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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 H2O). 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 H2O μV−1. 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 H2O, at 50%, 100%, and 150% of baseline NAVA level, respectively (P 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.

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.

ImportanceData on the association of COVID-19 vaccination with intensive care unit (ICU) admission and outcomes of patients with SARS-CoV-2–related pneumonia are scarce.ObjectiveTo evaluate whether COVID-19 vaccination is associated with preventing ICU admission for COVID-19 pneumonia and to compare baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU.Design, Setting, and ParticipantsThis retrospective cohort study on regional data sets reports: (1) daily number of administered vaccines and (2) data of all consecutive patients admitted to an ICU in Lombardy, Italy, from August 1 to December 15, 2021 (Delta variant predominant). Vaccinated patients received either mRNA vaccines (BNT162b2 or mRNA-1273) or adenoviral vector vaccines (ChAdOx1-S or Ad26.COV2). Incident rate ratios (IRRs) were computed from August 1, 2021, to January 31, 2022; ICU and baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU were analyzed from August 1 to December 15, 2021.ExposuresCOVID-19 vaccination status (no vaccination, mRNA vaccine, adenoviral vector vaccine).Main Outcomes and MeasuresThe incidence IRR of ICU admission was evaluated, comparing vaccinated people with unvaccinated, adjusted for age and sex. The baseline characteristics at ICU admission of vaccinated and unvaccinated patients were investigated. The association between vaccination status at ICU admission and mortality at ICU and hospital discharge were also studied, adjusting for possible confounders.ResultsAmong the 10 107 674 inhabitants of Lombardy, Italy, at the time of this study, the median [IQR] age was 48 [28-64] years and 5 154 914 (51.0%) were female. Of the 7 863 417 individuals who were vaccinated (median [IQR] age: 53 [33-68] years; 4 010 343 [51.4%] female), 6 251 417 (79.5%) received an mRNA vaccine, 550 439 (7.0%) received an adenoviral vector vaccine, and 1 061 561 (13.5%) received a mix of vaccines and 4 497 875 (57.2%) were boosted. Compared with unvaccinated people, IRR of individuals who received an mRNA vaccine within 120 days from the last dose was 0.03 (95% CI, 0.03-0.04; P P P P P o2) and fraction of inspiratory oxygen (FiO2) at ICU admission (median [IQR]: 138 [100-180] vs 120 [90-158] mm Hg; P = .007). Factors associated with ICU and hospital mortality were higher age, premorbid heart disease, lower Pao2/FiO2 at ICU admission, and female sex (this factor only for ICU mortality). ICU and hospital mortality were similar between vaccinated and unvaccinated patients.Conclusions and RelevanceIn this cohort study, mRNA and adenoviral vector vaccines were associated with significantly lower risk of ICU admission for COVID-19 pneumonia. ICU and hospital mortality were not associated with vaccinated status. These findings suggest a substantial reduction of the risk of developing COVID-19–related severe acute respiratory failure requiring ICU admission among vaccinated people.

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 &lt, 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.

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.

Background: Limited data are available on the use of prone position in intubated, invasively ventilated patients with Coronavirus disease-19 (COVID-19). Aim of this study is to investigate the use and effect of prone position in this population during the first 2020 pandemic wave.Methods: Retrospective, multicentre, national cohort study conducted between February 24 and June 14, 2020 in 24 Italian Intensive Care Units (ICU) on adult patients needing invasive mechanical ventilation for respiratory failure caused by COVID-19.Clinical data were collected on the day of ICU admission. Information regarding the use of prone position were collected daily. Follow-up for patient outcomes was performed on July 15, 2020. The respiratory effects of the first prone position were studied in a subset of 78 patients. Patients were classified as Responders if the PaO2/FiO2 ratio increased ≥ 20 mmHg during prone position. Results: Of 1057 included patients, mild, moderate and severe ARDS was present in 15, 50 and 35% of patients, respectively and had a resulting mortality of 25, 33 and 41%. Prone position was applied in 61% of the patients. Patients placed prone had a more severe disease and died significantly more (45% vs 33%, p2/FiO2 ratio, while no change in respiratory system compliance was observed. Seventy-eight % of patients were Responders to prone position. Non-Responders had a more severe respiratory failure and died more often in the ICU (65% vs. 38%, p=0.047).Conclusions: During the COVID-19 pandemic, prone position has been widely adopted to treat mechanically ventilated patients with respiratory failure. The majority of patients improved their oxygenation during prone position, most likely due to a better ventilation perfusion matching.Trial registration: clinicaltrials.gov number: NCT04388670

Respiratory failure (RF) is defined as the acute or chronic impairment of respiratory system function to maintain normal oxygen and CO2 values when breathing room air. ‘Oxygenation failure’ occurs when O2 partial pressure (PaO2) value is lower than the normal predicted values for age and altitude and may be due to ventilation/perfusion mismatch or low oxygen concentration in the inspired air. In contrast, ‘ventilatory failure’ primarily involves CO2 elimination, with arterial CO2 partial pressure (PaCO2) higher than 45 mmHg. The most common causes are exacerbation of chronic obstructive pulmonary disease (COPD), asthma, and neuromuscular fatigue, leading to dyspnoea, tachypnoea, tachycardia, use of accessory muscles of respiration, and altered consciousness. History and arterial blood gas analysis is the easiest way to assess the nature of acute RF and treatment should solve the baseline pathology. In severe cases mechanical ventilation is necessary as a ‘buying time’ therapy. The acute hypoxemic RF arising from widespread diffuse injury to the alveolar-capillary membrane is termed Acute Respiratory Distress Syndrome (ARDS), which is the clinical and radiographic manifestation of acute pulmonary inflammatory states.

Patients with sepsis are poorly protected against acute respiratory acid-base derangements due to a lower noncarbonic buffer power, which is caused both by a reduction in the major noncarbonic buffers, i.e. hemoglobin and albumin, and by a reduced buffering capacity of albumin. Electrolyte shifts from and to the red blood cells determining acute variations in strong ion difference are the major buffering mechanism during acute respiratory acid-base disorders.

