Copenhagen, DK-2100 Copenhagen 0, Denmark

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1 Journal of Physiology (1993), 470, pp With 2 figure8 Printed in Great Britain THE EFFECT OF EPIDURAL ANAESTHESIA WITH 1 % LIDOCAINE ON THE PRESSOR RESPONSE TO DYNAMIC EXERCISE IN MAN By D. B. FRIEDMAN*, J. BRENNUMt, F. SZTUK, 0. B. HANSEN, P. S. CLIFFORDt, F. W. BACH, L. ARENDT-NIELSENII, J. H. MITCHELL* AND N. H. SECHER From the Department of Anaesthesia, Rigshospitalet, Blegdamsvej 9, University of Copenhagen, DK-2100 Copenhagen 0, Denmark (Received 4 August 1992) SUMMARY 1. In order to examine the sensitivity to local anaesthetics of afferent neural feedback from working muscle during dynamic exercise, sixteen subjects cycled for 12 min before and after epidural anaesthesia using 1 % lidocaine. The presence of afferent neural blockade was verified by elimination of the blood pressure response to a cold pressor test, laser-induced evoked potentials and increases in pain detection and tolerance thresholds of the foot. Conversely, epidural anaesthesia had no effect on these variables in the unblocked skin areas or on electrically evoked potentials in blocked or unblocked skin. 2. During dynamic exercise, heart rate increased as did mean arterial pressure and cardiac output. Mean arterial pressure remained at the exercise level during post-exercise ischaemia, but heart rate and cardiac output decreased while total peripheral resistance increased. Epidural anaesthesia did not significantly affect these variables during rest, dynamic exercise, post-exercise ischaemia or recovery. 3. The results of this study show that, in order to affect blood pressure during dynamic exercise, epidural anaesthesia must block the pressor response to postexercise ischaemia. The implication of these data is that complete or almost complete block of group III and/or group IV muscle afferents is necessary to inhibit the pressor response to dynamic exercise in man. *Present address: Harry S. Moss Heart Center, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, USA. tpresent address: Department of Neurology, Gentofte Hospital, Niels Andersens vej 65, DK- 2900, Hellerup, Denmark. tpresent address: Department of Anesthesiology, Anesthesia Research, 151, VA Medical Center, Milwaukee, WI, USA. Present address: Department of Neurology, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen 0, Denmark. IlPresent address: Department of Medical Informaties, Alborg University, Denmark.

2 682 D. B. FRIEDMAN AND OTHERS INTRODUCTION Neural influence on cardiovascular responses to exercise may be elicited both by a central mechanism (feedforward control; Eldridge, Millhorn, Kiley & Waldrop, 1985; Waldrop, Henderson, Iwamoto & Mitchell, 1986; Hajduczok, Hade, Mark, Williams & Felder, 1991) and by a reflex mechanism from exercising muscle (feedback control; Mitchell & Schmidt, 1983). In man, experiments with partial neuromuscular blockade indicate that cardiovascular responses to dynamic exercise with large muscle groups are dominated by the level of activity performed as expressed by the oxygen uptake (Galbo, Kjaer & Secher, 1987). However, in a study utilizing epidural anaesthesia, the importance of afferent neural influence from working muscle for cardiovascular regulation during dynamic leg exercise could not be demonstrated (Freund, Rowell, Murphy, Hobbs & Butler, 1979). Other studies have found that the increase in mean arterial pressure during dynamic exercise is less when performed after epidural anaesthesia with 0 25 % bupivacaine (Kjaer, Secher, Bach, Sheikh & Galbo, 1989; Fernandes, Galbo, Kjoer, Mitchell, Secher & Thomas, 1990; Hanel, Worm, Secher, Perko & Kjaer, 1992). In addition to their effect on sensory nerves, higher concentrations of local anaesthetics also block motoneurons making voluntary exercise very difficult. Therefore, Strange, Secher, Pawelczyk, Christensen, Mitchell & Saltin (1993) used electrically induced contractions to perform one-leg, as well as two-leg, dynamic exercise during epidural anaesthesia with 2-0 % lidocaine or 0 5 % bupivacaine. Under this condition, electrically induced exercise does not elicit a pressor response while a normal response occurs without epidural anaesthesia. Together, these studies suggest a concentration-dependent effect of epidural anaesthesia on the blood pressure response to dynamic exercise. In the present study 1 % lidocaine was utilized to determine if a low concentration of epidural anaesthesia would attenuate the blood pressure response to dynamic exercise. Thus an