Tag Archives: #FOAMtox

TOXCARD: Hyperthermia in the toxicological setting

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

toxcard

Case Presentation:

A 32 year-old man presents to the emergency department with altered mental status. The patient is agitated but sleepy-appearing. He appears to be uncomfortable, shifting on the stretcher and unable to lie still. An empty bottle of cough syrup is found in his pocket. His vitals are HR 141, rectal temperature 103.6F, BP 214/110, RR 22, SpO2 98% in room air.

Question:

What is the differential diagnosis for hyperpyrexia with altered mental status? How is hyperthermia secondary to drug ingestion and toxic syndromes treated?

Pearl:

Drug-related hyperthermia is difficult to distinguish but may be differentiated based on components of history and physical exam. Hyperthermia secondary to toxic syndromes and drug ingestion will not respond to antipyretics like ibuprofen or acetaminophen and external cooling measures are key.

  • Fever is defined as a physiologic elevation in the hypothalamic set-point for body temperature induced by inflammatory cytokines in response to a stressor.
  • Hyperthermia in the toxicological setting differs from fever in that it results from an unregulated increase in body temperature either from increased heat production or decreased heat dissipation, usually resulting from increased skeletal muscle metabolism or activity.
  • Toxicological causes of increased heat production include serotonin syndrome, neuroleptic malignant syndrome, malignant hyperthermia, alcohol withdrawal, sedative-hypnotic withdrawal, and ingestions of sympathomimetics, anticholinergics, and ecstasy. Decreased heat dissipation through poor sweat production also occurs in anticholinergic ingestions.
  • Initially, fever and hyperthermia are difficult to distinguish but may be differentiated based on components of history and physical exam.

Hyperthermia Differential Diagnosis2

Toxic Syndrome CNS Other
Serotonin Syndrome Meningitis Sepsis
Neuroleptic Malignant Syndrome ICH Heat Stroke
Malignant Hyperthermia Hypothalamic stroke Pheochromocytoma
Alcohol/Sedative-Hypnotic Withdrawal Encephalitis Thyrotoxicosis
Sympathomimetic Syndrome (e.g. cocaine, amphetamines, PCP, MDMA, cathinones, etc.)

 

Status epilepticus Infection (Tetanus, malaria, etc)
Alcohol/Benzodiazepine Withdrawal
Anticholinergic Syndrome
Salicylate Toxicity

 

Some toxicological causes of hyperthermia and their differentiations:

HYPERTHERM

Table Source: Boyer E and Shannon M. The Serotonin Syndrome. N Engl J Med. 2005; 352:1112-1120. DOI: 10.1056/NEJMra041867.

  • Antipyretics have no role in the management of hyperthermia in the toxicological setting since the fever usually results from muscular hyperactivity, not an alteration in hypothalamic homeostasis.
  • Hyperthermia should be addressed promptly by using external cooling blankets, ice water submersion, evaporative cooling techniques, or cool IV fluids. Benzodiazepines should also be used to reduce excess heat production from muscle hyperactivity.
  • To prevent end-organ damage, the goal should be to reduce rectal temperature to below 40°C within 30 minutes of beginning cooling therapy.
  • In severe cases, internal cooling catheters can be used for more regulated cooling, using thermal regulation devices such as CoolLineR or CoolGardR. If necessary, cold fluids can be given through a NG or OG tube in intubated patients. Also the bladder can be irrigated with cool fluids using a foley catheter.

Main point:

Hyperthermia secondary to drug ingestion differs from infection-related fevers in that it results from an unregulated increase in body temperature, usually from increased skeletal muscle activity. Drug-related hyperthermia is difficult to distinguish but may be differentiated based on components of history and physical exam. Hyperthermia secondary to toxic syndromes and drug ingestion will not respond to antipyretics like ibuprofen or acetaminophen and external cooling measures are key.

References:

  1. Simon H. Hyperthermia. N Engl J Med. 1993; 329:483-487. DOI: 10.1056/NEJM199308123290708.
  2. LoVecchio F. Chapter 210: Heat Emergencies. In: Tintinalli J, ed. Tintinalli’s Emergency Medicine. 8th ed. McGraw Hill; 2016: 1365-1370.
  3. Boyer E and Shannon M. The Serotonin Syndrome. N Engl J Med. 2005; 352:1112-1120. DOI: 10.1056/NEJMra041867.

EM@3AM – Anticholinergic Toxicity

Author: Erica Simon, DO, MHA (@E_M_Simon, EM Chief Resident, SAUSHEC, USAF) and Daniel Sessions, MD (EM Associate Program Director, SAUSHEC, USAF / Medical Toxicologist, South Texas Poison Center) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit, EM Attending Physician, SAUSHEC, USAF)

Welcome to EM@3AM, an emdocs series designed to foster your working knowledge by providing an expedited review of clinical basics. We’ll keep it short, while you keep that EM brain sharp.


A 62 year-old female, escorted by her son, presents to the emergency department for altered mental status. The son reports his mother as being in her usual state of health during a visit the night prior, but per the family maid, was severely confused upon awakening one hour prior to arrival.  A phone call to the patient’s daughter reveals a ROS positive only for a medication change: chlorpromazine prescribed for hiccups.

 Triage VS: BP 172/101, HR 127, RR 28, T103.2°F Oral, SpO2 98% on room air

Accucheck: 137

Upon initial evaluation the patient is oriented only to herself. Her pupils are 5mm bilaterally, she is flushed, her skin is dry, and her capillary refill is > 3 seconds. Her abdominal exam is remarkable for a palpable, distended bladder.

What do you suspect as a diagnosis? What’s the next step in your evaluation and treatment?


