The PREVENNT randomised, double-blind, controlled trial of preoperative intravenous iron to treat anaemia before major abdominal surgery: an independent discussion.

Anaemia is a common finding in patients presenting for major elective surgery and is associated with poor outcomes including death and complications. Iron deficiency is the leading cause of perioperative anaemia. Intravenous (i.v.) iron is considered to be an effective and safe treatment for iron deficiency anaemia and is recommended by expert opinion for treatment of preoperative anaemia, although evidence from clinical trials is lacking. The PREVENTT trial was a large multicentre trial investigating the effects of i.v. iron on red cell transfusion, death, complications and quality of life in 487 patients undergoing major abdominal surgery. The principal finding of this multicentre randomised placebo controlled trial was that there was no difference in the co-primary outcomes of blood transfusion or death, or the number of transfusion episodes, within 30 days after surgery, in patients that received preoperative i.v. iron therapy compared to placebo. The major inferential differences in this independent discussion relate to the limitations of the PREVENTT trial and its implications for future practice. Although PREVENTT represents the best evidence available to guide perioperative use of i.v. iron, it is likely that the study was underpowered. In the context of already widespread adoption of preoperative i.v. iron therapy, many clinicians may have felt they lacked equipoise. In light of the PREVENTT study routine use of i.v. iron in patients undergoing elective abdominal surgery cannot be recommended. Further research should define the optimum red cell transfusion strategy for patients undergoing surgery and idenify other surgical groups who may benefit from this intervention

Long-term disease interactions amongst surgical patients: a population cohort study.

BACKGROUND: The average age of the surgical population continues to increase, as does prevalence of long-term diseases. However, outcomes amongst multi-morbid surgical patients are not well described. METHODS: We included adults undergoing non-obstetric surgical procedures in the English National Health Service between January 2010 and December 2015. Patients could be included multiple times in sequential 90-day procedure spells. Multi-morbidity was defined as presence of two or more long-term diseases identified using a modified Charlson comorbidity index. The primary outcome was 90-day postoperative death. Secondary outcomes included emergency hospital readmission within 90 days. We calculated age- and sex-adjusted odds ratios (OR) with 95% confidence intervals (CI) using logistic regression. We compared the outcomes associated with different disease combinations. RESULTS: We identified 20 193 659 procedure spells among 13 062 715 individuals aged 57 (standard deviation 19) yr. Multi-morbidity was present among 2 577 049 (12.8%) spells with 195 965 deaths (7.6%), compared with 17 616 610 (88.2%) spells without multi-morbidity with 163 529 deaths (0.9%). Multi-morbidity was present in 1 902 859/16 946 808 (11.2%) elective spells, with 57 663 deaths (2.7%, OR 4.9 [95% CI: 4.9-4.9]), and 674 190/3 246 851 (20.7%) non-elective spells, with 138 302 deaths (20.5%, OR 3.0 [95% CI: 3.0-3.1]). Emergency readmission followed 547 399 (22.0%) spells with multi-morbidity compared with 1 255 526 (7.2%) without. Multi-morbid patients accounted for 57 663/114 783 (50.2%) deaths after elective spells, and 138 302/244 711 (56.5%) after non-elective spells. The rate of death varied five-fold from lowest to highest risk disease pairs. CONCLUSION: One in eight patients undergoing surgery have multi-morbidity, accounting for more than half of all postoperative deaths. Disease interactions amongst multi-morbid patients is an important determinant of patient outcome

Cystatin C or creatinine for pre-operative assessment of kidney function and risk of post-operative acute kidney injury: a secondary analysis of the METS cohort study.

