Jiro Kurata

Effects of sevoflurane on central nervous system electrical activity in cats.

We analyzed the effect of a new volatile anesthetic, sevoflurane (2%-5% in oxygen) on the electroencephalogram (EEG) of the neocortex, amygdala, and hippocampus, cortical somatosensory evoked potential (SEP), and brainstem reticular multiunit activity (R-MUA) in cats. Sevoflurane suppressed the background activity of the neocortex more than the amygdala and hippocampus. With increasing concentration of sevoflurane, the cortical EEG progressed from high-amplitude slow waves to a suppression-burst pattern, which was followed by an isoelectric pattern and then spikes with isoelectricity. The amplitude of the SEP was augmented and the R-MUA was suppressed by sevoflurane in a dose-related manner. Repetitive peripheral electrical stimulation induced generalized seizures at 5% sevoflurane in 2 of 13 cats. These results suggest that sevoflurane suppresses the background central nervous system electrical activities in a dose-related manner, leaving the reactive capabilities facilitated at deep anesthesia.

Augmented cerebral activation by lumbar mechanical stimulus in chronic low back pain patients: an FMRI study.

Study Design. Cerebral activation by lumbar mechanical stimulus was investigated by functional magnetic resonance imaging in healthy subjects and patients with chronic low back pain (LBP). Objectives. To characterize the cerebral substrates of LBP, and to explore a possible pathologic pattern of cerebral activation in chronic LBP patients. Summary of Background Data. The cerebral substrates of LBP have been poorly defined in contrast to those of cutaneous somatic pain. Methods. Eight healthy volunteers and 6 patients with idiopathic, chronic LBP were recruited. Each subject was placed in the prone position on a 3 Tesla MRI scanner, and stimulated by manual pressure with the tail of an air-filled, 20-mL syringe at 5 cm left of the fourth-fifth lumbar spinal interspace. Three blocks of 30-second painful stimulus, calibrated at either 3 or 5 on the 10-cm visual analog scale (VAS), were applied with intervening 30-second rest conditions during whole-brain echo-planar imaging. VAS of pain intensity and unpleasantness were evaluated after each session. Functional imaging was analyzed using a multisubject general linear model with Bonferroni multiple comparisons at P < 0.05. Results. Pain thresholds were smaller (P < 0.05) and VAS of unpleasantness was larger in LBP patients than in healthy subjects. Activation was observed at the prefrontal, insular, posterior cingulate cortices (PCC), supplementary motor, and premotor areas predominantly in the right hemisphere, but not at the somatosensory cortices. LBP patients showed augmented activation compared with healthy volunteers specifically at the right insula, supplementary motor, and PCC. Conclusion. Chronic LBP patients showed increased tenderness at the lower back, higher aversive reaction to pain, and augmented LBP-related cerebral activation. The LBP-related activation is characterized by the absence of sensory-discriminative component and the involvement of PCC.

Nitric Oxide Synthase Inhibitor Does Not Reduce Minimum Alveolar Anesthetic Concentration of Halothane in Rats

Nitric oxide (NO) synthase inhibitor (Nω-nitro-L-arginine methyl ester [L-NAME]) has been reported to reduce minimum alveolar anesthetic concentration (MAC) of halothane when administered intravenously (IV) and to reduce thermal hyperalgesia, or produce antinociception in the formalin test, when administered intracerebroventricularly (ICV) or intrathecally (IT). This study attempts to identify the site(s) in the central nervous system (CNS) where L-NAME acts to reduce the halothane MAC. For this purpose, we examined the effects of IV, ICV, and IT administration of L-NAME on the halothane MAC in rats. In contrast to an earlier study, we did not observe any decrease in the halothane MAC after IV (10–30 mg/kg) administration of L-NAME. ICV (100 pg) and IT (100 pg and 1 mg) administration of L-NAME also did not alter the halothane MAC. These findings indicate that the L-arginine-NO pathway is not involved in the mechanism of action of halothane to suppress mechanical nociceptive response or in the nociceptive neural mechanism of mechanical stimulation.

