Tag Archives: toxicology

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]
  14. Watts SW, Morrison SF, Davis RP, Barman SM. Serotonin and blood pressure regulation. Pharmacol Rev. 2012;64:(2)359-88. [pubmed]
  15. Brown TM, Skop BP, Mareth TR. Pathophysiology and management of the serotonin syndrome. Ann Pharmacother. 1996;30:(5)527-33. [pubmed]
  16. Steele D, Keltner NL, McGuiness TM. Are neuroleptic malignant syndrome and serotonin syndrome the same syndrome? Perspect Psychiatr Care. 2011;47:(1)58-62. [pubmed]
  17. Prakash S, Gosai F, Brahmbhatt J, Shah C. Serotonin syndrome in patients with peripheral neuropathy: a diagnostic challenge. Gen Hosp Psychiatry. 2014;36:(4)450.e9-11. [pubmed]
  18. Shioda K, Nisijima K, Yoshino T, Kato S. Extracellular serotonin, dopamine and glutamate levels are elevated in the hypothalamus in a serotonin syndrome animal model induced by tranylcypromine and fluoxetine. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:(4)633-40. [pubmed]
  19. Mills KC. Serotonin syndrome. A clinical update. Crit Care Clin. 1997;13:(4)763-83. [pubmed]
  20. Lorenzini K, Calmy A, Ambrosioni J, et al. Serotonin syndrome following drug-drug interactions and CYP2D6 and CYP2C19 genetic polymorphisms in an HIV-infected patient. AIDS. 2012;26:(18)2417-8. [pubmed]
  21. Türkoğlu S. Serotonin syndrome with sertraline and methylphenidate in an adolescent. Clin Neuropharmacol. 2015;38:(2)65-6. [pubmed]
  22. Carlsson A, Lindqvist M. Central and peripheral monoaminergic membrane-pump blockade by some addictive analgesics and antihistamines. Pharm. Pharmacol. 1969; 21: 460–464
  23. Samartzis L, Savvari P, Kontogiannis S, Dimopoulos S. Linezolid is associated with serotonin syndrome in a patient receiving amitriptyline, and fentanyl: a case report and review of the literature. Case Rep Psychiatry. 2013;2013:617251. [pubmed]
  24. Joksovic P, Mellos N, van Wattum PJ, Chiles C. “Bath salts”-induced psychosis and serotonin toxicity. J Clin Psychiatry. 2012;73:(8)1125. [pubmed]
  25. Nelson EM, Philbrick AM. Avoiding serotonin syndrome: the nature of the interaction between tramadol and selective serotonin reuptake inhibitors. Ann Pharmacother. 2012;46:(12)1712-6. [pubmed]
  26. Abadie D, Rousseau V, Logerot S, Cottin J, Montastruc JL, Montastruc F. Serotonin Syndrome: Analysis of Cases Registered in the French Pharmacovigilance Database. J Clin Psychopharmacol. 2015;35:(4)382-8. [pubmed]
  27. Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome: presentation of 2 cases and review of the literature. Medicine (Baltimore) 2000;79:201-9
  28. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003 Sep;96(9):635-642.
  29. Sternbach H. The serotonin syndrome. Am J Psychiatry1991; 148:705–13
  30. Miller DG, Lovell EO. Antibiotic-induced serotonin syndrome. J Emerg Med. 2011;40:(1)25-7.
  31. Rao BS, Das DG, Taraknath VR, et al. A double blind controlled study of propranolol and cyproheptadine in migraine prophylaxis. Neurol India 2000; 48: 223–226.
  32. Da Costa AR, Monzillo PH and Sanvito WL. Use of chlorpromazine in the treatment of headache at an emergency service. Arq Neuropsiquiatr 1998; 56: 565–568.
  33. Silberstein SD, Peres MF, Hopkins MM, et al. Olanzapine in the treatment of refractory migraine and chronic daily headache. Headache 2002; 42: 515–518.
  34. Rushton WF, Charlton NP. Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacother. 2014;48:(12)1651-4. [pubmed]
  35. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm085845.htm
  36. Ahn AH, Basbaum AI. Where do triptans act in the treatment of migraine? Pain. 2005;115:(1-2)1-4. [pubmed]
  37. Evans RW, Tepper SJ, Shapiro RE, Sun-Edelstein C, Tietjen GE. The FDA alert on serotonin syndrome with use of triptans combined with selective serotonin reuptake inhibitors or selective serotonin-norepinephrine reuptake inhibitors: American Headache Society position paper. Headache. 2010;50:(6)1089-99. [pubmed]
  38. Sokoro AA, Zivot J, Ariano RE. Neuroleptic malignant syndrome versus serotonin syndrome: the search for a diagnostic tool. Ann Pharmacother. 2011;45:(9)e50.
  39. Jain RS, Gupta PK, Gupta ID, Agrawal R, Kumar S, Tejwani S. Reversible magnetic resonance imaging changes in a case of neuroleptic malignant syndrome. Am J Emerg Med. 2015;33:(8)1113.e1-3.
  40. Nielsen RE, Wallenstein Jensen SO, Nielsen J. Neuroleptic malignant syndrome-an 11-year longitudinal case-control study. Canadian journal of psychiatry. Revue canadienne de psychiatrie. 57(8):512-8. 2012. [pubmed]
  41. Strawn JR, Keck PE, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164:(6)870-6.
  42. Gurrera RJ. Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome. Am J Psychiatry. 1999;156:(2)169-80.
  43. Feibel JH, Schiffer RB: Sympathoadrenomedullary hyperactivity in the neuroleptic malignant syndrome: a case report. Am J Psychiatry 1981; 138:1115–1116.
  44. http://www.ncbi.nlm.nih.gov/pubmed/22863827
  45. http://www.ncbi.nlm.nih.gov/pubmed/21373307
  46. http://www.ncbi.nlm.nih.gov/pubmed/22555052

Core EM: Hyperinsulinemia Euglycemia Therapy (HIET) for BB and CCB Toxicity

Originally published at CoreEM.net, who are dedicated to bringing Emergency Providers all things core content Emergency Medicine available to anyone, anywhere, anytime. Reposted with permission.

