A Medical Toxicologist’s Approach to the Overdosed Patient

Author: James Dazhe Cao, MD (@JamesCaoMD, Assistant Professor of EM, Medical Toxicology Fellowship Director, UTSW / Parkland Memorial Hospital) // Edited by: Cynthia Santos, MD (Assistant Professor, Emergency Medicine, Medical Toxicology, Rutgers NJMS); Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital); and Brit Long, MD (@long_brit, EM Attending Physician, San Antonio, TX)

As a medical toxicologist, I have a different take on the world of overdoses. Paracelsus has said “All things are poisons, for there is nothing without poisonous qualities. It is only the dose which makes a thing poison.” The deadly dihydrogen monoxide has its merits – https://www.dhmo.org/facts.html. Paracelsus’ adage is something that all medical toxicologists live by; however, we understand there is much more depth to the art of toxicology than the dose makes the poison.

For emergency medicine physicians, overdose patients present regularly, especially in the current opioid epidemic. In 2017, U.S. poison centers recorded 656,235 human exposures managed at a healthcare facility – a bulk of which initially presented to the emergency department.¹  Other than calling the poison center for recommendations and advice (which I encourage everyone to do – 1-800-222-1222), a framework for the initial assessment and management of overdose patients is critical.

Scope

In this writeup, I will describe my approach to assessing and managing overdose patients in the emergency department through my lens as a medical toxicologist. I will not discuss the foundational knowledge of toxicology such as toxidromes and will not discuss envenomations. Many other finer details on the initial vital signs and considerations for treating overdose patients can be found in the Goldfrank’s Toxicologic Emergencies 11^thedition chapters 3 and 4.²  The textbook is also a valuable resource to read on some of the toxins mentioned in  this post.

Case 1

A 13-year-old girl presents to the children’s emergency department after an ingestion. She is tearful and withdrawn. She states that she has been feeling depressed and, in an attempt to harm herself, has taken 2 bottles worth of her grandmother’s medications. She has normal vital signs and appears stable.

Initial Impressions:

• As an emergency physician, the tenant of sick versus not sick is vitally important. This patient appears stable, but depending on the drug, this may be transient. Dr. Sahaphume Srisuma and I had published a study on potentially preventable deaths reported to the National Poison Data System (NPDS) from US poison centers. We showed a commonality between these toxins leading to preventable deaths – minimal early symptoms followed by precipitous deterioration³:
  • Fluoride containing products
  • Metformin
  • Toxic alcohols
  • Salicylates
• By no means is this a comprehensive list, but remember these drugs to keep that BAFERD Spidey sense sharp. I guarantee you that these drugs haunt my dreams and keep me up at night.
• For those patients who present acutely ill, remember the “ABCDE” of medical toxicology:
  • Airway
  • Breathing
  • Circulation
  • Dextrose and Decontamination (see below)
  • Exposure – remove potentially transdermal absorbed substance (i.e. fentanyl patches).
    Enhanced elimination (see below)
    Extracorporeal membrane oxygenation (ECMO) – becoming more common in emergency departments. Despite its complexity and risks, overdose patients may be perfect candidates for ECMO given the transient effects of most overdoses, so think about initiating it if you have ECMO available.
• Manage each step as necessary as one would resuscitate any acutely ill patient. Remember that the basic ACLS management is often more important than the targeted management for a given toxin. Yes, antidotes may help, but without oxygen and blood circulation, antidotes will not work.
• As you may have already noticed in my discussion thus far, I did not reveal what the patient has actually taken. I have my reasons for this. Keep your differential open when approaching toxicology cases. Even for my toxicology fellows, it is very easy to anchor and close your differential by “knowing” what the reported ingestion is. Many of our consults start with “the patient took drug X.” However, the patient may have been exposed to something other than what was reported because:
  • the patient is not truthful about the actual ingestion,
  • the patient falsely remembered the ingestion or remembered only part of the ingestion, or
  • the patient thought they took drug X but the contents were actually drug Y.
• I encourage my fellows to discuss this point when leaving a recommendation – does the reported ingestion makes sense in the context of the patient’s history, exam, and laboratory analysis?