indirect attempt was made to evaluate the size of afferent nerve fibres which are important for the normal blood pressure response during dynamic exercise in man. The types of nerve fibres blocked were evaluated indirectly by neurological examination, degree of muscle weakness, electrically (Lund, Selmer, Hansen, Hjorts0 & Kehlet, 1987; Brennum & Jensen, 1992) and laser- (Arendt-Nielsen, Anker-Moller, Bjerring & Spangsberg, 1991) induced evoked potentials, pain detection and tolerance thresholds to electrical stimuli (Brennum, Arendt-Nielsen, Secher, Jensen & Bjerring, 1992), a cold pressor test (Friedman, Jensen, Mitchell & Secher, 1990), the effect of epidural anaesthesia on the blood pressure response to post-exercise ischaemia (Freund et al. 1979; Fernandes et al. 1990), and the effect of epidural anaesthesia on plasma fl-endorphin release (Kjaer et al. 1989; Kjer, Secher, Bach, Galbo, Reeves & Mitchell, 1991). A possible systemic effect of epidural lidocaine affecting neural integration was evaluated by a cold pressor test of the hand, and by electrically and laser-induced evoked potentials as well as pain detection and tolerance thresholds in unblocked areas of the skin.

3 DYNAMIC EXERCISE AND SENSORY BLOCKADE 683 METHODS Five female and eleven male subjects with a mean age of 31 years (range years), weight of 69 kg (46-83 kg) and height of 177 cm ( cm) gave informed consent to participate in the study which was approved by the Ethical Committee of Copenhagen. Subjects were studied in a semi-supine position behind a Krogh cycle ergometer, the upper part of the body forming a 45 deg angle with the couch. The feet were placed in shoes fastened to the pedals in order to maintain tight contact. All experiments for a given subject were carried out on the same day. Thus, the epidural experiment followed the control experiment. During both the control and epidural experiments, subjects cycled for 12 min at a work rate of 126 (90-180) W (median and range) and a pedal frequency of 60 r.p.m. During the last 10 s of exercise, pneumatic cuffs around the thighs were inflated to 500 mmhg and this pressure was maintained for 2 min post-exercise. After exercise, the intensity of the effort and the pain associated with application of the cuffs were expressed on the Borg scale of 6-20 units (Borg, 1970) where 6 represents no effort (or pain) and 20 represents 'maximal' effort (or pain). Before and after each bout of exercise, quadriceps muscle strength was measured during brief static leg extension at a 90 deg knee angle. Following completion of control experiments, epidural anaesthesia was induced by injection of 24 ml of 1 % lidocaine (Sygehus Apotekerne i Danmark) through vertebral interspace L3-L4. Thirty-two (27-34) minutes (median and range) after drug administration, the protocol performed in the control condition was repeated. Exercise began 64 (47-89) min after administration of lidocaine. Neurological examination included the Achilles' tendon reflex as well as position sense determined by moving the big toe and having the subject guess its position (i.e. dorsiflexion). Vibration sense was determined by placing a vibrating tuning fork upon the patella and sole of the foot. A cotton ball run along the leg determined light touch; sharp and deep pain were evaluated by pin pricking and squeezing the Achilles' tendon, respectively. Two-point discrimination was determined as the minimal distance between two pins that a subject could differentiate as separate. The subject was asked to differentiate between warmed and cooled glass. Additionally, in ten subjects sensory loss was evaluated by measurement of electrically (Lund et al. 1987; Brennum & Jensen, 1992) and laser- (Arendt-Nielsen et al. 1991) induced evoked potentials as well as pain detection and tolerance thresholds before and after each exercise bout. For induction of evoked potentials, electrical stimuli of the same intensity were given using a Neuromatic 2000 C (DISA, Denmark); also a constant-intensity argon laser was applied with a Spectra-Physics 770 apparatus (USA) via a 1 mm quartz fibre. Evoked potentials were recorded with a platinum needle electrode (DANTEC/DISA 25C04) inserted over the vertex with a reference to the linked ear lobes. The electroencephalogram went through a second-order filter, was amplified (DANTEC/DISA 5C01) and sampled by a computer (Arendt-Nielsen et al. 1991). The average peak-to-peak amplitudes in the ms latency range for the electrical stimulus and in the ms range for the laser-evoked potential were determined. Additionally, the