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1.
Am J Respir Crit Care Med ; 203(10): 1266-1274, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33406012

RESUMO

Rationale: The physiological basis of lung protection and the impact of positive end-expiratory pressure (PEEP) during pronation in acute respiratory distress syndrome are not fully elucidated. Objectives: To compare pleural pressure (Ppl) gradient, ventilation distribution, and regional compliance between dependent and nondependent lungs, and investigate the effect of PEEP during supination and pronation. Methods: We used a two-hit model of lung injury (saline lavage and high-volume ventilation) in 14 mechanically ventilated pigs and studied supine and prone positions. Global and regional lung mechanics including Ppl and distribution of ventilation (electrical impedance tomography) were analyzed across PEEP steps from 20 to 3 cm H2O. Two pigs underwent computed tomography scans: tidal recruitment and hyperinflation were calculated. Measurements and Main Results: Pronation improved oxygenation, increased Ppl, thus decreasing transpulmonary pressure for any PEEP, and reduced the dorsal-ventral pleural pressure gradient at PEEP < 10 cm H2O. The distribution of ventilation was homogenized between dependent and nondependent while prone and was less dependent on the PEEP level than while supine. The highest regional compliance was achieved at different PEEP levels in dependent and nondependent regions in supine position (15 and 8 cm H2O), but for similar values in prone position (13 and 12 cm H2O). Tidal recruitment was more evenly distributed (dependent and nondependent), hyperinflation lower, and lungs cephalocaudally longer in the prone position. Conclusions: In this lung injury model, pronation reduces the vertical pleural pressure gradient and homogenizes regional ventilation and compliance between the dependent and nondependent regions. Homogenization is much less dependent on the PEEP level in prone than in supine positon.


Assuntos
Posicionamento do Paciente , Respiração com Pressão Positiva , Decúbito Ventral , Síndrome do Desconforto Respiratório/fisiopatologia , Síndrome do Desconforto Respiratório/terapia , Decúbito Dorsal , Animais , Modelos Animais de Doenças , Complacência Pulmonar/fisiologia , Lesão Pulmonar/complicações , Lesão Pulmonar/fisiopatologia , Lesão Pulmonar/terapia , Cavidade Pleural/fisiopatologia , Síndrome do Desconforto Respiratório/etiologia , Mecânica Respiratória/fisiologia , Suínos
2.
Am J Respir Crit Care Med ; 203(8): 969-976, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33091317

RESUMO

Rationale: Asymmetrical lung injury is a frequent clinical presentation. Regional distribution of Vt and positive end-expiratory pressure (PEEP) could result in hyperinflation of the less-injured lung. The validity of esophageal pressure (Pes) is unknown.Objectives: To compare, in asymmetrical lung injury, Pes with directly measured pleural pressures (Ppl) of both sides and investigate how PEEP impacts ventilation distribution and the regional driving transpulmonary pressure (inspiratory - expiratory).Methods: Fourteen mechanically ventilated pigs with lung injury were studied. One lung was blocked while the contralateral one underwent surfactant lavage and injurious ventilation. Airway pressure and Pes were measured, as was Ppl in the dorsal and ventral pleural space adjacent to each lung. Distribution of ventilation was assessed by electrical impedance tomography. PEEP was studied through decremental steps.Measurements and Results: Ventral and dorsal Ppl were similar between the injured and the noninjured lung across all PEEP levels. Dorsal Ppl and Pes were similar. The driving transpulmonary pressure was similar in the two lungs. Vt distribution between lungs was different at zero end-expiratory pressure (≈70% of Vt going in noninjured lung) owing to different respiratory system compliance (8.3 ml/cm H2O noninjured lung vs. 3.7 ml/cm H2O injured lung). PEEP at 10 cm H2O with transpulmonary pressure around zero homogenized Vt distribution opening the lungs. PEEP ≥16 cm H2O equalized distribution of Vt but with overdistension for both lungs.Conclusions: Despite asymmetrical lung injury, Ppl between injured and noninjured lungs is equalized and esophageal pressure is a reliable estimate of dorsal Ppl. Driving transpulmonary pressure is similar for both lungs. Vt distribution results from regional respiratory system compliance. Moderate PEEP homogenizes Vt distribution between lungs without generating hyperinflation.


Assuntos
Lesão Pulmonar/fisiopatologia , Lesão Pulmonar/terapia , Respiração com Pressão Positiva/métodos , Respiração Artificial/métodos , Mecânica Respiratória/fisiologia , Suínos , Animais , Modelos Animais
3.
Respir Care ; 66(3): 366-377, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32817445

