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M2E Too! Mellick's Multimedia EduBlog

The M2E Too! Blog by Larry Mellick, MD, presents important clinical pearls using multimedia.

By its name, M2E Too! acknowledges that it is one of many emergency medicine blogs, but we hope this will serve as a creative commons for emergency physicians.

Friday, November 1, 2013

Anaphylaxis and Epinephrine
I have a personal interest in anaphylaxis and epinephrine. My wife nearly died after being stung by hornets in 2009. Unfortunately, I was on a mission trip to Honduras, and it was up to my 7-year-old daughter to find the EpiPen and help administer the lifesaving injection to my wife. (A video of another patient with anaphylaxis from a wasp sting can be viewed here. It includes the 911 call from my daughter.)
Two major problems occur with anaphylaxis: recognition and management. The recognition problem is related to the very confusing and complex diagnostic criteria that have been established. (Ann Emerg Med 2006;47[4]:373.) I carefully reflected on these criteria, and several years ago simplified the definition for myself and our residents: If two organ systems are involved, then one has met the definition of anaphylaxis.
Adapted from Ann Emerg Med 2006;47[4]:373.
This definition approximates the criteria and the most common presentations of anaphylaxis quite well. It doesn’t exactly fit the isolated reduced blood pressure after exposure to a likely allergen, but that scenario seems to be relatively uncommon and relatively obvious diagnostically. Nevertheless, the presence or absence of hypotension is a critical decision in managing anaphylaxis. Diagnosed anaphylaxis should be divided into another two distinct categories: anaphylaxis without hypotension and anaphylaxis with hypotension. This fork in the road becomes important in managing anaphylaxis with epinephrine.
The management problems associated with anaphylaxis boil down to epinephrine. The recommendation to administer H1 and H2 blockers comes easily to most of us, but the epinephrine recommendations are downright confusing. There is a healthy and deserved respect and fear of epinephrine. Anyone who has practiced emergency medicine for any period of time has one or more stories to tell about epinephrine administration problems.
Dosing epinephrine can be extremely confusing because of different concentrations, different dosing settings and different routes of administration. The following information deserves a much more in-depth discussion, but the mnemonic “One, Two, Three, Four” provides a structured and easily recalled format for managing an anaphylaxis patient, and is suggested as a way to organize one’s thoughts on administering epinephrine in anaphylaxis.
One mL dose of epinephrine concentrations
• 1:1,000 concentration = 1000 mcg/mL (or 1 mg/mL)
• 1:10,000 concentration = 100 mcg/mL (or 0.1 mg/mL)
• 1:100,000 concentration = 10 mcg/mL (or 0.01 mg/mL)

Epinephrine concentration per milliliter.
Much of the confusion around administering epinephrine exists because three different concentrations of epinephrine can be used for anaphylaxis. Understanding how many micrograms are in one milliliter (mL) of the three concentrations helps one comprehend the dosing recommendations for epinephrine for each clinical category or level of anaphylaxis severity.
Two Clinical Categories of anaphylaxis
• Anaphylaxis without hypotension
• Anaphylaxis with hypotension
The presence or absence of hypotension in anaphylaxis is a critical decision element that guides the route of epinephrine administration. Anaphylaxis without hypotension is treated immediately with intramuscular epinephrine. On the other hand, documented hypotension should immediately prompt the health care provider to begin preparing immediately for the intravenous infusion of epinephrine and saline by placing large-bore intravenous catheters while still administering the first dose of intramuscular epinephrine. The patient also should be placed into a supine position with legs elevated. Usually these maneuvers are sufficient, but when they aren’t, these simultaneous preparations to administer intravenous epinephrine can be life-saving.
Three epinephrine concentrations used in anaphylaxis treatment
• 1:1,000 → Anaphylaxis without hypotension (IM)
• 1:10,000 → Cardiac arrest with anaphylaxis (IV)
• 1:100,000 → Anaphylaxis with hypotension* (IV)
* Anaphylaxis with hypotension should initially be treated with IM epinephrine, the 1:1000 concentration. The intravenous route for epinephrine must be considered when hypotension persists.
Three epinephrine concentrations used in anaphylaxis management.
These three concentrations are simply sequential epinephrine dilutions by factors of 10 beginning with the 1:1000 concentration. The higher concentration of intramuscular epinephrine (1:1000) allows smaller fluid volumes for injection into the muscles. The more dilute epinephrine concentrations (1:10,000 and 1:100,000) are most appropriate for intravenous administration during advanced cardiac life support or pulse dosing for children, adolescents, and adults.
Note: The 1:1000 comes in a small 1 ml glass vial, and is used also to treat asthma with IM drug. The 1:10,000 is the 10 ml prepackaged vial kept in crash carts for CPR. The 1:100,000 must be mixed by the clinician, and is not commercially available.
Pulse dosing of epinephrine for anaphylaxis with mild hypotension using the most dilute epinephrine formulation (1:100,000) is also proposed as a treatment option. Pulse dosing of vasopressors is a recognized adjunct for hypotension management, but it is generally not taught in managing anaphylaxis. The use of continuous intravenous infusions of epinephrine for persistent hypotension is more often recommended, but its administration is potentially delayed by the time demands associated with the preparation processes.
The preparation of epinephrine for pulse dosing, however, is simple and rapidly accomplished. Pulse dosing allows minute-to-minute, manual management of the patient’s hypotension and increasing the epinephrine doses as indicated by the patient’s condition. This concentration is not commercially available, but it is easily prepared by the clinician. It is prepared by filling a 10 mL syringe with 9 mL normal saline. Draw up 1 mL of epinephrine from a cardiac (ACLS) ampule (1:10,000), inject this amount into the 10 mL syringe, and shake well. This creates 10 mL of epinephrine with 1:100,000. Now one can pulse dose 5-10 mcg (0.5 to 1 mL or more if clinically indicated) every few minutes with a syringe epinephrine concentration of 10 mcg/mL. Pulse dose epinephrine can also be administered manually as a continuous infusion. Pulse dose epinephrine can be the intermediate step to starting a continuous infusion that is titrated up or down.
How to mix 1:100,000 epinephrine for pulse dosing of anaphylaxis associated with hypotension.
Four levels of severity that guide epinephrine concentration and dosing used.
Adult Anaphylaxis

