Anesth Analg 2000;91:480-485
© 2000 International Anesthesia Research Society
GENERAL ARTICLES
Isoflurane Does Not Depress the Hypoxic Response of Rabbit Carotid Body Chemoreceptors
Henning Joensen, MD*,
Christopher L. Sadler, PhD ,
José Ponte, PhD ,
Yuji Yamamoto, PhD§,
Sten G. E. Lindahl, PhD*, and
Lars I. Eriksson, PhD*
*Department of Anesthesiology and Intensive Care, Karolinska Hospital and Institute, Stockholm, Sweden;
Department of Anesthesia, St. Bartholomew’s Hospital;
Department of Anesthesia, King’s College School of Medicine and Dentistry, University of London, London, United Kingdom; and
§The Nobel Institute for Neurophysiology, Karolinska Institute, Stockholm, Sweden
Address correspondence and reprint requests to Henning Joensen, MD, Department of Anesthesiology and Intensive Care, Odense University Hospital, DK-5000 Odense C, Denmark. Address e-mail to henning.joensen{at}dadlnet.dk
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Abstract
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Whether volatile anesthetics have an effect on the peripheral chemoreceptors is controversial, possibly because of differences in end-tidal CO2 concentrations. We studied the effect of isoflurane on the hypoxic chemosensitivity of carotid body chemoreceptors at three different PaCO2 levels before and during the administration of 1.0% isoflurane (0.5 minimum alveolar anesthetic concentration) in six normothermic New Zealand white rabbits anesthetized with thiopental. The response of the chemoreceptors was fitted to the equation: Frequency (Hz) = a + b x PaCO2 + c x (1/PaO2) + Dx (1/PaO2)2. Mean values for the coefficients a, b, c and d for the control state were -4.5, 0.13, 771, and 6332, respectively. This relationship was not changed by addition of isoflurane at 1.0% end-tidal concentration (P = 0.40, analysis of variance). We conclude that isoflurane at 1.0% end-tidal concentration does not depress the hypoxic response of rabbit carotid body chemoreceptors during either hypo-, normo-, or hypercapnia.
Implications: By measuring single-fiber chemoreceptor activity in anesthetized rabbits, we showed that isoflurane at 1.0% end-tidal concentration does not depress the hypoxic chemosensitivity of peripheral chemoreceptors during either hypo-, normo-, or hypercapnia in this species.
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Introduction
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Initially, inhaled anesthetics were thought to have profound effects on peripheral chemoreceptor function during hypoxia. Halothane and isoflurane, even in subanesthetic end-tidal concentrations, have been associated with a marked depression of human hypoxic ventilatory response (HVR), an assumption supported by the early findings of Knill et al. (1–4) and later by Dahan et al. (5,6) and van den Elsen et al. (7,8). Based on isocapnic ventilatory tests, this depression was thought to be from an interaction with the peripheral chemoreceptor function (4–6,8). In contrast, Temp et al. (9,10) found a maintained isocapnic HVR during inhalation of subanesthetic concentrations of isoflurane, and Sjögren et al. (11,12) showed that the poikilocapnic HVR was intact at 0.85 minimum alveolar anesthetic concentration isoflurane, whereas the isocapnic HVR was reduced by approximately 50%. These data suggest that the hypoxic chemosensitivity is maintained or minimally reduced in humans. This controversy regarding the effect of subanesthetic levels of inhaled anesthetics on hypoxic ventilatory control was subsequently discussed by Robotham (13), who suggested that the contradiction was because of differences in state of consciousness among the subjects. The proposed influence of cerebral stimulation was later confirmed by van den Elsen et al. (7). Thus, the magnitude of ventilatory depression appears to be influenced not only by the PaCO2 (isocapnia versus hypocapnia), but also by the state of consciousness. This suggests that isoflurane may depress central neuronal structures or change the O2-CO2 interaction at the peripheral chemoreceptors, rather than solely depress these chemoreceptors. We sought to determine the effect of isoflurane (1% and 0.1% end-tidal concentrations corresponding to 0.5 and 0.05 minimum alveolar concentration, respectively) on the hypoxic chemosensitivity of carotid body chemoreceptors at different levels of arterial carbon dioxide tension.
