Mechanical and morphological characterization of the emphysematous lung tissue.

Irreversible alveolar airspace enlargement is the main characteristic of pulmonary emphysema, which has been extensively studied using animal models. While the alterations in lung mechanics associated with these morphological changes have been documented in the literature, the study of the mechanical behavior of parenchymal tissue from emphysematous lungs has been poorly investigated. In this work, we characterize the mechanical and morphological properties of lung tissue in elastase-induced emphysema rat models under varying severity conditions. We analyze the non-linear tissue behavior using suitable hyperelastic constitutive models that enable to compare different non-linear responses in terms of hyperelastic material parameters. We further analyze the effect of the elastase dose on alveolar morphology and tissue material parameters and study their connection with respiratory-system mechanical parameters. Our results show that while the lung mechanical function is not significantly influenced by the elastase treatment, the tissue mechanical behavior and alveolar morphology are markedly affected by it. We further show a strong association between alveolar enlargement and tissue softening, not evidenced by respiratory-system compliance. Our findings highlight the importance of understanding tissue mechanics in emphysematous lungs, as changes in tissue properties could detect the early stages of emphysema remodeling. STATEMENT OF SIGNIFICANCE: Gas exchange is vital for life and strongly relies on the mechanical function of the lungs. Pulmonary emphysema is a prevalent respiratory disease where alveolar walls are damaged, causing alveolar enlargement that induces harmful changes in the mechanical response of the lungs. In this work, we study how the mechanical properties of lung tissue change during emphysema. Our results from animal models show that tissue properties are more sensitive to alveolar enlargement due to emphysema than other mechanical properties that describe the function of the whole respiratory system.

Dynamic changes of hepatic vein Doppler velocities predict preload responsiveness in mechanically ventilated critically ill patients.

BACKGROUND: Assessment of dynamic parameters to guide fluid administration is one of the mainstays of current resuscitation strategies. Each test has its own limitations, but passive leg raising (PLR) has emerged as one of the most versatile preload responsiveness tests. However, it requires real-time cardiac output (CO) measurement either through advanced monitoring devices, which are not routinely available, or echocardiography, which is not always feasible. Analysis of the hepatic vein Doppler waveform change, a simpler ultrasound-based assessment, during a dynamic test such as PLR could be useful in predicting preload responsiveness. The objective of this study was to assess the diagnostic accuracy of hepatic vein Doppler S and D-wave velocities during PLR as a predictor of preload responsiveness. METHODS: Prospective observational study conducted in two medical-surgical ICUs in Chile. Patients in circulatory failure and connected to controlled mechanical ventilation were included from August to December 2023. A baseline ultrasound assessment of cardiac function was performed. Then, simultaneously, ultrasound measurements of hepatic vein Doppler S and D waves and cardiac output by continuous pulse contour analysis device were performed during a PLR maneuver. RESULTS: Thirty-seven patients were analyzed. 63% of the patients were preload responsive defined by a 10% increase in CO after passive leg raising. A 20% increase in the maximum S wave velocity after PLR showed the best diagnostic accuracy with a sensitivity of 69.6% (49.1-84.4) and specificity of 92.8 (68.5-99.6) to detect preload responsiveness, with an area under curve of receiving operator characteristic (AUC-ROC) of 0.82 ± 0.07 (p = 0.001 vs. AUC-ROC of 0.5). D-wave velocities showed worse diagnostic accuracy. CONCLUSIONS: Hepatic vein Doppler assessment emerges as a novel complementary technique with adequate predictive capacity to identify preload responsiveness in patients in mechanical ventilation and circulatory failure. This technique could become valuable in scenarios of basic hemodynamic monitoring and when echocardiography is not feasible. Future studies should confirm these results.

Impact of respiratory cycle during mechanical ventilation on beat-to-beat right ventricle stroke volume estimation by pulmonary artery pulse wave analysis.

