UMEM Educational Pearls - Pharmacology & Therapeutics

Consider esmolol IV 500 mcg/kg loading dose followed by a continuous infusion of 0-100 mcg/kg/min for patients in refractory ventricular fibrillation 

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Do you have a patient with renal insufficiency who is in need of an anticoagulation bridge to warfarin? Subcutaneous unfractionated heparin (UFH) as an initial dose of 333 Units/kg subcutaneously followed by a fixed dose of 250 Units/kg (actual body weight) every 12 hours may be an alternative to admission for heparin infusion with monitoring.

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What they did:

• End stage renal disease (ESRD) patients presenting to the ED for emergent hemodialysis (HD) with baseline QTc prolongation (>450 msec in men and >470 msec in women) were given antiemetics or antihistamines for symptomatic relief of nausea and pruritis. A repeat ECG was obtained 2 hours after medications were given.
• Most patients received oral or intravenous promethazine 25 mg, ondansetron 4-8 mg, or diphenhydramine 25-50 mg.

What they found:

• 44 patients had a mean initial QTc of 483.7 msec (SD 18.4). Two hours after medication administration, the mean QTc was 483.8 msec (SD 20.0).
• Among 13 patients with initial QTc intervals >500 msec, 9 had an increased QTc interval after medication administration (average increase 11.8 msec, SD 6.7 msec).
• 8 patients with baseline QTc <500 msec had QTc >500 msec after medication administration.
• No patients experienced dysrhythmias, death, or were admitted for dysrhythmia or syncope 1 week after medication administration.

Application to clinical practice:

• While the mean QTc did not change, the proportion of individuals who experienced an increase in QTc interval is not reported.
• Although greatly limited by a small sample size, this study suggests that usual doses of promethazine, ondansetron, or diphenhydramine in patients presenting for emergent HD with baseline QTc prolongation may be safe.
• Additional studies, especially in patients with QTc prolongation >500 msec, are warranted.

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Prothrombin complex concentrate (PCC) and fresh frozen plasma (FFP) are used for INR reversal in patients on vitamin K antagonists (VKA) (e.g., warfarin) with life-threatening bleeding. Guidelines from the Neurocritical Care Society and Society of Critical Care Medicine recommend using PCC over FFP for patients with VKA-associated hemorrhage and an INR >=1.4.

New study-INCH trial:

• Multi-center, prospective, randomized, open-label trial comparing FFP IV 20 ml/kg + phytonadione IV 10 mg versus 4-factor PCC IV 30 IU/kg + phytonadione IV 10 mg
• Adult patients on VKA with intracerebral or subdural hemorrhage with INR >=2.0 were included. Patients with traumatic intracranial hemorrhage were excluded.

What they found:

• Analysis included 50 (23 FFP and 27 PCC) patients (trial was stopped early after a safety analysis)
• 2 (9%) patients in the FFP group and 18 (67%) patients in the PCC group achieved an INR <=1.2 within 3 hours (adjusted OR 30.6, 95% CI 4.7-197.9; p=0.0003)
• Hematoma expansion at 3 hours was higher in those treated with FFP than PCC (adjusted difference 16.9 ml, 95% CI 2.5-31.3; p=0.023)
• Time until INR <=1.2 was longer in the FFP group than the PCC group (1482 vs 40 minutes; p=0.050)

Application to clinical practice:

• Of note, FFP 30 ml/kg has been suggested to provide more complete coagulation factor correction (this trial used 20 ml/kg), and package inserts for PCCs recommend doses based on INR and weight (this trial used 30 IU/kg for all patients)
• Although the sample size was small, this study suggests that in patients with VKA-associated non-traumatic intracranial hemorrhage and an elevated INR, PCC may provide faster INR correction than FFP, and may additionally be associated with a smaller degree of hematoma expansion.

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Amiodarone 150 mg IV over 10 minutes and procainamide IV 20-50 mg/min (up to 17 mg/kg) are two antiarrhythmic medications recommended in the American Heart Association (AHA) Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care for stable wide QRS complex tachycardia. [1]

What they did:

Multi-center, prospective, randomized, open-label trial comparing the incidence of major cardiac events in the acute treatment of hemodynamically stable patients with wide QRS monomorphic tachycardia (presumed to be VT) using amiodarone 5 mg/kg IV infused over 20 minutes versus procainamide 10 mg/kg IV infused over 20 minutes. [2] The study period was 40 minutes, starting from the beginning of the infusion.

