Pathophysiological mechanisms underlying increased circulating cardiac troponin in noncardiac surgery: a narrative review.

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.

Personalised perioperative dosing of ivabradine in noncardiac surgery: a single-centre, randomised, placebo-controlled, double-blind feasibility pilot trial.

BACKGROUND: Perioperative myocardial injury after noncardiac surgery is associated with postoperative mortality. Heart rate (HR) is an independent risk factor for perioperative myocardial injury. In this pilot trial we tested the feasibility of a randomised, placebo-controlled trial of personalised HR-targeted perioperative ivabradine. METHODS: This was a single-centre, randomised, placebo-controlled, double-blind, parallel group, feasibility pilot trial conducted at Geneva University Hospitals. We included patients ≥75 yr old or ≥45 yr old with cardiovascular risk factors planned for intermediate- or high-risk surgery. Patients were randomised to receive ivabradine (2.5, 5.0, or 7.5 mg) or placebo according to their HR, twice daily, from the morning of surgery until postoperative day 2. Primary outcomes were appropriate dosage and blinding success rates. RESULTS: Between October 2020 and January 2022, we randomised 78 patients (recruitment rate of 1.3 patients week-1). Some 439 of 444 study drug administrations were adequate (99% appropriate dosage rate). The blinding success rate was 100%. There were 137 (31%) administrations of Pill A (placebo in both groups for HR ≤70 beats min-1). Nine (11.5%) patients had a high-sensitive cardiac troponin T elevation ≥14 ng L-1 between any two measurements. The number of bradycardia episodes was eight in the placebo group and nine in the ivabradine group. CONCLUSIONS: This pilot study demonstrates the feasibility of, and provides guidance for, a future trial testing the efficacy of personalised perioperative ivabradine. Future studies should include patients at higher risk of cardiac complications. CLINICAL TRIAL REGISTRATION: NCT04436016.

ESAIC focused guideline for the use of cardiac biomarkers in perioperative risk evaluation.

BACKGROUND: In recent years, there has been increasing focus on the use of cardiac biomarkers in patients undergoing noncardiac surgery. AIMS: The aim of this focused guideline was to provide updated guidance regarding the pre-, post- and combined pre-and postoperative use of cardiac troponin and B-type natriuretic peptides in adult patients undergoing noncardiac surgery. METHODS: The guidelines were prepared using Grading of Recommendations Assessment Development and Evaluation (GRADE) methodology. This included the definition of critical outcomes, a systematic literature search, appraisal of certainty of evidence, evaluation of biomarker measurement in terms of the balance of desirable and undesirable effects including clinical outcomes, resource use, health inequality, stakeholder acceptance, and implementation. The panel differentiated between three different scopes of applications: cardiac biomarkers as prognostic factors, as tools for risk prediction, and for biomarker-enhanced management strategies. RESULTS: In a modified Delphi process, the task force defined 12 critical outcomes. The systematic literature search resulted in over 25,000 hits, of which 115 full-text articles formed the body of evidence for recommendations. The evidence appraisal indicated heterogeneity in the certainty of evidence across critical outcomes. Further, there was relevant gradient in the certainty of evidence across the three scopes of application. Recommendations were issued and if this was not possible due to limited evidence, clinical practice statements were produced. CONCLUSION: The ESAIC focused guidelines provide guidance on the perioperative use of cardiac troponin and B-type natriuretic peptides in patients undergoing noncardiac surgery, for three different scopes of application.

Noninvasive ventilation in COVID-19 patients aged ≥ 70 years-a prospective multicentre cohort study.

