Mechanical ventilation as a mediator of multisystem organ failure in acute respiratory distress syndrome.
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Humans↗
Biomedical subjects
A S Slutsky
Publications and source records attributed to A S Slutsky.
Mechanical ventilation: what's new when your patient is blue?
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Child↗
Production of tumour necrosis factor alpha by primary cultured rat alveolar epithelial cells.
Tumour necrosis factor alpha(TNF-alpha) is one of the most important pro-inflammatory cytokines, which plays an important role in host defense and acute inflammation related to tissue injury. The major source of TNF-alpha has been shown to be immune cells such as macrophages and neutrophils. In the present study, we demonstrated that LPS-treatment on alveolar epithelial cells isolated from adult rat lungs also induced a dose- and time-dependent release of TNF-alpha. The purity and identity of these cells were examined by immunofluorescent staining and confocal microscopy with antibodies for cytokeratin and pro-surfactant protein C, markers for epithelial cells and type II pneumocytes respectively. Positive staining of TNF-alpha was observed throughout the cell layer and localized intracellularly. LPS-induced TNF-alpha production from alveolar epithelial cells was blocked not only by cycloheximide, an inhibitor of protein translation, but also by actinomycin D, an inhibitor of gene transcription. The mRNA of TNF-alpha rapidly increased within 1 h of LPS stimulation. These data suggest that LPS-induced TNF-alpha production from alveolar epithelial cells is primarily regulated at the transcriptional level, which is different from that of macrophages and neutrophils. TNF-alpha produced by alveolar epithelial cells may function as an alert signal in host defense to induce production of other inflammatory mediators.
Animals↗
Oxygen free radicals in ARDS, septic shock and organ dysfunction.
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Antioxidants↗
Mechanotransduction, ventilator-induced lung injury and multiple organ dysfunction syndrome.
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Animals↗
Transplant immunosuppression increases and prolongs transgene expression following adenoviral-mediated transfection of rat lungs.
BACKGROUND: Gene therapy provides the potential to modify donor organs to better withstand transplantation, but this has yet to be realized. In vivo gene transfer using adenoviral vectors has had limited success because of host immune response that induces inflammation and limits the amount and duration of transgene expression. We hypothesize that transplantation immunosuppression can attenuate the post-transfection host-immune response to allow for improved gene transfer following adenoviral-mediated transfection. METHODS: We intratracheally transfected with adenovirus containing the beta-galactosidase gene and randomized the rats to either the immunosuppression group, receiving daily cyclosporine, azathioprine, and methylprednisolone, or the control group, receiving no immunosuppression. We evaluated transgene expression and post-transfection inflammation at time points ranging from 1 day to 5 weeks. RESULTS: Following transfection, control rats showed relatively low levels of transgene expression, which rapidly decreased to non-detectable levels. In contrast, immunosuppressed rats demonstrated significantly higher levels of transgene expression overall (p < 0.00005), peaking at almost 3 times that of the control group (p < 0.02), and showing prolonged and elevated transgene expression at 5 weeks (p < 0.02). On histologic sections of the lungs, immunosuppressed rats exhibited overall lesser grades of post-transfection inflammation. CONCLUSIONS: Transplant immunosuppression provides the means to attenuate the severe immune response to adenoviral-mediated gene transfection and thereby increase and prolong transgene expression.
Adenoviridae↗
Pressure-time curve predicts minimally injurious ventilatory strategy in an isolated rat lung model.
