Anesth Analg 2003;97:377-382
© 2003 International Anesthesia Research Society
PEDIATRIC ANESTHESIA
The Relationship Between Expired Concentration of Sevoflurane and Sympathovagal Tone in Children
Eric Wodey, MD PhD*,
Lotfi Senhadji, PhD
,
Patrick Pladys, MD PhD
,
François Carre, MD PhD
, and
Claude Ecoffey, MD*
*Department of Anesthesiology and Surgical Intensive Care,
LTSI,
Department of Pediatric and Neonatal Intensive Care, and
Department of Physiology, Université de Rennes 1, Paris, France
Address correspondence and reprint requests to Eric Wodey, MD, PhD, Service d’Anesthésie-Réanimation Chirurgicale 2, Centre Hospitalier Regional et Universitaire, 2 rue Henri le Guilloux, 35033 Rennes Cedex 9, France. Address e-mail to eric.wodey{at}chu-rennes.fr
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Abstract
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In children, sevoflurane depresses parasympathetic tone during induction more than halothane. The effects of sevoflurane on parasympathetic activity could explain the difference in heart rate (HR) changes described between infants and children. In this study, we sought to determine the relationship between the end-tidal concentration of sevoflurane and sympathetic and parasympathetic tone in children by spectral analysis of RR intervals. Thirty-three children, ASA physical status I, who required elective surgery were studied. In 10 children (Group A), recordings were performed while gradually decreasing the inspired sevoflurane concentration from 8% to the beginning of clinical awakening. In 23 other children (Group B), recordings were performed while children were awake and at a steady-state of 1 and 2 minimum alveolar anesthetic concentration of sevoflurane. A time-varying autoregressive modeling of the interpolated RR sequences was performed, and spectral density in low-frequency (LF; 0.04–0.15 Hz) and high-frequency (HF; 0.15–0.55 Hz) bands was calculated. In Group A, HR slowing paralleled the decrease in expired sevoflurane concentration. Conversely, the decrease in expired concentration of sevoflurane led to an increase in systolic blood pressure (SBP), HF, LF, and LF/HF. The increase in LF/HF preceded the increase in HF. In Group B, the baseline HF power spectrum and normalized values HFnu (HFnu = HF/LF + HF) were significantly increased in children older than 3 yr. Changes in HR induced by sevoflurane were negatively correlated with baseline HF and HFnu (R2 = 0.6; P < 0.001). These results demonstrate that withdrawal of parasympathetic tone is the main determinant for the change in HR induced by sevoflurane.
IMPLICATIONS: The effects of sevoflurane on parasympathetic activity could explain the difference in heart-rate changes described between infants and children during induction. This study describes the changes in heart rate and its variability induced by sevoflurane in children and shows that these changes are related to parasympathetic tone before the induction of anesthesia.
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Introduction
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Several studies have attempted to determine the cardiovascular effects of sevoflurane in children and infants (1–4). Compared with halothane, few cardiovascular side effects have been reported for sevoflurane (3–5). Recently, a study investigated the effects of sevoflurane on the autonomic nervous system during induction time and used spectral analysis of both heart rate (HR) and blood pressure variability (6). Using this method, Constant et al. (6) have recently demonstrated that, in children, sevoflurane depresses parasympathetic tone more than halothane during induction. The effects of sevoflurane on parasympathetic activity could explain the difference in HR changes described between infants and children during induction with this anesthetic gas (1). Indeed, Lerman et al. (1) have reported that HR increases in children older than 3 yr and remains unchanged in younger children (<3 yr) and infants. The purpose of this study was to determine the relationship between the end-tidal concentration of sevoflurane and the sympathetic and parasympathetic modulation of HR by using spectral analysis of RR intervals (7).
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Methods
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Thirty-three children, ASA physical status I, who required elective surgery were studied after approval by the Human Studies Committee and after informed parental consent was obtained. All children were unpremedicated. The induction of anesthesia was started with sevoflurane at 8% in oxygen, without nitrous oxide. Children breathed spontaneously during induction until endotracheal intubation. After placement of an IV catheter, the trachea was intubated, and the lungs were ventilated at a fixed respiratory rate (30 breaths/min in Group A and B1 and 20 breaths/min in Group B2). Anesthetic gas and carbon dioxide concentrations were measured. Recordings were started before induction (5 min) to determine baseline values for all children. Ten children were included in the first trial (Group A), and 23 were included in the second trial (Group B).
In Group A, inspired sevoflurane was maintained at an 8% concentration for 5 min and then was decreased by 1% every minute until 0% inspired concentration and the beginning of clinical awakening (8%, 7%, 6%,5%, 4%, 3%, 2%, 1%, and 0%). Recordings were then stopped and sevoflurane was increased to perform the surgical procedure.
