UMEM Educational Pearls - Toxicology

A new population-based case-control study in older adults has linked the administration of trimethoprim-sulfamethoxazole (Bactrim, TMP-SMX) to increased risk of sudden death in patients also receiving angiotensin converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB). [1]

Hyperkalemia is the suspected cause. [2] Compared to amoxicillin, TMP-SMX was associated with an increased risk of sudden death (adjusted odds ratio 1.38, 95% confidence interval 1.09 to 1.76) within 7 days of exposure to the antibiotic.

Practice Change

In older patients receiving ACE-Is or ARBs, TMP-SMX is associated with an increased risk of sudden death. When appropriate, alternative antibiotics should be considered.

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Digoxin-specific antibodies are produced in immunized sheep and have high binding affinity for digoxin and, to a lesser extent, digitoxin and other cardiac glycosides. The Fab fragment binds free digoxin and once the digoxin-Fab complex is formed, the digoxin molecule is no longer pharmacologically active.  The complex is renally eliminated and has a half-life of 14-20 hours (may increase 10-fold with renal impairment).  Reversal of signs of digoxin/digitalis intoxication usually occurs within 30-60 minutes, with complete reversal varying up to 24 hours.

Contraindication: None known.  Caution is warranted in patients with known sensitivity ot ovine (sheep) products.  Product may contain traces of papain and caution advised in patients with allergies to papain, papaya extracts, chymopapain.

Adverse effects: 

1) Monitor for potential hypersensitivity reactions and serum sickness

2) In patients with renal insufficiency and impaired renal clearance of dig-Fab complex, a delayed rebound of free serum digoxin levels may occur

3) Removal of the effect of digoxin/digitalis may exacerbate preexisting heart failure

4) Removal of digoxin/digitalis effect may cause hypokalemia

Laboratory interaction: Digoxin-Fab complex cross-reacts with the antibody commonly utilized in quantitative immunoassay techniques.  This results in falsely high serum concentrations of digoxin due to measurement of the inactive Fab complex.  Therefore, measure free digoxin levels, which may be useful for patients with renal impairment.

Dosing: Each vial of Fab product binds 0.5 mg of digoxin.

Digoxin-specific Fab (round up vial calculation)

# of vials = Digoxin concentration (ng/mL) x Pt Wt (kg)

                                               100

Tetracycline has seen an increase in utilization due to its effectiveness in MRSA (check your local biogram). Remember its adverse effects/toxicity:

1) Photosensitivity 

2) Nephrogenic Diabetes Insipidus

3) Pseudotumor cerebri

4) Myopia

5) Deposits in calcifying bone/teeth - do not use in pediatrics

Valproic acid (VPA) is often used to treat seizure disorder and mania as a mood stabilizer. The mechanism of action involves enhancing GABA effect by preventing its degradation and slows the recovery from inactivation of neuronal Na⁺ channels (blockade effect).

VPA normally undergoes beta-oxidation (same as fatty acid metabolism) in the liver mitochondria, where VPA is transported into the mitochondria by carnitine shuttle pathway.

In setting of an overdose, carnitine is depleted and VPA undergoes omega-oxidation in the cytosol, resulting in a toxic metabolite.

Elevation NH₃ occurs as the toxic metabolite inhibits the carbomyl phosphate synthase I, preventing the incorporation of NH₃ into the urea cycle.

Signs and symptoms of acute toxicity include:

• GI: nausea/vomiting, hepatitis
• CNS: sedation, respiratory depression, ataxia, seizure and coma/encephalopathy (with serum concentration VPA: > 500 mg/mL)

Laboratory abnormalities

• Serum VPA level: signs of symptoms of toxicity does not correlate well with serum level.
• NH₃: elevated
• Liver function test: elevated AST/ALT
• Basic metabolic panel: hypernatremia, metabolic acidosis
• Complete blood count: pancytopenia

Treatment: L-carnitine

• Indication: hyperammonemia or hepatotoxicity
• Symptomatic patients: 100 mg/kg (max 6 gm) IV (over 30 min) followed by 15 mg/kg IV Q 4 hours until normalization of NH3 or improving LFT
• Asymptomatic patients: 100 mg/kg/day (max 3 mg) divided Q 6 hours.

