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Anesth Analg 2004;98:1305-1311 © 2004 International Anesthesia Research Society doi: 10.1213/01.ANE.0000108484.91089.13
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Abstract |
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Exposure to general anesthesia may contribute to postoperative cognitive impairment in elderly patients, but the relationship remains poorly understood. We investigated whether aged mice, 18–19 mo, are more susceptible to postanesthetic cognitive impairment than young mice, 3–4 mo, using spatial memory (Barnes maze) and psychomotor (rotarod) tasks. Initially we studied the effect of a single anesthetic episode on asymptotic maze performance. We then tested whether repeated anesthesia would impair spatial memory and psychomotor performance to a greater extent in aged mice. Mice were anesthetized with isoflurane (1.4% atm) for 30 min; controls received 90% oxygen. Anesthesia, administered during the asymptotic period of maze learning, did not impair performance tested the following day (P > 0.05). Repeated anesthesia, 2–3 h after each session, did not impair overall maze or rotarod performance in young or aged mice (P > 0.05). Spatial learning appeared to be facilitated by anesthesia, F(1,204) = 7.97, P < 0.01 for pooled results. Asymptotic performance—when learning had stabilized—remained unimpaired in both the maze and rotarod tasks. These results suggest that an age-related risk of anesthetic-induced impairment appears to be limited to acquisition of a novel motor skill and that anesthesia alone does not lead to prolonged cognitive impairments in aged mice.
IMPLICATIONS: This study demonstrates that repeated isoflurane general anesthesia impaired psychomotor performance in aged mice during the initial learning period; however, spatial learning improved and, overall, spatial memory and psychomotor performance were unimpaired. Thus, general anesthesia alone does not appear to result in prolonged cognitive deficits in aged mice.
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Introduction |
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Persistent cognitive impairment after surgery and anesthesia is an important clinical problem. Elderly patients are at the most risk of developing prolonged cognitive impairment (1–3), with as many as 25% impaired 1 wk after surgery (3). These deficits, including difficulties with fine-motor coordination and impaired high-level cognitive functions, can increase patient morbidity, inconvenience and stress family members, and reduce patients’ quality-of-life. Though various causes have been proposed (4), exposure to general anesthesia is frequently cited as a potential risk factor (2,5–7). Clinical studies have provided clues about the role of anesthesia but are inherently limited in their ability to discriminate the effect of anesthesia from the physiological and psychological effects of surgery and often do not control for factors known to influence cognition such as postoperative medications. Alternatively, animal experiments allow anesthesia to be studied independently of surgery and permit greater experimental control. Currently, few studies have explored the relationships among age, anesthesia, and cognitive function in animals, and results are inconsistent. A study by van der Staay et al. (8) showed that general anesthesia with halothane and thiopental, administered on separate days, did not impair spatial working or reference memory in young (6 mo) or aged rats (30 mo). In contrast, Culley et al. (9) suggested that aged rats (18 mo) may experience sustained spatial learning impairments after a single episode of general anesthesia with isoflurane and nitrous oxide, and that young rats’ performance might actually improve. In both studies, general anesthesia was administered after learning had stabilized; therefore, it is possible that the effects of a single episode of anesthesia are too subtle to cause a substantial or consistent impairment, particularly on a well-learned task. Thus, the question of whether general anesthesia itself leads to prolonged cognitive impairment in aged rodents remains unanswered.
The overall aim of our study was to investigate whether general anesthesia alone leads to prolonged cognitive impairment in mice and whether age is a risk factor. We included both a spatial memory and a psychomotor task to determine whether the effects of general anesthesia are consistent across different cognitive domains. Initially, we tested whether a single exposure to general anesthesia would impair spatial memory performance when administered during the asymptotic learning period, after learning had stabilized. To address the possibility that deficits produced by a single anesthetic episode might be too subtle to detect, we attempted to augment the effect by repeatedly anesthetizing mice 2–3 h after every training session. We hypothesized that repeated general anesthesia with isoflurane would impair spatial and psychomotor learning and memory, compared with controls, and that aged mice would be more susceptible to anesthetic-induced impairments than young mice. The design of our repeated anesthesia experiments also allowed us to explore whether anesthesia impairs task acquisition more than asymptotic performance.
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Methods |
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After approval by the University of British Columbia Animal Care Committee 50 young (3–4 mo) and 50 aged (18–19 mo) female C57BL/6 mice were obtained from the National Institute of Aging. C57BL/6 mice were used because of the well established aging literature with this strain. Mice were identified with a 12-mm transponder (AVID Identification Systems Inc., Calgary, AB) injected subcutaneously, via a 12-gauge needle, dorsolaterally between the fore and hindlimb, using aseptic techniques, 3–4 days before experimentation. Mice were housed in groups of 10 with 12-h dark-light cycle (lights on from 6 AM to 6 PM) and had access to food and water ad libitum.
