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© 2000 International Anesthesia Research Society
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Abstract |
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Inhaled and other anesthetics profoundly affect the central nervous system, causing amnesia, immobility in the face of noxious stimulation, and depression of thermoregulation. Nonimmobilizers, inhaled compounds whose lipophilicity suggests that they should be anesthetics, do not produce immobility, but they do cause amnesia. Their effects on thermoregulation were the subject of the present study. We gave eight rats isoflurane on one occasion and the nonimmobilizer 2N (1,2-dichlorolhexafluorocyclobutane) on another. We measured the effect of various concentrations of each compound on thermoregulation provoked by body cooling. The specific outcome was increased metabolism, as reflected in increased output of carbon dioxide. Isoflurane decreased the temperature threshold for such increases and the maximum response intensity, doing so in a concentration-dependent manner, whereas 2N had a minimal or no effect at any concentration up to 0.9 minimum alveolar concentration (estimated from its lipophilicity). Thus, 2N may be a useful tool for studies of the mechanisms mediating the thermoregulatory depression produced by anesthetics: 2N should not affect such a mechanism.
Implications: Unlike inhaled anesthetics, the nonimmobilizer 2N (1,2-dichlorohexafluorocyclobutane) minimally affects temperature regulation in rats. Thus, 2N may be useful in mechanistic studies of temperature regulation. Cellular and molecular sites that mediate the capacity of inhaled anesthetics to depress thermoregulation should be influenced by anesthetics but not by 2N.
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Introduction |
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Inhaled anesthetics have predictable effects on the central nervous system, including immobility in response to surgical stimuli (1), amnesia (2), altered nociceptive thresholds (3), and impaired thermoregulatory responses (4). Nonimmobilizers (previously called nonanesthetics) are inhaled compounds expected from the Meyer-Overton hypothesis to have anesthetic properties. According to that relationship, the product of MAC (the minimum alveolar concentration of anesthetic required to abolish movement in response to noxious stimuli in 50% or subjects) and lipid solubility (measured by the oil/gas partition coefficient) is a constant. Nonimmobilizers, however, do not prevent movement in response to noxious stimuli (5), including thermal stimulation (i.e., tail flick latency) (3). Anesthetic-induced immobility and depression of tail-flick latency are both effects on spinal reflexes. Although they do not affect these reflexes, nonimmobilizers impair a higher function of the central nervous system, namely learning and memory. For example, nonimmobilizers interfere with fear conditioning at partial pressures predicted by lipophilicity to be anesthetic (6).
Because they share some anesthetic properties, but not others, nonimmobilizers are potentially useful probes of the relevance of putative targets of volatile anesthetics and have been used as controls in biochemical systems characterizing anesthetic mechanisms. For example, a receptor important to the immobilizing effect of anesthetics should be sensitive to an inhaled anesthetic but not respond to a nonimmobilizer. Likewise, a receptor important to the effect of anesthetics on fear conditioning should be affected similarly by both anesthetics and nonimmobilizers.
In humans, anesthetics decrease vasoconstriction and shivering thresholds (triggering core temperatures) and increase sweating thresholds, thus increasing the interthreshold range (temperatures not triggering autonomic thermoregulatory defenses) (7). All anesthetics so far tested markedly increase the interthreshold range (8–9). The gain of thermoregulatory responses (increment in response intensity with deviation of core temperature beyond the triggering threshold) remains unchanged with some anesthetics (10–11) but is decreased by others (12). Similarly, maximum response intensity of some responses remains normal (10,12), whereas maximum intensity in other cases is decreased (13). However, all anesthetics so far tested at the very least markedly increase the interthreshold range.
The thermoregulatory effects of nonimmobilizers are unknown. We therefore tested the hypothesis that the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (hereafter called 2N) does not reduce the threshold, gain, or maximum intensity of nonshivering thermogenesis.
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Methods |
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With the approval of the Committee on Animal Research of the University of California, San Francisco, we studied eight male Sprague-Dawley rats (Crl:CD(SD)BR) from Charles River Laboratories (Hollister, CA) weighing 312–564 g The animals were housed up to three per cage under 12:12 h light:dark cycles and supplied with rat chow and water ad libitum.
