睡眠觉醒环路与全身麻醉机制研究进展

背景 全身麻醉与睡眠都表现为觉醒水平的降低,以及对外界环境刺激反应的抑制,二者具有相似的脑电图和局部脑功能变化.近年研究表明,全身麻醉药通过抑制脑内促觉醒神经核团和戚激活促睡眠神经核团发挥镇静催眠及意识消失作用.目的 从睡眠觉醒环路的角度综述全身麻醉神经机制的研究进展.内容 麻醉药诱导的意识消失与自然睡眠觉醒产生的机制并非完全相同,每种麻醉药物作用的靶神经核团也存在一定的差异.趋向 深入研究睡眠觉醒环路及全身麻醉神经机制,将有助于研发新型安全有效的麻醉剂.     

内侧前额叶皮层不同类型神经元在全身麻醉机制中的研究进展

全身麻醉是指麻醉药通过呼吸道吸入、静脉或肌肉注射进入体内, 产生中枢神经系统的暂时抑制, 临床主要表现为意识消失、无痛、遗忘和肌肉松弛等。其中全身麻醉药导致意识消失的机制一直是研究的难点, 也是全球亟待解决的科学问题之一, 但其具体作用机制至今仍未阐明[1]。意识的产生依赖于皮层网络的存在。Lee等[2]研究表明, 丙泊酚、氯胺酮和七氟烷3种以不同受体为作用靶点的全身麻醉药, 应用于外科手术患者致意识消失后, 均能选择性地抑制额叶到顶叶的功能连接, 而不影响顶叶到额叶的功能连接, 认为破坏额叶到顶叶的功能连接可能是麻醉致意识消失的一个共同通路。可见, 额叶皮层(prefrontal cortex, PFC)环路在全身麻醉药致意识消失过程中扮演着重要的角色。而有研究者利用功能性近红外光谱技术监测PFC脱氧血红蛋白含量的变化发现, 在麻醉诱导和苏醒过程中伴随其功能的改变, 进而对PFC进行更深入分析发现只有内侧前额叶皮层(medial prefrontal cortex, mPFC)存在显著差异[3]。本课题组前期研究进一步证实:改变mPFC γ-氨基丁酸A型(gamma aminobut...     

认知解耦联与全身麻醉意识消失

背景 认知解耦联是指在大脑中特定的认知活动合成受损,是意识消失的一种模式.认知解耦联也许是不同麻醉药物作用的共同机制. 目的 综述认知解耦联的基本概念及其与全身麻醉意识消失的关系. 内容 以全身麻醉意识消失为中心,结合神经影像学、神经生理学证据,表明认知解耦联是麻醉诱导意识消失的直接原因.认知解耦联与睡眠和其他原因的意识障碍有一定的相关性,可能是全身麻醉和其他无意识状态的共同机制. 趋向 认知解耦联为全身麻醉意识消失机制的研究提供了新的方向,要求将电生理技术和影像学技术结合用于全身麻醉机制的研究.     

全身麻醉药物对睡眠影响的研究进展

全身麻醉和睡眠状态均表现为意识的可逆性丧失,对外界刺激反应性下降,并在行为学和脑电图等方面具有一定的相似性.全身麻醉过程和睡眠状态的产生可能共享部分分子靶点和神经环路.全身麻醉药物可通过改变睡眠结构、影响昼夜节律和调控睡眠-觉醒环路等机制对睡眠产生"双面性"和"多维度"的影响.全身麻醉和睡眠机制至今尚未阐明.全文将从全...     

