UMEM Educational Pearls - Toxicology

One of the treatment options for NYHA class III and IV pulmonary hypertension is prostanoids.  All of the prostanoid formulations have the limitations of a short half-life and a heterogeneous response to therapy.  Because the drugs need to be given by continuous infusion, patients may present to the ED due to pump failure.  Sudden cardiopulmonary collapse can occur with infusion interruption.  Here are some important points to remember regarding kinetics:

• Intravenous epoprostenol (Flolan®) has an extremely short half-life (2–3 min) and lacks stability at room temperature.  Interruption of the pump for even a short period can have drastic consequences.
• Treprostinil (Remodulin®) has theoretical advantages over epoprostenol because of its stability at room temperature, an elimination half-life of 4-6 hours (subcutaneous), and its ability to be administered by continuous subcutaneous infusion.

Vicks VapoRub Toxicity

With the removal of OTC product indications for children under the age of 2 for cough and colds, more parents are turning to other agents such as Vicks VapoRub for the relief of cough and cold symptoms. Unfortunately these agents are also associated with toxicities and the potential exists for an increased number of poisonings. The primary components of these agents are:

• Camphor
• Eucalyptus Oil
• Menthol

Menthol is used to relieve symptoms of chest congestion. There is NO data to support efficacy, and paradoxically, studies have indicated increased airflow resistance with application. There is a case report of an 18 month old who developed respiratory distress after application. Symptoms associated with overdose, or inappropriate route (mucosal, oral) are:

• Aspiration
• Apnea
• Laryngoconstriction
• Nausea
• Ataxia
• Cardiac and CNS toxicity (confusion, euphoria)

Camphor in products with higher concentrations such as Campho-phenique can cause additional toxicity with effects:

• GI symptoms
• CNS: confusion, hallucinations, excitation, coma, seizures
• Apnea
• Asystole

Treatment for both is supportive.
 

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To feed of off Dr. Liferidge's last pearl - a few more points relevant to your Emergency Department practice:

• Lidocaine toxicity ranges between 5-7mg/kg
• Typical vial used for suture repair is 10cc of 1% lidocaine. 
• 1% = (1g/100cc) thus 100mg lidocaine in one vial
• 70 kg x 5mg/kg = 350 mg typical adult toxic dose (3+vials)
• 10 kg x 5mg/kg = 50 mg peds toxic dose (<1vial)
• Case reports of viscous lidocaine (4%) causing seizures. Very classically in pediatric cases. Cause is from oral transmucosal absorption, bypassing the large first pass effect if absorbed from the stomach.
• Classic symptoms are termed "feeling drunk" progressing to seizure. Shortly after CNS effect can have suppression of intrinsic pacemaker leading to sinus arrest, AV block, hypotension and death

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Ciguatera

• Heat resistant toxin found in fish, thus cooking doesn't protect you
• Found in over 400 species of fish but bioaccumulates in fish so predator tropical reef fish have higher concentration: grouper, barrucuda, snapper, parrotfish
• Found in tropical areas (See attached map for hot bed locations - in case you vacation there)
• Clinical Findings: Very neat hot-cold reversal where you place you hand in bucket of ice water and it feels like it is burning and visa versa, GI symptoms, paresthesias, ataxia and even hallucinations (very cool)
• Treatment: attempts with mannitol and gabapentin are reasonable and safe but completely unproven. Supportive care

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One of the options in our armamentarium prior to inserting an NG tube or performing a non-emergent nasotracheal intubation is nebulized lidocaine. However, the total dose is always a concern with this anesthetic agent before we have to worry about toxicity such as lightheadedness, tremors, hallucinations, seizures, and cardiac arrest. Here are some points to remember:

• Maximum IV dose is 3 mg/kg when used as an antiarryhthmic in ACLS.
• Maximum subcutaneous/intradermal dose is 4.5 mg/kg. When used in combination with epinephrine, this value is increased to 7 mg/kg.
• One study evaluated lidocaine plasma levels after nebulized administration and found that a dose of 400 mg (5.7 mg/kg in a 70 kg patient) produced a peak of 1.1 mcg/ml, far below the 5 mcg/ml level associated with toxicity.
• Application to real-life: Using 4% topical lidocaine in a 5-mL nebulizer will give a total dose of 200 mg. This is within the range of safe, studied doses, and will provide the anesthetic effect you (and the patient) desires.

