CQiR is a series of questions that emerge in Resuscitation by Ashley Mogul, MD.

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IV Bolus Epinephrine for Anaphylaxis: A Double-Edged Sword

Classically, epinephrine is given IM for anaphylaxis which is advantageous as the absorption is usually complete and you can start treatment before IV access is obtained.  We have moved away from SQ epinephrine as the peak plasma levels are more rapid when given IM specifically to the thigh^1,2.  If you happen to be lucky enough to work in a place where the nurses are obtaining IV access faster than someone is able to travel to the med room to grab the epinephrine, you might wonder whether you could or should just give epinephrine through the IV.  I discussed this with both Dr. Ronna Campbell, anaphylaxis expert and EM doc at the Mayo Clinic and Kristina Kipp, EMCrit PharmD in EM/Critical Care at Penn Medicine to get two different perspectives.

Per Dr. Campbell, the main issue in using epinephrine via the IV route is the risk of overdose and the complications related to this.  There is significant confusion surrounding the different concentration formulations of epinephrine- a drug which has a relatively narrow therapeutic window.  Errors occur when the provider orders the wrong dose, the nurse administers the wrong dose, or there is confusion between the measurement unit being in milligrams vs. milliliters.  We don’t use epinephrine frequently outside the setting of a code situation so this relative unfamiliarity contributes to error, particularly in a high stress situation.

Dr. Campbell performed an observational cohort study of emergency department patients at the Mayo Clinic Hospital with anaphylaxis, comparing complications of epinephrine by route of administration.  All overdoses occurred when epinephrine bolus was given IV.  Adverse cardiovascular events occurred in 3 of the 30 IV doses given compared to 4 of the 316 IM doses for an odds ratio of 8.7.  The adverse events that occurred after IV bolus were more significant including ischemia and arrhythmia compared with the events of transient hypertension and angina with negative troponin after IM administration.  One patient did have ischemia following IM treatment, but with much more mild troponemia than the IV bolus counterparts³.

A literature review by Wood et al. again found that the most severe adverse events related to the use of epinephrine in anaphylaxis occurred when given by the IV route¹.  This holds true even when the traditional IM dosage is given via the IV route; Kanwar et al. reported two cases in which the IM dosage of 0.3 mg was inadvertently given IV, leading to transient inferior ST elevation without acute occlusion in one patient and to right coronary artery dissection in another⁴.  Other disastrous outcomes have occurred in the setting of inadvertent overdose of IV epinephrine including cardiogenic shock, ventricular tachycardia, and severe myocardial ischemia¹.  3 cases are reported in the literature in which doses of 1-3.5 mg IV bolus given for mild allergic symptoms lead to patient death⁵.

It is possible that the pathophysiology of anaphylaxis itself regardless of the treatment can contribute to myocardial ischemia: as atherosclerotic plaques are a site of mast cell accumulation, mast cell degranulation may promote plaque rupture and therefore ischemia⁶.  Despite this, with many examples of significant side effects, Kristina states she likely won’t routinely be giving my anaphylactic patient epinephrine IV.  But what about patients who are hypotensive and potentially with signs of bronchospasm despite IM epinephrine?  For Kristina, these are the patients in which you may consider giving small boluses of IV epinephrine likely while arranging to start a drip.

Pharmacokinetics/dynamics of Epinephrine

First, regarding the pharmacokinetics of epinephrine, much remains unclear.  Endogenous epinephrine levels are variable as is the effect of exogenously administered epinephrine.  In a study of healthy volunteers, the peak effect of IM epinephrine occurred in 3-9 minutes⁷.  Further, though it seems logical that there must be some IV dose equivalent to our traditional IM dose, there is currently no known IM to IV dose equivalent and no established dosing regimen for IV epinephrine.  It seems that giving this dose IV would take any variability in absorption out of the equation particularly in a critically ill patient.  One prospective study recommended a starting dose of 5-15 mcg/min drip for anaphylaxis⁸.  Current recommendations from the World Allergy Organization endorse giving epinephrine IM every 5-15 minutes as necessary to control symptoms in addition to adjunctive treatments such as steroids, antihistamines, etc. and to consider epinephrine infusion if patients are unresponsive or severly hypotensive in the setting of anaphylaxis or if they have failed to respond to several IM injections^1,6.

