Clues to revising the conventional diagnostic algorithm for endometriosis.

Endometriosis is a complex gynecologic disorder characterized primarily by symptoms of pelvic pain, infertility, and altered quality of life. National and international guidelines highlight the diagnostic difficulties and lack of conclusive diagnostic tools for endometriosis. Furthermore, guidelines are becoming questionable at an increasingly rapid rate as new diagnostic techniques emerge. This work aims to provide a knowledge synthesis of the relevance of various diagnostic tools and to assess areas of improvement of conventional algorithms. MEDLINE and Cochrane Library databases were searched from January 2021 to December 2023 using relevant key words. Articles evaluating the diagnostic relevance and performance of various tools were included and independently reviewed by the authors for eligibility. Included studies were assessed using the GRADE and QUADAS-2 tools. Of the 4204 retrieved articles, 26 were included. While anamnesis and clinical examination do contribute to diagnostic accuracy, their level of evidence and impact on the diagnostic process remains limited. Although imaging techniques are recommended to investigate endometriosis, ultrasonography remains highly operator dependent. Magnetic resonance imaging appears to exhibit higher sensitivities than ultrasound. However, concerns persist with regards to the terminology, anatomical definition of lesions, and accuracies of both ultrasound and magnetic resonance imaging. Recently, several biological markers have been studied and cumulative evidence supports the contribution of noncoding RNAs to the diagnosis of endometriosis. Marginal improvements have been suggested for anamnesis, clinical examination, and imaging examinations. Conversely, some biomarkers, including the saliva microRNA signature for endometriosis, have emerged as diagnostic tools which inspire reflection on the revision of conventional diagnostic algorithms.

Epidemiology of civilian's gunshot wound injuries admitted to intensive care unit: A retrospective, multi-center study.

BACKGROUND: Few studies investigated the outcome of patients admitted to intensive care unit (ICU) for gunshot wounds (GSW). The purpose of this study was to determine the 28-day mortality, and to analyze the impact of variables on the mortality of patients admitted to ICU with GSW in four French University Hospitals level-1 regional trauma centers. METHOD: All medical files of adult patients (above fifteen years old) admitted to four French University Hospitals level-1 regional trauma centers for GSW were retrospectively analyzed from January 1st 2015 to June 30th 2021. The primary aim was to determine 28-day death rate of patients admitted in ICU for GSW. The secondary aim was to describe biological parameters, injuries and management of patients admitted to our ICUs, and to identify the variables associated with the 28-day mortality rate. A multivariate analysis allowed determining independent mortality factors. A Kaplan-Meier analysis compared mortality according to head injury. RESULTS: Among 17,262 patients screened, 173 (1 %) were admitted for GSW and 162 were analyzed. The 28-day mortality rate was 24.7 %. 77.5 % of deaths occurred within the first 48 h after ICU admission, and 87.5 % of deaths within three days of ICU admission. The 28-day death rate of patients with head injury was significantly higher as compared to patients without head injury (p < 0.001). Out of forty deaths, twenty-three (57.5 %) were due to head injury, and nine (22.5 %) were due to bleeding. The mechanisms were assault (45.1 %), suicide (34.6 %), accident (4.9 %) and unidentified (15.4 %). In a multivariate analysis, variables associated with the 28-day death rate were age, pre-hospital Glasgow coma score, and Injury Severity Score. CONCLUSION: GSW represented 1 % of ICU admission. The 28-day mortality rate was 24.7 %. 77.5 % of deaths occurred within the first 48 h due to head injuries and bleeding. Head injuries were associated with significantly higher mortality rate.

Understanding antimicrobial pharmacokinetics in critically ill patients to optimize antimicrobial therapy: A narrative review.

