UMEM Educational Pearls - Toxicology

This retrospective population cohort study looked at  first time ED visits for adolescents and young adults comparing those with visits related to alcohol to those not related to alcohol. Patients in the alcohol related visit group had  a threefold increased one year mortality rate.  Cause of death was trauma, poisoning by drug and alcohol. Risk factors include being male, age 20-29, history of mental health and having a visit for withdrawal.  

Adolescents and young adults presenting to an emergency department for an alcohol related complaint are high risk for one year mortality and deserve intervention and appropriate referral.

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Bupropion associated cardiac toxicity widens the QRS complex by inhibiting the cardiac gap junction, not cardiac Na channel blockade. NaHCO3 is often administered when EKG changes are noted. But the effectiveness of NaHCO3 in bupropion toxicity is not well established. 

A retrospective study between 2010-2020 showed, that administration of NaHCO3 only decreased QRS duration by 2 msec (median). The median NaHCO3 administered was 100 mEq. Although this study was limited by the fact that it only had a small sample size of 13, NaHCO3 administration may provide limited clinical benefit in patients with QRS widening from bupropion overdose.

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Acetaminophen (APAP) is the leading cause of acute liver failure worldwide. Standard treatment for APAP overdose is with N-acetylcysteine (NAC), which is highly effective if given within 8 hours of ingestion.  However, in delayed presenters or massive ingestions patients can still develop hepatotoxicity. Adjunctive therapies can be considered in these cases including augmented NAC dosing, renal replacement, and fomepizole.

A small amount of APAP is metabolized to N-acetyl-p-benzoquinone imine (NAPQI) by cytochrome 2E1. In therapeutic doses, the body is able to detoxify the NAPQI using glutathione. In overdose, glutathione stores get depleted and NAPQI can cause hepatotoxicity. Mitochondrial damage in APAP overdose is mediated by the c-Jun-N-terminal Kinase (JNK) pathway. 

NAC works to replenish glutathione stores and detoxify NAPQI. In large overdoses, increased dosing of NAC may be necessary. Fomepizole is typically used for its alcohol dehydrogenase inhibitor property to treat methanol and ethylene glycol poisoning. Fomepizole is also a cytochrome 2E1 and JNK inhibitor and can be used in APAP overdose to block the formation of NAPQI and mitigate mitochondrial damage.  Dialysis can be used to eliminate APAP from the body completely in massive overdoses or if significant acidosis or renal failure. 

This study is a case series of 14 patients treated for APAP overdose between 2017 – 2021 at a tertiary hospital

• Patients treated with standard NAC therapy
• They also received IV fompeizole loading dose of 15 mg/kg followed by 10mg/kg every 12 hours at the discretion of the treating team
• Most cases received only the loading dose
• Some cases also received renal replacement therapies
• Patients had “better than expected outcomes” based on initial presentation, APAP levels, liver function tests, and expected clinical course
• No unfavorable outcomes
• No side effects

Limitations of the study:

• Patients were treated with NAC which is the standard of care
• No formal protocol for the administration or identification of patients treated with fompeizole

In summary:

• NAC is the standard of care in acetaminophen poisonings
• Consider fomepizole as an adjunctive therapy in patients that are critically ill
• Consult your poison center 1-800-222-1222 or friendly toxicologist for help in identifying these patients

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Age >36

LOC

Prolonged exposure (>24hrs)

COHgb level >25%

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Medical Cannabis is permitted in 39 states and Washington DC while 18 sates and Washington DC has legalized recreational cannabis use. As cannabis products become more available, pediatric exposure has also increased.

