UMEM Educational Pearls - Toxicology

Title: Drug induced Excited Delirium

Category: Toxicology

Keywords: EDS, Excited Delirium (PubMed Search)

Posted: 3/2/2017 by Kathy Prybys, MD
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Excited delirium syndrome (EDS) is a life-threatening condition caused by a variety of factors including drug intoxication.  EDS is defined as altered mental status, hyperadrenergic state, and combativeness or aggressiveness. It is characterized by tolerance to significant pain, tachypnea, diaphoresis, severe agitation, hyperthermia, non-compliance or poor awareness to direction from police or medical personnel, lack of fatigue, superhuman strength, and inappropriate clothing for the current environment. These patients are at high risk for sudden death. Toxins associated with this syndrome include:

  • Lysergic acid diethylamide (LSD)
  • Phencyclidine (PCP)
  • 3,4-methylenedioxymethamphetamine (Ecstasy)
  • Cocaine
  • Methamphetamine
  • Synthetic cathinones ("Bath salts")Mephedrone, Methylone,  Methylenedioxypyrovalerone (MDPV), designer drugs similar to amphetamine.
  • Synthetic cannbinoids

Ketamine at 4mg/kg dose can be given by intramuscular route and has been demonstrated to be safe and effective treatment for EDS.

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Title: Suboxone for managing opioid addiction

Category: Toxicology

Keywords: Buprenorphine, Suboxone (PubMed Search)

Posted: 2/16/2017 by Kathy Prybys, MD
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The current opioid epidemic is considered the worst drug crisis in American history responsible for 50,000 deaths per year in the US from overdose of heroin and opioid prescription drugs. A 200% increase in the rate of overdose deaths involving opioids occurred between 2000 and 2014. The continued rise in opioid related deaths calls for an urgent need for treatment. Three types of medication-assisted therapies (MATs) are available for treating patients with opioid addiction:methadone, buprenorphine, and naltrexone. Suboxone a combination of buprenorphine and naloxone, is emerging as one of the best choices for the following reasons:

  • Buprenorphine is a partial agonist that suppresses opioid withdrawal and cravings.
  • Binds opioid receptors with high affinity but low intrinsic activity.
  • Lasts 24 hours. Binds opioid receptors to prevent full opioid agonists such as heroin or prescription opioids from binding.
  • Less risk for dependency as increasing doses does not result in full opioid effect.
  • Less respiratory depression in overdose due to partial effect.
  • Naloxone, an opioid antagonist is poorly absorbed by oral route and is added to discourage injecting or snorting of suboxone as it can precipitate severe withdrawal.
  • Precipitated withdrawal can occur if other opioids are present with administration of Suboxone. This is particularly important with long acting opioids such as methadone.
  • Can be prescribed in the primary care setting and does not require a specialized clinic.
  • Comes in 2 or 8 mg tablet or sublingual film.

 

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Title: Methadone induced hypoglycemia Is there such a thing?

Category: Toxicology

Keywords: methadone overdose, hypoglycemia (PubMed Search)

Posted: 1/26/2017 by Hong Kim, MD
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Methadone overdose produces classic signs and symptoms of opioid intoxication - CNS and respiratory depression with pinpoint pupils. However, methadone overdose has also been associated with hypoglycemia – a relatively uncommon adverse effect.

Bottom line:

  • Methadone-induced hypoglycemia can occur, although rare, in an acute overdose.

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Title: Urine drug testing

Category: Toxicology

Keywords: Urine Drug Sreen (PubMed Search)

Posted: 1/19/2017 by Kathy Prybys, MD (Updated: 1/20/2017)
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Urine drug screens are most commonly performed by immunoassay technology utilizing monoclonal antibodies that recognizes a structural feature of a drug or its metabolites.  They are simple to perform. provide rapid screening, and qualitative results on up to 10 distinct drug classes with good sensitivity but imperfect specificity. This can lead to false positive results and the need for confirmatory testing. UDS  does not detect synthetic opiates or cannabinoids, bath salts (synthetic cathinones), and  gamma-hydroybutyrate. Most common drug classes detected are the following:

  • Opiates
  • Methadone
  • Benzodiazepines (not all)
  • Amphetamines 
  • Cocaine
  • THC metabolites
  • Barbituates
  • LSD
  • PCP
  • MDMA (Ecstasy)

 

 

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Title: Risk factors of severe outcome in acute salicylate poisoning

Category: Toxicology

Keywords: salicylate poisoning (PubMed Search)

Posted: 1/13/2017 by Hong Kim, MD (Updated: 12/5/2025)
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A small retrospective study of an acute poisoning cohort attempted to identify risk factors for severe outcome in salicylate poisoning.

