Saturday, August 30, 2014

EMPOWER Episode 4 - Rapid Oral Loading of Antiepileptic Drugs (AEDs) in the Emergency Department

Listen to the podcast by clicking on the link below (link on iTunes available here): 

EMPOWER Episode 4 - Rapid Oral Loading of Antiepileptic Drugs (AEDs) in the Emergency Department

Show Notes:
  • Core content from this episode discussed in:
    • DiPiro's Pharmacotherapy, 9th Edition, Chapter 40
    • Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th Edition, Chapter 21
    • Selection portions of Winter's Basic Clinical Pharmacokinetics, 3rd Edition

Friday, August 29, 2014

A Line CAST Too Far: An Evaluation of the Contraindications of Class Ic Antiarrhythmics

Flecainide and propafenone are the only Class Ic antiarrhythmic drugs (AADs) available in the United States. These agents block the fast sodium channels within cardiomyocytes, thereby decreasing the rate of rise and magnitude of the action potential. This causes a slowing of conduction velocity, without increasing the effective refractory period. While these agents are particularly useful for atrial fibrillation (AF) and atrial flutter, utilization remains low because their contraindications exclude many patients who would otherwise be candidates for therapy. In particular, the Class Ic AADs are contraindicated in patients with structural heart disease, and those with previous myocardial infarction. The latter is often extrapolated to include any degree of coronary artery disease (CAD). As a result, these agents are commonly reserved for patients with lone AF.

So why is this such a bummer? The reasons are primarily two-fold. Despite the modest effects achieved with antiarrhythmics as a class, the Class Ic AADs achieve some of the highest rates of successful cardioversion and subsequent maintenance of sinus rhythm (1). Second, the Class Ic agents do not exhibit some of the dose-limiting toxicities associated with other common antiarrhythmics, making them an invaluable addition to our armamentarium for rhythm control. In particular, while QT prolongation is a major concern with other AADs, the Class Ic agents do not significantly prolong the QT interval (2). While their contraindications are no mystery to those familiar with antiarrhythmic therapy, perhaps they should be. A deeper dive into the history behind these established contraindications may cause the astute clinician to be a bit skeptical.

Where did these contraindications originate from? It seems that they have been somewhat broadly extrapolated from the initial Cardiac Arrhythmia Suppression Trial (CAST I) (3). This trial sought to evaluate the safety and long-term outcomes of flecainide and encainide for suppression of premature ventricular contractions (PVCs) in patients with a recent myocardial infarction (MI). The investigators hypothesized that suppressing these PVCs would improve long-term survival after MI. Ultimately the study was terminated early because of a 2.6-fold increased risk of arrhythmic death when compared to placebo. Before delving further, it is important to note, that this trial had nothing to do with rhythm control for supraventricular arrhythmias – an indication for which the Class Ic AADs would be most sought for today.

So what type of patient population was studied? Indeed, this is a tough question to answer from reading just the final publication, since little demographic information is available. Upon further digging, it becomes clear that the overall population studied resembles only a tiny fraction of those lumped into the vague designations of “structural heart disease” or “coronary artery disease”. Specifically, rigorous inclusion criteria were enforced for entry into the CAST trial; those suffering an MI had to have subsequent PVCs and/or non-sustained ventricular tachycardia completely suppressed during open-label titration with one of the study drugs. Not surprisingly, only 60% of total patients screened met inclusion criteria for randomization (4). Thus, patients who met eligibility criteria likely represent a minority of all patients suffering an MI. Further, while the inclusion criteria stipulated maximum thresholds for ejection fraction, the average ejection fraction of all patients in the study was much lower, at just above 30% (5). Clearly, the CAST trial enrolled a much more specific population than those who might be excluded from these agents today.