Spatial learning and reference memory were tested using the Barnes circular maze, adapted for mice (10). The Barnes maze was chosen for three primary reasons. First, it has been shown to be sensitive to age-related as well as pharmacologically-induced cognitive impairment (11). Second, a well-defined learning curve with rodents can be established using the Barnes maze (10,11). Third, the Barnes maze has advantages over other common methods for measuring spatial learning and memory, the radial arm maze, and the Morris water maze. Specifically, bright light, which is the motivating stimulus to escape the Barnes maze, is less stressful for the mouse than is forced swimming (which is required in water maze tasks), and dietary restriction, which is required in radial arm tasks that use food as a reinforcer, is not necessary (11). Reference memory refers to memory for information that is useful across all task sessions, in contrast to working memory in which information is used later in the same session. The maze, elevated 54 cm off the ground, was a white acrylic disk, 122 cm in diameter, with 40 holes (5 cm diameter) equidistant from each other and 5 cm from the perimeter. One of the holes was designated as an escape hole and led to a darkened chamber directly underneath the maze. Each mouse was randomly assigned to a different escape hole that remained constant for that mouse across all training sessions. Three 500-watt lights were placed over the maze. Spatial cues surrounding the maze remained constant throughout the experiments and included a bench and two cabinets, window blinds, a white and gray tiled wall, and a divider. For each session, the mouse was placed in the center of the maze, within a cylindrical tube. The investigator stepped outside the testing area and lifted the cylinder with a rod, allowing the mouse to explore. Once the mouse located the escape hole and entered the chamber underneath, the lights were turned off, and the time was recorded. If the mouse did not escape after 5 min, it was placed in the escape chamber by the investigator (for 30 s) and given a score of 300 s. The maze was wiped with distilled water before and after each mouse. All testing was performed between 8 AM and 11 AM.
In the single anesthesia experiment, young (n = 10) and aged (n = 10) mice were trained for 15 consecutive days, by which time mice achieved asymptotic performance. Two to 3 h after the fifteenth session, half the young and half the aged mice were randomly chosen and anesthetized for 30 min with isoflurane. Performance was tested 21–22 h later.
In the repeated anesthesia experiment, a naive batch of young (n = 20) and aged (n = 20) mice were randomized to anesthesia and control groups. Mice were trained on the Barnes maze for 12 consecutive days; however, 2–3 h after each training session, mice in the anesthesia group were anesthetized for 30 min with isoflurane (Fig. 1). Control mice were placed in the same chamber with oxygen alone.
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An accelerating rotarod was used to test psychomotor performance because of its well-defined learning curve and sensitivity to age and to sedative-hypnotics (12,13). The rod was 3.2 cm in diameter, 60 cm long, covered with duct tape to create a non-slippery surface, and elevated 30 cm over woodchip bedding. The apparatus contained five sections permitting five mice to be tested simultaneously. The rod was attached to a DC motor and accelerated from 0–40 rpm over 90 s. Motor control and data collection were done with MacLab 2.0. On consecutive daily sessions mice were placed on a stationary rod and acceleration was initiated. For each session, the time to fall off the rod was averaged over 5 trials, with a 1-min break between each trial. All testing was performed between 8 AM and 10 AM.
A naive batch of young (n = 20) and old (n = 20) mice was randomly assigned to anesthesia and control groups. For each daily session, the time to fall off the accelerating rotarod (to a maximum of 90 s) was recorded and averaged over 5 trials. Mice from the anesthesia group were anesthetized for 30 min with isoflurane 2–3 h after the rotarod task (Fig. 1). Control mice were placed in the same chamber with oxygen.
General anesthesia was induced and maintained within a closed chamber system. The chamber, constructed of a 7-mm thick clear Plexiglas cylinder, was 54 cm in length and had a 10-cm internal diameter. A flat mesh grill was placed inside the chamber to prevent airway blockage and permit adequate distribution of anesthetic vapor, facilitated by an internal fan. A compartment containing soda lime was used to scavenge exhaled CO2.
Ten mice were placed in a chamber at one time. The chamber was then flushed with 100% oxygen until the concentration reached 95%. The oxygen was then turned off and liquid isoflurane injected to create a closed anesthetic system and a constant anesthetic concentration. The volume of anesthetic injected, 0.6 mL, was estimated using a previously established method (14) and verified using an Ohmeda gas analyzer to produce an atmospheric concentration of 1.4%, close to the accepted minimal alveolar concentration (MAC95) value for C57BL/6 mice (15). This concentration maintained anesthesia for all mice. To ensure the mice were anesthetized, the righting reflex was assessed every 5 min by rotating the chamber. The experimenters responsible for behavioral testing were blinded as to the treatment assignment.