RESUMO

BACKGROUND: During the COVID-19 pandemic, a need for innovative, inexpensive, and simple ventilator devices for mass use has emerged. The Oxylator (CPR Medical Devices, Markham, Ontario, Canada) is an FDA-approved, fist-size, portable ventilation device developed for out-of-hospital emergency ventilation. It has not been tested in conditions of severe lung injury or with added PEEP. We aimed to assess the performance and reliability of the device in simulated and experimental conditions of severe lung injury, and to derive monitoring methods to allow the delivery of safe, individualized ventilation during situations of surge. METHODS: We bench-tested the functioning of the device with an added PEEP valve extensively, mimicking adult patients with various respiratory mechanics during controlled ventilation, spontaneous breathing, and prolonged unstable conditions where mechanics or breathing effort was changed at every breath. The device was further tested on a porcine model (4 animals) after inducing lung injury, and these results were compared with conventional ventilation modes. RESULTS: The device was stable and predictable, delivering a constant flow (30 L/min) and cycling automatically at the inspiratory pressure set (minimum of 20 cm H2O) above auto-PEEP. Changes in respiratory mechanics manifested as changes in respiratory timing, allowing prediction of tidal volumes from breathing frequency. Simulating lung injury resulted in relatively low tidal volumes (330 mL with compliance of 20 mL/cm H2O). In the porcine model, arterial oxygenation, CO2, and pH were comparable to conventional modes of ventilation. CONCLUSIONS: The Oxylator is a simple device that delivered stable ventilation with tidal volumes within a clinically acceptable range in bench and porcine lung models with low compliance. External monitoring of respiratory timing is advisable, allowing tidal volume estimation and recognition of changes in respiratory mechanics. The device can be an efficient, low-cost, and practical rescue solution for providing short-term ventilatory support as a temporary bridge, but it requires a caregiver at the bedside.


Assuntos
Insuficiência Respiratória , Ventiladores Mecânicos , Benchmarking , COVID-19 , Desenho de Equipamento , Humanos , Insuficiência Respiratória/terapia , Mecânica Respiratória , Volume de Ventilação Pulmonar , Resultado do Tratamento
4.
Am J Respir Crit Care Med ; 198(9): 1165-1176, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29902384

RESUMO

RATIONALE: Ventilator management in acute respiratory distress syndrome usually focuses on setting parameters, but events occurring at ventilator disconnection are not well understood. OBJECTIVES: To determine if abrupt deflation after sustained inflation causes lung injury. METHODS: Male Sprague-Dawley rats were ventilated (low Vt, 6 ml/kg) and randomized to control (n = 6; positive end-expiratory pressure [PEEP], 3 cm H2O; 100 min) or intervention (n = 6; PEEP, 3-11 cm H2O over 70 min; abrupt deflation to zero PEEP; ventilation for 30 min). Lung function and injury was assessed, scanning electron microscopy performed, and microvascular leak timed by Evans blue dye (n = 4/group at 0, 2, 5, 10, and 20 min after deflation). Hemodynamic assessment included systemic arterial pressure (n = 6), echocardiography (n = 4), and right (n = 6) and left ventricular pressures (n = 6). MEASUREMENTS AND MAIN RESULTS: Abrupt deflation after sustained inflation (vs. control) caused acute lung dysfunction (compliance 0.48 ± 1.0 vs. 0.82 ± 0.2 m/cm H2O, oxygen saturation as measured by pulse oximetry 67 ± 23.5 vs. 91 ± 4.4%; P < 0.05) and injury (wet/dry ratio 6.1 ± 0.6 vs. 4.6 ± 0.4; P < 0.01). Vascular leak was absent before deflation and maximal 5-10 minutes thereafter; injury was predominantly endothelial. At deflation, left ventricular preload, systemic blood pressure, and left ventricular end-diastolic pressure increased precipitously in proportion to the degree of injury. Injury caused later right ventricular failure. Sodium nitroprusside prevented the increase in systemic blood pressure and left ventricular end-diastolic pressure associated with deflation, and prevented injury. Injury did not occur with gradual deflation. CONCLUSIONS: Abrupt deflation after sustained inflation can cause acute lung injury. It seems to be mediated by acute left ventricular decompensation (caused by increased left ventricular preload and afterload) that elevates pulmonary microvascular pressure; this directly injures the endothelium and causes edema, which is potentiated by the surge in pulmonary perfusion.


Assuntos
Lesão Pulmonar/etiologia , Lesão Pulmonar/fisiopatologia , Respiração com Pressão Positiva , Suspensão de Tratamento , Animais , Modelos Animais de Doenças , Pulmão/fisiopatologia , Masculino , Oximetria , Ratos , Ratos Sprague-Dawley , Mecânica Respiratória
5.
Anesthesiology ; 129(1): 163-172, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29708892

