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Intraoperative nociception monitoring

While a reliable monitor ensuring unconsciousness and painlessness is required, several systems have been investigated. Although the intraoperative anesthetic state results from the balance between the effects of surgical stimulation and the effects of anesthetic agents on the central nervous system, it remains unclear if any of the current methods for monitoring anesthetic adequacy completely reflects this balance. (Anesth Pain Med 2015; 10: 227-234)

Monitoring depth of anesthesia has been an aim of anesthesia for several decades. Monitoring of clinical parameters, such as cardiovascular signs, sweating, tearing and pupil signs has been routinely used. Many attempts have been made to develop systems for the accurate assessment of anesthetic depth. There have been some products available for monitoring hypnosis and sedation, and some partially acceptable measures for nociception monitoring have become available. Most of them are based on cerebral function monitoring (electroencephalogram) and autonomic responses. Awareness, with or without recall, is due to inadequate hypnosis, inadequate analgesia or increased levels of surgical stimulation at any stage during anesthesia. The ability to distinguish consciousness from unconsciousness and to detect nociception for a variety of anesthetic agents at equipotent doses is an essential element of a monitor and clinical end-point. Given the best sign of awareness is considered patient movement for any reason, neuromuscular blockade makes the assessment of depth of anesthesia difficult. While a reliable monitor ensuring unconsciousness and painlessness is required, several systems have been investigated. Although the intraoperative anesthetic state results from the balance between the effects of surgical stimulation and the effects of anesthetic agents on the central nervous system, it remains unclear if any of the current methods for monitoring anesthetic adequacy completely reflects this balance.

AND AWARENESS
The anesthetic state consists of numerous features such as respiration rate and systolic arterial pressure of the patients.
The conceptual framework of this state can be explained by four components: unconsciousness, analgesia, loss of reflexes and muscle paralysis. It is difficult to define anesthesia, because the nature of this state is still poorly understood. The poor understanding this phenomenon is so fundamental that there is no consensus even on whether anesthesia is a binary or continuous event. Some anesthetists think that anesthesia is a binary or continuous event [1] and that there is no such thing as "depth of anesthesia"; rather, it is either present or absent. Most anesthetists, however, regard anesthesia as a continuum, with different responses to different stimuli at different levels of anesthesia. Neuromuscular blockade and the suppression of automatic activity should not be considered components of anesthesia, but rather desirable supplements to the anesthetic state [1][2][3].
The requirements for this state differ by patient, each of whom would probably define anesthesia according to the presence or absence of that requirement. In other words, surgeons want the patient not to move, but the patient wants to be oblivious to any unpleasant event (pain, wakefulness or memory) during and after the operation. Thus, if a patient moves his legs in response to a painful stimulus during an operation without awareness or recall of intraoperative events, the surgeon may believe that the anesthesia was inadequate, while the patient may believe that was present throughout the operation.
If a patient becomes aware of his surroundings or of intraoperative events, awareness is said to have occurred due to inadequate anesthesia (inadequate hypnosis or inadequate analgesia) or an increased level of surgical stimulus at any stage during an anesthetic. Awareness has been defined as the ability to recall, with or without prompting, any events occurring during the period in which the patient is considered fully unconscious [4], or responsiveness to auditory stimuli without recall of the stimulus [5].
However, awareness is not always accompanied by recall.
Patients who suffer awareness under anesthesia, particularly those who suffer pain during surgery, may experience considerable distress [6,7], which can lead to long-term psychological problems such as depression, personality changes and sleep disturbances, on their own or as part of post-traumatic stress disorder [8].
The incidence of conscious awareness is reported to be about 0.2% [9]. Anesthetists are probably more aware of the problem and its serious effects than in previous decades, and thus are also more likely to report the problem. Nonetheless, the incidence does seem to be decreasing.
To control anesthesia, all of the features (reflex and hence the triad components of anesthesia) must be controlled.
Although a single anesthetic agent can do this, the supplied dose must be relatively high to control all of these features.
Such a high dose could also lead to undesirable side-effects that are not associated with the anesthetic state. Better control can be achieved by supplying several drugs, each aimed towards a specific feature. The supplied dosage of each drug only needs to be sufficient to control the features influenced by that drug, which leads to lighter and better controlled anesthesia. An example of this approach was the introduction of muscle relaxant drugs.

