High- versus Low-Flow Extracorporeal Respiratory Support in Experimental Hypoxemic Acute Lung Injury.

Rationale: In the EOLIA (ECMO to Rescue Lung Injury in Severe ARDS) trial, oxygenation was similar between intervention and conventional groups, whereas [Formula: see text]e was reduced in the intervention group. Comparable reductions in ventilation intensity are theoretically possible with low-flow extracorporeal CO2 removal (ECCO2R), provided oxygenation remains acceptable. Objectives: To compare the effects of ECCO2R and extracorporeal membrane oxygenation (ECMO) on gas exchange, respiratory mechanics, and hemodynamics in animal models of pulmonary (intratracheal hydrochloric acid) and extrapulmonary (intravenous oleic acid) lung injury. Methods: Twenty-four pigs with moderate to severe hypoxemia (PaO2:FiO2 ⩽ 150 mm Hg) were randomized to ECMO (blood flow 50-60 ml/kg/min), ECCO2R (0.4 L/min), or mechanical ventilation alone. Measurements and Main Results: [Formula: see text]o2, [Formula: see text]co2, gas exchange, hemodynamics, and respiratory mechanics were measured and are presented as 24-hour averages. Oleic acid versus hydrochloric acid showed higher extravascular lung water (1,424 ± 419 vs. 574 ± 195 ml; P < 0.001), worse oxygenation (PaO2:FiO2 = 125 ± 14 vs. 151 ± 11 mm Hg; P < 0.001), but better respiratory mechanics (plateau pressure 27 ± 4 vs. 30 ± 3 cm H2O; P = 0.017). Both models led to acute severe pulmonary hypertension. In both models, ECMO (3.7 ± 0.5 L/min), compared with ECCO2R (0.4 L/min), increased mixed venous oxygen saturation and oxygenation, and improved hemodynamics (cardiac output = 6.0 ± 1.4 vs. 5.2 ± 1.4 L/min; P = 0.003). [Formula: see text]o2 and [Formula: see text]co2, irrespective of lung injury model, were lower during ECMO, resulting in lower PaCO2 and [Formula: see text]e but worse respiratory elastance compared with ECCO2R (64 ± 27 vs. 40 ± 8 cm H2O/L; P < 0.001). Conclusions: ECMO was associated with better oxygenation, lower [Formula: see text]o2, and better hemodynamics. ECCO2R may offer a potential alternative to ECMO, but there are concerns regarding its effects on hemodynamics and pulmonary hypertension.

Ventilatory ratio, dead space, and venous admixture in patients with acute respiratory distress syndrome.

BACKGROUND: Ventilatory ratio (VR) has been proposed as an alternative approach to estimate physiological dead space. However, the absolute value of VR, at constant dead space, might be affected by venous admixture and CO2 volume expired per minute (VCO2). METHODS: This was a retrospective, observational study of mechanically ventilated patients with acute respiratory distress syndrome (ARDS) in the UK and Italy. Venous admixture was either directly measured or estimated using the surrogate measure PaO2/FiO2 ratio. VCO2 was estimated through the resting energy expenditure derived from the Harris-Benedict formula. RESULTS: A total of 641 mechanically ventilated patients with mild (n=65), moderate (n=363), or severe (n=213) ARDS were studied. Venous admixture was measured (n=153 patients) or estimated using the PaO2/FiO2 ratio (n=448). The VR increased exponentially as a function of the dead space, and the absolute values of this relationship were a function of VCO2. At a physiological dead space of 0.6, VR was 1.1, 1.4, and 1.7 in patients with VCO2 equal to 200, 250, and 300, respectively. VR was independently associated with mortality (odds ratio [OR]=2.5; 95% confidence interval [CI], 1.8-3.5), but was not associated when adjusted for VD/VTphys, VCO2, PaO2/FiO2 (ORadj=1.2; 95% CI, 0.7-2.1). These three variables remained independent predictors of ICU mortality (VD/VTphys [ORadj=17.9; 95% CI, 1.8-185; P<0.05]; VCO2 [ORadj=0.99; 95% CI, 0.99-1.00; P<0.001]; and PaO2/FiO2 (ORadj=0.99; 95% CI, 0.99-1.00; P<0.001]). CONCLUSIONS: VR is a useful aggregate variable associated with outcome, but variables not associated with ventilation (VCO2 and venous admixture) strongly contribute to the high values of VR seen in patients with severe illness.

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.

Lung Ultrasound and Electrical Impedance Tomography During Ventilator-Induced Lung Injury.

