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Summary Type 2 diabetes is a global health priority, given that it is driven, in part, by an ageing population, the role of immune senescence has been overlooked. This is surprising, as the functional impairments of senescent T cells show strong similarities to patients with hyperglycaemia. Immune senescence is typified by alterations in T cell memory, such as the accumulation of highly differentiated end-stage memory T cells, as well as a constitutive low-grade inflammation, which drives further immune differentiation. We show here in a preliminary study that people living with type 2 diabetes have a higher circulating volume of senescent T cells accompanied with a higher level of systemic inflammation. This inflammatory environment drives the expression of a unique array of chemokine receptors on senescent T cells, most notably C-X-C motif chemokine receptor type 2. However, this increased expression of migratory markers does not translate to improved extravasation owing to a lack of glucose uptake by the T cells. Our results therefore demonstrate that the presence of senescent T cells has a detrimental impact on immune function during type 2 diabetes.

Summary The systemic stress response triggered by surgical trauma is characterised by sterile inflammation preceding metabolic and neuroendocrine dysregulation. However, the relevance of the classically described ‘stress response' is now highly questionable in an era where profound physiological deconditioning is common in older, frail surgical patients. Commonly used assessment techniques do not accurately reflect hypothalamic–pituitary–adrenal axis integrity after major surgery. Clinical interpretation of plasma concentrations of cortisol, the prototypical stress hormone, is rarely accurate, because of study heterogeneity, the inherently dynamic characteristics of cortisol production, and assay variability. Before surgery, chronic psychosocial stress and common cardiorespiratory co-morbidities are clinically relevant modifiers of neuroendocrine activation to acute stress/inflammation. The frequent development of multi-morbidity after major surgery further clouds the compartmentalised, discrete model of neuroendocrine activation after initial tissue injury. Starvation, impaired mobility, and sepsis after surgery generate distinct neuroendocrine profiles that challenge the conventional model of neuroendocrine activation. Basic science studies suggest that high circulating levels of cortisol may directly cause organ injury. Conversely, randomised controlled clinical trials investigating glucocorticoid supplementation have delivered contrasting results, with some suggesting a protective effect in the perioperative period. Here, we consider many of the confounding factors that have emerged to challenge the conventional model of the surgical stress response, and suggest that a more nuanced understanding of changes in hypothalamic–pituitary–adrenal axis physiology is warranted to advance perioperative medicine. Re-examining the perioperative stress response presents opportunities for improving outcomes through enhancing the understanding of the neuroendocrine aspects of preparation for and recovery from surgery.

Infection is a frequent cause of postoperative morbidity and mortality. The incidence, risk factors, and outcomes for postoperative infections remain poorly characterised.This is a secondary analysis of a prospective international cohort study of patients aged ≥45 yr who had noncardiac surgery (VISION), including data describing infection within 30 days after surgery. The primary outcome was postoperative infection. The secondary outcome was 30 day mortality. We used univariable and multivariable logistic regression to identify baseline risk factors for infection. Results are presented as n (%) or odds ratio (OR) with 95% confidence intervals. Some denominators vary according to rates of missing data.Among 39 996 surgical patients, 3905 (9.8%) experienced 5152 postoperative infections and 715 (1.8%) died. The most frequent infection was surgical site infection (1555/3905 [39.8%]). Infection was most strongly associated with general surgery (OR: 3.74 [3.11-4.49]; P0.01) and open surgical technique (OR: 2.03 [1.82-2.27]; P0.01); 30 day mortality was greater amongst patients who experienced infection (262/3905 [6.7%] vs 453/36 091 patients who did not [1.3%]; OR: 3.47 [2.84-4.22]; P0.01). Mortality was highest amongst patients with CNS infections (OR: 14.72 [4.41-49.12]; P0.01).Infection is a common and important complication of noncardiac surgery, which is associated with high mortality. Further research is needed to identify more effective measures to prevent infections after surgery.

BackgroundMyocardial injury is more frequent after non-cardiac surgery in patients with preoperative cardiac vagal dysfunction as quantified by delayed heart rate recovery after cessation of cardiopulmonary exercise testing. Here, we hypothesised that serial and dynamic measures of perioperative cardiac vagal activity should also be associated with myocardial injury after non-cardiac surgery.MethodsSerial measures in cardiac vagal activity were quantified preoperatively and daily using heart rate variability and a standardised orthostatic challenge in patients undergoing elective non-cardiac surgery. The primary outcome was myocardial injury (high-sensitivity troponin (hsTnT) ≥15ng.L−1) within 48h of surgery. Clinicians, patients and investigators were blinded to hsTnT. The exposure of interest was cardiac vagal activity (high-frequency power spectral analysis [HFlog]) and heart rate recovery after a standardised orthostatic challenge.ResultshsTnT≥15ng.L−1 occurred in 48/189 [25%] patients, of whom 41/48 [85%] had a revised cardiac risk index score −1 were associated with an early loss (within 24h) of cardiac vagal activity (HFLog) post surgery compared to day of surgery (4.19 [95%CI:3.62-4.75] vs 5.22 [95%CI:4.64-5.81]; p−1 (5 beats minute−1 (95% CI: 3 −7), compared to heart rate recovery in patients who remained free of myocardial injury (10 beats minute−1 (95%CI:7 to 12]; p = 0.02).ConclusionsReal-time, serial heart rate measures indicating loss of cardiac vagal activity are associated with perioperative myocardial injury in lower-risk patients undergoing non-cardiac surgery.

Background Even mild and transient acute kidney injury (AKI), defined by increases in serum creatinine level, has been associated with adverse outcomes after major surgery. However, characteristic decreases in creatinine concentration during major illness could confound accurate assessment of postoperative AKI. Methods In a single-hospital, retrospective cohort study of non-cardiac surgery, the association between postoperative AKI, defined using the Kidney Disease: Improving Global Outcomes criteria, and 1-year survival was modelled using a multivariable Cox proportional hazards analysis. Factors associated with development of AKI were examined by means of multivariable logistic regression. Temporal changes in serum creatinine during and after the surgical admission in patients with and without AKI were compared. Results Some 1869 patients were included in the study, of whom 128 (6·8 per cent) sustained AKI (101 stage 1, 27 stage 2–3). Seventeen of the 128 patients with AKI (13·3 per cent) died in hospital compared with 16 of 1741 (0·9 per cent) without AKI (P < 0·001). By 1 year, 34 patients with AKI (26·6 per cent) had died compared with 106 (6·1 per cent) without AKI (P < 0·001). Over the 8–365 days after surgery, AKI was associated with an adjusted hazard ratio for death of 2·96 (95 per cent c.i. 1·86 to 4·71; P < 0·001). Among hospital survivors without AKI, the creatinine level fell consistently (median difference at discharge versus baseline –7 (i.q.r. –15 to 0) µmol/l), but not in those with AKI (0 (–16 to 26) µmol/l) (P < 0·001). Conclusion Although the majority of postoperative AKI was mild, there was a strong association with risk of death in the year after surgery. Underlying decreases in serum creatinine concentration after major surgery could lead to underestimation of AKI severity and overestimation of recovery.

