Publications by authors named "Alberto Zanella"

175 Publications

Addition of 5% CO2 to Inspiratory Gas Prevents Lung Injury in an Experimental Model of Pulmonary Artery Ligation.

Am J Respir Crit Care Med 2021 Jul 12. Epub 2021 Jul 12.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 9339, Department of Anesthesia, Critical Care and Emergency, Milan, Italy.

Rationale: Unilateral ligation of the pulmonary artery may induce lung injury through multiple mechanisms, which might be dampened by inhaled CO2.

Objectives: To characterize bilateral lung injury due to unilateral ligation of pulmonary artery in healthy swine undergoing controlled mechanical ventilation and its prevention by 5% CO2 inhalation. To investigate relevant pathophysiological mechanisms.

Methods: Sixteen healthy pigs were allocated to surgical ligation of the left pulmonary artery (Ligation group), 7 to surgical ligation of the left pulmonary artery and inhalation of 5% CO2 (Ligation + FiCO2 5%), and 6 to no intervention (No Ligation). Then, all animals received mechanical ventilation with tidal volume (Vt) 10 ml/Kg, positive end-expiratory pressure 5 cmH2O, respiratory rate 25 bpm and FiO2 50% (±FiCO2 5%) for 48 hours or until development of severe lung injury.

Measurements And Main Results: Histological, physiological and quantitative CT-scan data were compared between groups to characterize lung injury. Electrical impedance tomography and immunohistochemistry analysis were performed in a subset of animals to explore mechanisms of injury. Animals from the Ligation group developed bilateral lung injury as assessed by significantly higher histological score, larger increase in lung weight, poorer oxygenation, and worse respiratory mechanics in comparison to the Ligation + FiCO2 5% group. In the Ligation group, the right lung received larger fraction of Vt, and inflammation was more represented, while CO2 dampened both processes.

Conclusions: Mechanical ventilation induces bilateral lung injury within 48 hours in healthy pigs undergoing left pulmonary artery ligation. Inhalation of 5% CO2 prevents injury, likely through decreased stress to the right lung and anti-inflammatory effects. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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http://dx.doi.org/10.1164/rccm.202101-0122OCDOI Listing
July 2021

Alkaline Liquid Ventilation of the Membrane Lung for Extracorporeal Carbon Dioxide Removal (ECCOR): In Vitro Study.

Membranes (Basel) 2021 Jun 22;11(7). Epub 2021 Jun 22.

Anesthesia and Critical Care, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy.

Extracorporeal carbon dioxide removal (ECCOR) is a promising strategy to manage acute respiratory failure. We hypothesized that ECCOR could be enhanced by ventilating the membrane lung with a sodium hydroxide (NaOH) solution with high CO absorbing capacity. A computed mathematical model was implemented to assess NaOH-CO interactions. Subsequently, we compared NaOH infusion, named "alkaline liquid ventilation", to conventional oxygen sweeping flows. We built an extracorporeal circuit with two polypropylene membrane lungs, one to remove CO and the other to maintain a constant PCO (60 ± 2 mmHg). The circuit was primed with swine blood. Blood flow was 500 mL × min. After testing the safety and feasibility of increasing concentrations of aqueous NaOH (up to 100 mmol × L), the CO removal capacity of sweeping oxygen was compared to that of 100 mmol × L NaOH. We performed six experiments to randomly test four sweep flows (100, 250, 500, 1000 mL × min) for each fluid plus 10 L × min oxygen. Alkaline liquid ventilation proved to be feasible and safe. No damages or hemolysis were detected. NaOH showed higher CO removal capacity compared to oxygen for flows up to 1 L × min. However, the highest CO extraction power exerted by NaOH was comparable to that of 10 L × min oxygen. Further studies with dedicated devices are required to exploit potential clinical applications of alkaline liquid ventilation.
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http://dx.doi.org/10.3390/membranes11070464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306443PMC
June 2021

Low non-carbonic buffer power amplifies acute respiratory acid-base disorders in septic patients: an in-vitro study.

J Appl Physiol (1985) 2021 06 17. Epub 2021 Jun 17.

Department of Pathophysiology and Transplantation, University of Milan, Italy.

Rationale: Septic patients have typically reduced concentrations of hemoglobin and albumin, the major components of non-carbonic buffer power(β). This could expose patients to high pH variations during acid-base disorders.

Objectives: To compare, in-vitro, non-carbonic β of septic patients with that of healthy volunteers, and evaluate its distinct components.

Methods: Whole blood and isolated plasma of 18 septic patients and 18 controls were equilibrated with different CO mixtures. Blood gases, pH and electrolytes were measured. Non-carbonic β and non-carbonic β due to variations in Strong Ion Difference (β) were calculated for whole blood. Non-carbonic β and non-carbonic β normalized for albumin concentrations (β) were calculated for isolated plasma. Representative values at pH=7.40 were compared. Albumin proteoforms were evaluated via two-dimensional electrophoresis.

Measurements And Main Results: Hemoglobin and albumin concentrations were significantly lower in septic patients. Septic patients had lower non-carbonic β both of whole blood (22.0±1.9 vs. 31.6±2.1 mmol/L, p<0.01) and plasma (0.5±1.0 vs. 3.7±0.8 mmol/L, p<0.01). Non-carbonic β was lower in patients (16.8±1.9 vs. 24.4±1.9 mmol/L, p<0.01) and strongly correlated with hemoglobin concentration (r=0.94, p<0.01). Non-carbonic β was lower in patients (0.01 [-0.01 - 0.04] vs. 0.08 [0.06 - 0.09] mmol/g, p<0.01). Septic patients and controls showed different amounts of albumin proteoforms.

Conclusions: Septic patients are exposed to higher pH variations for any given change in CO due to lower concentrations of non-carbonic buffers and, possibly, an altered buffering function of albumin. In both septic patients and healthy controls, electrolyte shifts are the major buffering mechanism during respiratory acid-base disorders.
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http://dx.doi.org/10.1152/japplphysiol.00787.2020DOI Listing
June 2021

Targeted Next Generation Sequencing and Diagnosis of Congenital Hemolytic Anemias: A Three Years Experience Monocentric Study.

Front Physiol 2021 21;12:684569. Epub 2021 May 21.

UOS Fisiopatologia delle Anemie, UOC Ematologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Congenital hemolytic anemias (CHAs) are heterogeneous and rare disorders caused by alterations in structure, membrane transport, metabolism, or red blood cell production. The pathophysiology of these diseases, in particular the rarest, is often poorly understood, and easy-to-apply tools for diagnosis, clinical management, and patient stratification are still lacking. We report the 3-years monocentric experience with a 43 genes targeted Next Generation Sequencing (t-NGS) panel in diagnosis of CHAs; 122 patients from 105 unrelated families were investigated and the results compared with conventional laboratory pathway. Patients were divided in two groups: 1) cases diagnosed with hematologic investigations to be confirmed at molecular level, and 2) patients with unexplained anemia after extensive hematologic investigation. The overall sensitivity of t-NGS was 74 and 35% for families of groups 1 and 2, respectively. Inside this cohort of patients we identified 26 new pathogenic variants confirmed by functional evidence. The implementation of laboratory work-up with t-NGS increased the number of diagnoses in cases with unexplained anemia; cytoskeleton defects are well detected by conventional tools, deserving t-NGS to atypical cases; the diagnosis of Gardos channelopathy, some enzyme deficiencies, familial siterosterolemia, X-linked defects in females and other rare and ultra-rare diseases definitely benefits of t-NGS approaches.
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http://dx.doi.org/10.3389/fphys.2021.684569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176228PMC
May 2021

Early caloric deficit is associated with a higher risk of death in invasive ventilated COVID-19 patients.

