UMEM Educational Pearls - Toxicology

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.

Everyone has admitted an altered mental status, patient or bradycardic patient and all of your test results are coming back normal except for a mild increase in creatinine. Take a look at the medication list. Creatinine is a poor indicator of renal function and GFR may be severely impaired even with a mild elevation of creatinine. If you have a predominantly renally excreted drug, you can see toxic effects of a drug even if administered at therapeutic levels.

Common bradycardia inducing medication that is renally cleared: atenolol (very high renal excretion) and digoxin (70%).

Altered Mental Status and on Keppra? Keppra is 100% renally cleared!

Ask your pharmacist for help with the medication list with renal or hepatic insufficiency.

Current evidence does not support the use of fasciotomy or dermotomy following North American Crotalinae envenomation with elevated intracompartmental pressures. [1]

A new case report of a 17-month old bitten by a copperhead snake reinforces that early and adequate administration of crotaline Fab antivenin is the treatment of choice. [2]

Many experts recommend against measuring compartement pressures altogether; we know it will be elevated.

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Though an uncommon exposure, it can occur from chronic mercury exposure. One mode of exposure that I have seen is with elemental mercury thermometers that were broken to collect the beads of mercury - for entertainment. This occurred in a child's room and were forgotten.  One child presented with personality changes and pink hands and feet. The patient suffered from severe mercury poisoning and acrodynia due to prolonged exposure to the mercury vapor. 

Acrodynia or Pink Disease includes:

Irritability, shyness, photophobia, pink discoloration of the hands and feet and polyneuritis.

A new drug is coming onto the drug scene with some case reports beginning to build. The internet appears to have been a major driver or mode of distribution for this particular drug.

One study of users showed that this ketamine analog has more vivid hallucinations that would liken it to LSD. It has been theorized that this drug has the dissociative effects of ketamine but also has prominent serotninergic effects making additions more likely and hallucinations possible.

If you see a case in your ED, you can say you heard it here first!

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Can acetaminophen concentrations < 100 mcg/mL obtained between 1-4 hours after acute ingestion accurately predict a nontoxic 4-hour concentration? NO!

Despite a high negative predictive value, a new study found there are still cases with toxic concentrations after 4 hours despite earlier levels < 100 mcg/mL. 

The Rumack-Matthew nomogram is to be utilized starting at 4 hours after an acute acetaminophen ingestion. Unless the concentration is zero, a second level must be drawn at 4 hours if an earlier one is positive.

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