Antimicrobial De-Escalation in Critically Ill Patients.

Antimicrobial de-escalation (ADE) is defined as the discontinuation of one or more antimicrobials in empirical therapy, or the replacement of a broad-spectrum antimicrobial with a narrower-spectrum antimicrobial. The aim of this review is to provide an overview of the available literature on the effectiveness and safety of ADE in critically ill patients, with a focus on special conditions such as anti-fungal therapy and high-risk categories. Although it is widely considered a safe strategy for antimicrobial stewardship (AMS), to date, there has been no assessment of the effect of de-escalation on the development of resistance. Conversely, some authors suggest that prolonged antibiotic treatment may be a side effect of de-escalation, especially in high-risk categories such as neutropenic critically ill patients and intra-abdominal infections (IAIs). Moreover, microbiological documentation is crucial for increasing ADE rates in critically ill patients with infections, and efforts should be focused on exploring new diagnostic tools to accelerate pathogen identification. For these reasons, ADE can be safely used in patients with infections, as confirmed by high-quality and reliable microbiological samplings, although further studies are warranted to clarify its applicability in selected populations.

Lung microbiota composition, respiratory mechanics, and outcomes in COVID-19-related ARDS.

Few data are available on the lung microbiota composition of patients with coronavirus disease 2019-related acute respiratory distress syndrome (C-ARDS) receiving invasive mechanical ventilation (IMV). Moreover, it has never been investigated whether there is a potential correlation between lung microbiota communities and respiratory mechanics. We performed a prospective observational study in two intensive care units of a university hospital in Italy. Lung microbiota was investigated by bacterial 16S rRNA gene sequencing, performed on bronchoalveolar lavage fluid samples withdrawn after intubation. The lung bacterial communities were analyzed after stratification by respiratory system compliance/predicted body weight (Crs) and ventilatory ratio (VR). Weaning from IMV and hospital survival were assessed as secondary outcomes. In 70 C-ARDS patients requiring IMV from 1 April through 31 December 2020, the lung microbiota composition (phylum taxonomic level, permutational multivariate analysis of variance test) significantly differed between who had low Crs vs those with high Crs (P = 0.010), as well as in patients with low VR vs high VR (P = 0.012). As difference-driving taxa, Proteobacteria (P = 0.017) were more dominant and Firmicutes (P = 0.040) were less dominant in low- vs high-Crs patients. Similarly, Proteobacteria were more dominant in low- vs high-VR patients (P = 0.013). After multivariable regression analysis, we further observed lung microbiota diversity as a negative predictor of weaning from IMV and hospital survival (hazard ratio = 3.31; 95% confidence interval, 1.52-7.20, P = 0.048). C-ARDS patients with low Crs/low VR had a Proteobacteria-dominated lung microbiota. Whether patients with a more diverse lung bacterial community may have more chances to be weaned from IMV and discharged alive from the hospital warrants further large-scale investigations. IMPORTANCE: Lung microbiota characteristics were demonstrated to predict ventilator-free days and weaning from mechanical ventilation in patients with acute respiratory distress syndrome (ARDS). In this study, we observed that in severe coronavirus disease 2019 patients with ARDS who require invasive mechanical ventilation, lung microbiota characteristics were associated with respiratory mechanics. Specifically, the lung microbiota of patients with low respiratory system compliance and low ventilatory ratio was characterized by Proteobacteria dominance. Moreover, after multivariable regression analysis, we also found an association between patients' microbiota diversity and a higher possibility of being weaned from mechanical ventilation and discharged alive from the hospital. For these reasons, lung microbiota characterization may help to stratify patient characteristics and orient the delivery of target interventions. (This study has been registered at ClinicalTrials.gov on 17 February 2020 under identifier NCT04271345.).Registered at ClinicalTrials.gov, 17 February 2020 (NCT0427135).

Update on vitamin D role in severe infections and sepsis.