Effective treatment of sepsis not only demands prompt administration of appropriate antimicrobials but also requires precise dosing to enhance the likelihood of patient survival. Adequate dosing refers to the administration of doses that yield therapeutic drug concentrations at the infection site. This ensures a favorable clinical and microbiological response while avoiding antibiotic-related toxicity. Therapeutic drug monitoring (TDM) is the recommended approach for attaining these goals. However, TDM is not universally available in all intensive care units (ICUs) and for all antimicrobial agents. In the absence of TDM, healthcare practitioners need to rely on several factors to make informed dosing decisions. These include the patient's clinical condition, causative pathogen, impact of organ dysfunction (requiring extracorporeal therapies), and physicochemical properties of the antimicrobials. In this context, the pharmacokinetics of antimicrobials vary considerably between different critically ill patients and within the same patient over the course of ICU stay. This variability underscores the need for individualized dosing. This review aimed to describe the main pathophysiological changes observed in critically ill patients and their impact on antimicrobial drug dosing decisions. It also aimed to provide essential practical recommendations that may aid clinicians in optimizing antimicrobial therapy among critically ill patients.

Prolonged vs Intermittent Infusions of ß-Lactam Antibiotics in Adults With Sepsis or Septic Shock: A Systematic Review and Meta-Analysis.

Importance: There is uncertainty about whether prolonged infusions of ß-lactam antibiotics improve clinically important outcomes in critically ill adults with sepsis or septic shock. Objective: To determine whether prolonged ß-lactam antibiotic infusions are associated with a reduced risk of death in critically ill adults with sepsis or septic shock compared with intermittent infusions. Data Sources: The primary search was conducted with MEDLINE (via PubMed), CINAHL, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from inception to May 2, 2024. Study Selection: Randomized clinical trials comparing prolonged (continuous or extended) and intermittent infusions of ß-lactam antibiotics in critically ill adults with sepsis or septic shock. Data Extraction and Synthesis: Data extraction and risk of bias were assessed independently by 2 reviewers. Certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. A bayesian framework was used as the primary analysis approach and a frequentist framework as the secondary approach. Main Outcomes and Measures: The primary outcome was all-cause 90-day mortality. Secondary outcomes included intensive care unit (ICU) mortality and clinical cure. Results: From 18 eligible randomized clinical trials that included 9108 critically ill adults with sepsis or septic shock (median age, 54 years; IQR, 48-57; 5961 men [65%]), 17 trials (9014 participants) contributed data to the primary outcome. The pooled estimated risk ratio for all-cause 90-day mortality for prolonged infusions of ß-lactam antibiotics compared with intermittent infusions was 0.86 (95% credible interval, 0.72-0.98; I2 = 21.5%; high certainty), with a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality. Prolonged infusion of ß-lactam antibiotics was associated with a reduced risk of intensive care unit mortality (risk ratio, 0.84; 95% credible interval, 0.70-0.97; high certainty) and an increase in clinical cure (risk ratio, 1.16; 95% credible interval, 1.07-1.31; moderate certainty). Conclusions and Relevance: Among adults in the intensive care unit who had sepsis or septic shock, the use of prolonged ß-lactam antibiotic infusions was associated with a reduced risk of 90-day mortality compared with intermittent infusions. The current evidence presents a high degree of certainty for clinicians to consider prolonged infusions as a standard of care in the management of sepsis and septic shock. Trial Registration: PROSPERO Identifier: CRD42023399434.

Continuous vs Intermittent ß-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis: The BLING III Randomized Clinical Trial.

