Divergent effects of tumor necrosis factor (TNF) in sepsis: a meta-analysis of experimental studies.

INTRODUCTION: Experimental studies in animals have yielded conflicting results on the role of Tumor Necrosis Factor (TNF) in sepsis and endotoxemia, with some reporting adaptive and others inappropriate effects. A meta-analysis of the available literature was performed to determine the factors explaining this discrepancy. METHODS: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The protocol was registered with PROSPERO (CRD42020167384) prior to data collection. PubMed and Embase were the databases queried. Risk of bias was evaluated using the SYRCLE Risk of Bias Tool. All animal studies investigating sepsis-related mortality and modified TNF signaling were considered eligible. The exclusion criteria were: lack of mortality data, 7-day mortality rates below 10% in both wild type and TNF-altered pathway animals, and absence of an English abstract. To determine the role of TNF according to the experimental protocol, three approaches were used: first an approach based on the statistical significance of each experiment, then the pooled mortality was calculated, and finally the weighted risk ratio for mortality was assessed. RESULTS: A total of 175 studies were included in the analysis, comprising a total of 760 experiments and involving 19,899 animals. The main species used were mice (77%) and rats (21%). The most common method of TNF pathway modulation was TNF pathway inactivation that was primarily associated with an inappropriate secretion of TNF. At the opposite, TNF injection was associated with an adaptive role of TNF. Lipopolysaccharide (LPS) injection was the most used stimulus to establish an infectious model (42%) and was strongly associated with an inappropriate role of TNF. Conversely, live bacterial models, especially the cecal ligation and puncture (CLP) model, pneumonia, meningitis, and gastrointestinal infection, were associated with an adaptive role. This was particularly evident for Listeria monocytogenes, Streptococcus pneumoniae. CONCLUSION: The role of TNF during infection varies depending on the experimental model used. Models that mimic clinical conditions, based on virulent bacteria that cause high mortality even at low inocula, demonstrated an adaptive role of TNF. Conversely, models based on LPS or low-pathogenic live bacteria, administered at doses well above physiological thresholds and combined with early antibiotic therapy, were associated with an inappropriate role.

Sensitivity and specificity of strategies to identify patients with hemostasis abnormalities leading to an increased risk of bleeding before scheduled intervention: the Hemorisk study.

BACKGROUND: Preoperative identification of patients with hemostasis abnormalities leading to an increased bleeding risk is based on routine hemostasis tests: prothrombin time (PT), activated partial thromboplastin time (APTT), and platelet count. Because of their low predictive performance, guidelines recommend replacing them with structured bleeding risk questionnaires, but none is validated in this population. OBJECTIVES: To assess the diagnostic accuracy of 3 strategies, performed at the preanesthesia visit before scheduled interventions, and to identify patients with hemostasis abnormalities leading to an increased bleeding risk METHODS: A multicenter study was performed in 7 French academic hospitals, involving patients scheduled for surgical intervention, without antiplatelet/anticoagulant treatment. The 3 strategies consisted of 1-a structured screening questionnaire; 2-PT, APTT, and platelet count ordered in selected patients; and 3-systematic PT, APTT, and platelet count. The reference standard comprised von Willebrand factor activity/antigen, factor (F)VIII, FIX, FXI, platelet function analyzer, and, when required, FII, FV, FX, and FVII and hemostasis consultation. RESULTS: Eighteen (1.2%) of 1484 patients had a hemostasis abnormality leading to an increased bleeding risk according to reference standard. In the overall cohort, sensitivity of the questionnaire-based strategy was 50% (95% CI, 26%-74%; specificity, 87% [95% CI, 85%-88%]); sensitivity was 0% (95% CI, 0%-41%) in men vs 82% (95% CI, 48%-98%) in women. For selective routine tests, sensitivity was 33% (95% CI, 13%-59%) and specificity 97% (95% CI, 96%-98%). Corresponding values for systematic routine tests were 44% (95% CI, 22%-69%) and 93% (95% CI, 91%-94%). CONCLUSION: Sensitivity was low for all 3 strategies investigated. The structured screening questionnaire had clinically acceptable diagnostic accuracy only in women.

Femoro-axillary versus femoro-femoral veno-arterial extracorporeal membrane oxygenation for refractory cardiogenic shock: A monocentric retrospective study.

