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.

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.

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.

DHA, RvD1, RvD5, and MaR1 reduce human coronary arteries contractions induced by PGE2.

In patients with coronary artery disease (CAD), plasma levels of pro-inflammatory lipid mediators such as PGE2 and TxA2 are increased. They could increase vascular contraction while EPA and DHA could reduce it. Studies have been mostly conducted on animal vessels. Therefore, the aim of the study was to investigate if EPA, DHA, and DHA-derived metabolites: RvD1, RvD5 and MaR1 can modulate contraction of human coronary arteries (HCA) induced by PGE2 or TxA2 stable analogue (U46619). DHA and EPA relaxed HCA pre-contracted with PGE2. 18 h-incubation with DHA but not EPA reduced the PGE2-induced contractions. Pre-incubation with RvD1, RvD5 and MaR1 reduced the PGE2-induced contractions. Indomethacin did not significantly modify the PGE2 responses. L-NOARG (inhibitor of nitric oxide synthase), reduced only the PGE2-induced contractions in RvD1-treated rings. Finally, FPR2/ALX, GPR32 and LGR6 receptors are detected in HCA by immunofluorescence. Our results indicate that DHA and its metabolites could be beneficial for HCA blood flow and could be a therapeutic perspective for patients with CAD.

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.

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.

Peri-operative management of neuromuscular blockade: A guideline from the European Society of Anaesthesiology and Intensive Care.

Recent data indicated a high incidence of inappropriate management of neuromuscular block, with a high rate of residual paralysis and relaxant-associated postoperative complications. These data are alarming in that the available neuromuscular monitoring, as well as myorelaxants and their antagonists basically allow well tolerated management of neuromuscular blockade. In this first European Society of Anaesthesiology and Intensive Care (ESAIC) guideline on peri-operative management of neuromuscular block, we aim to present aggregated and evidence-based recommendations to assist clinicians provide best medical care and ensure patient safety. We identified three main clinical questions: Are myorelaxants necessary to facilitate tracheal intubation in adults? Does the intensity of neuromuscular blockade influence a patient's outcome in abdominal surgery? What are the strategies for the diagnosis and treatment of residual paralysis? On the basis of this, PICO (patient, intervention, comparator, outcome) questions were derived that guided a structured literature search. A stepwise approach was used to reduce the number of trials of the initial research ( n  = 24 000) to the finally relevant clinical studies ( n  = 88). GRADE methodology (Grading of Recommendations, Assessment, Development and Evaluation) was used for formulating the recommendations based on the findings of the included studies in conjunction with their methodological quality. A two-step Delphi process was used to determine the agreement of the panel members with the recommendations: R1 We recommend using a muscle relaxant to facilitate tracheal intubation (1A). R2 We recommend the use of muscle relaxants to reduce pharyngeal and/or laryngeal injury following endotracheal intubation (1C). R3 We recommend the use of a fast-acting muscle relaxant for rapid sequence induction intubation (RSII) such as succinylcholine 1 mg kg -1 or rocuronium 0.9 to 1.2 mg kg -1 (1B). R4 We recommend deepening neuromuscular blockade if surgical conditions need to be improved (1B). R5 There is insufficient evidence to recommend deep neuromuscular blockade in general to reduce postoperative pain or decrease the incidence of peri-operative complications. (2C). R6 We recommend the use of ulnar nerve stimulation and quantitative neuromuscular monitoring at the adductor pollicis muscle to exclude residual paralysis (1B). R7 We recommend using sugammadex to antagonise deep, moderate and shallow neuromuscular blockade induced by aminosteroidal agents (rocuronium, vecuronium) (1A). R8 We recommend advanced spontaneous recovery (i.e. TOF ratio >0.2) before starting neostigmine-based reversal and to continue quantitative monitoring of neuromuscular blockade until a TOF ratio of more than 0.9 has been attained. (1C).

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.

International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E2 Receptors (EP1-4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions.