Severe outcomes were defined as

  1. Acidemia pH < 7.3 or bicarbonate < 16 mEq/L
  2. Hemodialysis
  3. Death

A multivariate analysis of 48 patients showed that older age and increased respiratory rate were independent predictors of severe outcomes when adjusted for salicylate level.

Initial salicylate acid level was not predictive of severe outcome.  

Elevated lactic acid level was also a good predictor of severe outcome in univariate analysis but not in multivariate analysis.

Limitations

  1. Small sample size with single center study
  2. Retrospective study design
  3. Validation study of these predictors is needed.

 

Bottom line

  1. Older age and increases respiratory rate is associated with severe outcome (acidemia, hemodialysis or/and death) in this study.
  2. Data must be interpreted with caution due to small sample and retrospective study design.

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Title: Unexplained Lactic Acidosis, a clue to poisoning

Category: Toxicology

Keywords: Lactic acidosis (PubMed Search)

Posted: 1/5/2017 by Kathy Prybys, MD (Updated: 1/6/2017)
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Lactic acidosis is the most common cause of anion gap metabolic acidosis in all hospitalized patients. An elevated lactate level is an important marker of inadequate tissue perfusion causing subsequent shift to anaerobic metabolism and occuring in a variety of disease states such as sepsis. In patients with unexplained lactic acidosis without systemic hyoperfusion or seizure suspect  the following toxins:

  • Acetaminophen: Early on in massive ingestion usually associated with coma.
  • Cyanide
  • Metformin
  • HIV Drugs: Nucleotide reverse transcriptase inhibitors = Didanosine, stavudine, zidovudine due to mitochondrial toxicity.
  • Ethylene Glycol: Spuriously elevated lactate may occur with ethylene glycol toxicity due to the structural similarity between glycolic acid and lactate.Check for osmolar gap.
  • Kombucha ``mushroom'' tea 
 

 

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Smoke inhalation victims (house fires) are at risk of carbon monoxide (CO) and cyanide poisoning (CN). CO exposure/poisoning can be readily evaluated by CO - Oximetry but CN level can be obtained in majority of the hospital.

Lactic acid level is often sent to evaluate for CN poisoning.

 

Bottom line:

  1. Lactatic acid levels should be sent in all smoke inhalation victims.
  2. Elevate lactate > 10 mmol/L is highly suggestive of CN poisoning
    .

 

 

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Title: Acetaminophen induced liver failure

Category: Toxicology

Keywords: Acetaminophen, Liver Failure (PubMed Search)

Posted: 12/16/2016 by Kathy Prybys, MD
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Acetaminophen is one of the most common pharmaceutical ingestions in overdose and a leading cause of acute of liver failure in the U.S.  Early recognition and treatment is critical for prevention of morbidity.

  • Vigilance and screening is required for this "silent poison", available in hundreds of OTC products and in combination with numerous prescription medications. Symptoms may not be present early in course (for up to 24 hours) in poisoning.
  • Maximal benefit with antidote treatment, n-acetylcysteine (NAC) is time dependent within 8 hours of ingestion. Fulminant hepatotoxicity is unusual in acute overdoses treated with NAC within 10 hours of ingestion.
  • Early prediction of poor prognosis is essential to identify patients who may require life-saving liver transplantation.  Kings College Criteria: Arterial pH less than 7.30, INR greater than 6.5, Creatinine greater than 3.4, Grade III or IV encephalopathy combined with Lactate greater than 3.5 and Phosphate greater than 3.75 may increase sensitivity.

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Recent study evaluated whether an acetaminophen (APAP) level obtained less than 4-hour post acute ingestion can predict which patient would not require n-acetylcysteine (NAC).  APAP cutoff level of 100 ug/mL was used for analysis. This was a secondary analysis of the Canadian Acetaminophen Overdose Study database (retrospective study). 

