Respiratory Distress, Non-Cardiac

Medical conditions characteristic of respiratory dysfunctions can be lethal as they disrupt the arterial oxygenation level and impair the functional supply of oxygen to major organs. First case clinical study records described the development of severe or mild respiratory distress in patients with severe pancreatitis, sepsis, nonthoracic injuries, massive transfusion, and other conditions. Bouts of respiratory distress were reported in many patients during inpatient admissions and, sometimes, a few hours or days after discharge. To better explain the symptoms and presentations of the condition, the term acute respiratory distress syndrome (ARDS) was coined as descriptive medical terminology for the type of respiratory distress. As with other medical conditions, research and clinical studies unveiled new information about this condition, including reports of a similar presenting group of symptoms in children.

Olusola Cristiano, a 45-year-old Ghanaian immigrant, had earned an industry reputation for a rigorous work schedule and on-time project delivery. His recent work had him miss a few hours of sleep as he traveled across different time zones on business trips. In January, Olusola presented to the emergency department of the company's insurance provider with complaints of cough, chills, and severe, pulsating right-sided chest pain. He explained that the pain had lasted for one month, causing mild difficulties in breathing. He had no episodes of vomiting, muscle cramps, or myalgias.

His medical history reported a long-term childhood exposure to a relative diagnosed with Tuberculosis. In the last two months, he had lost approximately 35 pounds and had several episodes of nightly sweats. He denied recreational drug use but had smoked at least two packs of cigarettes weekly for the past two years. Before venturing into the construction industry, he had worked previously in a steel mill, collecting coins and cleaning them with mercury sprays. He is a known alcoholic, not currently on any medication, and has no clinical record of comorbidities.

On examination, Olusola's pain seemed pleuritic with an associated cough productive of yellowish, spotted sputum without hemoptysis. The attending resident admitted him into the General Observatory to treat community-acquired pneumonia. He was started on a prescription order for Azithromycin, Ceftriaxone, and oral pain relievers. The initial therapy plan was to manage him as an inpatient and recommend discharge once his condition improved. On the third day, Olusola reported improved pain control in the chest but complained of mild difficulties in breathing. On day 5 of hospital admission, the attending resident was urgently alerted to his respiratory status worsening.

He was transferred to the ICU for unexplained ARDS. On admission to the ICU, Olusola appeared dyspneic. On auscultation, breath sounds were diminished on the right side in the upper zone without the presence of adventitious sounds. The white blood cell count was 28 cells/µl, and the red blood cell count was 51 cells/µl. His blood pressure was 165/95 mmHg, heart rate was 131/min, respiratory rate was 32/min, and body temperature was 38.2 degrees Celsius. His oxygen saturation on room air was 77% and 90% on 40% venti-mask. He was ventilated and was on synchronized intermittent mandatory ventilation mode. Positive end-expiratory pressure (PEEP) was increased to 12 cm of H2O, the respiratory target was set at 20 breaths per minute, and the inspiration rate was 1:2. He was in a prone position and maintained with 0.9% normal saline at 40ml/hour.

On the subsequent evaluation round, his blood pressure dropped to 125/85 mmHg, and his lung function ratio improved from 192 to 300 and finally to 400. His breathing pattern had improved significantly, and arterial oxygen saturation had increased to 98%. The consultant recommended gradual oxygen weaning and adaptive support ventilation (ASV). The discharge order recommended 24-hour stabilized vitals before discharge can be considered.

In light of new clinical information, in 1994, the American-European Consensus Conference (AECC) developed a clear definition of this condition, ultimately renaming it (ARDS). ARDS was an acute condition characterized by bilateral pulmonary infiltrates and severe hypoxemia. In 2011, this definition was modified by the Berlin Definition of ARDS. ARDS has been redefined as a condition lasting at least one week with bilateral opacities and edema. These opacities are not fully explained by effusions, consolidation, or atelectasis (radiographic examination), and the edema is not explained by fluid overload, cardiac failure, or respiratory severity.

