Background Few small studies have described hospital-acquired infections (HAIs) during COVID-19. Research Question What patient characteristics in critically ill patients with COVID-19 are associated with HAIs and how do HAIs associate with outcomes in these patients? Study Design and Methods Multicenter retrospective analysis of prospectively collected data including adult patients with severe COVID-19, admitted to 8 Italian hub hospitals from February 20, 2020, to May 20, 2020. Descriptive statistics, univariable and multivariable Weibull regression models were used to assess incidence, microbial etiology, resistance patterns, risk factors (i.e., demographics, comorbidities, exposure to medication), and impact on outcomes (i.e., ICU survival, length of ICU and hospital stay and duration of mechanical ventilation) of microbiologically-confirmed HAIs. Results Of the 774 included patients, 359 (46%) patients developed 759 HAIs (44.7 infections/1000 ICU patient-days, 35% multi-drug resistant (MDR) bacteria). Ventilator-associated pneumonia (VAP) (389, 50%), bloodstream infections (183, 34%), and catheter related blood stream infections (74, 10%) were the most frequent HAIs, with 26.0 (23.6-28.8) VAPs/1000 patient intubation-days, 11.7(10.1-13.5) BSIs/1000 ICU patient-days, and 4.7 (3.8-5.9) CRBSIs/1000 patient-days. Gram-negative bacteria (especially Enterobacterales ) and Staphylococcus aureus caused 64% and 28% of VAPs. Variables independently associated with infection were age, PEEP and treatment with broad-spectrum antibiotic at admission. 234 patients (30%) died in ICU (15.3 deaths/1000 ICU patient-days). Patients with HAIs complicated by septic shock had almost doubled mortality (52% vs. 29%), while non-complicated infections did not affect mortality. HAIs prolonged mechanical ventilation (24(14-39) vs. 9(5-13) days; p<0.001), ICU and hospital stay (24(16-41) vs. 9(6-14) days, p=0.003; and (42(25-59) vs. 23(13-34) days, p<0.001). Interpretation Critically-ill COVID-19 patients are at high risk for HAIs, especially VAPs and BSIs due to MDR organisms. HAIs prolong mechanical ventilation and hospitalization, and HAIs complicated by septic-shock almost doubled mortality.

Background Septic shock is characterized by breakdown of the endothelial glycocalyx and endothelial damage, contributing to fluid extravasation, organ failure and death. Albumin has shown benefit in septic shock patients. Our aims were: (1) to identify the relations between circulating levels of syndecan-1 (SYN-1), sphingosine-1-phosphate (S1P) (endothelial glycocalyx), and VE-cadherin (endothelial cell junctions), severity of the disease, and survival; (2) to evaluate the effects of albumin supplementation on endothelial dysfunction in patients with septic shock. Methods This was a retrospective analysis of a multicenter randomized clinical trial on albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis Trial, ALBIOS). Concentrations of SYN-1, S1P, soluble VE-cadherin and other biomarkers were measured on days 1, 2 and 7 in 375 patients with septic shock surviving up to 7 days after randomization. Results Plasma concentrations of SYN-1 and VE-cadherin rose significantly over 7 days. SYN-1 and VE-cadherin were elevated in patients with organ failure, and S1P levels were lower. SYN-1 and VE-cadherin were independently associated with renal replacement therapy requirement during ICU stay, but only SYN-1 predicted its new occurrence. Both SYN-1 and S1P, but not VE-cadherin, predicted incident coagulation failure. Only SYN-1 independently predicted 90-day mortality. Albumin significantly reduced VE-cadherin, by 9.5% (p = 0.003) at all three time points. Conclusion Circulating components of the endothelial glycocalyx and of the endothelial cell junctions provide insights into severity and progression of septic shock, with special focus on incident coagulation and renal failure. Albumin supplementation lowered circulating VE-cadherin consistently over time. Clinical Trial Registration: ALBIOS ClinicalTrials.gov number NCT00707122.

