Reviewed and updated by Megan Doble, DNP, CRNP, FNP-C, AGACNP-C: April 22, 2024

A 42-year-old patient with no significant past medical history presented to the emergency department (ED) with severe abdominal pain and was diagnosed with acute pancreatitis. Further history revealed a long-standing history of heavy alcohol consumption and binge drinking which was the suspected etiology of the pancreatitis. Gallbladder disease, the most common cause of acute pancreatitis, was ruled out with imaging and laboratory studies. The patient was admitted to the hospital and treated according to the standard of care for management of acute pancreatitis which included fluid resuscitation and pain management. On hospital day 3, the patient developed mild shortness of breath. Although the cause of the respiratory symptoms was initially unclear, upon further inquiry, the patient recalled several episodes of vomiting before arrival in the ED. Your suspicion for aspiration and possible aspiration pneumonia is raised. The patient is placed on supplemental oxygen via nasal cannula with no improvement. High flow nasal oxygen (HFNO) is ordered and initiated with significant improvements in respiratory symptoms. A mild non-productive cough and low-grade fever are observed. A chest x-ray revealed mild vascular congestion and a possible right middle lobe opacity. The patient is pan-cultured and started empirically on antibiotics to cover aspiration pneumonia and given diuretics for suspected volume overload. Overnight, the patient became tachypneic with respiratory rate in the 40s and increased work of breathing. Peripheral oxygen saturation (SpO₂) was 82% despite titration of fraction of inspired oxygen (FiO₂) to 100% on HFNO. The patient was intubated, placed on mechanical ventilation, and transferred to the intensive care unit (ICU) for management. A chest x-ray following intubation revealed diffuse bilateral alveolar infiltrates. Initially placed on standard ventilatory settings with brief improvement but, over the next several hours, it became increasingly difficult to oxygenate the patient despite titration of FiO₂ to 85% on the ventilator. An additional dose of intravenous (IV) diuretic was administered with no improvement. An arterial blood gas (ABG) revealed arterial oxygen of 67 mmHg and a repeat CXR showed progression of diffuse bilateral infiltrates. Acute respiratory distress syndrome (ARDS) was suspected and ARDS-specific ventilator strategies were initiated.

Does this scenario sound familiar? Scary? Both? Respiratory symptoms are something we see daily across healthcare settings. Depending on your role, you may be the first person to recognize a critical change in respiratory status. Understanding the potential continuum of respiratory decompensation is essential to ensure the safe management of our patients. Respiratory failure is one of the most common conditions treated in intensive care units (ICUs). The etiology and presentation of respiratory failure can vary widely and may include acute respiratory infection (i.e., bacterial or viral pneumonia), acute exacerbations of chronic respiratory conditions (i.e., chronic obstructive pulmonary disease [COPD], asthma), congestive heart failure (i.e., cardiogenic pulmonary edema), or upper/lower airway obstruction (i.e., angioedema, foreign body). ARDS is a life-threatening complication of respiratory failure associated with high morbidity and mortality. It is characterized by an acute onset, diffuse, inflammatory lung injury leading to increased vascular permeability, increased lung weight, and loss of aerated lung tissues causing severe hypoxemia (ARDS Definition Task Force, 2012). While treatment outcomes have been improving due to advances in respiratory therapies, the mortality rate for ARDS remains 25-40% (Bellani et al., 2016).  Annually, ARDS affects close to 200,000 individuals and is responsible for 74,500 deaths in the United States (Rubenfeld et al., 2005).

Is this ARDS? Diagnosing and Classifying ARDS

Distinguishing ARDS from other forms of respiratory failure can be a challenge. There are several conditions placing one at risk for the development of ARDS. The most common risk factor, sepsis, from either a pulmonary or non-pulmonary source, accounts for 79% of ARDS cases (Rubenfeld et al., 2005). Other risk factors include aspiration, toxic inhalation, lung contusion/trauma, acute pancreatitis, blood product transfusion, near drowning, burn injury/smoke inhalation, and cardiopulmonary bypass (Howell & Davis, 2018; Rubenfeld et al., 2005). The presence of any of these conditions in the setting of an acute change in respiratory status should raise your suspicion for ARDS. 

