Impact of female sex on anaesthetic awareness, depth, and emergence: a systematic review and meta-analysis.

BACKGROUND: Suggested anaesthetic dose ranges do not differ by sex, likely because of limited studies comparing sexes. Our objective was to systematically synthesise studies with outcomes of unintended anaesthesia awareness under anaesthesia, intraoperative connected consciousness, time to emergence from anaesthesia, and dosing to achieve adequate depth of anaesthesia, and to compare between females and males. METHODS: Studies were identified from MEDLINE, Embase, and the Cochrane library databases until August 2, 2022. Controlled clinical trials (randomised/non-randomised) and prospective cohort studies that reported outcomes by sex were included. Results were synthesised by random effects meta-analysis where possible, or narrative form. RESULTS: Of the 19 749 studies identified, 64 (98 243 participants; 53 143 females and 45 100 males) were eligible for inclusion, and 44 citations contributed to meta-analysis. Females had a higher incidence of awareness with postoperative recall (33 studies, odds ratio 1.38, 95% confidence interval [CI] 1.09-1.75) and connected consciousness during anaesthesia (three studies, OR 2.09, 95% CI 1.04-4.23) than males. Time to emergence was faster in females, including time to eye-opening (10 studies, mean difference -2.28 min, 95% CI -3.58 to -0.98), and time to response to command (six studies, mean difference -2.84 min, 95% CI -4.07 to -1.62). Data on depth of anaesthesia were heterogenous, limiting synthesis to a qualitative review which did not identify sex differences. CONCLUSIONS: Female sex was associated with a greater incidence of awareness under general anaesthesia, and faster emergence from anaesthesia. These data suggest reappraisal of anaesthetic care, including whether similar drug dosing for females and males represents best care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022336087.

Sevoflurane dose and postoperative delirium: a prospective cohort analysis.

BACKGROUND: Recent trials are conflicting as to whether titration of anaesthetic dose using electroencephalography monitoring reduces postoperative delirium. Titration to anaesthetic dose itself might yield clearer conclusions. We analysed our observational cohort to clarify both dose ranges for trials of anaesthetic dose and biological plausibility of anaesthetic dose influencing delirium. METHODS: We analysed the use of sevoflurane in an ongoing prospective cohort of non-intracranial surgery. Of 167 participants, 118 received sevoflurane and were aged >65 yr. We tested associations between age-adjusted median sevoflurane (AMS) minimum alveolar concentration fraction or area under the sevoflurane time×dose curve (AUC-S) and delirium severity (Delirium Rating Scale-98). Delirium incidence was measured with 3-minute Diagnostic Confusion Assessment Method (3D-CAM) or CAM-ICU. Associations with previously identified delirium biomarkers (interleukin-8, neurofilament light, total tau, or S100B) were tested. RESULTS: Delirium severity did not correlate with AMS (Spearman's ρ=-0.014, P=0.89) or AUC-S (ρ=0.093, P=0.35), nor did delirium incidence (AMS Wilcoxon P=0.86, AUC-S P=0.78). Further sensitivity analyses including propofol dose also demonstrated no relationship. Linear regression confirmed no association for AMS in unadjusted (log (IRR)=-0.06 P=0.645) or adjusted models (log (IRR)=-0.0454, P=0.735). No association was observed for AUC-S in unadjusted (log (IRR)=0.00, P=0.054) or adjusted models (log (IRR)=0.00, P=0.832). No association of anaesthetic dose with delirium biomarkers was identified (P>0.05). CONCLUSION: Sevoflurane dose was not associated with delirium severity or incidence. Other biological mechanisms of delirium, such as inflammation and neuronal injury, appear more plausible than dose of sevoflurane. CLINICAL TRIAL REGISTRATION: NCT03124303, NCT01980511.

Connected consciousness after tracheal intubation in young adults: an international multicentre cohort study.

