Determinants of acute kidney injury during high-power mechanical ventilation: secondary analysis from experimental data.

BACKGROUND: The individual components of mechanical ventilation may have distinct effects on kidney perfusion and on the risk of developing acute kidney injury; we aimed to explore ventilatory predictors of acute kidney failure and the hemodynamic changes consequent to experimental high-power mechanical ventilation. METHODS: Secondary analysis of two animal studies focused on the outcomes of different mechanical power settings, including 78 pigs mechanically ventilated with high mechanical power for 48 h. The animals were categorized in four groups in accordance with the RIFLE criteria for acute kidney injury (AKI), using the end-experimental creatinine: (1) NO AKI: no increase in creatinine; (2) RIFLE 1-Risk: increase of creatinine of > 50%; (3) RIFLE 2-Injury: two-fold increase of creatinine; (4) RIFLE 3-Failure: three-fold increase of creatinine; RESULTS: The main ventilatory parameter associated with AKI was the positive end-expiratory pressure (PEEP) component of mechanical power. At 30 min from the initiation of high mechanical power ventilation, the heart rate and the pulmonary artery pressure progressively increased from group NO AKI to group RIFLE 3. At 48 h, the hemodynamic variables associated with AKI were the heart rate, cardiac output, mean perfusion pressure (the difference between mean arterial and central venous pressures) and central venous pressure. Linear regression and receiving operator characteristic analyses showed that PEEP-induced changes in mean perfusion pressure (mainly due to an increase in CVP) had the strongest association with AKI. CONCLUSIONS: In an experimental setting of ventilation with high mechanical power, higher PEEP had the strongest association with AKI. The most likely physiological determinant of AKI was an increase of pleural pressure and CVP with reduced mean perfusion pressure. These changes resulted from PEEP per se and from increase in fluid administration to compensate for hemodynamic impairment consequent to high PEEP.

Impact of mechanical power and positive end expiratory pressure on central vs. mixed oxygen and carbon dioxide related variables in a population of female piglets.

INTRODUCTION: The use of the pulmonary artery catheter has decreased overtime; central venous blood gases are generally used in place of mixed venous samples. We want to evaluate the accuracy of oxygen and carbon dioxide related parameters from a central versus a mixed venous sample, and whether this difference is influenced by mechanical ventilation. MATERIALS AND METHODS: We analyzed 78 healthy female piglets ventilated with different mechanical power. RESULTS: There was a significant difference in oxygen-derived parameters between samples taken from the central venous and mixed venous blood (S v ¯ $$ \overline{v} $$ O2 = 74.6%, ScvO2 = 83%, p < 0.0001). Conversely, CO2-related parameters were similar, with strong correlation. Ventilation with higher mechanical power and PEEP increased the difference between oxygen saturations, (Δ[ScvO2-S v ¯ $$ \overline{v} $$ O2 ] = 7.22% vs. 10.0% respectively in the low and high MP groups, p = 0.020); carbon dioxide-related parameters remained unchanged (p = 0.344). CONCLUSIONS: The venous oxygen saturation (central or mixed) may be influenced by the effects of mechanical ventilation. Therefore, central venous data should be interpreted with more caution when using higher mechanical power. On the contrary, carbon dioxide-derived parameters are more stable and similar between the two sampling sites, independently of mechanical power or positive end expiratory pressures.

Estimation of normal lung weight index in healthy female domestic pigs.

INTRODUCTION: Lung weight is an important study endpoint to assess lung edema in porcine experiments on acute respiratory distress syndrome and ventilatory induced lung injury. Evidence on the relationship between lung-body weight relationship is lacking in the literature. The aim of this work is to provide a reference equation between normal lung and body weight in female domestic piglets. MATERIALS AND METHODS: 177 healthy female domestic piglets from previous studies were included in the analysis. Lung weight was assessed either via a CT-scan before any experimental injury or with a scale after autopsy. The animals were randomly divided in a training (n = 141) and a validation population (n = 36). The relation between body weight and lung weight index (lung weight/body weight, g/kg) was described by an exponential function on the training population. The equation was tested on the validation population. A Bland-Altman analysis was performed to compare the lung weight index in the validation population and its theoretical value calculated with the reference equation. RESULTS: A good fit was found between the validation population and the exponential equation extracted from the training population (RMSE = 0.060). The equation to determine lung weight index from body weight was: [Formula: see text] At the Bland and Altman analyses, the mean bias between the real and the expected lung weight index was - 0.26 g/kg (95% CI - 0.96-0.43), upper LOA 3.80 g/kg [95% CI 2.59-5.01], lower LOA - 4.33 g/kg [95% CI = - 5.54-(- 3.12)]. CONCLUSIONS: This exponential function might be a valuable tool to assess lung edema in experiments involving 16-50 kg female domestic piglets. The error that can be made due to the 95% confidence intervals of the formula is smaller than the one made considering the lung to body weight as a linear relationship.

