Metabolic reprograming shapes neutrophil functions in severe COVID-19.

To better understand the mechanisms at the basis of neutrophil functions during SARS-CoV-2, we studied patients with severe COVID-19 pneumonia. They had high blood proportion of degranulated neutrophils and elevated plasma levels of myeloperoxidase (MPO), elastase, and MPO-DNA complexes, which are typical markers of neutrophil extracellular traps (NET). Their neutrophils display dysfunctional mitochondria, defective oxidative burst, increased glycolysis, glycogen accumulation in the cytoplasm, and increase glycogenolysis. Hypoxia-inducible factor 1α (ΗΙF-1α) is stabilized in such cells, and it controls the level of glycogen phosphorylase L (PYGL), a key enzyme in glycogenolysis. Inhibiting PYGL abolishes the ability of neutrophils to produce NET. Patients displayed significant increases of plasma levels of molecules involved in the regulation of neutrophils' function including CCL2, CXCL10, CCL20, IL-18, IL-3, IL-6, G-CSF, GM-CSF, IFN-γ. Our data suggest that metabolic remodelling is vital for the formation of NET and for boosting neutrophil inflammatory response, thus, suggesting that modulating ΗΙF-1α or PYGL could represent a novel approach for innovative therapies.

Nasal pressure swings as the measure of inspiratory effort in spontaneously breathing patients with de novo acute respiratory failure.

BACKGROUND: Excessive inspiratory effort could translate into self-inflicted lung injury, thus worsening clinical outcomes of spontaneously breathing patients with acute respiratory failure (ARF). Although esophageal manometry is a reliable method to estimate the magnitude of inspiratory effort, procedural issues significantly limit its use in daily clinical practice. The aim of this study is to describe the correlation between esophageal pressure swings (ΔPes) and nasal (ΔPnos) as a potential measure of inspiratory effort in spontaneously breathing patients with de novo ARF. METHODS: From January 1, 2021, to September 1, 2021, 61 consecutive patients with ARF (83.6% related to COVID-19) admitted to the Respiratory Intensive Care Unit (RICU) of the University Hospital of Modena (Italy) and candidate to escalation of non-invasive respiratory support (NRS) were enrolled. Clinical features and tidal changes in esophageal and nasal pressure were recorded on admission and 24 h after starting NRS. Correlation between ΔPes and ΔPnos served as primary outcome. The effect of ΔPnos measurements on respiratory rate and ΔPes was also assessed. RESULTS: ΔPes and ΔPnos were strongly correlated at admission (R2 = 0.88, p < 0.001) and 24 h apart (R2 = 0.94, p < 0.001). The nasal plug insertion and the mouth closure required for ΔPnos measurement did not result in significant change of respiratory rate and ΔPes. The correlation between measures at 24 h remained significant even after splitting the study population according to the type of NRS (high-flow nasal cannulas [R2 = 0.79, p < 0.001] or non-invasive ventilation [R2 = 0.95, p < 0.001]). CONCLUSIONS: In a cohort of patients with ARF, nasal pressure swings did not alter respiratory mechanics in the short term and were highly correlated with esophageal pressure swings during spontaneous tidal breathing. ΔPnos might warrant further investigation as a measure of inspiratory effort in patients with ARF. TRIAL REGISTRATION: NCT03826797 . Registered October 2016.

Patients Recovering from Severe COVID-19 Develop a Polyfunctional Antigen-Specific CD4+ T Cell Response.

Specific T cells are crucial to control SARS-CoV-2 infection, avoid reinfection and confer protection after vaccination. We have studied patients with severe or moderate COVID-19 pneumonia, compared to patients who recovered from a severe or moderate infection that had occurred about 4 months before the analyses. In all these subjects, we assessed the polyfunctionality of virus-specific CD4+ and CD8+ T cells by quantifying cytokine production after in vitro stimulation with different SARS-CoV-2 peptide pools covering different proteins (M, N and S). In particular, we quantified the percentage of CD4+ and CD8+ T cells simultaneously producing interferon-γ, tumor necrosis factor, interleukin (IL)-2, IL-17, granzyme B, and expressing CD107a. Recovered patients who experienced a severe disease display high proportions of antigen-specific CD4+ T cells producing Th1 and Th17 cytokines and are characterized by polyfunctional SARS-CoV-2-specific CD4+ T cells. A similar profile was found in patients experiencing a moderate form of COVID-19 pneumonia. No main differences in polyfunctionality were observed among the CD8+ T cell compartments, even if the proportion of responding cells was higher during the infection. The identification of those functional cell subsets that might influence protection can thus help in better understanding the complexity of immune response to SARS-CoV-2.

