Outcomes and Impact of Pre-ECMO Clinical Course in Severe COVID-19-Related ARDS Treated with VV-ECMO: Data from an Italian Referral ECMO Center.

Background: The efficacy of veno-venous extracorporeal membrane oxygenation (VV-ECMO) as rescue therapy for refractory COVID-19-related ARDS (C-ARDS) is still debated. We describe the cohort of C-ARDS patients treated with VV-ECMO at our ECMO center, focusing on factors that may affect in-hospital mortality and describing the time course of lung mechanics to assess prognosis. Methods: We performed a prospective observational study in the intensive care unit at the "Città della Salute e della Scienza" University Hospital in Turin, Italy, between March 2020 and December 2021. Indications and management of ECMO followed the Extracorporeal Life Support Organization (ELSO) guidelines. Results: The 60-day in-hospital mortality was particularly high (85.4%). Non-survivor patients were more frequently treated with non-invasive ventilatory support and steroids before ECMO (95.1% vs. 57.1%, p = 0.018 and 73.2% vs. 28.6%, p = 0.033, respectively), while hypertension was the only pre-ECMO factor independently associated with in-hospital mortality (HR: 2.06, 95%CI: 1.06-4.00). High rates of bleeding (85.4%) and superinfections (91.7%) were recorded during ECMO, likely affecting the overall length of ECMO (18 days, IQR: 10-24) and the hospital stay (32 days, IQR: 24-47). Static lung compliance was lower in non-survivors (p = 0.031) and differed over time (p = 0.049), decreasing by 48% compared to initial values in non-survivors. Conclusions: Our data suggest the importance of considering NIS among the common ECMO eligibility criteria and changes in lung compliance during ECMO as a prognostic marker.

Effectiveness of an Active and Continuous Surveillance Program for Intensive Care Units Infections Based on the EPIC III (Extended Prevalence of Infection in Intensive Care) Approach.

We evaluated the effectiveness of the Extended Prevalence of Infection in Intensive Care (EPIC) III data collection protocol as an active surveillance tool in the eight Intensive Care Units (ICUs) of the Intensive and Critical Care Department of the University Hospital of Turin. A total of 435 patients were included in a six-day study over 72 ICU beds. 42% had at least one infection: 69% at one site, 26% at two sites and 5% at three or more sites. ICU-acquired infections were the most common (64%), followed by hospital-associated infections (22%) and community-acquired (20%), considering that each patient may have developed more than one infection type. 72% of patients were receiving at least one antibiotic: 48% for prophylaxis and 52% for treatment. Mortality, the length of ICU and hospital stays were 13%, 14 and 29 days, respectively, being all estimated to be significantly different in patients without and with infection (8% vs. 20%; 4 vs. 20 and 11 vs. 50 (p < 0.001). Our data confirm a high prevalence of infections, sepsis and the use of antimicrobials. The repeated punctual prevalence survey seems an effective method to carry out the surveillance of infections and the use of antimicrobials in the ICU. The use of the European Centre for Disease Prevention and Control (ECDC) definitions and the EPIC III protocol seems strategic to allow comparisons with national and international contexts.

Effects of Steroids and Tocilizumab on the Immune Response Profile of Patients with COVID-19-Associated ARDS Requiring or Not Veno-Venous Extracorporeal Membrane Oxygenation.

