Tag Archives: #FOAMtox


Author: Brian P. Murray, DO (@bpatmurray Senior EM Resident Physician, Resident Brooke Army Medical Center) // Edited by: Cynthia Santos, MD (Senior Medical Toxicology Fellow, Emory University School of Medicine), Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital), and Brit Long, MD (@long_brit)
Case Presentation:

A 53-year-old man presents to the Emergency Department with a history of 12 alcoholics drinks daily. His last drink was 24 hours ago, and he is feeling anxious and jittery. Vital signs: HR 90, BP 135/90, RR 18, T 98.9oF, SpO2 97% room air.  


How can you determine the severity of withdrawal and the need for inpatient versus outpatient management?


The use of the 10 item CIWA-AR score is a rapid and effective tool that can help objectively rate the level of alcohol withdrawal. [1]

  • Alcohol withdrawal syndrome is a spectrum of disorders ranging from mild symptoms to life threatening seizures and delirium tremens. [2]
  • The CIWA-AR score cannot differentiate the different types of alcohol withdrawal syndromes nor between delirium tremens and medical causes of delirium. [3]
  • The score ranges from 0 (no withdrawal) to 67 (severe withdrawal) and can be easily repeated for evaluation of worsening or improving withdrawal.
  • The score incorporates the scores from the categories “Nausea and Vomiting” (0-7), “Tremors” (0-7), “Paroxysmal Sweats” (0-7), “Anxiety” (0-7), “Agitation” (0-7), “Tactile Disturbance” (0-7), “Auditory Disturbance” (0-7), “Visual Disturbance” (0-7), “Headache of Fullness” (0-7), and “Clouding of Sensorium” (0-4).
  • A score of 0-9 is considered mild withdrawal and can be managed as an outpatient with supportive can with or without medical management, at the discretion of the physician.
  • A score of 10-19 is considered moderate withdrawal and should be considered for admission for acute medical detoxification.
  • A score of >20 is considered severe withdrawal and the patient should be admitted to a high acuity unit, such as an ICU, for close monitoring and medical detoxification.
  • If the CIWA-AR score remains high even after adequate medical management, the patient likely has a comorbid medical delirium. [4]
  • A similar 20 item CIWA-B score is also available for use with acute benzodiazepine withdrawal. [5]
Main Point:

The CIWA-AR score is an effective tool that can be employed in less than 5 minutes to objectively score the level of withdrawal. It can also be repeated to assess efficacy of treatment of progression of withdrawal. The tool can be useful in determining the ultimate disposition of the patient; whether they can be discharged to outpatient care (score 0-9), require floor admission (10-19), or ICU admission (score >20).


1.      Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA‐Ar). British journal of addiction. 1989 Nov 1;84(11):1353-7.

2.      Kattimani S, Bharadwaj B. Clinical management of alcohol withdrawal: A systematic review. Industrial psychiatry journal. 2013 Jul;22(2):100.

3.      Chabria SB. Inpatient management of alcohol withdrawal: A practical approach. Signa Vitae. 2008;3:24–9.

4.      Bharadwaj B, Bernard M, Kattimani S, Rajkumar RP. Determinants of success of loading dose diazepam for alcohol withdrawal: A chart review. Journal of Pharmacology and Pharmacotherapeutics. 2012 Jul 1;3(3):270.

5.      Busto UE, Sykora K, Sellers EM. A clinical scale to assess benzodiazepine withdrawal. Journal of clinical psychopharmacology. 1989 Dec 1;9(6):412-6.

Tox Cards: Narcan (naloxone)

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


Case presentation:

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


What dose Narcan should you give?


