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Severe acute respiratory infections, such as community-acquired pneumonia, hospital-acquired pneumonia, and ventilator-associated pneumonia, constitute frequent and lethal pulmonary infections in the intensive care unit (ICU). Despite optimal management with early appropriate empiric antimicrobial therapy and adequate supportive care, mortality remains high, in part attributable to the aging, growing number of comorbidities, and rising rates of multidrug resistance pathogens. Biomarkers have the potential to offer additional information that may further improve the management and outcome of pulmonary infections. Available pathogen-specific biomarkers, for example, Streptococcus pneumoniae urinary antigen test and galactomannan, can be helpful in the microbiologic diagnosis of pulmonary infection in ICU patients, improving the timing and appropriateness of empiric antimicrobial therapy since these tests have a short turnaround time in comparison to classic microbiology. On the other hand, host-response biomarkers, for example, C-reactive protein and procalcitonin, used in conjunction with the clinical data, may be useful in the diagnosis and prediction of pulmonary infections, monitoring the response to treatment, and guiding duration of antimicrobial therapy. The assessment of serial measurements overtime, kinetics of biomarkers, is more informative than a single value. The appropriate utilization of accurate pathogen-specific and host-response biomarkers may benefit clinical decision-making at the bedside and optimize antimicrobial stewardship., (© 2024. The Author(s).)

Background: Acute respiratory distress syndrome (ARDS) is a frequent cause of hypoxemic respiratory failure with a mortality rate of approximately 30%. Identifying ARDS subphenotypes based on "focal" or "non-focal" lung morphology has the potential to better target mechanical ventilation strategies of individual patients. However, classifying morphology through chest radiography or computed tomography is either inaccurate or impractical. Lung ultrasound (LUS) is a non-invasive bedside tool that can accurately distinguish "focal" from "non-focal" lung morphology. We hypothesize that LUS-guided personalized mechanical ventilation in ARDS patients leads to a reduction in 90-day mortality compared to conventional mechanical ventilation., Methods: The Personalized Mechanical Ventilation Guided by UltraSound in Patients with Acute Respiratory Distress Syndrome (PEGASUS) study is an investigator-initiated, international, randomized clinical trial (RCT) that plans to enroll 538 invasively ventilated adult intensive care unit (ICU) patients with moderate to severe ARDS. Eligible patients will receive a LUS exam to classify lung morphology as "focal" or "non-focal". Thereafter, patients will be randomized within 12 h after ARDS diagnosis to receive standard care or personalized ventilation where the ventilation strategy is adjusted to the morphology subphenotype, i.e., higher positive end-expiratory pressure (PEEP) and recruitment maneuvers for "non-focal" ARDS and lower PEEP and prone positioning for "focal" ARDS. The primary endpoint is all-cause mortality at day 90. Secondary outcomes are mortality at day 28, ventilator-free days at day 28, ICU length of stay, ICU mortality, hospital length of stay, hospital mortality, and number of complications (ventilator-associated pneumonia, pneumothorax, and need for rescue therapy). After a pilot phase of 80 patients, the correct interpretation of LUS images and correct application of the intervention within the safe limits of mechanical ventilation will be evaluated., Discussion: PEGASUS is the first RCT that compares LUS-guided personalized mechanical ventilation with conventional ventilation in invasively ventilated patients with moderate and severe ARDS. If this study demonstrates that personalized ventilation guided by LUS can improve the outcomes of ARDS patients, it has the potential to shift the existing one-size-fits-all ventilation strategy towards a more individualized approach., Trial Registration: The PEGASUS trial was registered before the inclusion of the first patient, https://clinicaltrials.gov/ (ID: NCT05492344)., (© 2024. The Author(s).)

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., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Burden of bacteraemia is rising due to increased average life expectancy in developed countries. This study aimed to compare the epidemiology and outcomes of bacteraemia in two similarly ageing populations with different ethnicities in Singapore and Denmark. Historical cohorts from the second largest acute-care hospital in Singapore and in the hospitals of two Danish regions included patients aged 15 and above who were admitted from 1 January 2006 to 31 December 2016 with at least 1 day of hospital stay and a pathogenic organism identified. Among 13 144 and 39 073 bacteraemia patients from Singapore and Denmark, similar 30-day mortality rates (16.5%; 20.3%), length of hospital stay (median 14 (IQR: 9-28) days; 11 (6-21)), and admission rate to ICU (15.5%; 15.6%) were observed, respectively. Escherichia coli , Klebsiella pneumoniae , and Staphylococcus aureus ranked among the top four in both countries. However, Singaporeans had a higher proportion of patients with diabetes (46.8%) and renal disease (29.5%) than the Danes (28.0% and 13.7%, respectively), whilst the Danes had a higher proportion of patients with chronic pulmonary disease (18.0%) and malignancy (35.3%) than Singaporeans (9.7% and 16.2%, respectively). Our study showed that top four causative organisms and clinical outcomes were similar between the two cohorts despite pre-existing comorbidities differed.

