Which medication can be administered via the intramuscular route to treat anaphylaxis?

When treating anaphylaxis, epinephrine is generally given via an intramuscular [IM] route.  This is well established to be effective and life-saving.  One advantage of IM administration is immediate use [without requiring intravenous access], including by patient auto-injection. 

IM epinephrine is doubtless the best approach for patient self-treatment, for first responders, and for immediate treatment in the emergency department.  However, intravenous epinephrine has some advantages for patients within a hospital who already have IV access [e.g. peri-operative anaphylaxis or drug-induced anaphylaxis within an ICU]. 

This post is intended to apply to patients who have pre-existing IV access and are being managed by a resuscitationist who is comfortable with the use of IV epinephrine [e.g. in an ICU, practitioners may be more facile using IV than IM epinephrine].  Realistically, this scenario applies only to a small minority of anaphylaxis cases.  For the vast majority, IM epinephrine is probably the best way to go – so this post should not be misinterpreted as discouraging IM epinephrine in the slightest.

potential advantages of IV epinephrine in anaphylaxis

For an inpatient with pre-existing vascular access, IV epinephrine has several potential advantages. 

[1] Faster onset

One drawback of IM administration is that this route has a delayed onset of action.  This is true of any drug – including epinephrine. 

IM epinephrine takes several minutes to be reach peak blood levels.  For example, the figure by Simons 2001 suggests that peak blood levels may not be achieved for around 10 minutes:​1​

Some articles recommend repeating the dose of IM epinephrine in 5-15 minutes if there is a failure to respond.  This doesn’t make pharmacokinetic sense; in fact, it’s potentially a bit dangerous.  The first dose of IM epinephrine may not take effect until ~5-10 minutes.  Therefore, repeating a dose after 5 minutes is likely to cause dose-stacking – the second dose is given before the first dose takes effect, leading to an inappropriately large total dose being administered. 

In comparison, IV administration will immediately increase blood epinephrine levels.  When provided as an IV push, drug levels will be achieved within seconds – not minutes. 

[2] Smoother tapering

When given intramuscularly, epinephrine can have erratic pharmacokinetics.  For example, in the figure above, epinephrine levels decrease a bit but then increase to a second peak.

Another problem with IM epinephrine is abrupt cessation of efficacy.  Patients may respond well initially, but then after ~30-60 minutes drug levels can fall, leading to a recrudescence of anaphylaxis.  Exactly when drug levels will fall isn’t entirely predictable, making it challenging to know how to monitor patients and when to re-dose IM epinephrine.

In comparison, IV epinephrine can be smoothly tapered at a rate determined by the practitioner.  The amount of epinephrine that the patient is receiving is known, which can help clarify how the patient is responding to medication.  For example:

• If a patient remains stable after a single dose of IM epinephrine, it may be unclear whether there is some lingering epinephrine [which could cause the patient to deteriorate later on when the epinephrine completely wears off].
• If a patient is stable after stopping an infusion of IV epinephrine, then it is clear that the patient is clinically stable off epinephrine. 

[3] Ability to withdraw drug

During my training, I encountered a patient who was treated for anaphylaxis with IM epinephrine.  He subsequently developed hypertension, anginal chest pain, and ST depressions.  This was frankly a mess.  How should you treat this patient?  If you give a beta-blocker, that could exacerbate the anaphylaxis.  We didn’t know exactly how long the IM epinephrine would last  – making it unclear how long the ischemia would continue.  The underlying problem here was that we had given the patient more epinephrine than ideal and we couldn’t take back the epinephrine. 

An infusion of IV epinephrine provides greater control.  If the patient has an adverse event, then the epinephrine can be stopped or down-titrated.  Thus, using an epinephrine infusion may actually encourage the use of epinephrine overall – because you don’t have to make a commitment to give the drug for ~30 minutes.  

controversial opinion:  an expert resuscitationist with IV access should use IV epinephrine

Ultimately, there is no scientific rationale for a resuscitationist to use IM epinephrine in a situation with established IV access and available IV epinephrine.  Basic principles of pharmacology indicate that the IV route provides faster and more reliable access to the bloodstream.  In no other situation would the IM route be preferentially used to administer a catecholamine. 

The only rationale for using IM epinephrine is that practitioners aren’t comfortable or adequately trained in using IV epinephrine.  This issue should ideally be addressed by improving our understanding of IV epinephrine, rather than running away from it.

This debate regarding IV vs. IM epinephrine in anaphylaxis has actually been raging since the turn of the century.​2​  As such, it’s unlikely to be resolved anytime soon.  This blog will doubtless elicit several comments discussing that IM epinephrine is more idiot-proof, whereas IV epinephrine is potentially dangerous.

what is a reasonable dosing regimen of IV epinephrine in anaphylaxis?

There isn’t any solid evidence on this.  Therefore, it may be best to approach this problem from a few different angles.  Hopefully these different approaches will converge on a solution. 

[1] Very rough back-of-the-envelope calculation

For an adult patient, we would typically give ~0.4 mg epinephrine and expect this to work for perhaps ~20-40 minutes.  If we approximate this very roughly as a continuous infusion, this yields:

            400 mcg / 20 minutes = 20 mcg/min

            400 mcg / 40 minutes = 10 mcg/min

So, we might expect that an initial epinephrine infusion should be on the order of 10-20 mcg/min.  Certainly this is very crude, but it suggests a general range to begin titration.

