IL-1ra polymorphisms and risk of epidural-related maternal fever (EPIFEVER-2): study protocol for a multicentre, observational mechanistic cohort study.

BACKGROUND: Laboratory data suggest that insufficient circulating levels of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra) are associated with intrapartum inflammation and epidural-related maternal fever, both of which increase the rate of obstetric interventions and antibiotic use during labour. Genetic polymorphisms strongly influence IL-1ra levels in the general population. We aim to examine the association between IL-1ra polymorphisms and epidural-related maternal fever using Mendelian randomization analysis. METHODS: EPIFEVER-2 is a multicentre UK trial enrolling 637 women receiving epidural analgesia for labour. Blood samples obtained no later than four hours after epidural insertion will provide deoxyribonucleic acid for Taqman single-nucleotide polymorphism genotyping for presence/absence of rs6743376, rs1542176 alleles for IL-1ra, to establish the genetic score. The absence of both alleles is associated with the lowest IL-1ra levels. The primary outcome is pyrexia (>38°C) or intrapartum antibiotic administration. Secondary outcomes include mode of delivery, maternal and neonatal healthcare interventions. RESULTS: The EPIFEVER-2 study was prospectively registered (ISRCTN99641204) following ethical approval. Participant recruitment began in May 2021, with 221 women recruited across three centres as of November 21, 2021. CONCLUSIONS: EPIFEVER-2 will generate the largest prospective dataset detailing the incidence and consequences of epidural-related maternal fever. Using Mendelian randomisation analysis, a causative role for lower IL1-ra levels in determining the risk of epidural-related maternal fever and/or antibiotic administration before delivery will be examined.

Erratum to 'Angiotensin converting enzyme inhibitors and angiotensin receptor blockers' [BJA Education 20 (2020) 362-367].

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

Type 2 diabetes is associated with the accumulation of senescent T cells.

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.

Preoperative systemic inflammation and perioperative myocardial injury: prospective observational multicentre cohort study of patients undergoing non-cardiac surgery.

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<0.0001]. Myocardial injury was independently associated with lower absolute preoperative lymphocyte count [OR 1.80 (1.50-2.17); P<0.0001] and higher absolute preoperative monocyte count [OR 1.93 (1.12-3.30); P=0.017]. Monocyte ROS generation correlated with NLR (r=0.47; P=0.03). 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.

Cardiac vagal dysfunction and myocardial injury after non-cardiac surgery: a planned secondary analysis of the measurement of Exercise Tolerance before surgery study.

BACKGROUND: The aetiology of perioperative myocardial injury is poorly understood and not clearly linked to pre-existing cardiovascular disease. We hypothesised that loss of cardioprotective vagal tone [defined by impaired heart rate recovery ≤12 beats min-1 (HRR ≤12) 1 min after cessation of preoperative cardiopulmonary exercise testing] was associated with perioperative myocardial injury. METHODS: We conducted a pre-defined, secondary analysis of a multi-centre prospective cohort study of preoperative cardiopulmonary exercise testing. Participants were aged ≥40 yr undergoing non-cardiac surgery. The exposure was impaired HRR (HRR≤12). The primary outcome was postoperative myocardial injury, defined by serum troponin concentration within 72 h after surgery. The analysis accounted for established markers of cardiac risk [Revised Cardiac Risk Index (RCRI), N-terminal pro-brain natriuretic peptide (NT pro-BNP)]. RESULTS: A total of 1326 participants were included [mean age (standard deviation), 64 (10) yr], of whom 816 (61.5%) were male. HRR≤12 occurred in 548 patients (41.3%). Myocardial injury was more frequent amongst patients with HRR≤12 [85/548 (15.5%) vs HRR>12: 83/778 (10.7%); odds ratio (OR), 1.50 (1.08-2.08); P=0.016, adjusted for RCRI). HRR declined progressively in patients with increasing numbers of RCRI factors. Patients with ≥3 RCRI factors were more likely to have HRR≤12 [26/36 (72.2%) vs 0 factors: 167/419 (39.9%); OR, 3.92 (1.84-8.34); P<0.001]. NT pro-BNP greater than a standard prognostic threshold (>300 pg ml-1) was more frequent in patients with HRR≤12 [96/529 (18.1%) vs HRR>12 59/745 (7.9%); OR, 2.58 (1.82-3.64); P<0.001]. CONCLUSIONS: Impaired HRR is associated with an increased risk of perioperative cardiac injury. These data suggest a mechanistic role for cardiac vagal dysfunction in promoting perioperative myocardial injury.

