Although the diagnosis and treatment of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) has made great progress in recent years, the diagnosis and treatment of ALI/ARDS remains a challenge for the field of respiratory disease and indeed for all clinicians and scientists. Because the mortality rate is still high, the mechanisms leading to acute respiratory failure and multi-organ failure are not fully understood, and treatment strategies still need to be refined. Advances in the management of ALI/ARDS were one of the central topics of the 2006 American Thoracic Society Annual Meeting.
ALI/ARDS Definition and Diagnostic Criteria
Dr. Ferguson from the University of Toronto, Canada, reviewed the definition and diagnostic criteria of ALI/ARDS, and some scholars also discussed the problems of diagnostic criteria and future research.
1. Definition of ARDS
The earliest official definition was proposed by Ashbaugh, a respiratory and critical care physician at the University of Colorado, in 1967, and ARDS was defined as a patient with acute dyspnea, shortness of breath, severe hypoxemia, abnormal chest radiographs, and reduced static pulmonary compliance.
With the popularization of pulmonary artery catheters, ARDS was shown to be a non-cardiogenic pulmonary edema. Subsequent studies further showed that ARDS pathology is characterized by increased alveolar capillary membrane permeability, diffuse lung injury and proteinous alveolar edema fluid accumulation. The accompanying physiological abnormalities include severe hypoxemia and reduced pulmonary compliance. Therefore, scholars believe that ARDS is not a disease but a syndrome.
The proposed definition of ARDS provides a great help to the clinical diagnosis and treatment work, and helps to identify the group of patients with common clinical manifestations and to carry out early treatment.
2. Diagnostic criteria for ALI/ARDS
In 1994, the Joint Expert Review Meeting (AECC) of the North American Respiratory Diseases-European Society of Critical Care published a consensus on the diagnosis of ALI/ARDS.
ARDS is considered to be a severe stage of ALI, an inflammatory syndrome in which patients have increased pulmonary capillary membrane permeability and clinical, imaging and physiological abnormalities that cannot be explained by left heart failure and pulmonary hypertension.
The diagnostic criteria for ALI are oxygenation index (PaO2/FiO2) <300, chest radiograph showing bilateral pulmonary infiltrates, pulmonary artery wedge pressure <18 mmHg, and no clinical manifestations of left atrial hypertension. the diagnostic criteria for ARDS are PaO2/FiO2 <200, and the rest of the criteria are the same as those for ALI.
(1) Sensitivity of the criteria
The original purpose of proposing the above criteria was to unify understanding, but some investigators have identified problems with this strict diagnostic criterion, including the lack of sensitivity of this diagnostic criterion and the fact that patients diagnosed are usually already severe and have a poor prognosis themselves.
The reason for this poor sensitivity may be related to the need to place a pulmonary artery catheter to measure pulmonary wedge pressure. a 3-month follow-up by Rinaldo et al. showed that of 27 patients with a clinical diagnosis of ARDS, only 7 fully met the 4 diagnostic criteria for ARDS, and the mortality rate in these 7 patients was 70%, compared to 30% in the remaining 20 patients.
However, the use of pulmonary artery cannulation to diagnose ARDS delays the optimal timing of treatment for those with risk factors for ARDS. 50% of those at risk for ARDS will progress to ARDS within 24 hours, and pulmonary artery cannulation delays the time and reduces the success of interventional therapy.
(2) Specificity of diagnostic criteria
The diagnostic criteria for ALI/ARDS also lack specificity. Many pulmonary diseases with inflammatory processes can fully meet the four diagnostic criteria for ALI or ARDS, for example, patients with vasculitis and alveolar hemorrhage can meet the diagnostic criteria for ALI or ARDS, yet their pathogenesis is quite different. In addition, the diagnostic criteria for ARDS exclude those with elevated pulmonary artery wedge pressure, but those with hypervolemia and congestive heart failure can also present with pulmonary injury.
In addition, there is controversy as to whether ARDS includes patients with bilateral pneumonia, due to the different application of diagnostic criteria in each center. The current use of a single threshold for the diagnosis of ARDS, including imaging and blood gas abnormalities, is arbitrary, and the identification of PaO2/FiO2 and positive end-expiratory pressure ventilation (PEEP) as well as cardiogenic pulmonary edema and the significance of chest imaging for the diagnosis are issues that deserve to be explored. Therefore, there is a need to establish diagnostic criteria for ALI/ARDS that are more helpful in predicting prognosis.
(3) Areas in urgent need of research
①The search for ARDS-specific diagnostic indicators and prognostic predictors, which should be as meaningful as acute infarction markers such as myocardial enzyme profile or troponin, in order to improve the diagnosis of ARDS and improve the understanding of the syndrome;
(ii) The most important physiological feature of ARDS is the increased permeability of the pulmonary vascular endothelium and alveolar epithelium, leading to leakage of plasma proteins into the alveolar space; therefore, detection of pulmonary vascular permeability may be a practical method to assess lung injury;
(3) To develop a multidisciplinary and acceptable treatment protocol, the respiratory and critical care medical community also needs to widely apply and deeply understand the existing diagnostic criteria for ARDS to ensure the reliability and comparability of epidemiological studies in different clinical centers.
