JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Constant, I.
Right arrow Articles by Murat, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Constant, I.
Right arrow Articles by Murat, I.
Related Collections
Right arrow Cardiovascular
Right arrow Pediatrics
Right arrow Pharmacology

Anesth Analg 2004;99:360-369
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000123493.62447.08

PEDIATRIC ANESTHESIA

William J. Greeley Section Editor

Does Halothane Really Preserve Cardiac Baroreflex Better Than Sevoflurane? A Noninvasive Study of Spontaneous Baroreflex in Children Anesthetized with Sevoflurane Versus Halothane

Isabelle Constant, MD PhD*, Dominique Laude, BSc{dagger}, Elizabeth Hentzgen, MD*, and Isabelle Murat, MD PhD*

*Service d’Anesthésie Réanimation Pédiatrique, Hôpital Armand Trousseau, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; and {dagger}Institut National de la Santé et de la Recherche Médicale E0107, Paris, France

Address correspondence and reprint requests to Isabelle Constant, MD, PhD, Service d’Anesthésie, Hôpital d’enfants Armand Trousseau, AP-HP, 26 ave. du Dr. Arnold Netter, 75571 Paris, Cedex 12, France. Address e-mail to isabelle.constant{at}trs.ap-hop-paris.fr


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Heart rate profiles during the induction of anesthesia differ markedly between the administration of sevoflurane and halothane. Previous investigations have shown that halothane preserves cardiac parasympathetic activity more than sevoflurane. Because vagal drive to the sinus node is the main effector of arterial baroreflex control of heart rate, halothane may preserve cardiac baroreflex better than sevoflurane. To investigate cardiac baroreflex in anesthetized children, we used two noninvasive methods providing different approaches to the arterial blood pressure (BP) and R-R interval (RRI) relationship: the sequence methods investigating beat-to-beat changes in BP and RRI (time domain) and the cross-spectral analysis investigating relationships between oscillations of BP and RRI (frequency domain). Children were randomly assigned to mask induction with sevoflurane in 100% oxygen, sevoflurane in 50% nitrous oxide/50% oxygen, or halothane in 50% nitrous oxide/50% oxygen. After tracheal intubation, the inspired fraction of volatile anesthetic was reduced to 1 minimum alveolar anesthetic concentration (MAC). The spontaneous baroreflex (SBR) sensitivity was calculated with the sequence method at baseline, during induction, and after intubation. The cardiac baroreflex was also estimated with cross-spectral analysis at baseline and at 1 MAC (stationary conditions). In the three groups, the induction of anesthesia was associated with a marked decrease of SBR sensitivity, which occurred earlier with sevoflurane than with halothane. Five minutes after intubation (1 MAC), the sequence method showed a similar decrease of the SBR sensitivity in the three groups. Similarly, the cross-spectral analysis between systolic blood pressure and RRI showed a decrease of the gain calculated in the low-frequency band, but the gain in the respiratory band was higher with halothane compared with sevoflurane. In children, the induction of anesthesia with halothane and sevoflurane is associated with a marked decrease of cardiac baroreflex activity. The persistence of respiratory RRI fluctuations under halothane might reflect reflex respiratory arrhythmia rather than efficient parasympathetic baroreflex activity.

IMPLICATIONS: Using noninvasive methods of cardiac baroreflex investigation, we have demonstrated that despite the relative preservation of vagal activity during halothane anesthesia, halothane and sevoflurane have a similar depressor effect on cardiac baroreflex activity during the induction of anesthesia in children.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Sevoflurane, a recently introduced volatile anesthetic, has been demonstrated to have a safer respiratory and cardiovascular profile than halothane (1,2). Using spectral analysis of heart rate (HR) and systolic blood pressure (SBP) variability in children, we have demonstrated that sevoflurane anesthesia is associated with a lack of respiratory HR fluctuations that reflects a marked cardiac parasympathetic inhibition, whereas halothane anesthesia seems to preserve, at least in part, the vagal control on sinus node (3). These findings have confirmed the relative preservation of respiratory-related parasympathetic modulation of HR previously demonstrated in children anesthetized with halothane (4).

Physiological studies have established that baroreflex control of HR is primarily mediated by the cardiac parasympathetic response (5,6) and that spontaneous baroreflex (SBR) sensitivity is a direct function of background vagal activity (7,8). Respiratory HR fluctuations have been demonstrated to be an index of cardiac vagal outflow (9). Following these hypothesis, halothane might preserve arterial baroreflex control of HR better than sevoflurane. The latter has been demonstrated to depress the baroreflex-sympathetic reflex system in rabbits (10) and baroreflex control of HR in humans (11,12). However, halothane markedly impairs baroreflex responses to pharmacologically-induced arterial blood pressure (BP) changes in animals (13) and humans (14,15). Thus, the dose-dependent depressor effect of halothane on arterial baroreflex control of HR seems to be somewhat in contrast with the physiological assumption that vagal control of HR reflects baroreflex control on sinus node. This apparent paradox has not been explained.