Prostaglandins are derived from arachidonic acid metabolism through cyclooxygenase activities. Among prostaglandins (PGs), prostacyclin (PGI2) and PGE2 are strongly involved in the regulation of homeostasis and main physiologic functions. In addition, the synthesis of these two prostaglandins is significantly increased during inflammation. PGI2 and PGE2 exert their biologic actions by binding to their respective receptors, namely prostacyclin receptor (IP) and prostaglandin E2 receptor (EP) 1-4, which belong to the family of G-protein-coupled receptors. IP and EP1-4 receptors are widely distributed in the body and thus play various physiologic and pathophysiologic roles. In this review, we discuss the recent advances in studies using pharmacological approaches, genetically modified animals, and genome-wide association studies regarding the roles of IP and EP1-4 receptors in the immune, cardiovascular, nervous, gastrointestinal, respiratory, genitourinary, and musculoskeletal systems. In particular, we highlight similarities and differences between human and rodents in terms of the specific roles of IP and EP1-4 receptors and their downstream signaling pathways, functions, and activities for each biologic system. We also highlight the potential novel therapeutic benefit of targeting IP and EP1-4 receptors in several diseases based on the scientific advances, animal models, and human studies. SIGNIFICANCE STATEMENT: In this review, we present an update of the pathophysiologic role of the prostacyclin receptor, prostaglandin E2 receptor (EP) 1, EP2, EP3, and EP4 receptors when activated by the two main prostaglandins, namely prostacyclin and prostaglandin E2, produced during inflammatory conditions in human and rodents. In addition, this comparison of the published results in each tissue and/or pathology should facilitate the choice of the most appropriate model for the future studies.

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.

Perioperative trajectory of plasma viscosity: A prospective, observational, exploratory study in cardiac surgery.

OBJECTIVE: Plasma viscosity is one of the critical factors that regulate microcirculatory flow but has received scant research attention. The main objective of this study was to evaluate plasma viscosity in cardiac surgery with respect to perioperative trajectory, main determinants, and impact on outcome. METHODS: Prospective, single center, observational study, including 50 adult patients undergoing cardiac surgery with cardiopulmonary bypass between February 1, 2020 and May 31, 2021. Clinical perioperative characteristics, short term outcome, standard blood analysis, plasma viscosity, total proteins, and fibrinogen concentrations were recorded at 10 distinct time points during the first perioperative week. RESULTS: The longitudinal analysis showed that plasma viscosity is strongly influenced by proteins and measurement time points. Plasma viscosity showed a coefficient of variation of 11.3 ± 1.08 for EDTA and 12.1 ± 2.1 for citrate, similarly to total proteins and hemoglobin, but significantly lower than fibrinogen (p < .001). Plasma viscosity had lower percentage changes compared to hemoglobin (RANOVA, p < .001), fibrinogen (RANOVA, p < .001), and total proteins (RANOVA, p < .001). The main determinant of plasma viscosity was protein concentrations. No association with outcome was found, but the study may have been underpowered to detect it. CONCLUSION: Plasma viscosity had a low coefficient of variation and low perioperative changes, suggesting tight regulation. Studies linking plasma viscosity with outcome would require large patient cohorts.

One-Year Outcome After Cardiac Surgery for Patients With Cancer: An Observational Monocentric Retrospective Study.

OBJECTIVES: Cardiac surgery increasingly is being performed in patients with a history of or with active cancer. The aim of this study was to analyze the association between a history of cancer and 1-year mortality after cardiac surgery with cardiopulmonary bypass (CPB). DESIGN: An observational monocentric study, with data collected from a prospective institutional database was conducted. SETTING: A single academic center. PARTICIPANTS: All consecutive patients undergoing cardiac surgery with CPB between 2005 and 2017. INTERVENTION: None. METHODS: A history of cancer was preoperatively identified. Mortality rates were estimated by the Kaplan-Meier method. The 1-year mortality risk of patients with and without cancer was compared using a multivariate Cox model. MEASUREMENTS AND MAIN RESULTS: During the study period, 12,143 patients underwent cardiac surgery with CPB, including 4,681 (39%) isolated coronary artery bypass surgeries. Their median EuroSCORE II was 3.1, interquartile range 1.5-to-6.4. Nine hundred thirty patients (8%) had a diagnosis of cancer, out of whom 469 (50%) were diagnosed ≤5 years before the index surgery; 103 (11%) patients had hemopathy, and 825 (89%) had solid cancers. The estimated unadjusted 1-year mortality was significantly higher among patients with cancer, 11% (95% confidence interval [CI] 10-14) versus 8% (95%CI 7-9) p < 0.01. After adjustment, a diagnosis of cancer was not associated with the risk of 1-year mortality (adjusted hazard ratio = 1.17 [95%CI 0.96-1.43]; p = 0.13). CONCLUSIONS: In a large cohort of patients undergoing cardiac surgery with CPB, cancer was not independently associated with 1-year mortality. An isolated cancer history should not lead to denial of cardiac surgery. The impact of cancer on complications and long-term survival after cardiac surgery requires further research.