Molecular mechanisms linking autonomic dysfunction with poorer clinical outcomes in critical illness remain unclear. We hypothesized that baroreflex dysfunction alone is sufficient to cause cardiac impairment through neurohormonal activation of (nicotinamide adenine dinucleotide phosphate oxidase dependent) oxidative stress resulting in increased expression of G-protein-coupled receptor kinase 2, a key negative regulator of cardiac function.Laboratory/clinical investigations.University laboratory/medical centers.Adult rats; wild-type/nicotinamide adenine dinucleotide phosphate oxidase subunit-2-deficient mice; elective surgical patients.Cardiac performance was assessed by transthoracic echocardiography following experimental baroreflex dysfunction (sino-aortic denervation) in rats and mice. Immunoblots assessed G-protein-coupled receptor recycling proteins expression in rodent cardiomyocytes and patient mononuclear leukocytes. In surgical patients, heart rate recovery after cardiopulmonary exercise testing, time/frequency measures of parasympathetic variables were related to the presence/absence of baroreflex dysfunction (defined by spontaneous baroreflex sensitivity of6 ms mm Hg). The associations of baroreflex dysfunction with intraoperative cardiac function and outcomes were assessed.Experimental baroreflex dysfunction in rats and mice resulted in impaired cardiac contractility and upregulation of G-protein-coupled receptor kinase 2 expression. In mice, genetic deficiency of gp91 nicotinamide adenine dinucleotide phosphate oxidase subunit-2 prevented upregulation of G-protein-coupled receptor kinase 2 expression in conditions of baroreflex dysfunction and preserved cardiac function. Baroreflex dysfunction was present in 81 of 249 patients (32.5%) and was characterized by lower parasympathetic tone and increased G-protein-coupled receptor kinase 2 expression in mononuclear leukocytes. Baroreflex dysfunction in patients was also associated with impaired intraoperative cardiac contractility. Critical illness and mortality were more frequent in surgical patients with baroreflex dysfunction (relative risk, 1.66 [95% CI, 1.16-2.39]; p = 0.006).Reduced baroreflex sensitivity is associated with nicotinamide adenine dinucleotide phosphate oxidase subunit-2-mediated upregulation of G-protein-coupled receptor kinase 2 expression in cardiomyocytes and impaired cardiac contractility. Autonomic dysfunction predisposes patients to the development of critical illness and increases mortality.

[This corrects the article DOI: 10.1016/j.bjae.2020.07.004.].

BackgroundImpaired cardiac vagal function, quantified preoperatively as slower heart rate recovery (HRR) after exercise, is independently associated with perioperative myocardial injury. Parasympathetic (vagal) dysfunction may also promote (extra-cardiac) multi-organ dysfunction, although perioperative data are lacking. Assuming that cardiac vagal activity, and therefore heart rate recovery response, is a marker of brainstem parasympathetic dysfunction, we hypothesized that impaired HRR would be associated with a higher incidence of morbidity after noncardiac surgery.MethodsIn two prospective, blinded, observational cohort studies, we established the definition of impaired vagal function in terms of the HRR threshold that is associated with perioperative myocardial injury (HRR ≤ 12 beats min-1 (bpm), 60 seconds after cessation of cardiopulmonary exercise testing. The primary outcome of this secondary analysis was all-cause morbidity three and five days after surgery, defined using the Post-Operative Morbidity Survey. Secondary outcomes of this analysis were type of morbidity and time to become morbidity-free. Logistic regression and Cox regression tested for the association between HRR and morbidity. Results are presented as odds/hazard ratios [OR or HR; (95% confidence intervals).Results882/1941 (45.4%) patients had HRR≤12bpm. All-cause morbidity within 5 days of surgery was more common in 585/822 (71.2%) patients with HRR≤12bpm, compared to 718/1119 (64.2%) patients with HRR>12bpm (OR:1.38 (1.14-1.67); p = 0.001). HRR≤12bpm was associated with more frequent episodes of pulmonary (OR:1.31 (1.05-1.62);p = 0.02)), infective (OR:1.38 (1.10-1.72); p = 0.006), renal (OR:1.91 (1.30-2.79); p = 0.02)), cardiovascular (OR:1.39 (1.15-1.69); pConclusionsMulti-organ dysfunction is more common in surgical patients with cardiac vagal dysfunction, defined as HRR ≤ 12 bpm after preoperative cardiopulmonary exercise testing.Clinical trial registryISRCTN88456378.

Circulatory shock is accompanied, and likely to be preceded, by profound alterations in autonomic function. In stable conditions, sympathetic and parasympathetic limbs of the autonomic nervous system work in a highly coordinated manner, by virtue of physical and biochemical afferent signals being transduced into coordinated neural activity to maintain homeostasis in multiple organs innervated by specialized autonomic nerves. In this chapter, we assess how normal autonomic activity is regulated and the practical implications of how perturbation of the autonomic nervous system fuels further detrimental changes in shock. We will also highlight how autonomic regulation of cardiovascular and extra-cardiovascular physiology contributes to circulatory shock and define autonomic dysfunction practically in a clinical context.

Background: Physiological measures of heart failure are common in surgical patients, despite the absence of a diagnosis. Heart rate (HR) increases during exercise are frequently blunted in heart failure (termed chronotropic incompetence), which primarily reflects beta-adrenoreceptor dysfunction. We examined whether chronotropic incompetence was associated with myocardial injury after noncardiac surgery. Methods: This was a predefined analysis of an international cohort study where participants aged ≥40 yr underwent symptom-limited cardiopulmonary exercise testing before noncardiac surgery. Chronotropic incompetence was defined as the ratio of increase in HR during exercise to age-predicted maximal increase in HR 99th centile. Explanatory variables were biomarkers for heart failure (ventilatory efficiency slope [minute ventilation/carbon dioxide production] ≥34; peak oxygen consumption ≤14 ml kg −1 min −1 ; HR recovery ≤6 beats min −1 decrease 1 min post-exercise; preoperative N-terminal pro-B-type natriuretic peptide [NT pro-BNP] >300 pg ml −1 ). Myocardial injury was compared in the presence or absence of sympathetic (i.e. chronotropic incompetence) or parasympathetic (i.e. impaired HR recovery after exercise) thresholds indicative of dysfunction. Data are presented as odds ratios (ORs) (95% confidence intervals). Results: Chronotropic incompetence occurred in 396/1325 (29.9%) participants; only 16/1325 (1.2%) had a heart failure diagnosis. Myocardial injury was sustained by 162/1325 (12.2%) patients. Raised preoperative NT pro-BNP was more common when chronotropic incompetence was −1 decrease after exercise was associated with myocardial injury in the presence (OR: 1.62 [1.05–2.51]; P=0.03) or absence (OR: 1.60 [1.06–2.39]; P=0.02) of chronotropic incompetence. Conclusions: Chronotropic incompetence is common in surgical patients. In contrast to parasympathetic dysfunction which was associated with myocardial injury, preoperative chronotropic incompetence (suggestive of sympathetic dysfunction) was not associated with postoperative myocardial injury.

GLA is supported by British Journal of Anaesthesia/Royal College of Anaesthetists basic science Career Development award, British Oxygen Company research chair grant in anaesthesia from the Royal College of Anaesthetists and British Heart Foundation Programme Grant (RG/14/4/30736). HFG: funded by the Association of Anaesthetists of Great Britain and Ireland, the British Journal of Anaesthesia/Royal College of Anaesthetists and the Melville Trust. BGS: Chief Scientific Officer/NHS Research Scotland Career Research Fellow award. DGL: BBSRC; British Journal of Anaesthesia PhD studentship.