BACKGROUND: The same principle behind pulse wave analysis can be applied on the pulmonary artery (PA) pressure waveform to estimate right ventricle stroke volume (RVSV). However, the PA pressure waveform might be influenced by the direct transmission of the intrathoracic pressure changes throughout the respiratory cycle caused by mechanical ventilation (MV), potentially impacting the reliability of PA pulse wave analysis (PAPWA). We assessed a new method that minimizes the direct effect of the MV on continuous PA pressure measurements and enhances the reliability of PAPWA in tracking beat-to-beat RVSV. METHODS: Continuous PA pressure and flow were simultaneously measured for 2-3 min in 5 pigs using a high-fidelity micro-tip catheter and a transonic flow sensor around the PA trunk, both pre and post an experimental ARDS model. RVSV was estimated by PAPWA indexes such as pulse pressure (SVPP), systolic area (SVSystAUC) and standard deviation (SVSD) beat-to-beat from both corrected and non-corrected PA signals. The reference RVSV was derived from the PA flow signal (SVref). RESULTS: The reliability of PAPWA in tracking RVSV on a beat-to-beat basis was enhanced after accounting for the direct impact of intrathoracic pressure changes induced by MV throughout the respiratory cycle. This was evidenced by an increase in the correlation between SVref and RVSV estimated by PAPWA under healthy conditions: rho between SVref and non-corrected SVSD - 0.111 (0.342), corrected SVSD 0.876 (0.130), non-corrected SVSystAUC 0.543 (0.141) and corrected SVSystAUC 0.923 (0.050). Following ARDS, correlations were SVref and non-corrected SVSD - 0.033 (0.262), corrected SVSD 0.839 (0.077), non-corrected SVSystAUC 0.483 (0.114) and corrected SVSystAUC 0.928 (0.026). Correction also led to reduced limits of agreement between SVref and SVSD and SVSystAUC in the two evaluated conditions. CONCLUSIONS: In our experimental model, we confirmed that correcting for mechanical ventilation induced changes during the respiratory cycle improves the performance of PAPWA for beat-to-beat estimation of RVSV compared to uncorrected measurements. This was demonstrated by a better correlation and agreement between the actual SV and the obtained from PAPWA.

Coexistence of a fluid responsive state and venous congestion signals in critically ill patients: a multicenter observational proof-of-concept study.

BACKGROUND: Current recommendations support guiding fluid resuscitation through the assessment of fluid responsiveness. Recently, the concept of fluid tolerance and the prevention of venous congestion (VC) have emerged as relevant aspects to be considered to avoid potentially deleterious side effects of fluid resuscitation. However, there is paucity of data on the relationship of fluid responsiveness and VC. This study aims to compare the prevalence of venous congestion in fluid responsive and fluid unresponsive critically ill patients after intensive care (ICU) admission. METHODS: Multicenter, prospective cross-sectional observational study conducted in three medical-surgical ICUs in Chile. Consecutive mechanically ventilated patients that required vasopressors and admitted < 24 h to ICU were included between November 2022 and June 2023. Patients were assessed simultaneously for fluid responsiveness and VC at a single timepoint. Fluid responsiveness status, VC signals such as central venous pressure, estimation of left ventricular filling pressures, lung, and abdominal ultrasound congestion indexes and relevant clinical data were collected. RESULTS: Ninety patients were included. Median age was 63 [45-71] years old, and median SOFA score was 9 [7-11]. Thirty-eight percent of the patients were fluid responsive (FR+), while 62% were fluid unresponsive (FR-). The most prevalent diagnosis was sepsis (41%) followed by respiratory failure (22%). The prevalence of at least one VC signal was not significantly different between FR+ and FR- groups (53% vs. 57%, p = 0.69), as well as the proportion of patients with 2 or 3 VC signals (15% vs. 21%, p = 0.4). We found no association between fluid balance, CRT status, or diagnostic group and the presence of VC signals. CONCLUSIONS: Venous congestion signals were prevalent in both fluid responsive and unresponsive critically ill patients. The presence of venous congestion was not associated with fluid balance or diagnostic group. Further studies should assess the clinical relevance of these results and their potential impact on resuscitation and monitoring practices.

Mechanical Power of Ventilation: From Computer to Clinical Implications.

Mechanical ventilation is a lifesaving intervention that may also induce further lung injury by exerting excessive mechanical forces on susceptible lung tissue, a phenomenon termed ventilator-induced lung injury (VILI). The concept of mechanical power (MP) aims to unify in one single variable the contribution of the different ventilatory parameters that could induce VILI by measuring the energy transfer to the lung over time. Despite an increasing amount of evidence demonstrating that high MP values can be associated with VILI development in experimental studies, the evidence regarding the association of MP and clinical outcomes remains controversial. In the present review, we describe the different determinants of VILI, the concept and computation of MP, and discuss the experimental and clinical studies related to MP. Currently, due to different limitations, the clinical application of MP is debatable. Further clinical studies are required to enhance our understanding of the relationship between MP and the development of VILI, as well as its potential impact on clinical outcomes.