Answer: Anticholinergic Toxicity1-5

  • Precipitating Causes: Amantadine, antihistamines, antiparkinsonian medications, antipsychotics, cyclic antidepressants, dicyclomine, atropine, phenothiazines, scopolamine, Jimson weed.1 
  • Presentation: Classically “hot as a hare, dry as a bone, red as a beet, blind as a bat, mad as a hatter, full as a flask, tachy as a pink flamingo.”
  • Evaluation:
    • Focused H&P:1
      • Perform a medication reconciliation
      • VS: obtain rectal temperature, look for tachycardia
      • Neurologic examination: possible altered mental status, mydriasis, visual deficits
      • Additional exam findings: patient commonly flushed with dry skin and a prolonged capillary refill.  Palpate the abdomen in search of a distended bladder.
  • Treatment:1
    • Delirium/Agitation: benzodiazepines
      • Avoid haldoperidol – may worsen symptoms
    • Urinary retention: foley placement
    • Hyperthermia: active cooling with misting/fanning, cooled IV fluids; benzodiazepines for shivering
    • Hypotension: IVF; if intractable, consider norepinephrine
    • EKG demonstrating conduction delays: sodium bicarbonate to overcome impaired sodium conduction
    • Although physostigmine has traditionally been recommended only for patients with life-threatening anticholinergic toxicity (given concern regarding its associated complications, i.e. – severe agitation, seizures, persistent hypertension, and hemodynamic compromise secondary to tachycardia),3 newer data report its relative safety and efficacy in reversing the anticholinergic toxidrome; specifically anticholinergic delirium.4,5 
  •  Pearls:
    • Consider anticholinergic toxicity in the differential diagnosis of an altered patient with residual urine > 200-300 mL.2
    • Exercise caution in the use of physostigmine if there is concern for TCA toxicity, arrhythmias, or QRS/QTc prolongation, as upon administration physostigmine displays a dose dependent AV nodal conduction delay.2
    • In 2013, the American Association of Poison Control Centers reported three deaths secondary to an anticholinergic drug (benztropine).3


References:

  1. Thornton S and Ly B. Over-the Counter Medications. In: Emergency Medicine: Clinical Essentials. Philadelphia, Saunders Elsevier. 2013; 1334-1342.e1.
  2. Stilson M, Kelly K, Suchard J. Physostigmine as an antidote. Cal J Emerg Med. 2001. 2(4): 47-48.
  3. Mowry J, Spyker D, Cantilena L, McMillan N, Ford M. 2013 Annual report of the American Association of Poinson Control Centers’ National Poison Data System (NPDS): 31st annual report. Clin Toxicol. 2014; 52: 1032-1238.
  4. Watkins J, Schwarz E, Arroyo-Plasencia A, Mullins M; Toxicology Investigators Consortium Investigators. The use of physostigmine by toxicologists in anticholinergic toxicity. J Med Toxicol. 2015; 11(2):179-184.
  5. Dawson A and Buckley N. Pharmacological management of anticholinergic delirium – theory, evidence, and practice. Br J Clin Pharmacol. 2016; 81(3): 516-524.

 For Additional Reading:

Physostigmine for Anticholinergic Toxicity:

Physostigmine for Management of Anticholinergic Toxidrome

Toxcard: DigiFab for Digoxin Toxicity

Author: Adriana Garcia, MD (Fidel Velázquez Sánchez Hospital) // Edited by: Cynthia Santos, MD (Senior Medical Toxicology Fellow, Emory University School of Medicine), Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

toxcard
Case:

 A 73 y/o female with PMH of dementia, CHF, and atrial fibrillation presents with confusion, abdominal pain, nausea and vomiting. She is unable to provide a history due to her dementia and AMS. Vitals: BP 160/80 mmHg HR 60 T 36° RR 18. Her EKG demonstrates AV block. Na 140 K 5.3 Cl 105 CO2 20 BUN 40 Cr 2.1. Her digoxin level is 5ng/mL and she weighs 50 kg.

Question:

What dose of Digoxin-specific antibody fragments (DsFab) should you use? How do you administer it?

Pearl:

The dose of DsFab can be estimated in three ways 1) a formula if the dose is known 2) a formula if a serum digoxin level is known or 3) use of an empiric dose. 

1) If amount ingested is known:
  • In an acute overdose the # of vials can be calculated based on the ingested dose. Each vial neutralizes approximately 0.5mg of digoxin.[1,2]

Number of vials=   [(amount ingested in mg) x (0.8 bioavailability)]/(0.5 mg/vial)                                                                    

  • Note: The bioavailability for digoxin tablets is 0.8 and for digoxin capsules it is 1.[1]
  • The table below can also be used as a quick reference to calculate # of vials.
dig table
 Table source: www.drugs.com/pro/digibind.html
 
2) If serum digoxin level is known:

Number of vials=    [(serum digoxin level in ng/ml) x (weight in kg)]/100                                                                            

For our case, # of vials = 5 ng/ml x 50 kg/ 100 = 2.5

3) Emergent situations:

  • In an emergent situation involving an acute ingestion of unknown amount, 10 vials can be given initially for both adults and children. Observe for a response and can repeat with another 10 vials as needed. Monitor for volume overload in children.
  • In an emergent situation involving a chronic ingestion of unknown amount, 3-6 vials can be given for adults and 1-2 vials can be given for children.[1,2]

Indications for DsFab:

  • life-threatening dysrhythmia,
  • hyperkalemia: K+ > 5.0 mEq/L,
  • [digoxin] > 15 ng/ml at any time or > 10 ng/ml 6 hours post ingestion, regardless of clinical effects,
  • chronic elevation of [digoxin] associated with dysrhythmias, significant GI symptoms, or AMS,
  • acute ingestion of 10 mg in an adult or 4 mg in a child,
  • poisoning by non-digoxin cardiac glycoside. [2]

Note: In chronic poisoning, both the potassium and digoxin level may be NORMAL. In fact, it chronic overdoses the potassium level is often decreased.

