UMEM Educational Pearls - Toxicology

Dehydration and subsequent prerenal acute kidney injury can result when temperatures begin to rise in the summer months.  As a result, medications with narrow therapeutic indices that are primarily renally excreted may accumulate.  Here are the specific ones to look out for:

• Digoxin
• Lithium
• Colchicine
• Phenobarbital and theophylline (partially eliminated unchanged by the kidneys)

Certain medications can cause a certain dermatologic pattern. Many fall into a generic waste basket of "contact dermatitis" but here are some more characteristic findings and the drugs that can cause them:

Alopecia - anticoagulants, chemo, phenytoin, retinoids, selenium, thallium

Erythema multiforme - allopurinol, barbiturates, carbamazepine, cimetidine, some antibiotics

Toxic Epidermal Necrolysis (TEN) - allopurinol, bactrim (sulfonamides), mithramycin, PCN, sulfasalazine, nitrofurantoin, phenytoin, prazocin

The following list of medications have been associated with the development of Lupus Anticoagulants. Though it sounds like they should anticoagulate, they interfere with the Protein C system which means that they could induce a pro-thrombotic state - good short list to know:

Chlorpromazine (Thorazine

Procainamide (sorry Amal, I know you love that drug)

Hydralazine

Quinidine

Phenytoin

Several patients have recently presented with a medication history including tapentadol (Nucynta), the newest opioid formulation.  It is approved for treatment of acute moderate-severe pain.  Here are some key points:

• Mechanism similar to tramadol: mu-receptor agonist, also inhibits norepinephrine reuptake
• Potency stronger than tramadol, but less then morphine
• Usual dose is same as tramadol 50-100 mg every 4-6 hours prn pain
• Schedule II controlled substance, similar to morphine/oxycodone (tramadol is not a controlled substance)
• Overdose should present like other opioids, but potentially also including tachycardia, serotonergic effects, and seizures (similar to tramadol)

Treating a patient with clinical hypoglycemia (neuroglycopenia if you want to sound cool) is with "1 amp of D50". Then some are starting D5 drips and D10 drips. Here is the actual breakdown of what you are giving:

1 amp of D50 = 50% dextrose = 50g/100mL = 25g x 4Kcal/g carbs = 100 calories bolus

1 L D5W at 100mL/hr = 5% Dextrose = 5g/100mL x 1L = 50g x (4Kcal/g) = 200 cal infusion of 20 cal/hr!

1 L D10W at 100mL/hr = 10%D= 10g/100mLx1L= 100g x (4Kcal/g)= 400 cal at infusion of 40 cal/hr!

Snickers Bar = 271 calories in one serving - most people will eat in 5 minutes =  54.2cal/min

Take home message is feed your patient once they are awake and alert. Much more effective.

The ability to determine whether or not a patient is an alcoholic or will go into alcohol withdrawal syndrome (AWS) is not amenable to a clinical decision rule though many attempts have been made. The strongest predictor that a patient can develop AWS is a positive family history of AWS. Some clinical and biochemical predictors are:

ALT >50 U/L

K <3.6

These two in one study have had an odds ratio of 9.0 and 5.7 respectively though specificity was quite low. Ethanol levels has also found to be contradictory. Being able to predict AWS does not currently seem plausible but the treatment of AWS should and can involve a clinical decision rule like CIWA-Ar which is a scoring system that takes into account N/V, tremor, sweats, anxiety, agitation, hallucinations, headache and sensorium. Take a look at the scoring system that is most validated and utilized for symptom triggered therapy - often considered the most effective treatment for alcohol withdrawal.

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Attachments

1104212257_CIWA-Ar.pdf (10 Kb)

Kiwi fruit and latex share several antigens in common.  Thus, individuals who are allergic to either kiwi or latex may also suffer hypersensitivity reactions to the other material.

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·      In the event a nuclear power plant accident, people may be exposed to a mixture of radioactive products. The main radionuclides representing health risk are radioactive caesium and radioactive iodine.

·      Iodine-131 is concentrated in the thyroid gland and may eventually lead to development of thyroid nodules and thyroid cancer.

·      Radioiodine uptake by the thyroid can be blocked by taking potassium iodide (KI) pills or solution, preventing these effects.

·      KI should not be taken in the absence of a clear risk of exposure to a potentially dangerous level of radioactive iodine because KI can cause allergic reactions, skin rashes, salivary gland inflammation, hyperthyroidism or hypothyroidism.

·      Since radioactive iodine decays rapidly, current estimates indicate there will not be a hazardous level of reaching the United States from this accident.

·      There are three FDA approved KI products: Iosat, Thyrosafe and ThyroShield.

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Extravasation from radiocontrast, phenytoin and promethazine have resulted in significant tissue necrosis sometimes requiring surgical debridement and reconstructive plastic surgery. 