Clin Nutr 2021 Mar 2. Epub 2021 Mar 2.

Clinical Nutrition and Dietetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Electronic address:

Background & Aims: The aim of this study was to evaluate the nutritional support management in mechanically ventilated coronavirus disease 2019 (COVID-19) patients and explore the association between early caloric deficit and mortality, taking possible confounders (i.e. obesity) into consideration.

Methods: This was a prospective study carried out during the first pandemic wave in the intensive care units (ICUs) of two referral University Hospitals in Lombardy, Italy. Two hundred twenty-two consecutive mechanically ventilated COVID-19 patients were evaluated during the ICU stay. In addition to major demographic and clinical data, we recorded information on the route and amount of nutritional support provided on a daily basis.

Results: Among patients still in the ICUs and alive on day 4 (N = 198), 129 (65.2%) and 72 (36.4%) reached a satisfactory caloric and protein intake, respectively, mainly by enteral route. In multivariable analysis, a satisfactory caloric intake on day 4 was associated with lower mortality (HR = 0.46 [95%CI, 0.42-0.50], P < 0.001). Mild obesity (body mass index [BMI] ≥30 and < 35 kg/m) was associated with higher mortality (HR = 1.99 [95%CI, 1.07-3.68], P = 0.029), while patients with moderate-severe obesity (BMI≥35 kg/m) were less likely to be weaned from invasive mechanical ventilation (HR = 0.71 [95%CI, 0.62-0.82], P < 0.001).

Conclusions: This study confirmed the negative prognostic and clinical role of obesity in mechanically ventilated COVID-19 patients and suggested that early caloric deficit may independently contribute to worsen survival in this patients' population. Therefore, any effort should be made to implement an adequate timely nutritional support in all COVID-19 patients during the ICU stay.
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http://dx.doi.org/10.1016/j.clnu.2021.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921717PMC
March 2021

Use of eHealth Platforms and Apps to Support Monitoring and Management of Home-Quarantined Patients With COVID-19 in the Province of Trento, Italy: App Development and Implementation.

JMIR Form Res 2021 May 31;5(5):e25713. Epub 2021 May 31.

Fondazione Bruno Kessler, Trento, Italy.

Background: Italy was the first country to largely experience the COVID-19 epidemic among other Western countries during the so-called first wave of the COVID-19 pandemic. Proper management of an increasing number of home-quarantined individuals created a significant challenge for health care authorities and professionals. This was especially true when considering the importance of remote surveillance to detect signs of disease progression and consequently regulate access to hospitals and intensive care units on a priority basis.

Objective: In this paper, we report on an initiative promoted to cope with the first wave of the COVID-19 epidemic in the Spring/Summer of 2020, in the Autonomous Province of Trento, Italy. A purposefully built app named TreCovid19 was designed to provide dedicated health care staff with a ready-to-use tool for remotely monitoring patients with progressive symptoms of COVID-19, who were home-quarantined during the first wave of the epidemic, and to focus on those patients who, based on their self-reported clinical data, required a quick response from health care professionals.

Methods: TreCovid19 was rapidly developed to facilitate the monitoring of a selected number of home-quarantined patients with COVID-19 during the very first epidemic wave. The app was built on top of an existing eHealth platform, already in use by the local health authority to provide home care, with the following functionalities: (1) to securely collect and link demographic and clinical information related to the patients and (2) to provide a two-way communication between a multidisciplinary health care team and home-quarantined patients. The system supported patients to self-assess their condition and update the multidisciplinary team on their health status. The system was used between March and June 2020 in the province of Trento.

Results: A dedicated multidisciplinary group of health care professionals adopted the platform over a period of approximately 3 months (from March-end to June 2020) to monitor a total of 170 patients with confirmed COVID-19 during home quarantine. All patients used the system until the end of the initiative. The TreCovid19 system has provided useful insights of possible viability and impact of a technological-organizational asset to manage a potentially critical workload for the health care staff involved in the periodic monitoring of a relevant number of quarantined patients, notwithstanding its limitations given the rapid implementation of the whole initiative.

Conclusions: The technological and organizational model adopted in response to the COVID-19 pandemic was developed and finalized in a relatively short period during the initial few weeks of the epidemic. The system successfully supported the health care staff involved in the periodic monitoring of an increasing number of home-quarantined patients and provided valuable data in terms of disease surveillance.
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http://dx.doi.org/10.2196/25713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168637PMC
May 2021

Pulmonary volume-feedback and ventilatory pattern after bilateral lung transplantation using neurally adjusted ventilatory assist ventilation.

Br J Anaesth 2021 07 21;127(1):143-152. Epub 2021 Apr 21.

Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Italy.

Background: Bilateral lung transplantation results in pulmonary vagal denervation, which potentially alters respiratory drive, volume-feedback, and ventilatory pattern. We hypothesised that Neurally Adjusted Ventilatory Assist (NAVA) ventilation, which is driven by diaphragm electrical activity (EAdi), would reveal whether vagally mediated pulmonary-volume feedback is preserved in the early phases after bilateral lung transplantation.

Methods: We prospectively studied bilateral lung transplant recipients within 48 h of surgery. Subjects were ventilated with NAVA and randomised to receive 3 ventilatory modes (baseline NAVA, 50%, and 150% of baseline NAVA values) and 2 PEEP levels (6 and 12 cm HO). We recorded airway pressure, flow, and EAdi.

Results: We studied 30 subjects (37% female; age: 37 (27-56) yr), of whom 19 (63%) had stable EAdi. The baseline NAVA level was 0.6 (0.2-1.0) cm HO μV. Tripling NAVA level increased the ventilatory peak pressure over PEEP by 6.3 (1.8), 7.6 (2.4), and 8.7 (3.2) cm HO, at 50%, 100%, and 150% of baseline NAVA level, respectively (P<0.001). EAdi peak decreased by 10.1 (9.0), 9.5 (9.4) and 8.8 μV (8.7) (P<0.001), accompanied by small increases in tidal volume, 8.3 (3.0), 8.7 (3.6), and 8.9 (3.3) ml kg donor's predicted body weight at 50%, 100%, and 150% of baseline NAVA levels, respectively (P<0.001). Doubling PEEP did not affect tidal volume.

Conclusions: NAVA ventilation was feasible in the majority of patients during the early postoperative period after bilateral lung transplantation. Despite surgical vagotomy distal to the bronchial anastomoses, bilateral lung transplant recipients maintained an unmodified respiratory pattern in response to variations in ventilatory assistance and PEEP.

Clinical Trial Registration: NCT03367221.
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http://dx.doi.org/10.1016/j.bja.2021.03.010DOI Listing
July 2021

NDP-MSH treatment recovers marginal lungs during ex vivo lung perfusion (EVLP).