Administrating DsFab:

  • Each 40mg vial of DigiFab (which binds 0.5 mg digoxin) should be reconstituted with 4 mL sterile water to yield an isosmotic solution with a concentration of 10 mg/mL.
  • The reconstituted solution can be diluted in normal saline to an appropriate volume for administration.
  • Infuse over at least 30 minutes.
  • If cardiac arrest is imminent a bolus injection can be given.
  • The reconstituted solution should be used immediately, if not it can be refrigerated and used within 4 hours.
  • Adverse effects of DigiFab include hypokalemia (K should be monitored frequently) and worsening atrial fibrillation or congestive heart failure. Anaphylaxis is rare.[1,3]
  • Measuring total serum digoxin concentration after DsFab will not be useful since it represents the free plus bound digoxin. Free digoxin concentrations are more clinically useful but they are more difficult to perform, sometimes erroneous  and are not readily available. The patient’s cardiac status should be monitored for signs of recurrent toxicity.[3]

Note: DsFab is only available in the U.S. as DigiFab since 2011. Previously, Digibind was available and used successfully but was discontinued in 2011 when DigiFab came on the market. They are both very similar except that DigiFab is prepared using the digoxin derivative as the hapten.[3]

Main point:

The # of vials of DsFab can be calculated based on the amount ingested for acute overdoses or the digoxin serum concentration in chronic overdoses. In emergent situations where the ingested dose or the serum level is unknown 10 – 20 vials is the recommended for acute ingestions and 3-6 vials for chronic ingestions. Each vial of Digoxin Fab should be reconstituted in 4 mL of sterile water and given slowly over at least 30 minutes. Unless in cardiac arrest, in which a bolus injection can be given. Watch out for hypokalemia and worsening a fib or CHF with Digoxin Fab administration. Don’t rely on measuring digoxin levels after giving DigiFab; the patient’s cardiac status should be monitored for signs of recurrent toxicity.

Reference:
  1. Micromedex Drug Information, Digoxin Immune Fab. Available at: http://micromedex.com/
  2. Hack J. Cardioactive steroids (Chapter). In Goldfrank’s Toxicological Emergencies, 11th edition (2015). Editors: Hoffman R, Howland M, Lewin N, Nelson L, Goldfrank L. McGraw Hill; New York.
  3. Howland M. Antidotes in depth: Digoxin-Specific Antibody Fragments (Chapter). In Goldfrank’s Toxicological Emergencies, 11th edition (2015). Editors: Hoffman R, Howland M, Lewin N, Nelson L, Goldfrank L. McGraw Hill; New York.

Updates on Cannabis Use and Dangers in the U.S.

Authors: Dazhe James Cao, MD and Stacey Hail, MD, FACMT (EM Attending Physicians and Toxicologists, UTSW / Parkland Memorial Hospital) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

Background on Cannabis

Marijuana describes the dried plant material of Cannabis sativa which includes Cannabis sativa subspecies sativa, Cannabis sativa subspecies indica, and various hybridizations of subspecies. The plant is an annual flowering herb that can be grown both outdoors and indoors (via hydroponic techniques using artificial lighting and nutrient rich water). The plant has both male and female forms. The highest concentration of THC resides in the buds of the pistillate flowers of the female plant – typically ranging 10-12%, whereas THC concentrations in leaves are about 1-2%, in stalks 0.1-0.3%, and in the roots less than 0.03%.1 Increasingly in recent years, cultivation of cannabis has moved towards cloning of female plants, allowing the buds to grow without fertilization from the male plant. This technique is termed sinsemilla (Spanish for “no seed”) and has allowed THC concentrations in cannabis to increase. Given the risk of exposures to wind disseminated pollen from male plants (or hermaphroditic plants), the majority of these grow operations are performed indoors using hydroponics although outdoor sinsemilla production is feasible.

In the United States, Cannabis sativa can be sold in a variety of forms – most commonly as marijuana. Alternatively, active THC can be extracted from the plant to make either hashish or hash oil. Hashish is the extraction of resinous secretions using a sieve and yielding either a loose or pressed sticky powder. Hash oil results from the extraction of THC from plant material using an organic solvent (petroleum ether, ethanol, methanol, acetone, and more recently, butane). Higher concentration products can be solid at room temperature after solvents have evaporated and have been termed “dab,” “wax,” “honey,” “shatter,” “butane hash oil (BHO),” etc. Such products can be smoked in modified bongs or vaporizers. Further refined products can be used in edible products such as baked goods, candies, and soft drinks. Informal reports of hash oil products state THC concentrations upwards of 70-90%.2

As mentioned before, the principal active ingredient in cannabis is Δ9-tetrahydrocannabinol (THC). Numerous other cannabinoids (term used to describe compounds that activate cannabinoid receptors in the body) exist in marijuana with largely uncertain effects on the body. The other major cannabinoid often discussed is cannabidiol (CBD). Unlike THC, CBD does not activate any of the cannabinoid receptors directly but counteracts many of the stimulating effects of THC. CBD is being investigated as a potential therapy to treat seizures.3

Clinical and Adverse Effects of Cannabis

Acute cannabis intoxication ranges in clinical presentations from desired psychoactive effects to severe life-threatening respiratory depression. Most users of cannabis describe a sense of relaxation. Other reported effects include altered mood/sensation, slowed time, increased concentration, improved thinking, and increased appetite.4 In overdose, acute cannabis intoxication may lead to drowsiness/lethargy, tachycardia, agitation/irritability, confusion, vomiting, mydriasis, hallucinations/delusions, and dizziness/vertigo. Children less than 6 years old are more likely to have drowsiness/lethargy and respiratory depression.5 Multiple studies have reported children who required mechanical ventilation (machine to supply breaths) and/or intubation (tube inserted into the airway) to support their breathing.5-7 Serious cardiovascular and cerebrovascular events such as myocardial infarction, sudden cardiac death, and stroke have been associated with acute cannabis intoxication.8 However, the overall level of evidence to support these rare associations is low. Death after acute ingestion of cannabis is also rare. One death has been attributed to the ingestion of an edible THC infused cookie in March 2014 in Colorado. The 23-year-old man became erratic and hostile 2 hours after ingesting the cookie and jumped off a 4th floor balcony to his death.9 In reviewing United States poison center annual reports from 2011-2014, cannabis and analogs were implicated in 89 fatalities with exposures to other products and 11 fatalities with cannabis/analogs as single substance exposures.10-13

