Oxygen (DB09140): A Comprehensive Monograph on its Chemistry, Pharmacology, and Clinical Application

Section I: Introduction and Historical Context: From "Dephlogisticated Air" to Essential Medicine

Oxygen, the most abundant element in the Earth's crust, occupies a unique and paradoxical position within the modern pharmacopeia. It is simultaneously a fundamental component of the atmosphere essential for all aerobic life and a potent, regulated prescription drug with a defined therapeutic window and significant potential for toxicity. This dual identity—as both a life-sustaining substrate and a powerful therapeutic agent—frames the central challenge of its clinical application: the judicious use of a substance that can be life-saving when correcting hypoxia but life-threatening when administered in excess. The journey of oxygen from an unknown component of air to a cornerstone of medical therapy is a story of scientific revolution, contested discovery, and evolving understanding that mirrors the maturation of chemistry and medicine itself. This report provides a comprehensive monograph on oxygen (DrugBank ID: DB09140), detailing its history, physicochemical properties, complex pharmacology, diverse clinical applications, methods of administration, safety profile, and the unique regulatory framework that governs its use.

The scientific understanding of oxygen emerged from an intellectual landscape dominated by the phlogiston theory. In the 18th century, this theory posited that all combustible materials contained a fire-like element called "phlogiston," which was released during burning. What we now call oxidation was then understood as the release of phlogiston, and the remaining ash or calx was considered "dephlogisticated". It was within this paradigm that the first investigations into the nature of air and combustion took place, setting the stage for one of chemistry's most pivotal discoveries.[1]

The credit for the discovery of oxygen is a complex and contested issue, now generally shared among three key figures: Carl Wilhelm Scheele, Joseph Priestley, and Antoine-Laurent Lavoisier. Working in Uppsala, Sweden, the apothecary Carl Wilhelm Scheele was likely the first to isolate the gas, which he called "fire air," sometime between 1771 and 1772 by heating substances like mercuric oxide and potassium nitrate. However, a delay in the publication of his findings until 1777 meant his work was not widely known when others made similar discoveries.

Independently, on August 1, 1774, the English natural philosopher and minister Joseph Priestley conducted a now-famous experiment in Calne, Wiltshire.[1] Using a large magnifying lens to focus sunlight onto a sample of red calx of mercury (mercuric oxide), he generated a colorless gas.[1] Priestley observed that a candle burned with a "remarkably vigorous flame" in this new gas and, in a subsequent test, that a mouse could survive twice as long in it compared to an equal volume of common air.[1] A staunch believer in the phlogiston theory, he named his discovery "dephlogisticated air," believing it to be common air that was stripped of phlogiston and therefore able to absorb it more readily from burning materials.[1]

The crucial conceptual leap was made by the French chemist Antoine-Laurent Lavoisier. After Priestley visited him in Paris in late 1774 and described his experiments, Lavoisier replicated and extended the work.[1] Between 1775 and 1780, Lavoisier correctly interpreted the gas not as a modified form of air but as a distinct element. He recognized its central role in both combustion and respiration, demonstrating that it was the component of air that combined with substances when they burned. This insight allowed him to systematically dismantle the phlogiston theory and establish the foundations of modern chemistry. Lavoisier gave the element its modern name,

oxygène, from the Greek roots oxy genes, meaning "acid-forming," based on his (incorrect) belief that it was a constituent of all acids.

Remarkably, the transition from laboratory discovery to therapeutic application was swift. The first recorded medical use occurred in 1783, when the French physician Caillens administered oxygen inhalations to a young woman with tuberculosis, who was reported to have "very much benefited". Priestley himself had foreseen this potential, conjecturing that his "pure air, it may be conjectured, that it might be peculiarly salutary to the lungs in certain morbid cases".[1] In the same breath, he displayed an astonishing prescience for the dangers of oxygen toxicity, warning that just as a candle burns faster, "so we might, as may be said, live out too fast".[1] This early intuition prefigured the modern clinical understanding of the "oxygen paradox"—the fine line between therapeutic benefit and hyperoxic cellular damage. The evolution of oxygen therapy continued through the work of pioneers like Thomas Beddoes, considered the "father of respiratory therapy," and the development of delivery systems such as the oxygen tent by Alvan Barach in 1922, cementing oxygen's role as an indispensable tool in medicine.

Section II: Physicochemical Properties and Molecular Identification

Oxygen, in its most common elemental form, is a diatomic molecule (O₂). At standard temperature and pressure, it exists as a colorless, odorless, and tasteless gas that constitutes approximately 21% of the Earth's atmosphere by volume. While it is not combustible itself, it is a powerful oxidizing agent that vigorously supports and accelerates the combustion of other materials.[2] When cooled to its boiling point, it condenses into a transparent, light blue, and extremely cold cryogenic liquid.[2]

The molecular structure of oxygen is that of a diatomic molecule with a double bond between the two oxygen atoms, represented by the SMILES notation O=O. It is a paramagnetic diradical, a property that influences its reactivity. While diatomic oxygen is the most prevalent form, other allotropes exist. The most well-known is trioxygen, or ozone (O₃), a highly reactive gas formed when O₂ is exposed to ultraviolet radiation or electrical discharge. Less common solid allotropes, such as O₄ and O₈, can be formed under conditions of high pressure and low temperature. Naturally occurring oxygen is composed of three stable isotopes: the vast majority is ¹⁶O (99.759%), with trace amounts of ¹⁷O (0.037%) and ¹⁸O (0.204%).[2]

The physical properties of oxygen are fundamental to its production, storage, and medical delivery. Its low boiling point of -183 °C is the key principle enabling its large-scale industrial separation from air via cryogenic fractional distillation. Because it is a gas at ambient temperatures, it must be stored for medical use either as a compressed gas in high-pressure cylinders or as a cryogenic liquid in insulated containers (vacuum insulated evaporators, or VIEs) to achieve a practical storage density. These physical constraints directly shape the entire medical oxygen supply chain, from large-scale production plants to hospital pipeline systems and portable units for ambulatory patients.

