Respiratory complications of organophosphorus nerve agent and insecticide poisoning. Implications for respiratory and critical care

Abstract

Organophosphorus (OP) compound poisoning is a major global public health problem. Acute OP insecticide self-poisoning kills over 200,000 people every year, the majority from self-harm in rural Asia. Highly toxic OP nerve agents (e.g., sarin) are a significant current terrorist threat, as shown by attacks in Damascus during 2013. These anticholinesterase compounds are classically considered to cause an acute cholinergic syndrome with decreased consciousness, respiratory failure, and, in the case of insecticides, a delayed intermediate syndrome that requires prolonged ventilation. Acute respiratory failure, by central and peripheral mechanisms, is the primary cause of death in most cases. However, preclinical and clinical research over the last two decades has indicated a more complex picture of respiratory complications after OP insecticide poisoning, including onset of delayed neuromuscular junction dysfunction during the cholinergic syndrome, aspiration causing pneumonia and acute respiratory distress syndrome, and the involvement of solvents in OP toxicity. The treatment of OP poisoning has not changed over the last 50 years. However, a better understanding of the multiple respiratory complications of OP poisoning offers additional therapeutic opportunities.

Keywords: critical care; insecticide; nerve agent; organophosphorus.

Figure 1.

Structures of organophosphorus (OP) insecticides and chemical weapons. (A) Structures of the diethyl, dimethyl, and S-alkyl OP insecticides parathion, dimethoate, and profenofos, respectively. The great majority of insecticides are either dimethyl or diethyl; inhibition of acetylcholinesterase produces a diethylated or dimethylated phosphate atom that does not vary according to the individual OP involved. Both parathion and dimethoate are “thion” pro-poisons that require activation by cytochrome P450s to active “oxons” that have the P = O group. Profenofos exists as an oxon and does not require activation. (B) Structures of the OP nerve agents sarin and VX.

Figure 2.

Respiratory system toxicity secondary to organophosphorus (OP) poisoning. ARDS = acute respiratory distress syndrome; NMJ = neuromuscular junction.

Figure 3.

Effects of hematogenous organophosphorus (OP) and aspirated OP on minipig lung. Comparison of lung architecture in anesthetized minipigs 48 hours after administration of saline into the lung (control pig; A, D, and G), gastric contents and the agricultural OP insecticide dimethoate EC40 into the contralateral lung (indirect hematogenous injury; B, E, and H), and gastric contents and agricultural OP insecticide dimethoate EC40 into the right lung (direct injury; C, F, I). (A–C) Light microscopy images (original magnification: ×10–20) with hematoxylin and eosin. Compared with indirect injury, direct injury caused greater alveolar and interstitial edema, neutrophil infiltration, hemorrhage, fibrin deposition, vascular congestion, and necrosis. Images edited in PowerPoint. (D–F) Scanning electron microscopy images (original magnification: ×171–324) of the same lungs. Direct injury shows extensive destruction of the alveolar capillary framework, with fibrin mesh and clot formation. (G–I) Transmission electron microscopy images (original magnification: ×25,000) of the same lungs. Both indirect and direct injury cause alveolar capillary membrane swelling. The black arrow signifies the alveolar capillary membrane in control (G) and indirect (H) lungs. After direct injury, this has led to the alveolar epithelium peeling away into the alveolar space and fibrin deposition (red arrow) in and around the alveolar capillary membrane.

Figure 4.

Pulmonary complications of organophosphorus (OP) poisoning. Exposure to OP compounds causes the acute cholinergic syndrome characterized by reduction in central respiratory drive, bronchospasm and hypoxia due to bronchorrhea and alveolar edema, and depolarizing neuromuscular junction (NMJ) block. This may resolve or progress to acute respiratory failure that would be fatal without medical input. Reduced consciousness and loss of airway control in the cholinergic syndrome increases the risk of aspiration, resulting in chemical pneumonitis that will worsen oxygenation and may progress to ARDS. Overstimulation of the NMJ causes chronic peripheral dysfunction that may occur simultaneously with the acute cholinergic syndrome or after it has resolved with normal cerebral function (then termed the “intermediate syndrome”). This NMJ dysfunction often requires days and weeks of mechanical ventilation with associated risk of ventilator-associated pneumonia and barotrauma.