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The followings is a list of unique clinical findings related to a certain sedative-hypnotic overdose:

1) Hypothermia:Barbiturates, bromides, ethchlorvynol (others but these more pronounced)

2) Unique odors: chloral hydrate, ethchlorvynol (which is Placidyl)

3) Bradycardia: GHB (again others but pronounced in this OD)

4) Tachydysrhythmias: chloral hydrate

5) Muscular twitching: GHB, methaqualone, etomidate

6) Discolored urine: propofol (green/pink)

 

 

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A patient presents to the University of MD ED in generalized convulsive status epilepticus. Continuous seizure activity that is not stopped by any dose of benzodiazepine [This is actually a very rare entity]. What is your next move?

- Check your basics: Fingerstick blood glucose (hypoglycemics can cause SE)

- Phenytoin is not going to work fast enough, the clock is ticking and the patient's brain cannot handle continuous status epilepticus, after 45-60min permanent neurologic sequelae or death will occur. If the cause is toxin induced, it just won't work.

- In an area where HIV is endemic, you have to consider Isoniazid - an antituberculous drug - and administer antidotal therapy: empiric dosing of vitamin B6 (pyridoxine) 5g IV. It is the only thing that will work.

- From the ED perspective, you will also be using a barbituate though there is evidence to support the use of propofol (after intubation for both). This will hopefully stop the seizure

- General anesthesia is the last chance if all else fails.

 

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You have a patient that is on lithium and a serum concentration is checked: 4.3 mmol/l

Therapeutic range is between 0.5 and 1.5 mmol/l

The patient shows no symptoms - is that possible? what do you do?

Answer: highly unlikely that the patient would asymptomatic, at least nystagmus would be present. Remember the symptoms are cerebellar in nature. What may have happened is the blood was drawn in an inappropriate tube. There are green "Lithium Heparinized" tubes in our Emergency Department. They are typically used for cardiac enzymes. This has been a well reported source of error (1)

 

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The Alcoholic Patient in the ED

Well, we have all been there....EMS rolls in with "another drunk guy" found down in the street. The nurses tell you, "he is here all the time...he is just drunk." You should be scared any time you hear this phrase uttered. Always be a little nervous about this group of patients and you won't fall victim to many of the pitfalls that some of us have experienced.

Pearls and Pitfalls in Caring for the Intoxicated Patient in the ED:

• Get a glucose early. Many of these patients are hypoglycemic when they arrive.
• Assume the worst and NEVER tell yourself or others,"He's just drunk." That statement is the kiss of death. Always assume there is occult trauma present. Did they fall and sustain a head bleed, splenic injury, hip fracture?
• Reevaluate during your shift. There is nothing worse than placing an intoxicated patient in a room and ignoring them, only to find out that hours (or shifts) later that they won't wake up.
• Consider a head CT. Although you can't scan them all, have a low threshold to image them. They fall all the time, and you will be surprised at how many subdural hematomas you pick up when you scan this group of patients. If you don't image, perform reassessments frequently during your shift.

Patients who present to the ED with an elevated INR due to vitamin K antagonists many times do not need to be reversed.  Simply holding a dose is all that is usually necessary for patients with an INR < 9.  Fortunately, guidelines published in CHEST are available to help guide management.
 

• INR: >Therapeutic to 5.0 with no bleeding - Lower warfarin dose, or omit a dose and resume warfarin at a lower dose when INR is in therapeutic range
• INR: >5.0 to 9.0 with no bleeding - Omit the next 1 to 2 doses of warfarin, monitor INR more frequently, and resume treatment at a lower dose when INR is in therapeutic range, or omit a dose and administer 1 to 2.5 mg oral vitamin K.* [*This option is preferred in patients at increased risk for bleeding (eg, history of bleeding, stroke, renal insufficiency, anemia, hypertension.]
• INR: >9.0 with no bleeding - Hold warfarin and administer 5 to 10 mg oral vitamin K. Monitor INR more frequently and administer more vitamin K as needed.
• Any INR with serious or life-threatening bleeding - Hold warfarin and administer 10 mg vitamin K by slow IV infusion; supplement with prothrombin complex concentrate, fresh frozen plasma, or recombinant human factor VIIa, depending on clinical urgency. Monitor and repeat as needed.
   