Follow Dr. Swaminathan and CORE EM on twitter at @EMSwami and @Core_EM

Written by: Jenny Beck-Esmay, MD (@jbeckesmay) // Edited By:  Anand Swaminathan, MD (@EMSwami)


  • Cardiogenic shock due to beta-blocker (BB) or calcium channel blocker (CCB) toxicity is frequent and potentially lethal.
  • The most common cause of poison-induced cardiogenic shock is beta-blocker toxicity. In 2012 alone, there were 24,465 beta-blocker exposures(Mowry 2013).
  • Calcium channel blocker overdose is less frequent than that of beta-blockers, but has been associated with the highest mortality rates among the cardiovascular drug overdoses(Woodward 2014).

Mechanism of Toxicity (Kerns 2011):

  • BBs and CCBs lead to decreased intracellular calcium within the myocardial cells. This can lead to vasodilation, decreased systemic vascular resistance, bradycardia, conduction delay, decreased contractility, hypotension and cardiogenic shock.
  • As the myocardium becomes stressed, it switches from catabolizing free fatty acids to catabolizing carbohydrates. The liver responds to this increased demand by releasing glucose via gluconeogenesis, ultimately resulting in hyperglycemia.
  • Blockade of calcium channels leads to effects outside the cardiovascular system as well.
    • CCB inhibits insulin secretion from the beta-islet cells of the pancreas. As a result of lower insulin levels, glucose cannot move into the myocardial cells at a rate sufficient to respond to demand.
    • CCB inhibits lactate oxidation resulting in lactic acidosis

CCB Toxicity - www.healthforumworld.com

Traditional Management:

  • Traditional management includes fluid resuscitation, atropine, cardiac pacing, calcium, glucagon and vasopressors. When these fail care may escalate to ECMO.

High Dose Insulin – How it Works:

  • Under normal physiologic conditions the heart prefers to use free fatty acids as its primary energy source.
    • In a stressed state the heart turns to prefer carbohydrate and insulin appears to facilitate this preference.
    • In vitro and in vivo evidence has shown insulin’s positive inotropic and chronotropic effects(Reikeras 1985, Kline 1995).
    • Even in a CCB poisoned animal model insulin increases myocardial glucose uptake resulting in improved contractility.

Using Hyperinsulinemia Euglycemia Therapy(Lugassy 2015)

  • Hyperinsulinemia Euglycemia Therapy (HIET) Initiation:
    • Intravenous bolus of regular insulin at a dose of 1 unit/kg.
    • If serum glucose <250 mg/dL, concurrently administer a bolus of dextrose 25-50 g (or 0.5-1 g/kg) IV.
  • HIET Continuous Infusion
    • Regular insulin: 0.5 – 1 unit/kg/hr
    • Dextrose: 0.5 g/kg/hr (titrate to maintain glucose 110 – 150 mg/dL)
  • Continuous Monitoring
    • Serum glucose every 30 minutes for 1-2 hours until stable
    • Potassium every 1 hour
  • Insulin bolus infusion can take 20-30 minutes to induce clinical inotropic/chronotropic effect.
  • Increase insulin infusion by 0.5-1 unit/kg/hr every 60 minutes (similar to administration of a pressor to maintain desired hemodynamic effect.)
  • A wide range of continuous maintenance infusion of insulin for inotropic/chronotropic support have been reported with apparent safe use in the range of 3-5 Units/kg/hr.
  • In addition to monitoring glucose and electrolyte levels, it may be prudent to monitor ejection fraction. Obtain a bedside echocardiogram upon arrival to estimate the patient’s ejection fraction. Repeat after 1-2 hours of insulin therapy. An improvement in EF is a good sign the therapy is working.

Adverse Effects:

  • Most common adverse effects of HIET include hypoglycemia and electrolyte imbalances, especially hypokalemia. No irreversible adverse effects have been reported(Engebretsen 2011).
  • In a case series of seven patients with severe calcium-channel blocker overdoses in which HIET was used, serum glucose and potassium levels were monitored closely (every thirty minutes until stabilized and then every 1-2 hours). One patient had a serum glucose concentration of <65 mg/dL that was rapidly corrected. Two patients had potassium concentrations <3.5 mEq/L, but neither had ECG signs of hypokalemia of arrhythmias. No patient had clinically significant hypoglycemia or hypokalemia(Greene 2007).
  • Another case series examined twelve patients receiving HIET for drug-induced cardiogenic shock. Six patients developed a total of nineteen hypoglycemic effects and hypokalemia was seen in seven patients. No adverse arrhythmias were noted and no patients had adverse sequelae secondary to hypoglycemia or hypokalemia(Holger 2011).

Take Home Points

  • HIET has been shown to be a safe and effective treatment for BB and CCB toxicity
  • Although they have been rarely reported, hypoglycemia and hypokalemia are potential adverse events when using HIET. Monitor glucose and electrolytes closely while using this therapy.


