Top 8 Must-Know EM Pharmacotherapy Articles of 2016


Top 8 must-know EM pharmacotherapy articles of 2016For the third consecutive year, we provide a quick summary of some important Emergency Medicine pharmacotherapy articles from the last 12 months. We have tried to focus on articles you may have missed, but are potentially high-impact for improving clinical practice in the ED. Without further ado, we present the 8 must-know EM pharmacotherapy articles of 2016.

Top 8 EM EM Pharmacotherapy Articles of 2016

1. Vancomycin Loading Doses in ED Not Associated with Increased Nephrotoxicity2. Ketamine for Prehospital Agitation3. Does Succinylcholine Increase Mortality in Severe TBI Patients?4. Predicting Hemodynamic Response to Ketamine in Prehospital RSI5. Esmolol for Refractory Ventricular Fibrillation6. The Ceiling Effect of IV Ketorolac7. Piperacillin/Tazobactam and Risk of Acute Kidney Injury with Vancomycin8. Utility of Pre-4-Hour Acetaminophen Levels in Acute Overdose

Guidelines recommend loading doses of vancomycin (15-20 mg/kg, up to 30 mg/kg in critically ill patients), but the risk of nephrotoxicity is unknown. A new retrospective cohort study aimed to compare nephrotoxicity in ED sepsis patients who received vancomycin at high doses (>20 mg/kg) versus lower doses (20 mg/kg).

What They Found

  • 1,330 patients had 3 serum creatinine values assessed for the primary outcome
  • High-dose initial vancomycin was actually associated with a lower rate of nephrotoxicity (5.8% vs 11.1%)
  • After adjusting for age, gender, and initial serum creatinine, the risk of high dose vancomycin compared to low dose was decreased for the development of nephrotoxicity (RR=0.60; 95% CI: 0.44, 0.82)

Application to Clinical Practice

It appears initial loading doses of vancomcyin >20 mg/kg do not cause increased risk of nephrotoxicity.


Rosini J, Davis J, Muenzer J, et al. High Single-dose Vancomycin Loading Is Not Associated With Increased Nephrotoxicity in Emergency Department Sepsis Patients. Acad Emerg Med. 2016;23(6):744-746. [PubMed]

Originally posted Apr 2, 2016 as University of Maryland (UMEM, @UMEmergencyMed) pearl.

Ketamine is gaining traction as a prehospital option for managing severe agitation or excited delirium syndrome. Previous reports have mostly been case series, but a new prospective study adds some important information that may help delineate ketamine’s role in this setting. [1] An accompanying commentary was published in the same issue. [2]

What They Did

Open-label before-and-after prospective comparison of haloperidol (10 mg IM) versus ketamine (5 mg/kg IM) for the treatment of acute undifferentiated agitation.

What They Found

  • Ketamine demonstrated a statistically and clinically significant difference in median time to sedation compared to haloperidol, 5 min vs. 17 min (p < 0.0001, 95% CI: 9 15)
  • Complications: ketamine, 49%; haloperidol, 5%
    • Ketamine complications: hypersalivation (38%), emergence reaction (10%), vomiting (9%), and laryngospasm (5%)
  • Intubation rate: ketamine, 39%; haloperidol, 4%

Application to Clinical Practice

  • Ketamine works for prehospital agitation (and more rapidly)
  • Ketamine has a higher complication and intubation rate
  • Though this study did not find a dose relationship between ketamine and intubations, future studies should evaluate further and potentially use lower ketamine doses
  • At our institution, we start with 2-3 mg/kg IM and repeat if necessary after 5 min. Most patients have not required a second dose and none have been intubated. This allows time to place an IV line and initiate additional treatment.


Cole J, Moore J, Nystrom P, et al. A prospective study of ketamine versus haloperidol for severe prehospital agitation. Clin Toxicol (Phila). 2016;54(7):556-562. [PubMed]
Hayes B. Ketamine for agitation: a key cog in the prehospital treatment armamentarium wheelhouse. Clin Toxicol (Phila). 2016;54(7):545-546. [PubMed]

Originally posted June 9, 2016 as UMEM pearl.

An interesting new study was published looking at in-hospital mortality in traumatic brain injury (TBI) patients who received succinylcholine or rocuronium for RSI in the ED.