Background Systemic inflammation is pivotal in the pathogenesis of cardiovascular disease. As inflammation can directly cause cardiomyocyte injury, we hypothesised that established systemic inflammation, as reflected by elevated preoperative neutrophil-lymphocyte ratio (NLR) >4, predisposes patients to perioperative myocardial injury. Methods We prospectively recruited 1652 patients aged ≥45 yr who underwent non-cardiac surgery in two UK centres. Serum high sensitivity troponin T (hsTnT) concentrations were measured on the first three postoperative days. Clinicians and investigators were blinded to the troponin results. The primary outcome was perioperative myocardial injury, defined as hsTnT≥14 ng L−1 within 3 days after surgery. We assessed whether myocardial injury was associated with preoperative NLR>4, activated reactive oxygen species (ROS) generation in circulating monocytes, or both. Multivariable logistic regression analysis explored associations between age, sex, NLR, Revised Cardiac Risk Index, individual leukocyte subsets, and myocardial injury. Flow cytometric quantification of ROS was done in 21 patients. Data are presented as n (%) or odds ratio (OR) with 95% confidence intervals. Results Preoperative NLR>4 was present in 239/1652 (14.5%) patients. Myocardial injury occurred in 405/1652 (24.5%) patients and was more common in patients with preoperative NLR>4 [OR: 2.56 (1.92–3.41); P Conclusions Preoperative NLR>4 is associated with perioperative myocardial injury, independent of conventional risk factors. Systemic inflammation may contribute to the development of perioperative myocardial injury. Clinical trial registration NCT01842568.

Biological age is a better measure of functional capacity than chronological age.1 One of the measures of biological age is telomere length. Telomeres are nucleoprotein complexes that protect chromosome ends from damage. The DNA component of telomeres progressively shortens as biological age increases and thus acts as a read out for ‘miles on the biological clock’. 2 Telomere length progressively shortens as biological age increases. Within health care, ageing is almost exclusively described in terms of chronological age. Recent studies explored using biological age to stratify patients and predict outcomes.3 This project acts as a pilot study to investigate whether biological age is related to intensive care unit (ICU) outcomes and whether ICU patients age biologically at an accelerated rate. This project used blood samples from a previous study where patients underwent cardiac surgery and were admitted to the ICU. Blood samples were obtained before surgery and on days 1, 2, and 3 after surgery. The database contained the following physiological parameters: haemoglobin, urea, creatinine, RIFLE score, length of ICU stay, and whether renal replacement therapy was required. Information on co-morbidities and medication was also provided. DNA was isolated using a Maxwell machine and telomere length determined via quantitative PCR. One hundred and fifty-five blood samples from 46 patients underwent analysis. Telomere length did not differ significantly over the 4 days (P=0.662). No relationship was found between telomere length and any physiological parameter, co-morbidity, or medication. There was a trend towards significance with RIFLE score at day 3 increasing as telomere length decreased, although this was not statistically significant (P=0.09). No relationship between telomere length and the available physiological parameters, comorbidities, or medication was found. Telomere length did not vary during ICU stay. This study was limited by its small sample size. Future studies would benefit from a larger sample size; in addition, blood samples could also be obtained at 6 months after discharge to allow gradual alterations in biological age to be determined. Recent studies give evidence that telomere length is a weak biomarker of ageing,3 and that more meaningful data might be obtained using superior markers, such as CDKN2A expression or expression levels of non-coding RNAs.3

In terrestrial mammals, the oxygen storage capacity of the CNS is limited, and neuronal function is rapidly impaired if oxygen supply is interrupted even for a short period of time. However, oxygen tension monitored by the peripheral (arterial) chemoreceptors is not sensitive to regional CNS differences in partial pressure of oxygen (PO2 ) that reflect variable levels of neuronal activity or local tissue hypoxia, pointing to the necessity of a functional brain oxygen sensor. This experimental animal (rats and mice) study shows that astrocytes, the most numerous brain glial cells, are sensitive to physiological changes in PO2 . Astrocytes respond to decreases in PO2 a few millimeters of mercury below normal brain oxygenation with elevations in intracellular calcium ([Ca(2+)]i). The hypoxia sensor of astrocytes resides in the mitochondria in which oxygen is consumed. Physiological decrease in PO2 inhibits astroglial mitochondrial respiration, leading to mitochondrial depolarization, production of free radicals, lipid peroxidation, activation of phospholipase C, IP3 receptors, and release of Ca(2+) from the intracellular stores. Hypoxia-induced [Ca(2+)]i increases in astrocytes trigger fusion of vesicular compartments containing ATP. Blockade of astrocytic signaling by overexpression of ATP-degrading enzymes or targeted astrocyte-specific expression of tetanus toxin light chain (to interfere with vesicular release mechanisms) within the brainstem respiratory rhythm-generating circuits reveals the fundamental physiological role of astroglial oxygen sensitivity; in low-oxygen conditions (environmental hypoxia), this mechanism increases breathing activity even in the absence of peripheral chemoreceptor oxygen sensing. These results demonstrate that astrocytes are functionally specialized CNS oxygen sensors tuned for rapid detection of physiological changes in brain oxygenation. Significance statement: Most, if not all, animal cells possess mechanisms that allow them to detect decreases in oxygen availability leading to slow-timescale, adaptive changes in gene expression and cell physiology. To date, only two types of mammalian cells have been demonstrated to be specialized for rapid functional oxygen sensing: glomus cells of the carotid body (peripheral respiratory chemoreceptors) that stimulate breathing when oxygenation of the arterial blood decreases; and pulmonary arterial smooth muscle cells responsible for hypoxic pulmonary vasoconstriction to limit perfusion of poorly ventilated regions of the lungs. Results of the present study suggest that there is another specialized oxygen-sensitive cell type in the body, the astrocyte, that is tuned for rapid detection of physiological changes in brain oxygenation.

BackgroundAngiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are the most commonly prescribed antihypertensive medications in higher-risk surgical patients. However, there is no clinical consensus on their use in the perioperative period, in part, due to an inconsistent evidence-base. To help inform the design of a large multi-centre randomized controlled trial (ISRCTN17251494), we undertook a questionnaire-based survey exploring variability in ACEi/ARB prescribing in perioperative practice.MethodsThe online survey included perioperative scenarios to examine how consistent respondents were with their stated routine preoperative practice. Clinicians with an academic interest in perioperative medicine were primarily targeted between July and September 2017. STROBE guidelines for observational research and ANZCA Trials Group Survey Reporting recommendations were adhered to.Results194 responses were received, primarily from clinicians practicing in the UK. A similar minority of respondents continue ACEi (n = 57; 30%) and ARBs (n = 62; 32%) throughout the perioperative period. However, timing of preoperative cessation was highly variable, and rarely influenced by the pharmacokinetics of individual ACE-i/ARBs. Respondents’ stated routine practice was frequently misaligned with their management of common pre- and postoperative scenarios involving continuation or restarting ACE-i/ARBs.DiscussionThis survey highlights many inconsistencies amongst clinicians’ practice in perioperative ACE-i/ARB management. Studies designed to reveal an enhanced understanding of perioperative mechanisms at play, coupled with randomised controlled trials, are required to rationally inform the clinical management of ACE-i/ARBs in patients most at risk of postoperative morbidity.

