Na,K-ATPase gene transfer increases liquid clearance during ventilation-induced lung injury

Mechanical ventilation with high tidal volumes (HVT) downregulates alveolar Na,K-ATPase function and impairs lung liquid clearance. We hypothesized that overexpression of Na,K-ATPase in the alveolar epithelium could counterbalance these changes and increase clearance in a rat model of mild ventilation-induced lung injury. We used a surfactant-based system to deliver 4 x 10(9) plaque-forming units of E1a-/E3- recombinant adenovirus containing either a rat beta1 Na,K-ATPase subunit cDNA (adbeta1) or no cDNA (adnull) to rat lungs 7 days before ventilation with a VT of approximately 40 ml/kg (peak airway pressure of less than 35 cm H2O) for 40 minutes. Lung liquid clearance and Na, K-ATPase activity and protein abundance were increased in HVT adbeta1-infected lungs as compared with sham and adnull-infected HVT lungs. These results suggest that Na,K-ATPase subunit gene overexpression in the alveolar epithelium increases Na,K-ATPase function and lung liquid clearance in a model of HVT. We provide here the first evidence that using a genetic approach improves active Na+ transport and thus liquid clearance in the setting of mild ventilation-induced lung injury.     

Partial liquid ventilation

Mortality from the adult respiratory distress syndrome (ARDS) and the infant respiratory distress syndrome remains high despite numerous interventions and modalities. Perfluorocarbons (PFC) are inert liquids that can dissolve large amounts of oxygen and carbon dioxide and can be used as respiratory media. Partial liquid ventilation uses PFC to partially fill the lungs of patients with ARDS to improve gas exchange and support them. Studies in animals and humans (mostly neonates) using perflubron, which is currently the only PFC approved for clinical use, have shown that they are safe and effective in improving oxygenation. In this article the rationale of the technique, its historical background, and animal and clinical data to date are reviewed.     

Synthetic RGDS peptide attenuates mechanical ventilation-induced lung injury in rats

Pulmonary inflammation is the key pathological presentation of mechanical ventilation-induced lung injury (VILI), and synthetic RGDS peptide has been suggested to attenuate pulmonary inflammation. The present study aimed to determine whether RGDS peptide has protective effects on VILI. Rats received 4 hours of high tidal volume mechanical ventilation with or without pretreatment with RGDS. Rats that were kept on spontaneous respiration served as controls. At the end of 4 hours, rats that received 4 hours of mechanical ventilation exhibited serious pulmonary pathological changes, more polymorphonulear and mononuclear leukocyte recruitment, more tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) production, higher total protein contents in the bronchoalveolar lavage fluids (BALFs) and more lung phosphorylation of integrin β3 and nuclear factor-κB inhibitor (I-κB), and increased NF-κB p65 binding activity than did the control group. Administration of RGDS peptide tended to significantly inhibit all these changes induced by mechanical ventilation. These results suggested that RGDS pretreatment might improve VILI in rats by attenuating inflammatory cascade related to integrin αVβ3 and NF-κB.     

Effects of partial liquid ventilation on unilateral lung injury in dogs

STUDY OBJECTIVE: The overall physiologic effect of partial liquid ventilation (PLV) in the setting of unilateral lung injury remains unclear. Therefore, we evaluated the effect of PLV on gas exchange in unilateral lung injury. DESIGN AND METHODS: Left unilateral lung injury was induced in 14 adult dogs by oleic acid instillation into a left pulmonary artery. The animals were divided into two groups: gas ventilation (GV) and PLV. During both GV and PLV, systemic blood gas levels were analyzed. Oxygen consumption (O(2)), carbon dioxide production (CO(2)) and pulmonary blood flow (Q) of both the right lung (uninjured lung) and left lung (injured lung) were measured. RESULTS: During PLV, O(2) of the injured left lung (o(2)-injured), CO(2) of the injured left lung (CO(2)-injured), and Q of the injured left lung (Q-injured) were greater than those in GV (O(2)-injured, 41.6 mL/min vs 23.4 mL/min, p = 0.006; CO(2)-injured, 34.4 mL/min vs 25.5 mL/min, p = 0.026; and Q-injured, 0.47 L/min vs 0.22 L/min, p = 0.002, respectively). However, overall PaO(2) during PLV was less than that during GV, likely due to either a redistribution of Q toward the injured lung (PLV Q-injured, 0.47 L/min vs GV Q-injured, 0.22 L/min; p = 0.002) or reduced gas exchange efficiency in the healthy lung. CONCLUSIONS: We conclude that in our model, PLV increases O(2) and VCO(2) in the injured lung. However, over all gas exchange efficiency is reduced.     