Peptides 2021 Jul 15;141:170552. Epub 2021 Apr 15.

Center for Preclinical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via Pace 9, 20100, Milan, Italy.

The increasing use of marginal lungs for transplantation encourages novel approaches to improve graft quality. Melanocortins and their receptors (MCRs) exert multiple beneficial effects in pulmonary inflammation. We tested the idea that treatment with the synthetic α-melanocyte-stimulating hormone analogue [Nle4,D-Phe7]-α-MSH (NDP-MSH) during ex vivo lung perfusion (EVLP) could exert positive influences in lungs exposed to different injuries. Rats were assigned to one of the following protocols (N = 10 each): 1) ischemia/reperfusion (IR) or 2) cardiac death (CD) followed by ex vivo perfusion. NDP-MSH treatment was performed in five rats of each protocol before lung procurement and during EVLP. Pulmonary function and perfusate concentration of gases, electrolytes, metabolites, nitric-oxide, mediators, and cells were assessed throughout EVLP. ATP content and specific MCR expression were investigated in perfused lungs and in biopsies collected from rats in resting conditions (Native, N = 5). NDP-MSH reduced the release of inflammatory mediators in perfusates of both the IR and the CD groups. Treatment was likewise associated with a lesser amount of leukocytes (IR: p = 0.034; CD: p = 0.002) and reduced lactate production (IR: p = 0.010; CD: p = 0.008). In lungs exposed to IR injury, the NDP-MSH group showed increased ATP content (p = 0.040) compared to controls. In CD lungs, a significant improvement of vascular (p = 0.002) and airway (Ppeak: p < 0.001, compliance: p < 0.050, pO2: p < 0.001) parameters was observed. Finally, the expression of MC1R and MC5R was detected in both native and ex vivo-perfused lungs. The results indicate that NDP-MSH administration preserves lung function through broad positive effects on multiple pathways and suggest that exploitation of the melanocortin system during EVLP could improve reconditioning of marginal lungs before transplantation.
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http://dx.doi.org/10.1016/j.peptides.2021.170552DOI Listing
July 2021

The role of ex-situ hypothermic oxygenated machine perfusion and cold preservation time in extended criteria DCD and DBD.

Liver Transpl 2021 Apr 9. Epub 2021 Apr 9.

General and Liver Transplant Surgery Unit - Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan.

Hypothermic-oxygenated machine perfusion (HOPE) has the potential to counterbalance the detrimental consequences of cold and warm ischemia time in both brain death donors (DBD) and donors after circulatory death (DCD). Herein, we investigated the protective effects of HOPE in extended criteria (ECD) DBD and over-extended warm ischemia time (WIT) DCD grafts. The present retrospective case-series study included 50 livers subjected to end-ischemic HOPE or dual (D)HOPE in two liver transplant (LT) Centers from January 2018 to December 2019. All DCD donors were subjected to normothermic regional perfusion before organ procurement. Results are expressed as median (IQR). In the study period, 21 grafts derived from over-extended WIT DCD donors (total WIT 54 (40-60) min and 75% classified as futile), while 29 from ECD DBD. Three biliary complications and one case of ischemia-type biliary lesions were diagnosed. The rate of early allograft dysfunction (EAD) was 20% and those patients had higher comprehensive-complication index. Through a changing point analysis, cold preservation time (CPT) >9h was associated with prolonged hospital stay (p=0.02), higher rate of EAD (p=0.009) and worst post-LT complications (p=0.02). Logistic regression analyses indicated a significant relationship between CPT and early allograft dysfunction. No differences were showed in terms of early post-LT results between LT performed with DCD and BDB. Overall, our data are fully comparable with benchmark criteria in LT. In conclusion, the application of (D)HOPE allowed to obtain satisfactory and promising results using ECD-DBD and over-extended DCD grafts. Our findings indicate the need to reduce CPT also in the setting of DHOPE, particularly for grafts showing poor quality.
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http://dx.doi.org/10.1002/lt.26067DOI Listing
April 2021

Quantification of Recirculation During Veno-Venous Extracorporeal Membrane Oxygenation: In Vitro Evaluation of a Thermodilution Technique.

ASAIO J 2021 Mar 29. Epub 2021 Mar 29.

From the School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy Center for Preclinical Research, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy Department of Anesthesia and Critical Care, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy Department of Anesthesia and Critical Care, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

Veno-venous extracorporeal membrane oxygenation (vv-ECMO) represents one of the most advanced respiratory support for patients suffering from severe acute respiratory distress syndrome. During vv-ECMO a certain amount of extracorporeal oxygenated blood can flow back from the reinfusion into the drainage cannula without delivering oxygen to the patient. Detection and quantification of this dynamic phenomenon, defined recirculation, are critical to optimize the ECMO efficiency. Our study aimed to measure the recirculation fraction (RF) using a thermodilution technique. We built an in vitro circuit to simulate patients undergoing vv-ECMO (ECMO flow: 1.5, 3, and 4.5 L/min) with different cardiac output, using a recirculation bridge to achieve several known RFs (from 0% to 50%). The RF, computed as the ratio of the area under temperature-time curves (AUC) of the drainage and reinfusion, was significantly related to the set RF (AUC ratio (%) = 0.979 × RF (%) + 0.277%, p < 0.0001), but it was not dependent on tested ECMO and cardiac output values. A Bland-Altman analysis showed an AUC ratio bias (precision) of -0.21% for the overall data. Test-retest reliability showed an intraclass correlation coefficient of 0.993. This study proved the technical feasibility and computation validity of the applied thermodilution technique in computing vv-ECMO RF.
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http://dx.doi.org/10.1097/MAT.0000000000001428DOI Listing
March 2021

Mechanical ventilation parameters in critically ill COVID-19 patients: a scoping review.

Crit Care 2021 03 20;25(1):115. Epub 2021 Mar 20.

General Intensive Care Unit, Shaare Zedek Medical Center, Jerusalem, Israel.

Background: The mortality of critically ill patients with COVID-19 is high, particularly among those receiving mechanical ventilation (MV). Despite the high number of patients treated worldwide, data on respiratory mechanics are currently scarce and the optimal setting of MV remains to be defined. This scoping review aims to provide an overview of available data about respiratory mechanics, gas exchange and MV settings in patients admitted to intensive care units (ICUs) for COVID-19-associated acute respiratory failure, and to identify knowledge gaps.

Main Text: PubMed, EMBASE, and MEDLINE databases were searched from inception to October 30, 2020 for studies providing at least one ventilatory parameter collected within 24 h from the ICU admission. The quality of the studies was independently assessed using the Newcastle-Ottawa Quality Assessment Form for Cohort Studies. A total of 26 studies were included for a total of 14,075 patients. At ICU admission, positive end expiratory pressure (PEEP) values ranged from 9 to 16.5 cm of water (cmHO), suggesting that high levels of PEEP were commonly used for setting MV for these patients. Patients with COVID-19 are severely hypoxemic at ICU admission and show a median ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO/FiO) ranging from 102 to 198 mmHg. Static respiratory system compliance (Crs) values at ICU admission were highly heterogenous, ranging between 24 and 49 ml/cmHO. Prone positioning and neuromuscular blocking agents were widely used, ranging from 17 to 81 and 22 to 88%, respectively; both rates were higher than previously reported in patients with "classical" acute respiratory distress syndrome (ARDS).

