UMEM Educational Pearls - By Bryan Hayes

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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In a potentially ground breaking study of healthcare-associated pneumonia (HCAP) patients, atypical pathogens were identified in 10% of cases!

Application to clinical practice: Add atypical coverage with a macrolide or respiratory fluoroquinolone for HCAP patients who have been in the community for any length of time.

The study also identified HCAP patients who may not require 3 'big gun' broad-spectrum antibiotics. This is a practice changing article for ED providers. For more analysis of the study, please note the bonus reading links below.

Bonus reading:

Dr. Emily Heil (@emilylheil) analyzes the full study in more depth at Academic Life in Emergency Medicine: http://academiclifeinem.com/new-treatment-strategy-not-so-sick-health-care-associated-pneumonia/

Dr. Ryan Radecki (@emlitofnote) critiques the study at Emergency Medicine Literature of Note: http://www.emlitofnote.com/2013/10/down-titrating-antibiotics-for-hcap.html

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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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A recent meta-analysis has called into question whether contrast-induced AKI even occurs after an IV dye load for radiologic imaging. [1] This conclusion is most certainly up for debate.

Irrespective of that conclusion, prevention of contrast-induced nephropathy is still important. Is there any benefit to using N-acetylcysteine over normal saline in the ED? Probably not according to a new study. [2]

• The primary outcome was contrast-induced nephropathy, defined as an increase in creatinine level of 25% or 0.5 mg/dL, measured 48 to 72 hours after CT.
• The authors found no reduction in contrast-induced nephropathy in patients who received NAC vs normal saline (about 7% in each group).
• The important finding is that the contrast-induced nephropathy rate in patients receiving less than 1 L IV fluids in the ED was 13% compared to 3% for more than 1 L.

Conclusions

1. Contrast-induced AKI does happen after emergency CT.
2. NAC does not provide additional benefit over saline alone.
3. Giving more than 1 L of normal saline markedly reduces the risk.

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Toxicologists should be aware of non-toxicological mimics of delirium, including anti-NMDA receptor encephalitis. It is an under-recognized progressive neurological disorder caused by antibodies against NMDA receptors.

Cases often present with altered mental status, autonomic instability, increased muscle tone, and movement disorders. It can easily be mistaken for neuroleptic malignant syndrome (NMS). A new case series describes two such patients for which toxicologists were consulted.

Must read links:

Dr. Leon Gussow provides a great review of the case series on his Poison Review blog.

Dr. Chris Nickson reviews the basics of the disease on the Life in the Fast Lane blog.

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Treatment of patients with HIV/AIDS can frequently mean consideration for, and need to treat cryptoccocal meningitis.

Since 1997, studies have demonstrated that high-dose Amphotericin B combined with flucytosine has improved outcomes compared to low dose treatment or monotherapy.

A recent 2013 study reiterated this approach, showing significant decrease in deaths at 70 days post-treatment and increased rates of yeast clearance with combination therapy of Amphotericin B plus flucytosine. 

Recommendation:

Antifungal treatment of cryptococcal meningitis should start with Amphotericin B at 0.7-1 mg/kg IV daily plus concurrent flucytosine 25 mg/kg orally q6 hours. Fluconazole can be substituted in place of flucytosine if it is not available or not tolerated.

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With several new diabetes medications available, it is important to know which ones are likely to cause hypoglycemia after overdose. Based on mechanism of action and reported cases, the likelihood of hypoglycemia after overdose is listed below by drug class.

Keep in mind that other drugs can interact with antidiabetics resulting in hypoglycemia. This table applies only to single agent ingestion/administration.

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Although there is a paucity of data to guide dosing of antimicrobials in the critically ill obese patient, we can draw some conclusions from existing kinetic studies. Assuming normal renal and hepatic function, here's what to do:

Penicillins: Use the high end of dosing range. For example, if the plan is to use piperacillin/tazobactam 3.375 gm IV every 6 hours for a complicated intra-abdominal infection, use 4.5 gm instead.

Cephalosporins: Use the high end of the dosing range.

Carbapenems: Use the high end of the dosing range.

Quinolones: Use the high end of the dosing range.

Aminoglycosides: Dose using adjusted body weight. ABW (kg) = IBW + 0.4 X (actual body weight - IBW)

Vancomycin: 15-20 mg/kg actual body weight every 8 to 12 hours. Adjust based on trough level.

When dosing most antibiotics in critically ill obese patients, use the high end of the dosing range (if not more).

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There is minimal evidence of cross-reactivity between sulfonamide antibiotics and non-antibiotics [1-4]. Despite this, the U.S. FDA-approved product information for many non-antibiotic sulfonamide drugs contains warnings concerning possible cross-reactions.

Key Findings from a New Review Article [5]:

• An estimated 3-6% of the general population is allergic to sulfonamides.
• Structurally, none of the non-antibiotic sulfonamides exhibit both of the features shown to be responsible for sulfonamide reactions (i.e., an N-containing ring attached to the N1 nitrogen of the sulfonamide group and an arylamine group at the N4 position).
• A comprehensive literature search (1966-December 2011) identified only 9 case reports indicating possible cross-reactivity to sulfonamide medications; however, in most cases, adequate patient testing was not conducted to firmly establish either sulfa allergy or sulfonamide cross-sensitivity.