Cannabinoid hyperemesis syndrome (CHS) is an idiosyncratic reaction (occurs in some individuals but not others) to prolonged cannabis use. It is characterized by bouts of intense cyclic nausea and vomiting, epigastric (upper center) abdominal pain, and relief with hot showers/baths. Although patients with CHS believe continued cannabis use relieves the symptoms, ultimate resolution of the syndrome requires cessation of cannabis use.14 In Colorado after legalization of recreational cannabis, cyclic vomiting syndrome (a broader term that includes CHS) as a diagnosis in the emergency department (ED) increased from 41 per 113,266 ED visits to 87 per 125,095 ED visits.15

Driving while under the influence of cannabis increases the incidence of vehicular collisions. Blood concentrations of THC between 2-5 ng/mL are associated with driving impairment where the culpability of motor vehicle collisions increases with increasing concentrations of THC.16 Detectable blood concentrations of THC may have comparable risks to being responsible for motor vehicle collisions as with blood alcohol concentrations above 0.08%.17 In driving simulators, cannabis drivers compensate by driving slower and taking fewer risks yet are still less capable of handling complex tasks, are less capable of maintaining lane positions, and have increased response times.16

Cannabis use alters short-term memory and may be responsible for altered brain development. In animal studies, prenatal or in utero exposures to THC can re-calibrate sensitivity of reward systems to other drugs.17, 18 Studies have implicated cannabis as a gateway drug to the use of other illicit substances.18, 19 Adults who smoke cannabis regularly have fewer connections in the region of the brain that controls alertness, awareness, learning, and memory. Centers of the brain responsible for promoting habits, routines, and impulse control may also be impaired.17 In a longitudinal trial where individuals serve as their own control, heavier cannabis use led to lower IQ scores in early adulthood.20 The younger the age of cannabis initiation and heavier regular use of cannabis may both worsen brain development. As a result of both chronic use and short-term impairment of learning while intoxicated, cannabis use is associated with poorer educational outcomes and increased likelihood of dropping out.17

Finally, since the legalization of recreational cannabis in Colorado, there has been an increase in the number of patients who presented to the University of Colorado burn center in Aurora, Colorado secondary to the use of butane to extract THC from cannabis. A total of 31 admissions and 21 skin grafts (donor skin to replace areas of dead skin from burns) were required to treat these burns. Some burns involved greater than 70% total body surface area.15 The extraction process requires heating of the butane/THC mixture to yield the final hash oil product. During this process butane is ignited either from the heating source or from the individual lighting a marijuana cigarette.

Cannabis Use Disorder

Currently, cannabis is the most used illicit substance in the United States. In 2013, an estimated 19.8 million (7.5%) of Americans older than 12 years reported past month use of cannabis. The number of new users continues to increase by an average of 6,600 per day.21 To worsen the situation, the perceived risk of smoking cannabis in youths aged 12-17 years has declined from 54.6% in 2007 to 39.5% in 2013.21 Decreased perceived risk of cannabis use is further exaggerated in Colorado (where medical and recreational marijuana have been legalized) as compared to states without decriminalized medical marijuana.22

The official definition for substance use disorder was updated in 2013 in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The diagnosis of a substance use disorder is made when 2 or more of the following criteria are met over a 12-month period: (1) hazardous use, (2) social/interpersonal problems related to use, (3) neglected major roles to use, (4) legal problems, (5) withdrawal, (6) tolerance, (7) used larger amounts/longer, (8) repeated attempts to quit/control use, (9) much time spent using, (10) physical/psychological problems related to use, (11) activities given up to use, and (12) craving.23 Based on this definition, cannabis use disorder in the United States has a lifetime prevalence of 6.2% in 2013.24 Of first time users, 8.9% will go on to develop cannabis use disorder in their lifetime. In comparison, lifetime cumulative probability of dependence is 67.5% for first time nicotine users, 22.7% for alcohol users, and 20.9% for cocaine users.25 The earlier cannabis use is initiated or the heavier the cannabis use, the higher the probability of lifetime diagnosis of cannabis use disorder. Teenagers have a 1 in 6 (17%) lifetime probability, and daily cannabis users have a 25-50% lifetime probability.18

The process of addiction in the brain for cannabis is similar to other illicit drugs of abuse. Cannabis use increases the amount of dopamine (signaling molecule) in the nucleus accumbens (area of the brain controlling reward signaling) similar to the natural process of rewarding and reinforcing positive behavior.26 Furthermore, chronic cannabis use is complicated by a punishing withdrawal syndrome similar to, albeit milder than, that of alcohol and nicotine. The withdrawal syndrome is characterized by 3 or more of the following: (1) irritability, anger or aggression, (2) nervousness or anxiety, (3) sleep difficulty (insomnia), (4) decreased appetite or weight loss, (5) restlessness, (6) depressed mood, (7) physical symptoms causing significant discomfort from at least one of the following: stomach pain, shakiness/tremors, sweating, fever, chills, headache.27