Four animals were studied at a time. Animals were first studied with isoflurane and then on a later day with 2N. A colonic temperature probe (YSI Inc., Yellow Springs, OH) was inserted into each rat for evaluation of core temperature. The rats were each positioned in a gas-tight PlexiglasTM (McMaster-Carr, Los Angeles, CA) tube 8.5 cm in internal diameter by 40 cm in length. Throughout the study, gas flow was maintained at 1 L/min with calibrated flow meters (Air Products, Allentown, PA). Only oxygen was delivered to the chamber for a 30-min long equilibration period. Subsequently, either isoflurane (Baxter PPD, Liberty Corner, NJ) at 0.17, 0.34, 0.51, 0.69, or 0.86 MAC corresponding to 0.25%, 0.50%, 0.75%, 1.00%, or 1.25% atmospheres partial pressure respectively, or 2N (PCR Inc., Gainesville, FL) at 0.30, 0.60, or 0.9 predicted MAC corresponding to 1.25%, 2.50%, or 3.75% atmospheres partial pressure, respectively, was added to the oxygen using conventional anesthesia vaporizers. MAC for isoflurane was taken as 1.45% atmospheres partial pressure. MAC for 2N was calculated from its oil/gas partition coefficient of 43.5 (5) and the Meyer-Overton relationship that MAC x (oil/gas partition coefficient) = 1.82 (14), giving a predicted MAC of 4.2% atmospheres partial pressure. Mixed expired carbon dioxide for each animal was measured by capnography (Ohmeda model 5250 capnograph, Louisville, CO).
Rats were studied at each dose of each inhaled compound for 2 h. Ambient temperature was 22°C. During the first hour, baseline measurements of rectal temperature and mixed expired carbon dioxide were made every 10 min. After 1 h, plastic bags filled with ice were applied around the PlexiglasTM chambers for an additional hour, to trigger thermoregulatory responses to hypothermia. Measurements of carbon dioxide and temperature were continued every 10 min until the end of study. Isoflurane and 2N concentrations were analyzed by using gas chromatography (Gow-MAC Instrument Corp., Bridgewater, NJ). No animal was allowed to get colder than 32.0°C.
Three parameters were determined by three blinded observers using plots of mixed expired carbon dioxide versus time (after a 30-min equilibration period) for every animal at each dose of study compound. The parameters were 1) the minimum carbon dioxide plateau; 2) the maximum carbon dioxide plateau; and 3) the first point at which there was a sustained increase in carbon dioxide above the minimum. From these parameters, three thermoregulatory parameters were derived: 1) the thermoregulatory threshold temperature, which was the temperature at which there was a sustained increase in carbon dioxide; 2) the gain (in mm Hg/degree centigrade), which was calculated by using least squares linear regression of the points connecting the maximum and minimum carbon dioxide plateaus; and 3) the maximum response, which was defined by the ratio of the maximum carbon dioxide plateau to the minimum carbon dioxide plateau (Fig. 1).
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The thermoregulatory responses for each animal at each dose of study drug were taken as the median value from the blinded observers. The thermoregulatory parameters for each drug at its various doses were compared by using one-way analysis of variance and a Student-Newman-Keuls test. P < 0.05 was considered statistically significant.
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Results |
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Baseline core temperatures were comparable before administration of isoflurane versus 2N. Isoflurane produced a concentration-dependent reduction in the threshold for nonshivering thermogenesis, from 38.6°C (oxygen only) to the cutoff value of 32.0°C (at 0.86 MAC isoflurane) (P < 0.001). In contrast, 2N did not significantly decrease the threshold except at the highest partial pressure tested (0.9 MAC predicted) (P = 0.021 for analysis of variance, with P < 0.05 by Student-Newman-Keuls test for comparison of the oxygen control group with that receiving 0.9 MAC predicted of 2N). At 0.9 predicted MAC of 2N, the threshold was 37.3°C. This decline of 1.3°C from control animals breathing oxygen was one-fifth the 6.6°C decrease seen with a comparable MAC fraction of isoflurane (Fig. 2).
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Isoflurane also decreased the maximal carbon dioxide response (Fig. 3) (P < 0.001). However, unlike the threshold for nonshivering thermogenesis, the decrease was only significant (P < 0.05) at isoflurane concentrations exceeding 0.34 MAC. 2N did not affect the maximal carbon dioxide response (P = 0.28). No concentration of isoflurane (P = 0.80) or 2N (P = 0.54) affected the gain.
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Discussion |
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Homeothermic species tightly regulate core body temperature. In humans, the normal range of core temperatures, as defined by the sweating-to-vasoconstriction interthreshold range, is only about 0.2°C (15). In adults, the first autonomic response to hypothermia is arteriovenous shunt vasoconstriction. In contrast, shivering is observed only when body temperature decreases an additional 1°C (16). Rodents and other small animals use nonshivering thermogenesis instead of shivering as their primary defense against hypothermia (17). Nonshivering thermogenesis is therefore the thermoregulatory defense most commonly evaluated in rodent studies, and that is the response we tested.
