UMEM Educational Pearls - Toxicology

People who hide illicit drugs can be classified in to three different types.

1.     Body stuffers – people who ingest drugs that are poorly wrapped to “eliminate” evidence from police – e.g. street dealers.

2.     Body packers – people who ingest large amounts of “well” packed drug packets to transport drugs (usually internationally) – aka “mule.”

3.     Body pushers – people hiding drugs in rectum or vagina.

Body stuffers are more frequently encountered in local ED compared to body packers. Stuffers can become symptomatic as the ingested drugs (cocaine, heroin, amphetamines) are often poorly wrapped (e.g. in plastic bag/wrap, cellophane paper, aluminium oil, etc.).

Recent retrospective article looked at the utility of 6-hour observation period in the ED as a management strategy for body stuffers. (n=126)

Characteristics

1.     Ingested drugs (self-reported): heroin (48%), cocaine (46%), other drugs [cannabis, MDMA, diazepam, methamphetamine] (16%), unknown (8%)

2.     Time of ingestion to ED presentation

• < 2 hr: 58%
• 2-6 hr: 10%
• > 6 hr: 7%

Clinical findings

76% of the patients experience clinical signs of toxidrome at time of presentation.

Most common findings:

• Hypertension: 30%
• Tachycardia: 20%
• Agitation: 16%

Patients who ingested heroin were more symptomatic vs. cocaine (87% vs. 70%)

Patients were discharged:

• Within 6 hr: 72%
• Between 6 – 12 hr: 10%
• Between 12-24 hr: 10%
• > 24 hr: 8%

Conclusion

• Patients developed new or worsening drug toxicity within 6 hr of presentation
• Majority of patients were discharged within 6 hr.
• Asymptomatic patients at ED presentation should be observed for 6 hr.

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Flumazenil is generally avoided in most adult patients with suspected benzodiazepine overdose due to resedation, seizures/withdrawal, inconsistent reversal of respiratory depression, and the potential for proconvulsant coingestants.

Three relatively recent poison center studies have attempted to demonstrate the safety of flumazenil in this setting. [1-3] In the first study there were 904 adult patients with 13 reported seizures and 1 death. [1] A second study specific to pediatric patients reported 83 patients with no seizures and no deaths. [2] A third study found 80 patients with 1 seizure and 0 deaths. [3]

On the surface, it may appear that flumazenil is safe to give. But, retrospective poison center studies from voluntary reporting cannot be used to prove a drug's safety. The true denominator is unknown. In the pediatric study, we wouldn't expect children to experience withdrawal since they aren't on chronic benzodiazepine therapy. [2] So, it's no surprise there weren't any seizures or deaths.

A recent systematic review and meta-analysis of randomized trials summed it up perfectly: "Flumazenil should not be used routinely, and the harms and benefits should be considered carefully in every patient." [4] Cases in which to consider flumazenil are pediatric patients and reversal of procedural sedation if needed.

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Poison ivy, oak, and sumac (Toxicodendron sp) causes a highly puritic, allergic contact dermatitits (ACD) that affects between 10 and 50 million in the US every year. It is a significant occupational hazard as well a scourge for outdoor enthusiasts.

Toxicodendron species contain oleoresins, known as Urushiol compound, secreted by all parts of the plant. Contact with the oil usually occurs by brushing against or direct handling of the plant or contaminated items. This toxin triggers a type IV delayed hypersensitivity reaction in approximately 75% of the population. Within 12-24 hours an erythematous, often linear, vesicular rash develops but new lesions can occur up to 2 weeks later.

There is no ideal treatment for ACD induced by Toxicodendron species. Avoidance and barrier protection are the best strategies. Recommended medications include antihistamines, topical preparations, and systemic steroids. However, steroids require a 2-3 week course to prevent recrudescence of the rash and are not without undesirable side affects.

Zanfel, an OTC granular polyethlene paste, removes urushiol by binding with it to create an aggregate cluster that can be washed away with water. It is highly effective, providing rapid relief even as a sole agent but requires multiple initial applications and is expensive. Mean Green hand scrub has similar ingredients and is claimed to bond urushiol also. Excessive scrathing and abrasive scrubs can cause secondary cellulitis requiring antibiotics.

