For this episode, we discussed the dangers of too much oxygen. Just about everyone knows that hypoxia is problematic, but the same can be said of hyperoxia. In order to understand why excess oxygen is harmful, we went back a few billion years. This allowed us to understand how our atmosphere changed over time and how life evolved alongside those changes.
A long time ago…
Before life emerged Earth’s atmosphere was largely made up of nitrogen and carbon dioxide gases. There was very little oxygen. When cyanobacteria began using photosynthesis, oxygen was a byproduct. This led to the Great Oxidation Event with a dramatic increase in atmospheric oxygen.
While this may sound like a good thing, anaerobic life had not yet adapted to oxygen. And oxygen can transform into reactive oxygen species like superoxide, hydrogen peroxide. These are toxic molecules that cause harm. So, one result of the great oxidation event was one of the largest mass extinctions in Earth’s history.
Eventually, mechanisms evolved to handle oxygen and the toxic free radicals. These include binding with iron-containing heme and oxidation to water and carbon dioxide. And of course the former was eventually used as part of hemoglobin containing RBCs which now intentionally shuttle oxygen around. And the latter reaction is oxidative phosphorylation and the byproduct is a lot more ATP than glycolysis can afford. With more ATP comes more energy and larger organisms. Like us humans. You might say that hemoglobin and ATP are happy accidents of our need to neutralize harmful oxygen?
Fast forward… to the 1800s
In 1878, Paul Bert discovered that high increased oxygen leads to convulsion and death. A couple decades later, in 1899, James Lorrain Smith reported convulsions and harmful pulmonary effects when giving increased oxygen amounts to animals. For a while the CNS and pulmonary toxicities of hyperoxia were known as the Bert Effect and Lorraine Smith effect.
In 1943, Seymour Ketty and Carl Schmidt gave us a key clue to the underlying mechanism of injury. They showed that inhalation of 85-100% oxygen reduced cerebral blood flow by 13%. This was the result of increased vascular resistance, which also led to increased blood pressure.
One systematic review nicely summarizes hemodynamic effects of hyperoxia oxygen across multiple patient types. The most consistent changes were increased systemic vascular resistance and decreased cardiac output. You deliver more oxygen and systemic blood vessels will vasoconstrict.
Basically, in order to protect our organs from the harms of excess oxygen, they vasoconstrict. And in these studies, oxygen delivery was not increased by hyperoxia. Our bodies sense the increased oxygen and vasoconstrict, countering the increased partial pressure of oxygen in the blood.
But what’s the mechanism?
There are likely ways that oxygen leads to vasoconstriciton. One mechanism is a reduction in endothelium-derived nitric oxide (NO). More specifically, it is the reactive oxygen species which lead to a reduction in NO. Given that NO is a vasodilator, its reduction leads to vasoconstriction.
One interesting observation is that oxygen has the exact opposite effect in the lungs. We always talk about hypoxic vasoconstriction. With the systemic circulation, there is HYPERoxic vasoconstriction. The question follows: how do the pulmonary and systemic vascular beds deal with the same environmental change in such dramatically different ways?
Unfortunately, the biology is still being worked out. That said, research suggests that pulmonary and systemic arteries may have distinct mitochondria which respond differently to high and low oxygen levels. Actually, it is more accurate to say that they respond differently to reactive oxygen species. In ways that are not clear, the same exposure – local hypoxia – lead to a change in the generation of reactive oxygen species within the mitochondria. This leads to different downstream vascular responses depending on whether you’re in the pulmonary or systemic beds.
Is there evidence for harm?
Many of us learned “MONA” as the treatment regimen for acute myocardial infarction (NI). MONA stands for morphine, oxygen, nitro, and aspirin. The idea was that all patients with known or suspected MI should get all four of these therapies.
But, as we turn up the oxygen, systemic vascular resistance increases. More specific to MI, coronary vascular resistance increases. The result is either no improvement in oxygen delivery or maybe even a decrease.
A 1968 study of AMI showed an increased systemic vascular resistance and decreased cardiac output in response to increased supplemental oxygen. But, because lactate decreased, the authors say that maybe we should just give to everyone: “there may well be grounds for advocating this treatment in all patients, irrespective of the clinical severity of the illness.”
Subsequent randomized trials in patients with acute MI showed no benefit. Some demonstrated potential harm from increase in infarct size. For example, a 2015 study randomized patients with AMI to 8L/min versus no supplemental oxygen. The infarct size was larger and rates of recurrent MI were higher if you got oxygen.
Then came the 2017 DETO2X-SWEDEHEART study which randomized patients with suspected MI to 6L/min versus no supplemental. No benefit was seen in the supplemental oxygen group.
There are similar studies in critically ill patients. And, of course, we know that caution should be used when administering oxygen to patients with COPD. Regarding our goal SaO₂ of 88-92%, this partly comes from RCT data comparing O₂ titrated to this range versus high flow O₂. One study of 405 patients with acute COPD reported mortality of 9% for high flow O₂ 4% for titrated O₂.
What’s the goal?
In 2018 the British Medical Journal published a clinical practice guideline based on their review of the literature. For patients with confirmed or suspected MI, oxygen should be administered if SpO2 is <90%. This is a far cry from what I learned.
For most other acutely ill patients, clinicians should administer supplemental oxygen if SpO2 <90%-92% and target an SpO2 of no higher than 94%-96%.
For COVID, the World Health Organization suggests titrating oxygen to a target oxygen saturation of ≥94 percent during initial resuscitation and ≥90 percent for maintenance oxygenation.
Take Home Points
- Increased oxygen delivery has opposing effects on the pulmonary and systemic vasculature, leading to dilation in the former and constriction in the latter.
- The systemic vasoconstriction is partly mediated by decreased nitric oxide and is an attempt to protect tissues against free radical formation.
- SaO2 goals have shifted down over the years in response to these observations and data supporting better outcomes when aggressive supplemental oxygen is avoided.
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Credits & Citation
◾️Episode and show notes written by Tony Breu
◾️Audio edited by Clair Morgan of nodderly.com
Breu AC, Abrams HR, Cooper AZ. Why is too much oxygen bad? The Curious Clinicians Podcast. July 7, 2021