BACKGROUND: We tested the hypothesis that the pressure-time (P-t) curve during constant flow ventilation can be used to set a noninjurious ventilatory strategy. METHODS: In an isolated, nonperfused, lavaged model of acute lung injury, tidal volume and positive end-expiratory pressure were set to obtain: (1) a straight P-t curve (constant compliance, minimal stress); (2) a downward concavity in the P-t curve (increasing compliance, low volume stress); and (3) an upward concavity in the P-t curve (decreasing compliance, high volume stress). The P-t curve was fitted to: P = a. tb +c, where b describes the shape of the curve, b = 1 describes a straight P-t curve, b < 1 describes a downward concavity, and b > 1 describes an upward concavity. After 3 h, lungs were analyzed for histologic evidence of pulmonary damage and lavage concentration of inflammatory mediators. Ventilator-induced lung injury occurred when injury score and cytokine concentrations in the ventilated lungs were higher than those in 10 isolated lavaged rats kept statically inflated for 3 h with an airway pressure of 4 cm H2O. RESULTS: The threshold value for coefficient b that discriminated best between lungs with and without histologic and inflammatory evidence of ventilator-induced lung injury (receiver-operating characteristic curve) ranged between 0.90-1.10. For such threshold values, the sensitivity of coefficient b to identify noninjurious ventilatory strategy was 1.00. A significant relation (P < 0.001) between values of coefficient b and injury score, interleukin-6, and macrophage inflammatory protein-2 was found. CONCLUSIONS: The predictive power of coefficient b to predict noninjurious ventilatory strategy in a model of acute lung injury is high.
Animals↗
Partial liquid ventilation decreases serum tumor necrosis factor-alpha concentrations in a rat acid aspiration lung injury model.
OBJECTIVE: To examine the hypothesis that partial liquid ventilation (PLV) with perfluorocarbon would decrease serum tumor necrosis factor-alpha concentrations in a rat acid aspiration lung injury model. DESIGN: Prospective, controlled animal study. SETTINGS: Research laboratory in a university setting. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Treatment with intratracheal perflubron or control mechanical ventilation beginning 30 mins after acid aspiration. MEASUREMENTS AND MAIN RESULTS: PLV with perfluorocarbon compared with control ventilation resulted in significantly greater mean arterial blood pressures at 3 and 4 hrs and greater arterial Po2 at all times. Serum tumor necrosis factor-alpha at 2, 3, and 4 hrs was significantly less than that observed in the control group (4-hr values: 80+/-64 pg/mL vs. 658+/-688 pg/mL; p<.05), although no significant difference in tracheal fluid tumor necrosis factor-alpha concentrations (1425+/-1347 pg/mL vs. 2219+/-1933 pg/mL) was found. CONCLUSION: We conclude that the effects of PLV with perfluorocarbon can extend beyond improvements in pulmonary physiology and that PLV may be beneficial in reducing systemic sequelae of acute lung injury and inflammation.
Animals↗
Perfluorocarbon blocks tumor necrosis factor-alpha-induced interleukin-8 release from alveolar epithelial cells in vitro.
OBJECTIVE: To determine whether tumor necrosis factor (TNF)-alpha-induced interleukin (IL)-8 production by pulmonary alveolar epithelial cells is blocked by perfluorocarbon (PFC). DESIGN: Controlled, laboratory investigation of IL-8 production by pulmonary alveolar epithelial cells after exposure to PFC in vitro. SETTING: University research laboratory. SUBJECT: The human alveolar epithelial cell line with pulmonary type II (A549) cell properties. INTERVENTIONS: The A549 cells on a polycarbonate porous filter were stimulated either on the apical or the basolateral side with TNF-alpha. To determine TNF-alpha-induced IL-8 production, IL-8 was measured by using a human IL-8 kit in both control and experimental groups. MEASUREMENTS AND MAIN RESULTS: TNF-alpha stimulation induced a large increase in IL-8. When PFC was added to the medium immediately after TNF-alpha stimulation, PFC separated the medium from the cells and IL-8 production was markedly reduced (TNF-alpha alone, 8342+/-470 pg vs. TNF-alpha followed by PFC, 417+/-88 pg, p < .05). Preincubation of A549 cells with PFC for 24 hrs before stimulation with TNF-alpha followed by removal of PFC did not affect IL-8 production (8834+/-204 vs. 8342+/-470 pg; p = NS). When added to the lower chamber, TNF-alpha also induced IL-8 production unaffected by the addition of PFC to the upper chamber. The decrease in TNF-alpha-induced IL-8 production depended on the time of PFC administration after the initiation of TNF-alpha stimulation. The earlier PFC was added, the more pronounced the diminution was in IL-8. CONCLUSIONS: PFC appears to function as a physical barrier, thus reducing cytokines produced by alveolar epithelial cells in vitro. This mechanism may partially explain the decreased inflammatory response observed during liquid ventilation in models of acute lung injury.
