Tag Archives: toxicology

Treatment for Salicylate Poisoning

Author: Sean Kolowich (Emory University School of Medicine) // Edited by: Cynthia Santos, MD (Senior Medical Toxicology Fellow, Emory University School of Medicine), Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)


Case presentation:

A 53 year-old previously healthy female is brought into the ED by family members 4 hours after ingesting 100 tablets of aspirin (325mg, unknown formulation). She has no complaints and denies any co-ingestions. VS: Temp 98.1 (oral), HR 93, BP 136/87, RR 20, pulse ox 98% on room air. CMP and ECG are unremarkable, ASA 47.1 mg/dL, ABG pH 7.48, pCO2 20, pO2 122.


What treatments should a salicylate poisoned patient receive?


Patients with salicylate poisoning should receive IV bicarb to alkalinize the urine. Indications for hemodialysis include cerebral edema, pulmonary edema, renal failure, intractable acidosis, clinical deterioration, or ASA level > 100 mg/dL or > 70 mg/dL if chronic.

  • Support ABCs, prevent further organ toxicity by encouraging salicylate elimination
    • Alkalinize the serum/urine
      • 1-2 mEq/kg sodium bicarb. IV bolus followed by sodium bicarb. infusion (3 amps into 1L D5W) @ 1.5-2 X maintenance rate
        • goal serum pH ~7.5
        • goal urine pH >7.5
  • Salicylate overdose + IV sodium bicarbonate therapy = potential hypokalemia
    • Avoid hypokalemia because it prevents alkalization of the urine ® prolonged elimination of salicylate
      • goal K+ 4.0 to 4.5 mEq/L
    • Monitor calcium levels (ionized/total); IV NaHCO3 can cause hypocalcemia
  • Consider glucose supplementation if altered mental status
    • Serum glucose may be normal but CNS levels may be low 2/2 effects of salicylates
  • Indications for extracorporeal treatment (intermittent hemodialysis is ECTR of choice):
    • Salicylate level > 100 mg/dL (> 90 mg/dL if impaired kidney function) or > 70 md/dL if chronic.
    • Cerebral edema (altered mental status, seizures)
    • Renal failure
    • Pulmonary edema or new hypoxemia requiring supplemental O2
    • IF standard therapy fails AND:
      • Salicylate level > 90 mg/dL (> 80 mg/dL if impaired kidney function)
      • Systemic pH < 7.20
  • Continue IV sodium bicarb therapy b/w ECTR sessions
Main Point:

Patients presenting with acute salicylate toxicity should receive supportive care and alkalinization with IV sodium bicarbonate. Hemodialysis should be considered early in treatment and is indicated if there is evidence of end organ damage (AMS, ARDS), failure of standard therapy, or severely elevated salicylate levels.



  1. Lugassy DM. Salicylates. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. Eds. Goldfrank’s Toxicologic Emergencies, 10e. New York, NY: McGraw-Hill; 2015.
  2. Levitan R, Lovecchio F. Salicylates. In: Tintinalli JE, Stapczynski J, Ma O, Yealy DM, Meckler GD, Cline DM. eds. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e. New York, NY: McGraw-Hill; 2016.
  3. Juurlink DN, Gosselin S, Kielstein JT, et al. Extracorporeal Treatment for Salicylate Poisoning: Systematic Review and Recommendations From the EXTRIP Workgroup. Ann Emerg Med 2015; 66:165

Tox Cards: Narcan (naloxone)

Author: Cynthia Santos, MD (Senior Medical Toxicology Fellow, Emory University School of Medicine) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)


Case presentation:

25-year-old M brought in by EMS after being found not breathing, pupils are pinpoint. HR 61, BP 109/40, RR 6, T98, O2 Sat 70% RA. You ask for Narcan (Naloxone).


What dose Narcan should you give?


Start with small doses, i.e. 0.04 mg, and not the standard dose of 0.4 mg IV/IM.

  • The use of copious amounts of naloxone can precipitate opioid withdrawal.
  • Precipitated opioid withdrawal to an opioid-dependent person does not only cause patient distress and complicate care, but it can be life threatening.
  • Patients with precipitated opioid withdrawal (unlike regular opioid withdrawal) are at risk of seizures and arrhythmias.
  • The often referenced ‘standard dose’ and the dose usually given by EMS is 0.4 mg via the IV or IM route.
  • Although this ‘standard dose’ will reverse opioid-induced respiratory depressant effects in non-opioid-dependent patients, it can precipitate withdrawal in opioid-dependent persons.
  • Life-threatening complications like tonic-clonic seizure, and significant hypotension have occurred with IV/IM doses of 0.2 mg – 1.2 mg.[1, 2, 3]
  • Although severe life-threatening reactions after naloxone administration are relatively rare, it usually occurs when the ‘standard’ naloxone dose of 0.4mg IV/IM is given.

 Main Point:

Naloxone can be lifesaving. However, given the high prevalence of opioid addiction and the rare but potentially dangerous complication of precipitated opioid withdrawal, the use of initial small escalating doses of naloxone can avoid the development of precipitated opioid withdrawal. An appropriate strategy is to start with 0.04 mg and titrate up every 2-3 minutes as needed for ventilation to 0.5 mg, 2 mg, 5 mg, up to a maximum of 10-15 mg.[4, 5]



  1. Buajordet I., Næss A., Jacobsen D., Brørs O. Adverse events after naloxone treatment of episodes of suspected acute opioid overdose. Eur J Emerg Med. 2004;11: 19–23.
  2. Osterwalder J. Naloxone – for intoxications with intravenous heroin and heroin mixtures – harmless of hazardous? A prospective clinical study. Clin Toxicol. 1996;34: 409–416.
  3. Yealy DM, Paris PM, Kaplan RM, Heller MB, Marini SE. The safety of prehospital naloxone administration by paramedics. Ann Emerg Med. 1990; 19(8): 902-5.
  4. Boyer EW: Management of opioid analgesic overdose. N Engl J Med. 2012; 367:146-155).
  5. Kim HK, Nelson LS. Reversal of Opioid-Induced Ventilatory Depression Using Low-Dose Naloxone (0.04 mg): a Case Series. J Med Toxicol. 2016; 12(1):107-10.



Hydrofluoric Acid: The Burn that keeps on Burning

Authors: Brian Murray, DO (@bpatmurray, EM Senior Resident, SAUSHEC, USAF) and Brit Long, MD (@long_brit, EM Attending Physician, SAUSHEC) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

screen-shot-2016-12-04-at-5-29-47-pmA 40-year-old man presented to the Emergency Department with the complaint of pain to his right hand. Three-hours prior he had been using rust remover to clean the air-conditioning unit in his house. Now the patient has exquisite pain to his distal thumb, index finger, and middle fingers.


Figure 1 A & B: Two images of the affected fingers showing A) the bluish hue of the blanched right index finger with incisions used to relieve the pressure of local infusion of 10% calcium gluconate into the tips of the fingers and B) the arterial catheter placed for arterial infusion of 10% calcium gluconate.


Hydrofluoric acid (HF) is one of the most dangerous corrosive inorganic acids due to its ability to destroy body tissue.1 It is well known for its ability to dissolve silica and glass and is used in numerous industrial processes (e.g. glass etching, brick cleaning, microchip etching, electroplating, and leather tanning) and even as an active ingredient in several household chemicals such as rust remover, aluminum brighteners, and heavy-duty cleaners.2 Industrial HF can be as concentrated as 100%, termed anhydrous, while the household variants are usually no more concentrated than 10-40% HF. However, due to the local, and potentially systemic effects of HF, even dilute HF has the potential to cause significant morbidity and mortality.3 From 2011 – 2014 the American Association of Poison Control Centers reported over 2000 HF exposures and 4 deaths.4,5,6,7 Deaths have been reported with exposures of 100% HF covering as little as 2.5% total body surface area.8 One of these deaths was due to the ingestion of 1 oz of dilute 1.92% HF which caused severe fluorosis, hypocalcemia, and ultimately death due to ventricular fibrillation.4


HF burns are more damaging and serious than other acidic burns because it causes tissue damage through two distinct mechanisms. The first, common to all acids, is by the rapid release of hydrogen ions and subsequent tissue dehydration and coagulation necrosis.9 HF is a weak acid with a pKa of 3.20. By comparison, the pKa of citric acid if 3.13 and the pKa of sulfuric acid is <-2 (considered a strong acid),10 and HF is approximately 1000 times less disassociated than equimolar strong acids such as hydrochloric acid.11 This acidic burn generated by free hydrogen ions is relatively insignificant compared to its second mechanism: the release of the highly reactive free fluoride ion, F, after the uncharged HF molecule penetrates deeply into the underlying tissue.9 The F causes liquefaction necrosis and creates strong bonds with calcium and magnesium forming the insoluble salts CaF2 and MgF2. Potassium ions are released from the peripheral nerve endings in response to Ca2+ depletion, which produces the severe pain classically associated with HF exposure.2

The severity of the burn is a product of the concentration, the surface area involved, and the time of exposure. Because HF is a weak acid, there may be a delay of up to several hours with dilute concentrations.9 Concentrations exceeding 50% almost always result in immediate pain due to the corrosive action of hydrogen ion disassociation.12 This delay can lead to deep penetration of HF before exposure is identified, increasing exposure time and tissue damage due to the F ion. This also allows for greater potential for systemic toxicity. Systemic symptoms occur from hypocalcemia and hypomagnesemia in response to systemic fluorosis after the absorption of a significant amount of HF. However, a significant amount is a relative term as massive exposure and death can result from as little as a 1% total body surface area from a >50% hydrofluoric acid solution, or exposure of >5% total body surface area of hydrofluoric acid of any concentration.13 When death does occur, it is typically due to dysrhythmia secondary to profound hypocalcemia and hypomagnesemia,14 as well as hyperkalemia caused by an efflux of potassium ions from cells due to hypocalcemia.15

Aside from dermal toxicity, patients can be poisoned though inhalation/pulmonary, ingestion/gastrointestinal, and ocular routes as well. Patients exposed to very low-concentration HF fumes may experience minor respiratory tract irritation,16 while inhalation of more concentrated fumes can lead to throat burning and shortness of breath leading to hypoxia and systemic hypocalcemia.17 Given the high propensity for evaporation, especially in concentrations greater than 60% which have boiling points around or below room temperature, inhalation injury should be assessed in all patients with cutaneous burns, especially those with exposures that involve the head and neck.18  Clothing soaked in HF can also produce deadly concentrations of inspired HF.19 Frequently, pulmonary exposures are also associated with ocular exposures, and as such patients should be evaluated for occult HF ocular injuries.11

Ingestion of any concentration of HF causes significant gastritis, and patients will promptly develop pain and vomiting. Systemic symptoms and death nearly always follow due to the high surface area involved, the extended time of contact, and the high degree of absorption, although actual absorption occurs rapidly along with the development of systemic symptoms and fatal dysrhythmias.2 Patients may present with altered mental status, airway compromise, and dysrhythmia.11 There is one case report of a person who ingested 8% HF, suffered multiple episodes of ventricular fibrillation, and was successfully resuscitated.20 This is the exception and not the norm, as ingestion of HF is almost universally fatal.2,11

Ocular exposures to HF typically cause more extensive damage to ocular tissue than other acids.21 HF, either by liquid splashes or exposure to HF gas, causes corneal and conjunctival epithelial denuding, leading to stromal corneal edema, conjunctival ischemia, sloughing, and chemosis. Fluoride ions penetrate deeply within the anterior chamber leading to corneal opacification and necrosis of the anterior chamber structure.2 Usually the effects are noted within one day, however case reports have noted situations where corneal damage was not apparent until 4-days post exposure.22 Long-term complications include corneal ulcers.11


All exposures should be discussed with a toxicologist.  Initial evaluation consists of a thorough history and physical, particularly to the chemical used (to help in identification of the HF concentration), the time of exposure, and the area of exposure.2 Laboratory evaluation of patients poisoned with HF consists of monitoring serum electrolytes, particularly ionized calcium, magnesium, and potassium.23 Additionally, as toxicity progresses, a venous blood gas may be useful, as metabolic acidosis may develop.  An ECG should be obtained and trended over time to assess for clinically significant hypocalcemia (prolonged QT interval) and hyperkalemia (peaked T-waves). Serum fluoride levels can be obtained, but will often lag behind clinically significant levels.11


The first treatment that should be performed, as with any chemical exposure, is removing soaked clothing and copious irrigation with water.1,9 This would ideally be performed immediately upon contact with HF, helping to reduce the risk of acidic burn and deeper penetration, but it will have some benefit even if performed later.

