Thiopental is frequently used to facilitate the induction of anaesthesia, after which the anaesthesia is maintained with other agents. However, its use is often associated with adverse haemodynamic effects and a decrease in myocardial contractility. Induction of anaesthesia with thiopental in patients typically causes a decrease in systemic arterial pressure and cardiac output . An alteration in the function of the autonomic nervous system has been suggested as a possible mechanism of thiopental-induced cardiovascular depression [2–5]. The commonly observed tachycardia produced by thiopental is thought to be due to an inhibition of cardiac-vagal activity and/or an arterial baroreceptor reflex [2,6].
Spectral analysis of heart rate variability (HRV) is a widely used non-invasive technique to assess autonomic indexes of neural cardiac control [7–11]. The presence of low frequency (LF) and high frequency (HF) oscillatory rhythms in the variability of the R-R interval (RRI) is well established. It is thought that the LF oscillatory rhythm is mediated by the parasympathetic and sympathetic systems, whereas the HF oscillatory rhythm is mediated primarily by the parasympathetic system.
Therefore, the aim of this study was to test the hypothesis that thiopental anaesthesia affects HRV depending on the depth of hypnosis.
The Institutional Ethics Committee at Sapporo Medical University approved this study, and all patients gave written informed consent. Seventeen patients (ASA Class I), 28–54 yr of age (mean, 42 yr), scheduled for elective oral surgery were enrolled in this study. Patients were excluded if they suffered from severe ischaemic heart disease, congestive heart failure, diabetes mellitus or other disorders known to affect autonomic function. None of the patients was taking medications that affected cardiovascular function.
To assess the depth of hypnosis, we used the Bispectral Index (BIS; Aspect Medical Systems, Inc., Newton, MA, USA), a single composite electroencephalogram (EEG) measure, which is widely accepted to track electroencephalographic changes associated with different anaesthetic states [12,13]. We used the MemCalc method [11,14–17], a combination of the maximum entropy method (MEM) for spectral analysis and the non-linear least squares method (LSM) for fitting analysis, to assess the HRV.
Each patient fasted for at least 11 h prior to testing. On arrival in the operating room, standard monitoring and BIS monitoring were employed. BIS (Version 3.4) was measured continuously on an EEG monitor (Model A1050; Aspect Medical System, Natick, MA, USA) using BisSensor strips (Aspect Medical System). The strips consisted of three pregelled electrodes, two active and one ground. The impedance of each electrode was maintained at less than 2 kΩ. Patients were studied while in the supine position. Heart rate (HR) was monitored from leads II and V5 of the electrocardiogram. An 18-G catheter was inserted into a forearm vein and used for fluid and drug administration. Each subject received 10 mL kg−1 saline before initiation of the study. The inspired oxygen and end-tidal concentrations of carbon dioxide were measured continuously with a calibrated infrared gas analyser. All patients received 100% oxygen via a face mask for 2–3 min prior to induction of general anaesthesia, and control recordings were obtained from patients lying quietly in the supine position and breathing spontaneously. Patients received thiopental infusion at a rate of 100 mg kg−1h−1. Arterial oxygen saturation (SPO2) and end-tidal carbon dioxide (etCO2) were monitored, and normoventilation (etCO2 = 40−45 mmHg) was maintained with gentle intermittent positive pressure ventilation (IPPV) via a mask if required. In our preliminary experiment, the BIS decreased gradually after induction of anaesthesia. However, the minimum value of BIS did not reach 20. Therefore, the haemodynamic and HRV measurements were performed at BIS values of 80, 60, 40 and 30. After the end of protocol, thiopental infusion was stopped, and anaesthesia was maintained with sevoflurane plus nitrous oxide.
The fast peaks of R waves on the electrocardiogram were detected, and the RRI was measured. The RRI data were analysed by the MEM with high resolution (MemCalc, Suwa Trust, Tokyo, Japan), as described previously [11,14–17].
For real-time analysis of HRV, the data on RRI were obtained through on-line computer analysis with 2 ms sampling intervals. The powers of the RRI (ms2) with LF (0.04–0.15 Hz) and HF (0.15–0.5 Hz) bands were calculated. LF/HF in RRI variability was also assessed. In addition, in the programme of MemCalc, an entropy (ENT) was calculated from pulse time series of four RRI. HRV is expressed as randomness of the pulse interval. Thus, ENT is expressed as percentage from 0% (pulse series of regular interval, no variability) to 100% (maximal randomness such as noise).
Both BIS and HRV have time-lag for calculation. A lag time of 20 s is required by the BIS monitor to smooth the EEG signal; the BIS algorithm uses a rolling-averaging window to calculate the BIS value. In the programme of MemCalc, an entropy (ENT) was calculated from pulse time series of four RRI. It usually takes 5–7 s to obtain the new HRV parameters. Therefore, with both parameters, the real-time measurement may be accompanied by an error of a certain degree. We averaged three consecutive values in each HRV parameters corresponding to the BIS value to minimize an error by a time difference.
