Allergy & Asthma Disease Management Center: Ask the Expert: Anaphylaxis

- Anaphylaxis -

9/14/05 re: Beta blocker risk for anaphylaxis

I am a pharmacy student doing a rotation in a Family Medicine Clinic. I came across a patient with an interesting drug interaction and was wondering if you could share any insight.

A 70 year old woman is on Betapace (sotalol) to control her A-fib. She is allergic to bee stings and was given an Epipen to use prn. I ran a drug interaction screen on her through Micromedex, and I came up with a “major” drug interaction. It says that “nonselective beta blockers block the beta effects of epinephrine, resulting in unopposed alpha effects” which makes sense to watch for hypertension. But then it says that “nonselective beta blockers may also cause RESISTANCE to epinephrine in cases of anaphylaxis glucagon, which has some sympathomimetic effects mediated through cAMP activity that is not beta-receptor linked, has been effective in cases of resistant anaphylactic shock.” It makes sense theoretically, but I have never heard of it occurring clinically. I suppose if the beta-2 receptors are blocked, the epi cannot relax bronchial smooth muscle through this mechanism.

The package insert for Epipen has no contraindications for its use and it mentions nothing about this concurrent beta blocker use and the potential for resistance during anaphylaxis. I am concerned about this interaction and am wondering if patients on nonselective beta blockers should have some glucagon on hand along with their Epipen for resistant anaphylaxis episodes.

To respond to your questions, I obtained input from Dr. David Lang of the Cleveland Clinic. Dr. Lang has been one of the most active investigators of the effects of beta blocker (BB) therapy on the host response to allergic reactions and anaphylaxis/anaphylactoid reactions. Dr. Lang's response is enclosed below.

I should also add that one has to distinguish between the effects of the earlier non-selective BB agents such as propanolol which can predispose to bronchoconstriction in allergic reactions by blocking the beta 2 receptor vs. some of the more recent BB agents such as atenolol, which have little effect on the beta 2 receptor while blocking the beta 1 receptor. Indeed, a recent report showed no alteration of the bronchodilator effects of inhaled albuterol in those treated with beta 1 selective BB agents. Another (very recent) report found no increased frequency of systemic (anaphylactic) reactions to venomimmunotherapy in those on BB treatment. However, there may be some methodologic problems in the latter report.

Dr Lang's comments:

I appreciate your interest in the topic of the greater risk for more serious anaphylaxis associated with beta blocker exposure. You raise several questions that I will try to answer and in so doing will provide you with a number of references for additional reading. As you will note, reports of severe anaphylaxis in patients taking beta blockers were reported more than 25 years ago.

In 1979, Madowitz and Schweiger1 described a case of unusually severe anaphylactoid reaction during performance of coronary angiography in a 46 year old man receiving 320 mg of propranolol daily for hypertension. Based upon a prior history of anaphylactoid reaction from contrast media, he had been pretreated with H-1 antihistamine and corticosteroid.2 Seven minutes after contrast infusion, bronchospasm, cyanosis, chest pain, and pulmonary edema developed requiring administration of epinephrine, diphenhydramine, corticosteroids, and endotracheal intubation. After administration of epinephrine, his blood pressure rose paradoxically to 280/110. He subsequently recovered and successfully underwent coronary artery bypass grafting. The authors of this paper observed that premedication does not eliminate the possibility of a life-threatening anaphylactoid reaction with readministration of contrast media, but did not comment upon the potential importance of propranolol exposure. In 1981, three more cases of potentiated anaphylaxis were described in patients receiving propranolol. Jacobs, et al,3 described two severe non-fatal anaphylactic reactions that featured an inappropriately slow pulse during profound hypotension and a sluggish response to pharmacotherapy. A similar case was reported by Newman and Schultz.4. Since then, additional cases of unusually severe anaphylaxis in patients receiving ß-blockers have been described,5-15 including patients with anaphylactic reactions to hymenoptera venom. 4,7

Management of ß-blocker associated anaphylaxis is complicated by the possibility that the response to epinephrine and/or inhaled bronchodilators will be obtunded. The challenge of managing serious anaphylaxis in patients receiving ß-blockers, "whose response to catecholamines is likely to be absent or poor", was raised in 1971 by Corbascio.16 As illustrated in the case described above,1 epinephrine administration may also paradoxically worsen anaphylaxis through facilitating unopposed alpha-adrenergic and reflex vagotonic effects.

Based upon its mechanism of action, as you note, glucagon may be efficacious for the treatment of severe ß-blocker associated anaphylaxis. Glucagon raises cyclic adenosine monphosphate levels via noncatecholamine mechanisms and can exert potent chronotropic and inotropic effects. Zaloga, et al,15 described dramatic improvement of refractory hypotension during anaphylactoid reaction from contrast media following administration of intravenous glucagon, in a 75 year-old man receiving both atenolol and timolol eye drops. In a study of anaphylaxis in passively sensitized guinea pigs given propranolol, Serwonska and Frick 17 recorded greater survival with glucagon pretreatment.

As you are aware, the decision to suspend a medication (e.g., a beta blocker) needs to be considered carefully on an individualized risk/benefit basis for every patient. 18 For selected patients, particularly those with IgE mediated (anaphylactic) potential to hymenoptera venom, in which a clear indication exists to continue a beta blocker, we may elect to administer venom immunotherapy while maintaining beta blocker therapy.

Citations

1) Madowitz JS, Schweiger MJ. Severe anaphylactoid reaction to radiographic contrast media. JAMA 1979; 241: 2813-15.

2) Greenberger PA, Patterson R, Tapio CM. Prophylaxis against repeated radiocontrast media reactions in 857 cases. Arch Intern Med 1985; 145: 2197-2200.

3) Jacobs RL, Rake GW, Fournier DC, Chilton RJ, Culver WG, Beckmann

CH. Potentiated anaphylaxis in patients with drug-induced beta-adrenergic blockade. J Allergy Clin Immunol 1981; 68: 125-7.

4)Newman BR, Schultz LK. Epinephrine-resistant anaphylaxis in a patient taking propranolol hydrochloride. Ann Allergy 1981; 47: 35-37.

5) Awai LW, Mekori YA. Insect sting anaphylaxis and beta-adrenergic blockade: a relative contraindication. Ann Allergy 1984; 53: 48-9.

6) Laxenaire MC, Torrens J Moneret-Vautrin DA. Choc anaphylactoide mortel chez un malade traite par beta bloquants. Ann Fr Anesth Reanim 1984; 3: 453-5.

7) Benitah E, Nataf P, Herman D. Accidents anaphylactiques chez des patients traites par beta-bloquants. Therapie 1986; 41: 139-42.

8) Cornaille G, Leynadier F, Modiano, Dry J. Gravite du choc anaphylactique chez les malades traites par beta-bloquers. Presse Med 1985; 14: 790-1.

9) Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatalities fromimmunotherapy and skin testing. J Allergy Clin Immunol 1987; 660-77.

10) Too good JH. Beta-blocker therapy and the risk of anaphylaxis. Can Med Assoc J 1987; 136: 929-32.

11) Berkelman RL, Finton RJ, Elsen WR. Beta-adrenergic antagonists and fatal anaphylactic reactions to oral penicillin. Ann Intern Med 1986; 104: 134.

12) Capellier G, Boillot A, Cordier A, et al. Choc anaphylactique chez les alades sous betabloquers. Presse Med 1989; 18: 181.

13) Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J Allergy Clin Immunol 1986; 78: 76-83.

14) Hamilton G. Severe adverse reactions to urography in patients taking beta-adrenergic blocking agents. Can Med Assoc J 1985; 133: 122-26.

15) Zaloga GP, Delacey W, Holmboe E; et al. Glucagon reversal of hypotension in acase of anaphylactoid shock. Ann Intern Med 1986; 105: 65-6.

16) Corbascio AN. Propranolol (letter). Clin Pharmacol Thera 1971; 12:559-60.

