Prepare detailed, point‑wise notes with subheadings on oxygen toxicity, incorporating the latest guidelines and literature for exam preparation.

Oxygen Toxicity: Comprehensive Exam Notes

Definition and Clinical Significance

Oxygen toxicity occurs when exposure to elevated partial pressures of oxygen causes cellular damage through formation of reactive oxygen species (ROS), affecting multiple organ systems including pulmonary, central nervous system (CNS), cardiovascular, and ocular tissues. 1, 2

• Oxygen is a prescribable drug with specific biochemical actions, effective dose ranges, and well-defined adverse effects at high doses 2
• Toxicity results from oxygen-free radical formation within mitochondria, as byproducts of prostaglandin synthesis, and through xanthine oxidase-catalyzed reactions 1
• Clinical importance was not fully appreciated until the retrolental fibroplasia epidemic in the 1950s 1

Pathophysiology of Oxygen Toxicity

Mechanisms of Cellular Damage

Oxygen toxicity fundamentally results from formation of reactive oxygen species that overwhelm endogenous antioxidant defenses, leading to lipid peroxidation, protein damage, and DNA strand breakage. 1, 3

• Superoxide anion (O₂⁻) is the most commonly produced radical, which dismutates to hydrogen peroxide (H₂O₂) 1
• Hydrogen peroxide diffuses through lipid membranes and reacts with transition metals to produce highly reactive hydroxyl radicals (•OH) 1
• Hydroxyl radicals initiate chain reactions of lipid peroxidation leading to cell membrane rupture 1
• Oxidative stress causes DNA strand breakage and disruption of calcium ion metabolism within cells 3

Endogenous Defense Mechanisms

• Oxygen radical scavengers including superoxide dismutase (SOD) and catalase protect against normal levels of oxygen-free radicals 1
• These antioxidant defenses are not completely adequate, requiring additional repair systems for ROS-induced damage 3
• Mild oxidative stress induces upregulation of antioxidant defense enzymes, but severe stress overwhelms protective mechanisms 3

Types of Oxygen Toxicity

1. Acute Central Nervous System (CNS) Toxicity

CNS oxygen toxicity occurs with short exposures to high partial pressures of oxygen (>2.0 ATA), most commonly seen in divers or during hyperbaric oxygen therapy. 2, 4

Clinical Manifestations

• Acute cases occur with ≤5 hyperbaric oxygen treatments, averaging 4.0 ± 2.7 atmosphere-hours (AHs) 4
• Symptoms include seizures, visual disturbances, nausea, twitching, irritability, and dizziness 2
• Most acute cases are reversible when identified early and oxygen exposure is discontinued 4

Risk Thresholds

• The CNS oxygen toxicity index (PO₂ in ATA, time in minutes) should not exceed 26,108 for a 1% seizure risk 5
• The power equation for CNS toxicity uses PO₂ with a power term (c) of 6.8: Toxicity Index = t² × PO₂^6.8 5
• This non-linear relationship demonstrates that small increases in oxygen partial pressure dramatically increase toxicity risk 5

2. Chronic Central Nervous System Toxicity

Chronic CNS oxygen toxicity is idiosyncratic, unpredictable, and can occur even at pressures <2.0 ATA with cumulative exposures averaging 103-116 atmosphere-hours. 4

Clinical Features

• Chronic cases occur after >5 hyperbaric oxygen treatments with wide individual variability 4
• Neurological deterioration manifests as cognitive decline, personality changes, or worsening of underlying neurological conditions 4
• At 1.5 ATA oxygen, chronic toxicity averaged 116 ± 106 AHs; at >1.5 ATA averaged 103 ± 74 AHs 4
• Second episodes occur at lower cumulative doses (67-81 AHs), and third episodes at even lower doses (25-83 AHs) 4

