Effects of IFIH1 rs1990760 variants on systemic inflammation and outcome in critically ill COVID-19 patients in an observational translational study.

Background: Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. We hypothesized that IFIH1 rs199076 variants would modulate host response and outcome after severe COVID-19. Methods: Patients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations, and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modeled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials. Results: About 227 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile, and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to an MDA5 agonist showed an increase in IL6 expression after dexamethasone treatment. All patients with the TT variant not treated with steroids survived their ICU stay (hazard ratio [HR]: 2.49, 95% confidence interval [CI]: 1.29-4.79). Patients with a TT variant treated with dexamethasone showed an increased hospital mortality (HR: 2.19, 95% CI: 1.01-4.87) and serum IL-6. In-silico clinical trials supported these findings. Conclusions: COVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype. Funding: Centro de Investigación Biomédica en Red (CB17/06/00021), Instituto de Salud Carlos III (PI19/00184 and PI20/01360), and Fundació La Marató de TV3 (413/C/2021).

Patients with severe COVID-19 often need mechanical ventilation to help them breathe and other types of intensive care. The outcome for many of these patients depends on how their immune system reacts to the infection. If the inflammatory response triggered by the immune system is too strong, this can cause further harm to the patient. One gene that plays an important role in inflammation is IFIH1 which encodes a protein that helps the body to recognize viruses. There are multiple versions of this gene which each produce a slightly different protein. It is possible that this variation impacts how the immune system responds to the virus that causes COVID-19. To investigate, Amado-Rodríguez, Salgado del Riego et al. analyzed the IFIH1 gene in 227 patients admitted to an intensive care unit in Spain for severe COVID-19 between March and December 2020. They found that patients with a specific version of the gene called TT experienced less inflammation and were more likely to survive the infection. Physicians typically treat patients with moderate to severe COVID-19 with corticosteroid drugs that reduce the inflammatory response. However, Amado-Rodríguez, Salgado del Riego et al. found that patients with the TT version of the IFIH1 gene were at greater risk of dying if they received corticosteroids. The team then applied the distribution of IFIH1 variants among different ethnic ancestries to data from a previous clinical trial, and simulated the effects of corticosteroid treatment. This 'mock' clinical trial supported their findings from the patient-derived data, which were also validated by laboratory experiments on immune cells from individuals with the TT gene. The work by Amado-Rodríguez, Salgado del Riego et al. suggests that while corticosteroids benefit some patients, they may cause harm to others. However, a real-world clinical trial is needed to determine whether patients with the TT version of the IFIH1 gene would do better without steroids.

Methotrexate Ameliorates Systemic Inflammation and Septic Associated-Lung Damage in a Cecal Ligation and Puncture Septic Rat Model.

BACKGROUND: Sepsis is a serious, heterogeneous clinical entity produced by a severe and systemic host inflammatory response to infection. Methotrexate (MTX) is a folate-antagonist that induces the generation of adenosine and also inhibits JAK/STAT pathway; MTX it is widely used as an anti-inflammatory drug to control the immune system. OBJECTIVE: The aim of this study was to assess the beneficial effects of a single and low dose of MTX in the systemic response and acute lung injury (ALI) induced by sepsis. As in the clinics, we treated our animals with antibiotics and fluids and performed the source control to mimic the current clinic treatment. METHODS AND MAIN RESULTS: Sepsis was induced in rats by a cecal ligation puncture (CLP) procedure. Six hours after induction of sepsis, we proceeded to the source control; fluids and antibiotics were administered at 6 h and 24 h after CLP. MTX (2.5 mg/Kg) was administered 6 h after the first surgery in one CLP experimental group and to one Sham group. A protective effect of MTX was observed through a significant reduction of pro-inflammatory cytokines and a decrease infiltration of inflammatory cells in the lung. In addition, we found a regulation in adenosine receptor A2aR and the metalloproteinases by MTX. CONCLUSION: A single, low dose of MTX attenuates sepsis lung-associated damage by decreasing pro-inflammatory response, infiltration of pro-inflammatory cells and avoiding defective tissue lung remodeling.

