Low Tidal Volume Mechanical Ventilation Research Articles

Low Tidal Volume Ventilation Is Poorly Implemented for Patients in North American and United Kingdom ICUs Using Electronic Health Records

Low tidal volume ventilation (LTVV;< 8mL/kg predicted body weight [PBW]) is a well-established standard of care associated with improved outcomes. This study used data collated in multicenter electronic health record ICU databases from the United Kingdom and the United States to analyze the use of LTVV in routine clinical practice. What factors are associated with adherence to LTVV in the United Kingdom and North America? This was a retrospective, multicenter study across the United Kingdom and United States of patients who were mechanically ventilated. Factors associated with adherence to LTVV were assessed in all patients in both databases who were mechanically ventilated for > 48 h. We observed trends over time and investigated whether LTVV was associated with patient outcomes (30-day mortality and duration of ventilation) and identified strategies to improve adherence to LTVV. A total of 5,466 (Critical Care Health Informatics Collaborative [CCHIC]) and 7,384 electronic ICU collaborative research database [eICU-CRD] patients were ventilated for > 48h and had data of suitable quality for analysis. The median tidal volume (VT) values were 7.48mL/kg PBW (CCHIC) and 7.91mL/kg PBW (eICU-CRD). The patients at highest risk of not receiving LTVV were shorter than 160cm (CCHIC) and 165cm (eICU-CRD). Those with BMI > 30kg/m2 (CCHIC OR, 1.9 [95%CI, 1.7-2.13]; eICU-CRD OR, 1.61 [95%CI, 1.49-1.75]) and female patients (CCHIC OR, 2.39 [95%CI, 2.16-2.65]; eICU-CRD OR, 2.29 [95%CI, 2.26-2.31]) were at increased risk of having median VT > 8mL/kg PBW. Patients with median VT< 8mL/kg PBW had decreased 30-day mortality in the CCHIC database (CCHIC cause-specific hazard ratio, 0.86 [95%CI, 0.76-0.97]; eICU-CRD cause-specific hazard ratio, 0.9 [95%CI, 0.86-1.00]). There was a significant reduction in VT over time in the CCHIC database. There has been limited implementation of LTVV in routine clinical practice in the United Kingdom and the United States. VT > 8mL/kg PBW was associated with worse patient outcomes.

Effect of ventilator-induced lung injury on blood-brain barrier permeability in rats

To observe the effect of ventilator-induced lung injury (VILI) on blood-brain barrier permeability in rats. Forty-eight healthy clean male Sprague-Dawley (SD) rats were randomly divided into sham operation (Sham) group, low tidal volume (LVT) mechanical ventilation group (LVT group), normal tidal volume (NVT) mechanical ventilation group (NVT group) and high tidal volume (HVT) mechanical ventilation group (HVT group) with 12 rats in each group. After anesthesia, rats in the Sham group were intubated and kept spontaneous breathing. The rats in different tidal volume (VT) groups were mechanically ventilated by endotracheal intubation with VT of 6 mL/kg (LVT group), 10 mL/kg (NVT group), and 20 mL/kg (HVT group), respectively. The inspiration-expiration ratio of the three groups was 1:1, the ventilation frequency was 40 times/min, and the ventilation time was 3 hours. At the end of the experiment, the bronchoalveolar lavage fluid (BALF) of rats was collected, and the levels of pro-inflammatory factors [tumor necrosis factor-α (TNF-α), interleukins (IL-1β and IL-6)] in BALF were detected by enzyme-linked immunosorbent assay (ELISA). The lung tissues of rats were collected, and the lung wet/dry weight (W/D) ratio was calculated. The pathological changes of lung tissues were observed under light microscopy after hematoxylin-eosin (HE) staining, and lung injury scores were performed. The brain tissue of rats was taken to measure the brain water content, and the Evans blue (EB) content of brain tissue was measured to reflect the permeability of the blood-brain barrier. The tight junction proteins in the brain tissues were detected by Western blotting. After 3 hours of mechanical ventilation, with the increase of VT, the degree of lung injury in VILI rats gradually increased. When VT reached 20 mL/kg, lung tissue structure was significantly injured, alveolar wall edema, alveolar congestion, lung interstitial thickening, a large number of inflammatory cells infiltrated, and the lung injury score, lung W/D ratio, and the levels of TNF-α, IL-1β and IL-6 in BALF were significantly higher than those in the Sham group [lung injury score: 10.6±1.1 vs. 1.4±1.0, lung W/D ratio: 6.6±0.8 vs. 3.7±0.6, TNF-α (ng/L): 832.9±97.9 vs. 103.8±23.3, IL-1β (ng/L): 68.9±14.1 vs. 15.7±2.6, IL-6 (ng/L): 70.8±16.4 vs. 20.3±5.4, all P < 0.05]. Lung injury in rats was accompanied by aggravating brain injury. When VT reached 20 mL/kg, brain water content and EB content in brain tissue were significantly higher than those in the Sham group [brain water content: (85.4±3.6)% vs. (68.7±2.7)%, EB content in brain tissue (μg/g): 887±78 vs. 97±14, both P < 0.05], and the protein expressions of claudin-5, occluding and zonula occluden-1 (ZO-1) in the brain tissue were significantly lower than those in the Sham group [claudin-5 protein (claudin-5/β-actin): 0.67±0.12 vs. 1.45±0.19, occludin protein (occludin/β-actin): 0.48±0.11 vs. 0.99±0.21, ZO-1 protein (ZO-1/β-actin): 0.13±0.03 vs. 0.63±0.12, all P < 0.05]. VILI can induce brain edema and increase blood-brain barrier permeability in rats, which may be related to the down-regulation of tight junction protein expression in the brain tissue.

