Twelve-hour normothermic liver perfusion in a rat model: characterization of the changes in the ex-situ bio-molecular phenotype and metabolism.

The partial understanding of the biological events that occur during normothermic machine perfusion (NMP) and particularly during prolonged perfusion might hinder its deployment in clinical transplantation. The aim of our study was to implement a rat model of prolonged NMP to characterize the bio-molecular phenotype and metabolism of the perfused organs. Livers (n = 5/group) were procured and underwent 4 h (NMP4h) or 12 h (NMP12h) NMP, respectively, using a perfusion fluid supplemented with an acellular oxygen carrier. Organs that were not exposed to any procedure served as controls (Native). All perfused organs met clinically derived viability criteria at the end of NMP. Factors related to stress-response and survival were increased after prolonged perfusion. No signs of oxidative damage were detected in both NMP groups. Evaluation of metabolite profiles showed preserved mitochondrial function, activation of Cori cycle, induction of lipolysis, acetogenesis and ketogenesis in livers exposed to 12 h-NMP. Increased concentrations of metabolites involved in glycogen synthesis, glucuronidation, bile acid conjugation, and antioxidant response were likewise observed. In conclusion, our NMP12h model was able to sustain liver viability and function, thereby deeply changing cell homeostasis to maintain a newly developed equilibrium. Our findings provide valuable information for the implementation of optimized protocols for prolonged NMP.

Enhanced extracorporeal carbon dioxide removal by acidification and metabolic control.

BACKGROUND: Extracorporeal carbon dioxide removal (ECCO2R) promotes protective ventilation in patients with acute respiratory failure, but devices with high CO2 extraction capacity are required for clinically relevant impact. This study evaluates three novel low-flow techniques based on dialysate acidification, also combined with renal replacement therapy, and metabolic control. METHODS: Eight swine were connected to a low-flow (350 mL/min) extracorporeal circuit including a dialyzer with a closed-loop dialysate circuit, and two membrane lungs on blood (MLb) and dialysate (MLd), respectively. The following 2-hour steps were performed: 1) MLb-start (MLb ventilated); 2) MLbd-start (MLb and MLd ventilated); 3) HLac (lactic acid infusion before MLd); 4) HCl-NaLac (hydrochloric acid infusion before MLd combined with renal replacement therapy and reinfusion of sodium lactate); 5) HCl-ßHB-NaLac (hydrochloric acid infusion before MLd combined with renal replacement therapy and reinfusion of sodium lactate and sodium 3-hydroxybutyrate). Caloric and fluid inputs, temperature, blood glucose and arterial carbon dioxide pressure were kept constant. RESULTS: The total MLs CO2 removal in HLac (130±25 mL/min), HCl-NaLac (130±21 mL/min) and HCl-ßHB-NaLac (124±18 mL/min) were higher compared with MLbd-start (81±15 mL/min, P<0.05) and MLb-start (55±7 mL/min, P<0.05). Minute ventilation in HLac (4.3±0.9 L/min), HCl-NaLac (3.6±0.8 L/min) and HCl-ßHB-NaLac (3.6±0.8 L/min) were lower compared to MLb-start (6.2±1.1 L/min, P<0.05) and MLbd-start (5.8±2.1 L/min, P<0.05). Arterial pH was 7.40±0.03 at MLb-start and decreased only during HCl-ßHB-NaLac (7.35±0.03, P<0.05). No relevant changes in electrolyte concentrations, hemodynamics and significant adverse events were detected. CONCLUSIONS: The three techniques achieved a significant extracorporeal CO2 removal allowing a relevant reduction in minute ventilation with a sufficient safety profile.

Variable ventilation versus stepwise lung recruitment manoeuvres for lung recruitment: A comparative study in an experimental model of atelectasis.