History Taking:

• In my opinion as with most emergency department patients, history is one of the most important aspects of managing an overdose patient. For toxicology patients, I strongly encourage obtaining collateral from multiple sources to collaborate the patient story:
  • Family
  • Friends
  • Assisted living staff
  • EMS personnel
  • Law enforcement personnel
  • Pharmacies
  • Available pill bottles
• Collateral can help confirm or deny the patient’s history. Alternatively, other sources can help piece together the clinical picture that the patient either does not remember or will not admit to. For example, time of ingestion is one of the most common questions that we ask. Bracketing an unknown time is a useful technique especially for something that is time critical such as determination of starting N-acetylcysteine (NAC). Ask the collateral source when they last saw the patient normal, when they received a text message from the patient, or when the patient’s social media post was timestamped.
• EMS and law enforcement who were on the scene are important allies in obtaining an accurate history. Most EMS and law enforcement providers know to bring pill bottles and available paraphernalia. If they are available at the hospital, ask them what they saw and what was the environment around the patient when they retrieved him/her.
• Pharmacy history is typically an adjunct that is done by the toxicology consult service, as it is time consuming. Knowing what pills are available at home may be important to the clinical picture. Sometimes if the patient is out of your electronic medical record system, calling the patient’s pharmacy to obtain a medication list can be useful.
• Pill bottles hold important clues. Remember that the label does not necessarily indicate what is inside the bottle. Patients commonly reuse old prescription bottles and combine multiple pills into a single bottle. Many bottle labels describe the intended pills that are in there. Match the description on the label with the pills inside. Counting pills is a staple of a good toxicologic history. Note when the bottle was filled and how many pills are left in the bottle. As with bracketing a time, this may give you a sense of how many tablets a patient may have taken. The maximum number of pills is if one assumes the patient never took his/her pills on a daily basis and consumed all missing pills in this one ingestion. The minimum number of pills is reflected by daily use of the pills since the refill day and estimating the number of missing pills above that. For unknown pills, many online sources such as Epocrates can help identify pills. The poison center also has resources to help you identify unknown pill. 

Physical Exam:

• Airway: Knowing when to protect airway is challenging even for a toxicologist. Have a low threshold to do so, especially if you anticipate clinical deterioration.
  • Be aware that end-tidal CO2 may be a useful adjunct but understand its limitations and low sensitivity.⁴
  • Remember to reserve naloxone, flumazenil, and endotracheal intubation for respiratory depression and not isolated central nervous system (CNS) depression.
• Toxidromes: Know them and look for them. Remember that toxidromes typically only apply if a patient ingested substances from a single class of agents. In the 2017 NPDS report, 12.14% or 256,783 human exposure cases involved more than one substance.¹
• Elements of the physical exam to focus on:
  • Bowel sounds – helps suspect anticholinergic toxidrome and can direct decontamination measures (see below). So yes, you do have to use your stethoscope below the diaphragm!
  • Neuromuscular exam – needed to identify potential serotonin syndrome and neuroleptic malignant syndrome.
  • Toxicologist’s handshake – feel under the axilla for sweat – will be dry in anticholinergic toxidromes or in a really dehydrated patient. Yes, it is gross. Yes, I use gloves to do this.

Decontamination:

• Know about it, but largely this practice is going away. Decontamination as a percentage of total human exposures reported to U.S. poison centers from 1985-2017¹:

• Do not make administering decontamination modalities a knee-jerk response to an overdose patient. Think long and hard about the toxicity of the drug, the benefit of decontamination, and the risk of the procedure.
• However, for large ingestions of a toxic drug, decontamination may be one of the only modalities to potentially save a patient.