The central nervous system during lung injury and mechanical ventilation: a narrative review.

Mechanical ventilation induces a number of systemic responses for which the brain plays an essential role. During the last decade, substantial evidence has emerged showing that the brain modifies pulmonary responses to physical and biological stimuli by various mechanisms, including the modulation of neuroinflammatory reflexes and the onset of abnormal breathing patterns. Afferent signals and circulating factors from injured peripheral tissues, including the lung, can induce neuronal reprogramming, potentially contributing to neurocognitive dysfunction and psychological alterations seen in critically ill patients. These impairments are ubiquitous in the presence of positive pressure ventilation. This narrative review summarises current evidence of lung-brain crosstalk in patients receiving mechanical ventilation and describes the clinical implications of this crosstalk. Further, it proposes directions for future research ranging from identifying mechanisms of multiorgan failure to mitigating long-term sequelae after critical illness.

Tratamento prévio com adalimumabe reduz lesão pulmonar induzida por ventilação mecânica em um modelo experimental / Pretreatment with adalimumab reduces ventilator-induced lung injury in an experimental model

RESUMO Objetivo: Determinar se a administração de adalimumabe previamente à ventilação mecânica reduz a lesão pulmonar induzida por ventilação mecânica. Métodos: Randomizaram-se 18 ratos em três grupos submetidos à ventilação mecânica por 3 horas com uma fração inspirada de oxigênio de 0,40%. Os três grupos foram assim caracterizados: um grupo com baixo volume corrente (n = 6), no qual se utilizaram volume corrente de 8mL/kg e pressão expiratória final positiva de 5cmH2O; um grupo com alto volume corrente (n = 6), no qual se utilizaram volume corrente de 35mL/kg e pressão expiratória final positiva de zero; e um grupo pré-tratado com alto volume corrente (n = 6), no qual se administraram adalimumabe (100µg/kg) por via intraperitoneal 24 horas antes do início da ventilação mecânica, volume corrente de 35mL/kg e pressão expiratória final positiva de zero. Realizou-se ANOVA para comparação de dano histológico (com utilização de escores segundo o ATS 2010 Lung Injury Scoring System), edema pulmonar, complacência pulmonar, pressão parcial de oxigênio arterial e pressão arterial média entre os grupos. Resultados: Após 3 horas de ventilação, o escore médio de lesão histológica pulmonar foi mais elevado no grupo com alto volume corrente do que no grupo com baixo volume corrente (0,030 versus 0,0051; p = 0,003). O grupo com alto volume corrente demonstrou complacência pulmonar diminuída após 3 horas (p = 0,04) e hipoxemia (p = 0,018 versus controle). O grupo alto volume corrente tratado previamente teve melhora do escore histológico, principalmente devido à redução significante da infiltração leucocitária (p = 0,003). Conclusão: O exame histológico após 3 horas de ventilação lesiva revelou lesão pulmonar induzida por ventilação mecânica na ausência de modificações mensuráveis na mecânica pulmonar e na oxigenação; a administração de adalimumabe antes da ventilação mecânica diminuiu o edema pulmonar e o dano histológico.