 

Bottom line:

  1. If initial APAP level of 100 ug/mL was applied as a cutoff point, it missed 27 patients (N= 1821) who had toxic APAP level at > 4-hour post ingestion that require NAC.  
  2. Only a very low (< 15 ug/mL) or undetectable initial APAP reliably identify (sensitivity 100%) patients who do not require NAC.
  3. Absorption of APAP can be delayed by coingestion of opioids or antimuscarinics.

 

 

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Title: My patient really has all these drug allergies?

Category: Toxicology

Keywords: Drug Allergy, ADR, ADE (PubMed Search)

Posted: 12/1/2016 by Kathy Prybys, MD (Updated: 12/2/2016)
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Misclassification of adverse drug effects as allergy is commonly encountered in clinical practice and can lead to use of suboptimal alternate medications which are often less effective.

  • Nomenclature surrounding drug safety needs to be clear and unambiguous to avoid confusion. 
  • Adverse Drug Effect (ADE) = All drug induced disease. Majority are predictable based on drug's known pharmacology. Include harm related to medication errors and drug/food interactions. 
  • Adverse Drug Reaction (ADR) = Noxious or unintended reaction to a drug that is administered at therapeutic doses during normal use. Divided into predictable (majority 75-80%), related to pharmacologic actions of the drug in otherwise normal individuals) and unpredictable reactions (related to individual’s immunological response). 
  • "Drug allergies"  are relatively uncommon with cited incidence of 10%. Immunologically mediated reactions (type I to IV) to a pharmaceutical and/or formulation (excipient) in a sensitized person. They are dose independent and unrelated to pharmacological action of the drug. Most commonly, IgE-mediated type I (immediate) reactions caused by rapid release of vasoactive mediators from mast cells and peripheral basophils causing generalized reaction including urticaria, angioedema, stridor, wheezing, and cardiovascular collapse.
  • The skin is the most frequently and notably affected by drug induced allergic reactions.
  • Antibiotics, particuarly Beta-Lactams, are the most important cause of immediate hypersensitivity reactions. Approximately 10% of patients report a history of penicillin allergy, however after complete evaluation, up to 90% of these individuals are able to tolerate penicillin and are designated as having “penicillin allergy” unnecessarily.
  •  Pseudoallergy can occur with opioids due to histamine release. Codeine and morphine are most commonly associated with pseudoallergy. Coadministration of an antihistamine or use of a semi or synthethic opioid (Fentanyl, hydromorphone) can prevent this reaction.

 

 

 

 

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Title: Management of heroin overdose patients in prehospital and ED setting: How long do they need to be observed?

Category: Toxicology

Keywords: heroin overdose, observation period, bystander naloxone (PubMed Search)

Posted: 11/16/2016 by Hong Kim, MD (Updated: 11/17/2016)
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Recently a review paper was published regarding the duration of observation in heroin overdose patients who received naloxone.

It made several conclusions regarding heroin overdose:

  1. Treat (naloxone) and release in a prehospital setting may be safe.
  2. Short observation period (minimum of 1 hour) for heroin OD patients who were treated in the ED may be safe.
  3. Bystander and first responder naloxone administration is effective and safe.

It should be pointed out that this is a review paper of limited number of articles with variable quality. Additionally, the clinical history of “heroin use” may be unreliable as fentanyl and novel synthetic opioids are also sold as “heroin.” Providers should exercise appropriate clinical judgement when caring for these patients. 

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Title: Buprenorphine/naloxone (Suboxone) exposure in pediatric population

Category: Toxicology

Keywords: buprenorphine exposure, pediatrics, retrospective study (PubMed Search)

Posted: 10/26/2016 by Hong Kim, MD
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Recently, a retrospective study of unintentional buprenorphine/naloxone exposure among pediatric population was published. All patients were evaluated by toxicologists at the time of initial hospital presentation (or transfer) at the study center.

 

Bottom line

  • 83% and 80% of the patients experienced respiratory and CNS depression, respectively.
  • Majority of the patients became symptomatic within 8 hours of exposure (range not available).
  • Naloxone reversed respiratory depression. Median dose for single naloxone dose: 0.09 mg/kg; median dose for multiple naloxone doses: 0.19 mg/kg.
  • The reported “ceiling effect” on respiratory depression in adult does not exist in pediatric population.
  • The optimal time of observation is unclear but it is prudent to observe pediatric buprenorphine exposure for up to 24 hours.