To better understand this, we compared the effects on SBR of sevoflurane, an anesthetic that strongly depresses parasympathetic cardiac activity (3), with those of halothane, an anesthetic that seems to preserve parasympathetic cardiac activity (4). To investigate arterial baroreflex control of HR in children, we analyzed the hemodynamic data from a previous randomized study based on continuous noninvasive recordings of electrocardiogram (ECG) and finger BP during the induction of anesthesia with sevoflurane or halothane in children (3). We compared the effects of sevoflurane and halothane on SBR sensitivity (SBRs) assessed during induction either by the sequence methods or by the spectral analysis of SBP and R-R interval (RRI).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
To compare the effects of halothane and sevoflurane on SBR activity, we analyzed the hemodynamic data of children included in a published study (3). This randomized study included ASA physical status I children aged 2 to 12 yr scheduled for elective tonsillectomy who were assigned to 1 of 4 induction techniques: rapid induction with 7% sevoflurane in 100% oxygen (Group SrapidO2; n = 11), incremental induction with 2%, 4%, 6%, and 7% sevoflurane every five breaths in 100% oxygen (Group SO2; n = 11), incremental induction with sevoflurane in a mixture of oxygen and nitrous oxide (N2O) (50:50) (Group SN2O; n = 10), and incremental induction with 1%, 2%, 3%, and 3.5% halothane every five breaths in a mixture of oxygen and N2O (50:50) (Group HN2O; n = 13). Although the four groups were analyzed, the results of baroreflex investigation in Groups SrapidO2 and SO2 were strictly similar; therefore, to avoid redundant data, only the last three groups are presented. All children were premedicated 15 min before induction with 0.5 mg/kg midazolam given rectally. Children received no drug other than volatile anesthetic until completion of the study, i.e., 5 min after placement of the tracheal tube. Mask induction was performed by using an open circuit at high fresh gas flow (8 L/min). Expired gases and oxygen saturation were continuously recorded (Capnomac Ultima; Datex Instrument Corp., Helsinki, Finland). Ventilation was manually assisted before tracheal intubation at approximately 20 breaths/min. The time corresponding to manual ventilation was noted. Tracheal intubation was performed with a preformed oral cuffed tube after placement of the IV line and just after visualization of pupils in central position (16). After placement of the tracheal tube, the lungs were mechanically ventilated with a tidal volume of 10 mL/kg at 20 breaths/min (Servo 900D; Siemens), the inspired concentration of volatile anesthetic was reduced to obtain approximately 1 minimum alveolar anesthetic concentration (MAC) according to the age, and this expired concentration was maintained for 5 min. Surgery started after completion of the study. The study protocol was approved by our local ethics committee, and informed consent was obtained from parents and children.

Before the induction of anesthesia, a Finapres (Model 2300; Ohmeda, Trappes, France) was placed on the middle phalanx of the third finger of the right hand, which was passively maintained at heart level during the study. This noninvasive device is widely used in adults and children in laboratory settings for physiological studies. In children, its reliability for noninvasively assessing the main components of short-term SBP and diastolic BP variability has been demonstrated in intensive care (17) and during the perianesthetic period (18). To ensure optimal Finapres BP measurement, we used appropriate cuff sizes (S or M) according to the manufacturer’s instructions.

ECG measurements were taken with disposable electrodes attached to the thorax, placed to provide clear R waves, and connected to a Datex Cardiocap II monitor. RRI and BP were continuously recorded from baseline to 5 min after tracheal intubation.

The details of data sampling and analysis have been described (3). The analog output of the Datex monitor and of the Finapres device was connected to an analog-to-digital converter to permit data acquisition, storage, and analysis with a microcomputer. BP and ECG signals were digitized (300 Hz) and processed by an algorithm based on feature extraction to detect and measure the characteristics of a BP cycle and an R wave (Acqknowledge Version 3.25; Biopac Systems, Inc., Santa Barbara, CA). SBP was extracted from the BP signal, and RRI was calculated as time in milliseconds, measured from the corresponding R wave and the preceding one. According to the sample rate (300 Hz), the precision of the signal detection was 0.003 s, which represents the limits of resolution of the method.

