Table of Contents  
Year : 2015  |  Volume : 8  |  Issue : 1  |  Page : 31-35

Utilizing heart rate variability: Midazolam prevents the sympathovagal imbalance caused by fentanyl/propofol induction

Department of Anesthesia and Intensive Care, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission30-May-2014
Date of Acceptance23-Aug-2014
Date of Web Publication25-Mar-2015

Correspondence Address:
Sherif S Sultan
24 Muhammad Al-Maqreef St., Nasr City, Cairo 11762
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1687-7934.153935

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Heart rate variability (HRV) can monitor cardiac autonomic control. Sympathovagal imbalance is expected after fentanyl/propofol induction.
The aim of the study was to investigate the effects of intravenous midazolam on HRV and whether it prevents the sympathovagal imbalance caused by fentanyl/propofol induction.
Settings and design
This is a controlled, randomized, double-blinded study.
Patients and methods
The study included 50 patients undergoing knee arthroscopies under general anesthesia. Powers of low-frequency (LF: 0.04-0.15 Hz) and high-frequency (HF: 0.15-0.4 Hz) components of HRV, total power (TP), and LF/HF ratio were recorded using MemCalc software. Patients received midazolam 0.05 mg/kg (midazolam group) or an equivalent volume of normal saline (control group), followed by fentanyl 1 mcg/kg and then propofol 2 mg/kg intravenously.
Statistical analysis
The Mann-Whitney U-test and two-way repeated analysis of variance, followed by Bonferroni correction as a post-hoc test, were used to analyze the data.
Midazolam induced significant decrease in TP and HF powers, with unchanged LF power and LF/HF ratio. Fentanyl induced significant decrease in TP and LF powers with unchanged HF power and LF/HF ratio in both groups. Propofol induced a significant decrease in TP, HF, and LF powers in both groups. Propofol decreased the LF/HF ratio significantly in the control group but not in the midazolam group.
Midazolam premedication induced significant decrease in TP and HF powers without changes in LF power or LF/HF ratio. When fentanyl and propofol were given, midazolam was capable of modulating the net effects of both drugs on the HRV by minimizing the decrease in LF power to keep the LF/HF ratio unchanged. This modulatory effect of midazolam works in favor of maintaining the sympathovagal balance.

Keywords: cardiac autonomic function, heart rate variability, midazolam, premedication, propofol, sympathovagal balance

How to cite this article:
Sultan SS, Hegazy NA. Utilizing heart rate variability: Midazolam prevents the sympathovagal imbalance caused by fentanyl/propofol induction. Ain-Shams J Anaesthesiol 2015;8:31-5

How to cite this URL:
Sultan SS, Hegazy NA. Utilizing heart rate variability: Midazolam prevents the sympathovagal imbalance caused by fentanyl/propofol induction. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2023 Dec 11];8:31-5. Available from:

  Introduction Top

Heart rate variability (HRV) is a noninvasive technique that can monitor the autonomic control of cardiac functions [1] . Apart from the usual regularity of the cardiac rhythm, heart rate (HR) has a timely oscillatory rhythm. This oscillation, or variability, could be analyzed by dividing it into different components such as high-frequency (HF) (linked to parasympathetic control) [2] and low-frequency (LF) (linked to parasympathetic and sympathetic control) [3] waves. The ratio between LF and HF gives an indicator of the sympathetic to parasympathetic balance [4],[5] .

HRV is affected by different physiological, pathological, and pharmacological factors [6] . Anesthetic drugs are known to depress HRV markedly but to different extents according to the drugs and techniques used [7] . Induction of anesthesia is usually accompanied by depression in LF and HF but to different degrees, which may change the LF/HF ratio and therefore the sympathovagal balance.

Anesthesia induction with fentanyl and propofol is common practice. As with most opioids, fentanyl has a sympatholytic effect [8] . Propofol is known to induce a state of parasympathetic dominance [9] . Therefore, the sympathovagal imbalance is expected after fentanyl/propofol induction. Adding midazolam to anesthetic induction induces sedation and amnesia with hemodynamic and autonomic effects. We hypothesized that the vagolytic effects of midazolam [10] may oppose the cardiac autonomic effects of fentanyl/propofol induction. This study aims to investigate the effects of intravenous midazolam premedication on HRV and whether it prevents the sympathovagal imbalance caused by fentanyl/propofol induction.

  Patients and methods Top

This controlled, randomized, double-blinded study was conducted after obtaining approval from the Research Ethics Committee. Written informed consent was obtained from 50 patients scheduled for elective knee arthroscopic procedures under general anesthesia. Patients were of ASA physical status I or II. Exclusion criteria included history of myocardial infarction, diabetes mellitus, cardiac transplantation, and high cervical spinal cord trauma. Exclusion also included patients on medications likely to affect HRV - e.g. β-blockers, antiarrhythmics, and vagolytics.

