UMEM Educational Pearls - Toxicology

Everyone has admitted an altered mental status, patient or bradycardic patient and all of your test results are coming back normal except for a mild increase in creatinine. Take a look at the medication list. Creatinine is a poor indicator of renal function and GFR may be severely impaired even with a mild elevation of creatinine. If you have a predominantly renally excreted drug, you can see toxic effects of a drug even if administered at therapeutic levels.

Common bradycardia inducing medication that is renally cleared: atenolol (very high renal excretion) and digoxin (70%).

Altered Mental Status and on Keppra? Keppra is 100% renally cleared!

Ask your pharmacist for help with the medication list with renal or hepatic insufficiency.

Current evidence does not support the use of fasciotomy or dermotomy following North American Crotalinae envenomation with elevated intracompartmental pressures. [1]

A new case report of a 17-month old bitten by a copperhead snake reinforces that early and adequate administration of crotaline Fab antivenin is the treatment of choice. [2]

Many experts recommend against measuring compartement pressures altogether; we know it will be elevated.

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Though an uncommon exposure, it can occur from chronic mercury exposure. One mode of exposure that I have seen is with elemental mercury thermometers that were broken to collect the beads of mercury - for entertainment. This occurred in a child's room and were forgotten.  One child presented with personality changes and pink hands and feet. The patient suffered from severe mercury poisoning and acrodynia due to prolonged exposure to the mercury vapor. 

Acrodynia or Pink Disease includes:

Irritability, shyness, photophobia, pink discoloration of the hands and feet and polyneuritis.

A new drug is coming onto the drug scene with some case reports beginning to build. The internet appears to have been a major driver or mode of distribution for this particular drug.

One study of users showed that this ketamine analog has more vivid hallucinations that would liken it to LSD. It has been theorized that this drug has the dissociative effects of ketamine but also has prominent serotninergic effects making additions more likely and hallucinations possible.

If you see a case in your ED, you can say you heard it here first!

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Can acetaminophen concentrations < 100 mcg/mL obtained between 1-4 hours after acute ingestion accurately predict a nontoxic 4-hour concentration? NO!

Despite a high negative predictive value, a new study found there are still cases with toxic concentrations after 4 hours despite earlier levels < 100 mcg/mL. 

The Rumack-Matthew nomogram is to be utilized starting at 4 hours after an acute acetaminophen ingestion. Unless the concentration is zero, a second level must be drawn at 4 hours if an earlier one is positive.

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Reversal of the new anticoagulants rivaroxaban (Xarelto) and dabigatran (Pradaxa) has been challenging particularly in the ED setting with no definitive reversal agent. Intracerebral hemorrhage or critical GI bleed management becomes challenging and worsens mortality.

There is growing literature that states activated prothrombin complex concentrate or non-activated PCC may reverse these new anticoagulants. A volunteer study (1) showed its efficacy and concensus workgroups are now recommending aPCC as first line therapy(2).  The search goes on for a reliable reversal agent for these new anticoagulants which were suppose to solve more problems instead of create new ones.

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  1) Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M.  Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a  randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011 Oct 4;124(14):1573-9.     2) Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, Blais N,  Fontana P, Cohen A, Llau JV, Rosencher N, Schved JF, de Maistre E, Samama MM,  Mismetti P, Sié P; Working Group on Perioperative Haemostasis. Management of  major bleeding complications and emergency surgery in patients on long-term  treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors:  proposals of the working group on perioperative haemostasis (GIHP) - March 2013.  Arch Cardiovasc Dis. 2013 Jun-Jul;106(6-7):382-93.  

All benzodiazepines are metabolized by the liver. Some are just metabolized by pathways that are less dependent on global liver function.

The ‘LOT’ drugs are metabolized by conjugation, have no active metabolites, and have minimially affected half-lives even in the setting of liver disease.

• L – Lorazepam

• O – Oxazepam

• T – Temazepam

The rest of the benzodiazepines are primarily metabolized via hepatic CYP-mediated oxidation and may have prolonged duration of effect in patients with marked liver impairment.

For a bit more detail and commentary by Dr. David Juurlink, please read my recent post on the Academic Life in Emergency Medicine blog: http://academiclifeinem.com/all-benzodiazepines-are-metabolized-by-the-liver/

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You have a treat bag full of candy, which one can cause hypertension, hyopkalemia, metabolic alkalosis, rhabdomyolysis, low renin activity, thrombocytopenia and hypoaldosteronism. (scroll down for answer)

Licorice syrup or licorice extract contains glycyrrhizic acid which has a mineralcorticoid-like effect and can cause of all of the effects. Don't worry, Twizzlers and other usual licorice candies do not have true licorice extract in them. It is found in herbal remedies and some "natural" candies and licorice flavored cigars. Don't pick the licorice !

