Anesth Analg 2001;92:749-754
© 2001 International Anesthesia Research Society
REGIONAL ANESTHESIA AND PAIN MEDICINE
The Effect of Epidural Anesthesia on Respiratory Distress Induced by Airway Occlusion in Isoflurane-Anesthetized Cats
Tohru Ide, MD,
Yumi Okitsu, MD,
Shino Nehashi, MD,
Fumiko Yamamoto, MD, and
Takashi Nishino, MD
Department of Anesthesiology, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan
Address correspondence and reprint requests to Dr. Tohru Ide, Department of Anesthesiology, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan. Address e-mail to ide{at}med.m.chiba-u.ac.jp
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Abstract
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The role of afferent information from the chest wall in the genesis of dyspnea is not fully elucidated. We have developed an animal model for the study of airway occlusion (AO) and proposed new concepts of minimum alveolar anesthetic concentration for AO (MACAOR) and the duration from the start of AO to the onset of the positive motor response (DOCCL) to evaluate respiratory distress quantitatively. We examined the effects of thoracic epidural anesthesia on respiratory distress by using our animal model. Adult cats (n = 24) were anesthetized with isoflurane, and an epidural catheter was placed after T9 laminectomy. After determination of MACAOR, DOCCL was measured. Animals were then randomly assigned into three groups: the EPD Group (n = 12) received epidural 1% lidocaine (0.4 mL/kg), IM saline (0.4 mL/kg), and saline infusion. The IM Group (n = 6) received epidural saline (0.4 mL/kg), IM 1% lidocaine (1 mL/kg), and saline infusion. The PHE Group (n = 6) received epidural 1% lidocaine (0.4 mL/kg) and IV phenylephrine (0.5–1 µg · kg-1 · min-1) to maintain a stable arterial blood pressure. DOCCL and MACAOR were measured in each animal at 15 min after the administration of drugs. Plasma lidocaine concentrations were measured before and after epidural or IM injection. DOCCL was significantly longer after epidural injection in all groups than before the injection. Although there was no significant difference in the values of MACAOR between before and after the epidural injection in the EPD Group, the IM administration of lidocaine in the IM Group significantly reduced MACAOR. Plasma concentrations of lidocaine were similar in all groups at all measurement points. Our data indicate that thoracic epidural anesthesia using 1% lidocaine significantly reduced respiratory distress induced by AO. This effect is most likely caused by a systemic effect of lidocaine rather than by reduced afferent information from the chest wall.
Implications: Thoracic epidural anesthesia reduced respiratory distress induced by airway occlusion. This effect is most likely caused by the systemic effect of lidocaine, rather than by the reduced afferent information from the chest wall.
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Introduction
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Although dyspnea is a common symptom that is associated with many clinical conditions, the precise mechanism underlying this sensation remains unknown. The central projection and integration of afferent information arising from respiratory organs might be involved in dyspneic sensation. One of the important respiratory organs from which such information might originate is the chest wall. Afferent fibers from the chest wall proprioceptors ascend via the lateral funiculus of the spinal cord and project onto the medulla oblongata, the cerebral cortex, and the sensorimotor cortex (1–4). In this connection, subjects experience an unpleasant sensation of breathing when short-span vibration is applied to the chest wall out of phase with respiration (5,6).
Dyspnea is experienced not only by humans but also possibly by animals, as shown behaviorally. On the basis of the observation of the response to noxious respiratory stimulus, we have developed an animal model of respiratory distress with which animals show an escape behavior during airway occlusion below a certain threshold depth of inhaled anesthesia (7). The behavior would correspond to the breaking point during breath holding in awake subjects. The measurement of maximal breath-holding duration at the breaking point has often been used as a behavioral measure of the tolerable limit of the dyspneic sensation (8). In addition, we introduced the new concept of minimum alveolar anesthetic concentration (MAC) for airway occlusion (MAC airway occlusion response; MACAOR) (7). By using this animal model, we tested the hypothesis that thoracic epidural anesthesia interrupts the afferent information from the chest wall and may modulate respiratory distress induced by airway occlusion in isoflurane-anesthetized cats.