Issues regarding concurrent drug therapy also question the applicability of the study to contemporary practice, as less than 30% of these patients were taking beta blockers, despite what is now a class IA recommendation for beta blockers in this population (6). In fact, about 40% of patients in the study received nondihydropyridine calcium channel blockers (diltiazem or verapamil) (3); a class IIIB negative recommendation for these agents in heart failure with reduced ejection fraction (6). Indeed, a considerable number of deaths in the study were attributed to cardiogenic shock and asystole, causing one to wonder whether the study drugs were solely to blame.

Moreover, virtually no information is provided regarding the distribution of baseline demographics among the study arms (i.e. time from MI to study enrollment, concurrent medications, ejection fraction), causing a whole host of concerns about potential confounders skewing outcome results. Finally, where is the literature supporting harm with propafenone in these patients? Propafenone seems to be guilty by association.

While the aforementioned contraindications for flecainide and propefanone are often applied universally for all indications, it is interesting to note that their own FDA-approved labels are rather circumspect with regard to this, stating, “The applicability of the CAST results to other populations…is uncertain” (7, 8). Thus, while their use for supraventricular arrhythmias is still shunned in the presence of structural heart disease, world literature reveals a mere 0.4% incidence of proarrhythmic effects when used for paroxysmal atrial fibrillation (7).

Let’s apply the potential ramifications here to a hypothetical 75-year-old male, whose atrial fibrillation has been well-maintained on propafenone for the past two decades. At a recent appointment, complaints of moderate, persistent chest pain lead to angiography, upon which a severe stenosis of the LAD was found. Although a stent was placed, he never actually infarcted, and his ejection fraction remains normal. On medical rounds, the patient is diagnosed with CAD, and the astute resident picks up on the apparent contraindication. The patient is switched to dronedarone and discharged. Two weeks later, the patient presents to the ED, and is now poorly controlled and symptomatic. In addition to failing therapy, an ECG reveals a prolonged QT interval greater than 50% from baseline. In this situation, after evaluating the risks of alternate therapy as compared to continued propafenone, it becomes clear that justifying such broadly extrapolated contraindications may lead to unnecessary risks. Herein applies the old adage, “If it ain’t broke, don’t fix it”.

Current contraindications to the Class Ic AADs have been over-extrapolated from the CAST study to encompass other patient populations and treatment indications that were not evaluated in the trial. This may result in the unnecessary exclusion of patients who may otherwise benefit from these drugs. Critically defining the studied population, and knowing the literature behind the label is crucial in helping the risk-averse clinician determine the most appropriate therapy.

  1. Naccarelli G, Wolbrette D, Khan M, et al. Old and new antiarrhythmic drugs for converting and maintaining sinus rhythm in atrial fibrillation: comparative efficacy and results of trails. Am J Cardiol 2003; 91[Suppl]:15D-26D.
  2. Hume JR, Grant AO. Chapter 14. Agents Used in Cardiac Arrhythmias. In: Katzung BG, Masters SB, Trevor AJ. eds. Basic & Clinical Pharmacology, 12e. New York, NY: McGraw-Hill; 2012. Accessed August 13, 2014.
  3. Echt D, Liebson P, Mitchell B, et al. Mortality and morbidity in patients receiving encainide, flecainide or placebo. The Cardiac Arrhythmia Suppression Trial (CAST). NEJM 1991; 324:781-788.
  4. Capone R, Pawitan Y, El-Sherif N, et al. Events in the cardiac arrhythmia suppression trial: baseline predictors of mortality in placebo treated patients. JACC 1991; 18: 1434-1438.
  5. Epstein A, Bigger T, Wyse G, et al. Events in the cardiac arrhythmia suppression trial:  mortality in the entire population enrolled. JACC 1991; 18:14-19.
  6. Yancy CW, Jessup M, Bozkurt B et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62:1495-1539.
  7. Flecainide (Tambocor) [package insert]. Northridge, CA: 3M Pharmaceuticals; 2006. 
  8. Propafenone (Rythmol) [package insert]. Rockford, IL: UDL Laboratories; 2010.