Engebretsen KM et al High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Clin Toxicol 2011; 49(4): 277-283. PMID: 21563902

Greene SL et al. Relative safety of hyperinsulinaemia/euglycaemia therapy in the management of calcium channel blocker overdose: a prospective observational study. Intensive Care Med 2007: 33(11): 2019-2024. PMID: 17622512

Holger JS et al. High-dose insulin: a consecutive case series in toxin-induced cardiogenic shock.Clin Toxicol 2011; 49(7): 653-658. PMID: 21819291

Kerns, W. Antidotes in Depth (A18): Insulin-Euglycemia Therapy. Goldfrank’s Toxicologic Emergencies 2011, 9 e. L. S. Nelson, N. A. Lewin, M. Howland et al. New York, NY, McGraw-Hill.

Kline JA et al. (1995). Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine. Crit Care Med 1995; 23(7): 1251-1263. PMID: 7600835

Lugassy DM et al. The Critically Ill Poisoned Patient. Emergency Department Resuscitation of the Critically Ill 2015. M. E. Winters, American College of Emergency Physicians.

Mowry JB et al. 2012 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 30th Annual Report. Clin Toxicol 2012; 51(10): 949-1229. PMID: 24359283

Reikeras O et al. Haemodynamic effects of high doses of insulin during acute left ventricular failure in dogs. Eur Heart J 1985; 6(5): 451-457. PMID: 3899650

Woodward C et al. High dose insulin therapy, an evidence based approach to beta blocker/calcium channel blocker toxicity. Daru 2014; 22(1): 36. PMID: 24713415

The Approach to the Poisoned Patient

Author: Levi Kitchen, MD (EM Chief Resident, Naval Medical Center – Portsmouth) // Edited by: Alex Koyfman, MD, (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF)

This article will discuss the initial assessment, identification of toxidromes, and stabilization of patients suspected of toxic exposures. This discussion is by no means to be considered comprehensive, as Toxicology is a vast subject that cannot be quickly covered in depth. When in doubt, in the US, always call 1-800-222-1222 to speak to your regional poison control center and obtain directed advice.

General Approach

Most toxicologic exposures involve ingestions or localized chemical/biologic exposures involving single individuals with limited risk to medical personnel. In the uncommon event of an exposure which could be transmitted to emergency personnel, be sure to perform decontamination FIRST and OUTSIDE of the Emergency Department in order to not contaminate your personnel or life-saving equipment. At a minimum, the readily available PPE (cap, gown, gloves, mask, and eye protection) should be worn by all personnel in order to prevent accidental exposure.

As with all unstable patients, the initial assessment (once safe) begins with the ABCs. A detailed history and physical examination is key. Knowledge of medications, medical problems, and potential ingestions or exposures are very important historical facts in order to narrow down the list of potential toxic agents.

The physical exam should be comprehensive with special attention directed at finding evidence of a specific toxidrome. Also be wary of anchoring on the diagnosis of toxin exposure: don’t forget to keep trauma, CNS infection, and the myriad of other causes of altered mental status on the differential.

Also don’t forget the generally harmless “quick fix” medications that can rapidly reverse altered mental status in a previously comatose patient – naloxone and dextrose. Generally, patients will not be harmed with the indiscriminate provision of sugar and opioid reversal… though care should be taken in the chronic opioid abuser: lower doses are probably better such as 0.04-0.1mg IV at a time.

There are many, many reasons why drugs become toxic so remember that not all patients did something nefarious… many things affect drug clearance/protein binding/metabolism including underlying renal disease, hepatic dysfunction, dietary changes, iatrogenic, etc.

Initial orders

Now is not the time to be frugal. Full laboratory panels should be drawn, especially electrolytes, serum osmolarity, hepatic function, coags, urine beta HCG, aspirin, tylenol, ethanol, and any other specific levels based on your history and physical exam.

An EKG is a must in all unknown toxic exposures, as interval derangements and electrocardiographic clues to underlying toxicities are very common. Imaging with a chest Xray can be helpful in assessing for pulmonary edema, pill fragments, or other radiopaque objects in the chest or abdomen.

GI Decontamination

There are several methods of GI decontamination for toxic ingestions; some are very useful/beneficial while others can be harmful.

Forced Emesis – Generally never indicated, as “natural” emesis is just as good as forcing expulsion of gastric contents.

Gastric Lavage

  • Lavage with a large bore >36 French tube (not just NGT suction with a narrow tube) in order to empty the stomach of toxic contents. Awake patients should be lavaged in left lateral decubitus position to prevent aspiration and facilitate more complete gastric emptying.
  • Controversial but thought to be potentially helpful if performed within 4 hours of ingestion; preferred if initiated within one hour of ingestion.
  • Indicated if the airway is protected, removal of toxin is feasible (within a reasonable time frame), and will be beneficial if even a small amount is removed.
  • Contraindicated for caustic ingestions, large contents unlikely to be removed by lavage, unprotected airway, or timeframe when toxin has probably moved out of the stomach. 

Activated Charcoal (AC)

  • Binds toxins; not indicated for caustics, heavy metals such as lithium, lead, zinc and iron, toxic alcohols, hydrocarbons, and small molecules like sodium, chloride, etc.
  • Adult dose for unknown exposure is 60 – 90 grams, kids 1g/kg; best if can obtain a ratio of 10:1 of AC:toxin.
  • No clear timeframe for AC: definite benefit within one hour, suggested benefit within 4 hours; generally no harm in giving for any timeframe if no contraindications exist especially for large ingestions or sustained release preparations.
  • Contraindicated if absence of gut motility, perforation, risk of aspiration or if endoscopy will be needed; aspirated AC can cause severe pneumonitis.

