Adverse outcomes after surgery after a cerebrovascular accident or acute coronary syndrome: a retrospective observational cohort study.

BACKGROUND: Delaying surgery after a major cardiovascular event might reduce adverse postoperative outcomes. The time interval represents a potentially modifiable risk factor but is not well studied. METHODS: This was a longitudinal retrospective population-based cohort study, linking data from Hospital Episode Statistics for NHS England and the Myocardial Ischaemia National Audit Project. Adults undergoing noncardiac, non-neurologic surgery in 2007-2018 were included. The time interval between a preoperative cardiovascular event and surgery was the main exposure. The outcomes of interest were acute coronary syndrome (ACS), acute myocardial infarction (AMI), cerebrovascular accident (CVA) within 1 year of surgery, unplanned readmission (at 30 days and 1 year), and prolonged length of stay. Multivariable logistic regression models with restricted cubic splines were used to estimate adjusted odds ratios (aORs; age, sex, socioeconomic deprivation, and comorbidities). RESULTS: In total, 877 430 people had a previous cardiovascular event and 20 582 717 were without an event. CVA, ACS, and AMI in the year after elective surgery were more frequent after prior cardiovascular events (adjusted hazard ratio 2.12, 95% confidence interval [CI] 2.08-2.16). Prolonged hospital stay (aOR 1.36, 95% CI 1.35-1.38) and 30-day (aOR 1.28, 95% CI 1.25-1.30) and 1-yr (aOR 1.60, 95% CI 1.58-1.62) unplanned readmission were more common after major operations in those with a prior cardiovascular event. After adjusting for the time interval between preoperative events until surgery, elective operations within 37 months were associated with an increased risk of postoperative ACS or AMI. The risk of postoperative stroke plateaued after a 20-month interval until surgery, irrespective of surgical urgency. CONCLUSIONS: These observational data suggest increased adverse outcomes after a recent cardiovascular event can occur for up to 37 months after a major cardiovascular event.

Association between surgical admissions, cognition, and neurodegeneration in older people: a population-based study from the UK Biobank.

BACKGROUND: Previous studies have shown that major surgical and medical hospital admissions are associated with cognitive decline in older people (aged 40-69 years at recruitment), which is concerning for patients and caregivers. We aimed to validate these findings in a large cohort and investigate associations with neurodegeneration using MRI. METHODS: For this population-based study, we analysed data from the UK Biobank collected from March 13, 2006, to July 16, 2023, linked to the National Health Service Hospital Episode Statistics database, excluding participants with dementia diagnoses. We constructed fully adjusted models that included age, time, sex, Lancet Commission dementia risk factors, stroke, and hospital admissions with a participant random effect. Primary outcomes were hippocampal volume and white matter hyperintensities, both of which are established markers of neurodegeneration, and exploratory analyses investigated the cortical thickness of Desikan-Killiany-Tourville atlas regions. The main cognitive outcomes were reaction time, fluid intelligence, and prospective and numeric memory. Surgeries were calculated cumulatively starting from 8 years before the baseline evaluation. FINDINGS: Of 502 412 participants in the UK Biobank study, 492 802 participants were eligible for inclusion in this study, of whom 46 706 underwent MRI. Small adverse associations with cognition were found per surgery: reaction time increased by 0·273 ms, fluid intelligence score decreased by 0·057 correct responses, prospective memory (scored as correct at first attempt) decreased (odds ratio 0·96 [95% CI 0·95 to 0·97]), and numeric memory maximum correct matches decreased by 0·025 in fully adjusted models. Surgeries were associated with smaller hippocampal volume (ß=-5·76 mm³ [-7·89 to -3·64]) and greater white matter hyperintensities volume (ß=100·02 mm³ [66·17 to 133·87]) in fully adjusted models. Surgeries were also associated with neurodegeneration of the insula and superior temporal cortex. INTERPRETATION: This population-based study corroborates that surgeries are generally safe but cumulatively are associated with cognitive decline and neurodegeneration. Perioperative brain health should be prioritised for older and vulnerable patients, particularly those who have multiple surgical procedures. FUNDING: The Australian and New Zealand College of Anaesthetists (ANZCA) Foundation and the University of Sydney.

