All posts by Erik Zalewski

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Intranasal Epinephrine: The solution every dentist has been waiting for?

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ARS Pharmaceuticals, Inc.  has developed an intranasal (IN) epinephrine, “neffy”, designed for use in severe allergic reactions.  neffy is an aqueous epinephrine preparation with the addition of the functional excipient Intravail® A3 (dodecylmaltoside) to improve the bioavailability of the drug to increase absorption through nasal mucosa to injection-like levels without known injection-related adverse effects such as pain or irritation, and is already used in two other FDA-approved products.  

While still under review by the FDA, the data surrounding neffy’s safety and efficacy is pretty convincing.  Although there is no talk yet about what the cost will be, this could be a game changer for dentists.  Instead of buying expensive epinephrine autoinjectors or drawing up and injecting an intramuscular dose of 1:1000 epinephrine, a single dose sprayer can be applied into a patient’s nostril.  The sprayer device is identical in design to that which is already used to administer six other medications, including Narcan (naloxone).

In anticipation of neffy receiving FDA approval, Have Dummy Will Travel is working with our suppliers to provide this product to our clients.  In addition, we will be creating a brief training video to help relieve any anxiety over delivering medication through the intranasal route.     

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Sublingual Epinephrine?

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Intramuscular administration of epinephrine is considered to be the  treatment of choice in patients experiencing anaphylaxis in community settings.  Considering the skills that are needed to provide IM injections are often unfamiliar to dentists, many keep very expensive epinephrine auto injector devices in their emergency drug kits.  Since aqueous epinephrine degrades quickly in normal storage conditions, including exposure to light, heat, oxygen and neutral or alkaline pH values1, they have a relatively short shelf-life (12-14 months).  Wouldn’t it be great if there was a cheaper, easier to administer, and longer lasting alternative?

Sublingual epinephrine has been under development for at least 20 years, and a recently published study touts a new sublingual matrix, AQST-109, as a promising vehicle by which epinephrine may be administered2.  Results showed nearly equivalent, if not better, loading and peak concentrations, when compared to traditional intramuscular absorption.  

Don’t get too excited yet, as that study was only the first human study, as was performed on only 24 healthy adult volunteers.  While low molecular weight, lipophilic drugs such as epinephrine are likely absorbed across sublingual mucosa into venous circulation by transcellular diffusion3, there still is no evidence that absorption will be effective in the presence of edema in the lingus and other proximal mucosa, when the osmotic gradient favors mass movement to the interstitial space– a common occurrence during anaphylaxis.  In addition, a previous study4 found varied absorption rates of epinephrine delivered through the sublingual route.  To be fair, the epinephrine was in a powered formulation, different than the AQST-109 sublingual matrix, and included only 10 adult men in its dataset.  Another rabbit study5 hypothesized that sublingual absorption occurs in a series of peaks, as alpha effects of epinephrine causes vasoconstriction, limiting the amount of absorption possible after initial exposure.  

So for right now, we are in a holding pattern. 

This might also be a good time to think about the incidence of anaphylaxis in dentistry.  In my hundreds of conversations with dentists, it seems to me that anaphylactic shock is one of the most feared emergencies, yet very few have actually encountered a true anaphylactoid-like reaction in practice or elsewhere.  This inexperience is consistent with estimates that anaphylaxis occurs in 0.004 – 0.015 cases per dentist per year. 6-8  Morbidity occurs only in 0.5% to 1.5% of all anaphylaxis cases.9-11

Please do not get the impression that I am advocating for a dentist to abdicate responsibility to be prepared to manage an anaphylactoid-like scenario.  However, given the above, it seems difficult to justify spending upwards of $1000 every year or so on something you should not use during the off-chance of encountering a case of anaphylaxis.  Instead, you should know how to recognize anaphylactoid-like reactions, administer epinephrine, diphenhydramine and oxygen immediately, position the patient in the trendelenburg position (or as close as possible), and be ready to administer albuterol.  Most importantly, call 9-1-1 as soon as possible, keeping in mind that your emergency medical kit should be designed to keep your patient alive for 15 – 30 minutes.

