Last updated on September 25th, 2024 at 08:39 pm

Editor’s Note: While “hypoxia” (low oxygen in tissues) and “hypoxemia” (low oxygen in the blood) are not the same, we’ll use these terms interchangeably in this article for simplicity. Hypoxia is linked to tissue perfusion and can be assessed with tests like lactic acid levels, while hypoxemia is evaluated through O2 saturation or arterial blood gas (PaO2). Although rare in the ED, conditions like cyanide or carbon monoxide poisoning can cause hypoxia without hypoxemia (poor tissue perfusion without actual decrease in dissolved O2 in the blood). However, in discussing ARDS and poor gas exchange, we will refer to both interchangeably.

Introduction

There is nothing more terrifying than a critically ill patient who, despite doing all the right things, continues to decompensate. In a recent case simulation led by the great Dr. Sweetser, we were presented with a young patient who had been rescued from a drowning, but was unresponsive and severely hypoxic. Despite intubation and lung protective ventilation strategies, the patient in this case continues to be hypoxemic. This is often where we desperately try to get our pulmonary critical care colleagues involved – but what if it’s just you, the ventilator, and that alarming O2 sat monitor?

Background

Acute Respiratory Distress Syndrome (ARDS) is a constellation of life-threatening lung pathologies that can cause refractory hypoxemia. In ARDS, fluid builds up inside the alveoli and breaks down the surfactant that would normally help the lungs fully expand and prevent atelectasis. This leads to damage to the alveolar epithelium causing inflammation, apoptosis, and necrosis, leading to impaired gas exchange and poor lung compliance, especially at the lung bases^1,2. Some of the most common etiologies of ARDS include infection (pneumonia, COVID-19, severe extrapulmonary sepsis), environmental exposures (severe air pollution, inhalation of smoke or toxic fumes), aspiration, and trauma. While the mortality rate for ARDS in general is 9-20%, it is higher in older patients³. 

ARDS will often present with severe respiratory distress and hypoxemia, both in the setting of diffuse lung inflammation, decreased lung compliance, and noncardiogenic pulmonary edema. Diagnosis of ARDS is based on the Berlin Criteria⁴: 

• Acute onset (within 1 week) 
• Bilateral diffuse opacities on chest radiography or computed tomography (CT), or evidence of such on ultrasound (bilateral B lines and/or consolidations)
• PaO2/FiO2 ratio of <300 or SpO2/FiO2 ratio <315

Lung protective mechanical ventilation with low tidal volume (6 cc/kg) and supportive care are the primary treatments. Despite these treatments, there will be patients who continue to be hypoxic, which leads to 10-15% of death in ARDS patients. We won’t touch on the specifics of the ARDSnet trial here, but will focus on three therapies that can treat refractory hypoxia⁵: Proning, paralysis, and inhaled vasodilators. 

Proning

Proning became vogue during the peak of COVID. It is an effective intervention that promotes uniform distribution of ventilation, reduces ventilation-perfusion mismatch, and decreases compression of lung tissue by heart and abdominal organs. Overall, it improves gas exchange and reduces atelectasis. Proning is not just for mechanically ventilated patients. Non-intubated patients can be “proned” with noninvasive ventilation (high flow/velocity nasal canula or CPAP/BiPAP). In an intubated patient, proning sessions can last for 16-20 hours per day. The PROSEVA trial showed a significant mortality benefit in patients with severe ARDS who underwent early and prolonged proning within the first 48 hours of onset of ARDS. Proning should be considered in patients requiring FiO2 ≧60% who have a PaO2/FiO2 ratio <150 mm (20 kPa) despite 12-24 hours of optimization on the ventilator. Do not use proning in patients with contraindications to repositioning – commonly these are patients with spinal injuries, open abdominal wounds, or severe hemodynamic instability.⁶ 

Paralysis

The mechanism for paralysis improving refractory hypoxemia involves reduced metabolic activity, which will reduce CO2 production and O2 consumption, while limiting peak pressures to reduce risk of barotrauma. The ACURASYS trial evaluated early paralysis with cisatracurium for 48 hours among patients with PaO2/FiO2 <150 mm and showed improved adjusted 90-day survival and increased time off the ventilator, though this was only within an adjusted analysis. A larger multicenter randomized study, the ROSE (Reevaluation of Systemic Early Neuromuscular Blockade) trial compared neuromuscular blockade using cisatracurium with heavy sedation in comparison to usual care with lighter sedation. No significant difference in 90 day mortality between the two groups was found, nor was there any difference in ventilator free days, time to extubation, or ICU length of stay. Overall, the ROSE trial showed that neuromuscular blockade with deep sedation did not improve outcomes. Ultimately, when faced with refractory hypoxemia and ventilator dyssynchrony, paralysis is another tool to use after implementation of other therapies discussed, though with questionable benefit.⁷

Inhaled Vasodilators

Inhaled vasodilators include nitric oxide (NO) and prostacyclins, such as epoprostenol. Nitric oxide and prostacyclins help to open alveoli and appear to be similar in their efficacy for pulmonary vasodilation and redistribution of blood flow⁸. Bosch et al. in 2022 studied the outcome of successful extubation at hospitals that exclusively used nitric oxide and hospitals that exclusively used epoprostenol and found that there were no differences in the likelihood of successful extubation⁹. Consider epoprostenol in patients with an intracardiac right to left shunt or right ventricle (RV) failure as pulmonary vasodilators will decrease afterload and improve RV function. Nitric oxide is also a useful vasodilator, though in the critical care setting there are multiple risks to be aware of, including methemoglobinemia, acute kidney injury, and tachyphylaxis. Despite these side effects, the benefits may outweigh the risks in an unstable patient with refractory hypoxemia.¹⁰ Ultimately, there is no mortality benefit for inhaled vasodilators.

