Preoperative N-terminal pro-B-type natriuretic peptide and myocardial injury after stopping or continuing renin-angiotensin system inhibitors in noncardiac surgery: a prespecified analysis of a phase 2 randomised controlled multicentre trial.

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.

Discontinuation vs. continuation of renin-angiotensin system inhibition before non-cardiac surgery: the SPACE trial.

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) ≥ 15 ng/L within 48 h after surgery, or ≥5 ng/L increase when pre-operative hs-TnT ≥15 ng/L]. Pre-specified adverse haemodynamic events occurring within 48 h of surgery included acute hypertension (>180 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.

Transauricular nerve stimulation in acute ischaemic stroke requiring mechanical thrombectomy: Protocol for a phase 2A, proof-of-concept, sham-controlled randomised trial.

BACKGROUND: Labile blood pressure after acute ischaemic stroke requiring mechanical thrombectomy is independently associated with poor patient outcomes. OBJECTIVES: This study protocol describes is designed to determine whether transauricular nerve stimulation, improves baroreflex sensitivity, reduces blood pressure variability in the first 24 hours after acute ischaemic stroke requiring mechanical thrombectomy. DESIGN: PHASE 2A, PROOF-OF-CONCEPT, SHAM-CONTROLLED RANDOMISED TRIAL: Methods and Analysis: 36 individuals undergoing mechanical thrombectomy for acute ischaemic stroke with established hypertension aged >18 years will be randomly allocated to receive bilateral active or sham transauricular nerve stimulation for the duration of the mechanical thrombectomy procedure (AffeX-CT/001 investigational device). The intervention will be repeated for 1h the morning following the mechanical thrombectomy. Non-invasive blood pressure will be measured ≥2h for 24h after mechanical thrombectomy. Holter electrocardiographic monitoring will be recorded during transauricular nerve stimulation. Participants, clinicians and investigators will be masked to treatment allocations. The primary outcome will be the coefficient of variation of systolic blood pressure. Secondary outcomes include additional estimates of blood pressure variability and time/frequency-domain measures of autonomic cardiac modulation An adjusted sample size of 36 patients is required to have a 90% chance of detecting, as significant at the 5% level, a difference in the coefficient of variation in systolic blood pressure of 5±4mmHg between sham and active stimulation [assuming 5% non-compliance rate in each group]. Ethics: confirmed on 16 March 2023 by HRA and Health and Care Research Wales ethics committee (reference 23/WA/0013). DISCUSSION: This study will provide proof-of-concept data that examines whether non-invasive autonomic neuromodulation can be used to favourably modify blood pressure and autonomic control after acute ischaemic stroke requiring mechanical thrombectomy. TRIAL REGISTRATION: Trial registration number: NCT05417009.

Barriers to Quality Perioperative Care Delivery in Low- and Middle-Income Countries: A Qualitative Rapid Appraisal Study.

BACKGROUND: Provision of timely, safe, and affordable surgical care is an essential component of any high-quality health system. Increasingly, it is recognized that poor quality of care in the perioperative period (before, during, and after surgery) may contribute to significant excess mortality and morbidity. Therefore, improving access to surgical procedures alone will not address the disparities in surgical outcomes globally until the quality of perioperative care is addressed. We aimed to identify key barriers to quality perioperative care delivery for 3 "Bellwether" procedures (cesarean delivery, emergency laparotomy, and long-bone fracture fixation) in 5 low- and middle-income countries (LMICs). METHODS: Ten hospitals representing secondary and tertiary facilities from 5 LMICs were purposefully selected: 2 upper-middle income (Colombia and South Africa); 2 lower-middle income (Sri Lanka and Tanzania); and 1 lower income (Uganda). We used a rapid appraisal design (pathway mapping, ethnography, and interviews) to map out and explore the complexities of the perioperative pathway and care delivery for the Bellwether procedures. The framework approach was used for data analysis, with triangulation across different data sources to identify barriers in the country and pattern matching to identify common barriers across the 5 LMICs. RESULTS: We developed 25 pathway maps, undertook >30 periods of observation, and held >40 interviews with patients and clinical staff. Although the extent and impact of the barriers varied across the LMIC settings, 4 key common barriers to safe and effective perioperative care were identified: (1) the fragmented nature of the care pathways, (2) the limited human and structural resources available for the provision of care, (3) the direct and indirect costs of care for patients (even in health systems for which care is ostensibly free of charge), and (4) patients' low expectations of care. CONCLUSIONS: We identified key barriers to effective perioperative care in LMICs. Addressing these barriers is important if LMIC health systems are to provide safe, timely, and affordable provision of the Bellwether procedures.

