Nonionic surfactant attenuates acute lung injury by restoring epithelial integrity and alveolar fluid clearance.

Introduction: Acute lung injury (ALI) has a great impact and a high mortality rate in intensive care units (ICUs). Excessive air may enter the lungs, causing pulmonary air embolism (AE)-induced ALI. Some invasive iatrogenic procedures cause pulmonary AE-induced ALI, with the presentation of severe inflammatory reactions, hypoxia, and pulmonary hypertension. Pulmonary surfactants are vital in the lungs to reduce the surface tension and inflammation. Nonionic surfactants (NIS) are a kind of surfactants without electric charge on their hydrophilic parts. Studies on NIS in AE-induced ALI are limited. We aimed to study the protective effects and mechanisms of NIS in AE-induced ALI. Materials and methods: Five different groups (n = 6 in each group) were created: sham, AE, AE + NIS pretreatment (0.5 mg/kg), AE + NIS pretreatment (1 mg/kg), and AE + post-AE NIS (1 mg/kg). AE-induced ALI was introduced by the infusion of air via the pulmonary artery. Aerosolized NIS were administered via tracheostomy. Results: Pulmonary AE-induced ALI showed destruction of the alveolar cell integrity with increased pulmonary microvascular permeability, pulmonary vascular resistance, pulmonary edema, and lung inflammation. The activation of nuclear factor-κB (NF-κB) increased the expression of pro-inflammatory cytokines, and sodium-potassium-chloride co-transporter isoform 1 (NKCC1). The pretreatment with NIS (1 mg/kg) prominently maintained the integrity of the epithelial lining and suppressed the expression of NF-κB, pro-inflammatory cytokines, and NKCC1, subsequently reducing AE-induced ALI. Conclusions: NIS maintained the integrity of the epithelial lining and suppressed the expression of NF-κB, pro-inflammatory cytokines, and NKCC1, thereby reducing hyperpermeability, pulmonary edema, and inflammation in ALI.

Acute Hyperglycemia Aggravates Lung Injury via Activation of the SGK1-NKCC1 Pathway.

Acute lung injury (ALI) is characterized by severe hypoxemia and has significantly high mortality rates. Acute hyperglycemia occurs in patients with conditions such as sepsis or trauma, among others, and it results in aggravated inflammation and induces damage in patients with ALI. Regulation of alveolar fluid is essential for the development and resolution of pulmonary edema in lung injury. Pulmonary sodium-potassium-chloride co-transporter 1 (NKCC1) regulates the net influx of ions and water into alveolar cells. The activation of with-no-lysine kinase 4 (WNK4), STE20/SPS1-related proline/alanine rich kinase (SPAK) and the NKCC1 pathway lead to an increase in the expression of NKCC1 and aggravation of ALI. Moreover, hyperglycemia is known to induce NKCC1 expression via the activation of the serum-glucocorticoid kinase 1 (SGK1)-NKCC1 pathway. We aim to evaluate the influence of acute hyperglycemia on the SGK1-NKCC1 pathway in ALI. ALI was induced using a high tidal volume for four hours in a rat model. Acute hyperglycemia was induced by injection with 0.5 mL of 40% glucose solution followed by continuous infusion at 2 mL/h. The animals were divided into sham, sham+ hyperglycemia, ALI, ALI + hyperglycemia, ALI + inhaled bumetanide (NKCC1 inhibitor) pretreatment, ALI + hyperglycemia + inhalational bumetanide pretreatment, and ALI + hyperglycemia + post-ALI inhalational bumetanide groups. Severe lung injury along with pulmonary edema, alveolar protein leakage, and lung inflammation was observed in ALI with hyperglycemia than in ALI without hyperglycemia. This was concurrent with the higher expression of pro-inflammatory cytokines, infiltration of neutrophils and alveolar macrophages (AM) 1, and NKCC1 expression. Inhalational NKCC1 inhibitor significantly inhibited the SGK1-NKCC1, and WNK4-SPAK-NKCC1 pathways. Additionally, it reduced pulmonary edema, inflammation, levels of pro-inflammatory cytokines, neutrophils and AM1 and increased AM2. Therefore, acute hyperglycemia aggravates lung injury via the further activation of the SGK1-NKCC1 pathway. The NKCC1 inhibitor can effectively attenuate lung injury aggravated by acute hyperglycemia.

