Indian Journal for the Practising Doctor

Anaphylaxis is the most severe allergic emergency. There are perhaps no more frightening symptoms than those experienced by a patient in acute anaphylaxis. These symptoms may include shortness of breath, acute upper and lower airway closure, generalized flushing and pruritus, light-headedness, and a sense of impending doom. Treatment of acute anaphylaxis is a challenge for the attending physician.

The operational definition of anaphylaxis may be taken as the involvement of 2 or more organ systems (eg, skin and respiratory, skin and cardiovascular, respiratory and gastrointestinal, etc) or hypotension (systolic blood pressure < 100 mm Hg).

This article is a timely review of several aspects of this disorder, including the history and current recommendations for the use of epinephrine, the latest data on the emergency department (ED) management of anaphylaxis, and finally a review of the available data on the frequency and significance of delayed anaphylaxis or protracted anaphylaxis.

Epinephrine: Past, Present, and Future

A review of the history of epinephrine use shows that in 1897, John Abel prepared crude adrenal extracts and named them epinephrin. Shortly after the turn of the century in 1901, Jokichi Takamine from Japan patented an adrenal extract as Adrenalin, and epinephrine later became the generic name in the United States, Canada, and Japan. In 2000, epinephrine became the generic name worldwide.

Due to the unpredictable nature of anaphylaxis, there are no prospective, randomized, placebo-controlled studies regarding the use of epinephrine in human anaphylaxis (and probably never will be). There have been animal studies, however, and a fairly long history of observational studies regarding the use of epinephrine in the emergency management of anaphylaxis. Simons and colleagues [2] have also studied the use of epinephrine in Manitoba, Canada, and have found that .95% of the population had epinephrine dispensed, with dispensing rates ranging from 1.44% (< 17 years) to .32% (> 65 years).

Multiple studies supporting the need to give epinephrine early in the course of an anaphylactic reaction for maximal effectiveness have been reviewed and presented in various conferences. [1] Epinephrine in an "anaphylaxis dose" does not reverse established shock. [3] A recent study investigated anaphylactic reactions in allergen-sensitized dogs that were studied at the nadir of hemodynamic shock (50% mean arterial pressure). Mean arterial pressure, cardiac output, and stroke volume were monitored. Once shock had ensued, there was no sustained hemodynamic recovery over 180 minutes after treatment with epinephrine. Other studies have shown that epinephrine fails to effectively reverse established shock because much of the intravascular volume loss into tissues, etc, has already taken place by that point. To reverse this process, vigorous replacement of fluids is mandatory in cases in which shock has ensued as well as epinephrine, H-1 and H-2 antihistamines, and glucocorticoids.)

Comparison of the use of intramuscular vs subcutaneous epinephrine too has been studied. [4] This was a randomized, blinded, placebo-controlled, 6-way crossover study comparing serum maximum levels of epinephrine when injected intramuscularly (IM) vs subcutaneously (SC). The IM injections were administered in the thigh or upper arm, whereas the SC injections were administered in the upper arm. The time to maximum serum concentration of epinephrine was significantly shorter for IM epinephrine (approximately 5 minutes) vs SC epinephrine (approximately 20 minutes). The recommendation, therefore, is to administer epinephrine IM for the management of acute anaphylaxis. [4]

The study also showed that the effectiveness of epinephrine correlated with the number of months past the expiration date. (Epinephrine undergoes racemization over time to the inactive D-isomer.) It is therefore important for doctors to keep stocks whose date has not expired and for patients, who can afford self-injectable epinephrine(for example EpiPen), to renew their prescriptions for epinephrine to ensure its effectiveness.