BACKGROUND: Post-operative acute kidney injury (PO-AKI) is a common surgical complication consistently associated with subsequent morbidity and mortality. Prior kidney dysfunction is a major risk factor for PO-AKI, however it is unclear whether serum creatinine, the conventional kidney function marker, is optimal in this population. Serum cystatin C is a kidney function marker less affected by body composition and might provide better prognostic information in surgical patients. METHODS: This was a pre-defined, secondary analysis of a multi-centre prospective cohort study of pre-operative functional capacity. Participants were aged ≥40 years, undergoing non-cardiac surgery. We assessed the association of pre-operative estimated glomerular filtration rate (eGFR) calculated using both serum creatinine and serum cystatin C with PO-AKI within 3 days after surgery, defined by KDIGO creatinine changes. The adjusted analysis accounted for established AKI risk factors. RESULTS: A total of 1347 participants were included (median age 65 years, interquartile range 56-71), of whom 775 (58%) were male. A total of 82/1347 (6%) patients developed PO-AKI. These patients were older, had higher prevalence of cardiovascular disease and related medication, were more likely to have intra-abdominal procedures, had more intraoperative transfusion, and were more likely to be dead at 1 year after surgery 6/82 (7.3%) vs 33/1265 (2.7%) (P = .038). Pre-operative eGFR was lower in AKI than non-AKI patients using both creatinine and cystatin C. When both measurements were considered in a single age- and sex-adjusted model, eGFR-Cysc was strongly associated with PO-AKI, with increasing risk of AKI as eGFR-Cysc decreased below 90, while eGFR-Cr was no longer significantly associated. CONCLUSIONS: Data from over 1000 prospectively recruited surgical patients confirms pre-operative kidney function as major risk factor for PO-AKI. Of the kidney function markers available, compared with creatinine, cystatin C had greater strength of association with PO-AKI and merits further assessment in pre-operative assessment of surgical risk

Interleukin-1 receptor antagonist, mode of analgesia and risk of Caesarean delivery after onset of labour: a Mendelian randomisation analysis

BACKGROUND: Lower circulating levels of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra) are associated with intrapartum inflammation and epidural analgesia-related maternal fever, both of which increase the rate of obstetric interventions. We hypothesised that genetic variants determining IL-1ra levels would be associated with Caesarean delivery rates after the onset of labour. METHODS: We performed Mendelian randomisation analyses in parous women ≥16 yr old who received either non-neuraxial or neuraxial analgesia for their first two labours (UK Biobank). We used an established genetic score (calculated as 0-4, determined by the presence/absence of rs6743376 and rs1542176 alleles), in which the complete absence of both alleles causes the lowest IL-1ra levels. The primary outcome was Caesarean delivery after the onset of labour (odds ratio [OR]: 95% confidence intervals). RESULTS: There were 7731 women (mean [standard deviation] age at first birth: 25 [5] yr) who had complete genetic scores and delivery data. For women who received non-neuraxial analgesia, Caesarean delivery rates were different across allele scores (χ2=12.4; P=0.015): 104/596 (17.4%) women with zero allele score underwent Caesarean delivery, compared with 654/5015 (13.0%) with allele score ≥1 (OR 1.41; 1.12-1.77). For women who had neuraxial analgesia, Caesarean delivery was not different across allele scores, ranging from 18.1% to 20.8% (χ2=0.29; P=0.99). Caesarean delivery was independent of type of analgesia for 818/7731 (10.6%) women with zero allele scores (OR 0.93; 0.63-1.39), but was higher in women receiving neuraxial analgesia with allele scores ≥1 (OR 1.55; 1.35-1.79; P<0.001). CONCLUSIONS: Mendelian randomisation analysis suggests that higher IL-1ra levels are associated with reduced Caesarean delivery rate. Neuraxial analgesia appears to disrupt this link. CLINICAL TRIAL REGISTRATION: UK Biobank study 62745

