RESUMO
Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply1,2. Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism3,4, but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood5,6. Here we show, using experimental in vitro and in vivo animal models, that neuronal activity-dependent metabolic activation of astrocytes is mediated by neuromodulator adenosine acting on astrocytic A2B receptors. Stimulation of A2B receptors recruits the canonical cyclic adenosine 3',5'-monophosphate-protein kinase A signalling pathway, leading to rapid activation of astrocyte glucose metabolism and the release of lactate, which supplements the extracellular pool of readily available energy substrates. Experimental mouse models involving conditional deletion of the gene encoding A2B receptors in astrocytes showed that adenosine-mediated metabolic signalling is essential for maintaining synaptic function, especially under conditions of high energy demand or reduced energy supply. Knockdown of A2B receptor expression in astrocytes led to a major reprogramming of brain energy metabolism, prevented synaptic plasticity in the hippocampus, severely impaired recognition memory and disrupted sleep. These data identify the adenosine A2B receptor as an astrocytic sensor of neuronal activity and show that cAMP signalling in astrocytes tunes brain energy metabolism to support its fundamental functions such as sleep and memory.
Assuntos
Adenosina , Astrócitos , Encéfalo , Metabolismo Energético , Neurônios , Transdução de Sinais , Animais , Feminino , Masculino , Camundongos , Ratos , Adenosina/metabolismo , Astrócitos/metabolismo , Encéfalo/metabolismo , Encéfalo/citologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Glucose/metabolismo , Hipocampo/metabolismo , Hipocampo/citologia , Ácido Láctico/metabolismo , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Neurônios/metabolismo , Receptor A2B de Adenosina/deficiência , Receptor A2B de Adenosina/efeitos dos fármacos , Receptor A2B de Adenosina/genética , Receptor A2B de Adenosina/metabolismo , Reconhecimento Psicológico/fisiologia , Sono/genética , Sono/fisiologia , Sinapses/metabolismoRESUMO
The now-routine clinical deployment of continuous glucose monitoring has demonstrated benefit in real-world settings. We make the case that continuous glucose monitoring can help re-examine, at scale, the role that (stress) hyperglycaemia plays in fuelling organ dysfunction after tissue trauma. Provided robust perioperative data do emerge, well-established continuous glucose monitoring technology could soon help transform the perioperative landscape.
Assuntos
Diabetes Mellitus Tipo 1 , Hiperglicemia , Humanos , Glicemia/metabolismo , Automonitorização da Glicemia , Monitoramento Contínuo da Glicose , Insuficiência de Múltiplos ÓrgãosRESUMO
BACKGROUND: Patients with elevated preoperative plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP >100 pg ml-1) experience more complications after noncardiac surgery. Individuals prescribed renin-angiotensin system (RAS) inhibitors for cardiometabolic disease are at particular risk of perioperative myocardial injury and complications. We hypothesised that stopping RAS inhibitors before surgery increases the risk of perioperative myocardial injury, depending on preoperative risk stratified by plasma NT-proBNP concentrations. METHODS: In a preplanned analysis of a phase 2a trial in six UK centres, patients ≥60 yr old undergoing elective noncardiac surgery were randomly assigned either to stop or continue RAS inhibitors before surgery. The pharmacokinetic profile of individual RAS inhibitors determined for how long they were stopped before surgery. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury (plasma high-sensitivity troponin-T ≥15 ng L-1 or a ≥5 ng L-1 increase, when preoperative high-sensitivity troponin-T ≥15 ng L-1) within 48 h after surgery. The co-exposures of interest were preoperative plasma NT-proBNP (< or >100 pg ml -1) and stopping or continuing RAS inhibitors. RESULTS: Of 241 participants, 101 (41.9%; mean age 71 [7] yr; 48% females) had preoperative NT-proBNP >100 pg ml -1 (median 339 [160-833] pg ml-1), of whom 9/101 (8.9%) had a formal diagnosis of cardiac failure. Myocardial injury occurred in 63/101 (62.4%) subjects with NT-proBNP >100 pg ml-1, compared with 45/140 (32.1%) subjects with NT-proBNP <100 pg ml -1 {odds ratio (OR) 3.50 (95% confidence interval [CI] 2.05-5.99); P<0.0001}. For subjects with preoperative NT-proBNP <100 pg ml-1, 30/75 (40%) who stopped RAS inhibitors had myocardial injury, compared with 15/65 (23.1%) who continued RAS inhibitors (OR for stopping 2.22 [95% CI 1.06-4.65]; P=0.03). For preoperative NT-proBNP >100 pg ml-1, myocardial injury rates were similar regardless of stopping (62.2%) or continuing (62.5%) RAS inhibitors (OR for stopping 0.98 [95% CI 0.44-2.22]). CONCLUSIONS: Stopping renin-angiotensin system inhibitors in lower-risk patients (preoperative NT-proBNP <100 pg ml -1) increased the likelihood of myocardial injury before noncardiac surgery.