Yesterday's pearl generated several questions that I thought were worth answering briefly:

1) Why give it IM? Absorption rate is faster than SQ infiltration though theoretically could still cause necrosis

2) Is it only infilitration? Gangrene has occurred with inadvertent intra-arterial injection, SQ infiltration and even regular IV administration

3) Mechanism? Appears to be the drug and not diluent, diluting down the concentration as well as decreasing dose appears to help if you are going to give it IV

Here is a website if you wish to read more details:

https://www.ismp.org/newsletters/acutecare/articles/20060810.asp

If you are still using IV Phenergan, you need to be aware of the necrotic effect that occurs if it infiltrates. EDs have even removed it from their drug dispensing machines. It appears to be the drug and not the diluent. Mechanism is not completely understood. Below is a picture the plaintiff attorney will use about this well know adverse effect. If so many alternatives for IV antiemetic it is wise to reconsider IV phenergan.

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Drugs that cause hearing loss:

Reversible - Chloroquine, erythromycin, quinine, CO, loop diuretics, NSAIDS, ASA

Irreversible - aminoglycosides, bleomycin, vincristine, vinblastine, cisplatin, lead, mercury, arsenic

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Toxicologists should be aware of non-toxicological mimics of delirium, including anti-NMDA receptor encephalitis. It is an under-recognized progressive neurological disorder caused by antibodies against NMDA receptors.

Cases often present with altered mental status, autonomic instability, increased muscle tone, and movement disorders. It can easily be mistaken for neuroleptic malignant syndrome (NMS). A new case series describes two such patients for which toxicologists were consulted.

Must read links:

Dr. Leon Gussow provides a great review of the case series on his Poison Review blog.

Dr. Chris Nickson reviews the basics of the disease on the Life in the Fast Lane blog.

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With several new diabetes medications available, it is important to know which ones are likely to cause hypoglycemia after overdose. Based on mechanism of action and reported cases, the likelihood of hypoglycemia after overdose is listed below by drug class.

Keep in mind that other drugs can interact with antidiabetics resulting in hypoglycemia. This table applies only to single agent ingestion/administration.

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There are Type 1C Anti-Dysrhythmics, like propafenone and flecainide, that are utilized to suppress atrial fibrillation. They are called Type 1C due to their sodium channel blocking effects. Flecainide has a potent effect on the ECG and has caused significant and resistant widening of the QRS complex. 

Typically, a sodium channel blocker like a TCA can be treated with hypertonic sodium bicarbonate but flecainide has been resistant to this at times and there is a reported overdose utilizing magnesium sulfate. (1) Keep that in mind if you were to see a widened QRS complex in the face of a flecainide ingestion.

There has been a Brugada ECG pattern also reported (I know Amal is smiling)  (2) ontop of the widened QRS, PR intervals though minimal effect on the QT.

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  1: Cabrera Ortega M, Gell Aboy J, Díaz Berto E, Monagas Docasal V. [Acute  flecainide overdose]. An Pediatr (Barc). 2011 Jan;74(1):56-8.       2: Martínez-Mateo V, Arias MA, Rodríguez-Padial L. [Brugada electrocardiographic  pattern elicited by flecainide overdose]. Med Clin (Barc). 2011 Mar  19;136(7):320. 

We will all see a patient that comes into the Emergency Department stating they have ingested some wild or self-picked mushrooms. Usually they will be actively vomiting and there will be no mushroom to identify. If there is, identification may still be difficult. There are no other clinical relevant symptoms that you can see until its too late. Amanita species is lethal and may require liver transplant. The most important question you can ask after trying to identify the mushroom is:

When did you eat the mushroom and how long after did the vomiting start?

As a general rule (with some exceptions), Amanita species cause vomiting and diarrhea in a delayed fashion 5-6 hours after ingestion. The other non hepatotoxic species usually cause vomiting within 1-3 hours.

Immediate vomiting <6 hrs from time of ingestion is good (usually).

There is minimal evidence of cross-reactivity between sulfonamide antibiotics and non-antibiotics [1-4]. Despite this, the U.S. FDA-approved product information for many non-antibiotic sulfonamide drugs contains warnings concerning possible cross-reactions.

