Thursday, March 27, 2014

Corticosteroid-Induced Anaphylaxis

The bat phone rang. I went around the corner to take a listen.

The medics proceeded with their story of a 53-year-old female who experienced an acute onset of nausea, vomiting, near syncope with diffuse itching and a growing erythematous rash after taking prednisone. ABCs were maintained, and vital signs included a blood pressure of 153/80, pulse of 65, respiratory rate of 16, and oxygen saturation of 95% with 4 L of oxygen via nasal cannula. IV access was achieved.

The patient had already received 0.3 mg of epinephrine IM and a 500-mL bolus of IV fluids, and wanted to proceed to administer 50 mg of diphenhydramine IV push and 125 mg of methylprednisolone IV push. The physician stated to hold off on the methylprednisolone due to the fact that she took the prednisone, which may have triggered the reaction, and to go ahead with administration of the diphenhydramine, ending with, "Monitor and transport, we'll see you in fifteen minutes."

To me, it made absolutely no sense. How is it possible to have an anaphylactic reaction to a substance that our body technically makes endogenously? The physician and I discussed it for a bit, and I proceeded to conduct a frantic literature search, trying to find as much information as I could before the patient arrived in the emergency department.

After coming across a few case reports, the basic gist that I discovered regarding this phenomenon was that both type I and type IV allergic reactions associated with corticosteroids is quite possible and has been reported in the literature- more frequently than I imagined. However, the prevalence of an IgE-mediated anaphylactic type I allergic reaction secondary to systemic corticosteroids is relatively low; some reports suggest 0.3% (1). The mechanism behind this is not clear, and there are some reports that suggest that it may be due to either the drug itself, the excipients making up the drug, or both. Some have even hypothesized that the reaction may be due to inhibition of cyclooxygenase (2, 3).

Now the question that may come up: If a patient experiences a true allergic reaction to one corticosteroid, can they tolerate others? Is there a such thing as a cross-reactivity among different corticosteroids?

The short answer is that corticosteroids have been classified into five different categories based on their structural and chemical properties: groups A, B, C, D1, and D2. Below is a table with the different classes and common agents that we may encounter in the emergency department setting that fall under each of the categories (a more detailed list can be found here):

Mometasone furoate
Fluticasone propionate

A commonly described cross-reactivity reaction has been observed between agents in groups A and D2. In addition, budesonide has also been described to exhibit some cross-reactivity due to the fact that the compound itself is composed of a mixture of R and S stereoisomers. Cross reactions of corticosteroids within the same group can also occur due to structural similarities and common metabolic pathways shared among agents within the same group as well.

So here I was, equipped and ready with my references, since I could almost bet the question the resident would ask me once the patient arrived to the emergency department: "Can I give a corticosteroid to this patient to treat her anaphylactic reaction?" Bring it on.

Sure enough, fifteen minutes later, the resident came by and stated that he indeed wanted to give a corticosteroid to the patient. However, I wanted more details about what really and truly happened to the patient before I could provide a recommendation. The conversation went something like this:

Resident: "Nadia, I don't know if you heard about this patient who is here with an anaphylactic reaction after she took prednisone..."
Me: "Yes, I heard it on the bat phone. So when did she take it?"
Resident: "I'm not sure...I didn't get that far with my questions yet to her about it..."

The resident left to go ask the patient and came back and informed me that the patient indeed took the prednisone about thirty minutes PTA.

Me: "So what was she on the prednisone for anyway?"
Resident: "No idea. Let me go ask."

The resident left and came back with an answer ready at the healm.

Resident: "She said she was taking prednisone for her sinus infection. Her doctor prescribed it to her this morning."
Me: " A sinus infection. Hmmm. Interesting. Go ask what antibiotic she took at the same time as her prednisone."
Resident: "What do you mean? She said nothing about an antibiotic."
Me: "Just ask."

The resident left and came back, awestruck.

Resident: "How the heck did you know she took an antibiotic with the prednisone?? She said she took Ceftin at the same time."
Me: "Alright, let's go interview her together."