Heliox improves gas exchange during high-frequency ventilation in a pediatric model of acute lung injury.

Because heliox has a lower density as compared with air, we postulated that heliox would improve gas exchange during high-frequency oscillatory ventilation (HFOV) in a model of acute lung injury. In a prospective, cross-over trial, we studied 11 piglets with acute lung injury created by saline lavage. With initial conditions of permissive hypercapnia (Pa(CO(2)) 55-80 mm Hg), each piglet underwent HFOV with a fixed mean airway pressure, pressure oscillation, and ventilatory frequency. The following gas mixtures were used: oxygen-enriched air (60% O(2)/40% N(2)) and heliox (60% O(2)/ 40% He and 40% O(2)/60% He). Compared with oxygen-enriched air, the 40% and 60% helium gas mixtures reduced Pa(CO(2)) by an average of 10.5 and 20.3 mm Hg, respectively. A modest improvement in oxygenation was seen with the 40% helium mixture. We conclude that heliox significantly improves carbon dioxide elimination and modestly improves oxygenation during HFOV in a model of acute lung injury. On the basis of test lung data and plethysmography measurements, we also conclude that heliox improves carbon dioxide elimination primarily through increased tidal volume delivery. Although heliox improved gas exchange during HFOV in our model, increased tidal volume delivery may limit clinical applicability.     

部分液体通气治疗急性肺损伤家兔

目的 观察部分液体通气（ＰＬＶ）对急性肺损伤（ＡＬＩ）家兔肺内气体交换、肺顺应性、体循环功能的影响。方法 健康雄性新西兰兔２４只,用油酸制备成急性肺损伤模型后随机分为３组,每组８只。各组采用不同方法治疗：呼气末正压（ＰＥＥＰ）组,常规机构通气（ＣＭＶ）＋ＰＥＥＰ治疗;生理盐水（ＮＳ）组,肺内注入ＮＳ同时＋ＣＭＶ＋ＰＥＥＰ;ＰＤＣ组,肺内注入全氟碳化合物－全氟萘烷（ＦＤＣ）同时＋ＣＭＶ＋ＰＥＥＰ。分     

Surfactant treatment for ventilation-induced lung injury in rats: effects on lung compliance and cytokines

The objective of this study was to determine if exogenous surfactant therapy could prevent the harmful effects of ventilation at high tidal volumes without positive end-expiratory pressure (PEEP). Rats were randomized to either a nontreated control group (8 mL/kg 4 cm H2O PEEP), a nontreated injuriously ventilated group (20 mL/kg 0 cm H2O PEEP) or a treatment group of either 50 mg/kg, 50 mg/kg + 5% surfactant-associated protein A, 100 mg/kg exogenous surfactant followed by injurious ventilation. Isolated lungs from animals in all 5 groups were ventilated in a humidified box at 37 degrees C for 2 hours. Pressure-volume curves and light microscopy showed that surfactant treatment reduced the ventilation-induced lung injury (VILI). Inflammatory cytokines (tumor necrosis factor-alpha [TNFalpha], interleukin [IL]-1beta, and IL-6) in the lavage were significantly higher in injuriously ventilated lungs compared to the control group. However the 3 treatment groups had cytokine concentrations that were similar to the injuriously ventilated group. We conclude that surfactant treatment is beneficial in preventing VILI; however, it does not prevent the release of inrflammatory cytokines during mechanical ventilation.     

Peritoneal dialysis improves lung function in rats with lung injury induced by shock wave

<正>Objective To prove the efficacy of peritoneal dialysis on shock wave-induced acute lung injury of rats,and analyze its mechanisms.Methods Forty-five adult Sprague-Dawley rats were randomly divided into three groups:control group,sham operation(Sham) group     

Effects of partial liquid ventilation with FC-77 on acute lung injury in newborn piglets.