Efficacy of maintaining low-tidal volume mechanical ventilation as compared to resting lung strategy during coronary artery bypass graft cardiopulmonary bypass surgery: A post-hoc analysis of the MECANO trial

Study objectiveTo compare a low-tidal-volume with positive end-expiratory pressure strategy (VENT strategy) to a resting-lung-strategy (i.e., no-ventilation (noV) strategy) during cardiopulmonary bypass for coronary artery bypass graft surgery on the incidence of postoperative pulmonary complications. DesignPost-hoc analysis of the MECANO trial which was a prospective single-center, blind, randomized, parallel-group controlled trial. SettingTertiary care cardiac surgery center. PatientsPatients who underwent isolated on-pump coronary bypass surgery were randomized either to VENT or noV group. InterventionDuring the cardiopulmonary bypass phase of the cardiac surgery procedure, mechanical ventilation in the VENT group consisted of a tidal volume of 3 mL/kg, a respiratory rate of 5 per minute and a positive end-expiratory pressure of 5 cmH2O. Patients in the noV group received no ventilation during this phase. MeasurementsPrimary composite outcome combining death, early respiratory failure, ventilation support beyond day 2 and reintubation. Main resultsIn this post-hoc analysis, we retained 725 patients who underwent isolated CABG surgery, from the 1501 patients included in the original study. There were 352 in the VENT group and 373 patients in the noV group. Post-hoc comparison yielded no differences in baseline characteristics between these two groups. The primary outcome occurred less frequently in the VENT group than in the noV group, with 44 (12.5%) and 76 (20.4%) respectively (odds-ratio (OR) = 0.56 (0.37–0.84), p = 0.004). There were fewer early respiratory dysfunctions and prolonged respiratory support in the VENT group (respectively, OR = 0.34 (0.12–0.96) p = 0.033 and OR = 0.51 (0.27–0.94) p = 0.029). Complications related to mechanical ventilation were similar in the two groups. ConclusionsIn this post-hoc analysis, maintaining low-tidal ventilation compared to a resting-lung strategy was associated with fewer pulmonary postoperative complications in patients who underwent isolated CABG procedures.

ARDS IN THE SETTING OF SEROTONIN SYNDROME

ARDS IN THE SETTING OF SEROTONIN SYNDROME

Protective ventilation in a pig model of acute lung injury: timing is as important as pressure.