Critical Clinical Pitfalls

• If chronic CNS oxygen toxicity is ignored and HBOT continues, permanent morbidity and mortality can result 4
• No difference in susceptibility exists between adults and children (p = 0.72) 4
• Subacute cases (<3 months from injury) are more sensitive than delayed intervention cases (21.1 ± 8.8 vs. 123 ± 102 AHs, p = 0.035) 4
• A withdrawal syndrome has been identified when hyperbaric oxygen is discontinued 4

3. Pulmonary Oxygen Toxicity

Pulmonary toxicity results from longer exposures to elevated oxygen concentrations at normal atmospheric pressure, causing progressive respiratory dysfunction. 2, 1

Pathophysiology

• Affects the respiratory system through direct oxidative damage to alveolar-capillary membranes 1
• Results in tracheobronchitis, decreased vital capacity, and eventually acute respiratory distress syndrome 2

Risk Thresholds

• The pulmonary oxygen toxicity index (PO₂ in ATA, time in hours) should not exceed 250 5
• The power equation for pulmonary toxicity uses PO₂ with a power term of 4.57: Toxicity Index = t² × PO₂^4.57 5
• Limiting hyperoxia to maintain arterial oxygen saturation (SaO₂) ≥90% is recommended to prevent toxicity 1

Clinical Manifestations

• Substernal chest pain, cough, and dyspnea developing after 12-24 hours of high FiO₂ exposure 2
• Progressive decrease in vital capacity and pulmonary compliance 1
• Gastrointestinal symptoms may also occur with prolonged high oxygen exposure 1

4. Ocular Toxicity (Retrolental Fibroplasia)

Retrolental fibroplasia (retinopathy of prematurity) occurs in premature infants exposed to high oxygen concentrations, causing abnormal retinal vascularization and potential blindness. 1, 2

• This epidemic in the 1950s first highlighted the clinical importance of oxygen toxicity 1
• Results from longer exposure to elevated oxygen levels at normal atmospheric pressure 2
• Particularly affects premature infants with incompletely vascularized retinas 1

Clinical Guidelines for Oxygen Administration

Target Oxygen Saturations

For most acute medical conditions, target oxygen saturation should be 94-98% to avoid both hypoxemia and hyperoxemia. 6

Standard Target Range (94-98%)

• Applies to most acute medical emergencies including myocardial infarction, stroke, trauma, and sepsis 6
• Unnecessary use of high-concentration oxygen may increase infarct size in acute coronary syndromes 6
• Oxygen therapy may be harmful for non-hypoxaemic patients with mild-moderate strokes 6

Lower Target Range (88-92%)

• For patients with COPD, cystic fibrosis, neuromuscular disease, chest wall deformity, or morbid obesity, target saturation is 88-92% 6, 7
• Use 24% Venturi mask at 2-3 L/min or 28% Venturi mask at 4 L/min or nasal cannulae at 1-2 L/min 6
• These patients are at high risk for oxygen-induced hypercapnia requiring arterial blood gas monitoring within 30-60 minutes 6, 7
• Adjust target to 94-98% if PaCO₂ is normal (unless history of previous non-invasive or invasive mechanical ventilation) 6

Avoiding Hyperoxemia

Excessive hyperoxemia (PaO₂ >300 mm Hg or >40 kPa) should be avoided as it may lead to increased oxidative stress and organ damage. 8

• High-concentration oxygen may be harmful in conditions like acid aspiration, paraquat poisoning, or bleomycin lung injury 6
• For paraquat poisoning or bleomycin toxicity, avoid oxygen unless patient is hypoxaemic and target saturation is 85-88% 6
• Oxygen therapy may be harmful to the fetus if the mother is not hypoxaemic during pregnancy 6

Oxygen Delivery Systems and FiO₂ Thresholds

Use of PEEP to increase mean airway pressure may be employed to reduce inspired oxygen concentrations below potentially toxic thresholds (FiO₂ <0.60). 6

• Simple oxygen delivery systems (nasal cannula or face mask) should be used when possible to maintain SpO₂ approximately 90% 6
• For endotracheally intubated patients, PEEP recruitment prevents exposure to toxic oxygen concentrations 6
• Venturi mask flow should be increased by up to 50% if respiratory rate exceeds 30 breaths/min 6