Reference:

Ansell, J, Hirsh, J, Hylek, E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; (6 Suppl):160s.

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Oseltamivir (Tamiflu)

• Has low protein binding and does not inhibit CYP450 (resulting in a low incidence of drug interactions)
• Requires dosage adjustment with creatinine clearance of < 30 ml/min
• Does not require dosage adjustment in patients with liver failure or the elderly
• Most common adverse effects are nausea and vomiting
• Serious effects include anaphylaxis and skin reactions. Neuropsychiatric effects reported include hallucinations, delerium and abnormal behavior
• It may be administered to infants and children due to the high potential morbidity associated with influenza

 

For complete indications and dosing: www.cdc.gov/h1n1flu/recommendations.htm

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Your patient presents unresponsive with an empty bottle of alprazolam (Xanax). You order a urine and blood toxicology screen. The blood comes back negative for benzodiazepines but the urine test is positive. How do you interpret this result?

• The benzodiazepine toxicology screen typically looks for oxazepam. If it is present in sufficient quantity, the test will be positive.
• Three benzodiazepines are detected by this test: oxazepam (Serax), diazepam (Valium), and chlordiazepoxide (Librium); [diazepam and chlordiazepoxide are metabolized to oxazepam].
• Other benzodiazepines such as clonazepam, lorazepam, and alprazolam will generally test negative unless there is cross-reactivity or large quantity.
• The urine and blood immunoassays are exactly the same. For this patient, there was probably a low overall quantity of alprazolam in the blood but a concentrated amount in the urine. Therefore, the positive urine and negative blood.

• Recently, a study was published which compared adverse drug events in patients who had received either fomepizole or ethanol for ethylene glycol or methanol poisoning.
• Importantly, this is the first trial which has compared these events head to head.
• Retrospectively, 172 charts over a 9 year period were reviewed. Toxicologists identified at least 1 ADR in 74 of 130 ethanol treated cases (57%) versus 5 of 42 fomepizole treated cases (12%).
• Severe ADRs occurred in 20% of ethanol treated patients vs 5% fomepizole treated patients.
• This adds further data to support the use of choosing fomepizole over alcohol for treatment of toxic alcohol poisonings

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Ondansetron (Zofran) has been off patent and its price has dropped to the point that it has supplanted promethazine (Phenergan) and even metoclopramide (Reglan) as the antiemetic of choice. With its low side-effect profile and known efficacy it is now being utilized in hyperemesis gravidarum and in pediatric gastroenteritis. - A cochrane review showed ondansetron to be both safe and effective in the pediatric population. Consider it prior to attempting oral rehydration therapy to increase effectiveness. - Dose: 0.1 mg/kg - you can give the oral dissolvable tablet (ODT) - ages 4-11 you can give 4mg ODT - Above age 11 the dosing is the same as an adult.

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Colchicine is a drug used for the treatment of acute gout attacks. It inhibits microtubule formation vital for cellular mitosis. It is also a drug with a narrow therapeutic index and lethal toxicity:

- Colchicine can be lethal at 0.5 mg/kg or even lower. Though this would be about 50 tablets and seems alot, remember it is prescribed 2 tablets initially then every hour until diarrhea presents (i.e. preliminary toxicity)

- Toxicity presents in 3 stages:

1. 0-24hrs: Nausea, vomiting, diarrhea
2. 1-7days: Sudden cardiac death, pancytopenia, renal failure, ARDS
3. >7days: Alopecia, myopathy, neuropathy (if they survive)

- No antidote, supportive care only available.

- Presentation is similiar to that of a radiation exposure

 

Overdoses of insulin glargine (Lantus) are rarely reported in the literature.  In fact, there are only 6 case reports.  We recently had a patient in our ED who was hypoglycemic from insulin glargine.  The hypoglycemic episode was quite prolonged (> 24 hours) in the ED before being the patient was transferred to the MICU.  Here are a few points to remember:

• Insulin glargine does not peak; it was designed to mimic basal islet cell insulin secretion.
• In the therapeutic setting, its effects can last up to about 24 hours.  In overdose the hypoglycemic effects have been reported to last up to 60-130 hours!
• Be prepared to give IV dextrose 5% or 10% infusion for the duration of the patient's hypoglycemic effect.  This can be supplemented with food.
• Octreotide will be ineffective for exogenous insulin poisonings because its effect comes from its ability to suppress insulin secretion from the pancreas.