The sequence method was used to calculate sensitivity of the cardiac baroreflex during spontaneous fluctuations of BP and RRI (19,20). The computer software examined each 100-s data recording to select all sequences of 3 or more successive heartbeats in which there were concordant increases or decreases in SBP and RRI. The minimum change that was accepted for a spontaneous increase or decrease in SBP was 0.5 mm Hg. The minimum concomitant lengthening or shortening of RRI was 5 ms per beat. In a range of 0 to 1, we selected the lag with the most slopes for each subject and regression lines for which r > 0.85. In the case of sequence overlap, the sequence with the most beats was selected. A linear regression was applied to each of the sequences, and an average regression slope was calculated for the sequences detected during each recording period. The slope of this regression (ms/mm Hg) represents the mean cardiac SBRs for that time period and has been shown to reflect values obtained at the resting BP by using the vasoactive drug method (21). In this study, data were analyzed at the 7 following specified times: at baseline before starting induction (T0); at 1 min (T1), 3 min (T2), and 5 min (T3) after the start of induction; and 1 min (T4), 3 min (T5), and 5 min (T6) after tracheal intubation. At each point, the SBR activity was assessed by the number of beats involved in baroreflex sequences, the percentage of beats involved in baroreflex sequences of the total number of beats in the sample time (SBR%), and by the SBRs, as previously described.

The baroreflex activity was also determined by the closed-loop spectral analysis method described by Pagani et al. (22). To perform spectral analysis, a resampling rate of 10 Hz was chosen without interpolation, i.e., SBP and RRI values were replicated every 0.1 s until a new BP cycle or R wave occurred within a 0.1-s window. The evenly spaced sampling allowed direct spectral analysis by using a fast Fourier-transformed algorithm on a 512-point stationary time series. The low-frequency (LF) component was obtained by integration of the values of consecutive bands from 0.048 to 0.148 Hz of the SBP or HR spectrum to include the 10-s rhythm (0.1 Hz). The high-frequency (HF) oscillation was obtained by integration of consecutive bands from 0.205 to 0.605 Hz to include those corresponding to the spontaneous breathing rate of all children.

Transfer function analysis was used to assess the relationship between spontaneous SBP and RRI fluctuations in the frequency domain. The calculation of the transfer function from SBP to RRI was based on the cross-spectral technique (22,23). The gain and phase were calculated for the LF and the HF band, when the coherence was >0.5 in these frequency bands. Briefly, the squared coherence function quantifies the amount of linear coupling between 2 time series at any given frequency and is analogous to the square correlation coefficient in the time domain. The gain function defines the ratio between changes in RRI and changes in SBP (ms/mm Hg) at any given frequency. We calculated the baroreflex gain in the LF and HF bands (22–24). The phase function specifies the phase difference (lead or lag) between the two signals in the frequency domain. The cross-spectral analysis was performed only in stationary conditions at baseline (T0) and under a stable expired concentration of volatile anesthetic at approximately 1 MAC (T6).

Data were analyzed after logarithmic transformation. Differences among groups were tested by two-way analysis of variance with one repeated factor (time point) and one nonrepeated factor (group) followed by Scheffé post hoc tests when significance was achieved (StatView Version 5.0; Abacus Concepts, Inc., Berkeley, CA). Differences were considered to be statistically significant when P was <0.05. Data are expressed as mean ± SD.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The demographic and clinical data are presented in Table 1. The mean values of SBP and RRI measured at the 7 studied sample times are presented in Table 2. SBP profiles were similar in the three groups; however, at time of loss of eyelash reflex (T1), SBP tended to be increased in the sevoflurane groups compared to the halothane group. At all studied points under anesthesia, the mean RRI was higher in children anesthetized with halothane compared with sevoflurane. At baseline and T1, all subjects were breathing spontaneously. At T2, 5 subjects out of 13 in Group HN2O, 5 of 10 in Group SN2O, and 5 of 11 in Group SO2 required manually assisted ventilation. At T3, all subjects were manually ventilated. At T4, T5, and T6, all subjects were mechanically ventilated. Respiratory rate and end-tidal CO2 (ETCO2) are summarized in Table 3. Oxygen saturation was maintained at more than 96% throughout the study in all children. No hypercarbia (defined as ETCO2 >48 mm Hg) or hypocapnia (defined as ETCO2 <28 mm Hg) was observed in any group.