Physiological effects of high-flow nasal cannula oxygen therapy after extubation: a randomized crossover study.

BACKGROUND: Prophylactic high-flow nasal cannula (HFNC) oxygen therapy can decrease the risk of extubation failure. It is frequently used in the postextubation phase alone or in combination with noninvasive ventilation. However, its physiological effects in this setting have not been thoroughly investigated. The aim of this study was to determine comprehensively the effects of HFNC applied after extubation on respiratory effort, diaphragm activity, gas exchange, ventilation distribution, and cardiovascular biomarkers. METHODS: This was a prospective randomized crossover physiological study in critically ill patients comparing 1 h of HFNC versus 1 h of standard oxygen after extubation. The main inclusion criteria were mechanical ventilation for at least 48 h due to acute respiratory failure, and extubation after a successful spontaneous breathing trial (SBT). We measured respiratory effort through esophageal/transdiaphragmatic pressures, and diaphragm electrical activity (ΔEAdi). Lung volumes and ventilation distribution were estimated by electrical impedance tomography. Arterial and central venous blood gases were analyzed, as well as cardiac stress biomarkers. RESULTS: We enrolled 22 patients (age 59 ± 17 years; 9 women) who had been intubated for 8 ± 6 days before extubation. Respiratory effort was significantly lower with HFNC than with standard oxygen therapy, as evidenced by esophageal pressure swings (5.3 [4.2-7.1] vs. 7.2 [5.6-10.3] cmH2O; p < 0.001), pressure-time product (85 [67-140] vs. 156 [114-238] cmH2O*s/min; p < 0.001) and ΔEAdi (10 [7-13] vs. 14 [9-16] µV; p = 0.022). In addition, HFNC induced increases in end-expiratory lung volume and PaO2/FiO2 ratio, decreases in respiratory rate and ventilatory ratio, while no changes were observed in systemic hemodynamics, Troponin T, or in amino-terminal pro-B-type natriuretic peptide. CONCLUSIONS: Prophylactic application of HFNC after extubation provides substantial respiratory support and unloads respiratory muscles. Trial registration January 15, 2021. NCT04711759.

Effects of changes in trunk inclination on ventilatory efficiency in ARDS patients: quasi-experimental study.

BACKGROUND: Trunk inclination from semirecumbent head-upright to supine-flat positioning reduces driving pressure and increases respiratory system compliance in patients with acute respiratory distress syndrome (ARDS). These effects are associated with an improved ventilatory ratio and reduction in the partial pressure of carbon dioxide (PaCO2). However, these physiological effects have not been completely studied, and their mechanisms have not yet been elucidated. Therefore, this study aimed to evaluate the effects of a change in trunk inclination from semirecumbent (45°) to supine-flat (10°) on physiological dead space and ventilation distribution in different lung regions. RESULTS: Twenty-two ARDS patients on pressure-controlled ventilation underwent three 60-min steps in which trunk inclination was changed from 45° (baseline) to 10° (intervention) and back to 45° (control) in the last step. Tunk inclination from a semirecumbent (45°) to a supine-flat (10°) position resulted in a higher tidal volume [371 (± 76) vs. 433 (± 84) mL (P < 0.001)] and respiratory system compliance [34 (± 10) to 41 (± 12) mL/cmH2O (P < 0.001)]. The CO2 exhaled per minute improved from 191 mL/min (± 34) to 227 mL/min (± 38) (P < 0.001). Accordingly, Bohr's dead space ratio decreased from 0.49 (± 0.07) to 0.41 (± 0.06) (p < 0.001), and PaCO2 decreased from 43 (± 5) to 36 (± 4) mmHg (p < 0.001). In addition, the impedance ratio, which divides the ventilation activity of the ventral region by the dorsal region ventilation activity in tidal images, dropped from 1.27 (0.83-1.78) to 0.86 (0.51-1.33) (p < 0.001). These results, calculated from functional EIT images, indicated further ventilation activity in the dorsal lung regions. These effects rapidly reversed once the patient was repositioned at 45°. CONCLUSIONS: A change in trunk inclination from a semirecumbent (45 degrees) to a supine-flat position (10 degrees) improved Bohr's dead space ratio and reduced PaCO2 in patients with ARDS. This effect is associated with an increase in tidal volume and respiratory system compliance, along with further favourable impedance ventilation distribution toward the dorsal lung regions. This study highlights the importance of considering trunk inclination as a modifiable determinant of physiological parameters. The angle of trunk inclination is essential information that must be reported in ARDS patients.