End-Tidal to Arterial Pco2 Ratio as Guide to Weaning from Venovenous Extracorporeal Membrane Oxygenation.

Rationale: Weaning from venovenous extracorporeal membrane oxygenation (VV-ECMO) is based on oxygenation and not on carbon dioxide elimination. Objectives: To predict readiness to wean from VV-ECMO. Methods: In this multicenter study of mechanically ventilated adults with severe acute respiratory distress syndrome receiving VV-ECMO, we investigated a variable based on CO2 elimination. The study included a prospective interventional study of a physiological cohort (n = 26) and a retrospective clinical cohort (n = 638). Measurements and Main Results: Weaning failure in the clinical and physiological cohorts were 37% and 42%, respectively. The main cause of failure in the physiological cohort was high inspiratory effort or respiratory rate. All patients exhaled similar amounts of CO2, but in patients who failed the weaning trial, [Formula: see text]e was higher to maintain the PaCO2 unchanged. The effort to eliminate one unit-volume of CO2, was double in patients who failed (68.9 [42.4-123] vs. 39 [20.1-57] cm H2O/[L/min]; P = 0.007), owing to the higher physiological Vd (68 [58.73] % vs. 54 [41.64] %; P = 0.012). End-tidal partial carbon dioxide pressure (PetCO2)/PaCO2 ratio was a clinical variable strongly associated with weaning outcome at baseline, with area under the receiver operating characteristic curve of 0.87 (95% confidence interval [CI], 0.71-1). Similarly, the PetCO2/PaCO2 ratio was associated with weaning outcome in the clinical cohort both before the weaning trial (odds ratio, 4.14; 95% CI, 1.32-12.2; P = 0.015) and at a sweep gas flow of zero (odds ratio, 13.1; 95% CI, 4-44.4; P < 0.001). Conclusions: The primary reason for weaning failure from VV-ECMO is high effort to eliminate CO2. A higher PetCO2/PaCO2 ratio was associated with greater likelihood of weaning from VV-ECMO.

Mechanical power thresholds during mechanical ventilation: An experimental study.

The extent of ventilator-induced lung injury may be related to the intensity of mechanical ventilation--expressed as mechanical power. In the present study, we investigated whether there is a safe threshold, below which lung damage is absent. Three groups of six healthy pigs (29.5 ± 2.5 kg) were ventilated prone for 48 h at mechanical power of 3, 7, or 12 J/min. Strain never exceeded 1.0. PEEP was set at 4 cmH2 O. Lung volumes were measured every 12 h; respiratory, hemodynamics, and gas exchange variables every 6. End-experiment histological findings were compared with a control group of eight pigs which did not undergo mechanical ventilation. Functional residual capacity decreased by 10.4% ± 10.6% and 8.1% ± 12.1% in the 7 J and 12 J groups (p = 0.017, p < 0.001) but not in the 3 J group (+1.7% ± 17.7%, p = 0.941). In 3 J group, lung elastance, PaO2 and PaCO2 were worse compared to 7 J and 12 J groups (all p < 0.001), due to lower ventilation-perfusion ratio (0.54 ± 0.13, 1.00 ± 0.25, 1.78 ± 0.36 respectively, p < 0.001). The lung weight was lower (p < 0.001) in the controls (6.56 ± 0.90 g/kg) compared to 3, 7, and 12 J groups (12.9 ± 3.0, 16.5 ± 2.9, and 15.0 ± 4.1 g/kg, respectively). The wet-to-dry ratio was 5.38 ± 0.26 in controls, 5.73 ± 0.52 in 3 J, 5.99 ± 0.38 in 7 J, and 6.13 ± 0.59 in 12 J group (p = 0.03). Vascular congestion was more extensive in the 7 J and 12 J compared to 3 J and control groups. Mechanical ventilation (with anesthesia/paralysis) increase lung weight, and worsen lung histology, regardless of the mechanical power. Ventilating at 3 J/min led to better anatomical variables than at 7 and 12 J/min but worsened the physiological values.

Mechanisms of oxygenation responses to proning and recruitment in COVID-19 pneumonia.