View this table:
[in this window]
[in a new window]
  		Table 1. Demographic and Clinical Data (mean ± SD)
 

View this table:
[in this window]
[in a new window]
  		Table 2. Mean of Systolic Blood Pressure (SBP) and R-R Interval (RRI), Total Number of Beats Involved in Baroreflex Sequences, and Slope of Spontaneous Baroreflex Assessed by the Sequence Method (Mean ± SD)
 

View this table:
[in this window]
[in a new window]
  		Table 3. End-Tidal CO2 and Respiratory Rate (mean ± SD)
 
SBR mean slopes and SBR% calculated at the seven studied time samples are shown in Figure 1. At baseline, children showed an average SBR% of 33%, with a mean SBR slope of 16 ms/mm Hg. These values are close to those usually described in young healthy adults (22). The induction of anesthesia was associated with a large decrease of the SBR% (P < 0.001) and with a marked decrease of the SBR slope assessed by the sequence method (P < 0.001) (Fig. 1, Table 2). This depressor effect appeared earlier with sevoflurane than with halothane. Indeed, at T1, the SBR activity was still preserved with halothane compared with sevoflurane—SBR%: 20% ± 11% in HN2O versus 2.8% ± 4.2% in SN2O and 3.2% ± 3.5% in SO2, P < 0.001; SBR slope: 7.9 ± 6.9 ms/mm Hg in HN2O versus 2.1 ± 2.7 ms/mm Hg in SN2O and 2.0 ± 1.9 ms/mm Hg in SO2, P < 0.01. From the third minute after starting induction (T2), the depression of SBR activity was similar in the 3 groups, as estimated either by SBR% or by the mean slope of the regression between the SBP and RRI sequences. The sequence method allows separation of the up and down sequences of RRI and SBP, but in this study, no difference was observed between these two types of variations. Data of the SBR assessment with the cross-spectral analysis of SBP and RRI at baseline and at T6 are summarized in Figure 2.



View larger version (103K):
[in this window]
[in a new window]
  		Figure 1. Percentage of beats involved in baroreflex sequences out of the total number of beats in the sample time (A) and spontaneous baroreflex sensitivity (slope) (B) estimated by the sequence method during the induction of anesthesia with halothane (H) (continuous line) or sevoflurane (S) (dotted lines). T0 = baseline; T1 = 1 min after the start of induction; T2 = 3 min after the start of induction, T3 = 5 min after the start of induction; T4 = 1 min after intubation; T5 = 3 min after intubation; T6 = 5 min after intubation. *P < 0.05, ***P < 0.01, SO2 and SN2O versus HN2O.

 


View larger version (85K):
[in this window]
[in a new window]
  		Figure 2. Coherence, gain, and phase of the transfer function between systolic blood pressure and R-R interval calculated at baseline (open bars) and 5 min after intubation when the expired fraction of volatile anesthetic was stabilized at 1 minimum alveolar anesthetic concentration (T6) (closed bars). $P < 0.05, $$P < 0.01, $$$P < 0.001, T6 versus baseline; **P < 0.01, ***P < 0.001, sevoflurane (S)O2 and SN2O versus halothane (H)N2O. HF = high frequency; LF = low frequency.

 
At baseline, the mean gains in the LF and HF bands were less than the mean SBR slope calculated with the sequence method. However, these two different estimations of SBRs were highly correlated in the LF and HF bands (r = 0.80, P < 0.001; and r = 0.93, P < 0.001, respectively). At T6, sevoflurane anesthesia was associated with a decrease of the gain calculated in the LF and HF bands (P < 0.01). Halothane anesthesia was also associated with a decrease of the LF gain (P < 0.05); however, the gain of the cross-spectral analysis between SBP and RRI calculated in the HF band was similar to that observed at baseline, and the phase between the SBP and RRI signals was modified compared with baseline. These results are illustrated by an example of recordings under sevoflurane and halothane presented in Figure 3.



View larger version (29K):
[in this window]
[in a new window]
  		Figure 3. Examples of traces of arterial blood pressure (BP), electrocardiograph (ECG), respiration (Resp), systolic blood pressure (SBP), and R-R interval (RRI) recorded in stationary conditions at baseline (active ventilation) and when the end-tidal concentration of sevoflurane and halothane was stabilized at 1 minimum alveolar anesthetic concentration (passive ventilation). The inspiratory phases are underlined to show the relationship among respiration, respiratory SBP fluctuations, and respiratory RRI fluctuations. As expected under active ventilation, the decrease of SBP and RRI occurred during the inspiratory period; fluctuations of RRI and SBP were parallel, with a slight time lag. Under anesthesia and standardized passive ventilation, the inspiratory period was associated with a decrease of SBP. Respiratory fluctuations of heart rate were negligible under sevoflurane, whereas they were inverted compared with respiratory SBP oscillations under halothane. The interesting point is that the relationship between respiration and respiratory RRI fluctuations was visually similar to that at baseline (decrease of RRI during inspiration).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Using noninvasive assessment of SBR activity, we have demonstrated that arterial baroreflex control of HR is early and markedly altered during anesthetic induction with sevoflurane in children. Similarly, halothane induces a depression of SBRs when estimated with the sequence method, although cardiac parasympathetic activity was relatively preserved. However, there was a discrepancy between the latter method of SBR assessment and the cross-spectral analysis performed under stable anesthesia with halothane. Our findings suggest that halothane may exert a dissociated effect on the cardiac parasympathetic drive with a relative preservation of the cardiopulmonary reflex associated with an inhibition of the baroreflex control of HR.

