Anaesthetic depth can be defined as the degree at which central nervous system (CNS) is depressed by the use of an anaesthetic agent, based on the concentration and the potency of the anaesthetic agent n which it is given^[1]. One of the most important gains in anaesthesia was the recent admission that light anaesthesia, intraoperative awareness, awakening, and memory are all real problems with harmful psychological consequences for a notable portion of patients^[2]. On the other hand, deep anaesthesia appears to be associated with increased morbidity and mortality^[3]. Maintaining the adequate level of anaesthesia depth is critical. Very light or deep depth levels can be terrible in both the short and long run. The patient expects the procedure to be absolutely painless, and asleep throughout the surgery, without any insight or memory of what occurred during that period. It is very important to give emphasis on the concept that is applied to general anaesthesia, and a patient must be kept well informed of the anaesthetic approach is a regional anaesthesia with sedation, a situation which may have series of awakening that is not associated with pain or immobility. Depth of anaesthesia are based on two antagonizing factors: the anaesthetic used, which induces different anaesthesia components to a variable degree depending on the specific agent used; and the surgical stimulation, which may trigger the sympathetic nervous system and raise the level of consciousness of the patient and the somatic and autonomic reactivity^[4-6].

The Need for Anaesthesia Depth Monitoring

The state of general anaesthesia is defined as a controlled and reversible loss of consciousness with the loss of protective reflexes^[7], and it is induced by the anaesthetist to allow a multitude of surgical operations, and to take control of the regulation of patient’s physiology. Even though the delivery of general anaesthetics is associated with significant risks; the maintenance of adequate respiratory and cardiovascular functions is primordial. It is of importance to assess and maintain suitable depth of anaesthesia in each patient. If the depth becomes too shallow, the patient will be at an increased risk of accidental awareness during general anaesthesia (AAGA).

One of the aims of modern anaesthesia is to guarantee adequate depth of anaesthesia and to prevent awareness without overloading the patients with potent drugs unintentionally. One of the accomplishments of modern anaesthesia is the capability of monitoring depth of anaesthesia.

The overall occurrence of intraoperative awareness with recall is about 0.2–3%^[8,9], but it may be > 40% in some high risk patients, like, those with cardiac surgery, caesarean section, multiple trauma, and haemodynamically unstable patients^[10]. Intraoperative awareness is a major liability to the anaesthesiologists which may lead to postoperative psychosomatic dysfunction in the patient, and thus should be prevented at all costs^[11].

Clinical Monitoring of Anaesthetic Depth

Some physiological parameters are used to measure anaesthetic depth and guide the anaesthetic choice and dose titration. Blood pressure, pupil diameter, heart rate, breathing pattern changes, sweating, somatic and skeletal motor activities, lacrimation, and vasomotor skin reflexes are used^[12]. However, depending on patient’s clinical condition and on drugs used, these parameters may have poor representation in assessing anaesthetic depth^[13]. Tachycardia, hypertension, sweating, and lacrimation are usually considered inadequate analgesia signs. However, sympathetic stimulation is not always a result of the painful stimuli perception. There are circumstances in which the parasympathetic nervous system can be stimulated predominantly, for instance in the autonomic response due to nociceptive stimuli in the oesophagus. In this situation, vagal fibres are mostly involved, causing a slow heart rate^[12].

Introduction to Electroencephalography and the Bispectral index

Electroencephalography (EEG) was described first by a physician named Caton working at Liverpool Royal Infirmary, United Kingdom in the year 1875, describing the existence of currents of varying direction that can be detected on the skull of apes and dogs by the use of galvanometer and electrodes^[14]. Berger later advanced this work to the EEG in humans^[15]. The effect of some drugs (barbiturates, morphine, scopolamine, and ether) on EEG was noted around10 years later^[16]. Raw EEG has limited use in the measurement of depth of anaesthesia^[17]. Several monitors have been promoted for thispurpose; the most popular include NarcotrendTM (MonitorTechnik, Bad Bramstedt, Germany), M-EntropyTM (GE Healthcare, Helsinki, Finland) and BispectralIndex (BISTM Medtronic-Covidien, Dublin, Ireland). So, this review will concentrate on BIS, which is the most extensively studied monitor (mostly for its effect on the incidence of accidental awareness during general anaesthesia, (AAGA)), but similar principles apply to all EEG-based monitors. The EEG signal is acquired by placing gel on the forehead of the patient. This will be digitised, amplified and filtered to isolate EEG from other biological potentials such as ECG waveforms, ocular activity and main power interference. Scalp electromyography (EMG) is part of the device measurement, reported separately^[18-21]. The electrode strip can be difficult to apply in certain neurosurgical approaches (but very usefulin neuro-anaesthesia titration, since it is looking directly at the very organ being operated upon^[22] but has been validated because frontal lobe signals are detectable in this alternative montage when used across the bridge of the nose ^[23]. Fourier transformation is used to deconstruct the complex EEG waveform into individual sine waves of differing amplitude or frequency. The power spectrum is created by plotting the signal power (energy against time) of a given frequency as a graphical display. The ‘frequency domain’ can be envisaged crudely as the relative proportion of the component waveforms of different frequencies. A ‘time domain’ can be envisaged as how the pattern of these frequencies changes over time. Hence, there will be change over time in numerical BIS value according to the relative proportions of high vs. low frequency component waveforms within the EEG signal.