The target of extracorporeal membrane oxygenation (ECMO) support is to grant adequate gas exchange, while decreasing mechanical ventilation load on the natural lung and minimizing ventilator-induced lung injury in all of its aspects. However, mechanical ventilation is still necessary during veno-venous ECMO, in order to prevent lung atelectasis and/or in case of extracorporeal blood flows not sufficient to guarantee adequate gas exchange. In this chapter, we will first focus on the physiology of extracorporeal support. Then we will review the current mechanical ventilation settings adopted during extracorporeal support among ECMO, the rationale behind different approaches, and the potential use of ECMO to allow ultra-protective mechanical ventilation. Finally, the use of assisted or spontaneous ventilation will be discussed.

Extracorporeal support allows ultraprotective controlled and assisted ventilation, which can prevent lung and diaphragm injury. We focused on most recent findings in the application of extracorporeal support to achieve lung protection and diaphragm- protection, as well as on relevant monitoring.A recent randomized trial comparing the efficacy of extracorporeal support as a rescue therapy to conventional protective mechanical ventilation was stopped for futility but post hoc analyses suggested that extracorporeal support is beneficial for patients with very severe acute respiratory distress syndrome. However, the optimal ventilation settings during extracorporeal support are still debated. It is conceivable that they should enable the highest amount of CO2 removal with lowest mechanical power.Extracorporeal CO2 removal can minimize acidosis and enable the use of ultra-protective lung ventilation strategies when hypoxemia is not a major issue. Moreover, it can protect lung and diaphragm function during assisted ventilation through control of the respiratory effort.Lung mechanics, gas exchange, diaphragm electrical activity, ultrasound, electrical impedance tomography could be integrated into clinical management to define lung and diaphragm protection and guide personalized ventilation settings.Technological improvement and the latest evidence indicate that extracorporeal support may be an effective tool for lung and diaphragm protection.

Purpose: Open lung strategy during ARDS aims to decrease the ventilator-induced lung injury by minimizing the atelectrauma and stress/strain maldistribution. We aim to assess how much of the lung is opened and kept open within the limits of mechanical ventilation considered safe (i.e., plateau pressure 30cmH2O, PEEP 15cmH2O). Methods: Prospective study from two university hospitals. Thirty-three ARDS patients (5 mild, 10 moderate, 9 severe without extracorporeal support, ECMO, and 9 severe with it) underwent two low-dose end-expiratory CT scans at PEEP 5 and 15cmH2O and four end-inspiratory CT scans (from 19 to 40cmH2O). Recruitment was defined as the fraction of lung tissue which regained inflation. The atelectrauma was estimated as the difference between the intratidal tissue collapse at 5 and 15cmH2O PEEP. Lung ventilation inhomogeneities were estimated as the ratio of inflation between neighboring lung units. Results: The lung tissue which is opened between 30 and 45cmH2O (i.e., always closed at plateau 30cmH2O) was 10±29, 54±86, 162±92, and 185±134g in mild, moderate, and severe ARDS without and with ECMO, respectively (p&nbsp

The ROX (Respiratory rate-OXygenation) index is an early predictor of failure of nasal high flow (NHF), with lower values indicating higher risk of intubation. We measured the ROX index at set flow rate of 30 and 60 l/min in 57 hypoxemic patients on NHF. Patients with increased ROX index values at higher flow ( n = 40) showed worse baseline oxygenation, higher respiratory rate and lower ROX index in comparison to patients with unchanged or decreased ROX index values ( n = 17). The ROX index variation between flows was correlated with the change in end expiratory lung volume. Set flow rate during NHF might impact the ROX index value.

BACKGROUND: Endotracheal suctioning is mandatory to prevent complications caused by the retention of tracheal secretions. Endotracheal suctioning is often performed late, when patients show signs of respiratory and hemodynamic alterations. We conceived a prototype device that, when synchronized with the ventilator, automatically removes secretions collected below the endotracheal tube (ETT) cuff, thus avoiding endotracheal suctioning. The aim of our investigation was to assess the performance of this novel prototype in vitro. METHODS: Three studies were performed to examine the characteristics of the prototype. We tested device9s ability to generate an effective artificial cough flow (artificial cough maneuver) > 1 L/s by rapidly deflating the ETT cuff within the time of a sustained inflation (at 30 and at 40 cm H2O) (cough flow study). We also tested the prototype9s ability to remove the fluid positioned below the ETT cuff using saline dye (fluid removal study), and to prevent the aspiration of saline dye from above the ETT cuff during the deflation phase of the ETT cuff (aspiration study). The trachea model was positioned at 45° in the aspiration study, and horizontally in the other two studies. RESULTS: In the cough flow study, the prototype provided an effective artificial cough maneuver, with a mean ± SD of 1.78 ± 0.19 L/s (range, 1.42–2.14 L/s). The tracheal pressure after ETT cuff deflation never decreased below the PEEP level. In the fluid removal study, the prototype cleared the fluid from below the ETT cuff and the experimental trachea. No fluid was aspirated from the area above the ETT cuff toward the lower airways. CONCLUSIONS: We conceived an system capable of automatically expelling fluid from below the ETT cuff outside an experimental trachea by generating an artificial cough maneuver. This system may decrease the use of endotracheal suctioning and its complications. Future in vivo studies are needed to confirm this first in vitro evaluation.

Extracorporeal membrane oxygenation (ECMO) is intended to provide temporary extracorporeal respiratory support by the use of an artificial membrane lung in case of pulmonary failure unresponsive to conventional treatments. ECMO is indicated in case of high mortality risk, provided the underlying pathology is potentially reversible. In this chapter, we discuss the effects of venovenous ECMO on renal function in adult patients, focusing on the incidence and pathophysiology of renal failure in ECMO patients. Furthermore, we briefly describe the techniques available for combined ECMO and renal replacement therapy.