Phosphodiesterase-4 Inhibitor Roflumilast Attenuates Pulmonary Air Emboli-Induced Lung Injury.

BACKGROUND: Pulmonary air embolism (PAE)-induced acute lung injury (ALI) can be caused by massive air entry into the lung circulation. PAE can occur during diving, aviation, and some iatrogenic invasive procedures. PAE-induced ALI presents with severe inflammation, hypoxia, and pulmonary hypertension, and it is a serious complication resulting in significant morbidity and mortality. Phosphodiesterase-4 (PDE4) inhibitors can regulate inflammation and are therefore expected to have a therapeutic effect on ALI. However, the effect of the PDE4 inhibitor roflumilast on PAE-induced ALI is unknown. METHODS: The PAE model was undertaken in isolated-perfused rat lungs. Four groups (n = 6 in each group) were defined as follows: control, PAE, PAE + roflumilast 2.5 mg/kg, and PAE + roflumilast 5 mg/kg. Induction of PAE-induced ALI was achieved via the infusion of 0.7 cc air through the pulmonary artery. Roflumilast was administered via perfusate. All groups were assessed for pulmonary microvascular permeability, lung histopathology changes, pulmonary edema (lung weight/body weight, lung wet/dry weight ratio), tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-17, nuclear factor-kappa B (NF-κB), and inhibitor of NF-κB alpha (IκB-α). RESULTS: After the induction of air, PAE-induced ALI presented with pulmonary edema, pulmonary microvascular hyperpermeability, and lung inflammation with neutrophilic sequestration. The PAE-induced ALI also presented with increased expressions of IL-1ß, IL-6, IL-8, IL-17, TNF-α, and NF-κB and decreased expression of IκB-α. The administration of roflumilast decreased pulmonary edema, inflammation, cytokines, NF-κB, and restored IκB-α level. CONCLUSIONS: PAE-induced ALI presents with lung inflammation with neutrophilic sequestration, pulmonary edema, hyperpermeability, increased cytokine levels, and activation of the NF-κB pathway. Roflumilast attenuates lung edema and inflammation and downregulates the NF-κB pathway and cytokines.

Adaptive Support Ventilation Attenuates Ventilator Induced Lung Injury: Human and Animal Study.

Adaptive support ventilation (ASV) is a closed-loop ventilation, which can make automatic adjustments in tidal volume (VT) and respiratory rate based on the minimal work of breathing. The purpose of this research was to study whether ASV can provide a protective ventilation pattern to decrease the risk of ventilator-induced lung injury in patients of acute respiratory distress syndrome (ARDS). In the clinical study, 15 ARDS patients were randomly allocated to an ASV group or a pressure-control ventilation (PCV) group. There was no significant difference in the mortality rate and respiratory parameters between these two groups, suggesting the feasible use of ASV in ARDS. In animal experiments of 18 piglets, the ASV group had a lower alveolar strain compared with the volume-control ventilation (VCV) group. The ASV group exhibited less lung injury and greater alveolar fluid clearance compared with the VCV group. Tissue analysis showed lower expression of matrix metalloproteinase 9 and higher expression of claudin-4 and occludin in the ASV group than in the VCV group. In conclusion, the ASV mode is capable of providing ventilation pattern fitting into the lung-protecting strategy; this study suggests that ASV mode may effectively reduce the risk or severity of ventilator-associated lung injury in animal models.

Pre-Treatment with Ten-Minute Carbon Dioxide Inhalation Prevents Lipopolysaccharide-Induced Lung Injury in Mice via Down-Regulation of Toll-Like Receptor 4 Expression.