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., Competing Interests: None declared., (Thieme. All rights reserved.)

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., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Acute liver failure (ALF) is a rare disease with high mortality. Acute kidney injury (AKI) following ALF is frequent. We assessed AKI impact on long-term kidney function among ALF survivors., Methods: Observational cohort study including consecutive adult (age ≥16 years) patients with ALF or acute liver injury (ALI) admitted to a Portuguese tertiary center intensive care unit (ICU) between October 2013 and February 2020. KDIGO criteria were used to define AKI and chronic kidney disease (CKD). Primary outcome was the estimated glomerular filtration rate (eGFR), defined by the Chronic Kidney Disease Epidemiology Collaboration formula, at least 1 year after index ICU admission., Results: Among 104 patients with ALF ( n = 74) or ALI ( n = 30), mean (SD) age was 43.7 (18.0) years, and 44 were male. Among all patients ( n = 104), following adjustment for age and SOFA score, AKI during the first 7 ICU days ( n AKI = 57 and n renal replacement therapy [RRT] = 32) was independently associated with all-cause mortality (adjusted HR [95% CI] 11.61 [1.49-90.34]; p = 0.019). Among hospital survivors with long-term kidney function available ( n = 56), median (interquartile range) >1 year eGFR was 95.3 (75.0-107.7) mL/min/1.73 m 2 (mean [SD] follow-up of 3.1 [1.6] years). Among these hospital survivors, following adjustment for baseline eGFR, AKI during the first 7 ICU days ( n AKI = 19 and n RRT = 10) was not associated with >1 year eGFR ( p = 0.15). At least 1 year after index ICU admission, 5 patients developed CKD, none RRT-dependent., Conclusions: Among ALF or ALI survivors, AKI was not associated with significant long-term loss of kidney function., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s).Published by S. Karger AG, Basel.)

Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: PP received fees for lecture from Gilead and Pfizer, consulting from MSD and Sanofi and unrestricted research grant from Abionic. GG declare no conflict of interest.

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.

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.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. In this context, biomarkers could be considered as indicators of either infection or dysregulated host response or response to treatment and/or aid clinicians to prognosticate patient risk. More than 250 biomarkers have been identified and evaluated over the last few decades, but no biomarker accurately differentiates between sepsis and sepsis-like syndrome. Published data support the use of biomarkers for pathogen identification, clinical diagnosis, and optimization of antibiotic treatment. In this narrative review, we highlight how clinicians could improve the use of pathogen-specific and of the most used host-response biomarkers, procalcitonin and C-reactive protein, to improve the clinical care of patients with sepsis. Biomarker kinetics are more useful than single values in predicting sepsis, when making the diagnosis and assessing the response to antibiotic therapy. Finally, integrated biomarker-guided algorithms may hold promise to improve both the diagnosis and prognosis of sepsis. Herein, we provide current data on the clinical utility of pathogen-specific and host-response biomarkers, offer guidance on how to optimize their use, and propose the needs for future research., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

Ventilator-associated pneumonia (VAP) is the most common ICU-acquired infection among patients under mechanical ventilation (MV). It may occur in up to 50% of mechanically ventilated patients and is associated with an increased duration of MV, antibiotic consumption, increased morbidity, and mortality. VAP prevention is a multifaceted priority of the intensive care team. The use of specialized artificial airways and other devices can have an impact on the prevention of VAP. However, these devices can also have adverse effects, and aspects of their efficacy in the prevention of VAP are still a matter of debate. This article provides a narrative review of how different airway and respiratory devices may help to reduce the incidence of VAP.