Subsequently, the Berlin definition classified ARDS into three distinct categories differentiated by the severity of oxygenation compromise. Unlike the AECC's previous definition, it excluded acute lung injury (ALI) from the clinical characteristics of ARDS, removed the requirement for wedge pressure <18, and included the requirement of PEEP. The three categories identified were mild (PaO₂/ FiO2 200-300), moderate (PaO₂ / FiO₂ 100-200), and severe (PaO₂ / FiO₂ ≤100) (Matthay et al., 2021). Objective assessments, including echocardiogram, were recommended as diagnostics methods if risk factors for ARDS were absent. As with many medical conditions, basing the diagnosis of ARDS on clinical criteria was necessary as it is practically impossible to obtain direct measurements of lung injury by pathological samples of lung tissues in most patients.

Study surveys reported an increased number of respiratory distress symptoms in the pediatric population, highlighting the need for a harmonized ARDS diagnosis and management protocol in this population. Protocols and other clinical specifics were developed at the Pediatric Acute Lung Injury Consensus Conference (PALICC).

Specific terms developed from this include:

• Oxygenation index (OI)
• Oxygen saturation index (OSI)
• Pulse oximetric saturation to the fraction of inspired oxygen ratio (S/F, SPO₂/FiO₂)

The following was recommended for pediatric patients:

• The utilization of low tidal volume (5-8 mL/kg of predicted body weight)
• Limiting plateau pressure to 28-32 cm H₂O
• Permissive hypercapnia strategy
• PEEP in the range of 5-15 cm H₂O
• Acceptance of low SPO₂ in the range of 88-92% if PEEP is as high as 10 cm H₂O

The pathophysiology of this condition is challenging to pinpoint as the etiology is multifactorial. In the early research describing the pathophysiology of ARDS, a direct pulmonary or indirect extrapulmonary insult was implicated in the proliferation of inflammatory mediators promoting neutrophil accumulation in the microcirculation of the lung. With the current research on this condition, etiologies that trigger this syndrome have been grouped into direct and indirect causes. Direct causes trigger primary injuries to the lung epithelium and include pneumonia, aspiration, drowning, and toxic inhalation. Indirect causes, however, trigger diffuse damage to the lung's vascular endothelium and cause systemic lung inflammation. These triggers include:

• Extrapulmonary sepsis
• Non-cardiogenic shock
• Pancreatitis
• Adverse drug reactions
• Vasculitis
• Trauma
• Transfusions 

The histological hallmark of ARDS appears to be diffuse alveolar damage (DAD). These etiologies provoke a systemic inflammatory response in the lung.

Various pathways, mediators, and molecular systems contribute to altered alveolar endothelial and epithelium porosity. An adherens junctional protein, the vascular endothelial cadherin (VE-cadherin, has been identified to perfume critical physiological functions in maintaining barrier integrity in the lung microvessels. Disruption of the homophilic bonds on the VE-cadherin destabilizes lung barrier integrity. Antibodies against VE-cadherin and other destabilizing agonists such as thrombin, TNF, VEGF, and leucocyte signals have disrupted VE-cadherin bonds, prompting lung edema (Lupu et al., 2020). In sharp contrast, factors that stabilize VE-cadherin bonds, including genetic manipulation of VE-cadherin-catenin interactions or preventing the dissociation of a phosphatase group from VE-cadherin, reduce the influx of leucocytes and fluids into the alveolar space. The interaction has been proven in clinical studies exploring potential treatment options for ARDS in mice (Jones et al., 2022).

Recent studies on a new pathway implicated in alveolar epithelium damage focus on the role of a neutrophil-platelet complex. Neurons in the intravascular and extravascular compartments often form a complex with platelets. These platelets have intricate thrombo-inflammatory activities and, most importantly, the ability to deploy neutrophil extracellular traps (NETs). Histological researchers describe NETs as filamentous chromatin fiber complexed with neutrophil-derived antimicrobial proteins. These traps reportedly evolved as an innate mechanism for pathogen containment and clearance. However, they are also involved in inflammatory insults to major organs, including the lung (Lefrancais et al., 2018). In experimental models, NETs correlate with alveolar-capillary and epithelial disruptions causing alveolar edema and damage. Research observations have also suggested an early intravascular interaction of platelets with monocytes in an aggregation mechanism similar to the neutrophil-platelet association. These aggregations involving monocytes also reportedly drive the development of ARDS in patients at risk. The pathway involved in recruiting neutrophils and monocytes to the lung is influenced by intra-alveolar macrophages releasing chemotactic factors. These factors, including CC-Chemokine ligand 2 and IL-8, enhance neutrophil recruitment as a physiological response to acute pulmonary infections (Abdulnour et al., 2018).