ALI/ARDS mechanical ventilation treatment
With the increased understanding of the pulmonary pathology and pathophysiology of ALI/ARDS and ventilator-associated lung injury (VALI), lung-protective ventilation strategies have gradually been accepted. However, many clinicians are still skeptical of lung-protective ventilation strategies due to the influence of traditional ventilation strategies. Scholars have conducted in-depth discussions on the mechanism of VALI occurrence, preventive countermeasures, and mechanical ventilation strategies for ALI/ARDS.
1. Ventilator-related lung injury
The traditional ventilation strategy for ALI/ARDS is to use a large level of tidal volume (10~15ml/kg) to promote the reopening of atrophied alveoli, maintain normal arterial blood gas, and achieve adequate arterial oxygenation with minimal PEEP. Recent studies have shown that the traditional ventilation strategy is one-sided and harmful to the organism, which tends to lead to alveolar hyperinflation and cause VALI.
In fact, in the process of lung injury, the above-mentioned injuries often act simultaneously or sequentially and interact with each other, resulting in various manifestations of lung injury. the essence of VALI is biological lung injury (biotrauma), which then induces or aggravates local and systemic inflammatory responses, aggravates ALI/ARDS, and initiates the development of multi-organ dysfunction syndrome (MODS). Inappropriate mechanical ventilation therapy allows ALI/ARDS to progress to MODS, thereby increasing ARDS morbidity and mortality. This is a major research advancement in the last decade regarding the pathogenesis and prognosis of ALI/ARDS (especially the intrinsic link between ALI/ARDS and MODS).
Experimental and clinical evidence for ARDS ventilator-associated lung injury leading to MODS includes.
(1) the lung is an important site of inflammatory cell activation and accumulation
First, the alveoli are 50-100 m2 in size and contain large numbers of granulocytes within the huge capillary beds. Second, alveolar macrophages are the most abundant nonparenchymal cells in the lung. In the event of acute lung injury, a large number of inflammatory cells accumulate and activate in the lung and release a large number of inflammatory mediators, which then mediate tissue injury.
(2) Parenchymal lung cells can release inflammatory mediators
Not only alveolar macrophages can participate in the inflammatory response, but also alveolar epithelial cells, pulmonary capillary endothelial cells and mesenchymal cells can participate in the occurrence and amplification of the local inflammatory response. The expression of inflammatory cytokines such as tumor necrosis factor (TNF-α) and interleukin (IL) 8 is significantly increased when alveolar type I and type II epithelial cells are overstretched. This strongly suggests that mechanical stimulation of alveolar epithelial cells, such as mechanical stretching, during mechanical ventilation with conventional high tidal volumes or during alveolar hyperinflation, can produce inflammatory factors that can further cause or aggravate lung injury.
Injurious ventilation strategies such as conventional tidal volumes and low PEEP can lead to significantly higher concentrations of TNF-α and macrophage inflammatory protein 2 in the alveolar lavage fluid and plasma of animals.
(3) Involvement of pneumatic pressure injury in systemic inflammatory response
Pneumatic pressure injury can not only cause a local inflammatory response in lung tissue and aggravate lung injury, but also lead to the release of inflammatory mediators into the body circulation, mediating a systemic inflammatory response, which in turn causes MODS.
Therefore, it is imperative to explore and implement protective mechanical ventilation strategies for ALI/ARDS. With the understanding of pathophysiological idiosyncrasies, scholars in recent years have proposed pulmonary protective ventilation strategies to improve hypoxemia while avoiding VALI and MODS as much as possible.
ALI/ARDS mechanical ventilation strategies
1. Small tidal volume
Significantly reduced lung volume is the most important pathophysiological feature of ARDS. The lungs of ARDS patients are actually “small lungs” or “baby lungs”. Therefore, the application of conventional tidal volume for mechanical ventilation is bound to cause alveolar hyperinflation and VALI.
Low tidal volume ventilation and permissive hypercapnia (PHC) are among the most important pulmonary protective ventilation measures. In general, tidal volume ≤6ml/kg allows PaCO2 to increase to 60~80mmHg and pH to 7,10~7,20, which is usually well tolerated by patients. It has a pulmonary protective effect. The end-inspiratory Pplat reflects the alveolar transmural pressure and is useful in preventing VALI when Pplat is <30 cmH2O. PHC can prevent alveolar hyperinflation, which can prevent worsening lung injury and MODS, but is mainly indicated for severe ARDS.