Adam Spaulding, PharmD, BCPS (@PharmERAtom)
Emergency Medicine Pharmacist
The Waterbury Hospital
Waterbury, Connecticut

Editorial note:
Many of the points discussed by the author related to the inclusion criteria and baseline demographics of patients enrolled in CAST were addressed by experts in the field of cardiac electrophysiology in an editorial published in a subspecialty journal of Circulation. This is another instance where dogmas related to pharmacotherapy get passed on to generations of clinicians and are taken for granted as part of the learning experience without many questions raised, and more often than not, can have a true impact on clinical practice when applied to direct patient care. One scenario where the dogma related to the contraindications of the class Ic antiarrhythmics can have an influence in our practice in the emergency department is the "pill-in-the-pocket" approach for managing patients with paroxysmal atrial fibrillation, where both flecainide and propafenone may be commonly used as single doses due to their rapid onset of action and overall tolerability relative to other antiarrhythmic agents. This can lead to some dire consequences in our patients, especially if we institute therapies that are considered to be both less efficacious and potentially more harmful. A true examination of why we do things the way that we do in emergency medicine based on commonly accepted facts (or misconceptions, in this case) may lead us to debunk more and more myths as time progresses, and can ultimately not only change practice but also prevent perpetuation of these dogmas to future clinicians being taught in the didactic setting. As the saying goes, "Half of everything that we know is wrong; we just don't know which half." I'd like to add to that statement: "...until we really investigate the facts."

--Nadia Awad, Pharm.D., BCPS (@Nadia_EMPharmD)

Wednesday, August 20, 2014

Suspension Or Solution In The Setting Of Ruptured TMs

Topical antibiotic therapy for ear infections isn’t something you’re going to see as an earth shaking presentation at a good conference, or in a heated debate between the Swami and anyone who dare challenge him. It’s not even something that you would think is driven by dogma and anecdote rather than evidence.  Rarely is it even a thought that is questioned upon reviewing an order or writing a prescription. Generally, the whole subject is held in a state of apathy.  But you, my friends, (cue the pyrotechnics) would be foolish to think anything in emergency medicine is anything but filled with dissent, dogma and more questions than answers.

Acute otitis externa, we’re talking about AOE, an infection and inflammation of the external auditory canal. For which, topical antibiotic therapy is generally recommended.[1] It’s recommended that initial therapy include topical antibiotics that cover Pseudomonas aeruginosa, Staphylococcal spp., S. pneumonia, H. Influenzae, and M. catarrhalis. Luckily, most available ototopical antibiotics cover these pathogens.   But determining which agent is best; we must turn to the evidence.  The Cochrane folks conducted a systematic review of 18 trials (approx. 3300 pts) on this very subject.[2] While the data was tremendously heterogeneous, the authors concluded that there is no difference in the clinical outcome with an antiseptic (such as acetic acid) versus an antibacterial (such as an aminoglycoside) or with a steroid plus an antimicrobial versus an antimicrobial alone. However, there was suggested to be a benefit with an antimicrobial plus a steroid over a steroid alone. Steroids on their own do seem to reduce the duration of pain and itching (small rct of 51 patients using betamethasone).  But again, no benefit of any one antibiotic over another.

See enough earaches and eventually someone will say they can’t view the tympanic membrane so they want a suspension not a solution.  In an attempt to qualifying that request, they voice their concern that a solution will lead to higher risk of inner ear penetration and thus, ototoxicity.  This, of course, is base upon years and years of data.

According to Rosen’s – there is no mention that in the setting of presumed or confirmed TM rupture a solution is superior to a suspension (or vice versa).[3]  Tintinalli’s, however, does: “Acetic acid suspension should be used and not a solution; theoretically, this has less chance of middle ear penetration.”[4] While acetic acid was once used as an ototopical antiseptic, it is better used now for jellyfish stings or French fries. 

The guidelines for AOE recommend that in the setting of known or suspected TM perforation, including tympanostomy tube, the clinician should prescribe a non-ototoxic topical preparation.1  Solution or suspension? Does it even matter?

