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LETTERS TO THE EDITOR

Management of Severe Anaphylactic Reactions Should Include Administration of Alpha Adrenergic Agonists

Department of Anesthesiology, Duke University Medical Center, Durham, NC Department of Anaesthesia, Royal Victoria Hospital, Belfast, Northern Ireland

To the Editor:

The recently published review article provides a comprehensive review of current knowledge and best practice in this area (1).

We would like to add to the section on management, which made no mention of the use of pure alpha agonists in the treatment of severe life-threatening anaphylactic reactions unresponsive to epinephrine. This was described by Higgins and Gayatri in 1999 (2), in a series of case reports by McBrien et al. in 2001 (3), and two further cases in Australia in 2002 (personal communication, Alan Rainbird), which are currently being published. It is with regret that case reports of death from anaphylaxis still appear in the literature with the administration of only 2 mg epinephrine during resuscitation (4). The case reports mentioned above would suggest that resuscitation from a suspected anaphylactic reaction should not be discontinued without the administration of a significant bolus of a pure alpha-adrenergic agonist following repeated boluses of epinephrine. Higgins and Gayatri proposed that the use of a pure alpha agonist should be considered before resorting to a third dose of epinephrine (2). The possible mechanism for the efficacy of pure alpha-adrenergic agonists in this setting has previously been discussed (3).

Recently, the Association of Anesthetists of Great Britain and Ireland published guidelines (5) for the management of anaphylaxis noting that "other vasopressors such as metaraminol and norepinephrine may be tried" if patients do not respond to epinephrine. While this acknowledges the role of such drugs, this recommendation may not adequately reflect or emphasize the life saving use of pure alpha-adrenergic agonists that have been published in the literature. We agree that epinephrine is still the primary drug (along with the other treatments discussed in the review) in the resuscitation of cardiac arrest following anaphylaxis. However, anesthesiologists should be aware that the management of severe anaphylactic reactions should include the administration of a significant bolus of a pure alpha-adrenergic agonist before resuscitation is discontinued, and preferably early if no response is obtained following successive doses of epinephrine.

References

1. Hepner DL, Castells MC. Anaphylaxis during the perioperative period. Anesth Analg 2003; 97: 1381–95.[Abstract/Free Full Text]
2. Higgins DJ, Gayatri P. Methoxamine in the management of severe anaphylaxis. Anaesthesia 1999; 54: 1126.
3. McBrien ME, Breslin DS, Atkinson S, Johnston JR. Use of methoxamine in the resuscitation of epinephrine-resistant electromechanical dissociation. Anaesthesia 2001; 56: 1085–9.[Medline]
4. Konarzewski W, De’Ath S. Unrecognized fatal anaphylactic reaction to propofol or fentanyl. Anaesthesia 2001; 56: 497–8.[Medline]
5. Association of Anaesthetists of Great Britain and Ireland. Suspected anaphylactic reactions associated with anaesthesia. London: Association of Anaesthetists of Great Britain and Ireland, 2003.

Response

Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School, Boston, MA

In Response:

We wish to thank Dr. Russell, Drs. Roth and Shields, and Drs. Breslin and McBrien for their interest in our review article (1) and for their insightful comments and questions. It is interesting that all three letters dealt with medications used in the treatment of anaphylaxis. There are no randomized controlled trials in the treatment of anaphylaxis and, as eloquently stated by Dr. Fisher, treatment protocols for anaphylaxis are based on understanding its cellular mechanism, animal experiments, and clinical presentation (2).

Because the mechanism of sulfite sensitivity relates to direct mast cell activation and rarely involves the presence of IgE antibodies (3–5), no in vitro tests are available to assess sulfite sensitivity. Graded challenges have been performed but are not always positive in sulfite-sensitive individuals (3–5). Although positive skin tests to metabisulfites have been reported, the evaluation and mechanism of metabisulfite reactions is complex and the results must be interpreted with caution (6). There is one report of immunologic desensitization with a sulfite extract used parenterally (7). This showed no success after 3 months, but an 82% response after 6 months. In patients with a definitive history consistent with anaphylactic or anaphylactoid reactions to sulfites, avoidance of medications, including epinephrine, which contain metabisulfites as preservatives might be indicated. Airway support, fluid replacement with colloids, and vasoconstrictors such as methoxamine are the preferred agents. Steroids, bronchodilators, and anti-histamine H1 and H2 blockers should also be used in these patients to treat anaphylaxis. However, epinephrine is indicated in patients who continue to have severe and refractory anaphylaxis despite this treatment. The role of methoxamine is supported by recent publications as referenced by Drs. Breslin and McBrien. A recent comparison between epinephrine and methoxamine for the treatment of cardiac arrest found no difference in return of spontaneous circulation, neurologic status or survival (8). Methoxamine, a potent alpha agonist, should be used in cases of anaphylaxis with no response to multiple doses of epinephrine, or in cases in which epinephrine is contraindicated. It is interesting to note that glucocorticoids and colloids, used in the treatment of anaphylaxis, have also been implicated as causative agents for anaphylaxis (9–10) and should be avoided in sensitized patients.

A clarification about the different types of colloids is warranted. It is worthwhile to mention that we prefer to use generic over trade names throughout our review (1). Albumin, dextran, hetastarch, and gelatin are colloids commonly used in the operating room, and gelatin is the colloid most likely to lead to an allergic reaction. IgE-mediated anaphylaxis has been proven by demonstrating IgE antibodies and positive intradermal tests against gelatins, and there is no known cross-reactivity between the different groups of colloids. Different groups of colloids refer to the generic groups as described above. We are in agreement with Professor Russell that colloids that belong to the same group such as Hemaccel and Gelofusin (which are both gelatins) have been proven to have cross-reactivity (10). Therefore, an allergic reaction to either Hemaccel or Gelofusin should preclude the use of the other colloid.

The complexity and severity of anaphylaxis is such that no single algorithm can adequately treat all cases.

References

1. Hepner DL, Castells MC. Anaphylaxis during the perioperative period. Anesth Analg 2003; 97: 1381–95.
2. Fisher M. Fortnightly review: treatment of acute anaphylaxis. Br Med J 1995; 311: 731–3.[Abstract/Free Full Text]
3. Simon RA. Sulfite sensitivity. Ann Allerg 1987; 59: 100–5.[Medline]
4. Simon RA. Sulfite sensitivity. Ann Allergy 1986; 56: 281–8.[Medline]
5. Settipane GA. Adverse reactions to sulfites in drugs and foods. J Am Acad Dermatol 1984; 10: 1077–80.[Medline]
6. Boxer MB, Bush RK, Harris KE, et al. The laboratory evaluation of IgE antibody to metabisulfites in patients’ skin test positive to metabisulfites. J Allergy Clin Immunol 1988; 82: 622–6.[Medline]
7. Hosen H. Specific immunological therapy with the sulfite chemicals. J Asthma 1987; 24: 219–21.[Medline]
8. Patrick WD, Freedman J, McEwen T, et al. A randomized, double-blind examination of methoxamine and epinephrine in human cardiopulmonary arrest. Am J Respir Crit Care Med 1995; 152: 519–23.[Abstract]
9. Holz W, Ludwig A, Forst H. Anaphylactic shock following intravenous hydrocortisone succinate administration [in German]. Anaesthesist 2002; 51: 187–90.[Medline]
10. Russell WJ, Fenwick DG. Anaphylaxis to Haemaccel and cross reactivity to Gelofusin. Anaesth Intensive Care 2002; 30: 481–3.[Web of Science][Medline]

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