全身麻醉药诱发睡眠紊乱的研究进展

全身麻醉药可干扰机体的昼夜节律,诱发术后睡眠紊乱,但其具体的机制尚未完全阐明。研究表明,全身麻醉药可通过激活γ-氨基丁酸(γ-aminobutyric acid,GABA)能受体、抑制NMDA受体引起昼夜节律紊乱。文章简要阐明全身麻醉药诱发睡眠紊乱的机制,重点阐释时钟基因(circadian locomotor output kaput,Clock)在其中发挥的作用,有助于改善围手术期患者的睡眠问题,以期推进舒适化医疗;通过进一步阐释昼夜节律对全身麻醉药的作用,有助于提高麻醉质量,实现精准麻醉。     

上行网状激活系统与睡眠-觉醒和全身麻醉的研究进展

全身麻醉如何导致意识的可逆性消失是探究全身麻醉机制的核心内容。近年来，经过脂质学说、蛋白学说和离子通道学说三个阶段后，全身麻醉与神经通路之间的联系已成为研究热点。目前的研究表明，全身麻醉状态与生理性睡眠存在一定相似之处。上行网状激活系统包含多种神经元及核团，通过投射及释放相关神经递质，促进并维持生物的觉醒，而全身麻醉药也共享了其中的某些通路及递质。本文通过综述近年上行网状激活系统中关键核团在睡眠-觉醒过程中作用机制的研究进展，探讨网状激活系统与睡眠-觉醒、全身麻醉的关系，为阐明全身麻醉的药物作用机制、探寻临床治疗睡眠障碍新

方法 提供参考。     

全身麻醉机制与下丘脑腹外侧视前核睡眠通路

背景 全身麻醉与自然睡眠之间存在一定的相似性,但睡眠-觉醒核团是否参与全身麻醉药物致意识消失的过程目前仍未有定论. 目的 综述睡眠-觉醒通路中主要的促睡眠核团下丘脑腹外侧视前核(ventrolateral preoptic nucleus,VLPO)及其相关通路与全身麻醉机制之间的关系. 内容 全身麻醉药可能会通过兴奋主要的促睡眠核团和抑制关键的促觉醒核团产生镇静催眠效应. 趋向 探讨全身麻醉药物作用于睡眠核团及其相关通路的生理机制,为全身麻醉机制研究提供一新的思路.     

危重症患者睡眠障碍研究进展

睡眠障碍是重症患者在ICU停留期间较常见的问题之一,发生率为14%~50%。目前,联合应用非药物治疗和药物治疗是改善患者睡眠障碍的主要治疗方法。文章描述了ICU重症患者睡眠障碍的特点、ICU睡眠障碍对患者的不良影响、ICU重症患者睡眠障碍的影响因素、ICU重症患者睡眠监测的方法、目前ICU睡眠障碍的治疗及进展。如何真正...     

全身麻醉和睡眠的调节机制和功能间的联系与区别

<正>全身麻醉技术应用至今已有160多年,目前我国每年有大约3,000万患者经历麻醉和手术,他们中至少1/3会接受全身麻醉治疗。人们习惯把全麻引起的意识消失称为"睡眠"状态。与睡眠一样,全身麻醉也表现为可逆性的意识消失、无记忆、无自主活动和对相应强度的刺激不产生反应,已有的研究表明全身麻醉和睡眠享有部分相同的调节机制。然而全麻并不等同于睡眠,两者之间存有差异。睡眠紊乱可     

蓝斑-去甲肾上腺素能神经系统在全身麻醉中的作用

背景全身麻醉药应用于临床已有近170年,然而其作用的神经机制还不清楚。蓝斑去甲肾上腺素能神经系统（locus coeruleus-noradrenergic system, LC-NE）在全身麻醉状态调节中可能起到重要作用。目的综述LC-NE系统在调节全身麻醉中的研究进展。内容全身麻醉药可能通过对LC-NE系统的抑制从而产生镇静催眠效果。趋向探讨LC-NE神经系统在全身麻醉中所起到的作用,为揭示全身麻醉药的作用机制提供新思路。     

Sleep and general anesthesia

Purpose

The mechanisms through which general anesthetics cause reversible loss of consciousness are characterized poorly. In this review, we examine the evidence that anesthetic-induced loss of consciousness may be caused by actions on the neuronal pathways that produce natural sleep.

