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Oxygen Induced Cytokine Storm/Hyperinflammation in Covid-19 Patients.

Most dreaded possibility for Covid 19 patients is Hospitalization. You cant see your loved ones once you enter the hospital prison. You are locked in a glass-fiber enclosure and the health care professionals visit you wearing the scary PPEs. Many have died a lonely miserable death locked away in oblivion in these heartless hospitals. Not to blame the hospitals but the system itself has lost compassion and love for the patient. Hospitals and healthcare professionals just follow the protocols and procedures set by the CDC. Patient arrives to the hospital when his spo2 is below 92 to 94% (in most countries). Once inside the hospital, the first thing they do is connect the patir to supplemental oxygen through a face mask or nasal prongs. And this supplemental oxygen stays on him until his spo2 (oxygen saturation of your blood) reaches to safe point (around 94 to 95) or until he goes on to the ventilator. Mortality of Covid 19 patients is very high in Hospitals: 26% in Hospital admitted patients and 34% in ICU patients. Other drugs may vary from person to person but oxygen supplementation is common in all patients. 

What I have personally observed is that those patients who are on continuous oxygen support tend to end up on the ventilator. Hospitals tell the patients to keep the mask on all the time. Even patients want to take as much as oxygen as possible because they feel it will help them recover faster and some just do it as they are 'paying for it'. Once on the ventilator, its common knowledge that most of them die. Few months ago, people in India were using oxygen at home for mild to moderate infections and mortality increased in this time period. Oxygen consumption at home was so high that doctors and health authorities had to clarify to the people that using oxygen unnecessarily like a 'security blanket' was not at all useful. Click Here. This had created an oxygen shortage in the country where critical patients who really needed the oxygen couldn't get it. 

And patients with spo2 below 92% who were taking intermittent oxygen recovered faster. Was continuous oxygen doing some damage to these patients?

Oxygen Toxicity:

Oxygen is most essential for life but it might also be harmful. WHO recommends that oxygen be given to patients early and some studies suggested that early oxygen therapy resulted in good recovery rates. But there are no studies which look at continuous oxygen therapy vs intermittent oxygen therapy. Those patients who recovered with early oxygen therapy well might have been using the oxygen intermittently. 

  • In normal people, inhaling more than 50% oxygen can lead to slow lung damage and inhaling 100% oxygen can lead to severe lung damage after 24 hours. At most we get 30% to 40% oxygen by nasal prongs or face masks. So it may not be harmful to normal lungs. But to damaged lungs of covid19, what concentration of oxygen would be harmful? No studies are done on this. Click Here.
  • In normal humans, the first signs of Pulmonary toxicity appear after 10 hours of oxygen at 1 ATA. (atmospheres absolute) 1 ATA=normal air pressure at sea level. Remember, this is for normal people, how much oxygen would be 'toxic oxygen' for a covid19 patient with damaged lungs is yet to be determined by randomized control studies. Click Here.
  • Prolonged breathing of normobaric oxygen (usually over 12 hours) can lead to pulmonary lesions which can be frequently lethal. Click Here.
  • Oxygen can cause release of Reactive Oxygen Species (ROS-reactive oxidants) from cells under hyperoxia. The physiological manifestations of oxygen toxicity include decrease in vital capacity, diffusing capacity, lung compliance. Pathological changes of oxygen toxicity are not specific and resemble those of adult respiratory distress syndrome. Click Here. To summarize, oxygen toxicity mimics Covid19 infection related lung damage. 
  • Free radical formation during cellular metabolism under hyperoxic conditions is recognized as the biochemical basis of oxygen injury to cells and organs. This damage occurs when the defensive anti-oxidants in cells are exhausted by oxygen induced free radicals. There is currently no drug for preventing or delaying the development of oxygen toxicity. Use of lowest possible oxygen concentration, avoidance of certain drugs, attention to nutrition and metabolic factors are best means to minimize or avoid oxygen toxicity. Click Here.
  • Oxygen toxicity in a person depends on various variables like age, nutrition, endocrine status and previous exposure to oxygen and other oxidants. Click Here.
  • The damage to lung tissue can cause fluid leak into air spaces and worsen the condition. Click Here.
  • The reactive oxygen species react with surrounding biological tissues damaging, lipids, proteins and nucleic acids. Pulmonary epithelium is sensitive to the inflammatory damage by the oxidants and can lead to damage to alveolar capillary barrier, leading to impaired gas exchange and pulmonary edema. Also the ROS induce the release of cytokines and mobilize macrophages and monocytes into the lungs, increasing further release of ROS. Click Here.
  • ROS also damage the cell membrane unsaturated fatty acids by oxidation.
  • Oxygen can also induce lung damage by altering the lung and gut bacteria (microbiota). Click Here.
  • Note: Hyperoxia may not be evident in blood but it may be present in the epithelial cells lining the airways tracts and alveoli, which are in direct contact with the inhaled oxygen that passes in. 

Cytokine Storm Syndrome:

  • Sudden deterioration of a stable covid19 patient is usually because of 'Cytokine storm' or hyperinflammatory immune reaction where the immune system goes haywire and starts damaging body's own tissues (lung tissue especially). This can progress to SIRS (systemic inflammatory response syndrome) and MODS (multiple organ dysfunction syndrome), which are lethal. And Interleukin 6 (IL6) plays a key role in cytokine storm. Click Here.
  • ROS can stimulate the release of Cytokines and other proinflammatory mediators Click Here, thus contributing to cytokine storm syndrome. Click Here.
  • ROS degranulate the mast cells in lung tissue and affect permeability and tone of the vessels. Click Here.
  • NAC (N acetyl cysteine), which is an antioxidant and free radical scavenger may have a role in preventing cytokine storm in covid19 patients. Click Here.
  • ROS could stimulate various proinflammatory mediators and cause endothelitis, endothelial damage and blood clots in covi19 patients. Click Here.

Conclusion:

Prolonged oxygen supplimentation can cause release of ROS and other proinflammatory cytokines, which inturn can trigger cytokine storm in Covid-19 patients. 

In non covid patients, 100% oxygen given through a ventilator can be harmful on a long run. Among the patients who are on ventilator, conservative oxygenation (min spo2 target of 88% to 94%) was more beneficial than conventional oxygenation (min spo2 target of 96% to 97%) Click Here. A similar study needs to be done in patients on supplemental oxygen (on mask or nasal prongs) with continuous oxygenation vs intermittent oxygenation.

Can continuous supplemental oxygen be harmful in some covid19 patients? Though supplemental oxygen is helpful in recovery of covid19 patients, it also appears that it may be harmful in some patients, especially when administered continuously. Clinical studies need to be done focused on how continuous oxygen supplementation could trigger inflammatory mediators and deteriorate clinical outcomes in some patients. How much oxygen is too much in a covid19 patient? What are the variables which determine whether a given amount of oxygen could be harmful to a covid19 patient? 

Note: 
This is a hypothesis based on personal experience and observation. No concrete clinical study exists supporting this hypothesis. Such studies need to be done to either support or reject it. 

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