RESUMO
Mechanical ventilation contributes to the morbidity and mortality of patients in intensive care, likely through the exacerbation and dissemination of inflammation. Despite the proximity of the pleural cavity to the lungs and exposure to physical forces, little attention has been paid to its potential as an inflammatory source during ventilation. Here, we investigate the pleural cavity as a novel site of inflammation during ventilator-induced lung injury. Mice were subjected to low or high tidal volume ventilation strategies for up to 3 hours. Ventilation with a high tidal volume significantly increased cytokine and total protein levels in BAL and pleural lavage fluid. In contrast, acid aspiration, explored as an alternative model of injury, only promoted intraalveolar inflammation, with no effect on the pleural space. Resident pleural macrophages demonstrated enhanced activation after injurious ventilation, including upregulated ICAM-1 and IL-1ß expression, and the release of extracellular vesicles. In vivo ventilation and in vitro stretch of pleural mesothelial cells promoted ATP secretion, whereas purinergic receptor inhibition substantially attenuated extracellular vesicles and cytokine levels in the pleural space. Finally, labeled protein rapidly translocated from the pleural cavity into the circulation during high tidal volume ventilation, to a significantly greater extent than that of protein translocation from the alveolar space. Overall, we conclude that injurious ventilation induces pleural cavity inflammation mediated through purinergic pathway signaling and likely enhances the dissemination of mediators into the vasculature. This previously unidentified consequence of mechanical ventilation potentially implicates the pleural space as a focus of research and novel avenue for intervention in critical care.
Assuntos
Camundongos Endogâmicos C57BL , Cavidade Pleural , Lesão Pulmonar Induzida por Ventilação Mecânica , Animais , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia , Cavidade Pleural/metabolismo , Cavidade Pleural/patologia , Inflamação/patologia , Inflamação/metabolismo , Camundongos , Respiração Artificial/efeitos adversos , Volume de Ventilação Pulmonar , Macrófagos/metabolismo , Macrófagos/patologia , Trifosfato de Adenosina/metabolismo , Vesículas Extracelulares/metabolismo , Masculino , Citocinas/metabolismo , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Interleucina-1beta/metabolismoRESUMO
Invasive mechanical ventilation is a key supportive therapy for patients on intensive care. There is increasing emphasis on personalised ventilation strategies. Clinical decision support systems (CDSS) have been developed to support this. We conducted a narrative review to assess evidence that could inform device implementation. A search was conducted in MEDLINE (Ovid) and EMBASE. Twenty-nine studies met the inclusion criteria. Role allocation is well described, with interprofessional collaboration dependent on culture, nurse:patient ratio, the use of protocols, and perception of responsibility. There were no descriptions of process measures, quality metrics, or clinical workflow. Nurse-led weaning is well-described, with factors grouped by patient, nurse, and system. Physician-led weaning is heterogenous, guided by subjective and objective information, and 'gestalt'. No studies explored decision-making with CDSS. Several explored facilitators and barriers to implementation, grouped by clinician (facilitators: confidence using CDSS, retaining decision-making ownership; barriers: undermining clinician's role, ambiguity moving off protocol), intervention (facilitators: user-friendly interface, ease of workflow integration, minimal training requirement; barriers: increased documentation time), and organisation (facilitators: system-level mandate; barriers: poor communication, inconsistent training, lack of technical support). One study described factors that support CDSS implementation. There are gaps in our understanding of ventilation practice. A coordinated approach grounded in implementation science is required to support CDSS implementation. Future research should describe factors that guide clinical decision-making throughout mechanical ventilation, with and without CDSS, map clinical workflow, and devise implementation toolkits. Novel research design analogous to a learning organisation, that considers the commercial aspects of device design, is required.