Severe infections frequently require admission to the intensive care unit and cause life-threatening complications in critically ill patients. In this setting, severe infections are acknowledged as prerequisites for the development of sepsis, whose pathophysiology implies a dysregulated host response to pathogens, leading to disability and mortality worldwide.Vitamin D is a secosteroid hormone that plays a pivotal role to maintain immune system homeostasis, which is of paramount importance to resolve infection and modulate the burden of sepsis. Specifically, vitamin D deficiency has been widely reported in critically ill patients and represents a risk factor for the development of severe infections, sepsis and worse clinical outcomes. Several studies have demonstrated the feasibility, safety and effectiveness of vitamin D supplementation strategies to improve vitamin D body content, but conflictual results support its benefit in general populations of critically ill patients. In contrast, small randomised clinical trials reported that vitamin D supplementation may improve host-defence to pathogen invasion via the production of cathelicidin and specific cytokines. Nonetheless, no large scale investigations have been designed to specifically assess the impact of vitamin D supplementation on the outcome of critically ill septic patients admitted to the intensive care unit.

Clinical features and 28-day mortality predictors of vaccinated patients admitted to a COVID-19 ICU hub in Italy.

BACKGROUND: COVID-19 vaccination has been proved to be effective in preventing hospitalization and illness progression, even though data on mortality of vaccinated patients in the intensive care unit (ICU) are conflicting. The aim of this study was to investigate the characteristics of vaccinated patients admitted to ICU according to their immunization cycle and to outline the risk factors for 28-day mortality. This observational study included adult patients admitted to ICU for acute respiratory failure (ARF) due to SARS-CoV-2 and who had received at least one dose of vaccine. RESULTS: Fully vaccination was defined as a complete primary cycle from < 120 days or a booster dose from > 14 days. All the other patients were named partially vaccinated. One-hundred sixty patients (91 fully and 69 partially vaccinated) resulted eligible, showing a 28-day mortality rate of 51.9%. Compared to partially vaccinated, fully vaccinated were younger (69 [60-77.5] vs. 74 [66-79] years, p 0.029), more frequently immunocompromised (39.56% vs. 14.39%, p 0.003), and affected by at least one comorbidity (90.11% vs 78.26%, p 0.045), mainly chronic kidney disease (CKD) (36.26% vs 20.29%, p 0.035). At multivariable analysis, independent predictors of 28-day mortality were as follows: older age [OR 1.05 (CI 95% 1.01-1.08), p 0.005], history of chronic obstructive pulmonary disease (COPD) [OR 3.05 (CI 95% 1.28-7.30), p 0.012], immunosuppression [OR 3.70 (CI 95% 1.63-8.40), p 0.002], and admission respiratory and hemodynamic status [PaO2/FiO2 and septic shock: OR 0.99 (CI 95% 0.98-0.99), p 0.009 and 2.74 (CI 95% 1.16-6.48), p 0.022, respectively]. CONCLUSIONS: Despite a full vaccination cycle, severe COVID-19 may occur in patients with relevant comorbidities, especially immunosuppression and CKD. Regardless the immunization status, predisposing conditions (i.e., older age, COPD, and immunosuppression) and a severe clinical presentation were predictors of 28-day mortality.

Endotoxin activity trend and multi-organ dysfunction in critically ill patients with septic shock, who received Polymyxin-B hemadsorption: A multicenter, prospective, observational study.

BACKGROUND: The baseline endotoxin activity (EAT0) may predict the outcome of critically ill septic patients who receive Polymyxin-B hemadsorption (PMX-HA), however, the clinical implications of specific EA trends remain unknown. METHODS: Subgroup analysis of the prospective, multicenter, observational study EUPHAS2. We included 50 critically ill patients with septic shock and EAT0 ≥ 0.6, who received PMX-HA. The primary outcome of the study was the EA and SOFA score progression from T0 to 120 h afterwards (T120). Secondary outcomes included the EA and SOFA score progression in whom had EA at 48 h (EAT48) < 0.6 (EA responders, EA-R) versus who had not (EA non-responders, EA-NR). RESULTS: Septic shock was mainly caused by 27 abdominal (54%) and 17 pulmonary (34%) infections, predominantly due to Gram negative bacteria (39 patients, 78%). The SAPS II score was 67.5 [52.8-82.3] and predicted a mortality rate of 75%. Between T0 and T120, the EA decreased (p < 0.001), while the SOFA score and the Inotropic Score (IS) improved (p < 0.001). In comparison with EA-NR (18 patients, 47%), the EA-R group (23 patients, 53%) showed faster IS improvement and lower requirement of continuous renal replacement therapy (CRRT) during the ICU stay. Overall hospital mortality occurred in 18 patients (36%). CONCLUSIONS: In critically ill patients with septic shock and EAT0 ≥ 0.6 who received PMX-HA, EA decreased and SOFA score improved over 120 h. In whom high EA resolved within 48 h, IS improvement was faster and CRRT requirement was lower compared with patients with EAT48 ≥ 0.6.