Conclusions: Available data show that, in mechanically ventilated patients with COVID-19, respiratory mechanics and MV settings within 24 h from ICU admission are heterogeneous but similar to those reported for "classical" ARDS. However, to date, complete data regarding mechanical properties of respiratory system, optimal setting of MV and the role of rescue treatments for refractory hypoxemia are still lacking in the medical literature.
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http://dx.doi.org/10.1186/s13054-021-03536-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980724PMC
March 2021

Heparin-Free Lung Transplantation on Venovenous Extracorporeal Membrane Oxygenation Bridge.

ASAIO J 2021 Jan 28. Epub 2021 Jan 28.

From the Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy Department of Thoracic Surgery and Lung Transplant, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Extracorporeal membrane oxygenation (ECMO) bridge to lung transplantation (LuTX) exposes the patients to a high risk of perioperative bleeding secondary to systemic anticoagulation and coagulation factors deficiency. With this case series, we propose innovative "no-heparin" management of ECMO-bridge support during LuTX, based upon 1) control heparin resistance with antithrombin III in the preoperative period; 2) relying upon a fully functional, brand new heparinized ECMO circuit; 3) completely avoiding perioperative heparin; 4) hampering fibrinolysis with tranexamic acid; and 5) limiting venoarterial (VA) ECMO escalation, and the following need for full anticoagulation. Following the application of this new approach, we carried out three challenging clinical cases of bilateral ECMO-bridged LuTX effectively, with limited intraoperative blood requirement and no major postoperative bleeding or thromboembolic events. Of note, two of them had an extremely high risk for hemorrhage due to complete right lung anatomic derangement in case number 2 and surgical adhesion following first LuTX in case number 3, while for the case number 1, no blood products were administered during surgery. Despite the limited patient population, such an approach relies on a strong rationale and may be beneficial for managing ECMO bridging to LuTX. Prospective studies are necessary to confirm the validity of our strategy.
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http://dx.doi.org/10.1097/MAT.0000000000001371DOI Listing
January 2021

Overcoming the Limits of Reconditioning: Seventeen Hours of Ex-Vivo Lung Perfusion (EVLP) with Successful Transplantation from Uncontrolled Circulatory Death Donor.

Transplantation 2021 Jan 25. Epub 2021 Jan 25.

Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico of Milan, Milan, Italy. University of Milan, Milan, Italy. Anesthesia, Intensive Care and Emergency, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico of Milan, Milan, Italy. Pathology Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico of Milan, Milan, Italy. Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico of Milan, Milan, Italy. San Gerardo Hospital, ASST-Monza, Monza, Italy. University of Milano-Bicocca, Milan, Italy.

Background: Uncontrolled donors after circulatory death (DCD) are an extraordinary resource to increase the number of lungs available for transplantation. However, the risk of the warm ischemia resulting from cardiac arrest to irreversibly damage the organs is considerable. Moreover, graft preservation issues and organizational problems often worsen the dangerous effects of warm ischemia. Ex-Vivo Lung Perfusion (EVLP) enables to evaluate and recondition lungs whose functionality is doubtful, as well as to overcome the difficulties related to time and logistics.

Methods: We report the case of uncontrolled DCD lungs successfully treated with an exceptionally prolonged EVLP. Since the donor's blood count and liver biopsy showed signs of a possible leukaemia, EVLP was protracted up to seventeen hours while waiting for immunohistochemical analyses to rule out this diagnosis; eventually, the results came back negative and lungs were judged suitable for transplantation.

Results: The recipient was a 32-year old male with cystic fibrosis, colonized by Pandoraea pnomenusa. Bilateral transplantation required central extracorporeal membrane oxygenation. The patient was extubated after 36 hours and was discharged 21 days after the operation. Despite early re-colonization by Pandoraea pnomenusa and airway complications requiring pneumatic dilatation, he is alive and has a satisfactory respiratory function 15 months after transplantation.

Conclusions: Uncontrolled DCD represents a challenge due to both logistical issues and the complexity of grafts evaluation before procurement: EVLP with cellular perfusate could be a valuable tool to overcome these limits. Nonetheless, caution should be exercised when interpreting the effects of this technique on airway healing.
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http://dx.doi.org/10.1097/TP.0000000000003646DOI Listing
January 2021

Volatile Sedation for Acute Respiratory Distress Syndrome Patients on Venovenous Extracorporeal Membrane Oxygenation and Ultraprotective Ventilation.

Crit Care Explor 2021 Jan 8;3(1):e0310. Epub 2021 Jan 8.

Dipartimento di Medicina e Chirurgia, Università degli Studi di Milano-Bicocca, Monza, Italy.

Patients on extracorporeal support for severe acute respiratory distress syndrome may require a prolonged period of deep sedation. In these patients, volatile sedation may represent a valid alternative to IV drugs. The aim of our study was to describe the feasibility of volatile sedation in a large cohort of acute respiratory distress syndrome patients undergoing venovenous extracorporeal membrane oxygenation and ultraprotective ventilation.

Design: Retrospective monocentric study.

Setting: Adult ICU, ASST Monza, Italy.

Patients: Adult patients who underwent volatile sedation with isoflurane during venovenous extracorporeal membrane oxygenation between 2009 and 2019.

Interventions: Isoflurane was delivered via the AnaConDa system. The sedation level, hemodynamics, and laboratory tests were compared between the volatile sedation phase and the IV sedation phases before and after the isoflurane sedation period.

Measurements And Main Results: About 74 patients (50 yr [43-56 yr]) were included. Median duration of venovenous extracorporeal membrane oxygenation support was 22 days (14-51 d). Volatile sedation started on day 3 (2-6) of extracorporeal membrane oxygenation support, and its median duration was 7 days (4-13 d), ranging from 1 to 38 days. A total of 970 venovenous extracorporeal membrane oxygenation days were analyzed. During the volatile phase, the sedation level was slightly deeper (bispectral index 39 ± 6) compared with the IV phase before and after isoflurane (42 ± 8 and 43 ± 9, respectively, < 0.001). Requirements of fentanyl and remifentanyl were reduced during the volatile phase. Minor differences in hemodynamics were observed during volatile sedation: mean arterial pressure was lower (75 ± 13 vs 79 ± 14 and 80 ± 15; < 0.001), whereas cardiac output was higher (8.5 ± 1.9 vs 7.9 ± 1.8 and 8.0 ± 1.8; = 0.003). Aspartate aminotransferase levels were lower during the volatile sedation phases ( < 0.001), whereas alanine aminotransferase, triglycerides, and creatine phosphokinase were more altered during the IV sedation phase before isoflurane ( < 0.001).

Conclusions: Volatile sedation represents an alternative to IV agents to achieve long-term deep sedation in critically ill patients on extracorporeal membrane oxygenation undergoing ultraprotective ventilation.
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http://dx.doi.org/10.1097/CCE.0000000000000310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803679PMC
January 2021

Preparedness of ICU networks for pandemics.

Curr Opin Crit Care 2021 02;27(1):13-19

Department of Pathophysiology and Transplantation, University of Milan.