Chronic Treatment with Nitric Oxide Synthase (NOS) Inhibitor Profoundly Reduces Cerebellar NOS Activity and Cyclic Guanosine Monophosphate but Does Not Modify Minimum Alveolar Anesthetic Concentration

We previously found that acute administration of a nitric oxide synthase (NOS) inhibitor (Nomega-nitro-L-arginine methyl ester [L-NAME]) does not reduce the minimum alveolar anesthetic concentration (MAC) of halothane in rats. However, a recent study has suggested that brain NOS activity could not be inhibited by more than approximate equals 50% by acute administration of L-NAME. To investigate the effect of marked inhibition of NOS activity on the MAC of halothane, we measured cerebellar NOS activity, cerebellar cyclic guanosine monophosphate (cGMP) levels, and halothane MAC in rats chronically treated with L-NAME and compared the results to those of the saline-treated control group. Although the cerebellar NOS activity and cGMP levels were significantly decreased (14% and 2.7% of control, respectively) by L-NAME, the value of the halothane MAC was not significantly affected. These results suggest that the anesthetic action of halothane, as measured by its MAC in rats, is not related to NOS activity or cGMP levels in the brain. (Anesth Analg 1995;81:862-5)

The effect of xenon on spinal dorsal horn neurons : A comparison with nitrous oxide

We compared the effects of xenon (Xe) on the spinal cord dorsal horn neurons with those of nitrous oxide (N2 O) in cats anesthetized with chrolarose and urethane.We assessed the potency of both anesthetics by the inhibition of wide dynamic range neuron responses evoked by cutaneous noxious (pinch) stimulation to a hindpaw. During 70% Xe inhalation, the responses of 7 of 11 neurons to pinch stimulation were suppressed. N2 O, 70%, suppressed it in 8 of 11 neurons. The potency of Xe and N2 O was compared in six neurons that were suppressed by both anesthetics. After 20 min of Xe inhalation, the response to pinch was suppressed to 49.5% +/- 8.2% (mean +/- SE), while N2 O, 70% in oxygen, suppressed it to 45.9% +/- 7.9%. The difference between N2 O and Xe was not significant. We conclude that Xe and N2 O suppress the spinal cord dorsal horn neurons to a similar degree. (Anesth Analg 1997;84:1372-6)

Halothane and Diazepam Inhibit Ketamine-induced c-fos Expression in the Rat Cingulate Cortex

Background Ketamine, a noncompetitive N‐methyl‐D‐aspartate antagonist, has psychotomimetic side effects. Recent studies have shown that noncompetitive N‐methyl‐D‐aspartate antagonists cause morphologic damage to the cingulate and retrosplenial cortices and induce c‐fos protein (c‐Fos) in the same regions. Although benzodiazepines are effective in preventing these side effects, the neural basis of the drug interactions has not been established. Methods The effects of diazepam and halothane on c‐Fos expression induced by ketamine were studied. Diazepam (1 and 5 mg/kg) or vehicle were administered subcutaneously, followed 7 min later by 100 mg/kg ketamine given intraperitoneally. Halothane (1.0 and 1.8%), was administered continuously from 10 min before ketamine administration until brain fixation. Two hours after ketamine injection, rats were perfused and their brains fixed and extracted. Brain sections were prepared in a cryostat and c‐Fos expression was detected using immunohistochemical methods. Results Ketamine induced c‐Fos‐like immunoreactivity in the cingulate and retrosplenial cortices, thalamus, and neocortex. Diazepam suppressed the ketamine‐induced c‐Fos‐like immunoreactivity in the cingulate and retrosplenial cortices in a dose‐dependent manner, leaving the thalamus and neocortex less affected. Halothane suppressed the ketamine‐induced c‐Fos‐like immunoreactivity in the cingulate and retrosplenial cortices and the neocortex in a dose‐dependent manner, leaving the thalamus relatively unaffected. Conclusion Halothane and diazepam inhibited ketamine‐induced c‐Fos expression in the cingulate and retrosplenial cortices, leaving the thalamus relatively unaffected.

Effects of isoflurane on in vivo release of acetylcholine in the rat cerebral cortex and striatum.

Background: Acetylcholine (ACh) is one of the major excitatory neurotransmitters in the central nervous system, and changes in neural activity induced by anesthesia alter the release of ACh. However, the effects of isoflurane, one of the most widely used volatile anesthetics, on ACh release are not known. The present study attempts to clarify the dose–effect relationship of isoflurane on the in vivo release of ACh in rat brains.