What they found:

• Analysis included 62 (n=33 procainamide, n=29 amiodarone) patients from 16 hospitals
• Fewer patients treated with procainamide experienced major cardiac events during the study period compared to those who received amiodarone (9% vs 41%; OR =0.1, 95% CI 0.03-0.6; P=0.006). The most frequent adverse cardiac event was severe hypotension requiring electrical cardioversion.
• Termination of VT occurred more frequently in patients treated with procainamide (67% vs 38%; OR =3.3, 95% CI 1.2-9.3; P=0.026).

Application to clinical practice:

• Medication doses and patient weights are not reported in the results. A comparison of the doses used in the PROCAMIO study to those recommended in the AHA guidelines for a 70 kg and 100 kg patient are as follows:
  • Procainamide:
    • 70 kg patient would receive procainamide 35 mg/min for 20 minutes. This is in the middle of the dose range recommended by the AHA.
    • 100 kg patient would receive procainamide 50 mg/min for 20 minutes. This is the upper limit of the dose range recommended by the AHA.
  • Amiodarone:
    • 70 kg patient would receive amiodarone 350 mg over 20 minutes. This is approximately equal to administering 2 doses of 150 mg at the infusion rate recommended in the AHA guidelines.
    • 100 kg patient would receive amiodarone 500 mg over 20 minutes. This is approximately equal to administering 3 doses of 150 mg at an infusion rate over 1.5 times higher than that recommended in the AHA guidelines.

• The study size was small, and depending on patient weights, it is possible that amiodarone dosing was more aggressive compared to doses commonly used in the US. However, the results suggest that procainamide could offer improved safety and efficacy over amiodarone for stable wide QRS tachycardia.

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Fluoroquinolone antibiotics are used to treat a wide range of infections and as prophylaxis against infection in certain immune compromised patients. In 2008 the FDA issued a boxed warning for tendonitis and tendon rupture for the fluoroquinolone antibiotic class, and in May 2016 a statement recommending the use of alternate therapies for uncomplicated UTIs and upper respiratory infections was issued. The mechanism by which fluoroquinolones causes tendon injury has not been elucidated, but may be related to oxidative stress caused by the overproduction of reactive oxygen species in tenocytes.

Adverse event reporting to the FDA is performed voluntarily by healthcare professionals and consumers through MedWatch. An analysis of tendon rupture events associated with fluoroquinolone use reported to the FDA’s Adverse Event Reporting System (FAERS) database was recently published.

What they found:

• 2495 reported cases of tendon rupture associated with fluoroquinolones
• Most cases involved levofloxacin (n=1555), ciprofloxacin (n=606), or moxifloxacin (n=230).
• Concomitant corticosteroids were administered in 21.2% of cases.
• The mean age was approximately 60 +/- 5 years.
• The ratio of men:women was 1.16:1.
• Renal function was not reported in this study.

Application to clinical practice:

• There is a risk of tendonitis/tendon rupture with administration of fluoroquinolone antibiotics.
• Risk factors for fluoroquinolone-associated tendinopathies may include advanced age, impaired renal function, and use of concomitant corticosteroids.
• Alternatives to fluoroquinolone antibiotics should be considered for patients with tendinopathy risk factors.
• When indicated, fluoroquinolones should be used at the lowest effective dose for the shortest possible time period to minimize exposure.

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In settings where community-acquired MRSA is prevalent, which antibiotic is best for uncomplicated wound infections?

New Study

• A new multicenter, randomized, double-blind trial in 500 patients compared 7 days of clindamycin 300 mg 4 times daily to trimethoprim-sulfamethoxazole (TMP-SMX) 4 single strength tablets twice daily.
• Follow-up was performed on days 3 4 (on therapy), 8 10 (end of therapy), 14 21 (test of cure), and 49 63 (extended-follow-up).

What They Found

• Clinical cure rate was > 90% in both groups in the per-protocol population (p = 0.91), and also similar in the intention to treat populations.
• Cultured bacteria were similar between the two groups:
  • MRSA ~40%
  • MSSA ~25%
  • Coagulase-negative staph ~15%
  • Strep species ~5%

Application to Clinical Practice

1. It seems like either clindamycin or TMP-SMX are appropriate antimicrobial choices in uncomplicated wound infections.
2. In this study, strep species were a minor component of the total cases. TMP-SMX is generally not strong against strep species, while clindamycin has good coverage.
3. Consult your local antibiogram when appropriate. At our institution, clindamycin has poor in vitro susceptibility against MRSA.