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Methods
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IRB approval for the study was obtained from the Animal Care and Use Committee of Chiba University School of Medicine in accordance with the Guide for the Care and Use of Laboratory Animals (9).
Twenty-four adult cats of both sexes (20 male, 4 female) weighing 3.3–5.1 kg (4.2 ± 0.66 kg, mean ± SD) were used in the study. Each animal was placed in a chamber saturated with isoflurane vapor until cessation of spontaneous limb movement. After tracheal intubation, the animal was placed in the right lateral position and allowed to breathe spontaneously with 1%–3% isoflurane in oxygen. An endotracheal tube was connected to a nonrebreathing circuit via a three-way stopcock with a diameter of 6 mm. A side port of the three-way stopcock was connected to a pressure amplifier via a pressure transducer for continuous measurement of airway pressure. Airway gas was sampled from the other side port for continuous analysis of CO2, oxygen, and isoflurane concentration by use of an expired gas monitor (Model 1H21A; Acoma, Tokyo, Japan) and an anesthetic gas monitor (Model 303; Atom, Tokyo, Japan), respectively. The femoral vein was cannulated for continuous infusion of acetated Ringer’s solution containing 5% dextrose (10 mL · kg-1 · h-1 during surgical preparation, followed by 3 mL · kg-1 · h-1 administration). The right femoral artery was cannulated and connected to a pressure transducer and amplifier for monitoring arterial blood pressure and heart rate and for withdrawing blood samples for gas analysis with a blood gas analyzer (288 Blood Gas System; Ciba-Corning, Tokyo, Japan). Sodium bicarbonate (Ootsuka Chemical Industries, Tokyo, Japan) was administered as necessary to maintain base excess within normal range. Isoflurane was administered with a flow vaporizer, and a humidified gas flow of 4–5 L/min was used. Rectal temperature was continuously monitored and maintained at 37°C–38°C by using a water blanket and an infrared heating lamp. Arterial blood pressure, airway pressure, end-tidal CO2, oxygen, and isoflurane concentrations were all recorded on an eight-channel chart recorder. An epidural catheter was placed by dissecting the back muscles and removing the ninth thoracic spinous process. The ligamentum flavum was exposed, and a small hole was made with a sharp instrument. An epidural catheter (outer diameter, 0.85 mm) was inserted into the epidural space through the hole and advanced 2 cm cephalad. No evidence of dural puncture was observed in any animal. The catheter was secured to the 10th spinous process by silk sutures, and the laminectomy window was carefully packed with bone wax for hemostasis and prevention of leakage of epidurally administered solutions. The catheter was flushed with 1 mL of warm physiological saline to check for leakage. The dead space volume of the catheter was 0.2 mL. At the completion of the experiments, the vertebral column of the animal was dissected after autopsy to confirm the proper placement of the epidural catheter and the distribution of the local anesthetics in the epidural space, indicated by staining of the dura and spinal canal by the same volume of dye (crystal violet) as that of the epidurally administered solutions. Plasma concentrations of lidocaine were measured by fluorescence polarization immunoassay (SRL, Tokyo, Japan) on a later day.