ABSTRACT Objective: To determine whether adalimumab administration before mechanical ventilation reduces ventilator-induced lung injury (VILI). Methods: Eighteen rats randomized into 3 groups underwent mechanical ventilation for 3 hours with a fraction of inspired oxygen = 0.40% including a low tidal volume group (n = 6), where tidal volume = 8mL/kg and positive end-expiratory pressure = 5cmH2O; a high tidal volume group (n = 6), where tidal volume = 35mL/kg and positive end-expiratory pressure = 0; and a pretreated + high tidal volume group (n = 6) where adalimumab (100ug/kg) was administered intraperitoneally 24 hours before mechanical ventilation + tidal volume = 35mL/kg and positive end-expiratory pressure = 0. ANOVA was used to compare histological damage (ATS 2010 Lung Injury Scoring System), pulmonary edema, lung compliance, arterial partial pressure of oxygen, and mean arterial pressure among the groups. Results: After 3 hours of ventilation, the mean histological lung injury score was higher in the high tidal volume group than in the low tidal volume group (0.030 versus 0.0051, respectively, p = 0.003). The high tidal volume group showed diminished lung compliance at 3 hours (p = 0.04) and hypoxemia (p = 0,018 versus control). Pretreated HVt group had an improved histological score, mainly due to a significant reduction in leukocyte infiltration (p = 0.003). Conclusion: Histological examination after 3 hours of injurious ventilation revealed ventilator-induced lung injury in the absence of measurable changes in lung mechanics or oxygenation; administering adalimumab before mechanical ventilation reduced lung edema and histological damage.

Effects of nebulized antithrombin and heparin on inflammatory and coagulation alterations in an acute lung injury model in rats.

BACKGROUND: During acute respiratory distress syndrome, proinflammatory mediators inhibit natural anticoagulant factors, which alter the normal balance between coagulation and fibrinolysis leading to a procoagulant state. We hypothesize that pulmonary administration of anticoagulants might be beneficial to treat acute respiratory distress syndrome for their anticoagulant and antiinflammatory effects and reduce the risk of systemic bleeding. OBJECTIVES: Our aim is to study the effects of nebulized antithrombin (AT) and combined AT and heparin in an animal model of acute lung injury. METHODS: Acute lung injury was induced in rats by the intratracheal administration of hydrochloric acid and lipopolysaccharide. AT alone (500 IU/kg body weight) or combined with heparin (1000 IU/kg body weight) were nebulized after the injury. Control groups received saline instead. Blood, lung tissue, bronchoalveolar lavage, and alveolar macrophages (AM) isolated from bronchoalveolar lavage were collected after 48 hours and analyzed. RESULTS: Nebulized anticoagulant treatments reduced protein concentration in the lungs and decreased injury-mediated coagulation factors (tissue factor, plasminogen activator inhibitor-1, plasminogen, and fibrinogen degradation product) and inflammation (tumor necrosis factor α and interleukin 1ß) in the alveolar space without affecting systemic coagulation and no bleeding. AT alone reduced fibrin deposition and edema in the lungs. Heparin did not potentiate AT coagulant effect but promoted the reduction of macrophages infiltration into the alveolar compartment. Anticoagulants reduced nuclear factor-kB downstream effectors in AM. CONCLUSIONS: Nebulized AT and heparin attenuate lung injury through decreasing coagulation and inflammation without altering systemic coagulation and no bleeding. However, combined AT and heparin did not produce a synergistic effect.

Double Cycling During Mechanical Ventilation: Frequency, Mechanisms, and Physiologic Implications.

OBJECTIVES: Double cycling generates larger than expected tidal volumes that contribute to lung injury. We analyzed the incidence, mechanisms, and physiologic implications of double cycling during volume- and pressure-targeted mechanical ventilation in critically ill patients. DESIGN: Prospective, observational study. SETTING: Three general ICUs in Spain. PATIENTS: Sixty-seven continuously monitored adult patients undergoing volume control-continuous mandatory ventilation with constant flow, volume control-continuous mandatory ventilation with decelerated flow, or pressure control-continuous mandatory mechanical ventilation for longer than 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed 9,251 hours of mechanical ventilation corresponding to 9,694,573 breaths. Double cycling occurred in 0.6%. All patients had double cycling; however, the distribution of double cycling varied over time. The mean percentage (95% CI) of double cycling was higher in pressure control-continuous mandatory ventilation 0.54 (0.34-0.87) than in volume control-continuous mandatory ventilation with constant flow 0.27 (0.19-0.38) or volume control-continuous mandatory ventilation with decelerated flow 0.11 (0.06-0.20). Tidal volume in double-cycled breaths was higher in volume control-continuous mandatory ventilation with constant flow and volume control-continuous mandatory ventilation with decelerated flow than in pressure control-continuous mandatory ventilation. Double-cycled breaths were patient triggered in 65.4% and reverse triggered (diaphragmatic contraction stimulated by a previous passive ventilator breath) in 34.6% of cases; the difference was largest in volume control-continuous mandatory ventilation with decelerated flow (80.7% patient triggered and 19.3% reverse triggered). Peak pressure of the second stacked breath was highest in volume control-continuous mandatory ventilation with constant flow regardless of trigger type. Various physiologic factors, none mutually exclusive, were associated with double cycling. CONCLUSIONS: Double cycling is uncommon but occurs in all patients. Periods without double cycling alternate with periods with clusters of double cycling. The volume of the stacked breaths can double the set tidal volume in volume control-continuous mandatory ventilation with constant flow. Gas delivery must be tailored to neuroventilatory demand because interdependent ventilator setting-related physiologic factors can contribute to double cycling. One third of double-cycled breaths were reverse triggered, suggesting that repeated respiratory muscle activation after time-initiated ventilator breaths occurs more often than expected.

