Oxygenation in COVID-19 Patients

Clinical Question

Any other potential mechanisms for low tissue oxygenation after ventilation support? If true, what would be the proposed treatment/management?

Key Findings

  • There are cases of persistent/refractory hypoxia despite optimal ventilation, but there is no established mechanism. Two main theories suggest arterial hypoxemia and oxygen-hemoglobin disruption may be the etiology.
  • The arterial hypoxemia discourse suggests that hypoxia is due to pulmonary fibrosis and lung tissue damage. Gas-blood exchange is impaired despite ventilation support. Proposed treatment pursuant to this theory includes inhaled nitric oxide and prostacyclin as rescue therapies. If rescue therapies fail, ECMO should be considered. And, no studies have been conducted to evaluate the efficacy of inhaled pulmonary vasodilators in persistent hypoxia cases.
  • The oxygen-hemoglobin disruption discourse suggests that COVID-19 attacks heme and binds to porphyrin, preventing hemoglobins from carrying oxygen. Potential treatment pursuant to this theory includes erythrocytapheresis and hyperbaric oxygen therapy, but neither have been studied in persistent hypoxia cases.

Summary of Information

Hypoxia Despite Ventilator Optimization

COVID-19 patients with severe acute respiratory distress syndrome (ARDS) are mechanically ventilated as supportive management. Despite ventilation, persistent lung injury can lead to refractory hypoxemia and hypoxia. Tissue hypoxia results from either arterial hypoxemia or dysfunction of oxygen-hemoglobin transport system. One study found that most COVID-19 patients experienced a reduction in hemoglobin, and it is believed that SARS-CoV-2 viral proteins and porphyrins can cause a decrease in hemoglobin.[1] A homology modeling study found that viral proteins ORF8 and surface glycoprotein can bind to porphyrin and orf1ab, ORF10, ORF3a can attack the heme, ultimately allowing the virus to inhibit the normal function of heme and hemoglobin.[2] This study also validated the hypothesis regarding the theoretical positive effect of chloroquine and favipiravir. However, there is no experimental evidence to support the findings, and the docking methods employed could have led to misinterpretation.[3] Currently, there are no other studies nor models to examine the effect of COVID-19 on the oxygen-heme transport system; therefore, the role of these viral proteins on hypoxia despite optimal ventilation remains inconclusive.

The hypoxia could also be a result of hypoxemia due to pulmonary damage. COVID-19 ARDS observes elevated ventilation and perfusion mismatch.[4] COVID-19 patients show elevated D-dimers, higher pulmonary vascular resistance, and larger dead space. Pulmonary damage can be caused by pulmonary fibrosis due to COVID-19.[5] Fibrotic tissues reduce the capacity of lungs to regulate gas exchange. Should this be the case, patients would have impaired gas exchange despite robust ventilator support. However, this theory remains unproven and requires additional data to determine whether it is valid.

Potential Management Strategies

The exact mechanism of hypoxia in patients requiring mechanical ventilation remains unclear, which poses challenges in finding effective management options. Currently, the guideline suggests inhaled pulmonary vasodilators such as nitric oxide and prostacyclin as a rescue therapy to manage refractory hypoxemia despite optimal ventilation.[6] ECMO has been suggested as a last-line therapy after optimizing ventilation, using rescue therapies, and proning.[6][7][8] These suggestions build on the assumption that hypoxemia and hypoxia occur due to pulmonary damage.

If the etiology of hypoxia is the disruption of oxygen-hemoglobin transport, management will need to be targeted to restore the oxygen-hemoglobin interaction. Hyperbaric oxygen therapy was proposed, but no studies have been done on patients with hypoxia while on mechanical ventilation.

Gaps in knowledge

Some retrospective studies could be done to see if there are common independent identifiable factor(s) that led to hypoxia despite ventilation optimization. Future studies could also examine whether the use of inhaled nitric oxide and prostacyclin would manage persistently low tissue oxygenation while on mechanical ventilation.

Author Information

Authors: Jon Zhou, Pharm.D., MPH
Completed on: May 13, 2020
Last revised on: Not yet revised

Reviewed by: Gary Smithson MD
Reviewed on: May 20, 2020

This summary was written as part of the CoRESPOND Earth 2.0 COVID-19 Rapid Response at UC San Diego. For more information about the project, please visit http://earth2-covid.ucsd.edu


  1. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-513.  [PMID:32007143]
  2. Wenzhong L, Hualan L. COVID-19:Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism. Published online April 27, 2020. doi:10.26434/chemrxiv.11938173.v8
  3. Read R. Flawed methods in “COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism.” Published online May 5, 2020. doi:10.26434/chemrxiv.12120912.v2
  4. Mauri T, Spinelli E, Scotti E, et al. Potential for Lung Recruitment and Ventilation-Perfusion Mismatch in Patients With the Acute Respiratory Distress Syndrome From Coronavirus Disease 2019. Crit Care Med. 2020.  [PMID:32317591]
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  6. Alhazzani W, Møller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-887.  [PMID:32222812]
  7. MacLaren G, Fisher D, Brodie D. Preparing for the Most Critically Ill Patients With COVID-19: The Potential Role of Extracorporeal Membrane Oxygenation. JAMA. 2020.  [PMID:32074258]
  8. Chow J, Alhussaini A, Calvillo-Argüelles O, et al. Cardiovascular Collapse in COVID-19 Infection: The Role of Veno-Arterial Extracorporeal Membrane Oxygenation (VA-ECMO). CJC Open. 2020.  [PMID:32363334]
Last updated: July 1, 2020