Erik Zalewski is a Nationally Registered Paramedic and New York State EMS Certified Instructor Coordinator with almost 30 years experience responding to 9-1-1 calls for medical emergencies.  Erik has taught EMTs and paramedics at Stony Brook University and the Suffolk County, NY EMS academy.  He and his team at Have Dummy Will Travel, Inc. are dedicated to helping medical professionals respond to emergencies safely, efficiently and in the most cost-effective manner possible.  Call or text 631-849-4978 for additional information.  

References

  1. Rawas-Qalaji, M.M. et al (2013). Long term stability of epinehrine sublingual tablets for the potential first-aid treatment of anaphylaxis.  Annals of Allergy and Asthma Immunology. 111:567-579.
  2. Golden, D. et al. (2023). Pharmacokinetics and pharmacodynamics of epinephrine sublingual film versus intramuscular epinephrine.  Journal of Allergy and Clinical Immunology.  AB4.
  3. Birudaraj, R., Berner, Shen, S. & Li, X. (2005).  Buccal permeation of buspirone: mechanistic studies on transport pathways.  Journal of Pharmacological Science.  94:70-78.
  4. Simons, K.J., Gu, X., & Simons, F.E.R. (2004). Sublingual epinephrine administration in humans: A preliminary study. Journal of Allergy and Clinical Immunology.  113(2):S260.
  5. Rawas-Qalaji, M, Simons, F.E.R. & Simons, K.J. (2006). Sublingual epinephrine tablets versus intramuscular injection of epinephrine: Dose equivalence for potential treatment of anaphylaxis.  Journal of Allergy and Clinical Immunology. 117(2): 398-403.
  6. Girdler,  N.M. & Smith, D.G. (1999). Prevalence of emergency events in British dental practice and emergency management skills of British dentists. Resuscitation. 41:159–167. 
  7. Muller, M.P., Cansel, M., Stehr, S.N., Weber, S. & Koch T. (2008).  A statewide survey of medical emergency management in dental practices: incidence of emergencies and training experience. Emergency Medical Journal. 25:296–300. 
  8. Arasti, F., Montalli, V.A., Florio, F.M., et. al. (2010). Brazilian dentists’ attitudes about medical emergencies during dental treatment. Journal of Dental Education. 74:661–666.  
  9. Moneret-Vautrin, D., Morisset, M., Flabbee, J., Beaudouin E., & Kanny, G. (2005). Epidemiology of life-threatening and lethal anaphylaxis: a review. Allergy 60:443–451. 
  10. Helbling, A., Hurni, T., Mueller, U. & Pichler, W. (2004).  Incidence of anaphylaxis with circulatory symptoms: a study over a 3-year period comprising 940,000 inhabitants of the Swiss Canton Bern. Clinical and Experimental Allergy.  34:285–290. 
  11. Sheikh, A. &  Alves, B. (2001).  Age, sex, geographical and socio-economic variations in admissions for anaphylaxis: analysis of four years of English hospital data. Clinical and Experimental Allergy. 31:1571–1576.

Medical Emergencies

Why Glucagon Should NEVER, EVER Be In Your Emergency Drug Kit

A client recently called me looking to purchase glucagon for her emergency medications kit.  Intrigued, I asked probing questions to determine the reason.  Apparently, she had recently attended a lecture on managing medical emergencies in the office and was given advice to keep this drug in her kit for cases of anaphylactic shock that is refractory to epinephrine due to beta-blocker use.  The reasoning (as I understood the client’s explanation) was that glucagon can block the beta1 receptors on the heart, nullifying the effects of the beta blockers.  There is a tremendous amount to unpack here.

The first item we should explore is the incidence of anaphylaxis in dentistry.  In my hundreds of conversations with dentists, it seems to me that anaphylactic shock is one of the most feared emergencies, yet very few have actually encountered a true anaphylactoid-like reaction in practice or elsewhere.  This inexperience is consistent with estimates that anaphylaxis occurs in 0.004 – 0.015 cases per dentist per year. 1-3  

According to the CDC4, 22.3% of the American population between 40 and 79 is on beta blocking medication.  If we extrapolate that only 40 – 79 year old patients visit a dentist; therefore 22.3% of dental patients are on beta blockers, and if we conservatively estimate that beta blockers will block the effects of epinephrine in all patients, we can estimate that anaphylaxis refractory to epinephrine is between 0.00009 and 0.0003345 cases per dentist per year.  