The noninvasive approach of the SBR was the only method ethically correct in our pediatric population. The cross-spectral analysis and the sequence methods allowed different approaches to relationship between BP and RRI. The cross-spectral analysis investigates the relationship between oscillations of two signals (BP and RRI) and thus provides information in the frequency domain: in a given frequency band, oscillations of RRI are compared with oscillations of SBP, and if these oscillations are closely correlated, the gain reflecting the relative amplitude of RRI oscillations can be calculated. The sequence method is a time domain analysis that provides information on beat-to beat changes of BP and RRI, with some predefined constraints such as lag between the two signals, threshold of variations of signals, or number of beats in the sequence. This method is based on the detection of heartbeat sequences characterized by concordant increases or decreases in SBP and RRI reflecting arterial SBR control of RRI.

The sequence method was used to calculate the sensitivity of the cardiac baroreflex by measuring the beat-to-beat chronotropic responses to BP fluctuations (25). This method has been shown to yield a reliable index of parasympathetic responsiveness of the baroreflex within its resting operating range (21). The baroreflex sensitivity is defined by the ratio of change in RRI to change in SBP. It has been established that these variations in RRI are brought about by changes in parasympathetic and sympathetic efferent influences on the heart. However, the relative contribution of the two efferent pathways that control the RRI is not strictly simultaneous and reciprocal. In particular, it has been shown that in supine resting conditions, the parasympathetic pathway plays the major role in RRI control, whereas the sympathetic system provides a minor modifying influence (26).

Using the transfer function between variations in SBP and RRI, the cross-spectral analysis is based on concordant BP and RRI changes, independent of their direction. The gain of transfer function specifies the ratio between changes in RRI and changes in SBP (ms/mm Hg) in a specified frequency band. Therefore, this gain calculated in the frequency domain is comparable to the regression coefficient in the time domain. The gain of transfer function calculated in the LF band was first demonstrated to be an appropriate index of SBR activity assessed by pharmacological methods (23). The gain calculated in the respiratory frequency reflects cardiac parasympathetic activity and has also been suggested to be related to baroreflex sensitivity (27,28), although this remains to be unequivocally demonstrated.

Sevoflurane causes a concentration-related hemodynamic depression, particularly of mean BP (29). In our study, both halothane and sevoflurane induced an identical decrease in BP (~30%) during the induction of anesthesia. However, this decrease resulted from different mechanisms: both anesthetics alter myocardial contractility, but the effects of sevoflurane are less pronounced than those of halothane, and sevoflurane decreases peripheral vascular resistance, whereas the latter remains unchanged with halothane (1,2). Despite a similar decrease in BP during induction, HR control differs markedly between sevoflurane and halothane. Indeed, sevoflurane administration in children is associated with increased HR compared with halothane. This HR profile may suggest that sevoflurane is less a depressor than halothane on arterial baroreflex HR control. However, in humans, reflex HR and sympathetic nerve activity responses (quantified as the baroslope) to pressure pharmacological perturbations are diminished with increasing MAC of sevoflurane (11). In rabbits, sevoflurane decreases the baroreflex cardiovascular responses to pharmacological stress, even if the renal sympathetic nerve activity seems to be preserved up to 3% (30). Saeki et al. (10) suggested that sevoflurane may act by direct depression of the central nervous system or transmission in sympathetic ganglia rather than changes in the sensitivity of the aortic baroreceptors themselves. The SBR activity has never been studied in anesthetized children. Using a noninvasive procedure, we have demonstrated that sevoflurane induction is associated with an early and marked decrease of SBR activity. Basically, this depressor effect occurs from the time of the loss of the eyelash reflex and seems immediately maximal. This SBR activity depression is consistent with the marked parasympathetic inhibition previously demonstrated by using spectral analysis of HR variability during sevoflurane induction (3). Compared with halothane, the earlier depression of SBR activity may be explained by the lower blood/gas solubility of sevoflurane leading to a more rapid increase in the alveolar to inspired concentration ratio and a more rapid cerebral onset. These results are in agreement with electroencephalographic (EEG) data showing different profiles of EEG traces at loss of eyelash reflex and suggesting more rapid cerebral effects of sevoflurane compared with halothane (3). The use of incremental or large inspired concentrations does not significantly influence the time of occurrence of SBR activity depression, as we have previously observed for the clinical data. In healthy adults breathing a mixture of 40% N2O and 60% oxygen, N2O induces moderate alteration of the cardiac baroreflex-mediated tachycardia (31). However, we have previously demonstrated that brief exposure to 50% N2O does not alter the SBRs in children (32). In addition, when associated with a volatile anesthetic, N2O seems to exert only a minimal effect on baroreflex function (14,15,33). Our findings agree with these results.