Importance: Whether ß-lactam antibiotics administered by continuous compared with intermittent infusion reduces the risk of death in patients with sepsis is uncertain. Objective: To evaluate whether continuous vs intermittent infusion of a ß-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all-cause mortality at 90 days in critically ill patients with sepsis. Design, Setting, and Participants: An international, open-label, randomized clinical trial conducted in 104 intensive care units (ICUs) in Australia, Belgium, France, Malaysia, New Zealand, Sweden, and the United Kingdom. Recruitment occurred from March 26, 2018, to January 11, 2023, with follow-up completed on April 12, 2023. Participants were critically ill adults (≥18 years) treated with piperacillin-tazobactam or meropenem for sepsis. Intervention: Eligible patients were randomized to receive an equivalent 24-hour dose of a ß-lactam antibiotic by either continuous (n = 3498) or intermittent (n = 3533) infusion for a clinician-determined duration of treatment or until ICU discharge, whichever occurred first. Main Outcomes and Measures: The primary outcome was all-cause mortality within 90 days after randomization. Secondary outcomes were clinical cure up to 14 days after randomization; new acquisition, colonization, or infection with a multiresistant organism or Clostridioides difficile infection up to 14 days after randomization; ICU mortality; and in-hospital mortality. Results: Among 7202 randomized participants, 7031 (mean [SD] age, 59 [16] years; 2423 women [35%]) met consent requirements for inclusion in the primary analysis (97.6%). Within 90 days, 864 of 3474 patients (24.9%) assigned to receive continuous infusion had died compared with 939 of 3507 (26.8%) assigned intermittent infusion (absolute difference, -1.9% [95% CI, -4.9% to 1.1%]; odds ratio, 0.91 [95% CI, 0.81 to 1.01]; P = .08). Clinical cure was higher in the continuous vs intermittent infusion group (1930/3467 [55.7%] and 1744/3491 [50.0%], respectively; absolute difference, 5.7% [95% CI, 2.4% to 9.1%]). Other secondary outcomes were not statistically different. Conclusions and Relevance: The observed difference in 90-day mortality between continuous vs intermittent infusions of ß-lactam antibiotics did not meet statistical significance in the primary analysis. However, the confidence interval around the effect estimate includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03213990.

Liberal or Restrictive Transfusion Strategy in Patients with Traumatic Brain Injury.

BACKGROUND: The effect of a liberal transfusion strategy as compared with a restrictive strategy on outcomes in critically ill patients with traumatic brain injury is unclear. METHODS: We randomly assigned adults with moderate or severe traumatic brain injury and anemia to receive transfusion of red cells according to a liberal strategy (transfusions initiated at a hemoglobin level of ≤10 g per deciliter) or a restrictive strategy (transfusions initiated at ≤7 g per deciliter). The primary outcome was an unfavorable outcome as assessed by the score on the Glasgow Outcome Scale-Extended at 6 months, which we categorized with the use of a sliding dichotomy that was based on the prognosis of each patient at baseline. Secondary outcomes included mortality, functional independence, quality of life, and depression at 6 months. RESULTS: A total of 742 patients underwent randomization, with 371 assigned to each group. The analysis of the primary outcome included 722 patients. The median hemoglobin level in the intensive care unit was 10.8 g per deciliter in the group assigned to the liberal strategy and 8.8 g per deciliter in the group assigned to the restrictive strategy. An unfavorable outcome occurred in 249 of 364 patients (68.4%) in the liberal-strategy group and in 263 of 358 (73.5%) in the restrictive-strategy group (adjusted absolute difference, restrictive strategy vs. liberal strategy, 5.4 percentage points; 95% confidence interval, -2.9 to 13.7). Among survivors, a liberal strategy was associated with higher scores on some but not all the scales assessing functional independence and quality of life. No association was observed between the transfusion strategy and mortality or depression. Venous thromboembolic events occurred in 8.4% of the patients in each group, and acute respiratory distress syndrome occurred in 3.3% and 0.8% of patients in the liberal-strategy and restrictive-strategy groups, respectively. CONCLUSIONS: In critically ill patients with traumatic brain injury and anemia, a liberal transfusion strategy did not reduce the risk of an unfavorable neurologic outcome at 6 months. (Funded by the Canadian Institutes of Health Research and others; HEMOTION ClinicalTrials.gov number, NCT03260478.).

Low Percentage of Perforin-Expressing NK Cells during Severe SARS-CoV-2 Infection: Consumption Rather than Primary Deficiency.

