1Department of Anaesthesiology, University Hospital Charité, Campus Charité Mitte, Schumannstrasse 20/21, D-10117 Berlin, Germany. 2Department of Psychology, University of Michigan, Ann Arbor, Michigan, USA. 3Department of Anaesthesiology, University Hospital Eppendorf, Hamburg, Germany*Corresponding author
Accepted for publication: November 12, 2001
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Abstract |
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Methods. We studied 49 patients during recovery from general anaesthesia (isoflurane/nitrous oxide or propofol) to assess implicit and explicit memory function in relation to mid-latency MnSSER. The MnSSER recordings were made before anaesthesia, during steady-state anaesthesia, and at the end of the recovery period. The patients were interviewed 24 h later about their memory for the immediate wake up phase. Statistical analysis was by multivariate analysis of variance.
Results. Out of 49 patients, 23 recalled the recovery period, 11 had implicit memory for an object shown to them during the recovery period, and 15 did not have any memory for the recovery period. At RECOVERY the patients with recall had significantly shorter MnSSER latencies N45 and P50 and inter-wave conduction times LatN35 LatP45 than patients without memory (P<0.05).
Conclusions. We conclude that MnSSER components warrant further investigation for studying the effects of anaesthetic drugs on cognitive function.
Br J Anaesth 2002; 88: 3628
Keywords: somatosensory evoked responses, memory, anaesthesia
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Introduction |
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Median nerve somatosensory evoked responses (MnSSER) have not been studied in relation to memory during anaesthesia. However, MnSSER can be part of standard monitoring for neurosurgical, vascular, or orthopedic procedures, when nervous structures are at risk during the operation. Therefore, it is interesting to find out if they provide further information about cerebral signal processing other than information about the integrity of the sensory pathway. MnSSER can indicate cortical arousal during surgical stimulation.3 We do not know if they indicate the analgesic component during anaesthesia, whereas the AER may reflect the hypnotic component.4 5 We have shown, that MnSSER changes in relation to clinical awakening during recovery from general anaesthesia.6 Theoretically, MnSSER could be used for monitoring during anaesthesia, if AER recording was not practical, for example as a result of hearing problems in patients.
We set out to describe memory and mid-latency MnSSER during recovery from general anaesthesia. The recovery period was chosen because the incidence of persistent memory during surgical anaesthesia is supposed to be low. The present investigation describes memory performance, while recovery of MnSSER with decreasing anaesthetic dose has been published previously.6
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Patients and methods |
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Anaesthesia
All patients were given midazolam 7.5 mg orally as a pre-medication 45 min before anaesthesia. According to their date of birth, patients were allocated to two different anaesthetic treatments. In one group, anaesthesia (n=20) was induced with propofol 2 mg kg1, sufentanil 0.5 µg kg1, and vecuronium 0.1 mg kg1. After tracheal intubation, anaesthesia was maintained with propofol 8 mg kg1 h1. Supplementary doses of sufentanil 0.25 µg kg1 were given as necessary. The patients in the other group (n=29) received etomidate 0.3 mg kg1, fentanyl 1.5 µg kg1, and vecuronium 0.1 mg kg1 for induction of anaesthesia. After trachea intubation, anaesthesia was with isoflurane 0.6% (end-tidal) in nitrous oxide/30% oxygen supplemented with doses of fentanyl 0.5 µg kg1. At the end of surgery, when median evoked responses had been recorded during anaesthesia, the administration of the anaesthetics was stopped and 100% oxygen was given (fresh gas flow 3 litre min1). When breathing was adequate, the tracheal tube was removed.
Memory assessment
When the patients regained consciousness and opened their eyes spontaneously after anaesthesia, they were asked to name precisely an object that they were shown. This was a red booklet, which was opened and closed in front of them. They were asked to keep this booklet in mind.
The next day, the patients were asked about their memory after immediate waking using a structured interview. They were asked a broad variety of questions, and the relevant questions are listed in Table 1. If they did not recall anything spontaneously, five different objects including the red booklet were shown to them. They were asked to point at one of the objects.