To calculate the burst suppression ratio (BSR), EEG activity not exceeding 5.0 mV and lasting longer than 0.5 seconds is identified, and the time spent in this state calculated as a fraction of total time. Burst suppression of the EEG may be witnessed during periods of deep anaesthesia and as well as in hypoxia or brain trauma, but then again has also been associated with decrease in cerebral metabolic activity and can be used to titrate barbiturate coma therapy^[24,25]. The above values are incorporated into the final dimensionless (BIS) number between 0 (cortical electrical silence) and 100 (normal awake activity). Patients that are awake and unpremeditated have BIS values at or above 93. Loss of memory (10%) occurs at BIS values of 75–80^[26]. BIS values that are less than 60 have been linked to a low probability of recall and a high probability of unresponsiveness during surgery under general anaesthesia^[27-31], it has been recommended to have BIS values between 45 and 60 for anaesthetic maintenance during general anaesthesia^[32-34]. BIS does not predict spinal cord reflexes to painful stimuli such as movement or hemodynamic responses^[35].

Some Agents not effectively Monitored by BIS

There is no alteration in BIS values after inhalation of nitrous oxide up to 50%, nor does it cause unconsciousness^[36]. At 70% nitrous oxide, there is no response to voice command, but BIS does not change^[37]. The addition of nitrous oxide to stable plasma concentrations of propofol in volunteers reduced the probability of response to a range of stimuli at any given BIS level^[29]. Addition of 55–63% nitrous oxide to a propofol–remifentanil anaesthetic did not change the BIS but did prevent movement to laryngoscopy and intubation^[38].

According to these results, nitrous oxide seems to add little to hypnotic state and may be functioning predominantly as an analgesic^[39].

In contrast to other anaesthetic drugs, ketamine is a dissociative anaesthetic with excitatory effects on the EEG and is believed to produce anaesthesia by anexceptional mechanism^[40]. Ketamine doses of 0.25–0.5 mg/kg is enough to produce unresponsiveness, but did not decrease BIS^[41-45]. After ketamine was used in combination with propofol sedation, there was an additive interaction to reach hypnotic endpoints, but still ketamine did not bring any change to BIS values^[46,47]. BIS seems to monitor sedation and anaesthesia with propofol and low dose ketamine (0.2 mg/kg per hour)^[42]. The EEG effects of dexmedetomidine and etomidate have not been extensively studied, but the BIS index does appear to track the effects of these drugs^[48-51]. Opioids have complex and interesting effect on the interpretation of the EEG. When opioids are administered alone, they have relatively weak hypnotic effects, although high doses of opioids will certainly produce unconsciousness^[52]. Likewise, lower doses of opioids have weak effects on the EEG, but then again higher doses causes dramatic EEG slowing^[52]. There is a synergistic effect that strengthens the anaesthetic effect dramatically when opioids are combined with hypnotic drugs such as propofol ^[53]. In addition, opioids are particularly effective at preventing movement in response to a stimulus. This effectiveness is not necessarily reflected in the EEG because most of the effects are subcortical. Study by Bouillon and colleagues^[53] showed the effects of the mixing remifentanil and propofol on the BIS index, responsiveness to laryngoscopy, entropyand hypnosis. They found that low amounts of remifentanil dramatically decreased the quantity of propofol required to prevent responsiveness.

Bispectral index in Intensive Care Unit (ICU)

The BIS monitoring is used to assess the recall in anesthetised patients in the theatre room for short periods of time, which differs to its use in monitoring critically sick patients who may be getting continuous sedation and analgesia in the ICU for longer periods of time. Over sedation in ICU is related with higher rates of ventilator-associated pneumonia and longer stay in ICU^[54,55].

By the use of BIS as an objective guide for the dosage of sedating agents, it can also reduce the medical complications of over sedation, such as hypotension, depressed cardiac contractility and with a benefit of financial savings from lower drug doses and reduced time of extubation^[50,56].

BIS values can differ so much in patients that are sedated in the ICU and have been revealed in some studies to correlate poorly with the Sedation-Agitation Scale^[57-59]. We will look into some of the probable reasons for this wide variation in BIS. First, unlike for the patients undergoing painful operations, low levels of sedation is relatively required for patients in ICU because they rarely undergo much stimulation. Minor interferences can cause arousal and consequent fluctuating BIS scores. A second reason is the effect of neuromuscular blocking neuromuscular blocking drugs (NMBD)^[60]: A study showed that there is a decline in BIS values in a group of lightly sedated patients who were paralysed using NMBD, and afterward increased as soon as the paralysis wore off^[61].

BIS in neurological disorders

Beside the titration of anaesthetic in patientsat higher risk of AAGA, BIS can be used to help therapies for some of the neurological disorders or yield awareness into conscious levels in minimally conscious states. An emerging idea is that slightly conscious patients might actually be ‘aware’ and the EEG is one way to access the cognitive function in them^[62]. A very useful application of BIS is monitoring seizures in ICU that might be subclinical or not identified in patients receiving NMBD^[63]. BIS monitors can easily be used to guide burst suppression therapy, which is the goal throughout deep coma for the treatment of status epilepticusor for resistant raised intra-cranial pressure (ICP) (17).

BIS and outcomes

A recent Cochrane review found that the use of BIS decreased postoperative delirium^[64]. Studies have also shown that BIS levels correlate with outcome in other ways. A ‘triple low’ (the combination of a low BIS, low BP, and low minimum alveolar concentration (MAC)) appears to be correlated with a higher mortality^[65,66]. This might show excessive sensitivity to anaesthetic in the affected patients, and has been the driver for a large multicentre trial called the Balanced Study which aims to determine the effect of light vs. deep anaesthesia on all-cause mortality at 1 year postoperatively^[67].

Conflicts of interest: The authors declare no conflicts of interest.

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