BACKGROUND: Noninvasive ventilation (NIV) is a promising alternative to invasive mechanical ventilation (IMV) with a particular importance amidst the shortage of intensive care unit (ICU) beds during the COVID-19 pandemic. We aimed to evaluate the use of NIV in Europe and factors associated with outcomes of patients treated with NIV. METHODS: This is a substudy of COVIP study-an international prospective observational study enrolling patients aged ≥ 70 years with confirmed COVID-19 treated in ICU. We enrolled patients in 156 ICUs across 15 European countries between March 2020 and April 2021.The primary endpoint was 30-day mortality. RESULTS: Cohort included 3074 patients, most of whom were male (2197/3074, 71.4%) at the mean age of 75.7 years (SD 4.6). NIV frequency was 25.7% and varied from 1.1 to 62.0% between participating countries. Primary NIV failure, defined as need for endotracheal intubation or death within 30 days since ICU admission, occurred in 470/629 (74.7%) of patients. Factors associated with increased NIV failure risk were higher Sequential Organ Failure Assessment (SOFA) score (OR 3.73, 95% CI 2.36-5.90) and Clinical Frailty Scale (CFS) on admission (OR 1.46, 95% CI 1.06-2.00). Patients initially treated with NIV (n = 630) lived for 1.36 fewer days (95% CI - 2.27 to - 0.46 days) compared to primary IMV group (n = 1876). CONCLUSIONS: Frequency of NIV use varies across European countries. Higher severity of illness and more severe frailty were associated with a risk of NIV failure among critically ill older adults with COVID-19. Primary IMV was associated with better outcomes than primary NIV. Clinical Trial Registration NCT04321265 , registered 19 March 2020, https://clinicaltrials.gov .

Efficacy and safety of perioperative vitamin C in patients undergoing noncardiac surgery: a systematic review and meta-analysis of randomised trials.

BACKGROUND: Perioperative oxidative stress plays a role in organ injury and pain and could be improved by the antioxidant effects of vitamin C. METHODS: We performed a systematic review and meta-analysis of RCTs comparing perioperative vitamin C administration vs placebo or no treatment in adults undergoing noncardiac surgery. The primary outcome was hospital length of stay (LOS). RESULTS: Thirty-seven RCTs and 2747 patients were included. Administration of vitamin C was associated with no difference in LOS (mean difference=0.02 day; 95% confidence interval [CI], -0.30 to 0.35; P=0.88). Mortality did not differ between groups (relative risk=1.04; 95% CI, 0.52 to 2.08; P=0.5). No trials reported on other major postoperative complications. Vitamin C was associated with a reduction in postoperative pain score and cumulative morphine consumption up to 48 h after surgery. The incidence of complex regional pain syndrome was lower in orthopaedic patients receiving vitamin C. Adverse events were present in three RCTs (n=157), absent in 10 RCTs (n=957), and not reported in 25 RCTs (n=1570). One trial (n=20) in kidney transplantation surgery was stopped early because of safety concerns on vitamin C. The quality of evidence ranged from moderate to very low. CONCLUSIONS: Administration of vitamin C was not associated with a decrease in LOS after noncardiac surgery. The effects on morbidity and mortality are inconclusive and mostly uninvestigated. A small reduction in postoperative pain was found. Adverse events were rare but not systematically assessed. The evidence is uncertain, not supporting the use of vitamin C outside an experimental setting. STUDY PROTOCOL: PROSPERO database, CRD42021241654.

Patent foramen ovale and perioperative stroke in noncardiac surgery: a systematic review and meta-analysis.

BACKGROUND: Patent foramen ovale (PFO) is associated with perioperative stroke in noncardiac surgery. The magnitude of this association was assessed in a systematic review and meta-analysis. METHODS: Electronic databases were searched up to June 2022 for studies assessing the association between patent foramen ovale and perioperative stroke in adult patients undergoing noncardiac surgery. The primary analysis was limited to studies reporting effect estimates adjusted for significant clinical confounders. We calculated the adjusted odds ratio (aOR) and 95% confidence interval (CI). RESULTS: We included nine retrospective and two prospective observational studies, including 21 257 082 patients. The presence of a patent foramen ovale was independently associated with stroke at 30 days after surgery (aOR=6.68 [95% CI: 3.51-12.73]; P<0.001) and at longest follow-up available (aOR=7.36 [95% CI: 3.56-15.21]; P<0.001). The odds of stroke at 30 days varied according to surgical specialty: neurosurgery (aOR=4.52 [95% CI: 3.17-6.43]), vascular surgery (aOR=7.15 [95% CI: 2.52-20.22]), thoracic surgery (aOR=10.64 [95% CI: 5.97-18.98]), orthopaedic surgery (aOR=11.85 [95% CI: 5.38-26.08]), general surgery (aOR=14.40 [95% CI: 10.88-19.06]), and genitourinary surgery (aOR=17.28 [95% CI: 10.36-28.84]). CONCLUSIONS: The presence of a patent foramen ovale is associated with a large and consistent increase in odds of stroke across all explored surgical settings. Prospective trials should further explore this association by systematically assessing patent foramen ovale and stroke prevalence and identifying a specific population at risk. This is crucial for the elaboration of prevention plans and may improve perioperative outcomes.

