UMEM Educational Pearls - Pharmacology & Therapeutics

Background:

Epinephrine administration is a critical component of treating severe allergic reactions, and delayed administration is associated with increased morbidity and mortality. Epinephrine auto-injectors are the current standard of care and allow for rapid administration in all care settings, but compliance issues can limit their use. The most common reason patient’s site for failure to administer or delayed administration of auto-injectors is needle phobia (particularly with pediatric patients). This has led to interest in developing needle-free epinephrine delivery devices that are easy to administer.

New Drug Approval:

This August, the FDA approved an epinephrine nasal spray (brand name: Neffy) for use as emergency treatment for Type 1 allergic reactions, including life-threatening anaphylaxis. The approval was based on four studies, including 175 total patients, comparing epinephrine 2 mg nasal spray with an epinephrine 0.3 mg intramuscular injection in healthy adults and children. These studies showed similar blood concentrations of epinephrine between treatment arms through 60 minutes after administration. In addition, both treatment arms showed similar elevations in heart rate and systolic blood pressure.

• Who is it for?
  • Epinephrine 2 mg nasal spray is approved for all adult and pediatric patients who weight more than 30 kg (66 lbs).
• How is it supplied?
  • Epinephrine 2 mg nasal spray comes in single-use devices, as a unit-dose spray. This is the same device that is used for many other commercially available internasal products, including Narcan (naloxone) nasal spray.
• How it is given?
  • Epinephrine 2 mg nasal spray device should be fully inserted into one nostril pointing straight into the naris, and then the plunger should be depressed. If symptoms do not improve or worsen after the first dose, a second dose of epinephrine 2 mg nasal spray should be given into the same nostril.
• Common side effects?
  • The most common side effects are throat irritation, intranasal paresthesia, headache, nasal discomfort, feeling jittery, paresthesia, fatigue, tremor, rhinorrhea, nasal pruritis, sneezing, abdominal pain, gingival pain, oral hypoesthesia, nasal congestion, dizziness, nausea and vomiting. 

Bottom Line:

Epinephrine nasal spray is a newly approved option for the treatment of severe allergic reactions and anaphylaxis. While this approval was based on studies in healthy adults and children who did not currently have anaphylaxis, this medication may be worth considering for patients who have issues or concerns about using an injectable device to administer epinephrine.

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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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Question

At our institution we have developed a guideline for the use of hypertonic saline in hyponatremia.

Administration of 3% sodium chloride for acute or symptomatic hyponatremia

• Bolus doses are preferred over continuous infusion.
• Use in patients with rapid decline in serum sodium levels (>= 10 mEq decrease over 24 hours) or symptomatic (e.g. seizures).
• Do not attempt to normalize the serum sodium level in the first 24 hours.
• Serum sodium correction should be no more than 8-10 mEq/L in a 24-hour period.
  • 8 mEq/L (or less) should be used in patients at high risk for osmotic demyelination syndrome
  • High risk populations: chronic hyponatremia, hypokalemia, alcoholism, malnutrition, or liver disease
• Chronic hyponatremia should be corrected over days with a goal of 4-8 mEq/L in 24 hours.
  • Fluid restriction should be considered first-line for chronic hyponatremia.

Acute hyponatremia with severe symptoms

• Bolus 3% sodium chloride 150 mL over 10 minutes.
• If symptoms persist repeat up to 3 doses over 30 minutes.

Acute hyponatremia with moderate symptoms

• Bolus 3% sodium chloride 150 mL over 20 minutes once.