Examination of the effects of halothane on arterial baroreflex control of HR has revealed a dose-dependent reduction of baroreflex gain in animals (12) and humans (14,15). Seagard et al. (13) identified abnormalities that might account for the reduction of baroreflex gain, including the central efferent response to afferent stimuli, the sympathetic ganglion transmission, and the cardiac response to autonomic drive. However, even though all authors may agree that halothane markedly depresses reflex sympathetic HR control, its effects on parasympathetic cardiac control are more controversial. The lack of alterations in the dose response of HR to atropine during halothane anesthesia in children suggests that parasympathetic HR control is near normal levels before atropine administration (34). Moreover, using transfer function between respiration and HR, Oberlander et al. (4) demonstrated that during halothane exposure in infants, sympathetic control of HR decreased significantly, whereas parasympathetic control remained unchanged. We have previously demonstrated that halothane anesthesia is associated with a persistence of respiratory HR fluctuations either in spontaneous ventilation or under mechanical ventilation (3). Together, these results suggest that respiratory-related parasympathetic modulation of HR is relatively preserved during halothane anesthesia. Despite this persistence of cardiac vagal control, our results show that the SBRs assessed by the sequence method is as markedly reduced under halothane as it is under sevoflurane.

This surprising result was revealed by the transfer function between the SBP and RRI calculated in anesthetized children when expired concentrations of volatile anesthetics were stabilized at 1 MAC. Whereas halothane induced a decrease in baroreflex gain calculated in the LF band in accordance with the results from the sequence method, the gain in the HF band was in the same order as the one calculated before induction. However, the lag observed between SBP and RRI was modified in halothane-anesthetized children compared with baseline, suggesting a change in the relationship between the two signals. The discrepancy between the results from the sequence method and the cross-spectral analysis may be explained by the fact that cross-spectral analysis allows calculation of the gain between SBP and RRI, whatever the lag between the two signals, whereas with the sequence method, the lag is fixed, such that the RRI change is taken into account only if it occurs one beat after the SBP change. Both methods generally provide closely related results, especially in the respiratory band (28–35). However, in our study, there was an obvious difference between the two methods in the respiratory band. Close examination of the traces presented in Figure 3 suggests that RRI fluctuations are likely more dependent on respiration than on SBP fluctuations. It is the first report of dissociated results between the sequence method and the cross-spectral analysis relating to respiratory band. Our results suggest that halothane attenuates SBR activity, as attested to by the sequence method, although respiratory RRI oscillations persist (cross-spectral analysis in the HF band). Such specific vagal baroreflex inhibition with a persistence of respiratory sinus arrhythmia has been advocated (4). This dissociated effect may be due to a greater effect of halothane on arterial baroreflex control, which is mainly dependent on central processing of afferent inputs, rather than on respiratory sinus arrhythmia, which is dependent on cardiopulmonary reflex and central modulation.

There are some potentially important limitations to this study. The first is the conversion from spontaneous active ventilation to assisted passive ventilation. In the development of a closed-loop model of rapid cardiovascular control in the supine position, arterial baroreflex control of HR may be briefly ascribed to input (fluctuations of BP) and output (HR control) with a main effector pathway that is the vagus. These two components may be influenced by breathing patterns (36,37). Compared with active ventilation, passive ventilation seems to reduce respiratory HR fluctuations in awake (38) and anesthetized (39) adults. In awake subjects, ventilator-assisted breathing does not influence the sensibility of the carotid baroreflex control of HR (40). There is no study comparing SBRs during passive versus active ventilation under anesthesia. We cannot eliminate a depressor effect of passive ventilation on HR control. However, in our study, baroreflex depression was observed from the first minute of induction, before the conversion of active ventilation to passive ventilation. These results suggest that baroreflex depression was likely, at least in part, a consequence of anesthetic effects. Another limitation is that this study involved multiple measurements over a relatively short time period, when many factors were changing rapidly and blood and cerebral anesthetic concentrations were not equilibrated. Thus, our results must be interpreted in the context of the induction period and not extrapolated to other conditions.