Summary

ARDS has a relatively high mortality, and becomes infinitely more terrifying when a patient in front of you has refractory hypoxia despite your initial measures. Proning, paralyzing, and inhaled vasodilators are therapies that can help improve hypoxia in these patients. Here are the takeaways:

• Optimize mechanical ventilation first
• Try prone positioning, especially within 48 hours of onset of ARDS and for up to 16-20 hours per session. Prone positioning can be done regardless of mechanical ventilation status
• Consider paralysis/neuromuscular blockade, although evidence is mixed on the benefits
• Use inhaled vasodilators like epoprostenol (a prostacyclin) or nitric oxide as a temporary way to improve oxygenation, but know there are side effects for these therapies, and they are without mortality benefit
• Additional resources:
  • https://emcrit.org/ibcc/ards 
  • https://www.emdocs.net/em3am-acute-respiratory-distress-syndrome/ 
  • https://www.tamingthesru.com/blog/air-care-series/acute-respiratory-distress-syndrome

Cite this post: Neha Gupta, MD, Arman Hussain, MD, William Sweetser, MD. “Refractory Hypoxemia Treatment in Acute Respiratory Distress Syndrome (ARDS)”. GW EM Blog. September 21, 2024. Available at: https://gwemblog.com/ards-refractory-hypoxia/

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References

1. National Heart, Lung, and Blood Institute. (2022, March 24). What is acute respiratory distress syndrome? https://www.nhlbi.nih.gov/health/ards ↩︎
2. Diamond, M., Peniston, H. L., Sanghavi, D. K., et al. (2024). Acute respiratory distress syndrome. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK436002/ ↩︎
3. Diamond, M., Peniston, H. L., Sanghavi, D. K., et al. (2024). Acute respiratory distress syndrome. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK436002/ ↩︎
4. Pipeling, M. R., & Fan, E. (2010). Therapies for refractory hypoxemia in acute respiratory distress syndrome. JAMA, 304(22), 2521-2527. ↩︎
5. The Acute Respiratory Distress Syndrome Network. (2000). Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. New England Journal of Medicine, 342(18), 1301-1308. https://doi.org/10.1056/NEJM200005043421801 ↩︎
6. Farkas, J. (2024). Acute respiratory distress syndrome (ARDS). EM Crit: Internet Book of Critical Care. https://emcrit.org/ibcc/ards/ ↩︎
7. Papazian, L., Forel, J. M., Gacouin, A., Penot-Ragon, C., Perrin, G., Loundou, A., Jaber, S., Arnal, J. M., Perez, D., Seghboyan, J. M., Constantin, J. M., Courant, P., Lefrant, J. Y., Guérin, C., Prat, G., Morange, S., & Roch, A. (2010). Neuromuscular blockers in early acute respiratory distress syndrome. New England Journal of Medicine, 363(12), 1107-1116. https://doi.org/10.1056/NEJMoa1005372
   National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Moss, M., Huang, D. T., Brower, R. G., Ferguson, N. D., Ginde, A. A., Gong, M. N., Grissom, C. K., Gundel, S., Hayden, D., Hite, R. D., Hou, P. C., Hough, C. L., Iwashyna, T. J., Khan, A., Liu, K. D., Talmor, D., Thompson, B. T., Ulysse, C. A., … Yealy, D. M. (2019). Early neuromuscular blockade in the acute respiratory distress syndrome. New England Journal of Medicine, 380(21), 1997-2008. https://doi.org/10.1056/NEJMoa1901686 ↩︎
8. Walmrath, D., Schneider, T., Schermuly, R., Olschewski, H., Grimminger, F., & Seeger, W. (1996). Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine, 153(3), 991-996. https://doi.org/10.1164/ajrccm.153.3.8630585 ↩︎
9. Bosch, N. A., Shaefi, S., Juul, J., Devlin, J. W., Frendl, G., Sarge, T., Walkey, A. J., & Hibbert, K. A. (2022). Inhaled nitric oxide vs epoprostenol during acute respiratory failure. CHEST, 162(6), 1287-1296. https://doi.org/10.1016/j.chest.2022.06.023 ↩︎
10. Papazian, L., Forel, J. M., Gacouin, A., Penot-Ragon, C., Perrin, G., Loundou, A., Jaber, S., Arnal, J. M., Perez, D., Seghboyan, J. M., Constantin, J. M., Courant, P., Lefrant, J. Y., Guérin, C., Prat, G., Morange, S., & Roch, A. (2010). Neuromuscular blockers in early acute respiratory distress syndrome. New England Journal of Medicine, 363(12), 1107-1116. https://doi.org/10.1056/NEJMoa1005372 ↩︎