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US, Canadian and European critical care and toxicology societies recently published a consensus recommendation is the management of CCB poisoning.

Bottom line:

1. First line therapy remains unchanged: IV calcium, atropin, high-dose insulin (HIE) therapy, vasopressor support (norepinephrine and/or epinephrine).

2. Refractory to first line therapy: increase HIE, lipid-emulsion, transvenous pacemaker

3. Refractory shock, periarrest or cardiac arrest: Above (#1 & #2) plus ECMO if available.

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Title: "Leaves of 3 let them be"

Category: Toxicology

Keywords: Poison Ivy, Toxicodendron, Urushiol (PubMed Search)

Posted: 10/6/2016 by Kathy Prybys, MD (Updated: 10/7/2016)
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Fall clean up = Poison Ivy, oak, sumac (Toxicodendron species) which is ubiquitous in North America but it can also be found in British Columbia, Mexico and in parts of Asia. These plants are truly the scourge of outdoor enthusiasts and agricultural workers responsible for up to 40 million cases of miserable often temporarily incapacitating rashes annually.

Fast Facts:

  • Grows as plant, vine, or shrub with leaves ranging in color from light or glossy green to red and yellow in fall.
  • Exposure by direct contact with plant, indirectly from oil resin on objects, clothes, pets, or airborne from burning plant.
  • Urushiol toxin induced type IV hypersensitivity allergic contact dermatitis. This oily resin toxin is excreted from all parts of plant (stems, leaves, flowers, roots, vines). and is extremely stable staying active even after plant dies.
  • Intensely itchy blistering rash starts 12-72 hours after contact and lasts up to 21 days. Characterized by red streaks or linear configuration where skin brushed up against plant sap. Inflammation (redness, swelling, hives, blistering) to thick leathery plagues depending on severity and vulnerability of skin location. Intense inflammation can mimic cellulitis.
  • Rash is Not contagious but spread of oil on clothes, pets, tools, objects is!
  • Delayed reaction accounts for seemingly "spread" of rash. Eruption rate depends on thickness of skin and dose of urushiol oil.

Treatment Tips:

  • Prevention. Avoidance and universal precautions when gardening. Clusters of 3 leaves each trio growing on their own stem, hairy vines, no thorns, white berries.
  • Cover skin to prevent exposure and if known contact immediately wash skin, clothes, objects.
  • Hot water relieves itch as does cool compresses.
  • Domeboro or witch hazel are astringents can reduce inflammation.
  • External analgesics (e.g., benzocaine, lidocaine, benzyl alcohol) can help itching.
  • Highly viscous or granular cream surfactant washes bind urushiol and can reduce exposure. Zanfel, Mean green, Gojo orange, various generic poison ivy removal scrubs now available. (Zanfel works wonders used every few hours and may alleviate need for steroids but is $$$ and several tubes are required).
  • In severe cases, Steriod burst followed by 2-3 week taper to prevent relapse flare.

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Attachments



Naloxone has been used to reverse opioid-induced respiratory depression for decades. The “standard” dose of opioid intoxication has been 0.4 mg.  However, over the past decade, initial naloxone dose for opioid intoxication has evolved to recommend a lower initial dose (0.04 – 0.05 mg).

 

A recent article by Connors et al. reviewed 25 medical resources (internet, medical texts and study guides) of different medical specialties (internal medicine, medical toxicology, emergency medicine, pediatrics, anesthesiology, pain medicine and general medicine)

 

Findings:

  • 12 medical resources (48%) recommend using 0.05 mg or less IV as an initial dose.
  • 9 medical resources (36%) recommend using 0.4 – 0.5 mg or higher as an initial dose.
  • Maximum dose also ranged widely from 2 to 20 mg.

 

Recent editions of emergency medicine text (Rosen’s and Tinitinalli) recommend using 0.04 – 0.05 mg IV in ED patients with history of opioid dependence. Higher doses of naloxone are recommended for non-opioid dependent/apneic patients.

 

However, history of opioid dependence is difficult to obtain in patients with opioid induced CNS/respiratory depression.

 

Administering 0.4 mg or higher dose may/can acute agitation or opioid withdrawal symptoms that can utilize more ED resources to calm agitated patient/management of withdrawal. Thus it may be prudent to use low-dose strategy (0.04 mg IV with titration) to minimize the risk of precipitating naloxone-induced opioid withdrawal/agitation.