METHODS OF ASSESSMENT OF ANESTHETIC DEPTH (HYPNOSIS AND ANALGESIA)
Previously, clinical observation was the only means of assessing the depth of anesthesia. However, in the past decade, technological advances have enabled more objective techniques.
While the best indicator of inadequate anesthesia remains patient movement, due to inadequate hypnosis or analgesia, movement does not always indicate awareness because it may sometimes be due purely to spinal reflexes. Moreover, the administration of drugs to paralyze the patient abolishes this useful clinical sign.
Several methods have been evaluated to assess the effects of sedative and hypnotic drugs: movement of the patient, eye movement, the diameter and reactivity of pupils to light, autonomic signs such as sweating and hemodynamic signs.
However, there are many factors that make measuring depth of anesthesia difficult by these methods: neuromuscular blocking agents interfering with ability to move in response to pain, beta-blockers with vasodilating properties masking autonomic signs of light anesthesia. Hemodynamic signs are also poor in predicting anesthetic depth [10]. The electrophysiological techniques such as the spontaneous EEG, and its processed derivatives, Fast Fourier Transformation (FFT) [11], Median Frequency (MF) and Spectral Edge Frequency (SEF), have also been assessed as measures of depth of anesthesia. The raw EEG, however, is very difficult to analyze quickly in real-time by anesthetists, and MF and SEF have produced different study results with large variability and overlap in their values during consciousness and unconsciousness [12][13][14]. Lower esophageal contractility, has also been proved to be unsuitable as it was not good in detecting awareness [15]. Furthermore, in spite of its correlation with the end-tidal concentration of volatile anesthetics [16], lower esophageal contractility was not related to blood concentration of intravenous anesthetics [17].

Clinical signs
Clinical signs result from stimulation of the sympathetic nervous system. One of the early attempts to classify depth of anesthesia using these parameters was by Guedel in 1937.
Unfortunately this classification is no longer particularly meaningful, because it was specific to ether, and relied on signs that may no longer be valid during in anesthetic practice.
Administration of beta-blockers, neuromuscular blocking agents, anticholinergics, and opioids, which cause vasodilation, paralysis, mydriasis, and miosis, respectively will all interfere with the signs required by that classification.
Thus, clinical signs, despite their inadequacy, are currently the only practical, universally accepted method of assessing the anesthetic state [18,19]. As such, they are successfully used to guide the administration of thousands of anesthetics every day. More sophisticated trials have focused on the signs of sympathetic stimulation as indicators of anesthetic depth. "The patient response to surgical stimulation" score is commonly used, and uses pulse rate, systolic blood pressure and tear formation to generate a score [20]. Unfortunately the score is nonspecific, and is affected by vasoactive drugs, and conditions such as hypoxia and hypercarbia.

Auditory evoked potential and bispectral index
Unprocessed EEGs are difficult to assess, except perhaps by neurophysiologists, which makes it unsuitable for use as an anesthesia monitor in the hands of anesthetists. To be practical and useful, EEG data need to be processed and analyzed, and some variables based on EEG analyses have shown promise.
Frequency analysis forms the basis of several EEG parameters, and is done by Fourier transformation of the EEG signal. This produces a spectral array of power within the different frequencies present in the signal, which can be presented visually as a compressed or density spectral array.
Further analysis of a spectral array can provide more information. The most commonly used methods are the MF and the SEF, being the frequencies below which 50% and 95% of the EEG power lies. As anesthesia deepens there is a shift towards the lower frequencies, so that these values tend to decrease with increasing anesthetic concentration and thus with increasing anesthetic depth. Unfortunately there is a large overlap between the values observed in conscious and unconscious subjects, so these values are limited in their ability to predict whether an individual patient is awake or unconscious [21].
They have been alleged to detect awareness during anesthesia.
While there is no universally accepted method of monitoring the depth of anesthesia, the BIS and AEPindex might have been more promising than other techniques [13,14], because they provided anesthetists with objective and real-time indices from the anesthetised patients. In order to assess clinical value as anesthetic depth monitors, they were broadly investigated in the patients anesthetized with various volatile or intravenous anesthetics.
The AEP is derived by averaging the EEG signal recorded following repeated auditory stimuli. The AEP has been suggested to reflect the level of anesthesia (hypnosis and sedation) during general anesthesia using volatile and intravenous anesthetics.
The AEP has been shown to be a reliable detector of potential awareness during inhalational anesthesia in a limited number of studies [31,32].
Ketamine is a strong dissociative intravenous anesthetic. One study has shown no change in the AEP during ketamine anesthesia compared to the awake state [33], suggesting that ketamine anesthesia preserves primary processing of auditory stimuli in the primary auditory cortex. One study using benzodiazepines demonstrated marked changes in latencies and amplitudes of the AEP [34]. However in another study [35] the AEP showed little change following induction of general anesthesia, suggesting the AEP did not accurately monitor the depth of anesthesia during induction and maintenance of anesthesia with benzodiazepines. Anesthesia with different anesthetic agents has been reported previously to produce dissimilar effects on the BIS [36]. In the maintenance period in which patients are normally considered to be steady-state anesthetic conditions, several patients receiving ketamine showed extremely high BIS scores which would normally be interpreted to suggest that the patient is awake. This phenomenon has been demonstrated in the previous studies [14,37,38] which have also demonstrated a large variability and overlapping in BIS values at the different stages of sedation or anesthesia with a variety of anesthetic agents in spite of some other studies [39][40][41][42][43] suggesting good correlation of BIS with the degree of sedation. The explanation for considerable difference in BIS values between these studies may primarily be a result of the use of different anesthetic agents, different anesthetic methods, or premedication, etc. In previous studies, BIS was reported to be closely associated with blood concentration of propofol [13,44]. In contrast, AEPindex was shown to be related less to blood concentration of propofol [13].
The BIS, a derived variable of the EEG, has been proved to reflect the depth of anesthesia. The correlation of the BIS with anesthetic depth has been broadly demonstrated in intravenous and volatile anesthesia. As a numerical index based on the AEPs, the AEPindex has been shown to be a reliable indicator of potential awareness during intravenous anesthesia [13,14].
Nitrous oxide, a weak hypnotic and good analgesic, did not appear to alter AEP markedly in some comparative studies, compared with other volatile anesthetics [31,32]. Similarly, this unique effect of nitrous oxide on AEP may also be identical for the BIS. In reality there were some reports in which nitrous oxide was shown to have no effect on the BIS in subanesthetic concentration [45,46]. This may suggest that the shown to be a significant predictor of patient responses to incision [47]. However, in one publication, the BIS was not able to predict movement in response to laryngeal mask airway (LMA) insertion [48]. Surgical stimulation has been known to affect the AEP [30] and EEG [49].