PURPOSE: This study aimed at investigating the mechanisms underlying the oxygenation response to proning and recruitment maneuvers in coronavirus disease 2019 (COVID-19) pneumonia. METHODS: Twenty-five patients with COVID-19 pneumonia, at variable times since admission (from 1 to 3 weeks), underwent computed tomography (CT) lung scans, gas-exchange and lung-mechanics measurement in supine and prone positions at 5 cmH2O and during recruiting maneuver (supine, 35 cmH2O). Within the non-aerated tissue, we differentiated the atelectatic and consolidated tissue (recruitable and non-recruitable at 35 cmH2O of airway pressure). Positive/negative response to proning/recruitment was defined as increase/decrease of PaO2/FiO2. Apparent perfusion ratio was computed as venous admixture/non aerated tissue fraction. RESULTS: The average values of venous admixture and PaO2/FiO2 ratio were similar in supine-5 and prone-5. However, the PaO2/FiO2 changes (increasing in 65% of the patients and decreasing in 35%, from supine to prone) correlated with the balance between resolution of dorsal atelectasis and formation of ventral atelectasis (p = 0.002). Dorsal consolidated tissue determined this balance, being inversely related with dorsal recruitment (p = 0.012). From supine-5 to supine-35, the apparent perfusion ratio increased from 1.38 ± 0.71 to 2.15 ± 1.15 (p = 0.004) while PaO2/FiO2 ratio increased in 52% and decreased in 48% of patients. Non-responders had consolidated tissue fraction of 0.27 ± 0.1 vs. 0.18 ± 0.1 in the responding cohort (p = 0.04). Consolidated tissue, PaCO2 and respiratory system elastance were higher in patients assessed late (all p < 0.05), suggesting, all together, "fibrotic-like" changes of the lung over time. CONCLUSION: The amount of consolidated tissue was higher in patients assessed during the third week and determined the oxygenation responses following pronation and recruitment maneuvers.

Role of Fluid and Sodium Retention in Experimental Ventilator-Induced Lung Injury.

Background: Ventilator-induced lung injury (VILI) via respiratory mechanics is deeply interwoven with hemodynamic, kidney and fluid/electrolyte changes. We aimed to assess the role of positive fluid balance in the framework of ventilation-induced lung injury. Methods: Post-hoc analysis of seventy-eight pigs invasively ventilated for 48 h with mechanical power ranging from 18 to 137 J/min and divided into two groups: high vs. low pleural pressure (10.0 ± 2.8 vs. 4.4 ± 1.5 cmH2O; p < 0.01). Respiratory mechanics, hemodynamics, fluid, sodium and osmotic balances, were assessed at 0, 6, 12, 24, 48 h. Sodium distribution between intracellular, extracellular and non-osmotic sodium storage compartments was estimated assuming osmotic equilibrium. Lung weight, wet-to-dry ratios of lung, kidney, liver, bowel and muscle were measured at the end of the experiment. Results: High pleural pressure group had significant higher cardiac output (2.96 ± 0.92 vs. 3.41 ± 1.68 L/min; p < 0.01), use of norepinephrine/epinephrine (1.76 ± 3.31 vs. 5.79 ± 9.69 mcg/kg; p < 0.01) and total fluid infusions (3.06 ± 2.32 vs. 4.04 ± 3.04 L; p < 0.01). This hemodynamic status was associated with significantly increased sodium and fluid retention (at 48 h, respectively, 601.3 ± 334.7 vs. 1073.2 ± 525.9 mmol, p < 0.01; and 2.99 ± 2.54 vs. 6.66 ± 3.87 L, p < 0.01). Ten percent of the infused sodium was stored in an osmotically inactive compartment. Increasing fluid and sodium retention was positively associated with lung-weight (R 2 = 0.43, p < 0.01; R 2 = 0.48, p < 0.01) and with wet-to-dry ratio of the lungs (R 2 = 0.14, p < 0.01; R 2 = 0.18, p < 0.01) and kidneys (R 2 = 0.11, p = 0.02; R 2 = 0.12, p = 0.01). Conclusion: Increased mechanical power and pleural pressures dictated an increase in hemodynamic support resulting in proportionally increased sodium and fluid retention and pulmonary edema.

Mobilizing Carbon Dioxide Stores. An Experimental Study.

