When to Stop Antibiotics in the Critically Ill?

Over the past century, antibiotic usage has skyrocketed in the treatment of critically ill patients. There have been increasing calls to establish guidelines for appropriate treatment and durations of antibiosis. Antibiotic treatment, even when appropriately tailored to the patient and infection, is not without cost. Short term risks-hepatic/renal dysfunction, intermediate effects-concomitant superinfections, and long-term risks-potentiating antimicrobial resistance (AMR), are all possible consequences of antimicrobial administration. These risks are increased by longer periods of treatment and unnecessarily broad treatment courses. Recently, the literature has focused on multiple strategies to determine the appropriate duration of antimicrobial therapy. Further, there is a clinical shift to multi-modal approaches to determine the most suitable timepoint at which to end an antibiotic course. An approach utilising biomarker assays and an inter-disciplinary team of pharmacists, nurses, physicians, and microbiologists appears to be the way forward to develop sound clinical decision-making surrounding antibiotic treatment.

Challenges for a broad international implementation of the current severe community-acquired pneumonia guidelines.

Severe community-acquired pneumonia (sCAP) remains one of the leading causes of admission to the intensive care unit, thus consuming a large share of resources and is associated with high mortality rates worldwide. The evidence generated by clinical studies in the last decade was translated into recommendations according to the first published guidelines focusing on severe community-acquired pneumonia. Despite the advances proposed by the present guidelines, several challenges preclude the prompt implementation of these diagnostic and therapeutic measures. The present article discusses the challenges for the broad implementation of the sCAP guidelines and proposes solutions when applicable.

Choosing immunomodulating therapies for the treatment of COVID-19: recommendations based on placebo-controlled trial evidence.

BACKGROUND: Immunomodulatory therapy has been extensively studied in randomized clinical trials for the treatment of patients hospitalized for COVID-19 with inconsistent findings. Guideline committees, reviewing the same clinical trial data, have generated different recommendations for immunomodulatory therapy. OBJECTIVES: We hypothesize that trial design differences, specifically whether the study utilized an open-label or placebo-controlled design, accounted for the inconsistent mortality effects reported in clinical trials of immunomodulator therapies for COVID-19. SOURCES: We reviewed COVID-19 treatment guidelines (World Health Organization [WHO], Infectious Diseases Society of America [IDSA] and The National Institutes of Health [NIH]) and identified the meta-analyses associated with glucocorticoids, IL-6 inhibitors, JAK kinase inhibitors, and complement C5a inhibitors that were available to the guideline authors at the time recommendations were either made or updated. CONTENT: We identified a meta-analysis for each of the immunomodulator classes that are included in current COVID-19 treatment guidelines: glucocorticoids [WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: A meta-analysis. JAMA. 2021;326:499-518] (cited 419), IL-6 antagonists [WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: A meta-analysis. JAMA. 2021;326:499-518] (cited 419), JAK inhibitors [Kramer A, Prinz C, Fichtner F, Fischer AL, Thieme V, Grundeis F, et al. Janus kinase inhibitors for the treatment of COVID-19. Cochrane Database Syst Rev. 2022;6:CD015209] (cited 34), and complement C5a inhibitors [Tsai CL, Lai CC, Chen CY, Lee HS. The efficacy and safety of complement C5a inhibitors for patients with severe COVID-19: A systematic review and meta-analysis. Expert Rev Anti Infect Ther. 2023;21:77-86] (cited 1). Using the same randomized clinical trials, we evaluated the four meta-analyses accounting for trial design: placebo-controlled or open-label. Glucocorticoids (Risk Ratio [RR] 0.91 [95% CI, 0.49-1.69]), IL-6 inhibitors sarilumab (RR 1.17 [95% CI, 0.96-01.43]), and tocilizumab (RR 0.95 [95% CI, 0.76-1.19]) did not reduce mortality in placebo-controlled trials, whereas baricitinib did confer a large survival benefit (RR 0.65 [95% CI, 0.52-0.81]). The complement C5a inhibitor, vilobelimab, also reduced mortality in a single placebo-controlled trial (RR 0.76 [95% CI, 0.57-1.0]). IMPLICATIONS: Placebo-controlled trial evidence indicates that baricitinib should be the first choice immunomodulator for patients hospitalized for COVID-19 who require any form of oxygen support-low- or high-flow oxygen, non-invasive or invasive ventilation. Vilobelimab warrants study in a large placebo-controlled trial. Treatment guidelines for future pandemics should prioritize the results of placebo-controlled trials.