Let’s back up. To understand what formulation is best, we have to understand the mechanism of ototoxicity in this setting. The concern with ototoxic topical drugs I that if there is a ruptured TM, they may penetrate the inner ear structures and exert their damaging effects.  The ototoxic drugs that we’re concerned of are the aminoglycosides that are thought to be vestibulotoxic (gentamicin) or cochelotoxic (amikacin, neomycin and tobramycin), or both, acetic acid altering PH and affecting cochlear function and ploymixin B with an unknown mechanism.[5,6]

But to penetrate the inner ear and exert their toxicities, these drugs must pass through the round window membrane. RWM allows molecules < 1000 KDA to pass through. Lo, behold all aminoglycosides are below this size. Furthermore, all aminoglycoside otic products are solutions; they are only suspensions if the are co-formulated with a steroid. But, reviewing the basic chemistry concepts of a solution vs suspension: it’s the steroid that is in suspension – the AG is still in solution, is still the same size and theoretically still carries the same risk of ototoxicity.  Fortunately however, the incidence of ototoxicity from topical AG is relatively rare – 1994 study in Canada 1 in 10,000 have hearing loss after being exposed to topical AGs.[5,6]

So if neomycin/polymixin b/hydrocortisone is a suspension but contains two ototoxic drugs, is it still ototoxic? Probably.

Via process of elimination, and some knowledge of medication ADRs, fluoroquinolones (FQ) are the only remaining ototopical antibiotics that cover the spectrum of AOE but are not ototoxic.  They are unfortunately expensive… Unless you use ophthalmic FQs in the ear. Yup, you can do that. And they’re cheaper. On average, an otic Rx for ofloxacin 0.3% / 10mL is going to run about $119.00 USD, cash. Compared to ofloxacin 0.3% / 10mL ophthalmic is about $65.00 USD, cash. 

There is some limited data to support this change of routes. Further, all data uses AG products (which we’re avoiding here). But we may be able to make some assumptions to FQs. A RCT out of UC Davis in the late 1980’s randomized patients undergoing tympanostomy tube placement (majority of whom had persistent AOM with effusion) to topical OPHTHALMIC gentamicin to be used optically or no treatment.[7] Fourteen days post-op there were 9 (19.6%) patients with purulent otorrhea from one or both ears vs zero (0%) in the gentamicin ophthalmic group.  Then in 1991, a case series of 3 patients who received tobramycin ophthalmic drops for otic use all had clinical cure within 2 weeks with no evidence of ototoxicity.[8]

Pharmaceutically, the difference between ophthalmic products and otic products is that ophthalmic products are 1) sterile, and 2) buffered to a neutral pH. Otherwise, they are identical to their otic cousins.  

Ultimately, it depends on cost to the patient and presence of ruptured TM. If they may have trouble affording a $150 script for something that is likely self-limiting or a Rx that is about half the cost – but may mystify the pharmacist in the community. 

  1. Rosenfeld RM, Schwartz SR, Cannon CR, et al. Clinical Practice Guideline: Acute Otitis Externa. Otolaryngology – Head and Neck Surgery 2014; 150(2): 161-168
  2. Kaushik V, Malik T, Saeed SR. Interventions for acute otitis externa. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD004740
  3. Pfaff JA, Moore GP. Chapter 72 – Otolaryngology. In: Marx: Rosen's Emergency Medicine - Concepts and Clinical Practice, 8th ed. Philadelphia, PA. Saunders, An Imprint of Elsevier; 2010
  4. Silverberg M, Lucchesi M. Chapter 237. Common Disorders of the External, Middle, and Inner Ear. In: Tintinalli JE, Stapczynski J, Ma O, Cline DM, Cydulka RK, Meckler GD, T. eds. Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 7e. New York, NY: McGraw-Hill; 2011. Accessed August 20, 2014.
  5. Roland PS, Stewart MG, Hannley M, et al. Consensus panel on the role of potentially ototoxic antibiotics for topical middle ear use: introduction, methodology and recommendations. Otolaryngol Head Neck Surg 2004;130(Suppl 3):S51–6.
  6. Haynes DS, et al. Ototoxicity of ototopical drops: An update. Otolaryngol Clin N Am, 2007; 40: 669-683
  7. Baker S, Chole RA. A randomized clinical trial of topical gentamicin after typmanostomy tube placement. Arch Otolaryngol Head Neck Surg, 1988; 114:755-757
  8. Hoffman RA, Goldofsky E. Topical ophthalmologics in otology. Ear, nose & throat journal, 1991; 70(4):201-205