Summary Background Functional capacity is an important component of risk assessment for major surgery. Doctors' clinical subjective assessment of patients' functional capacity has uncertain accuracy. We did a study to compare preoperative subjective assessment with alternative markers of fitness (cardiopulmonary exercise testing [CPET], scores on the Duke Activity Status Index [DASI] questionnaire, and serum N-terminal pro-B-type natriuretic peptide [NT pro-BNP] concentrations) for predicting death or complications after major elective non-cardiac surgery. Methods We did a multicentre, international, prospective cohort study at 25 hospitals: five in Canada, seven in the UK, ten in Australia, and three in New Zealand. We recruited adults aged at least 40 years who were scheduled for major non-cardiac surgery and deemed to have one or more risk factors for cardiac complications (eg, a history of heart failure, stroke, or diabetes) or coronary artery disease. Functional capacity was subjectively assessed in units of metabolic equivalents of tasks by the responsible anaesthesiologists in the preoperative assessment clinic, graded as poor ( 10). All participants also completed the DASI questionnaire, underwent CPET to measure peak oxygen consumption, and had blood tests for measurement of NT pro-BNP concentrations. After surgery, patients had daily electrocardiograms and blood tests to measure troponin and creatinine concentrations until the third postoperative day or hospital discharge. The primary outcome was death or myocardial infarction within 30 days after surgery, assessed in all participants who underwent both CPET and surgery. Prognostic accuracy was assessed using logistic regression, receiver-operating-characteristic curves, and net risk reclassification. Findings Between March 1, 2013, and March 25, 2016, we included 1401 patients in the study. 28 (2%) of 1401 patients died or had a myocardial infarction within 30 days of surgery. Subjective assessment had 19·2% sensitivity (95% CI 14·2–25) and 94·7% specificity (93·2–95·9) for identifying the inability to attain four metabolic equivalents during CPET. Only DASI scores were associated with predicting the primary outcome (adjusted odds ratio 0·96, 95% CI 0·83–0·99; p=0·03). Interpretation Subjectively assessed functional capacity should not be used for preoperative risk evaluation. Clinicians could instead consider a measure such as DASI for cardiac risk assessment. Funding Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research, Innovation and Science, UK National Institute of Academic Anaesthesia, UK Clinical Research Collaboration, Australian and New Zealand College of Anaesthetists, and Monash University.

Objective: To determine the prognostic relevance, clinical characteristics, and 30-day outcomes associated with myocardial injury after noncardiac surgery (MINS) in vascular surgical patients. Background: MINS has been independently associated with 30-day mortality after noncardiac surgery. The characteristics and prognostic importance of MINS in vascular surgery patients are poorly described. Methods: This was an international prospective cohort study of 15,102 noncardiac surgery patients 45 years or older, of whom 502 patients underwent vascular surgery. All patients had fourth-generation plasma troponin T (TnT) concentrations measured during the first 3 postoperative days. MINS was defined as a TnT of 0.03 ng/mL of higher secondary to ischemia. The objectives of the present study were to determine (i) if MINS is prognostically important in vascular surgical patients, (ii) the clinical characteristics of vascular surgery patients with and without MINS, (iii) the 30-day outcomes for vascular surgery patients with and without MINS, and (iv) the proportion of MINS that probably would have gone undetected without routine troponin monitoring. Results: The incidence of MINS in the vascular surgery patients was 19.1% (95% confidence interval (CI), 15.7%-22.6%). 30-day all-cause mortality in the vascular cohort was 12.5% (95% CI 7.3%-20.6%) in patients with MINS compared with 1.5% (95% CI 0.7%-3.2%) in patients without MINS (P < 0.001). MINS was independently associated with 30-day mortality in vascular patients (odds ratio, 9.48; 95% CI, 3.46-25.96). The 30-day mortality was similar in MINS patients with (15.0%; 95% CI, 7.1-29.1) and without an ischemic feature (12.2%; 95% CI, 5.3-25.5, P = 0.76). The proportion of vascular surgery patients who suffered MINS without overt evidence of myocardial ischemia was 74.1% (95% CI, 63.6-82.4). Conclusions: Approximately 1 in 5 patients experienced MINS after vascular surgery. MINS was independently associated with 30-day mortality. The majority of patients with MINS were asymptomatic and would have gone undetected without routine postoperative troponin measurement.

Myocardial injury after noncardiac surgery (MINS) is a mostly asymptomatic condition that is strongly associated with 30-day mortality; however, it remains mostly undetected without systematic troponin T monitoring. We evaluated the cost and consequences of postoperative troponin T monitoring to detect MINS.We conducted a model-based cost-consequence analysis to compare the impact of routine troponin T monitoring versus standard care (troponin T measurement triggered by ischemic symptoms) on the incidence of MINS detection. Model inputs were based on Canadian patients enrolled in the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study, which enrolled patients aged 45 years or older undergoing inpatient noncardiac surgery. We conducted probability analyses with 10 000 iterations and extensive sensitivity analyses.The data were based on 6021 patients (48% men, mean age 65 [standard deviation 12] yr). The 30-day mortality rate for MINS was 9.6%. We determined the incremental cost to avoid missing a MINS event as $1632 (2015 Canadian dollars). The cost-effectiveness of troponin monitoring was higher in patient subgroups at higher risk for MINS, e.g., those aged 65 years or more, or with a history of atherosclerosis or diabetes ($1309).The costs associated with a troponin T monitoring program to detect MINS were moderate. Based on the estimated incremental cost per health gain, implementation of postoperative troponin T monitoring seems appealing, particularly in patients at high risk for MINS.Les lésions myocardiques après chirurgie non cardiaque (CNC) sont majoritairement asymptomatiques et fortement associées au risque de mortalité dans les 30 jours; toutefois, dans la plupart des cas, elles ne sont pas détectées en l'absence d'une surveillance systématique de la troponine T. Nous avons évalué les coûts et les conséquences d'une telle surveillance pour détecter les lésions myocardiques après CNC.Nous avons mené une analyse coût-conséquence modélisée pour comparer la surveillance systématique de la troponine T aux soins habituels seuls (mesure de la troponine T seulement s'il y a présence de symptômes d'ischémie) sur la fréquence de détection de lésions myocardiques après CNC. Les données ayant servi à l'analyse provenaient des patients canadiens ayant participé à l'étude de cohorte VISION, qui visait à évaluer les complications vasculaires chez les patients de 45 ans et plus ayant subi une CNC. Nous avons mené des analyses de probabilité avec 10 000 itérations et des analyses de sensibilité approfondies.Les données portaient sur 6021 patients (48 % du sexe masculin; âge moyen de 65 ans [écart-type de 12 ans]). Le taux de mortalité dans les 30 jours associé à une lésion myocardique après CNC était de 9,6 %. Nous avons déterminé que le coût marginal de la détection de la présence d'une lésion par surveillance de la troponine T était de 1632 $ (dollars canadiens en 2015). Le rapport coût-efficacité était plus bas pour les sous-groupes de patients à risque élevé de lésion myocardique après CNC, comme les patients de 65 ans et plus ou ceux ayant des antécédents d'athérosclérose ou de diabète (1309 $), que pour leurs pairs.Les coûts associés à un programme de surveillance de la troponine T pour détecter les lésions myocardiques après CNC étaient modérés. Le coût marginal estimé par gain de santé indique que la mise en œuvre de ce type de programme pourrait être une option intéressante, surtout pour les patients à risque élevé de lésion myocardique après CNC.