Various animal studies have shown beneficial effects of hypercapnia in lung injury. However, in patients with acute respiratory distress syndrome (ARDS), there is controversial information regarding the effect of hypercapnia on outcomes. The duration of carbon dioxide inhalation may be the key to the protective effect of hypercapnia. We investigated the effect of pre-treatment with inhaled carbon dioxide on lipopolysaccharide (LPS)-induced lung injury in mice. C57BL/6 mice were randomly divided into a control group or an LPS group. Each LPS group received intratracheal LPS (2 mg/kg); the LPS groups were exposed to hypercapnia (5% carbon dioxide) for 10 min or 60 min before LPS. Bronchoalveolar lavage fluid (BALF) and lung tissues were collected to evaluate the degree of lung injury. LPS significantly increased the ratio of lung weight to body weight; concentrations of BALF protein, tumor necrosis factor-α, and CXCL2; protein carbonyls; neutrophil infiltration; and lung injury score. LPS induced the degradation of the inhibitor of nuclear factor-κB-α (IκB-α) and nuclear translocation of NF-κB. LPS increased the surface protein expression of toll-like receptor 4 (TLR4). Pre-treatment with inhaled carbon dioxide for 10 min, but not for 60 min, inhibited LPS-induced pulmonary edema, inflammation, oxidative stress, lung injury, and TLR4 surface expression, and, accordingly, reduced NF-κB signaling. In summary, our data demonstrated that pre-treatment with 10-min carbon dioxide inhalation can ameliorate LPS-induced lung injury. The protective effect may be associated with down-regulation of the surface expression of TLR4 in the lungs.

With-No-Lysine Kinase 4 Mediates Alveolar Fluid Regulation in Hyperoxia-Induced Lung Injury.

OBJECTIVES: To investigate mechanisms involved in the regulation of epithelial ion channels and alveolar fluid clearance in hyperoxia-induced lung injury. DESIGN: Laboratory animal experiments. SETTING: Animal care facility procedure room in a medical center. SUBJECTS: Wild-type, STE20/SPS1-related proline/alanine-rich kinase knockout (SPAK(-/-)), and with-no-lysine kinase 4 knockin (WNK4(D561A/+)) mice. INTERVENTIONS: Mice were exposed to room air or 95% hyperoxia for 60 hours. MEASUREMENTS AND MAIN RESULTS: Exposure to hyperoxia for 60 hours increased the lung expression of with-no-lysine kinase 4 and led to STE20/SPS1-related proline/alanine-rich kinase and sodium-potassium-chloride cotransporter phosphorylation, which resulted in the suppression of alveolar fluid clearance and increase of lung edema. WNK4(D561A/+) mice at the baseline presented an abundance of epithelium sodium channel and high levels of STE20/SPS1-related proline/alanine-rich kinase and sodium-potassium-chloride cotransporter phosphorylation. Compared with the wild-type group, hyperoxia caused greater epithelium sodium channel expression in WNK4(D561A/+) mice, but no significant difference in STE20/SPS1-related proline/alanine-rich kinase and sodium-potassium-chloride cotransporter phosphorylation. The functional inactivation of sodium-potassium-chloride cotransporter by gene knockout in SPAK(-/-) mice yielded a lower severity of lung injury and longer animal survival, whereas constitutive expression of with-no-lysine kinase 4 exacerbated the hyperoxia-induced lung injury. Pharmacologic inhibition of sodium-potassium-chloride cotransporter by inhaled furosemide improved animal survival in WNK4(D561A/+) mice. By contrast, inhibition of epithelium sodium channel exacerbated the hyperoxia-induced lung injury and animal death. CONCLUSIONS: With-no-lysine kinase 4 plays a crucial role in the regulation of epithelial ion channels and alveolar fluid clearance, mainly via phosphorylation and activation of STE20/SPS1-related proline/alanine-rich kinase and sodium-potassium-chloride cotransporter.

Activated protein C attenuates ischemia-reperfusion-induced acute lung injury.

Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions, such as lung transplantation, acute pulmonary embolism after thrombolytic therapy, re-expansion of collapsed lung from pneumothorax, or pleural effusion, cardiopulmonary bypass, etc. Because mortality remains high despite advanced medical care, prevention and treatment are important clinical issues. Activated protein C (APC) manifests multiple activities with antithrombotic, profibrinolytic, and anti-inflammatory effects. We therefore conducted this study to determine the beneficial effects of APC in IR-induced ALI. IR-induced ALI was conducted in a rat model of isolated-perfused lung in situ. The animals were divided into the control group, IR group, and IR+APC group. There were six adult male Sprague-Dawley rats in each group. The IR caused significant pulmonary microvascular hyperpermeability, pulmonary edema and dysfuction, increased cytokines (tumor necrosis factor (TNF)-α, IL-17, CXCL-1), and neutrophils infiltration in lung tissues. Administration of APC significantly attenuated IR-induced ALI with improving microvascular permeability, pulmonary edema, pulmonary dysfunction, and suppression inflammatory response. The current study demonstrates the beneficial effects of APC in IR-induced ALI. This protective effect is possibly associated with the inhibition of TNF-α, IL-17A, CXCL1, and neutrophils infiltration in lung tissues. However, the current results were obtained in an animal model and it is still necessary to confirm these findings in human subjects. If we can demonstrate the benefits of APC to protect IR lung injury, we can postulate that APC is a potential therapeutic drug for lung preservation.