What They Did

  • Retrospective cohort study
  • 233 patients (149 received succinylcholine, 84 received rocuronium)
  • Groups were well matched overall (roc group was older, more hypotension in sux group)
  • Within the two groups, patients were separated based on head Abbreviated Injury Score (scores of 4 or 5 were considered severe)
  • The authors controlled for a lot of confounding factors

What They Found

  • Overall, mortality was the same in each group (23%)
    • Mortality within the roc group was the same irrespective of head AIS
    • Mortality within the sux group was significantly higher in the subset of patients with higher head AIS (OR 4.1, 95% CI 1.18-14.12, p = 0.026)

Application to Clinical Practice

  • Succonylcholine may increase mortality in severe TBI patients undergoing RSI in the ED compared to rocuronium.
  • The confidence interval was wide and these findings need to be confirmed in a prospective study
  • Though the patients were well matched and the authors controlled for many variables, it still is difficult to pinpoint one intervention as the cause for mortality in critically ill patients (eg, etomidate + sepsis).
  • With proper rocuronium dosing, intubating conditions are similar to succinylcholine. So if there is a potential for increased mortality in severe TBI patients with sux, rocuronium seems to provide a safer alternative.


Patanwala A, Erstad B, Roe D, Sakles J. Succinylcholine Is Associated with Increased Mortality When Used for Rapid Sequence Intubation of Severely Brain Injured Patients in the Emergency Department. Pharmacotherapy. 2016;36(1):57-63. [PubMed]

Originally posted Feb 6, 2016 as UMEM pearl.

Ketamine is often thought to be the induction agent least associated with hypotension in the peri-intubation period. However, reports of hypotension following ketamine do exist, including 2 cases of cardiac arrest [1]. There are limited objective means to predict which patients may have an adverse hemodynamic response.

New Study

A new prospective observational study followed 112 patients in the prehospital setting who received ketamine for rapid sequence intubation. 81 had a low shock index [< 0.9], 31 had a high shock index [2].

Shock index = HR / SBP

What They Found

Patients with a high shock index were more likely to experience hypotension (SBP < 90 mm Hg) in the peri-intubation period compared to those with a low shock index (26% vs 2%).

Application to Clinical Practice

  • This is the first study to evaluate a potential objective predictor for which patients may experience hypotension after RSI with ketamine. But, even with a high shock index, the majority of patients did not develop hypotension.
  • These findings should not lead to avoidance of ketamine in these situations, as other induction agents are equally or more likely to cause adverse hemodynamic effects.
  • It has been suggested to use lower induction doses in patients at risk for hypotension (with the same or higher paralytic dose). Patients with a high pre-RSI shock index may be the population in which to consider that approach.


Dewhirst E, Frazier W, Leder M, Fraser D, Tobias J. Cardiac arrest following ketamine administration for rapid sequence intubation. J Intensive Care Med. 2013;28(6):375-379. [PubMed]
Miller M, Kruit N, Heldreich C, et al. Hemodynamic Response After Rapid Sequence Induction With Ketamine in Out-of-Hospital Patients at Risk of Shock as Defined by the Shock Index. Ann Emerg Med. 2016;68(2):181-188.e2. [PubMed]

Originally posted May 7, 2016 as UMEM pearl.

Up until two years ago, beta blocker use for refractory ventricular fibrillation (VFib) had only been studied in animal models with sporadic human case reports. Two studies in humans have now been published and may provide some guidance in managing this difficult-to-treat condition.

First Human Study

In 2014, Dr. Steven Smith’s (@smithECGBlog) group published a retrospective evaluation of 25 patients with refractory VFib; 6 patients received esmolol during cardiac arrest and 19 patients did not [1]. Comparing the patients that received esmolol to those that did not: 67% and 42% had sustained return of spontaneous circulation (ROSC); 66% and 32% survived to intensive care unit admission; 50% and 16% survived to hospital discharge; and 50% and 11% survived to discharge with a favorable neurologic outcome, respectively.

New Human Study

In the October 2016 issue of Resuscitation, a new study from the Republic of Korea evaluated a similar cohort [2]. 41 patients were included in this single center, retrospective analysis: 16 patients received esmolol and 25 patients did not. Comparing the patients that received esmolol to those that did not: 56% vs. 16% (p = 0.007) had sustained ROSC; 56% and 16% (p = 0.007) survived to ICU admission; 19% and 8% survived to 30 days, 3 months, and 6 months (p = 0.36); and 19% and 8% had a good neurologic outcome at 30 days, 3 months, and 6 months (p = 0.36), respectively.