Assuntos
Traumatismos Cardíacos , Peptídeo Natriurético Encefálico , Feminino , Humanos , Idoso , Masculino , Troponina T , Sistema Renina-Angiotensina , Biomarcadores , Fragmentos de PeptídeosRESUMO
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.
Assuntos
Infarto do Miocárdio , Isquemia Miocárdica , Humanos , Infarto do Miocárdio/etiologia , Complicações Pós-Operatórias/diagnóstico , Isquemia Miocárdica/complicações , Miocárdio , Troponina , BiomarcadoresRESUMO
INTRODUCTION: Patients undergoing vascular procedures are prone to developing postoperative complications affecting their shortterm mortality. Prospective reports describing the incidence of longterm complications after vascular surgery are lacking. OBJECTIVES: We aimed to describe the incidence of complications 1 year after vascular surgery and to evaluate an association between myocardial injury after noncardiac surgery (MINS) and 1year mortality. PATIENTS AND METHODS: This is a substudy of a large prospective cohort study Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION). Recruitment took place in 28 centers across 14 countries from August 2007 to November 2013. We enrolled patients aged 45 years or older undergoing vascular surgery, receiving general or regional anesthesia, and hospitalized for at least 1 night postoperatively. Plasma cardiac troponin T concentration was measured before the surgery and on the first, second, and third postoperative day. The patients or their relatives were contacted 1 year after the procedure to assess the incidence of major postoperative complications. RESULTS: We enrolled 2641 patients who underwent vascular surgery, 2534 (95.9%) of whom completed 1year followup. Their mean (SD) age was 68.2 (9.8) years, and the cohort was predominantly male (77.5%). The most frequent 1year complications were myocardial infarction (224/2534, 8.8%), amputation (187/2534, 7.4%), and congestive heart failure (67/2534, 2.6%). The 1year mortality rate was 8.8% (223/2534). MINS occurred in 633 patients (24%) and was associated with an increased 1year mortality (hazard ratio, 2.82; 95% CI, 2.14-3.72; P <0.001). CONCLUSIONS: The incidence of major postoperative complications after vascular surgery is high. The occurrence of MINS is associated with a nearly 3fold increase in 1year mortality.
Assuntos
Traumatismos Cardíacos , Infarto do Miocárdio , Humanos , Masculino , Feminino , Estudos Prospectivos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Infarto do Miocárdio/etiologia , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Troponina TRESUMO
BACKGROUND AND AIMS: Haemodynamic instability is associated with peri-operative myocardial injury, particularly in patients receiving renin-angiotensin system (RAS) inhibitors (angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers). Whether stopping RAS inhibitors to minimise hypotension, or continuing RAS inhibitors to avoid hypertension, reduces peri-operative myocardial injury remains unclear. METHODS: From 31 July 2017 to 1 October 2021, patients aged ≥60 years undergoing elective non-cardiac surgery were randomly assigned to either discontinue or continue RAS inhibitors prescribed for existing medical conditions in six UK centres. Renin-angiotensin system inhibitors were withheld for different durations (2-3 days) before surgery, according to their pharmacokinetic profile. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury [plasma high-sensitivity troponin-T (hs-TnT) ≥ 15â ng/L within 48â h after surgery, or ≥5â ng/L increase when pre-operative hs-TnT ≥15â ng/L]. Pre-specified adverse haemodynamic events occurring within 48â h of surgery included acute hypertension (>180â mmHg) and hypotension requiring vasoactive therapy. RESULTS: Two hundred and sixty-two participants were randomized to continue (n = 132) or stop (n = 130) RAS inhibitors. Myocardial injury occurred in 58 (48.3%) patients randomized to discontinue, compared with 50 (41.3%) patients who continued, RAS inhibitors [odds ratio (for continuing): 0.77; 95% confidence interval (CI) 0.45-1.31]. Hypertensive adverse events were more frequent when RAS inhibitors were stopped [16 (12.4%)], compared with 7 (5.3%) who continued RAS inhibitors [odds ratio (for continuing): 0.4; 95% CI 0.16-1.00]. Hypotension rates were similar when RAS inhibitors were stopped [12 (9.3%)] or continued [11 (8.4%)]. CONCLUSIONS: Discontinuing RAS inhibitors before non-cardiac surgery did not reduce myocardial injury, and could increase the risk of clinically significant acute hypertension. These findings require confirmation in future studies.