 

Bottom line:

In opioid-induced respiratory depression/apneic patients:

  1. Ventilate with bag-valve mask for apnea/hypoxia
  2. Administer naloxone: 0.04 mg IV every 2 – 3 min until reversal of respiratory depression/hypoxia is achieved.

To make 0.04 mg naloxone solution:

  • Dilute 1 mL of 0.4 mg naloxone with 9 mL normal saline in 10 mL syringe. 

 

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Title: Atypical antipsychotics: are they truly safer than typical antipsychotics?

Category: Toxicology

Keywords: atypical antipsychotic toxicity (PubMed Search)

Posted: 9/8/2016 by Hong Kim, MD (Updated: 12/5/2025)
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Antipsychotic as a class has diverse range of toxicity. The atypical (2nd generation) antipsychotics are considered to possess less toxicologic manifestation compared to the typical (1st generation) antipsychotics - lower K channel blockade and minimum Na channel blockade properties. However, select atypical antipsychotics overdose can results in significant morbidity in addition to sedation.

 

Alpha-1 blockade (hypotension)

  • Clozapine
  • Olanzapine
  • Quetiapine
  • Risperidone
  • Ziprasidone

 

Antimuscarinic effect (anticholinergic toxicity)

  • Clozapine
  • Olanzapine
  • Quetiapine

 

Delayed rectifier K channel blockade (QT prolongation)

  • Ertindole
  • Ziprasidone

 

Bottom line:  Although lethal overdose from atypical antipsychotics are rare, they can result in significant clinical toxicity when ingested alone or in combintation with other classes of medications.

 

 



Title: Lethal in small dose or single pill in pediatric population (age < 5 years old)

Category: Toxicology

Keywords: One pill killers, pediatric (PubMed Search)

Posted: 8/17/2016 by Hong Kim, MD (Updated: 8/18/2016)
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In pediatric population, small dose or single pill ingestion can potential result in severe or lethal toxicity.

Clinicians should be mindful of potential toxicity following xenobiotic exposure (below) in pediatric population, especially under the age of 5 years old, even if the patient may initially appear asymptomatic.

  • Benzocaine
  • B-adrenergic antagonist (sustained release)
  • Calcium Channel blockers (sustained release) 
  • Camphor
  • Clonidine
  • TCAs
  • Diphenoxylate/atropine (Lomotil)
  • Toxic alcohol (methanol or ethylene glycol)
  • Methylsalicylate
  • MAO-Is
  • Opioids
  • Phenothiazines
  • Quinine or chloroquine
  • Sulfonylureas
  • Theophylline

 

Suspected ingestion of above medications/xenobiotics may warrent observation up to 24 hours in asymptomatic pediatric population.

 

 



Drug-induced hypoglycemia is an often severe and symptomatic. It is a potentially preventable cause of significant morbidity. In one large study, it accounted for 23% for hospital admissions due to adverse drug events and 4.4% of overall admissions. The majority of hypoglycemic events occur with insulin and sulfonylureas. However, multiple drugs can affect glucose homeostasis and have been cited to cause hypoglycemia in therapeutic dose alone or in combination with other medications or illness. Factors that predispose to low blood sugar include reduced food intake, age, hepatic and renal disease, and severe infection. Beware of the possibility of inducing hypoglycemia in patients taking the following:

  • Ethanol
  • Insulin
  • Pentamidine
  • Quinine
  • Quinolones (Gatifloxin others rare)
  • Sulfonylureas

Agents with lesser quality evidence as predisposing medications or illnesses were present:

  • Ace Inhibitors (with diabetic agents)
  • Propanolol ( less likely in other beta blockers)
  • Trimethoprim/sulfamethoxazole (in renal compromise)
  • Salicylates (high dose or intoxication)

Drugs induced hypoglycemia should always be considered in the differential diagnosis of every patient presenting with low blood glucose. Octreotide antagonizes pancreatic insulin secretion and should be considered for first-line therapy in the treatment of sulfonylurea-induced hypoglycemia particularly when glucose levels cannot be maintained by dextrose infusions. Octreotide is administered 50 mcg subcutaneously (1-10 mcg in children) every 12 hours.

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Title: Are synthetic opioids next novel designer drugs of abuse in the U.S?