Assuntos
Tomada de Decisão Clínica , Sistemas de Apoio a Decisões Clínicas , Respiração Artificial , Humanos , Respiração Artificial/métodos , Tomada de Decisão Clínica/métodos , Cuidados Críticos/métodos , Cuidados Críticos/normas , Desmame do Respirador/métodosRESUMO
Rationale: Mechanical ventilation is a mainstay of intensive care but contributes to the mortality of patients through ventilator-induced lung injury. eCypA (extracellular CypA [cyclophilin A]) is an emerging inflammatory mediator and metalloproteinase inducer, and the gene responsible for its expression has recently been linked to coronavirus disease (COVID-19). Objectives: To explore the involvement of eCypA in the pathophysiology of ventilator-induced lung injury. Methods: Mice were ventilated with a low or high Vt for up to 3 hours, with or without blockade of eCypA signaling, and lung injury and inflammation were evaluated. Human primary alveolar epithelial cells were exposed to in vitro stretching to explore the cellular source of eCypA, and CypA concentrations were measured in BAL fluid from patients with acute respiratory distress syndrome to evaluate the clinical relevance. Measurements and Main Results: High-Vt ventilation in mice provoked a rapid increase in soluble CypA concentration in the alveolar space but not in plasma. In vivo ventilation and in vitro stretching experiments indicated the alveolar epithelium as the likely major source. In vivo blockade of eCypA signaling substantially attenuated physiological dysfunction, macrophage activation, and MMPs (matrix metalloproteinases). Finally, we found that patients with acute respiratory distress syndrome showed markedly elevated concentrations of eCypA within BAL fluid. Conclusions: CypA is upregulated within the lungs of injuriously ventilated mice (and critically ill patients), where it plays a significant role in lung injury. eCypA represents an exciting novel target for pharmacological intervention.
Assuntos
Anti-Inflamatórios/imunologia , Ciclofilina A/imunologia , Inflamação/imunologia , Respiração Artificial/efeitos adversos , Síndrome do Desconforto Respiratório/imunologia , Mucosa Respiratória/imunologia , Lesão Pulmonar Induzida por Ventilação Mecânica/imunologia , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologia , Animais , COVID-19/genética , COVID-19/fisiopatologia , Células Cultivadas/efeitos dos fármacos , Ciclofilina A/farmacologia , Humanos , Inflamação/fisiopatologia , Masculino , Camundongos , Modelos Animais , Síndrome do Desconforto Respiratório/fisiopatologia , SARS-CoV-2 , Lesão Pulmonar Induzida por Ventilação Mecânica/genéticaRESUMO
Rationale: Clinical and epidemiologic data in coronavirus disease (COVID-19) have accrued rapidly since the outbreak, but few address the underlying pathophysiology.Objectives: To ascertain the physiologic, hematologic, and imaging basis of lung injury in severe COVID-19 pneumonia.Methods: Clinical, physiologic, and laboratory data were collated. Radiologic (computed tomography (CT) pulmonary angiography [n = 39] and dual-energy CT [DECT, n = 20]) studies were evaluated: observers quantified CT patterns (including the extent of abnormal lung and the presence and extent of dilated peripheral vessels) and perfusion defects on DECT. Coagulation status was assessed using thromboelastography.Measurements and Results: In 39 consecutive patients (male:female, 32:7; mean age, 53 ± 10 yr [range, 29-79 yr]; Black and minority ethnic, n = 25 [64%]), there was a significant vascular perfusion abnormality and increased physiologic dead space (dynamic compliance, 33.7 ± 14.7 ml/cm H2O; Murray lung injury score, 3.14 ± 0.53; mean ventilatory ratios, 2.6 ± 0.8) with evidence of hypercoagulability and fibrinolytic "shutdown". The mean CT extent (±SD) of normally aerated lung, ground-glass opacification, and dense parenchymal opacification were 23.5 ± 16.7%, 36.3 ± 24.7%, and 42.7 ± 27.1%, respectively. Dilated peripheral vessels were present in 21/33 (63.6%) patients with at least two assessable lobes (including 10/21 [47.6%] with no evidence of acute pulmonary emboli). Perfusion defects on DECT (assessable in 18/20 [90%]) were present in all patients (wedge-shaped, n = 3; mottled, n = 9; mixed pattern, n = 6).Conclusions: Physiologic, hematologic, and imaging data show not only the presence of a hypercoagulable phenotype in severe COVID-19 pneumonia but also markedly impaired pulmonary perfusion likely caused by pulmonary angiopathy and thrombosis.
Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Pulmão/irrigação sanguínea , Pneumonia Viral/complicações , Circulação Pulmonar/fisiologia , Doenças Vasculares/etiologia , Adulto , Idoso , COVID-19 , Infecções por Coronavirus/epidemiologia , Feminino , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , SARS-CoV-2 , Tomografia Computadorizada por Raios X , Doenças Vasculares/diagnóstico , Doenças Vasculares/fisiopatologiaRESUMO
The COVID-19 pandemic has led to an unprecedented surge in hospitalised patients with viral pneumonia. The most severely affected patients are older men, individuals of black and Asian minority ethnicity and those with comorbidities. COVID-19 is also associated with an increased risk of hypercoagulability and venous thromboembolism. The overwhelming majority of patients admitted to hospital have respiratory failure and while most are managed on general wards, a sizeable proportion require intensive care support. The long-term complications of COVID-19 pneumonia are starting to emerge but data from previous coronavirus outbreaks such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) suggest that some patients will experience long-term respiratory complications of the infection. With the pattern of thoracic imaging abnormalities and growing clinical experience, it is envisaged that interstitial lung disease and pulmonary vascular disease are likely to be the most important respiratory complications. There is a need for a unified pathway for the respiratory follow-up of patients with COVID-19 balancing the delivery of high-quality clinical care with stretched National Health Service (NHS) resources. In this guidance document, we provide a suggested structure for the respiratory follow-up of patients with clinicoradiological confirmation of COVID-19 pneumonia. We define two separate algorithms integrating disease severity, likelihood of long-term respiratory complications and functional capacity on discharge. To mitigate NHS pressures, virtual solutions have been embedded within the pathway as has safety netting of patients whose clinical trajectory deviates from the pathway. For all patients, we suggest a holistic package of care to address breathlessness, anxiety, oxygen requirement, palliative care and rehabilitation.
Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/terapia , Pneumopatias/terapia , Pneumonia Viral/complicações , Pneumonia Viral/terapia , Transtornos Respiratórios/terapia , Algoritmos , COVID-19 , Infecções por Coronavirus/diagnóstico , Humanos , Pneumopatias/diagnóstico , Pneumopatias/virologia , Pandemias , Pneumonia Viral/diagnóstico , Transtornos Respiratórios/diagnóstico , Transtornos Respiratórios/virologia , SARS-CoV-2RESUMO
OBJECTIVES: To ascertain: 1) the frequency of thrombocytopenia and heparin-induced thrombocytopenia; 2) positive predictive value of the Pretest Probability Score in identifying heparin-induced thrombocytopenia; and 3) clinical outcome of heparin-induced thrombocytopenia in adult patients receiving venovenous- or venoarterial-extracorporeal membrane oxygenation, compared with cardiopulmonary bypass. DESIGN: A single-center, retrospective, observational cohort study from January 2016 to April 2018. SETTING: Tertiary referral center for cardiac and respiratory failure. PATIENTS: Patients who received extracorporeal membrane oxygenation for more than 48 hours or had cardiopulmonary bypass during specified period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical and laboratory data were collected retrospectively. Pretest Probability Score and heparin-induced thrombocytopenia testing results were collected prospectively. Mean age (± SD) of the extracorporeal membrane oxygenation and cardiopulmonary bypass cohorts was 45.4 (± 15.6) and 64.9 (± 13), respectively (p < 0.00001). Median duration of cardiopulmonary bypass was 4.6 hours (2-16.5 hr) compared with 170.4 hours (70-1,008 hr) on extracorporeal membrane oxygenation. Moderate and severe thrombocytopenia were more common in extracorporeal membrane oxygenation compared with cardiopulmonary bypass throughout (p < 0.0001). Thrombocytopenia increased in cardiopulmonary bypass patients on day 2 but was normal in 83% compared with 42.3% of extracorporeal membrane oxygenation patients at day 10. Patients on extracorporeal membrane oxygenation also followed a similar pattern of platelet recovery following cessation of extracorporeal membrane oxygenation. The frequency of heparin-induced thrombocytopenia in extracorporeal membrane oxygenation and cardiopulmonary bypass were 6.4% (19/298) and 0.6% (18/2,998), respectively (p < 0.0001). There was no difference in prevalence of heparin-induced thrombocytopenia in patients on venovenous-extracorporeal membrane oxygenation (8/156, 5.1%) versus venoarterial-extracorporeal membrane oxygenation (11/142, 7.7%) (p = 0.47). The positive predictive value of the Pretest Probability Score in identifying heparin-induced thrombocytopenia in patients post cardiopulmonary bypass and on extracorporeal membrane oxygenation was 56.25% (18/32) and 25% (15/60), respectively. Mortality was not different with (6/19, 31.6%) or without (89/279, 32.2%) heparin-induced thrombocytopenia in patients on extracorporeal membrane oxygenation (p = 0.79). CONCLUSIONS: Thrombocytopenia is already common at extracorporeal membrane oxygenation initiation. Heparin-induced thrombocytopenia is more frequent in both venovenous- and venoarterial-extracorporeal membrane oxygenation compared with cardiopulmonary bypass. Positive predictive value of Pretest Probability Score in identifying heparin-induced thrombocytopenia was lower in extracorporeal membrane oxygenation patients. Heparin-induced thrombocytopenia had no effect on mortality.
