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      A Response to: Letter to the Editor Regarding “Neurophysiological Assessments During Continuous Sedation Until Death Put Validity of Observational Assessments Into Question: A Prospective Observational Study”

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          Abstract

          To the Editor, We would like to thank Prod’homme and colleagues for their thoughtful comments on our publication [1]. Their observations have prompted us to further clarify some aspects of this work. We agree with their first comment, indicating that the available data on ANI monitoring in the palliative population are too limited to consider it as a new golden standard. Indeed, more research is needed. The use of ANI monitoring in this population is still a new development and the primary goal of our research was to assess whether or not clinical observational assessments concur with neurophysiological monitoring. We included both caregiver assessments, assessments by established observational tools and neurophysiological indices of discomfort (ANI), and depth of sedation (WAVcns). Our results showed a poor correlation, which led us to conclude that the validity of observational assessments in this particular patient group needs to be further scrutinized. We would like to reiterate that the medication used to induce continuous sedation until death (CSD) also has an impact on motor responsiveness, while the traditionally used observation scales, as well as clinical assessments, mainly reside on inferences from the patient’s responsiveness and may therefore not be entirely reliable. Assessing awareness more independently from (the assessment of) motor responsiveness may therefore contribute to the quality of assessments of comfort during continuous sedation until death [2]. We further agree that neurophysiological correlates of depth of sedation and discomfort always need interpretation by a skilled caregiver; a correlate is not the same as the object it measures and additional research can help in clarifying different factors involved. In our study, we did not recommend using WAVcns- and ANI-monitoring as standalone measures, but as a top up besides clinical judgement and a tool to be included for guiding treatment decisions so that the principle of proportionality regarding titration of medication can be adhered to as good as currently possible [1, p. 386]. Our use of the term “objective” is meant to indicate that the numerical values of a monitoring device do not depend on a subjective appraisal, as is the case with behavior-based observation scales (and the problems associated with that, such as interrater disagreements, lack of validated tools for use in CSD etc.) [3]. Of course, these monitor values need to be interpreted as well, which is usually the case in medicine when correlates are used. As we mentioned in the discussion section of our publication, our epistemological stance is that for this particular problem (which is related to the hard problem of consciousness) falsification of the hypothesis is not possible, and therefore we have to make inferences based on our results, taking into account the results of other studies where closely related research was carried out. These other studies suggest that (1) neurophysiological monitoring of the level of consciousness by WAVcns, and pain/discomfort by ANI, is more “objective” than behavior based observational tools and (2) that these neurophysiological measures can more reliably detect insufficient sedation and exclude the possibility of significant pain [4, 5]. Further, Prod’homme et al. mention that ANI measures not only pain but is also influenced by stress and anxiety, and can be considered as a vagal tone index. Although studies have shown that pain can be detected by ANI, we do agree that ANI is not restricted to only pain detection. That’s why we, throughout our manuscript and on several occasions, used the term ‘pain/discomfort’. In a context of continuous palliative sedation until death, and within the concept of total pain, we believe it makes more sense to not only exclude the possible presence of (nociceptive) pain, but also discomfort such as stress and anxiety as well. The suggestion that when ANI is low, both pain-relief and anxiolytic treatments should be adjusted seems to make sense in that regard. It may be interesting to make the parallelism between the consciousness states potentially encountered during anesthesia, and those seen during end-of-life deep sedation. General anesthesia alters consciousness in a reversible way and, depending on the type of medication, may produce different states of consciousness. These include (1) complete absence of subjective experience (unconsciousness), (2) conscious experience without perception of the environment (disconnected consciousness, like during dreaming), and (3) episodes of oriented consciousness with awareness of the environment (connected consciousness) [6]. During end-of-life deep sedation, recall cannot be assessed afterwards (as with general anesthesia), but unpleasant disconnected consciousness episodes (e.g., nightmares) may potentially occur. This is difficult to assess in a non-communicative dying patient but detecting them and adapt sedation to avoid them could be a goal to further improve comfort in this situation [6]. We consider this as an important argument for also measuring depth of sedation in this context by using a processed EEG monitor (such as the NeuroSense in our study). In addition, as Prod’homme et al. rightly point out, an ANI monitor cannot detect neuropathic pain, and therefore depth of sedation should also be measured, as we did in this study, to allow a broader assessment of pain and discomfort and to ensure that no undetected residual pain (whether nociceptive or neuropathic) can be present or possibly consciously experienced. Regarding the comment about the complementarity of clinical hetero-assessment by family and caregivers and ANI assessment, claiming that neither is superior to the other, we feel more research is still needed to clarify this. It is still unclear how some of these assessment methods relate to each other; for example, previous research has shown that family members tend to overestimate pain in a loved one, while caregivers tend to underestimate pain [7]. Other factors such as cultural values and norms regarding pain and dying, and intergenerational differences could play a role as well [8, 9]. The time has indeed come to introduce various monitoring techniques as standard care to support medical decision-making and hetero-evaluation during continuous sedation until death. The final goal regarding comfort assessment during continuous sedation until death should be objective monitoring of both absence of pain and optimal sedation, thereby strengthening hetero-evaluation, which will ultimately lead to better care for the terminally ill patient. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