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In a precursor to a forthcoming international guideline on the management of calcium channel blocker poisoning, a new systematic review has been published assessing the available evidence.

A few findings from the systematic review:

• The majority of literature on calcium channel blocker overdose management is heterogenous, biased, and low-quality evidence.
• Interventions with the strongest evidence are high-dose insulin and extracorporeal life support.
• Interventions with less evidence, but still possibly beneficial, include calcium, dopamine, norepinephrine, 4-aminopyridine (where available), and lipid emulsion therapy.

Stay tuned for the international guideline coming out soon. One treatment recommendation from the new guideline, reported at the 8th European Congress on Emergency Medicine last month, is not to use glucagon.

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Cardioactive steroids are among the many treatments used for CHF, and for the control of ventricular response rate in atrial tachydysrhythmias. There are many sources of cardioactive steroids:

Pharmaceutial: Digoxin, Digitoxin

Plants: Oleander, Yellow Oleander, Foxglove, Lily of the Valley, Dogbane, Red Squill

Animal: Bufo marinus toad

It is a potent Na⁺-K+-ATPase inhibitor and can lead to hyperkalemia in acute ingestion with associated signs and symptoms of N/V, abdominal pain, bradycardia and possibly, hypotension.

Toxicity should be suspected with bidirectional ventricular tachycardia or atrial tachycardia with high-degree AV block

Therapeutic range of digoxin of 0.5 - 2.0 ng/mL is helpful but not a sole indicator of toxicity

Indication for antidote (Digoxin-specific Antibody Fragments) include:

1) Digoxin-related life-threatening dysrhythma

2) Serum K+ > 5.0 mEq/L in acute ingestion

3) Serum digoxin concentration >15ng/mL at any time, or >10 ng/mL 6 hours postingestion

4) Ingestion of 10 mg in adult; 4 mg in pediatric

5) Poisoning by non-digoxin cardioactive steroid

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When you prescribe certain medications, it may require some further instructions to avoid ethanol or a disulfiram like reaction (nausea, vomiting, flushing) may occur. Keep this short list in your brain:

1) Particular cephalosporins: cefotetan is a the one more likely

2) Nitrofurantoin

3) Sulfonylureas: chlorpropamide and tolbutamide

4) Metronidazole

5) Trimethoprim-sulfamethoxazole

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Food poisoning can occur with many different food groups/items, as well as how the food is prepared, handled or stored.

There are three specific “food poisonings” associated with fish consumption can cause serious toxicity/illness beyond GI symptoms: Ciguatera, Scrombroid, tetrodotoxin (puffer fish)

Ciguatera

• Endemic to warm tropical water and bottom reef dwelling large carnivorous fish: grouper, red snapper, barracuda, amberjack, parrot fish, etc. (> 500 species).
• Toxin: ciguatoxin: opens voltage gated Na channel
• Produced by dinoflagellates (gambierdiscus toxicus) and bioaccumulates in large fish through food chain (eating small fish).

Symptoms:

• GI symptoms: n/v/d and abdominal pain
• Hot/cold reversal
• Paresthesia of tongue/lip >> extremities
• Dental pain: “loose teeth”

May progress to develop…

• T wave changes, bradycardia, hypotension
• Respiratory paralysis and pulmonary edema

Treatment: supportive care and mannitol in presence of severe neurologic symptoms (limited evidence).

Scrombroid

• Endemic in (dark meat) fish living in temperate or tropical water: amberjack, skipjack, tuna, mackerel, albacore, mahi mahi, etc.
• Associated with poor refrigeration/storage after catching fish.
• Histidine in tissue is converted to histamine by bacteria on the fish skin.