Pearl: Keep the infiltrated peripheral IV in and inject hyaluronidase 3-5mL (150U/mL) into the same subcutaneous pocket of medication. Hyaluronidase will increase the systemic absorption of the drug, decreasing its time in the SQ tissue. Extremely safe drug (we have the enzyme in our body) and has been used in neonates as well as adults. Also used for SQ hydration in palliative care and pediatrics.

Controversy: Hot vs Cold - Heat will cause vasodilation and hopefully increase systemic absorption but will likely also increase SQ spread possibly increasing the surface area of injury. Cold will cause vasoconstriction and decrease size of injury however will concentrate drug and possibly worsen the local injury.

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  1: Sokol DK, Dahlmann A, Dunn DW. Hyaluronidase treatment for intravenous  phenytoin extravasation. J Child Neurol. 1998 May;13(5):246-7.     2: Cochran ST, Bomyea K, Kahn M. Treatment of iodinated contrast material  extravasation with hyaluronidase. Acad Radiol. 2002 Aug;9 Suppl 2:S544-6.     3: Few BJ. Hyaluronidase for treating intravenous extravasations. MCN Am J Matern Child Nurs. 1987 Jan-Feb;12(1):23.     4: Kuensting LL. Treatment of intravenous infiltration in a neonate. J Pediatr  Health Care. 2010 May-Jun;24(3):184-8. Epub 2010 Mar 20.     5: Raszka WV Jr, Kueser TK, Smith FR, Bass JW. The use of hyaluronidase in the  treatment of intravenous extravasation injuries. J Perinatol. 1990  Jun;10(2):146-9. 

Could this be another risk factor for DVT/PE. Maybe not yet but it is worth mention. A recent observatioal study in BMJ showed that there was  an associated increase with DVT or PE. From a database of 25,532 patients over a 3 year period of time and finding match controls, the results were:

1. 32% overall increase risk of DVT/PE in patient who were taking antipsychotics
2. Recent initiation of therapy within 3 months increased risk 2-fold
3. Risk was greater with atypical antipsychotics (Odds Ratio 1.73 Atypical vs 1.23 Old)
4. Risk was greater with lower dose than higher dose

Limitations were this is was an observational study with missing data. BMI was missing in these records and it is always difficult to tease out the multiple medications these patients are on.  Also don't have a great biological mechanism (yet). Still makes you go hmm....

Antipsychotic drugs and risk of venous thromboembolism, Parker, BMJ, 2010.

Most have converted from succinylcholine to rocuronium for their choice of paralytic in RSI. Succinylcholine-induced hyperkalemia secondary to muscle fasciculations is considered usually clinically insignificant though there may be a hyperkalemic renal patient that this may tip them over. The fasciculations also may worsen traumatic long bone fractures.  Here is the argument in a head to head comparison:

Duration = injection of drug to 25% recovery of single twitch height (clinically relevant recovery in ED - essentially breathing may return)

Recovery Index = time from 25% to 75% recovery of single twitch height

The main reason succinylcholine was utilized was because of its fast onset and short duration. Rocuronium is comparable enough to succinylcholine in these characteristics tilting the overall benefits to rocuronium. If the FDA ever approves it, suggamadex is a possible reversal agent for rocuronium - currently used in Europe. Imagine having that in your RSI kit.
 

Several medications/chemicals can cause unique toxicologic reactions in pediatric patients.

• Ethanol: hypoglycemia.  Reported with ethanol levels as low as 20 mg/dL.
• Clonidine and imidazolines: central nervous system effects.  Agents such as tetrahydrozoline, oxymetazoline, naphazoline, and clonidine can cause CNS depression, respiratory depression, bradycardia, miosis, and hypotension.
• Benzyl alcohol: gasping syndrome.  Preservative which has been removed from most medications and IV flush solutions used in neonates.  Syndrome includes severe metabolic acidosis, encephalopathy, respiratory depression, and gasping.
• Chloramphenicol: gray baby syndrome.  Broad-spectrum antibiotic not used frequently in U.S.  Syndrome includes abdominal distension, vomiting, metabolic acidosis, progressive pallid cyanosis, irregular respirations, hypothermia, hypotension, and vasomotor collapse.

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Recently a case report was published in which a child was incorrectly diagnosed with MRSA. He actually had systemic loxoscelism from a Brown Recluse spider bite.

A patient who has been bitten by brown recluse spider bite may present with pruritis, pain and swelling. The classic lesion has a bluish-purple central region, surrounded by concentric rings of pale ischemia and erythema. (“red, white and blue”) Bites may progress over days to a bleb with necrosis and eschar formation, followed by ulceration.

Systemic loxoscelism presents with a scarlatiniform rash that spreads dependently. It may have the classic purple lesion surrounded by concentric rings of pale ischemia and erythema. The patient may be uncomfortable but is usually stable. Treatment is supportive care.