Assuntos
Hipertensão , Hipotensão , Humanos , Sistema Renina-Angiotensina , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/induzido quimicamente , Hipotensão/induzido quimicamente , Hipotensão/prevenção & controle , Hipotensão/tratamento farmacológico , Antagonistas de Receptores de Angiotensina/efeitos adversosRESUMO
BACKGROUND: In previous analyses, myocardial injury after noncardiac surgery, major bleeding, and sepsis were independently associated with most deaths in the 30 days after noncardiac surgery, but most of these deaths occurred during the index hospitalization for surgery. The authors set out to describe outcomes after discharge from hospital up to 1 yr after inpatient noncardiac surgery and associations between predischarge complications and postdischarge death up to 1 yr after surgery. METHODS: This study was an analysis of patients discharged after inpatient noncardiac surgery in a large international prospective cohort study across 28 centers from 2007 to 2013 of patients aged 45 yr or older followed to 1 yr after surgery. The study estimated (1) the cumulative postdischarge incidence of death and other outcomes up to a year after surgery and (2) the adjusted time-varying associations between postdischarge death and predischarge complications including myocardial injury after noncardiac surgery, major bleeding, sepsis, infection without sepsis, stroke, congestive heart failure, clinically important atrial fibrillation or flutter, amputation, venous thromboembolism, and acute kidney injury managed with dialysis. RESULTS: Among 38,898 patients discharged after surgery, the cumulative 1-yr incidence was 5.8% (95% CI, 5.5 to 6.0%) for all-cause death and 24.7% (95% CI, 24.2 to 25.1%) for all-cause hospital readmission. Predischarge complications were associated with 33.7% (95% CI, 27.2 to 40.2%) of deaths up to 30 days after discharge and 15.0% (95% CI, 12.0 to 17.9%) up to 1 yr. Most of the association with death was due to myocardial injury after noncardiac surgery (15.6% [95% CI, 9.3 to 21.9%] of deaths within 30 days, 6.4% [95% CI, 4.1 to 8.7%] within 1 yr), major bleeding (15.0% [95% CI, 8.3 to 21.7%] within 30 days, 4.7% [95% CI, 2.2 to 7.2%] within 1 yr), and sepsis (5.4% [95% CI, 2.2 to 8.6%] within 30 days, 2.1% [95% CI, 1.0 to 3.1%] within 1 yr). CONCLUSIONS: One in 18 patients 45 yr old or older discharged after inpatient noncardiac surgery died within 1 yr, and one quarter were readmitted to the hospital. The risk of death associated with predischarge perioperative complications persists for weeks to months after discharge.