Spectral entropy
Spectral entropy (GE Healthcare, Helsinki, Finland) is another variable derived from both the EEG and EMG signals of the forehead. There are two different values calculated in this system: state entropy (SE) and response entropy (RE). A detailed explanation about the system was published elsewhere [50].
The SE measures the hypnotic component of anesthesia with volatile or intravenous anesthetics [51][52][53]. While response entropy and the RE-SE difference are alleged to measure the analgesic component of anesthesia using EMG, both parameters of SE also detected patients' movement to nociceptive stimuli during anesthesia with sevoflurane [54].

Surgical plethysmographic index
The surgical plethysmographic index (surgical pleth index; SPI), previously called the surgical stress index, was developed based on autonomic variables (plethysmographic pulse wave amplitude and heart beat interval) to detect responses to surgical stimuli during general anesthesia. This nocicep-tion-detecting function was evidenced by opioid consumption [55,56]. The SPI also monitors the hypnotic component of anesthesia regardless of the analgesic component. However, there are several confounding factors for the SPI, which include concomitant medication, volume status, pacemaker action, arrhythmias and posture changes.

Analgesia nociception index
The analgesia nociception index (ANI) represents a variable derived from analysis of the heart rate variability (HRV). The HRV is derived from a standard electrocardiography (ECG) signal. The ANI values are changed by surgical stimulations during anesthesia, such as skin incision or induction of pneumoperitoneum [57]. This system was shown to be dependent upon remifentanil effect site concentration [58]. However, the system was not able to predict patient movement in response to nociceptive stimulation, and also showed a large inter-individual variability in values after surgical stimulation. in paralyzed patients has been studied by some study groups, who used the isolated forearm technique intermittently throughout a prolonged period of surgery [59][60][61][62][63][64]. However, it cannot be routinely applicable for paralyzed patients because of some significant disadvantages (lack of reliability due to ischemic pain, frequent movement of the unparalyzed arm and ethical issues), but rather may have some value as an investigative tool.

INTRAOPERATIVE NOCICEPTION AND NEUROMUSCULAR BLOCKADE
From the discussion above it is clear that there is no widely accepted method available with which to make a detection of awareness during anesthesia in paralyzed patients deprived of movement. Thus, there is a need for improved techniques that allow objective assessments of the depth of anesthesia in such patients. In order to answer this need we should know how a response to verbal stimulation can be elicited in paralyzed patients in more sophisticated and objective ways. Since the CNS is the main site of general anesthetics, it is reasonable that all approaches to assessment of the depth of anesthesia have been focused on the brain. It has been suggested that neuromuscular blocking agents do not decrease anesthetic requirements [65][66][67]. However, other studies have shown different results, suggesting that the depth of anesthesia is affected by neuromuscular blocking agents [68][69][70].
There have been some reports investigating the effects of neuromuscular blocking agents on depth of anesthesia monitored by BIS. Flaishon et al. [71] showed that BIS might be able to provide a reliable method for predicting the probability of recovery of consciousness from anesthesia using thiopental or propofol in paralyzed patients. In their report, although they did not mention the direct effect of neuromuscular blocking agent on BIS, it was recognizable that the capability of BIS to predict the probability of a patient being aware was not affected by neuromuscular blockade. In contrast, Messner et al. There was an investigation which was not supportive of the role of neuromuscular blockade in increasing the depth of anesthesia. Greif et al. [75] documented that BIS was not changed by the degree of neuromuscular relaxation. They were against the theories that the reduction of electromyographic activity [72,73] or afferent signal from muscle [68,69] could decrease BIS. The reasons for the differences in the adequacy of BIS among study groups in indicating the depth of anesthesia during paralysis cannot be explained clearly. Of the possible reasons that can cause the differences, the neuromuscular blocking agent used in each study appears unlikely to explain the differences because the inconsistent effects with the same muscle relaxants were demonstrated. Some of the previous reports studying the effects of neuromuscular blockade on BIS obtained inconsistent results with vecuronium [71,73]. In other previous studies investigating the relationship between muscle relaxant and anesthetic requirement or depth of anesthesia, pancuronium was also shown to have conflicting effects [65,68,69].