Measurements were done in the right lateral position. After 1 h recovery time after the surgical preparation, the MACAOR was determined by using the bracketing procedure described in our previous study (7). Airway occlusion was performed by turning the three-way stopcock at functional residual capacity level. The equilibrium time for each concentration of isoflurane was 20 min. After the determination of MACAOR, anesthesia was maintained for 30 min with the largest concentration of isoflurane permitting a positive motor response during 6 min airway occlusion at functional residual capacity level. In each animal, the duration from the start of airway occlusion to the onset of the positive motor response (duration of airway occlusion, DOCCL) was measured at that concentration of isoflurane. After the aforementioned measurements, the animal was randomly assigned to one of three experimental groups. The first group (EPD Group, n = 12) received epidural 1% lidocaine 0.4 mL/kg (Fujisawa Pharmaceutical Co, Osaka, Japan), and then physiological saline was administered IM 1 mL/kg and infused IV at 1.5 mL/h. The second group (IM Group, n = 6) was intended to simulate absorbed lidocaine; the animals received epidural saline (0.4 mL/kg) and then 1% lidocaine IM (1 mL/kg), followed by continuous infusion of saline IV at 1.5 mL/h. The above dose of lidocaine was selected to produce serum lidocaine concentrations comparable to those obtained after epidural anesthesia (10,11). Animals of the third group (PHE Group, n = 6) received epidural 1% lidocaine (0.4 mL/kg) and IV phenylephrine hydrochloride 0.5–1 µg · kg-1 · min-1 (Kowa Phamaneutical Co, Tokyo, Japan) to maintain the mean arterial blood pressure at baseline values as before epidural lidocaine injection. Epidural injection of lidocaine or saline was completed over a period of 1 min. Fifteen minutes later, DOCCL was performed again in each animal. When no positive motor response occurred within 6 min of airway occlusion, DOCCL was calculated as 6 min, and MACAOR was determined using the bracketing procedure. In five animals of each group, arterial blood (1 mL) was sampled for determination of plasma lidocaine concentrations before epidural or IM injection (Time 0) and at 5, 10, 20, 30, and 60 min after the injections. Arterial blood was also sampled for analysis of blood gas tensions before the initiation and just after the termination of airway occlusion.
All values are expressed as mean ± SD. Data were analyzed by analysis of variance to determine differences between groups and within a single group before and after epidural or IM injection of lidocaine. Critical differences between the mean values were assessed with Scheffé’s F test. All results were considered statistically significant at P < 0.05.
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Results
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The largest concentrations of isoflurane allowing a positive motor response before epidural injection in each group (vol%) were 1.4 ± 0.2, 1.5 ± 0.3, and 1.5 ± 0.1 for the EPD, IM, and PHE Groups, respectively. The mean DOCCL after the injection in each of the three groups was significantly longer than before the injection ( Fig. 1). In addition, the mean DOCCL after the injection in the IM Group was significantly longer than those in the EPD and PHE Groups. Three cats in the EPD Group, six in the IM Group, and two in the PHE Group did not show a positive motor response within 6 min of airway occlusion after the injection. The values of MACAOR before and after the injection in each group were 1.6 ± 0.2 vs 1.4 ± 0.3 in the EPD Group, 1.7 ± 0.3 vs 1.4 ± 0.3 in the IM Group, and 1.7 ± 0.2 vs 1.5 ± 0.3 in the PHE Group. There was a significant difference between the values before and after the injection only in the IM Group.
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Figure 1. Mean duration of the period from the start of airway occlusion to the onset of the positive motor response (DOCCL) before and after epidural injection of lidocaine or saline in each group. The EPD Group received epidural 1% lidocaine and saline IM, the IM Group received epidural saline and 1% lidocaine IM, and the PHE Group received epidural 1% lidocaine and IV phenylephrine hydrochloride. Before = before epidural injection; After = after epidural injection. *P < 0.05 vs Before; &P < 0.05 vs EPD and PHE. Data are mean ± SD. The number of cats used in each group is shown in parentheses.
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The mean values of mean arterial blood pressure and heart rate, pH, PaCO2, and PaO2 before the initiation and just after the termination of airway occlusion are summarized in Tables 1 and 2, respectively. The data were obtained at the largest concentrations of isoflurane allowing a positive motor response before the injection in each group. Epidural injection was associated with a significant decrease in mean arterial blood pressure in the EPD Group but not in the IM Group and resulted in a significant slowing of the heart rate in the EPD and PHE Groups. In addition, after the epidural injection, there were significant differences in pH, PaCO2, and PaO2 between the IM Group and the other two groups just after the termination of airway occlusion, reflecting the duration of DOCCL. Also, the values of maximal occlusion pressure after thoracic epidural anesthesia were significantly lower than those before anesthesia (25.8 ± 4.7 mm Hg vs 27.8 ± 5.1 mm Hg; P < 0.05).