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MnSSER recording
The day before surgery the patients were accustomed to MnSSER recording to obtain awake baseline values. The MnSSER recording was performed in a standardized way with an Evomatic 4000® system (Dantec, Copenhagen, Denmark). In preference the right median nerve was stimulated, but if the planned operation made that difficult, the median nerve was used. The individual sensory and motor threshold was defined. The stimulus intensity was increased to the individual level of tolerance and kept constant throughout the whole study. Two replicate baseline recordings were performed. The stimulus frequency was 3 Hz, with a monophasic rectangular pulse of 0.2 ms. The MnSSER waveforms were recorded simultaneously on three amplifier channels using sterile platinum needle electrodes placed over the ipsilateral brachial plexus (Erbs point), the spinous process of the sixth cervical vertebra and the contralateral cortical hand area at the scalp (C3' or C4'). A frontal reference (Fpz) was used. Electrode impedances were kept below 10 k. For the baseline data a post-stimulus period of 90 ms was analysed, during anaesthesia and recovery a period of 180 ms. For each response, 200 stimuli were averaged and stored on disk for later analysis. The Evomatic device includes an automatic artefact rejection mode, and the evoked responses at Erbs point and at the spinous proces level served as a control for artefacts, analysed by visual inspection. The latencies and the peak-to-peak amplitudes were obtained using a software package (EvoPC®, Müller, Hamburg, Germany). The following peak latencies were obtained: N10 at Erb, N13 at C6 and three negative components (N20, N35, N50) and two positive peaks in between (P25, P45) at the scalp.
Two replicate MnSSER recordings were performed the day before surgery (AWAKE), during anaesthesia after surgery had finished (ANAESTHESIA) and when the patients opened their eyes spontaneously and named the shown object correctly after anaesthesia (RECOVERY).
Clinical measurements
We recorded heart rate (beats min1), mean arterial pressure (mm Hg), percutaneous oxygen saturation (%), and arm and body temperature, at the time the MnSSER recording was made. During and after anaesthesia the end-tidal carbon dioxide concentration was measured (either from the tracheal tube, or from a face mask, which was applied firmly and the patient was asked to take some deep breaths).
Statistical analysis
The statistical analysis was done using SPSS version 9.0 (Statistical Package for Social Sciences). The patient details of the different groups were compared a posteriori with Scheffés test. The mean and the standard deviations (SD) of the various cortical peak latencies and amplitudes were calculated, and the inter-wave conduction times of the latency components were calculated: LatN20 LatC6 (CCT=central conduction time), LatP25 LatN20, LatN35 LatP25, LatP45 LatN35, and LatN50 LatP45. The distribution of the data was tested by the KolmogorovSmirnov test. The correlation coefficients were separately defined for the five latencies, the five inter-peak latencies, and the four amplitudes.
Inter-group comparisons for the MnSSER latencies (five components), the latency differences (five components), and the amplitudes (four components) for the three memory groups were assessed by multivariate analysis of variance for repeated measurements (MANOVA, Hotellings T-square) including AWAKE and RECOVERY values. Multivariate comparisons were performed for the five latency components, the five inter-peak latency components and the four cortical amplitudes separately at AWAKE, ANAESTH, and RECOVERY values. For each MnSSER component, univariate analysis of variance compared the data at AWAKE and RECOVERY. The sensitivity and specificity were calculated for the significant MnSSER components to define cuff-off values for memory perfomance. P<0.05 was adopted for level of significance for all statistical tests.
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Results |
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MnSSER components
Satisfactory MnSSER traces were obtained at the different measurements from all patients. Figure 1 gives examples of the MnSSER recordings of three patients, one without any memory, one with implicit memory, and one with explicit memory. There was no difference for any of the MnSSER components at AWAKE among the three memory groups. Multivariate analysis showed an overall significant difference between the three groups, comparing the MnSSER data at AWAKE and RECOVERY for the latency components and for the inter-wave conduction times (Table 2AC). The cortical amplitudes did not differ significantly. The MnSSER data at ANAESTH were not included in the multivariate test, because N35 was completely suppressed in seven patients, P45 in 16 and N50 in 22 patients, thus reducing n for statistical testing markedly. However, univariate comparison at ANAESTH revealed significantly shorter latencies N20 and P25, comparing patients of group EXPLICIT with patients of group NO-MEM (P<0.05). The components 35 ms were completely reduced in more patients of group NO-MEM and IMPLICIT than in patients of group EXPLICIT (Fig. 2).
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The MnSSER data of the three memory groups did not differ in relation to the used anaesthetic. However, the changes of latencies P45 and N50 and inter-wave conduction times LatN35 LatP45 and LatP45 LatN50 were significantly correlated with the duration of anaesthesia (P=0.016 for latencies, P=0.007 for inter-wave conduction times).
