UMEM Educational Pearls - By Alicia Pycraft

Background:

Early antibiotic administration is consistently linked to improved mortality outcomes in patients with sepsis. As a result, time-to-antibiotic delivery is a critical metric in hospital sepsis quality improvement initiatives. Empiric treatment often consists of a broad-spectrum beta-lactam to cover both gram-positive and gram-negative organisms, alongside vancomycin to ensure coverage of methicillin-resistant Staphylococcus aureus (MRSA). When multiple agents are indicated, they may be given simultaneously; however, factors such as limited intravenous (IV) access or drug incompatibilities can necessitate sequential administration. Administration of vancomycin first may delay the administration of a beta-lactam agent by at least 60-120 minutes due to its prolonged infusion time. This raises an important clinical question: Does the order in which antibiotics are administered influence outcomes in sepsis? 

A 2022 retrospective study by Amoah et al. found that, among patients with confirmed bloodstream infections, a beta-lactam-first regimen was associated with a 52% reduction in the odds of short-term mortality compared to a vancomycin-first regimen. However, the generalizability of these findings to the broader population of patients with suspected sepsis, of whom only 15-20% ultimately have positive blood cultures, remains uncertain.  

What's new?

A recent retrospective, multi-center, cohort study by Kondo et al. evaluated the impact of a beta-lactam-first antibiotic strategy compared to a vancomycin-first strategy on in-hospital mortality in patients with suspected sepsis. Of the 25,391 patients with sepsis who were screened, 21,449 (84.4%) received a beta-lactam first and 3,942 (15.6%) received vancomycin first. Patients who received vancomycin first had lower comorbidity burden, lower illness severity, more skin/musculoskeletal infections, and received beta lactams a median of 3.5 hours later relative to ED arrival compared to those who received a beta-lactam first. Although the overall rate of documented bloodstream infections was similar between groups, MRSA-positive cultures were more common in the vancomycin-first group, both in clinical cultures (4.5% vs. 3.2%) and in blood cultures (1.8 vs. 1.2%). 

Beta-lactam administration prior to vancomycin was associated with an 11% reduction in the odds of in-hospital mortality (aOR: 0.89; 95% CI: 0.8-0.99; p=0.046). When the time-to-first antibiotic covariate was replaced with time-to-first beta-lactam, this association was no longer significant (aOR 0.93, 95% CI: 0.82-1.05, p=0.25), suggesting a possible link between time-to-first beta-lactam antibiotic and mortality. There was a trend toward lower in-hospital morality for the beta-lactam first regimen in several subgroups examined, including patients with positive blood cultures or positive MRSA cultures, and patients who received anti-pseudomonal beta-lactams; however, none reached statistical significance. 

Bottom line:

Given the observed mortality benefit and absence of harm associated with a beta-lactam-first approach, even among patients with positive MRSA cultures, the findings of this study support the prioritization of beta-lactam therapy in patients with sepsis.

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Background

Treatment of acute agitation often involves combining antipsychotics and benzodiazepines. Injectable olanzapine, a second-generation antipsychotic, uniquely carries a warning against concomitant use with parenteral benzodiazepines. The olanzapine prescribing information states that “concomitant administration of intramuscular (IM) olanzapine and parenteral benzodiazepines is not recommended due to the potential for excessive sedation and cardiorespiratory compromise”. The European Medicines Agency (similar to the United States FDA) cautions against use of the two within 60 minutes of each other using similar language.  

The above warnings were based on a 2010 publication of 160 adverse event reports from a post-marketing database maintained by the drug manufacturer, and have resulted in many institutions prohibiting co-administration of IM olanzapine and parenteral benzodiazepines. The publication cited 29 fatal adverse events involving injectable olanzapine, concluding that caution should be exercised when using IM olanzapine and parenteral benzodiazepines simultaneously. However, 25 of the 29 patients received other sedating medications in addition to olanzapine and benzodiazepines, and the majority of fatalities were >12 hours after the last dose of olanzapine. Following this publication, a 2013 randomized controlled trial by Chan et al. found no difference in adverse event rates between patients receiving IV midazolam alone and patients receiving IV midazolam plus IV olanzapine for acute agitation.

This December 2024 study by Cole et al. aimed to re-evaluate the risks of cardiorespiratory compromise with concomitant injectable olanzapine and injectable benzodiazepine administration.  

Study design

This was a single-center retrospective cohort study of 693 patients who received 2 parenteral doses of eligible sedating medications within 60 minutes of each other. A total of 549 patients received 2 doses of olanzapine, and 144 received olanzapine and a benzodiazepine (midazolam, lorazepam, or diazepam). To avoid cohorts with a higher baseline risk of sedation, patients who received other sedating medications and patients who received more than 2 doses of olanzapine or 1 dose of a benzodiazepine were excluded. 