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Methods
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Experiments were performed in six adult New Zealand white rabbits after approval from the local ethical committee for animal research. Anesthesia was induced with a 15–25 mg/kg IV bolus injection of thiopental, administered via a marginal ear vein and continued as an IV infusion as needed to keep the animal immobilized (8–12 mg · kg-1 · h-1). Neuromuscular blocking drugs were not given. A tracheostomy was performed via an anterior midline incision and the lungs were subsequently mechanically ventilated at a rate of 26–36 breaths/min by using a mixture of oxygen and air sufficient to keep PaO2 at approximately 110 mm Hg (FIO2 0.25–0.33). During preparation, PaCO2 was kept at approximately 35 mm Hg by adjusting the inspired tidal volume. The inspired and expired concentrations of O2, CO2, and isoflurane were monitored by using a Datex 254 airway gas monitor attached via a sampling line to the tracheal tube. The femoral artery and vein were cannulated for continuos monitoring of arterial blood pressure, for repeated blood sampling, for gas analysis and for IV drug administration. Body temperature was monitored by using a standard rectal probe and was maintained at 38.0°C ± 0.4°C by means of a servocontrolled heating blanket positioned under the animal.
The trachea and the esophagus were cut cranial to the tracheostomy and retracted cranially to expose the left carotid bifurcation. Under the microscope, the left glossopharyngeal and sinus nerves were identified and carefully dissected from the surrounding tissue. The sympathetic supply to the carotid body was left intact. The glossopharyngeal nerve was cut at its cranial and caudal ends, whereas the sinus nerve was cut at its junction with the glossopharyngeal nerve and covered with paraffin oil in the tissue pouch formed. The sinus nerve was placed on a plate of stainless steel and carefully split lengthwise into fine strands until a single chemoreceptor action potential was obtained. This signal was obtained from a bipolar platinum electrode with the sinus nerve fiber on one pole and an isolated strand of the glossopharyngeal nerve of the same length and thickness on the other pole. The signal was amplified, filtered, and sent to a window height discriminator, which fed an integrator reset at regular time intervals by using a period generator. The filtered signal was continuously monitored by using an audio amplifier/loudspeaker and a storage oscilloscope. The integrated chemoreceptor signal (Hz), arterial blood pressure (mm Hg), O2, and CO2 fractions (percentage) were continuously monitored on a screen and stored for off-line analysis.
The criteria for conducting an experiment on a chemoreceptor sinus nerve fiber were: 1) random firing with a resting frequency of 2–10 Hz during normoxia; 2) absence of interfering baroreceptor activity; 3) increasing firing frequency during brief hypoxia (FIO2 approximately 0.10) followed by decreasing frequency during hyperoxia (FIO2 > 0.50); and 4) only minor changes in amplitude and shape of the chemoreceptor action potential throughout the whole experimental procedure. Dual fiber preparations were accepted if the fibers were distinguishable and each of the fibers fulfilled the criteria.
The chemoreceptor activity in response to different levels of oxygenation was measured at three levels of PaCO2, at approximately 25 mm Hg (hypocapnia), 38 mm Hg (normocapnia), and 50 mm Hg (hypercapnia). The desired level of PaCO2 was obtained by an addition of CO2 to the inspired gas mixture while inspired tidal volume was kept constant. For each PaCO2 level, chemoreceptor activity was measured at four levels of oxygenation, aiming at PaO2 values of approximately 38, 50, 75, and 150 mm Hg. Arterial blood samples were taken 60 s after chemoreceptor activity and end-tidal oxygen and carbon dioxide concentrations had reached a steady state. If either PaO2 or PaCO2 differed too much from the target values, the measurement was repeated after appropriate adjustment of the inspired gases.
After control recordings, isoflurane was added to the inspired gas mixture, and the vaporizer was adjusted to keep the end-tidal isoflurane concentration at 1.0% for 20 min. Then, chemoreceptor activities were again recorded during hypo-, normo-, and hypercapnia. The vaporizer was then readjusted to maintain an end-tidal concentration of 0.1%, and after 20 min, a third series of measurements were made. Chemoreceptor frequencies were calculated off-line from the integrated signal as the mean frequency during a period of 40–60 s including the period of blood sampling. The thiopental infusion was kept constant throughout the measurement period.
