There is so much literature to sift through each year, it becomes nearly impossible to stay abreast of it. Here is a quick summary of the 10 must-know Emergency Medicine pharmacotherapy articles from 2015, in my humble opinion.
Top 10 EM Pharmacotherapy Articles of 2015
[su_tabs vertical=”yes”][su_tab title=”1. IV Magnesium for Acute Migraine Headache”]
Does IV magnesium have a role in the management of acute migraine headache in the ED? A new study says yes. [1]
Intervention
- 35 patients received IV magnesium 1 gm over 15 minutes.
- 35 patients received IV dexamethasone 8 mg + IV metoclopramide 10 mg over 15 minutes.
- Each group contained men and women.
- Initial pain score 8.2 in dexamethasone/metoclopramide group vs. 8.0 in magnesium group.
What They Found
Magnesium sulfate was more effective in decreasing pain severity at 20-min (pain scale 5.2 vs. 7.4) and 1-h (2.3 vs. 6.0) and 2-h (1.3 vs. 2.5) intervals after treatment (p < 0.0001) compared to treatment with dexamethasone/metoclopramide.
Application to Clinical Practice
Two previous studies found mixed results using magnesium (Corbo 2001, Cete 2005). This new study found that IV magnesium may be an additional option. The authors didn’t compare magnesium to more common treatments such as prochlorperazine or metoclopramide 20 mg (+/- ketorolac and diphenhydramine), which may limit its generalizability. However, magnesium’s pain lowering effect was good regardless of comparator group.
Shahrami A, et al. Comparison of therapeutic effects of magnesium sulfate vs. dexamethasone/metoclopramide on alleviating acute migraine headache. J Emerg Med 2015;48(1):69-76. [PMID 25278139]
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[su_tab title=”2. Ketamine for Alcohol Withdrawal”]
Background
In addition to the down regulation of GABA receptors in chronic ethanol users, there is an upregulation in NMDA receptor subtypes. Although the pathophysiology is much more complex, when ethanol abstinence occurs, there is a shortage of GABA-mediated CNS inhibition and a surplus of glutamate-mediated CNS excitation. If GABA agonists are the mainstay of treatment, why not also target the NMDA receptor? Enter ketamine.
The Data
Only one study exists and was published recently.
- Retrospective review of 23 adult patients administered ketamine specifically for management of AWS.
- Mean time to initiation of ketamine from first treatment of AWS, and total duration of therapy were 33.6 and 55.8 hours, respectively.
- Mean initial infusion dose and median total infusion rate were 0.21 and 0.20 mg/kg/h, respectively.
- No change in sedation or alcohol withdrawal scores within 6 hours of ketamine initiation.
- Median change in benzodiazepine requirements at 12 and 24 hours post-ketamine initiation were -40.0 and -13.3 mg, respectively.
- One documented adverse reaction of oversedation, requiring dose reduction.
- Authors concluded that ketamine appears to reduce benzodiazepine requirements and is well tolerated at low doses.
Application to Clinical Practice
While the dexmedetomidine studies should not be using reduction in benzodiazepine requirements as an endpoint, it may be acceptable for ketamine since it actually works on the underlying pathophysiology. More studies are needed but it’s good to see we’re starting to look at it.
Wong A, et al. Evaluation of adjunctive ketamine to benzodiazepines for management of alcohol withdrawal syndrome. Ann Pharmacother 2015;49(1):14-9. [PMID 25325907]
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[su_tab title=”3. Vancomycin Loading in Obese Patients”]
Vancomycin guidelines recommend an initial dose of 15-20 mg/kg based on actual body weight (25-30 mg/kg in critically ill patients) (Ryback 2009). The MRSA guidelines further recommend a max dose of 2 gm (Liu 2011).
But, what dose do you give for an obese patient that would require more than 2 gm?
A new study provides some answers to this question. Obese-specific, divided-load dosing achieved trough concentrations of 10 to 20 g/mL for 89% of obese patients within 12 hours of initial dosing and 97% of obese patients within 24 hours of initial dosing.
Application to Clinical Practice
- Calculate the total loading dose. At my institution we use actual body weight (the study used IBW).
- Divide the total dose to be given every 6 hours until load is complete. We cap each individual dose at 2 gm (the study used 1.5 gm).
- Measure a trough level before the third dose.
- Change to dosing frequency dictated by renal function once level moves into target range.
Caveats
The study used some more specific dosing calculations based on renal function and percentage above IBW. If patient’s renal function is abnormal, consultation with a pharmacist is recommended.
Denetclaw TH, et al. Performance of a divided-load vancomycin dosing strategy for obese patients. Ann Pharmacother 2015;49(8):861-8. [PMID 2598600]
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[su_tab title=”4. Early Glargine Administration at Start of DKA Treatment”]
Transitioning Diabetic Ketoacidosis (DKA) patients off an insulin infusion can be challenging. If a long-acting insulin, such as glargine or levemir, is not administered at the correct time to provide extended coverage, patients can revert back into DKA.
