We continue from Ukraine: Nerve Agent Civil Defense Part 2.

Edit: Corrected link to (MMSL) Antihistamines: Promising Antidotes of Organophosphorus Poisoning.

All small-molecule drugs have off-target effects, a.k.a. side effects. Viewing nerve agents as “evil drugs”, the same is true. The “simple story” of Part 2 applies most directly to sarin, tabun, and VX, but not soman or novichok. How these differences complicate the simple story is at this level mostly, but not entirely a distraction, something to be sorted out by the CW defense establishments.

The challengers have their own simplification,  study of organophosphate pesticide poisoning as a proxy for nerve agents. These pesticides are nerve agents for insects, specialized to insect AChE. They cross-react with human AChE, acting as weaker human nerve agents. Toxicity varies widely. You can drink malathion and get away with it; the active metabolite of parathion is paraoxon, which is 70% as toxic as sarin.

Treatment of parathion poisoning has mostly followed the orthodoxy of the simple story. But there have been  doubters, motivated by poor survival rates with the simple story standard of care. Alternative treatments were  used, based on the off-target anticholinergic effects of  first generation antihistamines, resulting in some papers. There have been so many cases that it has been possible to extract some evidence-based medicine. The principle papers are:

• (MMSL) Antihistamines: Promising Antidotes of Organophosphorus Poisoning.
• (NIH) Protective effects of the antihistamine promethazine against acute paraxon-methyl and dicrotophos toxicity in adult rats.
• (NIH) Efficacy of pralidoxime in organophosphorus poisoning: revisiting the controversy in Indian setting.

Quoting the last,

Results: During the study period, 150 patients were screened following which 120 patients were randomized to either of the treatment arms. Add-on pralidoxime therapy did not offer any appreciable benefit over atropine alone in terms of reducing mortality (18.33% (11/60) versus 13.33% (8/60)) and ventilator requirement (5% (3/60) versus 8.33% (5/60)). However, patients randomized in the add-on pralidoxime arm experienced longer duration of hospital stay (7.02 ± 1.12 days) than those receiving atropine-alone therapy (5.68 ± 1.87 days) (P < 0.001).

This is an astonishing result of evidence based medicine, in strong contradiction to the theory of the simple story. If it transfers to human  nerve agents,  the possibility presents that current orthodox treatment of some or most nerve agents is fundamentally wrong. Which agents, if any, and why, is a mystery.

The  antihistamines are:

• Cyclizine, Marezine, Valoid, Nausicalm,  generic. OTC.
• Diphenylhydramine, the active ingredient of the U.S. (but not EU) formulation of OTC Benadryl, available as a generic.
• Promethazine, by prescription, generic or branded: Phenergan, Promacot.

Some readers may wonder why diazepam (Valium) has been omitted, when it is a frequent adjunct. Atropine is blocked from entry into the brain by the blood brain barrier, but nerve agents penetrate. Untreated, this results in a continual epileptic seizure, with high lethality. Diazepam is an anticonvulsant. Whether diazepam is specific treatment, or merely supportive, is an open question. The antihistamines enter the brain, where they  are specific anticholinergics, possibly replacing diazepam. See (NIH) Diazepam in the treatment of organophosphorus ester pesticide poisoning and (PubMed) The role of diazepam in the treatment of nerve agent poisoning in a civilian population.

Why is atropine the historical choice? Perhaps because it appeared to be the cleaner drug. With the new awareness that nerve agents cause massive release of histamine, resembling the anaphylactic shock of a severe type 1 allergic reaction, anticholinergics that are also antihistamines become desirable.

Optimal treatments, which must be distinct for each agent, are not known.  Since identification of the actual agent is delayed, optimality might not have practical utility.

Takeaway so far: Nerve agent poisoning in humans is so deadly, and experimentation so infeasible, the standard of care may be wrong.

Conclusion follows shortly.

We continue from Ukraine: Nerve Agent Civil Defense Part 1.

Nota bene: This is not medical advice. It is an attempt to make accessible a few papers that are somewhat speculative, so that policymakers can ask intelligent questions of their CW defense establishments, (UK) Defence Science and Technology Laboratory and (U.S.) Edgewood Chemical Biological Center. 

Basics. The nervous system contains cells called neurons. In various forms, neurons are the computing elements of the brain. Neurons in the peripheral nervous system connect all the  functions of the body to the brain, for both conscious and involuntary control, by nerve impulses.

Within a single neuron fiber, which can be feet in length, a nerve impulse propagates in a way resembling an electric pulse aided by chemistry. It  isn’t simple, but is simple compared to when it has to jump from one one neuron to another, across a watery gap called a synapse. The sending neuron spritzes a puff of molecules called neurotransmitters into the gap. In mere milliseconds they are sniffed by receptors on the receiving neuron, which causes a new nerve impulse to start  up in the receptor. There are many neurotransmitters in the brain; the one of interest is acetylcholine.

