Wednesday, December 30, 2015

A Leap of Faith: My Clinical Sabbatical in Pediatric Pharmacy

When we reach the end of any year, it is generally a time for personal reflection. We reflect on major milestones that we have achieved, which includes moments that have defined us as well as moments that may have temporarily broken us, but we managed to pick ourselves up and keep running. During these times, we set out to accomplish any list of goals for the coming year, knowing in the back of our minds that there may be challenges that may face along the way.

For me, this year was certainly an interesting one, full of a few unexpected twists and turns in a professional capacity, and I have definitely learned and grown as an individual and as a pharmacist in more ways than one.

One of the ways in which this year will remain a memorable one for me is that for nearly three-quarters of it, I did not practice as an emergency medicine pharmacist.

This is not meant to be some sort of big revelation. If anyone had asked me at any point during the year, I would have provided the honest truth about the nature of my clinical practice; and I did when I was posed that very question throughout the year.

Towards the very beginning of 2015, I came to the realization that I simply needed to be challenged again. It was not that I disliked my joint gig of practicing as an emergency medicine pharmacist and clinical assistant professor; if anything, I appreciated most of what it had to offer. But I grew restless, and I was itching to do something new – and in a sense, something that required me to exercise my brain a bit. I also feared that I was becoming too comfortable with what I knew and applied in practice in the emergency department, and I felt that there was more for me to learn.

Granted, I realized that at that point, I was still relatively fresh out of residency training (just shy two years at the time) and some readers may believe that this should have been the time where I made the most of it, especially having a career in academia. I did everything by the book (and then some), and I was on the fast track to the inevitable in the climb toward the top of the beckoning ivory tower. And I knew that I was not confusing this with burnout; the timing was just not consistent, and if anything, it was the complete opposite; I was enthused to strengthen my clinical practice.

It was a difficult decision for me to make, but I knew I had to trust my gut feeling and take the next steps.

And so I did. An opportunity opened up at the institution where I completed my two years of post-graduate training – but it was in pediatric pharmacy. Pediatrics was not a completely foreign specialty to me; I trained in pediatrics for nearly two months as a PGY-1 pharmacy resident (one required rotation, and one elective rotation), and I had a positive experience on these rotations. In fact, I determined that pediatrics came in as a strong second after my first love in emergency medicine. However, I did come to terms with the fact that this would be a completely different experience, given that I would be the pharmacist (not trainee) covering the pediatric hospital, which consists of a multitude of units, including general pediatrics, pediatric intensive care, and neonatal intensive care.

One of the reasons that I chose pediatrics was that I wanted to gain some more practical hands-on experience in being part of the multidisciplinary team taking care of sick pediatric patients. From my previous experiences in emergency medicine, whenever we received word that we had a pediatric patient who would be coming to us requiring resuscitation, the room would swell with about two to three times more clinicians relative to an adult resuscitation, the chaos is outstanding (to say the least), and as the pharmacist in the room, there is a certain degree of comfort that is highly desired with dosing medications for these patients, as most are weight-based. One has to be at ease in recognizing concentrations of medications and safe methods for dilution, let alone identifying the rationale for said therapies, and with everything else that is happening simultaneously, it can be quite a harrying experience. I knew that if I ever had the opportunity to practice in emergency medicine again, I wanted to make sure that I knew exactly what to do and what to anticipate when a sick pediatric patient came in through the doors of the emergency department.

When I started my new position, it was quite a steep learning curve. I treated my experience as a second specialty residency, where I was my own program director, learning everything from the basics to the advanced level of clinical practice within the specialty of pediatrics. The pharmacists who trained me in pediatrics were stellar, and when it was time for me to practice solo, I also took it upon myself to read as much as I could on my own time anything that I could get my hands on related to pediatric pharmacotherapy. This is where my experiences in self-directed learning, including my engagement in #FOAMed, really came in quite handy, as I had already been doing so for a number of years. This was especially true at times when I managed a patient with a disease state that was uncommon where we instituted pharmacotherapies based on evidence that may not have been completely black and white. Of course, I was drawn to topics related to pediatric emergency medicine and critical care, and I thrived when I took care of those patients, and better yet, during those times when I was summoned to the emergency department for assistance in taking care of acutely ill pediatric patients.

