Fourth Generation Agents

Treatment

Syringe

Treatment

Meticulous attention to supportive and symptomatic care is the key to patient management. FGA exposures may be resistant to initial and typically recommended medication doses, requiring significantly higher doses and a longer duration of repeated dosing than other nerve agent exposures.

  • Along with supportive care and decontamination, anticholinergics (e.g., atropine), oxime AChE reactivators (e.g., 2-PAM), and anticonvulsants (e.g., the benzodiazepines - diazepam, midazolam, and lorazepam) are the mainstays of the management of nerve agent toxicity. A simple way to remember this paradigm is the ABCDDs: Airway, Breathing, Circulation (ABC - supportive care), Decontamination, and Drugs (anticholinergics, reactivators, and anticonvulsants).
    • Supportive care (the ABCs) ensures preservation of vital functions before and during decontamination and administration of medications.
    • Decontamination (D) is a medical intervention designed to minimize the conversion of an external dose (on the skin) to an internal dose (inside the body). It is as important as supportive care and medication can be lifesaving. Decontamination should be performed as soon as possible but with FGAs may still be effective even hours or days after exposure.
    • Drugs (D) include the anticholinergic atropine, the oxime AChE reactivator 2-PAM, and anticonvulsants such as the benzodiazepines, diazepam, midazolam, and lorazepam. Anticholinergics are given until secretions diminish and airway resistance (difficulty breathing, resistance to ventilation) resolves. 2-PAM is given as long as nicotinic effects such as muscle weakness (effects not treated by atropine) are present. Anticonvulsants are given initially in severe cases even in the absence of convulsions because of a positive interaction (synergism) of anticonvulsants with the other medications; they are also given to treat convulsions and should be continued until the convulsions resolve.
  • Auto-injectors (AI) have typically been used for administering drugs intramuscularly (IM) to treat nerve agent exposures in a military setting and are available for civilian use. They may be particularly expedient in the pre-hospital setting. However, if resources permit, intravenous (IV) or intraosseous (IO) administration would be preferred, especially in critically ill patients. Lorazepam is also available for intranasal (IN) administration.
    • Atropine and 2-PAM are available together in the same AI (DuoDote or Antidote Treatment Nerve Agent Autoinjector (ATNAA) are interchangeable), as separate AIs packaged together (Mark 1 kit) and as individual AIs (atropine AIs come in various doses - 2, 1, 0.5, and 0.25 mg; 2-PAM AI contains 600 mg).
    • The diazepam AI is called Convulsant Antidote for Nerve Agent (CANA); midazolam and lorazepam are not currently produced in AI form. When given IM, midazolam is absorbed much more rapidly than diazepam.

    For pre-hospital nerve agent treatment regimen, see table below.

  • EMS agencies should follow their established treatment protocols.
  • National Model EMS Clinical Guidelines are also acceptable.
  • More repeated dosing over a longer duration may be required to treat FGA compared to other nerve agent poisoning.

If refractory to standard therapy consider:

Respiratory Distress/Bronchospasm

  • Repeated doses of atropine 2-6 mg should be titrated to controlling bronchospasm and respiratory secretions. Cumulative doses may be much higher than used in most clinical situations.
  • If severe bronchoconstriction/airway resistance continues despite repeated doses of atropine, nebulizer therapy with preferably albuterol/ipratropium or albuterol alone should be used per protocol.

Seizures

  • Treat with repeated doses of benzodiazepines (diazepam, midazolam, or lorazepam) until seizures resolve.
  • Monitor for the need for mechanical ventilation after administering large doses of benzodiazepines.

Pre-Hospital Treatment Recommendations (Autoinjector-Based) Nerve Agent Poisoning

Patient Age

Antidotes

Additional Treatment

Mild/Moderate Symptoms

Severe Symptoms

Infant
(0-2 yrs)

Atropine 0.05 mg/kg IM or Atropine AI 0.25 mg or 0.5 mg

AND

2-PAM 15-30 mg/kg IM

Atropine 0.1 mg/kg IM or Atropine AI 0.25 mg or 0.5 mg

AND

2-PAM 45 mg/kg IM;

AND

Midazolam 0.15 mg/kg IM

OR

Lorazepam 4 mg IM

OR

Lorazepam 0.1 mg/kg IN

OR

Diazepam 0.2-0.5 mg/kg IM

For mild/moderate, repeat atropine (2 mg) (for child 3-7 yrs, 1 mg; for infant, 0.25-0.5 mg) at 5-10 minute intervals until secretions have diminished and breathing is comfortable or airway resistance has returned to near normal.

For severe, repeat atropine as above but at 2-5 minute intervals.

Anticonvulsant should be administered in severe cases whether seizures are apparent or not.

If convulsions are present, repeat benzodiazepine until convulsions resolve.

Assisted ventilation should be started as needed after administration of antidotes.

Child
(3-7 yrs;
13–25 kg)

1 Atropine AI 1 mg

AND

1 2-PAM AI or 2-PAM 15-30 mg/kg IM

1 DuoDote; OR 1 Atropine AI 2 mg

AND 1 2-PAM AI or 2-PAM 45 mg/kg IM;

AND

Midazolam 5 mg IM

OR

Lorazepam 4 mg IM OR

Lorazepam 0.1 mg/kg IN

OR

1 CANA

Child
(8-14 yrs;
26-50 kg)

1 DuoDote; OR 1 Atropine AI 2 mg

AND

1 2-PAM AI or 2-PAM 15-30 mg/kg IM

2 DuoDote; OR 2 Atropine AI 2 mg AND 2 2-PAM AI or 2-PAM 45 mg/kg IM;

AND

Midazolam 5 mg IM

OR

Lorazepam 4 mg IM OR

Lorazepam 0.1 mg/kg IN

OR

1 CANA

Adolescent
(>14 years)/ Adult

1 to 2 DuoDote; OR

1 to 2 Atropine AI 2 mg

AND
1 2-PAM AI

3 DuoDote;

AND

1 CANA

OR

Midazolam 10 mg IM

OR

Lorazepam 6 mg IM/IN

Elderly, frail

1 DuoDote

2 to 3 DuoDote; OR

1 to 2 Atropine AI 2 mg

AND

2 to 3 2-PAM AI;

AND

1 CANA

OR

Midazolam 10 mg IM

OR

Lorazepam 6 mg IM/IN

Autoinjector Products:

DuoDote = ATNAA = Mark 1 kit = Atropine 2 mg + 2-PAM 600 mg AI

Atropine AI = various doses, two different manufacturers*

2-PAM AI = 2-PAM 600 mg AI

CANA = Diazepam 10 mg AI

* Please see the following webpage for more information on FDA approved atropine AI products and current nerve agent emergency use authorization information: https://www.fda.gov/Drugs/EmergencyPreparedness/BioterrorismandDrugPreparedness/ucm063809.htm

Find more information on this substance at: Hazardous Substances Data Bank , TOXNET , PubMed