UMEM Educational Pearls - Toxicology

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.

Seizure is a very common effect seen in many overdoses.  Think about the following drugs which have a higher propensity for seizure as noted in a Swiss study of over 15000 patients and isolating to single drug overdoses:

The most prevalent pharmaceuticals were mefenamic acid (51 of the 313 cases), citalopram (34), trimipramine (27), venlafaxine (23), tramadol (15), diphenhydramine (14), amitriptyline (12), carbamazepine (11), maprotiline (10), and quetiapine (10).

The drug mefenanamic acid is not used much in the USA but citalopram, venlafaxine and tramadol as well as the most prelavent bupropion which was number one in the study are all commonly prescribed in the USA. Keep a watchful eye if you see any of these drugs on a drug list or as an overdose.

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Methylene blue is an extremely effective antidote for acquired methemoglobinemia but has important adverse effects if given in excess of recommended dose.

Below is the usual dose of methylene blue for treatment of methemoglobinemia

1-2 mg/kg of 1% solution IV with a repeat dose given if there is inadequate response to the first one

Adverse effects include:

• >4 m/kg -- Reversible skin, feces, and urine discoloration
• 5-7 mg/kg -- EKG abnormalities (T-wave inversions, diminished R-waves), shortness of breath, chest discomfort, diaphoresis, nausea, diarrhea, abdominal discomfort
• Paradoxically, between 4 and 15 mg/kg, it may cause methemoglobinemia

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Currently, no effective reversal agent for new oral anticoagulants (e.g. direct thrombin inhibitor, dabigatran, and factor Xa inhibitors: rivaroxaban and apixaban) exists for emergent management of hemorrhagic complications.

Boehringer Ingelheim, the manufacturer of dabigatran, is developing an antibody fragment (Fab) against dabigatran as a reversal agent.¹

A small ex-vivo porcine study demonstrated partial reversal of anticoagulation effects, measured by PT, aPTT, clotting time, clot formation time and maximum clot firmness, of dabigatran by PCC and activated PCC, while dabigatran-Fab achieved complete reversal. Recombinant fVIIa did not reverse the anticoagulation effect of dabigatran.²

Caution should be exercised when interpreting these finding as reversal of laboratory values does not necessarily correlate with clinical effect/outcome. However, dabigatran-Fab holds promise as an effective reversal agent of dabigatran.

Dabigatran-Fab is still under development and is not available/approved for clinical use.

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A placebo-controlled treatment trial in 26 cocaine-addicted subjects aimed to determine whether dexmedetomidine reverses MAP and HR increases after intranasal cocaine (3 mg/kg). 

Key Findings

• Low-dose dexmedetomidine (0.4 µg/kg) abolished cocaine-induced increases in MAP (+6 ± 1 versus -5 ± 2 mm Hg; P<0.01), but had no effect on HR (+13 ± 2 versus +9 ± 2 bpm; P=ns).  
• Skin sympathetic nerve activity and skin vascular resistance were significantly reduced.
• A higher sedating dose of dexmedetomidine (1.0 μg/kg) was needed to counteract the modest HR rise, but at the expense of increasing BP in one third of patients.

Application to Clinical Practice

In a low nonsedating dose, dexmedetomidine may be a potential (adjunct) treatment for cocaine-induced acute hypertension. However, higher sedating doses can increase blood pressure unpredictably during acute cocaine challenge and should be avoided.

Generous benzodiazepine should remain first-line therapy.

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A recent article showed that District of Columbia's Prescription Drug Monitoring program (PDMP) did not change the amount of opioids prescribed after conversion to MMEs (mg morphine equivalents). It is surprising to see a varying effect of PDMPs across the USA. Some have seen dramatic decreases up to 60% in Colorado versus an actual increase of over 50% in Connecticut. Usability, lack of interstate connectivity and quality of information have been seen as rate limiting factors in the efficacy of PDMPs.

PDMPs, by themselves, are not the answer to prescription drug abuse but are an excellent adjunct. Maryland ACEP and a committee chaired by Dr. Suzanne Doyon, Director of the Poison Center, have developed Opioid Prescribing Guidelines and a Discharge pamphlet that can utilized by hospitals to assist with this epidemic. The guidelines and pamphlet have been endorsed by MDPCC, MDACEP, DHMH and a multitude of other Maryland state agencies. I have attached the guidelines.

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Attachments

pamphlet.pdf (138 Kb)

SUPPLEMENT_PRESCRIPTION_GUIDELINES.docx (47 Kb)

Venomous snakes are believed to be everywhere in the United States except Maine, Hawaii, and Alaska. Most snakebites occur from months of April to October since snakes hibernate in the winter.  Most bites occur in the extremities (lower > upper).  One of the serious clinical manifestation of snakebite is compartment syndrome.

The following are risk factors for the development of increased intracompartmental pressures:

1) Envenomation of small children

2) Envenomation of digits

3) Application of ice or cold packs

4) Delayed use of antivenin

5) Inadequate dosing of antivenin

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Caustic ingestion can potentially cause significant esophageal and/or gastric injury that can lead to significant morbidity, including death.

Endoscopy is often performed:

·      To determine the presence of caustic injury.

·      To determine the severity of caustic injury (grade: I to III).