During my practice in pediatric pharmacy, I noted that there were many similarities to my own experiences from the emergency department, and many of the skills and clinical acumen that I developed within emergency medicine could be applied to pediatrics. For instance, I was accustomed to taking care of patients of a wide range of disease states of varying acuities in the emergency department, and this was something that I encountered on a daily basis within pediatrics. There were weeks where my patients ranged in age and weight from 23 weeks, 300 g (yes, 300 g) to 18 years, 120 kg. In addition, as the emergency department can be a highly stressful environment with patient volume and acuity, my evenings in pediatrics were that same way at times, especially when caring for patients in the pediatric intensive care unit. However, my pharmacy technicians often told me that even if it was that way, I never lost my 'cool' (substituted for another four-letter word that starts with ‘s’ and ends with ‘t’), which helped some during some of those challenging evenings. Again, this was a skill that I gained after practicing in the emergency department that made its way into my practice in pediatric pharmacy.

At times, it was strange to gain a handle on the fact that much of how we care for patients in the emergency department can set the tone of how patients are managed in the inpatient unit. But it really is the case, and communication is key, especially in this vulnerable population of patients. My colleagues in the emergency department and pediatrics and my attending physicians and nurses in the pediatric intensive care unit would often provide me with a heads up related to a patient who would be reaching us at some point during the evening. Regardless of how ill and complicated the patient may have been, those evenings for me went along quite smoothly, especially when information was communicated in a timely and appropriate manner.

One thing that I never fully appreciated about pediatrics until I practiced in the specialty is that these patients are very resilient. There were times that I honestly thought that some of the patients that I was managing in the intensive care units would not make it; yet somehow, not only would they make it through the next day, but they would also turn around and improve significantly to the point of being transferred to the general pediatric floor or better yet, discharged home. Not to say that it was all peachy, as I did have patients who did not make it. Those experiences were the hardest for me to face emotionally, especially when we exhausted all of our resources in attempts to resuscitate these patients; witnessing the team having to break the news to caregivers and other family members and their reactions was extremely difficult.

My experience in pediatric pharmacy was invaluable, and I am grateful that I had the opportunity to practice in the specialty. However, even as I was fully engaged and truly enjoyed my time in pediatric pharmacy, I knew that in my heart of hearts, I belonged in emergency medicine. While I was gaining and absorbing all the information and knowledge that I could related to pediatric pharmacy as it directly affected the care of my patients on a day-to-day basis, I was simultaneously still ensuring that I was keeping up to date with the latest literature in emergency medicine. I was hopeful that I would practice emergency medicine again at some point in the future. And so when an unexpected series of musical chairs took place in the emergency department at my institution and a position for an emergency medicine pharmacist became available, I knew that I could not not pursue it. I took the plunge, and threw my name in the ring, formally applied, interviewed, waited for a bit for the decision, and was offered the position a short time later, which I heartily accepted (I will admit that I cried tears of joy when I learned the news).

I started back in the emergency department a couple of short weeks ago, and even just in this time alone, I can truly say that I have achieved my goal of being able to anticipate the needs of sick pediatric patients in our emergency department in addition to our adult patients. In some ways, it seems odd to me that transitioning back to the emergency department after not practicing for some time feels like riding a bicycle, but perhaps this is because I made an effort to continue to learn and grow as a practitioner.

My ten-month clinical sabbatical of sorts in pediatric pharmacy, though risky, was one of the best decisions that I have made for my career, and I am glad that I did it. Although I may not have been too far along in my own career, being a formal learner again was a fulfilling and worthwhile experience. Do I recommend it? It certainly may not be for everyone, but depending on the timing and circumstances, it may be an experience worth pursuing mid-career as a means of gaining a new skill set and knowledge base in a different specialty. As a result of this entire experience, I appreciate my chosen specialty of emergency medicine more so than ever, and I have a renewed sense of purpose and drive in my clinical practice as an emergency medicine pharmacist, knowing now that there are ways that I can be more mindful of pediatrics within emergency medicine.

I am happy that I am practicing again in the emergency department. As to what the future holds, time will tell. I am taking it one day at a time, making sure that I thoroughly enjoy every bit of it along the way.

Wednesday, December 23, 2015

Top 10 Posts of 2015

2015 was such a great year at EMPharmD with so many new authors proividing amazing content.

I encourage any readers who have a great idea for a blog topic or want to write a post yourself to submit it to myself or Nadia for review. As you can see below, some of the best content is from guest authors!

Here are the top 10 posts from this past year.