The ubiquitous and multifaceted nature of oxygen across science, medicine, and industry is reflected in its extensive list of official identifiers across numerous databases. This is not merely redundant information but a map of its distinct identities: as a fundamental chemical (CAS: 7782-44-7), a regulated prescription drug (DrugBank: DB09140), a key biological metabolite (HMDB: HMDB0001377), a substance with a specific regulatory identifier (FDA UNII: S88TT14065), and a hazardous material for transport (UN Numbers 1072 and 1073).[2] A complete understanding of "medical oxygen" requires acknowledging these interconnected roles.

Property	Value	Source(s)
Identifiers
Name	Oxygen
DrugBank ID	DB09140
CAS Number	7782-44-7
IUPAC Name	molecular oxygen
Synonyms	Dioxygen, O₂, Pure oxygen
InChI	InChI=1S/O2/c1-2
InChIKey	MYMOFIZGZYHOMD-UHFFFAOYSA-N
SMILES	O=O
FDA UNII	S88TT14065
UN Number	1072 (compressed gas), 1073 (refrigerated liquid)
ATC Code	V03AN01
Molecular & Chemical Properties
Chemical Formula	O2​
Molecular Weight	31.9988 g/mol
Exact Mass	31.989829244 Da
Stability	Stable, but a strong oxidizing agent. Vigorously supports combustion. Incompatible with many organic materials, phosphorus, and powdered metals.
Physical Properties
Physical Form	Colorless, odorless, tasteless gas. Liquid form is light blue.	2
Melting Point	−218.4 °C to −218 °C
Boiling Point	−183 °C
Density (Gas)	1.429 g/L (at 0 °C)	2
Vapor Density	1.1 (Air = 1)
Water Solubility	Slightly soluble. 1 volume of gas dissolves in approximately 32 volumes of water at 20 °C.	2

Table 1: Identifiers and Physicochemical Properties of Oxygen (O₂)

Section III: Pharmacology: The Role of Oxygen in Human Physiology

The pharmacology of oxygen is unique, as its absorption, distribution, metabolism, and elimination (ADME) are governed not by the typical enzymatic processes that handle xenobiotics, but by the fundamental principles of respiratory physiology. Applying a standard pharmacokinetic lens is therefore a category error; one must instead analyze its movement through the body as a physiological cycle. Its pharmacodynamic effects are similarly profound, extending beyond the simple reversal of hypoxia to encompass complex roles as a signaling molecule with pleiotropic effects on cellular function, protection, and regeneration.

3.1 Pharmacodynamics (Mechanism of Action)

The primary mechanism of action of oxygen is its indispensable role in cellular respiration. In virtually all aerobic organisms, oxygen serves as the final electron acceptor in the mitochondrial electron transport chain.[3] This critical step, catalyzed by the terminal enzyme cytochrome c oxidase, allows for the efficient process of oxidative phosphorylation, which generates the vast majority of the cell's energy in the form of adenosine triphosphate (ATP).[3] In states of hypoxia, this process is impaired, leading to a shift toward less efficient anaerobic metabolism, the accumulation of lactic acid, and ultimately, cellular dysfunction and death. Oxygen therapy works to restore normal cellular activity by increasing the partial pressure of oxygen at the mitochondrial level, thereby facilitating successful aerobic respiration and correcting metabolic acidosis.[3]

Beyond this fundamental metabolic role, oxygen exhibits more complex, drug-like pharmacodynamic effects, acting as a key signaling molecule and modulator of cellular processes.

• Chemoreceptor Modulation: Oxygen levels in the blood are constantly monitored by peripheral chemoreceptors, primarily the glomus cells located in the carotid bodies. These specialized cells contain O₂-sensitive voltage-gated potassium channels. In the presence of normoxia or hyperoxia, these channels are active, leading to membrane hyperpolarization. During hypoxia, these channels close, causing cell depolarization, calcium influx, and neurotransmitter release. This signals the brainstem to increase the rate and depth of breathing, a response known as the hypoxic ventilatory drive.[3] Supplemental oxygen therapy directly acts on these chemoreceptors to modulate this drive.
• Cellular Protection and Regeneration: Oxygen plays a role in mitigating cellular damage. It has been shown to reduce hypoxia-induced mitochondrial depolarization, a key event that can trigger the generation of damaging reactive oxygen species (ROS) and initiate the apoptotic (programmed cell death) cascade.[3] Furthermore, under hyperbaric conditions, oxygen therapy demonstrates regenerative potential. Studies have indicated that hyperbaric oxygen (HBO) can stimulate the proliferation of neural stem cells and promote the mobilization of CD34+/CD45-dim leukocytes, which are progenitor cells that can contribute to neurological regeneration and accelerate recovery at sites of peripheral tissue injury.[3] This helps to explain its utility in conditions like non-healing wounds and post-injury recovery, which are not solely states of systemic hypoxemia.

3.2 Pharmacokinetics

The "pharmacokinetics" of oxygen describe its journey from the atmosphere to the mitochondria and back, a process best understood through the lens of gas exchange physiology.