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

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Funding for this study comes from more than 50 grants for VISION and its sub-studies: Canadian Institutes of Health Research (six grants); Heart and Stroke Foundation of Ontario (two grants); Academic Health Science Centres Alternative Funding Plan Innovation Fund Grant; Population Health Research Institute Grant; Clarity Research Group Grant; McMaster University, Department of Surgery, Surgical Associates Research Grant; Hamilton Health Science New Investigator Fund Grant; Hamilton Health Sciences Grant; Ontario Ministry of Resource and Innovation Grant; Stryker Canada, McMaster University, Department of Anesthesiology (two grants); Saint Joseph′s Healthcare, Department of Medicine (two grants); Father Sean O′Sullivan Research Centre (two grants); McMaster University, Department of Medicine (two grants); Hamilton Health Sciences Summer Studentships (six grants); McMaster University, Department of Clinical Epidemiology and Biostatistics Grant; McMaster University, Division of Cardiology Grant, and Canadian Network and Centre for Trials International Grant; Winnipeg Health Sciences Foundation Operating Grant; Diagnostic Services of Manitoba Research Grant; University of Manitoba, Faculty of Dentistry Operational Fund; Projeto Hospitais de Excelencia a Serviço do SUS grant from the Brazilian Ministry of Health in Partnership with Hcor (Cardiac Hospital Sao Paulo-SP); School of Nursing, Universidad Industrial de Santander; Grupo de Cardiología Preventiva, Universidad Autónoma de Bucaramanga; Fundación Cardioinfantil Instituto de Cardiología; Alianza Diagnóstica SA; University of Malaya Research Grant; and University of Malaya, Penyelidikan Jangka Pendek Grant. Roche Diagnostics provided the troponin T assays and some financial support for the VISION Study. Medical Research Council and British Journal of Anaesthesia clinical research training fellowship (grant reference MR/M017974/1 to T.E.F.A.); National Institute for Health Research professorship (to R.P.); British Journal of Anaesthesia and Royal College of Anaesthetists basic science fellowship (to G.A.); National Research Foundation of South Africa (to R.N.R.); Heart and Stroke Foundation of Ontario Career Investigator Award (to P.J.D.); Yusuf Chair in Cardiology (P.J.D.).Funding for this study comes from more than 50 grants for VISION and its sub-studies: Canadian Institutes of Health Research (six grants); Heart and Stroke Foundation of Ontario (two grants); Academic Health Science Centres Alternative Funding Plan Innovation Fund Grant; Population Health Research Institute Grant; Clarity Research Group Grant; McMaster University, Department of Surgery, Surgical Associates Research Grant; Hamilton Health Science New Investigator Fund Grant; Hamilton Health Sciences Grant; Ontario Ministry of Resource and Innovation Grant; Stryker Canada, McMaster University, Department of Anesthesiology (two grants); Saint Joseph′s Healthcare, Department of Medicine (two grants); Father Sean O′Sullivan Research Centre (two grants); McMaster University, Department of Medicine (two grants); Hamilton Health Sciences Summer Studentships (six grants); McMaster University, Department of Clinical Epidemiology and Biostatistics Grant; McMaster University, Division of Cardiology Grant, and Canadian Network and Centre for Trials International Grant;Winnipeg Health Sciences Foundation Operating Grant; Diagnostic Services of Manitoba Research Grant; University of Manitoba, Faculty of Dentistry Operational Fund; Projeto Hospitais de Excelencia a Serviço do SUS grant from the Brazilian Ministry of Health in Partnership with Hcor (Cardiac Hospital Sao Paulo-SP); School of Nursing, Universidad Industrial de Santander; Grupo de Cardiología Preventiva, Universidad Autónoma de Bucaramanga; Fundación Cardioinfantil Instituto de Cardiología; Alianza Diagnóstica SA; University of Malaya Research Grant; and University of Malaya, Penyelidikan Jangka Pendek Grant. Roche Diagnostics provided the troponin T assays and some financial support for the VISION Study. Medical Research Council and British Journal of Anaesthesia clinical research training fellowship (grant reference MR/M017974/1 to T.E.F.A.); National Institute for Health Research professorship (to R.P.); British Journal of Anaesthesia and Royal College of Anaesthetists basic science fellowship (to G.A.); National Research Foundation of South Africa (to R.N.R.); Heart and Stroke Foundation of Ontario Career Investigator Award (to P.J.D.); Yusuf Chair in Cardiology (P.J.D.)

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); P300 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.The METS Study was funded by peer-reviewed grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, National Institute of Academic Anaesthesia, UK Clinical Research Network, Australian and New Zealand College of Anaesthetists, and Monash University. TEFA was supported by a Medical Research Council and British Journal of Anaesthesia clinical research training fellowship (grant reference MR/M017974/1); RP is supported by a UK National Institute for Health Research Professorship; GLA is supported by British Journal of Anaesthesia/Royal College of Anaesthetists basic science Career Development award, British Oxygen Company research chair grant in anaesthesia from the Royal College of Anaesthetists and British Heart Foundation Programme Grant (RG/14/4/30736). BHC and DNW are supported in part by Merit Awards from the Department of Anesthesia at the University of Toronto. DNW is supported by a New Investigator Award from the Canadian Institutes of Health Researc

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