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a life-saving rescue therapy in patients with Acute Respiratory Distress Syndrome (ARDS). ECMO has been associated with development of lymphocytopenia that is also common in COVID-19. Hyperinflammation may complicate SARS-CoV-2 pneumonia, prompting therapy with steroids and immunomodulatory drugs. We aimed to evaluate the association of therapies such as steroids and Tocilizumab with trajectories of the total leukocytes, lymphocyte subpopulation count, and inflammatory and fibrinolysis markers in COVID-19-related ARDS, requiring or not VV-ECMO support. The association of the trajectories of the leukocytes, lymphocyte subpopulation count, and inflammatory and fibrinolysis markers with treatment with steroids (Steroids), Tocilizumab (Tocilizumab), both drugs (Steroids + Tocilizumab), and absence of treatment (No Treatment) were analyzed using mixed effects regression models, where ECMO was considered as a potential effect modifier. One hundred and thirty-nine leukocyte and eighty-one lymphocyte subpopulation counts were obtained from thirty-one patients who required (VV-ECMO, N = 13) or not (no VV-ECMO, N = 18) extracorporeal support. In both groups, treatment with Steroids + Tocilizumab was independently associated with a significant reduction of 46% and 67% in total lymphocytes, 22% and 60% in CD3+, and 61% and 91% in CD19+ (B lymphocytes) compared to those obtained without treatment, respectively. In the no VV-ECMO group, Tocilizumab was associated with a 79% increase in total lymphocytes and with a reduction in procalcitonin compared to no treatment. CD45+, CD3+CD4+ (Th cell), CD3+CD8+, CD4+/CD8+, the NK cell subpopulation, neutrophils, monocytes, and basophils were significantly reduced by Steroids + Tocilizumab without an effect modification by VV-ECMO support. In critically ill COVID-19 patients with ARDS, concomitant therapies with steroids and Tocilizumab, beside mitigating the inflammation and fibrinolysis, could reduce the total leukocyte, lymphocyte, and subpopulation count. Moreover, the effect of Tocilizumab in increasing the total lymphocytes and reducing procalcitonin might be blunted by VV-ECMO.

ECMO Support and Operator Safety in the Context of COVID-19 Outbreak: A Regional Center Experience.

Since the beginning of the COVID-19 emergency, the referral Intensive Care Unit for the Extracorporeal Membrane Oxygenation (ECMO) support of Piedmont Region (Italy), in cooperation with infectious disease specialists, perfusionists and cardiac surgeons, developed a protocol to guarantee operator safety during invasive procedures, among which the ECMO positioning or inter-hospital transport. The use of powered air-purifying respirators, filtering facepiece particles (FFP) 2-3 masks, protective suits, disposable sterile surgical gowns, and two pairs of sterile gloves as a part of a protocol seemed effective and feasible for trained healthcare workers and allow all the complex activities connected with the positioning of the ECMO support to be completed effectively. The simulation training on donning and doffing procedures and the presence of a dedicated team member to verify the compliance with the safety procedure effectively reassured operators and likely reduced the risk of self-contamination. From 1 March to 31 December 2020, we used the procedure in 35 severe acute respiratory distress syndrome (ARDS) patients and one acute respiratory failure caused by neoplastic total tracheal obstruction, all positive to COVID-19, to be connected to veno-venous ECMO in peripheral hospitals and centralized for ECMO management. This preliminary experience seems to confirm that the use of ECMO during COVID-19 outbreaks is feasible and the risks associated with its positioning and management are sustainable for the health-care workers and safe for patients.

Real-life study on the pharmacokinetic of remdesivir in ICU patients admitted for severe COVID-19 pneumonia.

Remdesivir is one of the most encouraging treatments against SARS-CoV-2 infection. After intravenous infusion, RDV is rapidly metabolized (t1/2 = 1 h) within the cells to its active adenosine triphosphate analogue form (GS-443902) and then it can be found in plasma in its nucleoside analogue form (GS-441524). In this real-life study, we describe the remdesivir and GS-441524 concentrations at three time points in nine ICU patients, through a validated ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method. The observed data confirmed the very rapid conversion of RDV to its metabolite and the quite long half-life of GS-441524. The mean Cmin , Cmax and AUC0-24 , were < 0.24 ng/mL and 122.3 ng/mL, 2637.3 ng/mL and 157.8 ng/mL, and 5171.2 ng*h/mL and 3676.5 ng*h/ml, respectively, for RDV and GS-441524. Three out of nine patients achieved a Cmax  > 2610 ng/mL and 140 ng/mL and AUC0-24  > 1560 ng*h/mL and 2230 ng*h/mL for RDV and GS-441524, respectively. The mean t1/2 value for GS-441524 was 26.3 h. Despite the low number of patients, these data can represent an interesting preliminary report on the variability of RDV and GS-441524 concentrations in a real-life ICU setting.