Three Reasons Not to Prescribe Tramadol
Matthew DeLaney, MD, FACEP, FAAEM (@MDeLaneyMD)
Assistant Professor of Emergency Medicine
Assistant Medical Director
University of Alabama at Birmingham

Steroids and Strep Throat
Meghan E. Groth, Pharm.D., BCPS (@EMpharmgirl)
Emergency Medicine Pharmacy Clinician
The University of Vermont Medical Center
Nadia Awad, Pharm.D., BCPS (@Nadia_EMPharmD)
Emergency Medicine Pharmacist
Robert Wood Johnson University Hospital
New Brunswick, New Jersey

Emily Richards, PharmD (@EmilyPharmD)
Pharmacy Practice Resident (PGY1)
Banner - University Medical Center Phoenix
Phoenix, Arizona
Mark Culver, PharmD, BCPS (@EMdruggist)
Emergency Medicine Pharmacist
Banner - University Medical Center Phoenix
Phoenix, Arizona

Use Pantoprazole Intermittently and Cancel the Infusion for Upper GI Bleed
Mark Culver, PharmD, BCPS (@EMdruggist)
Emergency Medicine Pharmacist
Banner - University Medical Center Phoenix
Phoenix, Arizona
Craig Cocchio, Pharm.D., BCPS (@iEMPharmD)
Clinical Pharmacist, Emergency Medicine
Trinity Mother Frances Hospital
Tyler, Texas

Kyle DeWitt, Pharm.D., BCPS (@EmergPharm)

Emergency Medicine Pharmacy Clinician
The University of Vermont Medical Center
Craig Cocchio, Pharm.D., BCPS (@iEMPharmD)
Clinical Pharmacist, Emergency Medicine
Trinity Mother Frances Hospital
Tyler, Texas
Maria Cardinale, PharmD, BCPS
Clinical Pharmacy Specialist, Critical Care
Clinical Assistant Professor, Rutgers, The State University of New Jersey

Inspiring Change Through Social Media: Our Moral Responsibility in 140 Characters or Less
Nadia Awad, Pharm.D., BCPS (@Nadia_EMPharmD)
Emergency Medicine Pharmacist
Robert Wood Johnson University Hospital
New Brunswick, New Jersey

Wednesday, December 16, 2015

Sugammadex, revisited

Sugammadex (I call it Suggs) is a selective muscle relaxant-binding agent. As a result of its chemical structure, modified cyclodextrin compound with a hydrophilic outer surface and a lipophilic central cavity, sugammadex encapsulates both rocuronium and vecuronium.  This encapsulation creates a concentration gradient by which rocuronium or vecuronium leaves the neuromuscular junction for the plasma and then subsequently bound by sugammadex (think DigiFab).  The result is a dramatically shortened duration of effect of rocuronium or vecuronium.  At a typical surgical reversal dose of 4 mg/kg the median time to reach train of four ratio of 0.9 is 2.4 minutes after rocuronium or 3.4 minutes for vecuronium compared to 49 minutes using neostigmine. 

In the emergency department, the use of a drug like this would open up the possibility of freely using rocuronium for paralysis after induction of anesthesia for intubation, putting succinylcholine out to pasture. But it’s not that simple. The Gas Exchange blog said it best: “If sugammadex is the answer what is the question?”

In this awesome post, Dr. Jolley describes several different reasonable situations where suggs could be used. The two I think best apply to emergency medicine are pre-planned reversal of rocuronium (patients with neuromuscular disorders; and patients with severe pulmonary disease with limited reserve) and unplanned rocuronium reversal (unexpected difficult airway / can’t intubate, can’t ventilate situations).  The latter, I would imagine, would be the hot topic surrounding its use in the ED given the potential to put succinylcholine out to pasture.

Real world practice is going to be different compared to the controlled setting of an investigational study in an OR. A study of elective surgical adult patients who required induction and paralysis were randomized to rocuronium+suggs or succinylcholine alone to compare the time from start of administration of rocuronium or succinylcholine to recovery of T1 to 10% of the baseline value. Suggs was administered to the rocuronium group 3 minutes after the start of the rocuronium bolus. In this OR setting, rocuronium+suggs compared to succinylcholine alone recovery from paralysis (T1 10%, and T1 90%) was significantly faster with rocuronium+suggs.  This difference was 2.7 (mean rocuronium+suggs 4.4 min vs succinylcholine 7.1 min) minutes faster to T1 10%.  But (as pointed out in the Gas Exchange blog as well) this is a controlled setting. If there is a situation where rocuronium needs to be reversed, that decision is made when the prevailing issue is discovered. In other words, not before a RSI attempt. Therefore, once a complication is discovered, suggs ordered, mixed (5-8 vials or so for a 16 mg/kg dose) and administered, that difference of 2.7 minutes is gone and succinylcholine would have worn off on its own. The better question is what is that situation where rocuronium must be emergently reversed in a critical airway patient setting? I am no expert in airway management, I am simply the pharmacist at the bedside, however if a patient needs to be intubated / needs an airway, if you revers the rocuronium paralysis… they STILL need an airway. Supraglottic airways or cric procedures may benefit from lingering paralysis.