Assuntos
Anticoagulantes/efeitos adversos , Ponte Cardiopulmonar/efeitos adversos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Heparina/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
Intracranial hemorrhage (ICH) is a serious complication in patients receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO) and is associated with high mortality. It is unknown whether ICH may be a consequence of the ECMO or of an underlying disease. The authors first aimed to assess the incidence of ICH at initiation and during the course of VV-ECMO and its associated mortality. The second aim was to identify clinical and laboratory measures that could predict the development of ICH in severe respiratory failure. Data were collected from a total number of 165 patients receiving VV-ECMO from January, 2012 to December, 2016 in a single tertiary center and treated according to a single protocol. Only patients who had a brain computed tomography within 24 hours of initiation of ECMO (n = 149) were included for analysis. The prevalence and incidence of ICH at initiation and during the course of VV-ECMO (at median 9 days) were 10.7% (16/149) and 5.2% (7/133), respectively. Thrombocytopenia and reduced creatinine clearance (CrCL) were independently associated with increased risk of ICH on admission; odds ratio (95% confidence interval): 22.6 (2.6-99.5), and 10.8 (5.6-16.2). Only 30-day (not 180-day) mortality was significantly higher in patients with ICH on admission versus those without (37.5% [6/16] vs 16.4% [22/133]; p = 0.03 and 43.7% [7/16] vs 26.3% [35/133]; p = 0.15, respectively). Reduced CrCL and thrombocytopenia were associated with ICH at initiation of VV-ECMO. The higher incidence of ICH at initiation suggests it is more closely related to the severity of the underlying lung injury than to the VV-ECMO itself. ICH at VV-ECMO initiation was associated with early mortality.
Assuntos
Oxigenação por Membrana Extracorpórea/efeitos adversos , Hemorragias Intracranianas/mortalidade , Insuficiência Respiratória/complicações , Humanos , Hemorragias Intracranianas/patologia , Taxa de SobrevidaRESUMO
OBJECTIVES: Extracorporeal circulatory support is a life-saving technique, and its use is increasing in acute coronary syndromes. A meta-analysis on pooled event rate of short-term mortality and complications of acute coronary syndrome patients treated with extracorporeal circulatory support was performed. DATA SOURCES: Articles were searched in MEDLINE, Cochrane Library, Google Scholar, and Biomed Central. STUDY SELECTION: Inclusion criteria were observational studies on acute coronary syndrome patients treated with extracorporeal circulatory support. Primary outcome was short-term mortality. Secondary outcomes were extracorporeal circulatory support-related complications, causes of death, long-term mortality, and bridge therapy. DATA EXTRACTION: Sixteen articles were selected. Data about clinical characteristics, acute coronary syndrome diagnosis and treatment, extracorporeal circulatory support setting, outcome definitions, and event rate were retrieved from the articles. Random effect meta-analytic pooling was performed reporting results as a summary point estimate and 95% CI. DATA SYNTHESIS: A total of 739 patients were included (mean age, 59.8 ± 2.9). The event rate of short-term mortality was 58% (95% CI, 51-64%), 6-month mortality was affecting 24% (95% CI, 5-63%) of 1-month survivors, and 1-year mortality 17% (95% CI, 6-40%) of 6-month survivors. The event rates of extracorporeal circulatory support-related complications were acute renal failure 41%, bleeding 25%, neurologic damage in survivors 21%, sepsis/infections 21%, and leg ischemia 12%. Between causes of death, multiple organ failure and brain death affected respectively 40% and 27% of patients. Bridge to ventricular assistance device was offered to 14% of patients, and 7% received a transplant. CONCLUSIONS: There is still a high rate of short-term mortality and complications in acute coronary syndrome patients treated with extracorporeal circulatory support. New studies are needed to optimize and standardize extracorporeal circulatory support.