Cutaneous Exposures

There are three levels of treatment specific for HF burns. The first is to topically apply a 2.5% calcium gluconate slurry, which is made by mixing 3.5 gm of calcium gluconate in 5 oz of a water based lubricant such as Surgilube® or K-Y Jelly®. This treatment has excellent efficacy at preventing further tissue damage and decreasing pain, especially if used soon after the exposure. Putting a glove over the exposed hand when using the calcium slurry can help keep the gel in place and prevent loss of the calcium. It has limited ability to penetrate to deeper tissues and only helps to neutralize superficial HF.1,2,9

If topical calcium is not effective at treating the patient’s pain after 30 minutes and the area of tissue damage continues to increase, local infiltration with 5-10% calcium gluconate, not exceeding 0.5 ml per cm2 of affected body surface area, is used (the only currently available dosing recommendation in the literature).2,9,11,13 This method is more effective at treating deeper exposures. Calcium gluconate is used instead of calcium chloride, as calcium chloride is irritating and toxic to local tissue. If infiltration is going to be performed in the pads of the fingers, a prophylactic fasciotomy is recommended to prevent compartment syndrome from the injection of a large amount of fluid into a small compartment.1,2,9

If the pain is still not controlled, intra-arterial infusion of 10 ml of 10% calcium gluconate or calcium chloride (in 40-50 ml 5% dextrose) over 4 hours will allow large amounts of calcium to be delivered directly to the damaged tissue, and this infusion can be repeated until the patient is pain free.2,9,24

Systemic calcium and magnesium depletion should be treated by replacing the depleted electrolytes.9

Ocular Exposures

The most important step in the treatment of ocular HF exposure is early irrigation with 1L normal saline, lactated ringer solution, or sterile water. The use of 1% calcium gluconate eye drops is controversial, with some reports showing benefit.25,26,27,28,29  However, it can also be irritating to the eye and toxic to subconjunctiva, and sufficient evidence to support its recommended use over saline irrigation alone is lacking.2,11 Prompt ophthalmologic evaluation is essential after irrigation.

Ingestion Exposures

Ingestion of HF is almost universally fatal11 and are frequently associated with dermal exposure and inhalation exposures. If the ingestion occurred <2 hours prior to evaluation, it is recommended to pass a nasogastric tube for decontamination.13 The addition of 10% calcium gluconate to the lavage fluid may help neutralize the remaining fluoride ions that have not yet absorbed.13,30 Aggressive systemic therapy is indicated, and gastroenterology evaluation is necessary to address local tissue damage.11

Inhalation Exposures

The primary treatment for inhalation exposures is 4ml of nebulized 2.5-5% calcium gluconate.31,32 This is a benign therapy and is recommended to be given to all patients with symptomatic inhalational exposures.33 Attention should be paid to the patient’s airway and ability to maintain adequate oxygen saturation, as tracheobronchopulmonitis and local edema may impair both.34 Corticosteroids and antibiotics are not routinely recommended for all patients and should only be administered in coordination with a Medical Toxicologist.35 The systemic absorption of fluoride from inhalation exposures is extremely rapid and carries a high risk of systemic toxicity, even from relatively dilute concentrations.36

Case Outcome

The chemical was compound the patient was using was Condenser Coil Brightener and Cleaner (compound 90-920) that he had purchased online.  90-920 contains 10% HF solution, and therefore the patient did not begin to feel pain until 3 hours post exposure. Topical calcium and local infusion of calcium were not sufficient to control his pain and an intra-arterial catheter was placed and an infusion of 10% calcium gluconate was started. The patient was admitted to the burn ICU, where he eventually required excision of the tips of his fingers due to tissue necrosis. He otherwise experienced an uneventful recovery.


  • The F ion causes significant tissue damage and pain through formation of insoluble salts and calcium depletion.
  • Even small burns with concentrated HF can lead to significant systemic toxicity and death.
  • Electrolytes, VBG, and ECG are necessary in the evaluation.
  • The Toxicology service must be consulted.
  • Treatment with 2.5% topical calcium gluconate, 0.5 ml/cm2 of 10% calcium gluconate, and 10ml of 10% calcium gluconate or chloride in 40-50 ml 5% dextrose over 4 hours may be needed to neutralize the F


References/Further Reading

  1. Anderson WJ, Anderson JR. Hydrofluoric acid burns of the hand: mechanism of injury and treatment. The Journal of hand surgery. 1988;13(1):52–7.
  2. Kirkpatrick JJ, Enion DS, Burd DA. Hydrofluoric acid burns: a review. Burns. 1995 Nov;21(7):483–93.
  3. Department of Health and Human Services. NIOSH Skin Notation Profiles: Hydrofluoric Acid. CDC. 2011. Accessed online: https://www.cdc.gov/niosh/docs/2011-137/ on 18 Nov 2016
  4. Bronstein AC, Spyker DA, Cantilena LR Jr, Rumack BH, Dart RC. 2011 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 29th Annual Report. Clinical Toxicology. 2012 Dec 7;50(10):911–1164.
  5. Mowry JB, Spyker DA, Cantilena LR Jr, Bailey JE, Ford M. 2012 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 30th Annual Report. Clinical Toxicology. 2013 Dec 8;51(10):949–1229.
  6. Mowry JB, Spyker DA, Cantilena LR Jr, McMillan N, Ford M. 2013 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 31st Annual Report. Clinical Toxicology. 2014 Oct 6;52(10):1032–283.
  7. Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015;53(10):962–1147.
  8. Tepperman PB. Fatality due to acute systemic fluoride poisoning following a hydrofluoric acid skin burn. J Occup Med. 1980;22:691-2.
  9. Bertolini JC. Hydrofluoric acid: a review of toxicity. J Emerg Med. 1992;10(2):163–8.
  10. “Appendix C: Dissociation Constants and pKa Values for Acids at 25°C”, appendix 3 from the book Principles of General Chemistry (v. 1.0) Accessed at: http://2012books.lardbucket.org/books/principles-of-general-chemistry-v1.0/s31-appendix-c-dissociation-consta.html on 10 November 2016
  11. Su M. Hydrofluoric Acid. In: Goldfrank’s Toxicologic Emergencies, 10e. 2016.
  12. Sheridan RL, Ryan CM, Quinby WC, Blair J, Tompkins RG, Burke JF. Emergency management of major hydrofluoric acid exposures. Burns. 1995 Feb;21(1):62–4.
  13. Hatzifotis M, Williams A, Muller M, Pegg S. Hydrofluoric acid burns. Burns. 2004 Mar;30(2):156–9.
  14. Yamaura K, Kao B, Iimori E, Urakami H, Takahashi S. Recurrent ventricular tachyarrhythmias associated with QT prolongation following hydrofluoric acid burns. Journal of Toxicology: Clinical Toxicology. 1997 Jan 1;35(3):311-3.
  15. Mclvor ME, Cummings CE, Mower MM, Wenk RE, Lustgarten JA, Baltazar RF, Salomon J. Sudden cardiac death from acute fluoride intoxication: the role of potassium. Annals of emergency medicine. 1987 Jul 31;16(7):777-81.
  16. Lee DC, Wiley JF II, Synder JW II. Treatment of inhalational exposure to hydrofluoric acid with nebulized calcium gluconate. J Occup Med. 1993;35:470.
  17. Wing JS, Brender JD, Sanderson LM et al. Acute health effects in a community after a release of hydrofluoric acid. Arch Environ Health. 1991;46:155–160.
  18. MacKinnon MA. Hydrofluoric acid burns. Dermatologic clinics. 1988 Jan;6(1):67-74.
  19. Mayer L, Guelich J. Hydrogen fluoride (HF) inhalation and burns. Archives of Environmental Health: An International Journal. 1963 Oct 1;7(4):445-7.
  20. Stremski ES, Grande GA, Ling LJ. Survival following hydrofluoric acid ingestion. Ann Emerg Med. 1992;21:1396–1399.
  21. McCulley JP, Whiting DW, Petitt MG, Lauber SE. Hydrofluoric acid burns of the eye. J Occup Med. 1983;25:447–450.
  22. Hatai JK, Weber JN, Doizaki K. Hydrofluoric acid burns of the eye: report of possible delayed toxicity. Journal of Toxicology: Cutaneous and Ocular Toxicology. 1986 Jan 1;5(3):179-84.
  23. Greco RJ, Hartford CE, Haith Jr LI, Patton ML. Hydrofluoric acid-induced hypocalcemia. Journal of Trauma and Acute Care Surgery. 1988 Nov 1;28(11):1593-6.
  24. Vance MV, Curry SC, Kunkel DB, Ryan PJ, Ruggeri SB. Digital hydrofluoric acid burns: treatment with intraarterial calcium infusion. YMEM. 1986 Aug;15(8):890–6.
  25. Bentur Y, Tannenbaum S, Yaffe Y, Halpert M. The role of calcium gluconate in the treatment of hydrofluoric acid eye burn. Ann Emerg Med. 1993;22:1488–1490.
  26. Dunser MW, Ohlbauer M, Rieder J et al. Critical care management of major hydrofluoric acid burns: a case report, review of the literature, and recommendations for therapy. Burns. 2004;30:391–398.
  27. Hatzifotis M, Williams A, Muller M, Pegg S. Hydrofluoric acid burns. Burns. 2004;30:156–159.
  28. Trevino MA, Herrmann GH, Sprout WL. Treatment of severe hydrofluoric acid exposures. Journal of Occupational and Environmental Medicine. 1983 Dec 1;25(12):861-3.
  29. Bentur Y, Tannenbaum S, Yaffe Y, Halpert M. The role of calcium gluconate in the treatment of hydrofluoric acid eye burn. Annals of emergency medicine. 1993 Sep 30;22(9):1488-90.
  30. Caravati EM. Acute hydrofluoric acid exposure. The American journal of emergency medicine. 1988 Mar 1;6(2):143-50.
  31. Kono K, Watanabe T, Dote T et al. Successful treatments of lung injury and skin burn due to hydrofluoric acid exposure. Int Arch Occup Environ Health. 2000;73(suppl):S93–S97.
  32. Lee DC, Wiley JF II, Synder JW II. Treatment of inhalational exposure to hydrofluoric acid with nebulized calcium gluconate. J Occup Med. 1993;35:470.
  33. Dunser MW, Ohlbauer M, Rieder J et al. Critical care management of major hydrofluoric acid burns: a case report, review of the literature, and recommendations for therapy. Burns. 2004;30:391–398.
  34. Upfal M, Doyle C. Medical management of hydrofluoric acid exposure. Journal of Occupational and Environmental Medicine. 1990 Aug 1;32(8):726-31.
  35. Flood S. Hydrofluoric acid burns. American family physician. 1988;37(3):175-82.
  36. Watson AA, Oliver JS, Thorpe JW. Accidental death due to inhalation of hydrofluoric acid. Medicine, Science and the Law. 1973 Oct 1;13(4):277-9.