Clinical implications of endotoxin activity and Polymyxin-B hemoperfusion in critically ill patients with septic cardiomyopathy: A single-center, retrospective, observational study.

BACKGROUND: To explore the association between endotoxin activity (EA) and septic cardiomyopathy (SCM), the relationship between endotoxin removal by Polymyxin-B hemoperfusion (PMX-HP) and recovery from SCM (R-SCM), and the correlation between R-SCM and the 28-day mortality in septic patients admitted to the intensive care unit (ICU). METHODS: Observational study that included patients admitted to two ICUs of a tertiary university hospital between April 2011 and December 2019, who received PMX-HP for sepsis/septic shock. The SCM and R-SCM were assessed by transthoracic echocardiography. RESULTS: Among 148 patients, SCM was diagnosed in 60 (46%) of them and had no relationship with median EA (SCM group: 0.73; no-SCM group: 0.66, p = 0.48). Recovery from SCM was observed in 24 patients (49%) and was independently associated with the PMX-HP (OR 4.19, 95%CI [1.22, 14.3]; p = 0.02) and the SAPS2 II score (OR 0.94, 95%CI [0.9, 0.98]; p = 0.006). In the SCM group, the 28-day mortality was 60% and was independently predicted by R-SCM (OR 0.02, 95%CI [0.001, 0.3] p = 0.005) and SAPS II score (OR 1.11, 95%CI [1.01, 1.23] p = 0.037). CONCLUSIONS: In septic patients, EA was not associated with SCM. However, endotoxin removal by Polymyxin-B hemoperfusion was associated with recovery from cardiomyopathy, which was a predictor of lower 28-day mortality.

Bloodstream infections in COVID-19 patients undergoing extracorporeal membrane oxygenation in ICU: An observational cohort study.

BACKGROUND: COVID-19 patients undergoing ECMO are at highly increased risk of nosocomial infections. OBJECTIVES: To study incidence, clinical outcomes and microbiological features of bloodstream infections (BSI) occurring during ECMO in COVID-19 patients. METHODS: Observational prospective cohort study enrolling consecutive COVID-19 patients undergoing veno-venous-ECMO in an Italian ICU from March 2020 to March 2022. RESULTS: In the study population of 68 patients (age 53 [49-60] years, 82% males), 30 (44%) developed bloodstream infections (BSI group) while 38 did not (N-BSI group) with an incidence of 32 events/1000 days of ECMO. In BSI group pre-ECMO respiratory support was shorter (6 [4-9] vs 9 [5-12] days, p = 0.02) and ECMO treatment was longer (18 [10-29] vs 11 [7-18] days, p = 0.03) than in N-BSI group. The overall ECMO and ICU mortality were 50% and 59%, respectively, without any inter-group difference (p = 1.00). A longer ECMO treatment was independently correlated with higher rate of BSI (p = 0.04, OR [95% CI] 1.06 [1.02-1.11]). Sixteen primary and 14 secondary infectious events were documented. Gram-positive pathogens were more common in primary than secondary BSI (88% vs 43%, p = 0.02) and Enterococcus faecalis (56%) was the most frequent one. Conversely, Gram-negative microorganisms were more often isolated in secondary rather than primary BSI (57% vs 13%, p = 0.02), with Acinetobacter baumannii (21%) and Pseudomonas aeruginosa (21%) as most represented species. The administration of Sars-CoV-2 antiviral drug showed independent correlation with a reduced rate of ICU mortality (p = 0.01, OR [95% CI] 0.22 [0.07-0.73]). CONCLUSIONS: Bloodstream infections represented a frequent complication without worsening clinical outcomes in our COVID-19 patients undergoing ECMO. Primary and secondary BSI events showed peculiar microbiological profiles.

