UMEM Educational Pearls - Toxicology

Zanamivir (Relenza) is another neuraminidase inhibitor effective against influenza strains A and B. We are currently reserving its use for patients with H1N1 that may develop resistance to oseltamivir (Tamiflu) since it has been effective in these situations with past influenza strains.

• Zanamivir is given by inhalation only (powder) and can therefore not be given to ventilated patients
• Treatment dose is 10 mg (two blister packs) BID for 5 days
• Prophylaxis is 10 mg (two blister packs) once daily for 10 days
• Most common adverse effects are respiratory related and include bronchospasm and cough
• Pregnancy category C (same as Tamiflu) and should be used in pregnant patients with suspected/confirmed H1N1 due to the increased risk of morbidity/mortality
  • In fact, zanamivir may be the preferable antiviral for pregnant women because of its limited systemic absorption

This is a semi-synthetic opiate with partial agonist activity at the mu receptor. For an example of what a partial agonist is - see attached illustration. It is used in opioid addiction but is not as regulated as methadone clinics. Take a small course and you are licensed to prescribed it.  Primary caregivers are now able to administer buprenorphine to assist addicts though it is not recommended if the patient is requiring more than 40mg of methadone (rules out everyone in Baltimore).

The tablets (Suboxone) also contain naloxone to prevent intravenous injection which would induce withdrawal. Naloxone is not orally bioavailable and thus can be mixed into the pill.

Overdose is treated like any other opioid and naloxone should work.

Buprenorphine can illicit an opioid withdrawal response if the patient is currently on an opioid and then takes buprenorphine. 

Suppose to be safer than methadone - no QT prolongation and less respiratory depression

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A 34 y/o m presents to the ED agitated and combative with the following vitals signs: T 104.6, P 136, BP 198/124. His urine toxicology screen is positive for amphetamines. 

• Controlled animal experience clearly contraindicates the use of phenothiazines (e.g. prochlorperazine, chlorpromazine) and butyrophenones (e.g. haloperidol, droperidol).
• In animal models, these drugs enhance toxicity (seizures) or lethality, or both.
• Additional concerns regarding these drugs include their ability to interfere with heat dissipation, exacerbate tachycardia, prolong the QTc interval, and induce torsades de pointes, or precipitate dystonic reactions.

Aripiprazole (Abilify): a new atypical antipsychotic partially agonizes D2 and serotonin receptors though its compelte mechanism is not known. Used in schizophrenia, in overdose you may see the following symptoms (from a retrospective study done over 4 years worth of calls to a PCC):

• Somnolence 89 (56%)
• Tachycardia 32 (20%, heart rate 102-186)
• Nausea/vomiting 29 (18%)
• Dystonic reactions 21 (13%)

The study was with over 255 patients. Though QT prolongation is listed, it is not common with this medication.

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     Most hand sanitizers contain ethanol, while some contain isopropyl alcohol. The concentration of alcohol in these products varies from 45% to 95%, with the most commonly used products containing 62%.  How much would a 15 kg child have to ingest to obtain a blood alcohol concentration of 100 mg/dL (or 0.1%)?

     Assuming a volume of distribution of 0.6 L/kg and 100% bioavailability, only 15-20 mL is required to produce this toxic level.  That is equivalent to 3-4 teaspoons or approximately 8-10 “squirts” of hand sanitizer!

WBI: whole bowel irrigation

Reminder from Poisondex:

OVERDOSE: SEVERE: Stupor, shock, acidosis, GI bleed, coagulopathy, hepatotoxicity, and coma. MILD/MODERATE: Nausea, vomiting, diarrhea, lethargy, leukocytosis, and hyperglycemia. Clinical phases: (1) 0-2 hours: Nausea, vomiting, diarrhea, and abdominal pain. Lethargy, shock, GI bleeding, and acidosis if severe; (2) Apparent recovery; (3) 2-12 hours: Acidosis, hypotension; (4) 2-4 days: Hepatotoxicity; (5) days-weeks: GI strictures.

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 Valproic Acid (Depakote)

• Can cause carnitine deficiency
• In overdose and therapeutic ingestions can cause hepatic enzyme elevation (idiosyncratic) but can also cause hyperammonemia without hepatic enyme elevation
• Have a patient with somnolence or altered mental status and is on valproic acid - check a level but also check an ammonia level
• Elevated ammonia levels can be treated with an antidote - carnitine (IV or PO)
• Very safe antidote (carnitine) since it is a nutritional supplement, consider in patients on valproic acid and decreased responsivness with elevated ammonia

Priapism - prolonged involuntary erection - is an adverse effect with some drugs. Here is a list of the more commonly reported:

• Androgens
• Anticoagulants
• Antihypertensives: Hydralazaine, labetolol, phentolamine, prazosin
• Antipsychotics
• Cantharidin
• Cocaine
• Diazepam
• Marijuana
• Sildenafil
• Trazadone
• Yohimbine

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.