One quandary that may confront the clinician is the fact that EpiPen comes in only 2 strengths: .15 mg (EpiPen, Jr.) and .3 mg (EpiPen). The usual dose for treating anaphylaxis is from .01mg/kg to .3-.5 mg given IM. What should a doctor do if the patient is a child who falls in between those 2 dosages? For example, if the normal dose for a 22-kg child is .22 mg (ie, .22 cm 3 of a 1:1000 dilution of epinephrine), should we "underdose" or "overdose" with the EpiPen? Experts provide some guidance by advising to treat with the full-strength EpiPen if one or more of the following condition(s) apply:

• Patient has a concurrent diagnosis of asthma;
• The trigger for the anaphylactic episode was a tree nut, a peanut, milk, eggs, or fish;
• There is poor access to emergency medical services;
• There is a dysfunctional family situation;
• No reliable transportation is available; and
• The patient has a history of previous life-threatening reactions.

Some possible new forms of epinephrine are now on the horizon, including sublingual epinephrine and inhaled large porous particles. Additional studies are needed on these formulations before they can be recommended for clinical use in this patient group.

ED Perspective on Anaphylaxis

Emergency Department experience has shown that various causes of anaphylaxis, include foods, drugs, medications, insect stings, and exposure to compounds, such as natural rubber latex.

The clinical manifestations of anaphylaxis [6] include cardiovascular signs, such as tachycardia, followed by hypotension, shock (indicating significant intravascular volume loss ), and occasional bradycardia and myocardial ischemia. Lower respiratory symptoms may include bronchoconstriction, wheeze, cough, and shortness of breath. Upper respiratory symptoms may include laryngeal or pharyngeal edema and rhinitis symptoms. Most patients with anaphylaxis experience cutaneous symptoms, including pruritus, urticaria, angioedema, and/or flushing. Gastrointestinal symptoms include nausea, vomiting, cramping, and diarrhea. Ocular symptoms may include itching, tearing, and redness. Symptoms that are less well appreciated include urinary urgency or uterine cramping.

The recommended treatment of acute anaphylaxis includes supplemental oxygen, maintenance of an airway, intravenous fluids, epinephrine, H-1 and H-2 blockers, corticosteroids (2 mg/kg of methylprednisolone intravenously or 1-2 mg/kg of oral prednisone [maximum, 75 mg]), inhaled beta-agonists, and (if the patient is on beta-blockers) glucagon.

A review of the results of a study that described ED management of anaphylactic reactions to foods in 678 patients treated in 21 North American EDs is quite informative. [7] The mean age of the patients was 29 years (±18 years). Some 18% of these patients arrived by ambulance. The patients often presented with a myriad of symptoms and that the diagnosis of food allergy was not always immediately apparent. Only 72% of these patients received antihistamines in the ED, whereas 48% received systemic steroids. Of concern, only 16% of these patients received injected epinephrine during the course of their stay in the ED. Despite this fact, 97% were discharged home, indicating that the vast majority improved enough to be sent home. Furthermore, and in contrast to clinical guidelines, only 16 % of these patients received a prescription for self-injectable epinephrine at the time of discharge, and only 12% were referred to an allergist for further evaluation. [7] The review revealed that, at a minimum, there was poor documentation of the medications prescribed at the time of discharge. In conclusion there was an urgent need for a widely accepted definition of anaphylaxis that can be used throughout the country for comparison of similar studies.

Experts note that the key to successful management of anaphylaxis includes:

• Prompt recognition of anaphylaxis;
• Early administration of IM epinephrine;
• Replacement of volume intravenously;
• Comfort and familiarity with second-line therapies; and
• Risk management, including education regarding allergen avoidance, a written emergency action plan, a prescription for self-injectable epinephrine, and referral to an allergy specialist.

Frequency and Significance of Late-Phase Anaphylaxis, [8]

There is a dire need to understand a difficult clinical scenario: the patient who experiences protracted or delayed onset of anaphylaxis. Experts describe 3 clinical presentations of anaphylaxis.