The dependent variables were latency to enter the escape hole and latency to fall off the rotarod, presented as means ± SEM. Repeated-measures analysis of variance (ANOVA) was used to assess the effects of sessions, treatment, and age. Wilcoxon’s ranked-sum test was used to assess the effect of anesthesia on retention in the first experiment. Statistics were performed with Number Cruncher Statistical Systems 2001 (NCSS and PASS, Kaysville, UT.).
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Results |
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Single Anesthesia After Spatial Learning Stabilized
An overall analysis of sessions showed main effects for age F(1,18) = 8.61, P < 0.01 and session F(14,252) = 18.22, P < 0.001. There were no significant interactions. During asymptotic performance, latency to find the escape hole was not significantly affected by anesthesia in either young or old mice, compared to age-matched controls, P > 0.05 (Fig. 2). Four of five aged mice actually performed better after anesthesia (Fig. 2b).
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Repeated Anesthesia Throughout Maze Training
An overall analysis with age as a factor showed no main effect or interaction effects attributable to age; thus the data from the young and old mice were pooled for all subsequent analysis. Spatial memory improved over the course of the training sessions in all mice, F(10,340) = 15.79, P < 0.001 (Fig. 3). There were no main or interaction effects attributable to treatment. A regression analysis confirmed that the last 4 sessions were asymptotic; thus, a separate analysis was performed on the acquisition period, sessions 2–8, which indicated there was a significant main effect for treatment F(1,204) = 7.97, P < 0.01 and session F(6,204) = 16.64, P < 0.001, with no interactions. Mice that received anesthesia escaped the Barnes maze faster than the control mice.
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Four aged mice were killed before experimentation because of severe dermatitis and scratching, known to be particularly severe in the C57BL/6 strain (16), and they were not included in analysis.
Repeated Anesthesia Throughout Rotarod Training
Psychomotor learning improved over the course of the training sessions in all mice, F(8,272) = 13.05, P < 0.001 (Fig. 4). An overall analysis revealed a significant main effect for age, F(1,34) = 10.13, P < 0.01, but no significant treatment effect, age x treatment interaction, or treatment x session interaction. Analysis of the acquisition period (sessions 2–6) indicated that the rate of psychomotor learning may have been impaired by anesthesia in the old mice, F(1,64) = 8.63, P < 0.01, although maximum performance did not differ (Fig. 4b). This effect was not observed in the young mice (Fig. 4a).
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Two old mice from the anesthesia group were killed after the first 5 days of experimentation because of severe dermatitis and were not included in analysis. The young and old mice weighed 24.1 ± 2.0 g and 27.6 ± 1.8 g, respectively.
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Discussion |
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A single exposure to general anesthesia after learning on a spatial memory task stabilized did not impair performance in young or old mice. Repeated general anesthesia throughout behavioral training did not impair overall performance in either a spatial memory or a psychomotor task in young or aged mice. Acquisition of the spatial memory task appeared to be facilitated by repeated anesthesia, regardless of age, but this effect was not observed in the psychomotor experiment. Taken together, these results indicate that exposure to general anesthesia, even when repeated daily throughout behavioral training, does not result in long-term cognitive deficits in aged mice.
The absence of cognitive impairment on a prelearned task after a single administration of general anesthesia is consistent with a comparable study by van der Staay et al. (8), who tested the effects of general anesthesia on spatial memory in young (6 month) and aged (30 month) rats, using a holeboard discrimination task. After performance had stabilized (after 22 days), rats were anesthetized with halothane for 60 minutes. Behavioral testing resumed 24 hours later and continued for 5 days, without showing any impairment on spatial working or reference memory. The rats were subsequently anesthetized with thiopental, 25 mg/kg IV. Again, testing resumed 24 hours later and continued for 4 more days with no significant impairment observed. In contrast, Culley et al. (9) reported that the effects of a single anesthetic administration may persist in aged rats. Rats were trained on a 12 arm radial maze task to standardized performance criteria and subsequently anesthetized with isoflurane (1.2% in 70% nitrous oxide/30% oxygen) for 2 hours. After 24-hour recovery, retention was retested for 6 consecutive days during the first and third week after recovery. Anesthesia appeared to attenuate further improvement in performance in the aged mice compared with controls. The conflicting results may have stemmed from differences in the sensitivity of behavioral task used in these studies; however, it is more likely that the effects of a single anesthetic are subtle, and particularly difficult to detect on a well-learned task. Accordingly, we anticipated that repeated general anesthesia might augment the effects.
After anesthetizing mice daily, 2–3 hours after each training session on the Barnes maze, we found no overall impairment in spatial reference memory performance in young or old mice. In fact, anesthesia appeared to facilitate learning during the acquisition period in both age groups, compared with controls. Though unexpected, improved postanesthetic spatial memory has been previously reported with young mice (17) and rats (9). It is possible that anesthesia enhances consolidation of the memory trace (17) and/or decreases retroactive interference; although the latter is unlikely because there were no cognitively challenging tasks performed by the mice after the maze task. In any case, these results cast doubt on the assumption that general anesthesia impairs higher level cognitive functioning.