Health-related quality of life in older patients surviving ICU treatment for COVID-19: results from an international observational study of patients older than 70 years.

BACKGROUND: health-related quality of life (HRQoL) is an important patient-centred outcome in patients surviving ICU admission for COVID-19. It is currently not clear which domains of the HRQoL are most affected. OBJECTIVE: to quantify HRQoL in order to identify areas of interventions. DESIGN: prospective observation study. SETTING: admissions to European ICUs between March 2020 and February 2021. SUBJECTS: patients aged 70 years or older admitted with COVID-19 disease. METHODS: collected determinants include SOFA-score, Clinical Frailty Scale (CFS), number and timing of ICU procedures and limitation of care, Katz Activities of Daily Living (ADL) dependence score. HRQoL was assessed at 3 months after ICU admission with the Euro-QoL-5D-5L questionnaire. An outcome of ≥4 on any of Euro-QoL-5D-5L domains was considered unfavourable. RESULTS: in total 3,140 patients from 14 European countries were included in this study. Three months after inclusion, 1,224 patients (39.0%) were alive and the EQ-5D-5L from was obtained. The CFS was associated with an increased odds ratio for an unfavourable HRQoL outcome after 3 months; OR 1.15 (95% confidence interval (CI): 0.71-1.87) for CFS 2 to OR 4.33 (95% CI: 1.57-11.9) for CFS ≧ 7. The Katz ADL was not statistically significantly associated with HRQoL after 3 months. CONCLUSIONS: in critically ill old intensive care patients suffering from COVID-19, the CFS is associated with the subjectively perceived quality of life. The CFS on admission can be used to inform patients and relatives on the risk of an unfavourable qualitative outcome if such patients survive.

Differences in mortality in critically ill elderly patients during the second COVID-19 surge in Europe.

BACKGROUND: The primary aim of this study was to assess the outcome of elderly intensive care unit (ICU) patients treated during the spring and autumn COVID-19 surges in Europe. METHODS: This was a prospective European observational study (the COVIP study) in ICU patients aged 70 years and older admitted with COVID-19 disease from March to December 2020 to 159 ICUs in 14 European countries. An electronic database was used to register a number of parameters including: SOFA score, Clinical Frailty Scale, co-morbidities, usual ICU procedures and survival at 90 days. The study was registered at ClinicalTrials.gov (NCT04321265). RESULTS: In total, 2625 patients were included, 1327 from the first and 1298 from the second surge. Median age was 74 and 75 years in surge 1 and 2, respectively. SOFA score was higher in the first surge (median 6 versus 5, p < 0.0001). The PaO2/FiO2 ratio at admission was higher during surge 1, and more patients received invasive mechanical ventilation (78% versus 68%, p < 0.0001). During the first 15 days of treatment, survival was similar during the first and the second surge. Survival was lower in the second surge after day 15 and differed after 30 days (57% vs 50%) as well as after 90 days (51% vs 40%). CONCLUSION: An unexpected, but significant, decrease in 30-day and 90-day survival was observed during the second surge in our cohort of elderly ICU patients. The reason for this is unclear. Our main concern is whether the widespread changes in practice and treatment of COVID-19 between the two surges have contributed to this increased mortality in elderly patients. Further studies are urgently warranted to provide more evidence for current practice in elderly patients. TRIAL REGISTRATION NUMBER: NCT04321265 , registered March 19th, 2020.

The impact of frailty on survival in elderly intensive care patients with COVID-19: the COVIP study.