Incidentally, this exactly matches the recommended rate of initial epinephrine infusion recommended in some literature [10-20 mcg/min].​3​

[2] Pharmacokinetic calculations

Abboud et al. evaluated the pharmacokinetics of IV epinephrine in the context of septic shock.​4​  They found that epinephrine pharmacokinetics could be well explained using a single-compartment pharmacokinetic model.  The average volume of distribution was 8 liters, with a half-life of ~3.5 minutes.  Based on these numbers, the elimination constant of epinephrine [Ke] is calculated at 0.2/minute. 

The therapeutic drug level of epinephrine in anaphylaxis isn’t well defined.  However, based on the measurement of blood levels achieved with standard doses of IM epinephrine, the therapeutic dose may be estimated at roughly ~5,000 pg/ml [or ~0.005 mcg/ml][see epinephrine serum concentration graph above]. 

Using these data, we can estimate an appropriate loading dose and maintenance infusion rate for epinephrine in anaphylaxis:

• Loading dose = [Vd][therapeutic concentration] = [8000 ml][0.005 mcg/ml] = 40 mcg
• Maintenance infusion = [Vd][therapeutic concentration][Ke] = [8000 ml][0.005 mcg/ml][0.2/min] = 8 mcg/min

According to these calculations we need an initial loading dose of ~40 mcg epinephrine, followed by an infusion of roughly ~10 mcg/min.  Incidentally, this explains why clinical outcomes with IV epinephrine are sometimes poor:  adverse events often result from bolusing insanely large doses of epinephrine [hundreds of micrograms]. 

[3] Clinical evidence

In a clinical study, Brown et al 2014 reported successful management of induced bee sting anaphylaxis using epinephrine infusion.​5​  Their protocol involved initiation of an epinephrine infusion at a dose of 5-15 mcg/min [depending on the severity of the reaction].  However, there was no hard limit on the infusion rate of epinephrine [e.g. at one point the infusion was increased to 30 mcg/min in a patient who was apparently refractory to IV epinephrine and was  subsequently found to have a dysfunctional IV line].

This study is small, describing the use of IV epinephrine in 19 patients.  All patients responded rapidly, with improvement in symptoms and blood pressure within 5 minutes [except for one patient who also required IV crystalloid].  Two patients were also treated with atropine for bradycardia.  Epinephrine was well tolerated, without appreciable adverse effects.  Nine patients experienced a recurrence of symptoms after stopping the epinephrine infusion, which required re-initiation. 

Although small, this study provides some clinical support for the use of an epinephrine infusion in anaphylaxis at a rate of ~5-15 mcg/min.  Of course, in reality this will be titrated to effect. 

proposed regimen for IV epinephrine in anaphylaxis

This approach aims to translate the pharmacology and the evidence above into a simple bedside strategy.

Very rarely, patients may be on the verge of immediate cardiovascular collapse [peri-arrest].  In this situation, it makes sense to give the initial loading dose as a bolus of 20-50 micrograms IV.  This is consistent with prior discussions regarding the use of push-dose epinephrine.  Note that in this situation, IM epinephrine will work far too slowly [with an onset of over several minutes]. 

More commonly, patients may be started on a loading epinephrine infusion at a rate of 20 mcg/min.  The goal here is to rapidly establish a therapeutic blood level of epinephrine.  Running this infusion for ~2 minutes should deliver ~40 mcg of epinephrine, which should quickly bring the blood epinephrine level to a therapeutic level.  For severe hypotension, it may be sensible to continue epinephrine at 20 mcg/min until the mean arterial pressure increases over 65 mm. 

Continuing an epinephrine infusion at 20 mcg/min will usually cause overshoot hypertension.  Therefore, after a couple minutes, the infusion rate should be dropped to a maintenance infusion of 10 mcg/min.  This may be an optimal rate for some patients, but ongoing titration will be required: 

• Initial goals:  When first starting the infusion, the aim is to provide a fair dose of epinephrine [to arrest the anaphylaxis] without causing excessive tachycardia or hypertension.
• Subsequent goals:  Once the patient is really turning around [e.g. after ~15 minutes], the goals shift a bit.  The goal at that point is to wean down the epinephrine infusion, without causing a recrudescence of anaphylaxis. 

Perhaps the greatest weakness of an epinephrine infusion for anaphylaxis is reluctance to wean it off.  Failure to actively wean off the epinephrine infusion may cause patients to receive an unnecessarily large total dose of epinephrine.  Thus, active weaning should start early and be fairly aggressive.  Close monitoring is obviously essential, with re-initiation of the epinephrine if there are recrudescent symptoms.  Ideally, other medications for anaphylaxis [e.g. antihistamines and steroids] should be started immediately, to facilitate prompt weaning down off epinephrine. 

• IM epinephrine is live-saving for patients without IV access. This is undoubtedly front-line therapy for the majority of patients presenting with anaphylaxis. The purpose of this post is not to discourage the use of IM epinephrine.
• Intravenous epinephrine has several potential advantages over IM epinephrine, including faster onset and greater titratability.
• If a patient develops anaphylaxis while in the hospital [with pre-existing vascular access], IV epinephrine may be an excellent option. However the use of IV epinephrine for anaphylaxis requires an understanding of how to dose and titrate epinephrine properly for this indication.

related:

• EMCrit CQiR by Ashley Mogul: IV bolus epinephrine for anaphylaxis: A double-edged sword
• EMCrit Podcast 205: Push Dose Pressors & prior Podcast 6.

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