UMEM Educational Pearls - By Alicia Pycraft

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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