Key Findings from a New Review Article [5]:

• An estimated 3-6% of the general population is allergic to sulfonamides.
• Structurally, none of the non-antibiotic sulfonamides exhibit both of the features shown to be responsible for sulfonamide reactions (i.e., an N-containing ring attached to the N1 nitrogen of the sulfonamide group and an arylamine group at the N4 position).
• A comprehensive literature search (1966-December 2011) identified only 9 case reports indicating possible cross-reactivity to sulfonamide medications; however, in most cases, adequate patient testing was not conducted to firmly establish either sulfa allergy or sulfonamide cross-sensitivity.

Bottom line: You can feel safe prescribing furosemide, glyburide, and hydrochlorothiazide to your patient with an allergy to sulfamethoxazole/trimethoprim.

Other blog reference on this topic: http://lifeinthefastlane.com/2011/04/sulfa-drug-discombobulation/

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Naloxone can be administered via pretty much any route. One that has gained popularity in the past several years is nebulized naloxone. Although anecdotal reports tout the benefits of nebulized naloxone, what does the literature say?

• Case report of 46 y/o f with initial oxygen saturation of 61%. Naloxone was administered by nebulizer and within 5 min oxygen saturation was 100% and mental status was normal. [1]
• Retrospective analysis of prehospital adminstration in 105 patients. 22% had "complete response" and 59% had "partial response." Problem is the initial respiratory rate was 14 bpm with GCS of 12. [2]
• Prospective analysis of 26 patients in an inner-city, academic ED. Pre-naloxone respiratory rate was 13 with GCS of 11. Post-naloxone respiratory rate was 16 with GCS of 13. Three patients (12%) experienced moderate-to-severe agitation and 2 (8%) were diaphoretic. [3]

Bottom Line: Many of the studied patients may not have needed naloxone in the first place (initial respiratory rate 13-14), with a few developing withdrawal symptoms. Nebulized naloxone may have a role in the not-too-sick opioid overdose in whom you want to prove your diagnosis and wake the patient up enough to obtain a history. It is not a therapy for the apneic opioid overdose.

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A recent article was published in the Journal of Medical Toxicology reviewing the use of sodium acetate for treatment of overdoses and poisonings.

Acetate is metabolized to bicarbonate, causing a net increase in cations; this increased strong anion difference leads to alkalemia.

It has been used to treat acidosis in uremia, diarrhea, and in trauma patients.

Although no studies have been conducted using sodium acetate as an antidote, if bicarbonate is unavailable this is a viable option for management of salicylate overdose, and for qrs widening or arrhythmias due to overdoses.

Sodium acetate, if given rapidly (in animals and hemodialysis patients), causes myocardial depression, hypotension, and hypopnea.

The bolus dose should be given as 1-2 mEq/L given over 15-20 minutes. For the maintenance infusion, dilute 150 mEq diluted to 1 L in dextrose 5%, infuse at 2X the maintenance rate.

It must be diluted in dextrose 5% and NOT normal saline.

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The internet has become a wealth of information and some books have now gained internet noteriety. A chemist and author of the book - TIKHAL: Tryptamines I Have Known and Loved is an excellent example. 

Tryptamines include drugs like LSD and alpha-methyltryptamine (AMT). Vivid visual hallucinations and serotonin agonism, these drugs were glamorized by this author. He would synthesize a tryptamine and then "taste it". Take a look at the link below where he first describes the biochemical synthesis he performed then describes his dose response effect when he tried the drug.

If you run into a drug or slang term in the ED you are not familiar with, the website www.erowid.org will likely have the translation. 

http://www.erowid.org/library/books_online/tihkal/tihkal48.shtml

In June 2013 the American College of Medical Toxicology (ACMT) released a Guidance Document on the Management Priorities in Salicylate Toxicity. Here are some key highlights:

• Continuous IV infusion of sodium bicarbonate is indicated even in the presence of mild alkalemia from the early respiratory alkalosis.
• Euvolemia is important.
• If intubation is required, administration of sodium bicarbonate by IV bolus at the time of intubation in a sufficient quantity to maintain a blood pH of 7.45-7.5 over the next 30 minutes is a reasonable management option during this critical juncture.
• Once airway control has been established, it is imperative that the increased minute ventilation and low PCO2 usually seen with salicylate intoxication are maintained.
• A salicylate concentration approaching 100 mg/dL warrants consideration of hemodialysis in the acute toxicity setting (40 mg/dL for chronic toxicity). Consult nephrology well before these threshold levels.

The full document can be accessed here.

The Poison Review blog by Dr. Leon Gussow discusses the guidance document here.

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