Liberal or restrictive antimicrobial prophylaxis for surgical site infection: systematic review and meta-analysis of randomised trials.

BACKGROUND: Antimicrobial prophylaxis is widely used to prevent surgical site infection. Amid growing concern about antimicrobial resistance, we determined the effectiveness of antimicrobial prophylaxis. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and WHO-ICTRP between January 1, 1990 and January 1, 2020 for trials randomising adults undergoing surgery to liberal (more doses) or restrictive (fewer or no doses) perioperative antimicrobial prophylaxis. Pairs of researchers reviewed articles and extracted data, and a senior author resolved discrepancies. The primary outcome measure was surgical site infection or bacteriuria for urological procedures. We calculated average risk difference (RD) with 95% confidence intervals and prediction intervals (PI) using random effects models, and present risk ratios (RR). We assessed evidence certainty using GRADE methodology, and risk of bias using the Cochrane Risk of Bias tool (PROSPERO: CRD42018116946). RESULTS: From 6593 records, we identified 294 trials including 86 146 patients. Surgical site infection occurred in 2237/44 113 (5.1%) patients receiving liberal prophylaxis vs 2889/42 033 (6.9%) receiving restrictive prophylaxis (RD -0.01 [-0.02 to -0.01]; relative risk 0.72 [0.67-0.77]; I2=52%, PI -0.05-0.02). There was a small benefit of prophylaxis in 161 trials comparing no prophylaxis with ≥1 dose (RD -0.02 [-0.03 to -0.02]; RR 0.58 [0.52-0.65]; I2=62%, PI -0.06-0.02). Treatment effect varied from a strong effect in urology to no benefit in 7/19 specialities. Tests for publication bias suggest 62 unreported trials and evidence certainty was very low. Treatment harms were reported in 43/294 trials. CONCLUSIONS: A systematic review and meta-analysis of randomised trials revealed that more liberal antimicrobial prophylaxis is associated with a small reduction in the risk of surgical site infection, although antimicrobial harms are poorly reported. Further evidence about the risks of antimicrobial prophylaxis to inform current widespread use is urgently needed.

Contemporary use of antimicrobial prophylaxis for surgical patients: An observational cohort study.

BACKGROUND: Antimicrobial prophylaxis is commonly used to prevent surgical site infection (SSI), despite concerns of overuse leading to antimicrobial resistance. However, it is unclear how often antimicrobials are used and whether guidelines are followed. OBJECTIVES: To describe contemporary clinical practice for antimicrobial prophylaxis including guideline compliance, the rate of postoperative infection and associated side effects. DESIGN: A prospective, multicentre, observational cohort study. SETTING: Twelve United Kingdom National Health Service hospitals. PARTICIPANTS: One thousand one hundred and sixteen patients, aged at least 18 years undergoing specific colo-rectal, obstetric, gynaecological, urological or orthopaedic surgical procedures. EXPOSURE: Compliance with guidelines for antimicrobial prophylaxis. OUTCOMES: The primary outcome was SSI within 30 days after surgery. Secondary outcomes were number of doses of antimicrobials for prophylaxis and to treat infection, incidence of antimicrobial-related side effects and mortality within 30 days after surgery. Data are presented as number with percentage (%) or median with interquartile range [IQR].Results of logistic regression analyses are presented as odds ratio/rate ratio (OR/RR) with 95% confidence intervals (95% CIs). RESULTS: 1102 out of 1106 (99.6%) patients received antimicrobial prophylaxis, which was compliant with local guidelines in 929 out of 1102 (84.3%) cases. 2169 out of 51 28 (42.3%) doses of antimicrobials were administered as prophylaxis (median 1 [1 to 2] dose) and 2959 out of 5128 (57.7%) were administered to treat an infection (median 21 [11 to 28] doses). 56 patients (5.2%) developed SSI. Antimicrobial prophylaxis administered according to local guidelines was not associated with a lower incidence of SSI compared with administration outside guidelines [OR 0.90 (0.35 to 2.29); P  = 0.823]. 23 out of 1072 (2.2%) patients experienced a side effect of antimicrobial therapy. 7 out of 1082 (0.6%) patients died. The median hospital stay was 3 [1 to 5] days. CONCLUSION: Antimicrobial prophylaxis was administered for almost all the surgical procedures under investigation. However, this was not always compliant with guidelines. Further research is required to determine whether the amount of prophylactic antimicrobials could be safely and effectively reduced without increasing the incidence of SSI.

Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) trial: study protocol for a multicentre international trial of cardiac output-guided fluid therapy with low-dose inotrope infusion compared with usual care in patients undergoing major elective gastrointestinal surgery.

INTRODUCTION: Postoperative morbidity and mortality in older patients with comorbidities undergoing gastrointestinal surgery are a major burden on healthcare systems. Infections after surgery are common in such patients, prolonging hospitalisation and reducing postoperative short-term and long-term survival. Optimal management of perioperative intravenous fluids and inotropic drugs may reduce infection rates and improve outcomes from surgery. Previous small trials of cardiac-output-guided haemodynamic therapy algorithms suggested a modest reduction in postoperative morbidity. A large definitive trial is needed to confirm or refute this and inform widespread clinical practice. METHODS: The Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) trial is a multicentre, international, parallel group, open, randomised controlled trial. 2502 high-risk patients undergoing major elective gastrointestinal surgery will be randomly allocated in a 1:1 ratio using minimisation to minimally invasive cardiac output monitoring to guide protocolised administration of intravenous fluid combined with low-dose inotrope infusion, or usual care. The trial intervention will be carried out during and for 4 hours after surgery. The primary outcome is postoperative infection of Clavien-Dindo grade II or higher within 30 days of randomisation. Participants and those delivering the intervention will not be blinded to treatment allocation; however, outcome assessors will be blinded when feasible. Participant recruitment started in January 2017 and is scheduled to last 3 years, within 50 hospitals worldwide. ETHICS/DISSEMINATION: The OPTIMISE II trial has been approved by the UK National Research Ethics Service and has been approved by responsible ethics committees in all participating countries. The findings will be disseminated through publication in a widely accessible peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: ISRCTN39653756.

Functional crosstalk between cardiac fibroblasts and adult cardiomyocytes by soluble mediators.

AIMS: Crosstalk between cardiomyocytes and fibroblasts in physiological conditions and during disease remains poorly defined. Previous studies have shown that fibroblasts and myocytes interact via paracrine communication, but several experimental confounding factors, including the use of immature myocytes and the induction of alpha-smooth muscle actin (α-SMA) expression in fibroblasts by prolonged culture, have hindered our understanding of this phenomenon. We hypothesize that fibroblasts and myofibroblasts differentially affect cardiomyocytes viability, volume, and Ca(2+) handling via soluble mediators. More specifically here: (i) we compare the effects of freshly isolated fibroblasts and cultured fibroblasts from normal rat hearts on adult cardiomyocytes; (ii) we compare the effects of (freshly isolated) normal fibroblasts and myofibroblasts from pressure-overloaded hearts; and (iii) we study the contribution of TGF-ß and the importance of the crosstalk between the two cell types. METHODS AND RESULTS: We used co-culture methods and conditioned medium to investigate paracrine interaction between fibroblasts and cardiomyocytes. All fibroblast types reduce cardiomyocyte viability and increase cardiomyocyte volume but α-SMA-negative fibroblasts increase cardiomyocyte Ca(2+) transient amplitude, whereas cultured fibroblasts and myofibroblasts from pressure-overloaded hearts decrease Ca(2+) transient amplitude. In turn, cardiomyocytes release soluble mediators that affect fibroblast proliferation. Using SB431542 to block TGF-ß type 1 receptors, we determined that TGF-ß directly causes cardiomyocyte hypertrophy and participates in bi-directional regulatory signalling between fibroblasts and cardiomyocytes. CONCLUSIONS: Fibroblasts have different roles during physiology and disease in regulating myocardial function via soluble mediators. A crosstalk between fibroblasts and cardiomyocytes, controlled by TGF-ß, is crucial in this interaction.

Characterisation of connexin expression and electrophysiological properties in stable clones of the HL-1 myocyte cell line.