BACKGROUND: The COVID-19 pandemic has led highly developed healthcare systems to the brink of collapse due to the large numbers of patients being admitted into hospitals. One of the potential prognostic indicators in patients with COVID-19 is frailty. The degree of frailty could be used to assist both the triage into intensive care, and decisions regarding treatment limitations. Our study sought to determine the interaction of frailty and age in elderly COVID-19 ICU patients. METHODS: A prospective multicentre study of COVID-19 patients ≥ 70 years admitted to intensive care in 138 ICUs from 28 countries was conducted. The primary endpoint was 30-day mortality. Frailty was assessed using the clinical frailty scale. Additionally, comorbidities, management strategies and treatment limitations were recorded. RESULTS: The study included 1346 patients (28% female) with a median age of 75 years (IQR 72-78, range 70-96), 16.3% were older than 80 years, and 21% of the patients were frail. The overall survival at 30 days was 59% (95% CI 56-62), with 66% (63-69) in fit, 53% (47-61) in vulnerable and 41% (35-47) in frail patients (p < 0.001). In frail patients, there was no difference in 30-day survival between different age categories. Frailty was linked to an increased use of treatment limitations and less use of mechanical ventilation. In a model controlling for age, disease severity, sex, treatment limitations and comorbidities, frailty was independently associated with lower survival. CONCLUSION: Frailty provides relevant prognostic information in elderly COVID-19 patients in addition to age and comorbidities. Trial registration Clinicaltrials.gov: NCT04321265 , registered 19 March 2020.

Relationship between the Clinical Frailty Scale and short-term mortality in patients ≥ 80 years old acutely admitted to the ICU: a prospective cohort study.

BACKGROUND: The Clinical Frailty Scale (CFS) is frequently used to measure frailty in critically ill adults. There is wide variation in the approach to analysing the relationship between the CFS score and mortality after admission to the ICU. This study aimed to evaluate the influence of modelling approach on the association between the CFS score and short-term mortality and quantify the prognostic value of frailty in this context. METHODS: We analysed data from two multicentre prospective cohort studies which enrolled intensive care unit patients ≥ 80 years old in 26 countries. The primary outcome was mortality within 30-days from admission to the ICU. Logistic regression models for both ICU and 30-day mortality included the CFS score as either a categorical, continuous or dichotomous variable and were adjusted for patient's age, sex, reason for admission to the ICU, and admission Sequential Organ Failure Assessment score. RESULTS: The median age in the sample of 7487 consecutive patients was 84 years (IQR 81-87). The highest fraction of new prognostic information from frailty in the context of 30-day mortality was observed when the CFS score was treated as either a categorical variable using all original levels of frailty or a nonlinear continuous variable and was equal to 9% using these modelling approaches (p < 0.001). The relationship between the CFS score and mortality was nonlinear (p < 0.01). CONCLUSION: Knowledge about a patient's frailty status adds a substantial amount of new prognostic information at the moment of admission to the ICU. Arbitrary simplification of the CFS score into fewer groups than originally intended leads to a loss of information and should be avoided. Trial registration NCT03134807 (VIP1), NCT03370692 (VIP2).

Role of Intermediate Care Unit Admission and Noninvasive Respiratory Support during the COVID-19 Pandemic: A Retrospective Cohort Study.

BACKGROUND: The COVID-19 pandemic has led to shortage of intensive care unit (ICU) capacity. We developed a triage strategy including noninvasive respiratory support and admission to the intermediate care unit (IMCU). ICU admission was restricted to patients requiring invasive ventilation. OBJECTIVES: The aim of this study is to describe the characteristics and outcomes of patients admitted to the IMCU. METHOD: Retrospective cohort including consecutive patients admitted between March 28 and April 27, 2020. The primary outcome was the proportion of patients with severe hypoxemic respiratory failure avoiding ICU admission. Secondary outcomes included the rate of emergency intubation, 28-day mortality, and predictors of ICU admission. RESULTS: One hundred fifty-seven patients with COVID-19-associated pneumonia were admitted to the IMCU. Among the 85 patients admitted for worsening respiratory failure, 52/85 (61%) avoided ICU admission. In multivariate analysis, PaO2/FiO2 (OR 0.98; 95% CI: 0.96-0.99) and BMI (OR 0.88; 95% CI: 0.78-0.98) were significantly associated with ICU admission. No death or emergency intubation occurred in the IMCU. CONCLUSIONS: IMCU admission including standardized triage criteria, self-proning, and noninvasive respiratory support prevents ICU admission for a large proportion of patients with COVID-19 hypoxemic respiratory failure. In the context of the COVID-19 pandemic, IMCUs may play an important role in preserving ICU capacity by avoiding ICU admission for patients with worsening respiratory failure and allowing early discharge of ICU patients.