Ventilator-induced lung injury (VILI) is a significant risk for patients with acute respiratory distress syndrome (ARDS). Management of the patient with ARDS is currently dominated by the use of low tidal volume mechanical ventilation, the presumption being that this mitigates overdistension (OD) injury to the remaining normal lung tissue. Evidence exists, however, that it may be more important to avoid cyclic recruitment and derecruitment (RD) of lung units, although the relative roles of OD and RD in VILI remain unclear. Forty pigs had a heterogeneous lung injury induced by Tween instillation and were randomized into four groups (n = 10 each) with higher (↑) or lower (↓) levels of OD and/or RD imposed using airway pressure release ventilation (APRV). OD was increased by setting inspiratory airway pressure to 40 cmH2O and lessened with 28 cmH2O. RD was attenuated using a short duration of expiration (∼0.45 s) and increased with a longer duration (∼1.0 s). All groups developed mild ARDS following injury. RD ↑ OD↑ caused the greatest degree of lung injury as determined by [Formula: see text]/[Formula: see text] ratio (226.1 ± 41.4 mmHg). RD ↑ OD↓ ([Formula: see text]/[Formula: see text]= 333.9 ± 33.1 mmHg) and RD ↓ OD↑ ([Formula: see text]/[Formula: see text] = 377.4 ± 43.2 mmHg) were both moderately injurious, whereas RD ↓ OD↓ ([Formula: see text]/[Formula: see text] = 472.3 ± 22.2 mmHg; P < 0.05) was least injurious. Both tidal volume and driving pressure were essentially identical in the RD ↑ OD↓ and RD ↓ OD↑ groups. We, therefore, conclude that considerations of expiratory time may be at least as important as pressure for safely ventilating the injured lung.NEW & NOTEWORTHY In a large animal model of ARDS, recruitment/derecruitment caused greater VILI than overdistension, whereas both mechanisms together caused severe lung damage. These findings suggest that eliminating cyclic recruitment and derecruitment during mechanical ventilation should be a preeminent management goal for the patient with ARDS. The airway pressure release ventilation (APRV) mode of mechanical ventilation can achieve this if delivered with an expiratory duration (TLow) that is brief enough to prevent derecruitment at end expiration.

Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure

In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes. To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, -7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, -2.1 [95% CI, -3.8 to -0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference. ClinicalTrials.gov Identifier: NCT02654327.

Effects of the Prone Position on Regional Neutrophilic Lung Inflammation According to 18F-FDG Pet in an Experimental Ventilator-Induced Lung Injury Model.

Ventilator-induced lung injury (VILI) can be life-threatening and it is important to prevent the development of VILI. It remains unclear whether the prone position affects neutrophilic inflammation in the lung regions in vivo, which plays a crucial role in the pathogenesis of VILI. This study aimed to assess the relationship between the use of the prone position and the development of VILI-associated regional neutrophilic lung inflammation. Regional neutrophilic lung inflammation and lung aeration during low tidal volume mechanical ventilation were assessed using in vivo 2-deoxy-2-[(18)F] fluoro-D-glucose (18F-FDG) positron emission tomography and computed tomography in acutely experimentally injured rabbit lungs (lung injury induced by lung lavage and excessive ventilation). Direct comparisons were made among three groups: control, supine, and prone positions. After approximately 7 h, tissue-normalized 18F-FDG uptake differed significantly between the supine and prone positions (SUP: 0.038 ± 0.014 vs. PP: 0.029 ± 0.008, P = 0.038), especially in the ventral region (SUP: 0.052 ± 0.013 vs. PP: 0.026 ± 0.007, P = 0.003). The use of the prone position reduced lung inhomogeneities, which was demonstrated by the correction of the disproportionate rate of voxel gas over the given lung region. The progression of neutrophilic inflammation was affected by the interaction between the total strain (for aeration) and the inhomogeneity. The prone position is effective in slowing down the progression of VILI-associated neutrophilic inflammation. Under low-tidal-volume ventilation, the main drivers of its effect may be homogenization of lung tissue and that of mechanical forces.