Data are expressed as mean (SD). Mean blood pressure (MBP) was calculated as diastolic blood pressure (DBP) plus 1/3 × (systolic blood pressure (SBP) − DBP). Changes in LF and HF were expressed as percentage change from baseline (awake) values. LF/HF and ENT were expressed as percentage. We decided that a 10% difference in percentage changes of HRV parameters relative to baseline would be important. Therefore, n = 15 patients would be necessary to detect such a difference if α = 0.05 and β = 0.1. Continuous variables were analysed using analysis of variance (ANOVA). P values <0.05 were considered statistically significant.
Administration of thiopental resulted in a significant increase in HR, but the induction of anaesthesia with thiopental had no significant effect on MBP (Table 1). LF, HF and ENT during awake steady state were 927 ± 1462 (ms2), 272 ± 521 (ms2) and 40 ± 16 (%), respectively. Changes in HRV parameters during induction of anaesthesia with thiopental are shown in Figures 1, 2, 3 and 4. Figure 1 shows the changes in LF during induction of anaesthesia with thiopental. After administration of thiopental, LF decreased in a BIS-dependent manner. Figure 2 shows the changes in HF during induction of anaesthesia with thiopental. HF significantly decreased after thiopental administration in a BIS-dependent manner. Figure 3 shows the changes in ENT during induction of anaesthesia with thiopental. Thiopental anaesthesia caused a significant decrease in ENT in a BIS-dependent manner. Figure 4 shows the changes in LF/HF during induction of anaesthesia with thiopental. Induction of anaesthesia with thiopental showed basically no effect on LF/HF.
The major findings of this study were as follows:
- Induction of anaesthesia with thiopental was associated with significant decreases in LF, HF and ENT in a BIS-dependent manner.
- Induction of anaesthesia with thiopental was associated with a significant increase in HR, whereas either MBP or LF/HF showed no significant change during the study period.
The concept of ENT, as it applies to signals like RRI, is to quantify the repetition of patterns in that signal. Larger values of ENT correspond to greater apparent randomness or irregularity, whereas smaller values correspond to more instances of recognizable patterns in the data. The ENT calculations, here applied to beat-to-beat HR, can be shown to obliquely provide a positively correlated barometer of the extent of complication of an underlying network model in many diverse systems, with larger values implying a more complex feedback or feed forward system . In fact, the ENT of RRI is reported to reflect parasympathetic modulation of HR under varying physiological conditions and in response to pharmacological denervation . This is consistent with our finding that changes in the ENT were directionally similar to changes in HF .
As the autonomic nervous system, especially the sympathetic nervous system, plays a major role in regulation of cardiovascular homoeostasis, knowledge of how anaesthetic agents modify sympathetic activity is important for understanding subsequent cardiovascular responses. Thiopental is known to cause a reduction in blood pressure (BP) in humans, and inhibition of sympathetic nerve activity is believed to be one of the major mechanisms underlying the thiopental-induced hemodynamic depression [2–5]. In a study measuring the peripheral sympathetic nerve activity, thiopental anaesthesia was found to reduce muscle sympathetic nerve activity (MSNA) in humans . These results indicate that thiopental anaesthesia reduces sympathetic nerve activity. However, it is not known whether MSNA reflects sympathetic outflow to the heart. Moreover, the effect of thiopental on parasympathetic nerve activity has not been studied in detail.
Although there is a general agreement that induction of anaesthesia with thiopental is associated with a reduction in HRV, there are some conflicting data regarding the effects of thiopental on cardiac sympathetic or parasympathetic tone. Scheffer and colleagues  observed a significant reduction in LF and HF power after administration of thiopental. They concluded that thiopental anaesthesia reduces both sympathetic and parasympathetic tone to the same degree. In contrast, Latson and colleagues  reported that induction of anaesthesia with thiopental was associated with a greater reduction in total power and that power is shifted toward LF dominance. Moreover, Ebert and colleagues  showed a decrease in tonic MSNA during thiopental anaesthesia in male. The shift toward LF dominance during thiopental anaesthesia is consistent with the known vagolytic effects of thiopental, whereas a decrease in MSNA could be interpreted as a relative vagotonic action.
At least two factors might be responsible for these conflicting results. First, analysis of HRV is a study of the spontaneous, seemingly random fluctuations about some mean value that are always present when HR is measured on a beat-to-beat basis, even in subjects in a ‘quiet state’. Interpretation of information contained in such seemingly chaotic signals is usually done by mathematical analyses in the time domain, in the frequency domain or as a measure of entropy. [7–10]. Thus, differences in methods for analysing HRV may be responsible for these conflicting results. Second, lack of information concerning the depth of anaesthesia may present difficulty in interpreting the results. As HRV is controlled under the central nervous system, the depth of anaesthesia should be considered to estimate the effects of anaesthetics on HRV.