Influences of pleural effusion on respiratory mechanics, gas exchange, hemodynamics, and recruitment effects in acute respiratory distress syndrome.

BACKGROUND: Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) cause substantial morbidity and mortality despite improvements in the understanding of lung injury and advances in treatment. Recruitment maneuver (RM) with high sustained airway pressures is proposed as an adjunct to mechanical ventilation to maintain alveolar patency. In addition, RM has been advocated to improve pulmonary gas exchange. However, many factors may influence responses to RM and the effect of pleural effusion (PLE) is unknown. METHOD: There were four groups in this study (n = 6 in each group). Group A was the control group, group B was the PLE group, group C was ARDS with RM, and group D was ARDS with PLE and RM. RM was performed in groups C and D, consisting of a peak pressure of 45 cm H2O with positive end-expiratory pressure of 35 cm H2O sustained for 1 min. Arterial blood gas, systemic and pulmonary hemodynamics, lung water, and respiratory mechanics were measured throughout. RESULT: After the induction of ALI/ARDS, there were significant decreases in partial pressure of oxygen in arterial blood, mean arterial pressure, systemic vascular resistance, and lung compliance. There were also significant increases in the alveolar-arterial O2 tension difference, partial pressure of arterial carbon dioxide, mean pulmonary arterial pressure, pulmonary vascular resistance, and lung water. The RM improved oxygenation, which was attenuated by PLE. CONCLUSIONS: ALI/ARDS leads to poor oxygenation and hemodynamics. RM results in improved oxygenation, but this improvement is attenuated by PLE.

The Effects of Automatic Inspiratory Rise Time and Flow Termination on Operation of Closed-Loop Ventilation.

BACKGROUND: Adaptive ventilation mode (AVM) is a automated mode of mechanical ventilation. AVM is comprable to adaptive support ventilation (ASV). Both recommend a tidal volume (VT) and breathing frequency (f) combination based on lung mechanics, but AVM also automatically adjusts rise time and flow termination of pressure support breaths. How these added features of AVM affect VT and f recommendations compared to ASV is not clear. The present study compared these 2 modes in a test lung with obstructive and restrictive mechanics. METHODS: The experiment was performed in a simulated lung model in which the compliance (C) and resistance (R) could be altered independently. The ventilatory parameters at different minute volumes (MinVol%) in AVM or ASV mode were recorded. RESULTS: When MinVol% was set at 100%, AVM provided a similar VT and f combination compared to ASV with decreasing compliance or increasing resistance. However, when MinVol% was increased to 250% simulating hyperventilation, for the severely obstructive lung (C60, R70) model, AVM provided a significantly higher f (26 ± 0.6 breaths/min vs 7.00 ± 0 breaths/min in ASV) and lower VT (240 ± 80 mL vs 491 ± 131 mL in ASV). CONCLUSIONS: The addition of automatic control of rise time and flow termination functions did not affect recommended ventilator settings in AVM in the noncompliant or obstructive lung when minute ventilation (V̇E) was low. At higher V̇E, AVM compared to ASV recommended a ventilatory strategy with lower VT and higher f. These results need to be validated in patients.

Hypercapnic acidosis attenuates reperfusion injury in isolated and perfused rat lungs.