To adjust the originally recorded chemoreceptor output for variations in obtained blood gas values around target values, the following procedure was used. Single fiber chemoreceptor afferent discharge (Hz) for a range of PaO2 values during hypo-, normo-, and hypercapnia was fitted to the following equation using least square regression analysis: F (Hz) = a + b x PaCO2+ C x (1/PaO2) + d x (1/PaO2)2. One set of coefficients (a, b, c, and d) was therefore, obtained for each experimental test (control, 1% and isoflurane, 0.1%) in each animal. By insertion of fixed PaO2 values (37.5, 50, 75, and 150 mm Hg) and fixed PaCO2 values (26, 37.5, and 50 mm Hg), chemoreceptor frequencies were estimated at comparable levels of PaO2 and PaCO2 in each animal and state. These estimated chemoreceptor frequencies were then compared by means of three-way analysis of variance for repeated measurements.
The effect of isoflurane on the chemoreceptor response to increases in PaCO2 was evaluated by subjecting the PaCO2 coefficients (b in the equation above) to a paired t-test. Interaction between PaO2 and PaCO2 was evaluated by applying linear regression to the residual (the difference between the actual measured frequency and frequency estimated by using the actual PaO2 and PaCO2 of that point) as a function of PaCO2/PaO2. Similarly, the effect of the blood pressure was assessed by subjecting the residual and the blood pressure of each measurement to linear regression. P < 0.05 were considered significant. The size of the type II error was estimated from the standard deviation of the isoflurane-induced changes in estimated chemoreceptor output, choosing 5% as both the type I and the type II error.
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Results
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Five single-fiber preparations and one dual fiber preparation (on Rabbit 4) were obtained. In all rabbits (n = 6) control measurements were followed by measurements during the administration of 1.0% isoflurane. In three animals, it was also possible to perform measurements at 0.1% isoflurane. In the remaining animals, the chemoreceptor fiber was lost. The chemoreceptor response curve was not depressed by isoflurane even if the background PaCO2 changed (Fig. 1). The fitting of the blood gas values and the frequency data to the equation was good (mean adjusted R2 = 0.95) in the individual animals and experimental states (Table 1).
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Figure 1. Original data from Rabbit 2. Chemoreceptor output frequency in Hz is presented as a function of PaO2 in mm Hg with separate plots for hypocapnia (PaCO2 < 30 mm Hg), normocapnia (PaCO2 35–45 mm Hg) and hypercapnia (PaCO2 > 45 mm Hg).
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Table 1. Adjusted R2-Values for Each Rabbit and Condition for the Equation: Frq = a + b x PaCO2 + c/PaO2 + d/(PaO2)2
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Using mean values of the coefficients (a, b, c and d) for the control state, the relationship between chemoreceptor activity and PaO2 and PaCO2 was described by the equation: Chemoreceptor frequency = -4.5 + 0.13 x PaCO2+ 771 x (1/PaO2) + 6332 x (1/PaO2)2. The estimated chemoreceptor frequencies at discrete PaO2 and PaCO2 levels are listed in Table 2 (hypocapnia), Table 3 (normocapnia) and Table 4 (hypercapnia). Regardless of the PaCO2, the chemoreceptor frequencies were not changed during the administration of isoflurane. The mean chemoreceptor response curves during control recording are compared with response curves during the administration of 1.0% isoflurane (Fig. 2), i.e., data from Tables 2–4.
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Figure 2. Mean estimated carotid body chemoreceptor frequencies for PaO2 = 37.5, 50, 75, and 150 mm Hg (from Table 2) during control recording and during the administration of isoflurane (1.0% end-tidal) at hypo-, normo-, and hypercapnia (26, 37.5, and 50 mm Hg, respectively).
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The change in chemoreceptor output caused by the administration of isoflurane (Table 5) was calculated from Tables 2–4 by subtracting isoflurane values from control values. Mean values for the isoflurane-induced change, calculated for each of the combinations of PaO2 and PaCO2 levels were <3 Hz and isoflurane did not depress the chemoreceptor function (P = 0.40, analysis of variance). By using the standard deviation of all values in Table 5, it is estimated that the risk of overlooking a real effect of isoflurane of 5 Hz is <5%.