• Absorption: The primary route of absorption for oxygen is inhalation. The immense surface area of the pulmonary alveoli (approximately 70 square meters) provides an efficient interface for gas exchange. Oxygen moves from the alveoli into the pulmonary capillaries via passive diffusion, driven by the partial pressure gradient between the inspired air and the mixed venous blood returning to the lungs. At rest, with a normal fraction of inspired oxygen (FiO₂) of 21%, total pulmonary absorption is approximately 250 ml/min. Negligible amounts of oxygen can also be absorbed through the skin (<1 ml/min) and mucous membranes.
• Distribution: Once in the bloodstream, oxygen has very low solubility in plasma. Consequently, over 98% of the oxygen transported in the blood is not dissolved but is reversibly bound to hemoglobin, the iron-containing protein within red blood cells, to form oxyhemoglobin.[3] The oxygen-carrying capacity of the blood is therefore almost entirely dependent on the concentration of hemoglobin and its percentage of saturation with oxygen (SaO₂ or SpO₂). The release of oxygen from hemoglobin to the peripheral tissues is a dynamic and exquisitely regulated process. In tissues with high metabolic demand, increased levels of carbon dioxide and acid (lower pH), and higher temperatures cause a rightward shift in the oxyhemoglobin dissociation curve—a phenomenon known as the Bohr effect. This shift decreases hemoglobin's affinity for oxygen, facilitating its release where it is most needed.[3]
• Metabolism: Oxygen is not metabolized in the conventional pharmacological sense, where a drug is structurally altered by enzymes into metabolites for excretion. Instead, oxygen is consumed as a final reactant in the process of cellular respiration, being reduced to water at the terminus of the electron transport chain.[3]
• Elimination: The primary route of elimination for carbon dioxide, the waste product of aerobic metabolism, is exhalation from the lungs. Unutilized oxygen is also eliminated via exhalation.[3] The reported half-life of approximately 122.24 seconds is not a metabolic half-life but likely represents the mean transit time of an oxygen molecule as it moves through the body's physiological compartments, from lung to tissue and back.[3]

Section IV: Clinical Applications and Therapeutic Indications

The therapeutic application of oxygen is broad, spanning from the management of chronic respiratory diseases to acute life-saving interventions in critical care, toxicology, and emergency medicine. While its primary indication is the correction of documented hypoxemia, its use in certain non-hypoxemic conditions reveals distinct pharmacological mechanisms of action. A significant paradigm shift is underway in clinical practice, moving away from the historical liberal use of oxygen toward a more conservative, targeted approach, driven by growing evidence that iatrogenic hyperoxia can be harmful.

4.1 Primary Indication: Management of Hypoxemia

The most fundamental and readily accepted indication for supplemental oxygen therapy is documented hypoxemia, defined as an abnormally low level of oxygen in the blood. This can be an acute or chronic condition. The primary goal of therapy is to maintain adequate tissue oxygenation while minimizing the work of breathing and the workload on the heart.

Clinically, oxygen therapy is typically initiated when a patient's peripheral oxygen saturation (SpO₂), measured by pulse oximetry, falls below 88-90% while breathing room air, or when the partial pressure of arterial oxygen (PaO₂), measured by an arterial blood gas (ABG) test, falls below 60 mmHg. At this point on the oxyhemoglobin dissociation curve, small decreases in PaO₂ lead to large drops in oxygen saturation, precipitating significant tissue hypoxia.

Crucially, modern guidelines emphasize titrating oxygen to specific target saturation ranges. For most patients, the target SpO₂ is 94–96%. Exceeding this range may offer no additional benefit and can increase the risk of hyperoxic damage. For patients with certain chronic respiratory conditions, particularly Chronic Obstructive Pulmonary Disease (COPD), who are at risk of hypercapnic respiratory failure (carbon dioxide retention), a lower target range of 88–92% is recommended. This conservative approach is necessary because in these patients, the primary stimulus to breathe can be hypoxia; high concentrations of supplemental oxygen can blunt this "hypoxic drive," leading to hypoventilation and a dangerous rise in blood CO₂ levels.

4.2 Respiratory and Critical Care Indications

Oxygen is a cornerstone of therapy for a wide array of respiratory diseases.

• Chronic Conditions: Long-term oxygen therapy (LTOT) is a standard treatment for patients with severe chronic hypoxemia due to conditions such as COPD, emphysema, chronic bronchitis, advanced pulmonary fibrosis, cystic fibrosis, bronchiectasis, and pulmonary hypertension. Landmark studies, including the Nocturnal Oxygen Therapy Trial (NOTT), demonstrated that continuous oxygen therapy in eligible COPD patients improves survival and quality of life.
• Acute Conditions: Oxygen is administered for acute respiratory illnesses like pneumonia, COVID-19, acute exacerbations of COPD, severe asthma attacks, and acute respiratory distress syndrome (ARDS). It is also a standard component of care for almost all critically-ill patients to prevent or treat hypoxemia.
• Clinical Trial Evidence: The use of oxygen in these settings is supported by ongoing clinical research. For instance, a completed Phase 1/2 trial (NCT04404816) explored the use of a helium-oxygen mixture in premature infants with RDS to potentially improve gas flow dynamics. Another completed Phase 3 trial (NCT00116584) investigated heliox-driven nebulized epinephrine in pediatric bronchiolitis, with oxygen as the carrier gas. Directly addressing the risk of hyperoxia, a Phase 4 trial (NCT04198077) is comparing conservative versus conventional oxygen administration strategies in critically ill patients, reflecting the clinical equipoise on this important issue.

4.3 Cardiovascular Indications

Oxygen is frequently used in the management of acute cardiac conditions.

• Acute Myocardial Infarction (AMI): Oxygen is traditionally administered to patients with ST-segment elevation myocardial infarction (STEMI) to increase myocardial oxygen supply and limit ischemic injury. However, this practice has become controversial. In patients who are not hypoxemic, supplemental oxygen can cause coronary vasoconstriction, potentially reducing blood flow to the heart and increasing oxidative stress, which may worsen ischemic injury. The role of routine oxygen administration is therefore being re-evaluated. A completed Phase 3 trial (NCT02290080) was designed to determine the role of oxygen in suspected AMI by assessing its effect on biomarkers of cardiac injury.
• Heart Failure: In patients with acute or late-stage congestive heart failure (CHF), hypoxemia can occur due to pulmonary edema. Supplemental oxygen is used in these cases to relieve dyspnea, reduce the work of breathing, and decrease the workload on the failing heart.