A retrospective study of National Poison Data System involving children < 6 years from 2017 and 2021 showed: Pre-COVID (2017-2019) & COVID (2020-2021)

• 7043 exposures: (increase of 1375%)
• 2017: 207  
• 2021: 3054 
• Residential exposure: 97% (n=6842)

Common Clinical effects

• CNS depression: 70% (n=3381)
  • Pre-COVID: 61.6% --> COVID: 72.9% (p<0.05)
• Tachycardia: 11.4% (N=548)
  • Pre-COVID: 10.3% -->COVID: 11.6% (p,0.05)
• Vomiting: 9.5% (n=4827)
  • Pre-COVID: 7.5% -->COVID: 10.0% (p<0.05)
• Ataxia: 7.4% (n=352)
• Confusion: 6.1% (n=294)
• Mydriasis: 5.9% (n=284)
• Respiratory depression: 3.1%

Disposition

• Admission: 22.7%
• Critical care: 8.1% (n=533)
  • Pre-COVID: 6.6% -->COVID: 8.6% (increase of 30%) (p<0.05)
• Non-critical care: 14.6% (n=1027)
  • Pre-COVID: 9.7% -->COVID: 16.3% (increase of 68%)(p<0.05)

Conclusion

• Pediatric cannabis exposure has increased between 2017 and 2021. consequently, more pediatrics patients developing toxicity and being hospitalized.

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Lithium toxicity can present acutely with gastrointestinal symptoms and chronically with neurologic symptoms such as tremor and ataxia. Diagnosis and treatment with normal saline hydration and/or dialysis depends on lithium levels in conjunction with signs and symptoms.

Lithium levels can be falsely elevated when blood samples are collected in green top tubes which contain lithium heparin, or if the blood collection volume is too small.  Not recognizing that a lithium level may be falsely elevated can lead to misdiagnosis as well as unnecessary hospitalizations and treatments. The study by Wills et al found lithium levels as high as 4 mmol/L (therapeutic range 0.6-1.2 mmol/L) in lithium naïve volunteers collected in the wrong tube and with small blood volumes. If a patient has an elevated lithium level in the absence of lithium toxicity symptoms, consider a falsely elevated level and redraw using the appropriate tube and sample size. 

In summary:

• Ensure the lithium sample is collected in a non heparin containing tube
• Confirm sufficient sample volume
• Look at the clinical picture when deciding on treatment for patient
• Have a low threshold to repeat the lithium level
• Consult your poison center 1-800-222-1222 or friendly toxicologist

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Calcium channel blocker (CCB) overdose can lead to severe shock/hypotension. A small study was conducted to compare the hemodynamic effects of high-dose insulin (HDI) for two classes of CCB (dihydropyridines vs. non-dihydropyridines) that work differently to manage hypertension.   

Study design:

• Retrospective study from a single poison center (2019 – 2021)

Study sample:

• Amlodipine poisoning cases: 18
• Non-dihydropyridine (non-DHP) poisoning cases: 15

Result

Median number of maximum concomitant vasopressors (p=0.04)

• Amlodipine: 3 (IQR: 2-5; range 0-6)
• Non-DHP: 2 (IQR: 1-3; range 0-5)

Median difference in max concomitant vasopressors: 1 (95% CI: 0 – 2)

Median max epinephrine dosing

• Amlodipine: 0.31 mcg/kg/min
• Non-DHP: 0.09 mcg/kg/min

Use of rescue methylene blue (p=0.009)

• Amlodipine: 7/18 (39%)
• Non-DHP: 0

Conclusion:

• Amlodipine poisoning on HDI required more vasopressors and higher doses of epinephrine compared to non-DHP (verapamil or diltiazem)
• This may be due to vasodilatory effect of amlodipine compared to non-DHPs

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Flumazenil is a reversal agent for benzodiazepine overdose.  Adverse events including seizure, agitation and cardiac arrhythmias have been reported but the frequency of adverse events is unknown.

AE and serious AEs were defined as:

AE: 

• Aggressive behavior, agitation, screaming, restlessness
• Nausea/vomiting, abdominal cramps
• Sweating, shivering, chills, hot flashes
• Headache, dizziness
• Anxiety, distress, depressed mood, abnormal crying
• Tremors 

Serious AE (SAE):

• Seizures
• Supraventricular arrhythmia
• Multiple ventricular beats
• Tachycardia
• Sudden fall in systolic BP

A systematic review/meta-analyses of 13 randomized controlled trials showed

• AEs more common in flumazenil group vs. placebo (risk ratio: 2.85; 95% CI: 2.11-3.84)
• SAEs more common in flumazenil group vs. placebo (risk ratio: 3.81; 95% CI: 1.28-11.39) 