Category: Toxicology

Keywords: novel synthetic opioid, U-47700 (PubMed Search)

Posted: 8/1/2016 by Hong Kim, MD (Updated: 12/5/2025)
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Recently, there have been several news reports regarding the emergence of synthetic opioids in the U.S. and Canada. There are multiple synthetic opioids that have been identified as potential agents of abuse including W-18, U-47700, fentanyl derivatives, AH-7921 and MT-45. These compounds share a similar story with synthetic cannabinoid where they were synthesized for research purpose or by pharmaceutical companies but were not marketed. They are often sold as “research chemicals” over the internet.

In July 2016, three case reports have been published regarding several cases of U-47700 intoxication in San Diego, CA and Dallas, TX.

  • Dallas, TX: A couple in their 20’s purchased U-47700 on the internet believing it to be “synthetic cocaine.” They both suffered CNS and respiratory depression after insufflation. Naloxone was not administered in both cases. The man was intubated while the woman was awake at time of presentation to the ED. U-47700 exposure was confirmed by liquid chromatography/tandem mass spectrometry.

 

  • San Diego, CA: a 22 year old man with history of heroin abuse was found unresponsive and apneic (4 breaths per minute and pulse oximetry of 60%). He received naloxone 2 mg IV which completely reversed his CNS and respiratory depression. He admitted to purchasing U-47700 on the internet and its use prior to being found unresponsive. U-47700 exposure was confirmed using liquid chromatography/mass spectrometry.

 

  • Central CA: 41 year old woman presented with CNS depression and pinpoint pupils after ingesting 3 tablets of “Norco” purchased from the street.  Her intoxication was completely reversed with naloxone 0.4 mg IV and discharged after 4 hour observation. Fentanyl and U-47700 was detected in serum blood test.

It is unknown if currently available heroin is cut with above mentioned synthetic opioids. Like other opioid receptor agonists, administration of naloxone will likely reverse the opioid toxidrome. But clinical experience in reversing synthetic opioids intoxication with naloxone is limited.  

 

Bottom line:

Irrespective of whether an ED patient is exposed to synthetic opioids or "traditional" opioids of abuse (prescription opioid pain medication or heroin), the management of opioid intoxication management remains unchanged for respiratory depression. 

  1. Airway management: bag-valve assisted ventilation if needed
  2. Naloxone administration (initial dose: 0.04 to 0.4 mg IV) with titration as needed. 
  • naloxone's clinical duration of effect ranges from 30 to 90 minutes.

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Title: Laundry detergent pods exposure - the hidden danger.

Category: Toxicology

Keywords: Pediatric exposure, laundry detergent pods (PubMed Search)

Posted: 6/23/2016 by Hong Kim, MD
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Laundry detergent pods were introduced in 2012 to make washing clothes more "convenient." Since then, pediatric exposures to laundry detergent pods have increased as the use of these detergent pods have become more common in homes. Like other household chemical exposure, small, colorful candy like appearances of laundry detergent pods can attract the attention of < 3 years old children resulting in unintentional exposure due to curiosity or taste.

Most frequent clinical effects (2013 - 2014 national poison center data) from exposure to detergents in general (laundry detergent pods and nonpods & dishwasher detergent):

  • GI: nausea & vomiting: 29.1%
  • Cough/choking: 8.3%
  • Ocular irritation/pain: 5.6%
  • Red eye/conjunctivitis: 3.4%
  • Drowsiness/lethargy: 2.8%

Laundry detergent pod vs. nonpods:

  • Higher referral to health care facility: 17.4% vs. 4.7%
  • Higher odds of experiencing > 1 clinical effects (OR: 3.9; 95% CI: 3.7 4.1)
  • Higher odds of hospital admission (OR: 4.8; 95% CI: 4.0 5.8)
  • Higher odd of intubation (OR: 6.9; 95% CI: 3.5 13.6)

Laundry detergent pods (only) also resulted in following:

  • Coma: 17 cases
  • Respiratory arrest: 6 cases
  • Pulmonary edema: 4 cases
  • Cardiac arrest: 2 cases

Cases of caustic exposure-like injuries have also been reported (corneal abrasion and esophageal injury)

Bottom line:

Pediatric laundry detergent (nonpods) exposures usually have self-limited symptoms. However, laundry detergent pod exposure can cause more serious clinical effects that may require hospitalization.

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