Expert consensus on peri-operative myocardial injury screening in noncardiac surgery: A literature review.

Peri-operative myocardial injury, detected by dynamic and elevated cardiac troponin (cTn) concentrations, is a common complication of noncardiac surgery that is strongly associated with 30-day mortality. Although active screening for peri-operative myocardial injury has been suggested in recent guidelines, clinical implementation remains tentative due to a lack of examples on how to tackle such an interdisciplinary project at a local level. Moreover, consensus on which assay and cTn cut-off values should be used has not yet been reached, and guidance on whom to screen is lacking. In this article, we aim to summarise local examples of successfully implemented cTn screening practices and review the current literature in order to provide information and suggestions for patient selection, organisation of a screening programme, caveats and a potential management pathway.

Effect of ivabradine on major adverse cardiovascular events and mortality in critically ill patients: a systematic review and meta-analyses of randomised controlled trials with trial sequential analyses.

BACKGROUND: Ivabradine lowers heart rate (HR) without affecting contractility or vascular tone. It is licensed for HR control in chronic heart diseases. We performed a systematic review and meta-analyses to examine whether ivabradine could decrease major adverse cardiovascular events (MACE) and mortality in critically ill patients. METHODS: We searched Medline, Embase, Cochrane Library, and Web of Science for RCTs. Trial quality was assessed using the Cochrane risk of bias tool. Random-effects meta-analyses were performed if at least three trials or 100 patients were available. Results are reported as weighted mean difference (WMD), odds ratio (OR), and 95% confidence intervals (CIs). Trial sequential analyses were performed to estimate the sample size needed to reach definitive conclusions of efficacy or futility. RESULTS: We included 13 RCTs (n=1497 patients). We found no evidence of an impact of ivabradine on MACE (three RCTs, 819 patients; OR=0.77; 95% CI, 0.53-1.11) or mortality (10 RCTs, 1356 patients; OR=1.07; 95% CI, 0.63-1.82), but sample sizes were not reached to allow definitive conclusions. Compared with placebo or standard care, ivabradine reduced HR (eight RCTs, 464 patients; WMD, -9.5 beats min-1; 95% CI, -13.3 to -5.8). Risk of bradycardia was not different between ivabradine and control (five RCTs, 434 patients; OR=1.2; 95% CI, 0.60-2.38). Risk of bias was overall high or unclear. CONCLUSIONS: Ivabradine reduces HR compared with placebo or standard care. The effect on MACE or mortality in acute care remains unclear. Further RCTs powered to detect changes in clinically relevant outcomes are warranted. CLINICAL TRIAL REGISTRATION: Prospero CRD42018086109.

A longitudinal study highlights shared aspects of the transcriptomic response to cardiogenic and septic shock.

BACKGROUND: Septic shock (SS) and cardiogenic shock (CS) are two types of circulatory shock with a different etiology. Several studies have described the molecular alterations in SS patients, whereas the molecular factors involved in CS have been poorly investigated. We aimed to assess in the whole blood of CS and SS patients, using septic patients without shock (SC) as controls, transcriptomic modifications that occur over 1 week after ICU admission and are common to the two types of shock. METHODS: We performed whole blood RNA sequencing in 21 SS, 11 CS, and 5 SC. In shock patients, blood samples were collected within 16 h from ICU admission (T1), 48 h after ICU admission (T2), and at day 7 or before discharge (T3). In controls, blood samples were available at T1 and T2. Gene expression changes over time have been studied in CS, SS, and SC separately with a paired analysis. Genes with p value < 0.01 (Benjamini-Hochberg multiple test correction) were defined differentially expressed (DEGs). We used gene set enrichment analysis (GSEA) to identify the biological processes and transcriptional regulators significantly enriched in both types of shock. RESULTS: In both CS and SS patients, GO terms of inflammatory response and pattern recognition receptors (PRRs) were downregulated following ICU admission, whereas gene sets of DNA replication were upregulated. At the gene level, we observed that alarmins, interleukin receptors, PRRs, inflammasome, and DNA replication genes significantly changed their expression in CS and SS, but not in SC. Analysis of transcription factor targets showed in both CS and SS patients, an enrichment of CCAAT-enhancer-binding protein beta (CEBPB) targets in genes downregulated over time and an enrichment of E2F targets in genes with an increasing expression trend. CONCLUSIONS: This pilot study supports, within the limits of a small sample size, the role of alarmins, PRRs, DNA replication, and immunoglobulins in the pathophysiology of circulatory shock, either in the presence of infection or not. We hypothesize that these genes could be potential targets of therapeutic interventions in CS and SS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02141607. Registered 19 May 2014.

