Importance of sequential methods in meta-analysis: implications for postoperative mortality, delirium, and stroke management.

Trial sequential analysis is an adaptation of frequentist sequential methods that can be used to improve inferences from meta-analysis. Trial sequential analysis can help preserve type I and type II error rates at desired levels for analyses conducted before the required information size. Through three case studies recently published in the British Journal of Anaesthesia, we show how trial sequential analysis can inform the interpretation of meta-analyses. Limitations of trial sequential analysis, which also include those of the meta-analysis to which it is applied, must be carefully considered alongside its benefits.

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.

Depth of anaesthesia and mortality after cardiac or noncardiac surgery: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Recent randomised controlled trials have failed to show a benefit in mortality by using processed electroencephalography (pEEG) to guide lighter anaesthesia. We performed a meta-analysis of mortality data from randomised trials of pEEG monitoring to assess the evidence of any protective effect of pEEG-guided light anaesthesia compared with deep anaesthesia in adults aged ≥18 yr. METHODS: Our study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. In February 2022, we searched three databases (Cochrane CENTRAL, OVID Medline, EMBASE) for RCTs of pEEG monitoring that provided mortality data at 30 days, 90 days, and/or 1 yr or longer. RESULTS: We included 16 articles from 12 RCTs with 48 827 total participants. We observed no statistically significant mortality reduction with light anaesthesia compared with deep anaesthesia in patients aged ≥18 yr when all studies were pooled (odds ratio [OR]=0.99; 95% confidence interval (CI), 0.92-1.08). This result did not change significantly when analysing mortality at 30 days, 90 days, 1 yr or longer. We observed no mortality benefit for pEEG monitoring compared with usual care (OR=1.02; 95% CI, 0.89-1.18), targeting higher pEEG index values compared with lower values (OR=0.89; 95% CI, 0.60-1.32), or low pEEG index value alerts compared with no alerts (OR=1.02; 95% CI, 0.41-2.52). CONCLUSIONS: pEEG-guided lighter anaesthesia does not appear to reduce the risk of postoperative mortality. The absence of a plausible rationale for why deeper anaesthesia should increase mortality has hampered appropriate design of definitive clinical trials. CLINICAL TRIAL REGISTRATION: CRD42022285195 (PROSPERO).

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.

Environmental and economic impact of using increased fresh gas flow to reduce carbon dioxide absorbent consumption in the absence of inhalational anaesthetics.

BACKGROUND: Increasing fresh gas flow (FGF) to a circle breathing system reduces carbon dioxide (CO2) absorbent consumption. We assessed the environmental and economic impacts of this trade-off between gas flow and absorbent consumption when no inhalational anaesthetic agent is used. METHODS: A test lung with fixed CO2 inflow was ventilated via a circle breathing system of an anaesthetic machine (Dräger Primus or GE Aisys CS2) using an FGF of 1, 2, 4, or 6 L min-1. We recorded the time to exhaustion of the CO2 absorbent canister, defined as when inspired partial pressure of CO2 exceeded 0.3 kPa. For each FGF, we calculated the economic costs and the environmental impact associated with the manufacture of the CO2 absorbent canister and the supply of medical air and oxygen. Environmental impact was measured in 100 yr global-warming potential, analysed using a life cycle assessment 'cradle to grave' approach. RESULTS: Increasing FGF from 1 to 6 L min-1 was associated with up to 93% reduction in the combined running cost with minimal net change to the 100 yr global-warming potential. Most of the reduction in cost occurred between 4 and 6 L min-1. Removing the CO2 absorbent from the circle system, and further increasing FGF to control CO2 rebreathing, afforded minimal further economic benefit, but more than doubled the global-warming potential. CONCLUSIONS: In the absence of inhalational anaesthetic agents, increasing FGF to 6 L min-1 reduces running cost compared with lower FGFs, with minimal impact to the environment.

BCG vaccination drives accumulation and effector function of innate lymphoid cells in murine lungs.

The tuberculosis (TB) vaccine bacille Calmette-Guérin (BCG) prevents disseminated childhood TB; however, it fails to protect against the more prevalent pulmonary TB. Limited understanding of the immune response to Mycobacterium tuberculosis, the causative agent of TB, has hindered development of improved vaccines. Although memory CD4 T cells are considered the main mediators of protection against TB, recent studies suggest there are other key subsets that contribute to antimycobacterial immunity. To that end, innate cells may be involved in the protective response. In this study, we investigated the primary response of innate lymphoid cells (ILCs) to BCG exposure. Using a murine model, we showed that ILCs increased in number in the lungs and lymph nodes in response to BCG vaccination. Additionally, there was significant production of the antimycobacterial cytokine IFN-γ by ILCs. As ILCs are located at mucosal sites, it was investigated whether mucosal vaccination (intranasal) stimulated an enhanced response compared to the traditional vaccination approach (intradermal or subcutaneous). Indeed, in response to intranasal vaccination, the number of ILCs, and IFN-γ production in NK cells and ILC1s in the lungs and lymph nodes, were higher than that provoked through intradermal or subcutaneous vaccination. This work provides the first evidence that BCG vaccination activates ILCs, paving the way for future research to elucidate the protective potential of ILCs against mycobacterial infection. Additionally, the finding that lung ILCs respond rigorously to mucosal vaccination may have implications for the delivery of novel TB vaccines.

Porous high-density polyethylene for orbital reconstruction.

OBJECTIVE: To determine the safety and efficacy of using porous high-density polyethylene (PHDPE) in the repair of orbital defects. DESIGN: Retrospective case series. SETTING: Academic tertiary care trauma center. Patients One hundred seventy patients with orbital defects requiring surgical repair. Intervention Orbital defect repair with PHDPE. Main Outcome Measure Our review documents surgical results and complications associated with the use of PHDPE. RESULTS: There was a 6.4% complication rate associated with the use of PHDPE. The infection rate was 1.8%. The persistent orbital malposition rate was 3.5%. The extrusion rate was 0%. CONCLUSIONS: This report represents the largest case series in the literature using PHDPE for orbital reconstructions. The use of PHDPE resulted in a low complication rate and excellent functional and cosmetic reconstructive results. Because of our success with the use of PHDPE, we have changed our clinical practice to minimize the use of autologous graft material, thereby eliminating donor site morbidity in cases involving orbital reconstruction.