Assuntos
Alta do Paciente , Sepse , Humanos , Estudos Prospectivos , Assistência ao Convalescente , Hemorragia , Complicações Pós-Operatórias/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND: Activation of central autonomic pathways, including those regulating the arterial baroreflex, might reduce acute pain. We tested the hypothesis that transcutaneous auricular nerve stimulation (TAN) reduces pain after orthopaedic trauma surgery through autonomic modulation. METHODS: A total of 86 participants aged >18 yr were randomly assigned to 50 min of either sham or active bilateral TAN, undertaken before, and again 24 h after, surgery for orthopaedic trauma. The primary outcome was absolute change in pain 24 h postoperatively, comparing the 100 mm visual analogue scale (VAS) before and after TAN. Secondary outcomes included the minimal clinically important difference in pain (>10 mm increase or reduction in VAS) before/after surgery, using intention-to-treat analysis. Holter monitoring, the analysis of which was masked to allocation, quantified autonomic modulation of heart rate. RESULTS: From June 22, 2021 to July 7, 2022, 79/86 participants (49 yr; 45% female) completed TAN before and after surgery. For the primary outcome, the mean reduction in VAS was 19 mm (95% confidence interval [CI]: 12-26) after active TAN (n=40), vs 10 mm (95% CI: 3-17) after sham TAN (n=39; P=0.023). A minimally clinically important reduction in postoperative pain occurred in 31/40 (78%) participants after active TAN, compared with 15/39 (38%) allocated to sham TAN (odds ratio 5.51 [95% CI: 2.06-14.73]; P=0.001). Only active TAN increased heart rate variability (log low-frequency power increased by 0.19 ms2 [0.01-0.37 ms2]). Prespecified adverse events (auricular skin irritation) occurred in six participants receiving active TAN, compared with two receiving sham TAN. CONCLUSION: Bilateral TAN reduces perioperative pain through autonomic modulation. These proof-of-concept data support a non-pharmacological, generalisable approach to improve perioperative analgesia.
Assuntos
Dor Aguda , Dor Pós-Operatória , Humanos , Feminino , Masculino , Método Simples-Cego , Dor Pós-Operatória/prevenção & controle , Dor Pós-Operatória/tratamento farmacológicoRESUMO
Background: Early intraoperative hypotension is associated with acute kidney and myocardial injury in patients undergoing noncardiac surgery. Precise arterial blood pressure measurement before and during the induction of general anaesthesia may avert early intraoperative hypotension. However, rapid arterial cannulation in anxious, conscious patients can be challenging. We describe the protocol for a randomised controlled trial designed to test the hypothesis that readily available, handheld ultrasound-guided arterial cannulation is the optimal method in conscious patients undergoing noncardiac surgery. Methods: Participants >45 yr undergoing noncardiac surgery expected to last >120 min and requiring an overnight hospital stay will be eligible. We will randomly allocate participants to undergo cannulation of the radial artery in the non-dominant arm before the induction of general or regional anaesthesia using either handheld ultrasound-guided dynamic needle position technique or palpation. The primary outcome is first-pass successful arterial cannulation, analysed by intention-to-treat. Secondary outcomes include adequacy/characteristics of the arterial waveform and complications within 24 h of cannulation. We will require 118 patients to demonstrate a doubling of successful first-pass arterial cannulation, from â¼30% using the palpation approach (α=0.05; 1-ß=0.1). Results: This study has been approved by the NHS Health Research Authority and Health Care Research Wales (21/WA/0403) and commenced recruitment in May 2022. Conclusions: This study will establish whether handheld ultrasound-guided arterial cannulation before the induction of anaesthesia should be the standard of care in patients at risk of developing perioperative organ injury after noncardiac surgery. Clinical trial registration: NCT05249036.
RESUMO
Background: Established or acquired loss of parasympathetic vagal tone is associated with complications, including pain, after noncardiac surgery. We describe a study protocol designed to test the hypothesis that transcutaneous auricular nerve stimulation may preserve efferent parasympathetic activity to reduce pain and morbidity after noncardiac surgery. Methods: Participants aged >18 yr scheduled for urgent/elective orthopaedic surgery (n=86) will be randomly allocated to bilateral transcutaneous auricular nerve stimulation or sham protocol for 50 min at the same time of day, before and 24 h after surgery. Holter monitoring, the analysis of which is masked to allocation, will quantify autonomic modulation of HR. The primary outcome will be pain, quantified by absolute changes in VAS 24 h after surgery following sham or stimulation. Secondary outcomes include presence or absence of >10 mm change in the 100 mm VAS (which defines a minimum clinically important change) and postoperative morbidity (Postoperative Morbidity Survey) before and 24 h after surgery. The relationship between the explanatory variable (HR variability), VAS, and morbidity will be examined using a multilevel (mixed-error component) regression model. Safety and complications of the intervention will also be recorded. The study was approved by the NHS Research Ethics Committee (21/LO/0272). As of 25 December 2021, 34/86 participants (mean [standard deviation] age: 48 [19] yr; 14 females [41.2%]) have been recruited, with complete collection of Holter data. Conclusions: This phase 2b study will explore whether noninvasive autonomic neuromodulation may reduce pain or morbidity using trans-auricular vagus nerve stimulation, providing proof-of-concept data for a non-pharmacological, generalisable approach to improve perioperative outcomes. Clinical trial registration: Researchregistry7566.