Symptoms:

• GI symptoms: n/v/d and abdominal pain
• Upper body flushing
• Puritis, urticarial and perioral swelling can occur
• Palpitation and mild hypotension

Tx: H1/H2 blockers and supportive care

Serious reactions: treat like allergic/anaphylactic reaction

Tetrodotoxin

• Ingestion of improperly prepared puffer fish (fugu) sushi (or bite from blue ring octopus)
• Toxin: tetrodotoxin: blocks voltage gated Na channel.
• Highest concentration in liver and ovary.

Symptoms:

• GI: n/v/d
• Progressive paresthesia and weakness (bulbar-> extremities), ataxia
• Ascending paralysis and respiratory distress/paralysis
• Dysrythmia and hypotension
• Mental status preserved.

Treatment: supportive care and intubated if needed.

Digoxin-specific antibody fragments (Fab) are safe and indicated in all patients with life-threatening dysrhythmias and an elevated digoxin concentration. However, full neutralizing doses of digoxin-Fab are expensive and may not be required (not to mention cumbersome to calculate).

Based on pharmacokinetic modeling and published data, a new review suggests a simpler, more stream-lined dosing scheme as follows:

• In imminent cardiac arrest, it may be justified to give a full neutralizing dose of digoxin-Fab.

• In acute poisoning, a bolus of 80 mg (2 vials), repeat if necessary, titrated against clinical effect, is likely to achieve equivalent benefits with much lower total doses.

• With chronic poisoning, it may be simplest to give 40 mg (1 vial) at a time and repeat after 60 min if there is no response.

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Dysrhythmia-induced sudden death, termed "sudden sniffing death syndrome," is well described phenomena due to inhalant (chlorinated and aromatic hydrocarbon) abuse. 

Common inhalants include:

Chlorinated hydrocarbons: Degreasers, spot removers, dry-cleaning agents

Fluorocarbons: Freon gas, deodarants

Toluene: Paint thinners, spray paint, airplane glue

Butane: Lighter fluid, fuel

Acetone: Nail polish remover

The common theory behind the syndrome is cardiac sensitization that increases susceptibility of the heart to systemic catecholamines (epinephrine, norepinephrine, etc).  Usually, it occurs after an episode of exertion in that any excess catecholamine exposure causes irritability of the myocardium, resulting in dysrhythmias (V. fib, V. tach) and cardiac arrest. 

If acute dysrhythmias is due to myocardial sensitization, sympathomimectis should be avoided.  Beta-adrenergic antagonist can be used for the catecholamine-sensitized heart.

E-cigarette popularity has increased and with that another possible source of toxicity. The most recent MMWR shows how e-cigarette use has increased over the past 5 years. The general toxicity involves nicotine toxicity with nausea, vomiting, eye irritation as the major sources of toxicity. Only one reported death where the nicotine reservoir was accessed and then injected IV in a suicide attempt.

There are some reports of asthma exacerbations but is more likely due to the vapor flavor and not the nicotine.

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Since synthetic cannabinoids arrived on the scene, we have become familiar with their sympathomimetic effects such as emesis, tachycardia, hypertension, agitation, hallucinations, and seizures.

Acute kidney injury is also being linked to synthetic cannabinoid use. Several clusters have been described in a handful of states, the most recent coming from Oregon with 9 patients.

AKI seems to be one more adverse effect to be on the lookout for when evaluating patients after synthetic cannabinoid use.

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Bath salts (synthetic cathinones) commonly contain multipe synthetic drugs and can be ingested, smoked, or administered intravenously.  The designer stimulant mephedrone (4-methylcathinone) is among the most popular of the derivatives of the naturally occurring psychostimulant cathinone.  Bath salt use is on the rise and is responsible for a large number of ED visits.

