Anesth Analg 2005;100:398-403
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000141677.16224.AD
ANESTHETIC PHARMACOLOGY
Carbon Dioxide Depresses the F Wave by a Central, Not Peripheral, Mechanism During Isoflurane Anesthesia
Carmen Dominguez, MD*,
Earl Carstens, PhD
, and
Joseph F. Antognini, MD*
*Department of Anesthesiology and Pain Medicine and Section of Neurobiology, Physiology and Behavior, University of California, Davis
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Abstract
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Carbon dioxide (CO2) has anesthetic properties and has been reported to depress the F wave of the evoked electromyogram; the F wave is thought to reflect motoneuron excitability. Anesthetics such as isoflurane also depress the F wave. Because CO2 can depress muscle contractile function, as well as spinal cord neurons, it is unclear whether CO2 depresses the F wave via a central or peripheral mechanism. We anesthetized rabbits with isoflurane (1.4%) and prepared for hindlimb bypass (with a membrane oxygenator) whereby the partial pressures of CO2 in the hindlimb muscle and torso could be independently adjusted. The F wave was recorded from the hindlimb plantar muscles when the CO2 was normal to the hindlimb and torso, and when it was increased (to 
90 mm Hg) in the hindlimb, the torso, or both. Increasing the CO2 to just the hindlimb had no significant effect on the F-wave amplitude, but increasing the CO2 to the torso depressed the F wave to 52% ± 32% of control; adding CO2 to the hindlimb during torso hypercarbia did not result in any additional depression of the F wave. CO2 depressed the F wave via a central, not peripheral, mechanism, although the precise mechanism is unknown.
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Introduction
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Inhaled anesthetics such as isoflurane and halothane might produce immobility in part by inhibition of spinal motor neurons (1–4). This effect has been observed in animals (1) and humans (2) by using analysis of the F wave, which is the myopotential that occurs when a peripheral nerve is electrically stimulated and impulses travel antidromically to the motoneuron, which then "backfires," thereby sending impulses to the muscle (5). The F wave is thought to reflect motoneuron excitability (5). Carbon dioxide has a central nervous system (CNS) depressant effect (6), and prior studies have shown that the F wave is depressed by CO2 (1,2). At partial pressures more than 245 mm Hg, CO2 behaves as a complete anesthetic; i.e., its MAC (minimum alveolar anesthetic concentration that produces immobility in 50% of subjects) is approximately 30% (7). However, the effect of CO2 on the F wave appears to be out of proportion to the MAC-sparing effect of CO2. For example, arterial CO2 partial pressures of 70–80 mm Hg significantly depress the F wave (1) but have no effect on MAC, and, in fact, MAC does not begin to decrease until CO2 is more than 100 mm Hg (7). Because CO2 has a well described depressant effect on muscle (8,9), we speculated that part of the effect of CO2 on the F wave could be the result of peripheral action in the muscle and, hence, that F-wave depression by CO2 would not necessarily reflect decreased motoneuron excitability. In this study, we examined in rabbits how the F wave is affected by CO2 administered systemically (via the lungs) and locally to the muscle, the latter accomplished by isolating the blood flow to the rabbit’s hindlimb by using an oxygenator/roller pump system that permitted control of the hindlimb CO2 partial pressure independent of the systemic CO2. We hypothesized that the effect of CO2 on the F wave was due in part to a direct peripheral effect in muscle.
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Methods
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This study was approved by the institutional animal care and use committee. Nine female New Zealand White rabbits (3.9 ± 0.2 kg) were anesthetized individually in a Plexiglas chamber with isoflurane, nitrous oxide (N2O), and oxygen. Once rabbits were unconscious, the trachea was intubated with an uncuffed pediatric endotracheal tube (inside diameter, 4 mm). The N2O administration was discontinued, and anesthesia was maintained with isoflurane. A 24-gauge catheter was inserted into an ear vein for the administration of lactated Ringer’s solution, and a 22-gauge arterial catheter was inserted into the central ear artery for hemodynamic monitoring. Systemic temperature was measured via a rectal probe and was maintained at 37.4°C ± 0.8°C with a heating blanket and lamp.