Comprehensive lung protection during circulatory arrest in aortic arch surgery

Aim. The aim of the study was to analyze the effectiveness of comprehensive lung protection in patients who underwent thoracic aortic surgery using circulatory arrest. Material and Methods. A total of 57 patients undergoing operations for aneurysms and thoracic aortic dissection were enrolled in the prospective study. The patients were divided into two groups. The experimental group of patients ( n = 27) underwent comprehensive lung protection with pulmonary artery perfusion and mechanical ventilation. Patients in the control group ( n = 30) did not undergo comprehensive lung protection measures. Results. The median duration of mechanical ventilation in the postoperative period was 14 hours in the experimental group and 23 hours in the control group of patients ( p < 0.001). The incidence of analyzed pulmonary complications did not significantly differ between the groups during the early postoperative period. The number of pneumonia cases was 8 (14%) including 4 (15%) cases in the experimental group and 4 (13%) episodes in the control group ( p = 0.87). Conclusion. Selective pulmonary artery perfusion in combination with low tidal volume mechanical ventilation during operations on the thoracic aorta using circulatory arrest significantly reduced the duration of postoperative mechanical ventilation.

A role for bronchial epithelial autotaxin in ventilator-induced lung injury

BackgroundThe pathophysiology of acute respiratory distress syndrome (ARDS) may eventually result in heterogeneous lung collapse and edema-flooded airways, predisposing the lung to progressive tissue damage known as ventilator-induced lung injury (VILI). Autotaxin (ATX; ENPP2), the enzyme largely responsible for extracellular lysophosphatidic acid (LPA) production, has been suggested to play a pathogenic role in, among others, pulmonary inflammation and fibrosis.MethodsC57BL/6 mice were subjected to low and high tidal volume mechanical ventilation using a small animal ventilator: respiratory mechanics were evaluated, and plasma and bronchoalveolar lavage fluid (BALF) samples were obtained. Total protein concentration was determined, and lung histopathology was further performedResultsInjurious ventilation resulted in increased BALF levels of ATX. Genetic deletion of ATX from bronchial epithelial cells attenuated VILI-induced pulmonary edema.ConclusionATX participates in VILI pathogenesis.

Management of hypercapnia in critically ill mechanically ventilated patients-A narrative review of literature.

The use of lower tidal volume ventilation was shown to improve survival in mechanically ventilated patients with acute lung injury. In some patients this strategy may cause hypercapnic acidosis. A significant body of recent clinical data suggest that hypercapnic acidosis is associated with adverse clinical outcomes including increased hospital mortality. We aimed to review the available treatment options that may be used to manage acute hypercapnic acidosis that may be seen with low tidal volume ventilation. The databases of MEDLINE and EMBASE were searched. Studies including animals or tissues were excluded. We also searched bibliographic references of relevant studies, irrespective of study design with the intention of finding relevant studies to be included in this review. The possible options to treat hypercapnia included optimising the use of low tidal volume mechanical ventilation to enhance carbon dioxide elimination. These include techniques to reduce dead space ventilation, and physiological dead space, use of buffers, airway pressure release ventilation and prone positon ventilation. In patients where hypercapnic acidosis could not be managed with lung protective mechanical ventilation, extracorporeal techniques may be used. Newer, minimally invasive low volume venovenous extracorporeal devices are currently being investigated for managing hypercapnia associated with low and ultra-low volume mechanical ventilation.

Clinical Predictors of Adherence to Low Tidal Volume Ventilation Practice: Is it Different on Weekend and Night Shifts?