Patient Population

• Average age of 35
• Mostly male
• Most patients were intoxicated with alcohol
  • 65% in olanzapine + olanzapine group
  • 88% of patients in olanzapine + benzodiazepine group
  • Median blood alcohol concentration of 210 mg/dL for both groups
• Average time between medications was about 30 minutes for both groups
• Most medications were given via IM route

Results

*One death during hospitalization was due to missed occlusion myocardial infarction

• No significant difference in rates of intubation
• No significant difference in rates of hypoxemia or hypotension at any time after drug administration while in the ED
• No significant differences in primary or secondary outcomes when inclusion criteria was expanded to 2 doses within 120 minutes of each other in pre-specified sensitivity analysis

Study Critique:

• Well-designed study that attempted to address limitations of prior studies by excluding patients who received additional sedatives or multiple doses
• Median time of 30 minutes between doses aligns with real-world practice and pharmacokinetics of each medication
• May not be generalizable to all institutions and types of agitation, as most patients were agitated secondary to alcohol intoxication
• Study was slightly underpowered

Key Takeaways

• The concomitant administration of IM olanzapine with parenteral benzodiazepines may pose less risk than labeled warnings suggest.
• With the increasing pool of literature showing improved safety, it may be time to re-evaluate our practices surrounding these agents.

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The benefits of calcium treatment for hyperkalemia have historically been attributed to “membrane stabilization,” as it has been hypothesized to restore cardiac resting membrane potential.  However, the true mechanism by which calcium improves cardiac function in this setting remains unclear. This has led to inconsistencies in the clinical threshold for treating hyperkalemia with calcium. 

Piktel et al. recently conducted an experimental study investigating the adverse electrophysiologic effects of hyperkalemia and therapeutic effects of calcium treatment in isolated canine myocytes using ex vivo tissue and in vivo cellular techniques. 

Key study findings:

Effects of hyperkalemia:

• Slowed cardiac conduction velocity by 67% ± 7% (p<0.001)
• Shortened cardiac action potential duration by 20% ± 10% (p<0.002)
• Elevated cardiac resting membrane potential
• Caused QRS widening in all preparations, with appearance of the “sine wave” pattern in severe hyperkalemia

Effects of calcium treatment in the setting of hyperkalemia:

• Increased cardiac conduction velocity by 44% ± 18% (p<0.002)
• Caused narrowing of the QRS complex and normalization of ECG
• NO effect on action potential or resting membrane potential
• Effects were reversed with the addition of L-type calcium channel blockade with verapamil

Limitation: 

• Does not account for concomitant acidosis, bradycardia, or arrhythmias which may be present in patients with hyperkalemia

Bottom line: Findings of this study suggest that calcium's beneficial effects in hyperkalemia are not attributed to “membrane stabilization,” but rather to restoration of conduction velocity through L-type calcium channels and subsequent narrowing of the QRS complex. This supports calcium treatment in hyperkalemia when the ECG shows conduction slowing and QRS widening.

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Myasthenia gravis (MG) is an autoimmune neuromuscular disorder that affects an estimated 14 to 20 patients per 100,000 in the United States. Most patients with MG have autoantibodies against acetylcholine receptors (AChRs), which disrupt neuromuscular transmission through downregulation, destruction, blocking of AChRs or disrupting receptors in the postsynaptic membrane.

Several medications may worsen MG or precipitate myasthenic crisis, however, incidence is difficult to describe as literature is largely limited to case reports and there is often presence of other confounding factors. There are two proposed mechanisms for medications to cause or exacerbate MG:

1. Eliciting an autoimmune reaction against neuromuscular junction 
2. Interference with neuromuscular transmission

Several medications commonly used in the emergency department are known to impair neuromuscular transmission and may induce or worsen MG. The following medications should be avoided, or used with extreme caution in patients with MG*: 

*This list contains several common medications utilized in the emergency department, but is not an all-inclusive list of medications that may exacerbate MG. Please refer to the reference section for additional information.

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Nirmatrelvir-ritonavir (Paxlovid™) is a combination of two protease inhibitors used for the treatment of mild-moderate symptomatic COVID-19. Nirmatrelvir inhibits the SARS-CoV2 main protease, and ritonavir inhibits metabolism of nirmatrelvir, acting as a “booster” to increase nirmatrelvir concentrations. 