Studies have shown that the balance between the protective and harmful innate and adaptive immune responses may also determine the severity of alveolar injuries. Acute inflammatory responses to pathogens and toxins in disease cycles of lung infections can precipitate ALI. These inflammatory responses release leucocyte protease, synthesis of chemokines and cytokines, toll-like receptor engagement, and generation of reactive oxygen species (Xie et al., 2021). Research submissions have also highlighted how molecular events governing the balance between angiotensin-converting enzymes 1 and 2 (ACE I and II) may also contribute to inflammatory lung injuries as a direct consequence of viral infection, acute injury, and sepsis (Wu et al., 2022). Injuries cause airspace and interstitium edema by developing a protein-rich neutrophilic exudate. The development of exudate compromises gas exchange and reduces the integrity of the normal respiratory cycle. Understanding the pathophysiology of ARDS regarding alveolar integrity involves studying the normal gas transfer flow of the lung.

A healthy lung is physiologically designed to exchange carbon dioxide and oxygen across the distal alveoli-capillary unit. The selectively permeable barrier establishing a gaseous exchange in the lung is formed by a single layer of the endothelial lining, aggregated together by tight junctions and plasma membrane structures such as adherens (Chen et al., 2021). The surface of this expansive boundary is lined by fat alveolar type 1 cells (ATI) and cuboid-shaped alveolar type 2 cells (ATII), forming a barrier restricting the free flow of solutes but allowing the diffusion of oxygen and carbon dioxide. Surfactants secreted by the Alveolar cells serve critical functions in the reduction of surface tension and in maintaining active gas exchange by keeping the alveoli complex open. Sodium channels and basolateral Na+/K+ -ATPase pumps on the alveolar cells help absorb excess fluid from the airspaces by vectorial ion support (Esquivel-Ruiz et al., 2021).

With this mechanism, there is the reabsorption of edematous fluid in the event of alveolar edema. Fluid reabsorption through this mechanism into the lung is primarily transported and removed by lung microcirculation and the lymphatic network. In addition to the tight barrier structure, the cellular makeup of a normal, healthy alveolus also includes alveolar macrophages ready for rapid deployment into the lung microcirculation. These macrophages and a cellular population of platelets, monocytes, and neutrophils control the defensive response of the healthy alveolus and have a critical function in the pathophysiology of ALI.

Image 1: Structure of an Alveolus 

In ARDS, the lung epithelium and the selective barrier on the alveoli surface are compromised, forcing liquid and protein across the endothelium. The absorption of protein and fluids across this barrier precipitates edema in the lung interstitium (Meyer et al., 2021). From the lung interstitium, fluid flows to the alveoli, taking advantage of damage to the alveolar epithelium. Increased alveolar-capillary permeability to protein, neutrophils, and blood cells results in the accumulation of fluids in the alveoli (Doig et al., 2022). Research studies have identified the impaired excretion of carbon dioxide due to alveolar-capillary compromise as the root component of respiratory failure in ARDS. Impaired carbon dioxide excretion results in elevated ventilation associated with a greater volume of breath participating in carbon dioxide excretion (an increase in pulmonary dead space). In addition to increased pulmonary dead space, a decrease in respiratory compliance is another independent predictor of mortality in ARDS (Patel et al., 2022).

