STEMI Meds TOT

Here is my attempt at a trick of the trade. This one is focused at the intubated STEMI patient in whom the EMS crew couldn’t get the 324mg of aspirin on board, and the cardiologist wants to load with clopidogrel 600mg as well as atorvastatin 80mg. Provided we can drop an OG tube before the patient gets sent to the cath-lab, this is how we get the meds into the patient:

Grab a Toomey Tip 60mL syringe, the meds, some water and something to crush the tablets (In our ED, commercial pill crushers disappear within a day, so we often use a blunt object located nearest t0 the pharmacy).

First, crush the tablets while still in the blister pack so fragments don’t go flying everywhere (easy to do with chewable aspirin, not so much with clopidogrel and atorvastatin).

Draw up about 25 mL of water into the syringe from the cup. While plugging the end of the Toomey tip with your thumb, remove the plunger of the syringe.

Dump the contents of the crushed tablet blister packs into the syringe through the opening created by the missing plunger.

Return the plunger into the syringe, and shake (Don’t take your thumb of the Toomey tip unless you want aspirin/Plavix/Lipitor shake all over the place).

Draw up some extra water (to a total of about 45-50mL).

If there are still some tablet fragments after administering, draw up an extra 25-30mL of water to flush.

Done and done.

Vancomycin Loading Dose In The ED

Vancomycin dosing in EDs has been on a journey from “a gram” for everyone towards a weight based dosing scheme.  This shift has been driven by a number of sources, but namely by the Infectious Disease Society of America, American Society of Health-System Pharmacists and Society of Infectious Disease Pharmacists' (IDSA/ASHP/SIDP) guideline recommendations for vancomycin therapeutic monitoring.¹

The change in dosing strategy is similar to other ID discussion nowadays; resistance and multidrug resistant pathogens are the impetus for pushing the envelope when it comes to antimicrobial dosing.  Usually this discussion involves gram-negative pathogens and their antimicrobial counterparts.  But, S. aureus, particularly MRSA (both community and hospital organisms) is becoming more resistant to vancomycin.  Resistant pathogens like hVISA and VRSA, although rare, are starting to pop up in the US.

In a collaboration of ID docs and ID pharmacists, these guidelines bring to light the importance of utilizing the pharmacokinetics of vancomycin to improve our dosing practices. Since the conventional dosing strategies (i.e., vancomycin 1g every 12 hours) were not developed to reach the target therapeutic troughs (15 – 20 mg/dL) more aggressive, weight based doses are recommended (IIIB). The recommended strategies to achieve target trough concentration consist of employing a loading dose (25 - 30 mg/kg) followed by a maintenance dose (15 – 20 mg/kg/dose divided every 8 to 12 hours).¹ These strategies make sense; with linear pharmacokinetics more drug equals higher concentration. Unfortunately, there is little prospective evidence to support the safety and efficacy of vancomycin loading doses, reflected by a IIIB recommendation. 

For us in the ED, identifying who should receive vancomycin loading doses can be challenging. Striking a balance between achieving a therapeutic trough and safety (particularly nephrotoxicity) is a constant experiment.  I think it is clear that the higher we push vancomycin dosing, the risk of nephrotoxicity increases.  Selecting the patients who are thought to have a benefit from higher dosing mirrors the population who is at highest risk of nephrotoxicity. Through retrospective data (again) independent risk factors associated with vancomycin nephrotoxicity include: total daily doses >4g, actual body weight >101.4kg, GFR <86.6mL/min and admission to an intensive care unit. ^2,3,4

We can however, limit the risk of toxicity by creating a threshold of the total daily dosing to < 4g and no more than 2g/dose, using adjusted body weight for obese patients to avoid overdosing and employing intensive therapeutic monitoring.  But what by way of efficacy are we sacrificing while adjusting for this risk?

While I hope to see prospective data on the efficacy and safety of these vancomycin-dosing strategies, I am not holding my breath.  Fortunately there are alternatives out there. Similar to the fosphyenytoin/phenytoin discussion vancomycin alternatives like linezolid, tigecycline, ceftaroline and daptomycin are expensive… for now.  Sure one agent alone cannot replace vancomycin, but using each in their own niches is certainly plausible. 