Partial liquid ventilation (PLV) with various types of perfluorochemicals (PFC) has been shown to be beneficial in treating acute lung injury. FC-77 is a type of PFC with relatively high vapor pressure and evaporative losses during PLV. This study tested the hypothesis that using FC-77 for PLV with hourly replacement is effective in treating acute lung injury. Fifteen neonatal piglets were randomly and evenly divided into 3 study groups: 1) lavage-induced lung injury followed by conventional mechanical ventilation (Lavage-CMV); 2) lavage-induced lung injury followed by PLV using FC-77 with hourly replacement (11.2 +/- 1.5 mL/kg/hr) (Lavage-PLV); and 3) sham lavage injury followed by conventional mechanical ventilation (Control). Immediately after induction, repeated saline lavages induced acute lung injury characterized by decreases in dynamic lung compliance, arterial oxygen tension, and arterial pH, and increases in arterial CO(2) tension and oxygenation index, whereas the sham lavage procedure failed to do so. During the 3-hr period of CMV, these pulmonary and cardiovascular parameters remained stable in the Control group, but deteriorated in the Lavage-CMV group. In contrast, after acute lung injury, low lung compliance, abnormal gas exchange, acidosis, and inadequate oxygenation significantly improved in the Lavage-PLV group. Histological analysis of these 3 study groups revealed that the Lavage-CMV group had the highest lung injury score and the Control group had the lowest. These results suggest that, in comparison to CMV, PLV with FC-77 and hourly replacement of FC-77 promotes more favorable pulmonary mechanics, gas exchange, oxygenation, and lung histology in a piglet model of acute lung injury.     

Variable tidal volume ventilation improves lung mechanics and gas exchange in a rodent model of acute lung injury

Random variations in breath rate and tidal volume during mechanical ventilation in the setting of acute lung injury have been shown to improve arterial oxygen tension. To test whether this improvement occurs over a specific range of variability, we examined several ventilation protocols in guinea pigs with endotoxin-induced lung injury. In Group I (n = 10), after 30 min of conventional volume-cycled ventilation, animals were ventilated with variable ventilation for 30-min intervals, during which time tidal volume was randomly varied by 10, 20, 40, and 60% of the mean, while simultaneously adjusting the frequency to maintain constant minute ventilation. In a second group of animals (Group II, n = 4), conventional volume-cycled ventilation was administered for 3 h. Variable ventilation significantly improved lung function over conventional volume-cycled ventilation. In Group I, lung elastance decreased, and blood oxygenation increased significantly during periods of 40 and 60% variable ventilation (p < 0.05) compared with conventional ventilation. These data indicate that variable ventilation is effective in improving lung function and gas exchange during acute lung injury.     

Preserved spontaneous breathing improves cardiac output during partial liquid ventilation.

The aim of this study was to examine whether preserved spontaneous breathing (SB) supported by proportional-assist ventilation (PAV) would improve cardiac output (CO) during partial liquid ventilation (PLV) in rabbits with and without lung disease if compared with time-cycled, volume-controlled ventilation (CV) combined with muscle paralysis (MP). PLV was initiated in 17 healthy rabbits and 17 surfactant-depleted rabbits using 12 to 15 ml/kg of perfluorodecaline. Both ventilatory modes, SB+PAV and CV+MP, were applied in random sequence using a crossover design. CO was measured by thermodilution. CO was significantly higher during SB+PAV than during CV+MP: 136 +/- 21 ml/kg x min (mean +/- SD) versus 120 +/- 30 ml/kg x min (p = 0.004) in healthy rabbits, and 147 +/- 19 ml/kg x min versus 111 +/- 13 ml/kg x min (p < 0.0001) in surfactant-depleted rabbits, resulting in an improved oxygen delivery. This difference was mainly caused by a larger stroke volume during SB+PAV, whereas there was little change in heart rate. In surfactant-depleted rabbits, SB+PAV resulted in improved arterial blood pressure and arterial and mixed venous pH and in a higher PaO2 at the same level of PEEP and mean airway pressure. We conclude that during PLV, CO is higher during SB+PAV than during CV+MP, resulting in an improved oxygen delivery. In surfactant-depleted rabbits, improved CO, oxygen delivery, and arterial blood pressure resulted in higher pH, possibly reflecting improved tissue perfusion and oxygenation.     

Mechanical ventilation affects alveolar fibrinolysis in LPS-induced lung injury.