Sedation and Analgesia for Toxic Epidermal Necrolysis in the Intensive Care Unit: Few Certainties, Many Questions Ahead.

Toxic epidermal necrolysis (TEN) is a rare, acute mucocutaneous life-threatening disease. Although research has focused on the pathophysiological and therapeutic aspects of the disease, there is a paucity of data in the literature regarding pain management and sedation in the intensive care unit (ICU). Most therapies have been extrapolated from other situations and/or the general ICU population. These patients present unique challenges during the progression of the disease and could end up requiring invasive mechanical ventilation due to inadequate pain management, which is potentially avoidable through a comprehensive treatment approach. In this review, we will present clinical and pathophysiological aspects of TEN, analyze pain pathways and relevant pharmacology, and propose therapeutic alternatives based on a rational and multimodal approach.

Beta-Lactam Antibiotics Can Be Measured in the Exhaled Breath Condensate in Mechanically Ventilated Patients: A Pilot Study.

Different techniques have been proposed to measure antibiotic levels within the lung parenchyma; however, their use is limited because they are invasive and associated with adverse effects. We explore whether beta-lactam antibiotics could be measured in exhaled breath condensate collected from heat and moisture exchange filters (HMEFs) and correlated with the concentration of antibiotics measured from bronchoalveolar lavage (BAL). We designed an observational study in patients undergoing mechanical ventilation, which required a BAL to confirm or discard the diagnosis of pneumonia. We measured and correlated the concentration of beta-lactam antibiotics in plasma, epithelial lining fluid (ELF), and exhaled breath condensate collected from HMEFs. We studied 12 patients, and we detected the presence of antibiotics in plasma, ELF, and HMEFs from every patient studied. The concentrations of antibiotics were very heterogeneous over the population studied. The mean antibiotic concentration was 293.5 (715) ng/mL in plasma, 12.3 (31) ng/mL in ELF, and 0.5 (0.9) ng/mL in HMEF. We found no significant correlation between the concentration of antibiotics in plasma and ELF (R2 = 0.02, p = 0.64), between plasma and HMEF (R2 = 0.02, p = 0.63), or between ELF and HMEF (R2 = 0.02, p = 0.66). We conclude that beta-lactam antibiotics can be detected and measured from the exhaled breath condensate accumulated in the HMEF from mechanically ventilated patients. However, no correlations were observed between the antibiotic concentrations in HMEF with either plasma or ELF.

Diaphragmatic Ultrasound Predictors of High-Flow Nasal Cannula Therapeutic Failure in Critically Ill Patients With SARS-CoV-2 Pneumonia.

OBJECTIVES: High flow nasal cannula (HFNC) is frequently used in patients with acute respiratory failure, but there is limited evidence regarding predictors of therapeutic failure. The objective of this study was to assess diaphragmatic ultrasound criteria as predictors of failure to HFNC, defined as the need for orotracheal intubation or death. METHODS: Prospective cohort study including adult patients consecutively admitted to the critical care unit, from July 24 to October 20, 2020, with respiratory failure secondary to SARS-CoV-2 pneumonia who required HFNC. After 12 hours of HFNC initiation we measured ROX index (ratio of SpO2 /FiO2 to respiratory rate), excursion and diaphragmatic contraction speed (diaphragmatic excursion/inspiratory time) by ultrasound, both in supine and prone position. RESULTS: In total, 41 patients were analyzed, 25 succeeded and 16 failed HFNC therapy. At 12 hours, patients who succeeded HFNC therapy presented higher ROX index in supine position (9.8 [9.1-15.6] versus 5.4 [3.9-6.8], P < .01), and higher PaO2 /FiO2 ratio (186 [135-236] versus 117 [103-162] mmHg, P = .03). To predict therapeutic failure, the supine diaphragmatic contraction speed presented sensitivity of 89% and a specificity of 57%, while the ROX index presented a sensitivity of 92.8% and a specificity of 75%. CONCLUSIONS: Diaphragmatic contraction speed by ultrasound emerges as a diagnostic complement to clinical tools to predict HFNC success. Future studies should confirm these results.