An Observational Study to Develop a Predictive Model for Bacterial Pneumonia Diagnosis in Severe COVID-19 Patients-C19-PNEUMOSCORE.

In COVID-19 patients, antibiotics overuse is still an issue. A predictive scoring model for the diagnosis of bacterial pneumonia at intensive care unit (ICU) admission would be a useful stewardship tool. We performed a multicenter observational study including 331 COVID-19 patients requiring invasive mechanical ventilation at ICU admission; 179 patients with bacterial pneumonia; and 152 displaying negative lower-respiratory samplings. A multivariable logistic regression model was built to identify predictors of pulmonary co-infections, and a composite risk score was developed using ß-coefficients. We identified seven variables as predictors of bacterial pneumonia: vaccination status (OR 7.01; 95% CI, 1.73-28.39); chronic kidney disease (OR 3.16; 95% CI, 1.15-8.71); pre-ICU hospital length of stay ≥ 5 days (OR 1.94; 95% CI, 1.11-3.4); neutrophils ≥ 9.41 × 109/L (OR 1.96; 95% CI, 1.16-3.30); procalcitonin ≥ 0.2 ng/mL (OR 5.09; 95% CI, 2.93-8.84); C-reactive protein ≥ 107.6 mg/L (OR 1.99; 95% CI, 1.15-3.46); and Brixia chest X-ray score ≥ 9 (OR 2.03; 95% CI, 1.19-3.45). A predictive score (C19-PNEUMOSCORE), ranging from 0 to 9, was obtained by assigning one point to each variable, except from procalcitonin and vaccine status, which gained two points each. At a cut-off of ≥3, the model exhibited a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 84.9%, 55.9%, 69.4%, 75.9%, and 71.6%, respectively. C19-PNEUMOSCORE may be an easy-to-use bedside composite tool for the early identification of severe COVID-19 patients with pulmonary bacterial co-infection at ICU admission. Its implementation may help clinicians to optimize antibiotics administration in this setting.

Personalized Respiratory Support in ARDS: A Physiology-to-Bedside Review.

Acute respiratory distress syndrome (ARDS) is a leading cause of disability and mortality worldwide, and while no specific etiologic interventions have been shown to improve outcomes, noninvasive and invasive respiratory support strategies are life-saving interventions that allow time for lung recovery. However, the inappropriate management of these strategies, which neglects the unique features of respiratory, lung, and chest wall mechanics may result in disease progression, such as patient self-inflicted lung injury during spontaneous breathing or by ventilator-induced lung injury during invasive mechanical ventilation. ARDS characteristics are highly heterogeneous; therefore, a physiology-based approach is strongly advocated to titrate the delivery and management of respiratory support strategies to match patient characteristics and needs to limit ARDS progression. Several tools have been implemented in clinical practice to aid the clinician in identifying the ARDS sub-phenotypes based on physiological peculiarities (inspiratory effort, respiratory mechanics, and recruitability), thus allowing for the appropriate application of personalized supportive care. In this narrative review, we provide an overview of noninvasive and invasive respiratory support strategies, as well as discuss how identifying ARDS sub-phenotypes in daily practice can help clinicians to deliver personalized respiratory support and potentially improve patient outcomes.

Cefiderocol-containing regimens for the treatment of carbapenem-resistant A. baumannii ventilator-associated pneumonia: a propensity-weighted cohort study.