BACKGROUND: Variable ventilation recruits alveoli in atelectatic lungs, but it is unknown how it compares with conventional recruitment manoeuvres. OBJECTIVES: To test whether mechanical ventilation with variable tidal volumes and conventional recruitment manoeuvres have comparable effects on lung function. DESIGN: Randomised crossover study. SETTING: University hospital research facility. ANIMALS: Eleven juvenile mechanically ventilated pigs with atelectasis created by saline lung lavage. INTERVENTIONS: Lung recruitment was performed using two strategies, both with an individualised optimal positive-end expiratory pressure (PEEP) associated with the best respiratory system elastance during a decremental PEEP trial: conventional recruitment manoeuvres (stepwise increase of PEEP) in pressure-controlled mode) followed by 50 min of volume-controlled ventilation (VCV) with constant tidal volume, and variable ventilation, consisting of 50 min of VCV with random variation in tidal volume. MAIN OUTCOME MEASURES: Before and 50 min after each recruitment manoeuvre strategy, lung aeration was assessed by computed tomography, and relative lung perfusion and ventilation (0% = dorsal, 100% = ventral) were determined by electrical impedance tomography. RESULTS: After 50 min, variable ventilation and stepwise recruitment manoeuvres decreased the relative mass of poorly and nonaerated lung tissue (percent lung mass: 35.3 ±â€Š6.2 versus 34.2 ±â€Š6.6, P  = 0.303); reduced poorly aerated lung mass compared with baseline (-3.5 ±â€Š4.0%, P  = 0.016, and -5.2 ±â€Š2.8%, P  < 0.001, respectively), and reduced nonaerated lung mass compared with baseline (-7.2 ±â€Š2.5%, P  < 0.001; and -4.7 ±â€Š2.8%, P  < 0.001 respectively), while the distribution of relative perfusion was barely affected (variable ventilation: -0.8 ±â€Š1.1%, P  = 0.044; stepwise recruitment manoeuvres: -0.4 ±â€Š0.9%, P  = 0.167). Compared with baseline, variable ventilation and stepwise recruitment manoeuvres increased Pa O 2 (172 ±â€Š85mmHg, P  = 0.001; and 213 ±â€Š73 mmHg, P  < 0.001, respectively), reduced Pa CO 2 (-9.6 ±â€Š8.1 mmHg, P  = 0.003; and -6.7 ±â€Š4.6 mmHg, P  < 0.001, respectively), and decreased elastance (-11.4 ±â€Š6.3 cmH 2 O, P  < 0.001; and -14.1 ±â€Š3.3 cmH 2 O, P  < 0.001, respectively). Mean arterial pressure decreased during stepwise recruitment manoeuvres (-24 ±â€Š8 mmHg, P  = 0.006), but not variable ventilation. CONCLUSION: In this model of lung atelectasis, variable ventilation and stepwise recruitment manoeuvres effectively recruited lungs, but only variable ventilation did not adversely affect haemodynamics. TRIAL REGISTRATION: This study was registered and approved by Landesdirektion Dresden, Germany (DD24-5131/354/64).

Lung Biomolecular Profile and Function of Grafts from Donors after Cardiocirculatory Death with Prolonged Donor Warm Ischemia Time.

The acceptable duration of donor warm ischemia time (DWIT) after cardiocirculatory death (DCD) is still debated. We analyzed the biomolecular profile and function during ex vivo lung perfusion (EVLP) of DCD lungs and their correlation with lung transplantation (LuTx) outcomes. Donor data, procurement times, recipient outcomes, and graft function up to 1 year after LuTx were collected. During EVLP, the parameters of graft function and metabolism, perfusate samples to quantify inflammation, glycocalyx breakdown products, coagulation, and endothelial activation markers were obtained. Data were compared to a cohort of extended-criteria donors after brain death (EC-DBD). Eight DBD and seven DCD grafts transplanted after EVLP were analyzed. DCD's DWIT was 201 [188;247] minutes. Donors differed only regarding the duration of mechanical ventilation that was longer in the EC-DBD group. No difference was observed in lung graft function during EVLP. At reperfusion, "wash-out" of inflammatory cells and microthrombi was predominant in DCD grafts. Perfusate biomolecular profile demonstrated marked endothelial activation, characterized by the presence of inflammatory mediators and glycocalyx breakdown products both in DCD and EC-DBD grafts. Early graft function after LuTx was similar between DCD and EC-DBD. DCD lungs exposed to prolonged DWIT represent a potential resource for donation if properly preserved and evaluated.