17) Serwonska MH, Frick OL. Anti-anaphylactic activity of glucagon in guinea pigs with beta-adrenergic blockade. J Allergy Clin Immunol 1988; 81: 238A.

18) TenBrook JA Jr, Wolf MP, Hoffman SN, et al. Should beta-blockers be given to patients with heart disease and peanut-induced anaphylaxis? A decision analysis. J Allergy Clin Immunol. 2004 113: 977-82

9/12/05 re: Seminal plasma sensitivity

I am a pediatrician in New York City looking for a local allergist who can test for semen allergy. I was referred to your website by an allergist colleague.

I suggest that you contact Dr. David Resnick, an allergist who has been associated with the Columbia-Presbyterian Medical Center in New York. Dr. Resnick has had a special interest in seminal plasma sensitivity (see enclosed abstract). He should be able to direct you to facilities where testing is done if he does not do such testing himself.

Allergy Asthma Proc. 2004 Jul-Aug;25(4):261-2.
Localized seminal plasma protein hypersensitivity.
Cohen A, Wong ML, Resnick D.
Albert Einstein University Hospital , Bronx , New York, USA.

Human seminal plasma protein hypersensitivity is a rare disorder. Since the first case report in 1958, allergic reactions to semen have gone relatively unnoticed or improperly diagnosed. Dozens of medical case reports and research prove that allergy to seminal fluid is a legitimate health concern.

9/8/05 re: Anaphylactic reaction induced by molds

I am a Family Nurse Practitioner and have a question regarding a case. A 29 year old female was staying at a motel which was damp and was later found to contain mold. She awoke at 2:00 am to sudden onset of abdominal cramps and diarrhea. This was followed by wheezing, SOB, and severe rhinitis. She had eaten about 5 hours prior. The only food which was unusual for her was macadamia nuts. One allergist completed skin testing and found an impressive reaction to molds. She was told the indoor mold caused the reaction and the food was not likely a contributing factor. After consulting with another allergist she was told that indoor molds do not cause immediate hypersensitivity or anaphylaxis and that it must have been the macadamia nuts. (Tested negative for nuts) My question is; do indoor mold species never cause anaphylactic reactions? What is the likelihood of reaction to food 5 hours after ingestion? I appreciate your assistance.

I am not aware that inhalation of molds, even in a very mold-sensitive individuals, has induced the G-I manifestations you described. Therefore, I referred your message to Dr. Emil Bardana of the Oregon Health Sciences Univ. in Portland for his input. Dr. Bardana is a leading expert in mold allergies. His response is enclosed below. His comments about a negative skin test (to macadamia nuts, we assume) not completely ruling out clinical sensitivity to that food is based on the recently reported experience by several groups that a definite minority of individuals have manifest clinical allergic reactions to double-blind food challenges and/or have a clear-cut history of such reactions despite the absence of a positive prick skin test response to the suspect food using the usual testing materials. Therefore, it would be prudent to have the patient avoid macadamia nuts.

Dr. Bardana's comments:

The reaction involved the GI tract and upper and lower respiratory tract. Assuming the patient had a preexisting allergy to mold, it is possible, but unlikely that inhalation of mold allergen precipitated acute asthma and rhinitis. This would be dependent on the concentration of mold propagules in the room and the species involved and the allergies she is said to have, i.e. it would have to be a very high concentration of the mold allergens to which she has an allergy. Since mold is much more prevalent outdoors than indoors it would be unlikely the room was the sole trigger. I don't have enough info to make an intelligent decision. Most important in this scenario is who tested and how were the tests done, i.e. percutaneous versus ID which recent literature suggest are next to useless (ID testing). Inhalation of mold allergen has never been associated with GI allergy. My best guess is that mold is the red herring and not at all involved. However I am not certain what the trigger was. A negative test for nuts would not dissuade me from keeping them on the list of possible causes. Fully a fifth of food allergy patients tested negative.

3/6/05 re: Anaphylaxis and angioedema

Hello. My name is Dr. Sanjay Swami. I am a member of AAAAI. I would like your suggestions regarding management of a patient of mine. She is a 34 year old with history of 4 episodes of anaphylaxis over the past year. None of these episodes were associated with exercise. Her symptoms include angioedema (eyes, face, throat, ankles), shortness of breath, vomiting, itching of her ears, mouth, and groin. She has awakened each morning over the past several months with non-pruritic swelling of her hands, lips, eyes, wrists, legs, and feet. The swelling resolves within 3 hours. Her most recent severe episode was associated with throat swelling causing shortness of breath. She did not use her Epi-Pen but instead took an aspirin 325 mg. The swelling resolved 2 hours later. Only one of these severe episodes occurred shortly after eating. She had pizza with pepperoni 1 - 2 hours before one of her episodes. She had taken Excedrin in the past but not just before these episodes. Normal lab tests include C1 esterase inhibitor function, tryptase level, complement C4 level, and a CBC with differential. She has an Epi-Pen with her at all times. I told her to use Tylenol rather than any NSAID. I gave her samples of fexofenadine a month ago without any improvement. I have given her more samples of desoratadine, cetirizine, and monteleukast. I am not sure whether any of these medications will help. I am not sure what to do next. She may have idiopathic anaphylaxis but I cannot explain the angioedema each morning. Thank you in advance for your help.

A subset of the patients with idiopathic anaphylaxis described originally by Dr. Paul Greenberger and colleagues also had episodes of angioedema without other manifestations at other times. Therefore, I referred your message to Dr. Greenberger, asking for his input. Dr. Greenberger's response is enclosed below. I should also mention that the serum total tryptase levels may be normal in some cases of anaphylaxis even when the blood specimen was obtained at an appropriate time (within 4 hours after onset of the anaphylaxis manifestations). However, the serum levels of the beta-tryptase sub-population of total tryptase may be increased, reflecting tryptase released in response to a mast cell- activating stimulus. To my knowledge, the tryptase level assessed by commercial labs is the total tryptase. To obtain the serum level of beta-tryptase, one must send a frozen serum specimen to the lab of Dr. Lawrence Schwartz in Richmond VA. You can obtain the procedure for sending specimens and payment for this assay by calling the office of Dr. Schwartz (found under his name in the AAAAI Membership Directory or through the members section of the AAAAI website (www.aaaai.org).

Dr. Greenberger's response:

Yes, it sounds like 1 or 4 episodes of IA-angioedema (instead of generalized) as there was presumed throat, upper airway involvement. There appears to be daily idiopathic angioedema as well. So the pt has 2 diagnoses. Presumably, the pt is not getting any ACE inhibitors or (rarely ARBs) or any other med that might be contibuting. Pts with IA typically are atopic and may have angioedema or urticaria (CIU) as well as occasional episodes of anaphylaxis. Years ago, we showed that the IA-A patients and ones with generalized reactions both have elevations in urine histamine in samples collected during or immediately after attacks.In terms of therapy, when individual drugs don't work, we add am and pm antihistamines. If that doesn't work, a trial on doxepin 10 mg may help unless it sedates. Some patients will improve with ketotifen (2 mg tid), obtained from Italy (a location we have been having pts use in the Vatican City ) or Canada. Oral Gastrocrrom (200 mg qid) is a possibility at $500/mon, some ridiculous amount for a medication that rarely works! Of course, she may need low dose qod prednisone too if nothing else works. That might help resolve the angioedema and possibly help the pt enter a remission

12/10/04 re: Epinephrine-induced arrhythmia

A patient received an influenza vaccine at a public clinic. She returned a short time later complaining of numbness in her thumb and a red rash that rapidly developed over the arm, chest and neck She was not exhibiting respiratory distress, however, it was noted that she had a change in quality of her voice and she was very pale and anxious. Per clinic protocol, epi 0.5 mg was administering SQ and she was transported to a local ER. Her BP at the time the epi was administered was 184/57. At the ER it was noted that she was in a trial fibrillation with a rapid ventricular response and had ST depression in an infererolateral distribution. She was treated with >IV Cardizem and converted to normal sinus rhythm. An MI was ruled out. Even though the patient was not in full blown shock, the rapid progression of her rash, the changed in vocal quality, and physical presentation, an impending anaphylactic reaction was suspected and therefore epi was administered. Could the epi have caused the artial fib or could that have been a result of an anaphylactic reaction? Should epi have been delayed until more signs of anaphylaxis were observed?