Background: Cefiderocol is a novel ß-lactam with activity against carbapenem-resistant Acinetobacter baumannii (CRAB), but its role in CRAB pulmonary infections is controversial due to limited evidence. Objectives: To assess the association between cefiderocol-containing regimens treatment and 28-day mortality in carbapenem-resistant A. baumannii ventilator-associated pneumonia (VAP). Methods: An observational cohort study including critically ill COVID-19 patients with CRAB-VAP admitted to two ICUs of a large academic hospital in Rome between September 2020 and December 2022. The primary outcome was 28-day all-cause mortality. A propensity score was created to balance the cefiderocol- and non-cefiderocol-containing groups. A propensity-weighted multiple logistic regression model was calculated to evaluate risk factors for 28-day mortality. Survival curves were calculated using the Kaplan-Meier method. Results: 121 patients were enrolled, 55 were treated with cefiderocol- and 66 with non-cefiderocol-containing regimens. The 28-day all-cause mortality was 56% (68/121). A statistically significant difference in 28-day mortality was found between cefiderocol- and non-cefiderocol- containing regimens groups (44% versus 67%, P = 0.011). In the propensity-adjusted multiple logistic regression, cefiderocol (OR 0.35 95% CI 0.14, 0.83) was a predictor of 28-day survival, Charlson comorbidity index (OR 1.36 95% CI 1.16, 1.78), SOFA score (OR 1.24 95% CI 1.09, 1.57) and septic shock (OR 3.71 95% CI 1.44, 12.73) were all associated with increased 28-day mortality. Conclusion: Cefiderocol-containing regimens were associated with reduced 28-day mortality in CRAB-VAP. The sample size and the observational design limit the study's conclusions. Future RCTs are needed to establish cefiderocol's definite role in these infections.

Sequential Extracorporeal Therapy in Sepsis.

Sepsis is a life-threatening syndrome initiated by a dysregulated host response to infection. Maladaptive inflammatory burst damages host tissues and causes organ dysfunction, the burden of which has been demonstrated as the paramount predictor of worse clinical outcomes. In this setting, septic shock represents the most lethal complication of sepsis and implies profound alterations of both the cardiovascular system and cellular metabolism with consequent high mortality rate. Although an increasing amount of evidence attempts to characterize this clinical condition, the complexity of multiple interconnections between underlying pathophysiological pathways requires further investigations. Accordingly, most therapeutic interventions remain purely supportive and should be integrated in light of the continuous organ cross-talk, in order to match a patient's specific needs. In this context, different organ supports may be combined to replace multiple organ dysfunctions through the application of sequential extracorporeal therapy in sepsis (SETS). In this chapter, we provide an overview of sepsis-induced organ dysfunction, focusing on the pathophysiological pathways that are triggered by endotoxin. Based on the need to apply specific blood purification techniques in specific time windows with different targets, we suggest a sequence of extracorporeal therapies. Accordingly, we reported the hypothesis that sepsis-induced organ dysfunction may benefit the most from SETS. Finally, we point out basic principles of this innovative approach and describe a multifunctional platform that allows SETS, in order to make clinicians aware of this new therapeutic frontier for critically ill patients.

Sodium glucose co-transporter-2 inhibitors in intensive care unit patients with type 2 diabetes: a pilot case control study.

BACKGROUND: Sodium glucose co-transporter-2 (SGLT2) inhibitors improve long-term cardiovascular and renal outcomes in individuals with type 2 diabetes. However, the safety of SGLT2 inhibitors in ICU patients with type 2 diabetes is uncertain. We aimed to perform a pilot study to assess the relationship between empagliflozin therapy and biochemical, and clinical outcomes in such patients. METHODS: We included 18 ICU patients with type 2 diabetes receiving empagliflozin (10 mg daily) and insulin to target glucose range of 10-14 mmol/l according to our liberal glucose control protocol for patients with diabetes (treatment group). Treatment group patients were matched on age, glycated hemoglobin A1c, and ICU duration with 72 ICU patients with type 2 diabetes exposed to the same target glucose range but who did not receive empagliflozin (control group). We compared changes in electrolyte and acid-base parameters, hypoglycemia, ketoacidosis, worsening kidney function, urine culture findings, and hospital mortality between the groups. RESULTS: Median (IQR) maximum increase in sodium and chloride levels were 3 (1-10) mmol/l and 3 (2-8) mmol/l in the control group and 9 (3-12) mmol/l and 8 (3-10) mmol/l in the treatment group (P = 0.045 for sodium, P = 0.059 for chloride). We observed no differences in strong ion difference, pH or base excess. Overall, 6% developed hypoglycemia in each group. No patient in the treatment group and one patient in the control group developed ketoacidosis. Worsening kidney function occurred in 18% and 29% of treatment and control group patients, respectively (P = 0.54). Urine cultures were positive in 22% of treatment group patients and 13% of control group patients (P = 0.28). Overall, 17% of treatment group patients and 19% of control group patients died in hospital (P = 0.79). CONCLUSIONS: In our pilot study of ICU patients with type 2 diabetes, empagliflozin therapy was associated with increases in sodium and chloride levels but was not significantly associated with acid-base changes, hypoglycemia, ketoacidosis, worsening kidney function, bacteriuria, or mortality.