Genetic defects in the ability to deliver effective perforin have been reported in patients with hemophagocytic lymphohistiocytosis. We tested the hypothesis that a primary perforin deficiency might also be causal in severe SARS-CoV-2 infection. We recruited 54 volunteers confirmed as being SARS-CoV-2-infected by RT-PCR and admitted to intensive care units or non-intensive care units and age- and sex-matched healthy controls. Compared with healthy controls, the percentage of perforin-expressing CD3-CD56+ NK cells quantified by flow cytometry was low in COVID-19 patients (69.9 ± 17.7 versus 78.6 ± 14.6%, p = 0.026). There was no correlation between the proportions of perforin-positive NK cells and T8 lymphocytes. Moreover, the frequency of NK cells producing perforin was neither linked to disease severity nor predictive of death. Although IL-6 is known to downregulate perforin production in NK cells, we did not find any link between perforin expression and IL-6 plasma level. However, we unveiled a negative correlation between the degranulation marker CD107a and perforin expression in NK cells (r = -0.488, p = 10-4). PRF1 gene expression and the frequency of NK cells harboring perforin were normal in patients 1 y after acute SARS-CoV-2 infection. A primary perforin defect does not seem to be a driver of COVID-19 because NK perforin expression is 1) linked neither to T8 perforin expression nor to disease severity, 2) inversely correlated with NK degranulation, and 3) normalized at distance from acute infection. Thus, the cause of low frequency of perforin-positive NK cells appears, rather, to be consumption.

Occurrences of post-traumatic stress disorder, anxiety, depression, and burnout syndrome in ICU staff workers after two-year of the COVID-19 pandemic: the international PSY-CO in ICU study.

PURPOSE: The present study aimed at assessing the prevalences of post-traumatic stress disorder (PTSD) (main objective), anxiety, depression, and burnout syndrome (BOS) and their associated factors in intensive care unit (ICU) staff workers in the second year of the COVID-19 pandemic. MATERIALS AND METHODS: An international cross-sectional multicenter ICU-based online survey was carried out among the ICU staff workers in 20 ICUs across 3 continents. ICUs staff workers (both caregivers and non-caregivers) were invited to complete PCL-5, HADS, and MBI questionnaires for assessing PTSD, anxiety, depression, and the different components of BOS, respectively. A personal questionnaire was used to isolate independent associated factors with these disorders. RESULTS: PCL-5, HADS, and MBI questionnaires were completed by 585, 570, and 539 responders, respectively (525 completed all questionnaires). PTSD was diagnosed in 98/585 responders (16.8%). Changing familial environment, being a non-caregiver staff worker, having not being involved in a COVID-19 patient admission, having not been provided with COVID-19-related information were associated with PTSD. Anxiety was reported in 130/570 responders (22.8%). Working in a public hospital, being a woman, being financially impacted, being a non-clinical healthcare staff member, having no theoretical or practical training on individual preventive measures, and fear of managing COVID-19 patients were associated with anxiety. Depression was reported in 50/570 responders (8.8%). Comorbidity at risk of severe COVID-19, working in a public hospital, looking after a child, being a non-caregiver staff member, having no information, and a request for moving from the unit were associated with depression. Having received no information and no adequate training for COVID-19 patient management were associated with all 3 dimensions of BOS. CONCLUSION: The present study confirmed that ICU staff workers, whether they treated COVID-19 patients or not, have a substantial prevalence of psychological disorders.

Pharmacokinetic and pharmacodynamic considerations for antifungal therapy optimisation in the treatment of intra-abdominal candidiasis.

Intra-abdominal candidiasis (IAC) is one of the most common of invasive candidiasis observed in critically ill patients. It is associated with high mortality, with up to 50% of deaths attributable to delays in source control and/or the introduction of antifungal therapy. Currently, there is no comprehensive guidance on optimising antifungal dosing in the treatment of IAC among the critically ill. However, this form of abdominal sepsis presents specific pharmacokinetic (PK) alterations and pharmacodynamic (PD) challenges that risk suboptimal antifungal exposure at the site of infection in critically ill patients. This review aims to describe the peculiarities of IAC from both PK and PD perspectives, advocating an individualized approach to antifungal dosing. Additionally, all current PK/PD studies relating to IAC are reviewed in terms of strength and limitations, so that core elements for the basis of future research can be provided.

Antimicrobial Multidrug Resistance: Clinical Implications for Infection Management in Critically Ill Patients.

