Citoesqueleto e mecanotransdução na fisiopatologia da lesão pulmonar induzida por ventilador Cytoskeleton and mechanotransduction in the pathophysiology of ventilator-induced lung injury

A ventilação mecânica é uma terapia importante, mas pode resultar em complicações. Uma das mais relevantes é a lesão pulmonar induzida por ventilador. Devido à hiperdistensão alveolar, o pulmão inicia um processo inflamatório, com infiltrado neutrofílico, formação de membrana hialina, fibrogênese e prejuízo de troca gasosa. Nesse processo, a mecanotransdução da hiperdistensão celular é mediada através do citoesqueleto da célula e de suas interações com a matriz extracelular e com as células vizinhas, de modo que o estímulo mecânico da ventilação se traduz em sinalização bioquímica intracelular, desencadeando ativação endotelial, permeabilidade vascular pulmonar, quimiotaxia leucocitária, produção de citocinas e, possivelmente, lesão de órgãos à distância. Estudos clínicos demonstram essa relação entre distensão pulmonar e mortalidade em pacientes com lesão pulmonar induzida por ventilador. Entretanto, apesar de o citoesqueleto ter um papel fundamental na patogênese da lesão pulmonar induzida por ventilador, a literatura carece de estudos utilizando modelos in vivo sobre as alterações do citoesqueleto e de suas proteínas associadas durante esse processo patológico.<br>Although mechanical ventilation is an important therapy, it can result in complications. One major complication is ventilator-induced lung injury, which is caused by alveolar hyperdistension, leading to an inflammatory process, with neutrophilic infiltration, hyaline membrane formation, fibrogenesis and impaired gas exchange. In this process, cellular mechanotransduction of the overstretching stimulus is mediated by means of the cytoskeleton and its cell-cell and cell-extracellular matrix interactions, in such a way that the mechanical stimulus of ventilation is translated into an intracellular biochemical signal, inducing endothelial activation, pulmonary vascular permeability, leukocyte chemotaxis, cytokine production and, possibly, distal organ failure. Clinical studies have shown the relationship between pulmonary distension and mortality in patients with ventilator-induced lung injury. However, although the cytoskeleton plays a fundamental role in the pathogenesis of ventilator-induced lung injury, there have been few in vivo studies of alterations in the cytoskeleton and in cytoskeleton-associated proteins during this pathological process

Análise da celularidade do lavado bronco-alveolar em pacientes submetidos à revascularização do miocárdio com circulação extracorpórea: relato de três casos Análisis de la celularidad del lavado bronco-alveolar en pacientes sometidos a revascularización del miocardio con circulación extracorpórea: relato de tres casos Broncho-alveolar lavage cellularity in patients submitted to myocardial revascularization with cardiopulmonary bypass: three case reports