We proceeded together to interview the patient and she indeed confirmed taking the first doses of both prednisone and cefuroxime at the same time for her sinus infection, as both were prescribed to her by her PMD earlier that day. She stated that she had been prescribed cefuroxime only once before, a few months ago, and had been able to tolerate it with no issues. No, she had no additional changes in her routine, including recent ingestion of any other foreign substances or foods that could have triggered this reaction.

At this point, I was a bit skeptical now that this was a case of corticosteroid-induced anaphylaxis. We were both now convinced that the patient experienced a hypersensitivity reaction to the cefuroxime, which is possible to develop even having tolerated a cephalosporin in the past. Because of this, the resident wanted to administer a corticosteroid, and even with all the information I provided regarding corticosteroid-induced anaphylaxis as described above and recommending to exercise extreme caution if he decided to administer it anyway (which I knew was going to happen, given the additional history we had now regarding the co-ingestion of the cephalosporin), it was eventually given. And the patient was observed for quite some time, and there were no issues following administration of the corticosteroid.

So much for a case of corticosteroid-induced anaphylaxis. The quintessential bubble bursted.

But indeed, this does emphasize the point of obtaining a good history of a patient who presents to the emergency department. And I was able to learn something new about corticosteroid-induced anaphylaxis. So all fared well in the end.


  1. Comaish S. A case of hypersensitivity to corticosteroids. Br J Dermatol 1969; 81:919-925.
  2. Dajani BM, Sliman NA, Shubair KS, et al. Bronchospasm caused by intravenous hydrocortisone sodium succinate (Solu-Cortef) in aspirin-sensitive asthmatics. J Allergy Clin Immunol 1981; 68:201-204.
  3. Sheth A, Reddymasu S, Jackson R. Worsening of asthma with systemic corticosteroids. J Gen Intern Med 2006; 21:196.

Tuesday, March 25, 2014

Extravasation of noncytotoxic medications in the ED

I must admit that I rarely read the primary publication in the pharmacy world (Pharmacotherapy) because of its general lack of anything new or interesting.  Ground breaking clinical research is simply not published in this journal, but it does have excellent review articles that are so over the top, hyper-detail oriented and nauseatingly thorough and make obsessive clinical pharmacists drool.  The latest review (Management of Extravasation Injuries: A Focused Evaluation of Noncytotoxic Medications) is a prime example. But all sarcastic ranting aside, this is an excellent article for a number of reasons. For us in the ED, it’s not so much about reviewing general vasopressor type extravasation (whoopee!), but rather remembering that many other drugs we administer routinely in the ED can cause devastating extravasation due to either hyperosmolarity or acidic/alkaline properties.  And remember, we do administer a number of these medications, undiluted in small peripheral lines.

Table 4 in the manuscript is the case and point example (and I wish the authors expanded further on these medications, not the tried an true vasopressor/calcium stuff).  But from that list here are the agents you may find familiar:

Aminophylline (10 mOsm/L) – the only hypotonic med on the list
Dextrose 50% Water (D50W) – 2520 mOsm/L
Mannitol 20% - 1369 mOsm/L
Hypertonic saline 3% - 1026 mOsm/L
Hypertonic saline 23.9% - 8008 mOsm/L!
Sodium Bicarb 8.4% - 2000 mOsm/L
Propylene glycol – a hyperosmolar vehicle found in various medicaions in the ED, namely: Etomidate, lorazepam, diazepam, nitroglycerin, digoxin
Phenytoin – pH 10-12, > 700 mOsm/L
The paper discusses hyaluronidase as an option to manage hyperosmolar extravasations.  But again, the critical information is found at the bottom footnote of Table 4, which is how the heck to administer to a patient (I mean its great to know the mechanism and kinetics and all, but administration tends to be an often overlooked, unsexy factor).

“Hyaluronidase is commonly diluted to a 1:10 ratio (0.1 ml reconstituted hyaluronidase, 0.9 ml normal saline). A series of five injections of 0.2 ml is then administered with a tuberculin syringe until all 15 units are given. Dosage is expressed in turbidity reducing units (TRUs ). One TRU will allow the dispersion of volumes up to 50 ml from the subcutaneous compartment.”