Although it was obvious the above patient was in severe respiratory distress, ARDS was not always first in the differential diagnosis. In this particular patient, the initial concerns were volume overload and aspiration pneumonia. In accordance with established definitions to diagnose ARDS, a patient must not only have an acute change in clinical condition, a high oxygen requirement, and diffuse bilateral infiltrates on radiographic studies, but the clinician must also rule out other conditions that could account for these respiratory findings.

There have been several definitions of ARDS since it was first described in the 1960s. The term acute lung injury, which had been used in past definitions, is no longer an accepted term with respect to the description of ARDS. Before 2024, the most current definition of ARDS developed by the ARDS definition task force in 2012, was the Berlin criteria. More recently, a new definition of ARDS has been recommended by ARDS experts that builds upon the Berlin definition and incorporates developments in the management of ARDS including the use of noninvasive ventilation and the use of non-invasive pulse oximetry as an alternative measure of oxygenation in place of arterial blood gases (Matthay et al., 2024).

The Berlin definition requires the presence of the following four criteria to diagnose ARDS:

1. Onset of respiratory symptoms beginning within one week of a known clinical insult, or patient must have new or worsening symptoms during the past week;
2. Presence of bilateral opacities on either chest x-ray or chest computed tomorgraphy (CT) scan consistent with pulmonary edema and are not explained by pleural effusions, lobar collapse, lung collapse, or pulmonary nodules;
3. Respiratory failure that cannot be fully explained by cardiac failure or fluid overload (consider echocardiogram or cardiac assessment if no other ARDS risk factors); and
4. Presence of a moderate to severe impairment of oxygenation, as defined by the partial pressure of oxygen (PaO₂) to fraction of inspired oxygen (FiO₂) ratio less than or equal to 300 (ARDS Definition Task Force, 2012).

ARDS is classified according to the degree of hypoxemia as follows (ARDS Definition Task Force, 2012):

• Mild - PaO₂/FiO₂ ratio of 201-300
• Moderate - PaO₂/FiO₂ ratio of 101-200
• Severe - PaO₂/FiO₂ ratio of 100

In the new proposed definition, which is called “The Global Definition of ARDS,” there is no change in the diagnostic criteria concerning the timing of symptom onset, risk factors, and origin of pulmonary edema. For the imaging criteria, in addition to bilateral opacities on chest x-ray or CT scan, the presence of bilateral B lines and/or consolidations by ultrasound has been added (Matthay et al., 2024).

The other major change in the new definition is the inclusion of non-invasive ventilation as a category of ARDS and the inclusion of oxygen saturation as measured by pulse oximetry (SpO₂) as a measure of severity in patients who are intubated.

The new ARDS classifications according to the degree of severity are as follows:

• Nonintubated ARDS
  • PaO₂/FiO₂ ratio is 300 mmHg or lower; or SpO₂/FiO₂ is 315 or lower (if SpO₂ is 97% or lower) on high flow nasal oxygen with flow of 30 L/min or higher or noninvasive ventilator/continuous positive airway pressure (CPAP) with at least 5 cm H₂O end-expiratory pressure
• Intubated Patients
  • Mild ARDS:
    • PaO₂/FiO₂ 201-300 mmHg
    • SpO₂/FiO₂ 236-315 (if SpO₂ is 97% or lower)
  • Moderate ARDS:
    • PaO₂/FiO₂ 101 -200 mmHg
    • SpO₂/FiO₂ 149-235 (if SpO₂ is 97% or lower)
  • Severe ARDS:
    • PaO₂/FiO₂ is 100 mmHg or lower
    • SpO₂/FiO₂ is 148 or lower (if SpO₂ is 97% or lower)

Looking back at the clinical history, our patient meets criteria for ARDS. The respiratory symptoms came on acutely, the clinical insult was pancreatitis and possible aspiration, the patient had the radiologic findings of diffuse bilateral opacities, and although aggressive fluid resuscitation was not administered, respiratory symptoms continued to deteriorate despite diuresis. Finally, the patient had a severe impairment in oxygenation. Based on a PaO₂ of 75 mmHg and FiO₂ of 85%, the PaO₂/FiO₂ ratio was less than 100 or lower classifying this as severe ARDS.