The increasing incidence of antimicrobial resistance (AMR) worldwide represents a serious threat in the management of sepsis. Due to resistance to the most common antimicrobials prescribed, multidrug-resistant (MDR) pathogens have been associated with delays in adequate antimicrobial therapy leading to significant increases in mortality, along with prolonged hospital length of stay (LOS) and increases in healthcare costs. In response to MDR infections and the delay of microbiological results, broad-spectrum antibiotics are frequently used in empirical antimicrobial therapy. This can contribute to the overuse and misuse of antibiotics, further promoting the development of resistance. Multiple measures have been suggested to combat AMR. This review will focus on describing the epidemiology and trends concerning MDR pathogens. Additionally, it will explore the crucial aspects of identifying patients susceptible to MDR infections and optimizing antimicrobial drug dosing, which are both pivotal considerations in the fight against AMR. Expert commentary: The increasing AMR in ICUs worldwide makes the empirical antibiotic therapy challenging in septic patients. An AMR surveillance program together with improvements in MDR identification based on patient risk stratification and molecular rapid diagnostic tools may further help tailoring antimicrobial therapies and avoid unnecessary broad-spectrum antibiotics. Continuous infusions of antibiotics, therapeutic drug monitoring (TDM)-based dosing regimens and combination therapy may contribute to optimizing antimicrobial therapy and limiting the emergence of resistance.

A protocol for an international, multicentre pharmacokinetic study for Screening Antifungal Exposure in Intensive Care Units: The SAFE-ICU study.

Objective: To describe whether contemporary dosing of antifungal drugs achieves therapeutic exposures in critically ill patients that are associated with optimal outcomes. Adequate antifungal therapy is a key determinant of survival of critically ill patients with fungal infections. Critical illness can alter an antifungal agents' pharmacokinetics, increasing the risk of inappropriate antifungal exposure that may lead to treatment failure and/or toxicity. Design setting and participants: This international, multicentre, observational pharmacokinetic study will comprise adult critically ill patients prescribed antifungal agents including fluconazole, voriconazole, posaconazole, isavuconazole, caspofungin, micafungin, anidulafungin, and amphotericin B for the treatment or prophylaxis of invasive fungal disease. A minimum of 12 patients are targeted for enrolment for each antifungal agent, across 12 countries and 30 intensive care units to perform descriptive pharmacokinetics. Pharmacokinetic sampling will occur during two dosing intervals (occasions): firstly, between days 1 and 3, and secondly, between days 4 and 7 of the antifungal course, collecting three samples per occasion. Patients' demographic and clinical data will be collected. Main outcome measures: The primary endpoint of the study is attainment of pharmacokinetic/pharmacodynamic target exposures that are associated with optimal efficacy. Thirty-day mortality will also be measured. Results and conclusions: This study will describe whether contemporary antifungal drug dosing achieves drug exposures associated with optimal outcomes. Data will also be used for the development of antifungal dosing algorithms for critically ill patients. Optimised drug dosing should be considered a priority for improving clinical outcomes for critically ill patients with fungal infections.

Corrigendum to "Statistical analysis plan for the BLING III study: a phase 3 multicentre randomised controlled trial of continuous versus intermittent ß-lactam antibiotic infusion in critically ill patients with sepsis" [Crit Care Resusc 23(3) (2021) 273-284].

[This corrects the article DOI: 10.51893/2021.3.oa4.].

Peri-operative pharmacokinetics of cefazolin prophylaxis during valve replacement surgery.