Quantitative Metabolomics of Tissue, Perfusate, and Bile from Rat Livers Subjected to Normothermic Machine Perfusion.

Machine perfusion (MP) allows the maintenance of liver cells in a metabolically active state ex vivo and can potentially revert metabolic perturbations caused by donor warm ischemia, procurement, and static cold storage (SCS). The present preclinical research investigated the metabolic outcome of the MP procedure by analyzing rat liver tissue, bile, and perfusate samples by means of high-field (600 MHz) nuclear magnetic resonance (NMR) spectroscopy. An established rat model of normothermic MP (NMP) was used. Experiments were carried out with the addition of an oxygen carrier (OxC) to the perfusion fluid (OxC-NMP, n = 5) or without (h-NMP, n = 5). Bile and perfusate samples were collected throughout the procedure, while biopsies were only taken at the end of NMP. Two additional groups were: (1) Native, in which tissue or bile specimens were collected from rats in resting conditions; and (2) SCS, in which biopsies were taken from cold-stored livers. Generally, NMP groups showed a distinctive metabolomic signature in all the analyzed biological matrices. In particular, many of the differentially expressed metabolites were involved in mitochondrial biochemical pathways. Succinate, acetate, 3-hydroxybutyrate, creatine, and O-phosphocholine were deeply modulated in ex vivo perfused livers compared to both the Native and SCS groups. These novel results demonstrate a broad modulation of mitochondrial metabolism during NMP that exceeds energy production and redox balance maintenance.

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

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.

Higher levels of IgA and IgG at sepsis onset are associated with higher mortality: results from the Albumin Italian Outcome Sepsis (ALBIOS) trial.

BACKGROUND: The role of intravenous immunoglobulins (IVIG) during sepsis is controversial, as different trials on IVIG have observed inconsistent survival benefits. We aimed to elucidate the possible association and clinical significance between circulating levels of immunoglobulins. METHODS: In a subset of 956 patients with severe sepsis and septic shock of the multicentre, open-label RCT ALBIOS, venous blood samples were serially collected 1, 2, and 7 days after enrolment (or at ICU discharge, whichever came first). IgA, IgG and IgM concentrations were assayed in all patients on day 1 and in a subgroup of 150 patients on days 2 and 7. Ig concentrations were measured employing a turbidimetric assay, OSR61171 system. RESULTS: IgA on day 1 had a significant predictive value for both 28-day and 90-day mortality (28-day mortality, HR: 1.50 (95% CI 1.18-1.92); 90-day mortality, HR: 1.54 (95% CI 1.25-1.91)). IgG, but not IgM, on day 1 showed similar results for 28-day (HR 1.83 (95% CI 1.33-2.51) and 90-day mortality HR: 1.66 (95% CI 1.23-2.25)). In addition, lower levels of IgG but not of IgA and IgM, at day 1 were associated with significantly higher risk of secondary infections (533 [406-772] vs 600 [452-842] mg/dL, median [Q1-Q3], p = 0.007). CONCLUSIONS: In the largest cohort study of patients with severe sepsis or septic shock, we found that high levels of IgA and IgG on the first day of diagnosis were associated with a decreased 90-day survival. No association was found between IgM levels and survival. As such, the assessment of endogenous immunoglobulins could be a useful tool to identify septic patients at high risk of mortality. Trial registration #NCT00707122, Clinicaltrial.gov, registered 30 June 2008.

Sharing Mechanical Ventilator: In Vitro Evaluation of Circuit Cross-Flows and Patient Interactions.

