Expiratory flow-limitation in mechanically ventilated patients: A risk for ventilator-induced lung injury?

Expiratory flow limitation(EFL), that is the inability of expiratory flow to increase in spite of an increase of the driving pressure, is a common and unrecognized occurrence during mechanical ventilation in a variety of intensive care unit conditions. Recent evidence suggests that the presence of EFL is associated with an increase in mortality, at least in acute respiratory distress syndrome(ARDS) patients, and in pulmonary complications in patients undergoing surgery. EFL is a major cause of intrinsic positive end-expiratory pressure(PEEPi), which in ARDS patients is heterogeneously distributed, with a consequent increase of ventilation/perfusion mismatch and reduction of arterial oxygenation. Airway collapse is frequently concomitant to the presence of EFL.When airways close and reopen during tidal ventilation, abnormally high stresses are generated that can damage the bronchiolar epithelium and uncouple small airways from the alveolar septa, possibly generating the small airways abnormalities detected at autopsy in ARDS. Finally, the high stresses and airway distortion generated downstream the choke points may contribute to parenchymal injury, but this possibility is still unproven. PEEP application can abolish EFL, decrease PEEPi heterogeneity, and limit recruitment/derecruitment.Whether increasing PEEP up to EFL disappearance is a useful criterion for PEEP titration can only be determined by future studies.

Driving pressure decoded:Precision strategies in adult respiratory distress syndrome management

Mechanical ventilation(MV)is an important strategy for improving the survival of patients with respiratory failure.However,MV is associated with aggravation of lung injury,with ventilator-induced lung injury(VILI)becoming a major concern.Thus,ventilation protection strategies have been developed to minimize complications from MV,with the goal of relieving excessive breathing workload,improving gas exchange,and minimizing VILI.By opting for lower tidal volumes,clinicians seek to strike a balance between providing adequate ventilation to support gas exchange and preventing overdistension of the alveoli,which can contribute to lung injury.Additionally,other factors play a role in optimizing lung protection during MV,including adequate positive end-expiratory pressure levels,to maintain alveolar recruitment and prevent atelectasis as well as careful consideration of plateau pressures to avoid excessive stress on the lung parenchyma.

Effects of dynamic ventilatory factors on ventilatorinduced lung injury in acute respiratory distress syndrome dogs

BACKGROUND:Mechanical ventilation is a double-edged sword to acute respiratory distress syndrome(ARDS) including lung injury,and systemic inflammatory response high tidal volumes are thought to increase mortality.The objective of this study is to evaluate the effects of dynamic ventilatory factors on ventilator induced lung injury in a dog model of ARDS induced by hydrochloric acid instillation under volume controlled ventilation and to investigate the relationship between the dynamic factors and ventilator-induced lung injuries(VILI) and to explore its potential mechanisms.METHODS:Thirty-six healthy dogs were randomly divided into a control group and an experimental group.Subjects in the experimental group were then further divided into four groups by different inspiratory stages of flow.Two mL of alveolar fluid was aspirated for detection of IL-8 and TNF-α.Lung tissue specimens were also extracted for total RNA,IL-8 by western blot and observed under an electronic microscope.RESULTS:IL-8 protein expression was significantly higher in group B than in groups A and D.Although the IL-8 protein expression was decreased in group C compared with group B,the difference was not statistically significant.The TNF-α ray degree of group B was significantly higher than that in the other groups(P<0.01),especially in group C(P>0.05).The alveolar volume of subjects in group B was significantly smaller,and cavity infiltration and cell autolysis were marked with a significant thicker alveolar septa,disorder of interval structures,and blurring of collagenous and elastic fiber structures.A large number of necrotic debris tissue was observed in group B.CONCLUSION:Mechanical ventilation with a large tidal volume,a high inspiratory flow and a high ventilation frequency can cause significant damage to lung tissue structure.It can significantly increase the expression of TNF-α and IL-8 as well as their mRNA expression.Furthermore,the results of our study showed that small tidal ventilation significantly reduces the release of proinflammatory media.This finding suggests that greater deterioration in lung injury during ARDS is associated with high inspiratory flow and high ventilation rate.