Rationale: Understanding the physiology of CO2 stores mobilization is a prerequisite for intermittent extracorporeal CO2 removal (ECCO2R) in patients with chronic hypercapnia.Objectives: To describe the dynamics of CO2 stores.Methods: Fifteen pigs (61.7 ± 4.3 kg) were randomized to 48 hours of hyperventilation (group "Hyper," n = 4); 48 hours of hypoventilation (group "Hypo," n = 4); 24 hours of hypoventilation plus 24 hours of normoventilation (group "Hypo-Baseline," n = 4); or 24 hours of hypoventilation plus 24 hours of hypoventilation plus ECCO2R (group "Hypo-ECCO2R," n = 3). Forty-eight hours after randomization, the current [Formula: see text]e was reduced by 50% in every pig.Measurements and Main Results: We evaluated [Formula: see text]co2, [Formula: see text]o2, and metabolic [Formula: see text]co2 ([Formula: see text]o2 times the metabolic respiratory quotient). Changes in the CO2 stores were calculated as [Formula: see text]co2 - metabolic V̇co2. After 48 hours, the CO2 stores decreased by 0.77 ± 0.17 l kg-1 in group Hyper and increased by 0.32 ± 0.27 l kg-1 in group Hypo (P = 0.030). In group Hypo-Baseline, they increased by 0.08 ± 0.19 l kg-1, whereas in group Hypo-ECCO2R, they decreased by 0.32 ± 0.24 l kg-1 (P = 0.197). In the second 24-hour period, in groups Hypo-Baseline and Hypo-ECCO2R, the CO2 stores decreased by 0.15 ± 0.09 l kg-1 and 0.51 ± 0.06 l kg-1, respectively (P = 0.002). At the end of the experiment, the 50% reduction of [Formula: see text]e caused a PaCO2 rise of 9.3 ± 1.1, 32.0 ± 5.0, 16.9 ± 1.2, and 11.7 ± 2.0 mm Hg h-1 in groups Hyper, Hypo, Hypo-Baseline, and Hypo-ECCO2R, respectively (P < 0.001). The PaCO2 rise was inversely related to the previous CO2 stores mobilization (P < 0.001).Conclusions: CO2 from body stores can be mobilized over 48 hours without reaching a steady state. This provides a physiological rationale for intermittent ECCO2R in patients with chronic hypercapnia.

Fluid administration for acute circulatory dysfunction using basic monitoring.

This review aims at evaluating the role and the effectiveness of basic hemodynamic monitoring to guide and to titrate fluid administration during acute circulatory dysfunction. Fluid infusion is a cornerstone of the management of acute circulatory dysfunction. This is a time-related situation, which should be promptly faced to avoid multi organ dysfunction. For this purpose, the recognition of clinical signs of acute circulatory dysfunction is of pivotal importance. A prompt fluid resuscitation in the early phase of acute circulatory failure is a key and recommended intervention, on the other hand the hemodynamic targets and the safety limits indicating whether or not stopping this treatment in already resuscitated patients are still undefined. Bedside clinical examination has been demonstrated to be a reliable instrument to recognize the mismatch between cardiac function and peripheral oxygen demand. Mottling skin and capillary refill time have been recently proposed using a semi-quantitative approach as reliable tool to guide shock therapy; lactate level, central venous oxygen saturation and venous-to-arterial CO2 tension difference are also useful to track the effect of the therapies overtime. Finally, the availability of echocardiography miniaturization of the machines has boosted this technique as part of the daily clinical assessment of patient, inside and outside the intensive care units (ICUs).

Extracorporeal CO2 Removal: The Minimally Invasive Approach, Theory, and Practice.

OBJECTIVES: Minimally invasive extracorporeal CO2 removal is an accepted supportive treatment in chronic obstructive pulmonary disease patients. Conversely, the potential of such technique in treating acute respiratory distress syndrome patients remains to be investigated. The aim of this study was: 1) to quantify membrane lung CO2 removal (VCO2ML) under different conditions and 2) to quantify the natural lung CO2 removal (VCO2NL) and to what extent mechanical ventilation can be reduced while maintaining total expired CO2 (VCO2tot = VCO2ML + VCO2NL) and arterial PCO2 constant. DESIGN: Experimental animal study. SETTING: Department of Experimental Animal Medicine, University of Göttingen, Germany. SUBJECTS: Eight healthy pigs (57.7 ± 5 kg). INTERVENTIONS: The animals were sedated, ventilated, and connected to the artificial lung system (surface 1.8 m, polymethylpentene membrane, filling volume 125 mL) through a 13F catheter. VCO2ML was measured under different combinations of inflow PCO2 (38.9 ± 3.3, 65 ± 5.7, and 89.9 ± 12.9 mm Hg), extracorporeal blood flow (100, 200, 300, and 400 mL/min), and gas flow (4, 6, and 12 L/min). At each setting, we measured VCO2ML, VCO2NL, lung mechanics, and blood gases. MEASUREMENTS AND MAIN RESULTS: VCO2ML increased linearly with extracorporeal blood flow and inflow PCO2 but was not affected by gas flow. The outflow PCO2 was similar regardless of inflow PCO2 and extracorporeal blood flow, suggesting that VCO2ML was maximally exploited in each experimental condition. Mechanical ventilation could be reduced by up to 80-90% while maintaining a constant PaCO2. CONCLUSIONS: Minimally invasive extracorporeal CO2 removal removes a relevant amount of CO2 thus allowing mechanical ventilation to be significantly reduced depending on extracorporeal blood flow and inflow PCO2. Extracorporeal CO2 removal may provide the physiologic prerequisites for controlling ventilator-induced lung injury.