Nebulized Heparin Attenuates Pulmonary Coagulopathy and Inflammation through Alveolar Macrophages in a Rat Model of Acute Lung Injury.

Objective Alveolar macrophages play a key role in the development and resolution of acute respiratory distress syndrome (ARDS), modulating the inflammatory response and the coagulation cascade in lungs. Anti-coagulants may be helpful in the treatment of ARDS. This study investigated the effects of nebulized heparin on the role of alveolar macrophages in limiting lung coagulation and inflammatory response in an animal model of acute lung injury (ALI). Methods Rats were randomized to four experimental groups. In three groups, ALI was induced by intratracheal instillation of lipopolysaccharide (LPS) and heparin was nebulized at constant oxygen flow: the LPS/Hep group received nebulized heparin 4 and 8 hours after injury; the Hep/LPS/Hep group received nebulized heparin 30 minutes before and 4 and 8 hours after LPS-induced injury; the LPS/Sal group received nebulized saline 4 and 8 hours after injury. The control group received only saline. Animals were exsanguinated 24 hours after LPS instillation. Lung tissue, bronchoalveolar lavage fluid (BALF) and alveolar macrophages isolated from BALF were analysed. Results LPS increased protein concentration, oedema and neutrophils in BALF as well as procoagulant and proinflammatory mediators in lung tissue and alveolar macrophages. In lung tissue, nebulized heparin attenuated ALI through decreasing procoagulant (tissue factor, thrombin-anti-thrombin complexes, fibrin degradation products) and proinflammatory (interleukin 6, tumour necrosis factor alpha) pathways. In alveolar macrophages, nebulized heparin reduced expression of procoagulant genes and the effectors of transforming growth factor beta (Smad 2, Smad 3) and nuclear factor kappa B (p-selectin, CCL-2). Pre-treatment resulted in more pronounced attenuation. Conclusion Nebulized heparin reduced pulmonary coagulopathy and inflammation without producing systemic bleeding, partly by modulating alveolar macrophages.

Role of heparin in pulmonary cell populations in an in-vitro model of acute lung injury.

BACKGROUND: In the early stages of acute respiratory distress syndrome (ARDS), pro-inflammatory mediators inhibit natural anticoagulant factors and initiate an increase in procoagulant activity. Previous studies proved the beneficial effects of heparin in pulmonary coagulopathy, which derive from its anticoagulant and anti-inflammatory activities, although it is uncertain whether heparin works. Understanding the specific effect of unfractioned heparin on cell lung populations would be of interest to increase our knowledge about heparin pathways and to treat ARDS. METHODS: In the current study, the effect of heparin was assessed in primary human alveolar macrophages (hAM), alveolar type II cells (hATII), and fibroblasts (hF) that had been injured with LPS. RESULTS: Heparin did not produce any changes in the Smad/TGFß pathway, in any of the cell types evaluated. Heparin reduced the expression of pro-inflammatory markers (TNF-α and IL-6) in hAM and deactivated the NF-kß pathway in hATII, diminishing the expression of IRAK1 and MyD88 and their effectors, IL-6, MCP-1 and IL-8. CONCLUSIONS: The current study demonstrated that heparin significantly ameliorated the cells lung injury induced by LPS through the inhibition of pro-inflammatory cytokine expression in macrophages and the NF-kß pathway in alveolar cells. Our results suggested that a local pulmonary administration of heparin through nebulization may be able to reduce inflammation in the lung; however, further studies are needed to confirm this hypothesis.