Although tachycardia, often with association pallor and palpitations occur commonly following epinephrine (Epi) administration, true arrhythmias occur only rarely in individuals without underlying significant cardiac disease, including as history of arrhythmias. As pointed out in an enclosed (below) excerpt from a very good review of epinephrine use in anaphylaxis (Ana) by Dr. Estelle Simons, an authority in this subject, arrhythmias may also been seen after receipt of very high dosage/IV epinephrine. However, a recent report describing effects of IV epinephrine used in the E.R. concluded that no serious cardiac adverse effects were seen. However, as noted in my previous review of that report for this AADMC website (enclosed below), the patients treated with IV Epi described in that report were all relatively young. Another recent review of Epi (called adrenaline in the UK ) treatment in anaphylaxis concluded that Epi may need still warranted in individuals with cardiac disease who have manifested hypotension (see enclosed excerpt). Another review from Yale concluded that no increased risk of serious adverse cardiac effects, even in older individuals provided no significant underlying cardiac disease. (see abstract of that review enclosed below).

How does all this information related to the clinical situation described by you? To respond to your questions: 1) You did not mention the patient's age or past cardiac history. It is possible for Ana to involve the heart. However, if cardiac involvement by the Ana caused the arrhythmia in this case, I would think that hypotension would have been present. 2) If epinephrine induced the arrhythmia, there is a fair likelihood that there is some underlying cardiac problem (intermittent A. Fib is not unusual in older individuals). Consider checking thyroid function, cardiac response to exercise, maybe even a full electro- physiologic assessment if any question. 3) Should the use of Epi been delayed until more definitive signs of Ana? Much depends on the suspicion that laryngeal edema was starting. Some authorities feel that Epi may not be needed if there is just skin manifestations. However, any evidence of upper or lower airways obstruction or hypotension warrants more aggressive treatment, including Epi. As reviewed by Simons in her article noted above, in a review of cases of fatal Ana reactions despite treatment with Epi the Epi treatment was delayed at least 30 minutes after onset of the reaction manifestations. So, if they suspected laryngeal involvement, the Epi treatment is likely warranted right away plus getting an anesthesiologist or otolaryngologist to look at the larynx right away if the laryngeal symptoms increase despite the Epi treatment (in case airway maintenance is needed). 4) As an aside, if there is a question whether an Ana reaction had occurred, a blood specimen should be obtained for clotting, removal of the serum for storage in the usual freezer and subsequent shipment to a lab that does a reliable serum tryptase assay. Tryptase is a mast cell enzyme released during acute allergic systemic reactions. Serum tryptase levels are more sensitive than plasma histamine levels in diagnosing an Ana reaction because the released histamine is rapidly catabolized whereas the tryptase levels stay elevated for up to several hours after the onset of the reaction. The best tryptase assays, in my opinion, are done in the lab of Dr. Lawrence Schwartz in Med Coll Virginia in Richmond where they assess both total and beta-tryptase levels (beta-tryptase level increase are a more sensitive probe). 5) Another aside - If the reaction you described was induced by the influenza vaccine, it is possible that the reaction was induced by egg components in the vaccine. This happens occasionally in egg-sensitive recipients. Suggest checking for a history of current egg allergy.

From review of eoinephrine treatment of anaphylaxis by Simons - JACI 2004;113: 837-44)

Rarely, and especially after overdose, it (epinephrine) may lead to ventricular arrhythmias, angina, myocardial infarction, pulmonary edema, sudden sharp increase in blood pressure, and intracranial hemorrhage. The risk of epinephrine adverse effects may be increased in individuals with some pre-existing cardiovascular, central nervous system, or thyroid diseases; in persons using monoamine oxidase inhibitors, which block epinephrine metabolism; or in those using tricyclic antidepressants or cocaine, in whom epinephrine duration of action is prolonged

Current Lit Item
TITLE - Is IV epinephrine treatment safe in severe asthma?

SUMMARY
Parenteral epinephrine (Epi) injections are often used in the treatment of acute severe asthma unresponsive to inhaled beta agonists. In very severe (life- threatening) cases. Some physicians would prefer to inject the Epi by the IV route. However, concerns have been raised about the potential for serious adverse effects of IV Epi. To determine if this was a major concern, Smith et al of the UCLA Medical Center in Los Angeles, CA retrospectively reviewed the cases of 27 asthmatics (ages 19-58 years) with acute severe asthma treated with IV Epi when unresponsive to inhaled beta agonists. In 24 of these individuals receiving loading doses of 50-1000 mcg of 1:10,000 solution followed in 14 patients with a continuous infusion of 1000mcg/hour. The other 3 patients received a continuous infusion without a prior loading dose.

No deaths or serious adverse events were recorded during the IV Epi treatment. One patient with pre-treatment chest pain experienced increased pain during the IV Epi infusion. However, there were no acute changes noted in the EKG or increases in serum levels of cardiac enzymes in any of the patients.

REFERENCE - Ann Emergency Med 2003;41:706-11

EDITOR'S COMMENTS
The IV Epi treatments described above were all given under close observation in the well-staffed Emergency Depts of two large hospitals and then observed closely in the ICU of these institutions. The patients appeared to tolerate the IV Epi well. However, several questions and concerns can be raised about this study and the authors' conclusions: 1) there were no patients above the age of 57 years and/or with underlying cardiac disease. Although it is true that many asthmatics would be younger individuals without cardiac problems, one has to be selective when seeing patients in a very acute situation; 2) one can raise the question why epinephrine was not tried by the IM route first (apparently not done in these patients). The authors' rationale for Epi use by the IV route is the rapid reliable effects seen. However, other studies have shown that Epi injected IM is absorbed very rapidly except in individuals with severe hypotension. Of note, recent studies by Simons et al have shown that Epi injected IM is absorbed more rapidly than Epi injected by the traditional subcutaneous route.

Excerpt from review of adrenaline treatment in anaphylaxis
BMJ 2003;327:1332-35

Is adrenaline safe?
Adrenaline is the recommended first line treatment in anaphylaxis (fig 1).10 Confusion arises because systemic allergic reactions can be mild, moderate, or severe. For example, generalized angioedema and urticaria without airway involvement would not be described as anaphylaxis. A good working definition is that an anaphylactic reaction involves one or both of the two severe features: respiratory difficulty (which may be due to laryngeal oedema or asthma) and hypotension (which may present as fainting, collapse, or loss of consciousness). Inappropriate use of adrenaline may be dangerous. Most adverse events with adrenaline usage occur when it is given in overdose or intravenously. Those particularly at risk include elderly patients and patients with hypertension, arteriopathies, or known ischaemic heart disease.7 8 10 w2 w3 As there are no controlled trials there is no way to estimate the risk in relation to benefit. Based on the current evidence, the benefit of using appropriate doses of intramuscular adrenaline far exceeds the risk (grade C). It should be stressed that adrenaline is not contraindicated in individuals with underlying ischaemic heart disease, as the decrease in filling pressure due to anaphylaxis is likely to result in further coronary is chaemia (grade C).1 Careful monitoring and avoidance of adrenaline overdose is necessary in these patients.