FOAMed Resource Series Part IV: Toxicology

Author: Brit Long, MD (@long_brit, EM Attending Physician, SAUSHEC) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW Medical Center / Parkland Memorial Hospital)

Today we cover Part IV of the FOAMed series: Toxicology. Prior posts have evaluated ECG (http://www.emdocs.net/foamed-resource-series-part-ecg/), ultrasound (http://www.emdocs.net/foamed-resource-series-part-ii-ultrasound/), and pediatrics (http://www.emdocs.net/foamed-resource-series-part-iii-pediatrics/). Toxicology is an ever-expanding subject, as new substances with potential for abuse and overdose are consistently being discovered. EM providers not only need to understand classic toxicology such as salicylate and acetaminophen overdose, but also new agents such as the synthetic opioid U-47700. FOAMed provides a means to accomplish this.

The following list is comprised of blogs/podcasts with great education pearls, valid contact, and major impact on EM, with clear reference citation. This list is not all-encompassing, and if you have found other great resources, please mention them in the comments below!


  1. http://www.thepoisonreview.com


The Poison Review from Dr. Leon Gussow is a site that provides “critical update and evaluation of recent scientific literature, news stories, and cultural events related to the field of medical toxicology.” The site is updated almost weekly, and literature is graded based on “skulls.” This is a must-read resource for those interested in toxicology and if you want to stay updated with the most recent literature.

  1. http://lifeinthefastlane.com/tox-library/


The toxicology library at LIFTL is a great resource, especially while on shift. The website contains several great features. “Tox Tutes” are 10-30 minute podcasts covering toxicology basics and literature updates, “Basic Science” provides a framework for understanding of toxicology, Cases with “Tox Conundrums,” and finally “Toxicology Basics” provides the basics of management.  Several lists (antidotes, toxins, venoms, and more) are provided for quick reference. LIFTL again hits it out of the park with this resource.

  1. http://toxnow.org


ToxTalk is a podcast from Matt Zuckerman. The podcast provides entertaining education in the form of cases and literature updates of common ingestions facing EM providers. Unfortunately, show notes are not provided for the podcast, but we can’t help but love the content of the podcasts.

  1. http://www.ohsu.edu/emergency/education/podcast/


The Oregon Poison Center provides weekly conferences that are broadcast in podcast form, providing pearls on evaluation and management of a multitude of ingestions/overdoses. The goal audience includes medical students, nurses, residents, attendings, and fellows. Podcasts also cover literature updates, with article listings provided.

  1. http://www.acmt.net/ACMTPodcasts.html


This site from the American College of Medical Toxicology is extremely useful through the provision of guidelines, antidote card, and a podcast. The site contains several vital resources for EM providers everywhere, and the antidote card is particularly useful – http://www.acmt.net/_Library/Membership_Documents/ACMT_Antidote_Card_May_2015.pdf

  1. https://emin5.com/archives/


Yes, EMin5 from Dr. Anna Pickens makes our FOAMed list again. The succinct 5 minute videos on toxicology topics provide a foundation for learners of all stages. The site currently contains content on acetaminophen, salicylates, calcium channel blockers, cyanide, digoxin, laundry detergent pod, and tricyclic antidepressants.

  1. http://curriculum.toxicology.wikispaces.net


This is a great resource with a large number of different components. Separate pages cover core information on the toxicology history and examination, as well as complete information on separate toxins. Pages are broken into toxidromes, natural toxins, drug and alcohol issues, and chemicals. The quality of information is similar to an online encyclopedia right at your fingertips.

Thanks for reading! If you’ve found other resources, please let us know. Stay tuned for the next installment: critical care.

Drug Withdrawal: Pearls and Pitfalls

Authors: Drew A. Long, BS (@drewlong2232, Vanderbilt University School of Medicine, US Army) and Brit Long, MD (@long_brit, EM Attending Physician at SAUSHEC, USAF) // Edited by: Courtney Cassella, MD (@Corablacas, EM Resident Physician, Icahn SoM at Mount Sinai) and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

Case 1: A 45-year-old male presents to the ED with one day of myalgias, sweating, and anxiety. He is tachycardic and appears uncomfortable.  On examination, you notice lacrimation, excessive yawning, and a significant tremor.  He denies any illicit drug use, but he does have a history of chronic back pain for which he uses oxycodone. However, he ran out of oxycodone three days ago.

 Case 2: A 33-year-old female presents to the ED feeling depressed.  She has also been sleeping 16 hours per day and experiencing extreme hunger. She is trying to stop meth, for which her boyfriend was recently incarcerated.  Her examination and vital signs are normal, but she wants to know if she needs to be concerned about her symptoms, and more importantly, what she can do to feel better.


This is the second of a two-part series covering withdrawal states. Our first post evaluated the diagnosis and management of alcohol withdrawal. This second discussion will not be all encompassing, but it will cover the more commonly abused agents.



The incidence of opioid abuse has risen drastically in the United States.  Worldwide, between 26.4 million and 36 million people abuse opioids.1 In 2012, an estimated 2.1 million people in the United States had prescription opioid substance use disorders.2 The number of prescription opioids has escalated from an estimated 76 million people in 1991 to 207 million in 2013.3 Specifically, the number of heroin users has increased from 373,000 in 2007 to 681,000 in 2013.4 Along with this increase in opioid prescriptions and opioid abuse, the number of people dependent on opioids and number of opioid overdoses have also increased.

screen-shot-2016-09-10-at-12-11-58-amOpioids are most commonly used for pain management.  Opioids act on transmembrane neurotransmitter receptors (mu, kappa, delta) coupled to G proteins.  These receptors are located in both the central and peripheral nervous systems.  When these receptors are stimulated by opioids, the signal transduction pathway leads to the effects of analgesia in addition to triggering the reward center.5

Opioid withdrawal occurs when a person who is physiologically dependent on opioids either reduces or abruptly stops using opioids.  The diagnosis of opioid withdrawal is made by the history and physical exam.  The signs and symptoms of opioid withdrawal are often vague and nonspecific.  While opioid withdrawal may be uncomfortable, it is rarely life-threatening.  Broad categories of manifestations include gastrointestinal distress, flu-like symptoms, and sympathetic nervous system arousal, which are categorized in Table 1.6


Other common symptoms of opioid withdrawal include yawning, sneezing, dizziness, myalgias, arthralgias, and leg cramps.  While not always present, yawning and lacrimation are helpful due to high specificity for opioid withdrawal.7

The course of opioid withdrawal greatly depends upon which opioid the patient was using.  An opioid must be consumed daily for 3 weeks or more for the patient to become physiologically dependent.  The withdrawal period typically lasts two to three times the half-life of the opioid.6 Characteristics of commonly abused opioids are shown in Table 2. screen-shot-2016-09-10-at-12-15-48-am

A thorough history and physical is vital when assessing a patient suspected of undergoing opioid withdrawal.  Concomitant substance use disorders, mental disorders, and other disorders are common in patients with opioid use disorder.  Nicotine use has been associated with up to 85% of patients undergoing opioid withdrawal.  Mental disorders may be found in up to 70% of patients undergoing opioid withdrawal.  These include major depression, panic disorder, general anxiety disorder, and post traumatic stress disorder.9-11 A systemic review found a prevalence of co-occurring depressive disorders to be 27% and co-occurring anxiety disorders to be 29%.12 It is important to consider that opioid withdrawal may exacerbate co-occurring mental disorders.  Other disorders to consider include comorbid alcohol and benzodiazepine withdrawal, comorbid cocaine and methamphetamine withdrawal, or personality disorders.

Mimics of opioid withdrawal include other intoxication or withdrawal syndromes.  As opioid users usually have insight into their addiction, the history is often enough to establish a diagnosis.  Several other withdrawal syndromes, specifically ethanol and sedative-hypnotic withdrawal, may appear similar to opioid withdrawal.  However, these are much more likely to cause significant tachycardia and hypertension compared to opioid withdrawal.  Additionally, these syndromes may produce seizures and/or hyperthermia.  Another syndrome that may mimic opioid withdrawal is sympathomimetic intoxication.  However, similar to ethanol and sedative-hypnotic withdrawal, this syndrome produces much more severe findings (mydriasis, agitation, tachycardia, hypertension) than opioid withdrawal.7

Opioid withdrawal is not life-threatening, and the mainstay of treatment is management of symptoms.  Patients suffering from opioid withdrawal can undergo medically supervised opioid withdrawal (detoxification).  Symptoms from withdrawal can be managed with multiple agents, including opioids and non-opioids.  Popular agents utilized for managing opioids withdrawal include methadone and buprenorphine.  Methadone is a long-acting opioid, while buprenorphine is a partial opioid agonist.7  Methadone, which may be used in a psychiatric setting, is not an option for ED providers due to inability for patient follow up in the ED setting and risk of overdose.  Buprenorphine is a partial opioid receptor agonist with high affinity. These properties provide a lower risk of respiratory depression which, along with its long duration of action, make it an effective and safe therapy for opioid withdrawal. However, its use is also controversial. This medication is a synthetic agent with less abuse potential and dependence, acting as a partial agonist. If a patient is opioid dependent and given this medication, withdrawal will occur, as buprenorphine has higher receptor affinity and less activity than other opioids.  It is approved in the U.S. for outpatient treatment of opioid dependence, given once daily. Providers are required to have a special waiver from the DEA to prescribe this medication.



