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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.

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.

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.

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.

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

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 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.

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.

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.

To assess the time interval required to reach a new steady state of oxygenation-, ventilation-, respiratory mechanics- and hemodynamics-related variables after decreasing/increasing positive end expiratory pressure (PEEP).In 23 patients (group 1) with acute respiratory distress syndrome (ARDS), PEEP was decreased from 10 to 5 cmH2O and, after 60', it was increased from 5 to 15 cmH2O. In 21 other ARDS patients (group 2), PEEP was increased from 10 to 15 cmH2O and, after 60', decreased from 15 to 5 cmH2O. Oxygenation, ventilation, respiratory mechanics and hemodynamic variables were recorded at time 5', 15', 30' and 60' after each PEEP change.When PEEP was decreased, PaO2, PaO2/FiO2, venous admixture and arterial oxygen saturation reached their equilibrium after 5'. In contrast, when PEEP was increased, the equilibrium was not reached even after 60'. The ventilation-related variables did not change significantly with PEEP. The respiratory system compliance, when PEEP was decreased, significantly worsened only after 60'. Hemodynamics did not change significantly with PEEP. In the individual patients the change of oxygenation-related variables and of respiratory system compliance observed after 5' could predict the changes recorded after 60'. This was not possible for PaCO2.We could not find a unique equilibration time for all the considered variables. However, in general, a decremental PEEP test requires far lower equilibrium time than an incremental PEEP test, suggesting a different time course for derecruitment and recruitment patterns.

Introduction Although computed tomography (CT) is widely used to investigate different pathologies, quantitative data from normal populations are scarce. Reference values may be useful to estimate the anatomical or physiological changes induced by various diseases. Methods We analyzed 100 helical CT scans taken for clinical purposes and referred as nonpathological by the radiologist. Profiles were manually outlined on each CT scan slice and each voxel was classified according to its gas/tissue ratio. For regional analysis, the lungs were divided into 10 sterno-vertebral levels. Results We studied 53 males and 47 females (age 64 ± 13 years); males had a greater total lung volume, lung gas volume and lung tissue. Noninflated tissue averaged 7 ± 4% of the total lung weight, poorly inflated tissue averaged 18 ± 3%, normally inflated tissue averaged 65 ± 8% and overinflated tissue averaged 11 ± 7%. We found a significant correlation between lung weight and subject's height (P

To describe the physiological meaning and the clinical application of the lung stress and strain concepts.The end-inspiratory plateau pressure and ratio of tidal volume/ideal body weight are inadequate surrogates for the end-inspiratory stress (equal to the transpulmonary pressure) and the end-inspiratory strain (change in lung volume relative to the resting volume). For a given plateau pressure or tidal volume/ideal body weight, stress and strain may vary largely due to the variability of chest wall elastance and the resting lung volume. The injurious limits of stress and strain in healthy lungs are reached when stress and strain reach the total lung capacity. This occurs when the resting lung volume (the baby lung in case of acute respiratory distress syndrome) is increased by two-fold to three-fold. As these limits are rarely reached in clinical practice and damage has been reported with stress and strain well below this upper limit, this implies the presence in the lung parenchyma of regions which act as stress raisers or pressure multipliers. These are primarily linked to the inhomogeneous distribution of local stress and strain.End-inspiratory stress and strain, as well as the lung inhomogeneity and the stress raisers, must be taken in account when setting mechanical ventilation.

Since its introduction into the management of the acute respiratory distress syndrome, mechanical ventilation has been so strongly interwoven with its side effects that it came to be considered as invariably dangerous. Over the decades, attention has shifted from gross barotrauma to volutrauma and, more recently, to atelectrauma and biotrauma. In this article, we describe the anatomical and physiologic framework in which ventilator-induced lung injury may occur. We address the concept of lung stress/strain as applied to the whole lung or specific pulmonary regions. We challenge some common beliefs, such as separately studying the dangerous effects of different tidal volumes (end inspiration) and end-expiratory positive pressures. Based on available data, we suggest that stress at rupture is only rarely reached and that high tidal volume induces ventilator-induced lung injury by augmenting the pressure heterogeneity at the interface between open and constantly closed units. We believe that ventilator-induced lung injury occurs only when a given threshold is exceeded; below this limit, mechanical ventilation is likely to be safe.