BACKGROUND: The association between intraoperative cardiovascular changes and perioperative myocardial injury has chiefly focused on hypotension during noncardiac surgery. However, the relative influence of blood pressure and heart rate (HR) remains unclear. We investigated both individual and codependent relationships among intraoperative HR, systolic blood pressure (SBP), and myocardial injury after noncardiac surgery (MINS). METHODS: Secondary analysis of the Vascular Events in Noncardiac Surgery Cohort Evaluation (VISION) study, a prospective international cohort study of noncardiac surgical patients. Multivariable logistic regression analysis tested for associations between intraoperative HR and/or SBP and MINS, defined by an elevated serum troponin T adjudicated as due to an ischemic etiology, within 30 days after surgery. Predefined thresholds for intraoperative HR and SBP were: maximum HR >100 beats or minimum HR 160 mm Hg or minimum SBP 100 bpm was associated with MINS (odds ratio [OR], 1.27 [1.07–1.50]; P < .01), myocardial infarction (OR, 1.34 [1.05–1.70]; P = .02), and mortality (OR, 2.65 [2.06–3.41]; P < .01). Minimum SBP 160 mm Hg was associated with MINS (OR, 1.16 [1.01–1.34]; P = .04) and myocardial infarction (OR, 1.34 [1.09–1.64]; P = .01) but, paradoxically, reduced mortality (OR, 0.76 [0.58–0.99]; P = .04). Minimum HR 100 bpm was more strongly associated with MINS (OR, 1.42 [1.15–1.76]; P < .01) compared with minimum SBP

Translational research in critically ill human patients presents many methodological challenges. Diagnostic uncertainty, coupled with poorly defined comorbidities, make the identification of a suitable control population for case–control investigations an arguably insurmountable challenge. Healthy volunteer experiments using endotoxin infusion as an inflammatory model are methodologically robust, but fail to replicate the onset of, and diverse therapeutic interventions associated with, sepsis/trauma. Animal models are also limited by many of these issues. Major elective surgery addresses many of these shortfalls and offers a key model for exploring the human biology underlying the sepsis syndrome. Surgery triggers highly conserved features of the human inflammatory response that are common to both tissue damage and infection. Surgical patients sustain a predictable and relatively high incidence of sepsis, particularly within the ‘higher risk’ group. The collection of preoperative samples enables each patient to act as their own control. Thus, the surgical model offers unique and elegant experimental design features that provide an important translational bridge between the basic biological understanding afforded by animal laboratory models and the de novo presentation of human sepsis.

Indirect measures of cardiac vagal activity are strongly associated with exercise capacity, yet a causal relationship has not been established. Here we show that in rats, genetic silencing of the largest population of brainstem vagal preganglionic neurons residing in the brainstem’s dorsal vagal motor nucleus dramatically impairs exercise capacity, while optogenetic recruitment of the same neuronal population enhances cardiac contractility and prolongs exercise endurance. These data provide direct experimental evidence that arasympatheticvagal drive generated by a defined CNS circuit determines the ability to exercise. Decreased activity and/or gradual loss of the identified neuronal cell group provides a neurophysiological basis for the progressive decline of exercise capacity with aging and in diverse disease states.

Background The management of elevated blood pressure before non-cardiac surgery remains controversial. Pulse pressure is a stronger predictor of cardiovascular morbidity in the general population than systolic blood pressure alone. We hypothesized that preoperative pulse pressure was associated with perioperative myocardial injury. Methods This is a secondary analysis of the Vascular Events in Non-cardiac Surgery Patients Cohort Evaluation (VISION) international cohort study. Participants were aged ≥45 yr and undergoing non-cardiac surgery at 12 hospitals in eight countries. The primary outcome was myocardial injury, defined using serum troponin concentration, within 30 days after surgery. The sample was stratified into quintiles by preoperative pulse pressure. Multivariable logistic regression analysis explored associations between pulse pressure and myocardial injury. We accounted for potential confounding by systolic blood pressure and other co-morbidities known to be associated with postoperative cardiovascular complications. Results One thousand one hundred and ninety-one of 15 057 (7.9%) patients sustained myocardial injury, which was more frequent amongst patients in the highest two preoperative pulse pressure quintiles {63–75 mm Hg, risk ratio (RR) 1.14 [95% confidence interval (CI): 1.01–1.28], P =0.03; >75 mm Hg, RR 1.15 [95% CI: 1.03–1.29], P =0.02}. After adjustment for systolic blood pressure, preoperative pulse pressure remained the dominant predictor of myocardial injury (63–75 mm Hg, RR 1.20 [95% CI: 1.05–1.37], P 75 mm Hg, RR 1.25 [95% CI: 1.06–1.48], P 160 mm Hg was not associated with myocardial injury in the absence of pulse pressure >62 mm Hg (RR 0.67 [95% CI: 0.30–1.44], P =0.31). Conclusions Preoperative pulse pressure >62 mm Hg was associated with myocardial injury, independent of systolic blood pressure. Elevated pulse pressure may be a useful clinical sign to guide strategies to reduce perioperative myocardial injury.

Background: Myocardial injury after noncardiac surgery (MINS) was defined as prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. The study’s four objectives were to determine the diagnostic criteria, characteristics, predictors, and 30-day outcomes of MINS. Methods: In this international, prospective cohort study of 15,065 patients aged 45 yr or older who underwent in-patient noncardiac surgery, troponin T was measured during the first 3 postoperative days. Patients with a troponin T level of 0.04 ng/ml or greater (elevated “abnormal” laboratory threshold) were assessed for ischemic features (i.e., ischemic symptoms and electrocardiography findings). Patients adjudicated as having a nonischemic troponin elevation (e.g., sepsis) were excluded. To establish diagnostic criteria for MINS, the authors used Cox regression analyses in which the dependent variable was 30-day mortality (260 deaths) and independent variables included preoperative variables, perioperative complications, and potential MINS diagnostic criteria. Results: An elevated troponin after noncardiac surgery, irrespective of the presence of an ischemic feature, independently predicted 30-day mortality. Therefore, the authors’ diagnostic criterion for MINS was a peak troponin T level of 0.03 ng/ml or greater judged due to myocardial ischemia. MINS was an independent predictor of 30-day mortality (adjusted hazard ratio, 3.87; 95% CI, 2.96–5.08) and had the highest population-attributable risk (34.0%, 95% CI, 26.6–41.5) of the perioperative complications. Twelve hundred patients (8.0%) suffered MINS, and 58.2% of these patients would not have fulfilled the universal definition of myocardial infarction. Only 15.8% of patients with MINS experienced an ischemic symptom. Conclusion: Among adults undergoing noncardiac surgery, MINS is common and associated with substantial mortality.

Background Preliminary data suggest that preoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) may improve risk prediction in patients undergoing noncardiac surgery. Objective To determine whether preoperative NT-proBNP has additional predictive value beyond a clinical risk score for the composite of vascular death and myocardial injury after noncardiac surgery (MINS) within 30 days after surgery. Design Prospective cohort study. Setting 16 hospitals in 9 countries. Patients 10 402 patients aged 45 years or older having inpatient noncardiac surgery. Measurements All patients had NT-proBNP levels measured before surgery and troponin T levels measured daily for up to 3 days after surgery. Results In multivariable analyses, compared with preoperative NT-proBNP values less than 100 pg/mL (the reference group), those of 100 to less than 200 pg/mL, 200 to less than 1500 pg/mL, and 1500 pg/mL or greater were associated with adjusted hazard ratios of 2.27 (95% CI, 1.90 to 2.70), 3.63 (CI, 3.13 to 4.21), and 5.82 (CI, 4.81 to 7.05) and corresponding incidences of the primary outcome of 12.3% (226 of 1843), 20.8% (542 of 2608), and 37.5% (223 of 595), respectively. Adding NT-proBNP thresholds to clinical stratification (that is, the Revised Cardiac Risk Index [RCRI]) resulted in a net absolute reclassification improvement of 258 per 1000 patients. Preoperative NT-proBNP values were also statistically significantly associated with 30-day all-cause mortality (less than 100 pg/mL [incidence, 0.3%], 100 to less than 200 pg/mL [incidence, 0.7%], 200 to less than 1500 pg/mL [incidence, 1.4%], and 1500 pg/mL or greater [incidence, 4.0%]). Limitation External validation of the identified NT-proBNP thresholds in other cohorts would reinforce our findings. Conclusion Preoperative NT-proBNP is strongly associated with vascular death and MINS within 30 days after noncardiac surgery and improves cardiac risk prediction in addition to the RCRI. Primary funding source Canadian Institutes of Health Research.

