Prevention of explicit memory function for intraoperative events (i.e., awareness with recall [AWR]) is a key deliverable for every general anaesthetic. Development of monitoring technologies, drugs, and anaesthetic techniques to achieve this objective is an important priority of contemporary anaesthesia research. The volatile anaesthetic concentrations associated with lack of memory function in the unstimulated state (i.e. MAC-amnesia) are not well known. This pilot study aimed to estimate MAC-amnesia using a variation of the continuous recognition memory task (CRMT). We hypothesised that MAC-amnesia would be slightly lower than MAC-awake.1

BACKGROUND:Ataxic breathing (AB) is a well-known manifestation of opioid effects in animals and humans, but is not routinely included in monitoring for opioid-induced respiratory depression (OIRD). We quantified AB in normal volunteers receiving increasing doses of remifentanil. We used a support vector machine (SVM) learning approach with features derived from a modified Poincaré plot. We tested the hypothesis that AB may be found when bradypnea and reduced mental status are not present. METHODS:Twenty-six healthy volunteers (13 female) received escalating target effect-site concentrations of remifentanil with a low baseline dose of propofol to simulate typical breathing patterns in drowsy patients who had received parenteral opioids. We derived respiratory rate (RR) from respiratory inductance plethysmography, mental alertness from the Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S), and AB severity on a 0 to 4 scale (categories ranging from none to severe) from the SVM. The primary outcome measure was sensitivity and specificity for AB to detect OIRD. RESULTS:All respiratory measurements were obtained from unperturbed subjects during steady state in 121 assessments with complete data. The sensitivity of AB for detecting OIRD by the conventional method was 92% and specificity was 28%. As expected, 69 (72%) of the instances not diagnosed as OIRD using conventional measures were observed to have at least moderate AB. CONCLUSIONS:AB was frequently present in the absence of traditionally detected OIRD as defined by reduced mental alertness (MOAA/S score of <4) and bradypnea (RR <8 breaths/min). These results justify the need for future trials to explore replicability with other opioids and clinical utility of AB as an add-on measure in recognizing OIRD.

Remifentanil-induced hyperalgesia (RIH) is a part of a general opioid-induced hyperalgesia (OIH) syndrome, seemingly resulting from abrupt cessation of continuous remifentanil infusion at rates equal or exceeding 0.3 mcg/kg/min. The intricate mechanisms of its development are still not completely understood. However, hyperactivation of the N -methyl d -aspartate receptor system, descending spinal facilitation and increased concentration of dynorphin (a κ-opioid ligand) are commonly proposed as possible mechanisms. Several ways of prevention and management have been suggested, such as slow withdrawal of remifentanil infusion, the addition of propofol, pretreatment with or concomitant administration of ketamine, buprenorphine, cyclooxygenase-2 inhibitors (NSAIDs), methadone, dexmedetomidine. In clinical and animal studies, these strategies exhibited varying success, and many are still being investigated.

Target-controlled infusion (TCI) is a mature technology that enables the delivery of intravenous anaesthetics in the concentration domain. The accuracy of the pharmacologic models used by TCI systems is imperfect, especially regarding pharmacodynamic predictions. This shortcoming of TCI devices is not critical. That TCI systems produce steady-state effect-site concentrations at or near a specified target is a more important attribute than a high level of accuracy because anaesthesiologists titrate to a stable level of drug effect whatever the actual concentration is. In this sense, TCI functions as a ‘gain switch’. Achieving a steady state is more important than perfect accuracy.

We appreciate the interest from Sarraf et al.1 in our recent clinical focus review of the drug titration paradox.2 Although their insights on anesthesiologists' dosing strategies are appreciated, their control systems' engineering-based interpretation might overlook the statistical and mathematical underpinnings of the paradox. This suggests a potential misunderstanding of the automaton-like behavior involved in titrating drug doses. The drug titration paradox is a form of Simpson's paradox,3 a statistical phenomenon that occurs when the relationship between two variables of interest (i.e., dose and effect in this case) is being confounded by another variable (i.e., different patient drug sensitivities here). We have previously demonstrated a mathematical proof that titration to effect associates lower doses with greater effect.4We agree that clinical concerns related to over- or underdosing contribute to the observed negative correlation. However, we assert that the titration paradox arises whenever drug dose is titrated to achieve a specific effect, whether through manual titration or by closed-loop control. Indeed, the authors' own simulation of closed-loop control exemplifies the titration paradox (fig. 1).As we discussed in our review, confounding factors in the causal pathway (e.g., changing levels of surgical stimulus) could lead to the titration paradox within individual patient data.5 We argue that anesthesiologists are not automatons; we vigilantly titrate drug doses while anticipating the impact of other confounding factors during surgery. Additionally, contrary to the authors' claim of no a priori knowledge, anesthesiologists do possess prior knowledge about appropriate target concentrations and effects from the literature.The authors declare no competing interests.

When anesthesiologists titrate doses to achieve desired effects, a titration paradox emerges resulting in increased drug doses which correlate with decreased effect. This challenges traditional pharmacologic understanding and requires careful analysis of potential confounding factors.

From the Department of Anesthesiology, University of Utah, Salt Lake City, Utah. Accepted for publication June 8, 2023. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the authors. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website. Address correspondence to Ken B. Johnson, MD, Department of Anesthesiology, University of Utah, 30 N, 1900 E, Suite 3C444, Salt Lake City, UT 84132. Address e-mail to [email protected].