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          General Anesthesia: A Probe to Explore Consciousness

          General anesthesia reversibly alters consciousness, without shutting down the brain globally. Depending on the anesthetic agent and dose, it may produce different consciousness states including a complete absence of subjective experience (unconsciousness), a conscious experience without perception of the environment (disconnected consciousness, like during dreaming), or episodes of oriented consciousness with awareness of the environment (connected consciousness). Each consciousness state may potentially be followed by explicit or implicit memories after the procedure. In this respect, anesthesia can be considered as a proxy to explore consciousness. During the recent years, progress in the exploration of brain function has allowed a better understanding of the neural correlates of consciousness, and of their alterations during anesthesia. Several changes in functional and effective between-region brain connectivity, consciousness network topology, and spatio-temporal dynamics of between-region interactions have been evidenced during anesthesia. Despite a set of effects that are common to many anesthetic agents, it is still uneasy to draw a comprehensive picture of the precise cascades during general anesthesia. Several questions remain unsolved, including the exact identification of the neural substrate of consciousness and its components, the detection of specific consciousness states in unresponsive patients and their associated memory processes, the processing of sensory information during anesthesia, the pharmacodynamic interactions between anesthetic agents, the direction-dependent hysteresis phenomenon during the transitions between consciousness states, the mechanisms of cognitive alterations that follow an anesthetic procedure, the identification of an eventual unitary mechanism of anesthesia-induced alteration of consciousness, the relationship between network effects and the biochemical or sleep-wake cycle targets of anesthetic agents, as well as the vast between-studies variations in dose and administration mode, leading to difficulties in between-studies comparisons. In this narrative review, we draw the picture of the current state of knowledge in anesthesia-induced unconsciousness, from insights gathered on propofol, halogenated vapors, ketamine, dexmedetomidine, benzodiazepines and xenon. We also describe how anesthesia can help understanding consciousness, we develop the above-mentioned unresolved questions, and propose tracks for future research.
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            Analgesia nociception index for the assessment of pain in critically ill patients: a diagnostic accuracy study.

            Behavioural pain tools are used in Intensive Care Unit (ICU) patients unable to self-report their pain-intensity but need sustained efforts to educate and train the ICU team because of the subjective nature of these clinical tools. This study measured the validity and performance of an electrophysiological monitoring tool based on the spectral analysis of heart rate variability, the Analgesia Nociception Index (ANI) which varies from 0 (minimal parasympathetic tone, maximal stress-response and pain) to 100 (maximal parasympathetic tone, minimal stress-response and pain).
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              Pain estimation: asking the right questions.

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                Author and article information

                Contributors
                stefaan.six@vub.be
                jan.poelaert@uzbrussel.be
                steven.laureys@uliege.be
                olivier.mairesse@vub.be
                peter.theuns@vub.be
                johan.bilsen@vub.be
                reginald.deschepper@vub.be
                Journal
                Pain Ther
                Pain Ther
                Pain and Therapy
                Springer Healthcare (Cheshire )
                2193-8237
                2193-651X
                12 March 2022
                12 March 2022
                June 2022
                : 11
                : 2
                : 743-746
                Affiliations
                [1 ]GRID grid.8767.e, ISNI 0000 0001 2290 8069, Mental Health and Wellbeing Research Group, , Vrije Universiteit Brussel, ; Laarbeeklaan 103, 1090 Jette, Belgium
                [2 ]GRID grid.8767.e, ISNI 0000 0001 2290 8069, Department of Anesthesiology and Perioperative Medicine, , Vrije Universiteit Brussel, ; Laarbeeklaan 103, 1090 Jette, Belgium
                [3 ]GRID grid.411374.4, ISNI 0000 0000 8607 6858, Coma Science Group, Cyclotron Research Centre and Neurology Department, , University and University Hospital of Liège, ; Avenue de l’hôpital 11, 4000 Liège, Belgium
                [4 ]GRID grid.8767.e, ISNI 0000 0001 2290 8069, Department of Experimental and Applied Psychology, , Vrije Universiteit Brussel, ; Pleinlaan 2, 1000 Brussels, Belgium
                Author information
                http://orcid.org/0000-0003-3584-6818
                Article
                369
                10.1007/s40122-022-00369-x
                9098768
                35286600
                0dfe07fa-30af-499b-b098-e04034d38548
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 10 February 2022
                : 16 February 2022
                Categories
                Letter
                Custom metadata
                © The Author(s) 2022

                continuous sedation until death,pain assessment,palliative medicine,unconsciousness,comfort assessment,palliative sedation,neurophysiological monitoring,wavelet anesthetic value, analgesia nociception index

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