RESUMO

BACKGROUND: In supine patients with acute respiratory distress syndrome, the lung typically partitions into regions of dorsal atelectasis and ventral aeration ("baby lung"). Positive airway pressure is often used to recruit atelectasis, but often overinflates ventral (already aerated) regions. A novel approach to selective recruitment of dorsal atelectasis is by "continuous negative abdominal pressure." METHODS: A randomized laboratory study was performed in anesthetized pigs. Lung injury was induced by surfactant lavage followed by 1 h of injurious mechanical ventilation. Randomization (five pigs in each group) was to positive end-expiratory pressure (PEEP) alone or PEEP with continuous negative abdominal pressure (-5 cm H2O via a plexiglass chamber enclosing hindlimbs, pelvis, and abdomen), followed by 4 h of injurious ventilation (high tidal volume, 20 ml/kg; low expiratory transpulmonary pressure, -3 cm H2O). The level of PEEP at the start was ≈7 (vs. ≈3) cm H2O in the PEEP (vs. PEEP plus continuous negative abdominal pressure) groups. Esophageal pressure, hemodynamics, and electrical impedance tomography were recorded, and injury determined by lung wet/dry weight ratio and interleukin-6 expression. RESULTS: All animals survived, but cardiac output was decreased in the PEEP group. Addition of continuous negative abdominal pressure to PEEP resulted in greater oxygenation (PaO2/fractional inspired oxygen 316 ± 134 vs. 80 ± 24 mmHg at 4 h, P = 0.005), compliance (14.2 ± 3.0 vs. 10.3 ± 2.2 ml/cm H2O, P = 0.049), and homogeneity of ventilation, with less pulmonary edema (≈10% less) and interleukin-6 expression (≈30% less). CONCLUSIONS: Continuous negative abdominal pressure added to PEEP reduces ventilator-induced lung injury in a pig model compared with PEEP alone, despite targeting identical expiratory transpulmonary pressure.


Assuntos
Músculos Abdominais/fisiologia , Modelos Animais de Doenças , Impedância Elétrica , Pressão , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controle , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologia , Animais , Impedância Elétrica/uso terapêutico , Suínos , Volume de Ventilação Pulmonar/fisiologia
6.
J Appl Physiol (1985) ; 125(1): 107-116, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29596015

RESUMO

We recently reported that continuous negative abdominal pressure (CNAP) could recruit dorsal atelectasis in experimental lung injury and that oxygenation improved at different transpulmonary pressure values compared with increases in airway pressure (Yoshida T, Engelberts D, Otulakowski G, Katira BH, Post M, Ferguson ND, Brochard L, Amato MBP, Kavanagh BP. Am J Respir Crit Care Med 197: 534-537, 2018). The mechanism of recruitment with CNAP is uncertain, and its impact compared with a commonly proposed alternative approach to recruitment, prone positioning, is not known. We hypothesized that CNAP recruits lung by decreasing the vertical pleural pressure (Ppl) gradient (i.e., difference between dependent and nondependent Ppl), thought to be one mechanism of action of prone positioning. An established porcine model of lung injury (surfactant depletion followed by ventilator-induced lung injury) was used. CNAP was applied using a plexiglass chamber that completely enclosed the abdomen at a constant negative pressure (-5 cmH2O). Lungs were recruited to maximal positive end-expiratory pressure (PEEP; 25 cmH2O) and deflated in steps of PEEP (2 cmH2O, 10 min each). CNAP lowered the Ppl in dependent but not in nondependent lung, and therefore, in contrast to PEEP, it narrowed the vertical Ppl gradient. CNAP increased respiratory system compliance and oxygenation and appeared to selectively displace the posterior diaphragm caudad (computerized tomography images). Compared with prone position without CNAP, CNAP in the supine position was associated with higher arterial partial pressure of oxygen and compliance, as well as greater homogeneity of ventilation. The mechanism of action of CNAP appears to be via selective narrowing of the vertical gradient of Ppl. CNAP appears to offer physiological advantages over prone positioning. NEW & NOTEWORTHY Continuous negative abdominal pressure reduces the vertical gradient in (dependent vs. nondependent) pleural pressure and increases oxygenation and lung compliance; it is more effective than prone positioning at comparable levels of positive end-expiratory pressure.


Assuntos
Pulmão/fisiologia , Decúbito Ventral/fisiologia , Animais , Pulmão/metabolismo , Complacência Pulmonar/fisiologia , Oxigênio/metabolismo , Posicionamento do Paciente/métodos , Respiração com Pressão Positiva/métodos , Pressão , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/fisiopatologia , Mecânica Respiratória/fisiologia , Fenômenos Fisiológicos Respiratórios , Suínos , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologia
7.
Anesthesiology ; 129(1): 143-153, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29474201

RESUMO

BACKGROUND: Lower tidal volumes are increasingly used in acute respiratory distress syndrome, but mortality has changed little in the last 20 yr. Therefore, in addition to ventilator settings, it is important to target molecular mediators of injury. Sepsis and other inflammatory states increase circulating concentrations of Gas6, a ligand for the antiinflammatory receptor Axl, and of a soluble decoy form of Axl. We investigated the effects of lung stretch on Axl signaling. METHODS: We used a mouse model of early injury from high tidal volume and assessed the effects of inhibiting Axl on in vivo lung injury (using an antagonist R428, n = 4/group). We further determined the effects of stretch on Axl activation using in vitro lung endothelial cells. RESULTS: High tidal volume caused mild injury (compliance decreased 6%) as intended, and shedding of the Axl receptor (soluble Axl in bronchoalveolar fluid increased 77%). The Axl antagonist R428 blocked the principal downstream Axl target (suppressor of cytokine signaling 3 [SOCS3]) but did not worsen lung physiology or inflammation. Cyclic stretch in vitro caused Axl to become insensitive to activation by its agonist, Gas6. Finally, in vitro Axl responses were rescued by blocking stretch-activated calcium channels (using guanidinium chloride [GdCl3]), and the calcium ionophore ionomycin replicated the effect of stretch. CONCLUSIONS: These data suggest that lung endothelial cell overdistention activates ion channels, and the resultant influx of Ca inactivates Axl. Downstream inactivation of Axl by stretch was not anticipated; preventing this would be required to exploit Axl receptors in reducing lung injury.


Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Respiração Artificial/efeitos adversos , Lesão Pulmonar Aguda/patologia , Animais , Benzocicloeptenos/farmacologia , Células Cultivadas , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Ratos , Respiração Artificial/tendências , Volume de Ventilação Pulmonar/efeitos dos fármacos , Volume de Ventilação Pulmonar/fisiologia , Triazóis/farmacologia
10.
Am J Respir Crit Care Med ; 196(11): 1411-1421, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28795839

RESUMO

RATIONALE: In the original 1974 in vivo study of ventilator-induced lung injury, Webb and Tierney reported that high Vt with zero positive end-expiratory pressure caused overwhelming lung injury, subsequently shown by others to be due to lung shear stress. OBJECTIVES: To reproduce the lung injury and edema examined in the Webb and Tierney study and to investigate the underlying mechanism thereof. METHODS: Sprague-Dawley rats weighing approximately 400 g received mechanical ventilation for 60 minutes according to the protocol of Webb and Tierney (airway pressures of 14/0, 30/0, 45/10, 45/0 cm H2O). Additional series of experiments (20 min in duration to ensure all animals survived) were studied to assess permeability (n = 4 per group), echocardiography (n = 4 per group), and right and left ventricular pressure (n = 5 and n = 4 per group, respectively). MEASUREMENTS AND MAIN RESULTS: The original Webb and Tierney results were replicated in terms of lung/body weight ratio (45/0 > 45/10 ≈ 30/0 ≈ 14/0; P < 0.05) and histology. In 45/0, pulmonary edema was overt and rapid, with survival less than 30 minutes. In 45/0 (but not 45/10), there was an increase in microvascular permeability, cyclical abolition of preload, and progressive dilation of the right ventricle. Although left ventricular end-diastolic pressure decreased in 45/10, it increased in 45/0. CONCLUSIONS: In a classic model of ventilator-induced lung injury, high peak pressure (and zero positive end-expiratory pressure) causes respiratory swings (obliteration during inspiration) in right ventricular filling and pulmonary perfusion, ultimately resulting in right ventricular failure and dilation. Pulmonary edema was due to increased permeability, which was augmented by a modest (approximately 40%) increase in hydrostatic pressure. The lung injury and acute cor pulmonale is likely due to pulmonary microvascular injury, the mechanism of which is uncertain, but which may be due to cyclic interruption and exaggeration of pulmonary blood flow.


Assuntos
Edema Pulmonar/complicações , Lesão Pulmonar Induzida por Ventilação Mecânica/complicações , Disfunção Ventricular Direita/complicações , Animais , Modelos Animais de Doenças , Ecocardiografia , Coração/fisiopatologia , Pulmão/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologia
11.
Thorax ; 72(6): 538-549, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28159772

RESUMO

RATIONALE: Hypercapnia is common in mechanically ventilated patients. Experimentally, 'therapeutic hypercapnia' can protect, but it can also cause harm, depending on the mechanism of injury. Hypercapnia suppresses multiple signalling pathways. Previous investigations have examined mechanisms that were known a priori, but only a limited number of pathways, each suppressed by CO2, have been reported. OBJECTIVE: Because of the complexity and interdependence of processes in acute lung injury, this study sought to fill in knowledge gaps using an unbiased screen, aiming to identify a specifically upregulated pathway. METHODS AND RESULTS: Using genome-wide gene expression analysis in a mouse model of ventilator-induced lung injury, we discovered a previously unsuspected mechanism by which CO2 can protect against injury: induction of the transporter protein for α-tocopherol, α-tocopherol transfer protein (αTTP). Pulmonary αTTP was induced by inspired CO2 in two in vivo murine models of ventilator-induced lung injury; the level of αTTP expression correlated with degree of lung protection; and, absence of the αTTP gene significantly reduced the protective effects of CO2. α-Tocopherol is a potent antioxidant and hypercapnia increased lung α-tocopherol in wild-type mice, but this did not alter superoxide generation or expression of NRF2-dependent antioxidant response genes in wild-type or in αTTP-/- mice. In concordance with a regulatory role for α-tocopherol in lipid mediator synthesis, hypercapnia attenuated 5-lipoxygenase activity and this was dependent on the presence of αTTP. CONCLUSIONS: Inspired CO2 upregulates αTTP which increases lung α-tocopherol levels and inhibits synthesis of a pathogenic chemoattractant.


