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.

Saturday, November 7, 2015

To Determine Abuse Potential Of A Drug Bring Two Turtles To The Temple Of The FDA

The FDA is wacky. Around every corner there seems to be another head scratching approval, denial, process or event. Answering a simple question took me down a new enlightening, and hilarious path. Now, this may sound Seinfeld-ish but ‘what’s the deal with controlled substances?’

Lacosamide is a newer antiepileptic drug that you have likely seen on a medication reconciliation profile of a patient to two in your emergency department by now. With this newer drug, there isn’t a whole lot of interesting pharmacokinetics or horrifying toxicities with normal therapeutic use. On the surface it’s pretty bland. However, I’m sure it has caused problems in terms of either stocking the drug or delivering it to nurses who are waiting on it to discharge the patient from the ED. The reason being, it’s a schedule C-V drug.

Why would this drug be any different from other newer antiepileptic drugs that are not controlled (levetiracetam, vigabatrin…)? I can’t say there are any frequent flyers coming in with allergies to phenytoin, keppra, carbamazepine and valproate that need that one that starts with a Vin-something, “yea, Vimpat… I need 50 of Benadryl with that too.” Or why is pregablin controlled and gabapentin not? How about Fioricet vs Fiorinal? Maybe the bigger question is who and how is abuse potential tested in drugs?
There is no easy way to say this so here it goes. Drugs are given to “experienced” drug users who rate the drug in question for any pleasurable effects. Literally asking “do you like the drug.”
One thing that I have learned in my brief experience is that the more I learn, the more I realize how little I know. Assuming a process or medical dogma is logically based on decent evidence, then after some investigation discovering poor quality or no evidence at all is becoming the rule rather than the exception. I have no idea why this abuse potential screening seems so strange to me, but it does. I hadn’t ever thought of how drugs were assigned to a controlled schedule, and this may very well be this is the best way to do it. Or perhaps it’s just another quirk with the FDA. (Reminds me of Nick Offerman talking about the book Leviticus of the Bible).
In the FDA’s draft guidance document for the process by which abuse potential is determined is outlined. Before drugs reach the human phase, these compounds are assessed in numerous ways to identify if they share structural or other qualities with existing controlled substances. These phases include: preclinical screening, chemistry and manufacturing, animal models and PK/PD studies. When in the human phase, as outlined above, the drug is administered to experienced, and sometimes naive individuals to determine if any euphoric or abuse potential effects exist.
With lacosamide, its abuse potential study was outlined in its prescribing information. Briefely, single doses of 200 mg and 800 mg lacosamide produced euphoria-type subjective responses that differentiated statistically from placebo. Interestingly, at 800 mg the drug displayed similar effects as alprazolam, but did not last nearly as long.
So like a CIV but not as long of a duration... ummm… CV!
This is concerning when we start to think about initiatives to increase the schedule of drugs like ketamine, or to think of how propofol is the most abused drug among anesthetists but is not controlled. How the FDA/DEA will act is unknown, but it will likely be a hair-brained process similar to this.

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