4.4 Specialized Applications: Neurology and Toxicology

The utility of oxygen in certain non-hypoxemic conditions highlights its distinct pharmacological mechanisms.

• Cluster Headaches: Inhalation of high-flow, 100% oxygen is a first-line, highly effective abortive treatment for acute cluster headache attacks. The standard protocol involves administration at a rate of 6-15 L/min via a non-rebreather mask for 15-30 minutes. The therapeutic effect is not related to correcting blood oxygen levels but is believed to stem from its properties as a potent cerebral vasoconstrictor, which may counteract the vasodilation implicated in headache attacks, and its ability to inhibit the activation of the trigeminoautonomic reflex pathway.[4]
• Carbon Monoxide (CO) Poisoning: Oxygen is a direct and critical antidote for CO poisoning. CO is toxic because it binds to hemoglobin with an affinity over 200 times that of oxygen, forming carboxyhemoglobin (COHb) and severely impairing the blood's ability to transport oxygen. It also binds to intracellular proteins like myoglobin and cytochrome oxidase, disrupting cellular respiration. Administering 100% normobaric oxygen works via the law of mass action, competitively displacing CO from hemoglobin and reducing its half-life from over 4 hours in room air to about 90 minutes. Hyperbaric oxygen therapy (HBOT), where a patient breathes 100% oxygen at 2-3 times normal atmospheric pressure, is even more effective. HBOT dramatically reduces the COHb half-life to about 20-25 minutes and, crucially, provides enough dissolved oxygen in the plasma to sustain tissues while also promoting the dissociation of CO from intracellular cytochromes, thereby reducing the risk of delayed neurological sequelae.[5]

4.5 Other Key Indications

• Wound Care: Oxygen is used to promote healing, particularly for infected or non-healing wounds. A completed clinical trial (NCT02687217) investigated the effect of peri-operative supplemental oxygen on preventing wound infections after appendectomy. HBOT is also an established treatment for certain chronic, problematic wounds (e.g., diabetic foot ulcers), serious infections, and burns, as the high oxygen tension enhances leukocyte killing of bacteria, promotes angiogenesis (new blood vessel formation), and supports collagen synthesis.[6]
• Decompression Sickness: HBOT is the definitive treatment for decompression sickness ("the bends") in divers. It accelerates the elimination of nitrogen bubbles from the tissues and blood, reduces inflammation, and re-oxygenates ischemic tissues.
• Emergency Medicine: High-concentration oxygen is a standard intervention during resuscitation from cardiac arrest and in the management of shock, sepsis, major trauma, and anaphylaxis to ensure adequate oxygen delivery to vital organs during periods of circulatory collapse.

Trial Identifier	Indication	Status	Phase	Purpose	Source(s)
NCT02687217	Infected Wound	Completed	Not Available	Prevention
NCT04404816	Respiratory Distress Syndrome	Completed	1 / 2	Basic Science
NCT02290080	ST Elevated Myocardial Infarction (STEMI)	Completed	3	Treatment
NCT04198077	Critically-ill Patients	Unknown Status	4	Treatment
NCT00116584	Bronchiolitis	Completed	3	Treatment

Table 2: Summary of Key Clinical Trials for Oxygen Therapy

Section V: Dosing, Administration, and Delivery Systems

The "dosing" of oxygen is fundamentally different from that of most pharmaceuticals. It is not prescribed by mass (e.g., milligrams) but by controlling two key variables: the flow rate of the gas, measured in liters per minute (L/min), and the Fraction of Inspired Oxygen (FiO₂), which is the concentration of oxygen in the gas mixture delivered to the patient. Room air has an FiO₂ of 21% (0.21). The primary goal of administration is to use these variables to titrate therapy to a patient-specific physiological endpoint, most commonly a target peripheral oxygen saturation (SpO₂). The choice of delivery device is critical, as it determines the precision and range of FiO₂ that can be achieved. A crucial, and often misunderstood, distinction exists between flow rate and FiO₂. For many common devices, a specific flow rate does not equate to a fixed FiO₂, as the final concentration inhaled by the patient is a mixture of the supplemental oxygen and entrained room air, making it highly dependent on the patient's own breathing pattern.

5.1 Delivery Systems

Oxygen delivery systems are broadly categorized as low-flow or high-flow. This classification does not refer to the flow rate on the flowmeter but to whether the device's total gas flow meets or exceeds the patient's peak inspiratory flow demand.