Bottom line: You can feel safe prescribing furosemide, glyburide, and hydrochlorothiazide to your patient with an allergy to sulfamethoxazole/trimethoprim.

Other blog reference on this topic: http://lifeinthefastlane.com/2011/04/sulfa-drug-discombobulation/

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Naloxone can be administered via pretty much any route. One that has gained popularity in the past several years is nebulized naloxone. Although anecdotal reports tout the benefits of nebulized naloxone, what does the literature say?

• Case report of 46 y/o f with initial oxygen saturation of 61%. Naloxone was administered by nebulizer and within 5 min oxygen saturation was 100% and mental status was normal. [1]
• Retrospective analysis of prehospital adminstration in 105 patients. 22% had "complete response" and 59% had "partial response." Problem is the initial respiratory rate was 14 bpm with GCS of 12. [2]
• Prospective analysis of 26 patients in an inner-city, academic ED. Pre-naloxone respiratory rate was 13 with GCS of 11. Post-naloxone respiratory rate was 16 with GCS of 13. Three patients (12%) experienced moderate-to-severe agitation and 2 (8%) were diaphoretic. [3]

Bottom Line: Many of the studied patients may not have needed naloxone in the first place (initial respiratory rate 13-14), with a few developing withdrawal symptoms. Nebulized naloxone may have a role in the not-too-sick opioid overdose in whom you want to prove your diagnosis and wake the patient up enough to obtain a history. It is not a therapy for the apneic opioid overdose.

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A recent review identified 5 key points to consider when prescribing fluids.

1. Fluids should be prescribed as drugs, recognizing that any fluid can be harmful if dosed incorrectly.
2. The differences in efficacy between administering a 'crystalloid versus colloid' are modest; however, the cumulative differences in safety appear more significant.
3. The qualitative toxicity associated with hydroxyethyl starch (HES) and isotonic saline remains a concern.
4. The differences in chloride load and strong ion difference between cystalloid solutions, such as isotonic saline compared with physiologically more balanced solutions, appear to have clinical relevance.
5. The 'default' resuscitation fluid for acutely ill patients should likely be physiologically balanced crystalloid solutions (eg, PlasmaLyte or Ringer's lactate ).

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In June 2013 the American College of Medical Toxicology (ACMT) released a Guidance Document on the Management Priorities in Salicylate Toxicity. Here are some key highlights:

• Continuous IV infusion of sodium bicarbonate is indicated even in the presence of mild alkalemia from the early respiratory alkalosis.
• Euvolemia is important.
• If intubation is required, administration of sodium bicarbonate by IV bolus at the time of intubation in a sufficient quantity to maintain a blood pH of 7.45-7.5 over the next 30 minutes is a reasonable management option during this critical juncture.
• Once airway control has been established, it is imperative that the increased minute ventilation and low PCO2 usually seen with salicylate intoxication are maintained.
• A salicylate concentration approaching 100 mg/dL warrants consideration of hemodialysis in the acute toxicity setting (40 mg/dL for chronic toxicity). Consult nephrology well before these threshold levels.

The full document can be accessed here.

The Poison Review blog by Dr. Leon Gussow discusses the guidance document here.

Follow me on Twitter (@PharmERToxGuy) 

A recent, randomized study evaluated two approaches for treating acute pain in an inner-city ED.

• Group 1 received hydromorphone 2 mg. Group 2 received hydromorphone 1 mg (with the option of a second 1 mg dose 15 minutes later).
• 1 hour after the dose, patients were asked if they wanted more pain medication.
• Both groups had an equal proportion of patients decline more pain medication at one hour (67%). 61% of patients in the 1 + 1 group only needed the initial dose of hydromorphone!
• Secondary outcomes and safety measures were also similar between the groups.
• Patients with chronic pain, age >64, weight <150 pounds, or opioid use within last 7 days were excluded. 

Application to clinical practice: For most patients with acute, severe pain in the ED, start with hydromorphone 1 mg. It may be all the patient needs and can potentially avoid giving them extra opioid they don't need.

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In the treatment of acetaminophen poisoning with N-acetylcysteine (NAC), the PT/INR can be slightly elevated even in the absence of hepatotoxicity. Considering Prothombin Time (PT) is one of the criteria used to assess severity of liver damage in this setting, it is important to know how much the PT/INR can be affected by NAC and if it has an actual effect on coagulation factor levels.

1. N-acetylcysteine has been shown to slightly increase the PT) by up to 3.5 seconds in healthy volunteers.
2. A more recent study by the same authors demonstrated a reduction in vitamin K-dependent clotting factor activity (II, VI, IX, and X) after NAC administration in healthy volunteers.

Clinical Practice Pearls

• The elevation in PT/INR after NAC administration is real, not simply laboratory interference.
• However, the PT/INR elevation and decrease in coagulation factors is modest and not likely clinical signficant.
• Many poison center guidelines allow for an INR up to 2 to be considered 'normal' to account for this phenomenon in this setting.

