Continuing Education Activity

Although the basics of evaluating and treating most unknown ingestants are well known, many overdoses require very specific treatment if the patient is to have any chance of survival. Despite widespread public education, childproof containers, and other safety measures, accidental overdoses continue to occur. In the United States, poison control centers receive over 2.2 million calls each year, 47% of which concern children less than six years of age. Most pediatric accidental ingestions involve cosmetics and personal care products, followed by cleaning products, and then analgesics and prescription medications. Adult overdoses usually are due to the intentional ingestion of analgesics and sedative-hypnotics. This activity reviews the deadly single dose toxic agents and discusses the interprofessional team's role in educating families on protecting children from exposure to these agents.

Objectives:

• Outline the challenges of public education in regard to preventing overdoses.
• Identify the common causes of pediatric and adult overdoses.
• Describe the common interventions for single-dose agent overdoses.
• Review the interprofessional team's role in educating families on protecting children from exposure to these deadly single-dose toxic agents.

Introduction

Although the basics of evaluating and treating most unknown ingestants are well known, many overdoses require very specific treatment if the patient is to have any chance of survival.[1] Countless studies have been published supporting Dr. Gideon Koren's 1993 landmark article "Medications Which Can Kill a Toddler with One Tablet or Teaspoonful" in the Journal of Toxicology.[2][3][4][5] while each has its own merits, most focus solely on pediatric overdoses, and relatively few of them provide an exhaustive list or act as a "quick-reference" when dealing with real-time ingestions. 

Despite widespread public education, childproof containers, and other safety measures, accidental overdoses continue to occur.  In the United States, poison control centers receive over 2.2 million calls each year, 47% of which concern children less than six years of age.  Most pediatric accidental ingestions involve cosmetics and personal care products, followed by cleaning products, and then analgesics and prescription medications.  Adult overdoses usually are due to the intentional ingestion of analgesics and sedative-hypnotics. 

Following are the list of toxic drugs (in decreasing severity/difficulty of treatment) included in this summary: 

1. Alpha-2 adrenergic agonists - clonidine, naphazoline, oxymetazoline, tetrahydrozoline
2. Sulfonylureas - chlorpropamide, glyburide, glipizide, glimepiride
3. Calcium channel blockers - nifedipine, verapamil, diltiazem, amlodipine, nicardipine
4. Beta-blockers - metoprolol, labetalol
5. Tricyclic antidepressants - imipramine, desipramine, amitriptyline, nortriptyline
6. Opioids - codeine, hydrocodone, methadone, morphine, heroin
7. Anti-diarrheals - diphenoxylate + atropine, loperamide
8. Salicylates/Methyl salicylates - wintergreen oil, bismuth subsalicylate, mentholated balms
9. Antipsychotics - loxapine, thioridazine, chlorpromazine
10. Antimalarials - chloroquine, hydroxychloroquine, quinine
11. Antiarrhythmics - quinidine, disopyramide, procainamide, flecainide
12. Terpenoid (camphor) - analgesic, anti-itch, and cooling gels, ointments, and balms
13. Non-alkaloid toxic lignan - podophyllin, podofilox
14. Plant toxin/secondary metabolite - colchicine
15. Oral acetylcholinesterase inhibitors - rivastigmine, donepezil, galantamine
16. Methylxanthine - theophylline: 1,3-dimethylxanthine
17. Partial opioid agonist/synthetics - buprenorphine/fentanyl
18. Toxic alcohols - methanol, ethylene glycol
19. Caustics /household products - acidic or alkaline household products, hydrofluoric acid, selenious acid, ammonia fluoride, methacrylic acid (cosmetic glue), naphthalene (mothballs)