Two Fatal Cases of Acute Liver Failure Due to HSV-1 Infection in COVID-19 Patients Following Immunomodulatory Therapies.

We report two fatal cases of acute liver failure secondary to herpes simplex virus 1 infection in COVID-19 patients, following tocilizumab and corticosteroid therapy. Screening for and prompt recognition of herpes simplex virus 1 reactivation in these patients, undergoing immunomodulatory treatment, may have potentially relevant clinical consequences.

Expansion of plasmablasts and loss of memory B cells in peripheral blood from COVID-19 patients with pneumonia.

Studies on the interactions between SARS-CoV-2 and humoral immunity are fundamental to elaborate effective therapies including vaccines. We used polychromatic flow cytometry, coupled with unsupervised data analysis and principal component analysis (PCA), to interrogate B cells in untreated patients with COVID-19 pneumonia. COVID-19 patients displayed normal plasma levels of the main immunoglobulin classes, of antibodies against common antigens or against antigens present in common vaccines. However, we found a decreased number of total and naïve B cells, along with decreased percentages and numbers of memory switched and unswitched B cells. On the contrary, IgM+ and IgM- plasmablasts were significantly increased. In vitro cell activation revealed that B lymphocytes showed a normal proliferation index and number of dividing cells per cycle. PCA indicated that B-cell number, naive and memory B cells but not plasmablasts clustered with patients who were discharged, while plasma IgM level, C-reactive protein, D-dimer, and SOFA score with those who died. In patients with pneumonia, the derangement of the B-cell compartment could be one of the causes of the immunological failure to control SARS-Cov2, have a relevant influence on several pathways, organs and systems, and must be considered to develop vaccine strategies.

Prone position in intubated, mechanically ventilated patients with COVID-19: a multi-centric study of more than 1000 patients.

BACKGROUND: Limited data are available on the use of prone position in intubated, invasively ventilated patients with Coronavirus disease-19 (COVID-19). Aim of this study is to investigate the use and effect of prone position in this population during the first 2020 pandemic wave. METHODS: Retrospective, multicentre, national cohort study conducted between February 24 and June 14, 2020, in 24 Italian Intensive Care Units (ICU) on adult patients needing invasive mechanical ventilation for respiratory failure caused by COVID-19. Clinical data were collected on the day of ICU admission. Information regarding the use of prone position was collected daily. Follow-up for patient outcomes was performed on July 15, 2020. The respiratory effects of the first prone position were studied in a subset of 78 patients. Patients were classified as Oxygen Responders if the PaO2/FiO2 ratio increased ≥ 20 mmHg during prone position and as Carbon Dioxide Responders if the ventilatory ratio was reduced during prone position. RESULTS: Of 1057 included patients, mild, moderate and severe ARDS was present in 15, 50 and 35% of patients, respectively, and had a resulting mortality of 25, 33 and 41%. Prone position was applied in 61% of the patients. Patients placed prone had a more severe disease and died significantly more (45% vs. 33%, p < 0.001). Overall, prone position induced a significant increase in PaO2/FiO2 ratio, while no change in respiratory system compliance or ventilatory ratio was observed. Seventy-eight % of the subset of 78 patients were Oxygen Responders. Non-Responders had a more severe respiratory failure and died more often in the ICU (65% vs. 38%, p = 0.047). Forty-seven % of patients were defined as Carbon Dioxide Responders. These patients were older and had more comorbidities; however, no difference in terms of ICU mortality was observed (51% vs. 37%, p = 0.189 for Carbon Dioxide Responders and Non-Responders, respectively). CONCLUSIONS: During the COVID-19 pandemic, prone position has been widely adopted to treat mechanically ventilated patients with respiratory failure. The majority of patients improved their oxygenation during prone position, most likely due to a better ventilation perfusion matching. TRIAL REGISTRATION: clinicaltrials.gov number: NCT04388670.

Incidence, risk factors and outcome of acute kidney injury (AKI) in patients with COVID-19.