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Table 2. Mean Values of pH, Paco2, Pao2, MBP, and HR Just After the Termination of Airway Occlusion in Three Groups
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Figure 2 shows the changes in plasma lidocaine concentrations in the three groups. There was no statistical difference among the groups at any measurement points. The mean dose of phenylepherine hydrochloride administered in the PHE Group was 0.87 ± 0.22 µg · kg-1 · min-1).
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Figure 2. Changes in plasma concentrations of lidocaine before epidural or IM injection (Time 0) and at 5, 10, 20, 30, and 60 min afterward in three groups. The EPD Group received epidural 1% lidocaine and saline IM, the IM Group received epidural saline and 1% lidocaine IM, and the PHE Group received epidural 1% lidocaine and IV phenylephrine hydrochloride. Before = before epidural injection; After = after epidural injection. Data are mean ± SD. The number of cats used in each group is shown in parentheses.
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Autopsy examination of the spinal canal revealed that in each cat, the tip of the epidural catheter was located in the epidural space beneath the eighth thoracic vertebra in the dorsal or lateral position. The extent of segmental distribution of the dye within the canal was T1–L2 (range, T1–T5 cephalad and T13–L2 caudal). The mean upper and lower margins of the dye in the EPD and PHE Groups were T, 3.1 ± 1.2 and L, 0.9 ± 1.0; and T, 2.8 ± 1.5 and L, 1.2 ± 1.2, respectively. The dye was distributed uniformly at the same cross-sectional level regardless of the dorsal or lateral orientation of the catheter tip.
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Discussion
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The major findings of our study were as follows: DOCCL was significantly longer after epidural injection in all groups than before the injection and 2) IM administration of lidocaine in the IM Group significantly reduced MACAOR. On the basis of these results, we conclude that the relief of respiratory distress induced by airway occlusion during thoracic epidural anesthesia is caused by a systemic effect of absorbed lidocaine, rather than by the reduced afferent information from the chest wall.
The ability to detect an added resistive load is impaired in some paraplegics, suggesting that chest wall proprioceptors can mediate the respiratory sensation (12). Also, several studies have shown that chest wall vibration considerably alters respiratory sensation (5,6), indicating that afferent information from the chest wall is an important factor influencing respiratory sensation. Thus, although the precise mechanism of the genesis of dyspnea is unknown, changes in afferent information arising from the chest wall proprioceptors may play important roles in the generation of dyspneic sensation. By using the same animal model as in this study, we have shown that pulmonary vagal afferents, presumably pulmonary stretch receptors, are important in the relief of respiratory distress during airway occlusion (13). In this study, we evaluated the effect of thoracic epidural anesthesia on respiratory sensation, because this issue has been almost neglected in the past. The rationale of this study is twofold. First, airway occlusion applied in our study can induce the activity of proprioceptors that increase their activity during tracheal occlusion (14,15). Second, epidural anesthesia can elucidate the role of proprioceptors in the generation of dyspnea, because epidural block can interrupt the afferent information from the proprioceptors.