BACKGROUND: Connected consciousness, assessed by response to command, occurs in at least 5% of general anaesthetic procedures and perhaps more often in young people. Our primary objective was to establish the incidence of connected consciousness after tracheal intubation in young people aged 18-40 yr. The secondary objectives were to assess the nature of these responses, identify relevant risk factors, and determine their relationship to postoperative outcomes. METHODS: This was an international, multicentre prospective cohort study using the isolated forearm technique to assess connected consciousness shortly after tracheal intubation. RESULTS: Of 344 enrolled subjects, 338 completed the study (mean age, 30 [standard deviation, 6.3] yr; 232 [69%] female). Responses after intubation occurred in 37/338 subjects (11%). Females (13%, 31/232) responded more often than males (6%, 6/106). In logistic regression, the risk of responsiveness was increased with female sex (odds ratio [ORadjusted]=2.7; 95% confidence interval [CI], 1.1-7.6; P=0.022) and was decreased with continuous anaesthesia before laryngoscopy (ORadjusted=0.43; 95% CI, 0.20-0.96; P=0.041). Responses were more likely to occur after a command to respond (and not to nonsense, 13 subjects) than after a nonsense statement (and not to command, four subjects, P=0.049). CONCLUSIONS: Connected consciousness occured after intubation in 11% of young adults, with females at increased risk. Continuous exposure to anaesthesia between induction of anaesthesia and tracheal intubation should be considered to reduce the incidence of connected consciousness. Further research is required to understand sex-related differences in the risk of connected consciousness.

An Introduction to Causal Diagrams for Anesthesiology Research.

Making good decisions in the era of Big Data requires a sophisticated approach to causality. We are acutely aware that association ≠ causation, yet untangling the two remains one of our greatest challenges. This realization has stimulated a Causal Revolution in epidemiology, and the lessons learned are highly relevant to anesthesia research. This article introduces readers to directed acyclic graphs; a cornerstone of modern causal inference techniques. These diagrams provide a robust framework to address sources of bias and discover causal effects. We use the topical question of whether anesthetic technique (total intravenous anesthesia vs. volatile) affects outcome after cancer surgery as a basis for a series of example directed acyclic graphs, which demonstrate how variables can be chosen to statistically control confounding and other sources of bias. We also illustrate how controlling for the wrong variables can introduce, rather than eliminate, bias; and how directed acyclic graphs can help us diagnose this problem.This is a rapidly evolving field, and we cover only the most basic elements. The true promise of these techniques is that it may become possible to make robust statements about causation from observational studies-without the expense and artificiality of randomized controlled trials.

Transient electroencephalographic alpha power loss during maintenance of general anaesthesia.

BACKGROUND: EEG activity in the extended alpha frequency range (7-17 Hz) during maintenance of general anaesthesia is primarily determined by effect-site concentrations of the hypnotic and analgesic drugs used. Intermittent alpha loss during surgery, unexplained by changes in anaesthetic or opioid concentrations, could represent arousal of the cortex as a result of increased surgical stimulation. METHODS: A generalised linear model was fitted to alpha power recorded from patients undergoing general anaesthesia from induction until waking using three explanatory variables: age-adjusted volatile anaesthetic effect-site concentration, and estimated effect-site propofol and opioid concentrations. Model residuals were decomposed into uncorrelated white noise and a fluctuating auto-correlated trend. Deviations of this local trend were classified as 'unexpected alpha dropout events'. To investigate whether these alpha dropouts might be explained by the effect of noxious stimulation, we related their occurrence to whether a patient was undergoing surgery involving the body cavity or not. RESULTS: Alpha power dropouts occurred in 73 of the 237 patients included in the final analysis (31%, median amplitude of -3.5 dB, duration=103 s). They showed a bimodal or broadly skewed distribution, being more probable soon after initial incision (32%), dropping to around 10% at 1 h, and then again increasing to >30% in operations lasting >3 h. Multivariate analysis showed that alpha dropouts were significantly associated with body cavity surgery (P=0.003) and with longer operations (P<0.001). CONCLUSIONS: A loss of alpha power, unexplained by changes in anaesthetic or opioid concentrations, is suggestive of thalamocortical depolarisation induced by body cavity noxious stimuli, and could provide a measure of nociception during surgery.

Non-sinusoidal waves in the EEG and their simulated effect on anaesthetic quantitative EEG monitors.

