The Case

https://www.businessinsider.com/how-planes-react-to-medical-emergencies-without-doctor-oboard-2020-3

H & P

44-year-old male with acute onset confusion & diaphoresis on airplane

Vomited → LOC → emergency landing
Evaluated at hospital ~2 hours after symptom onset
Comatose, hypersalivating, diaphoretic, bradycardic

Differential

What's on your differential for this patient?
Would you have landed the plane?

Case Continued

The patient arrived at the hospital and….

Organophosphate poisoning suspected
Labs: Labs: ↓↓ pseudocholinesterase, ↑ amylase/lipase, ↑ troponin

Management

What would your management be and where would you start?

ABCs…antidotes…decontamination
This patient's management
- Intubation with mechanical ventilation
- Atropine and obidoxime
- Midazolam for neuroprotection

Workup & Evaluation

Organophosphorus nerve agent - Novichok group
- Found in blood samples collected immediately after admission
  - Novichok is a class of nerve agents classified as a 4th generation chemical weapon, developed in 1970s by Soviet Union.

Follow Up

Gradually recovered transferred ICU → floor on day 26
At d/c (day 33) neuro exam showed enhanced physiological tremor & hyperactive DTRs, no pyramidal signs nor evidence of polyneuropathy.
At last f/u visit (day 55) near-complete recovery of neurological, neuropsychological, and neurophysiological findings without evidence of polyneuropathy

Organophosphates

Epidemiology & Exposure

Where?

https://www.britannica.com/technology/insecticide

Insecticides
- Organophosphates used as insecticides worldwide for >50 yrs.
- In the Western world, the occurrence of poisoning is less prevalent due to the declining availability of organophosphate pesticides d/t EPA regulation.
- Found in some popular household roach and ant sprays, including Raid and Black Flag
Nerve gases (i.e. tabin, sarin, soman)
- Developed in Germany during the 1940s.
- 1995 sarin attack on the Tokyo subway system by a religious cult
- Assassination of Kim Jong-un’s brother
- Syria attacks

Prevalence
- >8,000 cases reported in U.S. (2008)
- >700k cases reported annually worldwide
- Estimated >300 million cases
- Based on 2020 systematic review from published lit from 2006-2018
  - As early as 1990, a WHO task force estimated ~ 1 million unintentional pesticide poisonings occur annually, leading to ~20,000 deaths.
  - Difficulties in accuracy of cases/deaths due to non-unified system of reporting between countries, lack of databases/data collection, etc.
  - This recent systematic review, supplemented by mortality data from WHO, found approximately 740,000 annual cases of poisoning were reported by the extracted publications (7446 fatalities, 733,921 non-fatal cases)
- Highest fatality rate in Southern Asia
  - NCRB data indicate that pesticides were used in 441,918 reported suicides in India from 1995 to 2015.
  - According to WHO, pesticide poisoning accounts for ~1 in 5 of world’s suicides.
    - Pesticide self-poisoning has been a major clinical and public health problem in low- and middle-income countries for decades while being long ignored.
    - National Crime Records Bureau (NCRB)
      - Steady ↑ in suicides from start of green revolution in 1960s until late 1980s. # of suicides plateaued until 1995, then ↓ linearly until at least until 2015, when some pesticide bans were implemented

https://www.cdpr.ca.gov/docs/legbills/reports/reg/cholinesterase/appendix_a_3.pdf

Mechanism of Action

AChE breaks ACh into choline & acetic acid.
Choline then transported back into neurons to synthesize more Ach
Organophosphates & carbamates (red triangle) bind & inactivate AChE (yellow star)
- Carbamates → transient AChE inhibitors. Carbamate toxicity tends to be shorter duration, although the mortality rates are similar btwn the 2.
Inhibition → accumulation of Ach → overstimulation of the nerves → acute cholinergic syndrome via continuous neurotransmission
Binding is reversible at first. After some period (dependent on the chemical structure of the organophosphorus agent), the acetylcholinesterase-organophosphorus compound undergoes a conformational change, known as "aging," which renders the enzyme irreversibly resistant to reactivation by an antidotal oxime.

Clinical Features

Acute toxicity (minutes to hours)
- DUMBELS – Defecation, Urination, Miosis, Bronchorrhea/Bronchospasm/Bradycardia, Emesis, Lacrimation, Salvation
- Nicotinic → Tachycardia, weakness, flaccid paralysis, hypertension
  - Analogous to depolarizing effects of succinylcholine!
- Central → Respiratory insufficiency, lethargy, seizures, coma
- Other → cardiac arrhythmias/ischemia, thermoregulation disturbances
Intermediate (Neurologic) Syndrome
- 10-40% cases, 1-4 days after acute cholinergic resolution
- Rapid onset proximal muscle weakness & paralysis
  - Respiratory insufficiency!
- Generally resolves in 1-3 weeks
Organophosphorus Agent-Induced Delayed Peripheral Neuropathy (OPIDN)
- 1-3 weeks after exposure
- “stocking-glove” paresthesias → symmetrical ascending flaccid paralysis
- May resolve spontaneously, can be permanent
- Risk independent of severity of acute toxicity