Effectiveness of mid-regional pro-adrenomedullin (MR-proADM) as prognostic marker in COVID-19 critically ill patients: An observational prospective study.

OBJECTIVE: To test the effectiveness of mid-regional pro-adrenomedullin (MR-proADM) in comparison to C-reactive protein (CRP), procalcitonin (PCT), D-dimer, lactate dehydrogenase (LDH) in predicting mortality in COVID-19-ICU-patients. METHODS: All consecutive COVID-19 adult patients admitted between March and June 2020 to the ICU of a referral, university hospital in Northern-Italy were enrolled. MR-proADM and routine laboratory test were measured within 48 hours from ICU admission, on day 3, 7 and 14. Survival curves difference with MR-proADM cut-off set to 1.8 nmol/L were tested using log-rank test. Predictive ability was compared using area under the curve and 95% confidence interval of different receiver-operating characteristics curves. RESULTS: 57 patients were enrolled. ICU and overall mortality were 54.4%. At admission, lymphocytopenia was present in 86% of patients; increased D-dimer and CRP levels were found in 84.2% and 87.7% of patients respectively, while PCT values > 0.5 µg/L were observed in 47.4% of patients. MR-proADM, CRP and LDH were significantly different between surviving and non-surviving patients and over time, while PCT, D-dimer and NT-pro-BNP did not show any difference between the groups and over time; lymphocytes were different between surviving and non-surviving patients only. MR-proADM was higher in dying patients (2.65±2.33vs1.18±0.47, p<0.001) and a higher mortality characterized patients with MR-proADM >1.8 nmol/L (p = 0.016). The logistic regression model adjusted for age, gender, cardiovascular disease, diabetes mellitus and PCT values confirmed an odds ratio = 10.3 [95%CI:1.9-53.6] (p = 0.006) for MR-proADM >1.8 nmol/L and = 22.2 [95%CI:1.6-316.9] (p = 0.022) for cardiovascular disease. Overall, MR-proADM had the best predictive ability (AUC = 0.85 [95%CI:0.78-0.90]). CONCLUSIONS: In COVID-19 ICU-patients, MR-proADM seems to have constantly higher values in non-survivor patients and predict mortality more precisely than other biomarkers. Repeated MR-proADM measurement may support a rapid and effective decision-making. Further studies are needed to better explain the mechanisms responsible of the increase in MR-proADM in COVID-19 patients.

Occurrence of ventilator associated pneumonia using a tracheostomy tube with subglottic secretion drainage.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a significant cause of morbidity and mortality in critically ill patients who require mechanical ventilation (MV). Subglottic secretions above the endotracheal cuff are associated with bacteria colonization of lower respiratory tract, causing VAP. A preventive strategy to avoid subglottic secretion progression is the drainage with special tracheal tubes effective in preventing both early onset and late onset VAP. The purpose of this study was to measure VAP incidence in tracheostomized patients with suction above the cuff. METHODS: The authors performed a matched cohort study with historical control in three academic Intensive Care Units (ICUs): upon ICU admission, patients requiring MV were submitted to tracheostomy with a tracheal tube allowing drainage of subglottic secretions (treatment group). A control group without suctioning above the cuff was selected applying the propensity score matching on dataset of previous ELT Study. VAP occurrence at 28-days from intubation was the primary endpoint; hospital mortality and ICU-free days at 28-days were the secondary endpoints. RESULTS: Between July 2014 and April 2016, 125 tracheostomized patients were included in the analysis. 232 tracheostomized patients without suctioning were selected as a control group for the matched cohort study. The application of propensity score matching selected 60 patients to compare the two groups. Incidence of VAP was 8% in treatment group and 19.4% in the control group (P value =0.004). After balance with propensity score matching VAP was 8.3% and 21.7% (P value =0.0408), respectively. CONCLUSIONS: Subglottic secretion drainage reduces incidence of VAP in critically ill patients requiring ongoing MV via tracheostomy.