Antimicrobial Exposure in Critically Ill Patients with Sepsis-Associated Multi-Organ Dysfunction Requiring Extracorporeal Organ Support: A Narrative Review.

Sepsis is a leading cause of disability and mortality worldwide. The pathophysiology of sepsis relies on the maladaptive host response to pathogens that fosters unbalanced organ crosstalk and induces multi-organ dysfunction, whose severity was directly associated with mortality. In septic patients, etiologic interventions aiming to reduce the pathogen load via appropriate antimicrobial therapy and the effective control of the source infection were demonstrated to improve clinical outcomes. Nonetheless, extracorporeal organ support represents a complementary intervention that may play a role in mitigating life-threatening complications caused by sepsis-associated multi-organ dysfunction. In this setting, an increasing amount of research raised concerns about the risk of suboptimal antimicrobial exposure in critically ill patients with sepsis, which may be worsened by the concomitant delivery of extracorporeal organ support. Accordingly, several strategies have been implemented to overcome this issue. In this narrative review, we discussed the pharmacokinetic features of antimicrobials and mechanisms that may favor drug removal during renal replacement therapy, coupled plasma filtration and absorption, therapeutic plasma exchange, hemoperfusion, extracorporeal CO2 removal and extracorporeal membrane oxygenation. We also provided an overview of evidence-based strategies that may help the physician to safely prescribe effective antimicrobial doses in critically ill patients with sepsis-associated multi-organ dysfunction who receive extracorporeal organ support.

Use of High-Dose Nebulized Colistimethate in Patients with Colistin-Only Susceptible Acinetobacter baumannii VAP: Clinical, Pharmacokinetic and Microbiome Features.

(1) Background: Colistin-only susceptible (COS) Acinetobacter baumannii (AB) ventilator-associated pneumonia (VAP) represents a clinical challenge in the Intensive Care Unit (ICU) due to the negligible lung diffusion of this molecule and the low-grade evidence on efficacy of its nebulization. (2) Methods: We conducted a prospective observational study on 134 ICU patients with COS-AB VAP to describe the 'real life' clinical use of high-dose (5 MIU q8) aerosolized colistin, using a vibrating mesh nebulizer. Lung pharmacokinetics and microbiome features were investigated. (3) Results: Patients were enrolled during the COVID-19 pandemic with the ICU presenting a SAPS II of 42 [32-57]. At VAP diagnosis, the median PaO2/FiO2 was 120 [100-164], 40.3% were in septic shock, and 24.6% had secondary bacteremia. The twenty-eight day mortality was 50.7% with 60.4% and 40.3% rates of clinical cure and microbiological eradication, respectively. We did not observe any drug-related adverse events. Epithelial lining fluid colistin concentrations were far above the CRAB minimal-inhibitory concentration and the duration of nebulized therapy was an independent predictor of microbiological eradication (12 [9.75-14] vs. 7 [4-13] days, OR (95% CI): 1.069 (1.003-1.138), p = 0.039). (4) Conclusions: High-dose and prolonged colistin nebulization, using a vibrating mesh, was a safe adjunctive therapeutic strategy for COS-AB VAP. Its right place and efficacy in this setting warrant investigation in interventional studies.

Use of an innovative cuff pressure control and subglottic secretions drainage system in COVID-19 ARDS patients undergoing pronation.

We conducted a proof of concept study where Anapnoguard endotracheal tubes and its control unit were used in 15 patients with COVID-19 acute respiratory distress syndrome. Anapnoguard system provides suction, venting, rinsing of subglottic space and controls cuff pressure detecting air leakage through the cuff. Alpha-amylase and pepsin levels, as oropharyngeal and gastric microaspiration markers, were assessed from 85 tracheal aspirates in the first 72 h after connection to the system. Oropharyngeal microaspiration occurred in 47 cases (55%). Episodes of gastric microaspiration were not detected. Patient positioning, either prone or supine, did not affect alpha-amylase and pepsin concentration in tracheal secretions. Ventilator-associated pneumonia (VAP) rate was 40%. The use of the AG system provided effective cuff pressure control and subglottic secretions drainage. Despite this, no reduction in the incidence of VAP has been demonstrated, compared to data reported in the current COVID-19 literature. The value of this new technology is worth of being evaluated for the prevention of ventilator-associated respiratory tract infections.