Purpose Of Review: The recent COVID-19 outbreak has clearly shown how epidemics/pandemics can challenge developed countries' healthcare systems. Proper management of equipment and human resources is critical to provide adequate medical care to all patients admitted to the hospital and the ICU for both pandemic-related and unrelated reasons.

Recent Findings: Appropriate separate paths for infected and noninfected patients and prompt isolation of infected critical patients in dedicated ICUs play a pivotal role in limiting the contagions and optimizing resources during pandemics. The key to handle these challenging events is to learn from past experiences and to be prepared for future occurrences. Hospital space should be redesigned to quickly increase medical and critical care capacity, and healthcare workers (critical and noncritical) should be trained in advance.

Summary: A targeted improvement of hospital and ICU protocols will increase medical care quality for patients admitted to the hospital for any clinical reasons during a pandemic.
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http://dx.doi.org/10.1097/MCC.0000000000000792DOI Listing
February 2021

Right Ventricle Dysfunction in Patients With Adult Cystic Fibrosis Enlisted for Lung Transplant.

Transplant Proc 2021 Jan-Feb;53(1):260-264. Epub 2020 Nov 27.

Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Knowledge of preoperative right heart function of adult patients with cystic fibrosis (CF) awaiting lung transplant (LUTX) is limited. The echocardiography of adult patients with CF enlisted for LUTX was retrospectively analyzed and compared with standards and invasive analyses (right heart catheterization, multigated radionuclide ventriculography). We included 49 patients (reported as mean ± standard deviation; 29 ± 9 years of age; forced expiratory volume in first second of expiration, 31% ± 11% predicted; lung allocation score, 36 ± 5; invasive mean pulmonary artery pressure, 17 ± 5 mm Hg; multigated radionuclide ventriculography right ventricle [RV] ejection fraction, 50% ± 9%). Patients had increased RV end-diastolic area, RV wall thickness, and increased pulmonary artery acceleration time with subnormal tricuspid annular plane systolic excursion, tissue Doppler positive peak systolic velocity, and fraction area change. Subnormal tricuspid annular plane systolic excursion (< 23 mm), tissue Doppler positive peak systolic velocity (< 14 cm/s), and fraction area change (< 49%) had high sensitivity and negative predictive value in predicting impaired RV. EJECTION FRACTION: A good correlation between echocardiographic estimated and invasively measured systolic pulmonary artery pressure was observed (R = 0.554, P < .001). Adults with CF awaiting LUTX have morphologic alterations of the right heart, with subclinical impairment of RV systolic function. Echocardiography may be used as a bedside, repeatable, and reliable noninvasive test to screen further deterioration in RV function while on the waiting list for LUTX. More prospective follow-up echocardiographic studies are necessary to confirm such a hypothesis.
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http://dx.doi.org/10.1016/j.transproceed.2020.09.020DOI Listing
April 2021

Use of critical care resources during the first 2 weeks (February 24-March 8, 2020) of the Covid-19 outbreak in Italy.

Ann Intensive Care 2020 Oct 12;10(1):133. Epub 2020 Oct 12.

Department of Clinical, Integrated, and Experimental Medicine (DIMES), Respiratory and Critical Care, Sant'Orsola Malpighi Hospital, Bologna, Italy.

Background: A Covid-19 outbreak developed in Lombardy, Veneto and Emilia-Romagna (Italy) at the end of February 2020. Fear of an imminent saturation of available ICU beds generated the notion that rationing of intensive care resources could have been necessary.

Results: In order to evaluate the impact of Covid-19 on the ICU capacity to manage critically ill patients, we performed a retrospective analysis of the first 2 weeks of the outbreak (February 24-March 8). Data were collected from regional registries and from a case report form sent to participating sites. ICU beds increased from 1545 to 1989 (28.7%), and patients receiving respiratory support outside the ICU increased from 4 (0.6%) to 260 (37.0%). Patients receiving respiratory support outside the ICU were significantly older [65 vs. 77 years], had more cerebrovascular (5.8 vs. 13.1%) and renal (5.3 vs. 10.0%) comorbidities and less obesity (31.4 vs. 15.5%) than patients admitted to the ICU. PaO/FiO ratio, respiratory rate and arterial pH were higher [165 vs. 244; 20 vs. 24 breath/min; 7.40 vs. 7.46] and PaCO and base excess were lower [34 vs. 42 mmHg; 0.60 vs. 1.30] in patients receiving respiratory support outside the ICU than in patients admitted to the ICU, respectively.

Conclusions: Increase in ICU beds and use of out-of-ICU respiratory support allowed effective management of the first 14 days of the Covid-19 outbreak, avoiding resource rationing.
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http://dx.doi.org/10.1186/s13613-020-00750-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549086PMC
October 2020

Key Role of Respiratory Quotient to Reduce the Occurrence of Hypoxemia During Extracorporeal Gas Exchange: A Theoretical Analysis.

Crit Care Med 2020 12;48(12):e1327-e1331

Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Objectives: Extracorporeal respiratory support, including low blood flow systems providing mainly extracorporeal CO2 removal, are increasingly applied in clinical practice. Gas exchange physiology during extracorporeal respiratory support is complex and differs between full extracorporeal membrane oxygenation and extracorporeal CO2 removal. Aim of the present article is to review pathophysiological aspects which are relevant for the understanding of hypoxemia development during extracorporeal CO2 removal. We will describe the mathematical and physiologic background underlying changes in respiratory quotient and alveolar oxygen tension during venovenous extracorporeal gas exchange and highlight the clinical implications.

Design: Theoretical analysis of venovenous extracorporeal gas exchange.

Setting: Italian university research hospital.

Patients: None.

Interventions: None.

Measurements And Main Results: While the effect of extracorporeal CO2 removal on the respiratory quotient of the native lung has long been known, the role of extracorporeal oxygenation in dictating changes in the respiratory quotient has been less addressed. Indeed, both extracorporeal CO2 removal and extracorporeal oxygen delivery affect the respiratory quotient of the native lung and thus influence the alveolar PO2. Indeed, for the same amount of extracorporeal CO2 extraction, it is possible to reduce the FIO2, reduce the risk of absorption atelectasis, and maintain the same alveolar PO2, by increasing the extracorporeal oxygen delivery.

Conclusions: Worsening of hypoxemia is frequent during low-flow extracorporeal CO2 removal combined with ultraprotective mechanical ventilation. In this context, increasing extracorporeal oxygen delivery, increases the respiratory quotient of the native lung and could reduce both the occurrence of alveolar hypoxia and absorption atelectasis, thus optimizing the residual lung function.
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http://dx.doi.org/10.1097/CCM.0000000000004619DOI Listing
December 2020

Sequential Use of Normothermic Regional and Ex Situ Machine Perfusion in Donation After Circulatory Death Liver Transplant.

Liver Transpl 2021 02 8;27(3):385-402. Epub 2020 Nov 8.