Assuntos
Síndrome Coronariana Aguda/mortalidade , Síndrome Coronariana Aguda/terapia , Oxigenação por Membrana Extracorpórea/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Oxigenação por Membrana Extracorpórea/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Obesity has a complex impact on acute respiratory distress syndrome patients, being associated with increased likelihood of developing the syndrome but reduced likelihood of dying. We propose that such observations are potentially explained by a model in which obesity influences the iatrogenic injury that occurs subsequent to intensive care admission. This study therefore investigated whether fat feeding protected mice from ventilator-induced lung injury. DESIGN: In vivo study. SETTING: University research laboratory. SUBJECTS: Wild-type C57Bl/6 mice or tumor necrosis factor receptor 2 knockout mice, either fed a high-fat diet for 12-14 weeks, or age-matched lean controls. INTERVENTIONS: Anesthetized mice were ventilated with injurious high tidal volume ventilation for periods up to 180 minutes. MEASUREMENTS AND MAIN RESULTS: Fat-fed mice showed clear attenuation of ventilator-induced lung injury in terms of respiratory mechanics, blood gases, and pulmonary edema. Leukocyte recruitment and activation within the lungs were not significantly attenuated nor were a host of circulating or intra-alveolar inflammatory cytokines. However, intra-alveolar matrix metalloproteinase activity and levels of the matrix metalloproteinase cleavage product soluble receptor for advanced glycation end products were significantly attenuated in fat-fed mice. This was associated with reduced stretch-induced CD147 expression on lung epithelial cells. CONCLUSIONS: Consumption of a high-fat diet protects mice from ventilator-induced lung injury in a manner independent of neutrophil recruitment, which we postulate instead arises through blunted up-regulation of CD147 expression and subsequent activation of intra-alveolar matrix metalloproteinases. These findings may open avenues for therapeutic manipulation in acute respiratory distress syndrome and could have implications for understanding the pathogenesis of lung disease in obese patients.
Assuntos
Dieta Hiperlipídica , Obesidade/fisiopatologia , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controle , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologia , Animais , Gasometria , Citocinas/metabolismo , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/fisiologia , Neutrófilos/metabolismo , Obesidade/epidemiologia , Edema Pulmonar/fisiopatologia , Edema Pulmonar/prevenção & controle , Mecânica Respiratória , Volume de Ventilação Pulmonar , Lesão Pulmonar Induzida por Ventilação Mecânica/epidemiologiaAssuntos
COVID-19 , Neovascularização Patológica , Circulação Pulmonar , Diagnóstico por Imagem , Humanos , Pulmão , SARS-CoV-2Assuntos
COVID-19/terapia , Hemodinâmica/efeitos dos fármacos , Óxido Nítrico/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Vasodilatadores/uso terapêutico , Administração por Inalação , COVID-19/complicações , Humanos , Hipercapnia/prevenção & controle , Hipóxia/prevenção & controle , Óxido Nítrico/administração & dosagem , Síndrome do Desconforto Respiratório/etiologia , SARS-CoV-2 , Resultado do Tratamento , Vasodilatadores/administração & dosagemRESUMO
The lung has a unique structure consisting of three functionally different compartments (alveolar, interstitial, and vascular) situated in an extreme proximity. Current methods to localize lung leukocytes using bronchoalveolar lavage and/or lung perfusion have significant limitations for determination of location and phenotype of leukocytes. Here we present a novel method using in vivo antibody labeling to enable accurate compartmental localization/quantification and phenotyping of mouse lung leukocytes. Anesthetized C57BL/6 mice received combined in vivo intravenous and intratracheal labeling with fluorophore-conjugated anti-CD45 antibodies, and lung single-cell suspensions were analyzed by flow cytometry. The combined in vivo intravenous and intratracheal CD45 labeling enabled robust separation of the alveolar, interstitial, and vascular compartments of the lung. In naive mice, the alveolar compartment consisted predominantly of resident alveolar macrophages. The interstitial compartment, gated by events negative for both intratracheal and intravenous CD45 staining, showed two conventional dendritic cell populations, as well as a Ly6C(lo) monocyte population. Expression levels of MHCII on these interstitial monocytes were much higher than on the vascular Ly6C(lo) monocyte populations. In mice exposed to acid aspiration-induced lung injury, this protocol also clearly distinguished the three lung compartments showing the dynamic trafficking of neutrophils and exudative monocytes across the lung compartments during inflammation and resolution. This simple in vivo dual-labeling technique substantially increases the accuracy and depth of lung flow cytometric analysis, facilitates a more comprehensive examination of lung leukocyte pools, and enables the investigation of previously poorly defined "interstitial" leukocyte populations during models of inflammatory lung diseases.