Prehosp Emerg Care. 2001 Apr-Jun;5(2):200-7.
Subcutaneous epinephrine in the prehospital setting.
Safdar B, Cone DC , Pham KT.
Division of EMS, Section of Emergency Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. basmah98@hotmail.com

OBJECTIVES: To outline current practice regarding the prehospital use of subcutaneous epinephrine, and systematically review the existing literature to determine the level of support for its use in the elderly. Many health care personnel are reluctant to administer subcutaneous epinephrine for potentially life-threatening conditions such as asthma and anaphylaxis in older patients. This sytematic review examined the following focused question: "For older patients not known to have coronary artery disease, does administration of subcutaneous epinephrine carry a significant enough risk of cardiovascular side effects to mandate age as a relative contraindication to self-administration or emergency medical services administration in the prehospital setting?"
METHODS: The MEDLINE and Health Star databases were searched to identify studies evaluating the use of subcutaneous epinephrine in the treatment of asthma and anaphylaxis. Bibliographies from included studies, known reviews, and textbooks were examined to identify additional studies. The strength of evidence presented in each study was assessed in accordance with the classification system proposed by the American Heart Association's Emergency Cardiovascular Care Committee.
RESULTS: The review of the literature revealed only three case reports (level VII evidence) that record adverse reactions of epinephrine when used for anaphylaxis and allergy, while several level III and V studies found no adverse effects when used for asthma. No controlled trials documenting adverse effects were found.
CONCLUSIONS: The authors did not find significant evidence to contraindicate the use of subcutaneous epinephrine in older patients who are not known to have coronary artery disease, who present with either asthma or allergic reaction

10/29/04 re: Incidence of fatal food allergic reactions in the USA

I understand that fatal food allergy is quite rare. I am aware of the article published by Dr. Sampson, 6 fatal and 7 near fatal food reactions in children and adolescent. Do we know what the incidence of fatal food reaction in US is? eg, 500 deaths a year from penicillin allergy, 40 deaths from stinging insect allergy. Does FAAN keep a registry on this?

To help respond to your questions, I obtained input from Dr. Scott Sicherer, a co-investigator with Dr. Sampson, who has played a major role in setting up the registry of food allergy cases in the USA (in collaboration with the FAAN). Dr. Sicherer's prompt response is enclosed below. Of note, a recent analysis of the fatal anaphylaxis cases in the UK by Pumphrey came to an estimate of the annual incidence of food-related fatal anaphylaxis in the same range as mentioned by Dr. Sicherer (see Curr Opin Allergy Clin Immunol. 2004;4:285-290)

Dr. Sicherer's comments:

I am not aware of any specific studies in the US that attempt to determine the exact number of fatalities from food allergy. The person posing the question is correct that the Food Allergy & Anaphylaxis Network has a registry of fatalities (See Bock et al PMID: 11150011) and certainly there are reports and series of fatal reactions but that is a matter separate from the prevalence of fatal reactions. There have not been codes for fatal anaphylaxis from foods and there could always be misinterpreted/unknown/miscoded anaphylaxis deaths attributed to unknown causes or something other than anaphylaxis; these data would be hard to generate and reliability questioned. Based upon derived data from several angles, different authors have come up with an estimate of 150-200 deaths/year in the US . One such estimate can be derived from the paper by Yocum (PMID: 10452770), which is a prevalence study of anaphylaxis. Extrapolation of US deaths from that study (600-800/yr) and from identified causes (~1/3 from food) matches the ~200/year that has been estimated in other ways.

10/19/04 re: Correct epinephrine dosing

I am a public health nurse with a sexual health clinic. We have been told that our sexual health clinics should not use Epi-Pens in anaphylactic situations because the recommended dose for someone over 14 years is 0.5mg (maximum dose, using the 0.01ml/kg dosing). Instead of using Epi-Pens that administer 0.3mg of epinephrine, we have been advised to draw up the epinephrine from the glass vials to give a dose of 0.5mg. This information is based on the Canadian Immunization Guide, Health Canada , 2002, Sixth Edition, pg 16. Do you have any rationale that will support our desire to have Epi-Pens on hand to use in emergency situations? I am also wondering why the Epipen administers 0.3mg of epinephrine when the dosing for epinephrine is 0.01mg/kg, and anyone over 50kg would require 0.5mg?

I agree with you that the 0.3 mg dosing in Epi-Pen units is insufficient for the treatment of anaphylaxis or acute severe asthma episodes in some adults. To help respond to your question, I obtained input from Dr. Estelle Simons of the Univ. of Manitoba, one of the leading investigators of the clinical use of epinephrine. Her reply is enclosed below.

I have personally wondered whether the Epi-Pen manufacturer limited the dose to 0.3 mg because of concerns about possible “over-dosing” if a larger (0.5 mg) dose was self-injected by someone very sensitive to the adrenergic effects of epinephrine. As a pragmatic approach, I have instructed adult patients to carry two Epipen units of 0.3 mg each. The patient is instructed to use the second several minutes later if there is insufficient response of an anaphylactic reaction to the first Epi-Pen injection. Large-sized adult patients have been instructed to inject the second Epipen unit right after the first. However, I agree that it would be preferable to also have available epinephrine self-injection units which contain 0.5 mg epinephrine.

TO: Dr. Burton Zweiman
FROM: Dr. Estelle Simons
Susanne Medeiros raises a frequently asked question! We are trying to persuade auto-injector manufacturers to provide a broader range of fixed-dose epinephrine formulations, including a 0.5 mg dose.

9/15/04 re: Skin test during ACE inhibitor/ARB therapy

Is it contraindicated to skin-test for hymenoptera in patients on ARB's and/or ACEI's? I have found some literature that says ACEI's are contraindicated and given the similarity of the two I wanted to know if the ARB's are also.

Much of the published literature concerning ACE inhibitor-enhanced anaphylaxis of which I am aware has dealt with occasional anaphylactoid reactions triggered during “first use” of hemodialysis membrane filters such as the AN69. In such cases, it is thought that the dialysis membrane surface interacts with the blood, liberating bradykinin (BK). Because ACE also acts as a kininase, BK is present in higher levels and/or is more persistent in the plasma when such dialysis-related BK release occur in individuals on pre-existent ACE-I therapy. As a result, there may be more severe hypotension, possibly angioedema, etc.

Angiotensin receptor blockers (ARB) do not inhibit the breakdown of BK. Therefore, one would not expect an increased incidence/severity of anaphylactoid reactions in those treated with ARB. However, there have been occasional reports of this happening (see enclosed article). Therefore, some authors have cautioned about carrying out dialysis using AN69 filters in those receiving ARB therapy.

It is less clear how these findings relate to the risk for true anaphylaxis reactions that might occur during skin testing or IT. There is some evidence that BK may be released in such reactions. However, the relative importance of BK in the pathogenesis of such anaphylactic reactions is not well-defined. Nevertheless, because angiotensin may be part of the host response to the hypotension occurring in anaphylactic reactions, I would withhold ARB for an appropriate time period (duration depending on the particular ARB taken by the patient) before skin testing until more information becomes available.

Nephrol Dial Transplant (2001) 16: 1955-1956 - 2001

Letters

Anaphylactic reaction during haemodialysis on AN69 membrane in a patient receiving angiotensin II receptor antagonist
Biju John, Hameed Kannu Indiramma Anijeet and Rasheed Ahmad
Regional Renal Unit Royal Liverpool University Hospital Liverpool, UK

Sir,

Anaphylactic reactions during haemodialysis using AN69 membrane in patients receiving angiotensin-converting enzyme inhibitors (ACE-I) are well recognized [1]. However, anaphylactic reactions are rare in patients on angiotensin II receptor antagonists with AN69 dialysers. To our knowledge, there are only two reported cases of possible anaphylactoid reactions with the angiotensin II receptor antagonist, losartan [2]. We report a patient who had anaphylactic reaction while dialysing on AN69 and receiving losartan.

