UMEM Educational Pearls - By Bryan Hayes

Most antidotes have not been adequately studied in pregancy and hold a Pregnancy Risk Category 'C' by the FDA. However, there are a few antidotes that hold a category 'D' or 'X' rating (contraindicated).

1. Ethanol (toxic alcohols) - Category C
   • Reproduction studies have not been conducted with alcohol injection. Ethanol crosses the placenta, enters the fetal circulation, and has teratogenic effects in humans. When used as an antidote during the second or third trimester, Fetal Alcohol Syndrome AS is not likely to occur due to the short treatment period; use during the first trimester is controversial.
   • Alternative (preferred) antidote: fomepizole.
2. Methylene blue (methemoglobinemia) - Category X
   • Use during amniocentesis has shown evidence of fetal abnormalities, but it has been used orally without similar adverse events. IV may be ok.
3. Lorazepam and diazepam (seizures, nerve agents) - Category D
   • Teratogenic effects have been observed in some animal studies and in humans. Lorazepam/diazepam and their metabolite cross the human placenta.
4. Potassium iodide (radioactive iodine) - Category D
   • Iodide crosses the placenta (may cause hypothyroidism and goiter in fetus/newborn). Use for protection against thyroid cancer secondary to radioactive iodine exposure is considered acceptable based upon risk:benefit, keeping in mind the dose and duration.
5. Amyl nitrite (cyanide) - Category C (manufacturer contraindicates)
   • Animal reproduction studies have not been conducted. Because amyl nitrate significantly decreases systemic blood pressure and therefore blood flow to the fetus, use is contraindicated in pregnancy (per manufacturer).
   • Other options exist to treat cyanide exposure including sodium nitrite, sodium thiosulfate, and hydroxocobalamin.
6. Penicillamine (chelator) - Category D

In most cases, the benefits of short-term use probably outweigh the risk, especially when accounting for the health and prognosis of the mother.

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Intraosseus (IO) access has become quite popular in critically ill patients requiring immediate resuscitation. In a patient responsive to pain, however, pain and discomfort is associated with the force of high-volume infusion through the established line.

• Before flushing the line, consider administering preservative-free 2% lidocaine (without epinephrine) for patients responsive to pain prior to flush.

• The suggested dose is 20-40 mg (1-2 mL) of the 2% lidocaine, followed by the 10 mL saline flush.

If preservative-free 2% lidocaine is not stocked in your ED, now is the time to consider adding it.

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Several medications can produce a false-positive result for methadone on the urine drug screen: diphenhydramine, doxylamine, clomipramine, chlorpromazine, quetiapine, thioridazine, and verapamil.

Add a new one to the list. Tapentadol, a relatively new opioid analgesic similar to tramadol, can also produce a false-positive result for methadone on certain immunoassays.

A separate study concluded that tapentadol does not affect the amphetamine screen.

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The two available Tetanus/reduced diphtheria toxoid/acellular pertussis (Tdap) vaccine products in the U.S. are Boostrix and Adacel. Neither were originally approved in older adults age 65 and older. Boostrix received FDA-approval for use in this age group in July 2011, but Adacel never has.

However, in June 2012 ACIP issued new guidance recommending Tdap for all adults age 65 years and older. 

"When feasible, Boostrix should be used for adults aged 65 years and older; however, ACIP concluded that either vaccine administered to a person 65 years or older is immunogenic and would provide protection. A dose of either vaccine may be considered valid."

Bottom line: Regardless of which Tdap product is stocked at your institution, both are considered safe to use in adults 65 years and older.

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The more well known causes of toxin-induced hyperthermia include sympathomimetics and anticholinergics. In addition, neuroleptic malignant syndrome, serotonin syndrome, and malignant hyperthermia are high on the differential.

Several other xenobiotics can cause hyperthermia in overdose as well:

• Salicylates and dinitrophenol cause hyperthermia by uncoupling oxidative phosphorylation.
• Thyroid medications cause hyperthermia via thyroid hormone's thermogenic effect and psychomotor agitation. Hyperthermia can be extreme (>106°F, >41°C).
• Caffeine/theophylline, isoniazid, and strychnine cause hyperthermia through refractory seizures and muscle contraction. Highest temp recorded with strychnine is (109.4°F, 43°C).