The effect of anaesthetic drugs on the cortex are commonly estimated from the electroencephalogram (EEG) by quantitative EEG monitors such as the Bispectral Index (BIS). These monitors use ratios of high to low frequency power which assumes that each neurological process contributes a unique frequency pattern. However, recent research of the effect of deep brain stimulation on EEG beta oscillations suggests that wave shape, a non-sinusoidal feature that is only measurable in the time-domain, can change the frequency 'signature' of a neurological rhythmical process by the inclusion or removal of harmonic frequencies. If wave shape variations are present in the EEG of anaesthetised patients, then quantitative EEG monitors likely overestimate the anaesthetic drug effect. The purpose of this paper is to investigate alpha-wave shape in the EEG of anaesthetised patients and demonstrate the effect of wave shape on the frequency ratios that are commonly utilised in the BIS quantitative EEG monitor. EEG data, demographic information, and surgery details were collected prospectively from 305 patients undergoing a general anaesthetic for elective surgery. Alpha-wave shape was categorised by triangularity of the EEG extrema, a measure of how peaked (towards a sawtooth wave) or flat (towards a square wave) the extremum was. The alpha-wave was then artificially modified to either a sawtooth wave or square wave, and BetaRatio and PowerFastSlow metrics calculated. Age was found to be the only significant predictor of alpha wave triangularity. The artificially modified square-alpha waves increased the power in the frequency spectrum at 26 Hz by 1-5 dB, and increased the BetaRatio by 0.7. The alpha-wave of anaesthetised patients contains non-sinusoidal components which likely impact depth of anaesthesia calculations.

Incidence of Connected Consciousness after Tracheal Intubation: A Prospective, International, Multicenter Cohort Study of the Isolated Forearm Technique.

BACKGROUND: The isolated forearm technique allows assessment of consciousness of the external world (connected consciousness) through a verbal command to move the hand (of a tourniquet-isolated arm) during intended general anesthesia. Previous isolated forearm technique data suggest that the incidence of connected consciousness may approach 37% after a noxious stimulus. The authors conducted an international, multicenter, pragmatic study to establish the incidence of isolated forearm technique responsiveness after intubation in routine practice. METHODS: Two hundred sixty adult patients were recruited at six sites into a prospective cohort study of the isolated forearm technique after intubation. Demographic, anesthetic, and intubation data, plus postoperative questionnaires, were collected. Univariate statistics, followed by bivariate logistic regression models for age plus variable, were conducted. RESULTS: The incidence of isolated forearm technique responsiveness after intubation was 4.6% (12/260); 5 of 12 responders reported pain through a second hand squeeze. Responders were younger than nonresponders (39 ± 17 vs. 51 ± 16 yr old; P = 0.01) with more frequent signs of sympathetic activation (50% vs. 2.4%; P = 0.03). No participant had explicit recall of intraoperative events when questioned after surgery (n = 253). Across groups, depth of anesthesia monitoring values showed a wide range; however, values were higher for responders before (54 ± 20 vs. 42 ± 14; P = 0.02) and after (52 ± 16 vs. 43 ± 16; P = 0.02) intubation. In patients not receiving total intravenous anesthesia, exposure to volatile anesthetics before intubation reduced the odds of responding (odds ratio, 0.2 [0.1 to 0.8]; P = 0.02) after adjustment for age. CONCLUSIONS: Intraoperative connected consciousness occurred frequently, although the rate is up to 10-times lower than anticipated. This should be considered a conservative estimate of intraoperative connected consciousness.

Deconstructing delirium in the post anaesthesia care unit.

The course of neuro-cognitive recovery following anaesthesia and surgery is distinctive and poorly understood. Our objective was to identify patterns of neuro-cognitive recovery of the domains routinely assessed for delirium diagnosis in the post anaesthesia care unit (PACU) and to compare them to the cognitive recovery patterns observed in other studies; thereby aiding in the identification of pathological (high risk) patterns of recovery in the PACU. We also compared which of the currently available tests (3D-CAM, CAM-ICU, and NuDESC) is the best to use in PACU. This was a post hoc secondary analysis of data from the Alpha Max study which involved 200 patients aged over 60 years, scheduled for elective surgery under general anaesthesia lasting more than 2 h. These patients were assessed for delirium at 30 min following arrival in the PACU, if they were adequately arousable (Richmond Agitation Sedation Score ≥ -2). All tests for delirium diagnosis (3D-CAM, CAM-ICU, and NuDESC) and the sub-domains assessed were compared to understand temporal recovery of neurocognitive domains. These data were also analysed to determine the best predictor of PACU delirium. We found the incidence of PACU delirium was 35% (3D-CAM). Individual cognitive domains were affected differently. Few individuals had vigilance deficits (6.5%, n = 10 CAM-ICU) or disorganized thinking (19% CAM-ICU, 27.5% 3D-CAM), in contrast attention deficits were common (72%, n = 144) and most of these patients (89.5%, n = 129) were not sedated (RASS ≥ -2). CAM-ICU (27%) and NuDESC (52.8%) detected fewer cases of PACU delirium compared to 3D-CAM. In conclusion, return of neurocognitive function is a stepwise process; Vigilance and Disorganized Thinking are the earliest cognitive functions to return to baseline and lingering deficits in these domains could indicate an abnormal cognitive recovery. Attention deficits are relatively common at 30 min in the PACU even in individuals who appear to be awake. The 3D CAM is a robust test to check for delirium in the PACU.