Most common AEs

• Aggressive behavior, agitation, screaming: 26.2% (n=33/126)
• Nausea/vomiting, abdominal cramps: 20.6% (n=26/126)
• Anxiety, distress, depressed mood: 15.7% (n=19/126)

Most common SAEs

• Supraventricular arrhythmia: 30% (n=4/12)
• Seizure: 25% (n=3/12)
• Tachycardia: 25% (n=3/12)

Conclusion

• Administration of flumazenil to patients with known or suspected benzodiazepine overdose is associated with increased risk of AEs

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Xylazine is a central alpha-2 agonist (similar to clonidine) that is used as a veterinary tranquilizer. It also possesses analgesic, and muscle relaxant properties. Heroin/fentanyl is increasingly being adulterated with xylazine and resulting in severe adverse effects (CNS and respiratory depression, bradycardia, and hypotension), including deaths. 

According to CDC, 0.1%-5.5% of IMF death in US between 2019 – 2020 involved xylazine. 

In Philadelphia, PA:

The detection of xylazine in unintentional overdose death increased from

• 2010 – 2015: 2%
• 2016: 11%
• 2017: 10%
• 2018: 18%
• 2019: 31%

Approximately 25% of drug seizures in Philadelphia contained xylazine in 2019

There is no effective pharmacologic agent for xylazine toxicity. Similar to clonidine toxicity, high dose naloxone may be tried. But pediatric data show that approximately 50% of pediatric clonidine toxicity response to high-dose naloxone administration. Thus, naloxone administration may not reverse the CNS/respiratory depression, bradycardia and hypotension.

Conclusion

• There is increasing adulteration of heroin/fentanyl with xylazine
• Naloxone administration may not reverse the toxicity of xylazine

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Substance use disorder contributes significantly to pediatric exposure/poisoning. There has been an increase in the opioid overdose deaths in the US, placing pediatric population to possible exposure. A retrospective study of fatal pediatric poisoning in the US was investigated using the National Violent Death Reporting System (NVDRS) from 2012-2017.

17 US states (AK, CO, GA, KT, MD, MA, NJ, NM, NC, OH, OK, OR, RI, SC, UT, VA, WI) reported to NVDRS from 2012-2017.   

Age was limited to 0-9 years

Results

1850 violent deaths were identified: n=122 (7%) were poisoning related

Characteristics

• Male: 49%
• Approximately 25% were homicide-suicides

Region

• Midwest: 25%
• Northeast: 5%
• South: 53%
• West: 17%

Most common exposure/etiology

1. Opioid (50%)
2. Benzodiazepines (8%)
3. Amphetamines (7%)
4. Antidepressants (5%)

Conclusion

• A large proportion of poisoning related pediatric fatality was due to opioid exposure
• Largest proportion of death was reported from the Southern US.

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There are several clinical scoring systems (SAPS II, SAPS III, SOFA, etc.) to assess the severity and/or risk of mortality in critically ill patients. However, the routinely used physiologic scoring systems are not always suitable for poisoned patient. 

ICU requirement score (IRS) has been recently developed by investigators from Europe and a validation study (retrospective cohort) has been performed.

ICU requirement score (IRS) components (see inserted table)

• Age
• Systolic blood pressure
• Heart rate
• GCS
• Type of intoxication
• Comorbidities (dysrhythmia, cirrhosis, and/or respiratory insufficiency, secondary diagnosis requiring ICU admission)

Retrospective cohort 

• Study duration: Jan 1, 2009 to Dec 31 ,2019
• Positive IRS score: >= 6
• Comparison to SAPS II, SAPS III, SOFA score, and PSS
• End point: need for ICU treatment

Results

N=1503

Area under the curve for IRS ROC: 0.736 (95% CI: 0.702-0.770)

IRS <6

• Negative predictive value: 95% (95% CI: 93-97)
• Positive predictive value: 21% (95% CI: 18-24)
• Sensitivity: 89% (95% CI: 85-93)
• Specificity: 38% (95% CI:36-41)

Conclusion

• IRS of < 6 demonstrated excellent negative predictive value for ICU admission.
• A larger study of ICU requirement score will be needed to further assess its usefulness/limitation prior to clinical use.  