The aim of the present study was to determine the effects of mechanical ventilation on alveolar fibrin turnover in lipopolysaccharide (LPS)-induced lung injury. In a randomised controlled trial, Sprague-Dawley rats (n = 61) were allocated to three ventilation groups after intratracheal LPS (Salmonella enteritidis) instillations. Group I animals were subjected to 16 cmH(2)O positive inspiratory pressure (PIP) and 5 cmH(2)O positive end-expiratory pressure (PEEP); group II animals to 26 cmH(2)O PIP and 5 cmH(2)O PEEP; and group III animals to 35 cmH(2)O PIP and 5 cmH(2)O PEEP. Control rats (not mechanically ventilated) received LPS. Healthy rats served as a reference group. Levels of thrombin-antithrombin complex (TATc), D-dimer, plasminogen activator inhibitor (PAI) activity and PAI-1 antigen in bronchoalveolar lavage fluid were measured. LPS-induced lung injury increased TATc, D-dimer and PAI activity and PAI-1 antigen levels versus healthy animals. High pressure-amplitude ventilation increased TATc concentrations. D-dimer concentrations were not significantly raised. Instead, PAI activity increased with the amplitude of the pressure, from 0.7 U.mL(-1) in group I to 3.4 U.mL(-1) in group II and 5.0 U.mL(-1) in group III. There was no change in PAI-1 antigen levels. In conclusion, mechanical ventilation creates an alveolar/pulmonary anti-fibrinolytic milieu in endotoxin-induced lung injury which, at least in part, might be due to an increase in plasminogen activator inhibitor activity.     

Partial liquid ventilation for acute respiratory distress syndrome

PLV represents an intriguing alternative paradigm in the approach to the patient with ALI. Within the past decade, substantial information has become available regarding this technique. Clearly, PLV is feasible in patients with ALI and ARDS, and it appears to be safe with respect to short-term effects on hemodynamics and lung physiology, as well as long-term toxicity (although further research in this area is warranted). Although PLV has not yet been proven to be superior to traditional mechanical ventilation for patients with ALI or ARDS, PLV possesses an intriguing combination of physical, physiologic, and biologic effects: "Liquid PEEP" effect--e.g., more effective recruitment of dependent lung zones than achieved by gas ventilation Anti-inflammatory effects Lavage of alveolar debris Mitigation of ventilator-induced lung injury Direct anti-inflammatory effects--e.g., decreased macrophage release of proinflammatory cytokines, etc. Prevention of nosocomial pneumonia Combination with other modalities--e.g., exogenous surfactant replacement, inhaled NO, prone position Enhanced delivery of drugs or gene vectors into the lung. The results of ongoing and future clinical trials will be necessary to establish whether PLV improves clinical outcomes in patients with ALI or ARDS, or specific subgroups of such patients. Significant work also remains to be done to define the optimum dose level of PLV and the most appropriate ventilatory strategies.     

Partial liquid ventilation: effects of liquid volume and ventilatory settings on perfluorocarbon evaporation.

During partial liquid ventilation perfluorocarbons are eliminated mainly by evaporation via the airways. The effects of intrapulmonary perfluorocarbon volume, respiratory rate, tidal volume, as well as the level of end-expiratory pressure on perfluorocarbon elimination from isolated lungs, were studied. Nonperfused rabbit lungs underwent partial liquid ventilation (2-15 mL x kg(-1) perfluorocarbon) with variable levels of end-expiratory pressure (0-10 cmH2O), respiratory rates (15-60 breaths x min(-1)) and tidal volumes (3.3-10.0 mL x kg(-1)). Evaporative loss of perfluorocarbon was determined gravimetrically as rate of change in lung weight. At constant respiratory settings, intrapulmonary liquid volume determined evaporative loss in a nonlinear fashion. Mean evaporation at a liquid volume of 5 mL x kg(-1) was 13% lower compared to evaporation at a liquid volume of 15 mL x kg(-1). Any increase in end-expiratory pressure reduced perfluorocarbon evaporation, e.g. by approximately 50% when end-expiratory pressure was increased from 0 to 10 cmH2O. At constant end-expiratory pressure and perfluorocarbon filling evaporation increased in a linear fashion with increasing respiratory rate and tidal volume. In summary, the experiments suggested that evaporative loss of perfluorocarbons during partial liquid ventilation of isolated lungs is increased with increasing intrapulmonary liquid volume, respiratory rate and tidal volume and is reduced in a level-dependent fashion by the application of positive end-expiratory pressure.     