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

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

 Main Point:

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



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



Hydrofluoric Acid: The Burn that keeps on Burning

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

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


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


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


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

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

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

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

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


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


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

Cutaneous Exposures

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

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

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

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

Ocular Exposures

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

Ingestion Exposures

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

Inhalation Exposures

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

Case Outcome

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


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


References/Further Reading

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

A Case of Severe Brown Recluse Envenomation

Authors: Andrew Pirotte, MD (Department of Emergency Medicine, Lawrence Memorial Hospital, Lawrence, Kansas), Jacquelyn Wagner, MS2 (University of Kansas School of Medicine, Kansas City, Kansas), Matthew Pirotte, MD (Northwestern Memorial Hospital, Department of Emergency Medicine, Chicago, Illinois) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit, EM Attending Physician at SAUSHEC)

A 68-year-old male with history of diabetes mellitus, hypertension, and hyperlipidemia presents to the emergency department with a chief complaint of a severe right upper extremity (RUE) pain, hives, and diffuse erythema.  He reports a possible insect bite after donning a sweater.  He had initially visited an urgent care facility where he was diagnosed with cellulitis and prescribed doxycycline. His pain increased, and he developed a diffuse erythematous and urticarial rash, which led to his visit to the emergency department.

Initial vital signs include temperature 100.4 F (oral), heart rate 109, blood pressure 145/86, respirations 18, and pulse oximetry 95% on room air.  On physical examination, the patient has diffuse hives and erythema particularly over trunk and extremities without mucosal involvement. The right upper extremity has an 8 cm area of induration, mottling, and tenderness to palpation just distal to the axilla. The neurovascular exam of the affected extremity is intact.


The initial differential diagnosis included spider bite with a consideration of brown recluse envenomation (Loxosceles reclusa), worsening cellulitis, necrotizing skin and soft tissue infection, and allergic reaction.  The decision was made to monitor the patient in ED and draw labs for further evaluation. Diphenhydramine 50 mg PO x 1 was provided to treat possible allergic reaction from the doxycycline.

Labs return with the following: Hg 15.2, WBC 9.8, Plt 144, Chem 135/95/17/3.5/29/1.3, Gluc 146, and Lactic Acid 2.4

Upon reassessment, the hives and erythema had significantly improved, but he continued to complain of significant pain in his right upper extremity.  Admission was considered, though ultimately the patient was discharged home given improving clinical status, near-total resolution of hives, and non-toxic appearance.  As brown recluse bite was the leading diagnosis, complicated by likely allergic reaction to doxycycline, this antibiotic was discontinued, and the patient was started on antihistamines and analgesia (hydrocodone-acetaminophen 5-325 mg po q4-6 prn pain).  Steroids were withheld given the patient’s history of diabetes mellitus.

The following day, the patient returned to the ED with significant progression of swelling, pain, and redness. The patient reported that he now felt systemically ill. His repeat vitals were temperature 101.2 F (oral), heart rate 90, blood pressure 120/53, respirations 16, and pulse oximetry 98% on room air.  His hives and erythema had resolved.  His right upper extremity exam now demonstrated deepening of the previously noted mottling with two punctate puncture wounds centrally located suggestive of a bite. The surrounding tissue was edematous and ecchymotic with approximately 15 centimeter diameter of involved tissue.  The skin was warm to touch and markedly tender to palpation. No crepitus was noted.  An intravenous line was placed, IV fluids initiated, and labs were redrawn.


Repeat lab results included Hg 14.2 WBC 9.8, Plt 141, Chem 136/3.2/95/29/17/1.3/142, Lactic acid 2.1.

After IV fluids, patient continued to feel ill and his pain persisted despite IV analgesia.  Clinical history, laboratory results, and physical exam favored brown recluse bite (necrotic cutaneous loxoscelism) over cellulitis or necrotizing fasciitis, though his disposition was guarded. The patient was admitted for further monitoring, pain control, serial laboratory draws, and general surgery evaluation. Overnight the patient’s fever persisted despite antipyresis, and vancomycin was initiated.

screen-shot-2016-09-20-at-1-58-31-amThrough his subsequent 12-day hospitalization, the patient’s RUE lesion evolved significantly and caused persistent and severe pain requiring morphine patient-controlled analgesia (PCA).  Infectious disease and general surgery teams were consulted and recommended continued antibiotics and elevation.