Assuntos
Leucócitos , Pulmão , Infiltração de Neutrófilos , Pneumonia Aspirativa , Coloração e Rotulagem/métodos , Animais , Anticorpos/farmacologia , Citometria de Fluxo/métodos , Antígenos Comuns de Leucócito/metabolismo , Leucócitos/metabolismo , Leucócitos/patologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Pneumonia Aspirativa/metabolismo , Pneumonia Aspirativa/patologiaAssuntos
Anticoagulantes/administração & dosagem , Betacoronavirus/metabolismo , Infecções por Coronavirus , Pandemias , Ácidos Pipecólicos/administração & dosagem , Pneumonia Viral , Trombofilia , Doença Aguda , Adulto , Antitrombinas , Arginina/análogos & derivados , COVID-19 , Estudos de Coortes , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/etiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/etiologia , SARS-CoV-2 , Índice de Gravidade de Doença , Sulfonamidas , Trombofilia/sangue , Trombofilia/complicações , Trombofilia/epidemiologiaRESUMO
The ability of the alveolar epithelium to prevent and resolve pulmonary edema is a crucial determinant of morbidity and mortality in acute lung injury (ALI). TNF has been implicated in ALI pathogenesis, but the precise mechanisms remain undetermined. We evaluated the role of TNF signaling in pulmonary edema formation in a clinically relevant mouse model of ALI induced by acid aspiration and investigated the effects of TNF p55 receptor deletion, caspase-8 inhibition, and alveolar macrophage depletion on alveolar epithelial function. We found that TNF plays a central role in the development of pulmonary edema in ALI through activation of p55-mediated death signaling, rather than through previously well-characterized p55-mediated proinflammatory signaling. Acid aspiration produced pulmonary edema with significant alveolar epithelial dysfunction, as determined by alveolar fluid clearance (AFC) and intra-alveolar levels of the receptor for advanced glycation end-products. The impairment of AFC was strongly correlated with lung caspase-8 activation, which was localized to type 1 alveolar epithelial cells by flow cytometric analysis. p55-deficient mice displayed markedly attenuated injury, with improved AFC and reduced caspase-8 activity but no differences in downstream cytokine/chemokine production and neutrophil recruitment. Caspase-8 inhibition significantly improved AFC and oxygenation, whereas depletion of alveolar macrophages attenuated epithelial dysfunction with reduced TNF production and caspase-8 activity. These results provide in vivo evidence for a novel role for TNF p55 receptor-mediated caspase-8 signaling, without substantial apoptotic cell death, in triggering alveolar epithelial dysfunction and determining the early pathophysiology of ALI. Blockade of TNF-induced death signaling may provide an effective early-phase strategy for ALI.
