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Effects of depth of isoflurane anaesthesia on a cognition task in mice

2008; Elsevier BV; Volume: 101; Issue: 3 Linguagem: Inglês

10.1093/bja/aen228

1471-6771

Ana M. Valentim, Hélio Alves, Aura Silva, I. Anna S. Olsson, L. Antunes,

Anesthesia and Sedative Agents

Editor—Several clinical studies have suggested the existence of postoperative cognitive dysfunction (POCD), especially in elderly patients.1Dodds C Allison J Postoperative cognitive deficit in the elderly surgical patient.Br J Anaesth. 1998; 81: 449-462Abstract Full Text PDF PubMed Scopus (116) Google Scholar 2Monk TG Weldon BC Garvan CW et al.Predictors of cognitive dysfunction after major noncardiac surgery.Anesthesiology. 2008; 108: 18-30Crossref PubMed Scopus (1032) Google Scholar However, human studies carry many variables.3Moller JT Cluitmans P Rasmussen LS et al.Long-term postoperative cognitive dysfunction in the elderly ISPOCD 1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction.Lancet. 1998; 351: 857-861Abstract Full Text Full Text PDF PubMed Scopus (1808) Google Scholar As the sole effects of anaesthesia are difficult to study, we used mice without performing surgery to study the role of anaesthesia in cognitive dysfunction. Thirty 10–12-week-old inbred male mice (approved by DGV, Portugal) were randomly assigned into three groups: control group (animals not anaesthetized); Group I (anaesthetized with 1% isoflurane); and Group II (anaesthetized with 2% isoflurane). The animals were placed individually in an induction chamber, and anaesthesia was induced with 3% isoflurane (Isoflo, Esteve Farma, Carnaxide, Portugal) in 100% oxygen with a delivery rate of 5 litre min−1 until loss of righting reflex. After induction, the animals were moved into a plastic zip bag and placed in dorsal recumbence. Anaesthesia was then maintained with isoflurane in 100% oxygen with a flow of 1.5 litre min−1. Heart rate and ventilatory frequency were recorded over intervals of 10 min. Body temperature was maintained at 37±2°C by a homeothermic blanket (N-HB101-S-402, Panlab, Barcelona, Spain) placed under the zip bag. Animals remained anaesthetized for 1 h. Isoflurane concentration was monitored in the exhausted air with an agent gas monitor (Datex Capnomac Ultima, Helsinki, Finland), and no stimuli were applied. At recovery, all animals received 100% oxygen until the gain of righting reflex. Animals from the control group were not anaesthetized; however, they were manipulated and placed inside the induction chamber for 1 min (average time until loss of the righting reflex in anaesthetized animals) and were thereafter returned to their home cage to avoid isolation stress. One week before the procedure, a food restriction schedule was established to ensure feeding motivation in the spatial learning task.4Valentim AM Alves HC Olsson IA Antunes LM The effects of depth of isoflurane anesthesia on the performance of mice in a simple spatial learning task.J Am Ass Lab Animal Science. 2008; 47: 16PubMed Google Scholar At 28 and 56 h after anaesthesia, mice were tested in an eight-arm radial maze (RAM) where animals had to find a piece of cereal. During the test, only one of the choice arms was baited, and this arm remained the same throughout the experiment. Each trial was over when the mouse entered the correct arm and ate the reward. Each animal made 15 test trials per session. An error was recorded when a mouse entered an unrewarded arm. Number of errors before correct choice in each trial, and time to complete the trial was also recorded. Student's t-testing for independent samples showed that Group II had a significantly higher heart rate (P<0.0004) and a lower ventilatory frequency (P<0.0002) 20 min after induction of anaesthesia compared with Group I. No differences were detected between the groups concerning the number of errors and time to complete the task using repeated measures ANOVA. Twenty-eight hours post-anaesthesia, the control group had a higher number of trials with zero errors and a lower number of trials with one error compared with Group II, using Kruskal–Wallis and Mann–Whitney test (Fig. 1). At 56 h post-anaesthesia, animals did not show any difference at this level. Some studies showing cognitive impairment after surgery have indicated anaesthesia as one of the possible causes.1Dodds C Allison J Postoperative cognitive deficit in the elderly surgical patient.Br J Anaesth. 1998; 81: 449-462Abstract Full Text PDF PubMed Scopus (116) Google Scholar However, there are very few studies relating depth of anaesthesia and cognitive dysfunction.5Farag E Chelune GJ Schubert A Mascha EJ Is depth of anesthesia, as assessed by the bispectral index, related to postoperative cognitive dysfunction and recovery?.Anesth Analg. 2006; 103: 633-640Crossref PubMed Scopus (109) Google Scholar In rodents, the majority of studies compare cognitive performance of anaesthetized and non-anaesthetized animals.6Culley DJ Baxter MG Yukhananov R Crosby G Long-term impairment of acquisition of a spatial memory task following isoflurane–nitrous oxide anesthesia in rats.Anesthesiology. 2004; 100: 309-314Crossref PubMed Scopus (247) Google Scholar Our previous study4Valentim AM Alves HC Olsson IA Antunes LM The effects of depth of isoflurane anesthesia on the performance of mice in a simple spatial learning task.J Am Ass Lab Animal Science. 2008; 47: 16PubMed Google Scholar showed that the lowest isoflurane concentration impaired learning of mice in a T-maze test. In the present study, we used RAM in order to avoid possible ceiling effects of the T-maze task. Both studies had the main concern of comparing cognition between animals anaesthetized with two very different levels of isoflurane and non-anaesthetized animals without the confounding effects induced by surgical procedures. The number of errors showed no difference between the groups. This is the most important measure to evaluate the cognitive performance of mice because it indicates the animals’ decisions. Moreover, the only difference detected (number of trials with 0 and 1 error) was not presented 56 h post-anaesthesia, indicating the lack of long-lasting effects on this memory task. In general, the highest depth of isoflurane did not cause cognitive impairment compared with a lower anaesthetic level and with non-anaesthetized adult mice. Hence, in this case, higher concentrations of anaesthetics may be used without compromising cognition. Further studies involving humans should minimize the variables inherent to clinical studies in order to evaluate the true effect of the anaesthesia in POCD. Fundação para a Ciência e Tecnologia (POCTI/CVT/59056/2004).