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Attachments

• 2108191337_Untitled.pdf (252 Kb)

Canada legalized recreational cannabis use in 2017. A retrospective study of children (0-18 years) who presented to pediatric ED with cannabis intoxication/exposure was performed between Jan 1, 2008 to Dec 21, 2019 to assess the trend/severity of intoxication.

Methods

• Single center study: Hospital for Sick Children, Toronto
• Case identification by ICD 10 code for cannabis intoxication and positive urine drug screening test
• Pre-legalization period was defined as 1/1/2008 to 4/12/2017
• Peri-post legalization period was defined as 4/13/2017 to 12/31/2019

Result

A total of 298 patients were identified

• Pre-legalization period: 232 (77.8%)
• Peri-post legalization period: 66 (22.1%)
• Male: 150 (50.3%)
• Median age: 15.9 years (IQR: 15.0-16.8) 

Respiratory symptoms: tachypnea/bradypnea, cyanosis, O2 sat < 92%, bronchospasm, oxygen requirement

• Edible ingestion was a predictor of ICU admission (OR: 4.1; 95% CI: 1.2-13.7)

Conclusion

• Legalization of recreational cannabis in Canada was associated with increased rates of severe intoxication in children.

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Question

What is the mechanism of action of N-acetylcysteine that is used to treat acetaminophen induced liver injury/toxicity?

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There are three commonly household spices that can be abuse/misused or cause toxicity after exposure.

Pure vanilla extract contains at least 35% ethanol by volume per US Food and Drug Administration standards

• Results in alcohol intoxication
• Ingestion of 1.3 mL/kg in child will result in blood ethanol concentration of 100 mg/dL

Nutmeg contains myristicin – serotonergic agonist that possess psychomimetic properties. 

• Typical recreational dose: 5-30 gm. (tablespoon of ground nutmeg: 7 gm).

Clinical effects:

• GI symptoms: nausea, vomiting and abdominal pain
• Cardiovascular: hypertension and tachycardia
• CNS: hallucination, paranoia, seizure
• Others: flushing, mydriasis

Cinnamon contains cinnamaldehyde and eugenol – local irritants.

• Can cause contact dermatitis and ulceration from topical application
• Inhalation of cinnamon can result in chronic and significant pulmonary inflammation and fibrosis

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Diphenhydramine is commonly involved in overdose or misused. Although it is primarily used for its anti-histamine property, it also has significant antimuscarinic effect.

A recent retrospective study investigated the clinical characteristics associated with severe outcomes in diphenhydramine overdose using the multi-center Toxicology Investigators Consortium (ToxIC) Registry. 

Severe outcomes were defined as any of the following:

• Seizure
• Ventricular dysrhythmia
• Intubation

Results

863 cases of isolated diphenhydramine ingestion were identified between Jan 1, 2010 to Dec 31, 2016

• Females: 59.1% 
• Age < 18 years: 51.3%
• Intentional ingestion: 86.0%
  • Self-harm: 37.5%
  • Abuse/misuse: 11.5%

Most common symptoms:

• Delirium/toxic psychosis: 40.1% (n=346)
• Agitation: 33.1% (n=286)
• Severe outcome: 15.6% (n=135)

Factors associated with severe outcome

• Intubation: self-harm ingestion and male
• Acidemia: pH <7.2
• QRS prolongation: QRS > 120 msec
• Elevated anion gap: AG >20

Conclusion

• Acidemia, QRS prolongation and elevated anion gap was associated with severe outcome in diphenhydramine toxicity

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There are different occupational hazards depending on the nature of one’s trade/skill/employment. Although healthcare providers may not always inquire about patient’s occupation, knowledge of a patient’s occupation may provide insightful information when caring for patients with acute poisoning.

From a recent retrospective study of National Poison Data System, the top 10 occupational toxicants were:

1. Caustics (acids & alkalis)
2. Chlorines/hypochlorites
3. Carbon monoxide
4. Hydrocarbons
5. Cleansers/detergents
6. Ammonia
7. Cement
8. Hydrofluoric acid
9. Disinfectants
10. Hydrogen sulfide

Top 10 occupational toxicants associated with fatalities were:

1. Hydrogen sulfide
2. Ammonia
3. Carbon Monoxide
4. Simple asphyxiants
5. Chlorine/hypochlorites
6. Alkalis
7. Pyrethrins/pyrethroids
8. Toluene/xylene
9. Methane
10. Methylene chloride 

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Recently, there has been questions if standard n-acetylcysteine (NAC) dose is adequate for massive acetaminophen (APAP) overdose (ingestion of > 32 gm or APAP >300 mcg/mL).