RATIONALE: For veno-arterial extracorporeal membrane oxygenation (ECMO), the femoral artery is the preferred cannulation site (femoro-femoral: Vf-Af). This results in retrograde aortic flow, which increases the left ventricular afterload and can lead to severe pulmonary edema and thrombosis of the cardiac chambers. Right axillary artery cannulation (femoral-axillary: Vf-Aa) provides partial anterograde aortic flow, which may prevent some complications. This study aimed to compare the 90-day mortality and complication rates between VF-AA and VF-AF. METHODS: Consecutive adult patients with cardiogenic shock who received peripheral VA-ECMO between 2013 and 2019 at our institution were retrospectively included. The exclusion criteria were refractory cardiac arrest, multiple VA-ECMO implantations due to vascular access changes, weaning failure, or ICU readmission. A statistical approach using inverse probability of treatment weighting was used to estimate the effect of the cannulation site on the outcomes. The primary endpoint was the 90-day mortality. The secondary endpoints were vascular access complications, stroke, and other complications related to retrograde blood flow. Outcomes were estimated using logistic regression analysis. RESULTS: VA-ECMO was performed on 534 patients. Patients with refractory cardiac arrest (n = 77 (14%)) and those supported by multiple VA-ECMO (n = 92, (17%)) were excluded. Out of the 333 patients studied (n = 209 Vf-Aa; n = 124 VF-AF), the main indications for VA-ECMO implantation were post-cardiotomy (33%, n = 109), dilated cardiomyopathy (20%, n = 66), post-cardiac transplantation (15%, n = 50), acute myocardial infarction (14%, n = 46) and other etiologies (18%, n = 62). The median SOFA score was 9 [7-11], and the crude 90-day mortality rate was 53% (n = 175). After IPTW, the 90-day mortality was similar in the Vf-Aa and VF-AF groups (54% vs 58%, IPTW-OR = 0.84 [0.54-1.29]). Axillary artery cannulation was associated with significantly fewer local infections (OR = 0.21, 95% CI:0.09-0.51), limb ischemia (OR = 0.37, 95% CI:0.17-0.84), bowel ischemia (OR = 0.16, 95% CI:0.05-0.51) and pulmonary edema (OR = 0.52, 95% CI:0.29-0.92) episodes, but with a higher rate of stroke (OR = 2.87, 95% CI:1.08-7.62) than femoral artery cannulation. CONCLUSION: Compared to VF-AF, axillary cannulation was associated with similar 90-day mortality rates. The high rate of stroke associated with axillary artery cannulation requires further investigation.

Neuromuscular blocking agent drug challenge: a literature review and protocol proposal with biological evaluation.

BACKGROUND: Drug challenge is the gold standard for identifying causative agents of drug allergies. Although clinical guidelines have recently been published, they do not recommend neuromuscular blocking agent (NMBA) drug challenges. NMBA challenges are rendered difficult by the lack of homogeneity of routine allergy work-ups and the necessity of a specialised setting. Several scenarios support NMBA challenges, such as an ambiguous allergy work-up, a high suspicion of a false-positive skin test or identification of a well tolerated alternative NMBA strategy. Furthermore, routine allergy work-ups may not recognise non-IgE mechanisms, such as IgG or MRGPRX2, whereas drug challenges may reveal them. Finally, if the culprit NMBA is not identified, subsequent anaesthesia regimens will be challenging to implement, resulting in increased risk. OBJECTIVES: This literature review discusses the indications, strategies, doses, monitoring methods, limitations, and unresolved issues related to drug challenges for NMBAs. DESIGN: The literature review included randomised controlled trials, observational studies, reviews, case reports, series, and comments on humans. DATA SOURCES: Studies were retrieved from databases (PubMed) and electronic libraries (OVID, EMBASE, Scopus, etc.). ELIGIBILITY CRITERIA: All studies that referred to the NMBA challenge were included without publication date limitations. RESULTS: NMBA challenge may be considered in NMBA anaphylaxis patients with inconclusive or ambivalent IgE diagnostic work-up under controlled conditions (presence of anaesthetists and allergists with continuous monitoring in a secured environment). To illustrate its utility, a case report of a double NMBA challenge in a patient with NMBA cross-reactivity is presented, along with biological explorations to detect subclinical cellular activation, a novel aspect of this procedure. CONCLUSION: Drug challenges could be implemented during the NMBA allergy work-up under strict safety conditions at specialised centres with close collaboration between anaesthetists and allergists. This could decrease uncertainty and contribute to defining a safer strategy for subsequent anaesthetic drug regimens.