Purpose of Review: Severe infections are a common cause of ICU admission, with a high morbidity and mortality. Omics, namely proteomics and metabolomics, aim to identify, characterize, and quantify biological molecules to achieve a systems-level understanding of disease. The aim of this review is to provide a clear overview of the current evidence of the role of proteomics and metabolomics in severe infections., Recent Findings: Proteomics and metabolomics are technologies that are being used to explore new markers of diagnosis and prognosis, clarify mechanisms of disease, and consequently discover potential targets of therapy and finally of a better disease phenotyping. These technologies are starting to be used but not yet in clinical use., Summary: Our traditional way of approaching the disease as sepsis is believing that a process can be broken into its parts and that the whole can be explained by the sum of each part. This approach is highly reductionist and does not take the system complexity nor the nonlinear dynamics of the processes. Proteomics and metabolomics allow the analysis of several proteins and metabolites simultaneously, thereby generating diagnostic and prognostic signatures. An exciting future prospect for proteomics and metabolomics is their employment towards precision medicine., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Ventilator-associated pneumonia (VAP) is associated with high morbidity and health care costs, yet diagnosis remains a challenge. Analysis of airway microbiota by amplicon sequencing provides a possible solution, as pneumonia is characterised by a disruption of the microbiome. However, studies evaluating the diagnostic capabilities of microbiome analysis are limited, with a lack of alignment on possible biomarkers. Using bronchoalveolar lavage fluid (BALF) from ventilated adult patients suspected of VAP, we aimed to explore how key characteristics of the microbiome differ between patients with positive and negative BALF cultures and whether any differences could have a clinically relevant role., Methods: BALF from patients suspected of VAP was analysed using 16s rRNA sequencing in order to: (1) differentiate between patients with and without a positive culture; (2) determine if there was any association between microbiome diversity and local inflammatory response; and (3) correctly identify pathogens detected by conventional culture., Results: Thirty-seven of 90 ICU patients with suspected VAP had positive cultures. Patients with a positive culture had significant microbiome dysbiosis with reduced alpha diversity. However, gross compositional variance was not strongly associated with culture positivity (AUROCC range 0.66-0.71). Patients with a positive culture had a significantly higher relative abundance of pathogenic bacteria compared to those without [0.45 (IQR 0.10-0.84), 0.02 (IQR 0.004-0.09), respectively], and an increased interleukin (IL)-1β was associated with reduced species evenness (r s  = - 0.33, p < 0.01) and increased pathogenic bacteria presence (r s  = 0.28, p = 0.013). Untargeted 16s rRNA pathogen detection was limited by false positives, while the use of pathogen-specific relative abundance thresholds showed better diagnostic accuracy (AUROCC range 0.89-0.998)., Conclusion: Patients with positive BALF culture had increased dysbiosis and genus dominance. An increased caspase-1-dependent IL-1b expression was associated with a reduced species evenness and increased pathogenic bacterial presence, providing a possible causal link between microbiome dysbiosis and lung injury development in VAP. However, measures of diversity were an unreliable predictor of culture positivity and 16s sequencing used agnostically could not usefully identify pathogens; this could be overcome if pathogen-specific relative abundance thresholds are used., (© 2022. The Author(s).)

Objective: To establish current Portuguese critical care practices regarding analgesia, sedation, and delirium based on a comparison between the activities reported and daily clinical practice., Methods: A national survey was conducted among physicians invited to report their practice toward analgesia, sedation, and delirium in intensive care units. A point prevalence study was performed to analyze daily practices., Results: A total of 117 physicians answered the survey, and 192 patients were included in the point prevalence study. Survey and point prevalence studies reflect a high sedation assessment (92%; 88.5%), with the Richmond Agitated Sedation Scale being the most reported and used scale (41.7%; 58.2%) and propofol being the most reported and used medication (91.4%; 58.6%). Midazolam prescribing was reported by 68.4% of responders, but a point prevalence study revealed a use of 27.6%.Although 46.4% of responders reported oversedation, this was actually documented in 32% of the patients. The survey reports the daily assessment of pain (92%) using standardized scales (71%). The same was identified in the point prevalence study, with 91.1% of analgesia assessment mainly with the Behavioral Pain Scale. In the survey, opioids were reported as the first analgesic. In clinical practice, acetaminophen was the first option (34.6%), followed by opioids. Delirium assessment was reported by 70% of physicians but was performed in less than 10% of the patients., Conclusion: The results from the survey did not accurately reflect the common practices in Portuguese intensive care units, as reported in the point prevalence study. Efforts should be made specifically to avoid oversedation and to promote delirium assessment.

The high prevalence of infectious diseases in the intensive care unit (ICU) and consequently elevated pressure for immediate and effective treatment have led to increased antimicrobial therapy consumption and misuse. Moreover, the emerging global threat of antimicrobial resistance and lack of novel antimicrobials justify the implementation of judicious antimicrobial stewardship programs (ASP) in the ICU. However, even though the importance of ASP is generally accepted, its implementation in the ICU is far from optimal and current evidence regarding strategies such as de-escalation remains controversial. The limitations of clinical guidance for antimicrobial therapy initiation and discontinuation have led to multiple studies for the evaluation of more objective tools, such as biomarkers as adjuncts for ASP. C-reactive protein and procalcitonin can be adequate for clinical use in acute infectious diseases, the latter being the most studied for ASP purposes. Although promising, current evidence highlights challenges in biomarker application and interpretation. Furthermore, the physiological alterations in the critically ill render pharmacokinetics and pharmacodynamics crucial parameters for adequate antimicrobial therapy use. Individual pharmacokinetic and pharmacodynamic targets can reduce antimicrobial therapy misuse and risk of antimicrobial resistance.