In Group B, 2 periods of 5 min were recorded before the surgical procedure after stabilization of the expired sevoflurane concentration for at least 10 min at 1 and 2 minimum alveolar anesthetic concentration (MAC) adjusted for age (1). The analysis was performed in two separate subgroups: Group B1, children 
3 yr; and group B2, children >3 yr (1).
Capnograms and inspired and expired gas concentrations were recorded continuously to maintain normocapnia. Systolic blood pressure was measured every minute with an automated blood pressure cuff. Electrocardiogram (ECG) was recorded continuously and digitized at 400 Hz. The HR was obtained from the measurement of ECG cardiac cycle lengths (RR intervals).
Before power spectral density estimation, the RR sequence, which is intrinsically non-evenly spaced data, was interpolated to obtain a series of uniformly sampled data. The retained sampling rate was set to 2 Hz, and, by using a sliding window of 50 s, a time-varying autoregressive modeling of the interpolated RR sequences (i.e., the RR series) was performed (7). The spectral densities in the low-frequency (LF; 0.04–0.15 Hz) and high-frequency (HF; 0.15–0.55 Hz) ranges, as well as the total power (power spectrum (SP) = LF + HF, expressed in milliseconds squared) and the normalized high-frequency power spectrum (HFnu = HF/LF + HF), were calculated. The maximal limit for HF, classically set to 0.4 Hz, was increased to 0.55 Hz for the fast breathing rate of children in Groups A and B1 (30 breaths/min, i.e., 0.5 Hz). The SP analysis was performed with Matlab software (The Mathworks Inc., Natick, MA).
In Group A, the 18 intervals used for analysis were defined by ranges of expired sevoflurane concentration as follows: [Cn, Cn+ 1], where Cn+ 1 = Cn + 0.25%, C1 = 0%, and Cn+ 1 < 4.6% (maximum value of expired sevoflurane concentration obtained in all children with the 8% inspired concentration). Median values of SP, HF, LF, HFnu (HFnu = HF/LF + HF), and LF/HF, as well as the median value of the expired gas concentration, were then calculated in each interval.
A Kruskal-Wallis test was used to investigate the effect of sevoflurane on each variable. A Wilcoxon test was used to establish changes in heart rate variability (HRV) variables during various concentrations of sevoflurane. The Spearman rank test was used to study the correlation between continuous variables. Probability values <0.05 were considered significant. Calculation was performed with the BI LOGINSERM 1979/1987 software.
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Results
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The children’s ages ranged from 21 to 76 mo (median, 50 mo), 6 to 33 mo (median, 20 mo), and 38 to 123 mo (median, 75 mo) in Groups A, B1, and B2, respectively.
Group A
The maximal expired sevoflurane concentration recorded in children ranged from 4.6% to 5.81% (median, 5.51%). The beginning of the clinical awakening appeared at expired sevoflurane concentrations between 0.38% and 0.9% (median, 0.44%). HR slowing paralleled the decrease in expired sevoflurane concentration (Figs. 1 and 2 ). Conversely, the decrease in the expired concentration of sevoflurane led to an increase in systolic blood pressure, SP, HF, LF, and LF/HF (Figs. 2 and 3). During the decline in sevoflurane concentration, the increase in LF/HF preceded the increase in HF (Fig. 2). During the beginning of the clinical awakening, corresponding to the smallest values of sevoflurane concentration, HF remained significantly lower than the control values.
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Figure 1. Representative example of the changes in heart rate and heart rate variability during the decrease in expired sevoflurane concentration (top) in Group A: changes in the RR interval (middle; expressed in milliseconds) and in the RR interval minus the RR mean (bottom; expressed in milliseconds) are represented during the same period.
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Figure 2. Changes in heart rate (HR) (top left), in high-frequency range (HF; 0.15–0.55 Hz; bottom left), and in total power (SP; 0.04–0.55; top right) and the low-frequency (LF)/HF ratio (bottom right) during the progressive decrease of sevoflurane expired concentration in Group A. The first concentration window ranged from 4.5% to 4.25% (labeled 4.5), whereas the last concentration window was between 0.5% and 0.25% (labeled 0.5). (Min-10th-30th-median-70th-90th-max) of the population; P < 0.05 versus the larger concentration of sevoflurane; *P < 0.05 versus baseline.
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Figure 3. Evolution of systolic blood pressure (SBP) during the decrease in sevoflurane concentration (min-10th-30th-median-70th-90th-max). *P < 0.05 versus the first minute value, i.e., the larger concentration of sevoflurane.
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Group B
In awake children, HF SP was higher in children older than 3 yr (B2) than in younger children (B1) (Table 1). Conversely, the LF/HF ratio and HR appeared lower in the B2 than in the B1 group (Table 1). When compared with baseline values, the increase in HR was significant only at 2 MAC in children older than 3 yr (Group B2; Table 1). In contrast, HR did not change significantly at either 1 or 2 MAC in younger children (Group B1; Table 1). HF was significantly lower in both groups at, respectively, 1 and 2 MAC when compared with baseline (Table 1). Changes in HR induced by sevoflurane were negatively correlated with baseline HF and HFnu (R2 = 0.6; P < 0.001) (Fig. 4).