During the COVID-19 pandemic, a shortage of mechanical ventilators was reported and ventilator sharing between patients was proposed as an ultimate solution. Two lung simulators were ventilated by one anesthesia machine connected through two respiratory circuits and T-pieces. Five different combinations of compliances (30-50 mL × cmH2O-1) and resistances (5-20 cmH2O × L-1 × s-1) were tested. The ventilation setting was: pressure-controlled ventilation, positive end-expiratory pressure 15 cmH2O, inspiratory pressure 10 cmH2O, respiratory rate 20 bpm. Pressures and flows from all the circuit sections have been recorded and analyzed. Simulated patients with equal compliance and resistance received similar ventilation. Compliance reduction from 50 to 30 mL × cmH2O-1 decreased the tidal volume (VT) by 32% (418 ± 49 vs. 285 ± 17 mL). The resistance increase from 5 to 20 cmH2O × L-1 × s-1 decreased VT by 22% (425 ± 69 vs. 331 ± 51 mL). The maximal alveolar pressure was lower at higher compliance and resistance values and decreased linearly with the time constant (r² = 0.80, p < 0.001). The minimum alveolar pressure ranged from 15.5 ± 0.04 to 16.57 ± 0.04 cmH2O. Cross-flows between the simulated patients have been recorded in all the tested combinations, during both the inspiratory and expiratory phases. The simultaneous ventilation of two patients with one ventilator may be unable to match individual patient's needs and has a high risk of cross-interference.

Alkaline Liquid Ventilation of the Membrane Lung for Extracorporeal Carbon Dioxide Removal (ECCO2R): In Vitro Study.

Extracorporeal carbon dioxide removal (ECCO2R) is a promising strategy to manage acute respiratory failure. We hypothesized that ECCO2R could be enhanced by ventilating the membrane lung with a sodium hydroxide (NaOH) solution with high CO2 absorbing capacity. A computed mathematical model was implemented to assess NaOH-CO2 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 CO2 and the other to maintain a constant PCO2 (60 ± 2 mmHg). The circuit was primed with swine blood. Blood flow was 500 mL × min-1. After testing the safety and feasibility of increasing concentrations of aqueous NaOH (up to 100 mmol × L-1), the CO2 removal capacity of sweeping oxygen was compared to that of 100 mmol × L-1 NaOH. We performed six experiments to randomly test four sweep flows (100, 250, 500, 1000 mL × min-1) for each fluid plus 10 L × min-1 oxygen. Alkaline liquid ventilation proved to be feasible and safe. No damages or hemolysis were detected. NaOH showed higher CO2 removal capacity compared to oxygen for flows up to 1 L × min-1. However, the highest CO2 extraction power exerted by NaOH was comparable to that of 10 L × min-1 oxygen. Further studies with dedicated devices are required to exploit potential clinical applications of alkaline liquid ventilation.

Effects of two stepwise lung recruitment strategies on respiratory function and haemodynamics in anaesthetised pigs: A randomised crossover study.

BACKGROUND: Lung recruitment manoeuvres and positive end-expiratory pressure (PEEP) can improve lung function during general anaesthesia. Different recruitment manoeuvre strategies have been described in large international trials: in the protective ventilation using high vs. low PEEP (PROVHILO) strategy, tidal volume (VT) was increased during volume-controlled ventilation; in the individualised peri-operative open-lung approach vs. standard protective ventilation in abdominal surgery (iPROVE) strategy, PEEP was increased during pressure-controlled ventilation. OBJECTIVES: To compare the effects of the PROVHILO strategy and the iPROVE strategy on respiratory and haemodynamic variables. DESIGN: Randomised crossover study. SETTING: University hospital research facility. ANIMALS: A total of 20 juvenile anaesthetised pigs. INTERVENTIONS: Animals were assigned randomly to one of two sequences: PROVHILO strategy followed by iPROVE strategy or vice-versa (n = 10/sequence). In the PROVHILO strategy, VT was increased stepwise by 4 ml kg-1 at a fixed PEEP of 12 cmH2O until a plateau pressure of 30 to 35 cmH2O was reached. In the iPROVE strategy, at fixed driving pressure of 20 cmH2O, PEEP was increased up to 20 cmH2O followed by PEEP titration according to the lowest elastance of the respiratory system (ERS). MAIN OUTCOME MEASURES: We assessed regional transpulmonary pressure (Ptrans), respiratory system mechanics, gas exchange and haemodynamics, as well as the centre of ventilation (CoV) by electrical impedance tomography. RESULTS: During recruitment manoeuvres with the PROVHILO strategy compared with the iPROV strategy, dorsal Ptrans was lower at end-inspiration (16.3 ±â€Š2.7 vs. 18.6 ±â€Š3.1 cmH2O, P = 0.001) and end-expiration (4.8 ±â€Š2.6 vs. 8.8 ±â€Š3.4 cmH2O, P  < 0.001), and mean arterial pressure (MAP) was higher (77 ±â€Š11 vs. 60 ±â€Š14 mmHg, P < 0.001). At 1 and 15 min after recruitment manoeuvres, ERS was higher in the PROVHILO strategy than the iPROVE strategy (24.6 ±â€Š3.9 vs. 21.5 ±â€Š3.4 and 26.7 ±â€Š4.3 vs. 24.0 ±â€Š3.8 cmH2O l-1; P  < 0.001, respectively). At 1 min, PaO2 was lower in PROVHILO compared with iPROVE strategy (57.1 ±â€Š6.1 vs. 59.3 ±â€Š5.1 kPa, P = 0.013), but at 15 min, values did not differ. CoV did not differ between strategies. CONCLUSION: In anaesthetised pigs, the iPROVE strategy compared with the PROVHILO strategy increased dorsal Ptrans at the cost of lower MAP during recruitment manoeuvres, and decreased ERS thereafter, without consistent improvement of oxygenation or shift of the CoV. TRIAL REGISTRATION: This study was registered and approved by the Landesdirektion Dresden, Germany (DD24-5131/338/28).