Familial dysautonomia (Riley-Day syndrome) is a rare multisystem disorder associated with an excess risk of perioperative morbidity and mortality. Because life expectancy is limited, few reports consider the perioperative management of familial dysautonomia in adults with advanced disease and end-organ dysfunction. Here, we report on the management of an adult patient with familial dysautonomia, highlighting recent developments in perioperative technology and pharmacology of special relevance to this challenging population.

Astrocytes provide the structural and functional interface between the cerebral circulation and neuronal networks. They enwrap all intracerebral arterioles and capillaries, control the flux of nutrients as well as the ionic and metabolic environment of the neuropil. Astrocytes have the ability to adjust cerebral blood flow to maintain constant PO2 and PCO2 of the brain parenchyma. Release of ATP in the brainstem, presumably by local astrocytes, helps to maintain breathing and counteract hypoxia-induced depression of the respiratory network. Astrocytes also appear to be involved in mediating hypoxia-evoked changes in blood-brain barrier permeability, brain inflammation, and neuroprotection against ischaemic injury. Thus, astrocytes appear to play a fundamental role in supporting neuronal function not only in normal conditions but also in pathophysiological states when supply of oxygen to the brain is compromised.

Indirect measures of cardiac vagal activity are strongly associated with exercise capacity, yet a causal relationship has not been established. Here we show that in rats, genetic silencing of the largest population of brainstem vagal preganglionic neurons residing in the brainstem's dorsal vagal motor nucleus dramatically impairs exercise capacity, while optogenetic recruitment of the same neuronal population enhances cardiac contractility and prolongs exercise endurance. These data provide direct experimental evidence that parasympathetic vagal drive generated by a defined CNS circuit determines the ability to exercise. Decreased activity and/or gradual loss of the identified neuronal cell group provides a neurophysiological basis for the progressive decline of exercise capacity with aging and in diverse disease states., Demonstrating a causal relationship between cardiac vagal tone and exercise capacity has been previously limited by methodological constraints. Using genetic targeting, silencing and optogenetic recruitment of vagal motor neuron activity in rodents, Machhada et al. provide direct evidence that vagal drive determines the ability to exercise.

GLA is supported by a Basic science career development award (British Journal of Anaesthesia/Royal College of Anaesthetists) and British Heart Foundation programme grant (RG/14/4/30736). Part of this work was undertaken at UCLH/UCL who received a proportion of funding from the UK Department of Health’s NIHR Biomedical Research Centres funding scheme

Intrapartum fever is associated with excessive maternal interventions as well as higher neonatal morbidity. Epidural-related maternal fever (ERMF) contributes to the development of intrapartum fever. The mechanism(s) for ERMF has remained elusive. Here, we consider how inflammatory mechanisms may be modulated by local anesthetic agents and their relevance to ERMF. We also critically reappraise the clinical data with regard to emerging concepts that explain how anesthetic drug-induced metabolic dysfunction, with or without activation of the inflammasome, might trigger the release of nonpathogenic, inflammatory molecules (danger-associated molecular patterns) likely to underlie ERMF.

Ventral regions of the medulla oblongata of the brainstem are populated by astrocytes sensitive to physiological changes in PCO2/[H+]. These astrocytes respond to decreases in pH with elevations in intracellular Ca2+ and facilitated exocytosis of ATP-containing vesicles. Released ATP propagates Ca2+ excitation among neighboring astrocytes and activates neurons of the brainstem respiratory network triggering adaptive increases in breathing. The mechanisms linking increases in extracellular and/or intracellular PCO2/[H+] with Ca2+ responses in chemosensitive astrocytes remain unknown. Fluorescent imaging of changes in [Na+]i and/or [Ca2+]i in individual astrocytes was performed in organotypic brainstem slice cultures and acute brainstem slices of adult rats. It was found that astroglial [Ca2+]i responses triggered by decreases in pH are preceded by Na+ entry, markedly reduced by inhibition of Na+/HCO3− cotransport (NBC) or Na+/Ca2+ exchange (NCX), and abolished in Na+-free medium or by combined NBC/NCX blockade. Acidification-induced [Ca2+]i responses were also dramatically reduced in brainstem astrocytes of mice deficient in the electrogenic Na+/HCO3− cotransporter NBCe1. Sensitivity of astrocytes to changes in pH was not affected by inhibition of Na+/H+ exchange or blockade of phospholipase C. These results suggest that in pH-sensitive astrocytes, acidification activates NBCe1, which brings Na+ inside the cell. Raising [Na+]i activates NCX to operate in a reverse mode, leading to Ca2+ entry followed by activation of downstream signaling pathways. Coupled NBC and NCX activities are, therefore, suggested to be responsible for functional CO2/H+ sensitivity of astrocytes that contribute to homeostatic regulation of brain parenchymal pH and control of breathing.

The neurohormonal physiological response to various stressors is pivotal for maintaining homeostasis. However, the advent of modern critical care has distorted evolutionary biology by generating the entirely new (patho)physiological entity of critical illness. By extending the biological features of the ‘fight or flight’ response beyond the acute phase, distinct neurohormonal, and immune profiles have become increasingly apparent. Both direct and off-target effects of neurohormonal control on immune function are implicated in the disruption of bidirectional links between neurohormones and immune effectors that limit organ dysfunction. Iatrogenic factors introduced by critical care therapy may exacerbate neurohormonal dysregulation, further distorting the biology of the ‘fight or flight’ response. Neural mechanisms underlying this newly-characterized clinical syndrome remain poorly understood. Furthermore, the same neurohormonal responses are chronically dysregulated in pre-existing comorbidities diseases associated with an increased risk of sepsis, multi-organ failure and critical illness. Off-target local immune effects may explain the failure of clinical trials aimed at altering systemic neurohormonal physiology. Recent laboratory and translational human clinical studies, particularly in diseases characterized by chronic neurohormonal dysregulation, have provided new insights into the possibility of therapeutic interventions that could minimize the pathophysiological features of critical illness.

Aims Innate mechanisms of inter-organ protection underlie the phenomenon of remote ischaemic preconditioning (RPc) in which episode(s) of ischaemia and reperfusion in tissues remote from the heart reduce myocardial ischaemia/reperfusion injury. The uncertainty surrounding the mechanism(s) underlying RPc centres on whether humoral factor(s) produced during ischaemia/reperfusion of remote tissue and released into the systemic circulation mediate RPc, or whether a neural signal is required. While these two hypotheses may not be incompatible, one approach to clarify the potential role of a neural pathway requires targeted disruption or activation of discrete central nervous substrate(s). Methods and results Using a rat model of myocardial ischaemia/reperfusion injury in combination with viral gene transfer, pharmaco-, and optogenetics, we tested the hypothesis that RPc cardioprotection depends on the activity of vagal pre-ganglionic neurones and consequently an intact parasympathetic drive. For cell-specific silencing or activation, neurones of the brainstem dorsal motor nucleus of the vagus nerve (DVMN) were targeted using viral vectors to express a Drosophila allatostatin receptor (AlstR) or light-sensitive fast channelrhodopsin variant (ChIEF), respectively. RPc cardioprotection, elicited by ischaemia/reperfusion of the limbs, was abolished when DVMN neurones transduced to express AlstR were silenced by selective ligand allatostatin or in conditions of systemic muscarinic receptor blockade with atropine. In the absence of remote ischaemia/reperfusion, optogenetic activation of DVMN neurones transduced to express ChIEF reduced infarct size, mimicking the effect of RPc. Conclusion These data indicate a crucial dependence of RPc cardioprotection against ischaemia/reperfusion injury upon the activity of a distinct population of vagal pre-ganglionic neurones.