Whole Bowel Irrigation (WBI)

  • Instillation of up to 2L per hour (25mL/kg/h for children) of polyethylene glycol solution orally (or via NGT) until the rectal effluent is clear.
  • Can be used concurrently with AC but may actually compete with toxin for binding sites on AC.
  • Especially useful for body packers and stuffers.

Caustic Ingestions

Acids – Proton donators, cause injury with pH < 3, hydrogen ions desiccate mucosal cells and cause development of an eschar (coagulative necrosis) that prevents deep penetration.

  • Can lead to metabolic acidosis with systemic absorption of acids.
  • Toilet bowl cleaners, hydrofluoric acid, etc.

Alkalis – Proton acceptors, cause injury with pH > 11, hydroxide ions penetrate tissue surfaces and cause liquefactive necrosis until neutralized. Extent of injury is dependent on duration of contact, volume, pH, concentration, penetrating ability of the substance and the TAR (titratable acid or alkaline reserve) – basically the amount of neutralizing substance required to bring the substance to physiologic pH, the higher the TAR the more damaging the substance.

  • Most household cleaning agents are alkali – ammonium hydroxide (Windex), sodium hypochlorite (bleach), oven cleaners, Drano, detergents etc.

Initial symptoms can be misleading: all patients with stridor or oral lesions require early EGD (within 12-24 hours) in order to accurately diagnose the extent of injury and decrease the risk of iatrogenic perforation.

  • Combination of multiple symptoms such as drooling, emesis, and chest pain will also likely have high-grade lesions and will need early EGD.
  • No visible lesions does not mean there is not a high-grade lesion in the esophagus or lower: clinical history and physical exam should guide further investigation.

Initial management should be for decontamination of the patient’s skin and oropharynx as necessary, aggressive control of the airway by direct visualization (consider fiberoptics), and caution with paralytics in severe burns as this may distort airway anatomy with loss of muscular tone.

  • Consider IV decadron for airway edema.

Gastric decontamination is generally contraindicated unless very early presentation of large volume toxic exposure or with certain high-risk substances as guided by poison control.

  • Can consider NGT suction for the above if present within 30 minutes; after that there is a very high risk of iatrogenic perforation with NGT so placement should be under direct visualization with EGD.
  • Initial dilution of liquid caustic ingestions with milk or water may be beneficial but should be discussed with poison control first.

Most patients will require EGD for diagnosis. In the rare patient with late presentation and suspicion of perforation, esophagogram and CT of chest/abdomen are indicated. All high-grade lesions/perforations will require surgical consultation.

***All button batteries lodged in the esophagus require emergent endoscopic removal to prevent perforation***

Body Packers and Stuffers

Body stuffer – Spontaneous ingestion of poorly packaged drugs, for instance swallowing a bag of contraband just prior to arrest.

  • Likely will not require whole bowel irrigation, usually admitted for observation for 24 hours though some suggest 6 hour observation period and then discharge if no evidence of toxidrome.

Body packer – “Drug mule,” a carefully planned ingestion of presumably carefully packaged illicit drugs.

  • If asymptomatic but known packer, can CT scan to quantify packets, or just give AC and WBI until several clear stools without packets.
  • If second CT scan at this point is negative, then they are clear (if they remain asymptomatic).
  • If known or suspected cocaine packing and the patient is symptomatic, i.e. sympathomimetic toxidrome; highly likely one of the packets has burst or is leaking, which is an indication for emergent surgery.

General considerations for hemodialysis

  • Toxin must be very small particles (able to cross the membrane).
  • Toxin will produce harm if not removed.
  • Volume of distribution should be small (1L/kg) indicating most of the toxin is in serum.
  • Toxin should not be highly protein bound (some notable exceptions include aspirin and valproic acid which are almost entirely protein bound at therapeutic levels, but at toxic levels they saturate protein binding sites and the remainder is in serum and therefore dialyzable).
  • Toxin is unable to be cleared by the body (renal failure, hepatic failure, etc.).


Anticholinergic – The old mnemonic rules supreme here – blind as a bat (mydriasis), mad as a hatter (altered mental status), hot as Hades (hyperthermic), red as a beet (flushing), dry as a bone (no sweating), the bowel and bladder increase their tone (urinary retention, decreased bowel sounds), and the heart runs alone (tachycardia).

  • Commonly described symptoms
    • Lilliputian hallucinations (picking at unseen small objects on the body), “pleasantly altered.”
    • Synesthesia – crossed sensory stimuli such as “I can taste the music.”
  • Common offending agents (many)
    • Over-the-counter medicines such as antihistamines
    • Synthetic cannabinoids like spice
    • Antipsychotics, antidepressants, antiparkinsonian drugs, antiemetics (phenothiazines), muscle relaxants (cyclobenzaprine)
  • Differentiate from sympathomimetic toxidrome by:
    • Dry skin
    • Mydriasis with limited or absent pupillary response to light
      • In anticholinergic toxidrome there is inhibition of cholinergic input to the ciliary apparatus of the eye; therefore, pupillary response to light will be limited or absent, whereas the opposite is true in the sympathomimetic toxidrome.

