Multidrug-resistant pathogens and ventilator-associated pneumonia in critically ill COVID-19 and non-COVID-19 patients: a prospective observational monocentric comparative study.

BACKGROUND: The COVID-19 pandemic has increased the incidence of ventilator-associated pneumonia (VAP) among critically ill patients. However, a comparison of VAP incidence in COVID-19 and non-COVID-19 cohorts, particularly in a context with a high prevalence of multidrug-resistant (MDR) organisms, is lacking. MATERIAL AND METHODS: We conducted a single-center, mixed prospective and retrospective cohort study comparing COVID-19 patients admitted to the intensive care unit (ICU) of the "Città della Salute e della Scienza" University Hospital in Turin, Italy, between March 2020 and December 2021 (COVID-19 group), with a historical cohort of ICU patients admitted between June 2016 and March 2018 (NON-COVID-19 group). The primary objective was to define the incidence of VAP in both cohorts. Secondary objectives were to evaluate the microbial cause, resistance patters, risk factors and impact on 28 days, ICU and in-hospital mortality, duration of ICU stay, and duration of hospitalization). RESULTS: We found a significantly higher incidence of VAP (51.9% - n = 125) among the 241 COVID-19 patients compared to that observed (31.2% - n = 78) among the 252 NON-COVID-19 patients. The median SOFA score was significantly lower in the COVID-19 group (9, Interquartile range, IQR: 7-11 vs. 10, IQR: 8-13, p < 0.001). The COVID-19 group had a higher prevalence of Gram-positive bacteria-related VAP (30% vs. 9%, p < 0.001), but no significant difference was observed in the prevalence of difficult-to-treat (DTR) or MDR bacteria. ICU and in-hospital mortality in the COVID-19 and NON-COVID-19 groups were 71% and 74%, vs. 33% and 43%, respectively. The presence of COVID-19 was significantly associated with an increased risk of 28-day all-cause hospital mortality (Hazard ratio, HR: 7.95, 95% Confidence Intervals, 95% CI: 3.10-20.36, p < 0.001). Tracheostomy and a shorter duration of mechanical ventilation were protective against 28-day mortality, while dialysis and a high SOFA score were associated with a higher risk of 28-day mortality. CONCLUSION: COVID-19 patients with VAP appear to have a significantly higher ICU and in-hospital mortality risk regardless of the presence of MDR and DTR pathogens. Tracheostomy and a shorter duration of mechanical ventilation appear to be associated with better outcomes.

Liver transplantation with uncontrolled versus controlled DCD donors using normothermic regional perfusion and ex-situ machine perfusion.

In Italy, 20 minutes of continuous, flat-line electrocardiogram are required for death declaration, which significantly increases the risks of donation after circulatory death (DCD) LT. Despite prolonged warm ischemia time, Italian centers reported good outcomes in controlled donation after circulatory death LT by combining normothermic regional and end-ischemic machine perfusion. However, data on uncontrolled DCD (uDCD) LT performed by this approach are lacking. This was a multicenter, retrospective study performed at 3 large-volume centers comparing clinical outcomes of uncontrolled versus controlled DCD LT. The aim of the study was to assess outcomes of sequential normothermic regional perfusion and end-ischemic machine perfusion in uncontrolled DCD liver transplantation (LT). Of 153 DCD donors evaluated during the study period, 40 uDCD and 59 donation after circulatory death grafts were transplanted (utilization rate 52% vs. 78%, p = 0.004). Recipients of uDCD grafts had higher MEAF (4.9 vs. 3.5, p < 0.001) and CCI scores at discharge (24.4 vs. 8.7, p = 0.026), longer ICU stay (5 vs. 4 d, p = 0.047), and a trend toward more severe AKI. At multivariate analysis, 90-day graft loss was associated with recipient BMI and lactate downtrend during normothermic regional perfusion. One-year graft survival was lower in uDCD (75% vs. 90%, p = 0.007) but became comparable when non-liver-related graft losses were treated as censors (77% vs. 90%, p = 0.100). The incidence of ischemic cholangiopathy was 10% in uDCD versus 3% in donation after circulatory death, p = 0.356. uDCD LT with prolonged warm ischemia is feasible by the sequential use of normothermic regional perfusion and end-ischemic machine perfusion. Proper donor and recipient selection are key to achieving good outcomes in this setting.