Adenocarcinoma, Bronchiolo-Alveolar↗
Pulmonary surfactant is altered during mechanical ventilation of isolated rat lung.
OBJECTIVE: To test the hypothesis that the lung injury induced by certain mechanical ventilation strategies is associated with changes in the pulmonary surfactant system. DESIGN: Analysis of the pulmonary surfactant system from isolated rat lungs after one of four different ventilatory strategies. SETTING: A research laboratory at a university. SUBJECTS: A total of 45 Sprague-Dawley rats. INTERVENTIONS: Isolated lungs were randomized to either no ventilation (0-TIME) or to ventilation at 40 breaths/min in a humidified 37 degrees C chamber for either 30 mins or 120 mins with one of the following four strategies: a) control (CON, 7 mL/kg, 3 cm H2O positive end-expiratory pressure); b) medium volume, zero end-expiratory pressure (MVZP, 15 mL/kg, 0 cm H2O end-expiratory pressure); c) medium volume, high positive end-expiratory pressure (MVHP, 15 mL/kg, 9 cm H2O positive end-expiratory pressure); and d) high volume, zero end-expiratory pressure (HVZP, 40 mL/kg, 0 cm H2O end-expiratory pressure). MEASUREMENTS: Pressure-volume curves were determined before and after the ventilation period, after which the lungs were lavaged for surfactant analysis. MAIN RESULTS: Compared with 0-TIME, 30 mins of ventilation with the HVZP strategy or 120 mins of ventilation with CON and MVZP strategies caused a significant decrease in compliance. Groups showing a decreased compliance had significant increases in the amount of surfactant, surfactant large aggregates, and total lavage protein compared with 0-TIME. CONCLUSIONS: A short period of injurious mechanical ventilation can cause a decrease in lung compliance that is associated with a large influx of proteins into the alveolar space and with alterations of the pulmonary surfactant system. The changes of surfactant in these experiments are different from those seen in acute lung injury, indicating that they may represent an initial response to mechanical ventilation.
Animals↗
Alterations of nitric oxide synthase expression and activity during rat lung transplantation.
Decreased nitric oxide (NO) production has been reported during lung transplantation in patients. To study the effects of ischemia and reperfusion on endogenous NO synthase (NOS) expression, both an ex vivo and an in vivo lung injury model for transplantation were used. Donor rat lungs were flushed with cold low-potassium dextran solution and subjected to either cold (4 degrees C for 12 h) or warm (21 degrees C for 4 h) ischemic preservation followed by reperfusion with an ex vivo model. A significant increase in inducible NOS and a decrease in endothelial NOS mRNA was found after reperfusion. These results were confirmed in a rat single-lung transplant model after warm preservation. Interestingly, protein contents of both inducible NOS and endothelial NOS increased in the transplanted lung after 2 h of reperfusion. However, the total activity of NOS in the transplanted lungs remained at very low levels. We conclude that ischemic lung preservation and reperfusion result in altered NOS gene and protein expression with inhibited NOS activity, which may contribute to the injury of lung transplants.
Animals↗
Mechanical stretch stimulates macrophage inflammatory protein-2 secretion from fetal rat lung cells.
Ventilation-induced lung injury has been related to cytokine production. Immaturity and barotrauma are important contributors to the development of bronchopulmonary dysplasia in infants. In the present study, stretch of organotypic cultured fetal rat lung cells was used to simulate ventilation of preterm newborns. Cells were stimulated with lipopolysaccharide (LPS; 100 ng/ml) and/or mechanical stretch. After 4 h, stretch enhanced LPS-induced macrophage inflammatory protein (MIP)-2 production in a force- and frequency-dependent manner. The maximal effect of stretch was seen with 5% elongation at 40 cycles/min. In contrast, after 1 h of stimulation, stretch alone significantly increased MIP-2 production, which was not blocked by cycloheximide, an inhibitor of protein synthesis. At both the 1- and 4-h time points, only LPS increased MIP-2 mRNA levels. Stretch-induced MIP-2 release was associated with cell injury as measured by lactate dehydrogenase release and was not inhibited by gadolinium, a stretch-activated ion channel blocker. Taken together, these results suggest that the major effect of stretch on MIP-2 production from fetal rat lung cells is to stimulate its secretion.