General and Liver Transplant Surgery Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

In Italy, 20 minutes of a continuous flat line on an electrocardiogram are required for declaration of death. In the setting of donation after circulatory death (DCD), prolonged warm ischemia time prompted the introduction of abdominal normothermic regional perfusion (NRP) followed by postprocurement ex situ machine perfusion (MP). This is a retrospective review of DCD liver transplantations (LTs) performed at 2 centers using sequential NRP and ex situ MP. From January 2018 to April 2019, 34 DCD donors were evaluated. Three (8.8%) were discarded before NRP, and 11 (32.4%) were discarded based on NRP parameters (n = 1, 3.0%), liver macroscopic appearance at procurement and/or biopsy results (n = 9, 26.5%), or severe macroangiopathy at back-table evaluation (n = 1, 3.0%). A total of 20 grafts (58.8%; 11 uncontrolled DCDs, 9 controlled DCDs) were considered eligible for LT, procured and perfused ex situ (9 normothermic and 11 dual hypothermic MPs). In total, 18 (52.9%; 11 uncontrolled) livers were eventually transplanted. Median (interquartile range) no-flow time was 32.5 (30-39) minutes, whereas median functional warm ischemia time was 52.5 (47-74) minutes (controlled DCD), and median low-flow time was 112 minutes (105-129 minutes; uncontrolled DCD). There was no primary nonfunction, while postreperfusion syndrome occurred in 8 (44%) recipients. Early allograft dysfunction happened in 5 (28%) patients, while acute kidney injury occurred in 5 (28%). After a median follow-up of 15.1 (9.5-22.3) months, 1 case of ischemic-type biliary lesions and 1 patient death were reported. DCD LT is feasible even with the 20-minute no-touch rule. Strict NRP and ex situ MP selection criteria are needed to optimize postoperative results.
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http://dx.doi.org/10.1002/lt.25899DOI Listing
February 2021

Prone Positioning during Venovenous Extracorporeal Membrane Oxygenation in Acute Respiratory Distress Syndrome. A Multicenter Cohort Study and Propensity-matched Analysis.

Ann Am Thorac Soc 2021 03;18(3):495-501

Dipartimento di Anestesia, Terapia Intensive, e Emergenza, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Prone positioning reduces mortality in patients with severe acute respiratory distress syndrome (ARDS). To date, no evidence supports the use of prone positioning (PP) during venovenous extracorporeal oxygenation (ECMO). The aim of the study was to assess the feasibility, safety, and effect on oxygenation and lung mechanics of PP during ECMO. As a secondary exploratory aim, we assessed the association between PP and hospital mortality. We performed a multicenter retrospective cohort study in six Italian ECMO centers, including patients managed with PP during ECMO support (prone group; four centers) and patients managed in the supine position (control group; two centers). Physiological variables were analyzed at four time points (supine before PP, start of PP, end of PP, and supine after PP). The association between PP and hospital mortality was assessed by multivariate analysis and propensity score-matching. A total of 240 patients were included, with 107 in the prone group and 133 in the supine group. The median duration of the 326 pronation cycles was 15 (12-18) hours. Minor reversible complications were reported in 6% of PP maneuvers. PP improved oxygenation and reduced intrapulmonary shunt. Unadjusted hospital mortality was lower in the prone group (34 vs. 50%;  = 0.017). After adjusting for covariates, PP remained significantly associated with a reduction of hospital mortality (odds ratio, 0.50; 95% confidence interval, 0.29-0.87). Sixty-six propensity score-matched patients were identified in each group. In this matched sample, patients who underwent pronation had higher ECMO duration (16 vs. 10 d;  = 0.0344) but lower hospital mortality (30% vs. 53%;  = 0.0241). PP during ECMO improved oxygenation and was associated with a reduction of hospital mortality.
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http://dx.doi.org/10.1513/AnnalsATS.202006-625OCDOI Listing
March 2021

Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study.

Lancet Respir Med 2020 12 27;8(12):1201-1208. Epub 2020 Aug 27.

Dipartimento di Scienze Mediche e Chirurgiche, Anesthesia and Intensive Care Medicine, Policlinico di Sant'Orsola, Alma Mater Studiorum-Università di Bologna, Bologna, Italy. Electronic address:

Background: Patients with COVID-19 can develop acute respiratory distress syndrome (ARDS), which is associated with high mortality. The aim of this study was to examine the functional and morphological features of COVID-19-associated ARDS and to compare these with the characteristics of ARDS unrelated to COVID-19.

Methods: This prospective observational study was done at seven hospitals in Italy. We enrolled consecutive, mechanically ventilated patients with laboratory-confirmed COVID-19 and who met Berlin criteria for ARDS, who were admitted to the intensive care unit (ICU) between March 9 and March 22, 2020. All patients were sedated, paralysed, and ventilated in volume-control mode with standard ICU ventilators. Static respiratory system compliance, the ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air, ventilatory ratio (a surrogate of dead space), and D-dimer concentrations were measured within 24 h of ICU admission. Lung CT scans and CT angiograms were done when clinically indicated. A dataset for ARDS unrelated to COVID-19 was created from previous ARDS studies. Survival to day 28 was assessed.

Findings: Between March 9 and March 22, 2020, 301 patients with COVID-19 met the Berlin criteria for ARDS at participating hospitals. Median static compliance was 41 mL/cm HO (33-52), which was 28% higher than in the cohort of patients with ARDS unrelated to COVID-19 (32 mL/cm HO [25-43]; p<0·0001). 17 (6%) of 297 patients with COVID-19-associated ARDS had compliances greater than the 95th percentile of the classical ARDS cohort. Total lung weight did not differ between the two cohorts. CT pulmonary angiograms (obtained in 23 [8%] patients with COVID-19-related ARDS) showed that 15 (94%) of 16 patients with D-dimer concentrations greater than the median had bilateral areas of hypoperfusion, consistent with thromboembolic disease. Patients with D-dimer concentrations equal to or less than the median had ventilatory ratios lower than those of patients with D-dimer concentrations greater than the median (1·66 [1·32-1·95] vs 1·90 [1·50-2·33]; p=0·0001). Patients with static compliance equal to or less than the median and D-dimer concentrations greater than the median had markedly increased 28-day mortality compared with other patient subgroups (40 [56%] of 71 with high D-dimers and low compliance vs 18 [27%] of 67 with low D-dimers and high compliance, 13 [22%] of 60 with low D-dimers and low compliance, and 22 [35%] of 63 with high D-dimers and high compliance, all p=0·0001).

Interpretation: Patients with COVID-19-associated ARDS have a form of injury that, in many aspects, is similar to that of those with ARDS unrelated to COVID-19. Notably, patients with COVID-19-related ARDS who have a reduction in respiratory system compliance together with increased D-dimer concentrations have high mortality rates.

Funding: None.
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http://dx.doi.org/10.1016/S2213-2600(20)30370-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834127PMC
December 2020

Potential for Lung Recruitment and Ventilation-Perfusion Mismatch in Patients With the Acute Respiratory Distress Syndrome From Coronavirus Disease 2019.

Crit Care Med 2020 08;48(8):1129-1134

Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Objectives: Severe cases of coronavirus disease 2019 develop the acute respiratory distress syndrome, requiring admission to the ICU. This study aimed to describe specific pathophysiological characteristics of acute respiratory distress syndrome from coronavirus disease 2019.

Design: Prospective crossover physiologic study.

Setting: ICU of a university-affiliated hospital from northern Italy dedicated to care of patients with confirmed diagnosis of coronavirus disease 2019.

Patients: Ten intubated patients with acute respiratory distress syndrome and confirmed diagnosis of coronavirus disease 2019.

