating power spectra between 0.15 and 0.4 Hz, which were obtained from the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. HF represents the parasympathetic modulation of heart rate in response to respiration.	5 minutes before anesthesia induction
High-frequency power (HF) of heart rate variability (HRV) during 5 minutes after anesthesia induction	High-frequency power (HF) of heart rate variability (HRV) were calculated by integrating power spectra between 0.15 and 0.4 Hz, which were obtained from the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. HF represents the parasympathetic modulation of heart rate in response to respiration.	5 minutes after anesthesia induction
High-frequency power (HF) of heart rate variability (HRV) during 5 minutes after endotracheal intubation	High-frequency power (HF) of heart rate variability (HRV) were calculated by integrating power spectra between 0.15 and 0.4 Hz, which were obtained from the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. HF represents the parasympathetic modulation of heart rate in response to respiration.	5 minutes after endotracheal intubation
High-frequency power (HF) of heart rate variability (HRV) during 5 minutes before surgical incision	High-frequency power (HF) of heart rate variability (HRV) were calculated by integrating power spectra between 0.15 and 0.4 Hz, which were obtained from the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. HF represents the parasympathetic modulation of heart rate in response to respiration.	5 minutes before surgical incision
Total power (TP) of heart rate variability (HRV) during 5 minutes before anesthesia induction	Total power (TP) of heart rate variability (HRV) were calculated by integrating power spectra between 0 and 0.4 Hz, which were obtained from the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. TP represents the overall activity of the autonomic nervous system.	5 minutes before anesthesia induction
Total power (TP) of heart rate variability (HRV) during 5 minutes after anesthesia induction	Total power (TP) of heart rate variability (HRV) were calculated by integrating power spectra between 0 and 0.4 Hz, which were obtained from the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. TP represents the overall activity of the autonomic nervous system.	5 minutes after anesthesia induction
Total power (TP) of heart rate variability (HRV) during 5 minutes after endotracheal intubation	Total power (TP) of heart rate variability (HRV) were calculated by integrating power spectra between 0 and 0.4 Hz, which were obtained from the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. TP represents the overall activity of the autonomic nervous system.	5 minutes after endotracheal intubation
Total power (TP) of heart rate variability (HRV) during 5 minutes before surgical incision	Total power (TP) of heart rate variability (HRV) were calculated by integrating power spectra between 0 and 0.4 Hz, which were obtained from the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. TP represents the overall activity of the autonomic nervous system.	5 minutes before surgical incision
Low-to-high-frequency power ratio (LF/HF) of heart rate variability (HRV) during 5 minutes before anesthesia induction	Low-frequency power (LF) and high-frequency power (HF) of heart rate variability (HRV) were calculated with the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. LF/HF represents the sympathovagal balance.	5 minutes before anesthesia induction
Low-to-high-frequency power ratio (LF/HF) of heart rate variability (HRV) during 5 minutes after anesthesia induction	Low-frequency power (LF) and high-frequency power (HF) of heart rate variability (HRV) were calculated with the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. LF/HF represents the sympathovagal balance.	5 minutes after anesthesia induction
Low-to-high-frequency power ratio (LF/HF) of heart rate variability (HRV) during 5 minutes after endotracheal intubation	Low-frequency power (LF) and high-frequency power (HF) of heart rate variability (HRV) were calculated with the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. LF/HF represents the sympathovagal balance.	5 minutes after endotracheal intubation
Low-to-high-frequency power ratio (LF/HF) of heart rate variability (HRV) during 5 minutes before surgical incision	Low-frequency power (LF) and high-frequency power (HF) of heart rate variability (HRV) were calculated with the Fast Fourier Transform applied to a 5-minute-long electrocardiogram (ECG) waveform. LF/HF represents the sympathovagal balance.	5 minutes before surgical incision
Root mean square of the successive differences of the RR intervals (RMSSD) during 5 minutes before anesthesia induction	RMSSD represents the parasympathetic nervous activity mediated by a respiratory sinus arrhythmia.	5 minutes before anesthesia induction
Root mean square of the successive differences of the RR intervals (RMSSD) during 5 minutes after anesthesia induction	RMSSD represents the parasympathetic nervous activity mediated by a respiratory sinus arrhythmia.	5 minutes after anesthesia induction