Pharmacological Treatment of Acute Psychiatric Symptoms in COVID-19 Patients: A Systematic Review and a Case Series.

Delirium and psychomotor agitation are relevant clinical conditions that may develop during COVID-19 infection, especially in intensive care unit (ICU) settings. The psychopharmacological management of these conditions is receiving increasing interest in psychiatry, considering hyperkinetic delirium as one of the most common neuropsychiatries acute consequences in COVID-19 recovery patients. However, there are no actual internationally validated guidelines about this topic, due to the relatively newly introduced clinical condition; in addition, a standardized psychopharmacologic treatment of these cases is a complex goal to achieve due to the risk of both drug-drug interactions and the vulnerable conditions of those patients. The aim of this systematic review and case series is to evaluate and gather the scientific evidence on pharmacologic handling during delirium in COVID-19 patients to provide practical recommendations on the optimal management of psychotropic medication in these kinds of patients. The electronic databases PubMed, Embase and Web of Science were reviewed to identify studies, in accordance with the PRISMA guidelines. At the end of the selection process, a total of 21 studies (n = 2063) were included. We also collected a case series of acute psychomotor agitation in COVID-19 patients hospitalized in ICU. Our results showed how the symptom-based choice of the psychotropic medication is crucial, and even most of the psychotropic drug classes showed good safety, one must not underestimate the possible drug interactions and also the possible decrease in vital functions which need to be strictly monitored especially during treatment with some kinds of molecules. We believe that the evidence-based recommendations highlighted in the present research will enhance the current knowledge and could provide better management of these patients.

Remdesivir plus Dexamethasone in COVID-19: A cohort study of severe patients requiring high flow oxygen therapy or non-invasive ventilation.

INTRODUCTION: Remdesivir and Dexamethasone represent the cornerstone of therapy for critically ill patients with acute hypoxemic respiratory failure caused by Coronavirus Disease 2019 (COVID-19). However, clinical efficacy and safety of concomitant administration of Remdesivir and Dexamethasone (Rem-Dexa) in severe COVID-19 patients on high flow oxygen therapy (HFOT) or non-invasive ventilation (NIV) remains unknown. MATERIALS AND METHODS: Prospective cohort study that was performed in two medical Intensive Care Units (ICUs) of a tertiary university hospital. The clinical impact of Rem-Dexa administration in hypoxemic patients with COVID-19, who required NIV or HFOT and selected on the simplified acute physiology score II, the sequential organ failure assessment score and the Charlson Comorbidity Index score, was investigated. The primary outcome was 28-day intubation rate; secondary outcomes were end-of-treatment clinical improvement and PaO2/FiO2 ratio, laboratory abnormalities and clinical complications, ICU and hospital length of stay, 28-day and 90-day mortality. RESULTS: We included 132 patients and found that 28-day intubation rate was significantly lower among Rem-Dexa group (19.7% vs 48.5%, p<0.01). Although the end-of-treatment clinical improvement was larger among Rem-Dexa group (69.7% vs 51.5%, p = 0.05), the 28-day and 90-day mortalities were similar (4.5% and 10.6% vs. 15.2% and 16.7%; p = 0.08 and p = 0.45, respectively). The logistic regression and Cox-regression models showed that concomitant Rem-Dexa therapy was associated with a reduction of 28-day intubation rate (OR 0.22, CI95% 0.05-0.94, p = 0.04), in absence of laboratory abnormalities and clinical complications (p = ns). CONCLUSIONS: In COVID-19 critically ill patients receiving HFO or NIV, 28-day intubation rate was lower in patients who received Rem-Dexa and this finding corresponded to lower end-of-treatment clinical improvement. The individual contribution of either Remdesevir or Dexamethasone to the observed clinical effect should be further investigated.