First, patients may experience the classic "uniphasic" anaphylaxis, in which there is the onset of explosive allergic symptoms and then resolution. Second, there may be "protracted" anaphylaxis, in which the episode fails to resolve in a timely manner and simply continues in a protracted course. Third, there may be a "biphasic" course, in which there is the typical initial explosive event followed by apparent resolution, marked by a return of symptoms, usually 4-8 hours later, but recurrences have been described as late as 2-3 days.

One series of 25 patients experiencing anaphylaxis revealed that 13 of those patients had a uniphasic presentation, 5 had a biphasic presentation, and 7 had a protracted course. [9]Patients experiencing protracted anaphylaxis may have an unexpectedly large requirement for volume replacement to maintain blood pressure.

Biphasic anaphylactic reactions to foods may occur in one third of patients experiencing fatal or near-fatal, food-induced anaphylactic reactions. [10] The incidence of biphasic anaphylactic reactions has been reported in other studies and shown to occur in 2% to 20% of cases.

The factors associated with a biphasic reaction may include:

• A delay of 30 minutes or more after antigen exposure before the onset of symptoms;
• A delay in the administration of epinephrine;
• Failure to give epinephrine;
• Inadequate dose of epinephrine;
• Hypotension in the first phase of the reaction;
• Very severe early phase associated with a higher likelihood of a second phase; and
• Decreased dose of corticosteroid in the first phase that may be associated with a higher risk of a second phase, although this point appears to be controversial.

The longest reported interval between the first and second phase is 72 hours, with the shortest reported interval at 1 hour. There is no accurate way to establish an average, but , according to some experts, 6-10 hours is probable. It should be noted, however, that it is not uncommon to see the second phase of a biphasic reaction 24 hours after the first.

Although there are inconsistencies regarding the incidence and severity of protracted and biphasic reactions, it is clear that they occur. Therefore the possibility of such reactions needs to be considered when treating acute anaphylaxis; proper observation periods must be undertaken; and careful education and provision of self-injectable epinephrine must be given to the patient who has experienced such a reaction. This will maximize the chance of a successful outcome when managing this disorder.

References

1. Simons FER. Anaphylaxis: A Look at the Oldest of Allergic Problems: Epinephrine: past, present, and future. Program and abstracts of the American College of Allergy, Asthma and Immunology 2004 Annual Meeting; November 12-17, 2004; Boston, Massachusetts.
2. Simons FE, Peterson S, Black CD. Epinephrine dispensing patterns for an out-of-hospital population: a novel approach to studying the epidemiology of anaphylaxis. J Allergy Clin Immunol. 2002;110:647-651.
3. Bautista E, Simons FE, Simons KJ, et al. Epinephrine fails to hasten hemodynamic recovery in fully developed canine anaphylactic shock. Int Arch Allergy Immunol. 2002;128:151-164.
4. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol. 2001;108:871-873.
5. Simons FE, Gu X, Simons KJ. Outdated EpiPen and EpiPen Jr autoinjectors: past their prime? J Allergy Clin Immunol. 2000;105:1025-1030.
6. Camargo C. Anaphylaxis: A Look at the Oldest of Allergic Problems: Emergency department perspective on anaphylaxis. Program and abstracts of the American College of Allergy, Asthma and Immunology 2004 Annual Meeting; November 12-17, 2004; Boston, Massachusetts.
7. Clark S, Bock SA, Gaeta TJ, et al. Multicenter study of emergency department visits for food allergies. J Allergy Clin Immunol. 2004;113:347-352.
8. Lieberman P. Anaphylaxis: A Look at the Oldest of Allergic Problems: The frequency and significance of the late phase reaction in anaphylaxis. Program and abstracts of the American College of Allergy, Asthma and Immunology 2004 Annual Meeting; November 12-17, 2004; Boston, Massachusetts.
9. Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J Allergy Clin Immunol. 1986;78:76-83.
10. Sampson J. Clinical practice. Peanut allergy. N Engl J Med. 2002;346:1294-1299.

* MD ; Goteborg University, Sahlgrenska University Hospital, Goteberg, Sweden