The expansive pathophysiology of ARDS also includes eosinophilic depositions called hyaline membranes. Hyaline membranes are a defining feature of DAD (Cardinal-Fernandez et al., 2017). Other features described so far include fibrin deposition, alveolar hemorrhage, alveolar atelectasis, and accumulation of white blood cells. The acute exudative phase of ARDS lasts approximately 7 days and usually resolves completely. In some cases, residual pulmonary fibrosis may develop, with the alveolar space filled with mesenchymal cells and new blood vessels. With recent research on DAD, pulmonary fibrosis appears to be facilitated by interleukin 1 (IL-1). Pathological progression to the fibrosis stage may be predicted early by investigating the possibilities of increased procollagen peptide III (PCP-III) levels in the fluid obtained by bronchoalveolar lavage (BAL) and lung biopsy specimens (Davidson et al., 2020).

Hyperplasia of the alveolar cells follows in a proliferative phase. The proliferative phase usually lasts for about 3 weeks. Analyses of the lungs of patients dying from oxygen toxicity formed the basis for the original description of DAD phases in ARDS. However, recent clinical evidence identified similar histological changes in the lungs of patients with multiple other underlying conditions (Thille et al., 2017). In a post-mortem analysis of lung samples collected over two decades (1992-2010), researchers reported that 45% of patients who met the Berlin criteria for ARDS had DAD as the underlying pathology for alveolar dysfunction. Of the study population, 55% had pneumonia, with the infiltration of neutrophils in the alveoli and distal bronchioles as the underlying trigger for ARDS. Another meta-analysis of open lung biopsy samples in ARDS patients provides supporting evidence for the decade-long study. One study reported that DAD was only present in 48% of ARDS patients in their systematic review study and was associated with a higher mortality index (Kao et al., 2017). The severity of hypoxemia and the sequential organ failure assessment appears to vary with no significant pattern in patients with or without DAD. The other bulky half of the population presented with various ARDS triggers.

Early histology studies on ARDS identified the association of DAD with the severity of ARDS, with the acute exudative phase presenting the most viable window for therapeutic intervention. Electron microscopic analysis identifies multiple alterations in the physiological composition of the epithelia and endothelial cells (Ortiz et al., 2019). Focal epithelial destruction and denudation of the alveolar basement membrane have been identified in the early involvement of ATI cells. However, ultrastructural analysis of samples could not conclusively show abnormalities in the normal alveolar barrier structures responsible for regulating gas exchange, protein influx, and fluid movement across the lung capillaries. In many cases, the alveolar endothelial cells may be preserved morphologically with the continuity of the endothelial lining maintained. Studies have shown extensive epithelial necrosis in the exudative phase before mesenchymal cell invasion, with suggestive evidence for apoptosis (Hussain et al., 2021). The release of pro-coagulant factors and subsequent deposition of fibrin during the exudative phase appears to be triggered by injured but intact alveolar epithelial cells. Pro-coagulation factors and fibrin are also deposited adjacent to injured endothelial cells in the alveoli (Kaku et al., 2020).

Image 2: Diffuse Alveolar damage (DAD)

Although the complete mechanism of alveolar damage in ARDS remains under investigation, there are studies implicating apoptosis, pyroptosis, and other alternative cell death pathways. These occurrences are in addition to early submissions on the roles of increased lung vascular permeability and endothelial junction breakdown in the pathophysiology of ARDS. In the damaged alveoli, neutrophil deposition occurs due to endothelial activation. The neutrophil-platelet aggregates play a synergistic role in increasing lung vascular permeability to protein, blood cells, and fluid. Increased vascular permeability significantly increases the frequency and risk of hypovolemia and multiple organ failure. In autopsy analysis of damaged alveoli, the epithelial cell disruptions are significantly pronounced compared to ultrastructural alteration of alveolar endothelial cells (Kersten et al., 2020). Multiple autopsy studies have also implicated pathogens and barrier-destabilizing factors as prominent causes of alveolar endothelial disruption. Others include:

• Circulating leukocytes and platelets
• Pro-inflammatory signaling molecules such as tumor necrosis factor (TNF)
• IL-1β
• Angiopoietin 2
• Vascular endothelial growth factor
• Platelet-activating factor

Image 3: The Damaged Alveolus

Therapeutic interventions and early experimental therapy models focused on mitigating endothelial permeability and reducing excessive leukocyte accumulation by re-establishing the physiological integrity of the alveolar endothelial junction. Early research on this hypothesis explored the genetic replacement of VE-cadherin with a fusion construct that prevents its internalization. Research results suggest a significantly reduced alveolar neutrophil accumulation in LPS-challenged mice. The alveolar permeability index was also significantly reduced. In an experimental simulation of ALI, the alveolar epithelium showed more resistance to injury than the endothelium. However, injuries to both structures include the disruption of intercellular junctions. In most cases, the extent of epithelial injury directly describes the severity of ARDS.