Background: Low tidal volume ventilation (LTVV) strategy improves outcomes; however, despite recommended by guidelines, adherence to this practice is not high.Methods: Tidal volume for mechanically ventilated patients were recorded for each 12-hour shift, day and night shifts for consecutive 101 patients. Adherence was determined by comparing these tidal volumes to standard low tidal volumes of 6 ml/kg of ideal body weight. Adherence rates were calculated and adherence rates of daytime shifts were compared to those of night time shifts. Adherence rates for weekday shifts were compared with those of weekend shifts. Clinical variables were recorded to analyze predictors of adherence pattern.Results: The sample size was 101 patients with 870 patient-ventilator days with 1734 patient ventilator shifts. Shift adherence was only 47.5%. There was no significant difference between day and night shifts or weekday and weekend shifts. Stepwise multiple regression analysis shows that age, gender, body mass index (BMI), and partial pressure of carbon dioxide (PCO2) have significant correlation with adherence to LTVV practice.Conclusion: The study found that adherence to lung protective low tidal volume mechanical ventilation practice is low. Practice adherence is not different over weekend or night shifts. Age, gender, BMI, and PCO2 have significant correlation with adherence to LTVV practice.

Acute Respiratory Distress Syndrome: An Update and Review.

Acute respiratory distress syndrome (ARDS) is a life threatening condition characterized by severe hypoxemia due to pulmonary gas exchange failure and was first recognized in 1960s.Since its first description, it has undergone intensive research in the past few decades to understand its pathogenesis and therapies. Despite this, the recommended therapies to decrease mortality in ARDS remain limited and include low-tidal volume mechanical ventilation, prone ventilation and recently, the ECMO rescue therapy in extreme cases. This review article will summarize the key features of ARDS with a brief overview of the therapeutic options in the management of ARDS.

Dexmedetomidine reduces ventilator-induced lung injury (VILI) by inhibiting Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling pathway

Mechanical ventilation (MV) may lead to ventilator-induced lung injury (VILI). Previous research has shown that dexmedetomidine attenuates pulmonary inflammation caused by MV, but the underlying mechanisms remain unclear. Our study aims to test whether dexmedetomidine has a protective effect against VILI and to explore the possible molecular mechanisms using the rat model. Thirty adult male Wistar rats weighing 200-250 g were randomly assigned to 5 groups (n = 6): control, low tidal volume MV (LMV), high tidal volume (HVT) MV (HMV), HVT MV + dexmedetomidine (DEX), HVT MV + dexmedetomidine + yohimbine (DEX+Y). Rats were euthanized after being ventilated for 4 hours. Pathological changes, lung wet/dry (W/D) weight ratio, lung myeloperoxidase (MPO) activity, levels of inflammatory cytokines (i.e., interleukin [IL]-1β, tumor necrosis factor alpha [TNF-α], and IL-6) in the bronchoalveolar lavage fluid (BALF) and lung tissues, expression of Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB, and activation of NF-κB in lung tissues were measured. Compared with HMV, DEX group showed fewer pathological changes, lower W/D ratios and decreased MPO activity of the lung tissues and lower concentrations of the inflammatory cytokines in the BALF and lung tissues. Dexmedetomidine significantly inhibited the expression of TLR4 and NF-κB and activation of NF-κB. Yohimbine partly alleviated the effects of dexmedetomidine. Dexmedetomidine reduced the inflammatory response to HVT-MV and had a protective effect against VILI, with the inhibition of the TLR4/NF-κB signaling pathway, at least partly via α2-adrenoceptors.

Low tidal volume mechanical ventilation against no ventilation during cardiopulmonary bypass heart surgery (MECANO): study protocol for a randomized controlled trial

