Too much of anything in excess is not too good! How is Oxygen Dangerous?
Oxygen is a life-saving drug in many emergencies. However, having more oxygen levels or low oxygen levels is extremely harmful when it comes to oxygen. But what we widely talk about regarding oxygen is low oxygen levels; however, high levels of oxygen concentration are causing more harm than good.
Nice to know! The terminology
Oxygen toxicity is described as the harmful effects of inspired oxygen at pressures delivered to the lung over atmospheric pressure. Oxygen toxicity is iatrogenic (1). It is caused by the high partial pressure of inspired oxygen.
Hyperoxia: Described as the excess of oxygen in tissue
Hyperoxemia : Described as an excess of oxygen in the blood. Definition of hyperoxemia depends on the
setup.
Hypoxemia: Described as an amount less than 90% of oxygen saturation or less than 60mmhg of partial pressure of oxygen in arterial blood.
Pathophysiology of oxygen toxicity
This toxicity is well debated, and several mechanisms have been described.
Oxygen toxicity occurs when the partial pressure of alveolar oxygen exceeds the usual conditions we usually breathe. This high concentration of oxygen creates hyperoxic conditions, which are pathological and give rise to a generation of reactive oxygen species (ROS).
The free radicals are produced via the mitochondrial oxidoreductive pathway, auto-oxidative reduction, and enzymes. These free radicals induce lipid peroxidation, affect cell membranes, protein synthesis, and nucleic acids, damage epitheliums, and inactivate surfactants. (2)
What are the systems affected?
Cardiovascular system
Respiratory system
Nervous system
Immune system
Who is responsible? ROS
We administer oxygen to critically ill patients liberally; however, it has its own risk, but we are still not at a stage where we stop giving it due to its toxicity. Lung damage could happen at alveolar, cellular, and blood levels. The culprit is reactive oxygen species.
Who is at greater risk of oxygen toxicity?
• •
Patients who receive oxygen concentrations of >0.6 fio2 for a prolonged duration are at risk. However, 100% oxygen can be tolerated at sea level for 24-48hrs, but if the pressures are above 0.5 ATA, prolonged exposure can cause problems. (3)
People on certain drug therapy
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Bleomycin, and amiodarone pulmonary toxicity mechanism is poorly understood and dose-dependent. (4)
Bleomycin-induced lung injury-it has 4subtypes, and older people or those with renal diseases are more prone to toxicity.
Radiation patients are at risk of lung damage at lower levels of oxygen when compared to others.
Physiologic changes related to hyperoxia
Increased Respiratory Rate
Pulmonary vasodilatation leading to V/Q mismatch
Increased R to L shunt fraction
Increase susceptibility to mucus plugging due to dryness
Absorptive atelectasis
How do we prevent lung damage?
Adhere to the lowest possible fraction of inspired oxygen
Keep fio2 less than 0.6 for ventilated patients, and if the calculated hours exceed> 6 hours, need to start other therapeutic strategies to reduce the risk. e.g., Extracorporeal membrane oxygenation (ECMO), Positive end-expiratory pressure (PEEP), prone ventilation, and muscle paralysis.
An increased level of arterial carbon dioxide tension is associated with hyperoxia; however, it does not lead to significant Hypercarbia, but it could be considered in COPD patients.
What are the respiratory symptoms of early oxygen toxicity?
Cough
Shortness of breath
Chest pain
Heaviness in the chest Both hyperoxia and hypoxemia cause more harm in ARDS patients.
Special situations
Hyperoxia Acute Lung injury/ARDS
In acute respiratory failure, oxygen is used all the time. However, hyperoxia can promote cell damage and induce inflammation with high levels of FIo2 ventilation. Further reading-signal transduction pathway. (6) Hyperoxemia and Hypoxemia are Associated with Harm in Patients with ARDS (7)
Chronic Obstructive Pulmonary Disease (COPD)
The most widely used medication in prehospital care is oxygen. But prehospital hyperoxia in COPD patients does not show any green light. In COPD patients, two factors make their respiratory drive. That is hypercarbia and hypoxia. As these patients live with high levels of co2 in their blood for a long time, the hyperbaric respiratory drive is blunted. when we give too much oxygen, the respiratory rate falls. hence, administer 28% oxygen for COPD exacerbations.
Cardiovascular System Increased oxygen tension at the arterial level can lead to vasoconstriction. A retrospective study has shown that initial hypoxemia (pa02>300) in post-cardiac arrest cases showed increased mortality and worse outcomes. (9) AVOID study and hyperoxia This Air versus oxygen in myocardial infarction study was a randomized controlled trial done in Melbourne. It showed that hyperoxia might increase the infarct size. However, clinical trials are ongoing regarding this and trying to determine whether this is primarily due to perfusion issues, reactive oxygen species, or both.