In spite of their ban, bath salts are still available over the counter in specialty shops and through the Internet with common product names such as: "Ivory Wave," "Cloud 9," "Purple Wars," "Vanilla Sky," "Bliss," etc.  They are commonly marketed with the disclaimer, "not for human consumption." 

Their presentation mimics other sympathetic drugs through pathways similar to amphetamines.  The primary psychological effects have a duration of roughly 3-4 hours, with physiologic effects lasting from 6-8 hours.

Management is largely supportive and includes IV hydration, benzodiazepines, and close monitoring in the ICU setting.

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Ondansetron is a highly effective anti-emetic that, since it has gone generic, is also quite inexpensive. There have been some reports of QT prolongation and cardiac arrhythmias especially with the high-dose 32mg IV dose for chemotherapy patients.

Is still safe in our ED population? A large systematic review was done in this month's Ann Emerg Med July 2014,p19-31.

Take Home Points:

1) No reports of arrhythmia associated with single dose administration identified

2) 80% of 60 unique reports were IV

3) 83% had significant PMH or already on a QT prolonging drug

Conclusion: Ondansetron doesn't warrant routine EKG or electrolyt screening in oral administration.High dose IV and High Risk patients do require more vigilance with EKG and electrolyte screening.

Metformin is the first line medication for the treatment of type II diabetes. A rare complication of chronic metformin use is MALA.

• Incidence: 2-9 cases per 100,000 patients
• Mortality: 30-50%

The association between metformin accumulation and development of lactic acidosis is controversial as patients with suspected MALA experience concurrent illnesses such as sepsis/septic shock, tissue hypoxia, and/or organ dysfunction (especially renal failure).

• Greater than 90% of metformin (unchanged) is eliminated by the kidney.

• Metformin accumulation (from renal failure) leads to inhibition of complex I of the electron transport chain.^1,2

• A case series of 66 patients MALA experienced severe lactic acidosis (pH: 6.91+ 0.18; lactate 14.36+ 4.9 mmol/L) and renal failure (Cr 7.24 + 3.29 mg/dL)³

• Prodromal GI symptoms in 77%
• Clinical findings at time of admission/presentation:
• AMS/coma: 57%
• Dyspnea/hyperventilation: 42%
• Hemodynamic shock: 39%
• Hypotension (SBP < 100 mmHg): 23%

• No correlation between lactate and metformin level.

• Risk factors
  • Renal failure (metformin accumulation)
  • Elderly population (higher mortality)
  • Cardiac or respiratory insufficiency causing central hypoxia
  • Sepsis/septic shock
  • Liver disease
  • IV contrast use (resulting in renal insufficiency)

• Treatment: emergent hemodialysis

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In a single academic medical center, 273 poisonings required Pediatric ICU (PICU) admission over a 5-year period. This represented 8% of total PICU admissions during that time. Key findings include:

1. Most poisonings occurred in patients either ≤3 years or ≥13 years. 
2. Most admissions were for less than 48 h and 41% were for less than 24 h. Mean PICU length of stay was 1.2 + 0.7 days.
3. Analgesics and antidepressants were the most common substances.
4. 27 patients received mechanical ventilation. 

The majority of poisonings were non-fatal and required supportive care, close monitoring, and some specific treatment. Drug classes causing poisonings have changed to a higher percentage of opioids in younger patients and atypical antidepressants in adolescents.

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Colchicine tablets and injectable solution is frequently used for the treatment of gout and familial Mediterranean fever.  An overdose is extremely serious, with considerable mortality that is often delayed.  It is considered a cellular poison due to its inhibition of cellular mitosis of dividing cells. 

After an acute overdose, symptoms typically are delayed for 2-12 hours and include nausea, vomiting, abdominal pain, and severe bloody diarrhea.

Chronic poisoning presens with a more insidious onset.

Late complications include bone marrow suppression, particularly leukopenia and thrombocytopenia (4-5 days) and alopecia (2-3 weeks).