BackgroundPostoperative pulmonary complications are a leading cause of morbidity and mortality after cardiac surgery. There are no recommendations on mechanical ventilation associated with cardiopulmonary bypass (CPB) during surgery and anesthesiologists perform either no ventilation (noV) at all during CPB or maintain low tidal volume (LTV) ventilation. Indirect evidence points towards better pulmonary outcomes when LTV is performed but no large-scale prospective trial has yet been published in cardiac surgery.DesignThe MECANO trial is a single-center, double-blind, randomized, controlled trial comparing two mechanical ventilation strategies, noV and LTV, during cardiac surgery with CPB. In total, 1500 patients are expected to be included, without any restrictions. They will be randomized between noV and LTV on a 1:1 ratio. The noV group will receive no ventilation during CPB. The LTV group will receive 5 breaths/minute with a tidal volume of 3 mL/kg and positive end-expiratory pressure of 5 cmH2O. The primary endpoint will be a composite of all-cause mortality, early respiratory failure defined as a ratio of partial pressure of oxygen/fraction of inspired oxygen <200 mmHg at 1 hour after arrival in the ICU, heavy oxygenation support (defined as a patient requiring either non-invasive ventilation, mechanical ventilation or high-flow oxygen) at 2 days after arrival in the ICU or ventilator-acquired pneumonia defined by the Center of Disease Control. Lung recruitment maneuvers will be performed in the noV and LTV groups at the end of surgery and at arrival in ICU with an insufflation at +30 cmH20 for 5 seconds. Secondary endpoints are those composing the primary endpoint with the addition of pneumothorax, CPB duration, quantity of postoperative bleeding, red blood cell transfusions, revision surgery requirements, length of stay in the ICU and in the hospital and total hospitalization costs. Patients will be followed until hospital discharge.DiscussionThe MECANO trial is the first of its kind to compare in a double-blind design, a no-ventilation to a low-tidal volume strategy for mechanical ventilation during cardiac surgery with CPB, with a primary composite outcome including death, respiratory failure and postoperative pneumonia.Trial registrationClinicalTrials.gov, NCT03098524. Registered on 27 February 2017.

Translating evidence into practice in acute respiratory distress syndrome: teamwork, clinical decision support, and behavioral economic interventions

Although the treatment of the acute respiratory distress syndrome (ARDS) with low tidal volume (LTV) mechanical ventilation improves mortality, it is not consistently administered in clinical practice. This review examines strategies to improve LTV and other evidence-based therapies for patients with ARDS. Despite the well established role of LTV in the treatment of ARDS, a recent multinational study suggests it is under-utilized in clinical practice. Strategies to improve LTV include audit and feedback, provider education, protocol development, interventions to improve ICU teamwork, computer decision support, and behavioral economic interventions such as making LTV the default-ventilator setting. These strategies typically target all patients receiving invasive mechanical ventilation, effectively avoiding the problem of poor ARDS recognition in clinical practice. To more effectively administer advanced ARDS therapies, such as prone positioning, better approaches for ARDS recognition will also be required. Multiple strategies can be utilized to improve adherence to LTV ventilation in ARDS patients.

Middle age exacerbates acute respiratory distress syndrome in a double hit murine model

RationaleIn a recent systematic review, aging has been identified as the only factor independently associated with mortality during human acute respiratory distress syndrome (ARDS). We explored this age-dependent severity in a clinically relevant double hit murine ARDS model. MethodsYoung adult (Y, 10–12weeks) and middle-old (O, 12–13months) male C57BL6 mice underwent an aspiration of Escherichia coli lipopolysaccharide (LPS) or control saline vehicle. Twenty hours later, four groups of mice were sacrificed [Y(control), O(control), Y(LPS) and O(LPS)]. Four other groups of mice underwent 3h of low tidal volume (8mL/kg) mechanical ventilation (MV) [Y(MV), O(MV), Y(LPS+MV) and O(LPS+MV)]. Lung mechanics were assessed hourly during MV. Right ventricular pressure and cardiac output were measured at the end of the MV. After sacrifice, lung inflammation, edema and injury were explored with bronchoalveolar lavage (BAL) and histology. ResultsAfter saline aspiration, middle-old mice had a higher respiratory system compliance than young adult mice. LPS aspiration dramatically altered the baseline compliance in middle-old (O(LPS)), but not in young adult (Y(LPS)) mice. Middle-old mice had a more pronounced alteration in lungs mechanics during MV as compared to young adult mice. Lung inflammation (as assessed by the total cell count, IL-6, TNFα and MIP-2 concentrations in BAL fluid), systemic inflammation (as assessed by plasma IL-6 concentration) and alveolocapillary leak (as assessed by the total protein concentration of BAL fluid) were higher in O(LPS) and O(LPS+MV) mice as compared to Y(LPS) and Y(LPS+MV) mice, respectively. The combination of LPS+MV induced a higher lung injury as compared to LPS alone in middle-old mice but not in young adult mice. Hemodynamics (systemic blood pressure, cardiac output and pulmonary vascular resistances) were similar between Y(MV) and O(MV) on the one hand and between Y(LPS+MV) and O(LPS+MV) on the other hand. ConclusionMiddle-old mice were more susceptible to both LPS alone and the combination of LPS and low tidal volume MV as compared to their young adult counterparts. The synergism between LPS and MV was amplified in middle-old mice.