OBJECTIVES: Lung damage during mechanical ventilation involves lung volume and alveolar water content, and lung ultrasound (LUS) and electrical impedance tomography changes are related to these variables. We investigated whether these techniques may detect any signal modification during the development of ventilator-induced lung injury (VILI). DESIGN: Experimental animal study. SETTING: Experimental Department of a University Hospital. SUBJECTS: Forty-two female pigs (24.2 ± 2.0 kg). INTERVENTIONS: The animals were randomized into three groups (n = 14): high tidal volume (TV) (mean TV, 803.0 ± 121.7 mL), high respiratory rate (RR) (mean RR, 40.3 ± 1.1 beats/min), and high positive-end-expiratory pressure (PEEP) (mean PEEP, 24.0 ± 1.1 cm H2O). The study lasted 48 hours. At baseline and at 30 minutes, and subsequently every 6 hours, we recorded extravascular lung water, end-expiratory lung volume, lung strain, respiratory mechanics, hemodynamics, and gas exchange. At the same time-point, end-expiratory impedance was recorded relatively to the baseline. LUS was assessed every 12 hours in 12 fields, each scoring from 0 (presence of A-lines) to 3 (consolidation). MEASUREMENTS AND MAIN RESULTS: In a multiple regression model, the ratio between extravascular lung water and end-expiratory lung volume was significantly associated with the LUS total score (p < 0.002; adjusted R2, 0.21). The variables independently associated with the end-expiratory difference in lung impedance were lung strain (p < 0.001; adjusted R2, 0.18) and extravascular lung water (p < 0.001; adjusted R2, 0.11). CONCLUSIONS: Data suggest as follows. First, what determines the LUS score is the ratio between water and gas and not water alone. Therefore, caution is needed when an improvement of LUS score follows a variation of the lung gas content, as after a PEEP increase. Second, what determines the end-expiratory difference in lung impedance is the strain level that may disrupt the intercellular junction, therefore altering lung impedance. In addition, the increase in extravascular lung water during VILI development contributed to the observed decrease in impedance.

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.

Does Iso-mechanical Power Lead to Iso-lung Damage?: An Experimental Study in a Porcine Model.

BACKGROUND: Excessive tidal volume, respiratory rate, and positive end-expiratory pressure (PEEP) are all potential causes of ventilator-induced lung injury, and all contribute to a single variable: the mechanical power. The authors aimed to determine whether high tidal volume or high respiratory rate or high PEEP at iso-mechanical power produce similar or different ventilator-induced lung injury. METHODS: Three ventilatory strategies-high tidal volume (twice baseline functional residual capacity), high respiratory rate (40 bpm), and high PEEP (25 cm H2O)-were each applied at two levels of mechanical power (15 and 30 J/min) for 48 h in six groups of seven healthy female piglets (weight: 24.2 ± 2.0 kg, mean ± SD). RESULTS: At iso-mechanical power, the high tidal volume groups immediately and sharply increased plateau, driving pressure, stress, and strain, which all further deteriorated with time. In high respiratory rate groups, they changed minimally at the beginning, but steadily increased during the 48 h. In contrast, after a sudden huge increase, they decreased with time in the high PEEP groups. End-experiment specific lung elastance was 6.5 ± 1.7 cm H2O in high tidal volume groups, 10.1 ± 3.9 cm H2O in high respiratory rate groups, and 4.5 ± 0.9 cm H2O in high PEEP groups. Functional residual capacity decreased and extravascular lung water increased similarly in these three categories. Lung weight, wet-to-dry ratio, and histologic scores were similar, regardless of ventilatory strategies and power levels. However, the alveolar edema score was higher in the low power groups. High PEEP had the greatest impact on hemodynamics, leading to increased need for fluids. Adverse events (early mortality and pneumothorax) also occurred more frequently in the high PEEP groups. CONCLUSIONS: Different ventilatory strategies, delivered at iso-power, led to similar anatomical lung injury. The different systemic consequences of high PEEP underline that ventilator-induced lung injury must be evaluated in the context of the whole body.

Understanding Lactatemia in Human Sepsis. Potential Impact for Early Management.