Ultimately the patient was discharged on hospital day 13 with oral narcotics, amoxicillin, and silvadene, with general surgery follow up for wound care.

After discharge from the hospital the patient continued to experience persistent, severe pain.  His wound morphology continued to evolve:



The general surgery team subsequently escalated to wound debridement and placement of a commercial wound suction screen-shot-2016-09-20-at-1-59-47-amdressing (Day 23).

Despite these efforts, on day 24, the patient returned to the ED with continued severe RUE pain, in addition to vomiting and right upper quadrant abdominal pain.

Vitals were as follows: Temperature 100.4 F, heart rate 97, blood pressure 148/71, respirations 20, and pulse oximetry 91% on room air.

Lab results returned with Hg 12.9, WBC 10.3, Plt 222; Chem: 138/3.2/97/25/18/0.9, Gluc 135; Lipase 1252

AST 96, ALT 84, Tbili 1.1, Alk Phos 201; Lactic acid 2.1

Given these findings, particularly the transaminitis with elevated lipase, the initial working diagnosis was gallstone pancreatitis.  However, there was only moderate LFT/bilirubin elevation and no biliary dilation or stones noted on CT or ultrasound.  Another diagnostic consideration – though rare and ultimately not proven to be the case with this patient – was so-called viscerocutaneous loxoscelism (further explored in the discussion below).

The patient was readmitted to the hospital for IV fluids and analgesia. Due to the elevated LFTs and lipase, a decision was made to proceed with laparoscopic cholecystectomy. Following this procedure the patient’s LFTs and lipase began to downtrend, and he was discharged home.

Although the patient’s systemic symptoms had resolved, the RUE lesion continued to evolve showing severe tissue destruction, soft tissue defect, and minimal improvement with the wound vacuum.




On post-operative day 3, the initial outcome of the skin graft was acceptable, though some tissue loss was noted peripherally by the surgical team.screen-shot-2016-09-20-at-2-01-26-am

On post-operative day 10, there was a small area of tissue located proximally and medially that required intermittent packing, but a good general progression was noted by the surgical team.



At around day 100, the patient reported he was beginning to feel  normal again, with near total resolution of symptoms.

At approximately four months (Day 127) from initial bite, the patient’s arm began showing definitive healing.




The brown recluse spider, Loxosceles reclusa, is known commonly as Fiddleback, violin spider, and brown spider.  The scientific name translates as follows: Loxos – slanting or oblique; skeles – leg; reclusa – hermit or enclosed.  Combined these terms essentially become: Slanted-leg reclusescreen-shot-2016-09-20-at-2-04-05-am

These solitary spiders have six eyes arranged in dyads, are about 7mm in body length and are tan or brown, with their legs often darker than the cephalothorax. With legs extended the total width of the spiders is about 2.5 cm.  Upon close examination, a violin-shaped pattern is evident on the thorax – this pattern is common to all members of the loxosceles genus, although it is not present in juveniles (9)(6).screen-shot-2016-09-20-at-2-04-13-am


screen-shot-2016-09-20-at-2-04-23-amLoxosceles spiders are common in the North American mid-west, as they inhabit much of this geographic area. The genus as a whole includes thirteen species and inhabits a large portion of the United States (2).


Brown recluses are commonly found in many locations, though protected cover is most common. Examples of these may include leaf beds, rotting tree bark, wood piles.  Additionally, the spiders thrive in man-made environments.  Examples of these may include less disturbed areas such as basements, garages, and closets.  Recluses can also be found in clothing piles, boxes, shoes, etc., where they rest, breed, and form irregular webs (9). They are most active from spring to fall at night when they leave their webs to stalk food, which generally consists of silverfish and other insects.  They are incredibly resilient — capable of surviving 6 months without food or water (6). In addition, efforts to eliminate them with chemicals has questionable efficacy (6)(19).  As the name implies, brown recluse spiders are not social creatures.  Despite suggestions on the aggressiveness of their predatory nature, they do not seek out humans as prey.  Rather, Loxosceles reclusa bite in defense or in response to being crushed between an object and skin (15)(9).