What is actually happening in ARDS?

The pathophysiology involved in the development of ARDS is complex and may vary depending on the mechanism of injury. Furthermore, there are three phases in the progression of ARDS, the exudative phase, the proliferative phase and the fibrotic phase. These phases have distinct histopathologic and clinical features that go beyond the depth of this blog, but it is important to be aware of terminology surrounding ARDS. In general, the clinical sequelae of ARDS are related to increased vascular permeability and these distinct histopathologic changes in each phase of ARDS (Howell & Davis, 2018). The hallmark multifocal opacities are the results of tissue damage in the alveoli mediated by neutrophil, macrophage, and dendritic cell activation. Due to an overall inflammatory state with increased vascular permeability and release of inflammatory cytokines, a protein-rich fluid accumulates in the alveoli resulting in impaired gas exchange (Han & Mallampalli, 2015) and subsequent hypoxia. This alveolar damage increases physiologic dead space ventilation that does not participate in gas exchange. Think of it as the fluid accumulating in alveoli, blocking the blood’s access to absorb oxygen, and decreased lung compliance (elasticity of lungs) leading to the “stiff” lung often described in ARDS (the fluid accumulation makes it difficult for alveoli to inflate).

Treatment of ARDS

Despite the high morbidity and mortality associated with ARDS, there are limited evidence-based therapies known to reduce mortality. Treatment remains largely supportive and primarily involves mechanical ventilatory support which, unfortunately, can further potentiate lung injury. In 2017, updated treatment strategies were published jointly by the American Thoracic Society, the European Society of Intensive Care Medicine and the Society of Critical Care Medicine. The following treatment recommendations were made (Fan et al., 2017):

1. For all patients diagnosed with ARDS:
   • Lower tidal volume mechanical ventilation (4-8 mL/kg predicted body weight) and lower plateau pressures less than 30 cm H₂O; a generally accepted starting point is 6 mL/kg
     • Typical initial tidal volumes for those without ARDS is 6-8 mL/kg predicted body weight
     • It is recommended that tidal volume be adjusted to maintain goal plateau pressures
     • Low volume ventilation and lower plateau pressures, sometimes referred to as lung protective ventilation strategies are thought to prevent volutrauma (overdistension of alveolar units) and atelectrauma (cyclic changes in nonaerated lung).
   • Prone positioning for more than 12 hours/day in those with severe ARDS
     • Involves placing patient in the prone position while on ventilator, shifts weight of heart to ventral wall
     • Potentially improves ventilation-perfusion, increasing end-expiratory lung volume, and decreasing ventilator-induced lung injury by more uniform distribution of tidal volume through lung recruitment and alterations in chest wall mechanics (Gattinoni et al.,  2013).
2. For those with moderate to severe ARDS:
   • Higher PEEP as opposed to lower PEEP
     • In non-ARDS mechanical ventilation, typical initial PEEP is 5; however, PEEP can often be as high as 24 in the treatment of ARDS; increasing PEEP often allows for decreased FiO₂
     • Higher PEEP may improve alveolar recruitment, reduce lung stress and strain, and prevent atelectrauma (Fan et al. 2017)
   • Recruitment maneuvers (RMs)
     • A transient, sustained increase in airway pressure with goal to open collapsed alveoli
     • Involves applying high PEEP for a specified time and evaluating improvements in oxygenation
       • Example: 30-40 PEEP for 30-40 seconds
   • Both higher PEEP and RMs are thought to decrease atelectasis by improving alveolar recruitment (increasing the number of alveoli participating in tidal ventilation) and improving end-expiratory lung volumes.
3. It was noted that further research is necessary on the use of extracorporeal membrane oxygenation (ECMO) for treatment of refractory ARDS. 
   • Veno-venous ECMO works by pulling blood from the inferior vena cava through a circuit (outside of the body) which removes carbon dioxide and oxygenated blood returning it to the venous system via internal jugular vein.