Hyponatremia Fluid Rate Calculations (**Be Careful with Online Calculators**)

FYI: 3% Sodium Chloride (1.95 mL/mEq; 513 mEq/1 L); 0.9% Sodium Chloride (6.5 mL/mEq; 154 mEq/1 L)

Equations for Calculations

1. Sodium correction for HYPERglycemia
   1. Corrected Na=Observed Na + 0.016 x (serum glucose-100)
2. Calculated Sodium Deficit
   1. Female: (Desired Na – Observed Na) x 0.5 L/kg x weight (kg)
   2. Male: (Desired Na – Observed Na) x 0.6 L/kg x weight (kg)
   3. This equation will give you the total mEq of Na needed in 24 hours.
   4. Remember: Correction should be no more than 8 mEq/L in 24 hours in most cases.
3. Calculated Infusion Rate for Sodium Correction
   1. ___ mEq Na required (from Equation 2) x ___ mL/mEq of fluid = ___ mL of fluid
   2. ___ mL of fluid / 24 hours = ___ mL/hr of fluid

***See Visual Diagnosis for an Example with Calculations***

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Two recommendations from the recent GRACE 4 publication in Academic Emergency Medicine to consider:

1. Use phenobarbital along with benzodiazepines in patients with moderate to severe alcohol withdrawal. The evidence isn’t robust but is positive when compared to benzos alone.

2. Adults with alcohol use disorder can benefit from anti-craving medications such as naloxone and gabapentin at time of discharge.

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A panel comprised of 21 participants selected by four clinical toxicology societies (America’s Poison Centers, American Academy of Clinical Toxicology, American College of Medical Toxicology, and Canadian Association of Poison Control Centers) sought to develop consensus guidelines for management of acetaminophen poisoning in the US and Canada. Highlights from this framework include:

Acetylcysteine Stopping Criteria

A common misconception is that acetylcysteine is administered for 21 hours then discontinued. The consensus statement codifies the practice of reassessing the patient at the end of the acetylcysteine infusion and only stopping acetylcysteine if all of the following criteria are met:

• Acetaminophen concentration <10 mcg/mL
• INR <2.0
• ALT/AST normal for patient or if elevated have decreased from peak (25%-50%)
• Patient is clinically well

Ingestion of Extended-Release Acetaminophen Products

Extended release acetaminophen products are available on the US market. Management is largely the same as for instant release acetaminophen except for several exceptions:

• Activated charcoal may be useful >4 hours after ingestion if acetaminophen concentration is rising (indicating ongoing absorption)
• If a concentration drawn 4-12 hours after ingestion is >10 mcg/mL but below the Matthew-Romack treatment line, a second level should be drawn in four to six hours

Management of Repeated Supratherapeutic Acetaminophen Ingestion

When a patient presents following repeated acetaminophen ingestions over a period of greater than 24 hours the Matthew-Romack nomogram is no longer applicable for guiding decisions regarding treatment with acetylcysteine. The consensus statement recommends initiating treatment in this scenario if the patient’s acetaminophen concentration is > 20 mcg/mL or if patient’s AST/ALT are abnormal.

Final Thoughts:

These guidelines will function as a useful reference and officially codify a general framework with evidence-based recommendations for the management of acetaminophen poisoning. As always, a poison center or clinical toxicologist should be consulted for any complicated or serious acetaminophen poisoning.

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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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Naloxone is given frequently in the emergency department to improve the respiratory rate in patients with suspected or known opioid ingestion.  In order to minimize the risk of severe opioid withdrawal (nausea, vomiting, diarrhea, anxiety, piloerection, sweating, agitation, etc.), consider diluting naloxone and administering small aliquots of 0.04-0.08mg at a time.  This requires IV access and a patient with a present, but low respiratory rate.

Dilution instructions:

Supplies:

• 10 mL vial of 0.9% sodium chloride
• 1 vial of 0.4 mg/mL naloxone
• 1 empty 10 mL syringe/needle

Instructions:

1. Withdraw 9 mL of 0.9% sodium chloride into an empty syringe. 
2. Add 1 mL of naloxone 0.4 mg/mL
3. Label syringe as: Naloxone 0.04 mg/mL

Administer 1 -2 mL (0.04 – 0.08 mg) naloxone every 2 minutes and assess response.

Don't forget to prescribe/give naloxone upon discharge from the emergency department.

MYTH: Bactrim cannot be used as monotherapy for nonpurulent skin and soft tissue infections.

Not True!

Organisms of concern: Streptococcus spp.