Special Clinical Scenarios

Carbon Monoxide Poisoning

Carbon monoxide poisoning requires 100% oxygen despite concerns about oxygen toxicity, as CO binds hemoglobin with 220 times greater affinity than oxygen and shifts the oxyhemoglobin dissociation curve leftward. 9

• Standard pulse oximetry cannot differentiate oxyhemoglobin from carboxyhemoglobin, showing falsely normal SpO₂ readings (>90%) even with COHb levels as high as 25% 9
• Treatment with 100% oxygen reduces COHb half-life from 320 minutes on room air to approximately 74 minutes 9
• Do not delay oxygen administration while waiting for COHb measurement 9
• Continue 100% normobaric oxygen until COHb normalizes (<3%) and symptoms resolve, typically approximately 6 hours 9

Long-Term Oxygen Therapy (LTOT)

Patients with stable COPD and resting PaO₂ ≤7.3 kPa (55 mm Hg) should receive LTOT for at least 15 hours per day, which offers survival benefit without evidence of oxygen toxicity at this regimen. 6

• LTOT should also be prescribed for patients with PaO₂ ≤8.0 kPa (60 mm Hg) with peripheral edema, polycythemia (hematocrit ≥55%), or pulmonary hypertension 6
• In the MRC trial, there was no evidence of oxygen toxicity with this treatment regimen despite concerns about rising PaCO₂ 6
• Patients receiving 24 hours/day oxygen had blunted CO₂ response compared to 12 hours/day, but this did not translate to adverse outcomes 6
• LTOT should be ordered for patients with resting hypercapnia if they fulfill all other criteria 6

Hypercapnic Respiratory Failure

In patients at risk for hypercapnia, excessive oxygen can worsen respiratory acidosis through multiple mechanisms including loss of hypoxic pulmonary vasoconstriction and decreased respiratory drive. 6

Mechanisms of Hypercapnia

1. Increased concentration of carbon dioxide in inspired gas 6
2. Increased carbon dioxide production 6
3. Hypoventilation or ineffective ventilation 6
4. Increased external dead space 6

Management Algorithm

• Prior to blood gas availability, use controlled oxygen delivery targeting 88-92% saturation 6
• Obtain arterial blood gas within 30-60 minutes of starting oxygen therapy 6
• If PaCO₂ is elevated with respiratory acidosis (pH <7.35), consider non-invasive ventilation 7
• Hold or discontinue oxygen if toxicity develops and does not rapidly resolve with supportive measures 6

Monitoring for Oxygen Toxicity

Clinical Monitoring Parameters

During high-dose oxygen or hyperbaric oxygen therapy, comprehensive monitoring must include vital signs, pulse oximetry, neurologic assessment, and strict intake/output to detect early toxicity. 6

Essential Monitoring (adapted from IL-2/TIL therapy protocols applicable to oxygen toxicity monitoring)

• Vital signs every 4 hours (every 2 hours if hemodynamically unstable) 6
• Pulse oximetry every 4 hours; if saturation <92%, obtain chest X-ray 6
• Telemetry monitoring during therapy 6
• Neurologic assessment every 8 hours to detect CNS toxicity 6
• Daily weight monitoring and strict intake/output every 8 hours 6

Laboratory Monitoring

• Arterial blood gas analysis including PaO₂, PaCO₂, pH, and bicarbonate 7
• Calculate A-a gradient to assess for shunt physiology or severe V/Q mismatch 7
• Hematologic panel and complete metabolic panel before escalating oxygen therapy 6

Indications to Reduce or Discontinue Oxygen

Oxygen should be reduced or discontinued if signs of toxicity develop, including persistent oxygen requirement not meeting target, neurological changes, or progressive respiratory deterioration. 6, 4

• Persistent oxygen requirement (<92% on room air) that has not resolved warrants holding further high-dose oxygen 6
• Development of pulmonary edema or pleural effusions requiring diuresis indicates need to reassess oxygen delivery 6
• Any neurological deterioration during hyperbaric oxygen therapy requires immediate discontinuation 4
• Early identification of chronic CNS oxygen toxicity is reversible and aids in proper dosing of HBOT 4