Partial liquid ventilation in adult patients with acute respiratory distress syndrome

RATIONALE: Despite recent clinical trials demonstrating improved outcome in acute respiratory distress syndrome (ARDS), mortality remains high. Partial liquid ventilation (PLV) using perfluorocarbons has been shown to improve oxygenation and decrease lung injury in various animal models. OBJECTIVE: To determine if PLV would have an impact on outcome in patients with ARDS. METHODS: Patients with ARDS were randomized to (1) conventional mechanical ventilation (CMV; n=107), (2) "low-dose" perfluorocarbon (10 ml/kg; n=99), and (3) "high-dose" perfluorocarbon (20 ml/kg; n=105). Patients in all three groups were ventilated using volume ventilation, Vt or= 0.5, and positive end-expiratory pressure >or= 13 cm H(2)O. RESULTS: The 28-d mortality in the CMV group was 15%, versus 26.3% in the low-dose (p=0.06) and 19.1% in the high-dose (p=0.39) PLV groups. There were more ventilator-free days in the CMV group (13.0+/-9.3) compared with both the low-dose (7.4+/-8.5; p<0.001) and high-dose (9.9+/-9.1; p=0.043) groups. There were more pneumothoraces, hypoxic episodes, and hypotensive episodes in the PLV patients. CONCLUSIONS: PLV at both high and low doses did not improve outcome in ARDS compared with CMV and cannot be recommended for patients with ARDS.     

Clinicians' approaches to mechanical ventilation in acute lung injury and ARDS.

STUDY OBJECTIVES: To examine clinicians' approaches to mechanical ventilation in patients with acute lung injury (ALI; PaO(2)/fraction of inspired oxygen [FIO(2)] 35 cm H(2)O in 26% of patients. Seventy-eight percent of patients with ARDS received 相似文献   

Inhaled mannitol improves lung function in cystic fibrosis

BACKGROUND: The airways in patients with cystic fibrosis (CF) are characterized by the accumulation of tenacious, dehydrated mucus that is a precursor for chronic infection, inflammation, and tissue destruction. The clearance of mucus is an integral component of daily therapy. Inhaled mannitol is an osmotic agent that increases the water content of the airway surface liquid, and improves the clearance of mucus with the potential to improve lung function and respiratory health. To this end, this study examined the efficacy and safety of therapy with inhaled mannitol over a 2-week period. METHODS: This was a randomized, double-blind, placebo-controlled, crossover study. Thirty-nine subjects with mild-to-moderate CF lung disease inhaled 420 mg of mannitol or placebo twice daily for 2 weeks. Following a 2-week washout period, subjects were entered in the reciprocal treatment arm. Lung function, respiratory symptoms, quality of life, and safety were assessed. RESULTS: Mannitol treatment increased FEV(1) from baseline by a mean of 7.0% (95% confidence interval [CI], 3.3 to 10.7) compared to placebo 0.3% (95% CI, - 3.4 to 4.0; p < 0.001). The absolute improvement with mannitol therapy was 121 mL (95% CI, 56.3 to 185.7), which was significantly more than that with placebo (0 mL; 95% CI, - 64.7 to 64.7). The forced expiratory flow in the middle half of the FVC increased by 15.5% (95% CI, - 6.5 to 24.6) compared to that with placebo (increase, 0.7%; 95% CI, - 8.3 to 9.7; p < 0.02). The safety profile of mannitol was adequate, and no serious adverse events related to treatment were observed. CONCLUSIONS: Inhaled mannitol treatment over a period of 2 weeks significantly improved lung function in patients with CF. Mannitol therapy was safe and well tolerated. TRIAL REGISTRATION: (ClinicalTrials.gov) Identifier: NCT00455130.     

Biomarkers of lung injury after one-lung ventilation for lung resection

Background and objective: Acute lung injury contributes to the mortality of patients after lung resection and one‐lung ventilation (OLV). The objective of this study was to characterise the effect of lung resection and OLV on proposed biomarkers of lung injury in exhaled breath condensate (EBC) and plasma. Methods: In adults undergoing lung resection, EBC was collected before and at 30‐min intervals during OLV. Inflammatory mediators were assayed in plasma samples taken preoperatively, immediately postoperatively and 24 h postoperatively. Results: EBC pH decreased from 6.51 ± 0.43 preoperatively, to 6.17 ± 0.78 and 6.09 ± 0.83 at 30 and 60 min, respectively (mean ± SD, P = 0.034, n = 20). Plasma concentrations of the receptor for advanced glycation end‐products, von Willebrand factor and interleukin‐6 increased comparing preoperative and postoperative samples (all P < 0.001, n = 30). By contrast, levels of Krebs von den Lungen‐6 and surfactant protein‐D decreased (P < 0.001, n = 30), and correlated inversely with the extent of lung resected. Conclusions: Lung resection and OLV was associated with a rapid reduction in EBC pH and differential changes in plasma biomarkers of lung injury. Further investigation of EBC pH as a marker of ventilator‐induced lung injury is warranted.