Apologies for the delay in this month’s installment. With the COVID-19 pandemic a change of discussion direction seemed urgent and desirable.
Information about COVID-19 and therapeutic oxygen use is starting to emerge. To date use of the PubMed search term “COVID-19 and oxygen” yields 21 articles in all languages (12 English, 9 Chinese). In one article, an uncorrected proof version available on-line but soon to be published in Anesthesiology, Meng L., et al, report direct experience with the care of intubated and ventilated patients in Wuhan, China up to March 5, 2020 (accessed March, 23, 2020 at 1100 hrs EDST).
Our Wuhan colleagues’ article contains many ancillary details but their recommendations for physiological management targets reflect those found at: http://www.ardsnet.org/files/ventilator_protocol_2008-07.pdf.
Specifically, the physiologic goals pursued in sedated patients were: a PaO2 in the 55-80 mmHg range, a SpO2 in the 88-95% range, an arterial pH in the 7.30-7.45 range, and a higher than usual PaCO2 or what is considered “permissive hypercapnia” presumably to limit ventilator barotrauma. Their article’s Table 5 provides a summary of other “does and don’ts”, useful recommendations, and comments about unresolved issues.
Interestingly, some of their endotracheal intubation criteria, published in their article’s Figure 5 (N.B. not Table 5), overlap with some of their ventilated patient management goals. That said, a PaO2/FiO2 ratio of < 300 and a “room air” SpO2 < 93% (FiO2 = 0.21) coupled with a respiratory rate of >30/minute (no PaCO2 given) are rational warning signs. Clinical judgment and non-invasive measures are always warranted before escalating interventions and respiratory depressants should be avoided in the absence of a secure airway.
In the absence of tachypnea or a fixed cardiovascular shunt a “room air” SpO2 of 88% in an a stable elderly person (or child with congenital heart disease) whose cells have gradually accommodated to a lower oxygen tension and consumption rate might actually be at a baseline state. Though these persons might have a measured PaO2 of around 60 mmHg their functionality might be quite acceptable. Despite having a calculated PaO2/FiO2 of around 286, supplemental oxygen might be of little use to them or even contraindicated.
The COVID-19 respiratory support algorithm referenced above assumes a trial of “high-flow” oxygen therapy or “non-invasive ventilation” before endotracheal intubation. This, too, should be done with care. As always, clinical context and therapeutic considerations, not numbers alone, have to be the main factors used when making invasive intervention decisions.
Stepping back from clinical management considerations, it is instructive to ask a broader question: “How do viruses and oxygen interact?” A corollary questions is : “What do we know about viral infections that can influence oxygen therapy decisions?”
It turns out both questions have few answers. A PubMed search yields 9049 articles for the search term “viruses and oxygen” (March 23, 2020 at 1032 AM EDST). This is a surprisingly small number given how serious, frequent, and varied viral infections are.
Not surprisingly, most of the retrieved articles address tissue culture virology and viral oncology questions. Virtually absent are practical recommendations for clinical care when particular viral infections lead to oxygen use or mechanical ventilation.
Useful hints for further research and extrapolations with clinical relevance can be, nevertheless, gleaned from this very technical and complex literature.
One review article* raises three specific issues relevant to viruses and oxygen: 1) “Normoxia” is a relative term; regional and compartment-specific (alveoli, bone marrow, intra-hepatic regions, gastrointestinal lumen, etc.) high and low oxygen tensions must be maintained for a body to function optimally; 2) Virus replication almost universally triggers the Warburg effect, i.e., substitution of aerobic oxidative phosphorylation for anaerobic glycolytic metabolism that produces lactate, shuts down oxygen utilization in mitochondria, and diverts usually metabolized molecules toward viral replication; and 3) Both DNA and RNA viruses (like SARS-CoV-2) cause all infected cells to become pO2-sensitive, resulting in up-regulation or down-regulation replication effects that are mediated by Hypoxia Inducible Factor activity (HIF-1 alpha, HIF-1 beta, HIF-2, HIF-3) and non-HIF mechanisms.
Together these three issues (and I have simplified them considerably) imply an overarching fourth issue with theoretical as well as practical implications and it is this: If some viruses, like influenza, increase replication at an elevated oxygen tension; and another viruses induce intracellular hypoxia mechanisms that make oxygen useless; and excessive oxygen in the face of cell death increases reactive oxygen species (ROS) formation, does it make sense to use FiO2s at any point that exceed physiological PaO2s defined as safe laboratory values (i.e., PaO2s > 100 mmHg)?
Clearly we do not yet know how or if the RNA class SARS-CoV-2 virus causing the present COVID-19 pandemic alters cellular oxygen metabolism. Nor do we know if the virus renders oxygen therapy more or less dangerous to survival in the presence of depressed oxidative phosphorylation and overall oxygen consumption, though the probability this being the case is high if other viruses offer an example.
What we do know is that hospitalized critically ill patients who live are as likely as those who die when it comes to receiving supplemental oxygen. Its the default respiratory drug of choice and little regard is actually given to how best to use and monitor its effects in most medical settings.
Given the probabilities that oxygen consumption in critically ill sedated patients is reduced for at least two reasons (sedation and viral suppression) it makes eminent sense to follow a “lowest oxygen level acceptable” or LOLA standard.** Keeping the PaO2 in the 55-80 mmHg range, the SpO2 in the 88-95% range, and the arterial pH in the 7.30-7.45 range is entirely consistent with LOLA based management principles.
Perhaps this COVID-19 pandemic, coupled with the thoughtful management of the many intubated and ventilated patients it produces, will help us learn to use all our science to critically assess our reflexive and potentially harmful “oxygen culture.”
*Vassilaki N, Frakolaki E. Virus – host interactions under hypoxia. Microbes and Infection, 2017; 19:193-203
**Kopp VJ, Stavas JM. Point: Does low-dose oxygen expose patients with COPD to more radiation-like risks than patients without COPD? Yes. Chest, 2016; 149(2):303-306