In this study, we found that thoracic epidural anesthesia with 1% lidocaine with or without IV phenylephrine significantly prolonged DOCCL. However, in any study of the effect of thoracic epidural anesthesia on respiratory sensation, the systemic effect of absorbed local anesthetic should be considered, because a relatively large dose of local anesthetic is used to block the chest wall afferent fibers. In fact, our results showed that IM administration of lidocaine remarkably prolonged DOCCL and significantly reduced the value of MACAOR. Therefore, the observed prolongation of DOCCL after epidural anesthesia is likely produced by a systemic effect of absorbed lidocaine, not by the neural blocking effect of epidural anesthesia. Regarding the systemic effect of lidocaine, lidocaine exerts a dual effect on the central nervous system manifested by an initial selective depression of inhibitory pathways leading to unopposed excitatory activity, followed by generalized central nervous system depression at larger serum concentrations (16). Several studies have been conducted to elucidate the effect of lidocaine on the anesthetic depth or anesthetic effect of lidocaine itself. Himes et al. (17) reported that 3–6 µg/mL of lidocaine produced a 10%–25% decrease in halothane MAC in humans and dogs (17). A decrease in enflurane requirement induced by lidocaine has also been reported (18), consistent with results of similar studies with nitrous oxide in humans (17) and cyclopropane in rats (19). Thus, the combination of inhaled anesthetics and local anesthetics produces a purely additive effect, and it is assumed that lidocaine at the therapeutic levels can contribute to a 0.15 to 0.28 MAC fraction (17). In our study, the plasma concentration of lidocaine in the IM Group was maximally 3.00 ± 0.14 µg/mL, which reduced MACAOR from 1.7% ± 0.3% to 1.4% ± 0.3%. This reduction in MACAOR is compatible with the reduction of standard MAC observed in halothane-anesthetized dogs (17), supporting the idea that the systemic effect of lidocaine can produce a purely additive effect on the relief of the respiratory distress. Absorbed lidocaine may also interfere with every step involved in neuromuscular transmission and depress prejunctional and postjunctional impulse conduction (20). Therefore, the effect of systemic lidocaine on the efferent system in the motor response should be also considered.
In our study, there was no significant difference in the values of MACAOR as compared before and after thoracic epidural anesthesia, whereas there was a significant prolongation of DOCCL, suggesting that DOCCL is a more sensitive measure of respiratory distress. In contrast, IM lidocaine caused both the decrease in MACAOR and the prolongation of DOCCL, suggesting that IM lidocaine produces a more profound effect on the relief of respiratory distress than thoracic epidural anesthesia. Moreover, the values of DOCCL after thoracic epidural anesthesia were significantly shorter than those seen after IM lidocaine. These findings suggest that thoracic epidural anesthesia may exert some effects that partially counteract the relief of respiratory distress produced by the systemic effect of lidocaine. It is possible that such an effect of epidural anesthesia may be produced by the neural blocking effect, because afferent information from the chest wall is considered to play some role in the generation of the respiratory distress (5,6,12).
Cardiovascular changes produced by epidural anesthesia might have also affected the generation of respiratory distress. In general, hypotension stimulates the ventilatory drive (21). Because the increase in ventilatory drive is an important factor for generation of dyspneic sensation, the inhibitory effect of thoracic epidural anesthesia on respiratory distress may be partly associated with its circulatory effect. However, this possibility seems unlikely because the results obtained in the protocol in which IV phenylephrine was given to maintain arterial blood pressure at the baseline levels were essentially similar to those observed during hypotension after thoracic epidural anesthesia.
Altered muscle function, changes in the geometry of the respiratory system, or both during thoracic epidural anesthesia should also be considered. Killian et al. (22) demonstrated that the perceived magnitudes of both added resistive and elastic loads are directly related to inspiratory pressure (muscle force) and its duration. Although intercostal muscle force was not evaluated in this study, our results showed that the maximal occlusion pressure after thoracic epidural anesthesia in the EPD Group was significantly lower than that before anesthesia, suggesting that thoracic epidural anesthesia might have weakened the intercostal muscle force. Thus, the prolongation of DOCCL observed during epidural anesthesia could be partly caused by such an effect of thoracic epidural anesthesia. However, this possibility is unlikely because, as we observed in our previous study, the emergence of positive motor response does not correlate with occlusion pressure (7).
In conclusion, we have demonstrated that thoracic epidural anesthesia with 1% lidocaine significantly reduced the respiratory distress induced by airway occlusion. This effect is most likely caused by the systemic effect of lidocaine, rather than by the reduced afferent information from the chest wall.
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Acknowledgments
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Supported in part by a grant in aid (10671401) from the Ministry of Education, Science, and Culture, Tokyo, Japan, and by a grant for the Second-term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health and Welfare of Japan, Tokyo, Japan.
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Accepted for publication October 31, 2000.
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Abstract
Introduction