Effects of dexmedetomidine and propofol on patient-ventilator interaction in difficult-to-wean, mechanically ventilated patients: a prospective, open-label, randomised, multicentre study.

BACKGROUND: Dexmedetomidine can be used for sedation of mechanically ventilated patients and has minor respiratory effects. The aim of this study was to compare the incidence of patient-ventilator dyssynchronies during sedation with dexmedetomidine or propofol. METHODS: We conducted a multicentre, prospective, open-label, randomised clinical trial, comparing dexmedetomidine with standard propofol sedation at three intensive care units of university hospitals in Italy. Twenty difficult-to-wean patients for whom the first weaning trial had failed and who were on pressure support ventilation were randomised to receive sedation with either dexmedetomidine or propofol at a similar level of sedation (Richmond Agitation-Sedation Scale [RASS] score +1 to -2). The asynchrony index (AI) was calculated using tracings of airflow, airway pressure and electrical activity of the diaphragm sampled at 0, 0.5, 1, 2, 6, 12, 18 and 24 h. RESULTS: The mean AI was lower with dexmedetomidine than with propofol from 2 h onwards, although the two groups significantly differed only at 12 h (2.68 % vs 9.10 %, p < 0.05). No further difference was observed at 18 and 24 h. CONCLUSIONS: When sedation with propofol and dexmedetomidine was compared at similar RASS scores of patients in whom first weaning trial had failed, the AI was lower with dexmedetomidine than with propofol, and this difference was statistically significant at 12 h. These results suggest that sedation with dexmedetomidine may offer some advantages in terms of patient-ventilator synchrony.

Physiological Correlation of Airway Pressure and Transpulmonary Pressure Stress Index on Respiratory Mechanics in Acute Respiratory Failure.

BACKGROUND: Stress index at post-recruitment maneuvers could be a method of positive end-expiratory pressure (PEEP) titration in acute respiratory distress syndrome (ARDS) patients. However, airway pressure (Paw) stress index may not reflect lung mechanics in the patients with high chest wall elastance. This study was to evaluate the Pawstress index on lung mechanics and the correlation between Pawstress index and transpulmonary pressure (PL) stress index in acute respiratory failure (ARF) patients. METHODS: Twenty-four ARF patients with mechanical ventilation (MV) were consecutively recruited from July 2011 to April 2013 in Zhongda Hospital, Nanjing, China and Ospedale S. Giovanni Battista-Molinette Hospital, Turin, Italy. All patients underwent MV with volume control (tidal volume 6 ml/kg) for 20 min. PEEP was set according to the ARDSnet study protocol. The patients were divided into two groups according to the chest wall elastance/respiratory system elastance ratio. The high elastance group (H group, n = 14) had a ratio ≥30%, and the low elastance group (L group, n = 10) had a ratio <30%. Respiratory elastance, gas-exchange, Pawstress index, and PLstress index were measured. Student's t-test, regression analysis, and Bland-Altman analysis were used for statistical analysis. RESULTS: Pneumonia was the major cause of respiratory failure (71.0%). Compared with the L group, PEEP was lower in the H group (5.7 ± 1.7 cmH2O vs. 9.0 ± 2.3 cmH2O, P < 0.01). Compared with the H group, lung elastance was higher (20.0 ± 7.8 cmH2O/L vs. 11.6 ± 3.6 cmH2O/L, P < 0.01), and stress was higher in the L group (7.0 ± 1.9 vs. 4.9 ± 1.9, P = 0.02). A linear relationship was observed between the Pawstress index and the PLstress index in H group (R2 = 0.56, P < 0.01) and L group (R2 = 0.85, P < 0.01). CONCLUSION: In the ARF patients with MV, Pawstress index can substitute for PLto guide ventilator settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT02196870 (https://clinicaltrials.gov/ct2/show/NCT02196870).

