Gender differences in baroreflex response and heart rate variability in anaesthetized humans

M. Tanaka*, T. Kimura, T. Goyagi and T. Nishikawa

Department of Anaesthesia, Akita University School of Medicine, Akita-city 010-8543, Japan

*Corresponding author. E-mail: mtanaka{at}med.akita-u.ac.jp

Accepted for publication: January 29, 2004


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. In conscious humans, men have a greater cardiovagal baroreflex gain than women. We studied gender-related differences in baroreflex function during general anaesthesia.

Methods. Sixty healthy patients (30 male and 30 female) were anaesthetized with sevoflurane 2% end-tidal in air and oxygen, and their lungs were mechanically ventilated. We recorded the ECG and invasive arterial pressure. Baroreflex gain was measured as the linear relationship of R-R interval with systolic arterial pressure changes caused by doses of phenylephrine i.v., and also the spontaneous changes in R-R interval and arterial pressure. In addition, consecutive R-R intervals were analysed using a fast Fourier transformation.

Results. Baroreflex gains (mean (SD)) assessed by the pharmacological method in men (7.98 (5.12) ms mm Hg–1) was significantly greater than that in women (4.89 (3.87) ms mm Hg–1). Similarly, spontaneous baroreflex gains were significantly greater in men than in women, and correlated well with high-frequency power, but not with low-frequency power or low/high ratio, of heart rate variability in both genders.

Conclusions. Our results extend findings in conscious humans to sevoflurane anaesthesia. Men have greater cardiovagal reflex gains than women, which may reflect differences in parasympathetic action on heart rate.

Br J Anaesth 2004; 92: 831–5

Keywords: anaesthesia, general; anaesthetics volatile, sevoflurane; autonomic nervous system; heart rate, baroreflex; parasympathetic nervous system


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Using the phenylephrine pressor test, Abdel-Rahman and co-workers found that healthy young females have a smaller heart rate (HR) reflex gain than men of similar age,1 and this difference was confirmed using a modified pharmacological method.2 We speculated whether gender differences in cardiovagal reflex gain were present during general anaesthesia.

Consequently, we studied heart rate changes associated with both pharmacological and spontaneous changes in men and women during general anaesthesia.3 4 In addition, we used spectral analysis of HR to interpret beat-to-beat modulation of R-R intervals (RRI).5 6


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Subjects
We studied 60 consecutive patients (30 male and 30 female), aged 20–40 yr, ASA I, about to undergo general anaesthesia for elective surgery. They were all non-smokers, normotensive, with no cardiovascular or autonomic disease, and had not taken caffeine-containing beverages or alcohol for at least 24 h before the study. All procedures used in the study were approved by the human research committee of Akita University School of Medicine, and written informed consent was obtained from each subject.

General anaesthesia
All patients arrived in the operating room after an 8–10-h fast, without pre-medication. They lay supine, and a 20-Gauge i.v. catheter was placed using local anaesthesia. Lactated Ringer’s solution was given at 2 ml kg–1 h–1 throughout the study. Arterial pressure (AP) was measured from a radial arterial cannula and RRI measured from an ECG lead of highest signal to noise ratio (Hewlett Packard, Viridia CMS 2000TM, Boeblingen, Germany). Tympanic temperature was measured in each subject. No active warming was used and the ambient temperature was set to 25–30°C. General anaesthesia was induced using sevoflurane 5% in oxygen (6 litre min–1). After vecuronium 0.1 mg kg–1 i.v., the trachea was intubated and the lungs mechanically ventilated (tidal volume 7–9 ml kg–1 at a ventilatory frequency of 12 breath min–1). Anaesthesia was maintained with sevoflurane 2% end-tidal in air and oxygen (fraction of inspired oxygen=34%), and end-tidal carbon dioxide tension was maintained constant at 4.7 kPa by adjusting the tidal volume with the ventilatory frequency kept constant. End-tidal sevoflurane and carbon dioxide concentration were measured by a gas analyser (Capnomac Ultima SV; Datex, Helsinki, Finland), which was calibrated before each use. To ensure anaesthetic equilibration, end-tidal sevoflurane concentration was maintained constant for at least 20 min by frequently adjusting the inspired sevoflurane concentration. Before baroreflex gains and HR variability (HRV) were measured, we waited for cardiovascular stability. This was assumed when three consecutive measurements of systolic AP (SAP) and HR, measured at 1-min intervals, were within 5% of the previous value.

Assessment of cardiovagal reflex gains and HRV
To assess baroreflex gain pharmacologically, phenylephrine (80–200 µg) was given to increase SAP by 30 mm Hg. The dose of phenylephrine was chosen based on previous studies. The initial phase of an increase in SBP was analysed.7 To determine SBR gains and HRV, we recorded RRI and SAP for approximately 10 min before surgery started. These recordings always preceded pharmacological baroreflex determinations.