Benzodiazepines (BZDs) are sedative-hypnotic agents used for sedation and treatment of anxiety, seizures, withdrawal states, and insomnia.  BZDs act via modulation of the gamma-aminobutyric acid A (GABA-A) receptor, which is the main inhibitory neurotransmitter of the central nervous system.13


BZD withdrawal occurs when any chronic user abruptly decreases or ceases BZD consumption.  Rapid recognition and management of BZD withdrawal is vital as it can be life-threatening.  The signs and symptoms of BZD withdrawal are similar to those associated with withdrawal from other sedative-hypnotics (barbiturates, alcohol, etc.).  Milder symptoms of BZD withdrawal can include headache, nausea, vomiting, tremors, insomnia, agitation, and anxiety.  More severe symptoms may include hallucinations, psychotic behavior, altered mental status, and seizures.  Seizures, while uncommon, are a feared complication of benzodiazepine withdrawal.13,14

Like opioids, the timing of symptoms varies according to the half-life of the BZD involved.  Table 3 depicts the half-life of commonly abused BZDs.  In patients abusing BZDs with shorter half-lives (such as Xanax, Ativan, and Versed) withdrawal symptoms may occur in 1-2 days, while withdrawal symptoms from BZDs with longer half-lives may occur up to two weeks after cessation.15,16


Management of BZD withdrawal depends first on accurate diagnosis by history and characteristic signs and symptoms described above. After identifying withdrawal, treatment should be initiated with a BZD that has a prolonged clinical effect, such as diazepam.18-20 This BZD should be administered intravenously with a goal of eliminating symptoms of withdrawal without causing excessive sedation.  Patients undergoing withdrawal experiencing milder symptoms may be treated with a long-acting oral BZD.  While other agents have been used to treat BZD withdrawal (such as beta blockers, antipsychotics, SSRIs, and antihistamines), they have all been shown to be inferior with standard treatment.18,20 Valproic acid and carbamazepine have not shown any additional benefit and have not been extensively studied to be included in the standard management of BZD withdrawal.21,22

There are several scales for monitoring BZD withdrawal.  The Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) and Clinical Institute Withdrawal Assessment Scale-Benzodiazepines (CIWA-B) are two of the more commonly utilized scales.  The BWSQ is a 20-item self-report, validated questionnaire, while the CIWA-B uses 22-items to assess and monitor the severity of symptoms from withdrawal.  While these scales are helpful, they should not be solely relied upon to monitor complicated withdrawal.  Monitoring of withdrawal should always include careful observation and evaluation of the patient in addition to the Emergency Physician’s clinical judgment.23



Cocaine is a stimulant associated with many life-threatening complications, including seizure, stroke, and myocardial infarction.  Cocaine exerts its effect by enhancing monoamine neurotransmitters in the brain (dopamine, norepinephrine, and serotonin) via blockade of presynaptic reuptake of these neurotransmitters, both in the central and peripheral nervous systems.24


Withdrawal from cocaine, while uncomfortable, is not life-threatening.  The cocaine withdrawal syndrome is highlighted by prominent psychological features.  These include depression, anxiety, fatigue, difficulty concentrating, anhedonia, increased appetite, increased sleep, increased dreaming, and increased craving for cocaine.25,26  Intense symptoms at the beginning of the withdrawal period (the crash) may occur, which may include psychomotor retardation and severe depression with suicidal ideation.  Signs of cocaine withdrawal are typically minor and include musculoskeletal pain, tremors, chills, and involuntary motor movement.27Another potential complication of withdrawal includes myocardial ischemia, which is most commonly seen in the first week of withdrawal.28

Treatment for cocaine withdrawal is mainly supportive, including encouraging the patient to sleep and eat as necessary (especially if the patient is experiencing hypersomnia and increased appetite).29 No drugs have been shown to be beneficial in treating cocaine withdrawal.  For patients with severe agitation or insomnia, a short acting benzodiazepine may be helpful.  Patients with depression lasting several weeks or suicidal ideation may require admission to a psychiatric unit and treatment with antidepressants.29,30 As the relapse risk is high during the early withdrawal period, patients should be referred to an addiction treatment program for further support in abstaining from cocaine use.  Discharge from the ED is appropriate if the patient is stable with no other psychiatric concerns (severe depression, suicidal thoughts, etc.).



Similar to cocaine, methamphetamine is a stimulant that causes the release of monoamine neurotransmitters, while also blocking reuptake.  Amphetamine-type stimulants are the fastest rising drug of abuse worldwide and the second most widely used class of illicit drugs worldwide.31-33 Individuals with chronic amphetamine use have a high incidence of comorbid psychiatric disorders, including primary psychotic disorder, mood disorder, anxiety disorders, and ADHD.34 Depressive symptoms also commonly occur with methamphetamine use.35


Opposed to the euphoric effect of methamphetamine intoxication, withdrawal is marked by a dysphoric state, which is highlighted by depressive symptoms.  These include anhedonia, depression, anxiety, and social inhibition.26 Watson et al. reported that depression peaked at 2-3 days and persisted for 4 days following amphetamine cessation.36 Based on the initial dysphoric state, methamphetamine withdrawal can mimic major depressive disorder.  Other symptoms include irritability, poor concentration, hyperphagia, insomnia or hypersomnia, and psychomotor agitation or retardation.  These symptoms typically last 5 days to two weeks.37

Similar to the management of cocaine withdrawal, the mainstay of amphetamine withdrawal is supportive therapy.  No available treatment has shown to be effective in treatment of amphetamine withdrawal.  Similar to cocaine withdrawal, the patient must be evaluated for severity of depressive symptoms and suicidal ideation and receive in-patient psychiatric treatment if necessary.  If the patient is not actively suicidal nor is suffering from major depressive symptoms, they can be discharged home with warning to return if depressive symptoms worsen.  Importantly, they should be referred to an addiction support and treatment program to help in cessation of amphetamine abuse.38



Caffeinated beverages are the most consumed stimulants in the world.  About 90% of adults in the world consume caffeine on a daily basis.39 Consumption of up to 400 mg of caffeine on a daily basis is safe for most adults.40 Table 3 lists the caffeine content of various beverages.  The most common caffeinated beverages include coffee, tea, and soft drinks.  Caffeine is an antagonist of central and peripheral nervous system adenosine receptors, stimulating the release of excitatory neurotransmitters.41


Caffeine withdrawal, while uncomfortable, is not associated with any adverse medical consequences.  Withdrawal symptoms include headache, fatigue, decreased energy, decreased attentiveness, sleepiness, decreased sense of wellbeing, depressed mood, difficulty concentrating, and irritability.  Of these, headache is the most common symptom experienced.  It is estimated that only about 50 percent of chronic caffeine users experience withdrawal symptoms.  Symptoms typically begin to occur 12-24 hours after ceasing caffeine intake, peak at one to two days, and resolve within one week.43

Management of caffeine withdrawal is supportive.  Patients should be reassured that caffeine withdrawal is not associated with any adverse events or complications.  If the patient’s headache is severe, an anti-inflammatory agent such as ibuprofen can be utilized.  The patient can also be offered caffeine (any caffeinated beverage or soft drink), as re-administration of caffeine reverses the withdrawal symptoms.

Case Resolution

Case 1:  This 45-year-old male was diagnosed with opioid withdrawal from the history and physical.  On further evaluation, he denied any other substance abuse and had no psychiatric history or comorbidities.  As the patient requested detoxification, he was provided information for detoxification centers.

Case 2:  This 33-year-old female was concerned about cessation of methamphetamine.  On further evaluation, she stated she had been feeling down lately but denied any anhedonia or suicidal ideation.  On further evaluation, she admitted to intermittent alcohol use but denied any other substance abuse.  You reassure her that though these symptoms may last for up to two weeks, they are not life-threatening and will improve.  She expresses interest in cessation of methamphetamine abuse, and you refer her to an amphetamine addiction support group and counseling center.


  • The signs and symptoms of opioid withdrawal are often vague and nonspecific, and include gastrointestinal distress, flu-like symptoms, and sympathetic nervous system arousal. Yawning and lacrimation are specific for opioid withdrawal.
  • Alcohol withdrawal and stimulant intoxication can mimic opioid withdrawal. However, these are much more likely to cause significant tachycardia and hypertension compared to opioid withdrawal.
  • Quick recognition of benzodiazepine withdrawal is essential, as this syndrome can be life-threatening.
  • The onset and duration of symptoms of BZD withdrawal depends on the half-life of the BZD.
  • The mainstay of therapy for BZD withdrawal is a BZD with a prolonged clinical effect, with the goal of alleviating symptoms.
  • Both cocaine and amphetamine withdrawal can manifest with depressive symptoms. Patients should be evaluated for suicidal ideation and hospitalized if necessary.
  • Treatment for both cocaine and amphetamine withdrawal is supportive, in addition to consideration and care for any psychological symptoms.
  • Caffeine withdrawal is not associated with any adverse complications. If patients are requesting treatment for withdrawal symptoms, ibuprofen or a caffeinated beverage can provide timely relief.


References/Further Readin

  1. “World Drug Report 2012.”   United Nations Office on Drugs and Crime. http://www.unodc.org/unodc/en/data-and-analysis/WDR-2012.html
  2. “Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings.” NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013.
  3. “America’s Addiction to Opioids: Heroin and Prescription Drug Abuse.” National Institute on Drug Abuse. https://www.drugabuse.gov/about-nida/legislative-activities/testimony-to-congress/2016/americas-addiction-to-opioids-heroin-prescription-drug-abuse#_ftn5
  4. Jones CM, Logan J, Gladden RM, Bohm MK. Vital Signs: Demographic and Substance Use Trends Among Heroin Users-United States, 2002-2013. MMWR Morb Mortal Wkly Rep. 2015 Jul;64(26):719-25.
  5. Strain E. Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis. UpToDate. May 2016.
  6. Sevarino K. Opioid withdrawal: Clinical manifestations, course, assessment, and diagnosis. UpToDate. May 2016.
  7. Stolbach A, Hoffman RS. Opioid withdrawal in the emergency setting. UpToDate. May 2016.
  8. Choo C. Medications Used in Opioid Maintenance Treatment. US Pharm. 2009;34(11):40-53.
  9. Teoh BGJ, Yee A, Habil MH. Psychiatric comorbidity among patients on methadone maintenance therapy and its influence on quality of life. Am J Addict. 2016 Jan;25(1): 49-55. Epub 2015 Dec 21.
  10. Fareed A, Eilender P, Haber M, Bremner J, Whitfield N, Drexler K. Comorbid posttraumatic stress disorder and opiate addiction: a literature review. J Addict Dis. 2013;32(2):168-79.
  11. Rosen D, Smith ML, Reynolds CF. The prevalence of mental and physical health disorders among older methadone patients. Am J Geriatr Psychiatry. 2008 Jun;16(6):488-97.
  12. Goldner EM, Lusted A, Roerecke M, Rehm J, Fischer B. Prevalence of Axis-1 psychiatric (with focus on depression and anxiety) disorder and symptomatology among non-medical prescription opioid users in substance use treatment: systematic review and meta-analysis. Addict Behav. 2014 Mar;39(3):520-31. Epub 2013 Dec 2.
  13. Greller H, Gupta A. Benzodiazepine poisoning and withdrawal. UpToDate. May 2016.
  14. Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology (Berl). 2004;176(1):1.
  15. Hood HM, Metten P, Crabbe JC, Buck KJ. Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11. Genes Brain Behav. 2006;5(1):1.
  16. Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, et al. Benzodiazepine dependence: focus on withdrawal syndrome. Ann Pharm Fr. 2009 Nov;67(6):408-13. Epub 2009 Sep 18.
  17. Gussow L, Carlson A. Rosen’s Emergency Medicine, 8th Ed., Chapter 165, 2076-2083.e1. Philadelphia PA: Saunders, 2014.
  18. Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs. 2009;23(1):19.
  19. Voshaar RC, Couvee JE, van Balkom AJ, Mulder PG, Zitman FG. Strategies for discontinuing long-term benzodiazepine use: meta-analysis. Br J Psychiatry. 2006 Sep;189:213-20.
  20. Parr JM, Kavanagh DJ, Cahill L, Mitchell G, McD Young R. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction. 2009 Jan;104(1):13-24. Epub 2008 Oct 31.
  21. Lum E, Gorman SK, Slavik RS. Valproic acid management of acute alcohol withdrawal. Ann Pharmacother. 2006;40(3):441.
  22. Schweizer E, Rickels K, Case WG, Greenblatt DJ. Carbamazepine treatment in patients discontinuing long-term benzodiazepine therapy. Effects on withdrawal severity and outcome. Arch Gen Psychiatry. 1991;48(5):448.
  23. Alvanzo A. Management of Substance Withdrawal in Acutely Ill Medical Patients: Opioids, Alcohol, and Benzodiazepines. Society of General Internal Medicine 36th Annual Meeting. 27 April 2013.
  24. Gorelick DA. Cocaine use disorder in adults: Epidemiology, pharmacology, clinical manifestations, medical consequences, and diagnosis. UpToDate. May 2016.
  25. Coffey SF, Dansky BS, Carrigan MH, Brady KT. Acute and protracted cocaine abstinence in an outpatient population: a prospective study of mood, sleep and withdrawal symptoms. Drug Alcohol Depend. 2000;59(3):277.
  26. Lago JA, Kosten TR. Stimulant withdrawal. Addiction. 1994;89(11):1477.
  27. Khantzian EJ, McKenna GJ. Acute toxic and withdrawal reactions associated with drug use and abuse. Ann Intern Med. 1979;90(3):361.
  28. Nademanee K, Gorelick DA, Josephson MA, Ryan MA, Wilkins JN, Robertson HA, et al. Myocardial ischemia during cocaine withdrawal. Ann Intern Med. 1989;111(11):876.
  29. Schuckit MA. Drug and Alcohol Abuse. A Clinical Guide to Diagnosis and Treatment, 6th ed, Springer, New York 2007.
  30. Weiss RD, Greenfield SF, Mirin SM. Intoxication and withdrawal syndromes. In: Manual of Psychiatric Emergencies, Hyman, SE, (Ed), Little, Brown & Co, Boston, MA 1994. p. 279-93.
  31. Degenhardt L, Mathers B, Guarinieri M, Panda S, Phillips B, Strathdee SA, et al. Meth/amphetamine use and associated HIV: Implications for global policy and public health. Int J Drug Policy. 2010 Sep;21(5):347-58. Epub 2010 Feb 1.
  32. World Drug Report 2010, United Nations Publication, Vienna 2010.
  33. UNODC. World Drug Report 2012, Contract No: E.12.XI.1, United Nations Publication, New York 2012.
  34. Salo R, Flower K, Kielstein A, Leamon MH, Nordahl TE, Galloway GP. Psychiatric comorbidity in methamphetamine dependence. Psychiatry Res. 2011 Apr;186(2-3):356-61. Epub 2010 Nov 4.
  35. Zorick T, Sugar CA, Hellemann G, Shoptaw S, London ED. Poor response to sertraline in methamphetamine dependence is associated with sustained craving for methamphetamine. Drug Alcohol Depend. 2011 Nov;118(2-3):500-3. Epub 2011 May 17.
  36. Watson R, Hartmann E, Schildkraut JJ. Amphetamine withdrawal: affective state, sleep patterns, and MHPG excretion. Am J Psychiatry. 1972 Sep;129(3):263-9.
  37. McGregor C, Srisurapanont M, Jittiwutikarn J, Laobhripatr S, Wongtan T, White JM. The nature, time course and severity of methamphetamine withdrawal. Addiction. 2005 Sep;100(9):1320-9.
  38. Srisurapanont M, Jarusuraisin N, Kittirattanapaiboon P. Treatment for amphetamine withdrawal. Cochrane Library. 23 October 2001.
  39. Medicines in my Home: Caffeine and Your Body. Food and Drug Administration. http://www.fda.gov/downloads/UCM200805.pdf
  40. Heckman MA, Weil J, Gonzalez de Mejia E. Caffeine (1,3,7-trimethylxanthine) in foods: a comprehensive review on consumption, functionality, safety, and regulatory matters. J Food Sci. 2010 Apr;75(3):R77-87.
  41. Freholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev. 1999;51(1):83.
  42. Bordeaux B, Lieberman HR. Benefits and risks of caffeine and caffeinated beverages. UpToDate. May 2016.
  43. Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology (Berl). 2004;176(1):1.