Validation of the clinical frailty score (CFS) in French language.

BACKGROUND: Very old critical ill patients are a rapid expanding group. To better understand the magnitude of the challenges involved in intensive care practice for an ageing population and discuss a rational allocation of resources, healthcare practitioners need a reliable evaluation of frailty. In order to promote the adequate use of the Clinical Frailty Scale (CFS) in a wider panel of countries, we aimed to develop, validate and characterise a French (FR) version from the original English (EN) CFS. METHODS: We included participants recruited prospectively for the observational "The very old intensive care patient: A multinational prospective observation study" (VIP Study) at Geneva University Hospitals (FR speaking hospital). A FR version of the CFS was obtained by translation (EN- > FR) and back translation (FR- > EN). The final CFS-FR was then evaluated twice on the same participants with at least a 2-week interval by FR-speaking doctors and nurses. RESULTS: Inter-rater reliability was 0.87 (95%CI: 0.76-0.93) between doctors for the original CFS version and 0.76 (95%CI: 0.57-0.87) between nurses for the FR version. Inter-rater variability between doctor and nurse was 0.75 (95%CI: 0.56-0.87) for the original version, and 0.73 (95%CI: 0.52-0.85) for the FR version. Test-retest (stability) with the original vs the FR version was 0.86 (95%CI: 0.72-0.93) for doctors and 0.87 (95%CI: 0.76-0.93) for nurses. Differences between the evaluations of the CFS-EN and CSF-FR were not different from 0, with a mean difference of 0.06 (95%CI -0.24, 0.36) for the EN version and - 0.03 (95%CI -0.47, 0.41) for the FR version. Average original version ratings were slightly lower than FR version ratings, though this difference did not reach significance: -0.29 (95%CI -0.54, 0.04). CONCLUSION: In this prospective cohort of very old intensive care participants we developed and tested the basic psychometric properties (internal consistency, reproducibility) of a French version of the CFS. This manuscript provides clinically meaningful psychometric properties that have not been previously reported in any other language, including in the original EN version. The French cultural adaptation of this CFS has adequate psychometric properties for doctors or nurses to evaluate frailty in very old intensive care patients.

Huge variation in obtaining ethical permission for a non-interventional observational study in Europe.

BACKGROUND: Ethical approval (EA) must be obtained before medical research can start. We describe the differences in EA for an pseudonymous, non-interventional, observational European study. METHODS: Sixteen European national coordinators (NCs) of the international study on very old intensive care patients answered an online questionnaire concerning their experience getting EA. RESULTS: N = 8/16 of the NCs could apply at one single national ethical committee (EC), while the others had to apply to various regional ECs and/or individual hospital institutional research boards (IRBs). The time between applying for EA and the first decision varied between 7 days and 300 days. In 9/16 informed consent from the patient was not deemed necessary; in 7/16 informed consent was required from the patient or relatives. The upload of coded data to a central database required additional information in 14/16. In 4/16 the NCs had to ask separate approval to keep a subject identification code list to de-pseudonymize the patients if questions would occur. Only 2/16 of the NCs agreed that informed consent was necessary for this observational study. Overall, 6/16 of the NCs were satisfied with the entire process and 8/16 were (very) unsatisfied. 11/16 would welcome a European central EC that would judge observational studies for all European countries. DISCUSSION: Variations in the process and prolonged time needed to get EA for observational studies hampers inclusion of patients in some European countries. This might have a negative influence on the external validity. Further harmonization of ethical approval process across Europe is welcomed for low-risk observational studies. CONCLUSION: Getting ethical approval for low-risk, non-interventional, observational studies varies enormously across European countries.