Moderate Peep After Tracheal Lipopolysaccharide Instillation Prevents Inflammation and Modifies the Pattern of Brain Neuronal Activation.

BACKGROUND: Ventilatory strategy and specifically positive end-expiratory pressure (PEEP) can modulate the inflammatory response and pulmonary-to-systemic translocation of lipopolysaccharide (LPS). Both inflammation and ventilatory pattern may modify brain activation, possibly worsening the patient's outcome and resulting in cognitive sequelae. METHODS: We prospectively studied Sprague-Dawley rats randomly assigned to undergo 3 h mechanical ventilation with 7 mL/kg tidal ventilation and either 2 cmH2O or 7 cmH2O PEEP after intratracheal instillation of LPS or saline. Healthy nonventilated rats served as baseline. We analyzed lung mechanics, gas exchange, lung and plasma cytokine levels, lung apoptotic cells, and lung neutrophil infiltration. To evaluate brain neuronal activation, we counted c-Fos immunopositive cells in the retrosplenial cortex (RS), thalamus, supraoptic nucleus (SON), nucleus of the solitary tract (NTS), paraventricular nucleus (PVN), and central amygdala (CeA). RESULTS: LPS increased lung neutrophilic infiltration, lung and systemic MCP-1 levels, and neuronal activation in the CeA and NTS. LPS-instilled rats receiving 7 cmH2O PEEP had less lung and systemic inflammation and more c-Fos-immunopositive cells in the RS, SON, and thalamus than those receiving 2 cmH2O PEEP. Applying 7 cmH2O PEEP increased neuronal activation in the CeA and NTS in saline-instilled rats, but not in LPS-instilled rats. CONCLUSIONS: Moderate PEEP prevented lung and systemic inflammation secondary to intratracheal LPS instillation. PEEP also modified the neuronal activation pattern in the RS, SON, and thalamus. The relevance of these differential brain c-Fos expression patterns in neurocognitive outcomes should be explored.

Barrier-protective effects of activated protein C in human alveolar epithelial cells.

Acute lung injury (ALI) is a clinical manifestation of respiratory failure, caused by lung inflammation and the disruption of the alveolar-capillary barrier. Preservation of the physical integrity of the alveolar epithelial monolayer is of critical importance to prevent alveolar edema. Barrier integrity depends largely on the balance between physical forces on cell-cell and cell-matrix contacts, and this balance might be affected by alterations in the coagulation cascade in patients with ALI. We aimed to study the effects of activated protein C (APC) on mechanical tension and barrier integrity in human alveolar epithelial cells (A549) exposed to thrombin. Cells were pretreated for 3 h with APC (50 µg/ml) or vehicle (control). Subsequently, thrombin (50 nM) or medium was added to the cell culture. APC significantly reduced thrombin-induced cell monolayer permeability, cell stiffening, and cell contraction, measured by electrical impedance, optical magnetic twisting cytometry, and traction microscopy, respectively, suggesting a barrier-protective response. The dynamics of the barrier integrity was also assessed by western blotting and immunofluorescence analysis of the tight junction ZO-1. Thrombin resulted in more elongated ZO-1 aggregates at cell-cell interface areas and induced an increase in ZO-1 membrane protein content. APC attenuated the length of these ZO-1 aggregates and reduced the ZO-1 membrane protein levels induced by thrombin. In conclusion, pretreatment with APC reduced the disruption of barrier integrity induced by thrombin, thus contributing to alveolar epithelial barrier protection.