Objectives: Coronavirus disease 19 (COVID-19) is a major cause of hospital admission and represents a challenge for patient management during intensive care unit (ICU) stay. We aimed to describe the clinical course and outcomes of COVID-19 pneumonia in critically ill patients., Methods: We performed a systematic search of peer-reviewed publications in MEDLINE, EMBASE and the Cochrane Library up to 15th August 2020. Preprints and reports were also included if they met the inclusion criteria. Study eligibility criteria were full-text prospective, retrospective or registry-based publications describing outcomes in patients admitted to the ICU for COVID-19, using a validated test. Participants were critically ill patients admitted in the ICU with COVID-19 infection., Results: From 32 articles included, a total of 69 093 patients were admitted to the ICU and were evaluated. Most patients included in the studies were male (76 165/128 168, 59%, 26 studies) and the mean patient age was 56 (95%CI 48.5-59.8) years. Studies described high ICU mortality (21 145/65 383, 32.3%, 15 studies). The median length of ICU stay was 9.0 (95%CI 6.5-11.2) days, described in five studies. More than half the patients admitted to the ICU required mechanical ventilation (31 213/53 465, 58%, 23 studies) and among them mortality was very high (27 972/47 632, 59%, six studies). The duration of mechanical ventilation was 8.4 (95%CI 1.6-13.7) days. The main interventions described were the use of non-invasive ventilation, extracorporeal membrane oxygenation, renal replacement therapy and vasopressors., Conclusions: This systematic review, including approximately 69 000 ICU patients, demonstrates that COVID-19 infection in critically ill patients is associated with great need for life-sustaining interventions, high mortality, and prolonged length of ICU stay., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: We assessed C-reactive protein (CRP) and plasma albumin (PA) kinetics to evaluate community-acquired bloodstream infection (CA-BSI) patients' 1-year outcomes., Methods: Population-based study, with CRP and PA measurements on day 1 (D1) and D4. Relative CRP variations in relation to D1 CRP value were evaluated (CRP-ratio). Patients were classified as fast response, slow response, non-response, and biphasic response., Results: A total of 935 patients were included. At D4, the CRP-ratio was lower in survivors on D365 in comparison with D4-D30 non-survivors and D30-D365 non-survivors (p<0.001). In comparison with fast response patients, non-response and biphasic response patients had 2.74 and 5.29 increased risk, respectively, of death in D4-D30 and 2.77 and 3.16 increased risk, respectively, of death in D31-D365. PA levels remained roughly unchanged from D1-D4, but lower D1 PA predicted higher short and long-term mortality (p<0.001). The discriminative performance of the CRP-ratio and D1 PA to identify patients with poor short and long-term mortality after adjustments was acceptable (AUROC=0.79)., Conclusions: Serial CRP measurements at D1 and D4 after CA-BSI is clinically useful to identify patients with poor outcome. Individual patterns of CRP-ratio response with PA at D1 further refine our ability of predicting short or long-term mortality., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose of Review: Although pneumonia, either community or hospital-acquired, is the most frequent severe respiratory infection, it is an infection difficult to diagnose. At present, the diagnosis of pneumonia relies on a combination of clinical, radiologic, and microbiologic criteria. However, these criteria are far from perfect leading to uncertainty in the diagnosis, risk stratification, and choice of antibiotic therapy. Biomarkers have been used to bring additional information in this setting., Recent Findings: The aim of this review is to provide a clear overview of the current evidence for biomarkers to distinguish between patients in several clinical scenarios: to exclude pneumonia in order to withhold antibiotics, to identify the causative pathogen to target antimicrobial treatment, to identify phenotypes of inflammatory response to facilitate adjunctive treatments, to stratify the risk of severe pneumonia and provide the adequate level of care, and to monitor treatment response and de-escalate antibiotic therapy., Summary: In recent years the number of new biomarkers increased markedly in different areas like pathogen identification or host response. Although far from the ideal, there are several promising areas that could represent true evolutions in the management of pneumonia, in the near future.

Acute brain dysfunction (ABD) is a frequent and severe syndrome occurring in critically ill patients and early identification of high-risk patients is paramount. In the present analysis, we propose a clinically applicable model for early phenotype identification of ABD at the bedside in mechanically ventilated patients, improving the recognition of patients with prolonged ABD.Prospective cohort with 629 mechanically ventilated patients in two medical-surgical intensive care units at academic centers. We applied cluster analysis to identify phenotypes using clinical and biological data. We then tested the association of phenotypes and its respective clinical outcomes. We performed a validation on a new cohort of patients select on subsequent patients admitted to the participants intensive care units.A model with 3 phenotypes best described the study population. A 4-variable model including medical admission, sepsis diagnosis, simplified acute physiologic score II and basal serum C-reactive protein (CRP) accurately classified each phenotype (area under curve 0.82; 95% CI, 0.79-0.86). Phenotype A had the shorter duration of ABD (median, 1 day), while phenotypes B and C had progressively longer duration of ABD (median, 3 and 6 days, respectively; P < .0001). There was an association between the duration of ABD and the baseline CRP levels and simplified acute physiology score II score (sensitivity and specificity of 80%). To increase the sensitivity of the model, we added CRP kinetics. By day 1, a CRP < 1.0 times the initial level was associated with a shorter duration of ABD (specificity 0.98).A model based on widely available clinical variables could provide phenotypes associated with the duration of ABD. Phenotypes with longer duration of ABD (phenotypes B and C) are characterized by more severe inflammation and by significantly worse clinical outcomes.