Prone positioning has been used for over 30 years in the management of patients with acute respiratory distress syndrome (ARDS). This maneuver has consistently proven capable of improving oxygenation in patients with acute respiratory failure. Several mechanisms can explain this observation, including possible intervening net recruitment and more homogeneously distributed alveolar inflation. It is also progressively becoming clear that prone positioning may reduce the nonphysiological stress and strain associated with mechanical ventilation, thus decreasing the risk of ventilator-induced lung injury, which is known to adversely impact patient survival. The available randomized clinical trials, however, have failed to demonstrate that prone positioning improves the outcomes of patients with ARDS overall. In contrast, the individual patient meta-analysis of the four major clinical trials available clearly shows that with prone positioning, the absolute mortality of severely hypoxemic ARDS patients may be reduced by approximately 10%. On the other hand, all data suggest that long-term prone positioning may expose patients with less severe ARDS to unnecessary complications.

RATIONALE: The effects of high positive end-expiratory pressure (PEEP) strictly depend on lung recruitability, which varies widely during acute respiratory distress syndrome (ARDS). Unfortunately, increasing PEEP may lead to opposing effects on two main factors potentially worsening the lung injury, that is, alveolar strain and intratidal opening and closing, being detrimental (increasing the former) or beneficial (decreasing the latter). OBJECTIVES: To investigate how lung recruitability influences alveolar strain and intratidal opening and closing after the application of high PEEP. METHODS: We analyzed data from a database of 68 patients with acute lung injury or ARDS who underwent whole-lung computed tomography at 5, 15, and 45 cm H(2)O airway pressure. MEASUREMENTS AND MAIN RESULTS: End-inspiratory nonaerated lung tissue was estimated from computed tomography pressure-volume curves. Alveolar strain and opening and closing lung tissue were computed at 5 and 15 cm H(2)O PEEP. In patients with a higher percentage of potentially recruitable lung, the increase in PEEP markedly reduced opening and closing lung tissue (P < 0.001), whereas no differences were observed in patients with a lower percentage of potentially recruitable lung. In contrast, alveolar strain similarly increased in the two groups (P = 0.89). Opening and closing lung tissue was distributed mainly in the dependent and hilar lung regions, and it appeared to be an independent risk factor for death (odds ratio, 1.10 for each 10-g increase). CONCLUSIONS: In ARDS, especially in patients with higher lung recruitability, the beneficial impact of reducing intratidal alveolar opening and closing by increasing PEEP prevails over the effects of increasing alveolar strain.

To clarify whether the gas exchange response to prone position is associated with lung recruitability in mechanically ventilated patients with acute respiratory failure.In 32 patients, gas exchange response to prone position was investigated as a function of lung recruitability, measured by computed tomography in supine position.No relationship was found between increased oxygenation in prone position and lung recruitability. In contrast, the decrease of PaCO(2) was related with lung recruitability (R(2) 0.19; P = 0.01). Patients who decreased their PaCO(2) more than the median value (-0.9 mmHg) had a greater lung recruitability (19 +/- 16 vs. 8 +/- 6%; P = 0.02), higher baseline PaCO(2) (48 +/- 8 vs. 41 +/- 11 mmHg; P = 0.07), heavier lungs (1,968 +/- 829 vs. 1,521 +/- 342 g; P = 0.06) and more non-aerated tissue (1,009 +/- 704 vs. 536 +/- 188 g; P = 0.02) than those who did not.During prone position, changes in PaCO(2), but not in oxygenation, are associated with lung recruitability which, in turn, is associated with the severity of lung injury.

Lung injury caused by a ventilator results from nonphysiologic lung stress (transpulmonary pressure) and strain (inflated volume to functional residual capacity ratio).To determine whether plateau pressure and tidal volume are adequate surrogates for stress and strain, and to quantify the stress to strain relationship in patients and control subjects.Nineteen postsurgical healthy patients (group 1), 11 patients with medical diseases (group 2), 26 patients with acute lung injury (group 3), and 24 patients with acute respiratory distress syndrome (group 4) underwent a positive end-expiratory pressure (PEEP) trial (5 and 15 cm H2O) with 6, 8, 10, and 12 ml/kg tidal volume.Plateau airway pressure, lung and chest wall elastances, and lung stress and strain significantly increased from groups 1 to 4 and with increasing PEEP and tidal volume. Within each group, a given applied airway pressure produced largely variable stress due to the variability of the lung elastance to respiratory system elastance ratio (range, 0.33-0.95). Analogously, for the same applied tidal volume, the strain variability within subgroups was remarkable, due to the functional residual capacity variability. Therefore, low or high tidal volume, such as 6 and 12 ml/kg, respectively, could produce similar stress and strain in a remarkable fraction of patients in each subgroup. In contrast, the stress to strain ratio-that is, specific lung elastance-was similar throughout the subgroups (13.4 +/- 3.4, 12.6 +/- 3.0, 14.4 +/- 3.6, and 13.5 +/- 4.1 cm H2O for groups 1 through 4, respectively; P = 0.58) and did not change with PEEP and tidal volume.Plateau pressure and tidal volume are inadequate surrogates for lung stress and strain. Clinical trial registered with www.clinicaltrials.gov (NCT 00143468).

