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When I was a pediatric resident in the early 1980s we used a mantra to guide our actions during any resuscitation effort: Air goes in and out, blood goes round and round, oxygen is good.

At the same time we knew oxygen affected arterial reactivity in at least two ways. First, inhaled atmospheric oxygen hastened transition from fetal to neonatal circulation after birth by decreasing pulmonary artery resistance and increasing ductus arteriosus resistance so blood would go to the lungs instead of make a shunt right-to-left through the foramen ovale directly into the left ventricle. Second, we learned empirically that if we decreased the fractional inhaled oxygen (FiO2) temporarily, umbilical artery catheter (UAC) placement or arterial blood gas (ABG) sampling was just that much easier.

Yet as pediatricians we also learned the hard way from our neonatal intensive care (NICU) rotations that supra-atmospheric oxygen concentration use–at least in preemies– had downsides. These manifested in an alphabet soup of complications we didn’t fully understand: retrolentil fibroplasia (RLF) later called retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and the like.

There were probably other “oxygenopathies” we didn’t know we were inducing but at least folks were beginning to see they existed and could be mitigated or prevented, especially ROP. Because oxygen limits became de riguer in NICU circles–but also pediatric anesthesiology circles when surgical care was rendered–more damage may have been averted than anyone realized up until that time, in part because few ever questioned if “oxygen is good” outside of NICU settings.

I CAN’T BREATHE!

Are there any more powerful words in any language?

No puedo respirar!

Je ne peux pas respirer!

Ich kann nicht atmen!

No matter the language, the message is clear: breath and life are one.

Breath and justice are inextricable.

Without breath there is no oxygen delivery to mitochondria.

Without breath there is no elimination of carbon dioxide.

Without breath there is no life, there is no justice.

The force of one human knee on another’s neck, the weight of one human body on another’s trachea, the insensitivity of one human heart suffocating another’s life — science cannot answer the question, “Why do such things happen?”

Only a deep look into the human soul — which is breath — ruach — stands any chance of addressing this conundrum.

How can any human ignore such words croaked from the mouth of another human being?

How can one human deprive another human of oxygen — no matter what the circumstances?

Each time I began to plan an Oxygenologist post for April 2020, some new information emerged about the pulmonary complexity of COVID-19. It’s going to take some time to sort out the details, so this month’s entry will be a brief one.

It seems COVID-19 is more complicated physiologically than previously imagined: atypical pneumonia, blood clots everywhere, bi-phasic pulmonary compliance patterns, atypical oxygen requirements.

One thing I have noted, though, is how baffled my “adult” doctor colleagues are by what they are seeing. Those of us who cared for “preemies” back before surfactant rescued most acute Respiratory Distress Syndrome (RDS) patients from chronic Brocho-Pulmonary Dysplasia (BPD), may recognize familiar patterns, though of a reverse nature.

Take hypoxic preconditioning. Newborns emerge from months in an “hypoxic” (14%) intrauterine environment acutely into atmospheric (21%) or supra-atmospheric (>21% up to 100%) conditions. This shift induces monumental changes in cardiac and pulmonary vessel physiology that underscore how transcriptional and translational events govern rapid decreases in pulmonary resistance, induce patent ductus (PDA) closure, and reverse the intra-cardiac shunts present under neonatal hypoxic conditions.

Perhaps there is a lesson here that is relevant to adults: gradual onset of hypoxia over a period of days, as is seen in some patients with COVID-19, may be permissive for levels of hypoxic tolerance development.

Unlike in acute respiratory arrest, where one goes from adequate to inadequate arterial oxygen saturation (SaO2) in no time, a gradual decrease in arterial oxygen partial pressure (PaO2) over days may give cells time to adapt through HIF-system governed transcriptional and translational events to tolerate greater degrees of hypoxia.

While plausible, it must be understood that not all cells function optimally at the same oxygen tensions–most notably stem cells. Oxygen tensions that are salutatory for some cell populations may be toxic to others, as is illustrated by the apparent hypoxic-hyperoxic tolerance differences of white and gray matter, GI track cells, and cells in different bone marrow compartments.

Speculation is not science, however. More information is needed to understand what is happening in COVID-19 hypoxic circumstances in select patients.

Is the virus interfering with oxidative phosphorylation and mitochondrial chemiosmotic gradients to decrease oxygen utilization efficiency? Are micro-clots producing ventilation/perfusion (V/Q) mismatches that combine with pneumonia-induced V/Q mismatches to produce a bizarre picture of tolerable hypoxia? Are inflammatory responses causing amplification of Reactive Oxygen Species (ROS) effects that will manifest in a stochastic fashion in the not too distant future?