In general, benzodiazepines should be considered first-line therapy, followed by barbiturates, propofol, or other sedative hypnotics. Phenytoin rarely has a role in the management of toxin-induced seizures. Extrenal cooling measures are also warranted. Specifically for isoniazid, pyridoxine should be administered immediately with a benzodiazepine.

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In the rare circumstance you need to treat a patient with suspected PID and an allergy to doxycycline, what is the alternative?

For oral regimens, azithromycin is an option in place of doxycycline.

• In one randomized trial, azithromycin demonstrated short-term effectiveness when given 500 mg X 1, followed by 250 mg/day for 6 days.
• In another randomized study, the combination of ceftriaxone 250 mg IM single dose and azithromycin 1 g orally once a week for 2 weeks was effective.

Suggested regimen for PID with doxycycline allergy:

• Ceftriaxone 250 mg IM X 1
• Azithromcyin 500 mg IV/PO X 1, then 250 mg PO daily for 6 days
• plus/minus Metronidazole 500 mg PO twice daily for 14 days

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Background

• Patients who are intoxicated with, or emerging from, phencyclidine (PCP) highs present with acute agitation that can be challenging to treat

• Risks of physical restraints for combative patients include injury, hyperthermia, rhabdomyolysis, and increased agitation or excited delirium

• Haloperidol is an option for chemical restraint that is typically safe and rapid acting

• Some concerns related to haloperidol use in PCP-intoxicated patients include worsened PCP-induced hyperthermia, dystonic or anticholinergic reactions, lower seizure threshold, and hypotension

 Data

• A recent retrospective case series assessed the frequency of adverse effects from the combination of PCP and haloperidol

• Of 59 cases, only two patients experienced an adverse reaction, and neither could be conclusively linked to haloperidol administration

• This analysis had several major limitations including retrospective design for identifying adverse reactions, potential for false positive PCP screens, and possible haloperidol administration more than 24 hours after PCP intoxication

​Bottom Line

While haloperidol may be safe for agitated PCP-intoxicated patients, this paper adds nothing to refute or support its use. Benzodiazepines and calm environment are still first-line therapy.

It should be noted that no data exist showing poor outcomes in PCP-intoxicated patients administered haloperidol, which begs the question "Is there even an issue?" Dr. Leon Gussow, author of The Poison Review, provides a nice answer and summary of the article here.

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It seems we've finally put to bed the myth that 10% of penicillin-allergic patients will also react to cephalosporins. Dr. Campagna, et al. recently published a review article concluding that the true cross-reactivity is negligible except when side-chains are similar [PMID 21742459]. 

This topic was also the subject of a recent post on the Academic Life in EM blog (http://academiclifeinem.blogspot.com/2012/08/busting-myth-10-cephalosporin.html).

But what about the reverse question? Can I give a penicillin to a cephalosporin-allergic patient?

Dr. Romano's group tested 98 patients with skin-test postitive cepahlosprin allergy (mostly IgE -mediated anaphylaxis). Patients were then skin tested for penicillin allergy. Those testing negative were challenged with a penicillin.

• 25% of patients reacted to the penicillin

• Similar side-chain was a strong predictor of cross-reactivity

​A Letter to the Editor response to this study pointed out that the authors used a smaller-than-standard size threshold for a positive response to the penicllin AND used a higher-than-standard dose of amoxicillin for testing. In light of this, the rate of subjects with cephalosporin allergy who do not have a history of penicillin allergy but with true IgE-mediated allergy to penicillin might be much closer to 5%.

Bottom line: The cross-reactivity of penicillins in cephalosporin-allergic patients is somewhere between 5-25%.

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Activated charcoal is most effective if given within 1 hour of overdose.

Prehospital administration of charcoal can be challenging, but may save significant time compared to waiting until arrival to the ED. The patient has to be transported by EMS, registered, seen by a provider, order for charocal placed...

Two studies evaluated the time difference between prehospital and hospital administration of GI decontamination.

• Study 1 found median time to activated charcoal in the ED was 82 minutes.
• Study 2 found mean time to activated charcoal by EMS was 5 minutes, compared to 51 if held until arrival to ED.

Bottom line: Don't underestimate the amount of time that goes by before you evaluate non-crashing patients upon arrival to the ED. If the story supports an overdose and the patient doesn't have contraindications for receiving charcoal, recommend it be given in the prehospital setting for greatest potential benefit.

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Patients frequently report having a sulfa allergy. In most cases, the allergic reaction was secondary to a sulfonamide antimicrobial agent, such as sulfamethoxazole-trimethoprim.