For ALI and mild to moderate ARDS, strict implementation of PHC is not required, but close real-time monitoring of pulmonary mechanics idiosyncrasies is still necessary. Ensuring Pplat<30cmH2O and lung volume below the level of high turning point of pulmonary pressure-volume (PV) curve is the key to prevent and treat VALI.
2.Positive end-expiratory pressure ventilation
The sudden opening of a large number of collapsed alveoli at the end of expiration at the beginning of inspiration can produce shear force, and shear force damage can also occur between normal alveoli and atrophied alveoli. Therefore, PEEP is needed to prevent alveolar collapse and to maintain more alveoli in the open state. Implementation of a lung-protective ventilation strategy should include not only PHC but also the application of PEEP to reopen collapsed alveoli and avoid periodic alveolar collapse and reopening for the purpose of preventing VALI and MODS.
PEEP prevents alveolar collapse and improves gas exchange through the supportive effect of positive intra-alveolar pressure at the end of expiration, and its effect is closely related to the level of PEEP. Optimal PEEP can eliminate the shear force generated by repeated retensioning of collapsed alveoli and reduce lung injury, while increasing the functional residual air volume and improving the ventilation/blood flow ratio, thus improving hypoxemia. However, too high a level of PEEP can lead to alveolar hyperinflation, and the optimal PEEP is chosen to prevent both end-expiratory alveolar atrophy and alveolar hyperinflation.
The low turning point method of the static pressure-volume (PV) curve and the maximum oxygen delivery method are commonly used clinical methods to select the optimal PEEP, but both have poor utility. Recently, the low flow rate method (<8L/min) has been applied to determine the dynamic lung PV curve and obtain a quasi-static pressure-volume (PV) curve, which is highly correlated with the static PV curve, making it possible to select the optimal PEEP at the bedside. Generally, a pressure 2-3 cmH2O higher at the low turning point of the quasi-static PV curve is used as the optimal PEEP.
The application of optimal PEEP has led to the refinement of pulmonary protective ventilation strategies. Randomized clinical studies have confirmed that TNF-α, IL-1β and IL-6 levels in alveolar lavage fluid were significantly lower in patients in the lung protective ventilation strategy group (small tidal volume optimal PEEP), while concentrations of inflammatory mediators in alveolar lavage fluid were progressively higher in the conventional ventilation strategy group.
A multicenter randomized ARDS clinical randomized controlled trial hosted by the National Institutes of Health showed that optimal PEEP with small tidal volumes (6,2 ml/kg) significantly reduced the duration of mechanical ventilation in ARDS patients compared with conventional large tidal volumes (11,8 ml/kg), and the morbidity and mortality rates were significantly lower (39,8% and 31,0%, respectively), which marked a fundamental breakthrough in ARDS treatment This result marks a fundamental breakthrough in ARDS treatment strategy. The application of small tidal volume optimal PEEP as the main component of the lung protective ventilation strategy is not only an important supportive pulmonary treatment measure, but also an important means of ARDS etiology treatment and MODS prevention and treatment.
3.Other adjuvant ventilation strategies
High-frequency ventilation is the use of more than 4 times the frequency of normal breathing (>60 breaths/min) and very small tidal volume (1~5ml/kg) for ventilation, currently there are two kinds of high-frequency jet ventilation (HFJV) and high-frequency oscillatory ventilation (HFOV) commonly used, if combined with pulmonary resuscitation, it can make the lung tissue in the maximum state of recruitment, prevent alveolar atrophy and increase the amount of functional residual lung air, reduce VALI. However, to date, there are no reports of high-frequency ventilation improving survival in patients with ALI/ARDS.
Prone ventilation can expand the atrophied alveoli by reversing the negative thoracic pressure gradient and gravity, improve the distribution of air and blood in the lungs and pulmonary ventilation function, and eliminate the shear force caused by the periodic opening and closing of the atrophied alveoli with the ventilator, thus effectively reducing the factors causing VALI. Pulmonary resuscitation (the most common method used is intermittent high levels of continuous positive airway pressure of 35-40 cmH2O for 30-40 seconds) can effectively resuscitate atrophied lung tissue, increase lung volume, and improve pulmonary oxygenation function. Prone ventilation and pulmonary resuscitation can be used as an adjunct to pulmonary protective ventilation strategies for ALI/ARDS.
Pharmacological treatment of ALI/ARDS
Although several dozen drugs have been tried in the past 40 years for the treatment of ALI/ARDS, such as adrenocorticosteroids, pulmonary surface-active substances, and inhaled nitric oxide, all have had limited efficacy and require further study. The clinical use of adrenocorticosteroids is the most controversial, and although the early use of high doses of adrenocorticosteroids for ALI/ARDS has been discredited, many scholars still use them to “rescue” persistent ARDS in the proliferative phase.