Data analysis
Arterial pressure and ECG signals were digitised at a sampling rate of 200 Hz, using a 16-bit analog-digital converter (AD7120; ATM Communications, Tokyo, Japan). Subsequent analysis was off-line. We developed a program to process the digitized data, which detected R-waves in the ECG signal to determine RRI. The signal was monitored visually to allow removal of non-sinus beats or artifacts. Arterial pressure values and RRI were measured beat-by-beat to give systolic, diastolic, and mean arterial pressure, and the RRI value for each cardiac cycle. These values were used to calculate SBR gains and for power spectral analysis of HR. HR baroreflex gain was determined by least-square regression analysis of the linear portion of the sigmoid relation between SAP and RRI, when each RRI was plotted as a function of the preceding SAP (one-offset).9 SBR gain was measured from spontaneous sequences of three or more beats when RRI and SAP changed in the same direction, using linear regression analysis.3 8 Up-sequence and down-sequence were defined as increasing and decreasing sequences, respectively. Only sequences where successive pressure pulses differed by at least 1 mm Hg were selected. If the regression coefficients for pharmacological and SBR relationships were greater than 0.8, the data were accepted for subsequent analysis.

The method of spectral analysis of RRI variability has been described previously.9 For each study period, a series of 512 consecutive RRI values free of artifacts were selected. A fast Fourier transformation was applied to calculate variations of RRI as a function of power (power spectral density (units of ms2 Hz–1): RRI power (ms2) as a function of frequency (Hz)). The RRI power was the integrated area under the power spectral density plots, taken as an index of the frequency-specific degree of RRI variability. Spectral power was determined over the low-frequency (LF, 0.04–0.15 Hz) and high-frequency (HF, 0.15–0.4 Hz) ranges, and the LF/HF ratio was calculated.10

All the statistical analyses including the calculation of baroreflex gains were done by an investigator who did not know the treatment of subjects. From a previous similar study, we calculated that 25 subjects would provide a power greater than 0.8 (P=0.05) to detect a 25% difference in baroreflex gains between men and women.11 Haemo dynamic data were analysed by unpaired Student’s t-test to compare normally distributed variables between genders. Log transformation was used for non-normally distributed data, such as baroreflex gains, HF and LF power, before using the t-test. Correlations between baroreflex gains by the two methods and the LF, HF and LF/HF ratio of HRV were analysed by Pearson’s correlation coefficient. All data are presented as mean (SD), and P<0.05 was considered statistically significant.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The male patients were heavier and taller than the females, but we found no significant difference in body mass index and age between the genders (Table 1). During stable sevoflurane anaesthesia, BP, HR, and tympanic temperature were comparable between groups.


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Table 1 Patient details. Values are mean (range) for age or mean (SD). BMI=body mass index; SAP=systolic arterial pressure; DAP=diastolic arterial pressure; HR=heart rate; HF=high frequency; LF=low frequency. *P<0.05, male vs female subjects
 
For the pharmacological method, male and female subjects received similar doses of phenylephrine (both 2.0 (0.1) µg kg–1) and developed similar increases of SAP (29 (12) and 30 (12) mm Hg, respectively). The gain of the HR change in male subjects was significantly greater than that of females (P=0.004, Table 1) with similar correlation coefficients for men and women (0.92 (0.06) and 0.91 (0.08), respectively).

No up-sequence was found in four men and one woman mostly because the changes in AP were small, and thus no up-sequence baroreflex gain was calculated. Similarly, no down-sequence was found in five men and two women. Both up- and down-sequence SBR gains of men were significantly greater than those of women (Table 1). HF and LF power of the spectral analysis of HRV in the men were significantly greater than those in the women (Table 1).

There were significant correlations between the phenylephrine pressor test gain and log (HF power) in both men and women (P<0.001, R=0.92; and P<0.001, R=0.82, respectively; Fig. 1). There were also significant correlations in up- and down-sequence baroreflex gains and log (HF power) of HRV in male (P<0.001, R=0.81; and P<0.001, R=0.72, respectively; Fig. 1) and in female patients (P<0.001, R=0.85; and P<0.001, R=0.73, respectively; Fig. 1). However, no significant correlation was noted between log (LF power) or LF/HF ratio and the phenylephrine pressor test gain (0.27<P<0.97, –0.1<R<0.21), up-sequence baroreflex gain (0.34<P<0.83, –0.09<R<0.13), and down-sequence baroreflex gain (0.14<P<0.97, –0.34<R<0.04).



