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.
Cardiac Vagus and Exercise Gourine, Alexander V; Ackland, Gareth L
Physiology (Bethesda, Md.),
01/2019, Letnik:
34, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Lower resting heart rate and high autonomic vagal activity are strongly associated with superior exercise capacity, maintenance of which is essential for general well-being and healthy aging. Recent ...evidence obtained in experimental studies using the latest advances in molecular neuroscience, combined with human exercise physiology, physiological modeling, and genomic data suggest that the strength of cardiac vagal activity causally determines our ability to exercise.
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.
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).
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 <55 beats per minute (bpm); maximum SBP >160 mm Hg or minimum SBP <100 mm Hg. Secondary outcomes were myocardial infarction and mortality within 30 days after surgery.
After excluding missing data, 1197 of 15,109 patients (7.9%) sustained MINS, 454 of 16,031 (2.8%) sustained myocardial infarction, and 315 of 16,061 patients (2.0%) died within 30 days after surgery. Maximum intraoperative HR >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 <100 mm Hg was associated with MINS (OR, 1.21 1.05-1.39; P = .01) and mortality (OR, 1.81 1.39-2.37; P < .01), but not myocardial infarction (OR, 1.21 0.98-1.49; P = .07). Maximum 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 <55 bpm was associated with reduced MINS (OR, 0.70 0.59-0.82; P < .01), myocardial infarction (OR, 0.75 0.58-0.97; P = .03), and mortality (OR, 0.58 0.41-0.81; P < .01). Minimum SBP <100 mm Hg with maximum HR >100 bpm was more strongly associated with MINS (OR, 1.42 1.15-1.76; P < .01) compared with minimum SBP <100 mm Hg alone (OR, 1.20 1.03-1.40; P = .02).
Intraoperative tachycardia and hypotension are associated with MINS. Further interventional research targeting HR/blood pressure is needed to define the optimum strategy to reduce MINS.
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.
Throughout its 100-yr history, a key ambition of the British Journal of Anaesthesia has been to foster our academic community by addressing the needs of individuals in the early stages of their ...independent clinical and research careers. Longitudinal mentoring and peer networking are critical for establishing a community of like-minded peers and mentor-advisors required to navigate the challenges of academic medicine. In 2019, the Journal launched an Editorial Fellowship scheme, aimed at comprehensively demystifying the process of peer review, editing, and publishing through guided mentorship and experiential learning.
Assay-specific increases in circulating cardiac troponin are observed in 20–40% of patients after noncardiac surgery, depending on patient age, type of surgery, and comorbidities. Increased cardiac ...troponin is consistently associated with excess morbidity and mortality after noncardiac surgery. Despite these findings, the underlying mechanisms are unclear. The majority of interventional trials have been designed on the premise that ischaemic cardiac disease drives elevated perioperative cardiac troponin concentrations. We consider data showing that elevated circulating cardiac troponin after surgery could be a nonspecific marker of cardiomyocyte stress. Elevated concentrations of circulating cardiac troponin could reflect coordinated pathological processes underpinning organ injury that are not necessarily caused by ischaemia. Laboratory studies suggest that matching of coronary artery autoregulation and myocardial perfusion–contraction coupling limit the impact of systemic haemodynamic changes in the myocardium, and that type 2 ischaemia might not be the likeliest explanation for cardiac troponin elevation in noncardiac surgery. The perioperative period triggers multiple pathological mechanisms that might cause cardiac troponin to cross the sarcolemma. A two-hit model involving two or more triggers including systemic inflammation, haemodynamic strain, adrenergic stress, and autonomic dysfunction might exacerbate or initiate acute myocardial injury directly in the absence of cell death. Consideration of these diverse mechanisms is pivotal for the design and interpretation of interventional perioperative trials.
Perioperative hypotension has been repeatedly associated with organ injury and worse outcome, yet many interventions to reduce morbidity by attempting to avoid or reverse hypotension have floundered. ...In part, this reflects uncertainty as to what threshold of hypotension is relevant in the perioperative setting. Shifting population-based definitions for hypertension, plus uncertainty regarding individualised norms before surgery, both present major challenges in constructing useful clinical guidelines that may help improve clinical outcomes. Aside from these major pragmatic challenges, a wealth of biological mechanisms that underpin the development of higher blood pressure, particularly with increasing age, suggest that hypotension (however defined) or lower blood pressure per se does not account solely for developing organ injury after major surgery. The mosaic theory of hypertension, first proposed more than 60 yr ago, incorporates multiple, complementary mechanistic pathways through which clinical (macrovascular) attempts to minimise perioperative organ injury may unintentionally subvert protective or adaptive pathways that are fundamental in shaping the integrative host response to injury and inflammation. Consideration of the mosaic framework is critical for a more complete understanding of the perioperative response to acute sterile and infectious inflammation. The largely arbitrary treatment of perioperative blood pressure remains rudimentary in the context of multiple complex adaptive hypertensive endotypes, defined by distinct functional or pathobiological mechanisms, including the regulation of reactive oxygen species, autonomic dysfunction, and inflammation. Developing coherent strategies for the management of perioperative hypotension requires smarter, mechanistically solid interventions delivered by RCTs where observer bias is minimised.
The central nervous origins of functional parasympathetic innervation of cardiac ventricles remain controversial.
This study aimed to identify a population of vagal preganglionic neurons that ...contribute to the control of ventricular excitability. An animal model of synuclein pathology relevant to Parkinson’s disease was used to determine whether age-related loss of the activity of the identified group of neurons is associated with changes in ventricular electrophysiology.
In vivo cardiac electrophysiology was performed in anesthetized rats in conditions of selective inhibition of the dorsal vagal motor nucleus (DVMN) neurons by pharmacogenetic approach and in mice with global genetic deletion of all family members of the synuclein protein.
In rats anesthetized with urethane (in conditions of systemic beta-adrenoceptor blockade), muscarinic and neuronal nitric oxide synthase blockade confirmed the existence of a tonic parasympathetic control of cardiac excitability mediated by the actions of acetylcholine and nitric oxide. Acute DVMN silencing led to shortening of the ventricular effective refractory period (vERP), a lowering of the threshold for triggered ventricular tachycardia, and prolongation of the corrected QT (QTc) interval. Lower resting activity of the DVMN neurons in aging synuclein-deficient mice was found to be associated with vERP shortening and QTc interval prolongation.
Activity of the DVMN vagal preganglionic neurons is responsible for tonic parasympathetic control of ventricular excitability, likely to be mediated by nitric oxide. These findings provide the first insight into the central nervous substrate that underlies functional parasympathetic innervation of the ventricles and highlight its vulnerability in neurodegenerative diseases.
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).
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.
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.
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