Evolution of Δ9-tetrahydrocannabinol Concentrations

Cannabis in the United States is federally classified as a Schedule I substance. Cannabis research through federal funding is closely controlled by the National Institute on Drug Abuse (NIDA), who sponsors research on cannabis and cultivation of Cannabis sativa through the National Center for Natural Products Research (NCNPR) at the University of Mississippi. In cooperation with the Drug Enforcement Administration (DEA), NCNPR runs the Potency Monitoring Program for cannabis seized across the United States since the 1970s. The most recent publication by NCNPR tracked THC concentrations in confiscated cannabis from January 1, 1995 to December 31, 2014. The average THC concentration in cannabis increased over the study period with a small peak in 2012. The greatest contributor to this increase was the proportion of sinsemilla (seedless female plant buds) in relation to marijuana seized. Even in marijuana products, the proportion of buds (contains higher THC concentration) in comparison to loose material (including buds, leaves, and stems) increased. Sinsemilla accounted for less than 0.5% of the tested product in 1995, as compared to 80.5% in 2014. The average THC concentration of marijuana in 1995 was 3.95±1.74% and increased to 6.08±3.3% in 2014 with a peak concentration of 7.19±3.34% in 2007. The average THC concentration of sinsemilla in 1995 was 9.64±5.13% and increased to 13.18±6.39% in 2014 with a peak concentration of 14.5±6.38% in 2012.28 By interpreting the peak data in 2012, the upper 95th percentile THC concentration for sinsemilla was 27.3%. Unfortunately, the authors did not provide a range of concentrations in the samples tested. The THC concentrations of hashish and hash oil samples were about 40% and 54%, respectively, in 2014.28

The other interesting finding of the aforementioned study was the relative decrease of CBD concentration in comparison to the THC concentration. The ratio of THC:CBD concentrations remained stable between 10-20 until 2009 when the ratio increased dramatically to about 80 in 2014.28 The resulting products may be more stimulating and therefore more dangerous.

Pearls

  • Cannabis is sold in many forms including marijuana (dried plant product), hashish, and higher concentration products (“dab,” “wax,” “honey,” “shatter,” “butane hash oil”).
  • Acute cannabis intoxication can range from desired psychoactive effects to severe life-threatening respiratory depression with the latter being more common in children.
  • Cannabinoid hyperemesis syndrome, characterized by bouts of intense cyclic nausea/vomiting and relief with hot showers/baths, may be increasing with decriminalization of medical and recreational cannabis.
  • Consider secondary injuries related to cannabis use and production including motor vehicle collisions and severe burns.
  • Average THC concentrations of marijuana in the United States have increased related to the cultivation technique of sinsemilla (seedless female buds), which can yield an average concentration of 14.5% THC.

 

References / Further Reading:

  1. United Nations Office on Drugs, Recommended methods for the identification and analysis of cannabis and cannabis products, United Nations Publications: Vienna, 2009.
  2. Loflin M, Earleywine M. A new method of cannabis ingestion: the dangers of dabs? Addict Behav 2014;39:1430-3.
  3. Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 2014;55:791-802.
  4. Green B, Kavanagh D, Young R. Being stoned: a review of self-reported cannabis effects. Drug Alcohol Rev 2003;22:453-60.
  5. Cao D, Srisuma S, Bronstein AC, Hoyte CO. Characterization of edible marijuana product exposures reported to United States poison centers. Clin Toxicol (Phila) 2016:1-7.
  6. Wang GS, Roosevelt G, Heard K. Pediatric marijuana exposures in a medical marijuana state. JAMA Pediatr 2013;167:630-3.
  7. Lovecchio F, Heise CW. Accidental pediatric ingestions of medical marijuana: a 4-year poison center experience. Am J Emerg Med 2015;33:844-5.
  8. Thomas G, Kloner RA, Rezkalla S. Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to know. Am J Cardiol 2014;113:187-90.
  9. Hancock-Allen JB, Barker L, VanDyke M, Holmes DB. Notes from the Field: Death Following Ingestion of an Edible Marijuana Product–Colorado, March 2014. MMWR Morb Mortal Wkly Rep 2015;64:771-2.
  10. 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. Clin Toxicol (Phila) 2012;50:911-1164.
  11. 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;53:962-1147.
  12. 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. Clin Toxicol (Phila) 2013;51:949-1229.
  13. 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. Clin Toxicol (Phila) 2014;52:1032-283.
  14. Beech RA, Sterrett DR, Babiuk J, Fung H. Cannabinoid Hyperemesis Syndrome: A Case Report and Literature Review. J Oral Maxillofac Surg 2015;73:1907-10.
  15. Monte AA, Zane RD, Heard KJ. The implications of marijuana legalization in Colorado. JAMA 2015;313:241-2.
  16. Hartman RL, Huestis MA. Cannabis effects on driving skills. Clin Chem 2013;59:478-92.
  17. Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med 2014;370:2219-27.
  18. Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet 2009;374:1383-91.
  19. Fergusson DM, Horwood LJ. Does cannabis use encourage other forms of illicit drug use? Addiction 2000;95:505-20.
  20. Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RS, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A 2012;109:E2657-64.
  21. Substance Abuse and Mental Health Services Administration, Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-48, HHS Publication No. (SMA) 14-4863. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2014.
  22. Schuermeyer J, Salomonsen-Sautel S, Price RK, Balan S, Thurstone C, Min SJ, et al. Temporal trends in marijuana attitudes, availability and use in Colorado compared to non-medical marijuana states: 2003-11. Drug Alcohol Depend 2014;140:145-55.
  23. Hasin DS, O’Brien CP, Auriacombe M, Borges G, Bucholz K, Budney A, et al. DSM-5 criteria for substance use disorders: recommendations and rationale. Am J Psychiatry 2013;170:834-51.
  24. Grant BF, Saha TD, Ruan WJ, Goldstein RB, Chou SP, Jung J, et al. Epidemiology of DSM-5 Drug Use Disorder: Results From the National Epidemiologic Survey on Alcohol and Related Conditions-III. JAMA Psychiatry 2016;73:39-47.
  25. Lopez-Quintero C, Perez de los Cobos J, Hasin DS, Okuda M, Wang S, Grant BF, et al. Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drug Alcohol Depend 2011;115:120-30.
  26. Cami J, Farre M. Drug addiction. N Engl J Med 2003;349:975-86.
  27. Gorelick DA, Levin KH, Copersino ML, Heishman SJ, Liu F, Boggs DL, et al. Diagnostic criteria for cannabis withdrawal syndrome. Drug Alcohol Depend 2012;123:141-7.
  28. ElSohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC. Changes in Cannabis Potency Over the Last 2 Decades (1995-2014): Analysis of Current Data in the United States. Biol Psychiatry 2016;79:613-9.