Role of leucocyte caspase-1 activity in epidural-related maternal fever: a single-centre, observational, mechanistic cohort study.

BACKGROUND: Epidural-related maternal fever (ERMF) has been reported in ∼26% of labouring women. The underlying mechanisms remain unclear. We hypothesised that ERMF is promoted by bupivacaine disrupting cytokine production/release from mononuclear leucocytes [mononuclear fraction (MNF)]. We examined whether bupivacaine (i) reduces caspase-1 activity and release of the anti-pyrogenic cytokine interleukin (IL)-1 receptor antagonist (IL-1ra), and (ii) is pro-inflammatory through mitochondrial injury/IL-1ß. METHODS: In labouring women, blood samples were obtained before/after epidural analgesia was implemented. Maternal temperature was recorded hourly for the first 4 h of epidural analgesia. Time-matched samples/temperatures were obtained from labouring women without epidural analgesia, pregnant non-labouring, and non-pregnant women. The primary clinical outcome was change in maternal temperature over 4 h after the onset of siting epidural catheter/enrolment. The secondary clinical outcome was development of ERMF (temperature ≥ 38°C). The effect of bupivacaine/saline on apoptosis, caspase-1 activity, intracellular IL-1ra, and plasma IL-1ra/IL-1ß ratio was quantified in MNF from labouring women or THP-1 monocytes (using flow cytometry, respirometry, or enzyme-linked immunosorbent assay). RESULTS: Maternal temperature increased by 0.06°C h-1 [95% confidence interval (CI): 0.03-0.09; P=0.003; n=38] after labour epidural placement. ERMF only occurred in women receiving epidural analgesia (five of 38; 13.2%). Bupivacaine did not alter MNF or THP-1 apoptosis compared with saline control, but reduced caspase-1 activity by 11% (95% CI: 5-17; n=10) in MNF from women in established labour. Bupivacaine increased intracellular MNF IL-1ra by 25% (95% CI: 10-41; P<0.001; n=10) compared with saline-control. Epidural analgesia reduced plasma IL-1ra/IL-1ß ratio (mean reduction: 14; 95% CI: 7-30; n=30) compared with women without epidural analgesia. CONCLUSIONS: Impaired release of anti-pyrogenic IL-1ra might explain ERMF mechanistically. Immunomodulation by bupivacaine during labour could promote ERMF.

Arterial pulse pressure and postoperative morbidity in high-risk surgical patients.

BACKGROUND: Systemic arterial pulse pressure (systolic minus diastolic pressure) ≤53 mm Hg in patients with cardiac failure is correlated with reduced stroke volume and is independently associated with accelerated morbidity and mortality. Given that deconditioned surgical and heart failure patients share similar cardiopulmonary physiology, we examined whether lower pulse pressure is associated with excess morbidity after major surgery. METHODS: This was a prospective observational cohort study of patients deemed by their preoperative assessors to be at higher risk of postoperative morbidity. Preoperative pulse pressure was calculated before cardiopulmonary exercise testing. The primary outcome was any morbidity (PostOperative Morbidity Survey) occurring within 5 days of surgery, stratified by pulse pressure threshold ≤53 mm Hg. The relationship between pulse pressure, postoperative morbidity, and oxygen pulse (a robust surrogate for left ventricular stroke volume) was examined using logistic regression analysis (accounting for age, sex, BMI, cardiometabolic co-morbidity, and operation type). RESULTS: The primary outcome occurred in 578/660 (87.6%) patients, but postoperative morbidity was more common in 243/ 660 patients with preoperative pulse pressure ≤53 mm Hg{odds ratio (OR): 2.24 [95% confidence interval (CI): 1.29-3.38]; P<0.001). Pulse pressure ≤53 mm Hg [OR:1.23 (95% CI: 1.03-1.46); P=0.02] and type of surgery were independently associated with all-cause postoperative morbidity (multivariate analysis). Oxygen pulse <90% of population-predicted normal values was associated with pulse pressure ≤ 53 mm Hg [OR: 1.93 (95% CI: 1.32-2.84); P=0.007]. CONCLUSIONS: In deconditioned surgical patients, lower preoperative systemic arterial pulse pressure is associated with excess morbidity. These data are strikingly similar to meta-analyses identifying low pulse pressure as an independent risk factor for adverse outcomes in cardiac failure. Low preoperative pulse pressure is a readily available measure, indicating that detailed physiological assessment may be warranted. CLINICAL TRIAL REGISTRATION: ISRCT registry, ISRCTN88456378.