 Diagnostic Studies:

• Start with the basics as needed including but not limited to comprehensive metabolic panel, acetaminophen concentration, and an EKG. Acetaminophen ingestion may be asymptomatic, and a screening concentration may change management. Order concentrations for other drugs ingested and that your laboratory can turn around in a couple of hours, such as salicylates. No need to order send out testing in the emergency department, as this will not help initial management.
• Please have your nurses send some extra tubes of blood and urine down to lab for future testing, as the clinical course may change.
• Urine drug screen – know the limitations. See: https://emcrit.org/toxhound/uds-and-i/
• Determine the most likely drug or drugs in the ingestion and the lethality of potential toxic exposure. Consider three key aspects of the case:
  • Drug: How dangerous is the drug? If the patient is exposed to ibuprofen, the risk of toxicity is relatively minimal with almost no risk of mortality. However, if the patient ingested just 0.5 mg/kg of colchicine, then chances of death are high with little directed therapy.
  • Dose: Different drugs have different toxic ranges. Colchicine as mentioned becomes dangerous above 0.5 mg/kg, whereas we tolerate acute acetaminophen ingestions of 200 mg/kg. I do not try to remember all of the dose ranges of toxicity. Use your pharmacology references. I use Micromedex to get me in the ballpark: https://www.micromedexsolutions.com/home/dispatch(will need institution access if you have it).
  • Patient: Consider the patient’s co-morbidities – less physiologic reserve, the more dire the potential outcome.

Treatment:

• Excellent supportive care! While antidotal therapy can have dramatic affects, recommendations for antidotes are relatively rare. Including the use of NAC in 2017, only 59,619 instances of antidotes were given to the 2.1 million human exposures calls reported to U.S. poison centers. Even if only one antidote was administered to one exposure call, that represents only 2.8% of calls to the poison center.¹
• Enhanced Elimination – Use expert consensus guidelines on hemodialysis – https://www.extrip-workgroup.org/recommendationsfor the following drugs:
  • Acetaminophen
  • Barbiturates
  • Carbamazepine
  • Digoxin
  • Lithium
  • Metformin
  • Methanol
  • Phenytoin
  • Salicylates
  • Thallium
  • Theophylline
  • Tricyclic Antidepressants
  • Valproic Acid

In 2019, the ExTrip workgroup will provide evidence-based recommendations on: Baclofen, Ethylene glycol, Methotrexate, Isoniazid, Calcium Channel Blockers, Beta-Blockers, Dabigatran, Gabapentin/Pregabalin, Quinine/Chloroquine, Amatoxins.

Case 2:

A 49-year-old patient with no known past medical history presents with encephalopathy. The patient is obtunded, receives naloxone without improvement, and is intubated for airway protection. Initial laboratory evaluation and CT of the brain are unremarkable. The patient’s family state that he has been gradually worsening over the past two weeks.

This case represents a class of consults that I endearingly term “could this be tox?” These are cases of diagnostic uncertainty with some element of history reported to the primary provider suggesting a possible toxicologic etiology. We as toxicologists will further investigate. I do not expect emergency providers to have the time to dive into these histories and investigative work, but I wanted to share a glimpse of what we do.

History of Present Illness:

• As with the case above, the history is paramount. In this case, collateral is important since without it, you are searching for a needle in a haystack. The world of toxins is vast!
• If the patient is awake, start from the beginning of symptoms and explore circumstances leading to symptoms and surrounding potential exposures.
• Investigate all medications the person may have been exposed to – patient meds, family member medications. Ask about herbals and supplements, especially if they are from a foreign country! Even prescription medications from other countries can lead to toxicity as the medication may have been withdrawn from the U.S. markets by the FDA.

Social History:

• Anyone else sick in the home or at work? Targeting environmental exposures.
• Are any pets sick at home? Infectious disease can affect multiple humans, but environmental exposure effect multiple species. This is figuratively the canary in the coal mine.
• Any travel history or camping with consumption of wild flora?
• What is your occupation? Occupational exposures may have chronic health effects.
• What hobbies do you have? Unusual hobbies may mean chronic toxic exposures – look up fire gilding – https://en.wikipedia.org/wiki/Gilding#Fire-gilding.
• What is the home environment like? For example, if the house was built before 1978, lead paint may have been used. If one is concerned about methemoglobinemia, ask about well water consumption.