Root mean square of the successive differences of the RR intervals (RMSSD) during 5 minutes after endotracheal intubation	RMSSD represents the parasympathetic nervous activity mediated by a respiratory sinus arrhythmia.	5 minutes after endotracheal intubation
Root mean square of the successive differences of the RR intervals (RMSSD) during 5 minutes before surgical incision	RMSSD represents the parasympathetic nervous activity mediated by a respiratory sinus arrhythmia.	5 minutes before surgical incision
Standard deviation of the RR intervals of normal sinus beats originating from the sinoatrial node of the right atrium (SDNN) during 5 minutes before anesthesia induction	SDNN represents the parasympathetic nervous activity mediated by a respiratory sinus arrhythmia.	5 minutes before anesthesia induction
Standard deviation of the RR intervals of normal sinus beats originating from the sinoatrial node of the right atrium (SDNN) during 5 minutes after anesthesia induction	SDNN represents the parasympathetic nervous activity mediated by a respiratory sinus arrhythmia.	5 minutes after anesthesia induction
Standard deviation of the RR intervals of normal sinus beats originating from the sinoatrial node of the right atrium (SDNN) during 5 minutes after endotracheal intubation	SDNN represents the parasympathetic nervous activity mediated by a respiratory sinus arrhythmia.	5 minutes after endotracheal intubation
Standard deviation of the RR intervals of normal sinus beats originating from the sinoatrial node of the right atrium (SDNN) during 5 minutes before surgical incision	SDNN represents the parasympathetic nervous activity mediated by a respiratory sinus arrhythmia.	5 minutes before surgical incision
The percentage of adjacent normal-to-normal sinus beat RR intervals that have a more than 50 milliseconds difference between them (pNN50) during 5 minutes before anesthesia induction	pNN50 represents the parasympathetic nervous activity mediated by a respiratory sinus arrhythmia.	5 minutes before anesthesia induction
The percentage of adjacent normal-to-normal sinus beat RR intervals that have a more than 50 milliseconds difference between them (pNN50) during 5 minutes after anesthesia induction	pNN50 represents the parasympathetic nervous activity mediated by a respiratory sinus arrhythmia.	5 minutes after anesthesia induction
The percentage of adjacent normal-to-normal sinus beat RR intervals that have a more than 50 milliseconds difference between them (pNN50) during 5 minutes after endotracheal intubation	pNN50 represents the parasympathetic nervous activity mediated by a respiratory sinus arrhythmia.	5 minutes after endotracheal intubation
The percentage of adjacent normal-to-normal sinus beat RR intervals that have a more than 50 milliseconds difference between them (pNN50) during 5 minutes before surgical incision	pNN50 represents the parasympathetic nervous activity mediated by a respiratory sinus arrhythmia.	5 minutes before surgical incision
Standard deviation 1 (SD1) of a Poincaré plot during 5 minutes before anesthesia induction	A Poincaré plot is a scatter plot where each pair of preceding and succeeding RR intervals is plotted on the abscissa and ordinate, respectively. After fitting the ellipse around the plot, SD1 is calculated as the standard deviation of the distance of each point from the line of identity (y=x). SD1 reflects the short-term HRV as the length of the transverse axis of the ellipse. SD1 correlates with the baroreflex sensitivity and HF.	5 minutes before anesthesia induction
Standard deviation 1 (SD1) of a Poincaré plot during 5 minutes after anesthesia induction	A Poincaré plot is a scatter plot where each pair of preceding and succeeding RR intervals is plotted on the abscissa and ordinate, respectively. After fitting the ellipse around the plot, SD1 is calculated as the standard deviation of the distance of each point from the line of identity (y=x). SD1 reflects the short-term HRV as the length of the transverse axis of the ellipse. SD1 correlates with the baroreflex sensitivity and HF.	5 minutes after anesthesia induction
Standard deviation 1 (SD1) of a Poincaré plot during 5 minutes after endotracheal intubation	A Poincaré plot is a scatter plot where each pair of preceding and succeeding RR intervals is plotted on the abscissa and ordinate, respectively. After fitting the ellipse around the plot, SD1 is calculated as the standard deviation of the distance of each point from the line of identity (y=x). SD1 reflects the short-term HRV as the length of the transverse axis of the ellipse. SD1 correlates with the baroreflex sensitivity and HF.	5 minutes after endotracheal intubation
Standard deviation 1 (SD1) of a Poincaré plot during 5 minutes before surgical incision	A Poincaré plot is a scatter plot where each pair of preceding and succeeding RR intervals is plotted on the abscissa and ordinate, respectively. After fitting the ellipse around the plot, SD1 is calculated as the standard deviation of the distance of each point from the line of identity (y=x). SD1 reflects the short-term HRV as the length of the transverse axis of the ellipse. SD1 correlates with the baroreflex sensitivity and HF.	5 minutes before surgical incision