Positive End-expiratory Pressure and Mechanical Power.

BACKGROUND: Positive end-expiratory pressure is usually considered protective against ventilation-induced lung injury by reducing atelectrauma and improving lung homogeneity. However, positive end-expiratory pressure, together with tidal volume, gas flow, and respiratory rate, contributes to the mechanical power required to ventilate the lung. This study aimed at investigating the effects of increasing mechanical power by selectively modifying its positive end-expiratory pressure component. METHODS: Thirty-six healthy piglets (23.3 ± 2.3 kg) were ventilated prone for 50 h at 30 breaths/min and with a tidal volume equal to functional residual capacity. Positive end-expiratory pressure levels (0, 4, 7, 11, 14, and 18 cm H2O) were applied to six groups of six animals. Respiratory, gas exchange, and hemodynamic variables were recorded every 6 h. Lung weight and wet-to-dry ratio were measured, and histologic samples were collected. RESULTS: Lung mechanical power was similar at 0 (8.8 ± 3.8 J/min), 4 (8.9 ± 4.4 J/min), and 7 (9.6 ± 4.3 J/min) cm H2O positive end-expiratory pressure, and it linearly increased thereafter from 15.5 ± 3.6 J/min (positive end-expiratory pressure, 11 cm H2O) to 18.7 ± 6 J/min (positive end-expiratory pressure, 14 cm H2O) and 22 ± 6.1 J/min (positive end-expiratory pressure, 18 cm H2O). Lung elastances, vascular congestion, atelectasis, inflammation, and septal rupture decreased from zero end-expiratory pressure to 4 to 7 cm H2O (P < 0.0001) and increased progressively at higher positive end-expiratory pressure. At these higher positive end-expiratory pressure levels, striking hemodynamic impairment and death manifested (mortality 0% at positive end-expiratory pressure 0 to 11 cm H2O, 33% at 14 cm H2O, and 50% at 18 cm H2O positive end-expiratory pressure). From zero end-expiratory pressure to 18 cm H2O, mean pulmonary arterial pressure (from 19.7 ± 5.3 to 32.2 ± 9.2 mmHg), fluid administration (from 537 ± 403 to 2043 ± 930 ml), and noradrenaline infusion (0.04 ± 0.09 to 0.34 ± 0.31 µg · kg(-1) · min(-1)) progressively increased (P < 0.0001). Lung weight and lung wet-to-dry ratios were not significantly different across the groups. The lung mechanical power level that best discriminated between more versus less severe damage was 13 ± 1 J/min. CONCLUSIONS: Less than 7 cm H2O positive end-expiratory pressure reduced atelectrauma encountered at zero end-expiratory pressure. Above a defined power threshold, sustained positive end-expiratory pressure contributed to potentially lethal lung damage and hemodynamic impairment.

Reclassifying Acute Respiratory Distress Syndrome.