Interventions: We performed a two-step positive end-expiratory pressure trial with change of 10 cm H2O in random order.

Measurements And Main Results: At each positive end-expiratory pressure level, we assessed arterial blood gases, respiratory mechanics, ventilation inhomogeneity, and potential for lung recruitment by electrical impedance tomography. Potential for lung recruitment was assessed by the recently described recruitment to inflation ratio. In a subgroup of seven paralyzed patients, we also measured ventilation-perfusion mismatch at lower positive end-expiratory pressure by electrical impedance tomography. At higher positive end-expiratory pressure, respiratory mechanics did not change significantly: compliance remained relatively high with low driving pressure. Oxygenation and ventilation inhomogeneity improved but arterial CO2 increased despite unchanged respiratory rate and tidal volume. The recruitment to inflation ratio presented median value higher than previously reported in acute respiratory distress syndrome patients but with large variability (median, 0.79 [0.53-1.08]; range, 0.16-1.40). The FIO2 needed to obtain viable oxygenation at lower positive end-expiratory pressure was significantly correlated with the recruitment to inflation ratio (r = 0.603; p = 0.05). The ventilation-perfusion mismatch was elevated (median, 34% [32-45%] of lung units) and, in six out of seven patients, ventilated nonperfused units represented a much larger proportion than perfused nonventilated ones.

Conclusions: In patients with acute respiratory distress syndrome from coronavirus disease 2019, potential for lung recruitment presents large variability, while elevated dead space fraction may be a specific pathophysiological trait. These findings may guide selection of personalized mechanical ventilation settings.
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http://dx.doi.org/10.1097/CCM.0000000000004386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188034PMC
August 2020

Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy.

JAMA Intern Med 2020 10;180(10):1345-1355

Dipartimento Emergenza Urgenza, Unità Operativa Complessa (UOC) Anestesia e Rianimazione, ASST, Lodi, Italy.

Importance: Many patients with coronavirus disease 2019 (COVID-19) are critically ill and require care in the intensive care unit (ICU).

Objective: To evaluate the independent risk factors associated with mortality of patients with COVID-19 requiring treatment in ICUs in the Lombardy region of Italy.

Design, Setting, And Participants: This retrospective, observational cohort study included 3988 consecutive critically ill patients with laboratory-confirmed COVID-19 referred for ICU admission to the coordinating center (Fondazione IRCCS [Istituto di Ricovero e Cura a Carattere Scientifico] Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy) of the COVID-19 Lombardy ICU Network from February 20 to April 22, 2020. Infection with severe acute respiratory syndrome coronavirus 2 was confirmed by real-time reverse transcriptase-polymerase chain reaction assay of nasopharyngeal swabs. Follow-up was completed on May 30, 2020.

Exposures: Baseline characteristics, comorbidities, long-term medications, and ventilatory support at ICU admission.

Main Outcomes And Measures: Time to death in days from ICU admission to hospital discharge. The independent risk factors associated with mortality were evaluated with a multivariable Cox proportional hazards regression.

Results: Of the 3988 patients included in this cohort study, the median age was 63 (interquartile range [IQR] 56-69) years; 3188 (79.9%; 95% CI, 78.7%-81.1%) were men, and 1998 of 3300 (60.5%; 95% CI, 58.9%-62.2%) had at least 1 comorbidity. At ICU admission, 2929 patients (87.3%; 95% CI, 86.1%-88.4%) required invasive mechanical ventilation (IMV). The median follow-up was 44 (95% CI, 40-47; IQR, 11-69; range, 0-100) days; median time from symptoms onset to ICU admission was 10 (95% CI, 9-10; IQR, 6-14) days; median length of ICU stay was 12 (95% CI, 12-13; IQR, 6-21) days; and median length of IMV was 10 (95% CI, 10-11; IQR, 6-17) days. Cumulative observation time was 164 305 patient-days. Hospital and ICU mortality rates were 12 (95% CI, 11-12) and 27 (95% CI, 26-29) per 1000 patients-days, respectively. In the subgroup of the first 1715 patients, as of May 30, 2020, 865 (50.4%) had been discharged from the ICU, 836 (48.7%) had died in the ICU, and 14 (0.8%) were still in the ICU; overall, 915 patients (53.4%) died in the hospital. Independent risk factors associated with mortality included older age (hazard ratio [HR], 1.75; 95% CI, 1.60-1.92), male sex (HR, 1.57; 95% CI, 1.31-1.88), high fraction of inspired oxygen (Fio2) (HR, 1.14; 95% CI, 1.10-1.19), high positive end-expiratory pressure (HR, 1.04; 95% CI, 1.01-1.06) or low Pao2:Fio2 ratio (HR, 0.80; 95% CI, 0.74-0.87) on ICU admission, and history of chronic obstructive pulmonary disease (HR, 1.68; 95% CI, 1.28-2.19), hypercholesterolemia (HR, 1.25; 95% CI, 1.02-1.52), and type 2 diabetes (HR, 1.18; 95% CI, 1.01-1.39). No medication was independently associated with mortality (angiotensin-converting enzyme inhibitors HR, 1.17; 95% CI, 0.97-1.42; angiotensin receptor blockers HR, 1.05; 95% CI, 0.85-1.29).

Conclusions And Relevance: In this retrospective cohort study of critically ill patients admitted to ICUs in Lombardy, Italy, with laboratory-confirmed COVID-19, most patients required IMV. The mortality rate and absolute mortality were high.
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http://dx.doi.org/10.1001/jamainternmed.2020.3539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364371PMC
October 2020

Genomewide Association Study of Severe Covid-19 with Respiratory Failure.

N Engl J Med 2020 10 17;383(16):1522-1534. Epub 2020 Jun 17.