Anaesthesia induced by thiopental is frequently associated with tachycardia; however, the mechanism underlying this is not known. Since the autonomic nervous system plays an important role in regulation of HR, thiopental might induce tachycardia by altering the relative activities of the sympathetic and parasympathetic components. The commonly observed tachycardia produced by thiopental is thought to be due to an inhibition of cardiac-vagal activity . In the present study, thiopental anaesthesia caused a reduction in HF but not in LF/HF, indicating rapid sequence induction of anaesthesia with thiopental might reduce cardiac parasympathetic tone more than sympathetic tone. Similar results were obtained after induction of anaesthesia with thiopental in humans . Scheffer and colleagues  investigated the effects of thiopentone, etomidate and propofol on beat-to-beat HR and BP fluctuations in 35 unpremedicated female patients. They observed changes in HRV after a bolus injection of thiopentone (4 mg kg−1), propofol (2.5 mg kg−1) or etomidate (0.3 mg kg−1). Thiopentone decreased both LF (−46%) and HF (−59%). Propofol decreased HF (−62%) without significant change in LF, suggesting sympathetic dominance, and etomidate had no effect. Their results indicate that propofol, thiopentone and etomidate have different effects on HRV. They speculated that thiopental anaesthesia reduces cardiac parasympathetic tone more than sympathetic tone, resulting in the development of tachycardia. These findings concerning the effects of thiopental on HRV are in reasonably good agreement with our results.
There are several limitations of our study. First, we did not measure sympathetic and parasympathetic nerve activities per se. Although measurement of HRV is a widely used non-invasive technique to assess autonomic indexes of neural cardiac control, the changes in HRV might reflect the effects of anaesthetics not on the autonomic nervous system but on the reflex arc. In fact, baroreflex function and the autonomic nervous system are influenced by various physiologic and pathophysiologic factors , including gender , age , hypothermia  and pre-existing cardiopulmonary diseases [21,23]. However, there is no alternative method for assessing the effects of the autonomic nervous system on the cardiovascular system in vivo. Second, anaesthesia-induced changes in respiratory rate and tidal volume should influence HRV. The HF component of HRV is known to result from respiratory-related vagal modulation of HR, and the amplitude has been demonstrated to correlate with cardiac vagal tone . However, it has also been shown that the amplitude decreases with increase in respiratory frequency and increases with increase in tidal volume [24–26]. The respiratory influence on RRI fluctuations in the 0.01–0.05 Hz range has been associated with tidal volume changes and is considered to be a sign of instability of the ventilatory chemoreceptor feedback mechanisms [10,27]. Since intrathoracic pressure changes are relatively small, the direct mechanical transfer of tidal volume oscillations to the HR fluctuations was not taken into consideration [24,26]. Therefore, we might have underestimated the effects of anaesthetics on HRV if the induction of anaesthesia resulted in decreases in respiratory rate and tidal volume. In the present study, we tried to maintain steady state respiration to minimize the influences on HRV.
Third, the present study was done in a very limited, pre-selected population. In an actual clinical practice, it is almost impossible to find patients without any disorders which affect autonomic function or cardiac problems. HRV is an indicator of autonomic modulation of the cardiovascular system rather than a measure of autonomic per se . Oscillations in HR and BP that give rise to HRV are a consequence of reciprocal interaction of the sympathetic and parasympathetic branches of the autonomic nervous system as it continuously readjusts to meet altered cardiovascular demands. Pathologic conditions (hypertension, diabetes, coronary artery disease, heart failure, etc.) that offset normal sympathovagal balance would therefore be expected to induce changes in HRV. Therefore, it is difficult to interpret the results of the present study directly into the actual clinical situation. Fourth, the infusion of thiopental for induction of anaesthesia is rather unusual technique. However, we had to use an infusion technique to obtain an appropriate drop speed of BIS as it was difficult in a bolus injection of thiopental. This infusion technique may be responsible for less decrease in BP in our present study. Moreover, all patients in our present study had normal cardiovascular function. In the last, different HRV profiles might be expected when administering the drug differently (e.g.: as a bolus, as a continuous infusion at different rates, as a target controlled infusion (TCI) infusion using pharmacokinetic profiles). In fact, we recently reported that continuous infusion of propofol modulates HRV in a time- and dose-dependent manner . As it is uncertain that a thing the same as what was seen with propofol is seen with other anaesthetic, a further clinical study concerning about the anaesthetics administration method and HRV is necessary.
In summary, thiopental decreased LF, HF and ENT in a BIS-dependent manner without causing any significant change in LF/HF, indicating that cardiac parasympathetic nerve is inhibited to a greater degree than is sympathetic nerve during induction of anaesthesia with thiopental. Therefore, it is likely that thiopental-mediated tachycardia is due to cardiac parasympathetic nerve inhibition.
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