Morphometric analysis of airways in pre-COPD and mild COPD lungs using continuous surface representations of the bronchial lumen.

Introduction: Chronic Obstructive Pulmonary Disease (COPD) is a prevalent respiratory disease that presents a high rate of underdiagnosis during onset and early stages. Studies have shown that in mild COPD patients, remodeling of the small airways occurs concurrently with morphological changes in the proximal airways. Despite this evidence, the geometrical study of the airway tree from computed tomography (CT) lung images remains underexplored due to poor representations and limited tools to characterize the airway structure. Methods: We perform a comprehensive morphometric study of the proximal airways based on geometrical measures associated with the different airway generations. To this end, we leverage the geometric flexibility of the Snakes IsoGeometric Analysis method to accurately represent and characterize the airway luminal surface and volume informed by CT images of the respiratory tree. Based on this framework, we study the airway geometry of smoking pre-COPD and mild COPD individuals. Results: Our results show a significant difference between groups in airway volume, length, luminal eccentricity, minimum radius, and surface-area-to-volume ratio in the most distal airways. Discussion: Our findings suggest a higher degree of airway narrowing and collapse in COPD patients when compared to pre-COPD patients. We envision that our work has the potential to deliver a comprehensive tool for assessing morphological changes in airway geometry that take place in the early stages of COPD.

Preliminary evaluation of the effects of a 1:1 inspiratory-to-expiratory ratio in anesthetized and ventilated horses.

OBJECTIVE: To describe some cardiorespiratory effects of an inspiratory-to-expiratory (IE) ratio of 1:1 compared with 1:3 in ventilated horses in dorsal recumbency. STUDY DESIGN: Randomized crossover experimental study. ANIMALS: A total of eight anesthetized horses, with 444 (330-485) kg body weight [median (range)]. METHODS: Horses were ventilated in dorsal recumbency with a tidal volume of 15 mL kg-1 and a respiratory rate of 8 breaths minute-1, and IE ratios of 1:1 (IE1:1) and 1:3 (IE1:3) in random order, each for 25 minutes after applying a recruitment maneuver. Spirometry, arterial blood gases and dobutamine requirements were recorded in all horses during each treatment. Electrical impedance tomography (EIT) data were recorded in four horses and used to generate functional EIT variables including regional ventilation delay index (RVD), a measure of speed of lung inflation, and end-expiratory lung impedance (EELI), an indicator of functional residual capacity (FRC). Results were assessed with linear and generalized linear mixed models. RESULTS: Compared with treatment IE1:3, horses ventilated with treatment IE1:1 had higher mean airway pressures and respiratory system compliance (p < 0.014), while peak, end-inspiratory and driving airway pressures were lower (p < 0.001). No differences in arterial oxygenation or dobutamine requirements were observed. PaCO2 was lower in treatment IE1:1 (p = 0.039). Treatment IE1:1 resulted in lower RVD (p < 0.002) and higher EELI (p = 0.023) than treatment IE1:3. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggest that IE1:1 improved respiratory system mechanics and alveolar ventilation compared with IE1:3, whereas oxygenation and dobutamine requirements were unchanged, although differences were small. In the four horses where EIT was evaluated, IE1:1 led to a faster inflation rate of the lung, possibly the result of increased FRC. The clinical relevance of these findings needs to be further investigated.

Spontaneous breathing promotes lung injury in an experimental model of alveolar collapse.

Vigorous spontaneous breathing has emerged as a promotor of lung damage in acute lung injury, an entity known as "patient self-inflicted lung injury". Mechanical ventilation may prevent this second injury by decreasing intrathoracic pressure swings and improving regional air distribution. Therefore, we aimed to determine the effects of spontaneous breathing during the early stage of acute respiratory failure on lung injury and determine whether early and late controlled mechanical ventilation may avoid or revert these harmful effects. A model of partial surfactant depletion and lung collapse was induced in eighteen intubated pigs of 32 ±4 kg. Then, animals were randomized to (1) SB-group: spontaneous breathing with very low levels of pressure support for the whole experiment (eight hours), (2) Early MV-group: controlled mechanical ventilation for eight hours, or (3) Late MV-group: first half of the experiment on spontaneous breathing (four hours) and the second half on controlled mechanical ventilation (four hours). Respiratory, hemodynamic, and electric impedance tomography data were collected. After the protocol, animals were euthanized, and lungs were extracted for histologic tissue analysis and cytokines quantification. SB-group presented larger esophageal pressure swings, progressive hypoxemia, lung injury, and more dorsal and inhomogeneous ventilation compared to the early MV-group. In the late MV-group switch to controlled mechanical ventilation improved the lung inhomogeneity and esophageal pressure swings but failed to prevent hypoxemia and lung injury. In a lung collapse model, spontaneous breathing is associated to large esophageal pressure swings and lung inhomogeneity, resulting in progressive hypoxemia and lung injury. Mechanical ventilation prevents these mechanisms of patient self-inflicted lung injury if applied early, before spontaneous breathing occurs, but not when applied late.