Rationale: Hyperlactatemia in sepsis may derive from a prevalent impairment of oxygen supply/demand and/or oxygen use. Discriminating between these two mechanisms may be relevant for the early fluid resuscitation strategy.Objectives: To understand the relationship among central venous oxygen saturation (ScvO2), lactate, and base excess to better determine the origin of lactate.Methods: This was a post hoc analysis of baseline variables of 1,741 patients with sepsis enrolled in the multicenter trial ALBIOS (Albumin Italian Outcome Sepsis). Variables were analyzed as a function of sextiles of lactate concentration and sextiles of ScvO2. We defined the "alactic base excess," as the sum of lactate and standard base excess.Measurements and Main Results: Organ dysfunction severity scores, physiologic variables of hepatic, metabolic, cardiac, and renal function, and 90-day mortality were measured. ScvO2 was lower than 70% only in 35% of patients. Mortality, organ dysfunction scores, and lactate were highest in the first and sixth sextiles of ScvO2. Although lactate level related strongly to mortality, it was associated with acidemia only when kidney function was impaired (creatinine >2 mg/dl), as rapidly detected by a negative alactic base excess. In contrast, positive values of alactic base excess were associated with a relative reduction of fluid balance.Conclusions: Hyperlactatemia is powerfully correlated with severity of sepsis and, in established sepsis, is caused more frequently by impaired tissue oxygen use, rather than by impaired oxygen transport. Concomitant acidemia was only observed in the presence of renal dysfunction, as rapidly detected by alactic base excess. The current strategy of fluid resuscitation could be modified according to the origin of excess lactate.

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.

Septic shock-3 vs 2: an analysis of the ALBIOS study.

BACKGROUND: A reanalysis of the ALBIOS trial suggested that patients with septic shock - defined by vasopressor-dependent hypotension in the presence of severe sepsis (Shock-2) - had a survival benefit when treated with albumin. The new septic shock definition (Shock-3) added the criterion of a lactate threshold of 2 mmol/L. We investigated how the populations defined according to Shock-2 and Shock-3 differed and whether the albumin benefit would be confirmed. METHODS: This is a retrospective analysis of the ALBIOS study, a randomized controlled study conducted between 2008 and 2012 in 100 intensive care units in Italy comparing the administration of 20% albumin and crystalloids versus crystalloids alone in patients with severe sepsis or septic shock. We analyzed data from 1741 patients from ALBIOS with serum lactate measurement available at baseline. We compared group size, physiological variables and 90-day mortality between patients defined by Shock-2 and Shock-3 and between the albumin and crystalloid treatment groups. RESULTS: We compared the Shock-2 and the Shock-3 definitions and the albumin and crystalloid treatment groups in terms of group size and physiological, laboratory and outcome variables. The Shock-3 definition reduced the population with shock by 34%. The Shock-3 group had higher lactate (p < 0.001), greater resuscitation-fluid requirement (p = 0.014), higher Simplified Acute Physiology Score II (p < 0.001) and Sepsis-related Organ Failure Assessment scores (p = 0.022), lower platelet count (p = 0.002) and higher 90-day mortality (46.7% vs 51.9%; p = 0.031). Albumin decreased mortality in Shock-2 patients compared to crystalloids (43.5% vs 49.9%; 12.6% relative risk reduction; p = 0.04). In patients defined by Shock-3 a similar benefit was observed for albumin with a 11.3% relative risk reduction (48.7% vs 54.9%; 11.3% relative risk reduction; p = 0.22). CONCLUSIONS: The Sepsis-3 definition reduced the size of the population with shock and showed a similar effect size in the benefits of albumin. The Shock-3 criteria will markedly slow patients' recruitment rates, in view of testing albumin in septic shock. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00707122 . Registered on 30 June 2008.

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.

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.

Gas volume corrections in intensive care unit: needed or pointless?

The conditions of temperature, pressure, and saturation in which respiratory gas volumes are expressed [standard temperature and pressure, dry (STPD), ambient temperature and pressure, saturated (ATPS), or body temperature and pressure, saturated (BTPS)] are physiologically relevant, but often ignored or unknown in clinical practice. In this study, we aimed to investigate whether and at which extent the gas volume corrections, either in natural or artificial lung, may alter key respiratory and metabolic variables and the possible clinical consequences. We primarily referred to the effects of gas volume corrections on three physiological variables: physiological dead space, venous admixture, and total CO2 production (V̇co2) during extracorporeal support. We used three physiological models in which calculations of these variables have been performed with and without correction of gas volumes, both in a theoretical model and in 448 patients. The lack of gas volume correction leads to an error in the computation of physiological dead space fraction between 0.05 and 0.15, both in the theoretical model and in the patient population. The venous admixture was minimally affected by the absence of correction (0.01-0.04 error). During extracorporeal support, if the V̇co2 of natural and membrane lung is expressed in different conditions, potentially large errors (0%-18.4%) may occur in the computation of total V̇co2 (V̇co2tot = V̇co2ML + V̇co2NL). This may lead to inappropriate settings of mechanical ventilation with higher plateau pressure. As the dead space and the CO2 sharing between natural and artificial lung are relevant both as prognostic index and as a guide for appropriate mechanical ventilation, their inappropriate computation may lead to erroneous categorization of the patients and inappropriate mechanical treatment.NEW & NOTEWORTHY Gas volume conditions are often ignored or unknown in the clinical practice. However, they could have relevance for the calculation of some key variables in ICU setting. This study shows that gas volume corrections are mostly relevant when assessing CO2 clearance, both in mechanical ventilation and during extracorporeal support, whereas irrelevant for oxygenation assessment of patients. Knowing when the appropriate corrections are needed allows to better understand patients' clinical conditions and to tailor the treatment.