 

Toxcards: Alcohol Ketoacidosis

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

Case Presentation:

A 45 year old male presents intoxicated, smelling of alcohol and appears disheveled with vomit on his clothes. He is sleepy but arousable to noxious stimuli. His serum ethanol level is 143 mg/dL. Na 135, K 3.9, Cl 97, CO2 20, BUN 33, Cr 1.1. Lactate 3.1. pH 7.35, CO2 28, HCO3 15. His urine is negative for ketones. His vitals are HR 103, RR 30, BP 115/65, O2 98% RA.

toxcard

Question:

Could these laboratory results be consistent with alcohol ketoacidosis (AKA)?

Pearl:

The classic laboratory findings in patients with AKA include an elevated anion gap metabolic acidosis and an elevated lactate. Early in AKA patients may be negative for ketones when the nitroprusside test is used because it does not detect beta-hydroxybutyrate. As patients recover, the nitroprusside test will become positive as beta-hydroxybutyrate gets converted to acetone and acetate.

Acid/base status:

  • Patients with AKA typically have elevated anion gap metabolic acidosis. However, vomiting may cause a primary metabolic alkalosis and a compensatory respiratory alkalosis which may result in a normal or even elevated pH.
  • AKA patients, as compared to DKA patients, typically have higher pH, lower K and Cl, and higher HCO3 in their blood tests.

High Redox State (Excess NADH):

  • As ethanol is metabolized by ADH and ALDH to acetaldehyde and acetate, respectively, an increased amount of NADH forms which causes a high redox state and excess of reducing potential (increased NADH:NAD+ ratio).

ethanol pathway

Increased lactate due to pyruvate shunting:

  • Reduced caloric intake, decreased glycogen stores, and thiamine depletion results in amino acids being converted to pyruvate. The excess pyruvate that forms can then be diverted to gluconeogenesis, be converted to acetyl-CoA, which can enter the Kreb’s cycle, or can enter various biosynthetic pathways (e.g. fatty acids, ketones, etc.). Pyruvate can be diverted to these pathways if there is sufficient NAD+.
  • However ethanol causes a high redox state (excess NADH). In the setting of a high redox state ethanol results in increased lactate due to the conversion of pyruvate to lactate and diverts pyruvate from gluconeogenesis.
pyruvate to lactate

Figure source: Shull P, & Rapoport J.

Anion gap primarily due to beta-hydroxybutyrate:

  • The primary anion contributor in patients with AKA and diabetic ketoacidosis (DKA) is beta-hydroxybutyrate with lactate having less of a role.
  • Decreased caloric intake and glycogen stores results in increased fatty acid mobilization and oxidation resulting in increased acetyl-CoA. In normal states (when there is sufficient NAD+) acetyl-CoA can then enter the Kreb’s cycle or be used in fatty acid synthesis. Thiamine also facilitates the entry of acetyl-CoA into the Kreb’s cycle.
  • However, when there is a high redox state (excess NADH) and thiamine deficiency acetyl-CoA gets converted to acetoacetate which then gets converted to beta-hydroxybutyrate.

ketone production

Ketone production:

  • Early the main anion contributor is beta-hydroxybutyrate, which is not detected well by the nitroprusside test (used to detect ketones in serum and urine). The nitroprusside test does not detect beta-hydroxybutyrate, although it is good for detecting acetoacetate and acetone.
  • It is common for early AKA to have a falsely negative ketone test if the nitroprusside test is used because of the test’s inability to detect beta-hydroxybutyrate. If available, specific assays for beta-hydroxybutyrate should be done.
  • As patients recover and receive glucose and thiamine supplementation, ATP is made which reverses the pyruvate-to- lactate and NAD+-to-NADH ratios.  This allows beta-hydroxybutyrate to be converted to acetoacetate and as patients recover the nitroprusside test will actually become more positive due to the increased production of acetoacetate.

ketone body ratio in alcoholic ketoacidosis

Figure Source:  www.derangedphysiology.com

Main Point:

The classic laboratory findings in patients with AKA include an elevated anion gap metabolic acidosis, and elevated lactate that is insufficient to account for the gap. The main anion contributor early in AKA is beta-hydroxybutyrate, but it will not be detected when evaluating for ketones using the nitroprusside test. As patients recover and are given glucose and thiamine supplementation, the lactate will decrease as pyruvate is no longer shunted to lactate and instead enters the Kreb’s cycle and other biosynthetic pathways. The anion gap decreases as beta-hydroxybutyrate gets converted to acetone and acetate. The nitroprusside test then becomes positive for ketones later as patients recover.

Resources:
  1. Yip L. Ethanol, Chapter in Goldfrank’s Toxicological Emergencies. Tenth Edition. Editors: Hoffman R, Howland M, Lewin N, Nelson L, Goldfrank L. McGraw Hill (2015); New York.
  2. Woods W, Perrina D. Alcohol Ketoacidosis, Chapter in Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7th Edition. Editors: Tintinalli JE, et al. McGraw Hill (2011); New York.
  3. Shull P, & Rapoport J. Life-threatening reversible acidosis caused by alcohol abuse. Nature Reviews Nephrology (2010) 6, 555-559
  4. Diabetic, Alcoholic, and Starvation Ketoacidosis. Chapter 6.17. Available at:  http://www.derangedphysiology.com/main/core-topics-intensive-care/acid-base-disturbances/Chapter%206.1.7/diabetic-alcoholic-and-starvation-ketoacidosis

Toxcards: Sympathomimetic vs. Anticholinergic Toxidromes

Author: Patrick C Ng, MD (Chief Resident, San Antonio Military 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)

screen-shot-2017-01-08-at-11-30-27-pm

Case Presentation

An 18 year old female is brought in by EMS after an unknown suicidal ingestion. She is confused, her pupils are dilated, and she is tachycardic. She has no tremors or rigidity. She has no history of chronic substance abuse or withdrawal.