Standard deviation 2 (SD2) of a Poincaré plot during 5 minutes before anesthesia induction	A Poincaré plot is a scatter plot where each pair of preceding and succeeding RR intervals is plotted on the abscissa and ordinate, respectively. After fitting the ellipse around the plot, SD2 is calculated as the standard deviation of the distance of each point from the line passing through the centroid, which vertically intersects the line of identity (y=x). SD2 reflects the long-term HRV as the length of the long axis of the ellipse. SD2 correlates with the baroreflex sensitivity and LF.	5 minutes before anesthesia induction
Standard deviation 2 (SD2) of a Poincaré plot during 5 minutes after anesthesia induction	A Poincaré plot is a scatter plot where each pair of preceding and succeeding RR intervals is plotted on the abscissa and ordinate, respectively. After fitting the ellipse around the plot, SD2 is calculated as the standard deviation of the distance of each point from the line passing through the centroid, which vertically intersects the line of identity (y=x). SD2 reflects the long-term HRV as the length of the long axis of the ellipse. SD2 correlates with the baroreflex sensitivity and LF.	5 minutes after anesthesia induction
Standard deviation 2 (SD2) of a Poincaré plot during 5 minutes after endotracheal intubation	A Poincaré plot is a scatter plot where each pair of preceding and succeeding RR intervals is plotted on the abscissa and ordinate, respectively. After fitting the ellipse around the plot, SD2 is calculated as the standard deviation of the distance of each point from the line passing through the centroid, which vertically intersects the line of identity (y=x). SD2 reflects the long-term HRV as the length of the long axis of the ellipse. SD2 correlates with the baroreflex sensitivity and LF.	5 minutes after endotracheal intubation
Standard deviation 2 (SD2) of a Poincaré plot during 5 minutes before surgical incision	A Poincaré plot is a scatter plot where each pair of preceding and succeeding RR intervals is plotted on the abscissa and ordinate, respectively. After fitting the ellipse around the plot, SD2 is calculated as the standard deviation of the distance of each point from the line passing through the centroid, which vertically intersects the line of identity (y=x). SD2 reflects the long-term HRV as the length of the long axis of the ellipse. SD2 correlates with the baroreflex sensitivity and LF.	5 minutes before surgical incision
Mean arterial blood pressure during 5 minutes before anesthesia induction	Measured at any time during 5 minutes before anesthesia induction	5 minutes before anesthesia induction
Mean arterial blood pressure during 5 minutes after anesthesia induction	Mean arterial blood pressure corresponding to the lowest systolic blood pressure during 5 minutes after anesthesia induction	5 minutes after anesthesia induction
Mean arterial blood pressure during 5 minutes after endotracheal intubation	Measured at any time during 5 minutes after endotracheal intubation	5 minutes after endotracheal intubation
Mean arterial blood pressure during 5 minutes before surgical incision	Measured at any time during 5 minutes before surgical incision	5 minutes before surgical incision
Systolic blood pressure during 5 minutes before anesthesia induction	Measured at any time during 5 minutes before anesthesia induction	5 minutes before anesthesia induction
Systolic blood pressure during 5 minutes after anesthesia induction	The lowest systolic blood pressure during 5 minutes after anesthesia induction	5 minutes after anesthesia induction
Systolic blood pressure during 5 minutes after endotracheal intubation	Measured at any time during 5 minutes after endotracheal intubation	5 minutes after endotracheal intubation
Systolic blood pressure during 5 minutes before surgical incision	Measured at any time during 5 minutes before surgical incision	5 minutes before surgical incision
Bispectral index (BIS) during 5 minutes before anesthesia induction	The BIS value corresponding to blood pressure measured during 5 minutes before anesthesia induction	5 minutes before anesthesia induction
Bispectral index (BIS) during 5 minutes after anesthesia induction	The BIS value corresponding to the lowest systolic blood pressure during 5 minutes after anesthesia induction	5 minutes after anesthesia induction
Bispectral index (BIS) during 5 minutes after endotracheal intubation	The BIS value corresponding to blood pressure measured during 5 minutes after endotracheal intubation	5 minutes after anesthesia induction
Bispectral index (BIS) during 5 minutes before surgical incision	The BIS value corresponding to blood pressure measured during 5 minutes before surgical incision	5 minutes before surgical incision