Assuntos
Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/patologia , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/toxicidade , Lesão Pulmonar Aguda/metabolismo , Animais , Caspase 8/toxicidade , Morte Celular/imunologia , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/toxicidade , Macrófagos Alveolares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Edema Pulmonar/imunologia , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Receptores Tipo I de Fatores de Necrose Tumoral/deficiência , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/toxicidade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
IMPORTANCE: Most studies on acute respiratory distress syndrome (ARDS) group patients by severity based on their initial degree of hypoxemia. However, this grouping has limitations, including inconsistent hypoxemia trajectories and outcomes. OBJECTIVES: This study explores the benefits of grouping patients by resolver status based on their hypoxemia progression over the first 7 days. DESIGN SETTING AND PARTICIPANTS: This is an observational study from a large single-center database. Medical Information Mart for Intensive Care (MIMIC)-IV and MIMIC Chest X-ray JPEG databases were used. Mechanically ventilated patients that met the Berlin ARDS criteria were included. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of hypoxemia resolvers vs. nonresolvers in non-COVID-19 ARDS patients. Nonresolvers were defined as those whose hypoxemia worsened or remained moderate or severe over the first 7 days. Secondary outcomes included baseline admission characteristics, initial blood gases and ventilation settings, length of invasive mechanical ventilation, length of ICU stay, and ICU survival rates across resolver groups. RESULTS: A total of 894 ICU admissions were included in the study. Of these, 33.9% were hypoxemia nonresolvers. The resolver groups showed no significant difference in age, body mass index, comorbidities, or Charlson score. There was no significant difference in the percentage of those with initial severe hypoxemia between the two groups (8.1% vs. 9.2%; p = 0.126). The initial Pao2/Fio2 ratio did not significantly increase the odds ratio (OR) of being a nonresolver (OR, 0.84; 95% CI, 0.65-1.10). Nonresolver mortality was 61.4%, comparable to the survival rates seen in nonresolvers in a previous large COVID-19 ARDS study. CONCLUSIONS AND RELEVANCE: Our study shows that resolver status is a valuable grouping in ARDS. It has significant advantages over grouping by initial degree of hypoxemia, including better mapping of trajectory and comparable outcomes across other studies. While it may offer insights into disease-specific associations, future studies should include resolver status analysis for more definitive conclusions.
RESUMO
BACKGROUND: Diaphragmatic dysfunction is well documented in patients receiving mechanical ventilation. Inspiratory muscle training (IMT) has been used to facilitate weaning by strengthening the inspiratory muscles, yet the optimal approach remains uncertain. Whilst some data on the metabolic response to whole body exercise in critical care exist, the metabolic response to IMT in critical care is yet to be investigated. This study aimed to quantify the metabolic response to IMT in critical care and its relationship to physiological variables. METHODS: We conducted a prospective observational study on mechanically ventilated patients ventilated for ≥ 72 h and able to participate in IMT in a medical, surgical, and cardiothoracic intensive care unit. 76 measurements were taken on 26 patients performing IMT using an inspiratory threshold loading device at 4 cmH2O, and at 30, 50 and 80% of their negative inspiratory force (NIF). Oxygen consumption (VO2) was measured continuously using indirect calorimetry. RESULTS: First session mean (SD) VO2 was 276 (86) ml/min at baseline, significantly increasing to 321 (93) ml/min, 333 (92) ml/min, 351(101) ml/min and 388 (98) ml/min after IMT at 4 cmH2O and 30, 50 and 80% NIF, respectively (p = 0.003). Post hoc comparisons revealed significant differences in VO2 between baseline and 50% NIF and baseline and 80% NIF (p = 0.048 and p = 0.001, respectively). VO2 increased by 9.3 ml/min for every 1 cmH2O increase in inspiratory load from IMT. Every increase in P/F ratio of 1 decreased the intercept VO2 by 0.41 ml/min (CI - 0.58 to - 0.24 p < 0.001). NIF had a significant effect on the intercept and slope, with every 1 cmH2O increase in NIF increasing intercept VO2 by 3.28 ml/min (CI 1.98-4.59 p < 0.001) and decreasing the dose-response slope by 0.15 ml/min/cmH2O (CI - 0.24 to - 0.05 p = 0.002). CONCLUSIONS: IMT causes a significant load-dependent increase in VO2. P/F ratio and NIF impact baseline VO2. The dose-response relationship of the applied respiratory load during IMT is modulated by respiratory strength. These data may offer a novel approach to prescription of IMT. TAKE HOME MESSAGE: The optimal approach to IMT in ICU is uncertain; we measured VO2 at different applied respiratory loads to assess whether VO2 increased proportionally with load and found VO2 increased by 9.3 ml/min for every 1 cmH2O increase in inspiratory load from IMT. Baseline NIF has a significant effect on the intercept and slope, participants with a higher baseline NIF have a higher resting VO2 but a less pronounced increase in VO2 as the inspiratory load increases; this may offer a novel approach to IMT prescription. Trial registration ClinicalTrials.gov, registration number: NCT05101850. Registered on 28 September 2021, https://clinicaltrials.gov/ct2/show/NCT05101850.