Interleukin-6 displays lung anti-inflammatory properties and exerts protective hemodynamic effects in a double-hit murine acute lung injury

BackgroundInterleukin 6 (IL-6) is a predictive factor of poor prognosis in patients with acute respiratory distress syndrome (ARDS). However, its acute pulmonary hemodynamic effects and role in lung injury have not been investigated in a clinically relevant murine model of ARDS.MethodsWe used adult C57Bl6 wild-type (WT) and IL-6 knock-out (IL-6KO) mice. The animals received intravenous recombinant human IL-6 (rHuIL-6) or vehicle followed by intratracheal lipopolysaccharide (LPS) or saline before undergoing low tidal volume mechanical ventilation (MV) for 5 h. Before sacrifice, right ventricular systolic pressure and cardiac output were measured and total pulmonary resistance was calculated. After sacrifice, lung inflammation, edema and injury were assessed with bronchoalveolar lavage (BAL) and histology. In other experiments, right ventricular systolic pressure was recorded during hypoxic challenges in uninjured WT mice pretreated with rHuIL-6 or rHuIL-6 + non-selective nitric oxide synthase inhibitor L-NAME or vehicle.ResultsIL-6KO(LPS+MV) mice showed a faster deterioration of lung elastic properties and more severe bronchoalveolar cellular inflammation as compared to WT(LPS+MV). Treatment with rHuIL-6 partially prevented this lung deterioration. Total pulmonary resistance was higher in IL-6KO(LPS+MV) mice and this increase was abolished in rHuIL-6-treated IL-6KO mice. Finally, rHuIL-6 reduced hypoxic pulmonary vasoconstriction in uninjured WT mice, an effect that was abolished by co-treatment with L-NAME.ConclusionsIn a double-hit murine model of ARDS, IL-6 deficient mice experienced more severe bronchoalveolar cellular inflammation as compared to wild-type littermates. Furthermore, IL-6 deficiency caused marked acute pulmonary hypertension, which may be, at least partially, due to vasoactive mechanisms. A dysregulation of nitric oxide synthase may account for this observation, a hypothesis that will need to be investigated in future studies.

A Meta-analysis of Intraoperative Ventilation Strategies to Prevent Pulmonary Complications: Is Low Tidal Volume Alone Sufficient to Protect Healthy Lungs?

The clinical benefits of intraoperative low tidal volume (LTV) mechanical ventilation with concomittent positive end expiratory pressure (PEEP) and intermittent recruitment maneuvers-termed "protective lung ventilation" (PLV)-have not been investigated systematically in otherwise healthy patients undergoing general anesthesia. Our group performed a meta-analysis of 16 studies (n = 1054) comparing LTV (n = 521) with conventional lung ventilation (n = 533) for associated postoperative incidence of atelectasis, lung infection, acute lung injury (ALI), and length of hospital stay. A secondary analysis of 3 studies comparing PLV (n = 248) with conventional lung ventilation (n = 247) was performed. Although intraoperative LTV ventilation was associated with a decreased incidence of postoperative lung infection (odds ratio [OR] = 0.33; 95% confidence interval [CI], 0.16-0.68; P = 0.003) compared with a conventional strategy, no difference was noted between groups in incidence of postoperative ALI (OR = 0.38; 95% CI, 0.10-1.52; P = 0.17) or atelectasis (OR = 0.86; 95% CI, 0.26-2.81; P = 0.80). Analysis of trials involving protective ventilation (LTV + PEEP + recruitment maneuvers) showed a statistically significant reduction in incidence of postoperative lung infection (OR = 0.21; 95% CI, 0.09-0.50; P = 0.0003), atelectasis (OR = 0.36; 95% CI, 0.20-0.64; P = 0.006), and ALI (OR = 0.15; 95% CI, 0.04-0.61; P = 0.008) and length of hospital stay (Mean Difference = -2.08; 95% CI, -3.95 to -0.21; P = 0.03) compared with conventional ventilation. Intraoperative LTV ventilation in conjunction with PEEP and intermittent recruitment maneuvers is associated with significantly improved clinical pulmonary outcomes and reduction in length of hospital stay in otherwise healthy patients undergoing general surgery. Providers should consider application of all the 3 elements for a comprehensive protective ventilation strategy.