Thursday, August 14, 2014

EM PharmD Journal Club 8/13/2014

For those of you who participated in the EM PharmD JC, thank you!

Here is the video of the Google Hangout. If you have any questions or comments for the JC or to add to the discussion, please feel free to write in the comments in the Google+ feed of the event page or Twitter using the #EMPharmD hashtag. 

The citations for the articles again were:

Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet. 2009 Jul 25;374(9686):293-300. PMID: 19573904

Cohen L et al. The Effect of Ketamine on Intracranial and Cerebral Perfusion Pressure and Health Outcomes: A Systematic Review. Ann Emerg Med. 2014 Jul 16 [Epub ahead of print]. PMID: 25064742

Tuesday, August 12, 2014

EM PharmD JC Update

Please join us tomorrow (Wednesday, August 13th) at 2:00 PM EST for the EMPharmD JC.  We will be discussing the following articles:

Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet. 2009 Jul 25;374(9686):293-300. PMID: 19573904


Cohen L et al. The Effect of Ketamine on Intracranial and Cerebral Perfusion Pressure and Health Outcomes: A Systematic Review. Ann Emerg Med. 2014 Jul 16 [Epub ahead of print]. PMID: 25064742

Here is the link to the hangout.

If you're unable to tune in, don't worry! The session will be recorded (hopefully) and posted to this blog.

If you have any questions during the JC or to add to the discussion, please feel free to write in the comments in the Google+ feed of the event page or Twitter using the #EMPharmD hashtag. 

Thursday, August 7, 2014

Managing Overcorrection of Hyponatremia with DDAVP

So you have a patient who presents to your emergency department after being brought in by EMS with a three-day history of nausea and vomiting. The patient has had what he describes as a “pretty rough weekend” and admits to have consumed large quantities of alcoholic beverages. While you are examining the patient, the patient has two episodes of tonic-clonic seizures, both episodes subsiding with administration of benzodiazepines. Labs are collected, and the complete metabolic panel reveals a serum sodium concentration of 117 mEq/L. As the clinician, you are very diligent in correcting this patient’s acute episode of symptomatic hyponatremia and you perform the necessary calculations to determine the infusion rate for correcting the serum sodium with your fluid of choice (or you may even decide to go ahead and simply administer a 100 mL bolus of 3% sodium chloride).  The patient is not experiencing any further neurological deficits, but the patient is admitted for further monitoring and is on a relatively strict fluid restriction. Labs are drawn a couple of hours later, and results of the complete metabolic panel now reveal a serum sodium concentration of 131 mEq/L.

A few choice expletives are flying through your head now. What in the world happened? Here you are, with the best of intentions in correcting the sodium, but for some reason, you overshot and swung the sodium pendulum a bit too aggressively. For the time being, the patient is neurologically intact, but you are fearful that the patient may be at great risk of osmotic demyelination syndrome. So what are you going to do now?

There are some treatment options that you can initiate at this point, but bear in mind that they should be performed in conjunction with a nephrology consult. The nephrologist may recommend initiation of desmopressin (DDAVP).  DDAVP is a synthetic analog of vasopressin that binds to the V2 receptors within the collecting ducts of the kidneys to prevent the production of dilute urine and essentially increase water reabsorption. The mantra of “sodium follows water” applies here, and in doing so, the rate of correction of the serum sodium can become a bit more predictable and stable. With one exception (1), much of the evidence surrounding the use of DDAVP for treating the overcorrection of serum sodium in the setting of hyponatremia stems from research by Stern and colleagues (2, 3, 4).