Application to Clinical Practice

  • Both studies used similar inclusion criteria: VFib that was resistant to ≥3 defibrillations, 3 mg of epinephrine, and 300 mg of amiodarone (Lee et al added no ROSC after >10 min of CPR).
  • Though there are several limitations (namely single center, retrospective cohorts with small sample sizes), both studies demonstrated the potential for esmolol to increase the chance of neurologically good outcome in patients with refractory VFib.
  • Not all of the comparisons reached statistical significance (small sample sizes). However, the potential clinical significance of improved neurologically intact outcomes from a relatively benign therapy (esmolol) could be profound.
  • Based on these two small data sets, it may be reasonable to consider esmolol in refractory VFib cases earlier in the resuscitation (ie, before 10 minutes of CPR has transpired and before 3 doses of epinephrine).


Driver B, Debaty G, Plummer D, Smith S. Use of esmolol after failure of standard cardiopulmonary resuscitation to treat patients with refractory ventricular fibrillation. Resuscitation. 2014;85(10):1337-1341. [PubMed]
Lee Y, Lee K, Min Y, et al. Refractory ventricular fibrillation treated with esmolol. Resuscitation. 2016;107:150-155. [PubMed]

For acute pain in the ED, parenteral ketorolac is generally administered as 30 mg IV or 60 mg IM. Dr. Chris Bond (@socbmobem) has written about the ‘ceiling effect’ of NSAIDS. The question is: are we using too much ketorolac without getting additional pain benefit?

Hot-off-the-press is a new randomized, double-blind trial from Dr. Sergey Motov’s group (@painfreeED) that addresses this exact question.

What they did

240 patients with acute pain in a 711-bed urban community teaching hospital ED were randomized to receive 10 mg, 15 mg, or 30 mg of IV ketorolac as a single-dose.

  • Age 18 to 65 years
  • Acute flank, abdominal, musculoskeletal, or headache pain with an intensity of 5 or greater on a standard 0 to 10 numeric rating scale
  • Patients who would routinely be treated with IV ketorolac
  • Pain scores, vital signs, and adverse effects were recorded at baseline and 15, 30, 60, 90, and 120 minutes
  • Subjects still desiring pain medication 30 min after study drug administration were offered IV morphine 0.1 mg/kg as a rescue


The primary outcome was reduction in numeric rating scale pain score at 30 minutes from medication administration.

What they found

  1. There was no difference in reduction of pain scores between the groups: 10 mg – 7.7 to 5.2; 15 mg – 7.5 to 5.1; 30 mg – 7.8 to 4.8
  2. There were no differences between the groups with respect to use of rescue morphine analgesia at any time
  3. There were no clinically concerning changes in vital signs and no clinically significant adverse effects related to the study medication at any dose

There was no placebo group and the box plot (Figure 2) revealed wide variability in all of the treatment arms.

Implications for Clinical Practice

This is a well-conducted study demonstrating no difference in pain score reduction for various doses of IV ketorolac. Doses of 10 mg or 15 mg are just as effective as 30 mg and should be used preferentially over higher doses. Higher doses can cause more adverse effects, especially if more than one dose is administered.


Motov S, Yasavolian M, Likourezos A, et al. Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. December 2016. [PubMed]

A full review of this topic was covered in a previous ALiEM post and is updated as new articles are published. Previous (and subsequent) studies on this topic have largely been retrospective. This is the first prospective study to evaluate the observed incidence of AKI.

What They Did

Prospective, open label cohort study at a community academic medical center involving adult patients who received either:

  • the combination of pip-tazo + vancomycin OR
  • the combination of cefepime or meropenem + vancomycin for greater than 72 hours

AKI was defined using specific criteria introduced by Kidney Disease: Improving global outcomes (KDIGO) acute kidney injury work group in 2012.