Biomarkers: Are They Useful in Severe Community-Acquired Pneumonia?

Community acquired pneumonia (CAP) is a prevalent infectious disease often requiring hospitalization, although its diagnosis remains challenging as there is no gold standard test. In severe CAP, clinical and radiologic criteria have poor sensitivity and specificity, and microbiologic documentation is usually delayed and obtained in less than half of sCAP patients. Biomarkers could be an alternative for diagnosis, treatment monitoring and establish resolution. Beyond the existing evidence about biomarkers as an adjunct diagnostic tool, most evidence comes from studies including CAP patients in primary care or emergency departments, and not only sCAP patients. Ideally, biomarkers used in combination with signs, symptoms, and radiological findings can improve clinical judgment to confirm or rule out CAP diagnosis, and may be valuable adjunctive tools for risk stratification, differentiate viral pneumonia and monitoring the course of CAP. While no single biomarker has emerged as an ideal one, CRP and PCT have gathered the most evidence. Overall, biomarkers offer valuable information and can enhance clinical decision-making in the management of CAP, but further research and validation are needed to establish their optimal use and clinical utility.

Platelet transfusions in adult thrombocytopenic ICU patients: Protocol for a sub-study of the PLOT-ICU cohort.

INTRODUCTION: Platelet transfusions are frequently used in intensive care unit (ICU) patients, but contemporary epidemiological data are sparse. We aim to present contemporary international data on the use of platelet transfusions in adult ICU patients with thrombocytopenia. METHODS: This is a protocol and statistical analysis plan for a post hoc sub-study of 504 thrombocytopenic patients from the 'Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU)'. The primary outcome will be the number of patients receiving platelet transfusion in the ICU reported according to the type of product received (apheresis-derived versus pooled whole-blood-derived transfusions). Secondary platelet transfusion outcomes will include platelet transfusion volumes; timing of platelet transfusion; approach to platelet transfusion dosing (fixed dosing versus weight-based dosing) and platelet count increments for prophylactic transfusions. Secondary clinical outcomes will include the number of patients receiving red blood cell- and plasma transfusions during ICU stay; the number of patients who bled in the ICU, the number of patients who had a new thrombosis in the ICU, and the number of patients who died. The duration of follow-up was 90 days. Baseline characteristics and secondary clinical outcomes will be stratified according to platelet transfusion status in the ICU and severity of thrombocytopenia. Data will be presented descriptively. CONCLUSIONS: The outlined study will provide detailed epidemiological data on the use of platelet transfusions in adult ICU patients with thrombocytopenia using data from the large international PLOT-ICU cohort study. The findings will inform the design of future randomised trials evaluating platelet transfusions in ICU patients.

Delirium severity and outcomes of critically ill COVID-19 patients / Gravidade do delirium e desfechos de pacientes críticos com COVID-19

ABSTRACT Objective: To investigate the impact of delirium severity in critically ill COVID-19 patients and its association with outcomes. Methods: This prospective cohort study was performed in two tertiary intensive care units in Rio de Janeiro, Brazil. COVID-19 patients were evaluated daily during the first 7 days of intensive care unit stay using the Richmond Agitation Sedation Scale, Confusion Assessment Method for Intensive Care Unit (CAM-ICU) and Confusion Method Assessment for Intensive Care Unit-7 (CAM-ICU-7). Delirium severity was correlated with outcomes and one-year mortality. Results: Among the 277 COVID-19 patients included, delirium occurred in 101 (36.5%) during the first 7 days of intensive care unit stay, and it was associated with a higher length of intensive care unit stay in days (IQR 13 [7 - 25] versus 6 [4 - 12]; p < 0.001), higher hospital mortality (25.74% versus 5.11%; p < 0.001) and additional higher one-year mortality (5.3% versus 0.6%, p < 0.001). Delirium was classified by CAM-ICU-7 in terms of severity, and higher scores were associated with higher in-hospital mortality (17.86% versus 34.38% versus 38.46%, 95%CI, p value < 0.001). Severe delirium was associated with a higher risk of progression to coma (OR 7.1; 95%CI 1.9 - 31.0; p = 0.005) and to mechanical ventilation (OR 11.09; 95%CI 2.8 - 58.5; p = 0.002) in the multivariate analysis, adjusted by severity and frailty. Conclusion: In patients admitted with COVID-19 in the intensive care unit, delirium was an independent risk factor for the worst prognosis, including mortality. The delirium severity assessed by the CAM-ICU-7 during the first week in the intensive care unit was associated with poor outcomes, including progression to coma and to mechanical ventilation.