With this, you may ask the question of whether we should be preemptively administering DDAVP in conjunction with our fluid of choice in managing hyponatremia to prevent overcorrection of serum sodium. In a study published in the American Journal of Kidney Disease (5), this very question was posed and a retrospective review of 25 patients was undertaken to determine the rate of sodium correction and related outcomes following concomitant administration of both hypertonic saline and DDAVP in patients who presented with hyponatremia. The administration of both agents was aimed to maintain the increase in serum sodium concentrations by no more than 6 mEq/L in a 24-hour period. At 24 and 48 hours, the rate of increase in serum sodium concentrations was 5.8 ± 2.8mEq/L and 4.5 ± 2.2mEq/L, respectively. In addition, at the 24 and 48-hour time points, serum sodium concentrations did not increase by more than 12 mEq/L and 18 mEq/L, respectively, and none of the patients experienced any complications associated with this treatment strategy. The investigators do state that though this treatment strategy is seemingly successful, it may not be appropriate to utilize in all patients, and evaluation of the underlying cause of they hyponatremia is necessary to determine whether the patient may be able to tolerate this regimen.

In terms of dosing and administration of DDAVP, it generally ranges anywhere from 1 to 2 mcg intravenously or subcutaneously administered every 6 to 8 hours until you are comfortable with the level of correction in the serum sodium. Some folks may also advocate for concomitant administration of a weight-based fluid bolus of 5% dextrose in water (a dose of 6 mL/kg) infused over one to two hours, and this may help reduce the sodium concentration by 2 mEq/L. Again, much caution is advised when this technique is employed and nephrology should be on board to help guide the course of treatment.

Going back to our patient above, prompt recognition of the overcorrection in serum sodium leads you to consult nephrology, and both DDAVP and 5% dextrose in water are administered intermittently at 8-hour intervals over a 24-hour period. Serum sodium concentrations hover in the 133 to 137 mEq/L range during that time period. Sodium concentrations over the next couple of days stabilize back to normal, and with no further complications experienced during the course of the hospital stay, the patient is able to be safely discharged three days later.

Done and done.

  1. Tomlin SC, Williams R, Riley S. Preventing overcorrection of hyponatraemia with desmopressin. BMJ Case Rep 2011 Nov 8 (doi: 10.1136/bcr.07.2011.4512).
  2. Perianayagam A, Sterns RH, Silver SM, et al. DDAVP is effective in preventing and reversing inadvertent overcorrection of hyponatremia. Clin J Am Soc Nephrol 2008; 3:331-336.
  3. Mohmand HK, Issa D, Ahmad Z, Cappuccio JD, Kouides RW, Sterns RH. Hypertonic saline for hyponatremia: risk of inadvertent overcorrection. Clin J Am Soc Nephrol 2007; 2:1110-1117.
  4. Sterns RH, Hix JK, Silver S. Treating profound hyponatremia: a strategy for controlled correction. Am J Kidney Dis 2010; 56:774-779.
  5. Sood L, Sterns RH, Hix JK, Silver SM, Chen L. Hypertonic saline and desmopressin: a simple strategy for safe correction of severe hyponatremia. Am J Kidney Dis 2013; 61:571-578.

Wednesday, August 6, 2014

EM PharmD Journal Club

One week from today on Wednesday, August 13th at 2 PM EST I will be hosting the first EM PharmD Journal club via Google Hangout.

The current Rutgers EM Pharmacy PGY-2 residents will be presenting two articles.

Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet. 2009 Jul 25;374(9686):293-300 PMID: 19573904


Cohen L et al. The Effect of Ketamine on Intracranial and Cerebral Perfusion Pressure and Health Outcomes: A Systematic Review. Ann Emerg Med. 2014 Jul 16 [Epub ahead of print]. PMID: 25064742

Please join us for a discussion surrounding the impact (or lack there of) for these articles on practice.

More details regarding the Google Hangout to follow shortly.

Hope to see you in a week!