Pharmacologic approaches to the prevention of intraoperative awareness

Keywords::

• amnesia
• anesthesia awareness
• general anesthesia
• intraoperative awareness
• minimum alveolar concentration
• post-traumatic stress disorder

Intraoperative awareness is defined as the unintended experience and explicit memory of surgical events. Awareness is a potentially devastating complication and has been deemed a sentinel event by the Joint Commission on Accreditation of Healthcare Organizations. The incidence of awareness in patients at all surgical risk levels is approximately 1–2 out of 1000 [1], but for those at increased risk the incidence can be as high as 1 out of 100 [2]. Classic risk factors for awareness include hypovolemic trauma, cardiac surgery, emergency cesarean delivery, difficult intubation and patients with a history of awareness. Awareness is a concern to both clinicians and patients because it is associated with a high incidence of psychological sequelae, the most severe of which is post-traumatic stress disorder [3]. As such, the field of anesthesiology is motivated to prevent this dreaded event. Although recent efforts have focused on EEG techniques in the prevention of awareness, there are basic pharmacologic strategies that may also minimize the complication. Four major therapeutic end points of a successful general anesthetic state are unconsciousness, amnesia, analgesia and immobility in response to noxious stimulus. In this article, we discuss each of these features of general anesthesia and how our pharmacologic interventions can maximize the prevention of intraoperative awareness or minimize the psychological consequences if it does occur.

Unconsciousness

The most reliable way to prevent intraoperative awareness is to ensure unconsciousness

This may sound trite, but consciousness occurs during the administration of general anesthetics more commonly than one might imagine. A technique called the isolated forearm technique allows for the detection of consciousness during a surgery. A tourniquet is applied to one arm, protecting the hand from the effects of intravenously administered neuromuscular blocking agents; a patient can therefore squeeze his or her hand in response to simple commands. One study demonstrated that approximately two-thirds of surgical patients on a light plane of general anesthesia could respond meaningfully to commands [4]. Thus, conscious events may occur more often than we anticipate in the operating room. Of interest, only a fraction of the responders in this study later recalled being given the command. This makes it clear that we are often relying on the suppression of memory rather than consciousness in order to prevent awareness (see the next section on amnesia).

But what is the best method to ensure loss of consciousness? When using inhaled anesthetics, most anesthesia providers rely on the dosing metric known as minimum alveolar concentration (MAC), which is the concentration at which 50% of subjects do not move in response to a noxious stimulus [5]. Pharmacologically speaking, MAC is the ED₅₀ for inhaled anesthetics. A related concept is MAC-awake, which is the MAC at which 50% of subjects fail to respond appropriately to a verbal command. MAC-awake is approximately a third of MAC, but is typically an insufficient dose of anesthesia in a surgical patient. One large clinical trial in patients at a high risk for awareness found that a protocol, which incorporated an audible alert when end-tidal anesthetic concentration fell below 0.7 MAC, was not inferior to a processed EEG-based protocol in reducing the incidence of intraoperative awareness [6]. A follow-up trial that is larger and multicentered is currently ongoing [7]. Assuming this second trial is consistent with the first, instituting an audible alert when end-tidal anesthetic concentration drops below 0.7 age-adjusted MAC may emerge as a general recommendation to reduce the incidence of awareness. It is important to note that the use of a MAC threshold makes the critical assumption that the anesthesia provider is administering an inhaled anesthetic – the concept is meaningless for intravenous drugs. In the setting of total intravenous anesthesia, a target-controlled infusion pump (not available in the USA), an EEG monitor or both would be prudent. Propofol is currently the most popular intravenous anesthetic used for this purpose, typically in combination with an opioid analgesic, such as remifentanil. Techniques of measuring exhaled propofol concentrations in real time have been developed and are currently undergoing clinical testing. Preliminarily results suggest that exhaled propofol concentrations correlate well with blood levels [8]. The ability to routinely monitor exhaled propofol could potentially improve the safety and accuracy of total intravenous anesthesia.