So where does sugammadex fit into clinical practice? In critical airway management, perhaps the role is not as great as once thought.

There is more to the argument, of course. 1) While the above study used train of four analysis for a marker of neuromuscular function recovery, patient oriented outcomes (shorter vent time, LOS, mortality) have not been studied. Another expensive drug with nothing but surrogate markers to go on. 2) Cost. Probably a lot. Probably not worth it. 3) Patients with GFR < 30. The drug may accumulate since it is cleared by the kidneys. This could mean an attempt at re-paralysis with roc/vec would not be effective or reduced efficacy. The RESUS ME blog pointed out a published case where this occurred. 4) Allergic reactions. Reported in the literature and the possible culprit for the FDA reluctance to approve.

The problem is the same as with Praxbind or Kcentra. It is hard to justify not having it on hand. The case where it might help a patient is probably a rare one, but it would be a nice drug to have on hand for those n=1 situations.

Controlling widespread use will be a challenge. I’m certain OR staff will request it with the same argument as IV acetaminophen – it will shorten PACU times, and get patients out faster. Just like with IV APAP, that argument hasn’t been supported, and the cost has been a significant issue.

The story of suggs continues to unfold.

I would love to hear the experience from our colleagues from the rest of the world where this has been available.

Monday, December 7, 2015

EM PharmD at ASHP Midyear 2015

We want to meet you!

I'd love to hear from any readers or followers at Midyear. Or just stop by to say hi.

On Tuesday I will be at the PM residency showcase at the Trinity Mother Frances Hospital PGY 1 booth (6221).

Later that day, blog contributor Adam Spaulding and myself will be speaking about the evolution of the indications for ketamine in the emergency department at 4:15 in room 293.

Wednesday come check out the EM pearls seen hosted by Nadia Awad and feasting pearls by awesome EM pharmacist from all over.

That is if you behave and not consume too many hurricanes.

Wednesday, November 25, 2015

4 & 4 Por Favor: Prophylactic Ondansetron + Intravenous Opiate - Is It Necessary?

Ondansetron is the most documented medication given in emergency departments throughout the United States.1 We have all heard someone ask, “Can I get an order for 4 and 4 for this patient?” in reference to 4 milligram (mg) of intravenous (IV) morphine and 4 mg of IV ondansetron. It has become common practice in many institutions to provide a prophylactic antiemetic prior to administering an IV opiate. All opiates carry a FDA warning that nausea may occur, 2 so why not administer an antiemetic to prevent it? Opiates cause nausea and vomiting due to its interaction on the chemoreceptor trigger zone (CTZ), increased vestibular sensitivity, and hindered gastric emptying.3 The logic is to provide these patients with a 5-HT3 antagonist (i.e. ondansetron) to inhibit the opiate from exerting emetogenic properties on 5-HT3 receptors in the CTZ and prevent nausea and/or vomiting.
Of note, ondansetron is not FDA approved for the treatment or prophylaxis of acute nausea and/or vomiting (N/V) outside of chemotherapy, radiation, and postoperative use.

But how common is nausea and vomiting associated with IV opiates? Multiple studies illustrate that morphine-induced N/V is low, ranging from 2.0 – 20.2% in emergency department (ED) patients.4-9 When discussing with nurses in the ED, N/V is anecdotally associated with how quickly the IV opiate is administered and generally occurs within 5 minutes of administration. So we should give IV ondansetron to prevent this, right? A common misconception with IV ondansetron is its onset of action. In fact, it can take anywhere between 27-34 minutes before there is a 50% decrease in nausea severity following the administration of ondansetron.10,11 This begs the question, does it really make sense to provide prophylactic antiemetics with IV opiates?

We review the literature below:
Bradshaw et al.5
RCT- double blinded
Performed in United Kingdom

IV Morphine + placebo (n = 136)
IV Morphine + metoclopramide 10 mg (n = 123)
N/V between the two groups was not statistically significant (p = 0.3).
Overall incidence of N/V was low in both treatment groups (3.7% in placebo and 1.6% metoclopramide)
Determined pre-treating patients with metoclopramide was not necessary. 
Overall N/V associated with IV morphine was very low and recommended using antiemetics for patients who develop N/V
Bhowmik et al. 8
RCT- double blinded
Performed in India