Experimental study on the protective effect of ulinastatin on lung tissue in rats with severe scalded

Objective:To explore the potential protective effects of ulinastatin on ventilation-induced lung injuries of severe burned rats.Methods:Ninety Wistar rats were randomly divided into three experimental groups:the control group(n=30),the ventilation group(n=30)and the ventilation-ulinastatin group(n=30).After establishing the severe burn model,the rats of latter two groups were mechanically ventilated for 1 hour with or without the pre-treatment of ulinastatin.After severe scald,the protective effect of ulinastatin on lung injury caused by mechanical ventilation was estimated through the observation of the tissues samples,and evaluation of the pathological changes of lung tissue by HE staining,ultrastructure change by electron microscopy,lung coefficient,and the expression levels of lung tissue cytokines TNF-α,IFN-γ,IL-2 by immunohistochemical staining.Results:Edema in lung tissues of the control group and the ventilation group was obvious,the hemorrhagic focus could be seen,and the cut surface was observed to be scattered and swelling;Edema in lung tissues of the ventilation-ulinastatin group was mild.HE staining revealed that the pathological changes of the ventilation-ulinastatin group were milder than the ventilation group.Under the electron microscope,the lung tissue organelles of the control group and the ventilation group were seriously damaged;the corresponding changes in the ventilation-ulinastatin group were lighter.The lung coefficient of the ventilation-ulinastatin group was significantly lower than that in the ventilation group.The immunohistochemical results showed that the intensity of TNF-α,IL-2 and IFN-γin lung tissue of the ventilation-ulinastatin group was significantly lower than that in the ventilation group.Conclusions:Ulinastatin has protective effects on lung injury caused by mechanical ventilation in severe scalded rats,whose mechanism may be related to the capacity of ulinastatin to reduce the expression of cytokines including TNF-α,IL-2 and IFN-γ.

Molecular Mechanisms of Ventilator-Induced Lung Injury

Objective：Mechanical ventilation （MV） has long been used as a life-sustaining approach for several decades.However,researchers realized that MV not only brings benefits to patients but also cause lung injury if used improperly,which is termed as ventilator-induced lung injury （VILI）.This review aimed to discuss the pathogenesis of VILI and the underlying molecular mechanisms.Data Sources：This review was based on articles in the PubMed database up to December 2017 using the following keywords：＂ventilator-induced lung injury＂,＂pathogenesis＂,＂mechanism＂,and ＂biotrauma＂.Study Selection：Original articles and reviews pertaining to mechanisms of VILI were included and reviewed.Results：The pathogenesis of VILI was defined gradually,from traditional pathological mechanisms （barotrauma,volutrauma,and atelectrauma） to biotrauma.High airway pressure and transpulmonary pressure or cyclic opening and collapse of alveoli were thought to be the mechanisms of barotraumas,volutrauma,and atelectrauma.In the past two decades,accumulating evidence have addressed the importance of biotrauma during VILI,the molecular mechanism underlying biotrauma included but not limited to proinflammatory cytokines release,reactive oxygen species production,complement activation as well as mechanotransduction.Conclusions：Barotrauma,volutrauma,atelectrauma,and biotrauma contribute to VILI,and the molecular mechanisms are being clarified gradually.More studies are warranted to figure out how to minimize lung injury induced by MV.

Serum and lung endothelin-1 increased in a canine model of ventilator-induced lung injury