Hindlimb bypass was achieved by draining systemic blood from a carotid artery, passing it through a membrane oxygenator, and infusing it into an iliac artery (Fig. 1) by using a modification of a lower torso bypass preparation (10). In brief, a neck incision was made, and a carotid artery was dissected, isolated, and cannulated with a 16-gauge catheter. An incision was made in the lower flank to dissect and isolate the iliac artery. In preparation for hindlimb bypass, heparin 300 mg/kg was administered IV, and 150 mg/kg was given every 2–3 h thereafter. Exogenous rabbit blood (250 mL) was used to prime a bypass membrane oxygenator (Neonato; Braile Biomedica, Sao Jose do Rio Preto, Brazil). A 16-gauge catheter was inserted into the iliac artery and directed distally. Systemic blood was drained from the carotid artery into the oxygenator and, via the roller pump, infused into the hindlimb circulation. The period of ischemia to the hindlimb (e.g., from artery ligation to initiation of bypass) was usually <10 min. Initial gas flow into the oxygenator consisted of carbogen (95% oxygen/5% CO2) at a flow rate of 3–4 L/min. An isoflurane vaporizer was placed in line with the gas flow to the oxygenator. The isoflurane and CO2 concentrations in the bypass circuit and the systemic circulation were measured by a calibrated agent analyzer (Rascal II; Ohmeda, Salt Lake City, UT) from samples collected from the oxygenator exhaust and the endotracheal tube, respectively (4). Hindlimb temperature was monitored via an IM thermocoupler probe (BAT-12; IITC Inc., Life Science Instruments, Woodland Hills, CA). The hindlimb temperature was maintained at 36.7°C ± 1.1°C by adjusting the water bath temperature of the oxygenator. Systemic blood pressure was maintained at 73 ± 10 mm Hg.
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Figure 1. Schematic of bypass preparation. A carotid artery catheter permitted systemic blood to be drained into a membrane oxygenator/roller pump system. The blood from the oxygenator was infused into the hindlimb via a 16-gauge catheter placed into the iliac artery and directed distally. The F wave was measured from the plantar muscles of the hindpaw. Anesthetic (isoflurane) was added to the systemic circulation and hindlimb circulation with vaporizers (VAP); calibrated agent analyzers were used to measure isoflurane and CO2 partial pressures. The gas flow to the oxygenator normally was 95% oxygen and 5% CO2. The CO2 partial pressures in the systemic circulation and hindlimb could be increased by adding CO2 to the fresh gas flow to the ventilator and gas flow to the oxygenator, respectively.
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Hindlimb bypass was initiated at 40 mL/min. Before changes in the arterial CO2 were made, the baseline normal partial pressure of CO2 was verified by collecting blood samples from the hindlimb circulation (iliac arterial cannula of oxygenator) and the systemic circulation (carotid cannula). The partial pressure of oxygen was maintained at 456 ± 92 mm Hg and 532 ± 65 mm Hg in the systemic and hindlimb (oxygenator) circulation, respectively, throughout the entire study period.
Two needle electrodes (E-2; Grass Instruments, West Warwick, RI) were percutaneously inserted into the plantar muscles (interossei and digiti) of the hindpaw to record the F wave by using the F-wave protocol (11) of an Excel® neurophysiologic machine (Cadwell, Kennewick, WA). In brief, the tibial nerve was stimulated with two percutaneous needle electrodes. The evoked electromyographic activity was filtered (10 Hz to 10 kHz) and recorded. The stimulation current (square-wave pulse; duration, 0.1 ms) was gradually increased until maximal M-wave amplitude was obtained; the electrical current used to obtain the F waves was 2–3 times the current that evoked the maximal M wave. The electrical stimuli were delivered every 3–4 s; 2 sets of 10 artifact-free F-wave tracings were obtained at each experimental manipulation, and <1% of tracings were rejected. The F wave was determined on the basis of three criteria: stimulus threshold more than M-wave threshold, variable morphology, and plateau of F-wave amplitude with increasing stimulus current (1,11).
Before determining the effects of CO2 on the F wave, we determined whether isoflurane had a peripheral (muscle) effect on the F wave. The isoflurane in the torso was kept at 1.4% while the F wave was recorded with limited isoflurane delivery to the hindlimb or with isoflurane 1.4% to the hindlimb. The bypass preparation removes 80% of the isoflurane that is present in the systemic arterial blood (10); thus, the isoflurane concentration in the hindlimb was approximately 0.2%–0.3%, on the basis of the isoflurane concentration in the exhaust of the oxygenator.