Oral hypoglycemic agents (e.g. sulfonylureas) can cause symptomatic hypoglycemia. Unlike metformin, sulfonylureas stimulate the release of insulin from beta-cells (in pancreas) in response to serum glucose level.

ED management of hypoglycemia involves:

1. Dextrose (D₅₀ 50mL via IV) administration if symptomatic: e.g. altered mental status
2. Feeding: food items that are more substantial than juice: e.g. food tray or sandwich
3. Serial finger stick glucose check

However, for recurrent hypoglycemia (> 3 episodes of hypoglycemia), think about octreotide, rather than starting a dextrose (D₅) infusion.

For example, D₅ infusion at 150 mL/hour has only 7.5 gm of dextrose (calculation: D5% = 5gm/100 mL). One gram of dextrose contains about 4 calories (equivalent to one piece of Skittles) So, with a D₅ infusion at 150 mL/hour, you are giving your patients 8 pieces of Skittles per hour. A bottle of Snapple lemon ice tea (non-diet) has more calories (150 calories in 16 oz. or 473 mL)! 

Octreotide 50 mcg SQ (q6 hour) injection will decrease the insulin release from the beta-cell by blocking the voltage-gated Ca channel on the beta-cell.

All patient who received octreotide in the ED requires admission to the hospital for observation. Patients can be safely discharge from the hospital when finger stick glucose level remains normal for 24 hours after the last dose of octreotide.

Bottom line: In sulfonylrea-induced recurrent hypoglycemia, administer octreotide, rather than continuous infusion of dextrose (D₅) solution.

Physostigmine is a cholinergic agent (acetylcholine esterase inhibitor) that can be used to reverse anticholinergic toxicity. Its use has been declining since the publication of several case reports of physostigmine induced cardiac arrest in tricyclic antidepressant (TCA) overdose.

The first case report (and often cited) was by Pental P. et al. (Ann Emerg Med 1980), who presented 2 cases (32 and 25 year old) of asystole after administration of physostigmine (2 mg) in severe TCA overdose. These two cases both had widened QRS interval (120, 240 msec) due to TCA poisoning. Bradycardia preceded the asystole.

The second case report (Shannon M Pediatr Emerg Care 1998) reported a 15 year-old girl with QRS widening (120 msec) received 2 mg of physostigmine and developed severe bradycardia and then asystole.

Another case series (Knudson K et al. BMJ 1984) of 41 patients with overdose of maprotiline showed that physostigmine administration was associated with higher incidence of seizures. No asystole was noted.

Today physostigmine is contraindicated in TCA poisoning. But if we think about it, physostigmine administration probably wasn’t a good idea in the first place. Correcting anticholinergic toxicity of TCA has limited benefit; mortality from TCA overdose is usually associated with cardiac toxicity (Na-channel blockade) and should be treated with NaHCO₃ administration

Physostigmine still has a role in treating isolated anticholinergic toxicity  (e.g. diphenhydramine, benztropine, dimenhydrinate, scopolamine, jimson weed overdose). Prior to physostigmine administration:

1. Get a screening EKG to demonstrate there is no evidence of Na-channel blockade. Even diphenhydramine can cause Na-channel blockade and seizures in severe OD.
2. Have atropine at bedside. Physostigmine is a cholinergic agent. When given too much, your patient will develop cholinergic toxicity.
3. Administer 0.5 mg IV over 3-5 min. repeat as needed (every 3-5 min) to max dose of 2.0 mg for clinical effect (improvement of mental status).

Bottom line: If you suspect isolated anticholinergic toxicity, think about physostigmine. Like any medication, risk and benefit of administration should be considered prior to administration. 

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The New England Journal of Medicine and Lancet both published studies evaluating idarucizumab for reversal of dabigatran. It is a monoclonal antibody fragment that binds dabigatran with high affinity. Dr. Ryan Radecki summarizes the two articles on his EM Lit of Note blog.