Clinical recovery and symptom resolution of ARDS can be achieved with the repair of the injured alveolar epithelium. On average, the time frame for epithelial repair may be three weeks or several weeks, depending on the severity of the alveolar compromise (Beretta et al., 2021). Generating new ATI cells is critical to alveolar repair since these cell types comprise about 95% of the alveolar epithelium surface area. Beyond the structural composition, ATI cells play principal roles in gas exchange across the alveolar surface. In many cases, ATII cells proliferate to provide a provisional epithelial barrier before transdifferentiating into ATI cells. Alternate progenitor cells, including club cells, keratin-5- expressing cells (KRT5⁺), and bronchoalveolar stem cells, can be mobilized to create new alveolar epithelial cells through proliferation. These alternative proliferation pathways are complementary options to ATII cells for alveolar repair.

The biological process and drivers for differentiating ATII cells from ATI cells are not entirely understood. However, recent research focuses on the alternate progenitor cell and default cell cycle for ATI cells, suggesting the principal role of deactivating WNT–β-catenin (Liberti et al., 2021). In addition to WNT–β-catenin deactivation, hypoxia-inducible factor (HIF) and notch signaling drive ATII differentiation to ATI cells. HIF-NOTCH and the fibrocyte growth factor receptor 2 signalings drive the expansion of KRT5⁺ epithelial progenitors (Nabhan et al., 2018).

The process of repairing the compromised tight junction in damaged alveoli is regulated by crosstalk between the extracellular matrix and the multiple alveolar cell types. Clinical evidence indicates the restorative role of injury-inducing immune cells in this process. Recruited fibroblast secretes epithelial growth factors depositing moderate quantities of collagen (Cong et al., 2017). Damages to mitochondrial complexes are destroyed, reported by immune cell functions, and replaced via mitochondrial transfer or biogenesis. The intercellular junctions are reassembled in a process regulated by multiple mechanisms. Mechanisms include signals from the basement membrane and beneficial effects from angiopoietin 1 (Wick et al., 2021). Once the tight junction reassembly is completed, edematous fluid in the alveoli is reabsorbed by diffusion through the water channels or by paracellular pathway transport into the interstitium. The osmotic gradient established by sodium uptake through the epithelial sodium channels and sodium transport through the Na⁺/K⁺-ATPase pumps drives the diffusion process.

Image 4: The Functioning Alveolus

In many patients, therapeutic interventions provide less-than-expected results, forcing care plans to adopt ventilation support and other management techniques. In a report on ARDS, Thompson et al. (2017) highlighted how the search for a consensus therapy plan for ARDS has been challenging despite huge investments in preclinical research. With the exemption of supporting care plans, including conservative fluid therapy and lung-protective ventilation, there have been difficulties adapting therapy success in animal models to human cases. Recently, a few research studies have investigated the difficulties in modeling therapy options in humans. These studies provide important clinical insight into biological markers, including plasma inflammatory markers and the inhibitory mechanism delaying alveoli repair in ARDS.

Researchers have identified many endogenous reparative mechanisms biologically inhibited during alveolar repair. As this mechanism becomes pronounced in some ARDS cases, the crosstalk between the extracellular matrix and the alveolar cell types is inhibited. Mitochondrial transfer, immune cell action, and the secretion of epithelial growth factors are inhibited, prompting symptomatic deterioration and a delay in tight junction reassembly. Depending on the etiology, the inhibitory mechanism implicated in alveolar repair varies. In ARDS cases precipitated by influenza, the virus infects KRT5⁺ progenitors and delays tight junction reassembly (Zhong et al., 2022). Hypercapnia, hypoxemia, influenza infections, and factors that downregulate the sodium channels or impair the Na⁺/K⁺-ATPase function also impair the mechanisms responsible for the removal of edematous fluid in the damaged alveolar (Gwoździńska et al., 2017). In hypercapnia, the alveolar epithelial cell proliferation is delayed. In animal models, keratinocyte growth factors reportedly increase the susceptibility of ATII cells to influenza virus infection and raise the mortality index (Nikolaidis et al., 2017).