The question is: Can I use furosemide (or other non-antimicrobial agents containing a sulfa component)?

• There is minimal evidence of cross-reactivity between sulfonamide antimicrobials and non-antimicrobials.

• Despite this, the U.S. FDA-approved product information for many non-antimicrobial sulfonamide drugs contains warnings concerning possible cross-reactions.

Bottom line: If a patient had a true IgE-mediated anaphylatic reaction to a sulfonamide antimicrobial, it may be best to avoid other sulfa-related medications (use ethacrynic acid if a loop diuretic is needed). Otherwise, the available literature does not support cross-reactivity between sulfonamide antimicrobials and non-antimicrobials.

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Carbon monoxide (CO) and hydrogen cyanide (HCN) are two of the main gases causing injury and death from smoke inhalation in fire victims. During the first phase of a fire, and prior to depletion of oxygen reserves and subsequent production of CO, formation of HCN from the thermal breakdown of nitrogen-containing materials may be the primary cause of lethal poisoning in an enclosed-space fire.

A recent, retrospective, observational study from Poland assessed the prevalence of toxic HCN exposure in victims of enclosed-space fires.

Important findings:

• Of the 285 patients who died, 169 (59%) had detectable cyanide blood levels. 82% also had elevated carboxyhemoglobin (COHb) levels.
• Of the 40 patients who survived, 20 (50%) had detectable cyanide blood levels. All 20 had elevated COHb levels.

Conclusion: The high prevalence of coincident HCN concentrations and COHb levels in victims of enclosed-space fires emphasises the need to suspect HCN as a co-toxin in all persons rescued from fire who show signs and symptoms of respiratory distress.

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Carbapenems (meropenem, ertapenem, doripenem, imipenem/cilastatin) are broad-spectrum antibiotics that have good gram-negative and anaerobic coverage and are used to treat resistant bacterial infections.

• Early retrospective studies showed ~10% cross-reactivity in penicillin-allergic patients.

• More recent prospective studies verified penicillin allergy by the accepted standard (ie, skin test to the major and minor penicillin determinants) and tested for carbapenem allergy by administering a full therapeutic dose to carbapenem skin test-negative patients.

• The cross-reactivity between skin tests appears to be around 1%, with all carbapenem skin test-negative patients tolerating the challenge.

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There is a growing recognition of patients who have a subtoxic acetaminophen level at the 4-hour mark, but then still go on to have a toxic level later.

This is concerning in that we usually can exclude the chance for toxicity if the 4-hour, post-ingestion level is < 150 mcg/mL following an acute ingestion (plotted on Rumack-Matthew nomogram).

It still is not clear exactly what subset of patients need to have a second level drawn, but a recurring theme seems to be ingestion of acetaminophen in combination with agents that slow GI motility, such as diphenhydramine or opioids. It may be worth ordering a second APAP level (possibly at 8 hours) in patients ingesting these prodcuts.

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A recent paper reviewed 53 articles to assess the utility of vasopressors in cardiac arrest. The authors aimed to determine if vasopressors improved ouctomes in this patient population. Here are their conclusions:

1. Epinephrine is associated with improvement in short term survival outcomes as compared to placebo, but no long-term survival benefit has been demonstrated.
2. Vasopressin is equivalent for use as an initial vasopressor when compared to epinephrine during resuscitation from cardiac arrest.
3. There is a short-term, but no long-term, survival benefit when using high dose vs. standard dose epinephrine during resuscitation from cardiac arrest.
4. There are no alternative vasopressors that provide a long-term survival benefit when compared to epinephrine.

Although these conclusions don't support the use of vasopressors in cardiac arrest, we should not abandon these therapies. Most of the trials were completed before wide-spread recognition of the post-cardiac arrest syndrome, implementation of therapeutic hypothermia protocols, and early cardiac catheterization.

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 Levamisole is a pharmaceutical with anthelminthic and immunomodulatory properties that was previously used in both animals and humans to treat inflammatory conditions and cancer.

It has been identified as a cocaine adulterant in the U.S. since 2003, with the DEA estimating that by 2009 up to 70% of cocaine seized contained levamisole.

Leukopenia, agranulocytosis, and vasculitis are well known complications of levamisole use.