The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation.

PURPOSE: While our understanding of the pathogenesis and management of acute respiratory distress syndrome (ARDS) has improved over the past decade, estimates of its incidence have been controversial. The goal of this study was to examine ARDS incidence and outcome under current lung protective ventilatory support practices before and after the diagnosis of ARDS. METHODS: This was a 1-year prospective, multicenter, observational study in 13 geographical areas of Spain (serving a population of 3.55 million at least 18 years of age) between November 2008 and October 2009. Subjects comprised all consecutive patients meeting American-European Consensus Criteria for ARDS. Data on ventilatory management, gas exchange, hemodynamics, and organ dysfunction were collected. RESULTS: A total of 255 mechanically ventilated patients fulfilled the ARDS definition, representing an incidence of 7.2/100,000 population/year. Pneumonia and sepsis were the most common causes of ARDS. At the time of meeting ARDS criteria, mean PaO(2)/FiO(2) was 114 ± 40 mmHg, mean tidal volume was 7.2 ± 1.1 ml/kg predicted body weight, mean plateau pressure was 26 ± 5 cmH(2)O, and mean positive end-expiratory pressure (PEEP) was 9.3 ± 2.4 cmH(2)O. Overall ARDS intensive care unit (ICU) and hospital mortality was 42.7% (95%CI 37.7-47.8) and 47.8% (95%CI 42.8-53.0), respectively. CONCLUSIONS: This is the first study to prospectively estimate the ARDS incidence during the routine application of lung protective ventilation. Our findings support previous estimates in Europe and are an order of magnitude lower than those reported in the USA and Australia. Despite use of lung protective ventilation, overall ICU and hospital mortality of ARDS patients is still higher than 40%.

Injurious mechanical ventilation affects neuronal activation in ventilated rats.

INTRODUCTION: Survivors of critical illness often have significant long-term brain dysfunction, and routine clinical procedures like mechanical ventilation (MV) may affect long-term brain outcome. We aimed to investigate the effect of the increase of tidal volume (Vt) on brain activation in a rat model. METHODS: Male Sprague Dawley rats were randomized to three groups: 1) Basal: anesthetized unventilated animals, 2) low Vt (LVt): MV for three hours with Vt 8 ml/kg and zero positive end-expiratory pressure (ZEEP), and 3) high Vt (HVt) MV for three hours with Vt 30 ml/kg and ZEEP. We measured lung mechanics, mean arterial pressure (MAP), arterial blood gases, and plasma and lung levels of cytokines. We used immunohistochemistry to examine c-fos as a marker of neuronal activation. An additional group of spontaneously breathing rats was added to discriminate the effect of surgical procedure and anesthesia in the brain. RESULTS: After three hours on LVt, PaO2 decreased and PaCO2 increased significantly. MAP and compliance remained stable in MV groups. Systemic and pulmonary inflammation was higher in MV rats than in unventilated rats. Plasma TNFα was significantly higher in HVt than in LVt. Immunopositive cells to c-fos in the retrosplenial cortex and thalamus increased significantly in HVt rats but not in LVt or unventilated rats. CONCLUSIONS: MV promoted brain activation. The intensity of the response was higher in HVt animals, suggesting an iatrogenic effect of MV on the brain. These findings suggest that this novel cross-talking mechanism between the lung and the brain should be explored in patients undergoing MV.

Volumetric capnography in acute respiratory distress syndrome / Capnografia volumétrica na síndrome do desconforto respiratório agudo

Volumetric capnography is especially sensitive to disturbances affecting the efficiency of ventilation for gas exchange. Because lung homogeneity is a very fragile property, it is endangered in the majority of diseases that affect the airways, lung parenchyma, or alveolar microcirculation. Acute lung injury and acute respiratory distress syndrome can be conveniently monitored with volumetric capnography. The combination of two advanced technologies—airway flow monitoring and mainstream capnography—allows breath-by-breath bedside computerized determination of the physiological dead space, alveolar heterogeneity, and CO2 elimination. The use of volumetric capnography at the bedside can provide clinicians with important physiological and prognostic data, as well as allowing the effects of therapeutic interventions to be evaluated in critical ill patients receiving mechanical ventilation.