In Table 6, the CO2 responses (the b-coefficients) are given. The difference in CO2 response from 0.13 to 0.22 Hz/mm Hg after adding isoflurane to the inspired gas mixture was not significant (P = 0.11, t-test). By using 5% for both type I and type II error, it is calculated that a difference of <0.24 Hz/mm Hg could be overlooked.
We did not find any interaction between PaO2 and PaCO2 because the regression line for residuals versus PaCO2/PaO2 was: residual (Hz) = -0.094–0.15*PaCO2/PAO2, with P 0.54 for the slope being different from zero. Chemoreceptor frequencies were not related to mean arterial blood pressure (P = 0.66). In the three rabbits where the 0.1% isoflurane series could be completed, the activity was similar to the control and 1% isoflurane series (Table 2). No formal statistical analysis was done because of the small sample size.
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Discussion
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Our major finding was that rabbit carotid body chemoreceptors were not depressed by isoflurane at any of the three levels of PaCO2. The effect of inhaled anesthetics on peripheral chemoreceptor function in humans is currently under debate. Some researchers find the HVR in humans to be severely depressed by these anesthetics (1–8), whereas others found a smaller depression or no depression at all (9–12,14).
Animal data are more uniform. Biscoe and Miller (15) demonstrated that halothane did not depress whole-nerve chemoreceptor activity at a PaO2 < 80 mm Hg, whereas both Davies et al. (16) and Ponte and Sadler (17) found that volatile anesthetics induced a moderate depression of single-fiber chemoreceptor activity at a PaO2 > 40 mm Hg, but did not below this level. We did not find a depression of chemoreceptor function. The difference between our data and the data of others (15–17) may be because of the use of muscle relaxants by these researchers. Vecuronium can cause depression of the hypoxic response of the carotid body (18), suggesting an interaction between muscle relaxants and chemoreceptor function. In a recent study, Stuth et al. (19) found the phrenic nerve response to hypoxia to be depressed, but not abolished, by up to 2% halothane. Although halothane depressed the phrenic nerve response to hypoxia, the increase relative to normoxic phrenic nerve activity was not changed. This suggests that halothane does not selectively depress the peripheral chemoreceptors, a finding that supports the results of our study. The previously found effects on ventilatory responses are therefore, probably because of a depression of central respiratory neurons or their efferents, rather than caused by the carotid body chemoreceptors.
Lack of effect of inhaled anesthetics on chemoreceptor function has also been demonstrated for halothane. Van Dissel et al. (20) did not find a direct depressant effect on the peripheral chemoreceptors when they varied the PaO2, PaCO2, and halothane concentrations in the brainstem, independent of the rest of the body. Instead, they found a depressant action on the neuromechanical link between respiratory centers in the brainstem and ventilatory movements. Gaudy et al. (21) found that halothane reduced PaO2 and increased PaCO2 to the same extent in the intact and chemodenervated rat breathing air. Consequently, these data support the conclusion that inhaled anesthetics have little effect on the chemosensitivity of peripheral chemoreceptors.
There was a tendency for isoflurane to increase the CO2 response of the chemoreceptors. However, because of the large variation in CO2 response, we cannot make conclusive statements on the absence or presence of such an effect.
The unchanged chemoreceptor output at 0.1% isoflurane serves as an indicator that our preparation was reasonably stable during the experimental period. We were not able to strictly maintain the same arterial blood pressure during the control and isoflurane series. In some reports, chemoreceptor output increases during hypotension. However, most of these studies were performed on cats. In contrast, chemoreceptor output in rabbits does not increase, provided mean arterial blood pressure is more than 20 mm Hg (22), which we also confirmed. We did not find any interaction between PaO2 and PaCO2, although this is a common finding (23). However, a lack of interaction has been described by other investigators (19,24,25).
Our study demonstrates that the depressant effect of isoflurane on the ventilatory response to hypoxia is not because of depression of the carotid body chemoreceptors. We conclude that isoflurane at 1.0% end-tidal concentration does not change the hypoxic response of rabbit peripheral chemoreceptors during hypo-, normo-, or hypercapnia.
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Acknowledgments
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Supported, in part, by Grant K97–17X-10401–05C from the Swedish Medical Research Council.
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References
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Accepted for publication April 21, 2000.
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Abstract
Introduction
