ToxCard: Acute Organophosphate Toxicity

Authors: Daniel Escobar, MD (Emergency Physician, Mercy Hospital Northwest Arkansas, Rogers, Arkansas); Ann-Jeannette Geib, MD (Emergency Medicine Attending; Medical Toxicologist, Carolinas Medical Center, Charlotte, NC) // Reviewed by: James Dazhe Cao, MD (@JamesCaoMD, Associate Professor of EM, Medical Toxicology, UT Southwestern Medical Center, Dallas, TX); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case:

A 22-year-old female presents to the Emergency Department (ED) in respiratory distress and agitated.  She is speaking one word at a time and constantly coughing. She complains of dizziness, nausea, and abdominal cramps.

On exam, you notice there is a garlic-like odor filling the room. She is holding an emesis bag that she is constantly spitting into and intermittently having nonbilious non-bloody emesis. When looking at her you notice here pupils are 2 mm, equal and reactive bilaterally. She has active lacrimation.  She has no piloerection.  She is bradycardic without murmur.  Lung sounds reveal coarse rhonchi bilaterally.  She has slight weakness to her extremities with intermittent visible fasciculations. Muscle tone is however normal. Patellar reflexes are 2+.  As you’re completing your exam, she becomes unresponsive and begins demonstrating tonic-clonic extremity movements with eye deviation.

Vital signs: Temp: 99.1 F, HR 48, RR 28, BP 104/62, SPO2 88% on non-rebreather mask

The patient’s friend who brought her to the ED tells you the patient made suicidal statements earlier in the day and was found in her yard shed.

Questions:

1. What is the most likely causative xenobiotic that led to these findings?
   1. Influenza vaccine
   2. Methanol
   3. Organophosphate
   4. Paraquat

2. Are her symptoms reversible?
   1. Yes
   2. No

3. What therapy or therapies are critical for this patient?
   1. Atropine and Pralidoxime
   2. Diazepam
   3. Fomepizole with Folate
   4. Gastric lavage
   5. IVIG

Background:

• The focus of this Tox Card is the acute toxicity syndromes associated with organophosphate (OP) exposure.
• Sources of exposures:
  1. Organophosphates are one of many types of insecticide and are used worldwide to manage crops. Farm workers encounter these toxic agents usually due to less safe methods of spraying, leading to cholinergic toxidromes.^1-5 Farmers also treat sheep for parasites using OPs and may become symptomatic after exposure, an illness called Dipper’s Flu.⁶
  2. Some organophosphates have been developed as nerve agents used in chemical weapons.⁷
     • Check out ToxCard: Nerve Agents by Dr. Sahi & Dr. Santos from July 2018

• Organophosphates exert their toxic effects by inhibiting acetylcholinesterase within the synaptic cleft, which leads to accumulation of acetylcholine, with subsequent overstimulation of postsynaptic nicotinic and muscarinic receptors, and a predominant cholinergic effect. Note that there is also sympathetic stimulation due to nicotinic preganglionic synapse stimulation, however the parasympathetic response predominates and produces the characteristic toxidrome.⁷
• Unlike carbamates, organophosphates irreversibly bind to acetylcholinesterase, permanently inhibiting its enzymatic activity through a process called Aging where covalent bonds are formed between the agent and acetylcholinesterase (Figure 1). Aging can take anywhere from minutes to days and is dependent on the specific organophosphate.
• Once aging occurs, it can take weeks for enough acetylcholinesterase to be synthesized to allow for clinical resolution of symptoms.

Epidemiology:

• Agricultural workers may be exposed to organophosphates through inhalational, enteral, parenteral, or dermal exposure. The exposure can be either intentional or unintentional. Sufficient exposures, depending on dose and time of exposure, lead to symptoms of acute toxicity.^2,7 Organophosphate poisonings in agriculturally-centered communities are of public health concern in developing countries. Millions are poisoned, and hundreds of thousands die each year worldwide.^1,2,5

Clinical Presentation:

• There are 2 types of receptor effects:
  1. Nicotinic (first-order ganglion and neuromuscular junction): Causes weakness (paralysis), seizures
     • Mnemonic is Days of the week (Mon-Sa) “MTWtHFS”: mydriasis, tachycardia, weakness, hypertension, fasciculations, seizure
  2. Muscarinic: Causes parasympathetic findings
     • Mnemonic is SLUDGE: Salivation, lacrimation, urination, defecation, GI pain/cramping, emesis
     • Another common mnemonic is DUMBELS: Diarrhea, urination, miosis/muscle weakness/muscle fasciculations, bronchorrhea/bradycardia/bronchospasm, emesis, lacrimation, salivation/sweating
     • The Killer Bs are the most immediately lethal findings:
       • Bradycardia
       • Bronchorrhea
       • Bronchospasm
     • Two clinical syndromes that occur with acute organophosphate poisoning⁷:
       1. Acute poisoning
          • Predominant cholinergic toxidrome or cholinergic crisis within 8 to 24 hours from exposure that can be easily recalled by the mnemonics above.⁸
       2. Intermediate syndrome
          • Occurs 1 to 5 days after acute exposure in up to 40% on individuals.^7-9
          • Paralysis of neck flexor muscles, muscles innervated by cranial nerves, proximal extremity muscle weakness, and characteristically weakness of muscles used in respiration.^{7, 9}
          • Often have absence of excessive cholinergic stimulation.⁷
          • May lead to respiratory failure.^7-9
          • Usually, this resolves within a matter of 7 days.^7-9

Diagnosis:

• Diagnosis is clinical and should be based on history, physical exam findings of cholinergic toxidrome, garlic-like or hydrocarbon odor on the patient, or if presenting with neuromuscular dysfunction as above.
• Two assays are available to help confirm diagnosis. Low cholinesterase activity levels are consistent with organophosphate poisoning. These are send-out labs with turn-around times that make them unlikely to affect the ED course or guide treatment.⁸
  1. Plasma butyrylcholinesterase (“pseudocholinesterase”) activity
     • Easier to assay and is more widely available
  2. Red cell acetylcholinesterase (“true cholinesterase”) activity
     • More accurate and specific

Management:

• Patients require immediate intervention if there is concern for acute organophosphate poisoning. Laboratory testing methods have a prolonged turnaround time which can place the patient in a worse clinical state if you withhold treatment in lieu of confirmatory results. The goal is to act swiftly to prevent aging, dry respiratory secretions that lead to respiratory failure, and deter eventual cardiopulmonary collapse.
• Airway management should not be delayed.
• Disposition is often admission to an intensive care unit (ICU) setting.

1. Decontamination and Appropriate Personal Protective Equipment (PPE)
   1. This prevents ongoing exposure to the patient and ED staff. Remove patient clothing and wash patient thoroughly with soap and water if this is a dermal exposure. Dispose of clothing appropriately and wear PPE to prevent personal exposure.
   2. Organophosphates tend to adsorb onto leather goods such as shoes or belts, and these should be discarded with other hazardous waste, and not returned to the patient.⁷
   3. Airway management: consider early airway management. The most common cause of death in organophosphate poisoning is respiratory failure. This may result from any combination of hypoxemia and hypercarbia from uncontrolled bronchorrhea, bronchospasm, and neuromuscular weakness.
2. Mainstay Pharmacologic Therapy (Antidote = Atropine & Oximes)
   1. 1. Atropine sulfate⁸
         1. MOA: Competitive antagonist of acetylcholine at muscarinic receptors
         2. Dose 1-2 mg IV (0.02-0.1 mg/kg pediatrics)
         3. Double dose every 5 min
         4. Titrate up to end point of therapy and may require very large doses
         5. Target End Point of Therapy = clear chest sounds, HR > 80/min, pupil size greater than pinpoint, and dry axillae.¹⁰ Patients may require massive doses of atropine throughout their care.
         6. Once goal achieved, begin infusion at 10-20% of dose required to control secretions in mg/h and continue therapy until clinically resolved
      2. Pralidoxime (2-PAM)⁸
         1. MOA: An oxime that reactivates inhibited acetylcholinesterase that has not undergone the aging process. See figure below.¹¹
         2. Should be initiated as soon as possible to prevent organophosphate Aging process
         3. 30 mg/kg (max 2 g) IV loading dose in 100 mL 0.9% sodium chloride over 15-30 minutes; then Continue with infusion at 8 mg/kg/h (max 650 mg) IV
         4. Alternate regimen: 1-2 g IV loading dose, then repeat in 1 hour, then continue 1-2 g IV q10-12h
         5. Alternate regimen: 600 mg (15 mg/kg pediatric) IM, then repeat q15min for a total 1,800 mg
         6. May discontinue therapy once atropine is not required to manage secretions
      3. Diazepam
         1. Dose 5-10 mg IV bolus.
         2. Used for treatment of acutely symptomatic anxiety, muscle fasciculations, and seizures.⁸

Figure 1. The process of organophosphate age and its prevention with pralidoxime.