Here are a few take home points from these early studies:

1. Both studies were funded by Boehringer Ingelheim, who not suprisingly also markets dabigatran. Skepticism is always welcome when the same company makes the drug and the antidote.
2. The Lancet study was conducted in healthy volunteers, while the NEJM study was conducted in patients needing reversal but lacked a control group.
3. Idarucizumab seems to reverse laboratory markers of anticoagulation from dabigatran rapidly and completely, including dilute thrombin time and ecarin clotting time. Not all institutions have these assays available.
4. The dose that seems to 'work' the best is 5 gm given IV (two-2.5 gm infusions given no more than 15 minutes apart).
5. Median investigator-reported time to cessation of bleeding was 11.4 hours in the NEJM study.
6. 21 of the 90 patients in the NEJM study had 'serious adverse effects' including thrombotic events.
7. The acquisition cost of this medication will most assuredly be high if and when it is FDA-approved in the U.S.

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Recently, there has been a surge in synthetic cannabinoid in the U.S., including the Baltimore area. According to U.S. poison control center data, there has been 229% increase in calls related to SC between January to May of 2015 compared to similar time period in 2014.

The most commonly reported adverse/clinical effects included:

• Agitation: 35.3%
• Tachycardia: 29%
• Drowsiness/lethargy: 26.3%
• Vomiting: 16.4%
• Confusion: 16.4%

End-organ injuries have been also reported in case reports, including AKI, seizure, MI, and CVA.

Synthetic cannabinoid includes a list of chemical compounds that are structurally different compared to THC – the active compound in marijuana. However, they possess full CB1 (cannabinoid) receptor agonism effect, unlike the THC, which is a partial CB1 receptor agonist. 

These chemicals (particularly JWH series) were originally synthesized to study the effect of cannabinoid receptors. Overall, it is difficult to identify the compound and the dose within each packets of SC.

Commonly marketed names include: Spice, K2, K9, herbal highs, Scooby snax, WTF.

Table. Identified synthetic cannabinoids

Management: Majority of the patients with acute SC intoxication mostly requires supportive care, including benzodiazepine for acute agitation. However, ED providers should be mindful of potential end-organ injury. 

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The Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup has published their latest review, this time on extracorporeal treatment for salicylate poisoning. Here are their recommendations on when to dialyze:

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Electronic cigarettes are battery-powered devices that deliver nicotine, flavorings, (e.g. fruit, mint, and chocolate), and other chemicals via an inhaled aerosol. E-cigarettes are currently not regulated by the FDA. In many states, there are no restrictions on the sale of e-cigarettes to minors.

Electronic cigarette exposures involving young children are rapidly increasing. Such exposures tend to involve patients aged < 5 years and occur by ingestion of the nicotine-containing liquid. There is a potential for acute nicotine toxicity (nausea, vomiting, pallor, diaphoresis, tachycardia, hypertenstion initially). Respiratory muscle weakness with respiratory arrest is the most likely cause of death.

To date, the overwhelming majority of pediatric ingestions have not resulted in serious medical outcomes. The most commonly reported adverse events were nausea and vomiting.

However, in May of 2014, the first pediatric case of toxicity from ingestion of e-cigarette nicotine liquid was reported. A 10-month old ingested an unknown amount of e-liquid and developed vomiting, tachycardia, grunting respirations, and ataxia. The symptoms resolved by 6 hours after ingestion without specific treatment.

(1) The figure above shows the number of calls to poison centers for cigarette or e-cigarette exposures, by month, in the United States during September 2010 February 2014. E-cigarette exposure calls per month increased from one in September 2010 to 215 in February 2014.

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Methemoglobin (MetHb) is produce when Fe+2 in heme is oxidized to Fe+3 under oxidative stress (caused by mediation and chemicals). MetHb does not bind to oxygen and thus decrease RBC’s O2 carrying capacity.

Among medication, overdose of local anesthesia - benzocaine, dapsone, and phenazopyridine are often implicated. (Table 1)

Think about methemoglobinemia in presence of low pulse oximetry (~85%) with lack of response to supplemental oxygen, cyanosis, dyspnea, etc. (see Table 2 – signs and symptoms of MetHb) in patients who are taking or overdosed on medication listed in Table 1.

Diagnosis: CO-oximetry detects toxin-induced hemoglobinopathies, including COHb and MetHb.

Treatment: Methylene blue (1 mg/kg over 5 min) in symptomatic patients or MetHb level > 25%. Resolution of methemoglobinemia should be noted in 30 – 60 min.