International Delirium Pathophysiology & Electrophysiology Network for Data sharing (iDEPEND).

In an era of 'big data', we propose that a collaborative network approach will drive a better understanding of the mechanisms of delirium, and more rapid development of therapies. We have formed the International Delirium Pathophysiology & Electrophysiology Network for Data sharing (iDEPEND) group with a key aim to 'facilitate the study of delirium pathogenesis with electrophysiology, imaging, and biomarkers including data acquisition, analysis, and interpretation'. Our initial focus is on studies of electrophysiology as we anticipate this methodology has great potential to enhance our understanding of delirium. Our article describes this principle and is used to highlight the endeavour to the wider community as we establish key stakeholders and partnerships.

Mental illness comorbidity significantly impacts surgical outcomes for emergency surgical patients.

BACKGROUND: Whilst both mental illness comorbidity and the delivery of emergency surgery are commonplace in Australia, there is little evidence investigating any link between them. As such, this study examines the emergency surgical outcomes for patients with mental illness compared to other surgical patients within the Australian public surgical system. METHODS: Retrospective cohort study involving adult emergency and elective surgical patients treated at three public hospitals in Sydney, Australia between 2018 and 2019. Patients were identified using ICD-10 diagnosis codes, and grouped by those with decompensated mental illness, chronic depression, or those without mental illness. Outcome measures included those within the emergency department (ED), along with in-hospital mortality and surgical outcomes. RESULTS: Of 48 338 total patients, 31 890 (66.0%) had elective and 16 448 (34.0%) had emergency surgery. For patients with decompensated mental illness, only 228 (0.7%) had elective whilst 425 (2.6%) had emergency surgery. Their outcomes for this surgery type included being triaged significantly higher (Cat 1 or 2, 34% vs. 15%) and longer ED stays (8.3 vs. 6.6 h). They also had significantly more post-operative complications (26% vs. 8%) and total days in hospital (33.8 vs. 8.5 days). There was no significant difference for in-hospital mortality. CONCLUSION: Patients with mental illness are significantly more likely to have emergency surgery including presenting to the ED with more acute physical illness and to experience worse surgical outcomes compared to other surgical patients for every measure analyzed except mortality. There is considerable opportunity to further investigate how these differences might be improved.

Risk of Mortality Following Surgery in Patients With a Previous Cardiovascular Event.

Importance: There is a lack of consensus regarding the interval of time-dependent postoperative mortality risk following acute coronary syndrome or stroke. Objective: To determine the magnitude and duration of risk associated with the time interval between a preoperative cardiovascular event and 30-day postoperative mortality. Design, Setting, and Participants: This is a longitudinal retrospective population-based cohort study. This study linked data from the Hospital Episode Statistics for National Health Service England, Myocardial Ischaemia National Audit Project and the Office for National Statistics mortality registry. All adults undergoing a National Health Service-funded noncardiac, nonneurologic surgery in England between April 1, 2007, and March 31, 2018, registered in Hospital Episode Statistics Admitted Patient Care were included. Data were analyzed from July 2021 to July 2022. Exposure: The time interval between a previous cardiovascular event (acute coronary syndrome or stroke) and surgery. Main Outcomes and Measures: The primary outcome was 30-day all-cause mortality. Secondary outcomes were postoperative mortality at 60, 90, and 365 days. Multivariable logistic regression models with restricted cubic splines were used to estimate adjusted odds ratios. Results: There were 877 430 patients with and 20 582 717 without a prior cardiovascular event (overall mean [SD] age, 53.4 [19.4] years; 11 577 157 [54%] female). Among patients with a previous cardiovascular event, the time interval associated with increased risk of postoperative mortality was surgery within 11.3 months (95% CI, 10.8-11.7), with subgroup risks of 14.2 months before elective surgery (95% CI, 13.3-15.3) and 7.3 months for emergency surgery (95% CI, 6.8-7.8). Heterogeneity in these timings was noted across many surgical specialties. The time-dependent risk intervals following stroke and myocardial infarction were similar, but the absolute risk was greater following a stroke. Regarding surgical urgency, the risk of 30-day mortality was higher in those with a prior cardiovascular event for emergency surgery (adjusted hazard ratio, 1.35; 95% CI, 1.34-1.37) and an elective procedure (adjusted hazard ratio, 1.83; 95% CI, 1.78-1.89) than those without a prior cardiovascular event. Conclusions and Relevance: In this study, surgery within 1 year of an acute coronary syndrome or stroke was associated with increased postoperative mortality before reaching a new baseline, particularly for elective surgery. This information may help clinicians and patients balance deferring the potential benefits of the surgery against the desire to avoid increased mortality from overly expeditious surgery after a recent cardiovascular event.