Animals↗
A new ventilator for monitoring lung mechanics in small animals.
Researchers investigating the genetic component of various disease states rely increasingly on murine models. We have developed a ventilator to simplify respiratory research in small animals down to murine size. The new ventilator provides constant-flow inflation and tidal volume delivery independent of respiratory parameter changes. The inclusion of end-inspiratory and end-expiratory pauses simplifies the measurement of airway resistance and compliance and allows the detection of dynamic hyperinflation (auto-positive end-expiratory pressure). After bench testing, we performed intravenous methacholine challenge on two strains of mice (A/J and C57bl/bj) known to differ in their responses by using the new ventilator. Dynamic hyperinflation and a decrease in compliance developed during methacholine challenge whenever respiratory rates of 60-120 breaths/min were employed. In contrast, if dynamic hyperinflation was prevented by lengthening expiratory time, (respiratory rate = 20 breaths/min), static compliance remained constant. More importantly, the coefficient of variation of the results decreased when lung volume shifts were prevented. In conclusion, airway challenge studies have greater precision when dynamic hyperinflation is prevented.
Air Pressure↗
Invited review: mechanisms of ventilator-induced lung injury: a perspective.
Despite advances in critical care, the mortality rate in patients with acute lung injury remains high. Furthermore, most patients who die do so from multisystem organ failure. It has been postulated that ventilator-induced lung injury plays a key role in determining the negative clinical outcome of patients exposed to mechanical ventilation. How mechanical ventilation exerts its detrimental effect is as of yet unknown, but it appears that overdistension of lung units or shear forces generated during repetitive opening and closing of atelectatic lung units exacerbates, or even initiates, significant lung injury and inflammation. The term "biotrauma" has recently been elaborated to describe the process by which stress produced by mechanical ventilation leads to the upregulation of an inflammatory response. For mechanical ventilation to exert its deleterious effect, cells are required to sense mechanical forces and activate intracellular signaling pathways able to communicate the information to its interior. This information must then be integrated in the nucleus, and an appropriate response must be generated to implement and/or modulate its response and that of neighboring cells. In this review, we present a perspective on ventilator-induced lung injury with a focus on mechanisms and clinical implications. We highlight some of the most recent findings, which we believe contribute to the generation and propagation of ventilator-induced lung injury, placing a special emphasis on their implication for future research and clinical therapies.
Animals↗
Interobserver variation in interpreting chest radiographs for the diagnosis of acute respiratory distress syndrome.
To measure the reliability of chest radiographic diagnosis of acute respiratory distress syndrome (ARDS) we conducted an observer agreement study in which two of eight intensivists and a radiologist, blinded to one another's interpretation, reviewed 778 radiographs from 99 critically ill patients. One intensivist and a radiologist participated in pilot training. Raters made a global rating of the presence of ARDS on the basis of diffuse bilateral infiltrates. We assessed interobserver agreement in a pairwise fashion. For rater pairings in which one rater had not participated in the consensus process we found moderate levels of raw (0.68 to 0.80), chance-corrected (kappa 0.38 to 0.55), and chance-independent (Phi 0. 53 to 0.75) agreement. The pair of raters who participated in consensus training achieved excellent to almost perfect raw (0.88 to 0.94), chance-corrected (kappa 0.72 to 0.88), and chance-independent (Phi 0.74 to 0.89) agreement. We conclude that intensivists without formal consensus training can achieve moderate levels of agreement. Consensus training is necessary to achieve the substantial or almost perfect levels of agreement optimal for the conduct of clinical trials.
Adult↗
Compensation for increase in respiratory workload during mechanical ventilation. Pressure-support versus proportional-assist ventilation.