Purpose of Review: The successful treatment of surgical fungal infections depends of a timely and adequate source control alongside with the use of prompt systemic antifungals. The main challenge of antifungal use in critically ill surgical patients is to find a balance between rational versus indiscriminate use in order to accomplish an antifungal stewardship program., Recent Findings: Surgical fungal infections represent an important burden in the daily clinical activity in many ICUs. The efficacy of the available antifungal drugs has not been adequately assessed in randomized controlled trials with surgical fungal infections in ICU patients. Most clinical experience is limited to case reports or uncontrolled case series. Due to the lack of adequate scientific evidence to assess the role of the different antifungals in surgical ICU patients, it is usually suggested to follow the recommendations for invasive candidiasis and candidemia., Summary: Antifungal use in the surgical patients admitted to an ICU is a complex matter and there are several elements to consider like the presence of septic shock and multiorgan failure, local epidemiology and antifungal resistance, among others. The proper use of antifungals alongside early recognition and prompt source control, are critical factors for improved outcomes.

Background: No study has evaluated C-reactive protein (CRP) and plasma albumin (PA) levels longitudinally in patients with acute myeloid leukaemia (AML)., Methods: We studied defined events in 818 adult patients with AML in relation to 60,209 CRP and PA measures. We investigated correlations between CRP and PA levels and daily CRP and PA levels in relation to AML diagnosis, AML relapse, or bacteraemia (all ±30 days), and death (─30-0 days)., Results: On the AML diagnosis date (D0), CRP levels increased with higher WHO performance score (PS), e.g. patients with PS 3/4 had 68.1 mg/L higher CRP compared to patients with PS 0, adjusted for relevant covariates. On D0, the PA level declined with increasing PS, e.g. PS 3/4 had 7.54 g/L lower adjusted PA compared to PS 0. CRP and PA levels were inversely correlated for the PA interval 25-55 g/L (R = - 0.51, p < 10-5), but not for ≤24 g/L (R = 0.01, p = 0.57). CRP increases and PA decreases were seen prior to bacteraemia and death, whereas no changes occurred up to AML diagnosis or relapse. CRP increases and PA decreases were also found frequently in individuals, unrelated to a pre-specified event., Conclusions: PA decrease is an important biomarker for imminent bacteraemia in adult patients with AML.

Background: Respiratory virome is an integral part of the human microbiome and its characterization may contribute to a better understanding of the changes that arise in the disease and, consequently, influence the approach and treatment of patients with acute lower respiratory infections. The aim of this study was to evaluate the presence of respiratory viruses in the lower airways of individuals undergoing invasive mechanical ventilation, with and without acute lower respiratory infection (respectively WRI and WORI groups)., Methods: We studied 44 mini-bronchoalveolar lavage samples (collected with a double catheter, Combicath® kit) from patients with mean age in the seventh decade, 20 from WORI group and 24 from WRI group, who were hospitalized for acute respiratory failure in Intensive Care Units of two hospitals in the Lisbon area. Real-time PCR was applied to verify analyse the presence of 15 common respiratory viruses (adenovirus, human bocavirus, influenza virus A and B, repiratory syncytial virus, human parainfluenza virus types 1, 2, 3 and 4, human enterovirus, human rhinovirus, human metapneumovirus, human coronavirus group 1 (229E, NL63) and 2 (OC43, HKU1)., Results: Respiratory viruses were detected in six of the 20 patients in the WORI group: influenza AH3 (n = 2), parainfluenza virus 1/3 (n = 2), human rhinovirus (n = 2), respiratory syncytial virus (n = 1) and human metapneumovirus (n = 1). In the WRI group, respiratory viruses were detected in 12 of the 24 patients: influenza AH3 (n = 3), human rhinovirus (n = 3), respiratory syncytial virus (n = 3), human metapneumovirus (n = 3), human bocavirus (n = 2) and human enterovirus (n = 1). Simultaneous detection of two viruses was recorded in two samples in both groups., Conclusions: The results of this study suggest the presence of common respiratory viruses in the lower respiratory tract without causing symptomatic infection, even in carefully collected lower samples. This may have important implications on the interpretation of the results on the diagnostic setting.

Sepsis is a life-threatening condition that arises as a systemic inflammatory response syndrome to an infection. Its uncontrolled progression can in frequent cases lead to multiple organ failure, which is still associated with high mortality rates. Modern antibiotics made clear that the infection is only an initiating, and not always necessary, event of this syndrome as many patients with sepsis die despite effective eradication of the inciting pathogen. This observation critically contributed to a paradigm shift that focused the pathogenesis of sepsis on the host and not on the pathogen. However, therapeutic strategies based on the inhibition of proinflammatory critical mediators of sepsis or immunostimulation have so far failed to improve sepsis outcome and, therefore, this condition urgently needs transformative therapeutic ideas and strategies. Here we argue that the induction of tolerance, a defence strategy that minimises the impact of an infection on organ function without directly affecting the pathogen burden, is perhaps the missing but essential element to add to the current components of sepsis care and treatment.