For HRV analysis, a continuous ECG was conveyed to MemCalc (Suwa Trust, Tokyo, Japan) software downloaded into a personal computer. This software is a real-time analysis system and is capable of detecting peaks of R waves in ECG, detecting the R-R interval, recognizing and removing abnormal R-R interval (artifacts or premature beats), and then calculating and displaying the power spectrum densities within two frequency bands of the HR spectrum: LF power (LF: 0.04-0.15 Hz) and HF power (HF: 0.15-0.4 Hz). Power spectral densities were expressed as absolute values in ms 2 /Hz. Total power (TP: sum of both LF and HF powers) and the LF/HF ratio are displayed as well. In the present study, we preferred to present results of HRV variables as absolute values rather than as relative values. Relative values that represent normalized values as a proportion of TP may not be as reflective as absolute values when these variables are themselves related to each other. For example, if a given drug causes a decrease in LF without affecting the HF absolute values, there will be a false increase in HF proportion.

Patients were randomized to one of two groups: the midazolam group (25 patients), in which patients received midazolam as premedication, and the control group (25 patients), in which patients received normal saline. Randomization was performed by the hospital pharmacy through a computer-generated sequence contained in sealed, opaque envelopes. Through these envelopes the pharmacy sent a prefilled syringe to the operating room that contained either midazolam according to the patient's body weight or normal saline. The nature of contents of the prefilled syringes was not informed to the anesthesiologist injecting it or to the person collecting the data. Patients were shifted to the operating room and connected to an ECG, pulse oxymeter, and a noninvasive blood pressure (BP) monitor. MemCalc software was used. After preoxygenation, midazolam 0.05 mg/kg (or an equivalent volume of normal saline in the control group), followed by fentanyl 1 mcg/kg and then propofol 2 mg/kg, was injected intravenously within 3 min after each drug to allow full effect of drugs on the HRV. After induction of anesthesia with propofol, controlled or assisted ventilation through a face mask was initiated. Only 100% oxygen was used without inhaled anesthetics. Ventilation was adjusted to give a respiratory rate of 12/min and a tidal volume that could maintain an end-tidal CO 2 between 30 and 40 mmHg. Measurements were recorded at four time periods: at baseline (before premedication), after premedication (3 min after midazolam injection), after fentanyl injection (3 min after fentanyl injection) and after propofol induction (3 min after propofol injection). The mean arterial BP and HR were measured at the same time points. After taking the readings, the patients were left to the anesthetic team to continue the usual anesthetic management.

We did not find any study on midazolam that used absolute values for all HRV variables. Therefore, a pilot study was performed by the same research group before starting the present study to estimate the sample size (unpublished). In this pilot study, the effect of midazolam injection was tested on TP, HF, and LF. Midazolam was capable of decreasing TP from 2303 ± 382 to 1981 ± 343 ms 2 /Hz, HF from 753 ± 169 to 611 ± 105 ms 2 /Hz, and LF from 1518 ± 255 to 1308 ± 188 ms 2 /Hz. Therefore, a sample size of 23 in each group was sufficient to achieve a power of 80% with an α error of 0.05. We included 25 patients in each group.

Statistical analysis

Statistical analysis was performed using SPSS statistical package (version 20; SPSS Inc., Chicago, Illinois, USA), for Windows. Data were expressed as mean ± SD, except for age, height, and weight, for which data were presented as median (range). For demographic data, the Mann-Whitney U-test was performed, except for sex, for which the chi-square-test was chosen. Two-way repeated analysis of variance followed by Bonferroni's correction as a post-hoc test was performed for HR, BP, and HRV variables. A P-value less than 0.05 was considered statistically significant.

  Results Top

No statistically significant differences were found between groups concerning demographic data ([Table 1]).
Table 1 Demographic data

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[Table 2] shows HRV variables, HR, and mean arterial BP at the four time periods. Midazolam produced a significant decrease in TP and HF powers while maintaining the LF power and the LF/HF ratio without changes. Midazolam caused a significant increase in HR and decrease in mean arterial BP. Fentanyl produced a significant decrease in TP and LF powers without affecting the HF power and the LF/HF ratio in the two groups. Fentanyl caused significant decrease in HR and mean arterial BP in both groups. Propofol produced a significant decrease in TP, HF, and LF powers in both groups. In the control group, propofol induced significant decrease in LF/HF ratio, which was not the case in the midazolam group, in which there was no significant change in the ratio after induction with propofol compared with the previous period. Propofol caused a significant decrease in mean arterial BP, whereas no significant change in HR was produced.
Table 2: Heart rate variability variables and hemodynamics in the four time periods

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  Discussion Top

Previous studies that investigated the effects of anesthetics on HRV usually presented data in a nonuniform manner with a lot of discrepancies among these studies [11] . This makes interpretation of variables of HRV very controversial. Anesthetics cause a depression in the overall HRV, which is reflected in the decrease in TP. This was proven for many drugs such as propofol [7],[12],[13],[14] , thiopentone [4, 7, 8, 12], etomidate [8],[14] , ketamine [15] , sevoflurane [16] , isoflurane [17] , desflurane [17] , xenon [18] , and midazolam [15],[19] . However, these drugs differ in terms of their effect on HF and LF according to their ability to affect both sides of the autonomic nervous system. In anesthetic practice, it is uncommon to use a single drug, and therefore changes in HRV are usually due to the combined effects of a group of drugs. An example is when a sedative is given, followed by an opioid and an intravenous anesthetic, as investigated in the present study. We investigated a combination of drugs that is very commonly used in everyday anesthetic practice. The dose of midazolam used in the present study was chosen to be a more practical dose than that investigated for the effect of midazolam on HRV by Komatsu et al. [15] (0.3 mg/kg) or by Galletly et al. [10] (0.1 mg/kg).