***For treatment myths and pearls, please see prior post: http://www.emdocs.net/physostigmine-for-management-of-anticholinergic-toxidrome/***


Agents – Cocaine, MDMA (ecstasy), ephedrine, methamphetamine, khat, etc.

Toxidrome – Hypertension, tachycardia, diaphoresis, mydriasis, hyperthermia, CNS excitation and delirium.

  • Differentiate from anticholinergic toxidrome by diaphoresis and mydriasis with brisk pupillary response.

Treatment – Benzodiazepines are the mainstay of treatment in the patient suspected of a sympathomimetic ingestion/toxicity. Benzodiazepines restore inhibitory balance to the CNS to help prevent the tremendous sympathetic outflow stimulated by these agents. Life-threatening hyperthermia may also occur; aggressive cooling measures and benzodiazepine administration are keys to early treatment.

  • For refractory hypertension, consider phentolamine (pure alpha blocker).
  • Be wary of mixed alpha/beta antagonist drugs such as labetalol as the alpha:beta ratio is very much in favor of beta blockade, approx. 1:7 ratio. Efficient beta blockade of beta-2 receptors will worsen vasoconstriction, causing nearly unopposed alpha-agonism by the original toxic agent leading to worsening hypertension.
  • Beware dysrhythmias: SVT is common and sodium channel blockade often leads to wide complex tachycardia that may degenerate into non-perfusing rhythms.
    • SVT unresponsive to benzodiazepines and cooling can be treated with calcium channel blockade.
    • Wide complex tachyarrhythmia, especially in cocaine toxicity, should be treated with empiric bicarbonate bolus and ACLS measures.


Agents: Long/short acting opioids, heroin, methadone, buprenorphine, etc.

Toxidrome – Drowsy, hypoventilation, hypotension, apnea, miosis, decreased bowel sounds.

Treatment – Largely supportive (airway support, fluids, vasopressors), if acute overdose can use naloxone in higher doses (0.4-2mg IV).

    • Caution in the chronic opioid dependent patient or opioid abuser as may precipitate withdrawal, also the patient will become agitated and combative if completely reversed immediately so should start with lower doses of repeat aliquots of 0.04-0.2mg IV.
    • Generally the goal is to find the amount required to reverse the respiratory depression and allow spontaneous respiration: the total dose given to reach this goal should be multiplied by 2/3, and this amount given as a drip per hour.       Obviously the patient needs to be monitored but in a strict opioid overdose without other factors, reversal of respiratory depression is the most important step.


Agents: Barbiturates, benzodiazepines, alcohol, GHB, sleep aids, zolpidem, buspirone.

Toxidrome – Drowsy, slurred speech, nystagmus, hypotension, ataxia, coma, respiratory depression.

Treatment is supportive, intubation as necessary for airway control, fluids/vasopressors for hypotension. Few specific antidotes, flumazenil is antidote for benzodiazepine overdose but should almost never be used… unless it is a known iatrogenic overdose of a pure benzodiazepine without any possible stimulant medication in a person that is not a chronic user of benzodiazepines nor has a history of seizures. Otherwise, may cause seizures refractory to benzodiazepine administration.

***Please see http://www.emdocs.net/wp-content/uploads/2014/10/Flumazenil-Bodford-.pdf for further details.***


Agents – Organophosphate and carbamate pesticides, nerve agents; mechanism is poisoning of acetyl cholinesterase at ganglionic and neuromuscular junctions leading to increased acetylcholine neurotransmitter stimulation, with both muscarinic and nicotinic receptor stimulation effects.

Toxidrome – DUMBBELLS (Diarrhea/Diaphoresis, Urination, Miosis, Bradycardia, Bronchorrhea, Emesis, Lacrimation, Low BP, Salivation).

    • Killer B’s (from muscarinic stimulation) – Bradycardia, Bronchorrhea, Bronchospasm.
    • Will also get nicotinic stimulation effects such as fasciculations, tetany, paralysis and increased sympathetic ganglionic stimulation which may result in paradoxical tachycardia and hypertension early.
    • Seizures are common in overdose.

Treatment – These patients will commonly need prehospital decontamination, DO NOT bring into the ED until they have been adequately decontaminated. The most common cause of death is airway compromise so early securing of the airway is paramount.

  • Atropine in high doses of 2-4mg IV at a time, keep giving until oral secretions are dry.
  • Pralidoxime (2-PAM) in order to reverse acetyl cholinesterase inhibition. This must be given early before enzyme “aging.”
  • Benzodiazepines for seizures and agitation.

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.

– Position paper update: gastric lavage for gastrointestinal decontamination. AACT/EAPCCT. Clin Toxicol. 2013;51:140-146.

– Havanond C, Havanond P. Initial signs and symptoms as prognostic indicators of severe gastrointestinal tract injury due to corrosive ingestion. J Emerg Med. 2007; 33:349-53.




Physostigmine for Management of Anticholinergic Toxidrome

Authors: Sahaphume Srisuma, MD and James Dazhe Cao, MD (Rocky Mountain Poison and Drug Center) // Editor: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) & Justin Bright, MD (@JBright2021)


Physostigmine, a carbamate extracted from Physostigma venenosum (Calabar bean), is a reversible acetylcholinesterase inhibitor that increases synaptic acetylcholine at both nicotinic and muscarinic receptors. Physostigmine’s primary therapeutic role aims to ameliorate delirium as a result of the anticholinergic (more accurately, antimuscarinic) toxidrome resultant from the blockade of muscarinic receptors by agents such as atropine, antihistamines, tricyclic antidepressant (TCA), amongst other xenobiotics. It can also be used diagnostically for undifferentiated altered mental status where anticholinergic delirium is suspected. Although physostigmine at one point historically was given liberally as part of the “coma cocktail”, more recent concerns regarding adverse events have made clinicians wary of its use. Knowledge of the evidence of physostigmine’s efficacy and adverse effects may ease hesitancy over the use of physostigmine.