The epidemiology of ARDS has long been studied to understand the pathophysiology in special populations. An early prospective analysis study focused on the incidence of ARDS in adults was conducted in the United States. The study design used validated screening protocols to identify patients (Gottlieb et al., 2022). The identifying criteria were defined as diagnosed non-Heart Failure ARDS using bilateral chest radiographic opacities and partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO₂/FiO₂) greater than 300 mmHg. Using the data collated, the researchers reported an annual incidence of 190,000 ARDS cases in the United States with a mortality index of 38.5%. In a follow-up epidemiological study, the LUNG SAFE study provided data on ARDS epidemiology in a cross-section of 29,144 patients across 50 countries (Pham et al., 2017).

The prevalence of ARDS, as reported in the LUNG SAFE study, was pegged at 10% in intensive care patients and 23% in patients on ventilatory support (Pham et al., 2017). The study also reported a hospital mortality rate of 34.9% for patients with mild ARDS, 40% in patients with moderate ARDS, and 46.1% in patients with severe ARDS. There is limited research on how underlying comorbidities, including cancer and immunosuppression, influence mortality rates. A follow-up analysis of the study identified about 21% of the patients with clinical evidence of immunosuppression, and about 52% were non-immunocompromised patients (Cortegiani et al., 2018). Similar data from studies conducted between 2001 and 2008 suggest a decline in the incidence of ALI and ARDS in hospitalized adults (Song et al., 2021). The decline was partly related to the more widespread use of lung-protective ventilation, the adoption of multiple therapy plans, the use of blood products, and the reduction in hospital-acquired infections known to complicate the respiratory process (Toy et al., 2022).

Based on a recent ARDS Network trial published by the NIH HEART, Lung and Blood Institute (NHLBI), the 60-day mortality rate of ARDS has declined from 36% in 1997 to 26% in 2005. A decline of 22% in adult patients has also been recently published (Thomas et al., 2022).

Common conditions associated with an increased risk of ARDS include smoking, alcohol abuse, hypoalbuminemia, and air pollution (Reilly et al., 2019). For a reason that remains unclear, a low risk of ARDS has been identified in diabetic patients. Studies examining a possible link between the risk of ARDS and ethnicity have also been conducted. Available evidence shows a largely reported higher mortality rate in patients of Black and Hispanic descent. The rates are lower in White patients. On gender, male patients appear to have a higher ARDS-related mortality rate than women. However, the origins of these disparities remain largely under investigation.

Studies have also been designed to identify genetic factors that might be responsible for variations in the mortality rate of ARDS. Largely due to the phenotypic complexities of ARDS and the different risk factors involved, no specific loci associated with significant genetic variation for ARDS have been identified. However, candidate gene pathway analysis studies have identified important mechanisms linked with the mechanism of lung injuries that seem to influence the risk of ARDS. An example includes plasma angiopoietin 2, a protein marker and mediator of increased lung vascular permeability in a population of European ancestry (Reilly et al., 2018).

The Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology (PARDIE) cross-sectional study of 145 international pediatric intensive care units is considered the reference ARDS epidemiological study in children. Based on the study results, the population-based incidence of ARDS in children aged 2 weeks to 17 years is estimated as 2.2-5.7 per 100,000. The condition is diagnosed in 2.3-3% of hospital pediatric intensive unit admission cases, with an estimated mortality rate of 17% - 33% (Khemani et al., 2019). Regarding gender variations in children, ARDS appears more frequently diagnosed in boys than in girls. As in adults, the etiologies are almost the same, with over 60% of pediatric ARDS linked with pneumonia. However, mortality risk seems lower in children, with higher rates only identified in those with indirect lung injury from sepsis and shock. In pediatric trauma cases, the incidence of ARDS is pegged at 0.5%, with a mortality rate of 18% (de Roulet et al., 2019). In pediatric cases involving intubation, the PARDIE study identified a significantly higher ARDS mortality rate compared with cases requiring no instance of intubation. A clinical history of cancer or hemopoietic stem cell transplantation also increases the mortality rate of pediatric ARDS to 43% compared to 11% in those without such a history.