Principal findings

It is clear that many general anesthetics produce effects in the brain (detected on electroencephalogram recordings) that are similar to those seen during non-rapid eye movement non-(REM) sleep. Gamma aminobutyric acid (GABA)ergic hypnogenic neurons are thought to be critical for generating non-REM sleep through their inhibitory projections to wake-active regions of the brain. The postsynaptic GABA_A receptor is a major molecular target of many anesthetics and thus may be a point of convergence between natural sleep and anesthesia. Furthermore, we also present growing evidence in this review that modulating wake-active neurotransmitter (e.g., acetylcholine, histamine) release can impact on anesthesia, supporting the idea that this point of convergence is at the level of the brain arousal systems.

Conclusions

While it is clear that general anesthetics can have effects at various points in the sleep-wake circuitry, it remains to be seen which points are true anesthetic targets. It will be challenging to separate non-specific effects on baseline arousal from a causal mechanism. Sophisticated experimental approaches are necessary to address basic mechanisms of sleep and anesthesia and should advance our understanding in both of these fields.     

Effect sites of anesthetics in the central nervous system network--looking into the mechanisms for natural sleep and anesthesia

We showed the effect sites of anesthetics in the central nervous system (CNS) network. The thalamus is a key factor for loss of consciousness during natural sleep and anesthesia. Although the linkages among neurons within the CNS network in natural sleep are complicated, but sophisticated, the sleep mechanism has been gradually unraveled. Anesthesia disrupts the link-ages between cortical and thalamic neurons and among the cortical neurons, and thus it loses the integration of information derived from the arousal and sleep nuclei. It has been considered that anesthesia does not share the common pathway as natural sleep at the level of unconsciousness, because anesthetics have multiple effect sites within CNS network and may induce disintegration among neurons. Recent literatures have shown that the effects of anesthetics are specific rather than global in the brain. It is interesting to note that thalamic injection of anti-potassium channel materials restored consciousness during inhalation anesthesia, and that the sedative components of certain intravenous anesthesia may share the same pathway as natural sleep. To explore the sensitivity and susceptibility loci for anesthetics in the thalamocortical neurons as well as arousal and sleep nuclei within CNS network may be an important task for future study.     

Early pregnancy does not reduce the C(50) of propofol for loss of consciousness.

Requirements for inhaled anesthetics decrease during pregnancy. There are no published data, however, regarding propofol requirements in these patients. Because propofol is often used for induction of general anesthesia when surgery is necessary in early pregnancy, we investigated whether early pregnancy reduces the requirement of propofol for loss of consciousness using a computer-assisted target-controlled infusion (TCI). Propofol was administered using TCI to provide stable concentrations and to allow equilibration between blood and effect-site (central compartment) concentrations. Randomly selected target concentrations of propofol (1.5-4.5 microg/mL) were administered to both pregnant women (n = 36) who were scheduled for pregnancy termination and nonpregnant women (n = 36) who were scheduled for elective orthopedic or otorhinolaryngologic surgery. The median gestation of the pregnant women was 8 wk (range, 6-12 wk). Venous blood samples for analysis of the serum propofol concentration were taken at 3 min and 8 min after equilibration of the propofol concentration. After a 10-min equilibration period of the predetermined propofol blood concentration, a verbal command to open their eyes was given to the patients twice, accompanied by rubbing of their shoulders. Serum propofol concentrations at which 50% of the patients did not respond to verbal commands (C(50) for loss of consciousness) were determined by logistic regression. There was no significant difference in C(50) +/- SE of propofol for loss of consciousness between the Nonpregnant (2.1 +/- 0.2 microg/mL) and Pregnant (2.0 +/- 0.2 microg/mL) groups. These results indicate that early pregnancy does not decrease the concentration of propofol required for loss of consciousness. IMPLICATIONS: The C(50) of propofol for loss of consciousness in early pregnancy did not differ from that in nonpregnant women, indicating that there is no need to decrease the propofol concentration for loss of consciousness when inducing general anesthesia for termination of pregnancy.     