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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.

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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 three SCr 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 SCr, 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.

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A new guideline for convulsive status epilepticus in adults AND children was recently published. [1] An insightful commentary was published alongside it (both are open access). [2] The proposed algorithm is below. Here are a few additional points to note:

• The guideline applies to convulsive status epilepticus.
• A new level of evidence rating of "U" is utilized. It means "data inadequate or insufficient; give current knowledge, treatment is unproven."
• It addresses 5 specific questions:
  • Which anticonvulsants are efficacious as initial and subsequent therapy?
  • What adverse events are associated with anticonvulsant therapy?
  • Which is the most effective benzodiazepine?
  • Is IV fosphenytoin more effective than IV phenytoin?
  • When does anticonvulsant efficacy drop significantly?
• IM midazolam is incorporated as one of the recommended 1st choices of treatment.
• One of the second phase therapy recommendations is levetiracetam 60 mg/kg! It is a level U recommendation. Be prepared for neurology to request this dose. There is no data in adults to support this high of a dose.

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An interesting new study was published looking at in-hospital mortality in 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.

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After three failed attempts, the FDA finally granted approval for Merck's non-depolarizing neuromuscular blocker reversal agent sugammadex (Bridion). Though the product has been used in Europe and Asia for several years, hypersensitivity concerns led to the delayed approval in the U.S.

Important points

1. Reverses rocuronium, vecuronium, and to a lesser degree, pancuronium
2. Full reversal obtained about 3 minutes after administration
3. Eliminated entirely by the kidneys in about 8 hours (6 times longer in patients with CrCl < 30 mL/min)
4. Dosing is generally 2-4 mg/kg. Total body weight should be used in obese patients

Application to Clinical Practice

1. Potential for use in situations where a neuro exam is needed shortly after intubation (eg, status epilepticus, ICH)
2. The risk of serious hypersensitivity appears to be < 1% in published literature
3. Cost will most assuredly be high
4. Long duration in patients with reduced kidney function means further attempts to re-paralyze with roc, vec, or pancuronium may be unsuccessful

The EM PharmD blog discusses sugammadex's approval in more detail.

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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!

1. Mean total tramadol dose in last 24 hours (reported): 140 mg
2. Duration of tramadol use less than 10 days: 84.5%
3. Seizure within 6 hours of tramadol consumption: 74%

This was a retrospecitve 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.

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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.

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An excellent new review article provides a detailed look at how the drugs we give are affected by targeted temperature management. Here is a helpful chart of drug alterations that have data in reduced body temperature states:

Other Important Points:

1. Lingering effects of sedatives may confound prognostication and may even mimic brain death. Concentrations of remifentanil, propofol, and midazolam decrease during rewarming, whereas no change has been demonstrated for fentanyl, indicating that the pharmacokinetic alterations fentanyl incurs during induction and maintenance of hypothermia persist during and following the rewarming phase.
2. Continuous infusions of analgesics, sedatives, and hemodynamic support agents may require closer monitoring and smaller incremental changes compared to normothermic states.
3. The QTc interval is increased in TTM, though it has not been associated with an increased risk of torsades de pointes or in-hospital mortality.

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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

1. In an effort to reduce opioid use in the ED, low-dose ketamine may be a reasonable alternative to opioids for acute analgesia.
2. State nursing regulations govern who can administer IV ketamine in the ED.
3. What to prescribe on discharge? Lead author Dr. Motov recommends a "pain syndrome targeted" approach with "patient-specific opioid and non-opioid analgesics."

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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).

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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.

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Vancomycin guidelines recommend an initial dose of 15-20 mg/kg based on actual body weight (25-30 mg/kg in critically ill patients). [1] The MRSA guidelines further recommend a max dose of 2 gm. [2]

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. [3] 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

1. Calculate the total loading dose. At my institution we use actual body weight (the study used IBW).
2. 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).
3. Measure a trough level before the third dose.
4. 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.

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Aside from sodium chloride and sodium bicarbonate, several commonly used emergency department medications (namely IV antibiotics) contain a significant amount of sodium. In patients with heart failure or other conditions requiring sodium restriction, judicious use should be considered.

Notes:

• Available references all quote slightly differing sodum contents. Therefore, the daily totals are approximate, but within 100 mg of the various references.
• To convert mg to mEq or mmoL, divide by 23.

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