Deep Hypnosis as a Sign of “imbalance” in Balanced Anesthesia

In this issue of Anesthesia & Analgesia, Leslie et al. show a potential role of intraoperative bispectral index (BIS, Aspect Medical Systems, Norwood, MA) monitoring in reducing long-term morbidity and mortality after surgery under general anesthesia. The report was a post hoc analysis of the B-Aware trial that was undertaken to determine whether intraoperative BIS monitoring reduced awareness during surgery. In this original trial, the authors found that BIS-guided titration of an anesthetic reduced intraoperative awareness by as much as 82%. To test the hypothesis that BIS monitoring improved survival, they reanalyzed the same data including the perioperative parameters, together with added follow-up data on the prognosis (death, myocardial infarction, and stroke) from 1947 patients. The authors found that BIS monitoring itself did not affect survival but that in patients with a BIS decrease 40 for 5 min there was an association with decreased survival (a hazard ratio for death of 1.42) and increased rates of myocardial infarction and stroke compared with those patients who did not show such a BIS decrease. The main findings of this study might suggest the use of BIS monitoring in controlling the depth of anesthesia within the appropriate hypnotic range, between 40 and 60, to improve prognosis of surgical patients. As the authors noted, survival and morbidity of surgical patients might be determined by systemic circulatory status and organ perfusion rather than anesthetic depth itself as indicated by the BIS value. Because of the nature of this retrospective analysis, intraoperative circulatory data were not available in sufficient detail to search for a possible correlation between low BIS values and hypotension. For the BIS-monitored cohort of patients, each anesthesiologist tried to titrate anesthesia depth to keep BIS values within the range of 40–60 and recorded an unintended or unavoidable incidence of BIS 40 for 5 min manually on the anesthesia record. Such notations helped the authors identify “oversedation” cases and test the hypothesis that BIS-guided titration might lead to reduced morbidity and mortality after surgery. Before the introduction of BIS and other types of brain function monitors to gauge anesthetic depth, it had been customary to titrate anesthetic agents by targeting an appropriate range of hemodynamic parameters, such as heart rate and systemic blood pressure. In the present era of “balanced anesthesia,” we have disassociated 3 components of anesthesia, i.e., unconsciousness, analgesia, and immobility, which are independently controlled with a hypnotic, an analgesic, and a neuromuscular blocking agent, respectively. An increase in heart rate and blood pressure sometimes signals awareness or insufficient analgesia, especially if combined with neuromuscular blockade. A decrease in heart rate and blood pressure, however, might indicate a relative overdose of a hypnotic or analgesic drug. Such a decrease in hemodynamic parameters beyond physiologically acceptable levels could potentially be associated with hypoperfusion of major vital organs. Changes in these parameters thus signal an “imbalance” in balanced anesthesia and prompt us to titrate each agent to recover normal circulation. What happens when a hypnotic is administered in an amount larger than that needed to just induce unconsciousness? Electrical and metabolic activities of the brain are reduced, with electroencephalographic changes leading to lower BIS values. We actually do not know the exact impact of anestheticinduced hypotension on the function and viability of vital organs including the brain, the heart, the liver, and the kidney. We do know that each organ generally needs sufficient blood flow and perfusion pressure to maintain its normal function and that volatile or IV hypnotics might exert some protective effects in each organ by metabolic suppression and/or preconditioning. The vital organs might be tolerant against moderate hypoperfusion and/or hypoxia during anesthesia. Nevertheless, it is reasonable to assume that maintaining normal circulation and sufficient organ perfusion is the correct management to protect patients against the adverse outcomes of anesthesia. However, low BIS values are often observed during circulatory depression from causes other than anesthetic overdose, e.g., shock from excessive hemorrhage, heart failure, or peripheral vasodilatation, possibly from impaired cerebral neuronal activity secondary to reduced cerebral blood flow. Such critical conditions might well have led to a higher incidence of myocardial infarction or stroke. Indeed, the B-Aware trial involved high-risk patients undergoing From the Department of Anesthesia, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.

Dysfunction of Nucleus Accumbens Is Associated With Psychiatric Problems in Patients With Chronic Low Back Pain: A Functional Magnetic Resonance Imaging Study