Physiologic changes
Vasoconstriction: this will increase systemic vascular resistance and blood pressure, decreasing the cardiac output via the reflex mechanism. (11)
Does hyperoxia increase oxygen delivery to tissues, as we think? This is an exciting area for researchers. Unfortunately, few meta-analyses have demonstrated that giving more oxygen has not increased systemic oxygen delivery in healthy volunteers and heart failure patients. (10,11). Moreover, in septic patients, it has even decreased oxygen delivery at tissue levels which is surprising. (12) Liberal use of oxygen is more harmful!
Central Nervous System
Hyperoxia also leads to a reduction in nitric oxide-dependent vasodilatation of cerebral arteries. Thereby it leads to a reduction in cerebral blood flow. This will lead to delayed vasoconstriction in traumatic brain injury and strokes. Cerebral autoregulation is impaired in head injuries, strokes, or any pathological stage. (14)
Hyperbaric oxygen therapy is a new treatment modality that involves giving a high concentration of oxygen in a specific environment (pressurized chambers). studies have shown that hyperbaric oxygen therapy's central nervous system side effects include convulsions, loss of consciousness, and vertigo.
Neurotoxicity associated with hyperoxia was described more than 100 years ago. Acute oxygen toxicity, which manifests as convulsions, is explained in the Paul Bert effect.
Hyperbaric oxygen therapy carries a risk of CNS toxicity. (15)
Pediatrics
Retinopathy of prematurity is associated with oxygen toxicity.
Research related to oxygen toxicity
Oxygen therapy in sepsis: HYPERS2S trial
Oxygen therapy in ICU- OXYGEN-ICU
Conservative vs. liberal oxygenation –Mega Rox trial
Take home message Oxygen is a drug that needs to be carefully titrated to meet the patient's needs. It has side effects like in any other dug; hence titrate it carefully once the opportunity arises. Once the saturation hits above the target level, take a moment to think and act. Oxygen is a drug, handle with care!
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REFERENCES
Encyclopedia of respiratory medicine, 2006
Cooper JS, Phuyal P, Shah N. Oxygen Toxicity. [Updated 2022 Feb 7]. In: Stat Pearls [Internet]. Treasure Island (FL): Stat Pearls Publishing; 2022 Jan-
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Jackevicius CA, Tom A, Essebag V, Eisenberg MJ, Rahme E, Tu JV, Humphries K, Behlouli H, Pilote L. Population-level incidence, and risk factors for pulmonary toxicity associated with amiodarone. Am J Cardiol. 2011 Sep 1;108(5):705-10. doi: 10.1016/j.amjcard.2011.04.024. Epub 2011 Jun 23. PMID: 21704281.
Comroe JH, Dripps RD, Dumke PR, Deming M. The effect of inhalation of high concentrations of oxygen for 24 hours on normal men at sea level and at a simulated altitude of 18,000. JAMA 1945; 128:710.
Dias-Freitas F, Metelo-Coimbra C, Roncon-Albuquerque R Jr. Molecular mechanisms underlying hyperoxia acute lung injury. Respir Med. 2016; 119:23-28. doi: 10.1016/j.rmed.2016.08.010
Hyperoxaemia and Hypoxaemia are Associated with Harm in Patients With ARDS, Medscape
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Neumar RW. Optimal oxygenation during and after cardiopulmonary resuscitation. Curr Opin Crit Care. 2011;17(3):236-240. doi: 10.1097/MCC.0b013e3283454c8c
DALY WJ, BEHNKE RH. HEMODYNAMIC CONSEQUENCES OF OXYGEN BREATHING IN LEFT VENTRICULAR FAILURE. Circulation. 1963; 27:252-256. doi: 10.1161/01.cir.27.2.252
Smit B, Smulders YM, van der Wouden JC, Oudemans-van Straaten HM, Spoelstra-de Man AME. Hemodynamic effects of acute hyperoxia: systematic review and meta-analysis. Crit Care. 2018;22(1):45. Published 2018 Feb 25. doi:10.1186/s13054-018-1968-2
Rossi P, Tauzin L, Weiss M, Rostain JC, Sainty JM, Boussuges A. Could hyperoxic ventilation impair oxygen delivery in septic patients? Clin Physiol Funct Imaging. 2007;27(3):180-184. doi:10.1111/j.1475-097X.2007. 00732.x
Nishizawa H, Kudoh I. Cerebral autoregulation is impaired in patients resuscitated after cardiac arrest. Acta Anaesthesiol Scand. 1996;40(9):1149-1153. doi:10.1111/j.1399-6576. 1996.tb05579.x
Manning EP. Central Nervous System Oxygen Toxicity and Hyperbaric Oxygen Seizures. Aerosp Med Hum Perform. 2016;87(5):477-486. doi:10.3357/AMHP.4463.2016