Anesthesia awareness, also called unintended intraoperative awareness, is defined as the unintended experience and explicit recall of intraoperative events. The incidence of intraoperative awareness was reported to be 1.2% in 1960 [1]. Recent studies showed the incidence to be 0.1-0.2% in low-risk surgical procedures [2,3]; however, it can reach 1% for patients at increased risk [4,5]. General anesthesia was administered to 7 million patients in 2012 in the South Korea; therefore, intraoperative awareness can be estimated to occur in 7,000-14,000 cases [6].

Unintended intraoperative awareness is a potentially psychologically devastating complication of anesthesia associated with a high incidence of psychological sequelae, with post-traumatic stress disorders (PTSDs) being the most severe [7,8]. Intraoperative awareness is a serious iatrogenic complication causing high public concern, increases patients' apprehension of surgery and leads to medical-legal issues regarding anesthesia. In this review, unlike the connotation in cognitive science, the meaning of awareness implies both consciousness and explicit recall of the intraoperative period. As such, our use of awareness in this article implies explicit recall. Herein, we discuss the mechanisms of awareness and the clinical aspects of intraoperative awareness in adult patients, including risk factors, monitoring methods and prevention.

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The current fundamental limitation of clinical practice is a lack of ability to distinguish between the anesthetized and the awakened. The brain is a major target organ of general anesthesia; however, reliable methodologies for standard monitoring of drug action on brain function have not been elucidated. Current intraoperative monitors estimate the side effects rather than the primary effects of general anesthesia. The lack of standard cerebral function monitor under general anesthesia is considered insufficient understanding the effects of anesthetic drugs on the brain. Therefore, better understanding of the neurobiology mechanisms regarding awareness is important for improving the monitoring of intraoperative awareness.

A description of mechanisms classically begins at the molecular level; however, consciousness mechanisms result from complex interactions in the brain. Thus, explaining how the brain is aroused and how drugs used for general anesthesia modulate this process should be based on the sleep-wake mechanisms. Although sleep and anesthesia are substantially different phenomena, they share phenotypic characteristics and underlying mechanisms. The hypothesis that anesthetic drugs act via subcortical sleep centers was published in the mid-1990s [9], and further supported with empirical data [10,11]. Normal sleep-wake cycles are regulated by several nuclei located in the pons, midbrain, hypothalamus, and basal forebrain. These centers generally are de-active during sleep; on the other hand, other centers such as the ventrolateral preoptic nucleus are active. This phenomenon can be explained by the wake-on/sleep-off and sleep-no/wake-off nuclei that are thought to inhibit each other reciprocally, leading to the hypothesis of a flip-flop sleep-wake mechanism [12,13,14]. For example, the noradrenergic locus ceruleus in the pons and the histaminergic tuberomammillary nucleus in the posterior hypothalamus are active during wakefulness, whereas the γ-aminobutyric acid-transmitting (GAB-Aergic) ventrolateral preoptic nucleus is inhibited. Similarly, the ventrolateral preoptic nucleus becomes active during sleep and then inhibits the activity of the arousal-promoting locus ceruleus and tuberomammillary nuclei.

Anesthetic and sedative drugs act by modulating the activity of these structures. For example, the hypnotic effects of dexmedetomidine are associated with the activation of α₂-adrenergic receptors and inhibition of noradrenergic projections from the locus ceruleus [15]. The presence of electroencephalographic (EEG) sleep spindles during halothane anesthesia is associated with a reduction of cholinergic transmission from the pedunculopontine and laterodorsal tegmentum [16]. Other drugs, such as propofol or isoflurane may exert hypnotic effects by inhibiting or interrupting histaminergic transmission to the tuberomammillary nucleus [17,18]. The arousal-promoting orexinergic neurons in the hypothalamus are thought to play an essential role in the emergence from sevoflurane and isoflurane anesthesia [19], but not from halothane anesthesia [20]. This variability suggests that the effects of general anesthetic drugs on sleep-wake centers are specific to individual agents, meaning anesthetic and sedative drugs have agent specific effects. The ventro-lateral preoptic nucleus in the inhibitory center is activated by GABAergic drugs (e.g., propofol) and not by the N-methyl-D-aspartate glutamate receptor antagonist (e.g., ketamine) [18,21]. Additionally, on the behavioral level, various anesthetic drugs have differential effects on the sleep-regulating pathways [22].

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Risk factors for intraoperative awareness include multiple traumas, cardiac surgery, emergency cesarean section delivery, difficult intubation and patients with a previous history of awareness. According to epidemiological studies, risk factors can be classified into three subgroups: patients, surgical procedures, and anesthetic techniques.