JUSTIFICATIVA E OBJETIVOS: A circulação extracorpórea (CEC) é um dos principais determinantes da resposta inflamatória sistêmica (SIRS) em cirurgia cardíaca. Demonstrou-se em modelo experimental que a CEC pode levar a aumento na produção das citocinas. No intuito de avaliar a ativação celular no pulmão após CEC, foi estudada a celularidade no lavado bronco-alveolar (LBA) em pacientes submetidos à cirurgia de revascularização do miocárdio (RM) com CEC. RELATO DOS CASOS: Foram estudados, prospectivamente, três pacientes adultos submetidos à RM com CEC. Após indução de anestesia geral e intubação traqueal, a ventilação mecânica foi realizada com sistema circular valvular; exceto durante a CEC, o volume corrente foi mantido entre 8 e 10 mL.kg-1 com O2 e ar, numa proporção de 50%. Antes do despinçamento da aorta, foram realizadas insuflações pulmonares com pressão de 40 cmH2O e coletadas duas amostras de LBA de cada paciente, no início da intervenção cirúrgica e ao final do procedimento, após a reversão da anticoagulação. Após a infusão de 60 mL de solução fisiológica a 0,9% pelo canal do broncofibroscópio, foi aspirado o LBA, sendo o material encaminhado para processamento laboratorial. A análise evidenciou aumento do número total de células, em média, de 0,6.10(6) cél.dL-1 para 6,8.10(6) cél.dL-1 com aumento de neutrófilos de 0,8% para 4,7%; 0,6% para 6,2% e 0,5% para 5,3% em cada paciente, respectivamente. Observou-se na lâmina o aumento de celularidade no fluido pulmonar após a CEC. CONCLUSÕES: O influxo leucocitário é descrito em diversas condições clínicas pulmonares inflamatórias, como na síndrome da angústia respiratória do adulto. Sabe-se que a CEC está relacionada com a inflamação sistêmica e pulmonar, demonstrando aumento do número de células após a CEC com o predomínio de macrófagos.<br>JUSTIFICATIVA Y OBJETIVOS: La circulación extracorpórea (CEC) es uno de los principales determinantes de la respuesta inflamatoria sistémica (SIRS) en cirugía cardiaca. Quedó demostrado en modelo experimental que la CEC puede llevar a un aumento en la producción de las citocinas. Con el objetivo de evaluar la activación celular en el pulmón después del CEC, se estudió la celularidad en el lavado bronco-alveolar (LBA) en pacientes sometidos a la cirugía de revascularización del miocardio (RM) con CEC. RELATO DE LOS CASOS: Se estudiaron, como sondeo, tres pacientes adultos sometidos a la RM con CEC. Después de la inducción de anestesia general e intubación traqueal, la ventilación mecánica se realizó con sistema circular valvular; excepto durante la CEC, el volumen corriente se mantuvo entre 8 y 10 mL.kg-1 con O2 y aire, en una proporción de 50%. Antes del despinzamiento de la aorta, se realizaron insuflaciones pulmonares con presión de 40 cmH2O y recolectadas dos muestras de LBA de cada paciente, al comienzo de la intervención quirúrgica y al final del procedimiento, después de la reversión de la anticoagulación. Después de la infusión de 60 mL de solución fisiológica a 0,9% por el canal del broncofibroscopio, se aspiró el LBA, siendo el material enviado al laboratorio. El análisis mostró un aumento del número total de células, como promedio, de 0,6.10(6) cél.dL-1 para 6,8.10(6) cél.dL-1 con aumento de neutrófilos de 0,8% para 4,7%; 0,6% para 6,2% y 0,5% para 5,3% en cada paciente, respectivamente. Se observó en la lámina el aumento de celularidad en el fluido pulmonar después de la CEC. CONCLUSIONES: El influjo de leucocitos se describe en diversas condiciones clínicas pulmonares inflamatorias como en el síndrome de la angustia respiratoria del adulto. Se conoce que la CEC está relacionada con la inflamación sistémica y pulmonar, demostrando aumento del número de células después de la CEC con el predominio de macrófagos.<br>BACKGROUND AND OBJECTIVES: Cardiopulmonary bypass (CPB) is a primary determinant of systemic inflammatory response (SIRS) during cardiac procedures. It has been shown in an experimental model that CPB may increase cytokine production. This study aimed at evaluating post-CPB lung cell activation by investigating broncho-alveolar lavage (BAL) cellularity in patients submitted to myocardial revascularization (MR) with CPB. CASE REPORTS: Participated in this prospective study 3 adult patients submitted to MR with CPB. After general anesthesia induction and tracheal intubation, mechanical ventilation was installed with valve circle system; except during CPB, tidal volume was maintained between 8 and 10 mL.kg-1 with 50% O2 and air. Before aortic unclamping, 40 cmH2O pulmonary inflations were performed. Two BAL samples were collected from all patients at beginning and end of procedure, after anticoagulation reversion. BAL was aspired after 60 mL infusion of 0.9% saline through the bronchofibroscope tube. Material was then referred to laboratorial processing. Analysis has evidenced mean increase in total number of cells from 0.6 &times; 10(6)cel.dL-1 to 6.8 &times; 10(6) cel.dL-1 with increased neutrophils from 0.8% to 4.7%; 0.6% to 6.2% and 0.5% to 5.3% for each patient, respectively. There has been increased pulmonary fluid cellularity after CPB. CONCLUSIONS: Leukocyte inflow is described in different clinical pulmonary inflammatory conditions, such as adult respiratory distress syndrome. It is known that CPB is related to systemic and pulmonary inflammation with increased number of cells after CPB and predominance of macrophages

Randomized trials of therapeutic heparin for COVID-19: A meta-analysis.