BACKGROUND: Acute kidney injury (AKI) is a severe complication of coronavirus disease-2019 (COVID-19). This study aims to evaluate incidence, risk factors and case-fatality rate of AKI in patients with COVID-19. METHODS: We reviewed the health medical records of 307 consecutive patients with COVID-19 hospitalized at the University Hospital of Modena, Italy. RESULTS: AKI was diagnosed in 69 out of 307 (22.4%) COVID-19 patients. Stages 1, 2, or 3 AKI accounted for 57.9%, 24.6% and 17.3%, respectively. AKI patients had a mean age of 74.7 ± 9.9 years. These patients showed higher serum levels of the main markers of inflammation and higher rate of severe pneumonia than non-AKI patients. Kidney injury was associated with a higher rate of urinary abnormalities including proteinuria (0.44 ± 0.85 vs 0.18 ± 0.29 mg/mg; P = < 0.0001) and microscopic hematuria (P = 0.032) compared to non-AKI patients. Hemodialysis was performed in 7.2% of the subjects and 33.3% of the survivors did not recover kidney function after AKI. Risk factors for kidney injury were age, male sex, CKD and higher non-renal SOFA score. Patients with AKI had a mortality rate of 56.5%. Adjusted Cox regression analysis revealed that COVID-19-associated AKI was independently associated with in-hospital death (hazard ratio [HR] = 4.82; CI 95%, 1.36-17.08) compared to non-AKI patients. CONCLUSION: AKI was a common and harmful consequence of COVID-19. It manifested with urinary abnormalities (proteinuria, microscopic hematuria) and conferred an increased risk for death. Given the well-known short-term sequelae of AKI, prevention of kidney injury is imperative in this vulnerable cohort of patients.

Early Inspiratory Effort Assessment by Esophageal Manometry Predicts Noninvasive Ventilation Outcome in De Novo Respiratory Failure. A Pilot Study.

Rationale: The role of inspiratory effort still has to be determined as a potential predictor of noninvasive mechanical ventilation (NIV) failure in acute hypoxic de novo respiratory failure.Objectives: To explore the hypothesis that inspiratory effort might be a major determinant of NIV failure in these patients.Methods: Thirty consecutive patients with acute hypoxic de novo respiratory failure admitted to a single center and candidates for a 24-hour NIV trial were enrolled. Clinical features, tidal change in esophageal pressure (ΔPes), tidal change in dynamic transpulmonary pressure (ΔPl), expiratory Vt, and respiratory rate were recorded on admission and 2-4 to 12-24 hours after NIV start and were tested for correlation with outcomes.Measurements and Main Results: ΔPes and ΔPes/ΔPl ratio were significantly lower 2 hours after NIV start in patients who successfully completed the NIV trial (n = 18) compared with those who needed endotracheal intubation (n = 12) (median [interquartile range], 11 [8-15] cm H2O vs. 31.5 [30-36] cm H2O; P < 0.0001), whereas other variables differed later. ΔPes was not related to other predictors of NIV failure at baseline. NIV-induced reduction in ΔPes of 10 cm H2O or more after 2 hours of treatment was strongly associated with avoidance of intubation and represented the most accurate predictor of treatment success (odds ratio, 15; 95% confidence interval, 2.8-110; P = 0.001 and area under the curve, 0.97; 95% confidence interval, 0.91-1; P < 0.0001).Conclusions: The magnitude of inspiratory effort relief as assessed by ΔPes variation within the first 2 hours of NIV was an early and accurate predictor of NIV outcome at 24 hours.Clinical trial registered with www.clinicaltrials.gov (NCT03826797).

Endobronchial valve positioning for alveolar-pleural fistula following ICU management complicating COVID-19 pneumonia.

BACKGROUND: The main clinical consequences of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection are pneumonia and respiratory failure even requiring mechanical ventilation. In this context, the lung parenchyma is highly prone to ventilator-related injury, with pneumothorax and persistent air leak as the most serious adverse events. So far, endobronchial valve (EBV) positioning has proved efficacious in treating air leaks with a high success rate. CASE PRESENTATION: We report, for the first time, two cases of patients affected by SARS-CoV-2-related pneumonia complicated with bacterial super-infection, experiencing pneumothorax and persistent air leaks after invasive mechanical ventilation. Despite the severity of respiratory failure both patients underwent rigid interventional bronchoscopy and were successfully treated through EBV positioning. CONCLUSIONS: Persistent air leaks may result from lung tissue damage due to a complex interaction between inflammation and ventilator-related injury (VILI), especially in the advanced stages of ARDS. EBV positioning seems to be a feasible and effective minimally invasive therapeutic option for treating this subset of patients.