RATIONALE: The ratio of PaO2 to FiO2 (P/F) defines acute respiratory distress syndrome (ARDS) severity and suggests appropriate therapies. OBJECTIVES: We investigated 1) whether a 150-mm-Hg P/F threshold within the range of moderate ARDS (100-200 mm Hg) would define two subgroups that were more homogeneous; and 2) which criteria led the clinicians to apply extracorporeal membrane oxygenation (ECMO) in severe ARDS. METHODS: At the 150-mm-Hg P/F threshold, moderate patients were split into mild-moderate (n = 50) and moderate-severe (n = 55) groups. Patients with severe ARDS (FiO2 not available in three patients) were split into higher (n = 63) and lower (n = 18) FiO2 groups at an 80% FiO2 threshold. MEASUREMENTS AND MAIN RESULTS: Compared with mild-moderate ARDS, patients with moderate-severe ARDS had higher peak pressures, PaCO2, and pH. They also had heavier lungs, greater inhomogeneity, more noninflated tissue, and greater lung recruitability. Within 84 patients with severe ARDS (P/F < 100 mm Hg), 75% belonged to the higher FiO2 subgroup. They differed from the patients with severe ARDS with lower FiO2 only in PaCO2 and lung weight. Forty-one of 46 patients treated with ECMO belonged to the higher FiO2 group. Within this group, the patients receiving ECMO had higher PaCO2 than the 22 non-ECMO patients. The inhomogeneity ratio, total lung weight, and noninflated tissue were also significantly higher. CONCLUSIONS: Using the 150-mm-Hg P/F threshold gave a more homogeneous distribution of patients with ARDS across the severity subgroups and identified two populations that differed in their anatomical and physiological characteristics. The patients treated with ECMO belonged to the severe ARDS group, and almost 90% of them belonged to the higher FiO2 subgroup.

Effects of regional perfusion block in healthy and injured lungs.

BACKGROUND: Severe hypoperfusion can cause lung damage. We studied the effects of regional perfusion block in normal lungs and in the lungs that had been conditioned by lavage with 500 ml saline and high V T (20 ml kg-1) ventilation. METHODS: Nineteen pigs (61.2 ± 2.5 kg) were randomized to five groups: controls (n = 3), the right lower lobe block alone (n = 3), lavage and high V T (n = 4), lung lavage, and high V T plus perfusion block of the right (n = 5) or left (n = 4) lower lobe. Gas exchange, respiratory mechanics, and hemodynamics were measured hourly. After an 8-h observation period, CT scans were obtained at 0 and 15 cmH2O airway pressure. RESULTS: Perfusion block did not damage healthy lungs. In conditioned lungs, the left perfusion block caused more edema in the contralateral lung (777 ± 62 g right lung vs 484 ± 204 g left; p < 0.05) than the right perfusion block did (581 ± 103 g right lung vs 484 ± 204 g left; p n.s.). The gas/tissue ratio, however, was similar (0.5 ± 0.3 and 0.8 ± 0.5; p n.s.). The lobes with perfusion block were not affected (gas/tissue ratio right 1.6 ± 0.9; left 1.7 ± 0.5, respectively). Pulmonary artery pressure, PaO2/FiO2, dead space, and lung mechanics were more markedly affected in animals with left perfusion block, while the gas/tissue ratios were similar in the non-occluded lobes. CONCLUSIONS: The right and left perfusion blocks caused the same "intensity" of edema in conditioned lungs. The total amount of edema in the two lungs differed because of differences in lung size. If capillary permeability is altered, increased blood flow may induce or increase edema.

Driving pressure and mechanical power: new targets for VILI prevention.

Several factors have been recognized as possible triggers of ventilator-induced lung injury (VILI). The first is pressure (thus the 'barotrauma'), then the volume (hence the 'volutrauma'), finally the cyclic opening-closing of the lung units ('atelectrauma'). Less attention has been paid to the respiratory rate and the flow, although both theoretical considerations and experimental evidence attribute them a significant role in the generation of VILI. The initial injury to the lung parenchyma is necessarily mechanical and it could manifest as an unphysiological distortion of the extracellular matrix and/or as micro-fractures in the hyaluronan, likely the most fragile polymer embedded in the matrix. The order of magnitude of the energy required to break a molecular bond between the hyaluronan and the associated protein is 1.12×10-16 Joules (J), 70-90% higher than the average energy delivered by a single breath of 1L assuming a lung elastance of 10 cmH2O/L (0.5 J). With a normal statistical distribution of the bond strength some polymers will be exposed each cycle to an energy large enough to rupture. Both the extracellular matrix distortion and the polymer fractures lead to inflammatory increase of capillary permeability with edema if a pulmonary blood flow is sufficient. The mediation analysis of higher vs. lower tidal volume and PEEP studies suggests that the driving pressure, more than tidal volume, is the best predictor of VILI, as inferred by increased mortality. This is not surprising, as both tidal volume and respiratory system elastance (resulting in driving pressure) may independently contribute to the mortality. For the same elastance driving pressure is a predictor similar to plateau pressure or tidal volume. Driving pressure is one of the components of the mechanical power, which also includes respiratory rate, flow and PEEP. Finding the threshold for mechanical power would greatly simplify assessment and prevention of VILI.