Continuous external negative pressure improves oxygenation and respiratory mechanics in Experimental Lung Injury in Pigs - A pilot proof-of-concept trial.

BACKGROUND: Continuous external negative pressure (CENP) during positive pressure ventilation can recruit dependent lung regions. We hypothesised that CENP applied regionally to the thorax or the abdomen only, increases the caudal end-expiratory transpulmonary pressure depending on positive end-expiratory pressure (PEEP) in lung-injured pigs. Eight pigs were anesthetised and mechanically ventilated in the supine position. Pressure sensors were placed in the left pleural space, and a lung injury was induced by saline lung lavages. A CENP shell was placed at the abdomen and thorax (randomised order), and animals were ventilated with PEEP 15, 7 and zero cmH2O (15 min each). On each PEEP level, CENP of - 40, - 30, - 20, - 10 and 0 cmH2O was applied (3 min each). Respiratory and haemodynamic variables were recorded. Electrical impedance tomography allowed assessment of centre of ventilation. RESULTS: Compared to positive pressure ventilation alone, the caudal transpulmonary pressure was significantly increased by CENP of ≤ 20 cmH2O at all PEEP levels. CENP of - 20 cmH2O reduced the mean airway pressure at zero PEEP (P = 0.025). The driving pressure decreased at CENP of ≤ 10 at PEEP of 0 and 7 cmH2O (P < 0.001 each) but increased at CENP of - 30 cmH2O during the highest PEEP (P = 0.001). CENP of - 30 cmH2O reduced the mechanical power during zero PEEP (P < 0.001). Both elastance (P < 0.001) and resistance (P < 0.001) were decreased at CENP ≤ 30 at PEEP of 0 and 7 cmH2O. Oxygenation increased at CENP of ≤ 20 at PEEP of 0 and 7 cmH2O (P < 0.001 each). Applying external negative pressure significantly shifted the centre of aeration towards dorsal lung regions irrespectively of the PEEP level. Cardiac output decreased significantly at CENP -20 cmH2O at all PEEP levels (P < 0.001). Effects on caudal transpulmonary pressure, elastance and cardiac output were more pronounced when CENP was applied to the abdomen compared with the thorax. CONCLUSIONS: In this lung injury model in pigs, CENP increased the end-expiratory caudal transpulmonary pressure. This lead to a shift of lung aeration towards dependent zones as well as improved respiratory mechanics and oxygenation, especially when CENP was applied to the abdomen as compared to the thorax. CENP values ≤ 20 cmH2O impaired the haemodynamics.

Use of critical care resources during the first 2 weeks (February 24-March 8, 2020) of the Covid-19 outbreak in 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. PaO2/FiO2 ratio, respiratory rate and arterial pH were higher [165 vs. 244; 20 vs. 24 breath/min; 7.40 vs. 7.46] and PaCO2 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.

