Laboratory Testing Pitfalls in Toxicology Patients

Blood and urine lab test tube sample

Toxic Alcohols (ethylene glycol, methanol)

    • Large ingestions of toxic alcohols can cause significant morbidity and mortality.1 Serum concentrations are time-sensitive and important to guide therapy as well as predict clinical course.
    • Tips for successful ordering of labs through ARUP:
      • Order both ethylene glycol and methanol serum concentrations (usually separate orders)
      • Order with STAT priority (it is available, even if it may not appear so at first)
      • Courier sample to ARUP
    • Lactate gap2
      • Ethylene glycol is eventually metabolized to glycolate and glyoxylate. These compounds are misinterpreted as lactate by many (not all) point-of-care blood gas analyzers and will report a profoundly elevated lactate concentration.
      • However, when checking a serum lactate concentration, it is highly unlikely to be elevated to the same degree (in the setting of isolated toxic alcohol ingestion).
      • This difference between point-of-care blood gas analyzer lactate and serum lactate is known as a “lactate gap.” A lactate gap is a specific finding for ethylene glycol ingestion and can be helpful in its diagnosis.
        • Note: a lactate gap may not be present if ethylene glycol has not had time to be metabolized to glycolate and glyoxylate.

Expanded Drug Testing and Specific Drug Concentrations

    • Expanded drug screens and specific drug concentrations are send-out labs for most institutions. While these labs do not change the acute treatment, they do serve important purposes for unclear ingestions or ingestions of unknown substances:
      • For pediatric ingestions, this information is valuable for legal purposes to ensure the child is being responsibly taken care of and the ingestion was not a result of negligence or malicious intent.
      • Illicit drugs are frequently laced with substances, unbeknownst to the user, and new substances are being abused every day. Expanded drug testing allows outbreaks of laced drugs and new substances to be identified so public health officials and Utah Poison Control Center can better prepare and serve the community.
      • Scientific literature for toxicology is different from many other specialties due to difficulty in the logistics and ethics of designing a prospective trial. Many of the recommendations toxicologists provide for your patients are a result of published case studies and series. Therefore, it is highly important for new substances, presentations, and treatments to be written up and published. Expanded drug testing and drug concentrations provide valuable information for these case studies/series that may help save the life of another patient in the future.
        • Utah Poison Control Center is more than willing to write or collaborate in writing case studies.
    • Expanded drug tests commonly recommended by Utah Poison Control Center
      • ARUP Laboratories – Drug Profile, Expanded Targeted Panel by LC-MS/MS
      • National Medical Services (NMS) 1876, Drug Screen - Expanded
    • Tips for successful ordering of labs:
      • May require a “miscellaneous” or “other” order within the EHR if not available to order within the catalog
      • Ask your lab about logistics and coordinate collection of the lab test with other members of the healthcare team
        • Ask about type of tube top to collect in, inform nurse or phlebotomist regarding collection, inform lab once the sample has been collected
    • Drug concentrations that are commonly available STAT in many institutions and do not require a send- out lab3
      • Acetaminophen, salicylate, phenobarbital, phenytoin, lamotrigine, valproic acid, carbamazepine, lithium, digoxin, caffeine, ethanol
        • Acetaminophen, salicylate, and ethanol are standard concentrations to order for patients presenting with acute ingestion
        • Recommended to check any of the above drug concentrations if patient has known history of use

Urine Drug Screen3

    • Urine drug screens (UDS) are antibody-based and frequently detect metabolites. This means that a molecule must have structural similarity to the substance being tested for, and UDS are prone to cross-reactivity. Further, results of a UDS only provide information regarding exposure, not intoxication.
    • False positives
      • Methadone – diphenhydramine, doxylamine
      • TCAs – diphenhydramine, cyclobenzaprine, quetiapine, carbamazepine
      • Amphetamines – bupropion, pseudoephedrine, trazodone, aripiprazole, labetalol, propranolol
        • Note: difference between amphetamine positive and methamphetamine positive
    • False negatives
      • Opioids – oxycodone, methadone, fentanyl, tramadol
        • A screen for opiates (morphine, codeine, heroin, hydrocodone*) is a more common test and unlikely to detect opioids, which typically need specific lab tests to detect
          • *Hydrocodone is an opioid but will show up on opiate screens
      • Amphetamines – MDMA, bath salts
    • Reliable
      • Benzodiazepines – diazepam, chlordiazepoxide, temazepam
      • Barbiturates – sensitive and specific (potential false positive with ibuprofen)
      • Cocaine – detects benzoylecgonine within 2 – 3 days with exceeding specificity
    • Variable – call your lab for specific information
      • Benzodiazepines – lorazepam, alprazolam, clonazepam, midazolam