Here’s why:

• Sulfamethoxazole-Trimethoprim (Bactrim) disrupts folic acid synthesis & utilization.
• This prevents the biosynthesis of the nucleic acid thymidine by bacteria and causes them to die. 
• Some species of Strep, including S. pyogenes, are able to utilize exogenous sources of thymidine to continue their life cycle. 
• Guess what? The laboratory media that was originally used to test Strep spp. susceptibility to Bactrim contained thymidine - therefore the bacteria were able to use it and did not die!
• When tested using thymidine-depleted media, all 370 S. pyogenes isolates tested were highly susceptible to Bactrim!

TRUTH: Bactrim CAN be used as monotherapy for nonpurulent skin and soft tissue infections.

Prepared by Rianna Fedora, PharmD on 2/26/24

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Attachments

• SMX-TMP Myth Buster Inservice-65f3561ae6df0.pdf (58 Kb)

Empiric antimicrobial treatment for necrotizing soft tissue infections (NSTIs) should include coverage of a wide range of pathogens including Staphylococcus spp, Streptococcus spp, anaerobic bacteria and gram negative bacteria. Treatment should also include an agent that suppresses toxin production by group A Streptococcus (GAS), with the Infectious Diseases Society of America (IDSA) guidelines recommending clindamycin plus penicillin for treatment of GAS causing necrotizing fasciitis and toxic shock syndrome. A typical empiric NSTI regimen would be vancomycin plus clindamycin plus piperacillin-tazobactam. 

Linezolid is an appealing alternative to clindamycin and vancomycin, as it has anti-toxin effects via inhibition of exotoxin expression, potent in vitro activity against Streptococcus spp, activity against methicillin-resistant Staphylococcus aureus (MRSA), and potential for less adverse effects than clindamycin plus vancomycin. Several recent studies have looked at using linezolid in lieu of clindamycin plus vancomycin when treating NSTIs.

Published Studies:

Dorazio and colleagues published a retrospective single center study compared 62 matched pairs of patients who received linezolid vs. clindamycin plus vancomycin as part of their NSTI treatment.

• Primary outcome was mortality at 30 days and secondary outcomes were the rates of C. difficile infection and rates of acute kidney injury (AKI). 
• No statistically significant difference in any primary or secondary outcomes noted, although there was a trend towards more AKI with clindamycin plus vancomycin versus linezolid 
  • AKI rates: 9.68% in the clindamycin + vancomycin group vs 1.61% in the linezolid group; HR 6 [95% CI .73-276]

Heil and colleagues published a retrospective single center cohort study examined patients who received either linezolid (n = 29) or clindamycin (n = 26) for treatment invasive soft tissue infection or necrotizing fasciitis with GAS isolated from blood and/or tissue.

• There was no difference in any primary or secondary outcomes, which included inpatient mortality, duration of vasopressor requirement, hospital length of stay, rates adverse drug events and change in Sequential Organ Failure Assessment score from baseline through 72 hours of hospitalization.

Lehman and colleagues published a retrospective single center study compared patients who received linezolid (n = 21) versus clindamycin plus vancomycin (n = 28) in addition to gram-negative and anaerobic coverage for empiric treatment of NSTIs.

• The primary outcome of duration of MRSA-active therapy was 2.9 days in the linezolid group versus 3.9 days in the vancomycin group (p = 0.04)
• The only secondary outcome that reached statistical significance was new-onset AKI, with a rate of 38.1% in the vancomycin plus clindamycin group versus 0% in the linezolid group (0%)

Bottom Line:

When added to an agent with good gram negative and anaerobic coverage (i.e. piperacillin-tazobactam), linezolid may be a more viable option for coverage of MRSA and GAS toxin production during empiric NSTI treatment when compared to clindamycin plus vancomycin. This is largely due to a more favorable side effect profile.

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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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For the agitated geriatric patient, if verbal deescalation, distraction, and providing a safe quiet area do not work and you require chemical sedation use oral antipsychotics first.  Follow this with IV or IM antipsychotics. Avoid benzodiazepines due to often worsening delirium or respiratory depression. For dosing, start low and go slow.