RESUMO
BACKGROUND: Sex differences in sepsis are underexplored and incompletely understood. Cardiac function in early sepsis is pivotal in determining survival; hyperdynamic left ventricular ejection fraction is associated with higher mortality. Female sex may be cardioprotective, but variable experimental findings have not controlled for hypovolaemia. Sex-specific local cardiac versus peripheral inflammation in causing cardiovascular dysfunction also remain unclear. We therefore examined whether there are sex-specific differences in cardiac function in early sepsis, controlling for volaemic status and sex-specific differences in the peripheral inflammatory response initiated by tumour necrosis factor (TNFα). METHODS: We used an experimental polymicrobial sepsis (faecal slurry) model titrated to minimise hypovolaemia as a confounding factor. We quantified cardiac function (transthoracic cardiac echocardiography) 1 week before, and 18 h after, sepsis. Cardiac injury (troponin I), inflammation and immune cell infiltration (flow cytometry) were quantified in naïve and septic female and male mice 18 h after sepsis. To evaluate the sex-specific influence of TNFα derived from peripheral leukocytes, we repeated the experiments in iRHOM2-/- mice that are unable to shed TNFα exclusively from circulating leucocytes. RESULTS: Serum troponin I increased to 1.39 ± 0.38 ng mL-1 (from undetectable levels in controls) 18 h after onset of normovolaemic sepsis to a similar extent in both sexes. Stroke volume in male mice increased by 8 µL [(3-13); p = 0.004], compared to individualised pre-sepsis values. By contrast, stroke volume remained at baseline levels in females [mean difference: 4 µL (- 1 to 9)]. Messenger RNA levels of markers for cardiac injury/inflammation after sepsis (real-time polymerase-chain reaction) were elevated in male wild-type mice compared to female wild types (n = 10/sex), with higher cardiac mRNA levels of atrial natriuretic peptide, inflammation (TNFα) and oxidative stress (superoxide dismutase-1), although serum troponin I values were similarly elevated. Flow cytometry analysis of cardiac tissue showed doubling of CD4 + leukocyte infiltration in male mice. Sex-specific cardiac physiologic differences were similar in iRHOM2-/- mice that are unable to shed TNFα exclusively from leucocytes. CONCLUSIONS: In early normovolaemic polymicrobial sepsis, a relative hyperdynamic response develops in male mice. Myocardial stress/injury after early sepsis is limited in females, with less cardiac infiltration of CD4 + leukocytes but independent of shedding of TNFα from peripheral circulating leukocytes.
RESUMO
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.