Pilot Study
A prospective, randomized, controlled pilot study in 40 patients evaluated administration of glargine within 2 hours of insulin infusion initiation compared to waiting until the anion gap (AG) had closed.
What they did
- All patients received IV insulin.
- Experimental: Subcutaneous insulin glargine given within 2 hours of diagnosis.
- Control: Patients subsequently transitioned to long-acting insulin upon closure of AG.
What they found
Mean time to closure of AG, mean hospital LOS, incidents of hypoglycemia, rates of ICU admission, and ICU LOS were all similar between the groups.
Application to Clinical Practice
Although just a pilot study (using a convenience sample), early glargine administration seemed to be absorbed adequately (based on time to AG closure) and was not associated with increased risk of hypoglycemia. If confirmed in a larger study, this technique could help optimize care of DKA patients in the ED by eliminating the often-mismanaged transition step later on.
Doshi P, et al. Prospective randomized trial of insulin glargine in acute management of diabetic ketoacidosis in the emergency department: a pilot study. Acad Emerg Med 2015;22(6):657-62. [PMID 26013711]
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[su_tab title=”5. Reversing Dabigatran with Idarucizumab”]
The New England Journal of Medicine and Lancet both published studies evaluating idarucizumab for reversal of dabigatran. It is amonoclonal antibody fragment that binds dabigatran with high affinity. Dr. Ryan Radecki summarizes the two articles on his EM Lit of Note blog.
Here are a few take home points from these early studies:
- Both studies were funded by Boehringer Ingelheim, who not suprisingly also markets dabigatran. Skepticism is always welcome when the same company makes the drug and the antidote.
- The Lancet study was conducted in healthy volunteers, while the NEJM study was conducted in patients needing reversal but lacked a control group.
- Idarucizumab seems to reverse laboratory markers of anticoagulation from dabigatran rapidly and completely, including dilute thrombin time and ecarin clotting time. Not all institutions have these assays available.
- The dose that seems to ‘work’ the best is 5 gm given IV (two-2.5 gm infusions given no more than 15 minutes apart).
- Median investigator-reported time to cessation of bleeding was 11.4 hours in the NEJM study.
- 21 of the 90 patients in the NEJM study had ‘serious adverse effects’ including thrombotic events.
- The acquisition cost of this medication will most assuredly be high if and when it is FDA-approved in the U.S.
Pollack CV, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373(6):511-20. [PMID 26095746]
Glund S, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in health male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet 2015;386:680-90. [PMID 26088268]
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[su_tab title=”6. Blood Glucose Response to Rescue Dextrose”]
How much does the blood glucose concentration increase when dextrose 50% (D50) is administered?
A new study found a median increase of 4 mg/dL (0.2 mmol/L) per gram of D50 administered.
This retrospective study was conducted in critically ill patients who experienced hypoglycemia while receiving an insulin infusion. While it may not directly apply to all Emergency Department patients, an estimation of the expected blood glucose increase from rescue dextrose is helpful. If the blood glucose doesn’t respond as anticipated, it can help us troubleshoot possible issues (eg, line access).
Murthy MS, et al. Blood glucose response to rescue dextrose in hypoglycemic, critically ill patients receiving an insulin infusion. Ann Pharmacother 2015;49(8):892-6. [PMID 25986006]
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[su_tab title=”7. Ketamine vs. Morphine for Analgesia in the ED”]
A new prospective, randomized, double-blind trial compared subdissociative ketamine to morphine for acute pain in the ED.
What they did
- 45 patients received IV ketamine 0.3 mg/kg (mean baseline pain score 8.6)
- 45 patients received IV morphine 0.1 mg/kg (mean baseline pain score 8.5)
- Source of pain was abdominal for ~70% in each group
- Exclusion criteria was pretty standard
What they found
- Pain score at 30 minutes: 4.1 for ketamine vs. 3.9 for morphine (p = 0.97)
- No difference in the incidence of rescue fentanyl analgesia at 30 or 60 minutes
- No serious adverse events occurred in either group
- Patients in the ketamine group reported increased minor adverse effects at 15 minutes post-drug administration
Application to clinical practice
- In an effort to reduce opioid use in the ED, low-dose ketamine may be a reasonable alternative to opioids for acute analgesia.
- State nursing regulations govern who can administer IV ketamine in the ED.
- What to prescribe on discharge? Lead author Dr. Motov recommends a “pain syndrome targeted” approach with “patient-specific opioid and non-opioid analgesics.”
Motov S, et al. Intravenous subdissociative-dose ketamine versus morphine for analgesia in the emergency department: a randomized controlled trial. Ann Emerg Med 2015;66:222-9. [PMID 25817884]
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[su_tab title=”8. Avoid Opioids for Low Back Pain”]
If there weren’t enough reasons to avoid opioids, here is another: opioids don’t work for low back pain (LBP).