As an aside, morbidity occurs only in 0.5% to 1.5% of all anaphylaxis cases.5-7

Perhaps a 0.009% to 0.03% chance of having a patient in front of you who can, according to the lecturer, benefit from the use of glucagon is enough for you to want to spend upwards of $200 per milligram, just in case.  The following is a direct quote from the Journal of Oral and Maxillofacial Surgery8.  

The recommended dosage for glucagons [sic] is 1 to 5 mg (20 to 30 mg/kg [sic] [maximum dose, 1 mg] in children) administered intravenously over 5 minutes and followed by an infusion (5 to 15 mg/min) titrated to clinical response. Airway protection must be ensured because glucagon frequently causes emesis.

Raise your hand if you are comfortable starting an IV.  Many dentists I speak with tell me that they are uncomfortable giving an IM injection, at least until they take my training class.  Keep your hand up if you have IV start kits, fluids, tubing and catheters included in your emergency kit.  Keep it up if you are prepared to give an infusion over 5 minutes because you have an IV pump or flow-regulating device and feel comfortable enough to work out the mathematics involved in determining how many drops of  fluid to give per second after producing a particular concentration from adding the glucagon to an appropriately-sized fluid bag, and taking into account the size of the drops produced in your tubing.  Finally, keep your hand up if you have a cardiac monitor and the knowledge to recognize potential cardiac dysrhythmias and QT elongation before administering an IM/IV antiemetic like ondansetron for the airway complication you might create using glucagon.  Oh wait, do you have ondansetron?   

Still not convinced that glucagon is completely unnecessary and a waste of your hard-earned money?  Let’s look at the actual pharmacodynamics of glucagon and some of the other indicated medications we give patients in anaphylaxis.  

First, glucagon does NOT bind to or prevent beta blockers from binding to beta receptor sites in the heart.  Consistent with Hernández‑Cascales’ 9 meta-analysis of glucagon effects in both animal models and human ex situ experiments, glucagon is used in profound beta blocker overdoses because it has chronotropic effects on the myocardium– it causes the heart to beat faster.  Perhaps this is due to sympathetic nervous system stimulation at the hypothalamus and the elevation of circulating catecholamines.  Despite several papers describing the use of glucagon in beta blocker overdose, I have not been able to find any evidence that is not simply anecdotal– it seems that no clinical trials have been published.

Second, if we treat a patient in anaphylaxis properly, we would be using a multi-pronged approach.  Keep in mind that beta blockers are selective for beta1 receptors in the heart only and do not have an effect on beta2 receptors, located only in the lungs or alpha1 receptors located in the vasculature.  The first line medication is epinephrine, a non-selective alpha and beta agonist.  Since anaphylaxis is a form of distributive shock, alpha1 stimulation– peripheral vasoconstriction is really what we are looking for in epinephrine.  The lion’s share of the work is completed by shrinking the size of the venous reservoir, raising the blood pressure.  Increased chronotropy (beta1 effects) and bronchodilation (beta2 effects) are nice to have but much less important.  

Administering glucagon will increase blood sugar– that is its main job in the body.  Raising blood sugar causes blood acidosis.  Epinephrine is sensitive to pH and becomes less effective in severe metabolic acidosis (pH<6.8)10. 

The albuterol in your kit can be given for its beta2 effects (bronchial dilation).  It should be noted that albuterol is not purely beta2 in nature and that it does have some beta1 properties.  This is why xopenex is used  in patients where tachycardia is relatively contraindicated, as it is more purely beta2 in nature.   Albuterol will compete for the cardiac beta1 sites that are occupied by the beta antagonists, thus ameliorating at least some of the effects of beta blockers.