The Prognostic Role of Early Postoperative Troponin I in Lung Transplantation-A Retrospective 7-Year Analysis.

OBJECTIVES: Postoperative cardiac troponin I concentration is predictive of worsened outcomes in cardiac surgery. Lung transplantation (LT) surgery shares common features with cardiac surgery, but postoperative troponin has yet to be investigated. The authors aimed to evaluate the association between early postoperative troponin concentration and the 1-year mortality after transplantation. DESIGN: A retrospective, observational, single-center study. SETTING: At a tertiary care, university hospital. PARTICIPANTS: Patients who underwent lung transplantation from January 2011 to December 2017 INTERVENTIONS: For each patient, preoperative, intraoperative, and postoperative data were collected, as well as the troponin I measurement at the moment of postoperative intensive care unit admission. MEASUREMENTS AND MAIN RESULTS: Two hundred twenty LT procedures were analyzed. Troponin I was elevated in all LT patients, with a median of 3.82 ng/mL-1 (2-6.42) ng/mL-1 significantly higher in non-survivors than in survivors with 5.39 (2.88-7.44) v 3.50 ng/mL (1.74-5.76), p = 0.005. In the multivariate analysis, the authors found that only the Simplified Acute Physiology Score II score (hazard ratio [HR] 1.03; 95% confidence interval [CI] [1.001; 1.05]; p = 0.007) and the need to maintain extracorporeal life support at the end of surgery (HR 2.54; 95% CI [1.36; 4.73]; p = 0.003) were independently associated with the 1-year mortality. The multiple linear regression model found that troponin levels were associated with the need for extracorporeal life support (ECLS) (p = 0.014), the amount of transfused packed red blood cells (p = 0.008), and bilateral LT (p < 0.001). CONCLUSION: Early postoperative troponin serum levels were not independently associated with 1-year mortality. Early postoperative troponin I levels were correlated to bilateral LT, the need for ECLS, and intraoperative blood transfusion.

Current trends in anesthetic depth and antinociception monitoring: an international survey.

Current trends in anesthetic depth (i.e., hypnosis) and antinociception monitoring are unclear. We thus aimed to determine contemporary perspectives on monitoring these components of anesthesia during general anesthesia. Participants received and responded anonymously to an internet-based international survey supported by the European Society of Anaesthesiology and Intensive Care. Comparisons, when applicable, were carried out using Chi2 analysis or Fischer's exact test. A total of 564 respondents, predominantly from Europe (80.1%), participated. There was a strong participation from Belgium (11.5%). A majority (70.9%) of anesthetists considered hypnotic monitoring important on most occasions to always. In contrast, a majority (62.6%) never or only occasionally considered antinociception monitoring important. This difference in the perceived importance of anesthetic depth versus antinociception monitoring was significant (p < 0.0001). A majority of respondents (70.1%) believed that guiding hypnosis and antinociception using these monitors would improve patient care on most occasions to always. Nonetheless, a substantial number of participants were unsure if hypnotic (23%) or antinociception (32%) monitoring were recommended and there was a lack of knowledge (58%) of any published algorithms to titrate hypnotic and/or antinociceptive drugs based on the information provided by the monitors. In conclusion, current trends in European academic centers prioritize anesthesia depth over antinociception monitoring. Despite an agreement among respondents that applying strategies that optimize anesthetic depth and antinociception could improve outcome, there remains a lack of knowledge of appropriate algorithms. Future studies and recommendations should focus on clarifying goal-directed anesthetic strategies and determine their impact on perioperative patient outcome.

Clinical reasoning in anaphylactic shock: addressing the challenges faced by anaesthesiologists in real time: A clinical review and management algorithms.