ARDSNet recently reported preliminary results from a large randomized controlled trial that showed significant improvements in arterial blood pressure, oxygen and duration of mechanical ventilation in the adrenocorticosteroid group compared to the control group, but no difference in patient mortality rates at 28 and 60 days. Pulmonary surfactant abnormalities are present in both ALI/ARDS and infantile respiratory distress syndrome, but exogenous surfactant replacement therapy is not as effective in ALI/ARDS as it is in infantile respiratory distress syndrome. Several small clinical studies have shown that pulmonary surfactant replacement therapy improves pulmonary oxygenation, but the effect of pulmonary surfactants on long-term survival and the best way to use them (e.g., timing, dose, route, and preparation of exogenous surfactants) need to be further investigated.
Several large randomized controlled trials have demonstrated that inhaled nitric oxide may improve hypoxemia and lower pulmonary arterial pressure transiently (generally within 72 hours), but the long-term effects are poor and do not reduce the morbidity and mortality of patients. In addition, the use of anticoagulation therapy in patients with ALI/ARDS has received renewed attention. Many anticoagulants such as heparin, antiplatelet agents, tissue factor inhibitors, factor VIIa and activated protein C and thrombomodulators have been tried in patients with experimental and clinical sepsis and/or ALI, with activated protein C being the most notable.
The use of imaging techniques in ALI/ARDS
Electron computed tomography (CT), magnetic resonance imaging (MRI), positron emission computed tomography (PET) and optical coherence tomography (OCT) are widely used in the study of lung pathophysiology and other aspects of ALI/ARDS.
CT can well evaluate the distribution and extent of lung lesions, dynamically observe the degree of lung tissue recruitment, timely detect overinflation and expansion of lung tissue, and guide the clinical selection of appropriate mechanical ventilation parameters. MRI, on the other hand, has the characteristics of non-invasive, non-ionizing and reproducible in accurately determining the partial pressure of alveolar oxygen and the rate of oxygen consumption, and thus accurately calculating lung function. PET, on the other hand, can accurately measure local ventilation and blood flow distribution in lung tissue, capillary permeability, and the degree of pulmonary edema. In addition, PET can be used to observe the distribution of receptors, expression of target genes and cell proliferation in the lung, providing a good way to study molecular biology at a holistic level, while OCT is a new medical chromatography imaging method after CT and MRI, which can detect organisms non-invasively and obtain high-resolution cross-sectional images of the internal microstructure of biological tissues.
Stem cell transplantation for prevention and treatment of ALI/ARDS
Hematopoietic stem cells (HCS) and bone marrow mesenchymal stem cells (MSC) can both be differentiated into cells of multiple germ layer origin such as bronchial epithelial cells and alveolar epithelial cells under certain conditions, which can be used for the prevention and treatment of lung injury.
Since HCS and MSC are easy to obtain, can be expanded in large numbers in vitro, have little immunogenicity and are inexpensive to transplant, the use of HCS and MSC for the treatment of various lung diseases such as ALI/ARDS, interstitial lung disease and emphysema is a hot research topic this year.
It has been confirmed that after transplantation of autologous HCS or MSC to animals or patients with lung injury, HCS or MSC can differentiate into type II alveolar epithelial cells in the lung, and the latter can further differentiate into type I alveolar epithelial cells. It has also been found that stem cells can differentiate directly into type I alveolar epithelial cells.
In a study using a rat lung injury model, DAPI (a fluorescent dye) labeled MSCs were implanted in rats with lung injury. The results showed that MSC could survive in the injured rat lung tissue and could express keratin, which is unique to epithelial cells, indicating that the implanted MSC could differentiate into epithelial cells. Further pathological observations revealed that the proliferation of interstitial and fibroblastic cells in the lung of MSC-implanted rats with lung injury was significantly reduced, and the production of stromal components and collagen was significantly decreased, indicating that MSC implantation significantly reduced fibrotic lesions in the lung and slowed down the progression of the disease.
It was also shown that the mRNA expression of cytokines that play an important role in promoting pulmonary fibrosis (such as transforming growth factor β1, platelet-derived growth factors A and B, and insulin-like growth factors) was reduced to varying degrees in lung tissue of lung-injured rats after MSC implantation, indicating that MSC may also reduce the formation of pulmonary fibrosis by regulating the expression of cytokines. In addition, it has also been reported that type II alveolar epithelial cells are themselves endogenous stem cells that can be used to repair lung injury.
Compared with other organs, stem cell transplantation for lung diseases is a late start, and there are still many questions to be solved before it can be used in the clinical setting, such as how do stem cells nest after entering the lung? How to relate to the local microenvironment (Niche) and differentiate appropriately? How to control the survival and differentiation of transplanted stem cells? It is believed that in the near future, stem cell transplantation will definitely open a new chapter in the prevention and treatment of lung diseases such as ALI/ARDS.