Anesthetic mechanisms revealed by functional brain imaging

Recent advancement in functional brain imaging techniques has revealed much of the global effects of general anesthetics on the human brain. General anesthetics preferentially suppress specific brain areas including the parietal association cortex and the thalamus, part of which appears to mirror the default mode network. Low-level sensory areas are relatively preserved and remain activated even under deep sedation by anesthetics. Functional connectivity analysis by resting-state functional magnetic resonance imaging has shown that general anesthetics moderately suppress functional connectivity of the default mode network. Midazolam-induced loss of consciousness is associated with remarkable suppression of cortico-cortical propagation of evoked currents. Overall, those results prompt us to hypothesize that general anesthetics induce loss of consciousness by disrupting the integrative properties of the cerebral cortex.     

General anesthetic actions on norepinephrine,dopamine, and gamma-aminobutyric acid transporters in stably transfected cells

The effects of general anesthetics on neurotransmitter uptake by plasma membrane transporters are controversial. We analyzed the effects of representative volatile and IV general anesthetics on recombinant transporters for norepinephrine (human NET), dopamine (rat DAT), or gamma-aminobutyric acid (rat GAT-1) stably expressed in a porcine kidney cell line (LLC-PK(1)). This approach avoids complicating factors associated with neuronal preparations, such as the involvement of multiple transporters and the indirect effects of membrane potential. At clinical concentrations, human NET was inhibited only by halothane (50% inhibitory concentration [IC(50)] = 0.54 mM), rat DAT was sensitive to both halothane and isoflurane (IC(50) = 0.60 and 0.64 mM, respectively), and rat GAT-1 was insensitive to both volatile anesthetics. Human NET was inhibited in a dose-dependent fashion by propofol (IC(50) = 41 micro M), ketamine (IC(50) = 150 micro M), and etomidate (IC(50) > 200 micro M), but not by pentobarbital. Only propofol inhibited NET at a clinically relevant concentration (5 micro M). Rat DAT was inhibited in a dose-dependent fashion by propofol (IC(50) = 120 micro M), etomidate (IC(50) = 100 micro M), and ketamine (IC(50) = 210 micro M), but not by pentobarbital. None of these anesthetics was predicted to inhibit DAT at concentrations that produce anesthesia. Propofol inhibited rat GAT-1, but only at the largest concentration tested. General anesthetics have drug- and subtype-selective actions on neurotransmitter transporters. We conclude that effects on catecholamine, but not gamma-aminobutyric acid, transporters may contribute to secondary synaptic actions of certain anesthetics but are unlikely to be essential to their anesthetic properties. IMPLICATIONS: Previous studies have implicated neurotransmitter transporters as targets for general anesthetic effects on synaptic transmission. Recombinant transporters for norepinephrine and dopamine were sensitive to certain volatile and IV anesthetics, whereas gamma-aminobutyric acid transporters were insensitive. These anesthetic- and neurotransmitter-specific effects may underlie some of the secondary effects of general anesthetics.     