* Up to the entire syringe (10 ml or 100 mcg).
** These guidelines recommend the ACLS bradycardia epinephrine infusion dosing: 2-10 mcg/min.
This severity staging table is adapted from a grading system described in Lancet in 1977 for anaphylactoid reactions. (Lancet 1977;1(8009):466.) Other authors have also created similar grading systems for generalized hypersensitivity reactions. (J Allergy Clin Immunol 2004;114(2):371.)
Descriptions of the clinical presentation are linked to the recommended treatment, administration routes (intramuscular, intravenous, pulse dosing, etc.), epinephrine concentrations, specific dosing information, and frequency of administration.
Pediatric Anaphylaxis
* If hypotension persists, escalate pulse doses of epinephrine by two or three times (0.2 mL to 0.3 mL/kg/minute).
** Standard recommendation for pediatric epinephrine infusion is 0.1 to 1.0 mcg/kg/minute.

Relative amounts of epinephrine recommended for each severity stage of pediatric anaphylaxis.
The intramuscular dose of epinephrine would be administered first in almost all settings, as with adults, because it is the most familiar and most easily prepared (and frequently all that is needed). Immediate preparations for intravenous epinephrine should be started, however, if stage II or III anaphylaxis is not responsive to the intramuscular preparation.
The pulse dose epinephrine concentration can be used for children as well as adolescents and adults. Anaphylaxis with hypotension in children can also be treated with a continuous epinephrine infusion and the standard dosing is 0.1-1 mcg/kg/min titrated to effect. Pulse dosing, however, is potentially more timely and appropriate for the hypotensive child. The preparation of the pulse dose epinephrine concentration is the same for adults and children. The smaller pulse doses for a child would be 0.1 ml/kg/dose of the 1,100,000 pulse dose concentration. This amount is 0.001 mg/kg or 1 mcg/kg (compare with 10 mcg/kg for PALS dosing which is 0.1 mL/kg of the 1:10,000 concentration).
The administration per minute should be guided by keeping in mind the standard dosing of the pediatric continuous epinephrine infusions of 0.1 to 1 mcg/kg/min titrated. Both of the recommended pulse dose calculations per minute for adults and children start the intermittent intravenous epinephrine at the high end of the continuous epinephrine infusion recommendations. This is considered appropriate because hypotension associated with anaphylaxis is notoriously resistant to epinephrine administration, and at times it will be clinically appropriate to double or triple the pulse dose epinephrine in Stage III anaphylaxis. If a child progresses to cardiac arrest, pediatric ACLS dosing for cardiac arrest is 0.01 mg/kg or 10 mcg/kg (0.1 mL/kg of 1:10,000) and can be repeated every three to five minutes.
Charles Moore, MD, the chief resident in emergency medicine at Georgia Regents University, contributed editorial assistance for this post.