• Low-Flow Systems: These systems provide a portion of the patient's inspired gas, and the remainder is entrained from the surrounding room air. Therefore, the actual FiO₂ delivered is variable and depends on the oxygen flow rate, the device, and the patient's tidal volume and respiratory rate. A patient breathing rapidly and deeply will entrain more room air, resulting in a lower FiO₂ than a patient breathing slowly at the same oxygen flow rate.
• Nasal Cannula: A thin tube with two prongs inserted into the nostrils. It is comfortable and suitable for stable patients requiring low oxygen concentrations. It delivers flow rates of 1–6 L/min, providing an approximate FiO₂ range of 24% to 44%.[7]
• Simple Face Mask: A plastic mask covering the nose and mouth. It requires a minimum flow of 5–6 L/min to prevent rebreathing of exhaled carbon dioxide that can accumulate in the mask. It can deliver an FiO₂ of approximately 35% to 55%.
• Partial Rebreather Mask: A simple mask with an attached reservoir bag. It allows the patient to rebreathe the first third of their exhaled air, which is rich in oxygen from the anatomical dead space. At flow rates of 6–10 L/min, it can deliver an FiO₂ of 50% to 70%.
• High-Flow Systems: These systems are designed to deliver a total gas flow (oxygen plus entrained air) that exceeds the patient's peak inspiratory demand. This ensures delivery of a precise and fixed FiO₂, regardless of the patient's breathing pattern, making them ideal for patients who require carefully controlled oxygen concentrations.
• Venturi Mask (Air-Entrainment Mask): Considered the classic high-flow device. It uses a jet of oxygen to pull in a fixed proportion of room air through side ports. By using interchangeable, color-coded valves, it can deliver precise FiO₂ concentrations (e.g., 24%, 28%, 35%, 40%, 60%) at specific required flow rates set on the flowmeter.
• Non-Rebreather Mask: While structurally similar to a partial rebreather, this mask has a series of one-way valves that prevent exhaled air from entering the reservoir bag and prevent room air from being inhaled during inspiration. This design allows it to deliver the highest possible FiO₂ to a spontaneously breathing patient. It requires a high flow rate (10–15 L/min or "flush") to keep the reservoir bag inflated, achieving an FiO₂ of 70% to nearly 100%.
• High-Flow Nasal Cannula (HFNC): A more advanced system that delivers a heated, humidified mixture of air and oxygen at very high flow rates (up to 60 L/min) through a wide-bore nasal cannula. This technology not only delivers a high and consistent FiO₂ but also provides a small amount of positive airway pressure (PEEP), reduces anatomical dead space, and improves patient comfort and work of breathing, representing a significant evolution in respiratory support.
• Positive Pressure and Invasive Systems: For patients with respiratory failure, oxygen is delivered as part of broader ventilatory support.
• CPAP/BiPAP: Continuous or Bilevel Positive Airway Pressure systems deliver pressurized air and oxygen through a tight-fitting mask to support ventilation non-invasively.
• Mechanical Ventilator: In critically ill patients, oxygen is delivered with precise control of FiO₂ (up to 100%), volume, pressure, and rate via an endotracheal tube or tracheostomy, providing complete ventilatory support.

The technological progression from simple cannulas to advanced HFNC systems reflects a deepening understanding of respiratory care. It marks a shift from merely supplementing oxygen to actively managing the entire respiratory environment, prioritizing humidification to prevent airway irritation, ensuring patient comfort, and reducing the physiological work of breathing.

Delivery System	Typical Flow Rate	Approximate FiO₂ Range	Key Features and Limitations	Source(s)
Low-Flow Systems
Nasal Cannula	1–6 L/min	24%–44%	Comfortable, for stable patients. FiO₂ is variable and depends on patient's breathing pattern.	7
Simple Face Mask	6–10 L/min	35%–55%	Requires >5 L/min to prevent CO₂ rebreathing. FiO₂ is variable.
Partial Rebreather Mask	6–10 L/min	50%–70%	Reservoir bag must remain partially inflated. Higher FiO₂ than simple mask, but still variable.
High-Flow Systems
Venturi Mask	Varies by valve (e.g., 3–15 L/min)	24%–60% (Fixed)	Delivers a precise, predictable FiO₂. Ideal for patients requiring careful titration (e.g., COPD).
Non-Rebreather Mask	10–15 L/min (or Flush)	70%–100% (High, Fixed)	Delivers highest FiO₂ for spontaneously breathing patients. For emergency/critical illness.
High-Flow Nasal Cannula (HFNC)	Up to 60 L/min	Up to 100% (High, Fixed)	Delivers heated, humidified gas. Improves comfort, reduces work of breathing, provides PEEP.
Positive Pressure / Invasive
CPAP / BiPAP	Varies by settings	Varies (up to 100%)	Non-invasive ventilation. Provides pressure support in addition to oxygen.
Mechanical Ventilator	Varies by settings	21%–100% (Precise)	Invasive ventilation. Provides full respiratory support with precise control of all parameters.

Table 3: Oxygen Delivery Systems: Flow Rates and FiO₂ Capabilities

5.2 Titration Guidelines

Effective oxygen therapy requires active titration to achieve the desired physiological effect while minimizing the risk of toxicity.

• Initiation and Targets: Oxygen should be initiated based on clinical signs of hypoxemia and objective measures like SpO₂. A provider's order should specify the delivery device, initial flow rate or FiO₂, and the target SpO₂ range.[7] For most adults, the target is an SpO₂ of 94–98%. For patients at risk of hypercapnic respiratory failure, the target is 88–92%.
• Weaning: Once a patient is stable, oxygen should be weaned to the lowest possible level that maintains the target saturation.[7] Weaning should be done gradually, for example, by decreasing the nasal cannula flow by 1–2 L/min or the Venturi mask FiO₂ by small increments every 15–30 minutes.[7] After each change, the patient must be reassessed for respiratory rate, work of breathing, heart rate, and SpO₂.[7]
• Special Populations: Neonates, particularly premature infants, have very specific and lower SpO₂ targets (e.g., 91-95%) to balance the risks of hypoxia with the risk of retinopathy of prematurity and other complications of hyperoxia.

Section VI: Safety Profile: Toxicity, Adverse Effects, and Contraindications

The therapeutic use of oxygen is governed by its fundamental paradox: while essential for life, it is a potent drug that becomes toxic at elevated partial pressures. This phenomenon, known as hyperoxia, can cause significant cellular damage and lead to severe clinical syndromes affecting multiple organ systems. The risk of oxygen toxicity is dependent on both the concentration of oxygen administered (FiO₂) and the duration of exposure. Understanding this safety profile, including specific drug interactions and contraindications, is paramount for its safe clinical use.