Function

Toxicokinetics

1. Alpha-2 adrenergic agonists: alpha-2 receptors mediate the transmission of neurotransmitters (acetylcholine & norepinephrine) across the synapse, effectively antagonizing them
2. Sulfonylureas: stimulates the pancreas to increase insulin production
3. Calcium channel blockers: decrease cardiac inotropy and increase vasodilation; can also block insulin secretion in the setting of overdose, which can directly affect the heart and thereby worsening shock
4. Beta-blockers: direct action on the heart causing bradycardia (less severe in children); blockage of gluconeogenesis leading to hypoglycemia; central nervous system (CNS) depression (crosses blood-brain barrier due to high lipid solubility)
5. Tricyclic antidepressants: block fast sodium channels, leading to intraventricular conduction delay; wide QRS and right axis deviation on EKG
6. Opioids: direct suppression of CNS respiratory center leading to hypoxic respiratory failure
7. Anti-diarrheals: biphasic toxicity - first anticholinergic effects and then a longer-lasting opioid effect
8. Salicylates/Methyl salicylates: direct stimulation of CNS respiratory center (respiratory alkalosis) then metabolic acidosis 
9. Antipsychotics: block post-synaptic dopamine receptors and the reticular activating system (also some serotonin antagonism)
10. Antimalarials: sodium channel blockade; QRS widening
11. Antiarrhythmics: sodium channel blockade; QRS widening
12. Terpenoid (camphor): topical rubefacient induces local hyperemia and warmth
13. Non-alkaloid toxic lignans: interrupt cell mitosis by binding to tubulin and disrupting the microtubular network, thereby disturbing cellular protein assembly and leading to sepsis and multisystem organ failure
14. Plant toxins/secondary metabolites: same as the lignan. Interrupt cell mitosis by binding to tubulin and disrupting the microtubular network, thereby disturbing cellular protein assembly and leading to sepsis and multisystem organ failure
15. Oral acetylcholinesterase inhibitors: act on nicotinic and muscarinic receptors; cholinergic toxidrome
16. Methylxanthines: inhibit phosphodiesterase enzymes which increase cAMP and cGMP to cause bronchodilation
17. Partial opioid agonist/synthetics: direct suppression of CNS respiratory center (one lick can be enough to be toxic in a child)[6]
18. Toxic alcohols: metabolized into toxic chemicals like aldehyde, organic acids, acetone
19. Caustics/household products: direct mucosal and pulmonary damage (toxicity related to pH < 3 and > 13), methemoglobinemia (methacrylic acid), cyanide (a metabolite of acrylonitrile)

Symptoms/Physical Findings/Labs/EKG

1. Alpha-2 adrenergic agonists: opioid toxidrome, altered mental status
2. Sulfonylureas: anorexia, weakness, prolonged hypoglycemia up to 18 to 24 hours, lethargy, seizure, coma, headache, confusion, irritability
3. Calcium channel blockers: hyperglycemia, cardiovascular collapse, bradycardia, hypotension (verapamil and nifedipine worst)[7]
4. Beta-blockers: bradycardia and hypotension (generally not as severe in children), hypoglycemia, seizures, reflex tachycardia, 2nd- and 3rd-degree heart block, Torsades de pointes
5. Tricyclic antidepressants: seizures, anticholinergic toxidrome, hypotension, metabolic acidosis, cardiac conduction abnormalities (QRS prolongation and prominent R in aVR, hypotension, CNS depression, tachycardia then torsades de pointes)
6. Opioids: hypoxic respiratory failure, miosis, CNS depression
7. Anti-diarrheals: initially anticholinergic toxidrome then opioid toxidrome; cardiac dysrhythmias, ataxia, irritability, hypokalemia, myopathy, neuropathy, AMS, ocular toxicity, ototoxicity[8]
8. Salicylates/methyl salicylates: nausea and vomiting, diaphoresis, hyperthermia, tinnitus, CNS depression, hyperventilation, primary metabolic acidosis, pulmonary edema, cerebral edema, coma
9. Antipsychotics: seizures, anticholinergic toxidrome, prolonged QTc, wide QRS, tachycardia, hypotension
10. Antimalarials: delirium, coma, dysrhythmias, seizures, prolonged QT, widened QRS, hypotension, hypoglycemia, visual disturbances (blurry, diplopia, altered color perception)
11. Antiarrhythmics: nausea and vomiting, hypotension, QRS widening, heart block, hyperthermia, hypoglycemia, bradycardia, tachyarrhythmias, ventricular tachycardia/fibrillation, torsades de pointes
12. Terpenoid (camphor): respiratory suppression, status epilepticus, typical odor, GI distress, sense of warmth, CNS hyperactivity, then depression
13. Non-alkaloid toxic lignan: GI symptoms, CNS changes (confusion, coma, delirium, hallucinations), pancytopenia
14. Plant toxin/secondary metabolite: Same as lignan. GI symptoms, CNS changes (confusion, coma, delirium, hallucinations), pancytopenia[9]
15. Oral acetylcholinesterase inhibitors: increased level and duration of neurotransmitters
16. Methylxanthine: vomiting, anxiety, agitation, seizures, ventricular dysrhythmias, hypotension, tachycardia
17. Partial opioid agonist/synthetics: opioid toxidrome, agitation[10]
18. Toxic alcohols: confusion, vomiting, seizures, hypopnea, cyanosis, hypothermia, syncope
19. Caustics/household products: drooling, perioral burns, respiratory distress, dysphagia, metabolic effects (methemoglobinemia, hemolysis, cyanide toxicity)

Issues of Concern

Treatment/Management (currently recommended antidotes listed first)

