UMEM Educational Pearls - Pharmacology & Therapeutics

In a prospective cohort of 598 ED patients, 5 risk factors were independently associated with uncomplicated cellulitis patients who fail initial antibiotic therapy as outpatients and require a change of antibiotics or admission to hospital: 

1. Fever (temperature > 38°C) at triage (OR = 4.3, 95% CI = 1.6 to 11.7)
2. Chronic leg ulcers (OR = 2.5, 95% CI = 1.1 to 5.2)
3. Chronic edema or lymphedema (OR = 2.5, 95% CI = 1.5 to 4.2)
4. Prior cellulitis in the same area (OR = 2.1, 95% CI = 1.3 to 3.5)
5. Cellulitis at a wound site (OR = 1.9, 95% CI = 1.2 to 3.0)

Patients presenting with uncomplicated cellulitis and any of these risk factors may need to be considered for observation +/- IV antibiotics.

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Four small case series (one prospective, 3 retrospective) have concluded that dexmedetomidine (Precedex) may be a useful adjunct therapy to benzodiazepines for ethanol withdrawal in the ED or ICU. They are summarized on the Academic Life in EM blog.

A new randomized, double-blind trial evaluated 24 ICU patients with severe ethanol withdrawal.

Group 1: Lorazepam + placebo

Group 2: Lorazepam + dexmedetomidine (doses of 0.4 mcg/kg/hr and 1.2 mcg/kg/hr).

• 24-hour lorazepam requirements were reduced from 56 mg to 8 mg in the dexmedetomidine group (p=0.037).
• 7-day cumulative lorazepam requirements were similar.
• Clinical Institute Withdrawal Assessment or Riker sedation-agitation scale scores were similar within 24 hours.
• Bradycardia occurred more frequently in the dexmedetomidine group.

Take Home Points

1. Dexmedetomidine reduced short-term benzodiazepine requirements, but not long-term when using symptom-triggered approach.
2. Monitor for bradycardia when using dexmedetomidine.

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Acetaminophen spent much of 2013 being chased by paparazzi and sharing magazine covers with Miley Cyrus. What a fall from stardom after becoming known as the pain reliever “hospitals use most,” and the one, “recommended by pediatricians.” Slogans we know well based on $100 million/year spent on advertising.

Approximately 150 patients a year die from unintentional acetaminophen poisoning averaged over the past 10 years. From 2001 to 2010, annual acetaminophen-related deaths amounted to about twice the number attributed to all other over-the-counter pain relievers combined, 

The FDA sets the maximum recommended daily dose of acetaminophen at 4 grams, or eight extra strength acetaminophen tablets.

Ingestion of 150 mg/kg or approximately 10g for a 70 mg individual reaches the toxic threshold for a single ingestion. The toxic threshold decreases in cases of chronic ingestion.

Patients who “unintentionally” overdose have been found to take just over 8g per day (almost double the recommended maximum).  This is unlikely due to taking one extra 325mg tablet once or twice.

Before we all go on a mad NSAID prescribing binge, let's all be aware of the dangers, educate our patients and allow Acetaminophen to walk the red carpet again.

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A new study of almost 2 million prescriptions in VA patients compared the risk of cardiovascular death or dysrhythmia in patients receiving azithromcyin, levofloxacin, and amoxicillin.

What they found

Compared with amoxicillin, azithromycin was associated with a significant increase in mortality (HR = 1.48; 95% CI, 1.05-2.09) and dysrhythmia risk (HR = 1.77; 95% CI, 1.20-2.62) on days 1 to 5, but not 6 to 10.

Levofloxacin was associated with an increased risk throughout the 10-day period. Days 1-5 mortality (HR = 2.49, 95% CI, 1.7-3.64) and serious cardiac dysrhythmia (HR = 2.43, 95% CI, 1.56-3.79). Days 6-10 mortality (HR = 1.95, 95% CI, 1.32-2.88) and dysrhythmia (HR = 1.75; 95% CI, 1.09-2.82).

Important limitations

This study did not have a comparator group of patients getting no antibiotics. Previous data suggest patients on any antibiotic (eg, penicillin) have a higher risk of death or dysrhythmia.

The supplemental index shows that patients receiving azithromycin and levofloxacin had more serious infections (eg, PNA, COPD, etc.) which may have put them at higher risk for worse outcome irrespective of antibiotic choice.