minimal electrical stimulus that was perceived as painful (pain detection), and maximal stimulus that could be tolerated (pain tolerance) were determined by the ascending method of limit technique (Brennum et al. 1992). These measurements were performed on the leg (iliac crest) and hand before and after the epidural blockade, after each cold pressor test, and before and after each exercise bout. Plasma fl-endorphin (Bach, Fahrenkrug, Jensen, Dahlstr0m & Ekman, 1987) was measured during exercise and a cold pressor test of the foot. Subjects performed maximal knee extensions with force measured on a Peekel strain-gauge apparatus (540 DNH, Holland). Leg extension strength was taken as the greatest of three attempts. Also before and after each exercise period, the subjects underwent cold pressor tests of both the left hand and foot in random order. The hand or foot was placed in a bucket of iced water to the level of the wrist or ankle for 5 min. Rating of perceived pain induced by the cold pressor test was also assessed on a scale from 6 to 20 'pain units'. Blood pressure was measured via a 1P0 mm internal diameter (20-gauge) catheter in the brachial artery of the non-dominant arm connected to a transducer (Bentley, Holland) positioned at heart level. Heart rate was recorded with an electrocardiogram and monitored along with

4 684 D. B. FRIEDMAN AND OTHERS blood pressure on an S&W 8000 machine (Simonsen & Weel, Copenhagen, Denmark) and a Mingograf 803 recorder (Elema, Sweden). In eight of the subjects, a Doppler flow probe (Vingmed Sound CV 700, Norway) was used in the suprasternal notch window to measure aortic arch flow velocity. Stroke volume was determined by multiplying the aortic arch flow velocity integral by the cross-sectional area of the aortic valve measured by 2-D echocardiography (Magin, Stewart, Myers, von Ramm & Kisslo, 1981). Cardiac output was calculated by multiplying stroke volume by heart rate and total peripheral resistance was taken as the ratio of mean arterial pressure to cardiac output, assuming central venous pressure was close to zero. Values represent medians with range. Friedman's test was used to determine if significant changes occurred with time and between experiments with and without epidural anaesthesia (Siegel & Castelland, 1988). Such changes were then located by multiple comparison procedures. A P value of 0 05 was considered significant. RESULTS Re8t Heart rate and mean arterial pressure were 70 (56-85) beats min-' and 110 (98-135) mmhg, respectively in the control state, and a similar 68 (55-83) beats min-' and 113 ( ) mmhg, respectively after epidural blockade (Fig. 1). Stroke volume and cardiac output were 85 (68-91) ml and 5.5 ( ) 1 min-', respectively in the control state, and a similar 83 (67-91) ml and 6-0 (4'5-80) l min-', respectively, after epidural anaesthesia. Thus total peripheral resistance was also similar (20 (12-27) and 19 (14-27) mmhg min I`) in the control and epidural conditions. The,-endorphin level was similar before and after epidural anaesthesia: 6-0 ( ) pmol l-l. After epidural anaesthesia, neurological examination revealed cutaneous hypoalgesia with reduced sensation to sharp and deep pain and temperature below dermatomal level T10-L1 in all subjects. Light touch, two-point discrimination, vibratory and position senses and the Achilles' tendon reflex were not affected. Laser-evoked potentials from the leg decreased in amplitude from 7-8 (4-8-15),sV before, to 0 (0-4 2) 1sV after, the blockade (P < 0 004; Fig. 2). In contrast, electrically evoked potentials from the leg were 0-60 ( ) 1sV before, and a similar 0-67 ( ),u4V after, the epidural block. Laser- and electrically evoked potentials of the hand were 0-67 ( ) and 8-2 ( ) 1uV, respectively, and were unaffected by epidural anaesthesia. Electrical pain detection in the foot increased from 7-7 (5 7-23) ma before, to 21 (4 4-72) ma (P < 0'03) after, epidural anaesthesia. Pain tolerance in the leg increased from 20 (9 8-52) ma before, to 65 (12-100) ma after (P< 0 004), epidural anaesthesia. Neither pain detection nor tolerance was affected by exercise or the cold pressor test, nor were these variables affected in the unblocked hand. Epidural anaesthesia reduced quadriceps muscle strength bilaterally by approximately 25 % (Table 1). Epidural anaesthesia did not affect the cold pressor test of the hand, but eliminated the cold pressor response of the foot (Table 1). During the cold pressor test of the foot, rating of perceived pain was also reduced by the block (P< 0 05).