From the Institute of Clinical Molecular Biology, Christian-Albrechts-University (D.E., F.D., J.K., S. May, M. Wendorff, L.W., F.U.-W., X.Y., A.T., A. Peschuck, C.G., G.H.-S., H.E.A., M.C.R., M.E.F.B., M. Schulzky, M. Wittig, N.B., S.J., T.W., W.A., M. D'Amato, A.F.), and University Hospital Schleswig-Holstein, Campus Kiel (N.B., A.F.), Kiel, the Institute for Cardiogenetics, University of Lübeck, Lübeck (J.E.), the German Research Center for Cardiovascular Research, partner site Hamburg-Lübeck-Kiel (J.E.), the University Heart Center Lübeck (J.E.), and the Institute of Transfusion Medicine, University Hospital Schleswig-Holstein (S.G.), Lübeck, Stefan-Morsch-Stiftung, Birkenfeld (M. Schaefer, W.P.), and the Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Plön (O.O., T.L.L.) - all in Germany; Novo Nordisk Foundation Center for Protein Research, Disease Systems Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen (D.E.); the Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute-Donostia University Hospital-University of the Basque Country (L.B., K.G.-E., L.I.-S., P.M.R., J.M.B.), Osakidetza Basque Health Service, Donostialdea Integrated Health Organization, Clinical Biochemistry Department (A.G.C., B.N.J.), and the Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute (M. D'Amato), San Sebastian, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III (L.B., M. Buti, A. Albillos, A. Palom, F.R.-F., B.M., L. Téllez, K.G.-E., L.I.-S., F.M., L.R., M.R.-B., M. Rodríguez-Gandía, P.M.R., M. Romero-Gómez, J.M.B.), the Departments of Gastroenterology (A. Albillos, B.M., L. Téllez, F.M., M. Rodríguez-Gandía), Intensive Care (R.P., A.B.O.), Respiratory Diseases (D.J., A.S., R.N.), Infectious Diseases (C.Q., E.N.), and Anesthesiology (D. Pestaña, N. Martínez), Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, University of Alcalá, and Histocompatibilidad y Biologia Molecular, Centro de Transfusion de Madrid (F.G.S.), Madrid, the Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus (M. Buti, A. Palom, L.R., M.R.-B.), Hospital Clinic, University of Barcelona, and the August Pi i Sunyer Biomedical Research Institute (J.F., F.A., E.S., J.F.-A., L.M., M.H.-T., P.C.), the European Foundation for the Study of Chronic Liver Failure (J.F.), Vall d'Hebron Institut de Recerca (A. Palom, F.R.-F., A.J., S. Marsal), and the Departments of Biochemistry (A.-E.G.-F., F.R.-F., A.C.-G., C.C., A.B.-G.), Intensive Care (R.F.), and Microbiology (T.P.), University Hospital Vall d'Hebron, the Immunohematology Department, Banc de Sang i Teixits, Autonomous University of Barcelona (E.M.-D.), Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, Consortium for Biomedical Research in Epidemiology and Public Health and University of Barcelona, l'Hospitalet (V. Moreno), and Autonoma University of Barcelona (T.P.), Barcelona, Universitat Autònoma de Barcelona, Bellatera (M. Buti, F.R.-F., M.R.-B.), GenomesForLife-GCAT Lab Group, Germans Trias i Pujol Research Institute (A.C.N., I.G.-F., R.C.), and High Content Genomics and Bioinformatics Unit, Germans Trias i Pujol Research Institute (L. Sumoy), Badalona, Institute of Parasitology and Biomedicine Lopez-Neyra, Granada (J.M., M.A.-H.), the Digestive Diseases Unit, Virgen del Rocio University Hospital, Institute of Biomedicine of Seville, University of Seville, Seville (M. Romero-Gómez), and Ikerbasque, Basque Foundation for Science, Bilbao (M. D'Amato, J.M.B.) - all in Spain; the Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca (P.I., C.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (D. Prati, G.B., A.Z., A. Bandera, A.G., A.L.F., A. Pesenti, C.P., F.C., F.M.-B., F.P., F.B., G.G., G. Costantino, L. Terranova, L. Santoro, L. Scudeller, M. Carrabba, M. Baldini, M.M., N. Montano, R.G., S.P., S. Aliberti, V. Monzani, S. Bosari, L.V.), the Department of Biomedical Sciences, Humanitas University (R.A., A. Protti, A. Aghemo, A. Lleo, E.M.P., G. Cardamone, M. Cecconi, V.R., S.D.), Humanitas Clinical and Research Center, IRCCS (R.A., A. Protti, A. Aghemo, A. Lleo, A.V., C.A., E.M.P., H.K., I.M., M. Cecconi, M. Ciccarelli, M. Bocciolone, P.P., P.O., P.T., S. Badalamenti, S.D.), University of Milan (A.Z., A. Bandera, A.G., A.L.F., A. Pesenti, F.M.-B., F.P., F.B., G.G., G. Costantino, M.M., N. Montano, R.G., S.P., S. Aliberti, S. Bosari, L.V.), and the Center of Bioinformatics, Biostatistics, and Bioimaging (M.G.V.) and the Phase 1 Research Center (M. Cazzaniga), School of Medicine and Surgery, and the Departments of Emergency, Anesthesia, and Intensive Care (G.F.), Pneumologia (P.F.), and Infectious Diseases (P.B.); University of Milano-Bicocca, Milan, the European Reference Network on Hepatological Diseases (P.I., C.M.) and the Infectious Diseases Unit (P.B.), San Gerardo Hospital, Monza, the Pediatric Departement and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo (A. Biondi, L.R.B., M. D'Angiò), the Gastroenterology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (A. Latiano, O.P.), the Department of Medical Sciences, Università degli Studi di Torino, Turin (S. Aneli, G.M.), and the Italian Bone Marrow Donor Registry, E.O. Ospedali Galliera, Genoa (N.S.) - all in Italy; the Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases, and Transplantation, and the Research Institute for Internal Medicine, Division of Surgery, Inflammatory Diseases, and Transplantation, Oslo University Hospital Rikshospitalet and University of Oslo (M.M.G., J.R.H., T.F., T.H.K.), and the Section for Gastroenterology, Department of Transplantation Medicine, Division for Cancer Medicine, Surgery, and Transplantation, Oslo University Hospital Rikshospitalet (J.R.H., T.F., T.H.K.), Oslo; the School of Biological Sciences, Monash University, Clayton, VIC, Australia (T.Z., M. D'Amato); Private University in the Principality of Liechtenstein (C.G.); the Institute of Biotechnology, Vilnius University, Vilnius, Lithuania (S.J.); and the Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm (M. D'Amato).

Background: There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19.

Methods: We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels.

Results: We detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10) in the meta-analysis of the two case-control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P = 1.15×10; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P = 4.95×10, respectively). At locus 3p21.31, the association signal spanned the genes , , , , and . The association signal at locus 9q34.2 coincided with the blood group locus; in this cohort, a blood-group-specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P = 1.48×10) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P = 1.06×10).

Conclusions: We identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.).
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http://dx.doi.org/10.1056/NEJMoa2020283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315890PMC
October 2020

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

Liver Transpl 2020 10;26(10):1298-1315

Hepatobiliary Surgery and Liver Transplantation Unit, University of Padua Medical School Hospital, Padua, Italy.

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.
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http://dx.doi.org/10.1002/lt.25817DOI Listing
October 2020

Reply by Zanella to Swenson.

Am J Respir Crit Care Med 2020 09;202(6):908-909

University of Milan Milan, Italy.

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http://dx.doi.org/10.1164/rccm.202005-1842LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491387PMC
September 2020

Critically ill patients with COVID-19 in New York City.

Lancet 2020 06 19;395(10239):1740-1741. Epub 2020 May 19.

Dipartimento di Anestesia, Rianimazione ed Emergenza-Urgenza, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

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http://dx.doi.org/10.1016/S0140-6736(20)31190-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237179PMC
June 2020

One ventilator for two patients: feasibility and considerations of a last resort solution in case of equipment shortage.

Thorax 2020 06 23;75(6):517-519. Epub 2020 Apr 23.

Department of Medical and Surgical Sciences (DIMEC), Anesthesia and Intensive Care Medicine, Sant'Orsola-Malpighi Hospital, Alma Mater Studiorum University of Bologna, Bologna, Emilia-Romagna, Italy

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http://dx.doi.org/10.1136/thoraxjnl-2020-214895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211107PMC
June 2020

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

Minerva Anestesiol 2020 09 6;86(9):984-991. Epub 2020 Apr 6.

Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

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.
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http://dx.doi.org/10.23736/S0375-9393.20.14262-7DOI Listing
September 2020
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