Treatment includes aggressive supportive care, monitoring and treatment of fluid and electrolyte disturbances.

The usual cause of death from acute poisoning is due to hemodynamic collapse and cardiac arrhythmias (typically 24-36 hours after ingestion or could be sudden) or from infectious or hemorrhagic complications.

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NAC is an effective antidote against acetaminophen (APAP) toxicity in preventing acute hepatotoxicity. It provides cysteine that is essential for glutathione synthesis and its availability is rate limiting.

Currently, PO and IV formulation is available in the U.S. Regardless of the route, NAC is equally effective in preventing APAP induced acute hepatotoxicity when administered within 8 hours after single acute ingestion. ¹

Adverse effects of NAC

1.     Anaphylactoid reaction

a.     More frequently reported with IV administration and during the first regimen of NAC (150 mg/kg over 60 min) administration. (dose and rate dependent)

b.     Higher risk of anaphylactoid reaction in patients with negative APAP vs. patients with elevated APAP level.²

c.      Management: Benadryl as needed and slow infusion rate.

2.     Hyponatremia in children if inappropriate volume of diluent (D5W) used. Dose calculator: http://acetadote.com/dosecalc.php

3.     Laboratory: increase Prothrombin time (PT).3

4.     Fatality from iatrogenic NAC overdose has been reported.

Advantage of IV NAC

1.     Convenience

2.     100% bioavailability

3.     Shorter hospital length of stay

4.     Minimum GI symptoms (nausea & vomiting) compared to PO route

Indication of IV NAC

1.     Severe hepatotoxicity or fulminant liver failure

2.     APAP poisoning during pregnancy

3.     Unable to tolerate PO intake (nausea, vomiting, altered mental status)

However many clinicians administer IV NAC for their advantages over PO NAC.

 Take home message:

1.     PO and IV NAC are equally effective when administered within 8 hours after single acute ingestion.

2.     Anaphylactoid reaction is frequently encountered AE during the infusion of 1^st NAC regimen and patients with negative/low APAP level may be at higher risk.

3.     No emergent need to start NAC in presumed acetaminophen overdose patients prior to obtaining APAP level.

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Methadone prolongs the QTc interval. Is the degree of QTC widening correlated to worse outcomes after overdose?

The authors of a new study concluded the triage QTc can predict death, intubation, and respiratory arrest. QTc thresholds of 470, 447.5, and 450 msec had sensitivity (95 % CI) and specificity (95 % CI) of 87.5 (47.3-99.7), 86.8 (74.7-94.5), and 77.3 (62.2-88.5), respectively.

My Thoughts

Respiratory depression is the predominant cause of death in methadone overdoses. QTc interval prolongation may have the potential to help predict outcomes, but the QTc thresholds in this study were really not that prolonged. Patients on chronic methadone without overdose have baseline QTc intervals longer than those in this study after overdose.

Application to Clinical Practice

Many factors contribute to the ultimate disposition of methadone overdose cases. Even if QTc widening is correlated to outcomes, it really won't change our management.

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This is a must memorize simple table of the toxic doses of local anesthetics. Toxicity of local anesthetics starts with slurred speech, lethargy to seizures and lethal cardiac dysrhythmias. There should be zero tolerance to actual cause toxicity when repairing a laceration or performing a fascia iliaca block.

Remember that a Bupivcaine solution 0.5% = 0.5 g/dL (%=g/dL) so a 70kg person, you can use a  maximum of 2mg/kg x 70kg person. You can inject 140 mg in a 70kg person. This is a maximum volume injection of 28 mL if you were doing a fascia iliaca block. You can double the volume if you use a more dilute solution of 0.25%.

Treatment for cardiac dysrhythmias due to local anesthetics is 20% lipid emulsion therapy - don't follow ACLS protocol as epinephrine or other antidysrhythmics (especially lidocaine) will be lethal.