Acute hypersensitivity reactions to drugs occur infrequently during anaesthesia and the peri-operative period. When clinical presentation includes the classical triad, erythema, cardiovascular abnormalities and increased airway pressure, the diagnosis is evident and the challenge is to prescribe a therapeutic regimen according to guidelines and to manage refractory signs in a timely manner. In many situations, however, the initial clinical signs are isolated, such as increased airway pressure or arterial hypotension. Rendering a differential diagnosis with causes and mechanisms other than acute hypersensitivity reactions (AHRs) is difficult, delaying treatment with possible worsening of the clinical signs, and even death, in previously healthy individuals. In these difficult diagnostic situations, clinical reasoning is mandatory, and guidelines do not explicitly explain the elements on which clinical reasoning can be built. In this article, based on clinical evidence whenever available, experimental data and pathophysiology, we propose algorithms that have been evaluated by experts. The goal of these algorithms is to provide explicit elements on which the differential diagnosis of AHRs can be made, accelerating the implementation of adequate therapy.

Timing of ß-Blocker Reintroduction and the Occurrence of Postoperative Atrial Fibrillation after Cardiac Surgery: A Prospective Cohort Study.

BACKGROUND: For cardiac surgery patients under chronic ß-blocker therapy, guidelines recommend their early postoperative reintroduction to decrease the incidence of postoperative atrial fibrillation. The authors hypothesized that the timing of ß-blocker reintroduction affects their effectiveness on the incidence of postoperative atrial fibrillation. METHODS: This multicenter prospective French cohort study included patients on ß-blockers (more than 30 days before surgery) in sinus rhythm without a pacemaker. The primary outcome, time sequence of ß-blocker reintroduction, was analyzed for 192 h after surgery. The secondary outcome, relationship between the occurrence of postoperative atrial fibrillation and timing of ß-blocker reintroduction, was analyzed based on pre- and intraoperative predictors (full and selected sets) according to landmark times (patients in whom atrial fibrillation occurred before a given landmark time were not analyzed). RESULTS: Of 663 patients, ß-blockers were reintroduced for 532 (80%) but for only 261 (39%) patients in the first 48 h after surgery. Median duration before reintroduction was 49.5 h (95% CI, 48 to 51.5 h). Postoperative atrial fibrillation or death (N = 4) occurred in 290 (44%) patients. After performing a landmark analysis to take into account the timing of ß-blocker reintroduction, the adjusted odds ratios (95% CI) for predictor full and selected (increased age, history of paroxysmal atrial fibrillation, and duration of aortic cross clamping) sets for the occurrence of postoperative atrial fibrillation were: adjusted odds ratio (full) = 0.87 (0.58 to 1.32; P = 0.517) and adjusted odds ratio (selected) = 0.84 (0.58 to 1.21; P = 0.338) at 48 h; adjusted odds ratio (full) = 0.64 (0.39 to 1.05; P = 0.076) and adjusted odds ratio (selected) = 0.58 (0.38 to 0.89; P = 0.013) at 72 h; adjusted odds ratio (full) = 0.58 (0.31 to 1.07; P = 0.079) and adjusted odds ratio (selected) = 0.53 (0.31 to 0.91; P = 0.021) at 96 h. CONCLUSIONS: ß-Blockers were reintroduced early (after less than 48 h) in fewer than half of the cardiac surgery patients. Reintroduction decreased postoperative atrial fibrillation occurrence only at later time points and only in the predictor selected set model. These results are an incentive to optimize (timing, doses, or titration) ß-blocker reintroduction after cardiac surgery.

Interaction between PGI2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients.

Pulmonary hypertension (PH) is characterized by an elevation of mean pulmonary artery pressure and it is classified into five groups. Among these groups, PH Group-III is defined as PH due to lung disease or hypoxia. Prostacyclin (PGI2) analogues (iloprost, treprostinil) and endothelin-1 (ET-1) receptor antagonists (ERA) (used alone or in combination) are therapies used for treating PH. The mechanisms underlying the positive/negative effects of combination treatment are not well documented, and in this study, we tested the hypothesis that the combination of a PGI2 analogue (iloprost, treprostinil) and an ERA may be more effective than either drug alone to treat vasculopathies observed in PH Group-III patients. Using Western blotting, ETA and ETB receptor expression were determined in human pulmonary artery (HPA) preparations derived from control and PH Group-III patients, and the physiologic impact of altered expression ratios was assessed by measuring ET-1 induced contraction of ex vivo HPA and human pulmonary veins (HPV) in an isolated organ bath system. In addition, the effects of single agent or combination treatments with a PGI2 analogue and an ERA on ET-1 release and HPA smooth muscle cells (hPASMCs) proliferation were determined by ELISA and MTT techniques, respectively. Our results indicate that the increased ETA/ETB receptor expression ratio in HPA derived from PH Group-III patients is primarily governed by a greatly depressed ETB receptor expression. However, contractions induced by ET-1 are not impacted in HPA and HPV derived from PH Group-III patients as compared to controls. Also, we found that the combination of an ETA receptor antagonist (BQ123) with iloprost provides greater inhibition of hPASMCs proliferation (-48±14% control; -32±06% PH) than either agent alone. Of note, while the ETB receptor antagonist (BQ788) increases ET-1 production from PH Group-III patients' preparations (HPA, parenchyma), even under these more proliferative conditions, iloprost and treprostinil are still effective to inhibit hPASMCs proliferation (-22/-24%). Our findings may provide new insights for the treatment of PH Group-III by combining a PGI2 analogue and a selective ETA receptor antagonist.