The assessment of lung recruitability in patients with acute respiratory distress syndrome (ARDS) may be important for planning recruitment maneuvers and setting positive end-expiratory pressure (PEEP).To determine whether lung recruitment measured by respiratory mechanics is comparable with lung recruitment measured by computed tomography (CT).In 22 patients with ARDS, lung recruitment was assessed at 5 and 15 cm H2O PEEP by using respiratory mechanics-based methods: (1) increase in gas volume between two pressure-volume curves (P-Vrs curve); (2) increase in gas volume measured and predicted on the basis of expected end-expiratory lung volume and static compliance of the respiratory system (EELV-Cst,rs); as well as by CT scan: (3) decrease in noninflated lung tissue (CT [not inflated]); and (4) decrease in noninflated and poorly inflated tissue (CT [not + poorly inflated]).The P-Vrs curve recruitment was significantly higher than EELV-Cst,rs recruitment (423 ± 223 ml vs. 315 ± 201 ml; P 0.001), but these measures were significantly related to each other (R(2) = 0.93; P 0.001). CT (not inflated) recruitment was 77 ± 86 g and CT (not + poorly inflated) was 80 ± 67 g (P = 0.856), and these measures were also significantly related to each other (R(2) = 0.20; P = 0.04). Recruitment measured by respiratory mechanics was 54 ± 28% (P-Vrs curve) and 39 ± 25% (EELV-Cst,rs) of the gas volume at 5 cm H2O PEEP. Recruitment measured by CT scan was 5 ± 5% (CT [not inflated]) and 6 ± 6% (CT [not + poorly inflated]) of lung tissue.Respiratory mechanics and CT measure-under the same term, "recruitment"-two different entities. The respiratory mechanics-based methods include gas entering in already open pulmonary units that improve their mechanical properties at higher PEEP. Consequently, they can be used to assess the overall improvement of inflation. The CT scan measures the amount of collapsed tissue that regains inflation. Clinical trial registered with www.clinicaltrials.gov (NCT00759590).

Background The high-flow nasal cannula (HFNC) delivers up to 60 l/min of humidified air/oxygen blend at a temperature close to that of the human body. In this study, we tested whether higher temperature and flow decrease patient comfort. In more severe patients, instead, we hypothesized that higher flow might be associated with improved comfort. Methods A prospective, randomized, cross-over study was performed on 40 acute hypoxemic respiratory failure (AHRF) patients (PaO2/FiO2 ≤ 300 + pulmonary infiltrates + exclusion of cardiogenic edema) supported by HFNC. The primary outcome was the assessment of patient comfort during HFNC delivery at increasing flow and temperature. Two flows (30 and 60 l/min), each combined with two temperatures (31 and 37 °C), were randomly applied for 20 min (four steps per patient), leaving clinical FiO2 unchanged. Toward the end of each step, the following were recorded: comfort by Visual Numerical Scale ranging between 1 (extreme discomfort) and 5 (very comfortable), together with respiratory parameters. A subgroup of more severe patients was defined by clinical FiO2 ≥ 45%. Results Patient comfort was reported as significantly higher during steps at the lower temperature (31 °C) in comparison to 37 °C, with the HFNC set at both 30 and 60 l/min (p

Background: During mechanical ventilation, stress and strain may be locally multiplied in an inhomogeneous lung. The authors investigated whether, in healthy lungs, during high pressure/volume ventilation, injury begins at the interface of naturally inhomogeneous structures as visceral pleura, bronchi, vessels, and alveoli. The authors wished also to characterize the nature of the lesions (collapse vs. consolidation). Methods: Twelve piglets were ventilated with strain greater than 2.5 (tidal volume/end-expiratory lung volume) until whole lung edema developed. At least every 3 h, the authors acquired end-expiratory/end-inspiratory computed tomography scans to identify the site and the number of new lesions. Lung inhomogeneities and recruitability were quantified. Results: The first new densities developed after 8.4 ± 6.3 h (mean ± SD), and their number increased exponentially up to 15 ± 12 h. Afterward, they merged into full lung edema. A median of 61% (interquartile range, 57 to 76) of the lesions appeared in subpleural regions, 19% (interquartile range, 11 to 23) were peribronchial, and 19% (interquartile range, 6 to 25) were parenchymal (P < 0.0001). All the new densities were fully recruitable. Lung elastance and gas exchange deteriorated significantly after 18 ± 11 h, whereas lung edema developed after 20 ± 11 h. Conclusions: Most of the computed tomography scan new densities developed in nonhomogeneous lung regions. The damage in this model was primarily located in the interstitial space, causing alveolar collapse and consequent high recruitability.

Purpose: Partial pressure of carbon dioxide (Pco2), strong ion difference (SID), and total amount of weak acids independently regulate pH. When blood passes through an extracorporeal membrane lung, Pco2 decreases. Furthermore, changes in electrolytes, potentially affecting SID, were reported. We analyzed these phenomena according to Stewart's approach. Methods: Couples of measurements of blood entering (venous) and leaving (arterial) the extracorporeal membrane lung were analyzed in 20 patients. Changes in SID, Pco2, and pH were computed and pH variations in the absence of measured SID variations calculated. Results: Passing from venous to arterial blood, Pco2 was reduced (46.5 ± 7.7 vs 34.8 ± 7.4 mm Hg, P < .001), and hemoglobin saturation increased (78 ± 8 vs 100% ± 2%, P < .001). Chloride increased, and sodium decreased causing a reduction in SID (38.7 ± 5.0 vs 36.4 ± 5.1 mEq/L, P < .001). Analysis of quartiles of {increment}Pco2 revealed progressive increases in chloride (P < .001), reductions in sodium (P < .001), and decreases in SID (P < .001), at constant hemoglobin saturation variation (P = .12). Actual pH variation was lower than pH variations in the absence of measured SID variations (0.09 ± 0.03 vs 0.12 ± 0.04, P < .001). Conclusions: When Pco2 is reduced and oxygen added, several changes in electrolytes occur. These changes cause a Pco2-dependent SID reduction that, by acidifying plasma, limits pH correction caused by carbon dioxide removal. In this particular setting, Pco2 and SID are interdependent.