Objectives: The lung-protective strategy employs positive endexpiratory pressure to keep open otherwise collapsed lung regions (anatomical recruitment). Improvement in venous admixture with positive end-expiratory pressure indicates functional recruitment to better gas exchange, which is not necessarily related to anatomical recruitment, because of possible global/ regional perfusion modifications. Therefore, we aimed to assess the value of venous admixture (functional shunt) in estimating the fraction of nonaerated lung tissue (anatomical shunt compartment) and to describe their relationship. Design: Retrospective analysis of a previously published study. Setting: Intensive care units of four university hospitals. Patients: Fifty-nine patients with acute lung injury/acute respiratory distress syndrome. Interventions: Positive end-expiratory pressure trial at 5 and 15 cm H2O positive end-expiratory pressures. Measurements and Main Results: Anatomical shunt compartment (whole-lung computed tomography scan) and functional shunt (blood gas analysis) were assessed at 5 and 15 cm H2O positive end-expiratory pressures. Apparent perfusion ratio (perfusion per gram of nonaerated tissue/perfusion per gram of total lung tissue) was defined as the ratio of functional shunt to anatomical shunt compartment. Functional shunt was poorly correlated to the anatomical shunt compartment (r 2 .174). The apparent perfusion ratio at 5 cm H2O positive end-expiratory pressure was widely distributed and averaged 1.25 0.80. The apparent perfusion ratios at 5 and 15 cm H2O positive endexpiratory pressures were highly correlated, with a slope close to identity (y 1.10·x 0.03, r 2 .759), suggesting unchanged blood flow distribution toward the nonaerated lung tissue, when increasing positive end-expiratory pressure. Conclusions: Functional shunt poorly estimates the anatomical shunt compartment, due to the large variability in apparent perfusion ratio. Changes in anatomical shunt compartment with increasing positive end-expiratory pressure, in each individual patient, may be estimated from changes in functional shunt, only if the anatomicalfunctional shunt relationship at 5 cm H2O positive end-expiratory pressure is known. (Crit Care Med 2008; 36:669‐675)

CT has provided new insights on the pathophysiology of acute respiratory distress syndrome (ARDS), demonstrating that ARDS does not affect the lung parenchyma homogeneously. These findings suggest that lung edema, as assessed by CT scan, should be included in the definition. Lung CT findings may provide a firm rationale for tailoring tidal volume during mechanical ventilation. Ideally, tidal volume should be proportional to the portion of the lung open to ventilation, as assessed by CT scan, rather than to the body weight. CT assessment of lung recruitability seems to be a prerequisite for a rational setting of positive end-expiratory pressure.

The plasmatic strong ion difference (SID) is the difference between positively and negatively charged strong ions. At pH 7.4, temperature 37 degrees C and partial carbon dioxide tension 40 mmHg, the ideal value of SID is 42 mEq/l. The buffer base is the sum of negatively charged weak acids ([HCO3(-)], [A-], [H2PO4(-)]) and its normal value is 42 mEq/l. According to the law of electroneutrality, the amount of positive and negative charges must be equal, and therefore the SID value is equal to the buffer base value. The easiest assessment of metabolic acidosis/alkalosis relies on the base excess calculation: buffer base(actual) - buffer base(ideal) = SID(actual) - SID(ideal). The SID approach allows one to appreciate the relationship between acid-base and electrolyte equilibrium from a unique perspective, and here we describe a comprehensive model of this equilibrium. The extracellular volume is characterized by a given SID, which is a function of baseline conditions, endogenous and exogenous input (endogenous production and infusion), and urinary output. Of note, volume modifications vary the concentration of charges in the solution. An expansion of extracellular volume leads to acidosis (SID decreases), whereas a contraction of extracellular volume leads to alkalosis (SID increases). A thorough understanding of acid-base equilibrium mandates recognition of the importance of urinary SID.