Viability assessment of livers donated after circulatory determination of death during normothermic regional perfusion.

BACKGROUND: Abdominal normothermic regional perfusion (A-NRP) allows in-situ reperfusion and recovery of abdominal organs metabolism in donors after circulatory death (DCD). Besides improving liver transplantation outcomes, liver injury and function can be assessed during A-NRP. METHODS: To refine liver viability assessment during A-NRP, prospectively collected data of controlled DCD donors managed at our Institution between October 2019 and May 2022 were retrospectively analyzed. Baseline characteristics, procedural variables and A-NRP parameters of donors whose liver was successfully transplanted were compared to those of donors whose liver was discarded. RESULTS: Twenty-seven donors were included and in 20 (74%) the liver was accepted (positive outcome). No differences between study groups were observed concerning baseline characteristics and warm ischemia times (WIT). Initial lactate levels were positively correlated with functional WIT (r2 = 0.4, p = 0.04), whereas transaminase levels were not. Blood flow during A-NRP was comparable, whereas oxygen consumption (VO2 ) was significantly higher in the positive outcome group after 1 h. Time courses of lactate, AST and ALT were significantly different between study groups (p < 0.001). Donors whose liver was accepted showed faster lactate clearance, a difference which was amplified by normalizing lactate clearance to oxygen delivery (DO2 ) and VO2 . Lactate clearance was correlated to transaminase levels and DO2 -normalized lactate clearance was the parameter best discriminating between study groups. CONCLUSIONS: DO2 -normalized lactate clearance may represent an element of liver viability assessment during A-NRP.

Effectiveness of mid-regional pro-adrenomedullin, compared to other biomarkers (including lymphocyte subpopulations and immunoglobulins), as a prognostic biomarker in COVID-19 critically ill patients: New evidence from a 15-month observational prospective study.

Background: Mid-regional pro-adrenomedullin (MR-proADM), an endothelium-related peptide, is a predictor of death and multi-organ failure in respiratory infections and sepsis and seems to be effective in identifying COVID-19 severe forms. The study aims to evaluate the effectiveness of MR-proADM in comparison to routine inflammatory biomarkers, lymphocyte subpopulations, and immunoglobulin (Ig) at an intensive care unit (ICU) admission and over time in predicting mortality in patients with severe COVID-19. Methods: All adult patients with COVID-19 pneumonia admitted between March 2020 and June 2021 in the ICUs of a university hospital in Italy were enrolled. MR-proADM, lymphocyte subpopulations, Ig, and routine laboratory tests were measured within 48 h and on days 3 and 7. The log-rank test was used to compare survival curves with MR-proADM cutoff value of >1.5 nmol/L. Predictive ability was compared using the area under the curve (AUC) and 95% confidence interval (CI) of different receiver-operating characteristic curves. Results: A total of 209 patients, with high clinical severity [SOFA 7, IQR 4-9; SAPS II 52, IQR 41-59; median viral pneumonia mortality score (MuLBSTA)-11, IQR 9-13] were enrolled. ICU and overall mortality were 55.5 and 60.8%, respectively. Procalcitonin, lactate dehydrogenase, D-dimer, the N-terminal prohormone of brain natriuretic peptide, myoglobin, troponin, neutrophil count, lymphocyte count, and natural killer lymphocyte count were significantly different between survivors and non-survivors, while lymphocyte subpopulations and Ig were not different in the two groups. MR-proADM was significantly higher in non-survivors (1.17 ± 0.73 vs. 2.31 ± 2.63, p < 0.0001). A value of >1.5 nmol/L was an independent risk factor for mortality at day 28 [odds ratio of 1.9 (95% CI: 1.220-3.060)] after adjusting for age, lactate at admission, SOFA, MuLBSTA, superinfections, cardiovascular disease, and respiratory disease. On days 3 and 7 of the ICU stay, the MR-proADM trend evaluated within 48 h of admission maintained a correlation with mortality (p < 0.0001). Compared to all other biomarkers considered, the MR-proADM value within 48 h had the best accuracy in predicting mortality at day 28 [AUC = 0.695 (95% CI: 0.624-0.759)]. Conclusion: MR-proADM seems to be the best biomarker for the stratification of mortality risk in critically ill patients with COVID-19. The Ig levels and lymphocyte subpopulations (except for natural killers) seem not to be correlated with mortality. Larger, multicentric studies are needed to confirm these findings.

