UMEM Educational Pearls - By Michelle Hines

Linezolid is a weak, nonselective monoamine oxidase inhibitor (MAOI). A recent FDA Drug Safety Communication released in March 2016 noted reports of serotonin syndrome associated with certain opioids, particularly fentanyl and methadone. Development of serotonin syndrome after concomitant administration of linezolid with other serotonergic agents has been reported. Due to a potential risk of serotonin syndrome, a patient on chronic methadone should not be started on concomitant linezolid unless they will be monitored.

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The addition of diazepam to naproxen for patients with acute, nontraumatic, nonradicular lower back pain did not improve pain or functional outcomes at 1 week or 3 months after ED discharge compared to placebo.

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Below is a list of pharmacy-related pearls from the 2016 Surviving Sepsis Guidelines:

• Fluid resuscitation: 30 mg/kg IV crystalloids within 3 hours (strong recommendation, low quality evidence)
• Vasopressors:
  • MAP target 65 mm Hg (strong recommendation, low quality evidence)
  • Norepinephrine 1st line (strong recommendation, moderate quality evidence). Epinephrine (weak recommendation, low quality evidence) or up to 0.03 Units/min vasopressin (weak recommendation, moderate quality evidence) may be added to NE.
• Antibiotics:
  • Obtain blood cultures prior to administration, but do not delay antibiotics (best practice)
  • Initiate empiric broad-spectrum antibiotics within 1 hour (strong recommendation, moderate quality evidence)
  • Consider double gram-negative coverage in patients with septic shock at high risk of multidrug-resistant pathogen
  • Risk factors for invasive Candida infection: immunocompromised state, TPN, necrotizing pancreatitis, recent major abdominal surgery, recent fungal infection
  • Optimize pharmacokinetic/pharmacodynamic properties- e.g., IV loading dose of vancomycin of 25-30 mg/kg is favored (best practice)
• Corticosteroids: IV hydrocortisone 200 mg per day if hemodynamic stability is not achieved through crystalloids and vasopressors (weak recommendation, low quality evidence)

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In a study comparing ketorolac IV doses of 10 mg, 15 mg, and 30 mg, no difference in pain score reduction or need for rescue analgesia was observed.

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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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