Limited data exist on the correlation between higher flow rates of high-flow nasal cannula (HFNC) and its physiologic effects in patients with acute hypoxemic respiratory failure (AHRF). We assessed the effects of HFNC delivered at increasing flow rate on inspiratory effort, work of breathing, minute ventilation, lung volumes, dynamic compliance and oxygenation in AHRF patients. A prospective randomized cross-over study was performed in non-intubated patients with patients AHRF and a PaO2/FiO2 (arterial partial pressure of oxygen/fraction of inspired oxygen) ratio of ≤300 mmHg. A standard non-occlusive facial mask and HFNC at different flow rates (30, 45 and 60 l/min) were randomly applied, while maintaining constant FiO2 (20 min/step). At the end of each phase, we measured arterial blood gases, inspiratory effort, based on swings in esophageal pressure (ΔPes) and on the esophageal pressure–time product (PTPPes), and lung volume, by electrical impedance tomography. Seventeen patients with AHRF were enrolled in the study. At increasing flow rate, HFNC reduced ΔPes (p

Pressures and volumes needed to induce ventilator-induced lung injury in healthy lungs are far greater than those applied in diseased lungs. A possible explanation may be the presence of local inhomogeneities acting as pressure multipliers (stress raisers).To quantify lung inhomogeneities in patients with acute respiratory distress syndrome (ARDS).Retrospective quantitative analysis of CT scan images of 148 patients with ARDS and 100 control subjects. An ideally homogeneous lung would have the same expansion in all regions; lung expansion was measured by CT scan as gas/tissue ratio and lung inhomogeneities were measured as lung regions with lower gas/tissue ratio than their neighboring lung regions. We defined as the extent of lung inhomogeneities the fraction of the lung showing an inflation ratio greater than 95th percentile of the control group (1.61).The extent of lung inhomogeneities increased with the severity of ARDS (14 ± 5, 18 ± 8, and 23 ± 10% of lung volume in mild, moderate, and severe ARDS; P0.001) and correlated with the physiologic dead space (r(2) = 0.34; P0.0001). The application of positive end-expiratory pressure reduced the extent of lung inhomogeneities from 18 ± 8 to 12 ± 7% (P0.0001) going from 5 to 45 cm H2O airway pressure. Lung inhomogeneities were greater in nonsurvivor patients than in survivor patients (20 ± 9 vs. 17 ± 7% of lung volume; P = 0.01) and were the only CT scan variable independently associated with mortality at backward logistic regression.Lung inhomogeneities are associated with overall disease severity and mortality. Increasing the airway pressures decreased but did not abolish the extent of lung inhomogeneities.

In the prone position, computed tomography scan densities redistribute from dorsal to ventral as the dorsal region tends to reexpand while the ventral zone tends to collapse. Although gravitational influence is similar in both positions, dorsal recruitment usually prevails over ventral derecruitment, because of the need for the lung and its confining chest wall to conform to the same volume. The final result of proning is that the overall lung inflation is more homogeneous from dorsal to ventral than in the supine position, with more homogeneously distributed stress and strain. As the distribution of perfusion remains nearly constant in both postures, proning usually improves oxygenation. Animal experiments clearly show that prone positioning delays or prevents ventilation-induced lung injury, likely due in large part to more homogeneously distributed stress and strain. Over the last 15 years, five major trials have been conducted to compare the prone and supine positions in acute respiratory distress syndrome, regarding survival advantage. The sequence of trials enrolled patients who were progressively more hypoxemic; exposure to the prone position was extended from 8 to 17 hours/day, and lung-protective ventilation was more rigorously applied. Single-patient and meta-analyses drawing from the four major trials showed significant survival benefit in patients with PaO2/FiO2 lower than 100. The latest PROSEVA (Proning Severe ARDS Patients) trial confirmed these benefits in a formal randomized study. The bulk of data indicates that in severe acute respiratory distress syndrome, carefully performed prone positioning offers an absolute survival advantage of 10-17%, making this intervention highly recommended in this specific population subset.

Background: In ARDS, mechanical ventilation is a fundamental supportive therapy, but can also trigger/increase lung inflammation, applying unphysiologic stress and strain to the parenchyma, leading to increased mortality. Lung protective strategies, limiting tidal volume (Vt) and plateau pressure (Pplat), have been proposed, but they are poor surrogates of stress/strain (Chiumello D et al, AJRCCM 2008:178:346-55). Recently, airway driving pressure (ΔP =Vt/Crs [respiratory system9s compliance], or Pplat-PEEP) has been proposed as the key ventilatory variable associated with survival in ARDS (Amato MB et al, NEJM 2015:372:747-55). Objective: To assess if ΔP could accurately predict unsafe lung stress during mechanical ventilation in ARDS patients. Methods: 150 ARDS patients, deeply sedated and paralyzed, were ventilated with Vt of 6-8 mL/kg during a PEEP trial. ΔP and lung stress were measured at PEEP 5 and 15 cmH2O. Relationship between ΔP and lung stress was assessed by linear regression. Receiver operating characteristic (ROC) curve was used to verify the accuracy of ΔP in detecting a lung stress above safety threshold, defined at 24 cmH2O. Results: ΔP was significantly related to lung stress, both at PEEP 5 cmH2O (r2=0.581 p Conclusions: At PEEP 15 cmH2O, ΔP above 15 cmH2O predict unsafe lung stress, suggesting alternative approaches to support patient9s respiratory function.

Background Lung-protective ventilation strategy suggests the use of low tidal volume, depending on ideal body weight, and adequate levels of PEEP. However, reducing tidal volume according to ideal body weight does not always prevent overstress and overstrain. On the contrary, titrating mechanical ventilation on airway driving pressure, computed as airway pressure changes from PEEP to end-inspiratory plateau pressure, equivalent to the ratio between the tidal volume and compliance of respiratory system, should better reflect lung injury. However, possible changes in chest wall elastance could affect the reliability of airway driving pressure. The aim of this study was to evaluate if airway driving pressure could accurately predict lung stress (the pressure generated into the lung due to PEEP and tidal volume). Methods One hundred and fifty ARDS patients were enrolled. At 5 and 15 cmH2O of PEEP, lung stress, driving pressure, lung and chest wall elastance were measured. Results The applied tidal volume (mL/kg of ideal body weight) was not related to lung gas volume (r2 = 0.0005 p = 0.772). Patients were divided according to an airway driving pressure lower and equal/higher than 15 cmH2O (the lower and higher airway driving pressure groups). At both PEEP levels, the higher airway driving pressure group had a significantly higher lung stress, respiratory system and lung elastance compared to the lower airway driving pressure group. Airway driving pressure was significantly related to lung stress (r2 = 0.581 p

