General anaesthesia in end‐of‐life care: extending the indications for anaesthesia beyond surgery

Summary In this article, we describe an extension of general anaesthesia – beyond facilitating surgery – to the relief of suffering during dying. Some refractory symptoms at the end of life (pain, delirium, distress, dyspnoea) might be managed by analgesia, but in high doses, adverse effects (e.g. respiratory depression) can hasten death. Sedation may be needed for agitation or distress and can be administered as continuous deep sedation (also referred to as terminal or palliative sedation) generally using benzodiazepines. However, for some patients these interventions are not enough, and others may express a clear desire to be completely unconscious as they die. We summarise the historical background of an established practice that we refer to as ‘general anaesthesia in end‐of‐life care’. We discuss its contexts and some ethical and legal issues that it raises, arguing that these are largely similar issues to those already raised by continuous deep sedation. To be a valid option, general anaesthesia in end‐of‐life care will require a clear multidisciplinary framework and consensus practice guidelines. We see these as an impending development for which the specialty should prepare. General anaesthesia in end‐of‐life care raises an important debate about the possible role of anaesthesia in the relief of suffering beyond the context of surgical/diagnostic interventions.


Introduction
There is a potential role for general anaesthesia in end-of-life care, something which has been described previously but largely overlooked. We will start by reviewing the current place of sedation in end-of-life care and show how general anaesthesia is an extension of existing practices. However, introducing general anaesthesia in end-of-life care also requires an examination of the associated ethical, medicolegal and practical implications. We stress that general anaesthesia in end-of-life care is not a form of assisted dying or euthanasia [1,2], which are illegal in the UK.

The current role of sedation in end-oflife care
Many symptoms (delirium, dyspnoea and pain) can become resistant to treatment at the end of life [3]. Up to 84% of patients are reported to require opioids [4,5]. Additional interventions familiar to anaesthetists include the use of non-opiate medications, epidural and intrathecal regional anaesthesia, local anaesthesia infiltration or blocks, and even acupuncture or nerve stimulation [6]. Some patients may need antidepressants (which have analgesic properties in the context of chronic pain) or benzodiazepines to aid sleep and antipsychotics to manage delirium [7]. The palliative care formulary lists agents used at the end of life and examples of approaches used can be found in national and individual hospital guidelines [8,9].
Patients who are dying are particularly vulnerable to the cardiorespiratory adverse effects of some agents (e.g. opioids, midazolam, phenobarbital, ketamine). While there is little evidence that these occur with judicious use [5,10], it is important that fear of such adverse effects does not lead to restrictive treatment practices. The so-called 'doctrine of double effect' legally and ethically permits the intentional relief of suffering, even where it is foreseen that there is a significant risk of adverse effects that might hasten death [11].
The specific need for sedation over and above opioid analgesia in end-of-life care is variable, reported as being between 3% and 51% in different case series [12]. This may reflect differences in local practices [12,13] and the host of different terms used, including: 'palliative sedation', 'terminal sedation' or 'continuous deep sedation' [14]. In this paper, we will use the latter term. Current UK guidance from the National Institute for Health and Care Excellence (NICE), supported by the Royal College of Anaesthetists, makes no specific recommendations about sedation, and instead constitutes broad principles underlying the management of end-of-life care [15].
Regardless of the intended level of sedation, what is actually experienced by patients receiving continuous deep sedation varies [16]. Some patients are lightly sedated, others are mostly unconscious, stirring intermittently or only in response to vigorous stimulation, while others are almost anaesthetised [16][17][18][19][20]. In part, this is because a variety of techniques, drugs and doses are used. Benzodiazepines are employed commonly (usually midazolam), but other drugs, including barbiturates (such as phenobarbital), are also prescribed. Moreover, 'sedation' encompasses a continuous spectrum, with anxiolysis in an awake patient at one extreme and a state approaching general anaesthesia at the other. There is no clear clinical or neuroscientific cutoff between these states of loss of consciousness, and the term 'dysanaesthesia' has been used to describe one such 'in-between' state [21]. Sedation typically means that verbal contact with the patient is retained; that is, they are cooperative when aroused. By contrast, general anaesthesia refers to a state where the patient is unarousable even to painful stimuli [22].