RESUMO
BACKGROUND: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. METHODS: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2-7 months after hospital discharge and a later time point 10-14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). FINDINGS: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4-6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5-8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (-19%; 95% CI -20 to -16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18-39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27-41% of this effect. INTERPRETATION: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition. FUNDING: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council.
Assuntos
COVID-19 , Transtornos do Sono-Vigília , Humanos , COVID-19/complicações , COVID-19/epidemiologia , Estudos Prospectivos , Hospitalização , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/etiologia , Sono/fisiologia , Hospitais , Reino Unido/epidemiologia , PulmãoRESUMO
Previous animal models of acute lung injury (ALI) are limited as they only reproduce part of the complex pathobiology of clinical ALI. Here we develop a translational mouse model of ALI, which not only reflects the major clinical and pathological features but also enables investigation into ALI resolution. Anaesthetised mice underwent orotracheal instillation of hydrochloric acid. During the immediate period after instillation, mice were carefully maintained with supplemental oxygen to avoid mortality. At specified time-points, lung injury was assessed by analysis of blood gases, respiratory mechanics, bronchoalveolar lavage fluid, alveolar fluid clearance and lung histology. Animals exhibited significant weight loss, decreased oxygenation, increased respiratory elastance and pulmonary inflammation (intra-alveolar leukocyte influx/cytokine levels and histological injury scores). Moreover, mice displayed alveolar-capillary barrier dysfunction/epithelial injury as reflected by increased alveolar protein, lung wet/dry weight ratio and soluble receptor for advanced glycation end-products, as well as reduced alveolar fluid clearance. These injury parameters peaked between days 1 and 3, followed by almost complete recovery over days 5-10. Histology showed evidence of fibrosis on day 10. The results indicate that this resolving model of acid aspiration represents a powerful experimental tool to investigate the injurious, inflammatory, fibrotic, and resolving and reparative processes of ALI.
Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Modelos Animais de Doenças , Ácido Clorídrico/toxicidade , Pneumonia/induzido quimicamente , Pesquisa Translacional Biomédica , Lesão Pulmonar Aguda/terapia , Animais , Líquido da Lavagem Broncoalveolar/química , Citocinas/análise , Pulmão/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos , Oxigênio/sangue , Oxigenoterapia , Pneumonia/terapia , Fibrose Pulmonar/induzido quimicamente , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/análise , Recuperação de Função Fisiológica , Testes de Função RespiratóriaRESUMO
OBJECTIVE: Ventilator-induced lung injury is a crucial determinant of the outcome of mechanically ventilated patients. Increasing numbers of mouse studies have identified numerous pathways and mediators that are modulated by ventilation, but it is conceptually difficult to reconcile these into a single paradigm. There is substantial variability in tidal volumes used in these studies and no certainty about the pathophysiology that such varied models actually represent. This study was designed to investigate whether ventilation strategies ranging from "very high" to more "clinically relevant" tidal volumes induce similar pathophysiologies in healthy mice or represent distinct entities. DESIGN: In vivo study. SETTING: University research laboratory. SUBJECTS: C57/Bl6 mice. INTERVENTIONS: Anesthetized mice were ventilated with various tidal volumes up to 40 mL/kg. MEASUREMENTS AND MAIN RESULTS: Respiratory system compliance and arterial blood gases were used to evaluate physiological variables of injury. Lung wet:dry weight ratio, lavage fluid protein, and cytokines were used to assess pulmonary edema and inflammation. All ventilation strategies induced changes in respiratory system compliance, although the pattern of change was unique for each strategy. Ventilation with 10 mL/kg and 40 mL/kg also induced decreases in arterial PO2 and blood pressure. Any physiological changes induced during the 10, 20, and 30 mL/kg strategies were largely reversed by recruitment maneuvers at the end of the protocol. Markers of pulmonary edema and inflammation indicated that only 40 mL/kg induced substantial increases in both, consistent with development of lung injury. CONCLUSIONS: Tidal volumes up to 20 mL/kg are unlikely to induce substantial lung overstretch in models using healthy, young mice. Signs of injury/inflammation using such models are likely to result from other factors, particularly alveolar derecruitment and atelectasis. The results of such studies may need to be reevaluated before clinical relevance can be accurately determined.