The concept of peri-operative medicine to prevent major adverse events and improve outcome in surgical patients: A narrative review.

: Peri-operative Medicine is the patient-centred and value-based multidisciplinary peri-operative care of surgical patients. Peri-operative stress, that is the collective response to stimuli occurring before, during and after surgery, is, together with pre-existing comorbidities, the pathophysiological basis of major adverse events. The ultimate goal of Peri-operative Medicine is to promote high quality recovery after surgery. Clinical scores and/or biomarkers should be used to identify patients at high risk of developing major adverse events throughout the peri-operative period. Allocation of high-risk patients to specific care pathways with peri-operative organ protection, close surveillance and specific early interventions is likely to improve patient-relevant outcomes, such as disability, health-related quality of life and mortality.

Identification of a transcriptome profile associated with improvement of organ function in septic shock patients after early supportive therapy.

BACKGROUND: Septic shock is the most severe complication of sepsis and this syndrome is associated with high mortality. Treatment of septic shock remains largely supportive of hemodynamics and tissue perfusion. Early changes in organ function assessed by the Sequential Organ Function Assessment (SOFA) score are highly predictive of the outcome. However, the individual patient's response to supportive therapy is very heterogeneous, and the mechanisms underlying this variable response remain elusive. The aim of the study was to investigate the transcriptome of whole blood in septic shock patients with different responses to early supportive hemodynamic therapy assessed by changes in SOFA scores within the first 48 h from intensive care unit (ICU) admission. METHODS: We performed whole blood RNA sequencing in 31 patients: 17 classified as responders (R) and 14 as non-responders (NR). Gene expression was investigated at ICU admission (time point 1, or T1), comparing R with NR [padj < 0.01; Benjamini-Hochberg (BH)] and over time from T1 to T2 (48 h later) in R and NR independently (paired analysis, padj < 0.01; BH). Then the differences in gene expression trends over time were evaluated (Mann-Whitney, P <0.01). To identify enriched biological processes, we performed an over-representation analysis based on a right-sided hypergeometric test with Bonferroni step-down as multiple testing correction (padj < 0.05). RESULTS: At ICU admission, we did not identify differentially expressed genes (DEGs) between the two groups. In the transition from T1 to T2, the activation of genes involved in T cell-mediated immunity, granulocyte and natural killer (NK) cell functions, and pathogen lipid clearance was noted in the R group. Genes involved in acute inflammation were downregulated in both groups. CONCLUSIONS: Within the limits of a small sample size, our results could suggest that early activation of genes of the adaptive immune response is associated with an improvement in organ function.

Ammonium tetrathiomolybdate following ischemia/reperfusion injury: Chemistry, pharmacology, and impact of a new class of sulfide donor in preclinical injury models.

BACKGROUND: Early revascularization of ischemic organs is key to improving outcomes, yet consequent reperfusion injury may be harmful. Reperfusion injury is largely attributed to excess mitochondrial production of reactive oxygen species (ROS). Sulfide inhibits mitochondria and reduces ROS production. Ammonium tetrathiomolybdate (ATTM), a copper chelator, releases sulfide in a controlled and novel manner, and may offer potential therapeutic utility. METHODS AND FINDINGS: In vitro, ATTM releases sulfide in a time-, pH-, temperature-, and thiol-dependent manner. Controlled sulfide release from ATTM reduces metabolism (measured as oxygen consumption) both in vivo in awake rats and ex vivo in skeletal muscle tissue, with a superior safety profile compared to standard sulfide generators. Given intravenously at reperfusion/resuscitation to rats, ATTM significantly reduced infarct size following either myocardial or cerebral ischemia, and conferred survival benefit following severe hemorrhage. Mechanistic studies (in vitro anoxia/reoxygenation) demonstrated a mitochondrial site of action (decreased MitoSOX fluorescence), where the majority of damaging ROS is produced. CONCLUSIONS: The inorganic thiometallate ATTM represents a new class of sulfide-releasing drugs. Our findings provide impetus for further investigation of this compound as a novel adjunct therapy for reperfusion injury.