Characteristic of IgA and IgG antibody response to SARS-CoV-2 infection in an Italian referral COVID-19 Hospital.

INTRODUCTION: Antibody response plays a fundamental role in the natural history of infectious disease. A better understanding of the immune response in patients with SARS-CoV-2 infection could be important for identifying patients at greater risk of developing a more severe form of disease and with a worse prognosis. METHODS: We performed a cross-sectional analysis to determine the presence and the levels of both anti-SARS-CoV-2 IgG and IgA in a cohort of hospitalized patients with confirmed infection at different times in the natural history of the disease. Patients enrolled when admitted at the emergency department were prospectively followed up during hospital stay. RESULTS: Overall, 131 patients were considered with a total of 237 samples processed. Cross-sectional analysis showed that seroconversion for IgA seems to occur between days 6 and 15, while IgG response seems to occur slightly later, peaking at day 20 after symptoms onset. Both IgA and IgG were maintained beyond 2 months. Severe patients showed a higher IgA response compared with mild patients when analyzing optical density (8.3 versus 5.6, p < 0.001). Prospective analysis conducted on 55 patients confirmed that IgA appear slightly earlier than IgG. After stratifying for the severity of disease, both the IgA and IgG responses were more vigorous in severe cases. Moreover, while IgG tended to stabilize, there was a relevant decline after the first month of IgA levels in mild cases. CONCLUSION: IgA and IgG antibody response is closely related, although seroconversion for IgA occurs earlier. Both IgA and IgG are maintained beyond 2 months. Severe patients showed a more vigorous IgA and IgG response. IgA levels seem to decline after 1 month since the onset of symptoms in mild cases. Our results should be interpreted with cautions due to several limitations in our study, mainly the small number of cases, lack of data on viral load and clinical setting.

Non-invasive ventilatory support and high-flow nasal oxygen as first-line treatment of acute hypoxemic respiratory failure and ARDS.

The role of non-invasive respiratory support (high-flow nasal oxygen and noninvasive ventilation) in the management of acute hypoxemic respiratory failure and acute respiratory distress syndrome is debated. The oxygenation improvement coupled with lung and diaphragm protection produced by non-invasive support may help to avoid endotracheal intubation, which prevents the complications of sedation and invasive mechanical ventilation. However, spontaneous breathing in patients with lung injury carries the risk that vigorous inspiratory effort, combined or not with mechanical increases in inspiratory airway pressure, produces high transpulmonary pressure swings and local lung overstretch. This ultimately results in additional lung damage (patient self-inflicted lung injury), so that patients intubated after a trial of noninvasive support are burdened by increased mortality. Reducing inspiratory effort by high-flow nasal oxygen or delivery of sustained positive end-expiratory pressure through the helmet interface may reduce these risks. In this physiology-to-bedside review, we provide an updated overview about the role of noninvasive respiratory support strategies as early treatment of hypoxemic respiratory failure in the intensive care unit. Noninvasive strategies appear safe and effective in mild-to-moderate hypoxemia (PaO2/FiO2 > 150 mmHg), while they can yield delayed intubation with increased mortality in a significant proportion of moderate-to-severe (PaO2/FiO2 ≤ 150 mmHg) cases. High-flow nasal oxygen and helmet noninvasive ventilation represent the most promising techniques for first-line treatment of severe patients. However, no conclusive evidence allows to recommend a single approach over the others in case of moderate-to-severe hypoxemia. During any treatment, strict physiological monitoring remains of paramount importance to promptly detect the need for endotracheal intubation and not delay protective ventilation.

Immune Modulation in Critically Ill Septic Patients.

Sepsis is triggered by infection-induced immune alteration and may be theoretically improved by pharmacological and extracorporeal immune modulating therapies. Pharmacological immune modulation may have long lasting clinical effects, that may even worsen patient-related outcomes. On the other hand, extracorporeal immune modulation allows short-term removal of inflammatory mediators from the bloodstream. Although such therapies have been widely used in clinical practice, the role of immune modulation in critically ill septic patients remains unclear and little evidence supports the role of immune modulation in this clinical context. Accordingly, further research should be carried out by an evidence-based and personalized approach in order to improve the management of critically ill septic patients.