IV Morphine + placebo (n = 53)
IV Morphine + promethazine (n = 54)
IV Morphine + ramosetron     (n = 54)
IV Morphine + metoclopramide (n=54)
Overall incidence of N/V was low in all treatment groups (9.4% ramosetron, 18.5% metoclopramide, 10.2% in promethazine and 6.2% in placebo)
Rate of N/V was not statistically significant between any of the groups.
Incidence of N/V in patients was low in all treatment groups. Trial concluded that patients should receive antiemetic therapy only if experience N/V and not as a prophylactic agent with IV opiates.  
Per results patients that received placebo + morphine had less N/V compared to other treatment groups; however, NOT statistically significant. 
Sussan et al 9
Randomized Double masked multicenter trial
Performed in 9 countries
Investigated 2574 patients that received IV opiates and randomized 520 patients that developed N/V associated with IV opiates.
Group 1: placebo               (n = 94)
Group 2: ondansetron 8 mg (n = 214)
Group 3: ondansetron 16mg (n = 211)
Resolution of N/V was statistically more significant (p < 0.001) when comparing ondansetron therapy with placebo.                                                                     
Group 1:  45.7% N/V resolved
Group 2:  62.3% N/V resolved
Group 3:  68.7% N/V resolved

Concluded the best practice would be to treat patients’ N/V after development in patients that receive IV opiates.
Trial determined the prevalence of N/V is minimal and exposing patients to medication they do not need puts them at risk for additional adverse drug reactions. 

Each trial concluded that there was no statistical significance in outcomes when adding prophylactic antiemetics with IV opiates. After these institutions analyzed their findings, the investigators at their respective institutions made it common practice for patients to only receive antiemetics after a patient developed nausea or vomiting. So why is ondansetron still commonly used to pre-treat patients that receive IV opiates in the ED? The current available literature examines metoclopramide, promethazine, and ramosetron (5-HT3 antagonist), but literature related to prophylactic ondansetron is lacking. Even the literature to support the use of ondansetron for N/V in the emergency department could be challenged. Two randomized, placebo-controlled studies comparing ondansetron, metoclopramide, and saline in emergency department patients complaining of nausea showed no clinically important difference in the reduction of nausea between treatments and placebo.12,13  Yet in the ED, we still order ondansetron more than any other medication.
Currently, the prophylactic use of IV ondansetron with IV opiates is unproven. Previous literature has shown us that prophylactic antiemetic therapy with IV opiates is unnecessary, increases costs, and adds potential for adverse drug reactions. Our institution is currently undergoing a prospective study designed to determine the prophylactic utility of ondansetron with IV opiates in the ED. Perhaps, in the near future, there will be evidence to either cease the use of prophylactic IV ondansetron or evidence that validates its use.
Emily Richards, PharmD (@EmilyPharmD)
Pharmacy Practice Resident (PGY1)
Banner - University Medical Center Phoenix
Phoenix, Arizona

Mark Culver, PharmD, BCPS (@EMdruggist)
Emergency Medicine Pharmacist
Banner - University Medical Center Phoenix
Phoenix, Arizona

Peer reviewed by Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)
1.National Hospital Ambulatory Medical Care Survey: 2011 Emergency Department Summary. Available at Accessed 22 Nov 2015.
2. Red Book: pharmacy’s fundamental reference. Montvale, NJ: Thompson Healthcare Inc.; 2010
3. Smith H, Smith J, Seidner P. Opioid-induced nausea and vomiting. Annals of Palliative Medicine 2012;1(2):121-129
4. Paoloni R, Talbot-Stern J. Low incidence of nausea and vomiting with intravenous opiate analgesia in the ED. Amr J Emer Med 2002;20:604-608
5. Bradshaw M, A Sen. Use of prophylactic antiemetic with morphine in acute pain: randomized controlled trial. Emerg med J 2006; 23:210-212
6. Talbot-Stern J, Paoloni R. Prophylactic metoclopramide is unnecessary with intravenous analgesia in the ED. Amr J Emr Med 2000;18(6):653-7
7. Lambie B, Chambers J, Herbison P. The role of prophylactic anti-emetic therapy in emergency department patients receiving intravenous morphine for musculoskeletal trauma. Emer Med 1990; 
8. Bhowmik A, Dasgupta I, Barua S, et al. Evaluation of the need of prophylactic antiemetic with injection morphine in treating acute musculoskeletal pain in the Indian population. IJAR 2014;2:53-58
9. Sussan G, Shurman J, Creed M, et al. Intravenous ondansetron for the control of opioid-induced nausea and vomiting. Clinical Therapeutic. 1999; 21:1216-1227
10. Cotton J, Rowell L, Hood R, et al. A comparative analysis of isopropyl alcohol and ondansetron in the treatment of postoperative nausea and vomiting from the hospital setting to the home. AANA J. 2007; 75(1):21-6
11. Winston A, Rinehart R, Riley G, et al. Comparison of inhaled isopropyl alcohol and intravenous ondansetron for treatment of postoperative nausea. AANA J. 2003; 71(2):127-32

