UMEM Educational Pearls - Toxicology

High dose insulin (HDI) therapy is commonly used in patients with severe beta-adrenergic antagonist and calcium channel antagonist overdose. Hypoglycemia and hypokalemia are commonly known complication of HDI therapy. However, kinetics of insulin in patients who received HDI therapy is unknown.

A 51 year-old man with amlodipine overdose was infused HDI (10 unit/kg/hr) for 37 hours; Serial serum insulin levels were drawn after discontinuation of HDI.

Serum insulin levels are shown in below table

The serum insulin level remained significantly elevated during the first 24 hours (normal range: 2.6-24.9 microU/mL) and gradually decreased over 6 days.

Conclusion

• The supraphysiologic insulin levels persist after discontinuation of HDI where patient may continue to experience hypoglycemia
• These elevated insulin level may allow for more rapid titration or simply discontinue HDI when hemodynamic stability is achieved.

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2012312232_Untitled.pdf (39 Kb)

Antimuscarinic agents (e.g. diphenhydramine) are one of the commonly ingested substances in the US. Lorazepam is frequently used to treat delirium and agitation associated with antimuscarinic toxicity. Although physostigmine is also effective, its use is infrequent due to concerns of safety and provider’s limited experience with physostigmine.

A small blinded randomized clinical trial was conducted to compare physostigmine vs lorazepam for the treatment of antimuscarinic toxicity -delirium/agitation. 

Inclusion criteria

• Age: 10-17 years old
• At least one central and 2 peripheral antimuscarinic symptoms
• Delirium and moderate agitation

Intervention

1. Lorazepam 0.05 mg/kg IV bolus (max 2 mg). this dose could be repeated at 10 min if needed. then a 4 hr normal saline infusion 
2. Physostigmine 0.02 mg/kg IV bolus (max 2 mg; over 3-5 min). this dose could be repeated at 10 min if needed. then 0.02 mg/kg/hr (max 2 mg/h) physostigmine infusion for 4 hours.

Plus administration of lorazepam (0.05 mg/kg) IV bolus (max 2 mg) every 2 hours as needed for continued agitation or delirium (at the discretion of treatment team)

Delirium and agitation were assessed by Confusion Assessment Method for the Intensive Care Unit score (CAM-ICU) and Richmond Agitation Sedation Score

Result

Study duration: March 20, 2017 to June 30, 2020

• 175 patients presented with xenobiotic ingestion. But 19 patients were enrolled
• Physostigmine arm: 9 (47%)
• Lorazepam arm: 10 (53%)

Antimuscarinic agent ingested

• Diphenhydramine: 16 (84%)
• Dicyclomine: 1 (5%)
• Doxylamine: 1 (5%)
• Hyoscyamine: 1 (5%)

Proportion of subject with delirium by CAM-ICU

Prior to first bolus (p >0.99)

• Lorazepam arm: 9/10 (90%)
• Physostigmine arm: 9/9 (100%)

After 1^st bolus (p=0.01)

• Lorazepam: 10/10 (100%)
• Physostigmine: 4/9 (44.4%)

End of 4 hr infusion (p <0.001)

• Lorazepam: 10 (100%
• Physostigmine: 2 (22.2%)

No adverse events noted in both group

Conclusion

• Although this is a small study, it showed that physostigmine is better than lorazepam in treating antimuscarinic delirium and agitation.
• This study provides additional support to the finding from a prior retrospective study (Bruns MJ et al. Ann Emerg Med. 2000;35(4):374-381), which also showed the benefits of physostigmine over benzodiazepines in the management of antimuscarinic overdose associated delirium.

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Ethanol exposure among young children can result in significant morbidity. Infants and young children can be exposed to ethanol in many different ways: exploratory ingestion, mixed in formula-both intentionally and unintentionally, etc. 

A recently published study used national poison data system to characterize the ethanol exposure among infants < 12 months of age.

Results:

Between 2009-2018, 1,818 ethanol exposures among infants were reported. Oral ingestion was the most common (96.7%; n=1738). Annual number of ethanol exposure increased by 37.5% each year. 

Exposure site

• Residence: 96.7% (n=1,758)
• Public are/workplace or school: 1.6% (n=29)

Age

• 0-2 months: 16.3% (n=296)
• 3-5 months: 19.6% (n=357)
• 6-8 months: 18.8% (n=341)
• 9-11 months: 45.3% (n=824)

Clinically significant effects

• Coma: 20
• Hypoglycemia: 16
• Respiratory depression: 15
• Seizures: 13
• Hypothermia: 9
• Cardiac arrest: 4
• Respiratory arrest: 3
• Death: 5

563 infants (31%) were evaluated at hospital

38% (n=214) of the exposures were hospitalized

0-5 months of age 

• higher odds of admission: non-critical (OR: 2.35, 95% CI: 1.41-3.92) or critical care unit (OR: 2.39; 95% CI:1.5-3.79)
• higher odds of serious outcome (OR: 4.65; 95% IC: 3.18-6.79)

Conclusion

Ethanol exposure among infants is increasing each year and associated with serious clinical effects.  