Exploring congestion endotypes and their distinct clinical outcomes among ICU patients: A post-hoc analysis.

BACKGROUND: In the intensive care unit (ICU) patients, fluid overload and congestion are associated with worse outcomes. Because of the heterogeneity of ICU patients, we hypothesized that there may exist different endotypes of congestion. The aim of this study was to identify endotypes of congestion and their association with outcomes. METHODS: We conducted an unsupervised hierarchical clustering analysis on 145 patients admitted to ICU to identify endotypes. We measured several parameters related to clinical context, volume status, filling pressure, and venous congestion. These parameters included NT-proBNP, central venous pressure (CVP), the mitral E/e' ratio, the systolic/diastolic ratio of hepatic veins' flow velocity, the mean diameter of the inferior vena cava (IVC) and its variations, stroke volume changes following passive leg raising, the portal vein pulsatility index, and the venous renal impedance index. RESULTS: Three distinct endotypes were identified: (1) "hemodynamic congestion" endotype (n = 75) with moderate alterations of ventricular function, increased CVP and left filling pressure values, and moderate fluid overload; (2) "volume overload congestion" endotype (n = 50); with normal cardiac function and filling pressure despite high positive fluid balance (fluid overload); (3) "systemic congestion" endotype (n = 20) with severe alterations of left and right ventricular functions, increased CVP and left ventricular filling pressure values. These endotypes vary significantly in ICU admission reasons, acute kidney injury rates, mortality, and length of ICU/hospital stay. CONCLUSIONS: Our analysis revealed three unique congestion endotypes in ICU patients, each with distinct pathophysiological features and outcomes. These endotypes are identifiable through key ultrasonographic characteristics at the bedside. CLINICAL TRIAL GOV: NCT04680728.

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

In recent years, there has been increasing focus on the use of cardiac biomarkers in patients undergoing noncardiac surgery. 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. 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. 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. 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.

Rotational Thromboelastometry Coagulation Parameters (ROTEM®) May be Discriminative for Active Inflammatory Bowel Disease: A Prospective Observational Study.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is associated with increased risk of thromboembolic events. The rotational thromboelastometry (ROTEM®) is a validated integrative assessment of coagulation, but it has never been studied in IBD patients. METHODS: We performed a monocentric prospective observational study in a national tertiary center. Adult IBD patients underwent ROTEM® analysis on admission to our IBD Department. Parameters evaluated with ROTEM® tests (INTEM, EXTEM and FIBTEM) were clotting time (CT), the time of clot formation (CFT), clot firmness amplitude after 5 and 10 minutes (A5 and A10) and maximum clot firmness (MCF). ROC curves were performed in order to evaluate the ability of ROTEM® to predict active IBD. RESULTS: Several ROTEM® parameters were significantly associated with active IBD compared to patients in remission, towards a hypercoagulable status for patients with active disease: CT, CFT, A5, A10, MCF. ROC analysis demonstrated that parameters related to clot robustness showed a very good prediction ability of active IBD (AUC >0.8): A5, A10, MCF in INTEM (p<0.001), in EXTEM (p<0.001) and MCF in FIBTEM (p<0.001). ROTEM® parameters showed high correlations with inflammation markers as C-reactive protein (CRP) and faecal calprotectin (FC). CONCLUSIONS: Our study showed that ROTEM® parameters are modified in patients with active IBD, being correlating with inflammation markers and demonstrating a high prediction ability of active IBD. Future research is needed to validate ROTEM® as a method to discriminate patterns of active IBD and to guide anticoagulant therapy in patients with active IBD.

Cardiac surgery-associated acute kidney injury and perioperative plasma viscosity: is there a relationship?