The venom of Loxosceles reclusa contains a myriad of toxins including metalloproteinases, hyaluronidases, insecticidal peptides, deoxyribonucleases, and alkaline phosphatase (2).  Sphingomyelinase D is the toxic protein of most interest (present only in the genera Loxosceles and Sicarius). Once delivered, it acts quickly to attack phospholipid structure and integrity.  The toxin acts by altering the typical head/tail orientation of the phospholipid molecule into a ring structure, with complete destruction of the hydrophilic head. This creates a manipulated molecular structure, greatly dissimilar from the linear phospholipid, resulting in destabilization of the cell membranes (12).

Regarding host response, Loxosceles reclusa venom has been defined as an endothelial cell agonist that results in differential stimulation of the inflammatory response.  This causes a loss of endothelial cell integrity and junctions, which results in extracellular space edema, hemorrhage, vessel wall degeneration, polymorphonuclear lymphocyte accumulation, and edema of the immediate muscle and soft tissue (17)(18)(13).

In addition to these toxic effects, sphingomyelinase D induces red blood cell (RBC) hemolysis and platelet aggregation by degrading the sphingomyelin component of the erythrocyte membrane (17)(10).

Finally, Loxosceles reclusa venom can induce the cleavage of endogenous metalloproteinase, resulting in degradation of glycophorins on the RBC surface (17)(13). Complement-mediated lysis of the erythrocytes is then activated via the alternative pathway (17).


Generally speaking, bites from recluses are minimally symptomatic. When there is a significant response to envenomation, the syndrome is so-called loxoscelism.  This syndrome is most commonly a local response characterized by pain, erythema, soft tissue swelling, and central pallor around the bite site for the first several hours. Often the evolution of the bite stops at this stage.  In cases with progressive cutaneous change, the morphology of the bite evolves to a blotchy blue or violet color and a hard depressed center (17)(10).  Assuming the bite is on the torso or lower extremity, the expanding lesion is often oval shaped and wider inferiorly, possibly due to gravity ‘pulling’ the venom inferiorly.  Envenomation can also result in vesicles, blisters, or necrotic ulcers of the cutaneous tissue and tissue loss, known as necrotic arachnidism or necrotic cutaneous loxoscelism (1)(2). As the cutaneous lesion develops, the venom is capable of causing intravascular clotting resulting in the occlusion of venules and arterioles (10). In more severe cases wounds can cause significant geographic progression and skin sloughing. The site can extend up to 40 cm wide and can involve deep structures. These wounds can take many weeks to heal by secondary intent (17).

Rarely, envenomation from Loxosceles reclusa can result in a serious systemic response syndrome known as viscerocutaneous loxoscelism (as considered in the above case study). This response can include pancreatitis, hemolytic anemia, jaundice, fever, disseminated intravascular coagulation (DIC), rhabdomyolysis, myonecrosis, and renal failure (3).

While the mechanism of viscerocutaneous loxoscelism is not fully understood, recluse venom is likely capable of inflicting direct visceral damage, particularly to the renal, hematologic, and gastrointestinal systems.  Renal injury, for example, includes multiple pathways: glomerular edema, tubular necrosis, and hyalinization of tubules (7).  Immunofluorescence studies have shown dermonecrotic toxin deposits on renal intrinsic structures – suggesting renal insult is a direct result of the envenomation of Loxosceles reclusa, rather than simply a manifestation of severe systemic illness (7). These findings would suggest visceral injury is a direct result of the envenomation, rather than simply a manifestation of critical illness.