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Bottom Line: Droperidol is an effective alternative to haloperidol in the treatment of gastroparesis although most patients will also receive prokinetic agents as well such as metoclopramide. It may also have some analgesic benefit.

Prior studies have demonstrated the efficacy and safety of haloperidol in the management of gastroparesis. A recent retrospective study was conducted to assess the impact of droperidol as it is an effective antiemetic similar to haloperidol.

This study enrolled 233 patients.  Visits were matched with their most recent ED visit > 7 prior where droperidol was not administered. 

Most patients were female, 51% African American, and the median age was 40.  Doses ranged from 0.625 mg – 2.5 mg with the most common dose being 1.25 mg. 

Results:

• 46% of the droperidol visits received opioids compared to 60% when droperidol was not given (p=0.004)
• Droperidol was noted to reduce pain scores from 9 (IQR 7-10) to 5 (IQR 0-8) (p=0.0001)
• Droperidol visits were prescribed fewer antiemetic agents 60% vs 73% (p=0.0045)
• There was no difference in the use of prokinetic agents (metoclopramide)
• No difference in ED or hospital LOS or admission rates (~30%), cost, or adverse events

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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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DOACs (dabigatran*, apixaban, rivaroxaban) each have different dosing strategies based on indication and patient characteristics. While there is no official term for the doses, the higher initial doses for apixaban (10 mg BID for 7 days) and rivaroxaban (15 mg BID for 21 days) for the treatment of venous thromboembolism (VTE) are commonly referred to as “loading doses.” However, the term “loading dose” is actually a misnomer.

Loading doses are used to reach therapeutic drug levels quicker with medications such as vancomycin and phenytoin/fosphenytoin. However, this is not the purpose of the higher initial doses of apixaban and rivaroxaban. The purpose of the higher doses is to provide increased levels of anticoagulation during the acute phase of VTE when patients are hypercoagulable. For this reason, VTE and heparin-induced thrombocytopenia are the only indications where a higher dose is used initially, all other indications start with the standard dose. The difference in duration of these higher doses between apixaban (7 days) and rivaroxaban (21 days) are due to the durations used in trials by the drug company, versus any pharmacokinetic reasons.

To apply this concept:

Apixaban/Rivaroxaban: For the treatment of VTE, a higher dose is only required for the initial 7- (apixaban) or 21-day period (rivaroxaban). After this period, if there is any interruption in therapy, the standard dose can be restarted because therapeutic levels are rapidly achieved and higher doses are not needed outside of the acute phase.

One caveat to this would be if the patient developed a new VTE while therapy is interrupted, in which case another period of the higher dosing could be considered.

*Remember: Dabigatran cannot be used for initial treatment of VTE and must be started only after at least 5 days of a parenteral anticoagulant. (Dabigatran and the parenteral anticoagulant should not be overlapped).

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ACLS guidelines state that thrombolytics may be considered for suspected pulmonary embolism during cardiac arrest. There is limited data supporting the recommendation; however, it is noted that the benefits likely outweigh the risks. There is also no consensus on the appropriate thrombolytic timing, drug, or dose.

Our institution recently implemented the use of tenecteplase for acute ischemic stroke, ST-elevation myocardial infarction (STEMI), and pulmonary embolism (PE). When using tenecteplase for suspected PE during cardiac arrest, we use the same weight-based dose used for STEMIs. We include a label on the outside of the tenecteplase box that lists all the doses for the various indications.

 Tenecteplase Dose

<60 kg: 30 mg

≥60 to <70 kg: 35 mg

≥70 to <80 kg: 40 mg

≥80 to <90 kg: 45 mg

≥90 kg: 50 mg

The tenecteplase dose is administered as an IV bolus over 5 seconds.

There is also limited data for the duration of CPR after thrombolytic administration, with no recommendations being made in most literature. Our current institutional guidelines recommend to consider continuing CPR for 60-90 minutes before resuscitation efforts are terminated. The only guideline that makes any mention of duration of CPR is the European Resuscitation Council Guidelines 2021, which makes the same recommendation.