What it means

It seems azithromycin and levofloxacin may contribute to a small increase in cardiovascular mortality and dysrhythmia during their use. A previous study found this is more likely in those with existing cardiovascular disease.

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• Naloxone has technically always been able to be prescribed by physicians to individual patients.
   
• New laws however, make it acceptable for prescribers in many states to prescribe naloxone to “third parties,” e.g parents, friends, etc. of patients, with the assumption that the overdosed patient will not be capable of administering the antidote to themselves.

• Many states are offering short 10-20 minute training sessions on how bystanders can administer the reversal agent to the patient who has overdosed.

• If prescribed, it should be prescribed to the individual who completed the training, not the intended patient, and may be written for intranasal or intramuscular administration.

• Intranasal (IN) is “off label” and an approved intranasal preparation is not commercially available, but the intramuscular preparation can be prescribed along with an atomizer device. The usual IN dose is 1 mg per nostril which may be repeated in 3-5 minutes.

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Aseptic meningitis is meningitis with negative bacterial cultures. Overall, viral infections are the most common etiology, however medications can also cause this illness.

Well known causes of aseptic meningitis include: antimicrobials (particularly sulfamethoxazole/trimethoprim), NSAIDS, antivirals (valacyclovir), and antiepileptics.

Recently an abstract was published that suggests that patients on levetiracetam have a higher risk of developing aseptic meningitis than those on topiramate and gabapentin. Lamotrigine has also been implicated, but appears to have a lower risk than levetiracetam, topiramate and gabapentin.

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Background

The ACLS recommendation for epinephrine dosing in most cardiac arrest cases is 1 mg every 3-5 minutes. This dosing interval is largely based on expert opinion.

Primary Outcome

A new study reviewed 21,000 in-hospital cardiac arrest (IHCA) cases from the Get With the Guidelines-Resuscitation registry. The authors sought to examine the association between epinephrine dosing period and survival to hospital discharge in adults with an IHCA.

Methods

• For 6 to <7 min/dose, adjusted OR, 1.41 (95%CI: 1.12, 1.78)
• For 7 to <8 min/dose, adjusted OR, 1.30 (95%CI: 1.02, 1.65)
• For 8 to <9 min/dose, adjusted OR, 1.79 (95%CI: 1.38, 2.32)
• For 9 to<10 min/dose, adjusted OR, 2.17 (95%CI: 1.62, 2.92)

This pattern was consistent for both shockable and non-shockable cardiac arrest rhythms.

• This study only included in-hospital cardiac arrests.
• The data was retrospectively reviewed from a registry of prospectively collected data.
• This is certainly an interesting finding that needs to be explored further.
• Given that epinephrine in cardiac arrest has never been proven to work (and may cause harm), it's not too suprising that giving less of a potentially harmful drug portends better outcomes.

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Tranexamic Acid (TXA) topically applied was compared to anterior nasal packing in 216 patients with acute anterior epistaxis. Cotton pledgets (15 cm) soaked in injectable TXA (500 mg/5 ml) were inserted into the bleeding nostril and removed after bleeding had arrested. This was compared to standard anterior packing.

RESULTS

Bottom line: topical tranexamic acid looks promising for control of uncomplicated anterior epistaxis.

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In most situations (dependant on state laws and institutional policies), methadone-maintained patients enrolled in a drug abuse program are best managed by continuing methadone at the usual maintenance levels with once-a-day oral administration.

Pearl: In the event the methadone clinic is closed and/or the dose cannot be verified, 30-40 mg (10-20 mg IM) is generally enough to prevent withdrawal in most patients.

This is only a short-term measure and some patients may require additional methadone. Full doses of methadone should be reinstituted as soon as possible.

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46 patients treated with high-dose droperidol (10-40 mg) were studied prospectively with continuous holter recording.

What they did

Patients initially received 10 mg droperidol as part of a standardized sedation protocol (for aggression). An additional 10 mg dose was given after 15 min if required and further doses at the clinical toxicologist's discretion.

Continuous 12-lead holter recordings were obtained for 2-24 hours. QTc > 500 msec was defined as abnormal (with heart rate correction - QTcF).

What they found

Only 4 patients had abnormal QT measurements, three given 10 mg and one 20 mg. All 4 had other reasons for QT prolongation. No patient given > 30 mg had a prolonged QT. There were no dysrhythmias.