6.1 The Pathophysiology of Oxygen Toxicity

The mechanism of oxygen toxicity is rooted in the chemistry of cellular respiration. Under normal conditions, the reduction of oxygen to water in the mitochondria is highly efficient. However, a small fraction of oxygen is inevitably partially reduced, creating reactive oxygen species (ROS), such as superoxide anions (O2−​), hydrogen peroxide (H2​O2​), and highly reactive hydroxyl radicals (•OH). The body has a robust endogenous antioxidant system (e.g., superoxide dismutase, catalase, glutathione peroxidase) to neutralize these free radicals.

When a patient breathes high concentrations of oxygen, the partial pressure of oxygen in the tissues rises, leading to an overwhelming production of ROS that saturates and depletes the antioxidant defenses.[8] These excess free radicals then attack cellular components, causing widespread damage through lipid peroxidation of cell membranes, oxidation of proteins (inactivating enzymes), and damage to nucleic acids (DNA), ultimately leading to cellular dysfunction and death.[8] This process of oxidative stress is the universal mechanism underlying the diverse clinical manifestations of oxygen toxicity.

6.2 Clinical Manifestations of Toxicity

Oxygen toxicity can affect the central nervous system, the lungs, and the eyes, with distinct syndromes depending on the pressure and duration of exposure.

• Central Nervous System (CNS) Toxicity (The Paul Bert Effect): This is an acute phenomenon that typically occurs with exposure to very high oxygen pressures, such as during hyperbaric oxygen therapy (HBOT) or deep-sea diving. It is rarely seen with normobaric oxygen therapy. The onset can be sudden, with symptoms including visual disturbances (especially tunnel vision), auditory symptoms (tinnitus), nausea, dizziness, anxiety, confusion, and characteristic twitching of facial and hand muscles.[8] If exposure continues, these symptoms can progress rapidly to generalized tonic-clonic seizures, which, while not damaging in themselves, can lead to secondary injury.
• Pulmonary Toxicity (The Lorrain Smith Effect): This is the most common form of oxygen toxicity seen in clinical practice and results from prolonged exposure to elevated FiO₂ levels (>50-60%) at normal atmospheric pressure. Pulmonary effects can begin to appear within 24 hours of breathing 100% oxygen. The process begins as an inflammatory response in the airways (tracheobronchitis), causing a mild throat irritation, dry cough, and substernal or chest pain that worsens on inhalation.[8] As exposure continues, the damage extends to the alveoli. The production of surfactant by type II pneumocytes is impaired, and the alveolar-capillary membrane is damaged, leading to leakage of fluid into the interstitial and alveolar spaces (pulmonary edema), absorption atelectasis (collapse of alveoli), and a clinical picture that can be indistinguishable from Acute Respiratory Distress Syndrome (ARDS).[8]
• Ocular Toxicity: The developing retina of premature infants is exquisitely sensitive to oxygen levels. Hyperoxia can cause vasoconstriction and obliteration of retinal vessels, followed by an abnormal, disorganized proliferation of new vessels upon return to normoxia. This process, known as Retinopathy of Prematurity (ROP), can lead to retinal detachment and blindness.[8] In adults, prolonged oxygen exposure has been associated with the development of reversible myopia and may accelerate cataract formation.[8]

Organ System	Clinical Manifestations	Source(s)
Central Nervous System (CNS)	Acute, High-Pressure Exposure (Bert Effect) - Visual disturbances (tunnel vision, blurring) - Tinnitus - Nausea, dizziness - Anxiety, irritability, confusion - Muscle twitching (face, hands) - Tonic-clonic seizures	8
Pulmonary	Prolonged, Normobaric Exposure (Smith Effect) - Early: Substernal chest pain, dry cough, tracheal irritation - Progressive: Dyspnea (shortness of breath), uncontrollable coughing - Late: Pulmonary edema, absorption atelectasis, diffuse alveolar damage, ARDS-like presentation	8
Ocular	- Premature Infants: Retinopathy of Prematurity (ROP), retrolental fibroplasia - Adults: Reversible myopia, potential for accelerated cataract formation	8

Table 4: Manifestations of Oxygen Toxicity by Organ System

6.3 Drug Interactions and Contraindications

The risks of oxygen therapy are significantly amplified in the presence of certain drugs or pre-existing conditions. A critical cause-and-effect relationship exists where oxygen can transform from a therapy into a catalyst for toxicity.

• Drug Interactions:
• Bleomycin: This is a major and potentially fatal drug interaction. Bleomycin is a chemotherapeutic agent known to cause pulmonary toxicity. The concurrent administration of supplemental oxygen, even months or years after bleomycin treatment, dramatically increases the risk and severity of this lung injury, leading to pneumonitis, progressive pulmonary fibrosis, and death.[9] The risk is dose-dependent, with oxygen concentrations above 30% being particularly hazardous. This interaction fundamentally inverts the therapeutic goal; management requires accepting permissive hypoxemia to avoid fueling the toxic pulmonary process.
• Paraquat: This herbicide causes severe lung damage by generating ROS. Supplemental oxygen exacerbates this injury by providing more substrate for the toxic reaction. Therefore, in cases of paraquat poisoning, oxygen therapy is relatively contraindicated, and if required, it should be titrated to a lower SpO₂ target of 88–92% to minimize harm.
• Other Drugs (Primarily with HBOT): Certain other drugs, including the chemotherapeutic agents doxorubicin and cisplatin, and the alcohol-aversion drug disulfiram, are considered relative contraindications for HBOT due to concerns for potentiated toxicity.
• Contraindications:
• General Oxygen Therapy: There are no absolute contraindications to oxygen therapy when a patient has a clear and life-threatening indication, such as severe hypoxemia. The decision is always a risk-benefit assessment.
• Hyperbaric Oxygen Therapy (HBOT): The only absolute contraindication to HBOT is an untreated pneumothorax. The pressure changes inside the hyperbaric chamber would cause the trapped air in the pleural space to expand upon ascent, leading to a life-threatening tension pneumothorax. Relative contraindications are numerous and include conditions with a risk of air trapping (e.g., COPD, asthma, pulmonary blebs), recent thoracic or ear surgery, high fever (which can lower the seizure threshold), and claustrophobia.