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Citrate is an anticoagulant added to blood products to maintain stability for storage. With the administration of large volumes of blood products, citrate binds to ionized calcium, which can cause hypocalcemia. Evidence for specific calcium administration during massive transfusion protocols is limited; however, a proposed strategy has been to administer calcium gluconate 2 grams for every 2-4 units of red blood cells.

Robinson, et al. performed a retrospective analysis attempting to determine the optimal Citrate:Ca ratio (a novel ratio created for this study) to reduce 30-day mortality. They did not find any differences in mortality; however, they found a Citrate:Ca ratio of 2-3 produced a normalized ionized calcium level with 24 hours of a massive transfusion protocol.

Based on their calculations, this would equate to supplementing 1 g of calcium gluconate for every 3 units of red blood cells given.

***Reminder: Based on the amount of elemental calcium in each gram of calcium gluconate (4.7 mEq) and calcium chloride (13.6 mEq); 3 g calcium gluconate=1 g calcium chloride.***

Bottom Line: Supplementing with calcium gluconate 1 g for every 3 units of red blood cells should be sufficient to maintain normal ionized calcium levels after a massive transfusion protocol.

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Nitroglycerin easily migrates into polyvinyl chloride (PVC), a plastic commonly used in intravenous tubing due to its flexibility and low cost. A slow rate of flow and long tubing length increase the loss of nitroglycerin. While using less absorptive tubing (i.e. polyethylene or polypropylene) when administering nitroglycerin is recommended, most published clinical studies looking at nitroglycerin have used PVC tubing.

A 1989 study compared nitroglycerin delivery through PVC tubing and low sorbing tubing at various concentrations and flow rates.¹ Samples were obtained from the nitroglycerin bottle and the distal end of the tubing at several time points. 

• An average of 39.7% (SD 12.7) of nitroglycerin was lost at the distal end of PVC tubing, while an average of 2.3% (SD 9.3) of nitroglycerin was lost with low sorbing tubing.

A 2018 study enrolled 8 volunteers to receive nitroglycerin infusions through PVC tubing and low sorbing polyolefin tubing.² 

• The average max plasma concentration of nitroglycerin was 0.33 ng/ml (SD 0.19) in the PVC group, compared to 1.37 ng/ml (SD 0.89) with low sorbing tubing. 
• This small study showed a trend towards greater lowering of mean arterial pressure from baseline with low sorbing tubing when compared to the PVC group, although this was not statistically significant.

Bottom Line: Most studies evaluating nitroglycerin use in various clinical scenarios have used PVC tubing. Doses based on use with PVC tubing may be too high when using less absorptive tubing. Employing more conservative dosing strategies when using low sorbing tubing can help mitigate the risk of adverse effects (i.e. hypotension, headache).

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Emergency contraception is highly effective at preventing unwanted pregnancies and has been on the market for 20+ years.

Levonogestrel (LNG) 1.5 mg PO x 1 dose  (OTC Available)

Ulipristal acetate (UPA) 30 mg PO x 1 dose (Requires RX)

Original studies with LNG was estimated to prevent up to 80% of expected pregnancies.  In the subsequent trials that brought UPA to the market and compared the two medications, LNG prevented 69% (95% CI, 46-82%) and 52.2% (95% CI, 25.1-69.5%).

While pregnancy rates are low with both options there is concern with patients of higher weight/BMI that the effectiveness of levonorgestrel decreases as weight rises. One large study of over 1700 patients specifically noted that a weight > 75 kg was associated with up to 6.5% pregnancy rate (95% CI 3.1-11.5) compared to 1.4% (95% CI 0.5-3.0) in patients weighing 65-75 kg.  Patients weighing > 85 kg had similarly high rates at 5.7% (95% CI 2.9-10.0).