RESUMO Objetivo: Investigar como a gravidade do delirium afeta pacientes graves com COVID-19 e sua associação com os desfechos. Métodos: Estudo de coorte prospectivo realizado em duas unidades de terapia intensiva terciárias no Rio de Janeiro (RJ). Os pacientes com COVID-19 foram avaliados diariamente durante os primeiros 7 dias de internação na unidade de terapia intensiva usando a escala de agitação e sedação de Richmond, a Confusion Assessment Method for Intensive Care Unit (CAM-ICU) e a Confusion Assessment Method for Intensive Care Unit-7 (CAM-ICU-7). A gravidade do delirium foi correlacionada com os desfechos e a mortalidade em 1 ano. Resultados: Entre os 277 pacientes com COVID-19 incluídos, o delirium ocorreu em 101 (36,5%) durante os primeiros 7 dias de internação na unidade de terapia intensiva e foi associado a maior tempo de internação na unidade de terapia intensiva em dias (IQ: 13 [7 - 25] versus 6 [4 - 12]; p < 0,001), maior mortalidade hospitalar (25,74% versus 5,11%; p < 0,001) e maior mortalidade em 1 ano (5,3% versus 0,6%, p < 0,001). O delirium foi classificado pela CAM-ICU-7 em termos de gravidade, e escores maiores foram associados à maior mortalidade hospitalar (17,86% versus 34,38% versus 38,46%, IC95%, valor de p < 0,001). O delirium grave foi associado a um risco maior de progressão ao coma (RC de 7,1; IC95% 1,9 - 31,0; p = 0,005) e à ventilação mecânica (RC de 11,09; IC95% 2,8 - 58,5; p = 0,002) na análise multivariada, ajustada por gravidade e fragilidade Conclusão: Em pacientes internados com COVID-19 na unidade de terapia intensiva, o delirium foi fator de risco independente para o pior prognóstico, incluindo mortalidade. A gravidade do delirium avaliada pela CAM-ICU-7 durante a primeira semana na unidade de terapia intensiva foi associada a desfechos desfavoráveis, incluindo a progressão ao coma e à ventilação mecânica.

Detection of infections by computerized capture of peaks in longitudinally measured C-reactive protein levels.

We developed four algorithms for the automatic capture of C-reactive protein (CRP) peaks in 296 adult patients with acute myeloid leukemia who had bloodstream infection (BSI) episodes, negative blood cultures (BCs) or possible infections where no BCs were performed. The algorithms detected CRP peaks for 418-446 of the 586 documented BSI episodes (71.3-76.1%) and 2714-3118 of the 4382 negative BCs (61.9-71.2%). The four algorithms captured 382-789 CRP peaks in which there were neither BSI episodes nor negative BCs. We conclude that automatic capture of CRP peaks is a tool for the monitoring of BSI episodes and possibly other infections in patients with acute myeloid leukemia.

Evaluation of the Kinetics of Pancreatic Stone Protein as a Predictor of Ventilator-Associated Pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a severe condition. Early and adequate antibiotic treatment is the most important strategy for improving prognosis. Pancreatic Stone Protein (PSP) has been described as a biomarker that increases values 3-4 days before the clinical diagnosis of nosocomial sepsis in different clinical settings. We hypothesized that serial measures of PSP and its kinetics allow for an early diagnosis of VAP. METHODS: The BioVAP study was a prospective observational study designed to evaluate the role of biomarker dynamics in the diagnosis of VAP. To determine the association between repeatedly measured PSP and the risk of VAP, we used joint models for longitudinal and time-to-event data. RESULTS: Of 209 patients, 43 (20.6%) patients developed VAP, with a median time of 4 days. Multivariate joint models with PSP, CRP, and PCT did not show an association between biomarkers and VAP for the daily absolute value, with a hazard ratio (HR) for PSP of 1.01 (95% credible interval: 0.97 to 1.05), for CRP of 1.00 (0.83 to 1.22), and for PCT of 0.95 (0.82 to 1.08). The daily change of biomarkers provided similar results, with an HR for PSP of 1.15 (0.94 to 1.41), for CRP of 0.76 (0.35 to 1.58), and for PCT of 0.77 (0.40 to 1.45). CONCLUSION: Neither absolute PSP values nor PSP kinetics alone nor in combination with other biomarkers were useful in improving the prediction diagnosis accuracy in patients with VAP. CLINICAL TRIAL REGISTRATION: Registered retrospectively on August 3rd, 2012. NCT02078999.