Patients' desire to be unconscious
Patients have different wishes in relation to suffering and its alleviation. Sigmund Freud, when dying of throat cancer, preferred to have a clear head and 'think in torment' [23], refusing analgesia or sedation. Others may have the opposite preference. In a recent survey, 88% of a large online survey of the UK public expressed a wish to have the option of unconsciousness at the end of life [24].
The desire to be unconscious as a means of eliminating the experience of physical or mental suffering is understandable. Unconsciousness achieves the highest probability of being unaware that the body is going through an adverse process, since even that awareness may be psychologically traumatic to some. This is recognised in other very different contexts. For example, requests by healthy patients for general anaesthesia for minor surgery (e.g. dental extraction) are viewed as entirely acceptable by anaesthetists and by society, even when it is clear that mild sedation (or none at all) would be sufficient to avoid pain, and that anaesthesia poses a greater risk of adverse events. This is out of respect for patients' autonomy. At the end of life, patients may experience feelings of sadness, fear, anxiety, loneliness, vulnerability, embarrassment and loss of dignity [25], in addition to pain, suffocation and other suffering, not all of which may be relieved by targeted treatments.

Patients' expectations of unconsciousness
We now know that when many patients agree to 'sedation', they are in fact expecting to be unconscious. The proportion of patients who report being 'accidentally aware' during surgical interventions was higher when patients were sedated than when they received general anaesthesia [26].
Moreover, it has become apparent that patients appearing to be unconscious in several situations may in fact not be.
Patients who are critically ill, or those with severe head injury diagnosed as being in deep coma, have reported recall of events in critical care [26]. This also appears to be the case with current terminal sedation techniques, where bispectral index scores can remain > 60 in patients who appeared unconscious [27]. In patients diagnosed as being in a vegetative state, studies show that some apparently unconscious patients can reliably generate appropriate electroencephalographic responses to stimuli [28] or commands [29] and in some cases communicate 'yes' or 'no' answers (as evidenced by functional magnetic resonance imaging patterns [30]). This raises the possibility that some patients who are dying may be suffering when otherwise believed not to be. To avoid these complications, Moyle and others recommended very slow intravenous infusion by a pump at a carefully titrated dose (e.g. just 5 mg.h -1 vs. the 100-200 mg typically used as a bolus) [31]. The depth of anaesthesia achieved was inadequate for a surgical procedure, but was ideal for an undisturbed dying patient.
In a case series of 22 patients from a Swedish specialist palliative care unit, propofol infusions were provided in this way for continuous deep sedation for between 1 and 14 days (median 5 days) [34]. Notably, the protocol developed and used by Moyle did not require the level of continuous patient monitoring that might be necessary during surgical general anaesthesia [36]. This is not to imply that propofol is an anaesthetic whereas other drugs like benzodiazepines are not. Any suitable sedative given in sufficient doses will achieve unresponsiveness to painful stimulation. Rather, the distinctive element of this approach is the intended purpose of achieving general anaesthesia, rather than sedation. Since Moyle's description, there have been about 25 publications, case series and reviews of intended general anaesthesia using propofol infusions at the end of life. One international perspective is relevant. Since 2016, terminally ill patients in France have a legal right to unconsciousness once it is deemed they are dying, sustained until the point of death [37]. This has been labelled the 'French exception' emphasising the unique character of the French legal code in this regard [37]. As a result, the Haute Autorite de Sant e (the body responsible for setting medical standards) has issued clear guidance on how 'end of life' is to be defined, what protective steps should be taken to achieve medical consensus that sedation is desirable and the means of administering it [38]. These guidelines refer primarily to the use of intravenous midazolam but mention that propofol may also be used with expert anaesthetic input [38]. This is, therefore, a strong official implication that anaesthetists might, or should, be directly involved. The guidelines do not offer technical details, but it is theoretically straightforward to update Moyle's established protocol to the modern era, where propofol target-controlled infusions are commonly used in anaesthesia.

