UMEM Educational Pearls - By Matthew Poremba

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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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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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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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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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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Magnesium has been associated with function of serotonin and vascular tone regulation, both of which are mechanisms that implicate there may be a role in treatment of migraine. As this is a well-tolerated medication with a good safety profile, there is interest in utilizing this medication in the treatment of migraines. However, studies comparing magnesium to standard migraine treatments are lacking.

A recent single-center, double-blinded, randomized controlled trial compared magnesium, metoclopramide and prochlorperazine for treatment of migraine in the ED. Patients received either magnesium sulfate 2 grams, metoclopramide 10 mg or prochlorperazine 10 mg intravenously over 20 minutes. Adjunctive and rescue medications could be used at the providers discretion.

Pain was assessed with the 11-point Numeric Rating Scale at baseline and at several timepoints after completion of the infusion. Median change in pain score was found to be -3 in all groups at 30 minutes. Post-hoc analysis found magnesium to be non-inferior to prochlorperazine and metoclopramide at this time point. No difference in ED length of stay was found between groups. Adverse events were reported in 5% of patients receiving magnesium, 4.5% in patients receiving metoclopramide and 11.5% in prochlorperazine patients (p = 0.51). The most common adverse events were dizziness, akathisias, and anxiety.

Bottom Line: Magnesium can be used as an adjunctive agent in the treatment of migraines, and may also be considered as an alternative agent when other options such as prochlorperazine and metoclopramide are not appropriate. A reasonable dose would be 2 grams IV infused over 20 minutes. The team should follow-up 30-60 minutes after infusion to assess response to therapy.

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