Kinetics of C-Reactive Protein and Procalcitonin in the Early Identification of ICU-Acquired Infections in Critically Ill COVID-19 Patients.

The SARS-CoV-2 infection is a cause of hypoxemic acute respiratory failure, leading to frequent intensive care unit (ICU) admission. Due to invasive organ support and immunosuppressive therapies, these patients are prone to nosocomial infections. Our aim was to assess the value of daily measurements of C-reactive protein (CRP) and Procalcitonin (PCT) in the early identification of ICU-acquired infections in COVID-19 patients. METHODS: We undertook a prospective observational cohort study (12 months). All adult mechanically ventilated patients admitted for ≥72 h to ICU with COVID-19 pneumonia were divided into an infected group (n = 35) and a non-infected group (n = 83). Day 0 was considered as the day of the diagnosis of infection (infected group) and Day 10 was that of ICU stay (non-infected group). The kinetics of CRP and PCT were assessed from Day -10 to Day 10 and evaluated using a general linear model, univariate, repeated-measures analysis. RESULTS: 118 patients (mean age 63 years, 74% males) were eligible for the analysis. The groups did not differ in patient age, gender, CRP and PCT serum levels at ICU admission. However, the infected group encompassed patients with a higher severity (SOFA score at ICU admission, p = 0.009) and a higher 28-day mortality (p < 0.001). Before D0, CRP kinetics showed a significant increase in infected patients, whereas in noninfected it remained almost unchanged (p < 0.001), while PCT kinetics did not appear to retain diagnostic value to predict superinfection in COVID-19 patients (p = 0.593). CONCLUSION: COVID-19 patients who developed ICU-acquired infections exhibited different biomarker kinetics before the diagnosis of those infections. Daily CRP monitoring and the recognition of the CRP kinetics could be useful in the prediction of ICU-acquired infections.

Subsyndromal Delirium in Critically Ill Patients-Cognitive and Functional Long-Term Outcomes.

Subsyndromal delirium (SSD) in the Intensive Care Unit (ICU) is associated with an increased morbidity with unknown post-discharge functional and cognitive outcomes. We performed a prospective multicenter study to analyze the mental status of patients during their first 72 h after ICU admission and its trajectory, with follow-ups at 3 and 6 months after hospital discharge. Amongst the 106 included patients, SSD occurred in 24.5% (n = 26) and was associated with the duration of mechanical ventilation (p = 0.003) and the length of the ICU stay (p = 0.002). After the initial 72 h, most of the SSD patients (30.8%) improved and no longer had SSD; 19.2% continued to experience SSD and one patient (3.8%) progressed to delirium. The post-hospital discharge survival rate for the SSD patients was 100% at 3 months and 87.5% at 6 months. At admission, 96.2% of the SSD patients were fully independent in daily living activities, 66.7% at 3-month follow-up, and 100% at 6-month follow-up. Most SSD patients demonstrated a cognitive decline from admission to 3-month follow-up and improved at 6 months (IQCODE-SF: admission 3.13, p < 0.001; 3 months 3.41, p = 0.019; 6 months 3.19, p = 0.194). We concluded that early SSD is associated with worse outcomes, mainly a transitory cognitive decline after hospital discharge at 3 months, with an improvement at 6 months. This highlights the need to prevent and identify this condition during ICU stays.

Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU).