Relationship between D-dimers and dead-space on disease severity and mortality in COVID-19 acute respiratory distress syndrome: A retrospective observational cohort study.

BACKGROUND: Despite its diagnostic and prognostic importance, physiologic dead space fraction is not included in the current ARDS definition or severity classification. ARDS caused by COVID-19 (C-ARDS) is characterized by increased physiologic dead space fraction and hypoxemia. Our aim was to investigate the relationship between dead space indices, markers of inflammation, immunothrombosis, severity and intensive care unit (ICU) mortality. RESULTS: Retrospective data including demographics, gas exchange, ventilatory parameters, and respiratory mechanics in the first 24 h of invasive ventilation. Plasma concentrations of D-dimers and ferritin were not significantly different across C-ARDS severity categories. Weak relationships were found between D-dimers and VR (r = 0.07, p = 0.13), PETCO2/PaCO2 (r = -0.1, p = 0.02), or estimated dead space fraction (r = 0.019, p = 0.68). Age, PaO2/FiO2, pH, PETCO2/PaCO2 and ferritin, were independently associated with ICU mortality. We found no association between D-dimers or ferritin and any dead-space indices adjusting for PaO2/FiO2, days of ventilation, tidal volume, and respiratory system compliance. CONCLUSIONS: We report no association between dead space and inflammatory markers in mechanically ventilated patients with C-ARDS. Our results support theories suggesting that multiple mechanisms, in addition to immunothrombosis, play a role in the pathophysiology of respiratory failure and degree of dead space in C-ARDS.

Pathophysiology of COVID-19 pneumonia and respiratory treatment.

COVID-19 pandemic has seen an unprecedented number of patients presenting with acute respiratory distress syndrome to the intensive care units all over the world. Between August and November 2022, we performed research on PubMed screening all publications on COVID-19 disease and respiratory failure and its treatment. In this review we focused on COVID-19 most common manifestations concerning lung function. The respiratory infection develops in three broad phases: early, intermediate, and late. The mainstay of the disease is the frequent presence of severe hypoxemia associated - at least at the beginning - to a near normal lung mechanics and PaCO2 tension. The management of symptomatic patients, progressing through these temporal phases, is not possible without understanding the pathophysiology underlying the respiratory manifestation.

Energy dissipation during expiration and ventilator-induced lung injury: an experimental animal study.

The amount of energy delivered to the respiratory system is recognized as a cause of ventilator-induced lung injury (VILI). How energy dissipation within the lung parenchyma causes damage is still a matter of debate. Expiratory flow control has been proposed as a strategy to reduce the energy dissipated into the respiratory system during expiration and, possibly, VILI. We studied 22 healthy pigs (29 ± 2 kg), which were randomized into a control (n = 11) and a valve group (n = 11), where the expiratory flow was controlled through a variable resistor. Both groups were ventilated with the same tidal volume, positive end-expiratory pressure (PEEP), and inspiratory flow. Electric impedance tomography was continuously acquired. At completion, lung weight, wet-to-dry ratios, and histology were evaluated. The total mechanical power was similar in the control and valve groups (8.54 ± 0.83 J·min-1 and 8.42 ± 0.54 J·min-1, respectively, P = 0.552). The total energy dissipated within the whole system (circuit + respiratory system) was remarkably different (4.34 ± 0.66 vs. 2.62 ± 0.31 J/min, P < 0.001). However, most of this energy was dissipated across the endotracheal tube (2.87 ± 0.3 vs. 1.88 ± 0.2 J/min, P < 0.001). The amount dissipated into the respiratory system averaged 1.45 ± 0.5 in controls versus 0.73 ± 0.16 J·min-1 in the valve group, P < 0.001. Although respiratory mechanics, gas exchange, hemodynamics, wet-to-dry ratios, and histology were similar in the two groups, the decrease of end-expiratory lung impedance was significantly greater in the control group (P = 0.02). We conclude that with our experimental conditions, the reduction of energy dissipated in the respiratory system did not lead to appreciable differences in VILI.NEW & NOTEWORTHY Energy dissipation within the respiratory system is a factor promoting ventilator-induced lung injury (VILI). In this animal study, we modulated the expiratory flow, reducing the energy dissipated in the system. However, this reduction happened mostly across the endotracheal tube, and only partly in the respiratory system. Therefore, in healthy lungs, the advantage in energy dissipation does not reduce VILI, but the advantages might be more relevant in diseased lungs under injurious ventilation.