Purpose To develop a mathematical model of oxygenation during venovenous extracorporeal membrane oxygenation (vv-ECMO). Material and methods Total oxygen consumption, cardiac output, blood flow, recirculation, intrapulmonary shunt, hemoglobin, natural lung, and membrane lung oxygen fractions were chosen as inputs. Content, partial pressure, and hemoglobin saturation of oxygen in arterial, venous, pulmonary, and extracorporeal blood were outputs. To assess accuracy and predictive power of the model, we retrospectively analyzed data of 25 vv-ECMO patients. We compiled 2 software (with numerical, 2D and 3D graphical outputs) to study the impact of each variable on oxygenation. Results The model showed high accuracy and predictive power. Raising blood flow and oxygen fraction to the membrane lung or reducing total oxygen consumption improves arterial and venous oxygenation, especially in severe cases; raising oxygen fraction to the natural lung improves oxygenation only in milder cases; raising hemoglobin always improves oxygenation, especially in the venous district; recirculation fraction severely impairs oxygenation. In severely ill patients, increasing cardiac output worsens arterial oxygenation but enhances venous oxygenation. Oxygen saturation of ECMO inlet is critical to evaluate the appropriateness of oxygen delivery. Conclusions The model with the software can be a useful teaching tool and a valuable decision-making aid for the management of hypoxic patients supported by vv-ECMO.

We hypothesized that the ventilator-related causes of lung injury may be unified in a single variable: the mechanical power. We assessed whether the mechanical power measured by the pressure–volume loops can be computed from its components: tidal volume (TV)/driving pressure (∆P aw), flow, positive end-expiratory pressure (PEEP), and respiratory rate (RR). If so, the relative contributions of each variable to the mechanical power can be estimated. We computed the mechanical power by multiplying each component of the equation of motion by the variation of volume and RR: $${\text{Power}}_{\text{rs}} = {\text{RR}} \cdot \left\{ {\Delta V^{2} \cdot \left[ {\frac{1}{2} \cdot {\text{EL}}_{\text{rs}} + {\text{RR}} \cdot \frac{{\left( {1 + I:E} \right)}}{60 \cdot I:E} \cdot R_{\text{aw}} } \right] + \Delta V \cdot {\text{PEEP}}} \right\},$$ where ∆V is the tidal volume, ELrs is the elastance of the respiratory system, I:E is the inspiratory-to-expiratory time ratio, and R aw is the airway resistance. In 30 patients with normal lungs and in 50 ARDS patients, mechanical power was computed via the power equation and measured from the dynamic pressure–volume curve at 5 and 15 cmH2O PEEP and 6, 8, 10, and 12 ml/kg TV. We then computed the effects of the individual component variables on the mechanical power. Computed and measured mechanical powers were similar at 5 and 15 cmH2O PEEP both in normal subjects and in ARDS patients (slopes = 0.96, 1.06, 1.01, 1.12 respectively, R 2 > 0.96 and p

Background Obesity is associated in healthy subjects with a great reduction in functional residual capacity and with a stiffening of lung and chest wall elastance, which promote alveolar collapse and hypoxaemia. Likewise, obese patients with acute respiratory distress syndrome (ARDS) could present greater derangements of respiratory mechanics than patients of normal weight. Methods One hundred and one ARDS patients were enrolled. Partitioned respiratory mechanics and gas exchange were measured at 5 and 15 cm H2O of PEEP with a tidal volume of 6–8 ml kg−1 of predicted body weight. At 5 and 45 cm H2O of PEEP, two lung computed tomography scans were performed. Results Patients were divided as follows according to BMI: normal weight (BMI≤25 kg m−2), overweight (BMI between 25 and 30 kg m−2), and obese (BMI>30 kg m−2). Obese, overweight, and normal-weight groups presented a similar lung elastance (median [interquartile range], respectively: 17.7 [14.2–24.8], 20.9 [16.1–30.2], and 20.5 [15.2–23.6] cm H2O litre−1 at 5 cm H2O of PEEP and 19.3 [15.5–26.3], 21.1 [17.4–29.2], and 17.1 [13.4–20.4] cm H2O litre−1 at 15 cm H2O of PEEP) and chest elastance (respectively: 4.9 [3.1–8.8], 5.9 [3.8–8.7], and 7.8 [3.9–9.8] cm H2O litre−1 at 5 cm H2O of PEEP and 6.5 [4.5–9.6], 6.6 [4.2–9.2], and 4.9 [2.4–7.6] cm H2O litre−1 at 15 cm H2O of PEEP). Lung recruitability was not affected by the body weight (15.6 [6.3–23.4], 15.7 [9.8–22.2], and 11.3 [6.2–15.6]% for normal-weight, overweight, and obese groups, respectively). Lung gas volume was significantly lower whereas total superimposed pressure was significantly higher in the obese compared with the normal-weight group (1148 [680–1815] vs 827 [686–1213] ml and 17.4 [15.8–19.3] vs 19.3 [18.6–21.7] cm H2O, respectively). Conclusions Obese ARDS patients do not present higher chest wall elastance and lung recruitability.

Evidence based medicine is an attempt to optimize the medical decision process through methods primarily based on evidence coming from meta-analyses, systematic reviews, and randomized controlled trials ("evidence-based medicine"), rather than on "clinical judgment" alone. The randomized trials are the cornerstones of this process. However, the randomized trials are just a method to prove or disprove a given hypothesis, which, in turn, derives from a general observation of the reality (premises or theories). In this paper we will examine some of the most recent randomized trials performed in Intensive Care, analyzing their premises, hypothesis and outcome. It is quite evident that when the premises are wrong or too vague the unavoidable consequences will be a negative outcome. We should pay when designing the trial an equal attention in defining premises and hypothesis that we pay for the trial conduction.

To provide the most recent insights on the assessment of gas exchange in acute lung injury.Central venous blood may be used as a surrogate of arterial blood to assess carbon dioxide tension and acid-base status. In contrast arterial oxygenation cannot be estimated with confidence from venous blood. However, the use of venous blood associated with pulse oximetry may provide the SvO2 which is useful for monitoring and targeting the resuscitation therapy. Impaired CO2 clearance and increased dead space have been confirmed as useful prognostic indices of structural lung damage and mortality in acute respiratory failure. A simplified technique based on multiple inert gas technique has been described to assess ventilation-perfusion mismatch while a new analysis of pulse oximetry has been suggested to detect lung opening and closing. Finally, new insight has been provided on the relationship between lung anatomy, as detected by computed tomography, oxygenation and CO2 clearance.Although oxygenation assessment is of primary importance during respiratory lung injury, dead space and CO2 retention are more strictly associated with outcome. The association of central venous blood analysis and pulse oximetry may provide more information than arterial blood alone.