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Background

In the current era of community-acquired MRSA (CA-MRSA), most of our outpatient treatment options for cellulitis aim to cover MRSA. Choices include sulfamethoxazole/trimethoprim (SMZ-TMP), doxycycline, linezolid, and clindamycin (depending on local susceptibility patterns).

A New Study

• In a double-blind, placebo-controlled trial 146 patients with cellulitis were randomized to receive cephalexin alone or cephalexin + SMZ-TMP for 7-14 days
• Lots of exclusion criteria basically narrowed the patient population to uncomplicated cellultits with no history of diabetes or other immunocompromising conditions
• Cure rates up to 30 days post-treatment were the same between the two groups (>80%)

Take Home Clinical Points

• Even in communities with high prevalence of MRSA, uncomplicated cellulitis cases without pus generally seem to be strep species.
• Therefore, make sure to include an anti-streptococcal component (such as cephalexin) to the MRSA agent (doxycycline or SMZ-TMP). Clindamycin has sufficient strep coverage by itself (but may not adequately cover MRSA).
• Given the potential for MRSA infections to deteriorate quickly and the inability to differentiate staph from strep without cultures, MRSA coverage should still be considered.

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Strychnine poisoning is still occasionally found in rat poisons and in adulterated street drugs and herbal products. The typical symptoms are involuntary, generalized muscular contractions resulting in neck, back, and limb pain. The contractions are easily triggered by trivial stimuli (such as turning on a light) and each episode usually lasts for 30 seconds to 2 minutes, for 12 to 24 hours. Classic signs include opisthotonus, facial trismus, and risus sardonicus.

Differential diagnosis includes:

• Tetanus: However, the onset of symptoms is more gradual and the duration much longer than in the case of strychnine poisoning.
• Generalized seizures: However, strychnine poisoning presents with a normal sensorium during the period of diffuse convulsions.
• Dystonic reaction: However, dystonic reactions are usually static, whereas strychnine poisoning results in dynamic muscular activity. 
• Serotonin syndrome
• Malignant hyperthermia
• Neuroleptic malignant syndrome
• Stimulant use

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Introduction

Fosphenytoin is a prodrug and is metabolized quickly to phenytoin after administration. The conversion of fosphenytoin to phenytoin involves the release of phosphate. In fact, each mmol of fosphenytoin releases 1 mmol of phosphate.

Clinical Question

Are patients at risk for hyperphosphatemia after fosphenytoin loading?

Data

There are only two cases of reported hyperphosphatemia.

• A 17-year old African-American male with end-stage renal disease developed acute hyperphosphatemia to 3.9 mmol/L (12.1 mg/dL) following the IV administration of 1000 mg of fosphenytoin for an idiopathic complex partial seizure
• An infant in status epilepticus had marked hyperphosphatemia 8.4 mmol/L (25.9 mg/dL) after a 5-10 fold dosing error.

Bottom Line

Despite the phosphate load from fosphenytoin administration, hyperphosphatemia is very rare and probably associated with renal insufficiency and dosing errors.

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A new recommendation in the 2013 Ischemic Stroke Guidelines provides guidance on what to do in patients taking new oral anticoagulants who are deemed eligible for IV fibrinolysis. Here is what the guidelines say:

• The most helpful lab tests are not widely available.
• A detailed history is important, but not always obtainable.

Until further data are available, a history consistent with recent use of new oral anticoagulants generally precludes use of IV tPA.

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In 2013, the American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists published a second update to their position statement on gastric lavage for GI decontamination (original 1997, 1st update 2004).

• Gastric lavage should not be performed routinely, if at all, for the treatment of poisoned patients.
• Further, the evidence supporting gastric lavage as a beneficial treatment even in special situations is weak.
• In the rare instances in which gastric lavage is indicated, it should only be performed by individuals with proper training and expertise.

Bottom line: Gastric lavage generally causes more harm than good. It should not be thought of as a viable GI decontamination method.

Bonus: Dr. Leon Gussow (@poisonreview) reviews the position paper on his blog, The Poison Review, here: http://www.thepoisonreview.com/2013/02/23/gastric-lavage-fuggedaboutit/

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The newest iteration of 'Guidelines for the Early Management of Patients with Acute Ischemic Stroke' was recently published. Here are the key revisions specific to blood pressure management:

• In patients with markedly elevated blood pressure who do not receive fibrinolysis, a reasonable goal is to lower blood pressure by 15% during the first 24 hours after onset of stroke. The level of blood pressure that would mandate such treatment is not known, but consensus exists that medications should be withheld unless the systolic blood pressure is >220 mmHg or the diastolic blood pressure is >120 mmHg (Class I; Level of Evidence C).
• No data are available to guide selection of medications for the lowering of blood pressure in the setting of acute ischemic stroke. Labetalol and/or nicardipine are listed as preferred, but other options can be used (Class IIa; Level of Evidence C).
• Restarting antihypertensive medications is reasonable after the first 24 hours for patients who have preexisting hypertension and are neurologically stable (Class IIa; Level of Evidence B).

If administering rtPA, blood pressure needs to be <185/110 mm Hg. That recommendation didn't change.

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