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What is the cause of Mad honey poisoning?

Grayanotoxin

Grayanotoxin is a neurotoxin that is found in honey contaminated with nectar of Rhododendron plants. It binds to activated/open neuronal sodium channels and prevents inactivation of sodium channels. Case reports of mad honey poisoning is often reported in the eastern Black Sea region of Turkey. Commercial honey producers frequently mix honeys from multiple sources to decrease the grayanotoxin contamination.

Mad honey poisoning is rarely fatal and generally resolves within 24 hours. Commonly reported symptoms include dizziness, weakness, impaired consciousness/disorientation, excessive perspiration, nausea/vomiting, and paresthesia. In severe intoxication, patients can experience complete AV block, bradycardia/asystole, hypotension, and syncope. 

Management is primarily supportive with atropine and IV fluids.

Transfer of chemical from their original container to an unlabeled or different container (e.g. Gatorade bottle) is one of the common causes of unintentional poisoning. 

A retrospective study of National Poison Data System from 2007 – 2017 identified 45,512 cases of unintentional exposure/ingestion of chemicals contained in unlabeled/incorrectly labeled containers. 

Result

Annual reported cases increased from 3,223 in 2007 to 5,417 in 2017.

• Median age: 30 years (interquartile range: 6 – 53)
• Female: 52%

Most commonly involved products included

• Cleaning products: 38.2%
  • Bleach, 18.8%
  • Peroxides, 5.7%
  • Anionic cleaners, 4.6%
• Disinfectants: 17.3%
• Hydrocarbons: 5.0%

These exposures led to 

• ED visits: 9,369 (20.6%) 
• Hospitalization: 1,856 (4.1%) 
• Deaths: 23 (0.1%)

The majority of these exposures were non-toxic in nature (72%) but serious outcomes were noted in 4.4% of the cases, including 23 deaths.

Highest morbidity was associated with:

• Pesticides: 10.3%
• Prescription medications: 9.8%
• Herbicides: 7.6%

Deaths

• Hydrofluoric acid and herbicides accounted for 13 of 23 deaths (57%), followed by cleaning products (7/23).

Conclusion

• Transfer of a chemical to unlabeled/different container is a well-recognized risk factor of poisoning.
• Although small in number, the annual reported cases to the regional poison center are increasing.

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Dihydropyridine (calcium channel blocker) overdose is one of the leading causes of death from cardiovascular drug poisoning. In contrast, angiotensin-II receptors blockers (ARBs) and angiotensin converting enzyme inhibitor (ACEIs) causes minimal toxicity in overdose. Frequently, these medications are co-ingested with dihydropridines. 

Recently, a retrospective study was conducted to evaluate the hemodynamic impact of  dihydropyridines with ARBs/ACEIs co-ingestion.

Results

Cohort

• 68 mixed overdoses of dihydropyridines with ARBs/ACEIs
• 21 single agent overdose (dihydropyridines)

Mixed overdose group had:

• Lower median nadir mean arterial pressure: 62 vs. 75 mmHg (p<0.001)
• Higher OR for hypotension: OR 4.5, (95% CI: 1.7 – 11.9)
• Higher OR for bradycardia: OR 8.8 (95% CI: 1.1 – 70) 
• Lower minimum systolic blood pressure by 11.5 mmHg (95% CI: 4.9 – 18.1)

Higher proportion of the mixed overdose group received:

• IV fluids: OR 5.7, (95% CI: 1.8-18.6)
• Antidotes and/or vasopressor: OR 2.9 (95% CI: 1.004 – 8.6)

Conclusion

Combined overdose of dihydropyridines with ARBs/ACEIs can result in more significant hypotension.

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Question

What medication ingestion can lead to black urine?

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Extracorporeal membrane oxygenation use is increasing in the US for acute poisoning. 

A retrospective study of the National Poison Data System from 2000 to 2018 identified 407 ECMO cases (332 adults – age > 12 years, 75 pediatric – age < 12 years). Increase in ECMO use were more notable in adult population.