5 DYNAMIC EXERCISE AND SENSORY BLOCKADE E 140- i 120- * 100- K , E E 140- > 120 CD c15- E 10- o Exercise Cuff K E I E Time (min) Fig. 1. Heart rate (HR), mean arterial pressure (MAP), stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) during 12 min of submaximal exercise without (0) and with (0) epidural anaesthesia. Post-exercise muscle ischaemia is also demonstrated. Values are means with S.E.M. There is no significant difference between the studies with and without epidural anaesthesia (P< 0 05, compared to control).

6 686 D. B. FRIEDMAN AND OTHERS Heart rate was unchanged by either cold pressor tests and unaffected by epidural anaesthesia.,l-endorphin increased to 7-6 (5X0-11X5) pmol I` (P< 0 05) during the cold pressor test of the foot and was not affected by epidural anaesthesia * 0-0-6f S10-4/ 40- co C35-.e 30- < 20- E~~~~~~~~~~ 0-70] ~ c301- ~20j 10' Control After After exercise epidural Fig. 2. Laser- and electrically induced evoked potentials, pain detection, and pain tolerance thresholds in the leg (0) and hand (0) before and after 1% lidocaine epidural anaesthesia. Values before and after exercise are given. Values are means with S.E.M. *P< 0 05, compared to control. Exerci8e Epidural blockade remained stable during exercise as indicated by leg strength, the mean arterial pressure response and pain associated with the cold pressor test of the foot before and after exercise (Table 1). Heart rate and mean arterial pressure rose to 143 ( ) beats min-' and 143 ( ) mmhg (P< 0-01), respectively during exercise (Fig. 1). Stroke volume and cardiac output became elevated at

7 DYNAMIC EXERCISE AND SENSORY BLOCKADE 129 ( ) ml and 18 4 ( )1 min-', respectively, and total peripheral resistance fell to 7-5 ( ) mmhg min I` (P< 0 01).,-Endorphin increased to 9-6 ( ) pmol l` during exercise (P< 0 02). There was no significant difference in these variables between the control and epidural anaesthesia. Also, the rating of perceived exertion was 10 (6-14) 'exertion units' during control exercise and a similar 12 (6-16) 'exertion units' during exercise with the epidural blockade (Table 1). TABLE 1. Median values and ranges for quadriceps muscle strength, for results of cold pressor tests and post-exercise muscle ischaemia during control and epidural conditions Control Epidural anaesthesia Before After Before After Leg strength Left (N) 600 ( ) 620 ( ) 410 ( ) 430 ( )* Right (N) 630( ) 600( ) 470 ( )* 490 ( )* Cold pressor test, foot AIHR (beats min-') 2 (-1 to +6) 0 (-2 to +3) 1 (-2 to +3) 2 (-3 to +4) AMAP (mmhg) 18 (7-30)t 19 (12-32)t 2 (-3 to +8)* 0 (-2 to +8)* RPP ('pain units') 15 (12-20) 14(12-20) 10 (6-18)* 9 (6-17)* Cold pressor test, hand AHR (beats min-') -1(-3 to +6) 0 (-1 to +2) 2 (-2 to +2) 1 (-2 to +3) AMAP (mmhg) 20 (7-32)t 17 (10-32)t 22 (11-29)t 19 (9-32)t RPP('pain units') 15 (13-19) 15 (12-20) 14(13-20) 16(13-20) Rating of perceived exertion (RPE units) 10(6-14) 12 (6-16) Post-exercise muscle ischaemia (RPP'pain units') 14(8-18) 11 (7-17)* Before and After refer to the 12 min submaximal exercise bout. Changes in heart rate (AHR), changes in mean arterial pressure (AMAP), rating of perceived pain (RPP) and rating of perceived exertion (RPE) are shown. *P< 005, epidural anaesthesia compared to control; tp< 005, compared to rest. Post-exercise ischaemia During the post-exercise ischaemia, mean arterial pressure remained elevated at 137 ( ) mmhg, and decreased to 116 ( ) mmhg (P< 0 01) 1 min after cuff deflation (Fig. 1). Heart rate decreased to 111 (89-138) beats min-' during postexercise ischaemia (P< 0 01). Also, stroke volume decreased to 122 ( ) ml (P< 0 02) but increased again to 178 ( ) ml when the cuffs were released (P< 0 002). Thus cardiac output decreased to 12-8 (7-3-16'1) 1 min-' during postexercise ischaemia, but increased again to 16-6 (9-8-21P0) 1 min-' when the cuffs were released. Total peripheral resistance increased to 10-3 ( ) mmhg min 1` (P< 0 01), and decreased again to 6f6 ( ) mmhg min l` at 1 min after cuff deflation. Also after exercise, these variables were the same during control and epidural anaesthesia experiments. However, during post-exercise ischaemia, the rating of perceived pain was lower during epidural blockade than during control (Table 1). 687