OBJECTIVE: There is little prospective data to guide effective dosing for antibiotic prophylaxis during surgery requiring cardiopulmonary bypass (CPB). We aim to describe the effects of CPB on the population pharmacokinetics (PK) of total and unbound concentrations of cefazolin and to recommend optimised dosing regimens. METHODS: Patients undergoing CPB for elective cardiac valve replacement were included using convenience sampling. Intravenous cefazolin (2g) was administered pre-incision and re-dosed at 4 hours. Serial blood and urine samples were collected and analysed using validated chromatography. Population PK modelling and Monte-Carlo simulations were performed using Pmetrics® to determine the fractional target attainment (FTA) of achieving unbound concentrations exceeding pre-defined exposures against organisms known to cause surgical site infections for 100% of surgery (100% fT>MIC). RESULTS: From the 16 included patients, 195 total and 64 unbound concentrations of cefazolin were obtained. A three-compartment linear population PK model best described the data. We observed that cefazolin 2g 4-hourly was insufficient to achieve the FTA of 100% fT>MIC for Staphylococcus aureus and Escherichia coli at serum creatinine concentrations ≤ 50 µmol/L and for Staphylococcus epidermidis at any of our simulated doses and serum creatinine concentrations. A dose of cefazolin 3g 4-hourly demonstrated >93% FTA for S. aureus and E. coli. CONCLUSIONS: We found that cefazolin 2g 4-hourly was not able to maintain concentrations above the MIC for relevant pathogens in patients with low serum creatinine concentrations undergoing cardiac surgery with CPB. The simulations showed that optimised dosing is more likely with an increased dose and/or dosing frequency.

Repetitive mRNA vaccination is required to improve the quality of broad-spectrum anti-SARS-CoV-2 antibodies in the absence of CXCL13.

Since the initial spread of severe acute respiratory syndrome coronavirus 2 infection, several viral variants have emerged and represent a major challenge for immune control, particularly in the context of vaccination. We evaluated the quantity, quality, and persistence of immunoglobulin G (IgG) and IgA in individuals who received two or three doses of messenger RNA (mRNA) vaccines, compared with previously infected vaccinated individuals. We show that three doses of mRNA vaccine were required to match the humoral responses of preinfected vaccinees. Given the importance of antibody-dependent cell-mediated immunity against viral infections, we also measured the capacity of IgG to recognize spike variants expressed on the cell surface and found that cross-reactivity was also strongly improved by repeated vaccination. Last, we report low levels of CXCL13, a surrogate marker of germinal center activation and formation, in vaccinees both after two and three doses compared with preinfected individuals, providing a potential explanation for the short duration and low quality of Ig induced.

Practical considerations for individualizing drug dosing in critically ill adults receiving renal replacement therapy.

Critically ill patients with sepsis admitted to the intensive care unit (ICU) often present with or develop renal dysfunction requiring renal replacement therapy (RRT) in addition to antimicrobial therapy. While early and appropriate antimicrobials for sepsis have been associated with an increased probability of survival, adequate dosing is also required in these patients. Adequate dosing of antimicrobials refers to dosing strategies that achieve serum drug levels at the site of infection that are able to provide a microbiological and/or clinical response while avoiding toxicity from excessive antibiotic exposure. Therapeutic drug monitoring (TDM) is the recommended strategy to achieve this goal, however, TDM is not routinely available in all ICUs and for all antimicrobials. In the absence of TDM, clinicians are therefore required to make dosing decisions based on the clinical condition of the patient, the causative organism, the characteristics of RRT, and an understanding of the physicochemical properties of the antimicrobial. Pharmacokinetics (PK) of antimicrobials can be highly variable between critically ill patients and also within the same patient over the course of their ICU stay. The initiation of RRT, which can be in the form of intermittent hemodialysis, continuous, or prolonged intermittent therapy, further complicates the predictability of drug disposition. This variability highlights the need for individualized dosing. This review highlights the practical considerations for the clinician for antimicrobial dosing in critically ill patients receiving RRT.

How to improve the efficiency and the safety of real-time ultrasound-guided central venous catheterization in 2023: a narrative review.

Central venous catheterization (CVC) is a frequent procedure, practiced by intensivists, anesthesiologists and advanced practice nurses in intensive care units and operative rooms. To reduce CVC-associated morbidity, it is essential to strive for best practices, based on the latest evidence. This narrative review aims to synthesize current knowledge on evidence-based best practices for CVC that improve the use and feasibility of real-time ultrasound-guided insertion procedures. Optimization of the vein puncture technique and the development of new technologies are discussed to reinforce the use of the subclavian vein catheterization as first choice. The search for alternative site of insertions, without increasing infectious and thrombotic risks, deserves further research.