Case
A 43-year-old male, with end-stage renal disease secondary to anti-GBM disease was on regular haemodialysis. He was receiving 4-h dialysis three times a week and was using a Haemophan« membrane (COBE 400) dialyser. His medications were nifedepine LA 30 mg once daily, losartan 25 mg once daily, azathioprine 50 mg once daily, prednisolone 12.5 mg once daily, ranitidine 150 mg bid, aluminium hydroxide capsules 3 tid, calcium carbonate 3 bid, erythropoietin 2000 units s/c 3 days per week and iron saccharide 100 mg twice monthly. He was anuric and gained excessive weight in between dialysis. The urea removal rate (URR) was 46.79%. Since he was not being adequately dialysed, the dialyser was changed to AN69 (Filtral« 2800) but the other dialysis parameters were unchanged. About an hour into the first dialysis on the AN69, he developed breathlessness and became agitated with profuse sweating. He denied any chest pain. His pulse rate was 100 per minute and blood pressure was 202/108 mmHg. Chest examination revealed scattered basal crepitations. A clinical diagnosis of acute allergic reaction to the dialyser membrane was made and he was immediately taken off the machine. Intravenous hydrocortisone 200 mg along with chlorpheniramine 4 mg was given and his condition rapidly improved. The patient refused a trial of dialysis on AN69 after stopping losartan. Hence he was put back onto a Haemophan HG« membrane dialyser but with a higher surface area (COBE 600). The dialysis has since then remained uneventful. He has remained stable and his URR is now 65.38%.

Comment
The first use reactions are allergic in nature, which occurs with the use of a fresh dialyser. These have been linked to sterilant ethylene oxide and this has been overcome by gamma sterilization. Anaphylactic reactions in patients who dialyse on AN69 whilst taking ACE-I is well recognized [1]. The risks of reaction vary from unit to unit and even in the same unit only some patients develop reactions raising the possibility of individual susceptibility. Even the same patient does not always develop reactions. This lack of reproducibility should point towards a multifactorial aetiology. It has been hypothesized that bacterial pathogens are the initiating factors and these reactions were potentiated or amplified in patients on ACE-I [1]. Some researchers have suggested that high bradykinin levels were responsible for the anaphylactoid reactions possibly due to synthesis of bradykinin by the AN69 membrane along with reduced degradation by the presence of ACE-I [3]. Others have demonstrated a higher bradykinin level at the outlet of the AN69 membrane dialyser when compared to the inlet concentration [4]. However, Wakasa et al. did not find any significant difference in bradykinin levels in the two groups of patients on AN69 with and without ACE-I. It should be noted that none of the patients in this report developed any reactions during dialysis. They suggested that there might be an activation of the Hageman factor by the negative charge of the AN69 membrane leading to increased bradykinin synthesis [5]. Anaphylaxis has commonly been described with AN69 dialyser in ACE-I (i.e. captopril and enalapril) treated patients. These drugs alter bradykinin levels by virtue of their inhibition of angiotensin-converting enzyme. However, angiotensin II receptor antagonists have no effect on bradykinin metabolism. Our patient developed the anaphylactic reaction whilst on losartan.

In conclusion we therefore recommend caution in using angiotensin II receptor antagonists in patients using AN69 membrane dialysers.

References

1. Verresen L, Water M, Vanrenterghem Y, Michielsen P. Angiotensin converting enzyme inhibitors and anaphylactoid reactions to high flux membrane dialysis. Lancet1990; 336: 1360-1362[Medline]

2. Saracho R, Martin-Malo A, Martinez I, Aljama P, Montenegro J. Evaluation of the Losartan in Haemodialysis (ELHE) Study. Kidney Int1998; 68 [Suppl]: S125-129

3. Lemke HD, Fink E. Accumulation of the bradykinin formed by the AN69 or PAN17 Dx membrane in vitro (abstract). J Am Soc Nephrol1992; 3: 376

4. Akizawa T, Kinugasa E, Wakasa M, Kohojiro S, Koiwa F, Koshikawa S. Effects of dialysis membrane and ACE-inhibitors on bradykinin levels during haemodialysis. Clin Nephrol1994; 41: 241-244[Medline]

5. Wakasa M, Akizawa T, Kinugasa E, Koshikawa S. Plasma bradykinin levels during haemodialysis with PAN Dx and polysulfone with and without concurrent ACE-I inhibitors. Clin Nephrol1995; 44 [Suppl 1]: S29-S32[Medline]

8/9/04 re: Mastocytosis or anaphylaxis?

I have a 60 year old gentleman s/p CABG (still smoking a few cigarettes/day) with severe atrial fib/flutter who has not tolerated a recent trial off atenolol. He has frequent pruritis and urticaria with even minimal exertion (vacuuming his home). He was sent to me three months ago after becoming hypotensive and experiencing LOC with fast walking/mild jogging recommended by his cardiologist. I sent off a work up which revealed serum tryptases of 17, 17, and more recently, 21. Bone marrow and immunophenotypic flow analysis of his bone marrow fail to show increased mast cell numbers, and a skin biopsy was also negative. Other than mild generalized erythroderma, he does not have any urticarial or urticarial pigmentosa rash. I placed him on H1, H2 and recently added antileukotriene and gave him glucagon autoinjector when his atenolol was resumed. If he does not have mastocytosis, then does he have EIA with elevated baseline tryptase or idiopathic anaphylaxis exacerbated by exercise? Should he be started on corticosteroids and weaned to alternate day therapy if he continues to have pruritis/mild hives with minimal exertion? I am concerned that he is a walking time bomb who has the deck stacked against him.

In my recent discussion with him, Dr. Lawrence Schwartz of the Medical College of Virginia (MCV), one of the leading mast cell and tryptase experts in the world, told me that the serum total tryptase levels are well above 20 in over 90% of cases of systemic mastocytosis (SM) with systemic manifestations. There are occasional cases of SM with serum total tryptase levels in the 15-20 range. However, one must see other evidence such as mast cell clumps in the bone marrow before making a diagnosis of SM in such cases. Of course, increased serum total tryptase levels are found in some other conditions such as certain types of myelogenous leukemia. I assume that the bone marrow exam did not find evidence for leukemia. Your description suggests that your patient has some variant of EIA rather than idiopathic anaphylaxis since the episodic symptoms apparently do not occur when the patient is in the resting state. One might investigate this further by obtaining serum before and during exercise which induces anaphylaxis symptoms. However, serum levels of beta-tryptase would likely give more definitive evidence than levels of total tryptase reported by commercial or hospital labs. As you may know, the total tryptase level is more of a measure of the mast cell numbers while the beta-tryptase is more of a measure of the release of mast cell components as would occur in an anaphylactic reaction. The only lab that I know to be set up to do serum beta-tryptase as well as total tryptase levels is run by Dr. Schwartz in the MCV. A significant rise in beta-tryptase levels during exercise-induced symptoms would strongly support a diagnosis of EIA. If EIA is present, avoidance of body-overheating during exercise may control the problem. For example, lower the ambient room temperature before doing house-cleaning. As you may know, EIA occurs more commonly during running sports than during swimming (where the body temperature is less likely to rise). I would not commit the patient to long-term corticosteroid therapy unless there was definitive evidence of anaphylactic reactions at rest as well as during/after exercise. Although use of corticosteroids in an alternate-day regimen reduces the likelihood of infectious complications as compared to daily corticosteroids in the same dosage, I know of no evidence that the risk for osteoporosis/bone fractures is reduced by the alternate dose approach. Such bone problems are perhaps the most common current serious problems related to long-term therapy with low/moderate dose corticosteroids.

8/9/04 re: Epinephrine use following coronary vasospasm

Here is a real challenging case. A 50 year old man, stung by a bee developed hives and throat swelling, self injected Epi and went to E.R. and had hypotension and got 2 litres of fluid and seen by cardiologist and had mild elevation of enzymes and ST segment elevation and cath, which showed R Coronary spasm. Per cardiologist, he should never receive Epi as she thinks that the vasospasm was caused by Epi. Patient doesn't know what to do. He has made an appointment with the allergist. What is your opinion?