We also found that overall psychomotor performance was not impaired by repeated general anesthesia and that anesthetized mice reached the same asymptotic performance as controls, in both age groups. This result is consistent with our maze results. In contrast to the maze experiments, however, anesthesia impaired performance in aged mice during the acquisition period. Although statistically significant, the result is strongly influenced by the aberrant performance on session 3, and does not appear to represent an actual anesthetic-induced impairment.
The design of our repeated anesthesia studies also permitted exploration of retrograde and anterograde effects of anesthesia. Retrograde amnesia refers to an impaired ability to store or recall information acquired before anesthesia, and anterograde amnesia refers to an impaired ability to acquire information after anesthesia. Because anesthesia is produced 2–3 hours after each training session, the retrograde effects, if any, are expected to be stronger than the anterograde effects. Anesthetic-induced retrograde amnesia, which has been suggested to result from a disruption of neuronal processes necessary for memory consolidation (18,19), might explain the deficits during acquisition of the rotarod task in aged mice but would not explain improved spatial memory acquisition, which, as mentioned earlier, has been suggested to result from enhanced consolidation by anesthesia (17). The processes underlying these apparently contradictory effects require future study.
Although neither of our repeated anesthesia experiments showed prolonged deficits in the mice, Blokland et al. (20) reported that repeated general anesthesia is a biological factor that affects cognitive aging. Using a cohort study design, rats were trained on a choice reaction time task, anesthetized for 2–3 hours (pentobarbital 20 mg/kg IP), and tested 2 days later, every 2 months from the age of 6 months to 23.5 months. A final testing session occurred at 26 months. No significant impairments on motor time were detected at any time point; however, there was a decrease in mean reaction time and an increase in error rate in anesthetized rats at the last 2 test sessions, at 23.5 and 26 months of age. Interpretation of the results is limited by a few study caveats. Most notably, control rats were not handled the same as treated rats (i.e., did not receive sham injections), which may account for the subtle differences between the groups. In addition, rats were not anesthetized before the 26-month test thus the reason for the performance differences is not clear. Finally, the differences between anesthesia and control in the last 2–3 test sessions were not significant at the 0.05 critical level.
Our study had a number of potential limitations. The aged mice in the repeated anesthesia Barnes maze experiment were not impaired compared with the young mice. One of the arguments supporting the hypothesis of increased risk of cognitive impairment in aged animals after anesthesia rests on the assumption that the aged brain is already impaired (21). It is possible that this batch exhibited "healthy aging" and that mice at more extremes of age may exhibit performance deficits after exposure to repeated anesthesia; although, some investigators have failed to detect anesthetic-induced spatial memory impairments despite significant age-related impairments (8). Second, general anesthesia in our study was induced and maintained with a single volatile anesthetic, isoflurane. Clinically, however, combinations of anesthetics and adjuvant drugs, including opioids, benzodiazepines, and other drugs with antimuscarinic and anticholinergic properties, are often used. Furthermore, anesthetic-induced cognitive impairment may be drug specific. Thus, although isoflurane may not be neurotoxic (it is possibly even neuroprotective), studies have reported that nitrous oxide and ketamine can have neurotoxic effects in rats (22,23). Third, the MAC requirements of inhaled anesthetics are reduced by approximately 17% in both old humans (24) and rats (25); however, this would indicate that the aged mice received a larger dose of anesthetic, which should theoretically increase the chance of producing impairments.
In summary, our results demonstrate that a single episode of anesthesia is unlikely to cause an impairment in well-learned tasks regardless of age, that repeated general anesthesia may influence acquisition without affecting asymptotic performance, and that anesthesia has differential effects across cognitive domains, whereby psychomotor learning is impaired in aged mice, but spatial reference memory task acquisition is improved in young and aged mice. Taken together, these results suggest that general anesthesia alone may contribute to a certain degree of impairment in the acquisition of motor skills in the elderly but does not contribute to impairment in higher level cognitive function such as spatial memory and does not lead to prolonged cognitive impairment.
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Acknowledgments |
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Supported, in part, by the Shaughnessy Hospital Volunteer Society Fellowship in the Health Care and the Gertrude Langridge Graduate Scholarship in Medical Sciences.
We thank Mr. C. Caritey for building the maze, the rotarod device and the anesthetic chamber, Messrs. K. J. Burkat, S. Sharma and Ms. C. A. Federico for their assistance in data collection, and Dr. M. J. A. Walker and Dr. L. G. Franciosi for their comments in preparation of this manuscript.
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Footnotes |
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Presented, in part, at the 76th Annual International Anesthesia Research Society Congress, March 16–20, 2002.
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References |
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