Classical illicit recreational drugs like cocaine, ecstacy, and marajuana are sometimes difficult for teens to acquire. As a result, many are turning to their parents medicine cabinets as a source for recreational drugs.

[From the website drugabuse.gov] In 2008, 15.4 percent of 12th-graders reported using a prescription drug nonmedically within the past year. This category includes:

• amphetamines
• sedatives/barbiturates
• tranquilizers
• opiates other than heroin
  • hydrocodone, oxycodone

When adolescent patient presents to the ED, consider the possibility of a poly-pharmacy overdose. Always query parents about the presence of OTC and Rx medications in their home, and what is within reach of their kids.

While sedatives and analgesics are concerning, be alert for overdoses of more mundane medications like beta blockers and calcium-channel blockers which often pose a much more lethal threat. Consider overdose in adolescent patients with:

• GI or respiratory complaints
• Altered mental status (combative or somnolent)
• Abnormal vital signs
• History of depression or psychiatric illness

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Monitoring the Future Study: Trends in Prevalence of Various Drugs for 8th-Graders, 10th-Graders, and 12th-Graders

2005-2008 (in percent)*

	8th-Graders				10th-Graders				12th-Graders
	2005	2006	2007	2008	2005	2006	2007	2008	2005	2006	2007	2008
Any Illicit Drug Use
Lifetime Past Year Past Month	21.4 15.5   8.5	20.9 14.8   8.1	[19.0] [13.2]   7.4	19.6 14.1   7.6	38.2 29.8 17.3	36.1 28.7 16.8	35.6 28.1 16.9	34.1 26.9 15.8	50.4 38.4 23.1	48.2 36.5 21.5	46.8 35.9 21.9	47.4 36.6 22.3

Full chart available by clicking link in references.

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Serotonin is a neurotransmitter that has central and peripheral effects. It regulates the secretion of ADH from the hypothalamus and also controls the chemoreceptive trigger zone (CTZ) which induces emesis. Here are a list of medications categorized by the way they affect serotonin. Remember, any combination of these agonists could precipitate serotonin syndrome:

Enhance 5-HT synthesis: L-tryptophan

Direct HT agonists: Ergots, metoclopramide, sumatriptan, buspirone

Increase 5-HT release: amphetamines, cocaine, dextromethorphan, MDMA, L-dopa

Inhibit 5-HT breakdown: MAOIs, Linezolid

Inhibit 5-HT re-uptake: SSRIs (paxil), amphetamines, carbamazapine, tramadol, TCAs, citalopram, trazodone, lamotrigine, meperidine

 

Goldfrank's sniffing bar: no this is not a pub where toxicologist's hang out but rather a bar that assists with teaching the recognition of odors related to toxicology. Certain drugs and compounds have a distinct aroma.

The following is a list odors, see if you can name a medication or compound that has that odor - scroll down further to see the corresponding answers (if you really got all 5 email me and convince me):

1) Bitter Almond

2) Rotten Eggs

3) Wintergreen

4) Garlic

5) Sweet, Fruity (acetone)

 

Answers:

1) Cyanide; 2) N-acetylcysteine or Hydrogen Sulfide; 3) Methylsalicylate (like bengay); 4) Arsenic, organophosphate insecticides; 5) Chloroform, chloral hydrate

Add metoclopramide (Reglan) to the laundry list of medications with black box warnings from the FDA. Why was a black box warning added?

• Long-term metoclopramide use has been linked to tardive dyskinesia (involuntary and repetitive body movements) even after the drug is no longer being taken.
• Risk factors: Long-term or high-dose use, elderly, female gender.
• Recommended that metoclopramide treatment not exceed 3 months.

• None really.
• Just be aware of the dopamine antagonist effects (EPS - dystonic reactions) that are possible whenever you order metoclopramide in the acute setting.
• These effects can be treated effectively with an anticholinergic agent, such as diphenhydramine or benztropine.