There have been occasional case reports suggesting coronary vasospasm as an epinephrine treatment effect (see enclosed abstract). Obviously, hymenoptera avoidance measures and a cautious venom immunotherapy program should be considered to reduce your patient's risk for a repeat sting reaction. You did not mention any other risk factors for anaphylaxis in this case. If epinephrine were really needed for another anaphylactic reaction in the future, one might consider:

1) Start with a reduced dose of epinephrine (e.g.-the pediatric size Epi-pen)

2) Concomitant parenteral administration of a calcium channel blocker. Such blockers are thought to counteract coronary vasospasm in some cases (e.g.- “Prinzmetal angina”)

3) Avoid running or other exertion after the epinephrine injection (probably advisable in most anaphylaxis cases, anyways).

4) One might consider other agents used to treat marked hypotension in anaphylaxis such as glucagon or arginine-vasopressin, as has been reported recently (Int Arch Allergy Immunol 2004;134:260-1). However, I do not know whether such agents are less likely to affect coronary blood flow. It is also not clear how effective they would be for reducing airways obstruction.

Ann Allergy. 1993 May;70(5):396-8.
Myocardial infarction induced by coronary vasospasm after self-administration of epinephrine.
Saff R, Nahhas A, Fink JN.
Department of Medicine, Medical College of Wisconsin, Milwaukee.

A case of a 30-year-old man who developed a myocardial infarction after self-administering an Epi-Pen for an episode of idiopathic anaphylaxis is reported. The patient had numerous risk factors for coronary artery disease, and it was suspected that epinephrine-induced coronary spasm caused the infarct. The Epi-Pen Junior may be indicated in such adults with numerous risk factors for coronary artery disease who are at risk for recurrent anaphylaxis.

7/12/04 re: Anaphylactic vs. anaphylactoid reactions

On a regular basis I visit your very interesting and effective site and today I have a small question: Is there any reference which describes differences in recovery time after anaphylactic or anaphylactoid reactions? I have failed to identify any related articles. According to my understanding, the recovery time is principally dependant on intensity and expression of clinical symptoms and the effectiveness of medical treatment. Therefore a differentiation cannot be performed by “recovery time.” What is your opinion?

Several reviewers have concluded that anaphylactic and anaphylactoid reactions cannot be readily distinguished based on clinical grounds (see enclosed abstract for an example.) The duration of such reactions is generally thought to be dependent on the severity of the manifestations. However, as reviewed by Stark and Sullivan (J Allergy Clin Immunol 1986; 78:76), a biphasic temporal pattern occurs in about 15% of anaphylactic reactions. Thus, an anaphylactic reaction which appears to remit may recur hours later in a minority of cases. In contrast, such a biphasic temporal pattern appears to be very unusual in anaphylactoid reactions. For example, surveys of anaphylactoid reactions have shown that anaphylactoid reactions to intravenous radio contrast practically always occur within 30 minutes after the start of the infusion and rarely recur after the initial reaction remits. A similar monophasic pattern generally characterizes anaphylactoid reactions to opiate infusions.

The reasons for the different temporal patterns in anaphylactic and anaphylactoid reactions do not appear well-defined to me. However, one possible explanation may come from in vitro studies. Incubation of IgE-sensitized mast cells with the relevant allergen induces rapid release of pre-formed mediators such as histamine. In some cases, this is followed by secretion of new formed mediators such as prostanoids and certain cytokines which could be responsible for recurrent (biphasic) symptomatology in an anaphylactic reaction. In contrast, incubation of skin mast cells with an appropriate concentration of an opiate induces only release of pre-formed mediators but not significant secretion of newly formed mediators. This could explain the relative rarity of recurrence of symptoms hours later in anaphylactoid reactions.

In vivo evidence for these different temporal patterns may come from studies of skin test reactions. Intradermal allergen injection in very sensitive subjects is followed not only by the expected immediate whealing reaction but also a “late phase” reaction at the injection site, peaking at 6-12 hours. Such late phase reactions are rare following the prominent immediate whealing reaction and mast cell release of histamine at sites of opiate injection (see Current Opinion in Immunol 1993:5:950-955. for a review of late phase reactions written by me.)

Acta Clin Belg. 2004 Jan-Feb;59(1):34-43.
Allergic reactions occurring during an aesthesia: diagnostic approach.
Ebo DG, Hagendorens MM, Bridts CH, De Clerck LS, Stevens WJ.
Dept Immunology - Allergology - Rheumatology, University Antwerpen, Belgie.

Anaphylactic and anaphylactoid reactions to anesthetic and associated agents used during the perioperative period have been increasingly reported during the last 3 decades. The frequency of life-threatening hypersensitivity reactions occurring during anesthesia has been estimated to vary between 1/1.000 and 1/25.0000 procedures, with muscle relaxants being involved in almost three quarters of the cases. The mortality from these reactions is in the range of 3-6%. Nowadays, natural rubber latex also accounts for a significant number of perioperative anaphylaxis, particularly in children. Clinical manifestations do not allow differentiating between IgE-mediated anaphylaxis and anaphylactoid reactions resulting from non-specific mediator release. Successful management of these patients requires a multidisciplinary approach and includes prompt recognition and stabilization of the acute event by the attending anesthetist, determination of the responsible agent(s) with avoidance of subsequent administration of incriminated compound(s). The latter is based upon correct identification of the responsible drug and potentially cross-reactive compounds by the allergist and requires a detailed review of the anesthetic report as well as appropriate in vitro and in vivo allergy tests. At present, the overall performance of skin tests makes them the “gold standard” for diagnosis of muscle relaxant-induced perioperative hypersensitivity reactions. In addition, given their good negative predictive value, skin tests have been proven to be a useful tool to tailor the appropriate therapeutic alternative. For other compounds diagnosis is more difficult but newer techniques such as analysis of in vitro activated basophils can be helpful.

5/18/04 re: Anaphylaxis therapy in beta blocker-treated patients

I am a cardiologist. I realize beta-blockers reduce the effectiveness of epi-pens. I have patients who have absolute indications for beta-blockers and have risks of anaphylaxis for which they carry an epi-pen. If the patient is not fully beta-blocked, is the epi-pen helpful? Is there data showing the risk of beta-blocker induced unresponsiveness to epi-pen is so dangerous that such patients should not be on beta-blockers? Should such patients receive glucagon and epi-pen in the event of an anaphylactic episode? Should they check their pulse and take a second epi-pen if heart rate remains blocked? I am surprised that the dose of epi-pen would not overwhelm the effects of beta-blockers--is there data of degree of effect and has the effect been shown to be clinically significant?

You have raised questions in an area where there is still considerable uncertainty. To help respond to your questions, I obtained input from Dr. David Lang of the Cleveland Clinic Foundation who has extensively investigated the occurrence of anaphylaxis in beta blocker-treated patients. Dr. Lang's response is enclosed below.

You raise several questions regarding management of patients among whom administration of beta blockers is warranted, and who “have risks of anaphylaxis for which they carry an epi-pen.”

I believe it is appropriate to begin responding by mentioning the importance of classifying your patients based on their risk for experiencing anaphylaxis. Understandably, you would be more cautious about a patient who has experienced life threatening reactions following bee stings, is employed as a park ranger, and is receiving venom immunotherapy (which carries a risk for anaphylaxis with each injection). You would be less concerned about a health care worker who is allergic to latex but takes appropriate precautions and is less likely to experience a serious anaphylactic event requiring administration of epinephrine.

Similarly, you may also classify patients as to the relative importance of their requirement for a beta blocker. As you are well aware, several other classes of drugs (angiotensin converting enzyme inhibitors and calcium channel antagonists) have been introduced since beta-blockers became available in the 1960s, such that for patients with hypertension, equally efficacious alternatives may be used in many cases. For patients who require beta-blockers for myocardial re-infarction prophylaxis or congestive heart failure, however, there may be no equivalent substitute. In such cases, beta blocker administration may be favorable from an individualized risk-benefit standpoint [1]. It would be appropriate to advise these patients to take a beta blocker and carry portable epinephrine with them, as the heightened risk of premature mortality from fatal anaphylaxis in the setting of beta blocker use is exceeded by the benefit of prolonged survival in association with ongoing beta blocker therapy for cardiovascular disease.