What it means

There was little evidence supporting droperidol being the cause and QT prolongation was more likely due to pre-existing conditions or other drugs.

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Tranexamic acid (TXA) is an antifibrinolytic that prevents clot breakdown by inhibiting plasminogen activation and plasmin activity

The CRASH-2 trial enrolled 20,211 adult trauma patients with significant hemorrhage (SBP <90 or HR 110) or at significant risk of hemorrhage

Patients were randomized to 1 gram TXA over 10 minutes followed by an infusion of 1 gm over 8 hours vs placebo

There was a significant reduction in the relative risk off all cause mortality of 9% (14.5% vs 16%, RR 0.91, CI 0.85-0.97, p = 0.0035)

The patients that benefited most were those most severely injured, and in those treated in less than 3 hours of injury.

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JNC8 (the Eigth Joint National Commission) released their recommendations for blood pressure management this week. The full article as published in JAMA can be found at http://jama.jamanetwork.com/article.aspx?articleid=1791497

Highlights from this report are

• Older adults do not need to be placed on antihypertensive medications unless their SBP > 150 or DBP > 90. 
• Younger patients should still be started if their SBP > 140 or DBP > 90.
• Firstline drug treatment recommendations are:
  • Non-black patients: start with thiazide diuretics, calcium channel blockers, angiotension converting enzyme (ACE) inhibitors, or angiotension-receptor blockers (ARBs).
  • For black patients start with thiazide diuretics or calcium channel blockers.
  • Patients with chronic kidney disease should be on an ACE or ARB.

General Pearl:  Remember to be cautious in acutely lowering the blood pressure in asymptomatic patients.  Acute lowerings can cause watershed ischemia leading to strokes.
 

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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It has linear, predictable pharmacokinetics, achieves maximal concentration within 1-2 hours, is 50% renally excreted, and has a half life is 9-11 hours.

Edoxaban was evaluated in a recent trial comparing warfarin in patients with atrial fibrillation.

The primary end point or first stroke or systemic pulmonary embolic event occurred in 1.5% with warfarin, compared with 1.18% in the high dose edoxaban (HR 0.79; 97.5% CI 0.63-0.99, P<0.001). In the intention to treat there were trends favoring high dose edoxaban and unfavorable trends with the lower dose.

The principal safety end point of major bleeding occurred in 3.43% with warfarin versus 2.75% with high dose edoxaban (HR 0.86; 95% CI 0.71-0.91, P<0.001). 

Bottom line: Both high dose (60 mg) and low dose (30 mg) edoxaban were non-inferior to warfarin with prevention of stroke or systemic emboli, and were associated with significantly lower rates of bleeding and death from cardiovascular causes.

Currently it is approved for use in Japan.

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When patients with severe allergies to penicillin (urticarial, bronchospasm, anaphylaxis, angioedema) are excluded, the cross reactivity to cephalosporins is very low (approximately 0.1%)

The reaction is related to structures in the side chain, not the cyclical structure as thought in the past.

There are several cephalosporins with IDENTICAL side chains that should not be given to patients with allergies to specific penicillins, namely:

• Penicillin:   do not give cefoxitin
• Ampicillin:   do not give cefaclor or cephalexin
• Amoxicillin: do not give cefadroxil or cefprozil

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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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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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ACLS recommendation for procainamide in tachycardic rhythms is:

Loading dose 20 mg/minute (up to 50 mg/minute for more urgent situations) until:

• Arrhythmia is controlled
• Hypotension occurs
• QRS complex widens by 50% of its original width
• or total of 17 mg/kg is given

Maintenance infusion is 1 to 4 mg/min.

An easier method for dosing acute onset atrial fibrillation in stable patients was used in the Ottawa Aggressive Protocol, in which they administered 1 gm over 60 min, which was interrupted if BP < 100 mmHg; if corrected by a 250 ml IV bolus, the infusion was resumed. This was not used, however if the patient was to be admitted.

A strategy for treating stable monomorphic VT with procainamide used:

100 mg IV over 1-2 minutes, repeat as necessary until an endpoint of

• Termination of tachycardia
• Drug induced hemodynamic deterioration
• Completion of 800 mg maximal dose

If no slowing of the tachycardia occurred with a dose of 400 mg, the administration was ceased.

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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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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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