Altered Profile of Circulating Endothelial-Derived Microparticles in Ventilator-Induced Lung Injury.

Pulmonary endothelial cell injury is central to the pathophysiology of acute lung injury. Mechanical ventilation can cause endothelial disruption and injury, even in the absence of preexisting inflammation. Platelet-endothelial cell adhesion molecule-1 is a transmembrane protein connecting adjacent endothelial cells. We hypothesized that injurious mechanical ventilation will increase circulating lung endothelial-derived microparticles, defined as microparticles positive for platelet-endothelial cell adhesion molecule-1, which could serve as potential biomarkers and mediators of ventilator-induced lung injury. Prospective randomized, controlled, animal investigation. A hospital preclinical animal laboratory. Forty-eight Sprague-Dawley rats. Animals were randomly allocated to one of the three following ventilatory protocols for 4 hours: spontaneous breathing (control group), mechanical ventilation with low tidal volume (6 mL/kg), and mechanical ventilation with high tidal volume (20 mL/kg). In both mechanical ventilation groups, positive end-expiratory pressure of 2 cm H2O was applied. We analyzed histologic lung damage, gas exchange, wet-to-dry lung weight ratio, serum cytokines levels, circulating endothelial-derived microparticles, platelet-endothelial cell adhesion molecule-1 lung protein content, and immunohistochemistry. When compared with low-tidal volume mechanical ventilation, high-tidal volume ventilation increased lung edema score and caused gas-exchange deterioration. These changes were associated with a marked increased of circulating endothelial-derived microparticles and a reduction of platelet-endothelial cell adhesion molecule-1 protein levels in the high-tidal volume lungs (p < 0.0001). There is an endothelial-derived microparticle profile associated with disease-specific features of ventilator-induced lung injury. This profile could serve both as a biomarker of acute lung injury and, potentially, as a mediator of systemic propagation of pulmonary inflammatory response.

Platelet-rich plasma extract prevents pulmonary edema through angiopoietin-Tie2 signaling.

Increased vascular permeability contributes to life-threatening pathological conditions, such as acute respiratory distress syndrome. Current treatments for sepsis-induced pulmonary edema rely on low-tidal volume mechanical ventilation, fluid management, and pharmacological use of a single angiogenic or chemical factor with antipermeability activity. However, it is becoming clear that a combination of multiple angiogenic/chemical factors rather than a single factor is required for maintaining stable and functional blood vessels. We have demonstrated that mouse platelet-rich plasma (PRP) extract contains abundant angiopoietin (Ang) 1 and multiple other factors (e.g., platelet-derived growth factor), which potentially stabilize vascular integrity. Here, we show that PRP extract increases tyrosine phosphorylation levels of Tunica internal endothelial cell kinase (Tie2) and attenuates disruption of cell-cell junctional integrity induced by inflammatory cytokine in cultured human microvascular endothelial cells. Systemic injection of PRP extract also increases Tie2 phosphorylation in mouse lung and prevents endotoxin-induced pulmonary edema and the consequent decreases in lung compliance and exercise intolerance resulting from endotoxin challenge. Soluble Tie2 receptor, which inhibits Ang-Tie2 signaling, suppresses the ability of PRP extract to inhibit pulmonary edema in mouse lung. These results suggest that PRP extract prevents endotoxin-induced pulmonary edema mainly through Ang-Tie2 signaling, and PRP extract could be a potential therapeutic strategy for sepsis-induced pulmonary edema and various lung diseases caused by abnormal vascular permeability.