Question:

How can you distinguish an anticholinergic vs sympathomimetic toxidrome?

Pearl:

There are overlapping signs and symptoms in both toxidromes; historical clues and a physical exam targeting the pupils, skin, GI and GU systems can reveal the toxidrome.

anticholinergic sympathomimetic toxidromes

-Antihistamines, antidepressants, scopolamine, hyoscyamine, atropine, and plants containing anticholinergic alkaloids (Datura, Belladonna) can precipitate an anticholinergic syndrome.1

-Treatment for anticholinergic syndrome is mainly supportive. Benzodiazepines are the mainstay treatment. Physostigmine is given to diagnose and treat anticholinergic delirium. A widely followed recommendation is that Physostigmine should not be given if there are signs of sodium channel blockade on the EKG.2 However newer research is challenging this notion.3

-TCA overdose can present with an anticholinergic toxidrome. Physostigmine is contraindicated in TCA overdose due to the concern for Na channel blockade causing myocardial depression.4

-Amphetamines, synthetic cannabinoids and methylxanthines like caffeine, nicotine, and theophylline can precipitate a sympathomimetic syndrome.5

-Treatment for sympathomimetic syndrome is mainly supportive with IV fluids and benzodiazapines. Beta blockers should be avoided in patients presenting with sympathomimetic syndrome secondary to cocaine use secondary to the possible effect of unopposed alpha-stimulation.

-The differential diagnosis for sympathomimetic syndrome include anticholinergic syndrome, sedative-hypnotic withdrawal, alcohol withdrawal, neuroleptic malignant syndrome, opioid withdrawal, and serotonin syndrome. Medical conditions like hypoglycemia, heat stroke, encephalitis, pheochromocytoma, thyoid storm, and sepsis can also mimic sympathomimetic syndrome.5

toxidromes

Table source: Santos C, Olmedo R. Sedative-Hypnotic Drug Withdrawal Syndrome: Recognition and Treatment. Emergency Medicine Practice Guidelines. Evidence Based Medicine Journal. March 2017;19(7):1-20

Main Point:

The clinical picture of sympathomimetic and anticholinergic can appear similar. Both may have agitation, confusion, delirium, seizures, tachycardia, hypertension, fever, and mydriasis. Distinguishing characteristics for anticholinergic syndrome are dry skin, absent bowel sounds, and urinary retention. Remember the colloquial description for anticholinergic toxicity; “Blind as a bat, mad as a hatter, red as a beet, hot as Hades (or hot as a hare), dry as a bone, the bowel and bladder lose their tone, and the heart runs alone.” Both sympathomimetic and anticholinergic syndrome respond well to benzodiazepines. Physostigmine can be used to treat delirium associated with anticholinergic syndrome after checking the EKG for signs of Na channel blockade.

References                                

  1. Curry S, et al. Chapter 14: Neurotransmitters and Neuromodulators. Chapter in Goldfrank’s Toxicologic Emergencies, 10th edition. New York: McGraw-Hill Education, 2015, p173-201
  2. Burns MJ, Linden CH, Graudins A et al. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med. 2000;35:374-81.
  3. Rasimas JJ, Sachdeva KK, Donovan JW. Revival of an antidote: bedside experience with physostigmine. J Amer Acad Emerg Psychiatr. 2014;12:5–24.
  4. Suchard JR: Assessing physostigmine’s contraindication in cyclic antidepressant ingestions. J Emerg Med. 2003; 25:185-91.
  5. Santos C, Olmedo R. Sedative-Hypnotic Drug Withdrawal Syndrome: Recognition and Treatment. Emergency Medicine Practice Guidelines. Evidence Based Medicine Journal. March 2017;19(7):1-20

EM@3AM – Acute APAP Toxicity

Author: Erica Simon, DO, MHA (@E_M_Simon, EM Chief Resident, SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit, EM Attending Physician, SAUSHEC, USAF)

Welcome to EM@3AM, an emdocs series designed to foster your working knowledge by providing an expedited review of clinical basics. We’ll keep it short, while you keep that EM brain sharp.


A 14 year-old male with a history of major depressive disorder presents to the emergency department following a toxic ingestion. The patient reports consumption of approximately 40 extra strength Tylenol caplets (500mg each), two hours prior to arrival. The patient is nauseated and covered in non-bloody gastric contents. Upon initial examination: GCS 15. VS: HR 132, BP 128/84, RR 18, SpO2 98% on room air.

What is the patient’s diagnosis? What’s the next step in your evaluation and treatment?