The incidence of intraoperative awareness is threefold higher in females than males and females recover more rapidly than males form anesthesia [23,24]. Younger patients (< 60 years of age) showed a higher incidence of intraoperative awareness [2,25]; however, Pollard et al. [26] reported a higher incidence in elderly patients. The incidence of awareness in children increased to 0.8% [4,27]. Patients with addiction require a greater amount of anesthetic drugs; thus, those patients have an increased likelihood of experiencing intraoperative awareness [28,29]. A previous history of awareness is a strong predisposing factor that increases the incidence of a new intraoperative awareness to 1.6% [30]. In patients with difficulty airways, the incidence of intraoperative awareness is 4.5-7.5% [31]. Reportedly, the incidence of anesthesia awareness is greater in patients who require a lower dose of general anesthetic drug, which is thus titrated to reduce the probability of serious side effects according to the patient's physical condition; for example, a patient who is unstable hemodynamically, has hypothermia, or acute intoxication [28,32]. Surgical procedures typically identified as belonging to this category are cardiac, obstetric and multiple trauma surgeries [28]. Patients undergoing cardiopulmonary bypass have reported an awareness incidence from 1.1-23% [33,34]. The incidence of awareness related to obstetric anesthesia ranges from 0.4-1.3% [29,35,36]. Factors associated with obstetric anesthesia are rapid sequence induction and a reduced inhaled fraction of inhalant anesthetics [37]. Other risk factors for anesthesia awareness include the use of intravenous anesthesia as opposed to inhalant anesthetics and the premature lightening of anesthesia at the end of surgery to facilitate surgical turnover. Furthermore, the estimated anesthetic concentration in target organs informed by a target-controlled infusion system is not the real-time concentration of anesthetic in the patient during intravenous anesthesia. The use of neuromuscular blocking agents is associated with a higher incidence of intraoperative awareness (0.18% vs 0.1%) [3]. The administration of neuromuscular blocking agents may impede patient's movements which are a more useful and simpler method of detecting perioperative awareness [38,39].

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Patients experience awareness differently and have described auditory recalls (48%), feelings of difficult breathing (48%) and painful sensations (28%) [2]. Some patients state that occurrence of intraoperative awareness is their worst hospital experience and others are not willing to undergo surgery or anesthesia again. Patients commonly reported hearing intraoperative sounds or conversations. Other common experiences include pain sensation, being touched, fear, visual perceptions and feeling helpless.

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Preventing intraoperative awareness in patients undergoing general anesthesia can be challenging for an anesthesiologist. Although monitoring methods are available, recognition of intraoperative awareness is difficult. Intraoperative awareness cannot be detected during general anesthesia, because the awareness recall can be identified only postoperatively by obtaining information directly from the patient. To date, no reliable methodology exists due to the limitations in detecting awareness and an insufficient understanding of consciousness. Moreover, conventional indicators of physiological and motor responses, such as high blood pressure, rapid heart rate, or movement are often masked by the neuromuscular blocking agents used to achieve the necessary muscle relaxation during surgery, as well as the concurrent administration of other drugs such as beta-blockers or calciumchannel blockers.

To overcome the limitations of existing methods, new techniques of detecting intraoperative awareness that are less affected by the drugs are being developed. These devices focus on measuring brain activity rather than physiological responses; these EEG devices include the Bispectral Index® (BIS; Aspect Medical Systems, Natick, MA, USA), which are designed to prevent and detect intraoperative awareness in the high-risk patients. Evidence that these devices detect and prevent intraoperative awareness is lacking. However, regarding BIS monitoring, the US Food and Drug Administration stated that "Use of BIS monitoring to help guide anesthetic administration may be associated with the reduction of the incidence of awareness with recall in adults during general anesthesia and sedation."

In the present review, the ability to detect and prevent intraoperative awareness was estimated using a prediction probability (Pk) value. A Pk value resulting from correlational measurement provides a measure of how well a monitor or technique can differentiate between two different clinical states [40]. A Pk value of 1.0 indicates a perfect association and a Pk value of 0.50 a 50 : 50 probability.

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The percentage of patients reported to experience mental distress, including an indeterminate number with PTSDs is 33-69% [8,61]. The majority of these patients fear future surgery and anesthesia. An early emotional response after an intraoperative awareness experience is a risk factor for developing PTSDs [62].

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The risk of intraoperative awareness may be minimized using specific clinical practice principles.

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Anesthesia awareness can be experienced as a psychological trauma by patients undergoing general anesthesia; the psychological damage is unpredictable and immeasurable. Although the various EEG monitors are imperfect for detecting and preventing anesthesia awareness, attention to depth of anesthesia, appropriate use of anesthetic drugs and the judicious use of neuromuscular blocking agents should be strictly applied to patients undergoing general anesthesia. Various monitoring devices can be used to detect anesthesia awareness to minimize the incidence of this potentially devastating complication. Future work should include research and development of precise reliable detection systems, systems for real-time delivery and monitoring of intravenous anesthetic drugs, the identification of the appropriate lower MAC limit and the development of new drugs that target consciousness and memory while minimizing adverse effects.

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