The clinical presentation of ARDS is characterized by dyspnea and hypoxemia, which gradually worsen within 6 – 72 hours of clinical admission. In many cases, ventilation support of intensive care might be required within a few hours of presentation. In patients conscious enough to answer medical queries, complaints of mild dyspnea are often communicated as the respiratory condition worsens within 12 – 24 hours. Sometimes, mechanical ventilation might be urgently required to prevent hypoxia. Depending on the etiology, the precipitating cause or underlying condition may be identified, especially in cases of pneumonia and sepsis. In other cases, a detailed medical history might be needed to identify the instant case of respiratory distress. Generally, the physical presentation includes signs and symptoms associated with respiratory distress, including tachypnea and labored breathing. Systemic symptoms may also be evident depending on the severity of respiratory impairment. These include central or peripheral cyanosis, altered consciousness, and an altered mental status. Chest auscultations indicate rales, and the arterial oxygen saturation level remains low despite 100% oxygen supply.

In line with the 1994 AECC, the criteria for ARDS diagnosis include acute onset of hypoxia, noncardiogenic and bilateral infiltrates on chest radiographs, and the absence of left atrial hypertension. Hypoxemia, in this criterion, was quantified using the ratio of partial pressure of arterial oxygen and the fraction of inspired oxygen (Pao2/FiO2), with a Pao₂/FiO₂ < 200 mm Hg. With modification, the Berlin definition included:

• Bilateral opacities observable on anteroposterior chest radiographs
• A symptomatic period of at least one week following known clinical insult
• Hypoxemia -defined by a Pao₂/FiO₂ < 300 mm Hg
• A minimum PEEP ≥ 5 cm H₂O, not fully explained by cardiac failure or fluid overload

A CT scan may be required to correctly identify infiltrates as pulmonic.

A comprehensive review of physical presentation, medical history, radiographic imaging, and laboratory tests is required to evaluate the risk burden and possible etiology and make an informed diagnosis in ARDS management. If pulmonary infections are suspected, the typical diagnostic approach includes microscopic examination, respiratory specimen culture, and blood cultures. The medical history may identify a class of likely causative organisms or pathogens in community-acquired or hospital-acquired ARDS etiologies. Depending on geographic distribution and host immunity, the most commonly isolated organism in sepsis- and infection-induced ARDS include:

• The Middle East respiratory syndrome coronavirus (MERS-CoV)
• Avian influenza H5N1 and H7N9 viruses
• Hantavirus
• Human adenovirus subtype-55 (HAdV-55)
• Plasmodium species
• Blastomyces dermatitidis
• Coxiella burnetti
• Coccidioidomycosis
• Histoplasmosis
• Mycobacterium tuberculosis
• Yersinia pestis

In 2018, the guidelines for the management of ARDS were drafted by a multidisciplinary writing group constituted by the Joint Standards Committee of the Faculty of Intensive Care Medicine and Intensive Care Services. Since the first draft, this guideline has been extensively reviewed by stakeholders of the medical community and independent reviewers. The guideline focused on ten topics based on a committee member's existing recommendation regarding ARDS management. These topics include:

• Corticosteroids
• ECMO
• ECCO₂R
• Fluid strategy
• High-frequency oscillation ventilation (HFOV)
• Inhaled vasodilators (iVasoD)
• Lung protective ventilation: tidal volume (Vt)
• Neuromuscular blocking agent (NMBA)
• PEEP
• Prone Positioning

Using the PICO (Population, Intervention, Comparison, Outcome) formulation, each topic was developed into full protocols, using systemic reviews and meta-analyses of available clinical evidence on ARDS. The management of ARDS in its entirety is focused on respiratory support, fluid management, nutritional supplementation, and post-therapy rehabilitation.

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