Agent / Condition	Nature of Risk	Clinical Management / Recommendation	Source(s)
Bleomycin	Major Interaction: Oxygen potentiates bleomycin-induced pulmonary toxicity, increasing the risk of severe, potentially fatal pneumonitis and fibrosis.	Use extreme caution. Avoid high FiO₂ (>30%). Use of 100% oxygen for pulmonary function tests is contraindicated. Titrate to the lowest acceptable SpO₂.	9
Paraquat Poisoning	Relative Contraindication: Oxygen exacerbates paraquat-induced lung injury by increasing ROS production.	Avoid supplemental oxygen if possible. If necessary for life support, titrate to a lower target SpO₂ of 88%–92%.
Untreated Pneumothorax	Absolute Contraindication for HBOT: Risk of developing a life-threatening tension pneumothorax during pressure changes.	The pneumothorax must be treated (e.g., with a chest tube) before the patient can undergo HBOT.
Chronic Hypercapnia (e.g., severe COPD)	Relative Contraindication to High FiO₂: High oxygen concentrations can suppress the hypoxic respiratory drive, leading to hypoventilation and worsening hypercapnia (CO₂ retention).	Titrate oxygen carefully to a lower target SpO₂ of 88%–92% using a fixed-performance device like a Venturi mask if possible.

Table 5: Key Drug Interactions and Contraindications for Oxygen Therapy

Section VII: Manufacturing, Supply, and Regulatory Framework

Medical oxygen's journey from ambient air to a patient's bedside involves large-scale industrial manufacturing, a complex supply chain, and a unique, evolving regulatory framework that reflects its dual identity as both a bulk chemical and a prescription drug. The regulatory history of oxygen illustrates a fundamental tension between these two identities, a tension that has taken decades of industry effort and congressional action to resolve.

7.1 Manufacturing Processes

Medical-grade oxygen is produced by separating it from atmospheric air, which is composed of approximately 78% nitrogen, 21% oxygen, and 1% other gases. There are three primary methods of production:

• Cryogenic Air Separation: This is the dominant method for producing large volumes of high-purity (typically 99.5% or higher) medical oxygen.[10] The process, conducted in large facilities called Air Separation Units (ASUs), involves several steps:

1. Compression and Purification: Atmospheric air is compressed and filtered to remove dust, hydrocarbons, and moisture.[10]
2. Cooling and Liquefaction: The purified air is cooled to cryogenic temperatures (below -183 °C), causing it to turn into a liquid.
3. Fractional Distillation: The liquid air is pumped into a distillation column. Because the components of air have different boiling points (oxygen at -183 °C, nitrogen at -196 °C), they separate as the liquid is carefully warmed. Nitrogen boils off first, leaving behind a liquid rich in oxygen. The resulting liquid oxygen (LOX) is collected and stored.

• Pressure Swing Adsorption (PSA): This technology is often used for on-site oxygen generation at hospitals or in locations where transporting liquid oxygen is difficult. PSA plants work by taking in ambient air and passing it under pressure through vessels containing a molecular sieve material, typically zeolite. The zeolite preferentially adsorbs nitrogen, allowing the oxygen-enriched gas (typically 90–96% purity) to pass through and be collected.[10] The pressure is then released, the sieve regenerates by releasing the trapped nitrogen, and the cycle repeats.
• Oxygen Concentrators: These are smaller, often portable devices designed for individual patient use, particularly in home care settings. They operate on a principle similar to PSA, drawing in room air, separating out nitrogen, and delivering a continuous flow of concentrated oxygen (up to 95% purity). While convenient, their output is limited, and they are dependent on a reliable electricity source.

7.2 Supply and Distribution

The oxygen supply chain is structured to move vast quantities of gas efficiently. From large cryogenic production plants, oxygen is transported either as a liquid (LOX) in large, insulated tanker trucks or as a compressed gas in high-pressure cylinders. Hospitals typically maintain a large, stationary VIE (Vacuum Insulated Evaporator) that stores LOX and vaporizes it into a gas to supply a network of pipelines running to patient rooms and operating theaters. High-pressure cylinders serve as a backup supply and are used for patient transport or in areas without pipeline access.

7.3 Regulatory Framework (U.S. Food and Drug Administration)

In the United States, medical gases, including oxygen, are regulated as prescription drugs by the FDA under the Federal Food, Drug, and Cosmetic (FD&C) Act. This classification subjects them to stringent requirements for manufacturing, labeling, and safety reporting. However, because their production and handling are so different from traditional pills or injectables, applying standard pharmaceutical regulations has long been a challenge.

This regulatory friction led to decades of lobbying by the medical gas industry and ultimately to direct intervention by Congress. The Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 and the Consolidated Appropriations Act of 2017 mandated that the FDA create a tailored regulatory framework for medical gases. This long process culminated in the issuance of a final rule on June 18, 2024, which carves out a specific regulatory niche for these products. The COVID-19 pandemic likely served as a powerful catalyst for these reforms, as it exposed the fragility of the global oxygen supply chain and highlighted the critical need for a robust and clear regulatory system.