Study Design. A cross-sectional study. Objective. The aim of this study was to evaluate activity of the nucleus accumbens (NAc) in response to lumbar mechanical stimulation in patients with chronic low back pain (cLBP) using functional magnetic resonance imaging (fMRI). Summary of Background Data. Although a modified activity of the NAc was characterized in cLBP patients, its pathological significance has yet to be determined. We hypothesized that NAc activation in response to pain might differ depending on the extent of psychiatric problems, which might be associated with the affective/motivational background of chronic pain. Methods. Twenty-one patients with cLBP (four men, 17 women) were recruited. Subjects were divided into two groups on the basis of scores on the patient version of the Brief Scale for Psychiatric problems in Orthopaedic Patients (BS-POP) scores: ≥17 (High Score, HiS group) and <17 (non-High Score, non-HiS group). Each subject was placed in the prone position on a 3-Tesla magnetic resonance imaging (MRI) scanner and stimulated by mechanical stimulation on the left lower back. Three blocks of 30-second pain stimulus calibrated at either 3 or 5 on an 11-grade numerical rating scale (NRS) were applied with intervening 30-second rest conditions during whole-brain echo-planar imaging. Functional images were analyzed using a multisubject general linear model with Bonferroni multiple comparisons. Results. Subjects in the HiS group had more intense daily pain and lower quality of life than those in the non-HiS group (P < 0.05). Catastrophic thinking in relation to pain experience did not differ between the groups. Activation at the NAc was smaller in the HiS group than in the non-HiS group (P < 0.001). Conclusion. The presence of psychiatric problems was associated with attenuated activity of the NAc in cLBP patients. Dysfunction of the NAc might potentially be involved in the affective/motivational factors in the chronification of LBP. Level of Evidence. N/A