PURPOSE: Thrombocytopenia (platelet count < 150 × 109/L) is common in intensive care unit (ICU) patients and is likely associated with worse outcomes. In this study we present international contemporary data on thrombocytopenia in ICU patients. METHODS: We conducted a prospective cohort study in adult ICU patients in 52 ICUs across 10 countries. We assessed frequencies of thrombocytopenia, use of platelet transfusions and clinical outcomes including mortality. We evaluated pre-selected potential risk factors for the development of thrombocytopenia during ICU stay and associations between thrombocytopenia at ICU admission and 90-day mortality using pre-specified logistic regression analyses. RESULTS: We analysed 1166 ICU patients; the median age was 63 years and 39.5% were female. Overall, 43.2% (95% confidence interval (CI) 40.4-46.1) had thrombocytopenia; 23.4% (20-26) had thrombocytopenia at ICU admission, and 19.8% (17.6-22.2) developed thrombocytopenia during their ICU stay. Absence of acquired immune deficiency syndrome (AIDS), non-cancer-related immune deficiency, liver failure, male sex, septic shock, and bleeding at ICU admission were associated with the development of thrombocytopenia during ICU stay. Among patients with thrombocytopenia, 22.6% received platelet transfusion(s), and 64.3% of in-ICU transfusions were prophylactic. Patients with thrombocytopenia had higher occurrences of bleeding and death, fewer days alive without the use of life-support, and fewer days alive and out of hospital. Thrombocytopenia at ICU admission was associated with 90-day mortality (adjusted odds ratio 1.7; 95% CI 1.19-2.42). CONCLUSION: Thrombocytopenia occurred in 43% of critically ill patients and was associated with worse outcomes including increased mortality. Platelet transfusions were given to 23% of patients with thrombocytopenia and most were prophylactic.

European Network for ICU-Related Respiratory Infections (ENIRRIs): a multinational, prospective, cohort study of nosocomial LRTI.

PURPOSE: Lower respiratory tract infections (LRTI) are the most frequent infectious complication in patients admitted to the intensive care unit (ICU). We aim to report the clinical characteristics of ICU-admitted patients due to nosocomial LRTI and to describe their microbiology and clinical outcomes. METHODS: A prospective observational study was conducted in 13 countries over two continents from 9th May 2016 until 16th August 2019. Characteristics and outcomes of ventilator-associated pneumonia (VAP), ventilator-associated tracheobronchitis (VAT), ICU hospital-acquired pneumonia (ICU-HAP), HAP that required invasive ventilation (VHAP), and HAP in patients transferred to the ICU without invasive mechanical ventilation were collected. The clinical diagnosis and treatments were per clinical practice and not per protocol. Descriptive statistics were used to compare the study groups. RESULTS: 1060 patients with LRTI (72.5% male sex, median age 64 [50-74] years) were included in the study; 160 (15.1%) developed VAT, 556 (52.5%) VAP, 98 (9.2%) ICU-HAP, 152 (14.3%) HAP, and 94 (8.9%) VHAP. Patients with VHAP had higher serum procalcitonin (PCT) and Sequential Organ Failure Assessment (SOFA) scores. Patients with VAP or VHAP developed acute kidney injury, acute respiratory distress syndrome, multiple organ failure, or septic shock more often. One thousand eight patients had microbiological samples, and 711 (70.5%) had etiological microbiology identified. The most common microorganisms were Pseudomonas aeruginosa (18.4%) and Klebsiella spp (14.4%). In 382 patients (36%), the causative pathogen shows some antimicrobial resistance pattern. ICU, hospital and 28-day mortality were 30.8%, 37.5% and 27.5%, respectively. Patients with VHAP had the highest ICU, in-hospital and 28-day mortality rates. CONCLUSION: VHAP patients presented the highest mortality among those admitted to the ICU. Multidrug-resistant pathogens frequently cause nosocomial LRTI in this multinational cohort study.

Endothelial dysfunction triggers acute respiratory distress syndrome in patients with sepsis: a narrative review.

Acute respiratory distress syndrome (ARDS) is a severe organ failure occurring mainly in critically ill patients as a result of different types of insults such as sepsis, trauma or aspiration. Sepsis is the main cause of ARDS, and it contributes to a high mortality and resources consumption both in hospital setting and in the community. ARDS develops mainly an acute respiratory failure with severe and often refractory hypoxemia. ARDS also has long term implications and sequelae. Endothelial damage plays an important role in the pathogenesis of ARDS. Understanding the mechanisms of ARDS presents opportunities for novel diagnostic and therapeutic targets. Biochemical signals can be used in concert to identify and classify patients into ARDS phenotypes allowing earlier effective treatment with personalised therapies. This is a narrative review where we aimed to flesh out the pathogenetic mechanisms and heterogeneity of ARDS. We examine the links between endothelium damage and its contribution to organ failure. We have also investigated future strategies for treatment with a special emphasis in endothelial damage.