Successful treatment of antimuscarinic toxicity by the use of physostigmine is limited to case series and reports. No randomized controlled trials have been conducted in humans demonstrating the efficacy of physostigmine. There are two retrospective chart reviews that evaluated the efficacy and adverse effects of physostigmine treatment.

Dr. Burns et al. in 1999 conducted a retrospective chart review comparing responses to physostigmine versus benzodiazepine in 52 antimuscarinic poisoning patients with delirium or hallucination. The authors found that physostigmine controlled agitation in 96% of patients as compared to only 24% of patients treated with benzodiazepines. Physostigmine also reversed delirium in 87% of patients, whereas none with benzodiazepines. Mean response time to physostigmine was 10.9 ± 5.3 minutes. Of the cases with response to physostigmine, 78% of patients had relapse of symptoms with a mean time of 100 ± 42 minutes. All patients receiving physostigmine received multiple doses. Time to recovery without further relapse was shorter in cases using physostigmine, but there was no significant difference in overall hospital length of stay.[1]

Schneir et al. in 2003 reviewed retrospectively 39 cases where physostigmine was administered diagnostically in cases of delirium.

 Adverse Effects and Toxicities

The principal adverse effects of physostigmine are related to cholinergic excess including bradycardia, bronchospasm, bronchorrhea, seizure, and motor weakness. Less severe symptoms are nausea, vomiting, diarrhea, miosis, tremor, and fasciculation.

The most concerning and also controversial adverse effects of physostigmine are bradydysrhythmias and asystole in case with use for TCA poisoning. Widespread concern for the use of physostigmine followed the landmark series of two cases by Drs. Pentel and Peterson in 1980. One case was a severe amitriptyline poisoning presented with alteration of consciousness with response only to deep pain. After intubation, patient developed status epilepticus. Initial EKG showed very wide QRS complex (approximately 240 msec) and first degree AV block. After administration of physostigmine 2 mg IV over three minutes, patient developed nodal bradycardia and further asystole. The second case was of imipramine and propranolol poisoning that had two episodes of seizure and hypotension. Physostigmine 2 mg IV was given over five minutes after each episode of seizure. After second dose of physostigmine, patient developed bradycardia and progressed to asystole. The authors concluded that the “use of physostigmine in patients who have ingested an overdose of TCAs carries the risk of life-threatening bradyarrhythmias.”[11] Although the authors correctly noted that bradycardia is uncommon in TCA overdose, bradydysrhythmias and asystole may be terminal events in the setting of severe TCA toxicity.[10] NaHCO3 was not given to treat sodium channel blockade effect of severe TCA toxicity prior to cardiac arrest. Additionally, underlying conduction delay demonstrated by the first degree AV block in case one and co-ingestion of propranolol in case two may have contributed to the adverse outcomes. Even so, the case series yielded significant concern for the use of physostigmine in the setting of TCA overdose, QRS prolongation, and/or PR prolongation.

In Burns’ 1999 publication, there was no difference in side effects defined as complications arising within 30 minutes of medication administration and between cases treated with physostigmine and with benzodiazepine. However in this study, PR prolongation (>200 msec) or QRS widening (>100 msec and not related to bundle branch block) were considered as contraindication to physostigmine. Side effects were reported in five of 45 cases with physostigmine – one of each of the following: diaphoresis, emesis, diarrhea, asymptomatic bradycardia @ 51 beats/minute, and increased respiratory secretions. In the 25 cases with benzodiazepine, there were side effects reported in four cases including two with excessive sedations, one fecal incontinence, and one paradoxical agitation. There were five cases with TCA poisoning in this series, all had ingested amitriptyline at least 12 hours before physostigmine administration. None had coma, seizures, hypotension, cardiac conduction disturbances, or significant dysrhythmias although significant TCA toxicity would have likely been excluded from the study.[1]

In Schneir’s series, one of 39 cases had brief convulsions without adverse sequelae after treatment with physostigmine. The patient ingested doxylamine and presented after a witnessed 1-2 minutes of seizure. He was later suspected to have antimuscarinic delirium for which he received physostigmine 0.5 mg IV with full reversal of delirium. Twelve minutes after administration of physostigmine, the patient had a 30 second generalized convulsion without further convulsions or sequelae during the remainder of the hospitalization. EKG was available in 37 cases. Only one case had QRS > 120 msec (138 msec) which was known to be a preexisting right bundle branch block. Of the three TCA cases in the series, none of the patients had dysrhythmias. There were no cases of cholinergic excess following physostigmine administration.

Three other case series have described incidence of seizures temporally after physostigmine administration. Newton et al. in 1975 reported convulsions in two of 21 patients treated with physostigmine for TCA overdoses.[12] Walker et al. in 1976 described convulsions in three out of 26 overdose patients treated with physostigmine. Of the 26 patients, 17 were reported to have ingested TCAs.[13] Knudsen et al. in 1984 described a series of 41 patients after ingestion of maprotiline where six of seven patients treated with physostigmine developed convulsions.[10]

Discussion and Recommendation

            From the understanding of physostigmine’s mechanism of action and the above data, we would like to summarize key points and recommendations regarding the use of physostigmine. First, physostigmine is beneficial in reversing central antimuscarinic symptoms including agitation, delirium, and/or hallucinations. When properly administered, physostigmine may be more efficacious than benzodiazepines for management and lowers risk of excessive sedation from high doses of benzodiazepine. Physostigmine can also be applied diagnostically for undifferentiated delirium; preventing unnecessary investigation, especially in children.