Pentraxin-3, Troponin T, N-Terminal Pro-B-Type Natriuretic Peptide in Septic Patients.

OBJECTIVE: To investigate the behavior of pentraxin-3 (PTX3), troponin T (hsTnT), N-terminal pro-B type Natriuretic Peptide (NT-proBNP) in sepsis and their relationships with sepsis severity and oxygen transport/utilization impairment. DESIGN: Retrospective analysis of PTX3, hsTnT, NT-proBNP levels at day 1, 2, and 7 after admission in the intensive care unit in a subset of the Albumin Italian Outcome Sepsis database. SETTING: Forty Italian intensive care units. PATIENTS: Nine hundred fifty-eight septic patients enrolled in the randomized clinical trial comparing albumin replacement plus crystalloids and crystalloids alone. INTERVENTIONS: The patients were divided into sextiles of lactate (marker of severity), ScvO2 (marker of oxygen transport), and fluid balance (marker of therapeutic strategy). MEASUREMENTS AND MAIN RESULTS: PTX3 and hsTnT were remarkably similar in the two treatment arms, while NT-proBNP was almost double in the albumin treatment group. However, as the distribution of all these biomarkers was similar between control and treatment arms, for the sake of clarity, we analyzed the patients as a single cohort. PTX3 (71.8 [32.9-186.3] ng/mL), hsTnT (50.4 [21.6-133.6] ng/L), and NT-proBNP (4,393 [1,313-13,837] ng/L) were abnormally elevated in 100%, 84.5%, 93.4% of the 953 patients and all decreased from day 1 to day 7. PTX3 monotonically increased with increasing lactate levels. The hsTnT levels were significantly higher when ScvO2 levels were abnormally low (< 70%), suggesting impaired oxygen transport compared with higher ScvO2 levels, suggesting impaired oxygen utilization. NT-proBNP was higher with higher lactate and fluid balance. At ScvO2 levels < 70%, the NT-proBNP was higher than at higher ScvO2 levels. However, even with higher ScvO2, the NT-proBNP was remarkably elevated, suggesting volume expansion. Increased level of NT-proBNP showed the strongest association with 90-day mortality. CONCLUSIONS: The selected biomarkers seem related to different mechanisms during sepsis: PTX3 to sepsis severity, hsTnT to impaired oxygen transport, NT-proBNP to sepsis severity, oxygen transport, and aggressive fluid strategy.

Human Red Blood Cells as Oxygen Carriers to Improve Ex-Situ Liver Perfusion in a Rat Model.

Ex-situ machine perfusion (MP) has been increasingly used to enhance liver quality in different settings. Small animal models can help to implement this procedure. As most normothermic MP (NMP) models employ sub-physiological levels of oxygen delivery (DO2), the aim of this study was to investigate the effectiveness and safety of different DO2, using human red blood cells (RBCs) as oxygen carriers on metabolic recovery in a rat model of NMP. Four experimental groups (n = 5 each) consisted of (1) native (untreated/control), (2) liver static cold storage (SCS) 30 min without NMP, (3) SCS followed by 120 min of NMP with Dulbecco-Modified-Eagle-Medium as perfusate (DMEM), and (4) similar to group 3, but perfusion fluid was added with human RBCs (hematocrit 15%) (BLOOD). Compared to DMEM, the BLOOD group showed increased liver DO2 (p = 0.008) and oxygen consumption ( V O ˙ 2) (p < 0.001); lactate clearance (p < 0.001), potassium (p < 0.001), and glucose (p = 0.029) uptake were enhanced. ATP levels were likewise higher in BLOOD relative to DMEM (p = 0.031). V O ˙ 2 and DO2 were highly correlated (p < 0.001). Consistently, the main metabolic parameters were directly correlated with DO2 and V O ˙ 2. No human RBC related damage was detected. In conclusion, an optimized DO2 significantly reduces hypoxic damage-related effects occurring during NMP. Human RBCs can be safely used as oxygen carriers.