For the CO2 studies, the isoflurane concentration in the systemic and hindlimb circulations was maintained at 1.4%, which, according to our pilot studies, was approximately 0.8 MAC. We used a sub-MAC concentration because in pilot studies we had determined that isoflurane concentrations larger than 1 MAC significantly depressed the F wave, as previously described (1). The M-wave and F-wave amplitudes (maximal distance between peak and trough), ratio of F-wave amplitude and M-wave amplitude, and F-wave latency (time between stimulation and onset of F wave) were determined during each of the following interventions: 1) normal CO2 to torso and hindlimb; 2) high CO2 to torso and normal CO2 to hindlimb; 3) high CO2 to torso and hindlimb; 4) normal CO2 to torso and high CO2 to hindlimb; and 5) return to normal CO2 to hindlimb and torso. The order of interventions 2–4 was alternated from experiment to experiment. F-wave persistence was also determined for each intervention and equaled the number of tracings with a detectable F wave (>20 µV) divided by total number of tracings. The concentration of CO2 in the hindlimb and in the systemic arterial circulation was adjusted by administering additional CO2 to the oxygenator gas flow and gas flow to the anesthesia circuit, respectively. When adjusting the CO2 flows, we sought to achieve Pco2 90 mm Hg in the respective circulation; this usually required 15% CO2. We chose a Pco2 that we believed should have resulted in F-wave depression, but not MAC alterations, on the basis of the data reported by King and Rampil (1) and Eisele et al. (7). We waited 15 min after each CO2 change before determining F-wave responses. Within 5 min of obtaining each set of F-wave data, blood samples were obtained from the carotid catheter and the iliac arterial cannula for analysis of Po2 and Pco2. The blood samples were analyzed with a calibrated Nova-B blood gas analyzer (Nova Biomedical, Waltham, MA).
At the end of the experimental CO2 interventions, in five rabbits, we increased the CO2 to the hindlimb circulation and simultaneously obtained blood samples from the systemic arterial circulation (carotid), the hindlimb arterial circulation (iliac artery catheter), and the femoral vein of the bypassed hindlimb. We determined Pco2 in these samples to ensure that we were producing hypercarbia in the hindlimb.
Normally distributed data (F-wave latency and M-wave amplitude) are presented as mean and sd and were analyzed by using repeated-measures analysis of variance and post hoc testing with the Student-Newman-Keuls test. Unless otherwise noted, data not normally distributed (F-wave amplitudes) are presented as median and 10th, 25th, 75th, and 90th percentiles and were log-transformed (12) for analysis by using repeated-measures analysis of variance and post hoc testing with the Student-Newman-Keuls test. P < 0.05 was considered significant.
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Results
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With normocarbia to both hindlimb and torso, the F wave was easily elicited and had the characteristic varying morphology from trial to trial (Fig. 2). Increasing the CO2 to the hindlimb (Figs. 2 and 3) had no effect on the F-wave amplitude, whereas increasing the CO2 to the torso depressed the F wave to 52% ± 32% of control (P < 0.05) (Figs. 2 and 3). Addition of CO2 to the hindlimb during systemic hypercarbia did not cause further statistically significant depression (Figs. 2 and 3). Although the F wave was depressed, in only a few cases was it absent; thus, there was no significant change in persistence (from 100% in all animals during control to 83% ± 33% during hypercarbia to both torso and hindlimb; P > 0.05). Upon return to normocarbia in both hindlimb and torso, the F wave returned to control values, indicating that there was no time-related deterioration (Fig. 3); one rabbit died (inadvertent fluid overload) before obtaining its F-wave responses during return to normocarbia. Adding CO2 to the torso did not significantly depress the M-wave amplitude (Table 1). Thus, the F/M ratio followed the same pattern as the effect on F-wave amplitude, i.e., depression by systemic (torso) hypercarbia but not by hypercarbia in the hindlimb (data not reported). F-wave latency was slightly prolonged by torso and hindlimb hypercarbia (Table 1).
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Figure 2. Raw tracings of F wave. Shown are 10 tracings for each of 5 experimental conditions in which the partial pressures of CO2 in systemic circulation and hindlimb circulation were adjusted (shown below each set of tracings). Note that the addition of CO2 to the hindlimb circulation had no effect on the F-wave amplitude, but that the addition of CO2 to the systemic circulation depressed the F wave; adding CO2 to the hindlimb did not result in further depression.
