Effects of interventions targeting the systemic inflammatory response to cardiac surgery on clinical outcomes in adults.

BACKGROUND: Organ injury is a common and severe complication of cardiac surgery that contributes to the majority of deaths. There are no effective treatment or prevention strategies. It has been suggested that innate immune system activation may have a causal role in organ injury. A wide range of organ protection interventions targeting the innate immune response have been evaluated in randomised controlled trials (RCTs) in adult cardiac surgery patients, with inconsistent results in terms of effectiveness. OBJECTIVES: The aim of the review was to summarise the results of RCTs of organ protection interventions targeting the innate immune response in adult cardiac surgery. The review considered whether the interventions had a treatment effect on inflammation, important clinical outcomes, or both. SEARCH METHODS: CENTRAL, MEDLINE, Embase, conference proceedings and two trial registers were searched on October 2022 together with reference checking to identify additional studies. SELECTION CRITERIA: RCTs comparing organ protection interventions targeting the innate immune response versus placebo or no treatment in adult patients undergoing cardiac surgery where the treatment effect on innate immune activation and on clinical outcomes of interest were reported. DATA COLLECTION AND ANALYSIS: Searches, study selection, quality assessment, and data extractions were performed independently by pairs of authors. The primary inflammation outcomes were peak IL-6 and IL-8 concentrations in blood post-surgery. The primary clinical outcome was in-hospital or 30-day mortality. Treatment effects were expressed as risk ratios (RR) and standardised mean difference (SMD) with 95% confidence intervals (CI). Meta-analyses were performed using random effects models, and heterogeneity was assessed using I2. MAIN RESULTS: A total of 40,255 participants from 328 RCTs were included in the synthesis. The effects of treatments on IL-6 (SMD -0.77, 95% CI -0.97 to -0.58, I2 = 92%) and IL-8 (SMD -0.92, 95% CI -1.20 to -0.65, I2 = 91%) were unclear due to heterogeneity. Heterogeneity for inflammation outcomes persisted across multiple sensitivity and moderator analyses. The pooled treatment effect for in-hospital or 30-day mortality was RR 0.78, 95% CI 0.68 to 0.91, I2 = 0%, suggesting a significant clinical benefit. There was little or no treatment effect on mortality when analyses were restricted to studies at low risk of bias. Post hoc analyses failed to demonstrate consistent treatment effects on inflammation and clinical outcomes. Levels of certainty for pooled treatment effects on the primary outcomes were very low. AUTHORS' CONCLUSIONS: A systematic review of RCTs of organ protection interventions targeting innate immune system activation did not resolve uncertainty as to the effectiveness of these treatments, or the role of innate immunity in organ injury following cardiac surgery.

Clinical effectiveness and safety of spinal anaesthesia compared with general anaesthesia in patients undergoing hip fracture surgery using a consensus-based core outcome set and patient-and public-informed outcomes: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: We conducted a systematic review and meta-analysis of contemporary RCTs to determine the clinical effectiveness of spinal vs general anaesthesia (SA vs GA) in patients undergoing hip fracture surgery using a consensus-based core outcome set, and outcomes defined as important by patient and public involvement (PPI) initiatives. METHODS: RCTs comparing any of the core outcomes (mortality, time from injury to surgery, acute coronary syndrome, hypotension, acute kidney injury, delirium, pneumonia, orthogeriatric input, being out of bed at day 1 postoperatively, and pain) or PPI-defined outcomes (return to preoperative residence, quality of life, and mobility status) between SA and GA were identified from MEDLINE, Embase, Cochrane Library, and Web of Science (2000 to February 2022). Pooled relative risks (RRs) and mean differences (95% confidence intervals [CIs]) were estimated. RESULTS: There was no significant difference in the risk of delirium comparing SA vs GA (RR=1.07; 95% CI, 0.90-1.29). Comparing SA vs GA, the RR for mortality was 0.56 (95% CI, 0.22-1.44) in-hospital, 1.07 (95% CI, 0.52-2.23) at 30 days, and 1.08 (95% CI, 0.55-2.12) at 90 days. Spinal anaesthesia reduced the risk of acute kidney injury compared with GA: RR=0.59 (95% CI, 0.39-0.89). There were no significant differences in the risk of other outcomes. Few studies reported PPI-defined outcomes, with most studies reporting on one to three core outcomes. CONCLUSIONS: Except for acute kidney injury, there were no differences between SA and GA in hip fracture surgery when using a consensus-based core outcome set and patient and public involvement-defined outcomes. Most studies reported limited outcomes from the core outcome set, and few reported outcomes important to patients, which should be considered when designing future RCTs. PROSPERO REGISTRATION: CRD42021275206.