What was the outcome for our patient with ARDS? What treatment modalities were implemented?

References:
ARDS Definition Task Force, Ranieri, V. M., Rubenfeld, G. D., Thompson, B. T., Ferguson, N. D., Caldwell, E., Fan, E., Camporota, L., & Slutsky, A. S. (2012). Acute respiratory distress syndrome: the Berlin Definition. JAMA, 307(23), 2526–2533. https://doi.org/10.1001/jama.2012.5669
 
Bellani, G., Laffey, J. G., Pham, T., Fan, E., Brochard, L., Esteban, A., Gattinoni, L., van Haren, F., Larsson, A., McAuley, D. F., Ranieri, M., Rubenfeld, G., Thompson, B. T., Wrigge, H., Slutsky, A. S., Pesenti, A., LUNG SAFE Investigators, & ESICM Trials Group (2016). Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA, 315(8), 788–800. https://doi.org/10.1001/jama.2016.0291doblem

Fan, E., Del Sorbo, L., Goligher, E. C., Hodgson, C. L., Munshi, L., Walkey, A. J., Adhikari, N. K. J., Amato, M. B. P., Branson, R., Brower, R. G., Ferguson, N. D., Gajic, O., Gattinoni, L., Hess, D., Mancebo, J., Meade, M. O., McAuley, D. F., Pesenti, A., Ranieri, V. M., Rubenfeld, G. D., … American Thoracic Society, European Society of Intensive Care Medicine, and Society of Critical Care Medicine (2017). An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome. American journal of respiratory and critical care medicine, 195(9), 1253–1263. https://doi.org/10.1164/rccm.201703-0548ST     

Gattinoni, L., Pesenti, A., & Carlesso, E. (2013). Body position changes redistribute lung computed-tomographic density in patients with acute respiratory failure: impact and clinical fallout through the following 20 years. Intensive care medicine, 39(11), 1909–1915. https://doi.org/10.1007/s00134-013-3066-x

Han, S., & Mallampalli, R. K. (2015). The acute respiratory distress syndrome: from mechanism to translation. Journal of immunology (Baltimore, Md. : 1950), 194(3), 855–860. https://doi.org/10.4049/jimmunol.1402513

Howell, M. D., & Davis, A. M. (2018). Management of ARDS in Adults. JAMA, 319(7), 711–712. https://doi.org/10.1001/jama.2018.0307

Matthay, M. A., Arabi, Y., Arroliga, A. C., Bernard, G., Bersten, A. D., Brochard, L. J., Calfee, C. S., Combes, A., Daniel, B. M., Ferguson, N. D., Gong, M. N., Gotts, J. E., Herridge, M. S., Laffey, J. G., Liu, K. D., Machado, F. R., Martin, T. R., McAuley, D. F., Mercat, A., Moss, M., … Wick, K. D. (2024). A New Global Definition of Acute Respiratory Distress Syndrome. American journal of respiratory and critical care medicine, 209(1), 37–47. https://doi.org/10.1164/rccm.202303-0558WS

Rubenfeld, G. D., Caldwell, E., Peabody, E., Weaver, J., Martin, D. P., Neff, M., Stern, E. J., & Hudson, L. D. (2005). Incidence and outcomes of acute lung injury. The New England journal of medicine, 353(16), 1685–1693. https://doi.org/10.1056/NEJMoa050333