To define the rule according to which crystalloid solutions characterized by different strong ion difference (SID) modify the acid–base variables of human plasma. With a previously validated software, we computed the effects of diluting human plasma with crystalloid solutions ([SID] 0–60, 10 mEq/l stepwise). An equation was derived to compute the diluent [SID] required to maintain the baseline pH unchanged, at constant PCO2 and at every dilution fraction. The results were experimentally tested using fresh frozen plasma, re-warmed at 37°C, equilibrated at PCO2 35 and 78 mmHg, at baseline and after the infusion of crystalloid solutions with 0, 12, 24, 36, 48 mEq/l [SID]. The mathematical analysis showed that the diluent [SID] required to maintain unmodified the baseline pH equals the baseline bicarbonate concentration, [HCO 3 − ], assuming constant PCO2 throughout the process. The experimental data confirmed the theoretical analysis. In fact, at the baseline [HCO 3 − ] of 18.3 ± 0.3 mmol/l (PCO2 35 mmHg) the pH was 7.332 ± 0.004 and remained 7.333 ± 0.003 when the diluting [SID] was 18.5 ± 0.0 mEq/l. At baseline [HCO 3 − ] of 19.5 ± 0.3 mmol/l (PCO2 78 mmHg) the pH was 7.010 ± 0.003 and remained 7.004 ± 0.003 when the diluting [SID] was 19.1 ± 0.1 mEq/l. At both PCO2 values infusion with [SID] lower or greater than baseline [HCO 3 − ] led pH to decrease or increase, respectively. The baseline [HCO 3 − ] dictates the pH response to crystalloid infusion. If a crystalloid [SID] equals baseline [HCO 3 − ], pH remains unchanged at constant PCO2, whereas it increases or decreases if the [SID] is greater or lower, respectively.

In the last 2 years, several reports have dealt with recruitment/positive end-expiratory pressure (PEEP) selection. Most of them confirm previous results and few add new information.It has been definitely confirmed that opening pressures are different throughout the acute respiratory distress syndrome lung parenchyma, ranging from 5-10 up to 30-40 cmH2O. The highest opening pressures are required to open the most dependent lung regions. It has been found that in 2 s, most of the recruitable lung regions may be open when a proper pressure is applied. The best way to assess recruitment is computed tomography scanning, whereas lung mechanics are a reasonable bedside surrogate. Impedance tomography has been increasingly tested, whereas gas exchange is the less reliable indicator of recruitment. A large outcome study showed that higher PEEP might provide survival benefit in a subgroup of more severe patients as compared with lower PEEP. To set PEEP in each individual patient, the use of the expiratory limb of the pressure-volume curve has been suggested. Setting PEEP according to transpulmonary pressure has a robust physiological background, although it requires confirmatory study.Indiscriminate application of recruitment maneuver in unselected acute respiratory distress syndrome population does not provide benefits. However, in the most severe patients, recruitment maneuver has to be considered and higher PEEP applied. To individualize PEEP, the expiratory phase has to be considered, and the esophageal pressure measurement to compute the transpulmonary pressure should be progressively introduced in clinical practice.

Respiratory failure (RF) is defined as the acute or chronic impairment of respiratory system function to maintain normal oxygen and CO2 values when breathing room air. ‘Oxygenation failure’ occurs when O2 partial pressure (PaO2) value is lower than the normal predicted values for age and altitude and may be due to ventilation/perfusion mismatch or low oxygen concentration in the inspired air. In contrast, ‘ventilatory failure’ primarily involves CO2 elimination, with arterial CO2 partial pressure (PaCO2) higher than 45 mmHg. The most common causes are exacerbation of chronic obstructive pulmonary disease (COPD), asthma, and neuromuscular fatigue, leading to dyspnoea, tachypnoea, tachycardia, use of accessory muscles of respiration, and altered consciousness. History and arterial blood gas analysis is the easiest way to assess the nature of acute RF and treatment should solve the baseline pathology. In severe cases mechanical ventilation is necessary as a ‘buying time’ therapy. The acute hypoxemic RF arising from widespread diffuse injury to the alveolar-capillary membrane is termed Acute Respiratory Distress Syndrome (ARDS), which is the clinical and radiographic manifestation of acute pulmonary inflammatory states.

The chapter provides a comprehensive overview on extracorporeal membrane oxygenation (ECMO) for the treatment of acute lung injury. It focuses on venovenous ECMO. The historical aspects of ECMO are explored at the light of the most recent advances linked to the H1N1 pandemic. The basic physiology of lung gas exchange is addressed, as well as the specific aspects of gas exchange through an artificial lung. A section is dedicated to the technical aspects of cannulation, setting, and equipment. The chapter also addresses the main complications of ECMO, the pharmacological approach, the management of mechanical ventilation during ECMO, and possible new trends in this approach

To compare the positive end-expiratory pressure selection aiming either to oxygenation or to the full lung opening.Increasing positive end-expiratory pressure in patients with severe hypoxemia is associated with better outcome if the oxygenation response is greater and positive end-expiratory pressure tests may be performed in a few minutes. The oxygenation response to recruitment maneuvers was associated with better outcome in patients with acute respiratory distress syndrome from influenza A (H1N1). If, after recruitment maneuver, the recruitment is not sustained by sufficient positive end-expiratory pressure, the lung will unavoidably collapse. Several papers investigated the positive end-expiratory pressure selection according to the deflation limb of the pressure-volume curve. It is still questionable whether to consider oxygenation or respiratory mechanics change as the best marker for adequate selection. A growing interest is paid to the estimate of transpulmonary pressure, although no consensus is available on which methodology is preferable. Finally, the positive end-expiratory pressure adequate for full lung opening may be computed combining the computed tomography scan variables and the chest wall elastance.When compared, most of the methods give the same positive end-expiratory pressure values in patients with higher and lower recruitability. The positive end-expiratory pressure/inspiratory oxygen fraction tables are the only methods providing lower positive end-expiratory pressure in lower recruiters and higher positive end-expiratory pressure in higher recruiters.