A capnografia volumétrica é especialmente sensível aos problemas que afetam a eficiência da ventilação para a troca gasosa. Uma vez que a homogeneidade do pulmão é uma propriedade muito frágil, a medida da capnografia é um desafio na maioria das doenças que comprometem as vias aéreas, o parênquima pulmonar e a microcirculação alveolar. A lesão pulmonar aguda e síndrome do desconforto respiratório agudo são situações que devem ser monitoradas com a capnografia volumétrica. Essa tecnologia avançada é uma combinação da medida do fluxo aéreo e a capnografia convencional, fazendo com que seja possível computar, à beira do leito, parâmetros como espaço morto, heterogeneidade alveolar e eliminação do CO2. O uso da capnografia volumétrica à beira do leito pode fornecer aos clínicos importantes informações fisiológicas e sobre o prognóstico, assim como seguir o efeito de intervenções terapêuticas nos doentes críticos ventilados mecanicamente.

Mechanical ventilation modulates Toll-like receptor signaling pathway in a sepsis-induced lung injury model.

BACKGROUND: Experimental and clinical studies on sepsis have demonstrated activation of the innate immune response following the initial host-bacterial interaction. In addition, mechanical ventilation (MV) can induce a pulmonary inflammatory response. How these two responses interact when present simultaneously remains to be elucidated. We hypothesized that MV modulates innate host response during sepsis by influencing Toll-like receptor (TLR) signaling. DESIGN: Prospective, randomized, controlled animal study. SUBJECTS: Male, septic Sprague-Dawley rats. INTERVENTIONS: Sepsis was induced by cecal ligation and perforation. At 18 h, surviving animals had the cecum removed and were randomized to spontaneous breathing or two strategies of MV for 4 h: high (20 ml/kg) tidal volume (V (T)) with no positive end-expiratory pressure (PEEP) versus low V (T) (6 ml/kg) plus 10 cmH(2)O PEEP. MEASUREMENTS AND MAIN RESULTS: Histological evaluation, TLR-2, TLR-4, inhibitory kappaB alpha (IkappaBalpha), interleukin-1 receptor-associated kinase-3 (IRAK-3) gene expression, protein levels and immunohistochemical lung localization, inflammatory cytokines gene expression, and protein serum concentrations were analyzed. MV with low V (T) plus PEEP attenuated sepsis-associated TLR-4 activation, and produced a significant decrease of IRAK-3 gene expression and protein levels, a significant increase of IkappaBalpha, and a decrease in lung gene expression and serum levels of cytokines. High-V (T) MV caused a significant increase of TLR-4 and IRAK-3 protein levels, lung and systemic cytokines, and mortality, and a significant decrease of IkappaBalpha. CONCLUSIONS: Our findings suggest a novel mechanism that could partially explain how MV modulates the innate immune response in the lung by interfering with cellular signaling pathways that are activated in response to pathogens.

A new automated method versus continuous positive airway pressure method for measuring pressure-volume curves in patients with acute lung injury.