Assuntos
Proteínas de Transporte/fisiologia , Hipercapnia/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controle , Animais , Proteínas de Transporte/genética , Modelos Animais de Doenças , Deleção de Genes , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/fisiologia , Estudo de Associação Genômica Ampla , Leucotrieno B4/metabolismo , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo/fisiologia , RNA Mensageiro/genética , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologia , Lesão Pulmonar Induzida por Ventilação Mecânica/genética , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , alfa-Tocoferol/metabolismo
12.
Anesthesiology ; 122(4): 864-75, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25665049

RESUMO

BACKGROUND: Mechanical ventilation can injure the lung and induce a proinflammatory state; such ventilator-induced lung injury (VILI) is associated with neutrophil influx. Neutrophils release DNA and granular proteins as cytotoxic neutrophil extracellular traps (NETs). The authors hypothesized that NETs were produced in a VILI model and may contribute to injury. METHODS: In a two-hit lipopolysaccharide/VILI mouse model with and without intratracheal deoxyribonuclease (DNase) treatment or blockade of known inducers of NET formation (NETosis), the authors assessed compliance, bronchoalveolar lavage fluid protein, markers of NETs (citrullinated histone-3 and DNA), and markers of inflammation. RESULTS: Although lipopolysaccharide recruited neutrophils to airways, the addition of high tidal mechanical ventilation was required for significant induction of NETs markers (e.g., bronchoalveolar lavage fluid DNA: 0.4 ± 0.07 µg/ml [mean ± SEM], P < 0.05 vs. all others, n = 10 per group). High tidal volume mechanical ventilation increased airway high-mobility group box 1 protein (0.91 ± 0.138 vs. 0.60 ± 0.095) and interleukin-1ß in lipopolysaccharide-treated mice (22.4 ± 0.87 vs. 17.0 ± 0.50 pg/ml, P < 0.001) and tended to increase monocyte chemoattractant protein-1 and interleukin-6. Intratracheal DNase treatment reduced NET markers (bronchoalveolar lavage fluid DNA: 0.23 ± 0.038 vs. 0.88 ± 0.135 µg/ml, P < 0.001; citrullinated histone-3: 443 ± 170 vs. 1,824 ± 403, P < 0.01, n = 8 to 10) and attenuated the loss of static compliance (0.9 ± 0.14 vs. 1.58 ± 0.17 ml/mmHg, P < 0.01, n = 19 to 20) without significantly impacting other measures of injury. Blockade of high-mobility group box 1 (with glycyrrhizin) or interleukin-1ß (with anakinra) did not prevent NETosis or protect against injury. CONCLUSIONS: NETosis was induced in VILI, and DNase treatment eliminated NETs. In contrast to experimental transfusion-related acute lung injury, NETs do not play a major pathogenic role in the current model of VILI.


Assuntos
Armadilhas Extracelulares/metabolismo , Neutrófilos/metabolismo , Respiração Artificial/efeitos adversos , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Animais , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/fisiologia , Distribuição Aleatória , Volume de Ventilação Pulmonar/fisiologia
13.
J Physiol ; 592(20): 4507-21, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25085885

RESUMO

Hypercapnic acidosis, common in mechanically ventilated patients, has been reported to exert both beneficial and harmful effects in models of lung injury. Understanding its effects at the molecular level may provide insight into mechanisms of injury and protection. The aim of this study was to establish the effects of hypercapnic acidosis on mitogen­activated protein kinase (MAPK) activation, and determine the relevant signalling pathways. p44/42 MAPK activation in a murine model of ventilator­induced lung injury (VILI) correlated with injury and was reduced in hypercapnia. When cultured rat alveolar epithelial cells were subjected to cyclic stretch, activation of p44/42 MAPK was dependent on epidermal growth factor receptor (EGFR) activity and on shedding of EGFR ligands; exposure to 12% CO2 without additional buffering blocked ligand shedding, as well as EGFR and p44/42 MAPK activation. The EGFR ligands are known substrates of the matrix metalloprotease ADAM17, suggesting stretch activates and hypercapnic acidosis blocks stretch­mediated activation of ADAM17. This was corroborated in the isolated perfused mouse lung, where elevated CO2 also inhibited stretch­activated shedding of the ADAM17 substrate TNFR1 from airway epithelial cells. Finally, in vivo confirmation was obtained in a two­hit murine model of VILI where pharmacological inhibition of ADAM17 reduced both injury and p44/42 MAPK activation. Thus, ADAM17 is an important proximal mediator of VILI; its inhibition is one mechanism of hypercapnic protection and may be a target for clinical therapy.