G6PD deficiency: Prevalence in the U.S. is 4-7% with highest prevalence in African American population (11%). Methylene blue causes hemolytic anemia in patients with G6PD deficiency within 24 hours of administration. However, G6PD status is often unknown in ED patients.  When caring for patients with known G6PD deficiency and methemoglobinemia, providers must carefully consider the risk and benefit of treating MetHb (including severity of poisoning/MetHb) with methylene blue.

Table 1. Causes of MetHb

Table 2. Signs and symptoms

Dabigatran is an orally administered, potent, direct thrombin inhibitor approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and for the treatment and secondary prevention of venous thromboembolism.

Several pharmacokinectic studies have suggested that dabigatran possesses a number of ideal properties for expedited removal via extracorporeal methods.  Dabigatran has low oral bioavailability (3-7%) and is predominantly cleared (80%) by the kidneys.  It is not significantly protein bound, low-to-moderate steady state volume of distribution, and has a low molecular weight.  All of these attributes make it a candidate for extracorporeal removal.  Low protein binding may suggest redistribution into the plasma post extracorporeal removal.  

Dabigatran is a substrate for the multidrug efflux transporter P-glycoprotein.  Administration of the drug with potent P-glycoprotein inhibitors (ketoconazole, verapamil, amiodarone, quinidine) may significantly increase risk of toxicity, i.e. bleeding.

Most of the current evidence is based on case reports/case series where HD was the primary mode of removal.  

Caution: Redistribution effect in plasma dabigatran concentration was also observed in several cases within 20 min to 12 hours post cessation of renal replacement therapy.   Other limitations include:

1) Hemodynamic instability such as hypotension that may make initiation of extracoporeal removal difficult

2) Availability of indicators demonstrating effectiveness of extracorporeal removal 

3) Amount of time needed to prepare patient to receive extracorporeal therapy

4) Use of extracorporeal removal as a treatment modality has not been prospectively evaluated

Bottom line: Extracorporeal removal may be an option for patients in the setting of life-threatening bleeding but with consideration of several limitations and should not preclude or delay use of other supplemental hemostatic therapies.

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Background

In addition to the down regulation of GABA receptors in chronic ethanol users, there is an upregulation in NMDA receptor subtypes. Although the pathophysiology is much more complex, when ethanol abstinence occurs, there is a shortage of GABA-mediated CNS inhibition and a surplus of glutamate-mediated CNS excitation. If GABA agonists are the mainstay of treatment, why not also target the NMDA receptor? Enter ketamine.

The Data

Only one study exists and was published recently.

• Retrospective review of 23 adult patients administered ketamine specifically for management of AWS.
• Mean time to initiation of ketamine from first treatment of AWS, and total duration of therapy were 33.6 and 55.8 hours, respectively.
• Mean initial infusion dose and median total infusion rate were 0.21 and 0.20 mg/kg/h, respectively.
• No change in sedation or alcohol withdrawal scores within 6 hours of ketamine initiation.
• Median change in benzodiazepine requirements at 12 and 24 hours post-ketamine initiation were -40.0 and -13.3 mg, respectively.
• One documented adverse reaction of oversedation, requiring dose reduction.
• Authors concluded that ketamine appears to reduce benzodiazepine requirements and is well tolerated at low doses.

Application to Clinical Practice

While the dexmedetomidine studies should not be using reduction in benzodiazepine requirements as an endpoint, it may be acceptable for ketamine since it actually works on the underlying pathophysiology. More studies are needed but it's good to see we’re starting to look at it.

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There are some studies that have shown that NSTEMI patients have done worse when administered opioids. Most studies were not well controled and the exact mechanism was not clear. This study adds a biological mechanism to these fidnings.

Hobl et al. showed clopidogre concentrations delayt peak yhours, have overall decrease AUC and actually decrease active metabolites when morphine is administered IV. Morphine may not be the right choice in any ACS that receives clopidogrel.

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A new study from South Korea identified 3 potential clinical predictors of developing delirium tremens in patients presenting to the ED with alcohol withdrawal seizures.