8 688 D. B. FRIEDMAN AND OTHERS DISCUSSION An important finding of this study was that 1 % lidocaine in contrast to 0 25 % bupivacaine (Kjaer et al. 1989; Fernandes et al. 1990; Hanel et al. 1992), 0-5 % bupivacaine and 2 % lidocaine (Strange et al. 1992) does not affect the pressor response to dynamic exercise in man. This occurred even though the cold pressor response of the foot was abolished and the pain associated with the test was reduced during epidural anaesthesia. The laser-evoked potentials from the foot were almost eliminated and pain detection and tolerance thresholds also increased markedly. In accordance with the lack of effect of 1 % lidocaine in blocking the blood pressure response to exercise, this drug concentration did not affect the blood pressure response to post-exercise ischaemia (Freund et al. 1979; Fernandes et al. 1990). However, an effect of 1 % lidocaine during muscle ischaemia was noted in that the rating of perceived pain was reduced by the epidural blockade (Table 1). Furthermore, epidural anaesthesia with 1 % lidocaine had no systemic effect on cardiovascular or sensory variables as it did not affect a cold pressor response of the hand or the size of the laser- or electrically evoked potentials from the unblocked areas of the skin. Freund et al. (1979) studied four subjects during dynamic exercise with epidural anaesthesia. In one subject there was no block of the post-exercise ischaemic response and a normal blood pressure response to dynamic exercise, and this agrees with our present study. In one subject there was a partial block of the post-exercise ischaemic response and an attenuation of the blood pressure response to dynamic exercise (Kjaer et al. 1989; Fernandes et al. 1990; Hanel et al. 1992). However, in two subjects there was complete block of the post-exercise ischaemic response and a normal increase in blood pressure during dynamic exercise. This is a combination that is difficult to explain. The blockade used by Freund et al. (1979) resulted in a much greater reduction in strength than did the anaesthesia in our study, or that of Fernandes et al. (1990), Kjaer et al. (1989) and Hanel et al. (1992). Perhaps the subjects of Freund et al. (1979) were actually performing a type of exercise which simulates repeated static contractions. During static leg exercise, blood pressure is similar at the same force development with and without epidural anaesthesia (Mitchell, Reeves, Rogers & Secher, 1989; Kjser et al. 1991). It is possible that central command could provide all of the stimulus for increased sympathetic tone during dynamic exercise with epidural anaesthesia. Such an interpretation would be consistent with the results of the pilot study by Freund et al. (1979), but not with those of Kjar et al. 1989, Fernandes et al. (1990), Hanel et al. (1992) and Strange et al. (1992). In these studies involving a large muscle mass, afferent input from the working muscle dominates cardiovascular regulation during dynamic exercise. Only experiments with a smaller muscle mass as during one-leg exercise (Innes, de Cort, Evans & Guz, 1992) or after training (Klausen, Secher, Clausen, Hartling & Trap-Jensen, 1982) indicate that the central neural mechanism has an important influence on the cardiovascular responses to dynamic exercise. The pressor response during post-exercise ischaemia (Alam & Smirk, 1937; Rowell, Hermansen & Blackmon, 1976) is caused by an increased total peripheral resistance (Bonde-Petersen et al. 1978). In the present study, cardiac output continuously fell