Myocardial ischaemia–reperfusion injury can be significantly reduced by an episode(s) of ischaemia–reperfusion applied prior to or during myocardial ischaemia (MI) to peripheral tissue located at a distance from the heart; this phenomenon is called remote ischaemic conditioning (RIc). Here, we compared the efficacy of RIc in protecting the heart when the RIc stimulus is applied prior to, during and at different time points after MI. A rat model of myocardial ischaemia–reperfusion injury involved 30 min of left coronary artery occlusion followed by 120 min of reperfusion. Remote ischaemic conditioning was induced by 15 min occlusion of femoral arteries and conferred a similar degree of cardioprotection when applied 25 min prior to MI, 10 or 25 min after the onset of MI, or starting 10 min after the onset of reperfusion. These RIc stimuli reduced infarct size by 54, 56, 56 and 48% (all P < 0.001), respectively. Remote ischaemic conditioning applied 30 min into the reperfusion period was ineffective. Activation of sensory nerves by application of capsaicin was effective in establishing cardioprotection only when elicited prior to MI. Vagotomy or denervation of the peripheral ischaemic tissue both completely abolished cardioprotection induced by RIc applied prior to MI. Cardioprotection conferred by delayed remote postconditioning was not affected by either vagotomy or peripheral denervation. These results indicate that RIc confers potent cardioprotection even if applied with a significant delay after the onset of myocardial reperfusion. Cardioprotection by remote preconditioning is critically dependent on afferent innervation of the remote organ and intact parasympathetic activity, while delayed remote postconditioning appears to rely on a different signalling pathway(s).

The complement serum proteins C3 and C4 and the protease inhibitor α-2 macroglobulin are all members of the C3/α-2M thioester protein family, an evolutionarily ancient and conserved family that contains an intrachain thioester bond. The chemistry of the thioester bond is a key to the function of the thioester proteins. All these proteins function by covalently linking to their target by acyl transfer of the protein via the thioester moiety. We show that the signature thioester bond can be targeted with nucleophiles linked to a bioreporter molecule, site-specifically modifying the whole, intact thioester protein. Conditions were optimised to label selectively and efficiently pull-down unprocessed thioester-containing proteins from serum. We demonstrated pull-down of full-length C3, α-2M and C4 from sera in high salt, using a biotinylated nucleophile and streptavidin-coated resin, confirmed by MALDI-TOF MS identification of the gel bands. The potential for the development of a quantitative method for measuring active C3 in serum was investigated in patient sera pre and post operation. Quantifying active C3 in clinical assays using current methods is difficult. Methods based on antibody detection (e.g. nephelometry) do not distinguish between active C3 and inactive breakdown products. C3-specific haemolytic assays can be used, but these require use of relatively unstable reagents. The current work represents a promising robust, enzyme- and antibody-free chemical method for detecting active thioester proteins in blood, plasma or serum.

Objective: For several chronic inflammatory disease states, therapy is enhanced by improving the pharmacokinetic properties of anti-inflammatory drugs through conjugation with polyethylene glycol. We hypothesized that part of the beneficial action of PEGylated drugs may be derived from the anti-inflammatory properties of polyethylene glycol (PEG) itself.Design: Randomized, double-blinded, controlled ex vivo and in vivo laboratory studies.Setting: University research laboratories.Subjects: Human neutrophils and mononuclear cells, macrophage cell line, and adult rats and mice.Interventions: The effect of PEG (either low-molecular-weight [200-400] or high-molecular-weight [>4000]) was assessed on survival after systemic inflammation induced by lipopolysaccharide or zymosan. The effects of PEG on zymosan, lipopolysaccharide, or streptolysin-induced inflammatory and bioenergetic responses of immune cells were also assessed.Measurements and Main Results: Low-molecular-weight PEG reduced inflammatory cytokine expression, pyrexia, and mortality by >50% in both lipopolysaccharide and zymosan models of sepsis. Low-molecular-weight PEG reduced cytokine expression both in vivo and in vitro, and attenuated activation of human neutrophils in response to lipopolysaccharide or zymosan. By contrast, high-molecular-weight PEG conferred less significant survival effects after lipopolysaccharide and zymosan, and it did not exhibit such profound anti-inflammatory effects. Low-molecular-weight PEG attenuated lipopolysaccharide-induced activation of pro-apoptotic pathways (lysophosphatidic acid receptor and caspase-domain signaling) in the livers of endotoxemic rats.Streptolysin-induced necrosis of human neutrophils was reduced by low-molecular-weight PEG, indicating a mechanism that involves coating and/or stabilizing the cellular membrane. Low-molecular-weight PEG preserved human neutrophil responses to septic serum and bioenergetic function in macrophages and neutrophils.Conclusion: PEG is a commonly used, safe, nonimmunogenic molecule possessing hitherto unappreciated anti-inflammatory properties. Low-molecular-weight PEG may potentially play a role in the therapy of systemic inflammation and sepsis. (Crit Care Med 2010; 38:629-636)

Objective:To explore the hypothesis that beta-1 adrenoreceptor blockade may be protective through the attenuation of sympathetic hyperactivity and catecholaminergic inflammatory effects on cardiac and hepatic function.Design:Prospective, randomized, controlled study.Setting:Animal laboratory in a un

BACKGROUND: Postoperative cognitive dysfunction occurs in a proportion of patients after noncardiac surgery. Older patients are particularly vulnerable. We hypothesized that dehydration, a common perioperative problem in the elderly, may provoke cognitive dysfunction. We used a clinical scenario free of surgical/anesthetic intervention to determine whether dehydration caused by bowel preparation results in cognitive changes.METHODS: Thirty-eight patients of an age associated with a significant incidence of postoperative cognitive dysfunction were recruited in a prospective observational study. A further control group of 14 patients undergoing sigmoidoscopy, who did not receive any owe preparation, were matched for age, education, and gender.RESULTS: Loss of total body weight (1.5 kg [95% CI: 0.9-2.2]; P < 0.001) occurred in patients undergoing bowel preparation (2.0 [95% CI: 1.3-2.6] percent total body weight), whereas sigmoidoscopy patients' weight did not change (0.17 kg [95% CI: -0.2-0.6 kg]; P = 0.26). Total body water, derived from foot bioimpedance, indicated dehydration in the bowel preparation group only (mean impedance change 36 [Omega] [95% CI; 25-461, P < 0.001) with a calculated decrease of 2.6% in total body water (95% CI: 1.1-4.8; P < 0.001). Hematocrit increased after bowel preparation only (prebowel prep 0.41 [0.40-0.431 versus postbowel prep 0.43 [0.42-0.45]; P = 0.003). Despite this degree of dehydration, all cognitive tests were within 1 SD of the population mean of normal values. Repeated measures analysis of variance did not reveal significant changes for within group comparisons over time for motor speed (P = 0.51), executive function (P = 0.57), Trail Making Tests and recall (P = 0.88), other than a 3 s slowing in learning ability (Rey Auditory Verbal Learning Test; P = 0.04). Hydration status did not affect learning (P = 0.42), recall (P = 0.30) motor speed (P = 0.36), or executive function tests (P = 0.26).CONCLUSION: Dehydration alone does not result in cognitive dysfunction.