The diphenhydramine you have in your kit is also important in blocking the histamines that are released by degranulation of mast cells and neutrophils.  This has other important effects such as the prevention of edema in the airway as well as overall immune response to the allergen.  Oxygen is administered to a patient who received epinephrine, due to increased demand by the myocardium, thus reducing the production of lactic acid and preventing acidosis. 

Not in your kit, but worth mentioning is the use of steroids to quell the overall immune response and reduce inflammation and fluid boluses that are used to increase blood volume and thus pressure.   These can be administered by paramedics and hospital emergency rooms.  

Please do not get the impression that I am advocating for a dentist to abdicate responsibility to be prepared to manage an anaphylactoid-like scenario.  However, given the above, it seems difficult to justify spending upwards of $1000 every year or so on something you should not use during the off-chance of encountering a case of anaphylaxis that is refractory to epinephrine due to beta blocker use.  Instead, you should know how to recognize anaphylactoid-like reactions, administer epinephrine, diphenhydramine and oxygen immediately, position the patient in the trendelenburg position (or as close as possible), and be ready to administer albuterol.  Most importantly, call 9-1-1 as soon as possible, keeping in mind that your emergency medical kit should be designed to keep your patient alive for 15 – 30 minutes.

Erik Zalewski is a Nationally Registered Paramedic and New York State EMS Certified Instructor Coordinator with over 27 years experience responding to 9-1-1 calls for medical emergencies.  Erik has taught EMTs and paramedics at Stony Brook University and the Suffolk County, NY EMS academy.  He and his team at Have Dummy Will Travel, Inc. are dedicated to helping medical professionals respond to emergencies safely, efficiently and in the most cost-effective manner possible.  Call or text 631-849-4978 for additional information.  

References

  1. Girdler,  N.M. & Smith, D.G. (1999). Prevalence of emergency events in British dental practice and emergency management skills of British dentists. Resuscitation. 41:159–167. 
  2. Muller, M.P., Cansel, M., Stehr, S.N., Weber, S. & Koch T. (2008).  A statewide survey of medical emergency management in dental practices: incidence of emergencies and training experience. Emergency Medical Journal. 25:296–300. 
  3. Arasti, F., Montalli, V.A., Florio, F.M., et. al. (2010). Brazilian dentists’ attitudes about medical emergencies during dental treatment. Journal of Dental Education. 74:661–666.  
  4. Hales, C.M., Servais, J., Martin, C.B & Kohen, D. (2019).  Prescription Drug Use Among Adults Aged 40–79 in the United States and Canada.  NCHS Data Brief 347. www.cdc.gov/nchs/products/databriefs/db347.htm   Retrieved August 6, 2020.
  5. Moneret-Vautrin, D., Morisset, M., Flabbee, J., Beaudouin E., & Kanny, G. (2005). Epidemiology of life-threatening and lethal anaphylaxis: a review. Allergy 60:443–451. 
  6. Helbling, A., Hurni, T., Mueller, U. & Pichler, W. (2004).  Incidence of anaphylaxis with circulatory symptoms: a study over a 3-year period comprising 940,000 inhabitants of the Swiss Canton Bern. Clinical and Experimental Allergy.  34:285–290. 
  7. Sheikh, A. &  Alves, B. (2001).  Age, sex, geographical and socio-economic variations in admissions for anaphylaxis: analysis of four years of English hospital data. Clinical and Experimental Allergy. 31:1571–1576.
  8. Sharma, R., Sinha, R., Menon, P.S. & Sirohi, D.  (2010).  Glucagon for Persistent Hypotension in Patients Taking beta-Blockers.  Journal of Oral and Maxillofacial Surgery.  68(4):855-862.
  9. Hernández‑Cascales, J. (2018). Does glucagon have a positive inotropic effect in the human heart?  Cardiovascular Diabetology. 17:148.

Vidal, C., Grassin-Delyle, S., Devillier, P., Naline, E., Lansac, E., Menasche, P. & Faisy,C. (2014) Effect of severe acidosis on vasoactive effects of epinephrine and norepinephrine in human distal mammary artery.  The Journal of Thoracic and Cardiovascular Surgery. 147(5):1699.