Memory and awareness in anaesthesia

The 9th International Symposium on Memory and Awareness in Anesthesia (MAA9) was held in Tokyo, Japan on June 20–23, 2014, attracting over 70 delegates from around the world. It was chaired by Jiro Kurata, from the Tokyo Medical and Dental University, and was jointly sponsored by the British Journal of Anaesthesia to support research activities in the fields of awareness during anaesthesia, neurobiological mechanisms of general anaesthesia, consciousness, and memory. This topic complements the recently published National Audit Project NAP5 survey of accidental awareness under general anaesthesia conducted in the UK in 2012 and published in the British Journal of Anaesthesia last year.1–3 The present British Journal of Anaesthesia special issue on Memory and Awareness in Anaesthesia was planned by Hugh Hemmings, a co-organizer of MAA9, to present the most current findings and views on topics from selected presentations during the meeting, in addition to submissions in response to an open call for papers. All the MAA9 abstracts are also included in this special on-line-only issue. Details of the MAA9 programme can be found at the conference website (http://maa9.umin.jp/). The scope of previous MAA symposia has ranged from the neuroscience of anaesthetic action, memory, and consciousness to the clinical aspects of awareness during anaesthesia. The MAA9 followed this tradition, while emphasizing the clinical aspects: epidemiology, diagnosis, prevention, and treatment of intraoperative awareness, with a conference slogan of ‘Minding the Mind of Subconscious Self’. Although anaesthesiology has devoted tremendous efforts to studies of anaesthetic pharmacology and the mechanisms of anaesthetic-induced unconsciousness, which can be approached in a relatively direct manner through behavioural analyses, it has paid much less attention to subconscious processes of mind. At least part of memory is formed in the subconscious domain of mind,4 and for this reason could be resistant to clinical ranges of general anaesthetics aimed to produce elimination of conscious behaviour. The MAA9 was programmed to propose that anaesthesiology should now approach the next stage, the care for the subconscious mind. Detection of intraoperative awareness during anaesthesia has historically been a major focus of research and technology development in anaesthesiology. Currently, there are several kinds of anaesthetic depth monitors, in addition to real-time or simulated monitors of anaesthetic concentrations, available in most operating theatres. Behaviour-based standardization of mathematically processed EEG, cortical evoked potentials, or both has attempted to turn ‘probability of awareness’ into an anaesthetic depth index, or a ‘vital sign for consciousness’. In recent years, such indices for anaesthetic depth have been tested for efficacy in detecting intraoperative awareness compared with anaesthetic concentration monitors, which is summarized in the review by Mashour,5 along with some of the controversial and established aspects of intraoperative awareness. Despite such efforts, titrated administration of anaesthetics, using either an anaesthetic depth or a concentration monitor, has not been successful in decreasing the incidence of intraoperative awareness with recall. No single reliable anaesthetic technique or monitor is yet available to eliminate awareness with recall during general anaesthesia. A significant concern is the increasing reliance on EEG-based monitors of anaesthetic depth to titrate administration of anaesthetic agents. Some of the issues with using processed indices of the EEG rather than the raw waveform are addressed in the review by Hagihira,6 along with editorial commentary by Veselis.7 Purdon and colleagues8 report profound age-dependent changes in the EEG that also have important implications for depth-of-anaesthesia monitors relying on processed EEG signals. Greater sensitivity to anaesthetics evident in the increased susceptibility to burst suppression in the elderly7 is supported by animal studies that demonstrate delayed emergence and increased sensitivity to anaesthetics in old rats.9 This is highlighted in an editorial by Hudson and Proekt.10 Age-dependent changes in the EEG response to anaesthesia also occur in children, as demonstrated for sevoflurane by Akeju and colleagues;11 this phenomenon has implications for EEG-based monitors of anaesthetic depth in both the young and the elderly. The impact of the unique pharmacological profile of ketamine on its EEG signature is described in a study by Pal and colleagues,12 who show that ketamine, like other general anaesthetics, suppresses high-frequency γ activity and promotes a breakdown in cortical coherence. Reasons for failure of general anaesthesia in suppressing memory and awareness could include technical problems or mishaps, such as an inadvertent discontinuation or a low concentration of general anaesthetic agent. Neuromuscular blocking agents, which are non-hypnotics, could also conceal conscious behaviour and affect reliability of EEG-based depth-of-anaesthesia monitors. These issues are highlighted in two studies by Thomsen and colleagues13,14 from a Danish registry of patients with documented butyrylcholinesterase (plasma cholinesterase) deficiency, showing that prolonged paralysis due to impaired elimination of esterase-dependent neuromuscular blockers (succinylcholine or mivacurium) markedly increased the likelihood of awareness during emergence from anaesthesia, particularly when neuromuscular function monitoring was not used. The importance of not withholding neuromuscular function monitoring when paralytic drugs are used during anaesthesia is highlighted in the editorial by Avidan and Stevens.15 An important limitation of EEG-based depth-of-anaesthesia monitors is described by Schuller and colleagues16 in a fascinating study of volunteer anaesthetists who underwent intentional awake paralysis using the isolated forearm technique to show that the bispectral index monitor itself cannot always distinguish ‘anaesthesia’ from paralysis, the implications of which are highlighted in an editorial by Schneider and Pilge.17 Use of the isolated forearm technique as a monitor of depth of anaesthesia and as a research tool into mechanisms of anaesthesia is presented in a thought-provoking debate and review by Pandit and colleagues.18 Not all known cases of intraoperative awareness with recall, however, can be explained by such ‘logical’ causes. Should we now question the ability of general anaesthetics to produce unconsciousness and amnesia reliably? Targeting only conscious behaviour might not necessarily provide reliable protection of patients from traumatic memory of physical or psychological injuries during surgery and anaesthesia. The mechanisms of memory formation are reviewed by Veselis,4 while Pryor and colleagues19 used functional magnetic resonance imaging to show that propofol suppresses emotional memory formation through a hippocampal mechanism. Implicit memory formation during anaesthesia remains understudied and poses a significant problem that could be relevant to post-traumatic stress disorder, and possibly, postoperative delirium and cognitive dysfunction. A report from the Anesthesia Awareness Registry of the American Society of Anesthesiologists indicates that explicit recall of intraoperative awareness can have significant negative psychological impact on patients, which suggests that a more systematic response and follow-up care are necessary.20 Amongst the irreplaceable roles of the MAA conferences has been, and hopefully will continue to be, an investigation into subconscious processing of information during anaesthesia. Now that we have abundant, if not sufficient, evidence for anaesthetic-induced unconsciousness, we should investigate further the science of subconsciousness. The next meeting, MAA10, will continue this conversation around the clinical and basic science of memory and awareness in anaesthesia, to be chaired by Professor Sinikka Munte in Helsinki, Finland in 2017. Until the details of MAA10 are officially announced, the MAA9 facebook page (http://www.facebook.com/maa9.jp/) will remain a source of information on the development of MAA10. Please leave a comment on this page if you have suggestions or would like to be included in the mailing list for MAA10. We sincerely hope that this special issue, marking the up-to-date knowledge and insights on memory and awareness in anaesthesia, will help to promote further scientific inquiries and technological development to eliminate the most dreadful complication of general anaesthesia: intraoperative awareness. Caring for the whole human existence, conscious and subconscious, should continue to be the core mission of anaesthesiology. Finally, we would like to thank all the authors of these excellent articles, all the attendees, support staff, and sponsors of the MAA9, and Oxford University Press for realizing this special issue.