Assuntos
Proteínas ADAM/metabolismo , Hipercapnia/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Proteínas ADAM/genética , Proteína ADAM17 , Acidose/metabolismo , Acidose/fisiopatologia , Animais , Células Cultivadas , Células Epiteliais/metabolismo , Receptores ErbB/metabolismo , Hipercapnia/fisiopatologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologia
14.
Pediatr Res ; 75(6): 738-48, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24614799

RESUMO

BACKGROUND: Epinephrine is a component of all resuscitation algorithms. Vasopressin is a pulmonary vasodilator and systemic vasopressor. We investigated the effect of epinephrine vs. vasopressin on survival and hemodynamics after neonatal porcine cardiac arrest (CA). METHODS: A 4-min asphyxial CA was induced, after which cardiopulmonary resuscitation (CPR) was commenced. Animals were randomized to low- (LDE: 0.01 mg/kg) or high-dose epinephrine (HDE: 0.03 mg/kg), low- (LDV: 0.2 U/kg) or high-dose vasopressin (HDV: 0.4 U/kg), or control (saline). Clinical and echocardiography indexes were monitored. RESULTS: Sixty-nine animals were randomized. Survival was greater in HDV (n = 8 (89%); P < 0.05 ANOVA) vs. control (n = 7 (43%)) and LDE (n = 5 (36%)) but not vs. HDE (n = 7 (64%)) or LDV (n = 6 (75%)). Animals resuscitated with LDE required more shocks (2.5 (interquartile range: 2-6); P < 0.05) and higher doses of energy (15 J (interquartile range: 10-20); P < 0.05). Left ventricular output was comparable between groups, but a greater increase in superior vena caval flow was seen after HDV (P < 0.001 vs. control, LDE, and HDE). Plasma troponin was greatest in the HDE group (P < 0.05 vs. control and HDV). CONCLUSION: Vasopressin results in improved survival, lower postresuscitation troponin, and less hemodynamic compromise after CA in newborn piglets. Vasopressin may be a candidate for testing in human neonates.


Assuntos
Reanimação Cardiopulmonar/métodos , Epinefrina/uso terapêutico , Parada Cardíaca/tratamento farmacológico , Vasopressinas/uso terapêutico , Análise de Variância , Animais , Animais Recém-Nascidos , Relação Dose-Resposta a Droga , Ecocardiografia , Epinefrina/farmacologia , Suínos , Resultado do Tratamento , Troponina/sangue , Vasopressinas/farmacologia
15.
Crit Care Med ; 41(1): 151-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23128385

RESUMO

BACKGROUND: Sepsis is a common indication for mechanical ventilation, which, with higher tidal volume, can cause ventilator-associated lung injury. Inflammatory mediators in the plasma or bronchoalveolar fluid are sometimes proposed as biomarkers in ICU patients. OBJECTIVE: To test the hypothesis that "priming" with subthreshold sepsis in a clinically relevant model would worsen lung function, increase ventilator-induced mediator production, and differentially impact systemic vs. pulmonary mediator levels. The model used was cecal ligation and perforation modified so that alone it caused lung inflammatory responses but not injury. METHODS AND MAIN RESULTS: Anesthetized mice were randomized to cecal ligation and perforation (vs. sham) with or without dexamethasone and 6 hrs later further randomized to: 1) sham, nonventilated, saline; 2) cecal ligation and perforation, nonventilated, saline; 3) cecal ligation and perforation, nonventilated, dexamethasone; 4) sham, high tidal volume, saline; 5) sham, high tidal volume, dexamethasone; 6) cecal ligation and perforation, high tidal volume, saline; or 7) cecal ligation and perforation, high tidal volume, dexamethasone. Mediators associated with sepsis and lung injury (cytokines: interleukin-6, tumor necrosis factor-α; chemokine: keratinocyte stimulating factor) were measured in the plasma and the bronchoalveolar lavage, and lung function (compliance, oxygenation, alveolar protein leak) assessed. High tidal volume and cecal ligation and perforation increased individual bronchoalveolar lavage and plasma mediators; high tidal volume but not cecal ligation and perforation impaired lung function. Priming of high tidal volume by cecal ligation and perforation intensified plasma and bronchoalveolar lavage mediators; the plasma (but not the bronchoalveolar lavage) mediators were inhibited by dexamethasone pretreatment. CONCLUSIONS: Mediator-but not functional-responses to high tidal volume are augmented by subthreshold sepsis priming. There is important discordance among systemic and pulmonary mediators, physiologic function, and response to corticosteroids; thus, mediator levels may be incomplete surrogates for measures of lung injury or response to therapy in the context of systemic sepsis.


Assuntos
Mediadores da Inflamação/metabolismo , Respiração Artificial/efeitos adversos , Sepse/imunologia , Sepse/terapia , Lesão Pulmonar Induzida por Ventilação Mecânica/imunologia , Animais , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/imunologia , Quimiocinas/metabolismo , Mediadores da Inflamação/sangue , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Volume de Ventilação Pulmonar , Fator de Necrose Tumoral alfa/metabolismo
16.
Crit Care Med ; 40(6): 1864-72, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22610189