OBJECTIVE: Although ischemia-reperfusion injury is a major determinant of primary graft dysfunction after lung transplantation, an approach to extend preoperative lung preservation to postoperative protection has not yet been defined. The purpose of this study was to determine the protective effects of and the signal pathway regulated by hypercapnic acidosis in ischemia-reperfusion-induced lung injury. DESIGN: Animal study. SETTING: Animal care facility procedure room in a medical center. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: Lung injury was induced in a clinically relevant ex vivo animal model. Animals were divided into a control group (FICO(2), 5%; n = 6), ischemia-reperfusion group (FICO(2), 5%; n = 6), and hypercapnic acidosis (ischemia-reperfusion + hypercapnic acidosis) group (FICO(2), 10%; n = 6). MEASUREMENTS AND MAIN RESULTS: Ischemia-reperfusion caused significant increases in alveolar lavage and perfusate tumor necrosis factor-α, inflammatory cell infiltration, lung tissue malondialdehyde, bronchoalveolar lavage fluid protein concentration and lactate dehydrogenase activity, lung weight gain, and infiltration coefficient. Ventilation with 10% CO(2) significantly suppressed the inflammatory response and attenuated lung ischemia-reperfusion injury. Our results also showed that hypercapnic acidosis significantly inhibited the ischemia-reperfusion-induced phosphorylation and nuclear translocation of nuclear factor-κB. This was associated with elevation of inhibitor of nuclear factor-κB-α level and reduced IκB kinase-ß phosphorylation, suggesting a suppression of IκB kinase and thus IκB-α activation. CONCLUSIONS: Hypercapnic acidosis may attenuate lung ischemia-reperfusion injury by suppressing the activation of the IκB kinase-nuclear factor-κB pathway.

Slug confers resistance to the epidermal growth factor receptor tyrosine kinase inhibitor.

RATIONALE: Non-small cell lung cancers carrying epidermal growth factor receptor (EGFR) mutations respond well to EGFR tyrosine kinase inhibitors (TKIs), but patients ultimately develop drug resistance and relapse. Although epithelial-mesenchymal transition (EMT) can predict resistance to EGFR TKIs, the molecular mechanisms are still unknown. OBJECTIVES: To examine the role of EMT regulators in resistance to gefitinib. METHODS: The expression level of EMT regulators in gefitinib-sensitive cells (PC9) and gefitinib-resistant cells (PC9/gef) was determined using quantitative real-time reverse transcription-polymerase chain reaction and Western blot analysis. Molecular manipulations (silencing or overexpression) were performed to investigate the effects of EMT regulators on gefitinib resistance in vitro, and a xenograft mouse model was used for in vivo confirmation. In addition, cancer cells from 44 patients with malignant pleural effusions of lung adenocarcinoma were collected for analysis of EMT regulator mRNA by quantitative real-time reverse transcription-polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: Slug expression, but not that of snail, twist, or zeb-1, was significantly increased in PC9/gef compared with PC9 cells. Slug knockdown in PC9/gef cells reversed resistance to gefitinib, and overexpression of Slug in PC9 cells protected cells from gefitinib-induced apoptosis. Silencing of Slug in gefitinib-resistant cells restored gefitinib-induced apoptosis primarily through Bim up-regulation and activation of caspase-9. Slug enhanced tumor growth in a xenograft mouse model, even with gefitinib treatment. In clinical samples, Slug expression was significantly higher in cancer cells with resistance to EGFR TKIs than in treatment-naive cancer cells. CONCLUSIONS: Slug contributes to the resistance to gefitinib and may be a potential therapeutic target for treating resistance to EGFR TKIs.

Preventive use of noninvasive ventilation after extubation: a prospective, multicenter randomized controlled trial.

BACKGROUND: The effectiveness of noninvasive ventilation (NIV) after extubation in preventing post-extubation respiratory failure is still controversial. METHODS: We conducted a prospective, multicenter randomized controlled study involving patients on mechanical ventilation for > 48 hours who tolerated a 2-hour spontaneous breathing trial and were subsequently extubated. The patients were randomized to NIV or standard medical therapy. Re-intubation rate within 72 hours was the primary outcome measure. Multivariable logistic regression analysis was used to determine predictors for extubation failure. RESULTS: We randomized 406 patients to either NIV (no. = 202) or standard medical therapy (no. = 204). The 2 groups had similar baseline clinical characteristics. There were no differences in extubation failure (13.2% in control and 14.9% in NIV), intensive care unit or hospital mortality. Cardiac failure was a more common cause of extubation failure in control than in NIV. There was no difference in rapid shallow breathing index (RSBI) in extubation failure patients between control (80) and NIV (73). When using data from all patients, we found Acute Physiology and Chronic Health Evaluation (APACHE II) scores (odds ratio [OR] 1.13, 95% CI 1.07-1.20, P < .001), maximal inspiratory pressure (OR 1.04, 95% CI 1.00-1.08, P = .03), and RSBI (OR 1.03, 95% CI 1.02-1.05, P < .001) to be predictors of extubation failure. Abundant secretions were the most common reason (35.1%) for extubation failure identified by attending physicians. CONCLUSIONS: Preventive use of NIV after extubation in patients who passed spontaneous breathing trial did not show benefits in decreasing extubation failure rate or the mortality rate.