Saturday, November 21, 2015

The Dark Arts of Pharmacokinetics

It’s ok to give 1 gram of vancomycin. As long as they’re obese and the dosing interval is adjusted to follow the two compartment distribution model of vancomycin.
Single, double or triple? In terms of vancomycin dosing kinetics, it’s an important question.  Pharmacokinetic teachings tell us to select the simplest model and fewest compartments necessary to describe the data adequately. Thus the single compartment model is frequently used in initial dosing of vancomycin.  For the most part, vancomycin dosing teachings include solving patient cases using one compartment pk formulas such as the Sawchuck-Zaske.1

However, this simple view ignores the need of vancomycin to distribute into tissue where the infection exists (ie, skin, lung, bone, CNS, etc.).  It has been established that vancomycin demonstrates a two phased distribution; alpha, lasting about 30min to 1hour after the end of an infusion, and beta, the terminal elimination half-life. Simplified single compartment models don’t fully (or at all) take this into account. Never the less, we get away with the assumption of adequate distribution in most situations involving dosing vancomycin, but in models with altered volumes of distribution or clearance such as in obesity (> 30% above IBW) this model falls apart where troughs cannot be predicted accurately.
A two compartment model acknowledges the distribution of vancomycin from plasma into tissues.

This method, while being much more mathematically complex, can be simplified into the weight based dosing models with loading doses and some nomograms (modified Matzke).2 But we also encounter limitations with these models as well.  Loading doses, particularly in obese patients where following dosing recommendations lead to compromises in either adjusting the dose to 2g or less, or accepting the increased risk of nephrotoxicity.3  As a result success rates for achieving desired troughs in obese patients float around 39-42%.4,5
Troughs as a surrogate for AUC 0-24/MIC is a debate for another post, but in the real world the practice is to follow trough.6-8

Given this high rate of failure in such a prolific drug, I’m surprised that this paper has flown so far under the radar. Dr. Tina Denetclaw out of the UCSF School of Pharmacy recently published a protocol of divided loading doses in obese patients that achieved a target trough in 97% of patients at 24 hours.9
Population: This was a prospective analysis of the divided vancomycin loading protocol in consecutive patients weighing > 137% IBW (mean weight: 111 + 31 kg) and admitted to a single community hospital (Marin General Hospital). Patients were excluded if they had long-term paralysis, pregnant, receiving some other vancomycin protocol or had monitoring errors.

Comparison: No real control. Troughs were compared to historical patients who received a protocol by Reynolds et al.
Intervention: Divided load protocol was dependent on the IBW, % over IBW and CrCl. Most patients received 1g IV q6 x 4 doses unless they were a) very tall or b) low CrCl.

Outcome: Percent of patients within target trough range within 12 to 24 hours of dosing initiation.
Within 12 hours: 
  • Trough 10-20, n = 48 (89%); mean 14.5 + 3.2
  • Trough > 10, n = 51 (94%); including the above 48 patients, with the other 3 (6%) having troughs > 20 (20.5 – 22.5)
Within 24 hours: 31 patients had troughs drawn at 24 hours.  19 patients had dosing interval changes that moved the trough draw beyond 24 hours (unclear why, i.e. change in protocol, poor follow up, clinical event (AKI), etc.)
  • Trough 10-20, n = 30/32 (97%); mean 15.0 + 3.1

Authors’ conclusion:
“The biphasic, divided-load obese protocol described here achieved vancomycin trough concentrations in the range of 10-20 within the first 12 hours of treatment for 89% of patients weighing up to 245.2kg, and 97% of trough concentrations sampled during maintenance dosing for the patients were within target range.”

Of course this study has limitations:
No clinical outcomes or patient oriented outcomes.
Small sample, although met its predefined power at 12 hours.

Single center, essentially observational methods and no comparison also limit this study. It may very well be that the expertise of the clinical pharmacist is the reason this result was observed and it is unclear whether this could be externally extrapolated to hospitals with fewer or more limited clinical pharmacists.
Then there is whether it should be taken to a three compartment model.

The three compartment model makes logical sense with vancomycin given the different tissue distribution of the drug (CNS vs skin vs bone vs lung). But these models aren’t easily applied to functional nomograms or dosing protocols. However, my knowledge and understanding of the mathematics involved here left me long ago when I was on an engineering track.  A higher level discussion that is beyond my pk understanding is hopefully taking place somewhere.
We’re still between a rock and a hard place when it comes to dosing vancomycin in obese patients. This new approach seems logical and in this limited study and appears to achieve the desired outcome, but not necessarily improved patient oriented outcomes.  Clearly more evidence is needed to hash out how to dose vancomycin in obese patients, but this protocol could have a role in the future.

