What is the pathophysiology of acute inhalation lung injury caused by phosgene (COCl₂) and hydrogen fluoride (HF)?

Pathophysiology of Phosgene and Hydrogen Fluoride Inhalation Lung Injury

Phosgene causes delayed-onset non-cardiogenic pulmonary edema through direct acylation of cellular proteins and lipids in the distal airways, while hydrogen fluoride produces immediate corrosive injury with systemic fluoride toxicity leading to life-threatening electrolyte disturbances and cardiac arrhythmias.

Phosgene (COCl₂) Pathophysiology

Mechanism of Cellular Injury

• Phosgene reacts with nucleophilic groups (amino, hydroxyl, sulfhydryl) in cellular proteins and membrane lipids through acylation reactions, disrupting cellular integrity in the terminal bronchioles and alveoli 1, 2
• The gas penetrates deeply into the respiratory tract due to its low water solubility, reaching the alveolar-capillary membrane where it causes maximal damage 1, 3
• Direct chemical injury triggers oxidative stress through generation of reactive oxygen species and lipid peroxidation, amplifying the initial insult 2

Temporal Evolution of Lung Injury

• A characteristic latent period of 2-24 hours occurs between exposure and symptom onset, during which subclinical injury progresses 1, 3
• Initial mild symptoms (coughing, chest tightness, wheezing) belie the severity of developing injury 1
• Within 4-12 hours post-exposure, histopathology reveals alveolar and interstitial edema, fibrin deposition, hemorrhage, and inflammatory cell infiltration centered on terminal bronchiolar areas 3
• By 12-24 hours, severe non-cardiogenic pulmonary edema develops with protein-rich fluid flooding the airspaces, creating intrapulmonary shunting and refractory hypoxemia 1, 3, 4

Gas Exchange Disruption

• Phosgene exposure produces respiratory acidosis by decreasing pH and PaO₂ while increasing PaCO₂, with temporal increases in lung wet/dry weight ratios indicating progressive pulmonary edema 4
• Severe ventilation-perfusion mismatch develops as fluid-filled alveoli create shunt physiology 5, 4
• The injury can progress to acute respiratory distress syndrome (ARDS) with bilateral infiltrates, severe hypoxemia (PaO₂/FiO₂ <200 mmHg), and respiratory failure 1, 6

Inflammatory Response

• Neutrophilic infiltration, increased bronchoalveolar lavage fluid protein and lactate dehydrogenase (LDH), and leukocyte elevation occur within 24-48 hours, indicating ongoing inflammatory injury 3
• The hallmark of this injury pattern mirrors ARDS pathophysiology: alveolar epithelial inflammation, airspace flooding with plasma proteins and cellular debris, and loss of normal endothelial reactivity 5
• Cytokine activation and oxidant stress mediate progressive lung inflammation 5, 2

Recovery Phase

• From 48-72 hours post-exposure, partial resolution of edema occurs with epithelial and fibroblastic regeneration, though gravimetric parameters remain elevated 3, 4
• Blood gases may normalize within 24 hours despite persistent structural lung injury 4

Hydrogen Fluoride (HF) Pathophysiology

Direct Corrosive Injury

• Hydrogen fluoride causes immediate corrosive burns to respiratory epithelium upon contact, with injury severity proportional to concentration and duration of exposure 7
• Unlike phosgene's delayed presentation, HF produces rapid-onset symptoms due to its high water solubility and immediate tissue reactivity 7

Systemic Fluoride Toxicity

• Fluoride ions rapidly penetrate tissues and bind calcium and magnesium, causing life-threatening hypocalcemia, hypomagnesemia, and hyperkalemia 7
• Severe metabolic acidosis develops from systemic fluoride absorption and cellular dysfunction 7
• Hypocalcemia-induced cardiac arrhythmias (ventricular fibrillation, prolonged QT interval) represent the most immediate life-threatening complication and can occur rapidly without warning 7

Pulmonary Manifestations

• Direct inhalation causes chemical pneumonitis with potential progression to ARDS if exposure is severe 7
• When ARDS develops from HF exposure, the same pathophysiologic mechanisms apply: alveolar epithelial inflammation, protein-rich edema, surfactant dysfunction, and intrapulmonary shunting 5

Systemic Complications

• Severe metabolic acidosis, elevated lactate, leukocytosis, high C-reactive protein, renal failure, and thrombocytopenia indicate transmural tissue necrosis and predict increased mortality 7
• Multi-organ dysfunction can develop from systemic fluoride toxicity affecting cardiac, renal, and gastrointestinal systems 7

Critical Clinical Pitfalls

Phosgene-Specific

• The latent period creates a false sense of security; patients may appear well initially but deteriorate rapidly 6-24 hours post-exposure 1, 3
• Early discharge based on initial mild symptoms risks catastrophic decompensation during the delayed edema phase 3, 4
• Standard oxygen therapy may fail as severe shunting develops, requiring early consideration of mechanical ventilation with lung-protective strategies 6

Hydrogen Fluoride-Specific

• Absence of oral lesions or pain does not exclude severe gastrointestinal or pulmonary injury; systemic toxicity assessment is mandatory regardless of local symptoms 7
• Calcium replacement must not be delayed, as hypocalcemia-induced arrhythmias can be rapidly fatal 7
• Exclusive focus on pulmonary injury without monitoring systemic electrolytes and cardiac rhythm is dangerous 7
• Gastric lavage or induced vomiting after HF ingestion exacerbates tissue injury and should be avoided 7

Ventilatory Management Considerations

• In phosgene-related ARDS, protective ventilation with tidal volumes of 6-8 mL/kg predicted body weight, plateau pressure ≤30 cmH₂O, and permissive hypercapnia (pH >7.20) improves survival and reduces lung injury 7, 6
• Protective ventilation strategies in phosgene injury result in improved oxygenation, decreased shunt fraction, reduced mortality, and decreased histopathologic evidence of hemorrhage, neutrophilic infiltration, and intra-alveolar edema compared to conventional ventilation 6
• The principal cause of hypoxemia is extensive right-to-left intrapulmonary shunting, which may consume a large fraction of cardiac output 5