Characteristics

• Median age: 27 years (IQR: 15-39)
• Male: 52.6%
• Single substance exposure: 51.5%
• Median number of exposures: 3 (IQR: 2-4)
• Overall survival: 70%

Intentional exposure

• Age > 12 years: 72.6%
• Age < 12 years: 9.3%

Most common class of drug/poison exposure in adults

• Sedative/hypnotic: 26%
• Antidepressants: 25%
• Calcium channel blockers: 19%
• Opioids: 17%

Most common class of drug/poison exposure in children

• Hydrocarbons: 37%
• Antiarrhythmics: 15%
• Antihistamine: 8%
• Unknown: 8%

Most common states that used ECMO for poisoning

• Pennsylvania: 45
• Texas: 27
• Minnesota: 24
• Maryland: 22
• Michigan: 20
• New York: 20

Conclusion

• Increase in EMCO use was most notable in patients with age > 12 years
• There was no significant trend in mortality during the study period
• ECMO cases were mostly reported from urban areas 

Baclofen is a presynaptic GABA-B receptor agonist in the spinal cord that is primarily used for muscle spasms/spasticity. In large overdose, baclofen can produce CNS depression, respiratory depression, bradycardia/hypotension, hypothermia, seizure and coma.

Baclofen is primarily eliminated by the kidney. In patients with end-stage kidney disease/acute kidney failure, hemodialysis (HD) has been used to enhance baclofen clearance. However, it is unclear if there is a benefit of using HD in patients with normal kidney function. 

In a recently published case report, HD was implemented in an attempt to shorten the anticipated prolonged ICU course. 

Case: 14 year old (51 kg) woman ingested 60 tablets of baclofen (20 mg tablets)

Her symptoms were:

• Coma/CNS depression
• Tonic-clonic seizure
• Transient hypotension (95/47 mmHg – resolved with IV fluids)
• Flaccid extremities
• Initially intubated for airway protection --> no spontaneous breathing on mech. ventilation.

Baclofen level: 882 ng/mL (therapeutic range: 80 – 400 ng/mL)

Baclofen clearance from hemodialysis vs. urine

• 24 hour urine output: 2810 mL --> total baclofen urinary elimination: 42 mg
• 3 hours of HD #1: 3.05 mg removed. Total of 3 HD session performed.

Patient’s mental status improved on hospital day 6 and was extubated. She was discharged to psychiatry on hospital day 14.

 Conclusion:

• Although this is a single case report, it appears that hemodialysis does not remove baclofen effectively.

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What physical exam findings are associated with nitrous oxide abuse?

Nitrous oxide (NO) inhalation abuse, also called “whip-its” or “whippets”, inactivates vitamin B12 and create a vitamin B12 deficiency state. Chronic abuse of nitrous oxide can result in neurologic deficits/findings affecting the posterior/dorsal column of the spinal cord. 

Physical exam findings: 

1. Truncal ataxia
2. Decreased vibratory sensation and proprioception in lower extremities
3. Impaired coordination and rapid alternative movements
4. Lhermitte’s sign: paresthesia of the upper and lower extremities associated with flexion of the head/neck.
5. Rossolimo’s sign: exaggerated flexion of the toes when the tips of the toes are percussed

Tianeptine is an antidepressant with mu-opioid receptor agonism. It is available in several European countries for therapeutic use, but not available in the US.

There has been an increase in tianeptine exposure in the US since August 2019. Recently a retrospective observation study was done to characterize the clinical features associated with tianeptine exposure. 

Result

• 48 cases of tianeptine exposure were identified from January 1, 2015 to March 15, 2020 from a single poison center
• 37 cases (77%) occurred from May 2019 to March 2020.

Conclusion

• Tianeptine exposure is increasing in the US .
• Intoxication frequently results in lethargy and/or agitation.

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Question

What is the name of the toxin found in this seed/bean and its mechanism of toxicity?

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Carbon monoxide is an odorless gas that can cause neurologic and cardiovascular toxicity. It is produce by combustion of organic materials/fuel such as natural gas (furnace, gas stove, water heater, space heater) or gasoline.  DVT/PE has been reported among victims of CO poisoning. 

A recently published article investigated the risk of DVT/PE after CO poisoning. 

• Study design: cohort-cross over study (cross over at 1 year after CO poisoning)
• Setting: South Korea
• Data source: National Health Insurance Service database

Results

22,699 patients with CO poisoning were identified between 2004 and 2015

30 days after CO poisoning

• Risk of PE: OR of 22.0; 95% CI: 5.33 to 90.75
• Risk of DVT: OR of 10.33; 95% CI: 3.16 to 33.80

90 days after CO poisoning

• Risk of PE/DVT: OR of 3.96; 95% CI: 2.5 to 6.25

No significant increase in risk > 90 days.

Conclusion

• Patients are at highest risk of developing PE/DVT during first 30 days after CO poisoning.
• Increased risk of PE/DVT persisted up to 90 days after CO poisoning.

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Question

A 27 year-old man with history of rheumatoid arthritis presents to the emergency department after ingestion of hydroxychloroquine (20 tablets of 200 mg/tablet). He complains of nausea/vomiting. He appears lethargic. What is the anticipated hydroxychloroquine toxicity and management?