Astrocytes provide the structural and functional interface between the cerebral circulation and neuronal networks. They enwrap all intracerebral arterioles and capillaries, control the flux of nutrients as well as the ionic and metabolic environment of the neuropil. Astrocytes have the ability to adjust cerebral blood flow to maintain constant PO2 and PCO2 of the brain parenchyma. Release of ATP in the brainstem, presumably by local astrocytes, helps to maintain breathing and counteract hypoxia-induced depression of the respiratory network. Astrocytes also appear to be involved in mediating hypoxia-evoked changes in blood–brain barrier permeability, brain inflammation, and neuroprotection against ischaemic injury. Thus, astrocytes appear to play a fundamental role in supporting neuronal function not only in normal conditions but also in pathophysiological states when supply of oxygen to the brain is compromised.

The purine nucleotide ATP mediates several distinct forms of sensory transduction in both the peripheral and central nervous systems. These processes share common mechanisms that involve the release of ATP to activate ionotropic P2X and/or metabotropic P2Y receptors. Extracellular ATP signalling plays an important role in ventilatory control, mediating both peripheral and central chemosensory transduction to changes in arterial levels of oxygen and carbon dioxide. New data also suggest that extracellular ATP may play an important role in mediating certain neurophysiological responses to systemic inflammation. Here, we propose the novel concept that both peripheral and central neurophysiological effects of ATP may contribute to alterations in ventilatory control during inflammatory pathophysiological states.

High-sensitivity C-reactive protein (hsCRP) adds important prognostic information, not reflected by traditional risk factors, to the prediction of both the development and outcome of cardiovascular pathology. HsCRP levels also correlate inversely with cardiorespiratory fitness, an important determinant of peri-operative outcome. We hypothesised that pre-operative hsCRP should be associated with excess peri-operative morbidity and longer length of stay. Pre-operative hsCRP was measured blinded to standardised postoperative outcomes in 129 elective orthopaedic patients. HsCRP levels were divided into high (3 mg x l(-1)) or low (3 mg x l(-1)) groups (Center for Disease Control stratification). High-CRP patients had significant cardiovascular history, received cardiac medication or steroid therapy (p0.05). Higher pre-operative hsCRP was associated with longer length of stay: mean 7.5 days (95% CI: 6.2-8.8) vs 6.0 days (95% CI: 5.5-6.5; p = 0.03; log rank test). In 21 patients with8 days length of stay, high pre-operative hsCRP patients were over-represented (p = 0.04). Pre-operative hsCRP is related to length of stay and delayed postoperative complications.

Objective Reduced exercise capacity is well documented in end-stage chronic kidney disease (CKD), preceded by changes in cardiac morphology in CKD stage 3. However, it is unknown whether subclinical cardiopulmonary dysfunction occurs in CKD stage 3 independently of heart failure. Methods Prospective observational cross-sectional study of exercise capacity assessed by cardiopulmonary exercise testing in 993 preoperative patients. Primary outcome was peak oxygen consumption (VO2peak). Anaerobic threshold (AT), oxygen pulse and exercise-evoked measures of autonomic function were analysed, controlling for CKD stage 3, age, gender, diabetes mellitus and hypertension. Results CKD stage 3 was present in 93/993 (9.97%) patients. Diabetes mellitus (RR 2.49 (95% CI 1.59 to 3.89); p

Background.Postoperative morbidity has immediate and delayed consequences for surgical patients, including excess risk of premature death. Capturing these data objectively and routinely in large electronic databases using tools such as the Postoperative Morbidity Survey (POMS) would offer tremendous clinical and translational potential. However, POMS has thus far only utilised prospective data collection by research staff. We hypothesised that retrospective data collection from routinely collated hospital data from paper and electronic charts, medical and nursing notes was non-inferior to prospective data collection requiring research staff capturing POMS-defined morbidity in real-time.Methods.Morbidity was recorded by a trained investigator as defined by POMS prospectively on postoperative days 3 and 7. Separately, an independent investigator blinded to prospectively acquired data retrospectively assessed the same patients’ morbidity as defined by POMS criteria, using medical charts, nursing summaries and electronic data. Equivalence was accepted when the confidence limits for both modes of data collection fell completely inside the equivalence bounds, with the maximum equivalence difference (i.e., the largest value of the difference in sensitivities deemed to reach a conclusion of equivalence) set a priori at 0.2. Differences for confidence limits between retrospective and prospective data collection were based on Nam’s RMLE method. The relationship between morbidity on postoperative day 3 as recorded by each data collection method on time to become morbidity free and length of hospital stay was compared using the log-rank test.Results.POMS data from 85 patients undergoing elective or emergency surgery were analyzed. At postoperative day 3, POMS-defined morbidity was similar regardless of whether data were collected prospectively or retrospectively (95% CI [−0.13–0.013];p< 0.001). Non-inferiority for sensitivity was observed for all other POMS domains and timepoints. Time to become morbidity free Kaplan–Meier plots were indistinguishable between POMS obtained prospectively or retrospectively (hazard ratio: 1.09 (95% CI [0.76–1.57]);p= 0.33, log rank test). Similarly, the mode of data collection did not alter the association between early postoperative morbidity on postoperative day 3 and delayed hospital discharge.Conclusions.Postoperative morbidity as defined by the Post Operative Morbidity Survey can be assessed retrospectively. These data may therefore be easily captured using electronic patient record systems, thereby expanding the potential for bioinformatics approaches to generate new clinical and translational insights into recovery from surgery.

Summary Background Morbidity after major surgery is associated with low oxygen delivery. Haemodynamic therapy aimed at increasing oxygen delivery in an effort to reduce oxygen debt, tissue injury, and morbidity, is controversial. The most appropriate target for this strategy is unclear and might have several off-target effects, including loss of neural (parasympathetic)-mediated cellular protection. We hypothesised that individualised oxygen delivery targeted haemodynamic therapy (goal-directed therapy) in high-risk surgical patients would reduce postoperative morbidity, while secondarily addressing whether goal-directed therapy affected parasympathetic function. Methods In this multicentre, randomised, double-blind, controlled trial, adult patients undergoing major elective surgery were allocated by computer-generated randomisation to a postoperative protocol (fluid, with and without dobutamine) targeted to achieve their individual preoperative oxygen delivery value (goal-directed therapy) or standardised care (control). Patients and staff were masked to the intervention. The primary outcome was absolute risk reduction (ARR) in morbidity (defined by Clavien–Dindo grade II or more) on postoperative day 2. We also assessed a secondary outcome focused on parasympathetic function, using time-domain heart rate variability measures. Analyses were done on an intention-to-treat basis. The trial was registered with Controlled Clinical Trials (number ISRCTN76894700). Findings We enrolled 204 patients between May 20, 2010, and Feb 12, 2014. Intention-to-treat analysis of the 187 (92%) patients who completed the trial intervention period showed that early morbidity was similar between goal-directed therapy (44 [46%] of 95 patients) and control groups (49 [53%] of 92 patients) (ARR −7%, 95% CI −22 to 7; p=0·30). Prespecified secondary analysis showed that 123 (66%) of 187 patients achieved preoperative oxygen delivery (irrespective of intervention). These patients sustained less morbidity (ARR 19%, 95% CI 3–34; p=0·016), including less infectious complications. Goal-directed therapy reduced parasympathetic activity postoperatively (relative risk 1·33, 95% CI 1·01–1·74). Interpretation Achievement of preoperative oxygen delivery values in the postoperative phase was associated with less morbidity, but this was not affected by the use of an oxygen delivery targeted strategy. Reduced parasympathetic activity after goal-directed therapy was associated with the failure of this intervention to reduce postoperative morbidity. Funding Academy of Medical Sciences and Health Foundation Clinician Scientist Award.