Department of Anesthesiology, University of Utah, Salt Lake City, Utah, USA Correspondence to Talmage D. Egan, Department of Anesthesiology, University of Utah SOM RM 3C444, 30 North 1900 East, Salt Lake City, UT 84132, USA. Tel: +1 801 581 6393; fax: +1 801 581 4367; e-mail: [email protected]

Editor—I had the privilege of interviewing John (Iain) B. Glen in his home office in Knutsford, Cheshire, UK on April 22, 2023. My goal for the interview was to preserve some of the more personal aspects of the history of propofol from the perspective of the primary inventor. 1 Glen J.B. Try, try, and try again: personal reflections on the development of propofol. Br J Anaesth. 2019; 123: 3-9 Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar An audio recording of the interview, along with the transcript, are available in the supplementary material. In addition to personal reflections about the development of propofol, the interview covers Glen's upbringing and early days, his education and training as a veterinary physician, his path toward a career in anaesthesia-related pharmaceutical science, and his thoughts about the antecedents of success as an innovator.

Background: A fundamental concept in pharmacology is that increasing dose increases drug effect. This is the basis of anaesthetic titration: the dose is increased when increased drug effect is desired and decreased when reduced drug effect is desired. In the setting of titration, the correlation of doses and observed drug effects can be negative, for example increasing dose reduces drug effect. We have termed this the drug titration paradox. We hypothesised that this could be explained, at least in part, by intrasubject variability. If the drug titration paradox is simply an artifact of pooling population data, then a mixed-effects analysis that accounts for interindividual variability in drug sensitivity should 'flip ' the observed correlation, such that increasing dose increases drug effect. Methods: We tested whether a mixed-effects analysis could correctly reveal the underlying pharmacology using previously published data obtained during automatic feedback control of mean arterial pressure (MAP) with alfentanil (effect site concentration, CeAlf) during surgery. The relationship between MAP and CeAlf was explored with linear regression and a linear mixed-effects model. Results: A linear mixed-effects model did not identify the correct underlying pharmacology because of the presence of the titration paradox in the individual data. Conclusions: The relationship between drug dose and drug effect must be determined under carefully controlled experimental conditions. In routine care, where the effect is profoundly influenced by varying clinical conditions and drugs are titrated to achieve the desired effect, it is nearly impossible to draw meaningful conclusions about the relationship between dose and effect.

The drug titration paradox is an emerging concept in clinical pharmacology. The paradox refers to the observation that when drug is titrated to a specified level of effect in a population of patients, the expected positive correlation between dose and effect is reversed. That is, when titration rather than fixed dosing is used, greater drug exposure is associated with lesser effect, and vice versa. The drug titration paradox may have important implications for study design and data interpretation in anaesthesiology investigations, particularly in big data studies.

OBJECTIVES:Clinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators. DESIGN:A 2-day in-person meeting was held in Washington, DC, on March 28-29, 2019, followed by a three-round, online modified Delphi consensus process. PARTICIPANTS:Thirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process. MEASUREMENTS AND MAIN RESULTS:The final recommendations were iteratively refined based on the survey results, participants' reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization. CONCLUSIONS:These recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.

Conditions created by the COVID-19 pandemic have impacted many aspects of medical practice. Responding to this crisis has required health systems to rapidly address a multitude of concerns, including workforce safety, staff redeployment, supply shortages and physical space restructuring. The pace of change created by new information and evolving conditions has proven challenging for traditionally-structured academic departments in medicine. Pandemic medicine requires a nimbleness in decisionmaking, clarity of communication and comprehensiveness of services that may demand a temporary rearrangement of leadership structure and clinical service delivery. Furthermore, the uncertain nature of a pandemic may require reinstitution and dissolution of services as demand sporadically either rises or falls. As the global medical community continues to respond to what may be multiple COVID-19 peaks stretching over months or years, it is important that approaches to preparation and management of the pandemic are shared to enable the identification of best practices and an effective response. With the availability of open access and free communication technologies, these strategies can be easily shared among the global anaesthesia community. The approach outlined here represents one way to organise leadership and streamline communication in order to reinvent an academic department to match the dynamic requirements of crisis conditions. We describe our experience in offering new services such as an airway team, COVID-19 simulation training and personal protective equipment testing, as well as our approach to evaluating the rapid flow of research findings related to SARS-CoV-2 and COVID-19. We summarise lessons learnt and our adaptation to what may be a “new normal” in anaesthesiology practice.

The evidence supporting the intraoperative use of processed electroencephalography (pEEG) monitoring to guide anesthetic delivery is growing rapidly. This article reviews the key features of electroencephalography (EEG) waveforms and their clinical implications in select patient populations and anesthetic techniques. The first patient topic reviewed is the vulnerable brain. This term has emerged as a description of patients who may exhibit increased sensitivity to anesthetics and/or may develop adverse neurocognitive effects following anesthesia. pEEG monitoring of patients who are known to have or are suspected of having vulnerable brains, with focused attention on the suppression ratio, alpha band power, and pEEG indices, may prove useful. Second, pEEG monitoring along with vigilant attention to anesthetic delivery may minimize the risk of intraoperative awareness when administering a total intravenous anesthesia in combination with a neuromuscular blockade. Third, we suggest that processed EEG monitoring may play a role in anesthetic and resuscitative management when adverse changes in blood pressure occur. Fourth, pEEG monitoring can be used to better identify anesthesia requirements and guide anesthetic titration in patients with known or suspected substance use.