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Fig 1 Individual phenylephrine pressor test gains (A), up-sequence spontaneous baroreflex gains (B), and down-sequence spontaneous baroreflex gains (C) plotted against log (high-frequency power) of the spectral analysis of HRV in healthy patients during 2.0% end-tidal sevoflurane anaesthesia. Significant correlations by Pearson’s correlation coefficients were demonstrated between phenylephrine pressor test gain vs log (high-frequency power) in male and female patients (P<0.001, R=0.92; and P<0.001, R=0.82, respectively), between up-sequence baroreflex gain vs log (high-frequency power) (P<0.001, R=0.81; and P<0.001, R=0.85, respectively), and between down-sequence baroreflex gain vs log (high-frequency power) (P<0.001, R=0.72; and P<0.001, R=0.73, respectively).

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We found that changes in HR caused by the pressor test are greater in healthy males than females during general anaesthesia. We also found that both up- and down-sequence SBR gains were greater in men. These results during 1 MAC sevoflurane anaesthesia support a previous study in awake humans, in which a significantly greater baroreflex gain was found in men than women after bolus injection of phenylephrine.1 This study also found no difference in baroreflex gain after continuous infusion of phenylephrine,1 suggesting that the difference results from different vagal responses to hypertensive stimuli. Similarly, Beske and colleagues2 found a greater cardiovagal reflex gain in men than in women in the early follicular phase, but the threshold, saturation, operating range, and operating point were similar. In rats, block of muscarinic receptors abolishes the gender difference in baroreceptor-mediated bradycardia in response to bolus phenylephrine, while ß-adrenoceptor block attenuates the baroreflex-mediated bradycardia similarly in both genders, so that the gender difference in the baroreflex gain is preserved.12 We found that gender-related differences in baroreflex gain were associated with differences in HF power, which predominantly reflects vagal effects. If the results of animal experiments can be extrapolated to humans, our findings suggest that differences in vagal baroreflex gain between the genders result from differences in HR control by the parasympathetic nervous system during general anaesthesia. It is not clear if this comes from different responses of the heart, the central nervous system, or the baroreceptors.

Volatile anaesthetics depress HR baroreflexes in a concentration-dependent fashion, at several sites along the baroreceptor pathway, including the baroreceptors, afferent and efferent nerve pathways, central nervous system, peripheral ganglia, and the sino-atrial node of the heart.13 Isoflurane also decreases HF power in a concentration-dependent fashion.14 Our subjects were mechanically ventilated, which reduces cardiac vagal tone and HRV by activating lung stretch receptors.15 The considerably smaller baroreflex gains and HF power of HRV seen in our study compared with conscious humans probably reflect the combined effects of sevoflurane and intermittent positive pressure ventilation.

The HF power of HRV is affected predominantly by the ventilatory frequency and parasympathetic nervous activity, while LF power is influenced by parasympathetic, sympathetic and hormonal inputs to the heart.5 6 In conscious humans, total and LF power are greater in men than in women,16 17 while HF power differences are variable.1618 As the ventilatory frequency was fixed at 12 breath min–1 in our study, it is unlikely that respiratory effects caused significant confounding on the differences we noted.19 Significant correlation between pharmacologically induced and spontaneous reflex gains and the HF component of HRV, but not vs LF/HF ratio, suggest that these reflexes remain controlled by the parasympathetic nervous system during general anaesthesia.

Our results should be interpreted with caution. First, we did not observe up- or down-sequence SBR relationships in all patients, and some were excluded from data analysis, because spontaneous changes of SBP were too small. In awake humans, a step size of 1 mm Hg has been used to calculate SBR gain.4 20 During deep general anaesthesia, perhaps this threshold could be reduced to avoid unnecessary loss of data. However, re-analysis using a step size of 0.5 mm Hg did not change our conclusions. Secondly, we did not study HR responses to hypotension. In awake humans with or without autonomic block; however, there is a close correlation between the phenylephrine pressor test gain and the nitroprusside depressor test gain, and between the down-sequence SBR gain and the nitroprusside pressor test gain (0.98>R>0.75).8 However, no gender difference in the depressor test gain has been found in rats irrespective of the autonomic state.12 It is not known if differences between the genders would be found in HR responses to hypotension in anaesthetized humans. Last, even though HF power of HRV and baroreflex gains correlated well in both genders, this does not indicate a cause-effect relationship. Parasympathetic tone is influenced by baroreflex input, and tonic and phasic activities of the parasympathetic nervous system are frequently coupled under physiological conditions. However, these activities may be dissociated under certain experimental conditions including phenylephrine infusion and hypercapnia,21 22 indicating that parasympathetically mediated dynamic control of HR and HF power of HRV can be independently regulated.

In conclusion, we found that men have greater cardiovagal baroreflex gain than women during sevoflurane anaesthesia, when assessed by the phenylephrine pressor test and the SBR technique, which resembles the findings in conscious humans.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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