Variation in respiratory impedance may occur in mechanically ventilated patients. During pressure-targeted ventilatory support, this may lead to patient-ventilator asynchrony. We assessed the hypothesis that during pressure-support ventilation (PSV), preservation of minute ventilation (V E) consequent to added mechanical loads would result in an increase in respiratory rate (RR) due to the large reduction in tidal volume (VT). WITH proportional-assist ventilation (PAV), preservation of V E would occur through the preservation of VT, with a smaller effect on RR. We anticipated that this compensatory strategy would result in greater patient comfort and a reduce work of breathing. An increase in respiratory impedance was obtained by chest and abdominal binding in 10 patients during weaning from mechanical ventilation. V E remained constant in both ventilatory modes after chest and abdominal compression. During PSV, this maintenance of VE was obtained through a 58 +/- 3% increase in RR that compensated for a 29 +/- 2% reduction in VT. The magnitudes of the reduction in VT (10 +/- 3%) and of the increase in RR (14 +/- 2%) were smaller (p < 0. 001) during PAV. During both PSV and PAV, chest and abdominal compression caused increases in both the pressure-time product (PTP) of the diaphragm per minute (142.9 +/- 26.9 cm H(2)O. s/min, PSV, and 117.6 +/- 16.4 cm H(2)O. s/min, PAV) and per liter (13.4 +/- 2.5 cm H(2)O. s/L, PSV, and 9.6 +/- 0.7 cm H(2)O. s/L, PAV). These increments were greater (p < 0.001) during PSV than during PAV. The capability of keeping VT and V E constant through increases in inspiratory effort after increases in mechanical loads is relatively preserved only during PAV. The ventilatory response to an added respiratory load during PSV required greater muscle effort than during PAV.
Adult↗
A simple "new" method to accelerate clearance of carbon monoxide.
The currently recommended prehospital treatment for carbon monoxide (CO) poisoning is administration of 100% O(2). We have shown in dogs that normocapnic hyperpnea with O(2) further accelerates CO elimination. The purpose of this study was to examine the relation between minute ventilation (V E) and the rate of elimination of CO in humans. Seven healthy male volunteers were exposed to CO (400 to 1,000 ppm) in air until their carboxyhemoglobin (COHb) levels reached 10 to 12%. They then breathed either 100% O(2) at resting V E (4.3 to 9.0 L min) for 60 min or O(2) containing 4.5 to 4.8% CO(2) (to maintain normocapnia) at two to six times resting V E for 90 min. The half-time of the decrease in COHb fell from 78 +/- 24 min (mean +/- SD) during resting V E with 100% O(2) to 31 +/- 6 min (p < 0. 001) during normocapnic hyperpnea with O(2). The relation between V E and the half-time of COHb reduction approximated a rectangular hyperbola. Because both the method and circuit are simple, this approach may enhance the first-aid treatment of CO poisoning.
Adult↗
Adverse ventilatory strategy causes pulmonary-to-systemic translocation of endotoxin.
Accumulating evidence strongly suggests that ventilatory strategy has an important impact on development of lung injury and patient outcome. Adverse ventilatory strategies have been shown to cause release of pulmonary-derived cytokines and may permit bacterial translocation from the lung to the systemic circulation. Because endotoxin is a potent and clinically important stimulant of cytokine-mediated systemic inflammatory responses that can lead to multiorgan failure, we investigated the effects of ventilatory strategy on lung-to-systemic translocation of endotoxin. We studied the effects of protective (tidal volume [VT] 5 ml. kg(-)(1), positive end-expiratory pressure [PEEP] 10 to 12.5 cm H(2)O) versus nonprotective (VT 12 ml. kg(-)(1), PEEP zero) ventilatory strategy on translocation of endotracheally instilled endotoxin. Anesthetized New Zealand White rabbits were subjected to saline lung lavage, and 32 were randomized to one of four groups: PS (protective ventilation + instilled saline); PE (protective ventilation + instilled endotoxin); NS (nonprotective ventilation + instilled saline); NE (nonprotective ventilation + instilled endotoxin), and ventilated for 3 h. Plasma endotoxin levels increased significantly in the NE group, and remained low and unchanged in the other groups. Peak levels of plasma tumor necrosis factor-alpha (TNF-alpha) were higher in NE versus other groups. Pa(O(2)) and mean arterial pressure (Pa) were lowest, and requirement for pressor and bicarbonate support greatest, in the NE group. Finally, plasma endotoxin levels were significantly greater in eventual nonsurvivors than survivors. These data provide convincing evidence for pulmonary translocation of lung-derived endotoxin. This translocation depends on ventilatory strategy, and suggests a pathophysiologic link between ventilatory strategy and outcome.
Animals↗