Normothermic Regional Perfusion and Hypothermic Oxygenated Machine Perfusion for Livers Donated After Controlled Circulatory Death With Prolonged Warm Ischemia Time: A Matched Comparison With Livers From Brain-Dead Donors.

Prolonged warm ischemia time (WIT) has a negative prognostic value in liver transplantation (LT) using grafts procured after circulatory death (DCD). To assess the value of abdominal normothermic regional perfusion (A-NRP) associated with dual hypothermic oxygenated machine perfusion (D-HOPE) in controlled DCD LT, prospectively collected data on LTs performed between January 2016 and July 2021 were analyzed. Outcome of controlled DCD LTs performed using A-NRP + D-HOPE (n = 20) were compared to those performed with grafts procured after brain death (DBD) (n = 40), selected using propensity-score matching. DCD utilization rate was 59.5%. In the DCD group, median functional WIT, A-NRP and D-HOPE time was 43, 246, and 205 min, respectively. Early outcomes of DCD grafts recipients were comparable to those of matched DBD LTs. In DCD and DBD group, incidence of anastomotic biliary complications and ischemic cholangiopathy was 15% versus 22% (p = 0.73) and 5% versus 2% (p = 1), respectively. One-year patient and graft survival was 100% versus 95% (p = 0.18) and 90% versus 95% (p = 0.82). In conclusion, the association of A-NRP + D-HOPE in DCD LT with prolonged WIT allows achieving comparable outcomes to DBD LT.

Machine Perfusions in Liver Transplantation: The Evidence-Based Position Paper of the Italian Society of Organ and Tissue Transplantation.

The use of machine perfusion (MP) in liver transplantation (LT) is spreading worldwide. However, its efficacy has not been demonstrated, and its proper clinical use has far to go to be widely implemented. The Società Italiana Trapianti d'Organo (SITO) promoted the development of an evidence-based position paper. A 3-step approach has been adopted to develop this position paper. First, SITO appointed a chair and a cochair who then assembled a working group with specific experience of MP in LT. The Guideline Development Group framed the clinical questions into a patient, intervention, control, and outcome (PICO) format, extracted and analyzed the available literature, ranked the quality of the evidence, and prepared and graded the recommendations. Recommendations were then discussed by all the members of the SITO and were voted on via the Delphi method by an institutional review board. Finally, they were evaluated and scored by a panel of external reviewers. All available literature was analyzed, and its quality was ranked. A total of 18 recommendations regarding the use and the efficacy of ex situ hypothermic and normothermic machine perfusion and sequential normothermic regional perfusion and ex situ MP were prepared and graded according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. A critical and scientific approach is required for the safe implementation of this new technology.

Donation after circulatory death: possible strategies for in-situ organ preservation.

Donation after circulatory death (DCD) is an accepted strategy to expand the potential donor pool. The complexity of organ procurement from DCD donors requires the development of new strategies for organ preservation. Standard DCD organ recovery involves a super rapid technique, with cold thoracic and abdominal perfusion. However, the conventional methods of preservation based on static and hypothermic storage may not be the most appropriate for DCD grafts, especially in the presence of long warm ischemia times. New strategies designed to improve the preservation of in-situ DCD grafts include the use of normothermic regional perfusion (NRP) for abdominal organs and concomitant cold lung flushing. The use of in-situ NRP is a significant advance in abdominal organ retrieval and it has the potential to increase organ recovery rates due to its applicability in both controlled and uncontrolled DCD donors. We describe an innovative preservation strategy based on the combination of donor NRP for abdominal organ preservation and a normothermic open-lung approach with protective mechanical ventilation for lung preservation.

Successful preservation and transplant of warm ischaemic lungs from controlled donors after circulatory death by prolonged in situ ventilation during normothermic regional perfusion of abdominal organs.