Handling and Processing of Blood Specimens from Patients with COVID-19 for Safe Studies on Cell Phenotype and Cytokine Storm.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 heavily involves all those working in a laboratory. Samples from known infected patients or donors who are considered healthy can arrive, and a colleague might be asymptomatic but able to transmit the virus. Working in a clinical laboratory is posing several safety challenges. Few years ago, International Society for Advancement of Cytometry published guidelines to safely analyze and sort human samples that were revised in these days. We describe the procedures that we have been following since the first patient appeared in Italy, which have only slightly modified our standard one, being all human samples associated with risks. © 2020 International Society for Advancement of Cytometry.

Testicular pain as an unusual presentation of COVID-19: a brief review of SARS-CoV-2 and the testis.

RESEARCH QUESTION: Can the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus induce testis damage and dysfunction? DESIGN: This is the description of the case of a young man presenting with heavy testicular pain as the first symptom of COVID-19 infection. A review of the literature is also presented. RESULTS: SARS-CoV-2 may enter into the host cell by binding to angiotensin-converting enzyme 2. This receptor seems to be widely expressed in different testicular cell types, making possible the occurrence of orchitis in male patients with COVID-19 infection. From a review of the literature, it seems that there is currently no evidence of sexual transmission of SARS-CoV-2; however, the possibility of virus-induced testis damage and dysfunction cannot be excluded. CONCLUSIONS: Further studies are necessary on the pathological effect of SARS-CoV-2 in the male reproductive system and to ensure a proper andrological follow-up for male patients.

Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use.

Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.

Tracheostomy in the COVID-19 pandemic.

PURPOSE: The role of tracheostomy in COVID-19-related ARDS is unknown. Nowadays, there is no clear indication regarding the timing of tracheostomy in these patients. METHODS: We describe our synergic experience between ENT and ICU Departments at University Hospital of Modena underlining some controversial aspects that would be worth discussing tracheostomies in these patients. During the last 2 weeks, we performed 28 tracheostomies on patients with ARDS due to COVID-19 infection who were treated with IMV. RESULTS: No differences between percutaneous and surgical tracheostomy in terms of timing and no case of team virus infection. CONCLUSION: In our experience, tracheostomy should be performed only in selected patients within 7- and 14-day orotracheal intubation.

Use of Levosimendan in Intensive Care Unit Settings: An Opinion Paper.

Levosimendan is an inodilator that promotes cardiac contractility primarily through calcium sensitization of cardiac troponin C and vasodilatation via opening of adenosine triphosphate-sensitive potassium (KATP) channels in vascular smooth muscle cells; the drug also exerts organ-protective effects through a similar effect on mitochondrial KATP channels. This pharmacological profile identifies levosimendan as a drug that may have applications in a wide range of critical illness situations encountered in intensive care unit medicine: hemodynamic support in cardiogenic or septic shock; weaning from mechanical ventilation or from extracorporeal membrane oxygenation; and in the context of cardiorenal syndrome. This review, authored by experts from 9 European countries (Austria, Belgium, Czech republic, Finland, France, Germany, Italy, Sweden, and Switzerland), examines the clinical and experimental data for levosimendan in these situations and concludes that, in most instances, the evidence is encouraging, which is not the case with other cardioactive and vasoactive drugs routinely used in the intensive care unit. The size of the available studies is, however, limited and the data are in need of verification in larger controlled trials. Some proposals are offered for the aims and designs of these additional studies.

Incidence and outcome of invasive candidiasis in intensive care units (ICUs) in Europe: results of the EUCANDICU project.