Computed tomography (CT) has been utilized to study acute respiratory distress syndrome (ARDS) since the middle 1980s, when it revealed the inhomogeneous pattern of the lung lesion. Its advantages rely on the strict correlation between CT density and the lung physical density, allowing a quantification of lung compartments with different degrees of aeration. By CT scans, ARDS lung appeared to be "small" rather than "stiff," leading to the "baby lung" concept. The regional analysis revealed that this appearance derives from an evenly distributed lung edema, which tends, because of gravitational forces, to lie predominantly in the most dependent regions, leading to alveolar collapse. New data suggest that such a "sponge lung" is made by a "core," consolidated, lung portion, from which, through an inflammatory reaction, lung edema will spread, determining the collapsed and recruitable lung portion. The amount of recruitable lung varies among ARDS patients. This knowledge is necessary for a rational positive end-expiratory pressure (PEEP) setting because the amount of tissue maintained aerated by PEEP is closely associated with the amount of recruitable lung. CT scans may also help to diagnose ARDS because CT provides a good estimate of the high-permeability lung edema, the characteristic lesion of this syndrome.

Purpose of review The purpose of this paper is to review the mechanisms of ventilator-induced lung injury as a basis for providing the less damaging mechanical ventilation in patients with acute respiratory failure. Recent findings In normal lungs, high tidal volume causes an immediate gene upregulation and downregulation. Although the importance of alveolar inflammatory reaction is well known, recent findings suggest the potential role of airway distension in causing ventilator-induced lung injury. The initial activation has been shown to occur in the airways, accounting for the damages induced by high peak flow. The healthier lung regions are more exposed to the injury, since they may be subjected to strain. Challenge with endotoxin enhances in a synergistic manner the pulmonary inflammation induced by mechanical ventilation. However, mechanical strain and endotoxin seem to trigger lung inflammation through two different pathways. Despite convincing experimental and clinical evidences of lung injury, the clinical implementation of low tidal volume ventilation is still limited and has not yet become part of standard clinical practice. Setting positive end-expiratory pressure remains an open problem because the ALVEOLI study did not provide any exhaustive answers, likely because of methodologic problems and, unphysiologic design. Summary Gentle lung ventilation must be standard practice. Because stress and strain are the triggers of ventilator-induced lung injury, their clinical equivalents should be measured (transpulmonary pressure and the ratio between tidal volume and end-expiratory lung volume). For a rational application of positive end-expiratory pressure, the potential for recruitment in any single patient should be estimated.

Objective: To determine whether gas exchange improvement in response to the prone position is associated with an improved outcome in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Design: Retrospective analysis of patients in the pronation arm of a controlled randomized trial on prone positioning and patients enrolled in a previous pilot study of the prone position. Setting: Twenty-eight Italian and two Swiss intensive care units. Patients: We studied 225 patients meeting the criteria for ALI or ARDS. Interventions: Patients were in prone position for 10 days for 6 hrs/day if they met ALI/ARDS criteria when assessed each morning. Respiratory variables were recorded before and after 6 hrs of pronation with unchanged ventilatory settings. Measurements and Main Results: We measured arterial blood gas alterations to the first pronation and the 28-day mortality rate. The independent risk factors for death in the general population were the Pao 2/F102 ratio (odds ratio, 0.992; confidence interval, 0.986-0.998), the minute ventilation/Paco2 ratio (odds ratio, 1.003; confidence interval, 1.000-1.006), and the concentration of plasma creatinine (odds ratio, 1.385; confidence interval, 1.116-1.720). Pao2 responders (defined as the patients who increased their Pao2/F10 2 by ≥20 mm Hg, 150 patients, mean increase of 100.6 ± 61. 6 mm Hg [13.4 ± 8.2 KPa]) had an outcome similar to the nonresponders (59 patients, mean decrease -6.3 ± 23.7 mm Hg [-0.8 ± 3.2 KPa]; mortality rate 44% and 46%, respectively; relative risk, 1.04; confidence interval, 0.74-1.45, p = .65). The Paco2 responders (defined as patients whose Paco2 decreased by ≥1 mm Hg, 94 patients, mean decrease -6.0 ± 6 mm Hg [-0.8 ± 0.8 KPa]) had an improved survival when compared with nonresponders (115 patients, mean increase 6 ± 6 mm Hg [0.8 ± 0.8 KPa]; mortality rate 35.1% and 52.2%, respectively; relative risk, 1.48; confidence interval, 1.07-2.05, p = .01). Conclusion: ALI/ARDS patients who respond to prone positioning with reduction of their Paco2 show an increased survival at 28 days. Improved efficiency of alveolar ventilation (decreased physiologic deadspace ratio) is an important marker of patients who will survive acute respiratory failure.