1. Alpha-2 adrenergic agonists: naloxone (antidote); supportive care, airway protection, respiratory support, atropine, IV fluids, vasopressors
2. Sulfonylureas: octreotide (antidote); serial glucose monitoring, glucagon, GI decontamination, IV dextrose bolus (can overstimulate the pancreas and cause rebound hypoglycemia), 24-hour observation
3. Calcium channel blockers: high dose Insulin/euglycemic therapy (antidote); other antidotes (weaker evidence) such as lipid emulsion, IV calcium, methylene blue (amlodipine), ECMO for cardiovascular collapse, atropine, cardiac pacing, pressors[11][12]
4. Beta-blockers: glucagon (antidote); monitoring, vasopressors, cardiac pacing, whole bowel irrigation, calcium 
5. Tricyclic antidepressants: sodium bicarb/lipid emulsion (antidotes); aggressive ABCs, urine alkalinization, activated charcoal, benzodiazepines (may rapidly deteriorate)
6. Opioids: naloxone (antidote); supportive care, airway protection, respiratory support, 24 hours observation for longer-acting opioids
7. Anti-diarrheals: naloxone (antidote); fluids, airway support, supportive care
8. Salicylates/Methylsalicylates: sodium bicarbonate (antidote), urine alkalinization, supportive care, activated charcoal, dialysis. May require long observation (may not peak until 24 hours)
9. Antipsychotics: sodium bicarbonate (antidote); supportive care, benzodiazepines, cardiac monitoring, GI decontamination
10. Antimalarials: sodium bicarbonate (antidote); ECMO, supportive care, benzodiazepines, cardiac monitoring, glucose (severe – epinephrine, intubation, gastric lavage)
11. Antiarrhythmics: sodium bicarbonate (antidote); supportive care, cardiac monitoring, intravenous fluid bolus
12. Terpenoid (camphor): supportive care; benzodiazepines, airway monitoring, remove chemical if possible
13. Non-alkaloid toxic lignan: supportive care; remove topicals, GI decontamination 
14. Plant toxin/secondary metabolite: supportive care; remove topicals, GI decontamination
15. Oral acetylcholinesterase inhibitors: atropine, 2-PAM (pralidoxime), and diazepam
16. Methylxanthine: supportive care; IV fluids, benzodiazepines, antiemetics, activated charcoal, inotropes
17. Partial opioid agonist/synthetics: naloxone (antidote); supportive care, airway protection, respiratory support
18. Toxic alcohols: ethanol, fomepizole (antidote); supportive care, specific treatment depends on the type of alcohol
19. Caustics/household products: (multiple specific treatments) supportive care, airway protection, dilution, cyanide kit, methylene blue

Clinical Significance

Although there is little primary research into poisonings, there are numerous case reports and summary articles on the topic. Novel therapies are in development and testing all the time; for example, methylene blue in amlodipine overdose and “old” therapies such as ECMO are seeing more use and with greater success.[13][14] In treating patients, be sure to liberally utilize the regional poison control center to ensure the use of the latest therapies and best management available. Toxicologists are always standing by to assist. Also, numerous web resources, such as UpToDate and eMedicine, and textbooks, such as Goldfrank, provide very specific and current treatment protocols. Observation and supportive care are sufficient for most toxic ingestions, but some, like these highly dangerous substances, require specific treatment and a knowledgeable clinician.

Enhancing Healthcare Team Outcomes

Although identification and proper management of toxic ingestions are vital skills for emergency and acute care clinicians, one cannot forget those that support our mission both before arrival and after treatment and discharge.  Caring for these complicated overdoses is a daunting task, especially for the pre-hospital personnel, as well as those providing aftercare. Numerous studies and articles are now focusing on reducing unnecessary ER visits for minor ingestions and patient safety, and proper mental health or substance abuse referrals.[15] More evidence-based research is necessary on preventing recidivism, and more collaborative programs need to be developed to provide clear pathways to recovery for the patients who have intentionally overdosed. As the U.S. opioid crisis has received federal attention (and funding to address it) - now is the time to capitalize on the national momentum to improve our comprehensive care of these patients.  Now is also the time to build our care teams when these patients present to the ER. A collaboration of EMS, ED providers, clinical pharmacologists, poison control, intensivists, mental health providers, and addiction specialists is necessary for this patient's journey to full recovery.

Due to the complexity and risk of patients exposed to these agents, an interprofessional team approach will lead to the best outcomes. The nurse should help the clinician obtain an accurate patient and family history, including making calls as necessary to family members and pharmacists. The specialty-trained toxicology pharmacist should evaluate drug-drug interactions, select antidotes, and provide guidance for care to the team. The clinician should consult a clinical toxicologist in most cases to assist in guiding evaluation and therapy. Often a mental health counselor is involved as well. Only by working together as a team will these patients obtain the best care and chance for long-term survival. [Level 5]