Reporting conflicts of interest in randomised trials of patient blood management interventions in patients requiring major surgery: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to systematically review the effects of declared and undeclared conflicts of interest on randomised controlled trials (RCTs) of patient blood management (PBM) interventions. DESIGN: We performed a secondary analysis of a recently published meta-analysis of RCTs evaluating five common PBM interventions in patients undergoing major surgery. DATA SOURCES: The databases searched by the original systematic reviews were searched using subject headings and Medical Subject Headings terms according to search strategies from the final search time-points until 1 June 2019. ELIGIBILITY CRITERIA: RCTs on PBM irrespective of blinding, language, date of publication and sample size were included. Abstracts and unpublished trials were excluded. Conflicts of interest were defined as sponsorship, funding or authorship by industry, professional PBM advocacy groups or blood services. DATA EXTRACTION AND SYNTHESIS: Three independent reviewers extracted the data and assessed the risk of bias. Pooled treatment effect estimates were reported as risk ratios (RRs) or standardised mean difference with 95% CIs. Heterogeneity was quantified using the I2 statistic. RESULTS: Three hundred and eighty-nine RCTs totalling 53 635 participants were included. Thirty-two trials (8%) were considered free from important sources of bias. There was reporting bias favouring PBM interventions on transfusion across all analyses. In trials with no declared author conflicts of interest, the treatment effect on mortality was RR 1.12 (0.86 to 1.45). In trials where author conflicts of interest were declared, the treatment effect on mortality was RR 0.84 (0.69 to 1.03), with significant reporting bias favouring PBM interventions. Trials with declared conflicts linked to professional PBM advocacy groups (five studies, n=977 patients) reported statistically significant reductions in mortality RR 0.40 (0.17 to 0.92), unlike other groups. CONCLUSIONS: Low certainty of the evidence that guides PBM implementation is confounded by evidence of reporting bias, and the effects of declared and undeclared conflicts of interest, favouring PBM on important trial outcomes.

Perioperative oxygen therapy: a protocol for an overview of systematic reviews and meta-analyses.

BACKGROUND: Oxygen is routinely given to patients during and after surgery. Perioperative oxygen administration has been proposed as a potential strategy to prevent and treat hypoxaemia and reduce complications, such as surgical site infections, pulmonary complications and mortality. However, uncertainty exists as to which strategies in terms of amount, delivery devices and timing are clinically effective. The aim of this overview of systematic reviews and meta-analyses is to answer the research question, 'For which types of surgery, at which stages of care, in which sub-groups of patients and delivered under what conditions are different types of perioperative oxygen therapy clinically effective?'. METHODS: We will search key electronic databases (MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, CENTRAL, Epistemonikos, PROSPERO, the INAHTA International HTA Database and DARE archives) for systematic reviews and randomised controlled trials comparing perioperative oxygen strategies. Each review will be mapped according to type of surgery, surgical pathway timepoints and clinical comparison. The highest quality reviews with the most comprehensive and up-to-date coverage of relevant literature will be chosen as anchoring reviews. Standardised data will be extracted from each chosen review, including definition of oxygen therapy, summaries of interventions and comparators, patient population, surgical characteristics and assessment of overall certainty of evidence. For clinical outcomes and adverse events, the overall pooled findings and results of subgroup and sensitivity analyses (where available) will be extracted. Trial-level data will be extracted for surgical site infections, mortality, and potential trial-level effect modifiers such as risk of bias, outcome definition and type of surgery to facilitate quantitative data analysis. This analysis will adopt a multiple indication review approach with panoramic meta-analysis using review-level data and meta-regression using trial-level data. An evidence map will be produced to summarise our findings and highlight any research gaps. DISCUSSION: There is a need to provide a panoramic overview of systematic reviews and meta-analyses describing peri-operative oxygen practice to both inform clinical practice and identify areas of ongoing uncertainty, where further research may be required. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021272361.

Pharmacological interventions for the prevention of renal injury in surgical patients: a systematic literature review and meta-analysis.

BACKGROUND: The aim of this systematic review was to summarise the results of randomised controlled trials (RCTs) that have evaluated pharmacological interventions for renoprotection in people undergoing surgery. METHODS: Searches were conducted to update a previous review using the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE to August 23, 2019. RCTs evaluating the use of pharmacological interventions for renal protection in the perioperative period were included. The co-primary outcome measures were 30-day mortality and acute kidney injury (AKI). Pooled effect estimates were expressed as risk ratios (RRs) (95% confidence intervals). RESULTS: We included 228 trials enrolling 56 047 patients. Twenty-three trials were considered to be at low risk of bias across all domains. Atrial natriuretic peptides (14 trials; n=2207) reduced 30-day mortality (RR: 0.63 [0.41, 0.97]) and AKI events (RR: 0.43 [0.33, 0.56]) without heterogeneity. These effects were consistent across cardiac surgery and vascular surgery subgroups, and in sensitivity analyses restricted to studies at low risk of bias. Inodilators (13 trials; n=2941) reduced mortality (RR: 0.71 [0.53, 0.94]) and AKI events (RR: 0.65 [0.50, 0.85]) in the primary analysis and in cardiac surgery cohorts. Vasopressors (4 trials; n=1047) reduced AKI (RR: 0.56 [0.36, 0.86]). Nitric oxide donors, alpha-2-agonists, and calcium channel blockers reduced AKI in primary analyses, but not after exclusion of studies at risk of bias. Overall, assessment of the certainty of the effect estimates was low. CONCLUSIONS: There are multiple effective pharmacological renoprotective interventions for people undergoing surgery.