In conclusion, using noninvasive methods, we have demonstrated that, despite the relative preservation of vagal activity during halothane anesthesia, halothane does not preserve cardiac baroreflex activity better than sevoflurane in children. During induction, the decrease of SBR activity occurs earlier with sevoflurane than with halothane according to their respective pharmacokinetic properties. The magnitude of the depressor effect is identical at equianesthetic concentrations, although the two volatile anesthetics exhibit very different HR profiles. Using cross-spectral analysis associated with the sequence method, we have dissociated the inhibitory effects of halothane on baroreflex RRI fluctuations and the preservation of respiratory sinus arrhythmia.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Wodey E, Pladys P, Copin C, et al. Comparative hemodynamic depression of sevoflurane versus halothane in infants. Anesthesiology 1997; 87: 795–800.[Web of Science][Medline]
  2. Holzman RS, van der Velde ME, Kaus SJ, et al. Sevoflurane depresses myocardial contractility less than halothane during induction of anesthesia in children. Anesthesiology 1996; 85: 1260–7.[Web of Science][Medline]
  3. Constant I, Dubois MC, Piat V, et al. Changes in EEG and autonomic cardiovascular activity during induction of anesthesia with sevoflurane compared to halothane in children. Anesthesiology 1999; 91: 1604–15.[Web of Science][Medline]
  4. Oberlander TF, Berde CB, Saul JP. Halothane and cardiac autonomic control in infants: assessment with quantitative respiratory sinus arrhythmia. Pediatr Res 1996; 40: 710–7.[Web of Science][Medline]
  5. Pickering TG, Gribbin B, Petersen ES, et al. Effects of autonomic blockade on the baroreflex in man at rest and during exercise. Circ Res 1972; 30: 177–85.[Abstract/Free Full Text]
  6. Saul JP, Berger RD, Albrecht P, et al. Transfer function analysis of the circulation: unique insight into cardiovascular regulation. Am J Physiol 1991; 261: H1231–45.
  7. Hughson RL, Yamamoto Y, Blaber AP, et al. Effect of 28-day head-down bed rest with countermeasures on heart rate variability during LBNP. Aviat Space Environ Med 1994; 65: 293–300.[Medline]
  8. Kollai M, Jokkel G, Bonyhay I, et al. Relation between baroreflex sensitivity and cardiac vagal tone in humans. Am J Physiol 1994; 266: H21–7.
  9. Eckberg DL. Human sinus arrhythmia as an index of cardiac vagal outflow. J Appl Physiol 1983; 54: 961–6.[Abstract/Free Full Text]
  10. Saeki Y, Hasegawa Y, Shibamoto T, et al. The effects of sevoflurane, enflurane, and isoflurane on baroreceptor-sympathetic reflex in rabbits. Anesth Analg 1996; 82: 342–8.[Abstract]
  11. Ebert TJ, Harkin CP, Muzi M. Cardiovascular responses to sevoflurane: a review. Anesth Analg 1995; 81: S11–22.
  12. Tanaka M, Nishikawa T. Arterial baroreflex function in humans anaesthetized with sevoflurane. Br J Anaesth 1999; 82: 350–4.[Abstract/Free Full Text]
  13. Seagard JL, Hopp FA, Donegan JH, et al. Halothane and the carotid sinus reflex: evidence for multiple sites of action. Anesthesiology 1982; 57: 191–202.[Web of Science][Medline]
  14. Duke PC, Fownes D, Wade JG. Halothane depresses baroreflex control of heart rate in man. Anesthesiology 1977; 46: 184–7.[Web of Science][Medline]
  15. Duke PC, Trosky S. The effect of halothane with nitrous oxide on baroreflex control of heart rate in man. Can Anaesth Soc J 1980; 27: 531–4.[Web of Science][Medline]
  16. Stansky DR. Monitoring depth of anesthesia. In: Miller RD, ed. Anesthesia. 5th ed. New York: Churchill Livingstone, 2000: 1087–116.
  17. Triedman JK, Saul JP. Comparison of intraarterial with continuous noninvasive blood pressure measurement in postoperative pediatric patients. J Clin Monit 1994; 10: 11–20.[Web of Science][Medline]
  18. Constant I, Laude D, Elghozi JL, Murat I. Assessment of short-term blood pressure variability in anesthetized children: a comparative study between intraarterial and finger blood pressure. J Clin Monit 1999; 15: 205–14.[Web of Science]
  19. Blaber AP, Yamamoto Y, Hughson RL. Methodology of spontaneous baroreflex relationship assessed by surrogate data analysis. Am J Physiol 1995; 268: H1682–7.
  20. Parati G, Di Rienzo M, Bertinieri G, et al. Evaluation of the baroreceptor–heart rate reflex by 24-hour intra-arterial blood pressure monitoring in humans. Hypertension 1988; 12: 214–22.[Abstract/Free Full Text]