One important complication to keep in mind is the possibility of multifocal inflammatory leukoencephalopathy (MIL). Although no formal case of leukoencephalopathy in the setting of cocaine use has yet been reported, various neurological side effects were described with levamisole therapy, the most concerning complication being MIL.

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• IV alteplase (tPA) has many contraindications when administered for acute ischemic stroke. Among them is a history of warfarin use with INR > 1.7 (0-3 hours) or any history of warfarin use regardless of INR (3-4.5 hours).
• A recent retrospective analysis of a major stroke registry compared the risk of symptomatic intracerebral hemorrhage (ICH) following tPA in patients on warfarin with an INR < 1.7 (n - 1,802) with patients not on warfarin therapy (n = 21,635).
• After adjusting for differences in the two populations, the authors found no increased symptomatic ICH risk in patients with preadmission warfarin use (5.7% vs. 4.6%, p = 0.94).

Issue 1: Mean INR in study patients was only 1.22 (median 1.2). An INR of 1.2 represents very little actual anticoagulation.

Issue 2: In the small subgroup of patients with INR 1.5 to 1.7 (n = 269) there was a higher risk of ICH (7.8%), but did not reach statistical significance (it was significant in the unadjusted risk population).

Bottom line: Patients with INRs < 1.5 may be ok to receive tPA. Patients with INRs 1.5 or greater need further study.

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• Several macrolide antibiotics can cause QTc prolongation and dysrhythmias (e.g., erythromycin), but azithromycin is thought to have little cardiotoxicity.
• A cohort of patients taking azithromycin was compared to those taking no antibiotics, amoxicillin, ciprofloxacin, or levofloxacin.
• When compared to no antibiotics, amoxicillin, and ciprofloxacin, azithromycin was associated with a small but significant increased risk of cardiovascular death. Azithromycin was similar to levofloxacin.
• Important points:
  • Increased risk translates to 47 additional deaths per 1 million prescriptions.
  • Increased risk only occurs during the 5 day course and does not carry on after discontinuation.
  • Patients most likely to die were in the highest risk category based on preexisting cardiovascular diseases (245 deaths per 1 million prescriptions).
• Bottom line: Patients may start asking about this study finding when given a prescription for azithromycin. Although a small risk, it may be prudent to prescribe an alternative if patients have preexisting cardiovascular disease.

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Naltrexone and methylnaltrexone are both mu-receptor antagonists that look similar and have similar names. But, they have very different uses.

• Naltrexone (ReVia, Vivitrol)
  • Used to treat opioid/alcohol dependence or to prevent relapse following opioid detoxifcation
  • Dose: 25 to 100 mg PO daily or 380 IM every 4 weeks
  • Crosses blood-brain-barrier and can precipitate withdrawal

• Methylnaltrexone (Relistor)
  • Used to treat opioid-induced constipation
  • Dose (weight-based): 8 to 12 mg (or 0.15 mg/kg) subcutaneously once daily
  • Peripherally acting, does not cross blood brain barrier

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• Ethylene glycol can result in elevated lactate concentrations secondary to hypotension and organ failure in severely poisoned patients. However, lactate production by these mechanisms tends to result in serum concentrations less than 5 mmol/L.

• Unfortunately, higher lactate levels don't necessarily rule out ethylene glycol. The glycolate metabolite causes a false-positive lactate elevation when measured by some analyzers, particularly with whole blood arterial blood gas analyzers. Specific models implicated include: ABL 625, Radiometer ABL 700, Beckman LX 20, Chiron 865, Bayer (formerly Chiron) 860, Rapidlab (Bayer) 865, Integra and to a lesser extent, Hitachi 911 analyzers, but not the Vitros 950 or Vitros 250.

• The degree of lactate elevation directly correlates with the concentration of glycolate present, and the artifact probably results from the lack of specificity of the lactate oxidase enzyme used in these machines.

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The American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults is now available. 

The update differs in several ways from the 2003 edition. Medications that are no longer available have been removed, and drugs introduced since 2003 have been added. Research on drugs included in earlier versions has been updated and new information is provided about appropriate prescribing of medications for an expanded list of common geriatric conditions. 

Here is an abbreviated list of medications/classes on the list that we may use in the ED. Use caution.

• Anticholinergics
• Nitrofurantoin
• Clonidine
• Antidysrhythmics
• Digoxin
• Antipsychotics
• Benzodiazepines
• Insulin
• Metoclopromide
• NSAIDs

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