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Figure 3. Individual and summary data. The upper panel shows F-wave amplitude (logarithmic scale) in individual animals; note that most animals had depressed F-wave amplitudes only when CO2 was high to the torso (with or without hypercarbia to the hindlimb; see the mean CO2 values in the lower panel). One animal had complete depression of the F wave, and this is denoted by the 0. Box plots of each experimental condition are shown in the lower panel. Below each box plot are the mean and sd of partial pressures of CO2 in torso and limb circulations. The line through the box is the median; the bottom and top of the box are the 25th and 75th percentiles, respectively; and the error bars represent the 10th and 90th percentiles. *P < 0.05 compared with control (far left data set). Note that depression of the F wave occurred only when CO2 was added to the torso (systemic) circulation; n = 9 except for the return-to-normocarbia condition (far right data set), for which n = 8.
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The F-wave amplitude without isoflurane to the hindlimb circulation (620 ± 775 µV; mean ± sd) was not significantly different from F-wave amplitude (640 ± 781 µV) when isoflurane was present in the hindlimb, indicating that isoflurane did not have a peripheral effect on the F wave. Addition of CO2 to the hindlimb was associated with hypercarbia (87 ± 11 mm Hg) in the venous effluent of the hindlimb, whereas the CO2 simultaneously measured in the carotid artery and the arterial limb of the bypass oxygenator was 40 ± 6 mm Hg and 88 ± 6 mm Hg, respectively. These data indicate that the experimental model likely achieved significant hypercarbia in the distal hindlimb muscles where the F wave was recorded. The arterial pH during the initial control period was 7.39 ± 0.06 and was 7.34 ± 0.11 at the end of the study; this indicated little or no deterioration of the preparation.
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Discussion
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This study showed that increased systemic (torso) CO2 partial pressures depressed the F wave, whereas no effect was seen when the CO2 was increased in the hindlimb. These data, which suggest that CO2 depressed the F wave via a mechanism in the CNS, refute our hypothesis. Because the hypercarbia in the torso would have affected both the spinal cord and the brain, we cannot determine whether CO2 effects in either one of these alone or both together are responsible for the observed data.
The work of King and Rampil (1) suggests that the F wave can be used as a measure of anesthetic-induced depression of the motoneuron, an action presumably due to hyperpolarization of the motoneuron, which leads to immobility. Our data suggest, however, that the F wave is affected by conditions (e.g., hypercarbia) that do not affect movement. Thus, during isoflurane anesthesia, the F wave does not correlate exclusively with movement or lack thereof.
We found no significant decrease in the M-wave amplitude in the animals receiving large CO2 concentrations—this is similar to findings in humans (2) but is different from findings in rats, in which high and low partial pressures of CO2 slightly depressed M-wave amplitude (1). It is possible that had we studied more animals, we would have detected a similar small depressant effect. Several authors have reported that hypercapnia depresses muscle contractility (8,9). Mador et al. (8) found that adductor pollicis twitch force decreased 13% with mild hypercarbia (Pco2 60 mm Hg). Vianna et al. (9) reported similar findings, with twitch force depressed 26% at a Pco2 of 66 mm Hg. This amount of hypercarbia would be expected to result in moderate depression of the F wave, on the basis of the present data and prior data (1,2). Although, in the present study, CO2 had no significant effect on the M wave, the M wave and force of contraction do not measure the same phenomenon (13,14). This is analogous to the relationship of the electrocardiogram to myocardial contractility, whereby the former measures electrical activity and the latter measures mechanical activity. Thus, it is possible that there might be depression of the muscle contractility without significant depression of the M wave.
In a previous study we determined that isoflurane depressed the F wave, probably by a spinal action, because selective isoflurane delivery to the brain had a minimal effect on the F wave, at least in comparison to its spinal effect (11). However, we could not exclude a peripheral effect of isoflurane (11). In this study, we found that isoflurane action in the periphery (including muscle and distal nerve) did not alter the F wave, suggesting that isoflurane’s effect on the F wave is in the spinal cord. The F-wave latency was slightly prolonged by CO2 in the periphery, suggesting an effect on the muscle or nerve conduction that was unrelated to the effect on F-wave amplitude.