A single study showed a potential relationship between glucose-6-phosphate deficiency (G6PD) and viscerocutaneous loxoscelism (3). In this case series, two out of seven patients screened with VL were positive for G6PD, possibly manifesting VL through oxidative strain resulting in hemolytic anemia.

Finally, fatal loxoscelism is more commonly associated with a fellow member of the genus (Loxosceles laeta), which is found in South America (2).

Differential Diagnosis

When assessing a possible brown spider bite, two of the most important considerations are geographic location, and Loxosceles reclusa sighting or presence. Because there is a lack of a commercially available assay for L. reclusa venom, definitively diagnosing an envenomation is difficult. The lesions can mimic various infections, ulcerations from trauma, vascular diseases, pyoderma gangrenosum, Stevens-Johnson syndrome, erythema nodosum, or erythema multiforme (15)(17).  Cases within affected geographic areas, with a suggestive clinical story (eg pain following donning of clothing) should result in a high suspicion for recluse envenomation.


Routine first aid treatment of L. reclusa bites is generally indicated to control inflammation and pain. This includes immobilization, ice, elevation, local wound care, NSAID administration as needed, and tetanus prophylaxis (1)(8). Because the majority of bites are minimally symptomatic, most can be treated with little medical intervention.  Treatment of more severe manifestations of envenomation is more challenging.  For secondary infections at the wound site, characterized by suppuration, increased erythema, and fluctuance, antibiotics targeted at cellulitis are indicated (1)(11).  For necrotic wounds, multiple therapies have been considered, though are not well supported with outcome data.  As illustrated in the case above, prognostication for these bites can be challenging.  In addition to treatment, it is critical to counsel patients regarding the variable outcomes from suspected L. reclusa bites.


– Brown recluse spiders are found in southern North America, with six eyes and a violin pattern on the thorax.

– The spiders are commonly found in isolated, man-made locations with cover. These spiders are very resistant to adverse enviroments.

– A bite is normally in defense, with venom containing metalloproteinases, hyaluronidases, insecticidal peptides, deoxyribonucleases, and alkaline phosphatase. These proteins destroy cells, resulting in tissue death.

– Bites normally have few symptoms. Loxoscelism occurs with significant local response that may transition through stages, ultimately resulting in skin breakdown. Systemic reactions are rare.

– The differential includes infections, ulcerations from trauma, vascular diseases, pyoderma gangrenosum, Stevens-Johnson syndrome, erythema nodosum, or erythema multiforme.

– Treatment includes immobilization, ice, elevation, local wound care, NSAID administration as needed, and tetanus prophylaxis. For necrotic wounds, multiple therapies have been considered, though are not well supported with outcome data.


References / Further Reading:

  1. Andersen, Rebecca J., Jennifer Campoli, Sandeep K. Johar, Katherine A. Schumacher, and E. Jackson Allison. “Suspected Brown Recluse Envenomation: A Case Report and Review of Different Treatment Modalities.” The Journal of Emergency Medicine 41.2 (2011): E31-37. Web.
  2. Arnold, Thomas. “Brown Recluse Spider Envenomation.” Emedicine. Web. 18 March 2016.
  3. Barretto O, Cardoso L, De Cillo D. Viscerocutaneous Loxoscelism and Erythrocyte Glucose-6-PhosphateDeficiency. Rev Inst Med. Trop S. Paulo. Internet. 1985 October; 27(5): 264-267
  4. “Brown Recluse Spiders: Facts, Identification & Control” orkin.com. Web.
  5. “Brown Recluses – Brown Recluse Spider Map.” University of California Riverside Entomology. Web.
  6. “Brown Recluse: Loxosceles Reclusa.” Arachnipedia.wiki.com. Web. 23 March 2016.
  7. Chaim, Olga Meiri, Youssef Bacila Sade, Rafael Bertoni Da Silveira, Leny Toma, Evanguedes Kalapothakis, Carlos Chávez-Olórtegui, Oldemir Carlos Mangili, Waldemiro Gremski, Carl Peter Von Dietrich, Helena B. Nader, and Silvio Sanches Veiga. “Brown Spider Dermonecrotic Toxin Directly Induces Nephrotoxicity.” Toxicology and Applied Pharmacology 211.1 (2006): 64-77. Web. July 2016.
  8. Elston, Dirk M., Scott D. Miller, Russell J. Young, Jeff Eggers, David Mcglasson, William H. Schmidt, and Anneke Bush. “Comparison of Colchicine, Dapsone, Triamcinolone, and Diphenhydramine Therapy for the Treatment of Brown Recluse Spider Envenomation.” Archives of Dermatology 141.5 (2005): 595-97.
  9. Forks, T. P. “Brown Recluse Spider Bites.” The Journal of the American Board of Family Medicine 13.6 (2000): 415-23. Web.
  10. Futrell, Josephine M. “Loxoscelism.” The American Journal of the Medical Sciences 304.4 (1992): 261-67.
  11. Hogan, Christopher J., Katia Cristina Barbaro, and Ken Winkel. “Loxoscelism: Old Obstacles, New Directions.” Annals of Emergency Medicine 44.6 (2004): 608-24. Web.
  12. Lajoie, Daniel M., Pamela A. Zobel-Thropp, Vlad K. Kumirov, Vahe Bandarian, Greta J. Binford, and Matthew H. J. Cordes. “Phospholipase D Toxins of Brown Spider Venom Convert Lysophosphatidylcholine and Sphingomyelin to Cyclic Phosphates.” PLoS ONE 8.8 (2013): n. pag. Web.
  13. Patel, K. D., V. Modur, G. A. Zimmerman, S. M. Prescott, and T. M. Mcintyre. “The Necrotic Venom of the Brown Recluse Spider Induces Dysregulated Endothelial Cell-dependent Neutrophil Activation. Differential Induction of GM-CSF, IL-8, and E-selectin Expression.” Journal of Clinical Investigation J. Clin. Invest. 94.2 (1994): 631-42. Web. July 2016.
  14. Málaque, Ceila Maria Sant’ana, Jaime Enrique Castro-Valencia, João Luiz Costa Cardoso, Francisco Oscar De Siqueira França, Kátia Cristina Barbaro, and Wen Fan Hui. “Clinical and Epidemiological Features of Definitive and Presumed Loxoscelism in São Paulo, Brazil.” Revista Do Instituto De Medicina Tropical De São Paulo Rev. Inst. Med. Trop. S. Paulo 44.3 (2002): 139-43. Web.
  15. Potter, Mike. “Brown Recluse Spider.” UKY Entomology. University of Kentucky College of Agriculture, June 2005. Web. July 2016.
  16. Szalay, Jessie. “Brown Recluse Spiders: Facts, Bites, Symptoms.” LiveScience.com. Web.
  17. Swanson, David L., and Richard S. Vetter. “Loxoscelism.” Clinics in Dermatology 24.3 (2006): 213-21. Web July 2016.
  18. Vetter, Richard S., MS, and David L. Swanson, MD. “Bites of Recluse Spiders.” UpToDate. Ed. Daniel F. Danzl, Stephen J. Traub, and James F. Wiley. Web. July 2016.
  19. “Where Do Brown Recluse Spiders Live? (Dwellings & Range).” Orkin. Web. July 2016.


FOAMed Resource Series Part IV: Toxicology

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

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

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


  1. http://www.thepoisonreview.com


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

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


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

  1. http://toxnow.org


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

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


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

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


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

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


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

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


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

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

Drug Withdrawal: Pearls and Pitfalls

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

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

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


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



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

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

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


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

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

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

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

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



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


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

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


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

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



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


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

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



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


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

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



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


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

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

Case Resolution

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

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


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


References/Further Readin

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

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
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  46. http://www.ncbi.nlm.nih.gov/pubmed/22555052

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.