Extracorporeal Co2 removal in hypercapnic patients at risk of noninvasive ventilation failure: a matched cohort study with historical control.

OBJECTIVES: To assess efficacy and safety of noninvasive ventilation-plus-extracorporeal Co2 removal in comparison to noninvasive ventilation-only to prevent endotracheal intubation patients with acute hypercapnic respiratory failure at risk of failing noninvasive ventilation. DESIGN: Matched cohort study with historical control. SETTING: Two academic Italian ICUs. PATIENTS: Patients treated with noninvasive ventilation for acute hypercapnic respiratory failure due to exacerbation of chronic obstructive pulmonary disease (May 2011 to November 2013). INTERVENTIONS: Extracorporeal CO2 removal was added to noninvasive ventilation when noninvasive ventilation was at risk of failure (arterial pH ≤ 7.30 with arterial PCO2 > 20% of baseline, and respiratory rate ≥ 30 breaths/min or use of accessory muscles/paradoxical abdominal movements). The noninvasive ventilation-only group was created applying the genetic matching technique (GenMatch) on a dataset including patients enrolled in two previous studies. Exclusion criteria for both groups were mean arterial pressure less than 60 mm Hg, contraindications to anticoagulation, body weight greater than 120 kg, contraindication to continuation of active treatment, and failure to obtain consent. MEASUREMENTS AND MAIN RESULTS: Primary endpoint was the cumulative prevalence of endotracheal intubation. Twenty-five patients were included in the noninvasive ventilation-plus-extracorporeal CO2 removal group. The GenMatch identified 21 patients for the noninvasive ventilation-only group. Risk of being intubated was three times higher in patients treated with noninvasive ventilation-only than in patients treated with noninvasive ventilation-plus-extracorporeal CO2 removal (hazard ratio, 0.27; 95% CI, 0.07-0.98; p = 0.047). Intubation rate in noninvasive ventilation-plus-extracorporeal CO2 removal was 12% (95% CI, 2.5-31.2) and in noninvasive ventilation-only was 33% (95% CI, 14.6-57.0), but the difference was not statistically different (p = 0.1495). Thirteen patients (52%) experienced adverse events related to extracorporeal CO2 removal. Bleeding episodes were observed in three patients, and one patient experienced vein perforation. Malfunctioning of the system caused all other adverse events. CONCLUSIONS: These data provide the rationale for future randomized clinical trials that are required to validate extracorporeal CO2 removal in patients with hypercapnic respiratory failure and respiratory acidosis nonresponsive to noninvasive ventilation.

Extra Corporeal Membrane Oxygenation (ECMO) in three HIV-positive patients with acute respiratory distress syndrome.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a life-saving bridging procedure in patients with severe acute respiratory distress syndrome (ARDS). Official indications for ECMO are unclear for immunocompromised and HIV-positive patients affected by severe hypoxemia. Uncertainties are related to prognosis and efficacy of treatment of the underlying disease. However, the care of patients with HIV infection has advanced since the introduction of highly active antiretroviral therapy (HAART), with increased life expectancy and decreased mortality. CASE PRESENTATION: Three HIV-infected patients with AIDS were admitted to ICU and were treated with ECMO: a 21 years old Caucasian female with congenital HIV infection presented with Pneumocystis jirovecii pneumonia (PJP); a 38 years old Caucasian female with HIV-HCV infection and L. pneumophila pneumonia; a 24 years old Caucasian male with fever, cough weight loss and PJP pneumonia. Two patients were alive, with a good immunovirological profile and they went back to their previous quality of life. The last patient died with septic shock after three months of ICU stay. CONCLUSION: ECMO was effective in three HIV-positive patients with an otherwise fatal respiratory failure. All patients had severe immunosuppression and/or limited antiretroviral options. A multidisciplinary critical team is needed to individualize the use of ECMO in immunocompromised patients, including those with HIV infection.