Five-day course of budesonide inhalation suspension is as effective as oral prednisolone in the treatment of mild to severe acute asthma exacerbations in adults.

BACKGROUND: Limited evidence is available on the use of budesonide inhalation suspension (BIS) for the treatment of mild to severe acute asthma exacerbations (AAE) in adults in an inpatient setting. This study was conducted to evaluate the efficacy of a five-day course of BIS compared with oral prednisolone (OP) in the management of adults with AAE. METHODS: A retrospective study examined the response of 28 patients hospitalized with mild to severe acute asthma exacerbation from January 2003 to December 2003. These patients, who were steroid free ≥ 1 yr, were administered a five-day course of BIS (2 × 2 mg bid) or OP (2 × 15 mg bid). PEF, FEV(1) and asthma symptom scores were recorded daily. RESULTS: The BIS (n = 13) and OP (n = 15) treatment groups were comparable at baseline for demographic characteristics and prebronchodilator (fenoterol) FEV(1) of 52.4% predicted normal value and 54.6% predicted normal value, respectively. Mean change of morning PEF was 152 L/min during BIS treatment and 130 L/min for OP treatment; the mean changes of morning forced expiratory volumes in 1 s (FEV(1)) were 1.0 and 0.7 L, respectively. The mean change in daytime symptom scores were -1.6 and -1.3 in the BIS and the OP groups, respectively. Improvements in PEF, FEV(1) and daytime symptom scores were significantly different between baseline and after treatment in each treatment group (p < 0.05). However, improvements in both BIS and OP groups were similar. CONCLUSION: Budesonide inhalation suspension may be an alternative treatment of acute asthma exacerbation in adults who are at risk for systemic corticosteroids.

Glutamine protects ischemia-reperfusion induced acute lung injury in isolated rat lungs.

Glutamine has been used to treat a number of diseases via modulating the inflammatory response. The purpose of this study is to investigate whether glutamine has a beneficial effect in ischemia-reperfusion (IR) induced acute lung injury in an isolated rat lung model. Typical acute lung injury in rats was successfully induced by 60 min of ischemia and 60 min of reperfusion. At the end of experiment, bronchoalveolar lavage fluid (BALF), perfusate and lung tissues were collected to evaluate the degree of lung injury. Glutamine (20 mM) was administrated before ischemia or after ischemia. IR caused a significant increase in the capillary filtration coefficient; lung weight gain; lung weight to body weight ratio; wet to dry weight ratio; pulmonary arterial pressure; and protein concentration and lactate dehydrogenase level in BALF. Tumor necrosis factor-α and cytokine induced neutrophil chemoattractant-1 in perfusate, and malondialdehyde levels, carbonyl content and myeloperoxidase activities in lung tissue were also significantly increased. In addition, the lung tissues showed increased septal thickness and neutrophil infiltration. Furthermore, NF-κB activity and degradation of IκB-α were significantly increased in the lungs. Treatment with glutamine before ischemia or after ischemia significantly decreased the increase in these parameters. Our study showed that glutamine treatment decreased IR-induced acute lung injury. The protective mechanism may be due to the inhibition of NF-κB activation and the attenuation of oxidative stress.

Lateral position with the remaining lung uppermost improves matching of pulmonary ventilation and perfusion in pneumonectomized pigs.