Influenza pneumonia is associated with high number of severe cases requiring hospital and intensive care unit (ICU) admissions with high mortality. Systemic steroids are proposed as a valid therapeutic option even though its effects are still controversial. Heterogeneity of published data regarding study design, population demographics, severity of illness, dosing, type and timing of corticosteroids administered constitute an important limitation for drawing robust conclusions. However, it is reasonable to admit that, as it was not found any advantage of corticosteroid therapy in so diverse conditions, such beneficial effects do not exist at all. Its administration is likely to increase overall mortality and such trend is consistent regardless of the quality as well as the sample size of studies. Moreover it was shown that corticosteroids might be associated with higher incidence of hospital-acquired pneumonia and longer duration of mechanical ventilation and ICU stay. Finally, it is reasonable to conclude that corticosteroids failed to demonstrate any beneficial effects in the treatment of patients with severe influenza infection. Thus its current use in severe influenza pneumonia should be restricted to very selected cases and in the setting of clinical trials.

Introduction: Imported malaria is a frequent diagnosis in Portugal, and in the most severe clinical forms it may present a high mortality rate., Material and Methods: We present seven cases of severe imported malaria, admitted to an intensive care unit between 2000 and 2010, with particular focus on risk factors, clinical presentation, treatment and results., Results: All patients had a history of recent travel to African endemic areas for malaria. Plasmodium falciparum was the agent isolated in all cases. Most patients had an inadequate prophylaxis. High parasitaemia in non-immune patients and treatment delay were associated with more severe clinical presentation. All the cases were complicated by organ failure, and three patients needed organ support and in two exchange blood transfusions were performed. There was one single death that was associated with marked delay in the initiation of therapy., Conclusion: In these patients, early and aggressive treatment, with a organ support in a critical care setting, allowed a good outcome with low mortality and no significant sequelae, despite the severity of presentation.

Community-acquired pneumonia (CAP) is the most common infectious disease requiring admission to intensive care units (ICUs), and achieving an early and precise diagnosis of CAP remains a challenge. Biomarkers play an important role in improving clinical judgment in the emergency room and are adjuvant in evaluating treatment responses. Novel biomarkers, such as cortisol, pro-adrenomedullin and endothelin-1, have been shown to be associated with disease severity and short-term outcomes. This review article focuses on the clinical use of novel biomarkers, severity prediction and treatment monitoring as well as future directions of the field.

Objectives: Therapeutic hypothermia following cardiorespiratory arrest has been demonstrated to have cardio- and neuroprotective effects, resulting in improved survival and better neurological outcomes. The objective of this study was to assess the outcomes of patients undergoing therapeutic hypothermia following cardiorespiratory arrest., Methods: A prospective, 10-month observational study of patients admitted to an intensive care unit and undergoing therapeutic hypothermia after cardiorespiratory arrest was undertaken. Therapeutic hypothermia was induced by cold fluid administration and body surface cooling in patients admitted no more than 12 hours after resuscitation from cardiorespiratory arrest. A target temperature of 33ºC was maintained for 24 hours., Results: Overall, 12 patients were included (median age 64 years, 58% male). Half of the cardiorespiratory arrests were in-hospital. The median first-day Charlson Index, Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation II scores were of 2.9, 11 and 24.5, respectively. The intensive care unit mortality rate was 42% (N=5). Five of the 7 surviving patients recovered their pre-cardiorespiratory arrest neurological status. Hypothermia was initiated 120 min (median) after recovery of spontaneous circulation. Most patients (75%) required vasopressor support. During the first 3 days after cardiorespiratory arrest and therapeutic hypothermia, a progressive SOFA score decrease (median 11 on day 0, 10 on day 1 and 7 on day 2) was observed., Discussion: In this study, therapeutic hypothermia was applied to all post-cardiorespiratory arrest patients and demonstrated good neurological outcome in surviving patients.

Corticosteroids have been proposed for decades as adjunctive therapy of severe infections. These drugs have complex mechanisms of action involving anti-inflammatory and vasoactive properties. However, due to discordant results from clinical studies, the use of corticosteroids to treat patients with severe infections is still a matter of intense debate in the scientific and medical community. In the present article, we review the underlying mechanisms related to the potential benefits of corticosteroids and their impact on clinical management of severe sepsis.