  21. Parlow J, Viale JP, Annat G, et al. Spontaneous cardiac baroreflex in humans: comparison with drug-induced responses. Hypertension 1995; 25: 1058–68.[Abstract/Free Full Text]
  22. Pagani M, Furtan R, Pizzinelli P, et al. Spectral analysis of R-R and arterial pressure variabilities to assess sympatho-vagal interaction during mental stress in humans. J Hypertens 1989; 7: S14–5.[Web of Science]
  23. Robbe HW, Mulder LJ, Ruddel H, et al. Assessment of baroreceptor reflex sensitivity by means of spectral analysis. Hypertension 1987; 10: 538–43.[Abstract/Free Full Text]
  24. Hughson RL, Quintin L, Annat G, et al. Spontaneous baroreflex by sequence and power spectral methods in humans. Clin Physiol 1993; 13: 663–76.[Web of Science][Medline]
  25. Bertinieri G, di Rienzo M, Cavallazzi A, et al. A new approach to analysis of the arterial baroreflex. J Hypertens Suppl 1985; 3: S79–81.[Medline]
  26. Robinson BF, Epstein SE, Beiser GD, Braunwald E. Control of heart rate by the autonomic nervous system: studies in man on the interrelation between baroreceptor mechanisms and exercise. Circ Res 1966; 19: 400–11.[Abstract/Free Full Text]
  27. deBoer RW, Karemaker JM, Strackee J. Hemodynamic fluctuations and baroreflex sensitivity in humans: a beat-to-beat model. Am J Physiol 1987; 253: H680–9.
  28. Watkins LL, Grossman P, Sherwood A. Noninvasive assessment of baroreflex control in borderline hypertension: comparison with the phenylephrine method. Hypertension 1996; 28: 238–43.[Abstract/Free Full Text]
  29. Harkin CP, Pagel PS, Kersten JR, et al. Direct negative inotropic and lusitropic effects of sevoflurane. Anesthesiology 1994; 81: 156–67.[Web of Science][Medline]
  30. Ma D, Sapsed-Byrne SM, Chakrabarti MK, Whitwam JG. Effect of sevoflurane on spontaneous sympathetic activity and baroreflexes in rabbits. Br J Anaesth 1998; 80: 68–72.[Abstract/Free Full Text]
  31. Ebert TJ. Differential effects of nitrous oxide on baroreflex control of heart rate and peripheral sympathetic nerve activity in humans. Anesthesiology 1990; 72: 16–22.[Web of Science][Medline]
  32. Constant I, Abbas M, Boucheseiche S, et al. Non-invasive assessment of cardiovascular activity induced by brief exposure to 50% nitrous oxide in children. Br J Anaesth 2002; 88: 637–43.[Abstract/Free Full Text]
  33. Morton M, Duke PC, Ong B. Baroreflex control of heart rate in man awake and during enflurane and enflurane–nitrous oxide anesthesia. Anesthesiology 1980; 52: 221–3.[Web of Science][Medline]
  34. Palmisano BW, Setlock MA, Brown MP, et al. Dose-response for atropine and heart rate in infants and children anesthetized with halothane and nitrous oxide. Anesthesiology 1991; 75: 238–42.[Web of Science][Medline]
  35. Blaber AP, Yamamoto Y, Hughson RL. Change in phase relationship between SBP and R-R interval during lower body negative pressure. Am J Physiol 1995; 268: H1688–93.
  36. Hirsch JA, Bishop B. Respiratory sinus arrhythmia in humans: how breathing pattern modulates heart rate. Am J Physiol 1981; 241: H620–9.
  37. Elghozi JL, Laude D, Girard A. Effects of respiration on blood pressure and heart rate variability in humans. Clin Exp Pharmacol Physiol 1991; 18: 735–42.[Web of Science][Medline]
  38. Haggenmiller C, Baumert JH, Adt M, Frey AW. Modulation of respiratory sinus arrhythmia by breathing pattern. Clin Sci (Lond) 1996; 91: 40–2.
  39. Loula P, Jantti V, Yli-Hankala A. Respiratory sinus arrhythmia during anaesthesia: assessment of respiration related beat-to-beat heart rate variability analysis methods. Int J Clin Monit Comput 1997; 14: 241–9.[Web of Science][Medline]
  40. Melcher A. Carotid baroreflex heart rate control during the active and the assisted breathing cycle in man. Acta Physiol Scand 1980; 108: 165–71.[Web of Science][Medline]
Accepted for publication February 6, 2004.





This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Constant, I.
Right arrow Articles by Murat, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Constant, I.
Right arrow Articles by Murat, I.
Related Collections
Right arrow Cardiovascular
Right arrow Pediatrics
Right arrow Pharmacology

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2004 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press