RESUMO

RATIONALE: In acute lung injury, atelectasis is common and frequently develops in the dependent and diaphragmatic regions. Attempts to recruit lung with positive pressure constitute a major aim in the management of acute respiratory distress syndrome but are associated with overdistension and injury in nonatelectatic regions. OBJECTIVE: To test the hypothesis that continuous negative abdominal pressure using an iron lung would augment positive end-expiratory pressure in recruiting atelectatic lung. METHODS AND MAIN RESULTS: An in vivo rabbit model of ventilator-induced lung injury was used in which a recruitment maneuver followed by positive end-expiratory pressure (110 cm H2O) had no effect on oxygenation. Addition of sustained continuous negative abdominal pressure (-5 cm H2O) to the positive end-expiratory pressure significantly increased the end-expired lung volume and PaO2 but impaired ventricular preload and cardiac output (suggested by echocardiography). Addition of transient (15 mins) continuous negative abdominal pressure resulted in comparable and lasting (60 mins) increases in PaO2. Sustained, but not transient, continuous negative abdominal pressure was associated with hemodynamic depression and lactic acidosis, which appeared (illustrative echocardiography, n = 2) to be caused by decreased cardiac preload. Computerized tomography (n = 2) suggested that continuous negative abdominal pressure was an effective adjunct to positive end-expiratory pressure for recruiting atelectasis in dependent and diaphragmatic regions. In surfactant-depleted but noninjured lungs, sustained continuous negative abdominal pressure augmented lung recruitment and oxygenation in the setting of higher (but not lower) levels of positive end-expiratory pressure and reduced central venous oxygenation. CONCLUSIONS: Continuous negative abdominal pressure may be a potential adjunct to positive end-expiratory pressure in the recruitment of diaphragmatic atelectasis. The approach ultimately might be useful when ceilings exist on the level of desired positive end-expiratory pressure.


Assuntos
Pressão Negativa da Região Corporal Inferior/métodos , Respiração com Pressão Positiva , Atelectasia Pulmonar/terapia , Troca Gasosa Pulmonar , Animais , Modelos Animais de Doenças , Feminino , Atelectasia Pulmonar/fisiopatologia , Coelhos , Fatores de Tempo , Lesão Pulmonar Induzida por Ventilação Mecânica/complicações
17.
Am J Physiol Heart Circ Physiol ; 302(12): H2599-611, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22505643

RESUMO

Sustained therapeutic hypercapnia prevents pulmonary hypertension in experimental animals, but its rescue effects on established disease have not been studied. Therapies that inhibit Rho-kinase (ROCK) and/or augment nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling can reverse or prevent progression of chronic pulmonary hypertension. Our objective in the present study was to determine whether sustained rescue treatment with inhaled CO(2) (therapeutic hypercapnia) would improve structural and functional changes of chronic hypoxic pulmonary hypertension. Spontaneously breathing pups were exposed to normoxia (21% O(2)) or hypoxia (13% O(2)) from postnatal days 1-21 with or without 7% CO(2) (Pa(CO(2)) elevated by ∼25 mmHg) or 10% CO(2) (Pa(CO(2)) elevated by ∼40 mmHg) from days 14 to 21. Compared with hypoxia alone, animals exposed to hypoxia and 10% CO(2) had significantly (P < 0.05) decreased pulmonary vascular resistance, right-ventricular systolic pressure, right-ventricular hypertrophy, and medial wall thickness of pulmonary resistance arteries as well as decreased lung phosphodiesterase (PDE) V, RhoA, and ROCK activity. Rescue treatment with 10% CO(2), or treatment with a ROCK inhibitor (15 mg/kg ip Y-27632 twice daily from days 14 to 21), also increased pulmonary arterial endothelial nitric oxide synthase and lung NO content. In contrast, cGMP content and cGMP-dependent protein kinase (PKG) activity were increased by exposure to 10% CO(2), but not by ROCK inhibition with Y-27632. In vitro exposure of pulmonary artery smooth muscle cells to hypercapnia suppressed serum-induced ROCK activity, which was prevented by inhibition of PKG with Rp-8-Br-PET-cGMPS. We conclude that sustained hypercapnia dose-dependently inhibited ROCK activity, augmented NO-cGMP-PKG signaling, and led to partial improvements in the hemodynamic and structural abnormalities of chronic hypoxic PHT in juvenile rats. Increased PKG content and activity appears to play a major upstream role in CO(2)-induced suppression of ROCK activity in pulmonary arterial smooth muscle.


Assuntos
Dióxido de Carbono/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Quinases Associadas a rho/metabolismo , Animais , Dióxido de Carbono/administração & dosagem , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Hipertensão Pulmonar/enzimologia , Hipóxia/enzimologia , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/enzimologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Artéria Pulmonar/enzimologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Proteína rhoA de Ligação ao GTP/metabolismo
18.
Intensive Care Med ; 38(5): 879-85, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22349427