Elevated preoperative heart rate is associated with cardiopulmonary and autonomic impairment in high-risk surgical patients.

BACKGROUND: Elevated preoperative heart rate (HR) is associated with perioperative myocardial injury and death. In apparently healthy individuals, high resting HR is associated with development of cardiac failure. Given that patients with overt cardiac failure have poor perioperative outcomes, we hypothesized that subclinical cardiac failure, identified by cardiopulmonary exercise testing, was associated with elevated preoperative HR > 87 beats min -1 (HR > 87). METHODS: This was a secondary analysis of an observational cohort study of surgical patients aged ≥45 yr. The exposure of interest was HR > 87, recorded at rest before preoperative cardiopulmonary exercise testing. The predefined outcome measures were the following established predictors of mortality in patients with overt cardiac failure in the general population: ventilatory equivalent for carbon dioxide ( V˙E/V˙co2 ) ratio ≥34, heart rate recovery ≤6 and peak oxygen uptake ( V˙o2 ) ≤14 ml kg -1  min -1 . We used logistic regression analysis to test for association between HR > 87 and markers of cardiac failure. We also examined the relationship between HR > 87 and preoperative left ventricular stroke volume in a separate cohort of patients. RESULTS: HR > 87 was present in 399/1250 (32%) patients, of whom 438/1250 (35%) had V˙E/V˙co2 ratio ≥34, 200/1250 (16%) had heart rate recovery ≤6, and 396/1250 (32%) had peak V˙o2 ≤14 ml kg -1  min -1 . HR > 87 was independently associated with peak V˙o2 ≤14 ml kg -1  min -1 {odds ratio (OR) 1.69 [1.12-3.55]; P =0.01} and heart rate recovery ≤6 (OR 2.02 [1.30-3.14]; P <0.01). However, HR > 87 was not associated with V˙E/V˙co2 ratio ≥34 (OR 1.31 [0.92-1.87]; P =0.14). In a separate cohort, HR > 87 (33/181; 18.5%) was associated with impaired preoperative stroke volume (OR 3.21 [1.26-8.20]; P =0.01). CONCLUSIONS: Elevated preoperative heart rate is associated with impaired cardiopulmonary performance consistent with clinically unsuspected, subclinical cardiac failure. CLINICAL TRIAL REGISTRATION: ISRCTN88456378.

Association between preoperative pulse pressure and perioperative myocardial injury: an international observational cohort study of patients undergoing non-cardiac surgery.

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 <0.01; >75 mm Hg, RR 1.25 [95% CI: 1.06-1.48], P <0.01). Systolic blood pressure >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.

Acute kidney injury and mortality 1 year after major 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.

Baroreflex impairment and morbidity after major surgery.

BACKGROUND: Baroreflex dysfunction is a common feature of established cardiometabolic diseases that are most frequently associated with the development of critical illness. Laboratory models show that baroreflex dysfunction impairs cardiac contractility and cardiovascular performance, thereby increasing the risk of morbidity after trauma and sepsis. We hypothesized that baroreflex dysfunction contributes to excess postoperative morbidity after major surgery as a consequence of the inability to achieve adequate perioperative tissue oxygen delivery. METHODS: In a randomized controlled trial of goal-directed haemodynamic therapy (GDT) in higher-risk surgical patients, baroreflex function was assessed using the spontaneous baroreflex sensitivity (BRS) method via an arterial line placed before surgery, using a validated sequence method technique (one beat lag). The BRS was calculated during the 6 h postoperative GDT intervention. Analyses of BRS were done by investigators blinded to clinical outcomes. The primary outcome was the association between postoperative baroreflex dysfunction (BRS <6 mm Hg s(-1), a negative prognostic threshold in cardiovascular pathology) and early postoperative morbidity. The relationship between baroreflex dysfunction and postoperative attainment of preoperative indexed oxygen delivery was also assessed. RESULTS: Patients with postoperative baroreflex dysfunction were more likely to sustain infectious {relative risk (RR) 1.75 [95% confidence interval (CI): 1.07-2.85], P=0.02} and cardiovascular morbidity [RR 2.39 (95% CI: 1.22-4.71), P=0.008]. Prolonged hospital stay was more likely in patients with baroreflex dysfunction [unadjusted hazard ratio 1.62 (95% CI: 1.14-2.32), log-rank P=0.004]. Postoperative O2 delivery was 36% (95% CI: 7-65) lower in patients with baroreflex dysfunction in those not randomly assigned to GDT (P=0.02). CONCLUSIONS: Baroreflex dysfunction is associated with excess morbidity, impaired cardiovascular performance, and delayed hospital discharge, suggesting a mechanistic role for autonomic dysfunction in determining perioperative outcome. CLINICAL TRIAL REGISTRATION: ISCRTN76894700.