Distribution and Magnitude of Regional Volumetric Lung Strain and Its Modification by PEEP in Healthy Anesthetized and Mechanically Ventilated Dogs.

The present study describes the magnitude and spatial distribution of lung strain in healthy anesthetized, mechanically ventilated dogs with and without positive end-expiratory pressure (PEEP). Total lung strain (LSTOTAL) has a dynamic (LSDYNAMIC) and a static (LSSTATIC) component. Due to lung heterogeneity, global lung strain may not accurately represent regional total tissue lung strain (TSTOTAL), which may also be described by a regional dynamic (TSDYNAMIC) and static (TSSTATIC) component. Six healthy anesthetized beagles (12.4 ± 1.4 kg body weight) were placed in dorsal recumbency and ventilated with a tidal volume of 15 ml/kg, respiratory rate of 15 bpm, and zero end-expiratory pressure (ZEEP). Respiratory system mechanics and full thoracic end-expiratory and end-inspiratory CT scan images were obtained at ZEEP. Thereafter, a PEEP of 5 cmH2O was set and respiratory system mechanics measurements and end-expiratory and end-inspiratory images were repeated. Computed lung volumes from CT scans were used to evaluate the global LSTOTAL, LSDYNAMIC, and LSSTATIC during PEEP. During ZEEP, LSSTATIC was assumed zero; therefore, LSTOTAL was the same as LSDYNAMIC. Image segmentation was applied to CT images to obtain maps of regional TSTOTAL, TSDYNAMIC, and TSSTATIC during PEEP, and TSDYNAMIC during ZEEP. Compliance increased (p = 0.013) and driving pressure decreased (p = 0.043) during PEEP. PEEP increased the end-expiratory lung volume (p < 0.001) and significantly reduced global LSDYNAMIC (33.4 ± 6.4% during ZEEP, 24.0 ± 4.6% during PEEP, p = 0.032). LSSTATIC by PEEP was larger than the reduction in LSDYNAMIC; therefore, LSTOTAL at PEEP was larger than LSDYNAMIC at ZEEP (p = 0.005). There was marked topographic heterogeneity of regional strains. PEEP induced a significant reduction in TSDYNAMIC in all lung regions (p < 0.05). Similar to global findings, PEEP-induced TSSTATIC was larger than the reduction in TSDYNAMIC; therefore, PEEP-induced TSTOTAL was larger than TSDYNAMIC at ZEEP. In conclusion, PEEP reduced both global and regional estimates of dynamic strain, but induced a large static strain. Given that lung injury has been mostly associated with tidal deformation, limiting dynamic strain may be an important clinical target in healthy and diseased lungs, but this requires further study.

How far are we from predicting multi-drug interactions during treatment for COVID-19 infection?

Seriously ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and hospitalized in intensive care units (ICUs) are commonly given a combination of drugs, a process known as multi-drug treatment. After extracting data on drug-drug interactions with clinical relevance from available online platforms, we hypothesize that an overall interaction map can be generated for all drugs administered. Furthermore, by combining this approach with simulations of cellular biochemical pathways, we may be able to explain the general clinical outcome. Finally, we postulate that by applying this strategy retrospectively to a cohort of patients hospitalized in ICU, a prediction of the timing of developing acute kidney injury (AKI) could be made. Whether or not this approach can be extended to other diseases is uncertain. Still, we believe it represents a valuable pharmacological insight to help improve clinical outcomes for severely ill patients.