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Figure 4. Relationship between the changes in HR induced by sevoflurane in Group B and the corresponding values of high frequency (HF; left) (R2 = 0.6; P < 0.001) and normalized high frequency (HFnu; right) (R2 = 0.6; P < 0.001) observed in awake children (Group B).
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Discussion
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This study describes the changes in HR and HRV induced by sevoflurane in children and shows that these changes are related to parasympathetic tone before the induction of anesthesia. The results also suggest that withdrawal of parasympathetic tone was the main determinant for the decline in HR induced by sevoflurane. This could explain the difference in HR between infants and older children observed during induction with sevoflurane (1,8–10).
The analysis of HRV in the frequency domain mainly relies on the calculation of the SP in two frequency bands. The HF band usually ranges from 0.15 to 0.4 Hz, whereas the LF ranges from 0.04 to 0.15 Hz. Parasympathetic activity is usually described as the major contributor to the HF component. The physiological origin of the LF component appears more controversial (7). The HRV in this frequency band is mainly induced by the baroreflex and implicates both sympathetic and parasympathetic activity. The power ratio between LF and HF, noted as LF/HF, is considered by most investigators to mirror the sympathovagal balance and is often used in clinical studies (7).
In children at rest, a positive relationship between mean RR intervals, i.e., HR, and HF power has been reported (10). In children, the parasympathetic tone, i.e., HF power, increases from early infancy to the preschool age and then decreases (10,11). We found similar results in this study. Indeed, HF SP in Group B appeared higher in children older than three years than in younger children (three years or younger) (Table 1). Our findings regarding the effects of sevoflurane on HR are consistent with the findings of Lerman et al. (1), who reported that HR increased mainly in children older than three years and remained unchanged in younger children and infants. We observed a correlation in Group B between the HF SP in awake children and the percentage change in HR with sevoflurane (Fig. 4). A more pronounced HR increase was also observed in preschool children (older than three years) compared with younger children (Table 1). This difference appears linked to the baseline parasympathetic tone and to the withdrawal of parasympathetic activity induced by sevoflurane. The analysis of the effect of decreased sevoflurane concentration (Group A) confirms the predominant implication of parasympathetic tone in HR changes. We observed that as sevoflurane concentration decreased, HF, LF, and LF/HF increased progressively (Fig. 2). This suggests that sevoflurane led to a decrease in autonomic influences, which implicates both sympathetic and parasympathetic tone. The decrease in HR observed during the decrease in sevoflurane cannot, therefore, be attributed to a decrease in sympathetic influence but seems mainly determined by an increase in parasympathetic influence.
Constant et al. (6) reported that during induction in children, the LF/HF ratio increased during the loss of eyelash reflex and decreased at the time the pupils became centered. This transitory increase in sympathetic activity could explain the transitory increase in HR during induction. In our study, the simultaneous decrease in HF, LF, and LF/HF induced by sevoflurane suggests a decrease in the autonomic influences, with an absence of direct pharmacological sympathetic activation. This analysis confirms the results of a previous study in adults (12).
The evaluation of parasympathetic tone by using HF power can lead in some cases to misinterpretation. Changes in breathing rate can induce significant alterations in HF power without any changes in mean RR value (13). One consequence is that HF cannot be used as an index of parasympathetic tone during induction because various breathing rates are observed during this period. In this study, we chose to perform our analysis on intubated children with fixed respiratory frequencies. We observed that in Group A, the absolute value of the HF power at the beginning of the clinical awakening was less than at baseline. There are two possible explanations for this difference. First, in our study, all recordings were stopped when clinical signs of awakening were observed. Therefore, the sevoflurane concentration did not decrease at the zero value, and the residual pharmacological effect of this drug could maintain a significant depression on the parasympathetic tone. Second, with regard to the HF breathing effects, the higher range of breathing frequency used in our study could cause an artificial decrease in the HF value (13). Finally, in Group A, the delay between the expired sevoflurane concentration and the central nervous system concentrations must be taken into account in the analysis of the relationship between HRV and sevoflurane concentration. Thus, determination of an accurate threshold for the expired sevoflurane concentration required to maintain the autonomic nervous system activity should integrate the hysteresis phenomenon.
HR alteration induced by sevoflurane in children appeared mainly dependent on the pharmacological effect on the parasympathetic tone. This could explain, at least in part, the difference in HR variation previously reported during induction between younger and older children with regard to their respective parasympathetic tone.
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Acknowledgments
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The authors thank David James and Bupe Mwaikambo for their helpful English translation advice.
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References
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Accepted for publication March 10, 2003.
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Abstract
Introduction