A(H1N1)pdm09 hemagglutinin D222G and D222N variants are frequently harbored by patients requiring extracorporeal membrane oxygenation and advanced respiratory assistance for severe A(H1N1)pdm09 infection.

BACKGROUND: In patients with A(H1N1)pdm09 infection, severe lung involvement requiring admission to intensive care units (ICU) has been reported. Mutations at the hemagglutinin (HA) receptor binding site (RBS) have been associated with increased virulence and disease severity, representing a potential marker of critical illness. OBJECTIVES: To assess the contribution of HA-RBS variability in critically ill patients, A(H1N1)pdm09 virus from adult patients with severe infection admitted to ICU for extracorporeal membrane oxygenation support (ECMO) during influenza season 2009-2011 in Piemonte (4·2 million inhabitants), northwestern Italy, was studied. PATIENTS AND METHODS: We retrospectively analyzed HA-RBS polymorphisms in ICU patients and compared with those from randomly selected inpatients with mild A(H1N1)pdm09 disease and outpatients with influenza from the local surveillance program. RESULTS: By HA-RBS direct sequencing of respiratory specimens, D222G and D222N viral variants were identified in a higher proportion in ICU patients (n=8/24, 33·3%) than in patients with mild disease (n=2/34, 6%) or in outpatients (n=0/44) (Fisher's exact test P<0·0001; OR 38·5; CI 95% 4·494-329·9). Eleven ICU patients died (42%), three of them carrying the D222G variant, which was associated with RBS mutation S183P in two. D222G and D222N mutants were identified in upper and lower respiratory samples. CONCLUSIONS: A(H1N1)pdm09 HA substitutions D222G and D222N were harbored in a significantly higher proportion by patients with acute respiratory distress for A(H1N1)pdm09 severe infection requiring ICU admission and ECMO. These data emphasize the importance of monitoring viral evolution for understanding virus-host adaptation aimed at the surveillance of strain circulation and the study of viral correlates of disease severity.

Development and validation of a new UPLC-PDA method to quantify linezolid in plasma and in dried plasma spots.

Linezolid is an oxazolidinone antibiotic used for the treatment of pneumonia and uncomplicated and complicated skin and soft tissues infections caused by Gram positive bacteria. It is also used as second line agent in multi-drug resistant tuberculosis. Therapeutic drug monitoring (TDM) of linezolid represents a valid tool in clinical practice to optimize therapy, especially in critically ill patients. Spreading of TDM is mainly limited by high costs shipment and lack of laboratories that offer a TDM service. To overcome these problems, the use of dried plasma spots or dried blood spots is increasing. The aim of this work was to develop and validate a new chromatographic method to analyze linezolid in plasma and in dried plasma spots and to evaluate the correlation between the two extraction methods. Linezolid extraction from plasma and from dried plasma spots was obtained using acetonitrile. Quinoxaline was used as internal standard. Analysis was performed by an ultra performance liquid chromatography (UPLC) system coupled with photo diode array (PDA) detector, at 254nm. Both analytical methods were linear (r(2)>0.999) over the calibration range of 30-0.117mg/L. Limit of quantification and limit of detection were 0.117mg/L and 0.058mg/L, respectively. Intra and inter-day precision (R.S.D.%) and accuracy (%) were <15%. Long term stability of linezolid in dried plasma spots showed absence of degradation at room temperature (20-25°C) and at 4°C, for at least one month. Linear regression analysis confirmed that the two methods of extraction have good correlation. Thus they are suited for TDM of linezolid and for pharmacokinetic studies.