Acute lung injury secondary to hydrochloric acid instillation induces small airway hyperresponsiveness.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe form of respiratory failure characterized by altered lung mechanics and poor oxygenation. Bronchial hyperresponsiveness has been reported in ARDS survivors and animal models of acute lung injury. Whether this hyperreactivity occurs at the small airways or not is unknown. OBJECTIVE: To determine ex-vivo small airway reactivity in a rat model of acute lung injury (ALI) by hydrochloric acid (HCl) instillation. METHODS: Twelve anesthetized rats were connected to mechanical ventilation for 4-hour, and randomly allocated to either ALI group (HCl intratracheal instillation; n=6) or Sham (intratracheal instillation of 0.9% NaCl; n=6). Oxygenation was assessed by arterial blood gases. After euthanasia, tissue samples from the right lung were harvested for histologic analysis and wet-dry weight ratio assessment. Precision cut lung slice technique (100-200 µm diameter) was applied in the left lung to evaluate ex vivo small airway constriction in response to histamine and carbachol stimulation, using phase-contrast video microscopy. RESULTS: Rats from the ALI group exhibited hypoxemia, worse histologic lung injury, and increased lung wet-dry weight ratio as compared with the sham group. The bronchoconstrictor responsiveness was significantly higher in the ALI group, both for carbachol (maximal contraction of 84.5±2.5% versus 61.4±4.2% in the Sham group, P<0.05), and for histamine (maximal contraction of 78.6±5.3% versus 49.6±5.3% in the Sham group, P<0.05). CONCLUSION: In an animal model of acute lung injury secondary to HCL instillation, small airway hyperresponsiveness to carbachol and histamine is present. These results may provide further insight into the pathophysiology of ARDS.

Effect of positive end-expiratory pressure on lung injury and haemodynamics during experimental acute respiratory distress syndrome treated with extracorporeal membrane oxygenation and near-apnoeic ventilation.

BACKGROUND: Lung rest has been recommended during extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome (ARDS). Whether positive end-expiratory pressure (PEEP) confers lung protection during ECMO for severe ARDS is unclear. We compared the effects of three different PEEP levels whilst applying near-apnoeic ventilation in a model of severe ARDS treated with ECMO. METHODS: Acute respiratory distress syndrome was induced in anaesthetised adult male pigs by repeated saline lavage and injurious ventilation for 1.5 h. After ECMO was commenced, the pigs received standardised near-apnoeic ventilation for 24 h to maintain similar driving pressures and were randomly assigned to PEEP of 0, 10, or 20 cm H2O (n=7 per group). Respiratory and haemodynamic data were collected throughout the study. Histological injury was assessed by a pathologist masked to PEEP allocation. Lung oedema was estimated by wet-to-dry-weight ratio. RESULTS: All pigs developed severe ARDS. Oxygenation on ECMO improved with PEEP of 10 or 20 cm H2O, but did not in pigs allocated to PEEP of 0 cm H2O. Haemodynamic collapse refractory to norepinephrine (n=4) and early death (n=3) occurred after PEEP 20 cm H2O. The severity of lung injury was lowest after PEEP of 10 cm H2O in both dependent and non-dependent lung regions, compared with PEEP of 0 or 20 cm H2O. A higher wet-to-dry-weight ratio, indicating worse lung injury, was observed with PEEP of 0 cm H2O. Histological assessment suggested that lung injury was minimised with PEEP of 10 cm H2O. CONCLUSIONS: During near-apnoeic ventilation and ECMO in experimental severe ARDS, 10 cm H2O PEEP minimised lung injury and improved gas exchange without compromising haemodynamic stability.

Physiological and inflammatory consequences of high and low respiratory rate in acute respiratory distress syndrome.

Using protective mechanical ventilation strategies with low tidal volume is usually accompanied by an increment of respiratory rate to maintain adequate alveolar ventilation. However, there is no robust data that support the safety of a high respiratory rate concerning ventilator-induced lung injury. Several experimental animal studies have explored the effects of respiratory rate over lung physiology, using a wide range of frequencies and different models. Clinical evidence is scarce and restricted to the physiological impact of increased respiratory rate. Undoubtedly, the respiratory rate can influence respiratory mechanics in various ways as a factor of multiplication of the power of ventilation, and gas exchange, and also on alveolar dynamics. In this narrative review, we present our point of view over the main experimental and clinical evidence available regarding the effect of respiratory rate on ventilator-induced lung injury development.