Salicylates4

    • Salicylate toxicity has the potential to cause significant morbidity and mortality. Simultaneously, it requires frequent monitoring to ensure adequate treatment is being provided to the poisoned patient.
    • pH monitoring
      • A cornerstone of management for salicylate toxicity is sodium bicarbonate IV infusion. In the setting of aspirin overdose, an acidic environment is created that increases the number of unionized aspirin molecules that cause intracellular damage. Increasing the pH of the serum and urine through sodium bicarbonate infusion increases the number of ionized aspirin molecules that leave the cell and are then eliminated via the kidneys. It is important to frequently monitor the urine pH to ensure the environment is alkalotic enough to eliminate the aspirin molecule from the body (Goals: serum pH 7.5-7.55, urine pH 7.5 – 8).
    • Potassium monitoring
      • A side effect of sodium bicarbonate administration is hypokalemia. Hypokalemia is detrimental in this setting as the kidneys will resorb potassium in exchange for hydrogen ions, making it difficult to raise urine pH and eliminate aspirin. Therefore, it is important for serial monitoring and repletion of potassium while administering sodium bicarbonate (serum potassium goal: >4 mEq/L).
    • Aspirin concentration monitoring
      • The equilibrium of unionized and ionized aspirin molecules will shift while treating with sodium bicarbonate. Because of this, it is important to frequently check serial aspirin concentrations as newly ionized molecules move extracellularly and are eliminated. Sodium bicarbonate therapy should be continued until salicylate concentrations decrease below a certain threshold and clinical presentation improves.
        • Once sodium bicarbonate is discontinued, it is important to check another salicylate concentration a few hours later since salicylate concentrations may shift with a change in pH. Similarly, during sodium bicarbonate treatment, salicylate concentrations may be misleading of treatment response if urine pH is not reaching goal.
      • Salicylate concentrations may be falsely negative until at least 4 – 6 hours after ingestion
      • Pay attention to units. Most labs report salicylate concentrations in mg/dL but some report in mcg/mL or mg/L. Failure to recognize this difference can result in a ten-fold error and be harmful to patients.

Lithium

    • Green top lab test collection tubes typically contain lithiated-heparin that can cause a false positive (up to an additional 4 mEq/L) if a lithium concentration is collected in that tube.5

Acetaminophen6

    • Acetaminophen concentrations collected prior to four hours after ingestion are not helpful in guiding therapy for acetaminophen overdoses. The decision to administer N-acetylcysteine (NAC) is decided by where the acetaminophen concentration collected four hours (or more) after ingestion falls on the Rumack-Matthew nomogram.  Concentrations obtained before 4 hours, either high or low, do not correlate well with a 4-hour concentration and do not predict hepatotoxicity.
      • Further, NAC administration has consistently been shown to provide substantial benefit in preventing hepatotoxicity as long as it is administered within eight hours of ingestion, so there is no need to collect an acetaminophen concentration prior to four hours of known or estimated time of ingestion.
    • The United States empirically reduced the treatment line of the Rumack-Matthew nomogram from 200 mcg/ml to 150 mcg/ml at 4 hours to provide a margin of safety. Therefore, the treatment line on the Rumack-Matthew nomogram is quite sensitive, and it is highly unlikely for a patient who falls below the treatment to be at risk for acetaminophen-induced hepatotoxicity.

References

  1. Wiener SW. Toxic Alcohols. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank's Toxicologic Emergencies, 11e. McGraw Hill; 2019. Accessed October 29, 2022. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2569&sectionid=210275462.
  2. Hauvik LE, Varghese M, Nielsen EW. Lactate Gap: A Diagnostic Support in Severe Metabolic Acidosis of Unknown Origin. Case Rep Med. 2018;2018:5238240. Published 2018 Jul 24. doi:10.1155/2018/5238240.
  3. Grunbaum AM, Rainey PM. Laboratory Principles. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank's Toxicologic Emergencies, 11e. McGraw Hill; 2019. Accessed October 29, 2022. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2569&sectionid=210267566.
  4. Lugassy DM. Salicylates. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank's Toxicologic Emergencies, 11e. McGraw Hill; 2019. Accessed October 30, 2022. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2569&sectionid=210270941.
  5. Greller HA. Lithium. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank's Toxicologic Emergencies, 11e. McGraw Hill; 2019. Accessed October 29, 2022. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2569&sectionid=210274851.
  6. Hendrickson RG, McKeown NJ. Acetaminophen. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank's Toxicologic Emergencies, 11e. McGraw Hill; 2019. Accessed October 30, 2022. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2569&sectionid=210270383.
Author: Khalil Ford, PharmD, PGY2 Emergency Medicine Pharmacy Resident, University of Utah Health
Poison Control