3. Avoid Further Exposure
   1. Avoid cholinergic agents that will exacerbate symptoms.

Case Follow-up:

• The patient required benzodiazepine administration for seizure management and subsequent intubation for airway protection. Further management and resuscitation were required, and she had a lengthy ICU stay of 21 days until she was extubated. Upon successful recovery, she explained she had been depressed and attempted to harm herself by drinking a bottle of insecticide containing malathion, an organophosphate. She required further inpatient psychiatric care and was eventually discharged. Follow up was set up with outpatient primary care, psychiatry, and medical toxicology for her intentional organophosphate poisoning and supportive therapy.

Answers to Questions:

1. C, Organophosphate; 2. A, Yes; 3. Both A & B, Atropine and Pralidoxime, Diazepam

Clinical Pearls:

1. Exposure can occur via ingestion, dermal absorption, or inhalation from spraying.
2. There are two clinical syndromes with acute toxicity, Acute Poisoning and Intermediate Syndrome, that lead to cholinergic crisis, muscle weakness, respiratory failure, and neurologic complications.
3. Diagnosis is made clinically. Do not delay therapy in lieu of pending lab results.
4. Treatment mainstay is antidote therapy with Atropine (for control of pulmonary secretions and cardiopulmonary stability) and Pralidoxime (to prevent Aging process) and should be administered immediately. Otherwise, provide supportive care.
5. Titrate atropine therapy to pulmonary secretions/bronchospasm, not to the other cholinergic findings.

References:

1. Boostani R, Mellat A, Afshari R, et al: Delayed polyneuropathy in farm sprayers due to chronic low dose pesticide exposure. Iran Red Crescent Med J 16: e5072, 2014. [PMID: 25031861]
2. Malla G, Basnet B, Vohra R, Lohani SP, Yadav A, Dhungana V. Parenteral organophosphorus poisoning in a rural emergency department: a case report. BMC Res Notes. 2013; 6:524. Published 2013 Dec 9. doi:10.1186/1756-0500-6-524
3. Muñoz-Quezada MT, Lucero BA, Iglesias VP, et al. Chronic exposure to organophosphate (OP) pesticides and neuropsychological functioning in farm workers: a review. Int J Occup Environ Health. 2016;22(1):68-79. doi:10.1080/10773525.2015.1123848
4. Ecobichon DJ. Pesticide use in developing countries. Toxicology. 2001;160(1-3):27-33. doi:10.1016/s0300-483x(00)00452-2
5. Eddleston M, Chowdhury FR. Pharmacological treatment of organophosphorus insecticide poisoning: the old and the (possible) new. Br J Clin Pharmacol. 2016;81(3):462-470. doi:10.1111/bcp.12784
6. Povey AC, Rees HG, Thompson JP, Watkins G, Stocks SJ, Karalliedde L. Acute ill-health in sheep farmers following use of pesticides. Occup Med (Lond). 2012;62(7):541-548. doi:10.1093/occmed/kqs099
7. Tintinalli, J. E. (2019). Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 9th Edition. McGraw-Hill Education. Section 15: Toxicology: 1301-1303.
8. Cook Matt, Frey Aaron. Pesticides and Cholinergics. In: Mattu A and Swadron S, ed. CorePendium. Burbank, CA: CorePendium, LLC. https://www.emrap.org/corependium/chapter/recdvP3Xjhrp9vbC8/Pesticides-and-Cholinergics. Updated September 14, 2020. Accessed December 14, 2020.
9. Indira M, Andrews MA, Rakesh TP: Incidence, predictors, and outcome of intermediate syndrome in cholinergic insecticide poisoning: a prospective observational cohort study. Clin Toxicol (Phila) 51: 838, 2013. [PMID: 24047461]
10. Eddleston M, Buckley NA, Checketts H, Senarathna L, Mohamed F, Sheriff MH, Dawson A. Speed of initial atropinisation in significant organophosphorus pesticide poisoning–a systematic comparison of recommended regimens. J Toxicol Clin Toxicol. 2004;42(6):865-75. doi: 10.1081/clt-200035223. PMID: 15533026; PMCID: PMC1475556
11. Pralidoxime (2-PAM). (n.d.). Retrieved December 15, 2020, from http://tmedweb.tulane.edu/pharmwiki/doku.php/pralidoxime_2-pam