OBJECTIVES: The Berlin definition of acute respiratory distress syndrome has introduced three classes of severity according to PaO2/FIO2 thresholds. The level of positive end-expiratory pressure applied may greatly affect PaO2/FIO2, thereby masking acute respiratory distress syndrome severity, which should reflect the underlying lung injury (lung edema and recruitability). We hypothesized that the assessment of acute respiratory distress syndrome severity at standardized low positive end-expiratory pressure may improve the association between the underlying lung injury, as detected by CT, and PaO2/FIO2-derived severity. DESIGN: Retrospective analysis. SETTING: Four university hospitals (Italy, Germany, and Chile). PATIENTS: One hundred forty-eight patients with acute lung injury or acute respiratory distress syndrome according to the American-European Consensus Conference criteria. INTERVENTIONS: Patients underwent a three-step ventilator protocol (at clinical, 5 cm H2O, or 15 cm H2O positive end-expiratory pressure). Whole-lung CT scans were obtained at 5 and 45 cm H2O airway pressure. MEASUREMENTS AND MAIN RESULTS: Nine patients did not fulfill acute respiratory distress syndrome criteria of the novel Berlin definition. Patients were then classified according to PaO2/FIO2 assessed at clinical, 5 cm H2O, or 15 cm H2O positive end-expiratory pressure. At clinical positive end-expiratory pressure (11 ± 3 cm H2O), patients with severe acute respiratory distress syndrome had a greater lung tissue weight and recruitability than patients with mild or moderate acute respiratory distress syndrome (p < 0.001). At 5 cm H2O, 54% of patients with mild acute respiratory distress syndrome at clinical positive end-expiratory pressure were reclassified to either moderate or severe acute respiratory distress syndrome. In these patients, lung recruitability and clinical positive end-expiratory pressure were higher than in patients who remained in the mild subgroup (p < 0.05). When patients were classified at 5 cm H2O, but not at clinical or 15 cm H2O, lung recruitability linearly increases with acute respiratory distress syndrome severity (5% [2-12%] vs 12% [7-18%] vs 23% [12-30%], respectively, p < 0.001). The potentially recruitable lung was the only CT-derived variable independently associated with ICU mortality (p = 0.007). CONCLUSIONS: The Berlin definition of acute respiratory distress syndrome assessed at 5 cm H2O allows a better evaluation of lung recruitability and edema than at higher positive end-expiratory pressure clinically set.

To investigate the possibility of artificially decreasing intra-abdominal pressure (IAP) by applying continuous negative pressure around the abdomen. We investigated the effects of negative extra-abdominal pressure (NEXAP) on IAP and central venous pressure (CVP) in 30 patients admitted to our intensive care unit (age 57±17 years, BMI 26.1±4.0 kg/m2, SAPS II 41.8±17.0). Patients with severe hemodynamic instability and/or those admitted following a laparotomy were not studied. Measurements included bladder pressure as an estimate of IAP, CVP, invasive mean arterial pressure (MAP) and heart rate (HR). In five patients extensive hemodynamic measurements were also taken using a Swan-Ganz catheter. Following measurements at baseline (Basal), NEXAP (Life Care – Nev 100, Respironics) was applied on the abdomen, in random order, at a pressure equal to IAP (NEXAP0), 5 cmH2O (NEXAP-5) or 10 cmH2O (NEXAP-10) more negative than NEXAP0. Basal IAP ranged from 4 to 22 mmHg. NEXAP decreased IAP from 8.7±4.3 mmHg to 6±4.2 (Basal vs NEXAP0 p

Objectives: To review the physiologic approach to setting mechanical ventilation in acute lung injurylacute respiratory distress syndrome. Data Sources: MEDLINE search from 1979 to the present. Data Selection: Personal selection of some articles we believe relevant for understanding acute lung injury/acute respiratory distress syndrome physiopathology and its physiologic management. Data Summary: Knowing the underlying pathology is key to estimating the potential for recruitment. The potential for recruitment is rather low when the consolidation of pulmonary units exceeds collapse, as in diffuse pneumonia. In contrast, when pulmonary unit collapse exceeds consolidation, as in acute lung injurylacute respiratory distress syndrome from extrapulmonary origin, the potential for recruitment may be high. To exploit the potential for recruitment, a transpulmonary pressure greater than the opening pressure must be applied to the lung. To do so, chest wall elastance must be measured or estimated. To avoid collapse after recruitment, a positive end-expiratory pressure greater than the compressive forces operating on the lung and an alveolar ventilation sufficient to prevent absorption atelectasis must be provided. Indeed, avoidance of stretch (low airway plateau pressure) and prevention of cyclic collapse and reopening (adequate positive end-expiratory pressure and alveolar ventilation) are the physiologic cornerstones of mechanical ventilation in acute lung injury/acute respiratory distress syndrome. When considering all the randomized clinical trials reported so far, it is tempting to speculate that transpulmonary pressure and stresses, rather than tidal volume per se, are the key factors that may have an impact on mortality. Conclusions: The majority of physiologic, experimental, and clinical trial data converge on one simple concept: treat the lung gently.

Positive end-expiratory pressure exerts its effects keeping open at end-expiration previously collapsed areas of the lung; consequently, higher positive end-expiratory pressure should be limited to patients with high recruitability. We aimed to determine which bedside method would provide positive end-expiratory pressure better related to lung recruitability.Prospective study performed between 2008 and 2011.Two university hospitals (Italy and Germany).Fifty-one patients with acute respiratory distress syndrome.Whole lung CT scans were taken in static conditions at 5 and 45 cm H2O during an end-expiratory/end-inspiratory pause to measure lung recruitability. To select individual positive end-expiratory pressure, we applied bedside methods based on lung mechanics (ExPress, stress index), esophageal pressure, and oxygenation (higher positive end-expiratory pressure table of lung open ventilation study).Patients were classified in mild, moderate and severe acute respiratory distress syndrome. Positive end-expiratory pressure levels selected by the ExPress, stress index, and absolute esophageal pressures methods were unrelated with lung recruitability, whereas positive end-expiratory pressure levels selected by the lung open ventilation method showed a weak relationship with lung recruitability (r = 0.29; p0.0001). When patients were classified according to the acute respiratory distress syndrome Berlin definition, the lung open ventilation method was the only one which gave lower positive end-expiratory pressure levels in mild and moderate acute respiratory distress syndrome compared with severe acute respiratory distress syndrome (8 ± 2 and 11 ± 3 cm H2O vs 15 ± 3 cm H2O; p0.05), whereas ExPress, stress index, and esophageal pressure methods gave similar positive end-expiratory pressure values in mild, moderate, and severe acute respiratory distress syndrome. The positive end-expiratory pressure selected by the different methods were unrelated to each other with the exception of the two methods based on lung mechanics (ExPress and stress index).Bedside positive end-expiratory pressure selection methods based on lung mechanics or absolute esophageal pressures provide positive end-expiratory pressure levels unrelated to lung recruitability and similar in mild, moderate, and severe acute respiratory distress syndrome, whereas the oxygenation-based method provided positive end-expiratory pressure levels related with lung recruitability progressively increasing from mild to moderate and severe acute respiratory distress syndrome.