Preoperative heart rate and myocardial injury after non-cardiac surgery: results of a predefined secondary analysis of the VISION study.

BACKGROUND: Increased baseline heart rate is associated with cardiovascular risk and all-cause mortality in the general population. We hypothesized that elevated preoperative heart rate increases the risk of myocardial injury after non-cardiac surgery (MINS). METHODS: We performed a secondary analysis of a prospective international cohort study of patients aged ≥45 yr undergoing non-cardiac surgery. Preoperative heart rate was defined as the last measurement before induction of anaesthesia. The sample was divided into deciles by heart rate. Multivariable logistic regression models were used to determine relationships between preoperative heart rate and MINS (determined by serum troponin concentration), myocardial infarction (MI), and death within 30 days of surgery. Separate models were used to test the relationship between these outcomes and predefined binary heart rate thresholds. RESULTS: Patients with missing outcomes or heart rate data were excluded from respective analyses. Of 15 087 patients, 1197 (7.9%) sustained MINS, 454 of 16 007 patients (2.8%) sustained MI, and 315 of 16 037 patients (2.0%) died. The highest heart rate decile (>96 beats min(-1)) was independently associated with MINS {odds ratio (OR) 1.48 [1.23-1.77]; P<0.01}, MI (OR 1.71 [1.34-2.18]; P<0.01), and mortality (OR 3.16 [2.45-4.07]; P<0.01). The lowest decile (<60 beats min(-1)) was independently associated with reduced mortality (OR 0.50 [0.29-0.88]; P=0.02), but not MINS or MI. The predefined binary thresholds were also associated with MINS, but more weakly than the highest heart rate decile. CONCLUSIONS: Preoperative heart rate >96 beats min(-1) is associated with MINS, MI, and mortality after non-cardiac surgery. This association persists after accounting for potential confounding factors. CLINICAL TRIAL REGISTRATION: NCT00512109.

Randomized controlled trial of vagal modulation by sham feeding in elective non-gastrointestinal (orthopaedic) surgery.

BACKGROUND: Enhanced recovery, in part, aims to reduce postoperative gastrointestinal dysfunction (PGID). Acquired - or established- vagal dysfunction may contribute to PGID, even for surgery not involving the gastrointestinal tract. However, direct evidence for this is lacking. We hypothesized that chewing gum reduces morbidity (including PGID) by preserving efferent vagal neural activity postoperatively after elective orthopaedic surgery. METHODS: In a two-centre randomized controlled trial (n=106), we explored whether patients randomized to prescribed chewing gum for five days postoperatively sustained less morbidity (primary outcome, defined by the Postoperative Morbidity Survey), PGID and faster time to become morbidity free (secondary outcomes). In a subset of patients (n=38), cardiac parasympathetic activity was measured by serial Holter monitoring and assessed using time and frequency domain analyses. RESULTS: Between September 2011 and April 2014, 106 patients were randomized to chewing gum or control. The primary clinical outcome did not differ between groups, with similar morbidity occurring between patients randomized to control (26/30) and chewing gum (21/28; absolute risk reduction (ARR):13% (95%C I:- 6-32); P=0.26). However, chewing gum reduced PGID (ARR:20% (95% CI: 1-38); P=0.049). Chewing gum reduced time to become morbidity-free (relative risk (RR): 1.62 (95% CI: 1.02-2.58); P=0.04) and was associated with a higher proportion of parasympathetic activity contributing to heart rate variability (11% (95% CI: 1-20); P=0.03). CONCLUSIONS: Chewing gum did not alter overall morbidity, but reduced PGID. These data show for the first time that prescription of sham feeding preserves vagal activity in surgery not directly involving the gastrointestinal tract. CLINICAL TRIAL REGISTRATION: ISRCTN20301599.