BACKGROUND: Pneumonectomy is a major surgery. Severe hypoxemia sometimes occurs after pneumonectomy. Effective gas exchange depends on perfect pulmonary ventilation (V˙(A)) and perfusion (Q˙) matching. The effect of position on V˙(A)/Q˙ matching after pneumonectomy is not clear. We therefore conducted this study to examine the effects of supine, left lateral decubitus (LLD), and right lateral decubitus (RLD) positions on V˙(A)/Q˙ matching and gas exchange after pneumonectomy in a porcine model. METHODS: Twelve pigs were anesthetized and mechanically ventilated; six pigs received right pneumonectomy and six pigs received left pneumonectomy. The positions of the pigs were changed to supine, LLD, and RLD in random order after pneumonectomy. We applied intravenous and aerosolized high-resolution fluorescent microsphere technique (FMT) to mark V˙(A) and Q˙ in conjunction with arterial blood gas analysis to study these variables at different positions. Mechanical ventilation was kept constant throughout. RESULTS: Different positions after pneumonectomy lead to significant changes in heterogeneity and matching of V˙(A)/Q˙. In right pneumonectomized pigs, the highest PaO(2), lowest V˙(A)/Q˙heterogeneity, and highest matching of V˙(A)/Q˙ was in RLD. In left pneumonectomized pigs, the highest PaO(2), lowest V˙(A)/Q˙ heterogeneity, and highest matching of V˙(A)/Q˙ was in LLD. CONCLUSIONS: The lateral position with the remaining lung uppermost leads to the highest V˙(A)/Q˙ matching and best gas exchange after pneumonectomy.

Effects of implementing adaptive support ventilation in a medical intensive care unit.

BACKGROUND: Adaptive support ventilation (ASV) facilitates ventilator liberation in postoperative patients in surgical intensive care units (ICU). Whether ASV has similar benefits in patients with acute respiratory failure is unclear. METHODS: We conducted a pilot study in a medical ICU that manages approximately 600 mechanically ventilated patients a year. The ICU has one respiratory therapist who manages ventilators twice during the day shift (8:00 am to 5:00 pm). No on-site respiratory therapist was present at night. We prospectively enrolled 79 patients mechanically ventilated for ≥ 24 hours on pressure support of ≥ 15 cm H(2)O, with or without synchronized intermittent mandatory ventilation, F(IO(2)) ≤ 50%, and PEEP ≤ 8 cm H(2)O. We switched the ventilation mode to ASV starting at a "%MinVol" setting of 80-100%. We defined spontaneous breathing trial (SBT) readiness as a frequency/tidal-volume ratio of < 105 (breaths/min)/L on pressure support of ≤ 8 cm H(2)O and PEEP of ≤ 5 cm H(2)O for at least 2 h, and all spontaneous breaths. The T-piece SBT was considered successful if the frequency/tidal-volume ratio remained below 105 (breaths/min)/L for 30 min, and we extubated after successful SBT. The control group consisted of 70 patients managed with conventional ventilation modes and a ventilator protocol during a 6-month period immediately before the ASV study period. RESULTS: Extubation was attempted in 73% of the patients in the ASV group, and 80% of the patients in the non-ASV group. The re-intubation rates in the ASV and non-ASV groups were 5% and 7%, respectively. In the ASV group, 20% of the patients achieved extubation readiness within 1 day, compared to 4% in the non-ASV group (P = <.001). The median time from the enrollment to extubation readiness was 1 day for the ASV group and 3 days for the non-ASV group (P = .055). Patients switched to ASV were more likely to be liberated from mechanical ventilation at 3 weeks (P = .04). Multiple logistic regression analysis showed that, of the independent factors in the model, only ASV was associated with shorter time to extubation readiness (P = .048 via likelihood ratio test). CONCLUSIONS: Extubation readiness may not be recognized in a timely manner in at least 15% of patients recovering from respiratory failure. ASV helps to identify these patients and may improve their weaning outcomes.

Physical training is beneficial to functional status and survival in patients with prolonged mechanical ventilation.