Plasma viscosity (PV) is a key factor in microcirculatory flow resistance and capillary perfusion during hemodilution, we hypothesized a possible relationship between cardiac surgery-associated acute kidney injury (CSA-AKI) and PV. We conducted a prospective, observational, single-center study on 50 adult cardiac surgery patients with cardiopulmonary bypass (age 64 years, male sex 80%, baseline serum creatinine 1.04 mg/dL). We assessed perioperative characteristics, management, short-term outcomes, blood analysis, PV, serum creatinine, and diuresis. CSA-AKI was identified using KDIGO criteria. Data were collected at 10 time points during the first perioperative week. CSA-AKI occurred in 17 patients (34%): 12 (24%) stage 1, 1 (2%) stage 2, and 4 (8%) stage 3. Most patients (88%) developed CSA-AKI within 48 h post-surgery. Patients with CSA-AKI had higher body mass index (BMI), more frequent chronic kidney disease (CKD), and lower hemoglobin and hematocrit levels. The median baseline PV for the entire cohort was 1.50 cP on EDTA and 1.37 cP on citrate. No significant differences in PV levels were found between patients with CSA-AKI and normal kidney function, both at baseline and at the 48-h. Logistic and Cox regression analyses showed no significant relationship between PV and CSA-AKI. However, CSA-AKI was related to increased BMI, lower hemoglobin and hematocrit levels, and pre-existing CKD. The present study found no significant association between PV and CSA-AKI. Nevertheless, more research is needed to validate this finding and to investigate the role of PV in other clinical settings.

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.

The COVID-19 Vaccination Coverage in ICU Patients with Severe COVID-19 Infection in a Country with Low Vaccination Coverage-A National Retrospective Analysis.

BACKGROUND: Romania is one of the European countries with low COVID-19 vaccination coverage. The main goal of this study was to describe the COVID-19 vaccination status in patients admitted to Romanian ICUs with a severe COVID-19 infection. The study describes the patients' characteristics according to their vaccination status and evaluates the association between vaccination status and ICU mortality. METHODS: This retrospective, observational, multicenter study included patients with confirmed vaccination status admitted to Romanian ICUs from January 2021 to March 2022. RESULTS: Two thousand, two hundred and twenty-two patients with confirmed vaccination status were included. Five point one three percent of patients were vaccinated with two vaccine doses and one point seventeen percent of patients were vaccinated with one vaccine dose. The vaccinated patients showed a higher rate of comorbidities but had similar clinical characteristics at ICU admission and lower mortality rates compared to non-vaccinated patients. Vaccinated status and higher Glasgow Coma Scale at ICU admission were independently associated with ICU survival. Ischemic heart disease, chronic kidney disease, higher SOFA score at ICU admission and the need for mechanical ventilation in ICU were independently associated with ICU mortality. CONCLUSION: Lower rates of ICU admission were observed in fully vaccinated patients even in a country with low vaccination coverage. The ICU mortality was lower for fully vaccinated patients compared to non-vaccinated patients. The benefit of vaccination on ICU survival could be more important in patients with associated comorbidities.

Pholcodine exposure increases the risk of perioperative anaphylaxis to neuromuscular blocking agents: the ALPHO case-control study.

BACKGROUND: Neuromuscular blocking agents (NMBAs) are among the leading cause of perioperative anaphylaxis, and most of these reactions are IgE mediated. Allergic sensitisation induced by environmental exposure to other quaternary ammonium-containing compounds, such as pholcodine, has been suggested. The aim of this study was to assess the relationship between pholcodine exposure and NMBA-related anaphylaxis. METHODS: ALPHO was a multicentre case-control study, comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related perioperative anaphylaxis (cases) and control patients with uneventful anaesthesia in France. Each case was matched to two controls by age, sex, type of NMBA, geographic area, and season. Pholcodine exposure was assessed by a self-administered questionnaire and pharmaceutical history retrieved from pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated. RESULTS: Overall, 167 cases were matched with 334 controls. NMBA-related anaphylaxis was significantly associated with pholcodine consumption (odds ratio 4.2; 95% confidence interval 2.3-7.0) and occupational exposure to quaternary ammonium compounds (odds ratio 6.1; 95% confidence interval 2.7-13.6), suggesting that apart from pholcodine, other environmental factors can also lead to sensitisation to NMBAs. Pholcodine and quaternary ammonium sIgEs had a high negative predictive value (99.9%) but a very low positive predictive value (<3%) for identifying NMBA-related reactions. CONCLUSIONS: Patients exposed to pholcodine 12 months before NMBA exposure have a significantly higher risk of an NMBA-related anaphylaxis. The low positive predictive values of pholcodine and quaternary ammonium sIgEs precludes their use to identify a population with a high risk of NMBA-related anaphylaxis. CLINICAL TRIAL REGISTRATION: NCT02250729.