But for now, this is how I try to determine who is a candidate for vancomycin loading doses:

·       Age > 18 years

·       Creatinine clearance > 86.6 mL/min

·       Patients with suspected or proven infection caused by S. aureus

o   Bacteremia, endocarditis, osteomyelitis, meningitis, HCAP/HAP

·       With oneof the following:

o   WBC < 4,000 cells/mm3, or > 12,000 cells/mm3, or > 10% bands

o   Temperature < 97 °F, or > 100.4 °F

o   Heart rate > 90 bpm

o   Respiratory rate > 20 bpm or PaCO2 < 32 mmHg

1.     Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American society of health-system pharmacists, the infectious disease society of American, and the society of infectious disease pharmacists. CID 2009;49:325-7

2.     Hidayat LK, Hsu DI, Quist, et al. High-Dose Vancomycin Therapy for Methicillin-Resistant Staphylococcus aureus Infections: Efficacy and Toxicity. Arch Intern Med, 2006:166:2138-2144

3.     Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrobial agents and chemotherapy, 2008;52(4):1330-36

4.     Lodise TP, Patel N, Lomaestro GM, et al. Relationship between Initial Vancomycin Concentration-Time Profile and Nephrotoxicity among Hospitalized Patients. Clinical Infectious Diseases 2009;49:507-14

5.     Wang JT, Fang CT, Chen YC, Chang SC. Necessity of a loading dose when using vancomycin in critically ill patients. J Antimicrobe Chemother 2001; 47:246

Aminophylline and Bradyasystolic Cardiac Arrest

When it comes to drug therapy in cardiac arrest, we just can’t get it right.  Granted, the heterogeneity of the causes of cardiac arrest as well as patient population characteristics make it difficult to find a drug (or combination of drugs) that will improve survival.  But that doesn’t stop us from looking for one.  Take for instance, aminophylline. Yes, aminophylline.

The ethylenediamine salt of theophylline, aminophylline is thought to counteract the effects of adenosine on the heart (and lungs) by antagonizing the A1 receptor.  While various other mechanism of modulating inflammation exist, the PDE inhibiting effects of aminophylline leads to increases in cAMP and cGMP concentrations and has the potential to exert synergistic effects when given with beta-agonists though augmented cAMP concentrations. [1] These mechanisms provide bronchodilation during asthma exacerbations, and are thought to also produce favorable effects in bradyasystolic cardiac arrest.

Initial case reports and small trials suggested promising ROSC outcomes in patients who received aminophylline after other efforts in CPR failed. [2, 3, 4] These initial findings and theoretical benefits in cardiac arrest were put to the test in a large trail (N=971) in Canada [5]. In this study, patients who suffered an out-of-hospital cardiac arrest with asystole or pulseless electrical activity and who were unresponsive to initial treatment with epinephrine and atropine were randomized to blinded aminophylline or placebo. Aminophylline was administered as a 250mg IV bolus, which could be repeated after 90s for a total dose of 500mg (94% of patients received 500mg). Aminophylline did not improve any outcomes including ROSC or survival to hospital discharge.

Aside from other methodological limitations with this study, the use of aminophylline requires more attention.  When one considers aminophylline essentially as theophylline, nightmares of pharmacokinetics should swiftly come back to haunt the mind. The pharmacokinetics of theophylline varies widely between patients and cannot be predicted by age, body weight, sex or virtually any other characteristic. Dosing aminophylline at 500mg (typical dose used for asthma is 6mg/kg) will likely achieve a concentration of about 15 mcg/mL – the upper limit of the therapeutic window (5-15mcg/mL).  Not forgetting the complex kinetics (again), this concentration could be much higher, or much lower. Above the therapeutic window, seizures can occur though central A1 antagonism. Below the therapeutic window, the beneficial effects on the heart and lungs may not occur. The balancing of these effects and the drug interactions causing both decreased clearance and increased clearance make it difficult to dose safely and a less than ideal agent to use as a one-dose-fits-all strategy.

It seems that the search continues for a drug that will join the ranks of good quality early chest compressions and defibrillation.  Let’s move on and remember aminophylline as one of the many the cautionary tales of pharmacokinetics.

1. Barnes PJ. Chapter 36. Pulmonary Pharmacology. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com.libproxy2.umdnj.edu/content.aspx?aID=16671685. Accessed November 17, 2012.


2. Mader TJ, Gibson P. Adenosine receptor antagonism inrefractory asystolic cardiac arrest: results of a human pilot study. Resuscitation1997;35:3–7

3. Mader TJ, Smithline HA, Gibson P. Aminophylline in undifferentiated out-of-hospital asystolic cardiac arrest. Resuscitation 1999;41:39–45.

4. Mader TJ, Sminthline HA, Durkin L, et al. A randomized controlled trial of intravenous aminophylline for atropine-resistant out-of-hospital asystolic cardiac arrest. Acad Emerg Med 2003;10:192–7.