OBJECTIVES: Donation after circulatory death (DCD) potentially provides transplantable lungs suitable for a transplant, but in Italy, the need for 20 min of a no-touch period after cardiac arrest for legal declaration of death poses real challenges to organ preservation. METHODS: This is a single-institution, retrospective study using data collected prospectively between October and December 2017. After the approval of the multidisciplinary DCD study group of Regione Lombardia, Maastricht category III DCD donors became eligible for combined procurement of lungs and abdominal organs. Our group subsequently established a dedicated technical protocol. Our protocol consists of a non-rapid normothermic open-lung procurement process that takes place during abdominal normothermic regional perfusion, namely without pleural topical cooling before the start of pneumoplegia. After the lung is procured according to the technique described in the article, lung function is evaluated by ex vivo lung perfusion, which is run with the low-flow, open atrium, low haematocrit technique. RESULTS: During the study, we managed 5 controlled DCDs. In 3 cases, the lungs were successfully transplanted. All 3 patients are alive after 1 year, with good respiratory function. CONCLUSIONS: Our approach resulted in adequate lung preservation and successful transplants without detrimental effects on abdominal organ procurement, confirming the possibility of overcoming the obstacle of a long no-touch period in a DCD setting.

Successful donation after cardiac death liver transplants with prolonged warm ischemia time using normothermic regional perfusion.

The role of donation after cardiac death (DCD) in expanding the donor pool is mainly limited by the incidence of primary nonfunction (PNF) and ischemia-related complications. Even greater concern exists toward uncontrolled DCD, which represents the largest potential pool of DCD donors. We recently started the first Italian series of DCD liver transplantation, using normothermic regional perfusion (NRP) in 6 uncontrolled donors and in 1 controlled case to deal with the legally required no-touch period of 20 minutes. We examined our first 7 cases for the incidence of PNF, early graft dysfunction, and biliary complications. Acceptance of the graft was based on the trend of serum transaminase and lactate during NRP, the macroscopic appearance, and the liver biopsy. Hypothermic machine perfusion (HMP) was associated in selected cases to improve cold storage. Most notably, no cases of PNF were observed. Median posttransplant transaminase peak was 1014 IU/L (range, 393-3268 IU/L). Patient and graft survival were both 100% after a mean follow-up of 6.1 months (range, 3-9 months). No cases of ischemic cholangiopathy occurred during the follow-up. Only 1 anastomotic stricture completely resolved with endoscopic stenting. In conclusion, DCD liver transplantation is feasible in Italy despite the protracted no-touch period. The use of NRP and HMP seems to earn good graft function and proves safe in these organs. Liver Transplantation 23 166-173 2017 AASLD.

Organ allocation waiting time during extracorporeal bridge to lung transplant affects outcomes.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplant (LTX) is still being debated. METHODS: We performed a retrospective two-center analysis of the relationship between ECMO bridging duration and survival in 25 patients. Further survival analysis was obtained by dividing the patients according to waiting time on ECMO: up to 14 days (Early group) or longer (Late group). We also analyzed the impact of the ventilation strategy during ECMO bridging (ie, spontaneous breathing and noninvasive ventilation [NIV] or intubation and invasive mechanical ventilation [IMV]). RESULTS: Seventeen of 25 patients underwent a transplant (with a 76% 1-year survival), whereas eight patients died during bridging. In the 17 patients who underwent a transplant, mortality was positively related to waiting days until LTX (hazard ratio [HR], 1.12 per day; 95% CI, 1.02-1.23; P = .02), and the Early group showed better Kaplan-Meier curves (P = .02), higher 1-year survival rates (100% vs 50%, P = .03), and lower morbidity (days on IMV and length of stay in ICU and hospital). During the bridge to transplant, mortality increased steadily with time. Considering the overall outcome of the bridging program (25 patients), bridge duration adversely affected survival (HR, 1.06 per day; 95% CI, 1.01-1.11; P = .015) and 1-year survival (Early, 82% vs Late, 29%; P = .015). Morbidity indexes were lower in patients treated with NIV during the bridge. CONCLUSIONS: The duration of the ECMO bridge is a relevant cofactor in the mortality and morbidity of critically ill patients awaiting organ allocation. The NIV strategy was associated with a less complicated clinical course after LTX.