Answer: Acute Acetaminophen Toxicity1-3

  • Recommended dosing: 3-4g QD; toxic dose: 150mg/kg
  • Presentation varies according to stage of toxicity:
    • Stage 1 (0.5-24 hrs): mild nausea, emesis, weakness
    • Stage 2 (24-72 hrs): hepatotoxicity +/- nephrotoxicity => RUQ abdominal pain
    • Stage 3 (72-96 hrs): hepatotoxicity peaks => nausea, vomiting, jaundice, coagulopathy
    • Stage 4 (4 days -2 wks): recovery or decompensation resulting in death
  • Evaluation:
    • Use the Rumack-Matthew nomogram for single ingestions occurring <24 hours prior to arrival:
      • Obtain AST level at 4 hours s/p ingestion: utilize nomogram to determine the appropriateness of N-acetylcysteine (NAC) treatment
    • If the time of ingestion is unknown:
      • Obtain AST level and a serum acetaminophen level => if AST is elevated or serum acetaminophen concentration >10mcg/mL = initiate NAC2,3
  • Treatment:
    • If patient presents within one hour of toxic ingestion, consider NG lavage if no contraindications.
    • NAC Loading dose: 150 mg/kg IV (max 15g) infused over 1 hr or 140 mg/kg PO
  • Pearls:
    • Rumack-Matthew nomogram should not be employed in the setting of unknown time of ingestion or chronic acetaminophen therapy.
    • NAC is most effective if initiated within 8 hours of acetaminophen ingestion.
    • Evaluate for co-ingestions: serum salicylate, serum ETOH; calculate an anion gap and an osmolar gap as appropriate. Consider UDS.
    • End point of NAC treatment: AST <100 U/L and acetaminophen <10mcg/mL or if extended therapy required: normalization of INR, resolution of encephalopathy, and decreasing AST (<1,000 U/L).3

References:

  1. Tintinalli J, Kelen G, Stapczynski J, Ma O, Cline D, et al. Tintinalli’s Emergency Medicine. 8th ed. New York: McGraw-Hill; 2016. Chapter 190, Acetaminophen.
  2. Heard K. Acetylcysteine for acetaminophen poisoning. N Engl J Med. 2008; 359(3):285-292.
  3. Mottram A, Kumar A. Focus On: Acetaminophen Toxicity and Treatment. American College of Emergency Physicians Clinical and Practice Management. Available from: https://www.acep.org/Clinical—Practice-Management/Focus-On–Acetaminophen-Toxicity-and-Treatment/

TOXCARD: TOXIC ALCOHOL POISONING

Author: Kristin E. Fontes, MD (Emergency Physician, Santa Barbara Cottage Hospital and Goleta Valley Cottage Hospital) // 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, EM Attending Physician, San Antonio Military Medical Center)

screen-shot-2017-01-08-at-11-30-27-pm
Case presentation:

A 28-year-old female is brought to the emergency department by ambulance from home after her roommate found her disoriented and poorly responsive. The roommate reports finding a small container of antifreeze in the patient’s bedroom. Vital signs are as follows: T 37.0C, HR 65, BP 126/76, RR 32, and SpO2 98% on room air.  Venous blood gas shows pH 6.97, pCO2 21, pO2 38, HCO3 4.8, and lactate 6.75.

Question:

What are the laboratory abnormalities that can occur with toxic alcohol poisoning and how can it be treated?

Pearl:

Common features of toxic alcohol poisoning are elevated anion gap metabolic acidosis and elevated osmolar gap (the latter being a distinguishing feature from ethanol poisoning); osmolar gap usually elevated early after ingestion.(1,2)

Recall the toxic alcohol metabolites and their effects:

toxic alcohol metabolism

  • EG toxicity can cause significant renal failure due to oxalate crystal deposition in the kidneys and glycolic acid, which is directly nephrotoxic; hypocalcemia and tetany can also result due to oxalate binding to calcium.(1)
  • MeOH toxicity classically causes visual disturbances (“snowfield” vision) due to formic acid-induced optic neuropathy.(1)
  • Isopropanol toxicity causes ketosis without acidosis (no lactic acid formed!).  Usually benign clinical course but can occasionally cause hemorrhagic gastritis. Fomepizole and HD not usually indicated.(1)
  • Propylene glycol toxicity often due to intravenous medication preparations containing this alcohol (e.g., diazepam, lorazepam, esmolol, nitroglycerin, phenobarbital, phenytoin) can result in severe lactic acidosis.(1)
Treatment Approach:
  • Fomepizole competitively inhibits alcohol dehydrogenase, which is involved in the metabolism of all alcohols, including ethanol. It is given to prevent the buildup of toxic metabolites from ethylene glycol (glycolic acid, glyoxylic acid, and oxalic acid) and methanol (formic acid) whose deposition in tissues can cause irreparable damage.(1)
  • Fomepizole is indicated for MeOH or EG ingestion resulting in a metabolic acidosis with an elevated osmolar gap (not accounted for by ethanol) and a serum MeOH or EG level of at least 20 mg/dL.(1)
  • Fomepizole dosing: 1) Load: 15 mg/kg (max 1.5 g) IV, diluted in 100 mL of normal saline or 5% dextrose, infused over 30 minutes; 2) Maintenance: 10 mg/kg IV every 12 hours for 4 doses, then increase to 15 mg/kg until serum toxic alcohol level is less than 20 mg/dL.(1,3)
  • Hemodialysis is indicated for toxic alcohol poisoning with an elevated osmolar gap and/or severe metabolic acidosis refractory to standard therapy, refractory hypotension, or end organ damage (i.e. acute renal failure).(1,3)
  • Vitamin Supplementation: Give folic or folinic acid to patients with MeOH toxicity to divert metabolism away from formic acid to carbon dioxide and water. Give folic acid, pyridoxine, and thiamine to patients with EG toxicity to divert metabolism to nontoxic metabolites.(1,3)
Main points:

Consider toxic alcohol poisoning in a patient with an unexplained elevated anion gap metabolic acidosis and elevated osmolar gap. Consider fomepizole and/or HD in patients with severe toxic alcohol poisoning, especially if refractory to standard therapy.

 

References:
  1. Olson KR & California Poison Control System. (2012). Poisoning & drug overdose. New York: Lange Medical Books/McGraw-Hill.
  2. Emmett M and Palmer BF. Serum osmolal gap. In: UpToDate, Forman JP (Ed), UpToDate, Waltham, MA, 2016.
  3. LeBlanc C, Murphy N. Should I stay or should I go?: toxic alcohol case in the emergency department. Can Fam Physician 2009 Jan;55(1):46-9.