RESUMO

PURPOSE: Comparisons of negative versus positive pressure ventilation have imperfectly matched the pressure-time profile or the lung volume history, or have incompletely applied in vivo negative pressure to include the complete thoracic wall and abdomen. HYPOTHESIS: Negative pressure exerts the same pattern of lung distension as positive pressure when the pressure-time and volume history profiles are identical and the application of negative pressure is over the whole lung. METHODS: (1) In isolated (ex vivo) and (2) intact (in vivo) mouse lungs (n = 4/group) (sealed chamber enclosing either the whole lung or whole mouse except for external airway opening), identical and inverse-tidal, square-wave pressure-time profiles were obtained with positive and negative pressure ventilation. (3) Following an identical volume history, surfactant-depleted rabbits (n = 7) were randomly assigned to sustained, static equivalent positive versus negative pressures. (4) Surfactant-depleted anesthetized rabbits (n = 10) with identical volume histories were randomized to positive versus negative ventilation with identical pressure-time characteristics. RESULTS: Matched positive and negative pressure time profiles in ex vivo and in vivo mice resulted in identical tidal volumes. Identical (negative vs. positive) sustained static pressures resulted in similar PaO(2) and end expiratory lung volumes. Positive and negative ventilation with identical volume histories and pressure time characteristics showed no difference in oxygenation or lung volumes. Historical comparisons suggested better oxygenation with negative pressure when the volume history was not identical. CONCLUSIONS: These data do not support major biological differences between negative and positive pressure ventilation when waveforms and lung volume history are matched.


Assuntos
Respiração com Pressão Positiva , Respiradores de Pressão Negativa , Animais , Canadá , Complacência Pulmonar/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Coelhos , Distribuição Aleatória
19.
Am J Physiol Lung Cell Mol Physiol ; 300(4): L648-58, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21239530

RESUMO

Ventilator-induced lung injury (VILI) due to high tidal volume (V(T)) is associated with increased levels of circulating factors that may contribute to, or be markers of, injury. This study investigated if exclusively lung-derived circulating factors produced during high V(T) ventilation can cause or worsen VILI. In isolated perfused mouse lungs, recirculation of perfusate worsened injury (compliance impairment, microvascular permeability, edema) induced by high V(T). Perfusate collected from lungs ventilated with high V(T) and used to perfuse lungs ventilated with low V(T) caused similar compliance impairment and permeability and caused a dose-dependent decrease in transepithelial electrical resistance (TER) across rat distal lung epithelial monolayers. Circulating soluble factors derived from the isolated lung thus contributed to VILI and had deleterious effects on the lung epithelial barrier. These data demonstrate transferability of an injury initially caused exclusively by mechanical ventilation and provides novel evidence for the biotrauma hypothesis in VILI. Mediators of the TER decrease were heat-sensitive, transferable via Folch extraction, and (following ultrafiltration, 3 kDa) comprised both smaller and larger molecules. Although several classes of candidate mediators, including protein cytokines (e.g., tumor necrosis factor-α, interleukin-6, macrophage inflammation protein-1α) and lipids (e.g., eicosanoids, ceramides, sphingolipids), have been implicated in VILI, only prostanoids accumulated in the perfusate in a pattern consistent with a pathogenic role, yet cyclooxygenase inhibition did not protect against injury. Although no single class of factor appears solely responsible for the decrease in barrier function, the current data implicate lipid-soluble protein-bound molecules as not just markers but pathogenic mediators in VILI.


Assuntos
Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia , Animais , Citocinas/metabolismo , Impedância Elétrica , Epitélio/patologia , Técnicas In Vitro , Lipídeos/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Perfusão , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandinas/metabolismo , Desnaturação Proteica , Ratos , Solubilidade , Temperatura , Ultrafiltração
20.
Anesth Analg ; 112(1): 143-9, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21048090

RESUMO

BACKGROUND: We tested the hypothesis that inhibition of cyclooxygenase (COX) attenuates in vivo ventilator-induced lung injury (VILI) in a prospective, randomized laboratory investigation in a university-affiliated laboratory. Adult male rats were anesthetized and randomized with or without nonselective COX inhibition (ibuprofen) and were subjected to injurious mechanical ventilation (positive end-expiratory pressure = 0; peak inspiratory pressure = 21 mm Hg). METHODS: We investigated the profile of VILI (respiratory mechanics, cytokines, eicosanoids), expression of COX enzymes, and activation of nuclear factor (NF)-κB in ibuprofen- versus vehicle-treated animals. Injurious ventilation caused lung injury (i.e., decrement in compliance, tissue edema, and elevated inflammatory cytokines, eicosanoids, and COX-2). RESULTS: Pretreatment with ibuprofen that effectively inhibited eicosanoid synthesis and COX-2 activity increased survival and attenuated lung edema and decrement in respiratory mechanics. Ibuprofen had no modulatory effect on ventilator-induced activation of NF-κB or inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1ß, IL-6, GRO/KC [growth-related oncogene/keratinocyte chemoattractant]). COX activity seems important in the pathogenesis of VILI in the in vivo rat. Inhibition of COX provides significant protection (i.e., survival, pulmonary function) in VILI, but without affecting levels of important mediators (tumor necrosis factor-α, IL-1ß, IL-6, GRO/KC) or activation of NF-κB. CONCLUSIONS: These data confirm that nonselective COX inhibition provides partial protection against VILI and that the NF-κB signaling pathway is not exclusively eicosanoid dependent. Studies of COX inhibition in ventilator-associated lung injury might benefit from multimodal targeting that includes a comprehensive focus on inflammatory cytokines and NF-κB.


Assuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Lesão Pulmonar Induzida por Ventilação Mecânica/enzimologia , Animais , Gasometria/métodos , Masculino , Estudos Prospectivos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
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