The thermoregulatory effects of anesthetics and sedatives are far better characterized in humans than experimental animals. Isoflurane decreases the threshold for vasoconstriction and shivering in humans, 0.9 MAC decreasing these thresholds approximately 4.5°C (9). A similar MAC-fraction of isoflurane produced an equal or greater decrease in the nonshivering thermogenesis threshold in rats (6.6°C) even though volatile anesthetics peripherally impair nonshivering thermogenesis (18). Thus, anesthetics profoundly impair thermoregulatory response thresholds in both species.
The effects of isoflurane on the vasoconstriction threshold were initially thought to be rectilinear. However, subsequent research showed disproportionately greater decreases in vasoconstriction and shivering thresholds produced by higher anesthetic partial pressures of isoflurane (9) or desflurane (19). In our study, isoflurane appeared to linearly decrease the nonshivering thermogenesis threshold in rats (Fig. 2), although one might imagine a curving downward at the highest applied concentration of isoflurane (and recall that we stopped the study at 32°C and thus underestimated the decrease at this highest concentration). Whether this is a general feature of thermoregulatory responses in rodents or specific to nonshivering thermogenesis remains to be determined.
In humans, isoflurane anesthesia significantly reduces the maximum intensity of shivering (13). This result is consistent with our current observation that concentrations exceeding 0.34 MAC progressively decreased the maximum response intensity in rats, halving the response at approximately 0.9 MAC. Thus, in rats, isoflurane markedly decreased the threshold for nonshivering thermogenesis and the maximum intensity of this response.
In contrast, the nonimmobilizer 2N minimally affected the threshold and maximum intensity of nonshivering thermogenesis, and then only at the highest test concentration. That is, isoflurane profoundly impaired thermoregulation whereas 2N did not. The nonimmobilizer 2N does not affect thermoregulation. This lack of effect parallels its actions on mobility and nociception. Such results differ from the concentration-dependent capacity of 2N to impair learning and memory as measured by fear conditioning.
This has practical consequences for animal studies involving 2N. Core temperature tends to decline in animals exposed to anesthetics. Because this can interfere with behavioral measurements [e.g., MAC declines as core temperature decreases (20)] maintenance of normothermia is essential in animal studies of anesthetic action. This is only a minor issue with the nonimmobilizer 2N, because thermoregulatory defenses remain intact.
Hypothermia is an undesirable side effect of general anesthetics. The minimal or absent capacity of 2N to depress thermoregulatory mechanisms means that it may serve as a tool in studies of mechanisms by which anesthetics depress these mechanisms. A putative site that mediates the depression produced by anesthetics should be influenced by anesthetics but not by 2N. Whether other nonimmobilizers also have minimal effects on thermoregulation remains to be tested.
In summary, the nonimmobilizer 2N has essentially no effects on thermoregulation. Isoflurane strongly inhibits thermoregulation in rats by reducing the thermoregulatory threshold and response intensity.
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Acknowledgments |
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This work was supported, in part, by National Institutes of Health Grants 1P01GM47818 and GM58273, and the Joseph Drown Foundation.
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Footnotes |
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This work, in part, has been submitted for presentation at the Annual Meeting of the American Society of Anesthesiologists, San Francisco, CA, October 2000.
EIE, II, is a paid consultant to Baxter Pharmaceutical Products, Inc.
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References |
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- Chortkoff B, Bennett H, Eger EI. Subanesthetic concentrations of isoflurane suppress learning as defined by the category-example task. Anesthesiology 1993; 79: 16–22.[Web of Science][Medline]
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Sessler DI. Perioperative hypothermia. N Engl J Med 1997; 336: 1730–7.
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[Abstract/Free Full Text] - Ikeda T, Sessler DI, Tayefeh F, et al. Meperidine and alfentanil do not reduce the gain or maximum intensity of shivering. Anesthesiology 1998; 88: 858–65.[Web of Science][Medline]
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[Abstract/Free Full Text] - Lopez M, Sessler DI, Walter K, et al. Rate and gender dependence of the sweating, vasoconstriction, and shivering thresholds in humans. Anesthesiology 1994; 80: 780–8.[Web of Science][Medline]
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[Abstract/Free Full Text]
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