UMEM Educational Pearls - Toxicology

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.

Follow me on Twitter (@PharmERToxGuy) 

When reviewing a patient's medication list, there are always some that should catch your eye. Digoxin is one since we can measure it, has a low therapeutic index and elimination is effected when renal function is diminished. Another drug that should catch your eye is SOTALOL. Renally cleared and affected by even a minimally lower than normal magnesium. The toxic effect even at therapeutic levels is torsades de pointes.

One study, in a 736 bed hospital, showed 89% of patients prescribed sotalol were on an inappropriate dose due to renal function and an odds ratio of 3.7 increased re-admission rate at 6 months for the patients on the inappropriate dose of sotalol.

We can catch this in the ED. Involve your pharmacist, ED pharmacist or local toxicologist for dosing calculations.

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In the treatment of acetaminophen poisoning with N-acetylcysteine (NAC), the PT/INR can be slightly elevated even in the absence of hepatotoxicity. Considering Prothombin Time (PT) is one of the criteria used to assess severity of liver damage in this setting, it is important to know how much the PT/INR can be affected by NAC and if it has an actual effect on coagulation factor levels.

1. N-acetylcysteine has been shown to slightly increase the PT) by up to 3.5 seconds in healthy volunteers.
2. A more recent study by the same authors demonstrated a reduction in vitamin K-dependent clotting factor activity (II, VI, IX, and X) after NAC administration in healthy volunteers.

Clinical Practice Pearls

• The elevation in PT/INR after NAC administration is real, not simply laboratory interference.
• However, the PT/INR elevation and decrease in coagulation factors is modest and not likely clinical signficant.
• Many poison center guidelines allow for an INR up to 2 to be considered 'normal' to account for this phenomenon in this setting.

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• Opioid analgesia can actually INCREASE sensitivity to pain in some cases

• The exact cause is unclear, but may be due to up-regulation of NDMA receptors in spinal cord dorsal horn neurons

• Pain tends to be DIFFERENT and DIFFUSE from the underlying condition for which the narcotics were prescribed

• Switching from shorter acting opiates to methadone may be effective, as it is a weak NDMA antagonist and has only partial cross tolerance with other opioids

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Hyperglycemia in the setting of antipsychotic use has been reported mostly with olanzapine (Zyprexa) but does occur with other antipsychotics. A recent study from the NYC medical examiner's office details 17 deaths of DKA due to antipsychotics and found that (from highest to lowest incidence) quetiapine > olanzapine > risperidone were the atypical antipsychotics found with these deaths.

Remember hyperglycemia occurs with patients on antipsychotics and can lead to hyperglycemia hyperosmolar coma or DKA. Both can be lethal.

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Utilizing 20% lipid emulsion at a dose of 1.5 mL/kg (100 mL Bolus) IV with repeat in 15 minutes in no response is being recommended in patients hemodynamic instabiity due to poisoning.

Probably more effective in lipophilic drugs is a current theory for the mechanism of action - the "lipid sink". The idea is that the lipids envelope the drug pulling it off its receptors or sequestering it in the intravascular space. A recent paper has added another mechanism - direct inotropic and lusiptropic effects.(1)

Also, if you think the therapy is experimental, think again. Another recent paper surveyed Poison Control Centers and found 30/45 Poison Centers in the US have a defined protocol for utilization of lipid emulsion therapy. The PCCs are recommending it more.(2)

What was once considered just a purely experimental therapy only used at the very end of code is becoming more mainstream. Comfort with its safety profile and anectodotal effiicacy continues to mount.

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Strychnine poisoning is still occasionally found in rat poisons and in adulterated street drugs and herbal products. The typical symptoms are involuntary, generalized muscular contractions resulting in neck, back, and limb pain. The contractions are easily triggered by trivial stimuli (such as turning on a light) and each episode usually lasts for 30 seconds to 2 minutes, for 12 to 24 hours. Classic signs include opisthotonus, facial trismus, and risus sardonicus.

Differential diagnosis includes:

• Tetanus: However, the onset of symptoms is more gradual and the duration much longer than in the case of strychnine poisoning.
• Generalized seizures: However, strychnine poisoning presents with a normal sensorium during the period of diffuse convulsions.
• Dystonic reaction: However, dystonic reactions are usually static, whereas strychnine poisoning results in dynamic muscular activity. 
• Serotonin syndrome
• Malignant hyperthermia
• Neuroleptic malignant syndrome
• Stimulant use

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If you are working in a community hospital and have an acetaminophen overdose, one of the criteria to transfer the patient to a tertiary care center is presence of the King's College Criteria.

The below is taken from mdcalc.com -  http://www.mdcalc.com/kings-college-criteria-for-acetaminophen-toxicity/

Each one is assigned points and can be prognostic for severe toxicity and need for transplant. The lactate and phosphorus are new ones and have modified the criteria. Phosphorus is utilized to create glycogen. If the liver is injured and trying to heal, your phosphorus will be low (good). If the liver is injured and unable to repair itself the phosphorus will be high (bad). This single test has an excellent prognostic ability.

With recent events, a few notes about ricin seems appropriate:

1. Easy to make from castor bean though heat labile
2. No antidote, though Fab like digibind is in development
3. Granule size of the grain of sand can kill
4. Inhalation, IM, IV all effective
5. After immediate exposure likely no symptoms
6. Vomiting and diarrhea initially, acute lung injury and death in 3-5 days

CDC website: http://www.bt.cdc.gov/agent/ricin/

Cocaine toxicity is characterized by the sympathomimetic toxidrome: tachycardia, hypertension, hyperpyrexia, diaphoresis as well as sodium channel blocking effects that can cause local anesthesia topically, QRS widening and even seizure.

Usual treatment for a cocaine toxic patient is benzodiazepines and cooling. Be wary of end organ damage, trauma and seizures.

There was a recent study that looked at dexmedetomidine to treat the sympathomimetic effects. Placebo-controlled trial used cocaine-addicted volunteer and applied intranasal cocaine. Measuring skin sympathetic nerve activity and skin vascular resistance, this study, unfortunately, showed as the dose increased  MAP did not fall further and increased paradoxically in 4 of 12 subjects.

This highlights the incredible physiologic mechanism of catecholamine release from the CNS with cocaine. This mechanism overlaps some with the centrally acting alpha agonist - dexmedetomidine and was shown in the study by Kontak et al. 

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