What They Found

  • 85 patients were enrolled (59 in the pip-tazo + vancomycin group)
  • Incidence of AKI was significantly higher in the pip-tazo + vancomycin group (37.3%) compared with the cefepime or meropenem + vancomycin group (7.7%; χ2 = 7.80, P = .005)
  • Importantly, there was no difference in mean of steady state vancomycin trough levels between groups


  • The study did not reach the projected sample size of 120 patients and there were disproportionately more patients in the pip-tazo group, both decreasing the power of the study’s findings
  • Development of AKI was strictly by KDIGO definition and patients were not followed for the clinical significance of the AKI

Application to Clinical Practice

  • It seems time to acknowledge there is an association between pip-tazo and risk of AKI (with vancomycin). There have been 12 different groups with internal medicine, pediatric, and ICU patients (including this prospective study) demonstrating this adverse effect. Three meta-analyses, with 963 patients, 3,528 patients, and 3,549 patients, drew the same conclusion.
  • The prospective study supports the association, even with vancomycin trough levels the same in each group.
  • In ICU patients specifically, the results have been conflicting. All 3 ICU studies reported a high rate of AKI with vanc + pip-tazo (21.2-40.5%). Two of the ICU studies showed a significantly higher rate in the combo group compared with vancomycin alone; the other did not demonstrate a difference when pip-tazo was replaced with cefepime. A prospective study in ICU patients is needed.
  • Proposed mechanisms for pip-tazo induced AKI include acute interstitial nephritis or toxic effects on the renal tubule.
  • To me, this adds one more reason to at least think twice before reflexively ordering pip-tazo for every sick patient, especially when combined with vancomycin. The AKI association should be taken into account when creating sepsis order sets and treatment plans.

Further Reading

Dr. Josh Farkas (@PulmCrit) tackles the question ‘Is Piperacillin-Tazobactam Nephrotoxic?‘ on his blog at EMCrit.


Peyko V, Smalley S, Cohen H. Prospective Comparison of Acute Kidney Injury During Treatment With the Combination of Piperacillin-Tazobactam and Vancomycin Versus the Combination of Cefepime or Meropenem and Vancomycin. J Pharm Pract. February 2016. [PubMed]

A full review of this topic was covered in a previous ALiEM post.

What They Did

  • The authors examined serum APAP concentrations obtained less than 4 hours post-ingestion, and again 4 or more hours post-ingestion.
  • They specified a cutpoint of 100 mcg/mL (662 micromol/L) obtained between 2 and 4 hours and a subsequent 4 to 20 hour APAP concentration above the nomogram treatment line of 150 mcg/mL (993 micromol/L).

What They Found

  • Almost 2,500 patients were evaluated.
  • Concentrations drawn between 2-4 hours post-ingestion demonstrated a sensitivity of 0.96 [95% CI; 0.94, 0.97] and a negative likelihood ratio of 0.070 [0.048, 0.10]. Coingested opioids reduced this sensitivity to 0.91 [0.83, 0.95], and antimuscarinics to 0.86 [0.72, 0.94].
  • Only very low to undetectable APAP concentrations prior to 4 hours reliably excluded a subsequent concentration over the treatment line.
  • They concluded that applying an APAP concentration cutpoint of 100 mcg/mL (662 micromol/L) at 2-4 hours after an acute ingestion as a threshold for repeat testing and/or treatment would occasionally miss potentially toxic exposures.
  • Importantly, their data validated the practice of not retesting when the first post-ingestion APAP concentration is below the lower limit of detection.

Application to Clinical Practice

  1. The Rumack-Matthew nomogram is to be utilized starting at 4 hours after an acute APAP ingestion.
  2. Pre-4 hour APAP levels, if not repeated, can lead to unnecessary treatment, admissions, and adverse effects.
  3. If an APAP level is drawn before 1 hour, a second APAP level must be drawn again at the 4-hour mark.
  4. If an APAP level is drawn between 1-4 hours, and the level is:
    Undetectable –> you can stop additional APAP testing
    Detectable –> you should redraw a second APAP level at the 4-hour mark
  5. The current data supports waiting until 4 hours after ingestion to draw a level, but optimally less than 7 hours (to allow an hour to start acetylcysteine if needed).


Yarema M, Green J, Sivilotti M, et al. Can a serum acetaminophen concentration obtained less than 4 hours post-ingestion determine which patients do not require treatment with acetylcysteine? Clin Toxicol (Phila). October 2016:1-7. [PubMed]

Previous Annual Summaries

Bryan D. Hayes, PharmD, FAACT, FASHP

Bryan D. Hayes, PharmD, FAACT, FASHP

Chief Science Officer, ALiEM
Creator and Lead Editor, Capsules series, ALiEMU
Attending Pharmacist, EM and Toxicology, MGH
Assistant Professor of EM, Harvard Medical School