1.       Winter ME. Basic Clinical Pharmacokinetics.  3rd edition. Edited by Mary Anne Koda-Kimble, Applied Therapeutics Inc. Vancouver, WA. Copyright 1996
2.       Matzke GR et al.  Pharmacokinetics of vancomycin in patients with various degrees of renal function.  Antimicrob Agents Chemother 1984:25;433-7
3.       Rybak MJ, Lomaestro BM, Rotschafer JC et al. Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Pharmacotherapy. Nov 2009;29(11):1275–1279
4.       Wesner AR, Brackbill ML, Coyle LL, Kidd RS. Prospective trial of a novel nomogram to achieve updated vancomycin trough concentrations. Interdiscip Perspect Infect Dis. 2013;2013:839456. doi:10.1155/2013/839456
5.       Reynolds DC, Waite LH, Alexander DP, DeRyke CA. Performance of a vancomycin dosage regimen developed for obese patients. Am J Health Syst Pharm. 2012;69:944-950
6.       Brown J, Brown K, Forrest A. Vancomycin AUC24/MIC ratio in patients with complicated bacteremia and infective endocarditis due to methicillin-resistant Staphylococcus aureus and its association with attributable mortality during hospitalization. Antimicrob Agents Chemother. 2012;56:634-638. doi:10.1128/AAC.05609-11
7.       Lodise TP, Drusano GL, Butterfield JM, Scoville J, Gotfried M, Rodvold KA. Penetration of vancomycin into epithelial lining fluid in healthy volunteers. Antimicrob Agents Chemother. 2011;55:5507-5511
8.       Skhirtladze K, Hutschala D, Fleck T, et al. Impaired target site penetration of vancomycin in diabetic patients following cardiac surgery. Antimicrob Agents Chemother. 2006;50: 1372-1375
9.       Denetclaw TH, Yu MK, Moua M, Dowling TC, Steinke D. Performance of a divided-load intravenous vancomycin dosing strategy for obese patients. Ann Pharmacother 2015;49(8): 861-868

Monday, November 9, 2015

Vanishing Vasopressin

Vasopressin has gone by the way of atropine in the updated ACLS guidelines.1 But is this a reason to sachet into your next resuscitation/critical care meeting and suggest vasopressin be removed from your hospital’s crash carts? No. Don’t do it. Don’t just read the guidelines; read the primary literature. 

First and foremost, when we’re comparing vasopressin to epinephrine, one must remember the comparison agent (epinephrine) has not been shown to improve patient oriented outcomes, ie, neurologically intact survival.2-5 This is true particularly with out of hospital cardiac arrest (OHCA) and somewhat less consistent with in hospital cardiac arrest (IHCA).  In fact, the role of vasopressin in cardiac arrests has potential benefit in IHCA (VSE trial) or OHCA with initial rhythms of asystole (theoretical in combination with epi +/- steroids, certainly debatable).6-9 The leading theories include improved coronary perfusion in these subgroups, particularly with epinephrine where there may be a synergistic effect.6,7,10 IHCA in particular, vasopressin may be used in a lower 20 IU dose with epinephrine and methylprednisolone followed by hydrocortisone, which IS suggested in these new 2015 guidelines.1,6,7 However, where vasopressin has fallen short in OHCA is in patients with ventricular fibrillation and pulseless ventricular tachycardia (VFib/pVT). This subgroup demonstrates improved ROSC (or similar rate of ROSC), but not improved survival to hospital discharge vs epinephrine.
Secondly, similar to atropine, vasopressin has been removed from the ACLS algorithm not because of evidence showing harm, but rather evidence showing a lack of clear benefit. The objective of the AHA here is to focus ACLS trained providers towards interventions that HAVE evidence to improve survival such as early and high quality CPR, defibrillation.1 Resuscitation can go beyond what’s recommended in these guidelines. They are GUIDElines after all, not gospel.
Critically examining the primary literature cited in the 2010 and 2015 guidelines will demonstrate that there are only two additional papers referenced (J Emerg Med, 2011; Resuscitation, 2012).1,11 The first, briefly, a small (N=44) RCT of epinephrine vs epi+vaso vs epi+vaso+nitro where the combinations did not achieve a higher diastolic blood pressure than did epinephrine.12 The second larger RCT (N=727) did not demonstrate a difference in the rate of survival at discharge between patients who received epi or vasopressin upon arrival to the ED. No difference, but not worse than epinephrine.9
If you practice in an environment where you take care of IHCA patients, vasopressin should remain in the crash/code carts. More awareness of VSE (c’mooooon knowledge translation) needs to happen (RebelEM: great post by Hannah Davis, Pharm.D).