The EPIC-HR trial, which included non-hospitalized adults with mild-moderate COVID-19 who were unvaccinated and at risk of progressing to severe disease, showed an 89% reduction in COVID-19-related hospitalization or 28-day all-cause mortality in patients treated with nirmatrelvir-ritonavir compared to placebo. The efficacy rates in this trial were similar to remdesivir (87% relative risk reduction), and greater than molnupiravir (31% relative risk reduction), two alternative agents used for treatment of mild-moderate COVID-19. However, these three agents have never been directly compared. Nirmatrelvir-ritonavir was initially approved by the FDA under Emergency Use Authorization (EUA), but is now fully FDA-approved as of May 2023. 

Which patients benefit?

• Mild – moderate COVID-19 symptoms
  • ED or outpatients
  • Hospitalized patients who are admitted for reasons other than COVID-19
• Not requiring supplemental oxygen above baseline needs
• Presenting within 5-7 days of symptom onset
• Risk factor(s) for progression to severe disease
  • Age > 65
  • Comorbidities such as diabetes, chronic lung disease, asthma, malignancy, etc.
  • Immunocompromise

Drug-Drug Interactions:

• Ritonavir strongly inhibits the CYP3A4 enzyme, which may significantly increase serum concentrations of medications metabolized by CYP3A4. Several common medications are metabolized by this enzyme and concomitant use may pose serious risk of toxicity.
• In many cases, drug-drug interactions can be managed safely with close monitoring or dose adjustments. Some may require use of alternative COVID-19 therapies such as remdesivir or molnupiravir.

Dosing:

• eGFR 60 mL/min or above: Nirmatrelvir 300 mg (2 tabs) + ritonavir 100 mg (1 tab) twice daily for 5 days
• eGFR >30 - <60 mL/min: Nirmatrelvir 150 mg (1 tab) + ritonavir 100 mg (1 tab) twice daily for 5 days
• eGFR <30 mL/min: Use is not recommended per the manufacturer, but retrospective studies have shown that reduced dosing is well-tolerated.

Common side effects:

• Diarrhea (3%)
• Altered sense of taste (5%)

Bottom Line: Paxlovid is appropriate for patients with symptomatic mild-moderate COVID-19 with risk factors for progression to severe disease. Ask your pharmacist for assistance evaluating drug-drug interactions!

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Background: It is estimated that nearly 6% of U.S. adults and children report having a food allergy.^1,2 Epinephrine autoinjectors are used to provide life-saving pre-hospital treatment for patients experiencing anaphylaxis in the community, but can have serious consequences if administered incorrectly. Accidental finger-stick injuries with epinephrine auto-injector can result in significant pain and ischemia due to vasoconstriction and decreased blood flow to the digit. Treatments for digital epinephrine injection include supportive care, topical vasodilators, and injectable vasodilators.³

Supportive care^3,4:

• Warm compresses are preferred to increase local blood flow and enhance removal of the drug. Cold compresses may result in worsening ischemia. 
• Apply for 15 minutes every 6 hours

• Increases production of nitric oxide which relaxes smooth muscles and causes vasodilation
• Literature shows variable symptomatic improvement for adults and neonates, but safe use as an adjunct to injectable vasodilators or as monotherapy.
• Apply a 1-inch strip of nitroglycerin 2% ointment over the affected area and repeat every 8 hours until symptoms resolve
• Patients should be monitored for hypotension after application, as topical nitroglycerin is systemically absorbed.

• Alpha-1 adrenergic antagonist that competitively blocks alpha-adrenergic receptors to produce brief antagonism of circulating epinephrine and norepinephrine. Phentolamine also promotes vasodilation and increases capillary blood flow. 
• Evidence for use after accidental injection of epinephrine autoinjector is mostly described in case reports, but one study showed that phentolamine was more effective at vasodilation than either nitroglycerin or sodium nitroprusside for treatment of digital norepinephrine injection. In another study of epinephrine-injected patients, subjects reported normal fingertip sensation in an average of 120 minutes after injection of phentolamine compared to 549 minutes after injection of saline. It took an average of 85 minutes for the epinephrine-injected digits to return to normal color after phentolamine injection compared to an average of 320 minutes after injection with saline.
• Preparation/application: Dilute 5 mg of phentolamine in 10 mL of 0.9% sodium chloride. Inject small amounts subcutaneously into the affected area.

• Beta-2 adrenergic agonist that causes vasodilation and attenuates the effect of alpha adrenoreceptor-mediated vasoconstriction.
• Evidence shows that terbutaline has resulted in immediate and complete resolution of symptoms following accidental digital epinephrine injections if administered within 2 hours of the incident and it may be considered if phentolamine is not available.
• Preparation/application: Dilute 1 mg of terbutaline with 1 mL of 0.9% sodium chloride and inject subcutaneously into the affected area.
• May cause elevations in heart rate and blood pressure, as well as ECG changes. Terbutaline should be used cautiously in patients with cardiovascular disease.

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