Based on a handful of cases she has experienced, Kristina recommends 20-60 mcg slow IV push over 3-5 minutes while monitoring hemodynamics and redosing if needed for a max 100 mcg.  Giving 10 mcg over 1-2 minutes and reassessing may also be a reasonable and safe approach.  Case reports have shown detrimental effects when greater than 200 mcg was used.  Keep in mind that these are pretty small doses relative to the ACLS syringe of epinephrine that we are used to using.

Kristina recently had a case demonstrating a win for IV bolus epinephrine.  A healthy male in his 50s presented with anaphylaxis secondary to a bee sting.  He received epinephrine IM, methylprednisolone, diphenhydramine, and fluids in route by EMS.  Despite this he was hypotensive with initial blood pressure 65/38 and continued to have SBP 60-70 despite an additional dose of IM epinephrine.  He did not have any airway compromise or respiratory distress.  At that point, the decision was made to give a small aliquot bolus of 20 mcg via slow IV push.  5 minutes later a second bolus was given due to continued hypotension; at this time an epinephrine drip was available and was titrated up to 5 mcg/min at maximum.  The patient’s blood pressure gradually improved as did his symptoms.  He had lab abnormalities of hypokalemia requiring repletion and a troponin leak peaking at 0.13 without any chest pain or EKG changes.  He was able to be weaned off the epinephrine drip and was admitted to the ICU for monitoring in a condition significantly improved from initial presentation.

This may be a win for push dose epi if this is something that you are already familiar with as the risk of dosing error due to failure of communication is eliminated.  There is also an element of safety as even if the whole syringe of push dose epi was given to the patient, this would be 100 mcg, the upper limit recommended for IV bolus epinephrine in anaphylaxis.

Take Home Points:

• Continue giving your initial dose of epinephrine IM
• In IV bolus epinephrine: low dose, slow push
• Don’t give dead people doses of epinephrine to alive people

I would like to acknowledge Diane Lum, PharmD and Guang Mei Fung, PharmD for their assistance with my literature review.

Comments from Weingart

There must be an equivalent IV infusion dose to our standard IM dosing! But I'll be damned if I can find out what it is… So my best clinical recs based on experience actual patients we have tried this on.

• Start at 5 mcg/min
• this will almost always be too low
• titrate every couple of minutes up to 10, 15, 20 mcg
• For a patient that is peri-code, consider 20-40 mcg/min (as best I can tell, the 0.3 mg IM we give is expected to last approx. 10 minutes, so 30 mcg/min is probably the mean over those 10 minutes (though I'm sure there is a peak/trough rather than steady state)). If someone is truly going down the poop shoot, giving half of an ml of cardiac epi (50 mcg) or 5 mls of EMCrit-style push-dose pressors (50 mcg) may be warranted.

References

1. Wood JP, Traub SJ, Lipinski C. Safety of epinephrine for anaphylaxis in the emergency setting. World J Emerg Med 2013; 4(4): 245-251. PMID: 25215127
2. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol 2001; 108(5): 871-873. PMID: 11692118
3. Campbell et al. Epinephrine in anaphylaxis: Higher risk of cardiovascular complications and overdose after administration of intravenous bolus epinephrine compared with intramuscular epinephrine. J Allergy Clin Immunol Pract 2015; 3(1): 76-80. PMID: 25577622
4. Kanwar M et al. Confusion about epinephrine dosing leading to iatrogenic overdose: A life-threatening problem with a potential solution. Ann Emerg Med 55(4): 341-344. PMID: 20031267
5. Pumphrey RSH. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy 2000; 30(8): 1144-1150. PMID: 10931122
6. Kemp SF, Lockey RF, Simons FER. Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization. Allergy 2008; 63: 1061-1070. PMID: 18691308
7. Edwards ES et al. Bioavailability of epinephrine from Auvi-Q compared with EpiPen. Ann Allergy Asthma Immunol 2013; 111(2): 132-137. PMID: 23886232
8. Lieberman P et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3): e1-42. PMID: 20692689
9. Barach EM, Nowak RM, Lee TG, Tomlanovich MC. Epinephrine for treatment of anaphylactic shock. JAMA 1984; 251(16): 2118-2122. PMID: 6708262