9 DYNAMIC EXERCISE AND SENSORY BLOCKADE and total peripheral resistance rose causing the maintenance of an elevated mean arterial pressure during the post-exercise ischaemic period. Thus, the mechanism for the increase in blood pressure during dynamic exercise is different from that during post-exercise ischaemia. This is supported by the finding that sympathetic nerve activity to resting muscle is greater during the post-exercise ischaemic response than it is during dynamic exercise (Seals & Victor, 1991). The rise in,8-endorphin during submaximal but not during maximal dynamic exercise is eliminated by 0-25 % bupivacaine epidural anaesthesia (Kjser et al. 1989, 1991). In contrast to 0-25 % bupivacaine, 1 % lidocaine did not block the release of /-endorphin. Furthermore, /1-endorphin rose in response to a cold pressor test in the present study and that by Casale, Pecorini, Cuzzoni & De Nicola (1985). However, Moret et al. (1990) demonstrated no change in this hormone during a cold pressor test of the hand. The effectiveness of the afferent blockade was confirmed by the neurological examination, the cold pressor response (Table 1) and laser-evoked potentials of the leg (Fig. 2). Also, pain detection and tolerance thresholds increased. This study is the first to demonstrate that local anaesthesia of afferent nerves causes a selective reduction of evoked potentials. Electrically evoked potentials are thought to be transmitted along group II (Afl) and III (Ad) sensory fibres (Bromm, 1984; Brennum & Jensen, 1992) in contrast to the laser-induced potentials which are carried by the smaller group III (A8) fibres (Bromm, 1984; Strichart & Coumo, 1988; Arendt-Nielsen et al. 1991). Lund et al. (1987) were able to decrease the electrically derived evoked potentials with 0 5 % bupivacaine. We blocked the laser-, but not the electrically evoked responses, suggesting that group III, but not group II afferents were affected. In addition we demonstrated that 1 % lidocaine epidural anaesthesia increased pain detection and tolerance thresholds for electrically induced stimuli. Sharp and deep pain as well as temperature sensation are thought to be transmitted via group III and group IV fibres, and these functions were reduced by 1 % lidocaine. In contrast, vibratory and position sense which are conducted in group II fibres were not affected by the epidural blockade. These sensory tests indicate only a partial blockade of group III and IV afferents. The muscle afferents thought to be responsible for cardiovascular regulation during exercise are thinly myelinated group III and unmyelinated group IV fibres (Mitchell & Schmidt, 1983) which are highly sensitive to local anaesthetics. However, we have reduced pain while leaving intact the exercise pressor response to dynamic exercise, and this degree of afferent blockade did significantly reduce the cold pressor response and laser-evoked potentials, while increasing pain detection and tolerance thresholds within the distribution of the blockade. Afferent fibres are not blocked as an all-or-none phenomenon by local anaesthetics (Strichart & Coumo, 1988; Brennum et al. 1992) and there is considerable multiplicity of the fibres which are responsible for the exercise pressor reflex (Wilson, Wall, Matsukawa & Mitchell, 1991). Conversely, the evoked potentials, and sensations of pain and temperature may be more dependent on the integrity of all fibres involved (Brennum et al. 1992). The implication of the present study is that a complete or almost complete block of group III and/or IV afferents is necessary to inhibit increases in blood pressure during dynamic exercise in man. 689

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