5. Abu-Laban RB, McIntyre CM, Christenson JM, et al. Aminophylline in bradyasystolic cardiac arrest: a randomised placebo-controlled trial. Lancet 2006;367:1577–84.

Pharmacy Consult: Nitroglycerin Paste to IV Conversion

While I’m not a huge fan of nitroglycerin paste, I understand it’s clinical usefulness. The ability of slapping on an inch of paste to relieve chest discomfort is certainly non-invasive and can achieve effective results.  With this simplicity, a degree of randomness exists with regard to the ability to titrate the dose.  If the desired clinical effect is not achieved, how much more can we apply safely? Conversely, if hypotension results, how long will the effects last after the paste is wiped off?

Though more invasive, IV nitroglycerin provides greater control and titratablility and one study suggests a dose conversion between the dosage forms. (Am J Crit Care. 1998 Mar;7(2):123-30)

The conversion from IV to PASTE is relatively straightforward. Apply the appropriate amount of PASTE, and then stop the infusion of nitroglycerin 30 minutes later. (see table below for conversions)

Converting from PASTE to IV is a little more difficult (and has not been studied).  After removal of the nitropaste, the duration of effect of nitroglycerin is anywhere from 2 hours to 12 hours. So titration to IV will be more difficult and require close attention. It would therefore make more sense to target the lower end of the conversion range. For example, if 1 inch was applied and the conversion range is 10-39 mcg/min, the IV rate should be started at 10 mcg/min about 1 hour after the paste is removed and subsequently titrated.

Of course if the decision to convert to IV was because the paste is not achieving the desired effect, the infusion could be started earlier, but still targeting the lower dose range.

PASTE	IV
0.5"	5 mcg/min
1.0"	10 – 39 mcg/min
1.5"	40 – 59 mcg/min
2.0"	60 – 100 mcg/min

Pharmacy Consult: Extended Zosyn Infusion in the ED

Extended infusion beta-lactam antibiotic administration is a growing trend in US hospitals. This dosing strategy takes advantage of the pharmacodynamics properties of drugs like Zosyn (piperacillin/tazobactam), improving time over the MIC (T>MIC) to susceptible bacteria while providing cost savings. Based on computer Monte-Carlo simulations, dosing Zosyn 3.375g IV q8 infused over 4 hours, the same probability of achieving a therapeutic T>MIC is reached as dosing Zosyn 3.375g IV q6 infused over 30 minutes.  It’s a good strategy that can be beneficial to both patients and the pharmacy budget, in certain situations.[1] That is, if the infecting pathogen is not pseudomonas. [2,3]

In most hospitals in the US, the breakpoint for susceptibility of pseudomonas to Zosyn is and MIC of 64 mg/L. In other words, the pseudomonas isolate will be reported as “S” if the MIC is less than or equal to 64 mg/L. So when the MIC to zosyn is between 32 and 64 mg/L, which would still be reported as “S,” the probability of achieving a therapeutic T>MIC is less than 40%. The closer you get to 64, the chances of having a therapeutic concentration of Zosyn are essentially zero, whether an extended infusion is used or not.

Lodise TP, et al. Clinical Infectious Diseases 2007; 44:357-63

So what can be done for critically ill septic patients that may be infected with pseudomonas isolates? If there is a chance the suspected pathogen is pseudomonas for the sick septic patient in the ED, Zosyn could be considered for use as an empric antibiotic when given as a standard intermittent infusion over 30 min at a dose of 4.5g.  If the septic patient is bound for the ICU, and Zosyn is to be continued, utilizing a higher dosing strategy like 4.5g IV q6 infused over 3 hours may offer a theoretically higher chance of achieving therapeutic levels.  Although the data for the addition of an aminoglycoside (amikacin or tobramycin) as “double coverage” isn’t favorable I would still recommend it as a logical alternative in the critically ill.[4] Cefepime is one of the few alternative agents with better susceptibilities that could be used empirically to cover pseudomonas.  As always, check your hospitals antibiogram to see which agents may be considered appropriate (ceftazidime, aztreonam, levofloxacin/ciprofloxacin).

1. Lodise TP, et al. Clinical Infectious Diseases 2007; 44:357-63

2. Tam VH, et al. Clinical Infectious Diseases 2008; 46:862-7

3. Mah GT, et al. Ann Pharmacother 2012;46:265-75

4. Johnaon SJ, et al. Am J Health-Syst Pharm. 2011; 68:119-24