Protein Shakes and Dietary Supplements: What are their ingredients and how much is too much?

Author: Adrianna Levesque, MD (Senior EM Resident at SAUSHEC, US Army) // Edited by: Jennifer Robertson, MD, MSEd and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)


Athletes, active adults, and military personnel consume protein drinks with the intent to enhance exercise performance, maximize ability to develop muscle mass, and improve recovery after exercise. However, the decision of which supplements to utilize are based largely on marketing claims instead of available evidence-based medicine. It is questionable as to whether some of these supplements are effective at all. Additionally, some supplements require very specific timing of consumption in conjunction with exercise for best results and others enhance performance in only certain exercise regimens.  More importantly, a few of these supplements have been implicated in adverse events requiring hospitalization.1

What are the intended ingredients in your dietary supplements?

Supplements contain several sources of protein, which most commonly are: whey, casein, soy, pea, and rice proteins. Many of these products also contain glutamine, creatine, antioxidants, essential fatty acids, and several minerals such as selenium, zinc, iron and chromium. Additionally, these products may contain caffeine, yohimbine, and synephrine

 What are the expected benefits of dietary supplementation?

The estimated consumption of protein supplements in college athletes, recreationally active adults, and active duty military personnel is approximately 20%. Most people who consume protein products assume that they will enhance muscle strength, improve performance, promote health, provide energy, and enhance weight loss.2 The theory is that amino acid intake stimulates uptake into muscle increasing synthesis.3 While scientific evidence does indicate that supplemental protein may confer metabolic advantages to moderately active people during periods of sustained energy deficit, it is likely that the majority of these people who consume a normal diet can meet their dietary protein needs without supplementation.2

One study indicated that supplementation with whey protein and creatine in male subjects increased lean body mass as well as performance on specific exercise measures.4 Another study looked at supplementation with essential fatty acids with and without protein supplementation and demonstrated that the addition of protein supplements after exercising increased the amount of net whole body protein gain. Thus, this study demonstrates that the timing of protein supplement consumption may be the key to benefits gained.5

What are the cons of consuming too many dietary supplements?

Dietary supplements often contain multiple ingredients and are often used as meal replacements. Some of the ingredients in these products may be harmful if ingested in excess. Over a one-year period, the California Poison Control Center reported 275 patients with adverse events related to dietary supplements. Of these, 112 had sympathomimetic symptoms. Eight of those adverse events required hospitalization, three of which were admitted to intensive care units. One death was reported and was due to a stroke in a patient who took multiple caffeine- and yohimbine-containing supplements.6

One of the most common issues seen with dietary supplements is that many of their components do not improve performance or increase weight loss, muscle mass or lean body mass.1,7-9 There is some concern that excessive protein intake may lead to kidney injury; however, in healthy individuals with normal kidney function, there is no solid evidence to support this.10 Some studies have shown hepatotoxicity associated with dietary supplement consumption, however there has been no direct link to specific causative agents within these supplements.



What are the expected benefits of creatine supplementation?Studies suggest that this supplement provides the most benefit in both male and female athletes involved in short stints of high-intensity exercise.12,13 Common sports that seem to benefit from creatine include soccer, football, squash, and lacrosse. The majority of the literature indicates that supplementation with creatine does lead to increased body mass.13 Furthermore, studies show that creatine may be beneficial as a supplement in heart disease, neuromuscular disorders, diabetes, and in people with low bone density.14-16

A loading phase of creatine at 0.07 g/kg of ideal body weight four times per day for 2-3 days followed by a once daily dose of 0.03 g/kg of ideal body weight for maintenance is a regimen that should provide ideal levels of muscle creatine without overusing the supplement. This regimen of creatine should be combined with a high-carbohydrate meal or beverage without high-fructose ingredients.15 There is no literature to suggest that creatine supplementation at recommended dosing negatively affects renal or liver function in healthy individuals.9,13,17

What are the cons of too much creatine consumption?

Research indicates that creatine supplementation is not useful for isometric or endurance exercises.8,9 The most common reported adverse event from creatine supplementation is gastrointestinal distress, including abdominal cramping, nausea, vomiting and diarrhea. There are other anecdotal reports of muscle cramping and water retention, but there is no solid evidence to support these claims.9,13  Studies have shown that if creatine is consumed in higher doses, kidney injury may occur. However, the results of these studies were either rare, or were seen in patients with underlying kidney disease 13,14


What are the expected benefits of glutamine supplementation?

Glutamine is the most abundant amino acid in human muscle and is utilized at high rates by rapidly dividing cells.18 Research shows that glutamine may stimulate muscle development and improve immune function.18,19

What are the cons of too much glutamine consumption?

A study of military police officers showed no difference in exercise strength or endurance with glutamine supplementation.8 Otherwise, there is little concrete evidence of dangers.



What additional ingredients that may be harmful?

  • The FDA warns that there is “an emerging trend where over-the-counter products, frequently represented as dietary supplements, contain hidden active ingredients that could be harmful. Consumers may unknowingly take products laced with varying quantities of approved prescription drug ingredients, controlled substances, and untested and unstudied pharmaceutically active ingredients”. The FDA notes that these hidden ingredients are increasingly becoming a problem in products promoted for bodybuilding and may be harmful. Note that the FDA does not test all products on the market.20
  • In the USA, dietary and protein supplements may contain up to 25% of contaminants. There is a paucity of surveillance and regulation of the contents in these products.21
  • Research shows that some protein supplements may contain anabolic steroids that are not declared on the labels. Other contaminants may include dicyandiamide and dihydrotriazenes and stimulants such as caffeine, ephedrine, methylenedioxymetamphetamie and sibutramine, 22,23 The stimulants may also be absent from product labels. 12,
  • Protein supplements with aim to promote weight loss may contain synephrine. Synephrine has been associated with adverse cardiac events, including hypertension, tachyarrhythmia, variant angina, cardiac arrest, QT prolongation, ventricular fibrillation, myocardial infarction, and sudden death.
  • Selenium has been shown to decrease oxidant stress after exercise in overweight individuals, but it is unclear if this is clinically significant.24 However, some of the dietary supplements contain selenium for this reason. One particular protein supplement caused several cases of selenium toxicity as it actually contained 200 times the labeled concentration of selenium. This led to 201 cases of selenium toxicity in 10 states, with 1 hospitalization.25 Symptoms of selenium toxicity include dyspnea, respiratory distress, vomiting, diarrhea, abdominal pain, eye irritation, alopecia, depigmentation and peripheral nerve damage.26
  • Interestingly, several studies have demonstrated an association with those who take bodybuilding or performance enhancing substances and high risk behaviors such as anabolic steroid use, heavy drinking, drinking while driving and getting involved in fights. Thus, the reported adverse events associated with these supplements such as hepatotoxicity, heart palpitations, autonomic symptoms and even death may possibly be a result of the combination of supplements and high-risk behaviors.27,28


  • Of 15 commonly consumed protein drinks (BSNÒ, EASÒ, GNCÒ, Jillian Michaels Pure ProteinÒ, Muscle MilkÒ, Optimum NutritionÒ, Six Star Pro NutritionÒ & Solgar Whey to GoÒ) tested by Consumer Reports, all drinks had at least one or more of the following contaminants: arsenic, cadmium, lead and mercury. Consuming only three servings of these per day may lead to higher than permissible daily exposure allowances.29,30
    • Arsenic ranges from 0.6-16.9 mcg/3 servings.
    • Cadmium ranges from 1.6-5.6 mcg/3 servings.
    • Lead ranges from 0.4-13.5 mcg/3 servings.
    • Mercury ranges from 0.2-1.1 mcg/3 servings

Symptoms of heavy metal contaminant toxicities:

  • Arsenic: headaches, drowsiness, confusion, seizures, encephalopathy, peripheral neuropathy, abdominal pain, nausea, vomiting, diarrhea, anemia, hemolysis, hypotension, generalized weakness, muscle aches, chills, fever, hyperkeratosis, hyperpigmentation, exfoliative dermatitis, cardiomyopathy, renal tubular necrosis, ventricular arrhythmias, intestinal hemorrhage and jaundice.
  • Cadmium: vomiting, diarrhea, kidney disease, lung cancer, electrolyte disorders, lactic acidosis and shock.
  • Lead: irritability, lethargy, headache, vomiting, abdominal pain, anorexia, constipation, dysarthria, renal injury, hyperproteinemia, pallor, anemia, ataxia, encephalopathy, seizures, papilledema, confusion and hallucinations.
  • Mercury: fatigue, depression, sluggishness, irritability, headaches, dyspnea, respiratory depression, pulmonary edema, pulmonary fibrosis, confusion, ataxia, choreoathetosis, polyneuropathy, seizures, dysarthria, visual impairment, acrodynia, erythema, hyperesthesia, gingivitis, abdominal pain, vomiting and bloody diarrhea.26


  • The main treatment of heavy metal poisoning is termination of exposure to the metal.
  • Treatment should also be symptomatic and supportive.
    • In cases of cerebral edema, treatment with Mannitol and corticosteroid drugs, along with intracranial monitoring is required.
    • Kidney failure may require hemodialysis.
  • In some cases, gastric lavage or whole bowel irrigation may be indicated depending on the exposure (acute versus chronic). Activated charcoal will not bind these heavy metals effectively and is therefore not recommended.
  • Treatment also consists of the use of chelating agents including dimercaprol (BAL), dimercaptopropane sulfonate (DMPS), and succimer (DMSA).31
  • There is no proven effective therapy for the treatment of cadmium poisoning.26


  • When choosing to consume dietary supplements, it is essential to evaluate all of the ingredients on the labeled supplement. In addition, consultation with a nutritionist or physician should be considered prior to starting any supplements.
  • It appears that the majority of dietary supplements’ ingredients are not toxic when consumed at the doses recommended on the labels.
  • There is mixed evidence as to the benefits of consuming these dietary supplements, however it would appear that the evidence demonstrates some benefit when appropriate timing and amount of creatine supplementation is utilized.
  • Many of the products available may contain contaminants that are not listed on the labels, which may be harmful and cause toxicity when consumed in excessive amounts.
  • More resources should be utilized to focus attention on the large amount of contaminants in these supplements sold over-the-counter and perhaps more stringent regulation on the companies manufacturing these products.

References / Further Reading

  1. McLellan TM, Pasiakos SM, Lieberman HR. Effects of protein in combination with carbohydrate supplements on acute or repeat endurance exercise performance: a systematic review. Sports Med. 2014;44(4):535-550.
  2. Pasiakos SM, Montain SJ, Young AJ. Protein supplementation in U.S. military personnel. J Nutr. 2013;143(11):1815S-1819S.
  3. Wolfe RR. Protein supplements and exercise. Am J Clin Nutr. 2000;72(2 Suppl):551S-557S.
  4. Burke DG, Chilibeck PD, Davidson KS, Candow DG, Farthing J, Smith-Palmer T. The effect of whey protein supplementation with and without creatine monohydrate combined with resistance training on lean tissue mass and muscle strength. Int J Sport Nutr Exerc Metab. 2001;11(3):349-364.
  5. Levenhagen DK, Carr C, Carlson MG, Maron DJ, Borel MJ, Flakoll PJ. Postexercise protein intake enhances whole-body and leg protein accretion in humans. Med Sci Sports Exerc. 2002;34(5):828-837.
  6. Haller C, Kearney T, Bent S, Ko R, Benowitz N, Olson K. Dietary supplement adverse events: report of a one-year poison center surveillance project. J Med Toxicol. 2008;4(2):84-92.
  7. Peternelj TT, Coombes JS. Antioxidant supplementation during exercise training: beneficial or detrimental? Sports Med. 2011;41(12):1043-1069.
  8. da Silveira CL, de Souza TS, Batista GR, et al. Is long term creatine and glutamine supplementation effective in enhancing physical performance of military police officers? J Hum Kinet. 2014;43:131-138.
  9. Bemben MG, Lamont HS. Creatine supplementation and exercise performance: recent findings. Sports Med. 2005;35(2):107-125.
  10. Tipton KD, Wolfe RR. Protein and amino acids for athletes. J Sports Sci. 2004;22(1):65-79.
  11. Pittler MH, Schmidt K, Ernst E. Adverse events of herbal food supplements for body weight reduction: systematic review. Obes Rev. 2005;6(2):93-111.
  12. Mesa JL, Ruiz JR, Gonzalez-Gross MM, Gutierrez Sainz A, Castillo Garzon MJ. Oral creatine supplementation and skeletal muscle metabolism in physical exercise. Sports Med. 2002;32(14):903-944.
  13. Poortmans JR, Francaux M. Adverse effects of creatine supplementation: fact or fiction? Sports Med. 2000;30(3):155-170.
  14. Persky AM, Brazeau GA. Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacol Rev. 2001;53(2):161-176.
  15. Persky AM, Brazeau GA, Hochhaus G. Pharmacokinetics of the dietary supplement creatine. Clin Pharmacokinet. 2003;42(6):557-574.
  16. Gualano B, Artioli GG, Poortmans JR, Lancha Junior AH. Exploring the therapeutic role of creatine supplementation. Amino Acids. 2010;38(1):31-44.
  17. Pline KA, Smith CL. The effect of creatine intake on renal function. Ann Pharmacother. 2005;39(6):1093-1096.
  18. Walsh NP, Blannin AK, Robson PJ, Gleeson M. Glutamine, exercise and immune function. Links and possible mechanisms. Sports Med. 1998;26(3):177-191.
  19. Castell L. Glutamine supplementation in vitro and in vivo, in exercise and in immunodepression. Sports Med. 2003;33(5):323-345.
  20. Tainted Body Building Products. 2015; http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/MedicationHealthFraud/ucm234523.htm. Accessed Mar 1, 2016.
  21. Petroczi A, Taylor G, Naughton DP. Mission impossible? Regulatory and enforcement issues to ensure safety of dietary supplements. Food Chem Toxicol. 2011;49(2):393-402.
  22. Geyer H, Parr MK, Koehler K, Mareck U, Schanzer W, Thevis M. Nutritional supplements cross-contaminated and faked with doping substances. J Mass Spectrom. 2008;43(7):892-902.
  23. Geyer H, Parr MK, Mareck U, Reinhart U, Schrader Y, Schanzer W. Analysis of non-hormonal nutritional supplements for anabolic-androgenic steroids – results of an international study. Int J Sports Med. 2004;25(2):124-129.
  24. Savory LA, Kerr CJ, Whiting P, Finer N, McEneny J, Ashton T. Selenium supplementation and exercise: effect on oxidant stress in overweight adults. Obesity (Silver Spring). 2012;20(4):794-801.
  25. MacFarquhar JK, Broussard DL, Melstrom P, et al. Acute selenium toxicity associated with a dietary supplement. Arch Intern Med. 2010;170(3):256-261.
  26. Heavy Metal Poisoning. 2015; http://rarediseases.org/rare-diseases/heavy-metal-poisoning/. Accessed March 3, 2015.
  27. Kao TC, Deuster PA, Burnett D, Stephens M. Health behaviors associated with use of body building, weight loss, and performance enhancing supplements. Ann Epidemiol. 2012;22(5):331-339.
  28. Stephens MB, Olsen C. Ergogenic supplements and health risk behaviors. J Fam Pract. 2001;50(8):696-699.
  29. Health risks of protein drinks: You don’t need the extra protein or the heavy metals our tests found. 2010; http://www.consumerreports.org/cro/2012/04/protein-drinks/index.htm. Accessed Mar 1, 2016.
  30. Elemental Impurities – Limits. 2015; http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/key-issues/m5192.pdf. Accessed March 1, 2016.
  31. Tomassoni AJ, French RN, Walter FG. Toxic industrial chemicals and chemical weapons: exposure, identification, and management by syndrome. Emerg Med Clin North Am. 2015;33(1):13-36.

Toxicologic Tachycardias

Author: Levi Kitchen, MD (EM Attending Physician, Naval Hospital Guam) // Edited by: Jennifer Robertson, MD, MSEd and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

Basic Physiology of Toxicologic Mediated Tachycardia: Review

There are two general classes of drugs that can cause increased heart rate (HR), or tachycardia: sympathetic agonists or parasympathetic antagonists.

  1. Sympathomimetics (sympathetic agonists): activate the sympathetic nervous system (SNS) and increase myocardial sensitization

SNS activation

> Post-ganglionic neurons release norepinephrine (NE) which stimulates alpha and beta receptors, but alpha > beta

> Adrenal glands are stimulated by the SNS and release mostly epinephrine (epi) which stimulates beta > alpha receptors.

*Alpha1 receptors induce peripheral vasoconstriction

*Alpha2 receptors have multiple effects, including:

  • Central nervous system (CNS) sedation and decreased sympathetic outflow via a negative feedback mechanism
  • Initially, peripheral nervous system (PNS) stimulation at the presynaptic terminal and release of norepinephrine (NE). This causes transient increases in sympathetic tone (HR and blood pressure (BP)). However, there is a negative feedback loop which will cause a net decrease in sympathetic tone by blocking the release of NE from the pre-synaptic nerve terminal.

*Beta1 receptors are located mainly in the myocardium when stimulated, will increase chronotropy and inotropy

*Beta2 receptors are mainly peripherally located and activation causes vasodilation. Note vasodilation can lead to reflex tachycardia. Stimulation of beta 2 receptors also causes bronchodilation.

Increased myocardial sensitization

> Increased automaticity (speeds up ectopic pacemaker cell depolarization)

> Early after depolarizations (EAD) – potassium (K+) channel blockade prolongs the QT segment on the electrocardiogram (ECG). K+ channel blockade also causes non-uniform repolarization throughout the myocardium, which leads to an early impulse, causing calcium (Ca2+) channel opening prior to complete repolarization. This may cause an EAD, which is significant because EADs may lead to arrhythmias such as PVCs or a R on T phenomenon leading to ventricular fibrillation or tachycardia (VF or VT) or Torsade de Pointes.

  1. Parasympathetic Antagonist

> Postganglionic nerve terminals release acetylcholine (Ach)

> Blockade causes tachycardia due to increased sympathetic tone by 2 mechanisms, either by antagonizing Ach receptors or decreasing the release of Ach from the nerve terminal

Case 1:  26-year old (yo) previously healthy male is brought in by emergency medical services (EMS).  His friends note they have been up all night “partying.”  The patient is combative, agitated, confused, and diaphoretic. He also has mydriatic pupils that are reactive to light.

Vital Signs (VS): BP 240/130, Pulse (P) 145, Respiratory Rate (RR) 32, Temperature (Temp) 99.9, Oxygen Saturation (SpO2) 96% room air (RA)

What toxidrome is he exhibiting?  What’s the most likely toxic agent in this population?  What’s the treatment?