Key elements of the current FDA regulatory framework include:

• Current Good Manufacturing Practices (CGMPs): The 2024 final rule establishes a new, specific set of CGMPs for medical gases under 21 CFR Part 213. These are tailored to the unique aspects of gas manufacturing, such as preventing mix-ups and ensuring the integrity of cylinders and cryogenic containers, rather than focusing on issues like sterility that are paramount for other drugs.
• Certification of Designated Medical Gases: FDASIA created a streamlined pathway for "designated medical gases" (which includes oxygen, nitrogen, carbon dioxide, etc.). Instead of submitting a full New Drug Application (NDA), manufacturers can obtain a certification, which is deemed equivalent to an approved application.
• Labeling Requirements: The FDA mandates specific labeling for medical oxygen. The 2024 rule strengthened these requirements, mandating a clear warning statement and graphic symbol advising against smoking, vaping, or having open flames near the oxygen container to reduce the risk of fire.
• Postmarketing Safety Reporting: The new rule also tailors safety reporting. For example, it recognizes that oxygen is commonly administered during end-of-life care and exempts manufacturers from submitting an Individual Case Safety Report when a patient dies, unless there is evidence to suggest the oxygen itself caused the death.
• Prescription Status and Exemptions: While medical oxygen is a prescription drug, the FDA provides an important exemption from the prescription requirement for oxygen intended for emergency use (e.g., by first responders or for scuba diving incidents). This is permitted as long as the equipment is properly labeled for emergency use only and can deliver a minimum flow of 6 L/min for at least 15 minutes, and it is administered by properly trained personnel.

Section VIII: Synthesis and Expert Recommendations

The comprehensive analysis of oxygen (DB09140) reveals a substance of profound duality. It is not merely an elemental substrate for life but a potent, pleiotropic drug with a narrow therapeutic index. Its history traces the very arc of modern chemistry, while its pharmacology bridges the gap between basic physiology and complex cellular signaling. The overarching narrative that emerges is one of an evolution in medical thought: from viewing oxygen as a simple, universally beneficial supplement to recognizing it as a powerful therapeutic agent that demands the same rigor, precision, and respect as any modern pharmaceutical. Its clinical application is a constant balance of the "oxygen paradox"—the need to correct life-threatening hypoxia while avoiding the equally dangerous consequences of iatrogenic hyperoxia. This advanced understanding necessitates a shift in clinical practice toward more vigilant and evidence-based protocols.

8.1 Expert Recommendations for Clinical Practice

Based on the totality of the evidence presented, the following recommendations are provided to guide the safe and effective clinical use of oxygen therapy:

1. Treat Oxygen as a Prescription Drug: Oxygen should be prescribed with the same diligence as any other medication. The prescription should include a clear indication, a specific dose (defined by delivery device and flow rate/FiO₂), a target physiological endpoint (e.g., SpO₂ range), and a planned duration. The practice of administering oxygen routinely for "comfort" or without a documented indication like hypoxemia should be abandoned.
2. Embrace Targeted Titration: A "one-size-fits-all" approach to oxygen administration is obsolete and potentially harmful. Clinicians must actively titrate oxygen to achieve and maintain specific, evidence-based SpO₂ targets. For most patients, this range is 94–98%. For patients at risk of hypercapnic respiratory failure, a more conservative target of 88–92% is critical to prevent suppression of the respiratory drive. The goal is to use the lowest effective dose for the shortest necessary duration.
3. Know Your Delivery Devices: A thorough understanding of the capabilities and limitations of different oxygen delivery systems is essential for effective therapy. Clinicians must be able to distinguish between low-flow systems (which deliver a variable FiO₂) and high-flow systems (which deliver a fixed, predictable FiO₂) and select the appropriate device to match the clinical goal, whether it be general supplementation or precise titration.
4. Maintain Vigilance for Toxicity: Clinicians must be acutely aware of the signs and symptoms of oxygen toxicity, particularly pulmonary toxicity in patients receiving high FiO₂ (>60%) for prolonged periods (>24-48 hours). The onset of new or worsening cough, substernal pain, or dyspnea in a patient on high-flow oxygen should prompt consideration of toxicity and an effort to reduce the FiO₂.
5. Screen for Critical Interactions and Contraindications: A patient's medication history and comorbidities are critical determinants of oxygen safety. The interaction between oxygen and bleomycin is a major, often underappreciated risk that can lead to fatal pulmonary fibrosis; extreme caution must be exercised in these patients. Similarly, oxygen should be used judiciously, if at all, in cases of paraquat poisoning. For patients undergoing HBOT, a thorough pre-treatment screening for an untreated pneumothorax is mandatory.

8.2 Future Directions

The future of oxygen therapy is poised to advance along two parallel and complementary tracks: technological refinement for its mainstream applications and pharmacological exploration of its niche, drug-like effects.

• Technological Innovation: The trend toward precise, targeted oxygen therapy creates a clear need for more advanced delivery systems. The future lies in the development and widespread adoption of "smart," closed-loop systems that integrate real-time physiological monitoring (e.g., continuous SpO₂) with automated feedback control of the delivery device. Such systems could automatically titrate the FiO₂ to keep a patient within their prescribed target range, minimizing periods of both hypoxia and hyperoxia and reducing the burden on clinical staff.
• Pharmacological Exploration: The discovery of oxygen's more subtle pharmacodynamic effects—such as its ability to modulate the trigeminoautonomic reflex, prevent apoptosis, and mobilize stem cells—opens a new frontier of research. Future investigations should aim to harness these effects for novel therapeutic applications. This could include exploring its role as an adjunctive therapy in neurodegenerative diseases, as a tool to enhance regenerative medicine protocols, or as a targeted anti-inflammatory agent. This track treats oxygen not as a respiratory supplement, but as a novel signaling molecule with untapped therapeutic potential.

In conclusion, oxygen, the first gas to be discovered and the first to be used therapeutically, remains a subject of active investigation and evolving clinical practice. Its journey from "dephlogisticated air" to a precisely regulated drug is a testament to the progress of medical science. Continued research and a commitment to evidence-based, patient-centered care will ensure that this ancient and essential molecule is used to its greatest therapeutic advantage while minimizing its inherent risks.

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