In the present study, when midazolam was given at a dose 0.05 mg/kg, it induced a significant decrease in TP and HF power, reflecting decreased parasympathetic activity. There was a decrease in LF power that did not reach statistical significance. Midazolam induced a decrease in BP with concomitant increase in HR, indicating that baroreflex activity was compensated and not depressed [9] . This was reflected as maintaining an unchanged LF power after midazolam injection. Therefore, the effect of midazolam on HRV was due to a decrease in parasympathetic activity more than being an increase in sympathetic activity. Midazolam injection did not change the LF/HF ratio, reflecting a balanced autonomic effect on the heart. This vagolytic effect of midazolam was proven previously after a 0.1 mg/kg dose was given to volunteers [10] and after conscious sedation for dental procedures [9] but not after a 0.3 mg/kg dose was given for induction of anesthesia [15] in which sympathetic depression was thought to accompany large doses of midazolam [9],[13] .

Midazolam has significant effects on HRV after induction of anesthesia with fentanyl and propofol. In the present study, both groups received fentanyl, which caused a significant decrease in TP and LF powers while the HF power and the LF/HF ratio were not affected. The decrease in LF power is due to depressed sympathetic action known to be mediated centrally by opioids [8] . Bradycardia and hypotension that accompanied fentanyl injection reflect baroreflex depression. Although sympathetic depression was more than parasympathetic depression, fentanyl maintained the sympathovagal balance, which was reflected by an unchanged LF/HF ratio. The effects of fentanyl on HRV in the present study are consistent with those shown by Riznyk et al. [7] .

Following fentanyl injection, anesthesia was induced with propofol. The control group showed a significant decrease in TP, LF, and HF powers and LF/HF ratio. From the significant decrease in LF/HF ratio it is clear that propofol decreased the sympathetic tone more than it did the parasympathetic tone, allowing parasympathetic dominance. Propofol caused hypotension without affecting the HR, which proves the attenuated baroreflex reaction [20] . The effects of propofol on HRV in the present study were consistent with those of Win et al. [9] . This was not the case in the midazolam group, which showed a significant decrease in TP, LF, and HF powers while keeping the LF/HF ratio unchanged. The decrease in LF power in both groups was statistically significant compared with the previous period; however, the decrease in LF power in the midazolam group was only 17%, compared with 53% in the control group. The greater sympathetic depression in the control group was the reason behind the low LF/HF ratio. The maintained LF/HF ratio in the midazolam group was reflected clinically in the net effect on HR after midazolam, fentanyl, and propofol, wherein a significantly higher HR was seen when compared with fentanyl and propofol injection in the control group. This is similar to the study by Win et al. [13] , in which midazolam-propofol coinduction produced a significantly higher HR compared with induction with propofol alone.

Collectively, midazolam was able to maintain the autonomic nervous system balance whether when given alone or when given before fentanyl and propofol induction. The sympathovagal imbalance is said to predispose to malignant arrhythmias and sudden cardiac death both in healthy and in high-risk patients [21],[22] . Win et al. [13] proved that compensated hemodynamic changes are related to the increase in LF/HF ratio. The modulatory effects of midazolam also produced compensated effects on HR and stroke index [13] . The extent of these changes in HRV in elderly and critically ill patients is not yet known and needs further investigation.

It is important to note that the depth and frequency of ventilation are linked to the HF component of the HRV and any change in ventilation will affect the reading of HRV [16] . For this reason we maintained constant ventilatory conditions after propofol injection until HRV variables were recorded, which was followed by delivering the patient to the anesthesia team to manage the airway and ventilation. This minimized the effects of ventilation on HRV in our study.

In conclusion, when midazolam is given intravenously as premedication at a dose of 0.05 mg/kg before induction of general anesthesia with fentanyl and propofol, it induces significant changes in HRV in the form of a significant decrease in TP and HF powers without changes in LF power or LF/HF ratio. When fentanyl and propofol followed midazolam, the latter was capable of modulating the net effects of both drugs on HRV by minimizing the decrease in LF power to keep the LF/HF ratio unchanged. This modulatory effect of midazolam works in favor of maintaining the sympathovagal balance, which seems to be crucial for the perioperative outcome. Further studies are needed to determine these effects in elderly and critically ill patients.

  Acknowledgements Top

Conflicts of interest

There are no conflicts of interest.

  References Top

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