OBJECTIVE: To compare pressure-volume (P-V) curves obtained with the Galileo ventilator with those obtained with the CPAP method in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). DESIGN: Prospective, observational study. SETTING: General critical care center. PATIENTS AND PARTICIPANTS: Patients with ALI/ARDS and receiving mechanical ventilation. INTERVENTIONS: Pressure-volume curves were obtained in random order with the CPAP technique and with the software PV Tool-2 (Galileo ventilator). MEASUREMENTS AND RESULTS: In ten consecutive patients, airway pressure was measured by a pressure transducer and changes in lung volume were measured by respiratory inductive plethysmography. P-V curves were fitted to a sigmoidal equation with a mean R (2) of 0.994 +/- 0.003. Intraclass correlation coefficients were all >0.75 (P < 0.001 at all pressure levels). Lower (LIP) and upper inflection (UIP), and deflation maximum curvature (PMC) points calculated from the fitted variables showed a good correlation between methods with intraclass correlation coefficients of 0.98 (0.92, 0.99), 0.92 (0.69, 0.98), and 0.97 (0.86, 0.98), respectively (P < 0.001 in all cases). Bias and limits of agreement for LIP (0.51 +/- 0.95 cmH(2)O; -1.36 to 2.38 cmH(2)O), UIP (0.53 +/- 1.52 cmH(2)O; -2.44 to 3.50 cmH(2)O), and PMC (-0.62 +/- 0.89 cmH(2)O; -2.35 to 1.12 cmH(2)O) obtained with the two methods in the same patient were clinically acceptable. No adverse effects were observed. CONCLUSION: The PV Tool-2 built into the Galileo ventilator is equivalent to the CPAP method for tracing static P-V curves of the respiratory system in critically ill patients receiving mechanical ventilation.

Effects of expiratory tracheal gas insufflation in patients with severe head trauma and acute lung injury.

OBJECTIVE: This study analyzed the effect of phasic tracheal gas insufflation at mid- to end-expiration in patients with severe head trauma and acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). DESIGN AND SETTING: A prospective interventional study in a 16-bed intensive care unit. PATIENTS: Seven patients with severe head trauma (Glasgow Coma Scale <9) and ALI/ARDS. INTERVENTIONS: Patients were ventilated in assist/control mode with a ventilatory strategy providing adequate oxygenation (PaO(2) >70 mmHg) and normocapnia (PaCO(2) between 35-40 mmHg). Mid to end expiratory tracheal gas insufflation at 8 l/min flow rate was delivered for 90 min while normocapnia was maintained by simultaneous reductions in tidal volume. We measured (hemodynamics, oxygenation, lung mechanics, and cerebral parameters) in basal situation and during and after tracheal insufflation. MEASUREMENTS AND RESULTS: Tracheal gas insufflation allowed a significant decrease in tidal volume from 9.1 to 7.2 ml/kg, with associated reduction in driving pressure (plateau pressure minus positive end-expiratory pressure, PEEP) from 18.1 to 13.2 cm H(2)O. Total PEEP increased from 9.3 to 12.7 cm H(2)O due to the generation of lung hyperinflation. Oxygenation improved slightly during tracheal gas insufflation, and this improvement remained after stopping tracheal insufflation. No changes in hemodynamic or cerebral parameters were observed during the study. CONCLUSIONS: In patients with severe head trauma and ALI receiving mechanical ventilation, expiratory tracheal gas insufflation allowed the targeted arterial PCO(2) level to be maintained together with a substantial reduction in tidal volume.

Unilateral lung injury.

Mechanical ventilation is a supportive lifesaving therapy that can potentially cause lung injury if periodic alveolar overdistension, or cyclic collapse, and reopening occur. The use of a low tidal volume with moderate to high positive end-expiratory pressure improves the survival of patients with acute lung injury and acute respiratory distress syndrome. Positioning the patient with the "good lung down" and using differential ventilation with selective positive end-expiratory pressure are the two currently accepted ventilatory strategies to be applied in patients with severe unilateral lung injury. However, both have serious limitations in clinical practice. Lung injury may be rather inhomogeneous-confined to one lung or preferentially distributed toward the dependent lung areas. In unilateral lung injury, ventilatory strategies that allow recruitment of injured lung and that avoid overdistension of uninjured lung parenchyma should be applied. Experimental studies have shown that the use of selective tracheal gas insufflation and partial liquid ventilation facilitates low tidal volume with appropriate gas exchange while reducing cyclic lung stretch and shear stresses. Further studies are needed to determine future applications of these therapies in humans.