Effects of Positive End-Expiratory Pressure and Spontaneous Breathing Activity on Regional Lung Inflammation in Experimental Acute Respiratory Distress Syndrome.

OBJECTIVES: To determine the impact of positive end-expiratory pressure during mechanical ventilation with and without spontaneous breathing activity on regional lung inflammation in experimental nonsevere acute respiratory distress syndrome. DESIGN: Laboratory investigation. SETTING: University hospital research facility. SUBJECTS: Twenty-four pigs (28.1-58.2 kg). INTERVENTIONS: In anesthetized animals, intrapleural pressure sensors were placed thoracoscopically in ventral, dorsal, and caudal regions of the left hemithorax. Lung injury was induced with saline lung lavage followed by injurious ventilation in supine position. During airway pressure release ventilation with low tidal volumes, positive end-expiratory pressure was set 4 cm H2O above the level to reach a positive transpulmonary pressure in caudal regions at end-expiration (best-positive end-expiratory pressure). Animals were randomly assigned to one of four groups (n = 6/group; 12 hr): 1) no spontaneous breathing activity and positive end-expiratory pressure = best-positive end-expiratory pressure - 4 cm H2O, 2) no spontaneous breathing activity and positive end-expiratory pressure = best-positive end-expiratory pressure + 4 cm H2O, 3) spontaneous breathing activity and positive end-expiratory pressure = best-positive end-expiratory pressure + 4 cm H2O, 4) spontaneous breathing activity and positive end-expiratory pressure = best-positive end-expiratory pressure - 4 cm H2O. MEASUREMENTS AND MAIN RESULTS: Global lung inflammation assessed by specific [F]fluorodeoxyglucose uptake rate (median [25-75% percentiles], min) was decreased with higher compared with lower positive end-expiratory pressure both without spontaneous breathing activity (0.029 [0.027-0.030] vs 0.044 [0.041-0.065]; p = 0.004) and with spontaneous breathing activity (0.032 [0.028-0.043] vs 0.057 [0.042-0.075]; p = 0.016). Spontaneous breathing activity did not increase global lung inflammation. Lung inflammation in dorsal regions correlated with transpulmonary driving pressure from spontaneous breathing at lower (r = 0.850; p = 0.032) but not higher positive end-expiratory pressure (r = 0.018; p = 0.972). Higher positive end-expiratory pressure resulted in a more homogeneous distribution of aeration and regional transpulmonary pressures at end-expiration along the ventral-dorsal gradient, as well as a shift of the perfusion center toward dependent zones in the presence of spontaneous breathing activity. CONCLUSIONS: In experimental mild-to-moderate acute respiratory distress syndrome, positive end-expiratory pressure levels that stabilize dependent lung regions reduce global lung inflammation during mechanical ventilation, independent from spontaneous breathing activity.

Performances of CPAP Devices With an Oronasal Mask.

BACKGROUND: The aim of this bench study was to investigate the performances of 8 devices for noninvasive CPAP. METHODS: Eight devices for noninvasive CPAP with an orofacial mask were studied: Ventumask, Ventumask 30, EasyVent, EasyVent Emergency, Compact Model II, Flowone, Superflow, Boussignac CPAP valve. Each device was tested at oxygen input flows from 5 to 20 L/min, and the output gas flow was measured in static conditions. Each device was evaluated during a eupneic and a tachypneic simulated breathing test. RESULTS: The gas output flow generated by each device increased with higher oxygen input flow; EasyVent and Flowone produced the highest output flow (P < .001). At the simulated eupneic breathing test, Superflow and EasyVent showed a more stable pressure swing at different PEEP levels, whereas the other masks had a greater swing, between 10 and 15 cm H2O PEEP (P = .002 for all pairwise comparisons). During the tachypneic breathing test, the pressure swing was stable with Flowone and EasyVent (P = .055), whereas it had increased with other masks (P = .002 for all pairwise comparisons). CONCLUSIONS: We found a significant variation in the performances of the 8 CPAP devices examined in this study. The technical characteristics and limitations of different CPAP devices should be considered when using in patients with hypoxemic acute respiratory failure.