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Deceleration capacity (DC) during 5 minutes before anesthesia induction	The quasi-periodic decelerations in short-term heart rate are calculated using a phase-rectified signal averaging technique. The calculated deceleration (deceleration capacity: DC) represents parasympathetic nervous activity.	5 minutes before anesthesia induction
Deceleration capacity (DC) during 5 minutes after anesthesia induction	The quasi-periodic decelerations in short-term heart rate are calculated using a phase-rectified signal averaging technique. The calculated deceleration (deceleration capacity: DC) represents parasympathetic nervous activity.	5 minutes after anesthesia induction
Deceleration capacity (DC) during 5 minutes after endotracheal intubation	The quasi-periodic decelerations in short-term heart rate are calculated using a phase-rectified signal averaging technique. The calculated deceleration (deceleration capacity: DC) represents parasympathetic nervous activity.	5 minutes after endotracheal intubation
Deceleration capacity (DC) during 5 minutes before surgical incision	The quasi-periodic decelerations in short-term heart rate are calculated using a phase-rectified signal averaging technique. The calculated deceleration (deceleration capacity: DC) represents parasympathetic nervous activity.	5 minutes before surgical incision
Diastolic blood pressure during 5 minutes before anesthesia induction	Measured at any time during 5 minutes before anesthesia induction	5 minutes before anesthesia induction
Diastolic blood pressure during 5 minutes after anesthesia induction	Diastolic blood pressure corresponding to the lowest systolic blood pressure during 5 minutes after anesthesia induction	5 minutes after anesthesia induction
Diastolic blood pressure during 5 minutes after endotracheal intubation	Measured at any time during 5 minutes after endotracheal intubation	5 minutes after endotracheal intubation
Diastolic blood pressure during 5 minutes before surgical incision	Measured at any time during 5 minutes before surgical incision	5 minutes before surgical incision

Collaborators and Investigators

• Sponsor: Daegu Catholic University Medical Center
• Collaborators: Hana Pharm Co., Ltd.
• Investigators: Principal Investigator: Jonghae Kim, M.D., Daegu Catholic University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2022
• Primary Completion (Actual): September 30, 2023
• Study Completion (Actual): September 30, 2023

Study Registration Dates

• First Submitted: November 23, 2022
• First Submitted That Met QC Criteria: November 23, 2022
• First Posted (Actual): December 2, 2022

Study Record Updates

• Last Update Posted (Actual): October 3, 2023
• Last Update Submitted That Met QC Criteria: October 2, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Hypnotics and Sedatives; Anesthetics; Propofol
• Other Study ID Numbers: CR-22-138

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No