Spectral EEG correlations from the different phases of general anesthesia.

Introduction: Electroencephalography (EEG) signals contain transient oscillation patterns commonly used to classify brain states in responses to action, sleep, coma or anesthesia. Methods: Using a time-frequency analysis of the EEG, we search for possible causal correlations between the successive phases of general anesthesia. We hypothesize that it could be possible to anticipate recovery patterns from the induction or maintenance phases. For that goal, we track the maximum power of the α-band and follow its time course. Results and discussion: We quantify the frequency shift of the α-band during the recovery phase and the associated duration. Using Pearson coefficient and Bayes factor, we report non-significant linear correlation between the α-band frequency and duration shifts during recovery and the presence of the δ or the α rhythms during the maintenance phase. We also found no correlations between the α-band emergence trajectory and the total duration of the flat EEG epochs (iso-electric suppressions) induced by a propofol bolus injected during induction. Finally, we quantify the instability of the α-band using the mathematical total variation that measures possible deviations from a flat line. To conclude, the present correlative analysis shows that EEG dynamics extracted from the initial and maintenance phases of general anesthesia cannot anticipate both the emergence trajectory and the extubation time.

AMPK activation by metformin protects against pulmonary hypertension in rats and relaxes isolated human pulmonary artery.

Pulmonary hypertension (PH) is associated with pulmonary vasoconstriction and endothelial dysfunction leading to impaired nitric oxide (NO) and prostacyclin (PGI2) pathways. Metformin, the first line treatment for type 2 diabetes and AMP-activated protein kinase (AMPK) activator, has been recently highlighted as a potential PH treatment. AMPK activation has been reported to improve endothelial function by enhancing endothelial NO synthase (eNOS) activity and to have relaxant effects in blood vessels. In this study, we examined the effect of metformin treatment on PH as well as on NO and PGI2 pathways in monocrotaline (MCT)-injected rats with established PH. Moreover, we investigated the anti-contractile effects of AMPK activators on endothelium-denuded human pulmonary arteries (HPA) from Non-PH and Group 3 PH patients (due to lung diseases and/or hypoxia). Furthermore, we explored the interaction between treprostinil and the AMPK/eNOS pathway. Our results showed that metformin protected against PH progression in MCT rats where it reduced the mean pulmonary artery pressure, pulmonary vascular remodeling and right ventricular hypertrophy and fibrosis compared to vehicle-treated MCT rats. The protective effects on rat lungs were mediated in part by increasing eNOS activity and protein kinase G-1 expression but not through the PGI2 pathway. In addition, incubation with AMPK activators reduced the phenylephrine-induced contraction of endothelium-denuded HPA from Non-PH and PH patients. Finally, treprostinil also augmented eNOS activity in HPA smooth muscle cells. In conclusion, we found that AMPK activation can enhance the NO pathway, attenuate vasoconstriction by direct effects on smooth muscles, and reverse established MCT-induced PH in rats.

Neuromuscular blocking agent induced hypersensitivity reaction exploration: an update.

Acute hypersensitivity reactions (AHRs) occurring in present-day anaesthesia can have severe, sometimes fatal, consequences and their incidence is increasing. The most frequent allergens responsible for AHR during anaesthesia are neuromuscular blocking agents (NMBAs) (70% of the cases) followed by antibiotics (18%), patent blue dye and methylene blue dye (5%), and latex (5%). Following an AHR, strategies for subsequent anaesthetic procedures (especially the choice of an NMBA) may be difficult to formulate due to inconclusive diagnostic analysis in up to 30% of AHRs. Current diagnosis of AHR relies on the detection of mast cell degranulation products and drug-specific type E immunoglobulins (IgE) in order to document an IgE-mediated anaphylaxis (IgE endotype). Nonetheless, other IgE-independent pathways can be involved in AHR, but their detection is not currently available in standard situations. The different mechanisms (endotypes) involved in peri-operative AHR may contribute to the inconclusive diagnostic work-up and this generates uncertainty concerning the culpable drug and strategy for subsequent anaesthetic procedures. This review provides details on the IgE endotype; an update on non-IgE related endotypes and the novel diagnostic tools that could characterise them. This detailed update is intended to provide explicit clinical reasoning tools to the anaesthesiologist faced with an incomplete AHR diagnostic work-up and to facilitate the decision-making process regarding anaesthetic procedures following an AHR to NMBAs.