2010 Guidelines
2015 Guidelines
What the What?
Lindner KH, et al.Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. Lancet. 1997;349:535–537
Not included in 2010… perhaps it was in the review article they cite below.
Wenzel V, et al; European Resuscitation Council Vasopressor during Cardiopulmonary Resuscitation Study Group. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med. 2004;350:105–113
Wenzel V, et al; European Resuscitation Council Vasopressor during Cardiopulmonary Resuscitation Study Group. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med. 2004;350:105–113
Stiell IG, et al. Vasopressin versus epinephrine for inhospital cardiac arrest: a randomised controlled trial. Lancet. 2001;358:105–109
Not sure where this one went.
Aung K, Htay T. Vasopressin for cardiac arrest: a systematic review and meta-analysis. Arch Intern Med. 2005;165:1724
Review article, shouldn’t have been included
Callaway CW, et al. Usefulness of vasopressin administered with epinephrine during out-of-hospital cardiac arrest. Am J Cardiol. 2006;98:1316–1321
Callaway CW, et al. Usefulness of vasopressin administered with epinephrine during out-of-hospital cardiac arrest. Am J Cardiol. 2006;98:1316–1321
Gueugniaud PY, et al. Vasopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation. N Engl J Med. 2008;359:21–30
Gueugniaud PY, et al. Vasopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation. N Engl J Med. 2008;359:21–30
Mukoyama T, Kinoshita K, Nagao K, Tanjoh K. Reduced effectiveness of vasopressin in repeated doses for patients undergoing prolonged cardiopulmonary resuscitation. Resuscitation. 2009;80:755–761
Mukoyama T, Kinoshita K, Nagao K, Tanjoh K.Reduced effectiveness of vasopressin in repeated doses for patients undergoing prolonged cardiopulmonary resuscitation. Resuscitation. 2009;80:755761
Ducros L, et al. Effect of the addition of vasopressin or vasopressin plus nitroglycerin to epinephrine on arterial blood pressure during cardiopulmonary resuscitation in humans. J Emerg Med. 2011;41:453–459
Published after 2010
Ong ME, et al. A randomised, double-blind, multi-centre trial comparing vasopressin and adrenaline in patients with cardiac arrest presenting to or in the Emergency Department. Resuscitation. 2012;83:953–960
Published after 2010


1.       2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132(18) supplement 2.

2.       Hagihara A et al. Prehospital Epinephrine Use and Survival Among Patients with OHCA. JAMA 2012; 307(11):1161-68.
3.       Nakahara S et al. Evaluation of pre-hospital administration of adrenaline (epinephrine) by emergency medical services for patients with out of hospital cardiac arrest in Japan: controlled propensity matched retrospective cohort study. BMJ December 2013.
4.       Olasveengen TM, Sunde K, Brunborg C, et al. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA 2009; 302:2222–2229.
5.       Jacobs IG, Finn JC, Jelinek GA, et al. Effect of adrenaline on survival in out-of hospital cardiac arrest: a randomised double-blind placebo-controlled trial. Resuscitation 2011; 82:1138–1143.
6.       Mentzelopoulos S, Zakynthinos S, Tzoufi M, et al. Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch Intern Med 2009;169:15-24. PMID: 19139319
7.       Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial. JAMA. 2013;310(3):270-9. PMID: 19139319
8.       Varvarousi G, Stefaniotou A, Varavaroussis D, et al. Glucocorticoids as an emergency pharmacologic agent for cardiopulmonary resuscitation. Cardiovasc Drugs Ther. 2014;28:477-88. PMCID: PMC4163188
9.       Ong ME, et al. A randomised, double-blind, multi-centre trial comparing vasopressin and adrenaline in patients with cardiac arrest presenting to or in the Emergency Department. Resuscitation. 2012;83:953-960.
10.   Mayr V, et al. Developing a vasopressor combination in a pig model of adult asphyxia cardiac arrest. Circulation, 2001;104:1651-1656.
11.   2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science. Circulation. 2010; 122(18) supplement 3.
12.   Ducros L, et al. Effect of the addition of vasopressin or vasopressin plus nitroglycerin to epinephrine on arterial blood pressure during cardiopulmonary resuscitation in humans. J Emerg Med. 2011;41:453-459.

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