The HL-1 atrial line contains cells blocked at various developmental stages. To obtain homogeneous sub-clones and correlate changes in gene expression with functional alterations, individual clones were obtained and characterised for parameters involved in conduction and excitation-contraction coupling. Northern blots for mRNAs coding for connexins 40, 43 and 45 and calcium handling proteins (sodium/calcium exchanger, L- and T-type calcium channels, ryanodine receptor 2 and sarco-endoplasmic reticulum calcium ATPase 2) were performed. Connexin expression was further characterised by western blots and immunofluorescence. Inward currents were characterised by voltage clamp and conduction velocities measured using microelectrode arrays. The HL-1 clones had similar sodium and calcium inward currents with the exception of clone 2 which had a significantly smaller calcium current density. All the clones displayed homogenous propagation of electrical activity across the monolayer correlating with the levels of connexin expression. Conduction velocities were also more sensitive to inhibition of junctional coupling by carbenoxolone (∼ 80%) compared to inhibition of the sodium current by lidocaine (∼ 20%). Electrical coupling by gap junctions was the major determinant of conduction velocities in HL-1 cell lines. In summary we have isolated homogenous and stable HL-1 clones that display characteristics distinct from the heterogeneous properties of the original cell line.

Influence of ivabradine on reverse remodelling during mechanical unloading.

AIMS: Ivabradine (Iva) has shown beneficial structural and functional effects in clinical and experimental heart failure (HF), but its action in combination with mechanical unloading (MU), such as during treatment with left ventricular assist devices (LVAD), is unknown. The aim of this study was to investigate the effects of Iva during MU, in a rodent model of HF. METHODS AND RESULTS: We studied the chronic effects (4 weeks) of Iva (10 mg/kg/day) alone and in combination with MU [induced by heterotopic abdominal heart transplantation (HATx)] on whole-heart and cellular structure, function, and excitation-contraction (E-C) coupling in a rodent (rat) model of HF, 12 weeks post-left coronary artery (LCA) ligation. Effects of Iva were compared with those of ß-blockade using metoprolol [(Met), 250 mg/kg/day]. Iva, but not Met, reversed myocardial fibrosis, alone and in combination with MU. MU-induced restoration of deranged E-C coupling was enhanced by Iva to a greater extent than Met: both Iva and Met enhanced the recovery of the Ca(2+) transient amplitude and the sarcoplasmic reticulum (SR) Ca(2+) content, but Iva alone maintained MU-induced normalization of L-type Ca(2+) current and t-tubule abnormalities. Met prevented MU-induced reduction in the myocardial size (myocardial atrophy); Iva had no effect on this parameter. CONCLUSION: Iva shows beneficial structural and E-C coupling effects during MU: Iva reverses myocardial fibrosis and enhances the restoration of deranged E-C coupling, displaying more beneficial effects than that of Met. These results suggest that Iva may prove effective in enhancing functional recovery in heart failure patients receiving LVAD therapy.

Mechanical unloading reverses transverse tubule remodelling and normalizes local Ca(2+)-induced Ca(2+)release in a rodent model of heart failure.

AIMS: Ca(2+)-induced Ca(2+) release (CICR) is critical for contraction in cardiomyocytes. The transverse (t)-tubule system guarantees the proximity of the triggers for Ca(2+) release [L-type Ca(2+) channel, dihydropyridine receptors (DHPRs)] and the sarcoplasmic reticulum Ca(2+) release channels [ryanodine receptors (RyRs)]. Transverse tubule disruption occurs early in heart failure (HF). Clinical studies of left ventricular assist devices in HF indicate that mechanical unloading induces reverse remodelling. We hypothesize that unloading of failing hearts normalizes t-tubule structure and improves CICR. METHODS AND RESULTS: Heart failure was induced in Lewis rats by left coronary artery ligation for 12 weeks; sham-operated animals were used as controls. Failing hearts were mechanically unloaded for 4 weeks by heterotopic abdominal heart transplantation (HF-UN). HF reduced the t-tubule density measured by di-8-ANEPPS staining in isolated left ventricular myocytes, and this was reversed by unloading. The deterioration in the regularity of the t-tubule system in HF was also reversed in HF-UN. Scanning ion conductance microscopy showed the reappearance of normal surface striations in HF-UN. Electron microscopy revealed recovery of normal t-tubule microarchitecture in HF-UN. L-type Ca(2+) current density, measured using whole-cell patch clamping, was reduced in HF but unaffected by unloading. The variance of the time-to-peak of the Ca(2+) transient, an index of CICR dyssynchrony, was increased in HF and normalized by unloading. The increased Ca(2+) spark frequency observed in HF was reduced in HF-UN. These results could be explained by the recoupling of orphaned RyRs in HF, as indicated by immunofluorescence. CONCLUSIONS: Our data show that mechanical unloading of the failing heart reverses the pathological remodelling of the t-tubule system and improves CICR.