UMEM Educational Pearls - Toxicology

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

• 1405012045_pamphlet.pdf (138 Kb)
• 1405012045_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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Reversal of the new anticoagulants rivaroxaban (Xarelto) and dabigatran (Pradaxa) has been challenging particularly in the ED setting with no definitive reversal agent. Intracerebral hemorrhage or critical GI bleed management becomes challenging and worsens mortality.

There is growing literature that states activated prothrombin complex concentrate or non-activated PCC may reverse these new anticoagulants. A volunteer study (1) showed its efficacy and concensus workgroups are now recommending aPCC as first line therapy(2).  The search goes on for a reliable reversal agent for these new anticoagulants which were suppose to solve more problems instead of create new ones.

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  1) Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M.  Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a  randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011 Oct 4;124(14):1573-9.     2) Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, Blais N,  Fontana P, Cohen A, Llau JV, Rosencher N, Schved JF, de Maistre E, Samama MM,  Mismetti P, Sié P; Working Group on Perioperative Haemostasis. Management of  major bleeding complications and emergency surgery in patients on long-term  treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors:  proposals of the working group on perioperative haemostasis (GIHP) - March 2013.  Arch Cardiovasc Dis. 2013 Jun-Jul;106(6-7):382-93.  

All benzodiazepines are metabolized by the liver. Some are just metabolized by pathways that are less dependent on global liver function.

The ‘LOT’ drugs are metabolized by conjugation, have no active metabolites, and have minimially affected half-lives even in the setting of liver disease.

• L – Lorazepam

• O – Oxazepam

• T – Temazepam

The rest of the benzodiazepines are primarily metabolized via hepatic CYP-mediated oxidation and may have prolonged duration of effect in patients with marked liver impairment.

For a bit more detail and commentary by Dr. David Juurlink, please read my recent post on the Academic Life in Emergency Medicine blog: http://academiclifeinem.com/all-benzodiazepines-are-metabolized-by-the-liver/

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You have a treat bag full of candy, which one can cause hypertension, hyopkalemia, metabolic alkalosis, rhabdomyolysis, low renin activity, thrombocytopenia and hypoaldosteronism. (scroll down for answer)

Licorice syrup or licorice extract contains glycyrrhizic acid which has a mineralcorticoid-like effect and can cause of all of the effects. Don't worry, Twizzlers and other usual licorice candies do not have true licorice extract in them. It is found in herbal remedies and some "natural" candies and licorice flavored cigars. Don't pick the licorice !

Yesterday's pearl generated several questions that I thought were worth answering briefly:

1) Why give it IM? Absorption rate is faster than SQ infiltration though theoretically could still cause necrosis

2) Is it only infilitration? Gangrene has occurred with inadvertent intra-arterial injection, SQ infiltration and even regular IV administration

3) Mechanism? Appears to be the drug and not diluent, diluting down the concentration as well as decreasing dose appears to help if you are going to give it IV

Here is a website if you wish to read more details:

https://www.ismp.org/newsletters/acutecare/articles/20060810.asp