Update of the European Society of Anaesthesiology and Intensive Care Medicine evidence-based and consensus-based guideline on postoperative delirium in adult patients.

Postoperative delirium (POD) remains a common, dangerous and resource-consuming adverse event but is often preventable. The whole peri-operative team can play a key role in its management. This update to the 2017 ESAIC Guideline on the prevention of POD is evidence-based and consensus-based and considers the literature between 01 April 2015, and 28 February 2022. The search terms of the broad literature search were identical to those used in the first version of the guideline published in 2017. POD was defined in accordance with the DSM-5 criteria. POD had to be measured with a validated POD screening tool, at least once per day for at least 3 days starting in the recovery room or postanaesthesia care unit on the day of surgery or, at latest, on postoperative day 1. Recent literature confirmed the pathogenic role of surgery-induced inflammation, and this concept reinforces the positive role of multicomponent strategies aimed to reduce the surgical stress response. Although some putative precipitating risk factors are not modifiable (length of surgery, surgical site), others (such as depth of anaesthesia, appropriate analgesia and haemodynamic stability) are under the control of the anaesthesiologists. Multicomponent preoperative, intra-operative and postoperative preventive measures showed potential to reduce the incidence and duration of POD, confirming the pivotal role of a comprehensive and team-based approach to improve patients' clinical and functional status.

Delirium is associated with loss of feedback cortical connectivity.

INTRODUCTION: Post-operative delirium (POD) is associated with increased morbidity and mortality but is bereft of treatments, largely due to our limited understanding of the underlying pathophysiology. We hypothesized that delirium reflects a disturbance in cortical connectivity that leads to altered predictions of the sensory environment. METHODS: High-density electroencephalogram recordings during an oddball auditory roving paradigm were collected from 131 patients. Dynamic causal modeling (DCM) analysis facilitated inference about the neuronal connectivity and inhibition-excitation dynamics underlying auditory-evoked responses. RESULTS: Mismatch negativity amplitudes were smaller in patients with POD. DCM showed that delirium was associated with decreased left-sided superior temporal gyrus (l-STG) to auditory cortex feedback connectivity. Feedback connectivity also negatively correlated with delirium severity and systemic inflammation. Increased inhibition of l-STG, with consequent decreases in feed-forward and feed-back connectivity, occurred for oddball tones during delirium. DISCUSSION: Delirium is associated with decreased feedback cortical connectivity, possibly resulting from increased intrinsic inhibitory tone. HIGHLIGHTS: Mismatch negativity amplitude was reduced in patients with delirium. Patients with postoperative delirium had increased feedforward connectivity before surgery. Feedback connectivity was diminished from left-side superior temporal gyrus to left primary auditory sensory area during delirium. Feedback connectivity inversely correlated with inflammation and delirium severity.

Resolution of elevated interleukin-6 after surgery is associated with return of normal cognitive function.

BACKGROUND: Unresolved surgical inflammation might induce chronic cognitive decline in older adults. Although inflammatory biomarkers have been correlated with perioperative cognitive impairment and delirium, the effects of prolonged inflammation on cognition are not well studied. This prospective cohort study investigated 1-yr dynamics in plasma interleukin-6 levels and executive function. METHODS: Patients undergoing major surgery (n=170) aged ≥65 yr completed Trail Making Test B and other neuropsychological assessments with plasma interleukin-6 levels collected on postoperative days 1-9 and 90, and at 1-yr. Mixed-effects analyses were conducted for Trail Making Test B (and other assessments), including interleukin-6 levels, time, and additional confounders (fixed effects), and a random effect for participant. RESULTS: Changes in interleukin-6 levels were associated with changes in Trail Making Test B over 1 yr in a generalised additive model (ß=0.074, P<0.001) supporting that unresolved inflammation impaired executive function. This result was robust to confounders, outlier rejection, and fitting to non-linear models. Changes in interleukin-6 levels also correlated with changes in Trail Making Test A and Controlled Oral Word Association Test. Sensitivity analyses conducted on binary definitions of cognitive decline (>1, >1.5, or >2 standard deviations from baseline) were also associated with interleukin-6 changes. CONCLUSIONS: Delayed resolution of inflammation is associated with cognitive impairment after surgery. Monitoring interleukin-6 might provide an opportunity to intervene with anti-inflammatory therapies in vulnerable patients. CLINICAL TRIAL REGISTRATION: NCT01980511, NCT03124303.