The spritz of neurotransmitter has to go away before the next spritz, or the system locks up — spasms, convulsions, paralysis, death. The cleanup job is handled by a catalyst molecule that destroys neurotransmitters without damage to itself. In this case, AChE. Each molecule of AChE destroys about 25,000 acetylcholine molecules before it takes a hit, so the body replaces AChE very slowly..

A nerve agent binds to AChE, so that AChE can no longer remove acetylcholine from the synapse. The nervous system locks up; death ensues. This is the simple story, upon which orthodox treatment relies:

• Reduce the activity of the excess acetylcholine, with an anticholinergic medication, such as atropine, which fits into acetylcholine receptors, blocking them.
• Reactivate the AChE, by ripping off the nerve agent, with a class of medications known as oximes. A frequent choice is pralidoxime.

There is a challenge to this recipe, asserting that, while it is well motivated by theory,  it is  incompletely supported by evidence based medicine. It asserts that the simple story neglects other effects of nerve agents, which compete with the simple story for lethality. According to the challenge,

• Treating these other effects may be more important than reactivating AChE, which may not be possible, or which may happen anyway  by mechanisms that are not currently understood.
• Some  OTC medications may work better than atropine as anticholinergics.
• These OTC medications counteract another effect of nerve agents, which resembles a massive, lethal allergic reaction.

I take no position. This is an attempt to make the literature accessible.

This discussion has a lot of big words. Digest this; conclusion follows.

(CNN) Former sailors on Navy aircraft carrier describe working conditions

The Navy has a culture problem. See Why I Defend Captain Crozier. Quoting,

Sometimes the hardest task is the most perfectly done. Because land warfare is so upfront personal, the Army and the Marines had no choice but to excel in human resource management.  The last steps of perfection have come only in the past few years. The Navy is a little behind.  While PBS Carrier displays the best of Navy human resources, there have been serious lapses, concentrated in the commissioned ranks.

The George Washington is such a lapse, preceded by the firing of Brett Crozier, C.O. of USS Theodore Roosevelt. A  hero to his crew, he actually cared about their welfare. The Navy has endorsed the mindset of (Wikipedia version ) Six Phases of a Project:

1. 1. Unbounded Enthusiasm,
   2. Total Disillusionment,
   3. Panic, hysteria and overtime,
   4. Frantic Search for the guilty,
   5. Punishment of the innocent, and
   6. Reward for the uninvolved.

Defenders of the Navy might point out that it has the (USNI News) lowest suicide rate of the services. Given the specific remediable circumstances,  it’s not good enough.

Contemporary with the George Washington: (Navy Times) ‘Passion bordering on anger’: The inside story behind the CO’s firing on the destroyer Forrest Sherman.

(CNN) Putin may soon officially declare war on Ukraine, US and Western officials say.

This would allow mobilization of reserves and open deployment of conscripts to Ukraine. Both are inherently less combat effective than the volunteer core. Reservists lack intense immersive training; conscripts don’t want to be there.  The U.S. makes no use of reserve armor in actual combat roles; it is considered impractical compared to full-up training of new units.

Russian mobilization will be an attempt to swamp Ukraine with massive numbers of troops of even lower quality than those currently deployed, perhaps capable of little more than passive occupation. To increase combat effectiveness, nerve agents may be used, subject initially to the restrictions  outlined in Russian Use of CW Agents in Ukraine, in Detail. 

If  Russian goals continue to be frustrated, these restrictions may not hold, replaced by acts of astonishing barbarity. The reasoning:

• Any lie can be told by state media, and believed by  the majority of Russians. Nerve agents are, compared to tactical nukes, very easy to lie about.
• The transparency of lies outside of Russia is of no concern; Russia is in the late stages of cultural divorce from the West, to become the new “hermit kingdom.” See Exploiting Cracks in the Kremlin; Putin, the New Stalin?
• Kleptocracy in Russia does not imply Putin is himself motivated by personal wealth. Money is simply part of his scheme of social control. The Kremlin will be pressured by economics, but as long as the gas flows, the  cost of ostracism by the West is not anticipated.
• Exposure of Russia as indefensible is intolerable. Failure of the clay-footed Russian military colossus must be disguised at any cost.

Western combatants are issued protective clothing, gas masks, and antidote kits. As prophylaxis, the kits are dangerous to use, possibly causing brain damage. Administered within minutes of exposure, they save lives, though exposed individuals do not remain combat effective. Immediate followup  care is required.

World supplies of antidote kits are not sufficient for a civilian population. A civilian in the bulls-eye of a nerve agent munition, who receives the incredibly small lethal dose of a modern nerve agent, cannot be saved by anything other than an antidote kit. Visualize exposure zones as a set of concentric rings surrounding the bulls-eye.  There may be options for the next zone out, LD50, where half of those exposed die, and more distant rings: those who are sickened, and those exposed to the agent after a delay.

Next: possible OTC nerve agent antidotes.