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Continuing with the synthetic/designer drug theme. Last time we were discussing synthetic marijuana.  Another old drug making a resurgence under the designer drug category is mephedrone.This amphetamine-like drug has been purportedly the active substance in "bath salts". It has also been sold as "plant food" - still trying to figure that one out.

Sold in head shops under the name Bliss or Cloud 9 - they have been reported to be available in Baltimore, MD recently. They can also be bought over the internet. Crushed, snorted or ingested, the effect is similiar to cocaine with a largely sympathomimetic toxidrome. Mephedrone has been labeled an entactogen with users behaving similiar to an MDMA ingestion. A Baltimore news station incorrectly called it "synthetic cocaine" - though the effect may be similiar, completely different molecular structure.

Treatment is cooling, check lytes (especially sodium), check for rhabdomyolysis and sedation with benzodiazepines. Below is one link from a Denver News Station. Attached is a picture of a bath salt product.

The latest and greatest on the street - synthetic marijuana and bath salts!

http://www.thedenverchannel.com/news/26567376/detail.html

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1102241706_bath-salts.jpg (38 Kb)

Sold under the name of K2, Spice. Patients exposed to this will present with dry mouth, paranoia, tachycardia, hallucinations but will resolved rather quickly over several hours. Observation in the ED and supportive care is usually all that is needed. A little history about synthetic marijuana:

• JWH-018 is a synthetic cannabinoid (SC) that acts at cannabinoid receptors.
• Synthetic cannabinoids were created s in the 1960’s and continued to be developed as appetite stimulants (e.g., dronabinol).
• The JWH series of SCs are named for the chemist who first synthesized them, John W. Huffman, Ph.D. (thus the JWH prefix).
• SCs recently appeared for sale in smoke shops and other outlets (such as gas stations) as herbal incense.
• These products contain plant material that mimics smell and appearance of marijuana but is adulterated with one or more SCs.

Attachments

1102180659_Spice_drug.jpg (558 Kb)

Many consider Paracelsus (1493–1541) as the father of modern toxicology.

• He was the first to emphasize the chemical nature of toxic agents.
• He stressed the need for proper observation and experimentation regarding the true response to chemicals.
• He underscored the need to differentiate between the therapeutic and toxic properties of chemicals when he stated in his Third Defense, "What is there that is not poison? All things are poison and nothing [is] without poison. Solely, the dose determines that a thing is not a poison."

The introduction of the dose–response concept might have been his most important contribution to toxicology, meaning that everything is toxic at the right dose (even oxygen and water).

Dabigatran (Pradaxa), an antithrombin medication, was discussed in an earlier pearl and thought I would play devil's advocate and explain the possible concerns:

• Yes you don't need INRs to evaluate therapeutic levels but the problem is also don't know if its subtherapeutic or supratherapeutic. This can be an issue during times of transition fromLWMH or coumadin. There are specific protocols to follow for "bridging".
• Though not clinically significant, there was an increase in myocardial infarction in thedabigatran (Pradaxa) group when compared to coumadin - remember vioxx?
• FDA approved dabigatran for stroke prevention, embolism, in AF patients. Though people will automatically translate all of the indications coumadin has that cannot be done yet.
• No reversal agent so in an acute (ED) setting, you are in trouble and are depending on the relatively short half-life to get you out of trouble.

Toxicology Mantra: You never want to be the first person or the last person to use a drug

The Rumack-Matthew nomogram is a well studied and validated tool to help assess the potential for liver toxicity following acute acetaminophen poisoning.  Here is a brief review of when it is best utilized.

• Prior to 4 hours post-ingestion: Not helpful to determine likelihood for toxicity.  Only use is to confirm an ingestion took place.
• Between 4 and 24 hours post-ingestion: Plot the patient's level vs. time after ingestion.  If above the toxicity line, treat with acetylcysteine.
• More than 24 hours post-ingestion: Any elevated acetaminophen level is toxic and should be treated with acetylcysteine.

Outside-the-box situations:

• Chronic exposures: Nomogram not indicated.
• Overdoses with co-ingestants that slow GI motility (e.g., opioids, diphenhydramine) OR extended release products (e.g., Tylenol Arthritis): If the level at 4 hours post-ingestion is not toxic, repeat it at 8 hours post-ingestion.  If either level is toxic, treat with acetylcysteine.

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• Vitamin K can be used intravenously for management of the NON bleeding patient with a high INR (>9).
• Although anaphylactoid reactions have been described, most cases occurred with large doses of vitamin K, administered rapidly, and with little dilution.
• It is estimated that the incidence of anaphylaxis is 3:10,000 doses.
• The subcutaneous route of administration is not recommended because of its delayed and unpredictable responses.

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