Pathophysiology of Hypoxia vs. Hyperoxia

Mechanisms of Hypoxaemia

Hypoxaemic hypoxia results from alveolar hypoxia or incomplete gas exchange due to reduced inspired PO₂, intrapulmonary shunt, V/Q mismatching, alveolar hypoventilation, or diffusion impairment. 6

Alveolar Gas Equation

• PAO₂ = PIO₂ - PACO₂/RER 6
• Where PIO₂ = FiO₂ × (barometric pressure - water vapor pressure) 6
• Alveolar hypoxia can be induced by decreased PIO₂ or increased PACO₂ 6

Other Mechanisms of Hypoxia

• Anaemic hypoxia: reduced oxygen-carrying capacity from anemia or carbon monoxide poisoning 6
• Stagnant hypoxia: low cardiac output reducing oxygen delivery despite normal PaO₂ 6
• Histotoxic hypoxia: inability to metabolize oxygen at mitochondrial level (severe sepsis, certain poisonings) 6

Mechanisms of Hyperoxia

Hyperoxia exists only in the presence of high PIO₂ or low PACO₂ from hyperventilation, and can be caused by hyperoxaemia or polycythaemia. 6

• Considering the alveolar gas equation, hyperoxaemia requires high inspired oxygen or hyperventilation 6
• Most clinicians use "hyperoxia" only when PaO₂ is elevated, not for polycythaemia without hyperoxaemia 6

Relationship Between PaO₂ and SaO₂

Understanding the oxyhemoglobin dissociation curve is essential for interpreting oxygen status and avoiding both hypoxemia and hyperoxemia. 6

Key Values from Oxygen Dissociation Curve

• PaO₂ 8 kPa (60 mm Hg) = SaO₂ 90.7% 6
• PaO₂ 10 kPa (75 mm Hg) = SaO₂ 94.9% 6
• PaO₂ 13 kPa (97.5 mm Hg) = SaO₂ 97.8% 6
• PaO₂ ≥17 kPa (≥127.5 mm Hg) = SaO₂ ≥99.0% 6

Clinical Implications

• The sigmoid shape of the curve means small decreases in PaO₂ below 8 kPa cause large drops in saturation 6
• Conversely, increasing PaO₂ above 13 kPa provides minimal additional oxygen saturation benefit 6
• This explains why targeting SaO₂ 94-98% avoids both hypoxemia and unnecessary hyperoxemia 6

Key Exam Points Summary

High-Yield Facts for Maximum Marks

1. Oxygen toxicity results from reactive oxygen species formation, specifically superoxide anion converting to hydrogen peroxide and then hydroxyl radicals causing lipid peroxidation 1

2. CNS toxicity index should not exceed 26,108 (PO₂ in ATA, time in minutes) for 1% seizure risk; pulmonary toxicity index should not exceed 250 (PO₂ in ATA, time in hours) 5

3. Chronic CNS oxygen toxicity is idiosyncratic, occurring at average 103-116 atmosphere-hours with wide variability, and is reversible if identified early 4

4. Target oxygen saturation is 94-98% for most patients, but 88-92% for COPD, neuromuscular disease, and obesity to prevent oxygen-induced hypercapnia 6, 7

5. FiO₂ should be kept <0.60 when possible using PEEP to recruit alveoli and reduce toxic oxygen exposure 6

6. Carbon monoxide poisoning requires 100% oxygen despite toxicity concerns because CO binds hemoglobin 220 times more avidly than oxygen and shifts dissociation curve left 9

7. LTOT for ≥15 hours/day in COPD with PaO₂ ≤7.3 kPa shows survival benefit without evidence of oxygen toxicity at this regimen 6

8. Pulse oximetry cannot detect hyperoxemia, carbon monoxide poisoning, or methemoglobinemia; arterial blood gas with co-oximetry is required 9, 7