You posed several questions regarding anaphylaxis management in such patients. Some of your questions appear to be based on the assumption that the risk which exists with beta blocker use is associated with suboptimal response to epinephrine. However, several lines of evidence imply severe anaphylaxis is more frequent in the setting of beta blocker exposure: 1) Beta blockers may amplify the severity of anaphylaxis via enhanced mediator release, and decreased cardiac contractility with perpetuation of hypotension and bradycardia [2]; 2) Greater risk for more severe anaphylaxis has been associated with beta blocker exposure [3,4]. In a case control study of contrast media reactions, moderate-severe anaphylactoid reaction was observed significantly more frequently among patients receiving beta-blockers (OR = 3.43, 95% CI = 1.45 - 8.15, p = 0.005).

Beta-blocker exposure was specifically associated with greater risk for severe anaphylactoid reaction with bronchospasm (OR = 3.73, 95% CI = 1.18 - 11.75; p = 0.025), and this risk was independent of underlying cardiovascular conditions for which beta blockers were being prescribed. Patients receiving beta-blockers were also almost eight times (OR = 7.67, 95% CI = 1.79 - 32.85, p = 0.029) more likely to be hospitalized after anaphylactoid reaction in this study – an observation that may reflect the influence of beta blockade on preventing optimal response to epinephrine.

As you know, beta-blockers exert their effects by competitive inhibition of catecholamine binding at beta-adrenoceptor sites, such that the dose response curve for the agonist is shifted to the right. Based upon this rationale, use of higher than customary doses of a beta-agonist may seem indicated to overcome the beta blockade [5]. However, a lower dose of epinephrine may also be justifiable in the setting of beta-blocker associated anaphylaxis, in order to avoid unopposed alpha-adrenergic effects leading to paradoxical hypertension and coronary vasoconstriction -- several cases of this have been reported [6-8].

You also inquired about the role of adequate beta blockade for determining risk, or for influencing management with epinephrine. This is a very good question, but I am unaware of any data that could provide an answer.

The therapeutic utility of glucagon for refractory hypotension during anaphylactoid reaction from contrast media has been reported (9), in a 75 year-old man receiving both atenolol and timolol eye drops. Glucagon raises cyclic adenosine monophosphate levels via noncatecholamine mechanisms and can exert potent chronotropic and inotropic effects. Based upon its mechanism of action and widespread effects, glucagon may be efficacious for the treatment of severe beta-blocker associated anaphylaxis. For this reason, patients who take beta blockers and carry portable epinephrine to administer for anaphylaxis may be advised to purchase medic-alert jewelry indicating this, so that emergency department personnel will be made aware and can consider administration of glucagon.

I appreciate your interest in this area, which clearly requires more investigation. In my experience, optimal management of patients with anaphylactic potential who have indications for beta blockers frequently requires close collaboration between Allergy/Immunology and Cardiology physicians.

Please contact me if I can provide you with additional information.

1) Tenbrook JA, et al. Should beta blockers be given to patients with heart disease and peanut-induced anaphylaxis? A decision analysis. J Allergy Clin Immunol 2004; 113: 977-82.

2) Toogood JH. Risk of anaphylaxis in patients receiving beta-blocker drugs. J Allergy Clin Immunol 1988; 81: 1-3.

3) Lang DM, Alpern MB, Visintainer PF, Smith ST. Increased risk for anaphylactoid reaction from contrast media in patients on -adrenergic blockers or with asthma. Ann Intern Med 1991; 115:270-6.

4) Lang DM, Alpern MB, Visintainer PF, Smith ST. Elevated risk of anaphylactoid reaction from radiographic contrast media is associated with both ¯-blocker exposure or cardiovascular disorders. Arch Intern Med 1993; 153: 2033-40

5) Lewis RV, Lofthouse C. Adverse reactions with ¯-adrenoceptor blocking drugs. Drug Safety 1993; 9: 272-9.

6) Madowitz JS, Scheweiger MJ. Severe anaphylactoid reaction to radiographic contrast media. JAMA 1979; 241: 2813-15.

7) Jacobs RL, Rake GW, Fournier DC, Chilton RJ, Culver WG, Beckmann CH. Potentiated anaphylaxis in patients with drug-induced beta-adrenergic blockade. J Allergy Clin Immunol 1981; 68: 125-7.

8) Newman BR, Schultz LK. Epinephrine-resistant anaphylaxis in a patient taking propranolol hydrochloride. Ann Allergy 1981; 47:35-37.

9) Zaloga GP, Delacey W, Holmboe E; et al. Glucagon reversal of hypotension in a case of anaphylactoid shock. Ann Intern Med 1986;105: 65-6.

5/6/04 re: Treatment of anaphylactic shock

I am a third year nursing student at UWS and I am currently undertaking an assessment for my high dependency subject, in which we have to design a concept map and complete a report on a topic of our choice. I have chosen anaphylactic shock as my topic. I was wondering if you could provide me with information on anaphylactic shock as the information on the Web site seems to be more addressing anaphylaxis in general and not anaphylactic shock. I am also having difficulty finding guideline procedures on how to treat a patient in anaphylactic shock in an emergency situation preferably in the hospital environment. There is no information on NSW health Web site they just refer me to you. Any specific information in relation to anaphylactic shock cause, pathophysiology, nursing treatment, medical treatment, prevention and signs and symptoms would be great. Or if you could provide me with information on how I could obtain this information I would really appreciate it.

To help answer your question, I have enclosed below a portion of a chapter on anaphylaxis (ANA) I have co-authored. This describes treatment of shock associated with ANA. I also suggest that you read the relatively recent article by Dr. Hugh Sampson (reference also enclosed).

But first let me emphasize that in most cases the hypotension in an ANA reaction is due predominantly to depletion of vascular volume due to a rapid loss of fluid from the blood into extravascular spaces. This leakage is due to marked vasodilatation and increased vascular permeability in ANA. This leakage may not be obvious as edema, at least in the initial phases of ANA. However, as a result, appropriate treatment of shock in ANA requires not only adequate doses of epinephrine (adrenalin), sometimes needed repeatedly, but also adequate amounts of intravenous fluid, generally infused fairly rapidly. The guidelines for whether the amount of fluids being given is adequate are based on frequent monitoring of the blood pressure. If the blood pressure has returned to normal, check for orthostatic effects as a sensitive measure of whether there is still hemodynamic instability.

In a small percentage of ANA cases, the hypotension may be due to direct cardiac involvement by the ANA reaction. This is sometimes manifest as an arrythmia. If such involvement is profound it can contribute to shock in ANA. Rapid fluid infusion in such cases may lead to pulmonary vascular congestion. The same situation may occur if the patient has underlying cardiac disease that compromises cardiac output capacity. So close observation for fluid overload is important. One must also remember that symptoms in individuals receiving beta blocker drugs at the time of the ANA reaction may not respond as well to epinephrine therapy.

Portion of my chapter

Pharmacologic therapy - Depending on the severity of clinical findings, patients may require treatment with catecholamines, antihistamines, corticosteroids, or intravenous fluids (show table 5).

* Epinephrine is the drug of choice for anaphylaxis because it can reverse associated hypotension and bronchospasm. Fatality rates are highest in patients in whom treatment with epinephrine is delayed [14].

Patients with severe upper airway edema, severe bronchospasm, or severe hypotension should receive 0.5 to 1.0 mL of 1:10,000 epinephrine intravenously at intervals of 5 to 10 minutes, preferably with cardiac monitoring. Alternatively, a continuous infusion of epinephrine (1.0 to 10.0 ¦g/min) titrated to effect may be administered. If intravenous access cannot be obtained immediately, epinephrine can be delivered via the endotracheal tube. Aerosolized beta-agonists should also be used in patients with bronchospasm.