The cost difference is minimal between products, especially when considering costs associated with treatment failures and subsequent need for care- the largest difference is with respect to access as LNG is OTC and UPA requires an RX.  Either can be administered in an ED setting as long as they are on formulary.

ACOG also recommends that ulipristal be utilized for it higher overall efficacy compared to levonorgestrel. 

Consider:

For patients above 75 kg, ulipristal can be used as first line emergency contraception for up to 5 days following unprotected intercourse.

Patients < 75 kg and < 72 hours following unprotected intercourse can use levonorgestrel or ulipristal as an appropriate emergency contraception method.

Patients < 75 kg and 72-120 hours following unprotected intercourse should use ulipristal due to its efficacy beyond 72 hours.

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Myasthenia gravis is an autoimmune disease of the neuromuscular junction, most commonly due to antibodies attacking acetylcholine receptors in the postsynaptic membrane. Up to 30% of patients with myasthenia gravis will experience a myasthenic crisis during their disease course. If rapid sequence intubation is indicated, the unique characteristics of this patient population must be considered in the event use of a paralytic is necessary. All paralytic agents can be expected to last significantly longer, and an unpredictable response may be seen with depolarizing agents - therefore non-depolarizing agents are preferred in this population.

Non-Depolarizing Agents (Rocuronium, Vecuronium)

• MG patients have increased sensitivity to non-depolarizing agents and require lower doses than typically used
• It is reasonable to dose non-depolarizing agents at one-half the standard dose used. For example, rocuronium would be dosed at 0.5-0.6 mg/kg instead of the standard 1-1.2 mg/kg

Depolarizing Agents (Succinylcholine)

• MG patients have decreased expression of normal acetylcholine receptors which are required for depolarizing agents to work effectively and require higher doses than typically used
• Succinylcholine is typically dosed at 1.5-2.0 mg/kg (roughly double the dose used in other patient populations)

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Non-dihydropyridine calcium channel blockers, verapamil and diltiazem, can induce hypotension when administered intravenously (IV) in approximately 4% of patients.  It has previously been taught that administering IV calcium before administering these medications may prevent the hypotension.  Previously, this theory was tested for verapamil and found success with reducing hypotension.  Only one study has been done exclusively with diltiazem and it found no benefit. 

In a new multicenter retrospective cohort study of adults in the ED, patients were randomized into two groups: those who received diltiazem alone and those who received calcium with diltiazem for atrial fibrillation/atrial flutter (AF/AFL) with a HR ≥ 120 bpm. Patients were excluded if they required electrocardioversion, had other agents prior to diltiazem, incomplete information, were pregnant or incarcerated. The primary outcome was change in SBP 60 minutes (+/-30 minutes) after diltiazem administration.

Baseline characteristics: 73 year old, equal male:female, predominantly white patients.  40% had new onset AF/AFL and the initial HR was 140 in both groups. There were 198 patients in the diltiazem group and 56 patients in the combination group.  Notably, patients in the combination group had a lower presenting SBP 109 (101-121) vs 123 (114-132) P<0.0001 which matches classical teaching for when to consider calcium use. Additionally, patients in the combination group received a lower diltiazem dose of 10mg vs 15mg in the monotherapy group p=0.004 with both group receiving doses lower than the standard 0.25 mg/kg dosing recommendation.

Outcomes:

• Median change in SBP was not different between the monotherapy and combination therapy groups: (-2 mmHg vs -1.5 mmHg, p= 0.642)
• There was no difference in:
  • Time to rate control (1.4 vs 1.8 hours, p= 0.141)
  • Time to sustained rate control (7.9 vs 7.7 hours, p=0.570)
  • Change in HR at 60 minutes: (-33 vs -34 bpm, p=0.428)
• A subgroup analysis looking at timing of calcium (i.e. before or with diltiazem administration) also found no difference.

Take Home Point:

Administration of IV calcium may not be as beneficial as previously thought to prevent hypotension induced by diltiazem administration.  This particular study is confounded by the relatively low doses of diltiazem overall, but utilizing a lower dosing strategy in patients with low SBP is a reasonable safety strategy.

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