The definition of septic shock includes sepsis-induced hypotension despite adequate fluid resuscitation, along with the presence of organ perfusion abnormalities, and ultimately cell dysfunction. To restore adequate organ perfusion and cell homeostasis, cardiac output should be restored with volume infusion plus vasopressor agents as indicated. Appropriate arterial pressure for each individual patient and proper arterial oxygen content are key elements to restoring perfusion. Tissue perfusion can be monitored by markers of organ and mitochondrial function, namely urine output, level of consciousness, peripheral skin perfusion, central or mixed venous oxygen saturation, and lactate. The hemodynamic effects of the different vasopressor agents depend on the relative affinity to adrenergic receptors. Those with predominant alpha-agonist activity produce more vasoconstriction (inoconstrictors) while those with predominant beta-agonist stimulation increase cardiac performance (inodilators). The debate about whether one vasopressor agent is superior to another is still ongoing. The Surviving Sepsis Campaign guidelines refer to either norepinephrine or dopamine as the first-choice vasopressor agent to correct hypotension in septic shock. However, recent data from observational and controlled trials have challenged these recommendations concerning different adrenergic agents. As a result, our view on the prescription of vasopressors has changed from a probably oversimplified "one-size-fits-all" approach to a multimodal approach in vasopressor selection.

Objective: Guidelines for the adrenergic support of septic shock are controversial. In patients with community-acquired septic shock, we assessed the impact of the choice of vasopressor support on mortality., Design: Cohort, multiple center, observational study., Setting: Seventeen Portuguese intensive care units (ICUs)., Patients: All adult patients admitted to a participating ICU between December 2004 and November 2005., Interventions: None., Measurements and Main Results: Patients were followed up during the first five ICU days, the day of discharge or death, and hospital outcome. Eight hundred ninety-seven consecutive patients with community-acquired sepsis (median age, 63 years; 577 men; and hospital mortality, 38%) were studied. Of the 458 patients with septic shock, 73% received norepinephrine and 50.5% dopamine. The norepinephrine group had a higher hospital mortality (52% vs. 38.5%, p = 0.002). A Kaplan-Meier survival curve showed diminished 28-day survival in the norepinephrine group (log-rank = 22.6, p < 0.001). A Cox proportional hazard analysis revealed that the administration of norepinephrine was associated with an increased risk of death (adjusted hazard ratio, 2.501; 95% confidence interval, 1.413-4.425; p = 0.002). In a multivariate analysis with ICU mortality as the dependent factor, Simplified Acute Physiology Score II and norepinephrine administration were independent risk factors for ICU mortality in patients with septic shock., Conclusions: In patients with community-acquired septic shock, our data suggest that norepinephrine administration could be associated with worse outcome.

Purpose of Review: This article reviews recent data on the usefulness of serum markers in community-acquired pneumonia and ventilator-associated pneumonia. The focus is on clinical studies, with an emphasis on adult critically ill patients., Recent Findings: Serum markers have demonstrated potential value in early prediction and diagnosis of pneumonia, in monitoring the clinical course and in guiding antibiotic therapy. C-reactive protein appears to perform better in diagnosing infection, because several studies have shown that procalcitonin may remain undetectable in some patients, specifically those with pneumonia. Procalcitonin exhibited a better correlation with clinical severity, however. Furthermore, one report demonstrated the efficacy and safety of procalcitonin-guided antibiotic therapy in community-acquired pneumonia., Summary: Serum markers should only be used as a complementary tool to support the current clinical approach. Use of serum markers, in particular procalcitonin and C-reactive protein, represents a promising strategy in the clinical decision-making process in patients in whom pneumonia is suspected. Specifically, these markers can be used to guide culture sampling and empirical antibiotic prescription, and to monitor the clinical course, adjust the duration of antibiotic therapy and identify nonresponders, in whom an aggressive diagnostic and therapeutic approach may prevent further clinical deterioration.

Introduction: The purpose of this review was to evaluate the impact of corticosteroids on the outcomes of patients with severe community-acquired pneumonia (CAP)., Methods: We performed a systematic MEDLINE, Cochrane database, and CINAHL search (1966 to November 2007) to identify full-text publications that evaluated the use of corticosteroids in CAP., Results: An initial literature search yielded 109 articles, and 105 studies were excluded after the first analysis. We found four studies eligible for analysis. On the basis of their results, the use of corticosteroids as adjunctive therapy in severe CAP should be categorized as a weak recommendation (two studies) and a strong recommendation (two studies) with either low- or moderate-quality evidence. However, no evidence of adverse outcomes or harm is present in the evaluated studies., Conclusion: According to the GRADE system, available studies do not support the recommendation of corticosteroids as a standard of care for patients with severe CAP. Further randomized controlled trials with this aim should enroll a larger number of severely ill patients. However, in patients needing corticosteroids, it may be reasonable to conclude that corticosteroid administration is safe in patients with severe infections receiving antimicrobial therapy.