Assuntos
Hipertensão , Hipotensão , Pressão Sanguínea/fisiologia , Humanos , Hipotensão/tratamento farmacológico , Hipotensão/terapia , InflamaçãoRESUMO
BACKGROUND: Autonomic dysfunction promotes organ injury after major surgery through numerous pathological mechanisms. Vagal withdrawal is a key feature of autonomic dysfunction, and it may increase the severity of pain. We systematically evaluated studies that examined whether vagal neuromodulation can reduce perioperative complications and pain. METHODS: Two independent reviewers searched PubMed, EMBASE, and the Cochrane Register of Controlled Clinical Trials for studies of vagal neuromodulation in humans. Risk of bias was assessed; I2 index quantified heterogeneity. Primary outcomes were organ dysfunction (assessed by measures of cognition, cardiovascular function, and inflammation) and pain. Secondary outcomes were autonomic measures. Standardised mean difference (SMD) using the inverse variance random-effects model with 95% confidence interval (CI) summarised effect sizes for continuous outcomes. RESULTS: From 1258 records, 166 full-text articles were retrieved, of which 31 studies involving patients (n=721) or volunteers (n=679) met the inclusion criteria. Six studies involved interventional cardiology or surgical patients. Indirect stimulation modalities (auricular [n=23] or cervical transcutaneous [n=5]) were most common. Vagal neuromodulation reduced pain (n=10 studies; SMD=2.29 [95% CI, 1.08-3.50]; P=0.0002; I2=97%) and inflammation (n=6 studies; SMD=1.31 [0.45-2.18]; P=0.003; I2=91%), and improved cognition (n=11 studies; SMD=1.74 [0.96-2.52]; P<0.0001; I2=94%) and cardiovascular function (n=6 studies; SMD=3.28 [1.96-4.59]; P<0.00001; I2=96%). Five of six studies demonstrated autonomic changes after vagal neuromodulation by measuring heart rate variability, muscle sympathetic nerve activity, or both. CONCLUSIONS: Indirect vagal neuromodulation improves physiological measures associated with limiting organ dysfunction, although studies are of low quality, are susceptible to bias and lack specific focus on perioperative patients.
Assuntos
Dor Pós-Operatória/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Estimulação do Nervo Vago/métodos , Sistema Nervoso Autônomo/metabolismo , Frequência Cardíaca/fisiologia , HumanosRESUMO
BACKGROUND: Maintaining adequate oxygen delivery (DO2) after major surgery is associated with minimising organ dysfunction. Skin is particularly vulnerable to reduced DO2. We tested the hypothesis that reduced perioperative DO2 fuels inflammation in metabolically compromised skin after major surgery. METHODS: Participants undergoing elective oesophagectomy were randomised immediately after surgery to standard of care or haemodynamic therapy to achieve their individualised preoperative DO2. Abdominal punch skin biopsies were snap-frozen before and 48 h after surgery. On-line two-dimensional liquid chromatography and ultra-high-definition label-free mass spectrometry was used to characterise the skin proteome. The primary outcome was proteomic changes compared between normal (≥preoperative value before induction of anaesthesia) and low DO2 (Assuntos
Esofagectomia/métodos
, Oxigênio/administração & dosagem
, Proteômica
, Pele/metabolismo
, Idoso
, Idoso de 80 Anos ou mais
, Biópsia
, Método Duplo-Cego
, Procedimentos Cirúrgicos Eletivos
, Feminino
, Humanos
, Masculino
, Pessoa de Meia-Idade
, Assistência Perioperatória/métodos
, Proteínas/metabolismo
RESUMO
BACKGROUND: In the general adult population, lymphopaenia is associated with an increased risk for hospitalisation with infection and infection-related death. The quality of evidence and strength of association between perioperative lymphopaenia across different surgical procedures and mortality/morbidity has not been examined by systematic review or meta-analysis. METHODS: We searched MEDLINE, Embase, Web of Science, Google Scholar, and Cochrane databases from their inception to June 29, 2020 for observational studies reporting lymphocyte count and in-hospital mortality rate in adults. We defined preoperative lymphopaenia as a lymphocyte count 1.0-1.5×109 L-1. Meta-analysis was performed using either fixed or random effects models. Quality was assessed using the Newcastle-Ottawa Scale. The I2 index was used to quantify heterogeneity. The primary outcome was in-hospital mortality rate and mortality rate at 30 days. RESULTS: Eight studies met the inclusion criteria for meta-analysis, comprising 4811 patients (age range, 46-91 yr; female, 20-79%). These studies examined preoperative lymphocyte count exclusively. Studies were of moderate to high quality overall, ranking >7 using the Newcastle-Ottawa Scale. Preoperative lymphopaenia was associated with a threefold increase in mortality rate (risk ratio [RR]=3.22; 95% confidence interval [CI], 2.19-4.72; P<0.01, I2=0%) and more frequent major postoperative complications (RR=1.33; 95% CI, 1.21-1.45; P<0.01, I2=6%), including cardiovascular morbidity (RR=1.77; 95% CI, 1.45-2.15; P<0.01, I2=0%), infections (RR=1.45; 95% CI, 1.19-1.76; P<0.01, I2=0%), and acute renal dysfunction (RR=2.66; 95% CI, 1.49-4.77; P<0.01, I2=1%). CONCLUSION: Preoperative lymphopaenia is associated with death and complications more frequently, independent of the type of surgery. PROSPERO REGISTRY NUMBER: CRD42020190702.