***For a review of toxidromes, please see: http://www.emdocs.net/the-approach-to-the-poisoned-patient


Mechanism of action

  • alpha agonist
  • blocks presynaptic reuptake of neurotransmitters (NE, dopamine (DA), Serotonin (5-HT))
  • increases NE release
  • blocks sodium channels, leading to cardiac conduction effects and also local analgesia
  • increases endothelial production of endothelin and decreases release of nitric oxide (net effect of vasoconstriction)

Clinical Effects= Sympathomimetic Toxidrome

General: Hyperthermia, euphoria, agitation, seizures, intracranial hemorrhage, hyperactivity, mydriasis, rhinorrhea

Cardiovascular (CV): tachycardia, HTN, coronary vasoconstriction; increased risk of acute coronary syndrome (ACS); QRS widening and hypotension due to sodium channel blocking effect

Pulmonary: asthma exacerbation, diffuse alveolar hemorrhage, pneumonitis, bronchiolitis obliterans organizing pneumonia (BOOP), “crack lung”

Other: ischemic bowel, renal failure (rhabdomyolysis), placental abruption


  • decreased mortality demonstrated only with benzodiazepine administration and cooling
  • NO BETA BLOCKERS! Beta blocker use theoretically may lead to unopposed alpha receptor agonism causing significant hypertension and coronary vasoconstriction
  • consider phentolamine (pure alpha blocker) for refractory hypertension and/or other cardiovascular effects
  • provide standard treatment for ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI)
  • if the patient is a body stuffer, give activated charcoal and observe for 6 hours
  • if the patient is a body packer – provide whole bowel irrigation (WBI) and obtain computed tomography (CT) scanning; consult surgery emergently if a ruptured packet is suspected

Case 2: An 18 yo female brought in by EMS for a “seizure” that was witnessed by her parents at home. Per EMS, she remains confused and agitated.  The patient’s parents note that she is otherwise healthy without a seizure disorder, has been having trouble at school due to a bully.  Her parents found an open and empty bottle of TheoDur on the patient’s night stand which is her grandmother’s medication.

VS:  BP 80/40, P 155, RR 26, Temp 99.0, SpO2 95% RA

 The patient forcefully vomits then begins seizing again…


  • caffeine, theophylline, theobromine
  • large volume of distribution, 100% bioavailable, metabolized by liver
  • exposures to theophylline usually medicinal, caffeine exposures usually via OTC meds
  • Structurally similar to adenosine

Therapeutic doses

  • release of endogenous epi from adrenals (due to loss of normal adenosine mediated feedback inhibition)
  • adenosine antagonism (adenosine causes smooth muscle constriction via histamine release)
    • this is the desired effect for use in chronic obstructive pulmonary disease (COPD) treatment


  • inhibit phosphodiesterase leading to increased levels of cAMP and enhanced adrenergic effects
  • CNS adenosine antagonism (loss of tonic CNS inhibition by adenosine leads to refractory seizures)

 Clinical Effects

  • CNS: agitation, irritability, seizure
  • Gastrointestinal (GI): severe nausea and emesis, frequently refractory to antiemetics
  • CV: palpitations, tachycardia, dysrhythmia; MAT is common, MI/cardiac morbidity is main cause of death in overdose.
    • vasodilation due to beta 2 receptor stimulation leading to widened pulse pressure and hypotension
  • Metabolic: hypokalemia, acidosis, hyperglycemia, hyperthermia
  • Musculoskeletal (MSK): increases intracellular calcium leading to increased contractility and rhabdomyolysis


GI decontamination: includes multi-dose activated charcoal (MDAC), which is the mainstay of therapy. Methxylxanthines have a high affinity for charcoal and MDAC helps enhance serum elimination. Consider WBI (whole bowel irrigation) for sustained-release preparations

Cardiac/Supportive Care: includes fluids for hypotension, but if hypotension is refractory, phenylephrine or NE can be given. Beta blockers (BB) can be used as a last resort. Propanalol is best, but can also give beta-1 selective medications if there is a concern for asthma or COPD.

If SVT occurs, adenosine is unlikely to be effective. The patient will likely need a calcium channel blocker (CCB) or BB drip

If a ventricular dysrhythmia occurs, give lidocaine or a BB

If seizures occur, provide standard treatment along with benzodiazepines

 Extracorporeal removal (ECR): Charcoal hemoperfusion preferred, but provide hemodialysis (HD) if unavailable.

  • ECR for any patient with theophylline level > 40ug/mL + seizure / hypotension / ventricular dysrhythmia / protracted vomiting preventing administration of MDAC
  • ECR for any theophylline level > 90ug/mL

 Case 3:  A 16- yo male brought in by parents for “strange behavior.”  The patient had been spending the night at a friend’s house when he unexpectedly returned home “speaking gibberish.”  His parents spoke to the friend who noted they were trying to “robo-trip” so they drank a bottle of robitussin each and took “a handful” of diphenhydramine.  The patient is alert but anxious, picking at his clothes, mydriatic pupils minimally reactive to light.

VS: BP 120/80, P 126,  RR 28,  Temp 100.8,  SpO2 99% on RA

What toxidrome is this?  What is the treatment?  What are some potential lethal side effects of this ingestion?


These medications are widely available in over the counter and prescription formulations. Therefore, anticholinergics are very common sources of toxicologic tachycardias.


  • Autonomic nervous system muscarinic receptor blockade, cardiac muscarinic blockade leads to tachycardia
  • Also have CNS effects, variable based on the agent’s ability to penetrate CNS
  • Many drug classes: anticholinergics (atropine, benztropine, scopolamine, glycopyrrolate), antihistamines, antipsychotics, antispasmodics, cyclic antidepressants, mydriatics.

Clinical Effects

  • Anticholinergic Toxidrome
  • Cardiac specific: many agents with anticholinergic properties, such as antihistamines and cyclic antidepressants, cause significant cardiac toxicity through sodium channel and potassium channel blockade. This can lead to prolonged QRS and QT on the ECG
    • Diphenhydramine has type 1A antiarrhythmic properties and thus, QRS and QT prolongation can occur, leading to wide complex dysrhythmias
    • Cyclic antidepressants may cause conduction delays, sinus tachycardia, rightward axis shift, and/or prolonged QRS/QT/PR intervals on the ECG. This may lead to VT or VF. Patients may also develop refractory hypotension.


  • Observe on telemetry
  • Decontaminate the GI system with MDAC and potentially orogastric lavage
  • Aggressively cool
  • Hypertonic saline or sodium bicarbonate may be considered. These can reverse sodium channel blockade and therefore narrow the QRS. (Go here for further details: http://www.emdocs.net/efficacy-of-hypertonic-saline-for-tricyclic-antidepressant-overdose/)
  • Type 1A, 1C, III anti-dysrhythmics are contraindicated due to their sodium channel blocking effects (may be synergistic with cardiac effects of anticholinergic tox inducing agents)
  • Lidocaine may be administered for dysrhythmia control due to its unique pharmacokinetics.
  • Magnesium can be given if torsade is present. It may also be helpful as a general anti-dysrhythmic agent.
  • Physostigmine is controversial. It can be used to reverse anticholinergic effects in patients with a pure anticholinergic toxidrome; however it can lead to fatal arrhythmias in certain co-ingestions.  Consult poison control before administering. (Go here for further details: http://www.emdocs.net/physostigmine-for-management-of-anticholinergic-toxidrome/)

References / Further Reading

-Rosen’s Emergency Medicine – Concepts and Clinical Practice.  8th Edition.

-Goldfrank’s Toxicologic Emergencies 2002.

-An intensive review course in clinical toxicology.  New York City Poison Control Center and Bellevue Hospital Center Course Syllabus March 13 and 14; 2014.







Serotonin Syndrome and Neuroleptic Malignant Syndrome: Pearls & Pitfalls

Authors: Jacob Avila, MD and Jonathan Bronner, MD (EM Attending Physicians, University of Kentucky) // Edited by: Alex Koyfman, MD (EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital, @EMHighAK) and Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF)

Your next 3 patients…

#1: 35yo M w/ fever and agitation

#2: 21yo F w/ “jitteriness” s/p a med change

#3: 40yo F from nursing home w/ “stiffness”

Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are two types of pathologies that often give a very confusing picture. They are both associated with psychiatric diseases and are often seen in the setting of polypharmacy,1,2 which give the provider a broad differential to work through when these patients present in the emergency department (ED).2-8 To get a better understanding of how to differentiate between the two, let’s look at each of these diseases a bit more in depth.

Why do we care about this disease? We care about this because the medical community often misses it. In a previously published survey study, as many as 85% of physicians didn’t know what SS was.9 While that number is probably much better these days, SS still often goes unrecognized. At least part of the reason why we miss this disease is due to the fact that mild cases can present with non-specific symptoms such as tremors, diarrhea, and tachycardia.4 Often when SS starts advancing from the mild into the moderate category, we may inadvertently treat the condition with more serotonergic medications, further precipitating decline.10 Most importantly, it can be deadly. Unrecognized SS can quickly deteriorate into irreparable kidney damage, respiratory failure, or DIC.8 The mortality rate of severe SS has been reported to be 2-12%.6 Work hour restrictions in the US were first established after a case of missed SS where an intern continued to give serotonergic medications for agitation in a patient with SS, likely resulting in her death.11

So now that we’re scared, how do we not miss this deadly disease? First, let us consider the mechanism for how SS occurs. While most of the total body serotonin is found in the periphery,5 what we care about is the serotonin that causes SS, namely, the serotonin produced in the central nervous system (CNS). The overall level of serotonin in the CNS doesn’t matter as much as how much of it is stuck in the neuronal synapses, causing the effects of SS.7 Serotonin in the CNS is mostly produced in the pons and upper brainstem. Once released, it will bind to post-synaptic receptors and remains viable until it is either degraded by monoamine oxidase (MAO) or removed from the synapse by reuptake pumps.5 In the CNS, serotonin functions by modulating core body temperature, wakefulness, analgesia, sexual behavior, mood, affect, perception, personality, emesis, and eating behavior (among other things).7,12 The broad effects of serotonin are mediated by multiple receptors. There are 7 types of receptors, several of which have unique receptor subclasses. As a whole, this results in around 14 distinct serotonin receptors found throughout the body, though only two are thought to be involved in the mechanism of SS: 5-HT1A and 5-HT2A. As far as SS goes, the less important one is 5-HT1A, which is thought to be responsible for myoclonus, hyperreflexia, and alterations on mental status.5,13-15 The most important receptor in SS is 5-HT2A,12,16,17 which increases heart rate, elevates blood pressure and temperature, and has a role in neuromuscular excitement.5,13,15,16 These abnormalities in vital physiologic homeostasis reflect adrenal gland stimulation of catecholamine release12,14,18 and stimulation of the hypothalamus manifesting as fever.5,13,15,16 Using this basic molecular understanding of the neurohormonal pathway, the triad associated with SS – mental status changes, increased neuromuscular tone, and autonomic instability in the setting of an individual who has taken a serotonergic medication – becomes more tangible. 3,4,7,8,17 One of the reasons this disease can be tricky do diagnose is that there is such a variable presentation. Not all patients with SS will present with the classic triad. In fact, the most commonly reported symptom (myoclonus) is only seen in 57% of patients.19

So now that we have an appreciation for the pathophysiology and how SS may present, how do we diagnose it? The first step is to recognize patients at higher risk of developing SS even before they’re exposed to serotonergic medications. Smokers, individuals with cardiovascular disease, and those with liver disease may develop acquired deficits in MAO activity and serotonin metabolism.7,15 Ethanol can stimulate the release of serotonin from neurons,15 and there is an increased incidence of SS in patients on dialysis who are also taking selective serotonin reuptake inhibitors (SSRI’s).12 Patients with defective CYP2C19 and CYP2D6 enzymes (either acquired or congenital) may also be at a higher risk since these enzymes are responsible for the break down of many serotonergic medications. 8,20 So which medications have been known to cause serotonin syndrome? This long list includes MAOI, TCA, SSRI, SNRI, anti-emetics, street drugs/drugs of abuse, diet pills, antibiotics, opioids (including tramadol), dextromethorphan, Benadryl, linezolid, methylphenidate, and lithium.5,13,15,21-25 These medications increase the synaptic concentration of serotonin via multiple mechanisms— by increasing the synthesis or release of serotonin, increasing receptor stimulation, inhibiting serotonin reuptake, or decreasing the breakdown of serotonin. 5,25