Diagnosis

Clinical Diagnosis
Atropine challenge
- 1mg IV in adults
- 0.01-0/02mg/kg in children

RBC AChE (butyrylcholinesterase level/activity)

Management - Acute Toxicity

ABCs
- 100% O2
- Early intubation often required
  - Avoid succinylcholine with RSI - metabolized by AChE (which is inhibited by OP compounds) → exaggerated & prolonged NM blockade in poisoned patients!
  - Non-depolarizing agents (eg, Roc) can be used, but may be less effective at standard doses d/t competitive inhibition at NM junction. Therefore, ↑ doses will likely be needed.
Decontamination

Aggressive dermal & ocular irrigation, discard clothing
Activated charcoal 1g/kg (if ingestion within 1 hr)
Atropine
- Reverses peripheral & central muscarinic toxicity
- 2-5 mg IV/IM/IO bolus (0.05 mg/kg IV in kids) with escalation
- Titrate until clearing of respiratory secretions and cessation of bronchoconstriction

http://www.embracecatalog.org/Drugs_Non-Narcotic_-DuoDote_Auto-Injector_Atropine_and_Pralidoxime_C.html

Pralidoxime (2-PAM)
- Reactivates AChE, reversing peripheral muscarinic AND nicotinic symptoms (NM dysfunction).
- Ineffective once aging occurs
- 2g IV slowly over 30min (25 mg/kg in kids)
  - May repeat q 30min, continuous infusion if severe (8mg/kg/hr)
  - Only administer with atropine
    - Avoids worsening symptoms due to transient oxime-induced AChE inhibition

Benzodiazepines
- Organophosphorus agent-induced seizures should be treated with a benzodiazepine
- Prophylactic diazepam has been shown to decrease neurocognitive dysfunction after organophosphorus agent poisoning
- Military development of a 10 mg autoinjector of diazepam for use in the setting of chemical attack
- Diazepam 10mg IV (0.1-0.2mg/kg in children)
  - Repeat PRN seizures

Summary

Organophosphate poisoning continues to be a worldwide public health issue, especially in developing countries and those without strict pesticide regulations
Organophosphates are potent AChE inhibitors, allowing for excessive buildup ACh in synapses, which leads to cholinergic toxicity
Clinical diagnosis!
DUMBELS, muscle weakness, paralysis, fasciculations, respiratory depression, seizure, coma
Resuscitation – intubate early!
Decontamination, early administration of Atropine + Oxime (i.e. Pralidoxime), and benzodiazepine

POST BY: DR. KALEE ROYSTER, PGY1

FACULTY EDITING BY: DR. LAUREN PORTER, MED TOXICOLOGIST

References

Aardema H, Meertens JH, Ligtenberg JJ, Peters-Polman OM, Tulleken JE, Zijlstra JG. Organophosphorus pesticide poisoning: cases and developments. Neth J Med. 2008 Apr;66(4):149-53. PMID: 18424861.
Abedin MJ, Sayeed AA, Basher A, et al. Open-label randomized clinical trial of atropine bolus injection versus incremental boluses plus infusion for organophosphate poisoning in Bangladesh. J Med Toxicol 2012; 8:108.
Amend N, Langgartner J, Siegert M, et al. A case report of cholinesterase inhibitor poisoning: cholinesterase activities and analytical methods for diagnosis and clinical decision making. Arch Toxicol 2020; 94: 2239–47.
Boedeker, W., Watts, M., Clausing, P. et al. The global distribution of acute unintentional pesticide poisoning: estimations based on a systematic review. BMC Public Health 20, 1875 (2020).
Gummin DD, Mowry JB, Beuhler MC, et al. 2019 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 37th Annual Report. Clin Toxicol (Phila) 2020; 58:1360.
Hulse EJ, Haslam JD, Emmett SR, Woolley T. Organophosphorus nerve agent poisoning: managing the poisoned patient. Br J Anaesth 2019; 123: 457–63.
Maselli RA, Leung C. Analysis of neuromuscular transmission failure induced by anticholinesterases. Ann N Y Acad Sci 1993; 681: 402–04.
Steindl, D., Boehmerle, W., Körner, R., Praeger, D., Haug, M., Nee, J., Schreiber, A., Scheibe, F., Demin, K., Jacoby, P., Tauber, R., Hartwig, S., Endres, M., & Eckardt, K. U. (2021). Novichok nerve agent poisoning. The Lancet, 397(10270), 249–252.
Thiermann H, Mast U, Klimmek R, et al. Cholinesterase status, pharmacokinetics and laboratory findings during obidoxime therapy in organophosphate poisoned patients. Hum Exp Toxicol 1997; 16: 473–80.

Tox in The Land: Organophosphate Toxicity