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Procedimentos Cirúrgicos Eletivos/mortalidade , Mortalidade Hospitalar , Linfopenia/mortalidade , Linfopenia/cirurgia , Complicações Pós-Operatórias/mortalidade , Cuidados Pré-Operatórios/mortalidade , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Procedimentos Cirúrgicos Eletivos/tendências , Mortalidade Hospitalar/tendências , Humanos , Morbidade/tendências , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Cuidados Pré-Operatórios/métodos , Cuidados Pré-Operatórios/tendências , Estudos ProspectivosRESUMO
BACKGROUND: Control of blood pressure remains a key goal of peri-operative care, because hypotension is associated with adverse outcomes after surgery. OBJECTIVES: We explored whether increased vigilance afforded by intra-arterial blood pressure monitoring may be associated with less morbidity after surgery. DESIGN: A prospective observational cohort study. SETTING: Four UK secondary care hospitals. PATIENTS: A total of 4342 patients ≥45âyears who underwent noncardiac surgery. METHODS: We compared outcome of patients who received peri-operative intra-arterial blood pressure monitoring with those whose blood pressure was measured noninvasively. OUTCOMES: The primary outcome was peri-operative myocardial injury (high-sensitivity troponin-T ≥ 15 ng l-1 within 72âh after surgery), compared between patients who received intra-arterial versus noninvasive blood pressure monitoring. Secondary outcomes were morbidity within 72âh of surgery (postoperative morbidity survey), and vasopressor and fluid therapy. Multivariable logistic regression analysis explored associations between morbidity and age, sex, location of postoperative care, mode of blood pressure/haemodynamic monitoring and Revised Cardiac Risk Index. RESULTS: Intra-arterial monitoring was used in 1137/4342 (26.2%) patients. Myocardial injury occurred in 440/1137 (38.7%) patients with intra-arterial monitoring compared with 824/3205 (25.7%) with noninvasive monitoring [OR 1.82 (95% CI 1.58 to 2.11), Pâ<â0.001]. Intra-arterial monitoring remained associated with myocardial injury when adjusted for potentially confounding variables [adjusted OR 1.56 (1.29 to 1.89), Pâ<â0.001). The results were similar for planned ICU versus ward postoperative care. CONCLUSIONS: Intra-arterial monitoring is associated with greater risk of morbidity after noncardiac surgery, after controlling for surgical and patient factors. These data provide useful insights into the design of a definitive monitoring trial.
Assuntos
Complicações Pós-Operatórias , Procedimentos Cirúrgicos Operatórios , Pressão Sanguínea , Estudos de Coortes , Humanos , Morbidade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Procedimentos Cirúrgicos Operatórios/efeitos adversosRESUMO
BACKGROUND: Elevated plasma or serum troponin, indicating perioperative myocardial injury (PMI), is common after noncardiac surgery. However, underlying mechanisms remain unclear. Acute coronary syndrome (ACS) is associated with the early appearance of circulating microRNAs, which regulate post-translational gene expression. We hypothesised that if PMI and ACS share pathophysiological mechanisms, common microRNA signatures should be evident. METHODS: We performed a nested case control study of samples obtained before and after noncardiac surgery from patients enrolled in two prospective observational studies of PMI (postoperative troponin I/T>99th centile). In cohort one, serum microRNAs were compared between patients with or without PMI, matched for age, gender, and comorbidity. Real-time polymerase chain reaction quantified (qRT-PCR) relative microRNA expression (cycle quantification [Cq] threshold <37) before and after surgery for microRNA signatures associated with ACS, blinded to PMI. In cohort two, we analysed (EdgeR) microRNA from plasma extracellular vesicles using next-generation sequencing (Illumina HiSeq 500). microRNA-messenger RNA-function pathway analysis was performed (DIANA miRPath v3.0/TopGO). RESULTS: MicroRNAs were detectable in all 59 patients (median age 67 yr [61-75]; 42% male), who had similar clinical characteristics independent of developing PMI. In cohort one, serum microRNA expression increased after surgery (mean fold-change) hsa-miR-1-3p: 3.99 (95% confidence interval [CI: 1.95-8.19]; hsa-miR-133-3p: 5.67 [95% CI: 2.94-10.91]; P<0.001). These changes were not associated with PMI. Bioinformatic analysis of differentially expressed microRNAs from cohorts one (n=48) and two (n=11) identified pathways associated with adrenergic stress and calcium dysregulation, rather than ischaemia. CONCLUSIONS: Circulating microRNAs associated with cardiac ischaemia were universally elevated in patients after surgery, independent of development of myocardial injury.