Objective
A well-done, double-blind, randomized controlled trial from JAMA set out to compare functional outcomes and pain at 1 week and 3 months after an ED visit for acute LBP among patients randomized to a 10-day course of (1) naproxen + placebo; (2) naproxen + cyclobenzaprine; or (3) naproxen + oxycodone/acetaminophen.
Intervention
- Nontraumatic, nonradicular LBP of 2 weeks’ duration or less
-
All patients were given 20 tablets of naproxen, 500 mg, to be taken twice a day.
- They were randomized to receive either 60 tablets of placebo; cyclobenzaprine, 5 mg; or oxycodone, 5 mg/acetaminophen, 325 mg. Participants were instructed to take 1 or 2 of these tablets every 8 hours, as needed for LBP.
- Patients received a standardized 10-minute LBP educational session prior to discharge.
Outcome
Neither oxycodone/acetaminophen nor cyclobenzaprine improved pain or functional outcomes at 1 week compared to placebo, and more adverse effects were noted.
Application to Clinical Practice
Among patients with acute, nontraumatic, nonradicular LBP presenting to the ED, avoid adding opioids or cyclobenzaprine to the standard NSAID therapy.
Friedman BW, et al. Naproxen with Cyclobenzaprine, Oxycodone/Aceaminophen, or Placebo for Treating Acute Low Back Pain: A Randomized Clinical Trial. JAMA 2015;314(15):1572-80. [PMID 26501533]
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[su_tab title=”9. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity”]
Not to be outdone by the recent FDA approval of Idarucizumab to reverse dabigatran, a new factor Xa reversal agent is under investigation. “Andexanet binds and sequesters factor Xa inhibitors within the vascular space, thereby restoring the activity of endogenous factor Xa and reducing levels of anticoagulant activity, as assessed by measurement of thrombin generation and anti factor Xa activity, the latter of which is a direct measure of the anticoagulant activity.”
Design
Two parallel randomized, placebo-controlled trials (ANNEXA-A [apixaban] and ANNEXA-R [rivaroxaban]) were conducted in healthy vounteers to evaluate the ability of andexanet to reverse anticoagulation, as measured by the percent change in anti factor Xa activity after administration.
What they Found
Compared to placebo, andexanet significantly reduced anti-factor Xa activity, increased thrombin generation, and decreased unbound drug concentration in both the apixaban and rivaroxaban groups.
Application to Clinical Practice
- This drug is not yet FDA approved.
- These trials were funded by the maker of andexanet (Portola Pharmaceuticals) and supported by the makers of apixaban and rivaroxaban.
- Studies are needed in patients requiring urgent reversal.
- The trials looked only at laboratory markers of anticoagulation. We don’t know how fast (or the extent of) the reversal activity is in the clinical setting.
Siegal DM, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med 2015;373(25)2413-25. [PMID 26559317]
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[su_tab title=”10. Therapeutic Tramadol Use Significantly Increases Seizure Risk”]
Tramadol has a reputation for being a safe, non-opioid alternative to opioids. Nothing could be further from the truth. Several blogs have published about the dangers of tramadol:
- Tramadol: When to Avoid It from ALiEM blog
- Three Reasons Not to Prescribe Tramadol from EM PharmD blog
- Hypoglycemia: Another Adverse Effect Associated with Tramadol from Poison Review blog
But what about seizure risk? Previous studies have been unable to confirm an increased seizure risk with therapeutic doses of tramadol (Seizure Risk Associated with Tramadol Use from EM PharmD blog). However, a new study refutes that premise.
22% of first-seizure patients had recent tramadol use!
- Mean total tramadol dose in last 24 hours (reported): 140 mg
- Duration of tramadol use less than 10 days: 84.5%
- Seizure within 6 hours of tramadol consumption: 74%
This was a retrospective study without laboratory confirmation of tramadol intake. Nevertheless, it behooves us not to think of tramadol as a safer alternative to opioids. It is an opioid after all, and it comes with significant adverse effects.
Asadi P, et al. Prevalence of Tramadol Consumption in First Seizure patients; a One-Year Cross-sectional Study. Emerg (Tehran) 2015;3(4):159-61. [PMID 26495407]
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[su_tab title=”Bonus Article“]
Pickard R, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet 2015;386:341-9. [PMID 25998582]
Take Home: Tamsulosin 0.4 mg and nifedipine 30 mg are not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients with expectantly managed ureteric colic.
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[su_tab title=”Favorite Article of the Year“]
It’s not technically a pharmacotherapy article, but this is my favorite article of the year:
Favaloro EJ, et al. Laboratory Testing in the Era of Direct or Non–Vitamin K Antagonist Oral Anticoagulants: A Practical Guide to Measuring Their Activity and Avoiding Diagnostic Errors. Semin Thromb Hemost 2015;41:208–27. [PMID 25703514]
It’s the most comprehensive and practical review of laboratory interpretation for oral anticoagulants I’ve seen. It includes excellent algorithms for how to confirm/exclude various oral anticoagulants based on commonly available labs. An absolute must-read and an outstanding resource to keep in your Dropbox or Google Drive.
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