BACKGROUND/PURPOSE: Early physical training is necessary for severely deconditioned patients undergoing prolonged mechanical ventilation (PMV), because survivors often experience prolonged recovery. Long-term outcomes after physical training have not been measured; therefore, we investigated outcome during a 1-year period after physical training for the PMV patients. METHODS: We conducted a prospective randomized control trial in a respiratory care center. Thirty-four patients were randomly assigned to the rehabilitation group (n = 18) and the control group (n = 16). The rehabilitation group participated in supervised physical therapy training for 6 weeks, and continued in an unsupervised maintenance program for 6 more weeks. The functional independence measurement (FIM) was used to assess functional status. Survival status during the year after enrollment, the number of survivors discharged, and the number free from ventilator support were collected. These outcome parameters were assessed at entry, immediately after the 6 weeks physical therapy training period, after 6 weeks unsupervised maintenance exercise program, and 6 months and 12 months after study entry. RESULTS: The scores of total FIM, motor domain, cognitive domain, and some sub-items, except for the walking/wheelchair sub-item, increased significantly in the rehabilitation group at 6 months postenrollment, but remained unchanged for the control group. The eating, comprehension, expression, and social interaction subscales reached the 7-point complete independence level at 6 months in the rehabilitation group, but not in the control group. The 1-year survival rate for the rehabilitation group was 70%, which was significantly higher than that for the control group (25%), although the proportion of patients discharged and who were ventilator-free in the rehabilitation and control groups did not differ significantly. CONCLUSION: Six weeks physical therapy training plus 6 weeks unsupervised maintenance exercise enhanced functional levels and increased survival for the PMV patients compared with those with no such intervention. Early physical therapy interventions are needed for the PMV patients in respiratory care centers.

Impact of peripheral muscle strength on prognosis after extubation and functional outcomes in critically ill patients: a feasibility study.

The influence of peripheral muscle strength on prognosis after extubation and subsequent functional outcomes is not evident. The objectives of this study were to determine (1) whether peripheral muscle strength can be used as a predictor for patients' prognoses after extubation, and (2) whether the peripheral muscle strength before extubation is correlated with patients' subsequent ambulation ability and in-hospital mortality. This study was a prospective observational cohort study. A hand-held dynamometer was used for evaluated the muscle strength of the biceps and quadriceps right before extubation. Besides, after the patients had been transferred from the ICU to the general ward, a 2-minute walk test was performed. A total of 52 patients were enrolled in this study, and the rate of extubation failure was 15%. The muscle strength of the quadriceps was significantly correlated with the prognosis after extubation, 48% of the patients were able to ambulate after being transferred to the general ward. The overall mortality rate was 11%, and there was a significant correlation between the biceps muscle strength and in-hospital mortality. Peripheral muscle strength may serve as an important predictor of a patients' prognoses after extubation. Poor peripheral muscle strength is indicative of not only a higher risk of re-intubation but also higher in-hospital mortality and poorer functional outcomes.Trial registration: ISRCTN16370134. Registered 30 May 2019, prospectively registered. https://www.isrctn.com/ISRCTN16370134 .

Surfactant Attenuates Air Embolism-Induced Lung Injury by Suppressing NKCC1 Expression and NF-κB Activation.

Excessive amounts of air can enter the lungs and cause air embolism (AE)-induced acute lung injury (ALI). Pulmonary AE can occur during diving, aviation, and iatrogenic invasive procedures. AE-induced lung injury presents with severe hypoxia, pulmonary hypertension, microvascular hyper-permeability, and severe inflammatory responses. Pulmonary AE-induced ALI is a serious complication resulting in significant morbidity and mortality. Surfactant is abundant in the lungs and its function is to lower surface tension. Earlier studies have explored the beneficial effects of surfactant in ALI; however, none have investigated the role of surfactant in pulmonary AE-induced ALI. Therefore, we conducted this study to determine the effects of surfactant in pulmonary AE-induced ALI. Isolated-perfused rat lungs were used as a model of pulmonary AE. The animals were divided into four groups (n = 6 per group): sham, air embolism (AE), AE + surfactant (0.5 mg/kg), and AE+ surfactant (1 mg/kg). Surfactant pretreatment was administered before the induction of pulmonary AE. Pulmonary AE was induced by the infusion of 0.7 cc air through a pulmonary artery catheter. After induction of air, pulmonary AE was presented with pulmonary edema, pulmonary microvascular hyper-permeability, and lung inflammation with neutrophilic sequestration. Activation of NF-κB was observed, along with increased expression of pro-inflammatory cytokines, and Na-K-Cl cotransporter isoform 1 (NKCC1). Surfactant suppressed the activation of NF-κB and decreased the expression of pro-inflammatory cytokines and NKCC1, thereby attenuating AE-induced lung injury. Therefore, AE-induced ALI presented with pulmonary edema, microvascular hyper-permeability, and lung inflammation. Surfactant suppressed the expressions of NF-κB, pro-inflammatory cytokines, and NKCC1, thereby attenuating AE-induced lung injury.