Background: Extracorporeal carbon dioxide removal has been proposed to achieve protective ventilation in patients at risk for ventilator-induced lung injury. In an acute study, the authors previously described an extracorporeal carbon dioxide removal technique enhanced by regional extracorporeal blood acidification. The current study evaluates efficacy and feasibility of such technology applied for 48 h. Methods: Ten pigs were connected to a low-flow veno-venous extracorporeal circuit (blood flow rate, 0.25 l/min) including a membrane lung. Blood acidification was achieved in eight pigs by continuous infusion of 2.5 mEq/min of lactic acid at the membrane lung inlet. The acid infusion was interrupted for 1 h at the 24 and 48 h. Two control pigs did not receive acidification. At baseline and every 8 h thereafter, the authors measured blood lactate, gases, chemistry, and the amount of carbon dioxide removed by the membrane lung (VCO2ML). The authors also measured erythrocyte metabolites and selected cytokines. Histological and metalloproteinases analyses were performed on selected organs. Results: Blood acidification consistently increased VCO2ML by 62 to 78%, from 79 ± 13 to 128 ± 22 ml/min at baseline, from 60 ± 8 to 101 ± 16 ml/min at 24 h, and from 54 ± 6 to 96 ± 16 ml/min at 48 h. During regional acidification, arterial pH decreased slightly (average reduction, 0.04), whereas arterial lactate remained lower than 4 mEq/l. No sign of organ and erythrocyte damage was recorded. Conclusion: Infusion of lactic acid at the membrane lung inlet consistently increased VCO2ML providing a safe removal of carbon dioxide from only 250 ml/min extracorporeal blood flow in amounts equivalent to 50% production of an adult man.

Background: Diaphragm atrophy and dysfunction are consequences of mechanical ventilation and are determinants of clinical outcomes. We hypothesize that partial preservation of diaphragm function, such as during assisted modes of ventilation, will restore diaphragm thickness. We also aim to correlate the changes in diaphragm thickness and function to outcomes and clinical factors. Methods: This is a prospective, multicentre, observational study. Patients mechanically ventilated for more than 48 h in controlled mode and eventually switched to assisted ventilation were enrolled. Diaphragm ultrasound and clinical data collection were performed every 48 h until discharge or death. A threshold of 10% was used to define thinning during controlled and recovery of thickness during assisted ventilation. Patients were also classified based on the level of diaphragm activity during assisted ventilation. We evaluated the association between changes in diaphragm thickness and activity and clinical outcomes and data, such as ventilation parameters. Results: Sixty-two patients ventilated in controlled mode and then switched to the assisted mode of ventilation were enrolled. Diaphragm thickness significantly decreased during controlled ventilation (1.84 ± 0.44 to 1.49 ± 0.37 mm, p < 0.001) and was partially restored during assisted ventilation (1.49 ± 0.37 to 1.75 ± 0.43 mm, p < 0.001). A diaphragm thinning of more than 10% was associated with longer duration of controlled ventilation (10 [5, 15] versus 5 [4, 8.5] days, p = 0.004) and higher PEEP levels (12.6 ± 4 versus 10.4 ± 4 cmH 2 O, p = 0.034). An increase in diaphragm thickness of more than 10% during assisted ventilation was not associated with any clinical outcome but with lower respiratory rate (16.7 ± 3.2 versus 19.2 ± 4 bpm, p = 0.019) and Rapid Shallow Breathing Index (37 ± 11 versus 44 ± 13, p = 0.029) and with higher Pressure Muscle Index (2 [0.5, 3] versus 0.4 [0, 1.9], p = 0.024). Change in diaphragm thickness was not related to diaphragm function expressed as diaphragm thickening fraction. Conclusion: Mode of ventilation affects diaphragm thickness, and preservation of diaphragmatic contraction, as during assisted modes, can partially reverse the muscle atrophy process. Avoiding a strenuous inspiratory work, as measured by Rapid Shallow Breathing Index and Pressure Muscle Index, may help diaphragm thickness restoration.

We previously described a highly efficient extracorporeal CO2 removal technique called respiratory electrodialysis (R-ED). Respiratory electrodialysis was composed of a hemodiafilter and a membrane lung (ML) positioned along the extracorporeal blood circuit, and an electrodialysis (ED) cell positioned on the hemodiafiltrate. The ED regionally increased blood chloride concentration to convert bicarbonate to CO2 upstream the ML, thus enhancing ML CO2 extraction (VCO2ML). In this in vitro study, with an aqueous polyelectrolytic carbonated solution mimicking blood, we tested a new R-ED setup, featuring an ML positioned on the hemodiafiltrate after the ED, at increasing ED current levels (0, 2, 4, 6, and 8 A). We measured VCO2ML, electrolytes concentrations, and pH of the extracorporeal circuit. Raising levels of ED-current increased chloride concentration from 107.5 ± 1.6 to 114.6 ± 1.3 mEq/L (0 vs. 8 A, p< 0.001) and reduced pH from 7.48 ± 0.01 to 6.51 ± 0.05 (0 vs. 8 A, p < 0.001) of the hemodiafiltrate entering the ML. Subsequently, VCO2ML increased from 27 ± 1.7 to 91.3 ± 1.5 ml/min (0 vs. 8 A, p < 0.001). Respiratory electrodialysis is efficient in increasing VCO2ML of an extracorporeal circuit featuring an ML perfused by hemodiafiltrate. During R-ED, the VCO2ML can be significantly enhanced by increasing the ED current.