Drowning patients are at risk to develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) after the rescue. Few data are available regarding the ventilator management of this specific group of patients. However, based on the pathophysiological characteristics of ARDS in drowning, it seems reasonable to use protective lung ventilation which has been previously demonstrated to improve the outcome in patients with ARDS from other causes.

Background: It has been suggested that higher positive end-expiratory pressure (PEEP) should be used only in patients with higher lung recruitability. In this study, the authors investigated the relationship between the recruitability and the PEEP necessary to counteract the compressive forces leading to lung collapse. Methods: Fifty-one patients with acute respiratory distress syndrome (7 mild, 33 moderate, and 11 severe) were enrolled. Patients underwent whole-lung computed tomography (CT) scan at 5 and 45 cm H2O. Recruitability was measured as the amount of nonaerated tissue regaining inflation from 5 to 45 cm H2O. The compressive forces (superimposed pressure) were computed as the density times the sternum-vertebral height of the lung. CT-derived PEEP was computed as the sum of the transpulmonary pressure needed to overcome the maximal superimposed pressure and the pleural pressure needed to lift up the chest wall. Results: Maximal superimposed pressure ranged from 6 to 18 cm H2O, whereas CT-derived PEEP ranged from 7 to 28 cm H2O. Median recruitability was 15% of lung parenchyma (interquartile range, 7 to 21%). Maximal superimposed pressure was weakly related with lung recruitability (r 2 = 0.11, P = 0.02), whereas CT-derived PEEP was unrelated with lung recruitability (r 2 = 0.0003, P = 0.91). The maximal superimposed pressure was 12 ± 3, 12 ± 2, and 13 ± 1 cm H2O in mild, moderate, and severe acute respiratory distress syndrome, respectively, (P = 0.0533) with a corresponding CT-derived PEEP of 16 ± 5, 16 ± 5, and 18 ± 5 cm H2O (P = 0.48). Conclusions: Lung recruitability and CT scan–derived PEEP are unrelated. To overcome the compressive forces and to lift up the thoracic cage, a similar PEEP level is required in higher and lower recruiters (16.8 ± 4 vs. 16.6 ± 5.6, P = 1).

In patients with acute respiratory distress syndrome (ARDS), in supine position, there is a decrease of inflation along the sternum vertebral axis, up to lung collapse. In 1991 we published a report showing that, in ARDS patients, shifting from supine to prone position led immediately to the inversion of the inflation gradient and to a redistribution of densities from dorsal to ventral lung regions. This led to a "sponge model" as a wet sponge, similar to a heavy edematous lung, squeezes out the gas in the most dependent regions, due to the weight-related increase of the compressive forces. The sponge model accounts for density distribution in prone position, for which the unloaded dorsal regions are recruited, while the loaded ventral region, collapses. In addition, the sponge model accounts for the mechanism through which the positive end-expiratory pressure acts as counterforce to oppose the collapsing, compressing forces. The final result of proning was that the inversion of gravitational forces, together with other factors such as lung-chest wall shape-matching and the heart weight led to a more homogeneous distribution of inflation throughout the lung parenchyma. This is associated with oxygenation improvement as the dorsal recruitment, for anatomical reasons, prevails on the ventral de-recruitment. The more homogeneous distribution of inflation (i.e. of stress and strain) decreases/prevents the ventilator-induced lung injury, as consistently shown in animal experiments. Finally, and a series of clinical trials led to the conclusion that in patients with severe ARDS, the prone position provides a significant survival advantage.

Assessment and monitoring of hemodynamics is a cornerstone in critically ill patients as hemodynamic alteration may become life-threatening in a few minutes. Defining normal values in critically ill patients is not easy, because 'normality' is usually referred to healthy subjects at rest. Defining 'adequate' hemodynamics is easier, which embeds whatever pressure and flow set is sufficient to maintain the aerobic metabolism. We will refer to the unifying hypothesis proposed by Schrier several years ago. Accordingly, the alteration of three independent variables - heart (contractility and rate), vascular tone and intravascular volume - may lead to underfilling of the arterial tree, associated with reduced (as during myocardial infarction or hemorrhage) or expanded (sepsis or cirrhosis) plasma volume. The underfilling is sensed by the arterial baroreceptors, which activate primarily the sympathetic nervous system and renin-angiotensin-aldosterone system, as well as vasopressin, to restore the arterial filling by increasing the vascular tone and retaining sodium and water. Under 'normal' conditions, therefore, the homeostatic system is not activated and water/sodium excretion, heart rate and oxygen extraction are in the range found in normal subjects. When arterial underfilling occurs, the mechanisms are activated (sodium and water retention) - associated with low central venous oxygen saturation (ScvO2) if underfilling is caused by low flow/hypovolemia, or with normal/high ScvO2 if associated with high flow/hypervolemia. Although the correction of hemodynamics should be towards the correction of the independent determinants, the usual therapy performed is volume infusion. An accepted target is ScvO2 >70%, although this ignores the arterial underfilling associated with volume expansion/high flow. For large-volume resuscitation the worst solution is normal saline solution (chloride load, strong ion difference = 0, acidosis). To avoid changes in acid-base equilibrium the strong ion difference of the infused solution should be equal to the baseline bicarbonate concentration.