A retrospective study from a single poison center (1/1/2010 to 12/31/2019) investigated the clinical outcome of massive APAP overdose (APAP > 300 mcg/mL at 4 hour post ingestion) treated with standard dosing of NAC.

Results

1425 cases of APAP overdose identified; 104 met the criteria of massive APAP overdose. 

• 300-449 mcg/mL: 59.6% (n=62)
• 450-599 mcg/mL: 14.4% (n=15)
• >600 mcg/mL: 25.9% (n=27)

• No acute liver injury/hepatotoxicity: 76% (n=79)
• Hepatotoxicity: 24% (n=25)

Among cases that received NAC within 8 hours post ingestion (n=44)

• Only 9% (n=4) cases developed hepatotoxicity

Among cases that received NAC > 8 hours post ingestion (n=60)

• 35% (n=21) developed hepatotoxicity 

Odds of hepatotoxicity

• 5.5 If NAC initiated > 8 hours post ingestion
• 3.8 if 4 h post ingestion APAP level >600 mcg/mL  

Conclusion

• Cohort: no acute liver injury/hepatotoxicity in 76% (n=79)
• Standard NAC dosing initiated within 8 hours prevented hepatotoxicity in 91% (n=40/44)

Patients with cannabis hyperemesis syndrome experience recurrent/protracted nausea/vomiting. Cases of cannabis hyperemesis syndrome may increase as cannabis use becomes more common in the United States.

A randomized control trial (triple-blind) was conducted to compare haloperidol (0.05 or 0.1 mg/kg) IV or ondansetron 8 mg IV. Primary outcome was reduction of abdominal pain and nausea from baseline (on a 10 cm visual analog scale) 2 hours after treatment.

Results

• 33 subjected were randomized to haloperidol (n=13) and ondansetron (n=17)
• 30 used 1.5 gm/day since 19 years of age.
• Haloperidol was superior to ondansetron
  • 2.3 cm difference in pain and nausea
  • Less use of rescue antiemetics (31% vs. 59%)
  • Shorter time to ED departure (3.1 hours vs. 5.6 hours)

Conclusion

• In this small trial, haloperidol (0.05 or 0.1 mg/kg IV) was superior to ondansetron (8 mg IV) in the treatment of acute cannabis associated hyperemesis  

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Anion gap metabolic acidosis is often found in ED patients. It can be difficult to distinguish between toxic alcohol (TA) ingestion and alcoholic ketoacidosis (AKA).  A retrospective study attempted to identify risk factors associated with AKA when TA ingestion was the alternative diagnosis.

New York City poison center data was reviewed from Jan 1, 2000 to April 30, 2019.

Case definition of AKA included

1. Documented alcohol use disorder
2. Urine or serum ketones or elevated blood beta-hydroxybutyrate concentration
3. Anion gap >=14 mmol/L

Case definition of TA ingestion

1. Detectable methanol or ethylene glycol concentration

Results

• 699 patients were screened.
• AKA diagnosis: 86
• TA ingestion: 36

Univariate analysis showed following variables to be associated with AKA diagnosis

• Ethanol level: OR 1.007 (95% CI: 1.001 – 1.013)
• Anion gap: OR 1.063 (95% CI: 1.007-1.122)
• Age (years): OR 1.036 (95% CI: 1.005 – 1.068)

Multivariate logistic regression showed elevated ethanol concentration was associated with increased odd of AKA diagnosis 

Conclusion

• In this retrospective study, the odd of AKA diagnosis increased as ethanol concentration increased.
• TA ingestion remains challenging diagonsis without the availability of obtaining real time TA concentration.

Please see attachment for the table of serum insulin levels

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Attachments

• 2012312227_Untitled.pdf (39 Kb)