Background Nitric oxide （NO） plays an important role in acute lung injury （ALl）, acute respiratory distress syndrome （ARDS）, and in ventilator-induced lung injury （VILI）. A change in the balance of endothelin-1 （ET-1） and NO in the ALI/ARDS can also add to these problems. However, the profile of ET-1 and the balance of ET-1 and NO are still unknown in a VILI model. Methods Models of oleic acid induced ALl were established in dogs; these models were then randomized into three groups undergone different tidal volume （VT） mechanical ventilation, which included a VT6 group （VT equaled to 6 ml/kg body weight, positive end expiratory pressure （PEEP） equaled to 10 cmH20, n=-6）, a VT10 group （VT equaled to 10 ml/kg body weight, PEEP equaled to 10 cmH20, n=-4） and a VT20 group （VT equaled to 20 ml/kg body weight, PEEP equaled to 10 cmH20, n=-6） for 6-hour ventilation. The levels of ET-1 and NO in serum and tissue homogenates of lung were observed throughout the trial. Results PaO2 was increased after mechanical ventilation, but hypercapnia occurred in the VT6 group. The magnitudes of lung injury in the VT20 group were more severe than those in the VT6 group and the VT10 group. Serum levels of ET-1 and NO increased after ALl models were established and slightly decreased after a 6-hour ventilation in both the VT6 group and the VT20 group. The serum ET-1 level in the VT20 group was higher than that in the VT6 group and the VT10 group after the 6-hour ventilation （P 〈0.05） while the serum NO levels were similar in the three groups （all P 〉0.05）. There was no significant difference in serum ratio of ET-1/NO between any two out of three groups （P 〉0.05）, although there was a significant positive relationship between serum ET-1 and serum NO （r=0.80, P 〈0.01）. The levels of ET-1 and NO in the lung were increased after ventilation. The lung ET-1 level in the VT20 group was significantly higher than that in the VT6 group and VT10 group （both P 〈0.05） while there was no significant difference in lung NO levels between two groups （P〉0.05）. In the lung tissue, the ratio of ET-1/NO was significantly higher in the VT20 group than in the VT6 group and VT10 group after the 6-hour ventilation （P 〈0.05） as there was a significant positive relationship between ET-1 and NO in the lung （r=0.54, P 〈0.05）. Conclusions The production of ET-1 and NO was increased in serum and lung tissue in a VILI model. But the ET-1 levels increased much more than the NO levels in the lung, though there was a significant positive relationship between levels of ET-1 and NO. These results showed that there was an interaction between ET-1 and NO in a VILI model and changing the balance of ET-1 and NO levels might contribute to the pathophysiologic process of VILI.

Mesenchymal Stem Cell Attenuates Neutrophil-predominant Inflammation and Acute Lung Injury in an In Vivo Rat Model of Ventilator-induced Lung Injury

Background： Subsequent neutrophil （polymorphonuclear neutrophil [PMN]）-predominant inflammatory response is a predominant feature of ventilator-induced lung injury （VILI）, and mesenchymal stem cell （MSC） can improve mice survival model of endotoxin-induced acute lung injury, reduce lung impairs, and enhance the repair inflammatory in the VILI is still unknown. This study aimed to inflammatory in the mechanical VILI. of VILI. However, whether MSC could attenuate PMN-predominant test whether MSC intervention could attenuate the PMN-predominate Methods： Sprague-Dawley rats were ventilated for 2 hours with large tidal volume （20 mL/kg）. MSCs were given before or after ventilation. The inflammatory chemokines and gas exchange were observed and compared dynamically until 4 hours after ventilation, and pulmonary pathological change and activation of PMN were observed and compared 4 hours after ventilation. Results： Mechanical ventilation （MV） caused significant lung injury reflected by increasing in PMN pulmonary sequestration, inflammatory chemokines （tumor necrosis factor-alpha, interleukin-6 and macrophage inflammatory protein 2） in the bronchoalveolar lavage fluid, and injury score of the lung tissue. These changes were accompanied with excessive PMN activation which reflected by increases in PMN elastase activity, production of radical oxygen series. MSC intervention especially pretreatment attenuated subsequent lung injury, systemic inflammation response and PMN pulmonary sequestration and excessive PMN activation initiated by injurious ventilation. Conclusions： MV causes profound lung injury and PMN-predominate inflammatory responses. The protection effect of MSC in the VILI rat model is related to the suppression of the PMN activation.

Efficacy of prone position in acute respiratory distress syndrome patients: A pathophysiology-based review

Acute respiratory distress syndrome(ARDS) is a syndrome with heterogeneous underlying pathological processes. It represents a common clinical problem in intensive care unit patients and it is characterized by high mortality. The mainstay of treatment for ARDS is lung protective ventilation with low tidal volumes and positive end-expiratory pressure sufficient for alveolar recruitment. Prone positioning is a supplementary strategy available in managing patients with ARDS. It was first described 40 years ago and it proves to be in alignment with two major ARDS pathophysiological lung models; the "sponge lung"- and the "shape matching"-model. Current evidence strongly supports that prone positioning has beneficial effects on gas exchange, respiratory mechanics, lung protection and hemodynamics as it redistributes transpulmonary pressure, stress and strain throughout the lung and unloads the right ventricle. The factors that individually influence the time course of alveolar recruitment and the improvement in oxygenation during prone positioning have not been well characterized. Although patients' response to prone positioning is quite variable and hard to predict, large randomized trials and recent meta-analyses show that prone position in conjunction with a lung-protective strategy, when performed early and in sufficient duration, may improve survival in patients with ARDS. This pathophysiology-based review and recent clinical evidence strongly support the use of prone positioning in the early management of severe ARDS systematically and not as a rescue maneuver or a last-ditch effort.