Modulation of frontal EEG alpha oscillations during maintenance and emergence phases of general anaesthesia to improve early neurocognitive recovery in older patients: protocol for a randomised controlled trial.

BACKGROUND: Postoperative delirium may manifest in the immediate post-anaesthesia care period. Such episodes appear to be predictive of further episodes of inpatient delirium and associated adverse outcomes. Frontal electroencephalogram (EEG) findings of suppression patterns and low proprietary index values have been associated with postoperative delirium and poor outcomes. However, the efficacy of titrating anaesthesia to proprietary index targets for preventing delirium remains contentious. We aim to assess the efficacy of two strategies which we hypothesise could prevent post-anaesthesia care unit (PACU) delirium by maximising the alpha oscillation observed in frontal EEG channels during the maintenance and emergence phases of anaesthesia. METHODS: This is a 2 × 2 factorial, double-blind, stratified, randomised control trial of 600 patients. Eligible patients are those aged 60 years or over who are undergoing non-cardiac, non-intracranial, volatile-based anaesthesia of expected duration of more than 2 h. Patients will be stratified by pre-operative cognitive status, surgery type and site. For the maintenance phase of anaesthesia, patients will be randomised (1:1) to an alpha power-maximisation anaesthesia titration strategy versus standard care avoiding suppression patterns in the EEG. For the emergence phase of anaesthesia, patients will be randomised (1:1) to early cessation of volatile anaesthesia and emergence from an intravenous infusion of propofol versus standard emergence from volatile anaesthesia only. The primary study outcomes are the power of the frontal alpha oscillation during the maintenance and emergence phases of anaesthesia. Our main clinical outcome of interest is PACU delirium. DISCUSSION: This is a largely exploratory study; the extent to which EEG signatures can be modified by titration of pharmacological agents is not known. The underlying concept is maximisation of anaesthetic efficacy by individualised drug titration to a clearly defined EEG feature. The interventions are already clinically used strategies in anaesthetic practice, but have not been formally evaluated. The addition of propofol during the emergence phase of volatile-based general anaesthesia is known to reduce emergence delirium in children; however, the efficacy of this strategy in older patients is not known. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry, ID: 12617001354370 . Registered on 27/09/2017.

Inattentive Delirium vs. Disorganized Thinking: A New Axis to Subcategorize PACU Delirium.

Background: Assessment of patients for delirium in the Post Anesthesia Care Unit (PACU) is confounded by the residual effects of the varied anesthetic and analgesic regimens employed during surgery and by the physiological consequences of surgery such as pain. Nevertheless, delirium diagnosed at this early stage has been associated with adverse clinical outcomes. The last decade has seen the emergence of the confusion assessment method-intensive care unit (CAM-ICU) score as a quick practical method of detecting delirium in clinical situations. Nonetheless, this tool has not been specifically designed for use in this immediate postoperative setting. Methods: Patients enrolled in a larger observational study were administered the CAM-ICU delirium screening tool 15 min after the latter of return of responsiveness to command or arrival in the post-anesthesia care unit. Numerical pain rating scores were also recorded. In addition, we reviewed additional behavioral observations suggestive of disordered thinking, such as hallucinations, a non-reactive eyes-open state, or an inability to state a pain score. Results: Two-hundred and twenty-nine patients underwent CAM-ICU testing in PACU. 33 patients (14%) were diagnosed with delirium according to CAM-ICU criteria; 25 of these were inattentive with low arousal, seven were inattentive with high arousal, and one was inattentive and calm and with disordered thinking. Using our extended criteria an additional eleven patients showed signs of disordered thinking. CAM-ICU delirium was associated with increased length of operation (p = 0.028), but a positive CAM-PACU designation was associated with both increased operation length and age (p = 0.003 and 0.010 respectively). Two of the CAM-ICU positive patients with inattention and high arousal reported high pain scores and were not classified as CAM-PACU positive. Conclusion: Disordered thinking is correlated with older patients and longer operations. The sensitivity of the existing CAM-ICU score in diagnosing delirium or disordered thinking in PACU patients is improved by the inclusion of a few extra criteria, namely: patients having perceptual hallucinations, in an unreactive eyes-open state, or who cannot state a pain score. We present this alternative screening tool for use in the post-anesthetic period, which we have named CAM-PACU.