·      Placement of orogastric or nasograstic tube for nutritional support if needed (grade IIb and III)

Evidence for predictor of esophageal injury (frequently cited) comes from mostly studies involving pediatric population and unintentional ingestion:

1.     Gaudreault et al. Pediatrics 1983;71:767-770.

o   Studied signs/symptoms: nausea, vomiting, dysphagia, refusal to drink, abdominal pain, drooling or oropharyngeal burn

o   Presence of symptoms: Grade 0/I lesion: 82%; Grade II: 18%

o   Absence of symptoms: Grade 0/I: 88%; Grade II: 12%

2.     Crain et al. Am J Dis Child. 1984;138(9):863-865

o   Presence of 2 or more (vomiting, drooling and stridor) identified all (n=7) grade II and III lesion.

o   Presence of 1 or no symptoms: no grade II/III lesions

o   Stridor alone associated with grade II/III lesions (n=2)

o   10% of patients without oropharyngeal burns had grade II/III lesions.

3.     Gorman et al. Am J Emerge Med 1990;10(3):189-194.

o   Two or more symptoms: vomiting, dysphagia, abdominal pain or oral burns

o   Sensitivity: 94%; specificity 49%

o   Positive predictive value 43% ; negative predictive value: 96%

o   Stridor alone (n=3): grade II or greater lesion

4.     Previtera et al. Pediatric Emerg Care 1990;6(3):176-178.

o   Esopheal injury in 37.5% of patients without oropharyngeal burn

o   Grade II/III injury: 8 patients

Available data suggests that there are no “good” or reliable predictors for esophageal injury.

However, high suspicion for gastrointestinal injury should be considered with GI consultation for endoscopy in the presence of

·      Stridor alone

·      Two or more sx: vomiting, drooling or stridor (Crain et al)

·      Intentional suicide attempt

In a 12-week treatment course,150 alcohol-dependent patients were randomized to receive placebo, gabapentin 900 mg/day, or gabapentin 1,800 mg/day.

• The abstinence rate was 4.1% (95%CI, 1.1%-13.7%) in the placebo group, 11.1% (95%CI, 5.2%-22.2%) in the 900-mg group, and 17.0% (95%CI, 8.9%-30.1%) in the 1,800-mg group (P = .04 for linear dose effect; number needed to treat [NNT] = 8 for 1,800 mg).

• The no heavy drinking rate was 22.5% (95%CI, 13.6%-37.2%) in the placebo group, 29.6% (95%CI, 19.1%-42.8%) in the 900-mg group, and 44.7% (95%CI, 31.4%-58.8%) in the 1,800-mg group (P = .02 for linear dose effect; NNT = 5 for 1,800 mg).

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What are characteristics that increase the chance a patient is at risk for opioid-related death? A recent JAMA article begins to tackle this very issues. Baumblatt et al. found the following:

1) Patient with 4 or more prescribers had adjusted odds ratio 6.5 for opioid-related death

2) Patient with 4 or more pharmacies where they get their prescriptions aOR - 6.0

3) Patient with more than 100 mg of morphine equivalents mean per day aOR - 11.2

With the new Maryland Prescription Drug Monitoring program (PDMP)  we can start looking at a patient's prescription drug use pattern. The recent JAMA article can help you identify patients at high risk to die an opioid-related death. Use the PDMP and be wary if a patient has more than 4 prescribers or pharmacies or has >100mg of morphine equivalents per day.

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Carbon Monoxide Half-Life:

• Average elimination on room air: 5-6 hours
• 100% Oxygen: 70-130 minutes
• 100% Oxygen under hyperbaric conditions at 3 ATA: 23 minutes

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In a collaborative effort between the Illinois Poison Center and the Illinois Hospital Association, a new study sought to determine a poison center's effect on hospital length of stay (LOS) and hospital charges.

While the methodology was understandably complex, the authors compared ~5,000 toxicology inpatients with poison center assistance to 5,000 toxicology inpatients without poison center assistance.

After adjusting for confounders, the LOS among patients with posion center assistance was 0.58 days shorter compared to that of patients without poison center assistance (CI 95%: -0.66, -0.51, p<0.001). Though hospital charges for poison center-assisted patients in the lower quintiles were significantly higher than patients without poison center-assistance (+$953; p<0.001), they were substantially lower in the most costly quintile of patients (-$4852; p<0.001).

Poison center assistance was associated with lower total charges only among the most expensive to treat. However, this outlier group is very important when discussing medical costs.

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Acid and Alkali burns are all known for their caustic cellular injury to local tissue. Acid burns and specifically hydrofluoric acid has systemic toxicity. HF can be lethal even if there is only a 5-10% total body surface area burn. You can find HF in brick cleaner, glass etching and wheel cleaner. They main metabolic derangement is hypocalcemia which can lead to cardiac dysrrhythmias and death.

Treatment has ranged from IV calcium or even intra-arterial calcium in the affected limb to treat the local severe pain associated with an HF burn. Checking a serum calcium to be sure IV calcium replacement is also necessary.

Remember HF -> severe pain, minimal tissue damage, hypocalcemia, hyokalemia, dysrrhythmias

Seizures can be the presenting manifestation of acute poisoning in children.

A 3-year data set from the Toxicology Investigators Consortium (ToxIC) Case Registry identified 142 cases of drug-induced seizures in children < 18 years old. 75% were teenagers.

Antidepressants were most commonly associated with causing seizures, especially bupropion and citalopram. Diphenhydramine was also a commonly identified cause.

The authors conclude that clinicians managing teenagers presenting with seizures should have a high index of suspicion for intentional ingestion of antidepressants.

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Ondansetron (Zofran) is a great anti-emetic that, since it has gone generic, is also inexpensive. High dose ondansetron has been reported to cause QT prolongation and that practice is largerly discontinued now in the oncology world. Another uncommon adverse drug reaction may be dystonia. Though we think of ondansetron as a 5-HT3 blocker and should not cause the dystonic reaction like we see in metoclopramide, there are case reports of this reaction occurring.