Clinical measurements
There was no difference among the three memory groups in their physical characteristics (Table 3) or the clinical measurements between the three memory groups at AWAKE, ANAESTH, or RECOVERY. The time of extubation and RECOVERY, when the patients opened their eyes spontaneously, did not differ among the groups. In contrast, the time of anaesthesia was significantly less in the patients of the group EXPLICIT (mean 88 (SD 32) min) than in the group IMPLICIT (113 (40) min), and the group NO-MEM (112 (28) min; Table 2).
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Discussion |
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We wished to assess in a descriptive way the recovery of memory and MnSSER changes in clinical circumstances. We cannot attribute our findings to a single anaesthetic substance or anaesthetic regimen, because the statistical power to evaluate this question is low (three memory groups, two anaesthetic regimens). However, all the patients were pre-medicated with midazolam, a substance to be amnesic.7 A more pronounced effect would have been expected in the patients in whom the total time of anaesthesia was shorter. In contrast, these patients especially, had explicit memory in the present study. Therefore, we concluded that midazolam did not affect our results.
The total time of anaesthesia was significantly shorter in the patients who had recall. Because the infusion rate for propofol and the concentration of isoflurane were fixed, the total quantity of anaesthetic increased with the duration of anaesthesia. Therefore, most probably residual anaesthetic agents would be different in the patients and affect memory performance. The chosen clinical endpoint of the patients responsiveness, that is that all patients were able to recognize and verbally define a shown object, did not allow prediction of the patients memory. Dutton and colleagues8 found no evidence of memory formation in 13 out of 28 patients, as long as the patients did not sustain wakefulness sufficiently long enough to complete four hand squeezes. Unfortunately we did not test this clinical sign.
The latency of the primary cortical complex of the tibial nerve SSER is changed by high doses of fentanyl and sufentanil.9 In the present study the time of the last dose and amount of opioids given per hour did not differ between the groups. Although the effect sizes of the group differences found in the present study do not suggest any clinical relevance, further studies are needed to exclude the effects of opioids on memory performance and/or MnSSER changes.
Our findings support data from volunteer studies, that memory is impaired by subanaesthetic concentrations, when responses to command are still present. Dwyer and colleagues10 showed in 12 healthy volunteers that conscious as well as unconscious memory was completely suppressed at 0.45 MAC isoflurane, while 0.6 MAC nitrous oxide suppressed conscious memory only. Veselis and colleagues11 found a marked reduction in short-term memory capacity and dramatically impaired free recall and recognition during a low-dose infusion of propofol (75 µg kg1 min1) in 10 volunteers.
We found selective uptake of sensory information in patients during emergence from anaesthesia. The human brain contains at least five anatomically distinct networks involved in sensation to cognition,12 but we do not know how anaesthetics act on the different systems of memory formation. Block and co-workers13 found different effects of nitrous oxide on psychophysical tests involving declarative or procedural memory. Alkire and colleagues14 demonstrated in PET-studies, that anaesthetic effects are not uniformly distributed in different brain areas. In the present study the MnSSER components P45 and N50 differed between the patients with and without explicit memory, whereas the earlier components did not. Different parts of the brain are responsible for the MnSSER components.15 16 The parts that form P45 and N50 could be affected in the same way as the neurons which are involved in memory formation, so that impairment of memory formation and changes of MnSSER components occur simultaneously. It is unlikely that MnSSER changes directly reflect memory formation of other sensory systems, like the visual system, which was activated in memory processing for the shown object.
Evidence suggests that EEG measures may suggest the likelihood of memory formation intra-operatively. Liu and colleagues found that the bispectral index, a variable derived from the spontaneous EEG, correlated with intra-operative picture recall during propofol bolus injection.17 In patients having cardiac surgery, an increase of the AER latency Pa of greater or less than 12 ms distinguished among patients with and without implicit memory post-operatively.18 Some recognition of an auditory stimulus may be related to other potentials (P300) intra-operatively.19 20 In the present study the MnSSER measurements were not related to implicit memory formation. However, the experimental design, gave a chance of 20% of guessing the shown object from the four distractor objects. This might have suggested a greater number of patients with implicit memory than really existed and may have confused this measure of memory.
In conclusion, we found that the MnSSER component P45 and N50 were prolonged when post-operative recall was absent during recovery from general anaesthesia. However, sensitivity and specificity are not sufficient to recommend MnSSER as a measurement for everyday clinical routine. More research is needed to show if MnSSER components indicate memory during surgical anaesthesia.
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