BACKGROUND: The objective of this study was to assess the cumulative incidence of invasive candidiasis (IC) in intensive care units (ICUs) in Europe. METHODS: A multinational, multicenter, retrospective study was conducted in 23 ICUs in 9 European countries, representing the first phase of the candidemia/intra-abdominal candidiasis in European ICU project (EUCANDICU). RESULTS: During the study period, 570 episodes of ICU-acquired IC were observed, with a cumulative incidence of 7.07 episodes per 1000 ICU admissions, with important between-center variability. Separated, non-mutually exclusive cumulative incidences of candidemia and IAC were 5.52 and 1.84 episodes per 1000 ICU admissions, respectively. Crude 30-day mortality was 42%. Age (odds ratio [OR] 1.04 per year, 95% CI 1.02-1.06, p < 0.001), severe hepatic failure (OR 3.25, 95% 1.31-8.08, p 0.011), SOFA score at the onset of IC (OR 1.11 per point, 95% CI 1.04-1.17, p 0.001), and septic shock (OR 2.12, 95% CI 1.24-3.63, p 0.006) were associated with increased 30-day mortality in a secondary, exploratory analysis. CONCLUSIONS: The cumulative incidence of IC in 23 European ICUs was 7.07 episodes per 1000 ICU admissions. Future in-depth analyses will allow explaining part of the observed between-center variability, with the ultimate aim of helping to improve local infection control and antifungal stewardship projects and interventions.

Mortality in Patients With Septic Shock by Multidrug Resistant Bacteria: Risk Factors and Impact of Sepsis Treatments.

BACKGROUND:: Patients with septic shock by multidrug resistant (MDR) microorganism maybe considered a specific population of critical patients at very high risk of death in whom the effects of standard sepsis treatment has never been assessed. The objective of this retrospective analysis was to evaluate the risk factors for 30-day mortality and the impact of sepsis management in patients with septic shock caused by MDR bacteria. METHODS:: Patients with septic shock by MDR bacteria admitted to the mixed intensive care unit (ICU) of Modena University Hospital during a 6-year period were studied. The clinical and microbiological characteristics and sepsis treatments provided were analyzed and compared between survivors (S) and nonsurvivors (NS) at 30 days after septic shock appearance. RESULTS:: Ninety-four patients were studied. All therapeutic interventions applied to patients during their ICU stay did not show statistical significance between S and NS groups, except for administration of immunoglobulin M (IgM) preparation which were provided more frequently in S group ( P < .05). At the multivariate adjusted analysis, preexisting cancer (odds ratio [OR] = 2.965) and Acinetobacter baumannii infections (OR = 3.197) were independently correlated with an increased risk of 30-day mortality, whereas treatment with IgM preparation was protective (OR = 0.283). CONCLUSIONS:: This retrospective study showed that in patients with septic shock caused by MDR bacteria, history of cancer and infection sustained by A baumannii increase the risk of mortality and that standard sepsis treatments do not seem to provide any protective effect. Adjunctive therapy with IgM preparation seems to be beneficial, but further appropriate studies are needed to confirm the results observed.

A Position Paper on IgM-Enriched Intravenous Immunoglobulin Adjunctive Therapy in Severe Acute Bacterial Infections: The TO-PIRO SCORE Proposal.

IgM-enriched immunoglobulins (e-IgM) may be useful in patients with severe acute bacterial infections. The evidence for the administration of e-IgM is not extensive and a definitive consensus has never been reached on its best use in patients with acute infections as well as in critically ill patients. However, the official indication in several countries, including Italy, is quite wide and mainly refers to supportive treatment of patients with acute severe bacterial infections. A multidisciplinary meeting of Italian Experts in Infectious Diseases, Anesthesia and Critical Care, Pneumology, Microbiology and Oncohaematology aimed to produce a statement on the best practical methodological score that could improve the use of e-IgM in patients with different infections, variable severity of disease and etiology. The Expert Panel reviewed the literature and the available guidelines, discussed the experience and eventually proposed to adapt the PIRO score to the practical methodological needs of a simple tool that could guide the administration of e-IgM.

Real-time monitoring of Pseudomonas aeruginosa biofilm formation on endotracheal tubes in vitro.