Updating the Moyle protocol for anaesthesia in end-of-life care
Ultra-slow intravenous induction is now described in at least two contexts. One is to mimic an inhalational induction of anaesthesia (spontaneous respiration using intravenous anaesthesia, STRIVE) [39]. The second is in basic neuroscience experimentation, where ultra-slow propofol target-controlled infusions (0.2 µg.ml -1 increments over 50 min) are titrated to maintain spontaneous respiration while volunteers are lying in a functional MRI scanner [40].
Interestingly, these experiments have revealed brain activity patterns of 'thalamic isolation', temporally associated with the behavioural effect of the subjects becoming inattentive or disinterested in their surroundings, consistent with the notion of dysanaesthesia. Specific adaptations of methods like these have been discussed by Bodnar [41]; further technical details are outside the scope of this article but should be self-evident to most anaesthetists. Table 1 indicates the potential place of general anaesthesia in endof-life care alongside other more standard options and makes a distinction between intended sedation vs.
intended general anaesthesia.

Patient autonomy
One key argument in favour of anaesthesia in end-of-life care revolves around the significance of patient preference 1310 and their personal concept of a good death [11]. General anaesthesia in end-of-life care is not intended to replace analgesia or sedation for symptom control. However, it should be an additional option for those who want more reliable or complete loss of consciousness than can be

Offering effective treatments
It is a fundamental ethical principle in medicine that doctors should promote and act in patients' best interests (beneficence), and by extension, offer them the therapy option most likely to achieve the desired outcome [42]. If a competent, dying patient wishes to be unconscious (and not just sedated) as a specifically stated aim to help relieve their suffering, then general anaesthesia in end-of-life care provides the greatest assurance of meeting this wish and is, therefore, in the best interests of the patient.  [26]. If sedation at the end of life leaves the patient in a semi-conscious state but unable to communicate meaningfully, there is concern they would have severely aversive experiences similar to, or even worse than, patients who have reported distressing 'accidental awareness' during surgery. We now know that unconsciousness is better achieved with intended general anaesthesia. In the absence of neuromuscular blocking drugs, the incidence of accidental awareness is in the order of 1 in 136,000 [26].

Avoidance of hastening death
There may be a concern (in our view, misplaced) that anaesthesia in end-of-life care will, unintentionally, hasten death [44]. There is no statistically significant difference in mean survival time between patients at the end of life who receive continuous deep sedation and those who do not [45,46]. Data are limited for general anaesthesia in end-oflife care but a propofol infusion has been continued for up to 14 days without suppressing spontaneous breathing [34], and in another study in paediatric oncology patients, propofol was continued for up to 10 days [34,35]; these do not appear foreshortened times to death. None of the studies describing the technique suggest death was hastened [31,32,34,35].
In law, the possibility of medical interventions at the end of life unintentionally hastening death is covered by the 'doctrine of double effect', as discussed above. If it is wrongly assumed that general anaesthesia in end-of-life care (being anaesthesia) is inherently and prohibitively riskier than continuous deep sedation (which is sedation), then there may arise a concern that this doctrine may not be applied by courts or regulators because they judge there to be, in their minds, a safer alternative. However, there is no empirical evidence in this or any other context that deep sedation is inherently safer than anaesthesia.
To minimise concerns about hastening death, one practical option for anaesthesia in end-of-life care would be to limit its application to patients who are predicted to die within a period of up to 14 days, as suggested in the French guidance [37,38]. The rationale for this timeframe is that   [50].
Implementing any practical guidance will require collaboration with palliative care physicians, nurses, patient groups and others. Moreover, a fundamental challenge for national anaesthetic societies will be to accept the novel notion that administration of general anaesthesia has a place in the relief of suffering generally, not just confined to facilitating surgery, critical care or diagnostic interventions.
The speciality already has a self-declared mission to extend the role of anaesthetists beyond the operating theatre in its strategy of championing 'peri-operative medicine' [51]. Our redefinition of the scope and reach of general anaesthesia through end-of-life care, radical though it is, would be entirely in line with that philosophy, recognising that anaesthetists have skills that can help alleviate suffering for the dying patient.