Approximately 60% of SS is caused by drug-drug interactions – usually paroxetine and tramadol – while 40% is triggered by a single drug. The most common individual culprits are SSRIs, with opioids coming in second. 26 After ingestion of an offending medication or medication combination, symptoms often begin within hours. 4 In fact, the majority of patients will present with SS 6 hours after administration of the provoking agent.5,27 While the gold standard for the diagnosis is an examination by a medical toxicologist,5, 28 there are methods available to help you diagnose SS at bedside. The Sternbach and Hunter criteria are the most common and most accessible for the Emergency Physician,28, 29 though the Sternbach criteria is less sensitive and specific for serotonin syndrome when compared to the newer Hunter criteria.4,30, 28 The reason for this discrepancy is that the Sternbach criteria are more likely to miss mild, early, or subacute cases of SS. 8 While the Hunter criteria may also miss mild, early or subacute cases of SS, it has been reported to have a sensitivity of 84% and a specificity of 97%.28

Sternbach Criteria
Sternbach Criteria
Hunter Criteria
Hunter Criteria

Aside from the history and physical exam, there are ancillary tests that can be helpful in diagnosis. While there is no definitive test that can diagnose SS 4,25 a basic laboratory assessment and a CT of the head are helpful in both ruling out other diseases that present similarly to SS as well as monitoring the severity of the patient’s symptoms. 8 Other diseases that should be on your differential when you suspect SS are NMS, malignant hyperthermia, anticholinergic poisoning, sympathomimetic poisoning, opioid withdrawal, CNS infection, sepsis, delirium tremens, and heat stroke. 4-8

Once you’ve arrived at a diagnosis of SS, how should the emergency physician initiate treatment? As with most acute pathologies, you must start with the ABC’s, but in a simultaneous fashion the effort to stop the serotonergic medication is of utmost importance.30 In mild cases, this is usually all that is required. When evaluating a patient in the moderate category you might need to start benzodiazepines for agitation, tachycardia, and hypertension. 4,6 When things start to look bad, you may need to give serotonin antagonists. Although there are no randomized controlled trials supporting its use in this setting,5,30 cyproheptadine – a non-selective histamine H1 receptor and serotonin receptor antagonist – is the drug of choice to treat moderate and severe cases of SS.4, 17, 23 The initial recommended dose is 12 mg, followed by 4-8 mg every 6 hours as needed.4, 5 Some sources recommend starting at 12 mg, then tapering the dose down by 2 mg every 2 hours as needed. 6 The main downsides to this drug is sedation (which may actually assist in the patient’s care) and the fact that it is only available in oral form.5 In an uncooperative, agitated patient any medication by mouth may be difficult to administer. Other options are chlorpromazine (Thorazine),31-33 which can be given IV or IM, olanzapine (Zyprexa)31-33 which can be given IM, dexmedetomidine (Precedex)34 or propofol (Diprivan),34 both of which are given IV. Care must be taken when treating with chlorpromazine, since it has potential to cause serious hypotension and lower the seizure threshold. 6,7

The main things you need to consider when weighing treatment options is the autonomic instability and increased neuromuscular tone. More specifically, the hemodynamics and the temperature of the patient. There are two theories of how the fever develops – central versus peripherally mediated. From the central perspective, serotonin acts to stimulate receptors in the hypothalamus, thus increasing the set point for the body temperature. 5,13,15,16 The peripherally mediated theory suggests that the body’s temperature increases due to the hypermetabolic state caused by increased muscular tone. 6, 7 The truth is that they probably both play a role. Regardless of etiology, fever and hemodynamic instability are of critical therapeutic importance as these are the pathways leading to patient mortality. Up to 14% of patients with SS present with hypotension19 and when the vital organs aren’t perfused, patient outcomes suffer significantly. Impaired temperature regulation can also be deadly due to the sequelae of the fever itself as well as the processes that cause the fever. Patients with uncontrolled muscle spasms spill myoglobin into their serum and suffer renal failure due to rhabdomyolysis.3 If a patient’s muscle rigidity is difficult to control, you should consider intubation and neuromuscular paralysis. If the patient does undergo rapid sequence intubation, care should be taken with the administration of succinylcholine and the potential for elevated serum potassium.3 Typically after discontinuing the offending medication, symptoms are gone within 24 hrs.5,7,27 Still, some SSRI’s have half-lives of 1-2 weeks so symptoms can persist up to 6 weeks after cessation.12

There are a few other SS-inducing medications worthy of special mention. First, not all opioids cause SS. There are two broad classes of opioids called phenanthrenes and non-phenanthrenes. The phenanthrenes are divided into those with an oxygen bridge and those without. The only one in the latter class is dextromethorphan. The phenanthrenes with an oxygen bridge include buprenorphine, codeine, oxycodone, hydrocodone, hydromorphone, morphine, naloxone, and naltrexone. Theoretically speaking, none of these narcotics should cause SS. However, despite the biochemical structure, there have been case reports of SS associated with hydromorphone, buprenorphine, naloxone, and oxycodone. Specifically, synthetic medications such as fentanyl, meperidine, methadone, and tramadol have been associated with SS. On the other hand, there have been no case reports of SS associated with hydrocodone, morphine, or codeine.1 The second class of drugs necessitating mention are triptans. You know those anti-headache medications? They’re serotonin agonists. In 2006 the FDA sent out a warning about the potential for SS when using triptans and SSRI’s or SNRI’s in combination.35 Interestingly, the evidence for this phenomenon is not entirely convincing. Triptans are selective agonists of 5-HT1B, 5-HT1D, and 5-HT1F.36 If you recall, SS is primarily mediated by 5-HT2a and 5-HT1A. Additionally, the FDA alert was based off of 29 cases of suspected SS, only 10 of which met Sternbach’s criteria. None of the 29 met the Hunter criteria.37


Neuroleptic malignant syndrome (NMS) is a disease that tends to occur in a similar population as SS and can manifest in a similar manner.38 Previously, NMS was reported to occur in 0.2%-3.2% of patients on neuroleptics,39 but due to increased awareness of the disease and decreased use of 1st generation anti-psychotics the incidence of NMS has declined to 0.01-0.02% of all patients at risk.39 However, even though the incidence is low, the mortality rate has been reported to be as high as 55%.2 There is a certain population of patients that are at higher risk for the development of NMS, and those include dehydrated patients, patients with underlying brain damage and dementia, and those on high dosages of dopaminergic medications.3 As stated previously, the administration of neuroleptics (also known as anti-psychotics) are the medications most commonly associated with NMS. First generation anti-psychotics have an odds ratio of 23.4, while 2nd generation anti-psychotics have an odds ratio of 4.8 for the development of NMS.40 One of the differences between NMS and SS is the time of onset. While SS will usually manifest within 24 hours after the offending medication is administered, only about 16% of patients who develop NMS will do so within 24 hours, and 66% will develop symptoms within the first week.41

So now that we know a little background on NMS, what are the symptoms? In order to understand the symptoms, one must consider the pathophysiology of how NMS affects the body. It is very likely that there are multiple mechanisms involved, but the most probable theory is that dopamine acts as a tonic inhibitor of the central sympathetic nervous system (SNS).42 When the dopamine is removed, the SNS becomes unopposed. The evidence behind this isn’t grade A, but the pathophysiology of the theory makes sense, and multiple studies have found elevated levels of catecholamines in both the serum and the CSF.38,41-43 NMS manifests classically as extrapyramidal symptoms, altered mental status, and autonomic dysfunction.38 The extrapyramidal symptoms appear as Parkinsonian features such as rigidity, tremor, dystonia, and akinesia, and the autonomic dysfunction manifests as tachycardia, diaphoresis, hyperthermia, and labile blood pressure. Just as in SS, getting an adequate history and a medication list is crucial. That being said, often patients in extremis and with altered mental status present without any past medical history, and we then have to rely on the physical exam. The main differentiating feature of SS and NMS are reflexes. SS will typically be hyperreflexic whereas NMS will have rigidity.

The initial treatment of NMS is identical to SS, which includes stopping the offending medication and administering supportive care, including benzodiazepines. However, if that doesn’t work, escalating care may be necessary. This is where the similarities between the treatment of SS and NMS diverge. The three main medications that are given are bromocriptine, amantadine, or dantrolene.41 The two former medications are dopamine agonists, and the latter blocks calcium release. Other options include L-dopa,3 and surprisingly, electroconvulsive therapy has successfully been used in refractory cases.3,41


Even though both NMS and SS are relatively rare clinical entities, their incidences are expected to increase due to both enhanced awareness as well as a rise in medication administration. 34 Understanding the complex presentations is a critical initial step in identification of the process. If you do suspect SS or NMS, make sure to review the patient’s medications. At the bedside you will need to remember to check reflexes, especially in the lower extremities. These initial clues, along with a few other things, such as autonomic instability, mental status changes, extrapyramidal symptoms, and increased neuromuscular tone, will help you differentiate SS from NMS or from other pathologies and begin treating your patient appropriately.


References / Further Reading

  1. Jhun P, Bright A, Herbert M. Serotonin syndrome and opioids – what’s the deal? Ann Emerg Med. 2015;65:(4)434-5. [pubmed]
  2. Su YP, Chang CK, Hayes RD, et al. Retrospective chart review on exposure to psychotropic medications associated with neuroleptic malignant syndrome. Acta Psychiatr Scand. 2014;130:(1)52-60. [pubmed]
  3. Carbone JR. The neuroleptic malignant and serotonin syndromes. Emerg Med Clin North Am. 2000;18:(2)317-25, x. [pubmed]
  4. Hillman AD, Witenko CJ, Sultan SM, Gala G. Serotonin syndrome caused by fentanyl and methadone in a burn injury. Pharmacotherapy. 2015;35:(1)112-7. [pubmed]
  5. Iqbal MM, Basil MJ, Kaplan J, Iqbal MT. Overview of serotonin syndrome. Ann Clin Psychiatry. 2012;24:(4)310-8. [pubmed]
  6. Frank C. Recognition and treatment of serotonin syndrome. Can Fam Physician. 2008;54:(7)988-92. [pubmed]
  7. Heitmiller DR. Serotonin syndrome: a concise review of a toxic state. R I Med J (2013). 2014;97:(6)33-5. [pubmed]
  8. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352:(11)1112-20. [pubmed]
  9. Mackay FJ, Dunn NR, Mann RD. Antidepressants and the serotonin syndrome in general practice. Br J Gen Pract 1999;248:96–103.
  10. Tintinalli, J. (2011). Tintinalli’s emergency medicine: A comprehensive study guide(7th ed.). New York: McGraw-Hill. Chapter 172
  11. Lerner BH, (2006 November). A Case That Shook Medicine. The Washington Post Retried 9/22/15 from http://www.washingtonpost.com/wp-dyn/content/article/2006/11/24/AR2006112400985.html
  12. Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin syndrome. Ochsner J. 2013;13:(4)533-40. [pubmed]
  13. Tanaka T, Takasu A, Yoshino A, et al. Diphenhydramine overdose mimicking serotonin syndrome. Psychiatry Clin Neurosci. 2011;65:(5)534. [pubmed]
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