睡眠障碍患者血浆食欲素A对丙泊酚靶控输注效应室靶浓度的影响

目的观察睡眠障碍患者接受丙泊酚全身麻醉靶控输注效应室靶浓度(target concentration of effect-site,Ce)的变化,探讨血浆食欲素A与丙泊酚Ce的相关性。方法选取2018年6-12月择期手术患者66例,男31例,女35例,年龄40~60岁,ASAⅠ或Ⅱ级,于术前1 d根据PSQI量表得分分为两组:睡眠障碍组(SD组,n=32)和正常睡眠组(NS组,n=34)。入室后常规心电监护、面罩吸氧,留取静脉血检测血浆食欲素A浓度。在BIS监测下进行丙泊酚阶梯式血浆靶控输注,初始血浆靶浓度(target concentration of plasma,Cp)设定为1.0μg/ml,当Ce达到1.0μg/ml后,每30秒以0.2μg/ml递增Cp,并呼唤患者姓名直至意识消失。继续每30秒以0.2μg/ml递增Cp直至BIS<60稳定30 s以上,停止增加Ce稳定5 min后停止输注。停药后每30秒轻拍并呼唤患者姓名直至有反应。记录患者意识消失时丙泊酚Ce(Ce1)、BIS<60稳定30 s以上对应的丙泊酚Ce(Ce2)和苏醒时丙泊酚Ce(Ce3)。采用Pearson检验分析Ce与食欲素A浓度的相关性。结果与NS组比较,SD组丙泊酚Ce1[(2.53±0.26)μg/ml vs(2.38±0.30)μg/ml]、Ce2[(3.30±0.35)μg/ml vs(3.15±0.28)μg/ml]和Ce3[(1.76±0.38)vs(1.59±0.26)μg/ml]浓度均明显升高(P<0.05),血浆食欲素A浓度明显升高[(75.09±16.50)pg/ml vs(39.96±13.78)pg/ml,P<0.05]。NS组血浆食欲素A浓度与Ce1、Ce2、Ce3均存在中度正相关(r=0.636,0.578,0.344),SD组血浆食欲素A浓度与Ce1、Ce2、Ce3也存在中度正相关(r=0.635,0.415,0.467)(P<0.05)。结论术前合并睡眠障碍患者接受丙泊酚全身麻醉需要更高的效应室靶浓度,潜在的机制可能与血浆食欲素A浓度升高有关。     

Sleep disorders: a systematic review of an emerging major clinical issue in renal patients

The prevalence of sleep disorders is significantly higher (up to 80%) in patients with chronic uremia compared to the general population. Sleep disorders appear even in the early stages of chronic kidney disease. These disturbances are complex, including difficulties in falling asleep and awakening, interrupted sleep, nightmares, restless legs syndrome, sleep apnea syndrome, etc. There are still disagreements on the major etiological factors of sleep disorders in the uremic patient. Older age, long dialysis vintage, alcohol and tobacco abuse and, particularly, the presence of significant comorbidities are major determinants of sleep disorders in dialysis patients. Proper assessment of sleep disorders in the renal population is still under investigation; recent studies have mostly addressed patients’ perception based on questionnaires. More precise polysomnographic assessments are less studied in renal patients. Sleep disorders significantly affect quality of life in dialysis patients. An accurate and early identification of such disturbances would lead to a significant improvement in quality of life, and probably also in outcome, in uremic patients. Sleep apnea syndrome is extremely frequent in dialysis patients, with obvious consequences for cardiovascular morbidity and mortality. Proper diagnosis and therapy of sleep apnea syndrome could significantly reduce cardiovascular risk. Although sleep quality improves after renal transplantation, allograft recipients still have significantly more sleep disorders than healthy individuals. Here, we review recent data on sleep disturbances in renal patients, focusing on the end-stage renal disease patient treated by dialysis.     

The relationship of individual sensitivities to fentanyl and those to propofol

BACKGROUND: Individual variation in the sensitivity to anesthetics induces the delayed awakening and the severe postoperative pain at an inappropriate dose. We designed the study to see the correlation of the individual sensitivity to fentanyl and that to propofol which have different mechanism. METHODS: General anesthesia was induced using target controlled infusion system of fentanyl and propofol. Fentanyl effect-site concentration gradually increased towards a target plasma concentration of 3 ng x ml(-1) until the appearance of the subjective symptom such as dizziness, a sensation of warmth and other reactions. After this, propofol effect-site concentration gradually increased towards a target plasma concentration of 4 microg x ml(-1) until loss of consciousness (LOC). The effect-site concentrations of fentanyl at the symptom and propofol at loss of consciousness were measured. RESULTS: The correlation between the estimated effect-site concentration of fentanyl and propofol is not significant in the whole patient. However, a positive correlation between fentanyl and propofol was found in patients from 50s to 70s years of ages (r = 0.59). CONCLUSIONS: The correlation of the individual sensitivity to fentanyl and propofol was found in older age groups.