Fluid expansion improve ventriculo-arterial coupling in preload-dependent patients: a prospective observational study.

BACKGROUND: The objectives of the present study was to evaluate the effect of fluid challenge (FC) on ventriculo-arterial (V-A) coupling, its determinants: arterial elastance and ventricular elastance, and ability to predict fluid responsiveness. METHODS: Thirty patients admitted to cardio-thoracic ICU in whom the physician decided to perform FC were included. Arterial pressure, cardiac output, arterial elastance, and ventricular elastance, were measured before and after FC with 500 ml of lactated Ringer's solution. Fluid responders were defined as patients with more than a 15% increase in stroke volume. V-A coupling was evaluated by the arterial elastance to ventricular elastance ratio. RESULTS: Twenty-three (77%) of the 30 patients included in the study were fluid responders. Before FC, responders had higher arterial elastance and arterial elastance to ventricular elastance ratio. FC significantly increased mean arterial pressure, stroke volume and cardiac output, and significantly decreased systemic vascular resistance, arterial elastance and consequently the arterial elastance to ventricular elastance ratio. Changes in arterial elastance were correlated with changes in stroke volume, systemic vascular resistance, and arterial compliance. Baseline arterial elastance to ventricular elastance ratio over 1.4 predicted fluid responsiveness (area under the curve [95% confidence interval]: 0.84 [0.66-1]; p < 0.0001). CONCLUSIONS: Fluid responsiveness patients had V-A coupling characterized by increase arterial elastance to ventricular elastance ratio, in relation to an increase arterial elastance. Fc improved the V-A coupling ratio by decreasing arterial elastance without altering ventricular elastance. Arterial elastance changes were related to those of systemic vascular resistance (continue component) and of arterial compliance (pulsatile component).

Levosimendan in the light of the results of the recent randomized controlled trials: an expert opinion paper.

Despite interesting and unique pharmacological properties, levosimendan has not proven a clear superiority to placebo in the patient populations that have been enrolled in the various recent multicenter randomized controlled trials. However, the pharmacodynamic effects of levosimendan are still considered potentially very useful in a number of specific situations.Patients with decompensated heart failure requiring inotropic support and receiving beta-blockers represent the most widely accepted indication. Repeated infusions of levosimendan are increasingly used to facilitate weaning from dobutamine and avoid prolonged hospitalizations in patients with end-stage heart failure, awaiting heart transplantation or left ventricular assist device implantation. New trials are under way to confirm or refute the potential usefulness of levosimendan to facilitate weaning from veno-arterial ECMO, to treat cardiogenic shock due to left or right ventricular failure because the current evidence is mostly retrospective and requires confirmation with better-designed studies. Takotsubo syndrome may represent an ideal target for this non-adrenergic inotrope, but this statement also relies on expert opinion. There is no benefit from levosimendan in patients with septic shock. The two large trials evaluating the prophylactic administration of levosimendan (pharmacological preconditioning) in cardiac surgical patients with poor left ventricular ejection fraction could not show a significant reduction in their composite endpoints reflecting low cardiac output syndrome with respect to placebo. However, the subgroup of those who underwent isolated CABG appeared to have a reduction in mortality. A new study will be required to confirm this exploratory finding.Levosimendan remains a potentially useful inodilator agent in a number of specific situations due to its unique pharmacological properties. More studies are needed to provide a higher level of proof regarding these indications.