'Where there's smoke': longitudinal cognitive disintegration after postoperative delirium?

Postoperative delirium is an important complication of surgery and is associated with poor long-term cognitive outcomes, although the neural basis underlying this relationship is poorly understood. Neuroimaging studies and network-based approaches play an important role in our understanding of the mechanism by which delirium relates to longitudinal cognitive decline. A recent resting state functional MRI study is reviewed, which shows reduced global connectivity up to 3 months after delirium, supporting recent models of delirium and opening the door for applying this approach to understanding the complex inter-relationship between delirium and dementia.

Prospective analysis of plasma amyloid beta and postoperative delirium in the Interventions for Postoperative Delirium: Biomarker-3 study.

BACKGROUND: The effect of postoperative delirium on the amyloid cascade of Alzheimer's dementia is poorly understood. Using early postoperative plasma biomarkers, we explored whether surgery and delirium are associated with changes in amyloid pathways. METHODS: We analysed data from 100 participants in the Interventions for Postoperative Delirium: Biomarker-3 (IPOD-B3) cohort study in the USA (NCT03124303 and NCT01980511), which recruited participants aged >65 yr undergoing non-intracranial surgery. We assessed the relationship between the change in plasma amyloid beta ratio (AßR; Aß42:Aß40) and delirium incidence (defined by the 3-Minute Diagnostic Confusion Assessment Method) and severity (quantified by the Delirium Rating Scale-Revised-98, the study's primary outcome). We also tested the relationship between plasma amyloid beta and intraoperative variables. RESULTS: Across all participants, the plasma AßR increased from the preoperative period to postoperative Day 1 (Wilcoxon P<0.001). However, this increase was not associated with delirium incidence (Wilcoxon P=0.22) or peak severity after adjusting for confounders (log[incidence rate ratio]=0.43; P=0.14). Postoperative Day 1 change in plasma AßR was not associated with postoperative Day 1 change in plasma tau, neurofilament light, or inflammatory markers (interleukin [IL]-1ß, IL-1Ra, IL-2, IL-4, IL-6, IL-8, IL-10, and IL-12), or with operative time or low intraoperative arterial pressure. CONCLUSIONS: Perioperative changes in plasma amyloid do not appear to be associated with postoperative delirium. Our findings do not support associations of dynamic changes in amyloid with postoperative delirium. CLINICAL TRIAL REGISTRATION: .NCT03124303 and NCT01980511.

Postoperative Use of the Muscle Relaxants Baclofen and/or Cyclobenzaprine Associated With an Increased Risk of Delirium Following Lumbar Fusion.

STUDY DESIGN: Retrospective, single-center, cohort study. OBJECTIVE: Investigate whether the incidence of postoperative delirium in older adults undergoing spinal fusion surgery is associated with postoperative muscle relaxant administration. SUMMARY OF BACKGROUND DATA: Baclofen and cyclobenzaprine are muscle relaxants frequently used for pain management following spine surgery. Muscle relaxants are known to cause central nervous system side effects in the outpatient setting and are relatively contraindicated in individuals at high risk for delirium. However, there are no known studies investigating their side effects in the postoperative setting. METHODS: Patients over 65 years of age who underwent elective posterior lumbar fusion for degenerative spine disease were stratified into two treatment groups based on whether postoperative muscle relaxants were administered on postoperative day one as part of a multimodal analgesia regimen. Doubly robust inverse probability weighting with cox regression for time-dependent covariates was used to examine the association between postoperative muscle relaxant use and the risk of delirium while controlling for variation in baseline characteristics. RESULTS: The incidence of delirium was 17.6% in the 250 patients who received postoperative muscle relaxants compared with 7.9% in the 280 patients who did not receive muscle relaxants ( P=0.001 ). Multivariate analysis to control for variation in baseline characteristics between treatment groups found that patients who received muscle relaxants had a 2.00 (95% CI: 1.14-3.49) times higher risk of delirium compared with controls ( P=0.015 ). CONCLUSION: Postoperative use of muscle relaxants as part of a multimodal analgesia regimen was associated with an increased risk of delirium in older adults after lumber fusion surgery. Although muscle relaxants may be beneficial in select patients, they should be used with caution in individuals at high risk for postoperative delirium.