Amnesia

If you cannot ensure unconsciousness, then prevent memory

As per the definition above, intraoperative awareness implies both consciousness and memory – therefore, if the clinician can prevent memory formation, he or she can prevent awareness. An anesthesia provider might be confronted with this situation when a patient’s poor cardiovascular reserve precludes the appropriate dose of a general anesthetic, for fear of cardiovascular collapse. In this setting, the focus should shift to amnesia, often using benzodiazepines such as midazolam. Of note, no trials to date have clearly demonstrated that the use of benzodiazepines reduces the incidence of intraoperative awareness [2,6]. However, this may be due to the fact that these drugs are underdosed or not adequately redosed during the surgery. An alternative that has been employed during trauma surgery is the antimuscarinic, anticholinergic drug scopolamine. In general, these pharmacologic routes to amnesia result in the inhibition of antegrade memory formation – that is, memories formed after the drug has been administered [9]. In other words, a suspected event of consciousness of surgical events cannot be ‘erased’ after the experience. In this setting, reassuring words spoken to the patient followed by a sedative–hypnotic drug are appropriate steps. Interestingly, most intravenous and inhaled anesthetic agents block memory consolidation at much lower doses than are required for hypnosis [10]. Thus, there is usually a margin of safety – when patients emerge from general anesthesia they are typically not forming long-term memories. However, pain and emotional stress may modify this amnesic safety cushion. In addition, research has demonstrated that molecular alterations of the GABA receptor can lead to selective resistance to the amnesic effects of certain anesthetic agents [11]. Similar resistance in humans could possibly account for one of several potential predispositions to intraoperative awareness.

Analgesia

If you cannot ensure unconsciousness or amnesia, then provide pain relief

It is reasonable to assume that experiencing the events of surgery is better tolerated with adequate pain control. The use of opioids, such as fentanyl, is generally well-tolerated from a cardiovascular perspective and can help attenuate the negative emotional valence of an awareness experience. Opioids do not prevent awareness; indeed, cases such as cardiac surgery, in which high-dose opioids were traditionally used, have been associated with a high incidence of awareness [12]. Furthermore, patients can still experience anxiety and distress in the absence of pain. However, common sense suggests that careful attention to analgesia throughout the care, rather than simply towards completion, is prudent. Furthermore, adequate analgesia may reduce the incidence of subsequent post-traumatic stress disorder.

Mobility

If you cannot ensure unconsciousness or amnesia, & you cannot provide analgesia, then preserve mobility

The administration of neuromuscular blocking agents to facilitate endotracheal intubation or surgical conditions is standard in modern anesthesia practice. However, the use of such drugs precludes an important sign of insufficient anesthesia: patient movement. The incidence of intraoperative awareness has been found to be higher in paralyzed patients [13], and the subjective experience of paralysis has been demonstrated to be associated with the development of psychological sequelae [14]. The judicious use of paralytic agents should be considered as a method of reducing the incidence and impact of awareness. Currently, muscle relaxants are used routinely in many settings where they might not be required. For example, patients undergoing heart surgery are at increased risk for awareness. Paralysis of the heart muscles to facilitate surgery is achieved with high-dose potassium (cardioplegia). Whether nondepolarizing muscle relaxants are needed to facilitate cardiac surgery at all is a matter of debate.

Conclusion

The foregoing recommendations were presented in a step-wise fashion, but they can and should be performed in parallel. Attention to depth of anesthesia, appropriate use of amnesics, consistent analgesia and the judicious use of paralytic agents can all be employed as pharmacologic methods to minimize a potentially catastrophic complication. Future work in anesthetic pharmacology should include: the identification of the appropriate lower limit of MAC; more reliable methods of dosing, delivering and monitoring intravenous anesthetics; and the development of new drugs that target consciousness and memory while minimizing adverse effects on the cardiovascular system that can constrain anesthetic dosing.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.