Respiratory mechanics in brain injury: A review

Several clinical and experimental studies have shown that lung injury occurs shortly after brain damage. The responsible mechanisms involve neurogenic pulmonary edema, inflammation, the harmful action of neurotransmitters, or autonomic system dysfunction. Mechanical ventilation, an essential component of life support in brain-damaged patients(BD), may be an additional traumatic factor to the already injured or susceptible to injury lungs of these patients thus worsening lung injury, in case that non lung protective ventilator settings are applied. Measurement of respiratory mechanics in BD patients, as well as assessment of their evolution during mechanical ventilation, may lead to preclinical lung injury detection early enough, allowing thus the selection of the appropriate ventilator settings to avoid ventilatorinduced lung injury. The aim of this review is to explore the mechanical properties of the respiratory system in BD patients along with the underlying mechanisms, and to translate the evidence of animal and clinical studies into therapeutic implications regarding the mechanical ventilation of these critically ill patients.

Driving pressure:A useful tool for reducing postoperative pulmonary complications

The operating room is a unique environment where surgery exposes patients to non-physiological changes that can compromise lung mechanics.Therefore,raising clinicians’awareness of the potential risk of ventilator-induced lung injury(VILI)is mandatory.Driving pressure is a useful tool for reducing lung complications in patients with acute respiratory distress syndrome and those undergoing elective surgery.Driving pressure has been most extensively studied in the context of single-lung ventilation during thoracic surgery.However,the awareness of association of VILI risk and patient positioning(prone,beach-chair,parkbench)and type of surgery must be raised.

Progress of mechanical power in the intensive care unit

Mechanical power of ventilation,currently defined as the energy delivered from the ventilator to the respiratory system over a period of time,has been recognized as a promising indicator to evaluate ventilator-induced lung injury and predict the prognosis of ventilated critically ill patients.Mechanical power can be accurately measured by the geometric method,while simplified equations allow an easy estimation of mechanical power at the bedside.There may exist a safety threshold of mechanical power above which lung injury is inevitable,and the assessment of mechanical power might be helpful to determine whether the extracorporeal respiratory support is needed in patients with acute respiratory distress syndrome.It should be noted that relatively low mechanical power does not exclude the possibility of lung injury.Lung size and inhomogeneity should also be taken into consideration.Problems regarding the safety limits of mechanical power and contribution of each component to lung injury have not been determined yet.Whether mechanical power-directed lung-protective ventilation strategy could improve clinical outcomes also needs further investigation.Therefore,this review discusses the algorithms,clinical relevance,optimization,and future directions of mechanical power in critically ill patients.

Does airway pressure release ventilation offer new hope for treating acute respiratory distress syndrome?

Mechanical ventilation(MV)is an essential life support method for patients with acute respiratory distress syn-drome(ARDS),which is one of the most common critical illnesses with high mortality in the intensive care unit(ICU).A lung-protective ventilation strategy based on low tidal volume(LTV)has been recommended since a few years;however,as this did not result in a significant decrease of ARDS-related mortality,a more optimal venti-lation mode was required.Airway pressure release ventilation(APRV)is an old method defined as a continuous positive airway pressure(CPAP)with a brief intermittent release phase based on the open lung concept;it also perfectly fits the ARDS treatment principle.Despite this,APRV has not been widely used in the past,rather only as a rescue measure for ARDS patients who are difficult to oxygenate.Over recent years,with an increased under-standing of the pathophysiology of ARDS,APRV has been reproposed to improve patient prognosis.Nevertheless,this mode is still not routinely used in ARDS patients given its vague definition and complexity.Consequently,in this paper,we summarize the studies that used APRV in ARDS,including adults,children,and animals,to illustrate the settings of parameters,effectiveness in the population,safety(especially in children),incidence,and mechanism of ventilator-induced lung injury(VILI)and effects on extrapulmonary organs.Finally,we found that APRV is likely associated with improvement in ARDS outcomes,and does not increase injury to the lungs and other organs,thereby indicating that personalized APRV settings may be the new hope for ARDS treatment.