Background Pulmonary endothelial injury and microcirculatory thromboses likely contribute to hypoxemic respiratory failure, the most common cause of death, in patients with COVID-19. Randomized controlled trials (RCTs) suggest differences in the effect of therapeutic heparin between moderately and severely ill patients with COVID-19. We did a systematic review and meta-analysis of RCTs to determine the effects of therapeutic heparin in hospitalized patients with COVID-19. Methods We searched PubMed, Embase, Web of Science, medRxiv, and medical conference proceedings for RCTs comparing therapeutic heparin with usual care, excluding trials that used oral anticoagulation or intermediate doses of heparin in the experimental arm. Mantel-Haenszel fixed-effect meta-analysis was used to combine odds ratios (ORs). Results and Conclusions There were 3 RCTs that compared therapeutic heparin to lower doses of heparin in 2854 moderately ill ward patients, and 3 RCTs in 1191 severely ill patients receiving critical care. In moderately ill patients, there was a nonsignificant reduction in all-cause death (OR, 0.76; 95% CI, 0.57-1.02), but significant reductions in the composite of death or invasive mechanical ventilation (OR, 0.77; 95% CI, 0.60 0.98), and death or any thrombotic event (OR, 0.58; 95% CI, 0.45-0.77). Organ support-free days alive (OR, 1.29; 95% CI, 1.07-1.57) were significantly increased with therapeutic heparin. There was a nonsignificant increase in major bleeding. In severely ill patients, there was no evidence for benefit of therapeutic heparin, with significant treatment-by-subgroup interactions with illness severity for all-cause death (P = .034). In conclusion, therapeutic heparin is beneficial in moderately ill patients but not in severely ill patients hospitalized with COVID-19

Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial.

OBJECTIVE To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. DESIGN Randomised controlled, adaptive, open label clinical trial. SETTING 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. PARTICIPANTS 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). INTERVENTIONS Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. MAIN OUTCOME MEASURES The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. RESULTS The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m2. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). CONCLUSIONS In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. TRIAL REGISTRATION ClinicalTrials.gov NCT04362085

Avaliação da função pulmonar e da qualidade de vida em pacientes submetidos à ressecção pulmonar por neoplasia Assessment of pulmonary function and quality of life in patients submitted to pulmonary resection for cancer

OBJETIVO: Avaliar as repercussões da ressecção pulmonar sobre a função pulmonar e a qualidade de vida (QV) de pacientes com câncer de pulmão primário ou metastático. MÉTODOS: Estudo de coorte prospectivo que incluiu todos os pacientes que realizaram ressecção pulmonar por neoplasia no Hospital A. C. Camargo entre setembro de 2006 e março de 2007. Os pacientes foram avaliados no pré-operatório e após seis meses do procedimento cirúrgico através de espirometria. Após seis meses de pós-operatório, os pacientes responderam a um questionário de QV geral (Medical Outcomes Study 36-item Short-form Health Survey) e um específico para sintomas respiratórios (Saint George's Respiratory Questionnaire). Os valores de QV obtidos foram comparados a valores de uma população geral e aos de uma população de portadores de DPOC. RESULTADOS: Foram incluídos 33 pacientes (14 homens e 19 mulheres), com idade entre 39 e 79 anos. Todos os pacientes, tabagistas ou não, apresentaram piora significativa da função pulmonar. Observamos uma redução de aproximadamente 5% na média dos escores do questionário de QV geral em comparação àquela da população geral. Houve uma redução de 50-60% nos vários domínios do questionário específico para sintomas, quando comparado aos resultados da população geral, e um aumento de aproximadamente 20%, quando comparado aos resultados da população com DPOC. CONCLUSÕES: Existe impacto direto da ressecção pulmonar na deterioração da função pulmonar e na QV com ênfase nos aspectos diretamente ligados à função pulmonar. Cabe ressaltar a importância da avaliação da função pulmonar destes pacientes no pré-operatório para se estimar sua evolução pós-cirúrgica.<br>OBJECTIVE: To evaluate the effects that pulmonary resection has on pulmonary function and quality of life (QoL) in patients with primary or metastatic lung cancer. METHODS: This was a prospective cohort study involving all patients submitted to pulmonary resection for cancer between September of 2006 and March of 2007 at the A. C. Camargo Hospital in São Paulo, Brazil. Patients underwent spirometry in the preoperative period and at six months after the surgical procedure. After a postoperative period of six months, the patients completed an overall QoL questionnaire (the Medical Outcomes Study 36-item Short-form Health Survey) and another one, specific for respiratory symptoms (the Saint George's Respiratory Questionnaire). The scores obtained in our study were compared with those previously obtained for a general population and for a population of patients with COPD. RESULTS: We included 33 patients (14 males and 19 females), ranging in age from 39 to 79 years. All of the patients, smokers and nonsmokers alike, presented significant worsening of pulmonary function. The mean scores on the overall QoL questionnaire were approximately 5% lower than those obtained for the general population. The scores of various domains of the symptom-specific QoL questionnaire were 50-60% lower than those obtained for the general population and approximately 20% higher than those obtained for the population with COPD. CONCLUSIONS: Pulmonary resection has a direct negative impact on pulmonary function and QoL, especially on the QoL related to aspects directly linked to pulmonary function. We highlight the importance of preoperative assessment of pulmonary function in patients undergoing pulmonary resection, in order to predict their postoperative evolution