These and other questions intrigue, remain to be answered, and may underscore some mysteries surrounding the atypical nature of COVID-19 pulmonary disease.

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

Chemical or medicinal “oxygen” is never just one homogeneous substance. Apart from impurities found in commercial-grade preparations—welder’s oxygen is “purer” than medicinal oxygen—there are at least ten reactive forms to be reckoned with when considering “generic” oxygen. These can be classed as subtypes of atomic oxygen, O; molecular oxygen (dioxygen), O2; and ozone, O3.

The importance of oxygen subtypes or forms is illustrated by ozone and superoxide. Other reactive forms maybe as—or more—important at sub-molecular levels. When it comes to understanding oxygen in biological systems much remains to be learned about how the whole spectrum of oxygen forms behave for good and ill.

Ozone—present in the ambient air from which much medicinal oxygen is derived—plays a dual role in the biosphere. It contributes to earth’s upper atmospheric shield against harmful cosmic radiation while helping to trap climate-altering carbon dioxide. As a reactive ground-level oxygen form, it exerts trans-species, physical adverse effects on respiratory functions and subcellular structural integrity. Think asthma, inflammation, and lipid membrane damage.

But there are also non-biological macro-level effects. For example, ozonolysis of unsaturated bonds, through ambient exposure, produces compounds with oxygen double bonds that alter some structural substances’ compositions and functional integrity. This is illustrated by the elastic deterioration of rubber bands and the cracking of rubber tires exposed to “normal” ozone-containing atmospheres. Concentrated exposures are more deleterious.

Superoxide—formed when molecular oxygen (dioxygen) gains an electron in its outer shell—is a second oxygen form with great importance. Its role in biological electron transfer reactions warrants a page all its own, something I will write about in next month’s installment of Oxygenologist.

Greetings in 2020.

One of the pleasures of cleaning up at the end of one year before the start of the next is the re-discovery of things misplaced or forgotten.

In this case I refer to a book purchased in 2015 but misplaced when I retired and moved out of my office at the University of North Carolina at Chapel Hill’s School of Medicine’s Department of Anesthesiology, where my interest in oxygen took root and was nourished by dual careers as a Pediatrician and Anesthesiologist who specialized in pediatric anesthesia.

Relevant to all Oxygenologist followers, the title of this now-dated but still useful volume is Oxygen and Living Processes: An Interdisciplinary Approach, edited by Daniel L. Gilbert (New York: Springer-Verlag, 1981).

In 18 chapters organized into four parts, the authors write about most aspects of oxygen of interest to the curious novice.

Part I: General Aspects of Oxygen, includes essays about the “discovery” of oxygen, its astronomical origins as a terrestrial element, its ecology in the biosphere, and the significance of its reactive forms.

Part II: Biology of Oxygen, includes entries about oxygen production by photosynthesis, its toxic effects on unicellular organisms, oxygen exchange and transport in various biological systems, its biological chemistry, and the role antioxidants play in the face of oxygen radical chemistry.

Part III: Human Aspects of Oxygen, covers pulmonary oxygen toxicity, oxygen use in closed environments, consideration of how oxygen “tension” varies in different clinical scenarios, and the special risk oxygen poses to premature infants–a risk we now understand applies in different ways to all humans who require “medicinal” oxygen.

Part IV: Concluding Remarks, closes the volume with an overall biological view cast in terms of the risks and effects posed by hypoxia, hyperoxia, normoxia, and the practical and clinical considerations as they were understood in 1981, before closing with a succinct summary.

At the time of its publication, Oxygen and Living Processes: An Interdisciplinary Approach, may have been the most complete, authoritative source on oxygen in existence. Even so, it appeared when integrated understanding of oxygen’s place in planetary ecology, climate, biological niches, and clinical settings was in its toddlerhood if not infancy.

Over the coming months I will offer nuggets extracted from this excellent book to enhance the conversation about oxygen. Until the next time, Take a Deep Breath…and Think.

Peace.

Greetings. Welcome to an updated version of Oxygenologist.

After a hiatus from posting on Oxygenologist, I hope to be more regular in 2020.

In the coming months I plan to update readers on the current status of the medical use of oxygen, explore shifting biological issues related to oxygen relative to climate change, and delve more deeply into new discoveries related to oxygen chemistry in the biological and physical sciences.

I trust you will keep me informed, accurate, and honest in what I convey. Comments are welcome and new insights encouraged from all who find oxygen as fascinating as I do.

Peace