Eisele et al. (7) studied the anesthetic properties of CO2 in dogs and found that complete anesthesia could be produced by CO2 partial pressures >245 mm Hg, corresponding to a MAC of 30%. This was related to changes in cerebrospinal fluid (CSF) pH, and not CO2 itself, because minimizing pH changes in CSF decreased the MAC-sparing effect of CO2. Although CO2 is normally associated with CNS depression, excitation can also occur. For example, Eisele et al. (7) reported that approximately 25% of dogs in their study developed seizures that did not interfere with the generation of purposeful movement when a supramaximal noxious stimulus was applied. Finally, it should be noted that Eisele et al. used 20% changes in halothane concentrations to determine MAC, so small alterations in MAC could have been missed (E. Eger, University of California, San Francisco, personal communication, 2004)
Narcosis induced by CO2 is mediated by alteration in CSF pH, and not peripheral pH, thus suggesting that the depressant effect of CO2 occurs in the CNS—this is consistent with our results. The F-wave depression induced by hypercapnia might be mediated not only in spinal cord, but also in brain; however, CO2 depresses spinal motoneurons in functionally decerebrate animals (15), and, thus, a direct spinal action seems the most likely explanation. We cannot exclude an effect of CO2 on peripheral nerves. We speculate that, in this study, the "watershed" area where systemic blood and bypass blood mixed was in the midthigh area; hence, hypercarbia to the hindlimb would have likely involved distal nerves. The fact that hindlimb hypercarbia did not alter the F wave suggests that an action on peripheral nerves is an unlikely cause of the results.
Although CO2 produces immobility only at partial pressures exceeding 245 mm Hg, CO2 can produce sedation at 60–80 mm Hg (16). Furthermore, these levels of CO2 can slow the electroencephalogram of anesthetized animals (17). These data suggest that the supraspinal sites are more sensitive to CO2 than is the movement response to noxious stimulation, which is likely initiated in the spinal cord. This is in accord with the relative effects of anesthetics on consciousness and movement responses to noxious stimuli, whereby consciousness is abolished at approximately 25%–40% of the isoflurane concentration and approximately 60% of the N2O concentration needed to prevent movement (18).
The mechanism by which CO2 induces anesthesia is unclear. The effect is not toxic, because animals can awaken from CO2 anesthesia with no untoward effects. A generalized depression of biological function (e.g., depressed enzymatic activity) seems unlikely, because other physiological functions are minimally affected or might even be enhanced. For example, CO2 administration in humans increases arterial blood pressure and heart rate (16). The effect of CO2 on neuronal function has been extensively investigated, although the results are divergent. Some authors have reported both hyperpolarization and depolarization of neuronal cell membranes (15). Hypercapnia (80–90 mm Hg) depresses nociception (19,20), but this degree of hypercapnia does not alter MAC (7). Decreased pH is associated with decreased glutamate release (21) and could explain hypercapnic-induced CNS depression. The marked change in H+ concentration that occurs with CO2 inhalation likely affects the intracellular and extracellular electrolyte balance via various exchange pumps, such as the Na+/H+ ion-exchange pump, and could alter neuronal function. The inward rectifying K+ channel is inhibited by CO2, and this could lead to altered balance of intracellular and extracellular K+, thereby depolarizing the cell membrane and increasing neuronal excitability (22). Membrane depolarization, however, might inactivate voltage-sensitive Na+ channels, thus rendering neurons less excitable. Furthermore, increased H+ concentration has been reported to directly depress Na+ channel function (23). Local anesthetics (such as lidocaine) block Na+ channels, and it is interesting to note that both CO2 narcosis and local anesthetic toxicity are associated with CNS depression (e.g., sedation) as well as excitation (e.g., seizures). Thus, an effect of CO2 at Na+ channels might explain these divergent phenomena.
In summary, we found that CO2 administration to the torso, but not hindlimbs, depressed the evoked F wave during isoflurane anesthesia, suggesting that the effect of CO2 on the F wave occurs within the CNS—presumably, the spinal cord. The depression of the F wave at CO2 partial pressures that have no effect on MAC suggests that the F wave might not be an exclusive marker for anesthetic effects on the motoneuron.
The authors acknowledge the excellent technical assistance of Richard Atherley and Emilio Bravo.
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Footnotes
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Supported in part by National Institutes of Health Grants GM61283 and GM57970 (JFA).
Accepted for publication July 20, 2004.
Address correspondence to Joseph F. Antognini, MD, TB-170, UC Davis, Davis, CA 95616. Address e-mail to jfantognini{at}ucdavis.edu. Reprints will not be available.
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Abstract
Introduction