VS: Temp: afebrile, BP: 95/55 mmHg, RR: 23 breaths/min, O2 saturation: 99%

ECG:

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Over the past several days, riot control agents have been used against the protest participants (related to Mr. George Floyd’s death). There are 3 widely used riot control “lacrimating” agents: 

1. Mace (2-chloroacetophenone)
2. Pepper spray (capsaicins)
3. Tear gas (O-chlorobenzylidene malonitrile)

These agents (irritants) primarily affect the eye, skin, and respiratory tract.

Mangement:

• Initial management involves copious irritation of the affected area with water. 
• There is limited evidence that decontamination with milk, milk of magnesia, or baby shampoo is better than water. 
• Always consider projectile or blunt trauma that may be associated with the riot-control-related ED visits/complaint. 
• Protect yourself by wearing PPE when evaluating/treating these patients.

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ILE is considered as one of the “last resort” therapy in cases of life-threatening drug-induced cardiogenic shock or cardiac arrest. Although there are numerous case reports and case series that showed “successful” or “positive” outcome with ILE, here is no clear evidence that lipid emulsion therapy is effective. 

A group of researcher reviewed the National Poison Data System (NPDS) to investigate the failure of ILE therapy by reviewing the overdose fatalities reported to NPDS between 2010 and 2015.

Result:

• Out of 6026 fatalities, 459 fatal overdose cases received ILE.
• Majority involved either CCB or BB overdose (n=285; 62.1%)

Response to therapy (study cohort)

• No response: 45%
• Unknown response: 38%
• Transient/minimal response: 7%
• ROSC: 7.4%
• Immediate worsening: 3%

Adverse effect (n=49)

• ARDS with hypoxemia: 39
• Lipemia causing delay in laboratory evaluation: 3
• Lipemia causing failure of CRRT filter: 2
• Worsening/new seizure: 2
• Asystole: 2
• Fat embolism: 1

Conclusion

• The number of published cases of failed ILE outnumbers the published cases of ILE success.
• Less than 5% of the patients with CCB or BB overdose had ROSC after ILE therapy.

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Question

A 19 year old man presents with a scalp lesions/burns after an exposure to incendiary agent. His wounds were smoking and they flouresce under UV light. 

What is the causative agent?

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Recently, “disinfectants,” or germicides, has gain public attention during COVID-19 pandemic. So, what types of agents are considered as “disinfectants?”

Germicides as classified into three broad categories

1.    Antiseptics – chemicals applied to living tissue to kill or inhibit microorganisms

a.    Iodine & iodophors (e.g. Povidone-iodine; aka Betadine)

b.    Chlorine, bleach (sodium hypochlorite)

c.     Chlorhexidine

d.    Hydrogen peroxide

e.    Alcohols (ethanol and isopropanol)

2.    Disinfectants – chemicals applied to inanimate objects to kill or inhibit microorganisms

a.    Formaldehyde

b.    Phenol (aka carbolic acid)

c.     Substituted phenols (e.g. hexachlorophene; aka pHisoHex)

d.    Quaternary ammonium compounds (benzalkonium chloride; aka Zephiran)

3.    Sterilants – chemicals applied to inanimate objects to kill all microorganisms including spores

a.    Ethylene oxide

b.    Glutaraldehyde

Although ethanol is frequently found in alcoholic beverage and consumable, no other chemicals should be ingested or injected.

Buprenorphine (BUP) is increasingly prescribed/used to treat opioid use disorder (OUD) in the United State. BUP is mainly metabolized by CYP3A4 where its enzymatic activity can be either induced or inhibited by many agents. 

For example, a study showed that Rifampin administration for 15 days, a potent 3A4 inducer, resulted in (1): 

• Reduction of plasma BUP concentration (70% reduction in area under the curve [AUC]) 
• 50% of the study subjects (12 out of 24) experienced opioid withdrawal symptoms (OWS)
• 4 out of 12 who experience OWS received transient increase in their BUP dose (25-100%)

On the contrary, exposure to voriconazole – strong 3A4 inhibitor - resulted in (n=12 health volunteers) (2):

• Increased the plasma BUP AUC by 4.3 fold
• Increased peak BUP concentration by 3.9 fold
• Documented adverse effects were dizziness and nausea only

Cannabis use – (CBD is a CYP 3A4 inhibitor) also increased the BUP concentration by 2.7 fold. (3)

Bottom line:

1. Be mindful of drug-drug interaction when initiating a new medication in patients with OUD on BUP
2. Inquire about any recent medication change in patients who may be experiencing OWS while on steady dose of BUP for their OUD. 

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Question

A 7 year-old Spanish speaking female presents to the emergency room after ingestion of 2 – 3 tablets of her sister’s medication. She complains of nausea/vomiting with diarrhea, periorbital/facial swelling, and flushing of her skin. Her urine is reddish but there is no blood is shown in urinalysis/urine microscopic analysis. The patient's sister is taking the medication for a respiratory condition.

Which medication did she take?

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