I fortunately have not had any experience with this in the ED, so can’t comment on the ease or feasibility of effectively determining the volume of extravasated drug and subsequent estimation of dose.  I would imagine it is more of a guess and empiric dose than anything.

I would encourage any ED pharmacists to review the article, since it is quite a good review, but be ready to do some heavy reading and digging into the references for the best outcomes. 

Thursday, March 6, 2014

Nicardipine for Acute Decompensated Heart Failure

In a post on this blog last week, the topic of the nitroglycerin shortage was discussed, with the alternative of nesiritide as offered as a potential option in the setting of this shortage for patients with acute decompensated heart failure, and the data surrounding the use of nesiritide for this indication was reviewed.

Interestingly enough, we received a comment on the post that alluded to the fact that nicardipine could potentially be utilized as an alternative as well.

Upon reading this, at first, this did not make a whole lot of sense to me. Yes, I have mentioned several times on this blog that nicardipine is one of my favorite drugs to utilize in patients in the emergency department. But for acute decompensated heart failure? No way. However, after a little digging (which included having to retrieve articles that were published in the 1980s and 1990s), I have a new perspective regarding this.

Calcium channel antagonists as a class in and of itself have been long-touted to have negative inotropic effects, which can potentially worsen the hemodynamic effects observed in acute decompensated heart failure. However, compared to the other calcium channel antagonists, I found that these effects in nicardipine are actually relatively minimal, as found to be the case in several animal models and in vitro studies (1, 2, 3).

And then I stumbled upon this study:


There were actually two trials conducted within this one study. Patients were enrolled in the trials if they met the following criteria:
  • Age betweeen 20 and 80 years
  • Systolic blood pressure (SBP) > 100 mmHg
  • Cardiac index < 2.5 mL/min/m2
  • Pulmonary diastolic or wedge pressure > 15 mmHg

The first trial evaluated fourteen patients who received nicardipine at a dose of 0.5 mcg/kg/min, with an increase in the dose to 1 mcg/kg/min over the course of a two-hour period to determine if any improvement was made in increasing the cardiac index and decreasing diastolic pulmonary arterial pressure (the latter associated with systemic vascular resistance). In the majority of patients, the effects were more pronounced at doses of 1 mcg/kg/min.

In the second trial, 53 patients were randomized to receive nicardipine at a dose of 1 mcg/kg/min, 2 mcg/kg/min, or 3 mcg/kg/min over two hours. Across all treatment groups, the same effects were observed as in the first trial: cardiac index increased by 41%, 32%, and 35% after two hours, respectively, and diastolic pulmonary arterial pressure decreased by 27%, 26%, and 31% with each respective dose, all of which were found to be statistically significant. One major difference that was observed was that a greater decrease in SBP occurred with doses of 3 mcg/kg/min of nicardipine compared to 1 mcg/kg/min (which is to be expected). The investigators concluded that 1 mcg/kg/min for nicardipine is the optimal dose for the patients evaluated for the purposes of acute decompensated heart failure.

Imagine my surprise with this. Not only do we have an agent, where contrary to popular belief of negative inotropic effects across the board with calcium channel blockers, the effects seen do not occur to the same extent necessarily, but we also have evidence to show that in patients with acute decompensated heart failure, cardiac output is improved and a decrease in left ventricular end diastolic pressure can be achieved.

Suffice it to say that nicardipine has just gone up in my book. It's off the pages now in terms of being THE favorite agent that I use in the emergency department.

  1. Razetti R, Bongrani S, Schiantarelli P. In vitro effects of nicardipine on vascular and cardiac muscle preparations. Pharmacol Res Commun 1984; 16:795-808.
  2. Rousseau MF, Vincent MF, Cheron P, et al. Effects of nicardipine on coronary blood flow, left ventricular inotropic state, and myocardial metabolism in patients with angina pectoris. Br J Clin Pharmacol 1985; 20:147S-157S.
  3. Bongrani S, Razetti R, Schiantarelli P. Cardiovascular effects of nicardipine in anesthetized open-chest dogs in the absence and presence of beta-adrenergic blockade: a comparison with nifedipine and verapamil. J Cardiovasc Pharmacol 1985; 7:899-905.

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