Background and Objectives: Pressure ulcers (PU) constitute an important health problem in particular in the intensive care unit (ICU). The objective of the study was to identify the number, degree and total score of PU on admission, ICU stay and discharge as well as to recognize factors influencing the appearance or development of PU and to identify the number of healed PU, thus so the incidence and prevalence., Methods: All patients admitted > 24 hrs were prospectively included during one year. Seventy patients were excluded for insufficient data. The prevention protocol (Norton scale; positioning according the risk grade) and therapeutic protocol (hydrocolloid dressings; hydrogel dressings if tissue necrosis and/or devitalized and alginate dressings if ulcer bleeds) was applied to all patients., Results: One hundred and fifty five patients were studied. Eighteen patients were admitted already with PU. During ICU stay, 40 patients developed a total of 125 PU. The prevalence of PU was 37.41% and incidence was 25.8%. The development of new PU occurred on average by the 7th day. Patients with PU presented 2.6 PU on the average. Seventy nine percent of the patients admitted in the ICU remained stable or improved. Patients admitted with PU had a SAPS 2 significantly higher than those without, 54 ± 8.7 and 44 ± 17, respectively (p = 0.015). At the day of discharge, patients classified as high risk had significantly more PU (p = 0.039). Non-survivors had significantly more PU than survivors (p < 0.001). Patients with longer ICU stay had more PU (p < 0.001) CONCLUSIONS: In our patient population we found 37.41% prevalence and 25.8% incidence of PU. The present prevention protocol of PU was effective in 79% of the patients; severely ill patients developed PU more frequently.

Background: The aim of the present study was to evaluate the C-reactive protein level, the body temperature and the white cell count in patients after prescription of antibiotics in order to describe the clinical resolution of severe community-acquired pneumonia., Methods: A cohort of 53 consecutive patients with severe community-acquired pneumonia was studied. The C-reactive protein levels, body temperature and white cell count were monitored daily., Results: By day 3 a C-reactive protein level 0.5 times the initial level was a marker of poor outcome (sensitivity, 0.91; specificity, 0.59). Patients were divided according to their C-reactive protein patterns of response to antibiotics, into fast response, slow response, nonresponse, and biphasic response. About 96% of patients with a C-reactive protein pattern of fast response and 74% of patients with a slow response pattern survived, whereas those patients with the patterns of nonresponse and of biphasic response had a mortality rate of 100% and 33%, respectively (P < 0.001). On day 3 of antibiotic therapy, a decrease in C-reactive protein levels by 0.31 or more from the previous day's level was a marker of good prognosis (sensitivity, 0.75; specificity, 0.85)., Conclusion: Daily C-reactive protein measurement after antibiotic prescription is useful in identification, as early as day 3, of severe community-acquired pneumonia patients with poor outcome. The identification of the C-reactive protein pattern of response to antibiotic therapy was useful in the recognition of the individual clinical course, either improving or worsening, as well as the rate of improvement, in patients with severe community-acquired pneumonia.

Introduction: Manifestations of sepsis are sensitive but are poorly specific of infection. Our aim was to assess the value of daily measurements of C-reactive protein (CRP), temperature and white cell count (WCC) in the early identification of intensive care unit (ICU)-acquired infections., Methods: We undertook a prospective observational cohort study (14 month). All patients admitted for > or =72 hours (n = 181) were divided into an infected (n = 35) and a noninfected group (n = 28). Infected patients had a documented ICU-acquired infection and were not receiving antibiotics for at least 5 days before diagnosis. Noninfected patients never received antibiotics and were discharged alive. The progression of CRP, temperature and WCC from day -5 to day 0 (day of infection diagnosis or of ICU discharge) was analyzed. Patients were divided into four patterns of CRP course according to a cutoff value for infection diagnosis of 8.7 mg/dl: pattern A, day 0 CRP >8.7 mg/dl and, in the previous days, at least once below the cutoff; pattern B, CRP always >8.7 mg/dl; pattern C, day 0 CRP < or =8.7 mg/dl and, in the previous days, at least once above the cutoff; and pattern D, CRP always < or =8.7 mg/dl., Results: CRP and the temperature time-course showed a significant increase in infected patients, whereas in noninfected it remained almost unchanged (P < 0.001 and P < 0.001, respectively). The area under the curve for the maximum daily CRP variation in infection prediction was 0.86 (95% confidence interval: 0.752-0.933). A maximum daily CRP variation >4.1 mg/dl was a good marker of infection prediction (sensitivity 92.1%, specificity 71.4%), and in combination with a CRP concentration >8.7 mg/dl the discriminative power increased even further (sensitivity 92.1%, specificity 82.1%). Infection was diagnosed in 92% and 90% of patients with patterns A and B, respectively, and in only two patients with patterns C and D (P < 0.001)., Conclusion: Daily CRP monitoring and the recognition of the CRP pattern could be useful in the prediction of ICU-acquired infections. Patients presenting maximum daily CRP variation >4.1 mg/dl plus a CRP level >8.7 mg/dl had an 88% risk of infection.

We evaluated the usefulness of monitoring daily C-reactive protein (CRP) levels after initiation of antimicrobial therapy in 44 patients with bloodstream infection. The ratio of the CRP level during therapy to the level at the start of antimicrobial therapy (CRP ratio) was measured. A CRP ratio of >0.58 at day 4 of therapy was a marker of poor outcome (sensitivity, 0.89; specificity, 0.69). The recognition of a pattern of CRP-ratio response was useful in the prediction of individual clinical course.