NAs are compounds chemically similar to civilian-use pesticides but modified to increase lethality (10). Their toxicity relies on covalent binding to acetylcholinesterase (AChE), inhibiting its function and causing a cholinergic crisis. However, clinical outcomes vary depending on the structural groups attached to the central phosphorus atom (4, 11).

Three groups of NA agents are described: Group G (sarin, soman, tabun), Group V (VX and related), and Group A (Novichok and related) (10). While “in vitro” toxicity can be estimated, the actual toxicological impact of an NA compound also depends on factors such as route of exposure, chemical stability, lipid affinity and thus tissue distribution (4). These parameters, while theoretical in nature, have critical implications for toxicity, symptom duration, and post-exposure management. For instance, inhalational exposure to volatile agents like sarin differs greatly from the transdermal exposure typically seen with less volatile agents like VX from a pharmacodynamic standpoint, which has significant clinical implications (12).

These toxicodynamic differences in agent behavior—along with lipid affinity, chemical stability, and both volume and kinetics of distribution—are key determinants of their clinical effects. Animal studies have shown that inhaled sarin leads to rapid distribution and elimination, whereas percutaneous VX exposure results in a gradual increase in blood concentration with a plateau of at least five hours (13).

Post-inhibition behavior of NAs also affects treatment efficacy, as rapid “aging” of AChE limits the effectiveness of oxime-based reactivators (14). These toxicodynamic differences influence not only clinical severity but also duration of antidotal and supportive therapy, as well as the potential therapeutic window (4).

Standard treatment for OP poisoning includes supportive care and administration of atropine, oximes, and benzodiazepines. Atropine and benzodiazepines offer only symptomatic relief. Atropine blocks muscarinic parasympathetic symptoms and often requires high initial doses followed by continuous infusion until toxic effects are reversed (10). Despite its availability, large-scale events could exhaust existing medical supplies.

Oximes are intended to reactivate AChE, but their efficacy, especially pralidoxime and obidoxime, against certain NAs like Novichok is questioned in the literature (15). Both OPs and NAs can cross the blood-brain barrier, leading to persistent seizures through cholinergic receptor overstimulation, GABA suppression, and glutamatergic hyperactivation, potentially resulting in long-term neurological damage. Benzodiazepines, particularly fast-acting agents such as midazolam, may offer neuroprotection in this context (16).

HA is an extracorporeal technique that enables the removal of harmful circulating molecules through weak chemical interactions, such as hydrophobic, ionic, and Van der Waals forces, with an adsorbent material. It is an alternative to dialysis in situations where this treatment is not effective (for example, intoxication with protein-bound toxins or drugs or poisoning with non–water-soluble toxins).

Current HA cartridges use cross-linked divinylbenzene polymers, structured into beads and often coated with polysulfone to enhance biocompatibility. These structures provide adsorption surfaces exceeding 1000 m²/g, with cartridges containing 200–300g of sorbent (6).

Patient blood is exposed to the sorbent in a dialysis-like circuit, which can be used adjunctively with standard RRT. While clinical experience is limited, HA is increasingly used in sepsis and cardiac surgery to reduce circulating cytokines and endotoxins. It has also shown utility in removing excess levels of certain drugs such as apixaban, carbamazepine, or myoglobin. However, the lack of randomized clinical trials limits broader adoption (17).

OP poisoning is considered an indication for HA. A 2022 meta-analysis by Zhang et al. that included a total of 11 randomized controlled trials with 811 patients, compared outcomes in patients treated with standard RRT alone versus combined RRT and HA. Results favored HA in reducing mortality, hospital stay duration, mechanical ventilation needs, atropine dosage, and AChE recovery time (8).

Theoretically, lipophilic toxins with medium-to-high molecular weight and significant protein binding may be suitable for HA removal, particularly when resin-based sorbents are used. In contrast, toxins with high volume of distribution and slow intercompartmental kinetics are less amenable to RRT and HA (18).

While the octanol-water partition coefficient (LogP) helps estimate lipophilicity, it does not reliably predict HA efficacy alone. Molecular weight (MW) seems less influential, although HA performs better than traditional RRT in clearing medium- to high-MW molecules (19).

HA is only capable of removing the NA from the vascular space. However, when combined with oximes and RRT, it can reduce the acute cholinergic phase and significantly contribute to the restoration of fluid, electrolyte, and acid-base homeostasis associated with the toxidrome (8).

For NA poisoning, the therapeutic relevance of HA may depend on agent-specific toxicodynamics, particularly regarding AChE aging rates and the duration the NT remains in the bloodstream. As previously mentioned, the expected kinetics in poisoning with agents such as VX suggest a stable neurotoxin concentration in blood for several hours (13), thereby making its removal through extracorporeal purification techniques a feasible intervention. Moreover, the mechanism of action of NA involves the phosphorylation of the serine hydroxyl group in the active site of AChE by the organophosphate compound. Initially, this phosphorylated enzyme can be reactivated by nucleophilic agents such as oximes.

However, over time, a secondary chemical process known as “aging” may occur. Aging refers to the dealkylation of one of the side chains on the phosphorus atom of the OP moiety covalently bound to AChE. This reaction results in the formation of a more stable phosphate-enzyme complex, refractory to reactivation by oximes or other nucleophiles.

The rate at which aging occurs varies significantly depending on the chemical structure of the OP compound. For instance, soman causes enzyme aging within minutes, whereas VX may take up to 37 hours (14).

This kinetic variability may have important implications for the use of extracorporeal therapies such as HA. HA aims to remove circulating toxic agents from the bloodstream before they exert irreversibly damage. If aging occurs rapidly, a significant proportion of AChE may become irreversibly inhibited before the OP is cleared from the circulation, limiting the clinical utility of HA.

In cases where aging is delayed, HA could theoretically reduce the plasma concentration of the parent OP compound, thereby decreasing the amount available to inhibit AChE and potentially preserving enzymatic activity (20).

Beyond these considerations, some agents, especially Group V compounds, require hepatic metabolism via cytochrome P450 enzymes to generate toxic metabolites, unlike sarin, which acts directly (21), so part of the toxin or its circulating metabolites can be removed from the circulation with HA, decreasing the absorbed dose and reducing its systemic effects.

IS is a delayed-onset neurological syndrome involving respiratory paralysis and cranial nerve dysfunction (III, IV, X), observed in a subset of OP poisonings (28). It is currently assumed that CWAs do not cause this syndrome (10), which may be related more to the limited number of analyzed cases involving NTs and their high associated lethality than to chemical differences. However, some studies show that HA combined with conventional treatment reduces IS incidence in OP poisoning (9). Given the limited clinical experience in the management of CWA poisonings, it remains unclear whether patients receiving intensive care for NT intoxication are at increased risk of developing IS. It is plausible that, due to improved survival associated with intensive supportive therapy, these patients may live long enough to manifest delayed complications such as IS. Nevertheless, drawing on clinical experience with OP poisoning (9), it is reasonable to hypothesize that the use of HA in combination with RRT may reduce the incidence of IS in NT intoxications. Therefore, early consideration of HA as an adjunctive therapy may be warranted in the clinical management of these patients.