Second, physostigmine will NOT treat symptoms from pathophysiology other than antimuscarinic effects. Without any antimuscarinic symptoms, do NOT use physostigmine to treat unspecified coma or dysrhythmias. Physostigmine may help with antimuscarinic effect of tricyclic antidepressant but is unlikely to reverse serotonergic effect or alpha adrenergic blockade of TCAs. Physostigmine has no direct reversing properties for sodium channel blockade in TCAs. Theoretically by slowing the heart rate, physostigmine may improve cardiac sodium channel blockade. However, data for this hypothesis is virtually nonexistent in humans and conflicting in animal studies. Therefore in cases of TCA overdose, it is very important to focus on which clinical symptoms are significant and need to be treated.

Third, when using physostigmine, understand the risks and adverse effects. The concerning adverse effects of cholinergic excess include seizure, bradycardia, bronchospasm, and bronchorrhea. We recommend AGAINST using physostigmine for treatment of seizures caused by an anti-muscarinic agent. Benzodiazepine may be the most appropriate first choice. We also recommend AGAINST using physostigmine in cases with bradycardia or AV block. The use of physostigmine for cases with QRS widening remains controversial. We recommend focusing on therapies targeted at reversing cardiac sodium channel blockade by either administration of NaHCO3 or hypertonic saline.

Dosing Recommendations

We recommend 1-2 mg (0.05 mg/kg, maximum initial dose of 0.5 mg in children) IV slow infusion over at least 5 minutes to reduce the risk of seizures. Dose may be repeated for incomplete response after 5 to 10 minutes up to a maximum of 2 mg in children and 4 mg in adults. Always have atropine and a benzodiazepine at bedside in case of significant cholinergic excess symptoms or seizures, respectively. Response to physostigmine can occur rapidly (within minutes), but the duration of effect of physostigmine tends to be shorter than that of antimuscarinic agents. Observe for recurrence of antimuscarinic symptoms, and assess if the patient will need repeated dosing of physostigmine.


Physostigmine is beneficial for central and peripheral antimuscarinic symptoms. With appropriate use, it has a low risk of side effects and complications.


References / Further Reading

[1] Burns MJ, Linden CH, Graudins A, Brown RM, Fletcher KE. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Annals of emergency medicine. 2000;35:374-81.

[2] Schneir AB, Offerman SR, Ly BT, Davis JM, Baldwin RT, Williams SR, et al. Complications of diagnostic physostigmine administration to emergency department patients. Annals of emergency medicine. 2003;42:14-9.

[3] Glatstein MM, Alabdulrazzaq F, Garcia-Bournissen F, Scolnik D. Use of physostigmine for hallucinogenic plant poisoning in a teenager: case report and review of the literature. American journal of therapeutics. 2012;19:384-8.

[4] Johnson PB. Physostigmine in tricyclic antidepressant overdose. Jacep. 1976;5:443-5.

[5] Rumack BH. Anticholinergic poisoning: treatment with physostigmine. Pediatrics. 1973;52:449-51.

[6] Phillips MA, Acquisto NM, Gorodetsky RM, Wiegand TJ. Use of a physostigmine continuous infusion for the treatment of severe and recurrent antimuscarinic toxicity in a mixed drug overdose. Journal of medical toxicology: official journal of the American College of Medical Toxicology. 2014;10:205-9.

[7] Padilla RB, Pollack ML. The use of physostigmine in diphenhydramine overdose. The American journal of emergency medicine. 2002;20:569-70.

[8] Cole JB, Stellpflug SJ, Ellsworth H, Harris CR. Reversal of quetiapine-induced altered mental status with physostigmine: a case series. The American journal of emergency medicine. 2012;30:950-3.

[9] Weizberg M, Su M, Mazzola JL, Bird SB, Brush DE, Boyer EW. Altered Mental Status from Olanzapine Overdose Treated with Physostigmine. Clinical toxicology. 2006;44:319-25.

[10] Knudsen K, Heath A. Effects of self poisoning with maprotiline. Br Med J (Clin Res Ed). 1984;288:601-3.

[11] Pentel P, Peterson CD. Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Annals of emergency medicine. 1980;9:588-90.

[12] Newton RW. Physostigmine salicylate in the treatment of tricyclic antidepressant overdosage. JAMA : the journal of the American Medical Association. 1975;231:941-3.

[13] Walker WE, Levy RC, Hanenson IB. Physostigmine–its use and abuse. Jacep. 1976;5:436-9.

[14] http://www.ncbi.nlm.nih.gov/pubmed/25510306

[15] http://www.ncbi.nlm.nih.gov/pubmed/22461927


Intern Report Collection, Vol. 5

To kick off your weekend reading pleasure, here’s another batch of excellent write-ups from the EM interns at UT Southwestern (@DallasEMed) courtesy of Alex Koyfman (@EMHighAK) . Our ongoing intern report series is the product of first-year residents exploring clinical questions they have found to be particularly intriguing, with an intended audience of med students & junior residents. Enjoy!