To test the capability of optoelectronic plethysmography (OEP) to monitor positive end-expiratory pressure (PEEP)-induced changes of end-expiratory lung volume (EELV) changes in mechanically ventilated paralyzed patients.Laboratory and clinical investigation.Intensive care unit of the Ospedale Maggiore Policlinico di Milano.A total of eight patients with respiratory failure of various degrees, sedated and paralyzed.PEEP variations (+/-5 cm H2O) relative to the baseline PEEP of 10 cm H2O.In the model protocol, we tested the reproducibility of the OEP by repeating volume measurements of a plastic torso model over a 21-hr period, every 30 mins. The variations of OEP measurements of the torso model (9337 mL value) were encountered in a range of 16 mL (sd = 4 mL). In the patient protocol, we measured the end-expiratory volume of the chest wall (EEVCW) breath-by-breath by OEP before, during, and after the PEEP increase/decrease and we compared its variations with the corresponding variations of EELV measured by helium dilution technique. The regression line between EELV changes measured by helium and EEVCW changes measured by OEP resulted very close to the identity line (slope 1.06, intercept -0.02 L, r(2) = 0.89) and their difference was not related to their absolute magnitude. After PEEP increase, the new steady state of EEVCW was reached approximately in 15 breaths; and, after PEEP decrease, in 3-4 breaths. The slow increase in EEVCW was mainly because of the abdominal compartment.OEP measurements of EEVCW accurately reflect the changes of EELV. Furthermore, OEP allows a continuous compartmental analysis, even during unsteady conditions.

Bicarbonate infusion is traditionally used to increase pH during metabolic acidosis, but it has been also suggested to increase the pH during permissive hypercapnia. In this paper we will discuss the physicochemical effect of adding (Na+ HCO3-), first in a closed system (venous blood) and then in an open system (the blood after the lung). According to Stewart model, in the closed system two independent variables are changed (CO2 and strong ion difference). As a first result changes in pH are negligible. If the CO2 is cleared by the lung and the PCO2 is maintained as before the infusion, the rise in pH is due to the SID increase caused by the (Na+) rise. The effect is independent on (HCO3-) infusion and equivalent to adding (Na+ OH-) instead of (Na+ HCO3-).

Ventilator-induced lung injury is a side-effect of mechanical ventilation. Its prevention or attenuation implies knowledge of the sequence of events that lead from mechanical stress to lung inflammation and stress at rupture. A literature review was undertaken which focused on the link between the mechanical forces in the diseased lung and the resulting inflammation/rupture. The distending force of the lung is the transpulmonary pressure. This applied force, in a homogeneous lung, is shared equally by each fibre of the lung9s fibrous skeleton. In a nonhomogeneous lung, the collapsed or consolidated regions do not strain, whereas the neighbouring fibres experience excessive strain. Indeed, if the global applied force is excessive, or the fibres near the diseased regions experience excessive stress/strain, biological activation and/or mechanical rupture are observed. Excessive strain activates macrophages and epithelial cells to produce interleukin-8. This cytokine recruits neutrophils, with consequent full-blown inflammation. In order to prevent initiation of ventilator-induced lung injury, transpulmonary pressure must be kept within the physiological range. The prone position may attenuate ventilator-induced lung injury by increasing the homogeneity of transpulmonary pressure distribution. Positive end-expiratory pressure may prevent ventilator-induced lung injury by keeping open the lung, thus reducing the regional stress/strain maldistribution. If the transpulmonary pressure rather than the tidal volume per kilogram of body weight is taken into account, the contradictory results of the randomised trials dealing with different strategies of mechanical ventilation may be better understood. Eur Respir J 2003; 22: Suppl. 47, 15s-25s.