Surgeon-Specific Treatment Selection Bias and Heterogeneous Perioperative Practices in an Observational Spine Surgery Study. A Statistical Tutorial with Implications for Analysis of Observational Studies of Perioperative Interventions.

BACKGROUND: It is essential that treatment effects reported from retrospective observational studies are as reliable as possible. In a retrospective analysis of spine surgery patients, we obtained a spurious result: tranexamic acid (TXA) had no effect on intraoperative blood loss. This statistical tutorial explains how this result occurred and why statistical analyses of observational studies must consider the effects of individual surgeons. METHODS: We used an observational database of 580 elective adult spine surgery patients, supplemented with a review of perioperative medication records. We tested whether common statistical methods (multivariable regression or propensity score-based methods) could adjust for surgeons' selection bias in TXA administration. RESULTS: Because TXA administration (frequency, timing, and dose) and surgeon were linked (collinear), estimating and testing the independent effect of TXA on outcome using multivariable regression without including surgeon as a variable would provide biased (spurious) results. Likewise, because of surgeon/TXA linkage, assumptions of propensity score-based analysis were violated, statistical methods to improve comparability between groups failed, and spurious blood loss results were worsened. Others numerous differences among surgeons existed in intraoperative and postoperative practices and outcomes. CONCLUSIONS: In observational studies in which individual surgeons determine whether their patients receive the treatment of interest, consideration must be given to inclusion of surgeon as an independent variable in all analyses. Failure to include the surgeon in an analysis of observational data carries a substantial risk of obtaining spurious results, either creating a spurious treatment effect or failing to detect a true treatment effect.

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).

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.

Perioperative ischaemic brain injury and plasma neurofilament light: a secondary analysis of two prospective cohort studies.

BACKGROUND: Ischaemic brain infarction can occur without acute neurological symptoms (covert strokes) or with symptoms (overt strokes), both associated with poor health outcomes. We conducted a pilot study of the incidence of preoperative and postoperative (intraoperative or postoperative) covert strokes, and explored the relationship of postoperative ischaemic brain injury to blood levels of neurofilament light, a biomarker of neuronal damage. METHODS: We analysed 101 preoperative (within 2 weeks of surgery) and 58 postoperative research MRIs on postoperative days 2-9 from two prospective cohorts collected at the University of Wisconsin (NCT01980511 and NCT03124303). Participants were aged >65 yr and undergoing non-intracranial, non-carotid surgery. RESULTS: Preoperative covert stroke was identified in 2/101 participants (2%; Bayesian 95% confidence interval [CI], 0.2-5.4). This rate was statistically different from the postoperative ischaemic brain injury rate of 7/58 (12%, 4.9-21.3%; P=0.01) based on postoperative imaging. However, in a smaller group of participants with paired imaging (n=30), we did not identify the same effect (P=0.67). Patients with postoperative brain injury had elevated peak neurofilament light levels (median [inter-quartile range], 2.34 [2.24-2.64] log10 pg ml-1) compared with those without (1.86 [1.48-2.21] log10 pg ml-1; P=0.025). Delirium severity scores were higher in those with postoperative brain injury (19 [17-21]) compared with those without (7 [4-12]; P=0.01). CONCLUSION: Although limited by a small sample size, these data suggest that preoperative covert stroke occurs more commonly than previously anticipated. Plasma neurofilament light is a potential screening biomarker for postoperative ischaemic brain injury.