[Note: These are PDF files.]

Lipid Emulsion Therapy


Intravenous lipid emulsion (ILE, also known as lipid emulsion therapy, lipid resuscitation therapy, lipid rescue, intravenous fat emulsion and Intralipid®) has been used in the past for caloric supplementation and treatment of essential fatty acid deficiency.  Since 1998, ILE has been considered for resuscitative therapy in drug-induced cardiovascular and neurologic toxicity.  The use of ILE has been best described for cardiovascular collapse and seizures caused by local anesthetic systemic toxicity (LAST) with successful animal trials and human case reports.  Subsequent to these findings, the use of ILE in LAST is recommended by the latest guidelines for the American Heart Association, American Society of Regional Anesthesia and Pain Medicine (ASRA), and the Association of Anaesthetists of Great Britain and Ireland.  ILE has also been used as a resuscitative agent for a number of lipid- and water-soluble xenobiotics that induce cardiac and/or neurologic toxicity including tricyclic antidepressants, non-dihydropyridine calcium channel blockers, bupropion, citalopram, venlafaxine, atypical anti-psychotics, beta-blockers, diphenhydramine, etc.  See table 1 for a complete list of xenobiotics for which ILE has been attempted in case reports and abstracts.

Proposed Mechanisms

The exact mechanism of action has yet to be elucidated.  Two theoretical mechanisms of action have been widely described: partitioning and enhanced metabolism.  The partitioning theory or otherwise termed the “lipid sink” theory postulates that the administration of lipids compartmentalizes the offending xenobiotic into lipid phase and away from the target receptors.  Resuscitation of toxicity mediated by xenobiotics with high lipid solubility (defined as log P, octanol:water partition coefficient, greater than 2) are more likely to be successful although the intervention has worked for water-soluble xenobiotics.  The enhanced metabolism theory argues that the infusion of triglyceride and phospholipids are capable of providing fatty acid energy source to myocytes under toxic conditions.  Myocardium is capable of utilizing fatty acids for energy although in stressed states, cardiac myocytes preferentially utilized carbohydrates, a theory that gives credence to the use of high dose insulin therapy in calcium channel and beta blocker toxicity.

Administration Recommendations

Current recommendation from ARSA for 20% lipid emulsion therapy for LAST:

  1. Bolus 1.5 mL/kg (lean body mass) intravenously over one minute (Note that the dose is in volume, not weight)
    • 100 mL for a 70 kg patient
    • Repeat bolus for persistent cardiovascular collapse
  2. Continuous infusion 0.25 mL/kg/min
    • 18 mL/min for a 70 kg patient
    • Can double the infusion rate for persistent hemodynamic instability
    • Continue infusion for at least 10 minutes after hemodynamic recovery

In the setting of persistent cardiovascular collapse or hemodynamic instability, the upper limits of therapy are also not established.  ARSA recommends the upper limits of 10 mL/kg (700 mL in a 70 kg patient) over the first 30 minutes.


Elevated serum triglycerides may interfere and prevent routine laboratory analysis including serum electrolytes, hematocrit, liver function tests, and coagulation function.  A false negative aspartate transaminase (AST) resulted in the premature discontinuation of n-acetylcysteine in a co-ingestion of acetaminophen, amitriptyline, and diphenhydramine.  A 13-year-old female developed acute pancreatitis and acute respiratory distress syndrome after receiving the ARSA recommended dose of lipid emulsion therapy for a tricyclic antidepressant overdose.  Serum amylase elevations have also been reported.

Bottom Line

Unfortunately, the lack of high-quality controlled human studies precludes lipid emulsion therapy as a first-line agent for indications other than local anesthetic systemic toxicity.  In the setting of severe hemodynamic compromise caused by a lipid-soluble xenobiotic or drugs with cardiovascular and/or neurologic toxicity, lipid emulsion therapy should be considered early in the resuscitation but is not the standard of care at this time.

Discussion Questions

  • What is the evidence supporting the use of intravenous lipid emulsion (ILE) in this patient?
  • Under what other acute poisonings should emergency department providers consider the use of ILE?
  • How should ILE be administered?
  • What are reported and potential adverse effects of ILE?
  • How does ILE adversely impact laboratory monitoring?
  • What are the considerations for stocking ILE in emergency departments?

Further Reading

  1. Weinberg GL. Lipid emulsion infusion: resuscitation for local anesthetic and other drug overdose. Anesthesiology. 2012;117:180-7.
  2. Neal JM, Mulroy MF, Weinberg GL, American Society of Regional A, Pain M. American Society of Regional Anesthesia and Pain Medicine checklist for managing local anesthetic systemic toxicity: 2012 version. Regional Anesthesia and Pain Medicine. 2012;37:16-8.
  3. American College of Medical Toxicology. ACMT position statement: interim guidance for the use of lipid resuscitation therapy. Journal of Medical Toxicology. 2011;7:81-2.
  4. http://www.ncbi.nlm.nih.gov/pubmed/24338451
  5. http://www.ncbi.nlm.nih.gov/pubmed/23518248
  6. http://www.ncbi.nlm.nih.gov/pubmed/23992445
  7. http://www.ncbi.nlm.nih.gov/pubmed/23685061
  8. http://www.ncbi.nlm.nih.gov/pubmed/20923546
  9. http://www.ncbi.nlm.nih.gov/pubmed/20688937
Edited by Alex Koyfman, MD


Table 1: Xenobiotic overdose responses to ILE from 2006 to 2013 in case reports and abstracts.