BACKGROUND: Pseudomonas aeruginosa is an opportunistic bacterial pathogen responsible for both acute and chronic infections in humans. In particular, its ability to form biofilm, on biotic and abiotic surfaces, makes it particularly resistant to host's immune defenses and current antibiotic therapies as well. Innovative antimicrobial materials, like hydrogel, silver salts or nanoparticles have been used to cover new generation catheters with promising results. Nevertheless, biofilm remains a major health problem. For instance, biofilm produced onto endotracheal tubes (ETT) of ventilated patients plays a relevant role in the onset of ventilation-associated pneumonia. Most of our knowledge on Pseudomonas aeruginosa biofilm derives from in vitro studies carried out on abiotic surfaces, such as polystyrene microplates or plastic materials used for ETT manufacturing. However, these approaches often provide underestimated results since other parameters, in addition to bacterial features (i.e. shape and material composition of ETT) might strongly influence biofilm formation. RESULTS: We used an already established biofilm development assay on medically-relevant foreign devices (CVC catheters) by a stably transformed bioluminescent (BLI)-Pseudomonas aeruginosa strain, in order to follow up biofilm formation on ETT by bioluminescence detection. Our results demonstrated that it is possible: i) to monitor BLI-Pseudomonas aeruginosa biofilm development on ETT pieces in real-time, ii) to evaluate the three-dimensional structure of biofilm directly on ETT, iii) to assess metabolic behavior and the production of microbial virulence traits of bacteria embedded on ETT-biofilm. CONCLUSIONS: Overall, we were able to standardize a rapid and easy-to-perform in vitro model for real-time monitoring Pseudomonas aeruginosa biofilm formation directly onto ETT pieces, taking into account not only microbial factors, but also ETT shape and material. Our study provides a rapid method for future screening and validation of novel antimicrobial drugs as well as for the evaluation of novel biomaterials employed in the production of new classes of ETT.

Procalcitonin-guided antibiotic therapy: an expert consensus.

BACKGROUND: Procalcitonin (PCT) is a useful biomarker of bacterial infection and its use is associated to reduced duration of antibiotic therapy in the setting of intensive care medicine. To address the need of practical guidance for the use of PCT in various clinical settings, a group of experts was invited to participate at a consensus process with the aims of defining the rationale for appropriate use of PCT and for improving the management of critically ill patients with sepsis. METHODS: A group of 14 experts from anesthesiology and critical care, infectious diseases, internal medicine, pulmonology, clinical microbiology, laboratory medicine, clinical pharmacology and methodology provided expert opinion through a modified Delphi process, after a comprehensive literature review. RESULTS: The appropriateness of use of PCT in terms of diagnosis, prognosis and antimicrobial stewardship was assessed for different scenarios or settings such us management of infection in the emergency department, regular wards, surgical wards or in the intensive care unit. Similarly, appropriateness and timing of PCT measurement were evaluated. All the process consisted in three Delphi rounds. CONCLUSIONS: PCT use is appropriate in algorithms for antibiotic de-escalation and discontinuation. In this case, reproducible, high sensitive assays should be used. However, initiation or escalation of antibiotic therapy in specific scenarios, including acute respiratory infections, should not be based solely on PCT serum levels. Clinical and radiological findings, evaluation of severity of illness and of patient's characteristics should be taken into proper account in order to correctly interpret PCT results.

Oxygen in the critically ill: friend or foe?

PURPOSE OF REVIEW: To examine the potential harmful effects of hyperoxia and summarize the results of most recent clinical studies evaluating oxygen therapy in critically ill patients. RECENT FINDINGS: Excessive oxygen supplementation may have detrimental pulmonary and systemic effects because of enhanced oxidative stress and inflammation. Hyperoxia-induced lung injury includes altered surfactant protein composition, reduced mucociliary clearance and histological damage, resulting in atelectasis, reduced lung compliance and increased risk of infections. Hyperoxemia causes vasoconstriction, reduction in coronary blood flow and cardiac output and may alter microvascular perfusion. Observational studies showed a close relationship between hyperoxemia and increased mortality in several subsets of critically ill patients. In absence of hypoxemia, the routine use of oxygen therapy in patients with myocardial infarction, stroke, traumatic brain injury, cardiac arrest and sepsis, showed no benefit but rather it seems to be harmful. In patients admitted to intensive care unit, a conservative oxygen therapy aimed to maintain arterial oxygenation within physiological range has been proved to be well tolerated and may improve outcome. SUMMARY: Liberal O2 use and unnecessary hyperoxia may be detrimental in critically ill patients. The current evidence supports the use of a conservative strategy in O2 therapy to avoid patient exposure to unnecessary hyperoxemia.