Assuntos
Procedimentos Cirúrgicos Eletivos/efeitos adversos , Traumatismos Cardíacos/sangue , MicroRNAs/sangue , Complicações Pós-Operatórias/sangue , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/etiologia , Síndrome Coronariana Aguda/genética , Idoso , Estudos de Casos e Controles , Mapeamento Cromossômico , Matriz Extracelular/química , Feminino , Traumatismos Cardíacos/genética , Humanos , Masculino , Redes e Vias Metabólicas , MicroRNAs/genética , Pessoa de Meia-Idade , Isquemia Miocárdica/sangue , Isquemia Miocárdica/genética , Complicações Pós-Operatórias/genética , Estudos ProspectivosRESUMO
BACKGROUND: Infection is a frequent cause of postoperative morbidity and mortality. The incidence, risk factors, and outcomes for postoperative infections remain poorly characterised. METHODS: 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. RESULTS: 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]; P<0.01) and open surgical technique (OR: 2.03 [1.82-2.27]; P<0.01); 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]; P<0.01). Mortality was highest amongst patients with CNS infections (OR: 14.72 [4.41-49.12]; P<0.01). CONCLUSIONS: 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.
Assuntos
Infecções/epidemiologia , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Procedimentos Cirúrgicos Operatórios/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Procedimentos Cirúrgicos Operatórios/métodosRESUMO
BACKGROUND: Elevated high-sensitivity troponin (hsTnT) after noncardiac surgery is associated with higher mortality, but the temporal relationship between early elevated troponin and the later development of noncardiac morbidity remains unclear. METHODS: Prospective observational study of patients aged ≥45 yr undergoing major noncardiac surgery at four UK hospitals (two masked to hsTnT). The exposure of interest was early elevated troponin, as defined by hsTnT >99th centile (≥15 ng L-1) within 24 h after surgery. The primary outcome was morbidity 72 h after surgery, defined by the Postoperative Morbidity Survey (POMS). Secondary outcomes were time to become morbidity-free and Clavien-Dindo ≥grade 3 complications. RESULTS: Early elevated troponin (median 21 ng L-1 [16-32]) occurred in 992 of 4335 (22.9%) patients undergoing elective noncardiac surgery (mean [standard deviation, sd] age, 65 [11] yr; 2385 [54.9%] male). Noncardiac morbidity was more frequent in 494/992 (49.8%) patients with early elevated troponin compared with 1127/3343 (33.7%) patients with hsTnT <99th centile (odds ratio [OR]=1.95; 95% confidence interval [CI], 1.69-2.25). Patients with early elevated troponin had a higher risk of proven/suspected infectious morbidity (OR=1.54; 95% CI, 1.24-1.91) and critical care utilisation (OR=2.05; 95% CI, 1.73-2.43). Clavien-Dindo ≥grade 3 complications occurred in 167/992 (16.8%) patients with early elevated troponin, compared with 319/3343 (9.5%) patients with hsTnT <99th centile (OR=1.78; 95% CI, 1.48-2.14). Absence of early elevated troponin was associated with morbidity-free recovery (OR=0.44; 95% CI, 0.39-0.51). CONCLUSIONS: Early elevated troponin within 24 h of elective noncardiac surgery precedes the subsequent development of noncardiac organ dysfunction and may help stratify levels of postoperative care in real time.