Physical Exam:

• Same as above except here I am looking for more subtle toxicologic findings (i.e. Mees’ lines for heavy metal poisoning) to provide clues. 

Diagnostic Studies:

• Here we may be sending out more specific toxicologic testing. At our children’s hospital, we have access to a comprehensive urine drug screen using advanced methods like liquid chromatography–mass spectrometry (LC-MS). LC-MS can be helpful to confirm or exclude differential diagnoses, but because of the delay in results, testing is not useful in the initial management.
• I frequently get asked about management of unexplained metabolic acidosis. I use the mnemonic KULTO:
  1. K = Ketones (diabetic ketoacidosis, alcoholic ketoacidosis, and starvation ketoacidosis)
  2. U = Uremia
  3. L = Lactate – read this excellent review: https://www.ncbi.nlm.nih.gov/pubmed/28447886
  4. T = Toxins (salicylates, toluene, and toxic alcohols)
  5. O = Organic acids (inborn error of metabolism and 5-oxoprolinuria from chronic acetaminophen)
• Differential Generation: Use the available history, physical, and laboratory findings to narrow the differential as much as possible. This process tends to be organ based depending on the presentation. Goldfrank’s textbook chapters 15-29 are organized by organ system and has tables listing toxins that cause those organ system dysfunctions.²

Other Useful Toxicology Resources:

1. Agency for Toxic Substances & Disease Registry (ATSDR) – Information about toxic substances by the CDC: https://www.atsdr.cdc.gov/substances/index.asp
2. American College of Medical Toxicology (ACMT): https://www.acmt.net/resources_tex.html
   2015. ACMT Antidote Card: https://www.acmt.net/_Library/Membership_Documents/ACMT_Antidote_Card_May_2015.pdf
3. CredibleMeds – List of drugs that prolong QTc and have risk of Torsades: https://crediblemeds.org/
4. Dietary Supplement Label Database – figure out what ingredients may be in supplements: https://www.dsld.nlm.nih.gov/dsld/index.jsp
5. LiverTox – Look up for drugs causing liver injury: https://livertox.nih.gov
6. Flockhart Table – CYP450 drug interaction chart: https://drug-interactions.medicine.iu.edu/Main-Table.aspx
7. Toxnet – look up health effects of esoteric toxins: http://toxgate.nlm.nih.gov
   1. Also includes LactMed – drugs and lactation database
   2. Developmental Toxicology Literature – reproductive toxicology database

Summary – Key Take Home Points:

1. Avoid premature closure by verifying through history and exam that the patient’s presentation is consistent with what the reported ingestion was.
2. A thorough toxicology history with relevant social history elements take time, but learn to start incorporating some of these questions if diagnostic uncertainty is present – i.e. ask if pets are also sick at home.
3. Manage and stabilize patients as you would any critically ill patient with attention to ABCs and supportive care. Add in considerations of antidote, decontamination, and enhanced elimination based on suspected exposure.
4. Know your toxicology resources listed above and call your local poison center or medical toxicologist for clinical assistance.

References/Further Reading:

1. Gummin DD, Mowry JB, Spyker DA, Brooks DE, Osterthaler KM, Banner W. 2017 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 35th Annual Report.Clinical toxicology. 2018;56:1213-1415.
2. Nelson L. Goldfrank’s toxicologic emergencies. Eleventh edition. ed. New York: McGraw-Hill Education; 2019.
3. Srisuma S, Cao D, Kleinschmidt K, Heffner AC, Lavonas EJ. Missed opportunities?: an evaluation of potentially preventable poisoning deaths. Clinical toxicology. 2016;54:441-446.
4. Viglino D, Bourez D, Collomb-Muret R, et al. Noninvasive End Tidal CO2 Is Unhelpful in the Prediction of Complications in Deliberate Drug Poisoning. Annals of emergency medicine. 2016;68:62-70 e61.