1. Low platelet count
2. High blood level of homocysteine
3. Low blood level of pyridoxine

If one or more is present, these findings may help assess alcohol withdrawal patients for the risk of developing DTs.

Application to Clinical Practice

• The problem is that in the U.S., homocysteine and pyridoxine levels may not be readily available at all institutions.
• Adjunctive treatment options including vitamin B12, folate, and pyridoxine may be considered if levels are available, but it is unknown if 'treating the numbers' actually prevents development of DTs.
• At the very least, these clinical predictors may help risk assess patients for appropriate disposition.

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Elevation of AST or ALT >1000 after acute ingestion of acetaminophen indicate hepatic toxicity. N-acetylcysteine (NAC) is an effective treatment for acute acetaminophen poisoning. However, in a setting a significant transaminitis, (> 1000s) NAC infusion is continued beyond the routine 21-hour protocol.

Currently, there is no specific guideline or “level” of AST or ALT where discontinuing NAC is deemed safe and appropriate.

A recent retrospective study (n = 37 patients with 343 pairs of AST/ALT) evaluated AST/ALT ratio as a possible indicator for discontinuing NAC infusion after an acute acetaminophen induced hepatic toxicity.

This study found that post peak AST/ALT ratio of < 0.4 had sensitivity of 99% for identifying patients with resolving hepatic injury.

This finding requires validation prior to clinical application but this may be the first step to identifying a safe indicator to help guide clinician when NAC can be discontinued safely.

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In the midst of an unprecedented opioid epidemic, there have been considerable efforts to expand access to naloxone (Doyon S, et al. J Med Toxicol 2014;10:431-4). If the situation arises when you need to write a prescription for it, here's how:

Option 1: Naloxone vial and needle traditional IM/SQ using 0.4 mg/mL injection vial and needles (least expensive $40, FDA approved)

Naloxone 0.4 mg/mL single dose vial and 3 cc, 23 g, 1 inch syringes, #2 each

SIG: Inject 1 mL intramuscularly upon signs of opioid overdose. May repeat X 1. Call 911.

Option 2: IMS/Amphastar 2 mg/2 mL prefilled syringe and mucosal atomization device ($95/kit, products FDA approved but intranasal administration is off-label)

Naloxone 2 mg/2 mL prefilled syringe and intranasal atomizer device, #2 each

SIG: Spray one-half of syringe (1 mL) into each nostril upon signs of opioid overdose. May repeat X 1. Call 911.

Option 3: Evzio Autoinjector ($200-700 per Rx though many insurances cover it and the company has vouchers available, FDA approved in 2014, evzio.com/hcp)

Evzio 0.4 mg, #1 two-pack

SIG: Use as directed upon signs of opioid overdose. May repeat X 1. Call 911.

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Question

Patient has the following Head CT, what is your differential diagnosis? There are only a few characteristic toxins that can cause this type of finding on CT.

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A new review summarized published adverse effects when IV lipid emulsion is used along with venous-arterial extracorporeal membrane oxygenation (VA-ECMO) in patients with cardiotoxic drug poisoning.

Not surprisingly, running fat through the ECMO circuit can cause some issues. Here's what's been published:

• cracking of stopcocks
• fat emulsion agglutination
• clogging and associated malfunction of the membrane oxygenator
• increased blood clot formation in the circuit

It's unclear how these findings should change management if using both treatment modalities, but at the very least, be aware that fat depostion in the VA-ECMO circuits and increased blood clot formation can occur.

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(***)Values are after typical use; values in parentheses are after heavy or prolonged use.

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Tetrodotoxin is lethal poison that blocks sodium channels. A famous sushi called "Fugu" is cut from a puffer fish that contains this poison. The idea is to get just enough of the toxin to cause peri-oral paresthesia but not too much to get seizures, paralysis and cardiac dysrrhythmias. A recent outbreak in Minneapolis, Minnesota was just reported in the MMWR so it can really happen anywhere, its a great read - dried puffer was bought from a market in NYC.

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6351a2.htm

2-3 mg of the toxin is lethal to an adult human. No antidote exists though I would try hypertonic sodium bicarbonate for the cardiac dysrrhythmias and appropraite supportive. If the patient survives 24 hrs, the patient will do well without sequelae if appropriately supported.