Patients presenting with mild to moderate symptoms, but without evidence of refractory laryngeal edema, bronchospasm, or severe hypotension, should receive 0.3 to 0.5 mL of 1:1000 epinephrine subcutaneously or intramuscularly [37]. This may be repeated every 10 to 15 minutes up to a total of three doses.

* Patients on beta-blockers may be resistant to treatment with otension and bradycardia. Glucagon has inotropic and chronotropic effects that are not mediated through beta-receptors, and should be administered in this subset of patients [38]. An intravenous bolus of 1 mg is recommended.

* Rapid administration of intravenous fluids is required to treat the shift of volume to the extracellular space secondary to increased vascular permeability. Large volumes may be required; colloid and crystalloid appear equally effective. Any patient with orthostatic hypotension or evidence of intravascular volume depletion, such as low urine output, should receive intravenous fluids.

* Vasopressor medications should be utilized in patients with persistent hypotension despite intravenous fluid administration. In addition to epinephrine, dopamine (5 to 20 ¦g/kg/min), norepinephrine (0.5 to 30 ¦g/min), or phenylephrine (30 to 180 ¦g/min) are effective for this indication. Invasive hemodynamic monitoring is often required to guide vasopressor therapy. (See "Swan-Ganz catheterization: Indications and complications").

* Antihistamines should be given to all patients with anaphylaxis. A combination of H1 and H2 blockers is superior to either agent alone [39]. Diphenhydramine (25 to 50 mg intravenously every 4 to 6 hours) should be administered in conjunction with cimetidine (300 mg intravenously every 8 to 12 hours). These drugs should be continued until anaphylactic symptoms completely resolve.

* Corticosteroids are effective in preventing late phase reactions in other IgE-mediated diseases such as asthma [40], although their effectiveness in preventing biphasic anaphylactic reactions has been challenged [29]. Hydrocortisone, 100 mg intravenously every 6 hours, or the equivalent dose of other corticosteroids, is recommended.

Sampson, H.- Anaphylaxis and emergency treatment. Pediatrics 2003;111:1601-1608

4/7/04 re: Antihistamine use in anaphylaxis

Are there any reviews or studies that demonstrate any superior efficacy with second-generation antihistamines vs. first when treating anaphylaxis? I am a physician and was told by a patient that another physician had recommended Zyrtec instead of Benedryl for her 3 year old daughter if she started developing an acute allergic reaction in addition to epi and other standard treatments. All the recommendations I have seen always recommend Benedryl in an emergent situation in addition to our other ER protocols. I have not seen anything to suggest that Zytec should be substituted in this situation. I have seen reports of increased psycho-motor performance with the first-generation AH's but nothing suggest superior efficacy with the 2nd generation AH's in a patient having an anaphylactic reaction. Can you please clarify this for me?

I am not aware of any intrinsic advantages of the second generation antihistamines (AH) over the older first generation AH in the treatment of anaphylactic reactions. In addition, the second generation AH are generally not available in parenteral preparations. Since rapidity of the onset of action is very important in the treatment of an impending or already manifest anaphylactic reactions, the lack of a parenteral preparation would be a major disadvantage, particularly if the patient had eaten recently, slowing G-I absorption of an oral AH preparation. However, to be sure that I have not missed some information in this area, I consulted Dr. Phil Lieberman of the Univ. of Tennessee, an expert in the treatment of anaphylaxis, who has written a number of review articles about anaphylaxis. His reply and an abstract of one of his review articles are enclosed below. Although his article raised the possibility that second generation AH might be given in higher doses (with less side-effects) with possibly greater blocking efficacy, Dr. Lieberman told me that this consideration was just theoretical without convincing evidence in clinical situations.
__________________________________________________________________
To my knowledge there are no studies that document any superiority of second-generation antihistamines over first-generation antihistamines in terms of therapy for any condition, including allergic rhinitis, urticaria, or anaphylaxis. Thus, in terms of efficacy, I do not believe there is any reason to feel that Zyrtec, in the situation you described, would be more effective than Benadryl. The issues that divide the first- and second-generation antihistamines are related to their side effect profile and duration of activity, and not to their efficacy.
__________________________________________________________________

Clin Allergy Immunol. 2002;17:287-317.
Histamine and antihistamines in anaphylaxis.
Winbery SL, Lieberman PL.
University of Tennessee College of Medicine, Memphis, Tennessee, USA.

Anaphylaxis and anaphylactoid reactions are potentially fatal. These disorders are sometimes iatrogenic, and increase with increased exposure to drugs, synthetic substances, and medical procedures. Non-IgE-mediated anaphylactoid reactions are common in medical settings and are clinically indistinguishable from anaphylaxis. These reactions may be unrecognized if a rigid classic definition of anaphylaxis is used. Histamine is a primary mediator of anaphylaxis and signs and symptoms of anaphylaxis can be reproduced by histamine infusion. Histamine triggers a cascade of inflammatory mediators and modulates its own release. H1-antihistamines are adjunctive treatment therapy for acute anaphylaxis and anaphylactoid reactions, in which many mediators of Inflammation are involved. Compared with epinephrine, the first-response medication of choice, antihistamines have a slow onset of action, and they cannot block events that occur subsequent to histamine binding to its receptors. Antihistamines are an important component of regimens for the prevention of anaphylaxis and anaphylactoid reactions in patients at risk, and may eventually have more widespread application in the perioperative setting. In some instances, such as with exercise-induced anaphylaxis and reactions to latex in sensitized individuals, prophylaxis regimens are not always effective. H2-antagonists are not detrimental in the therapy of anaphylaxis and many studies show a favorable outcome when combining H1- and H2-antagonist therapy for prophylaxis. They should be added to therapy at the discretion of the treating physician. Because of decreased antimuscarinic and central nervous system side effects, the newer antihistamines can be given in high doses, allowing more complete blockade of histamine receptors. These agents should lead to a reevaluation of the usefulness of antihistamines in both the treatment of acute anaphylaxis and in prophylactic regimens. The unavailability of parenterally administered second-generation H1-antagonists limits their usefulness in acute anaphylaxis and perioperative prophylaxis.

2/23/04 re: Cause of pruritis with exercise

I have a 33 y/o WF patient that c/o severe pruritis and erythema (from toes to waist) that occurs when she walks over a mile or runs more than 100 yards and is greatly worsened if doing these activities in cold temperatures. Is this a type of allergic reaction or a vascular insufficiency of some sort?

I assume from your lack of mentioning it that your patient has not had the symptoms of pruritis and/or erythema at rest in or not in cold environments. If that is the case, the picture you describe sounds to me most like a relatively mild expression of exercise-induced anaphylaxis (EIA). This disorder is characterized by generalized pruritis, sometimes urticaria and (in severe cases) anaphylactic shock. Of interest, asthmatic symptoms are unusual in EIA. Thus, EIA has to be contrasted with another exercise-triggered disorder exercise-induced bronchoconstriction, in which asthmatic symptoms occur during exercise without the symptoms commonly seen in EIA.

When EIA is present, symptoms occur at the end of vigorous exercise, generally involving walking/running activities, or shortly thereafter. Although a major theory of the cause of EIA involves overheating of the involved person, there have been occasional cases in which EIA occurs particularly in cold environments. This could explain why your patient may have more symptoms when exercising in cold environments.

Some investigators feel that the diagnosis of EIA can be confirmed by obtaining serum tryptase levels before exercise and during EIA. The serum specimens obtained at those times should be frozen immediately and sent frozen to a lab that carries out tryptase levels reliably. I prefer the lab associated with Dr. Lawrence Schwartz of the Medical College of Virginia in Richmond, because they assay for both total and beta-type tryptase (most commercial labs test for only total tryptase levels). Dr. Schwartz and his colleagues have shown convincingly that it is predominantly the beta-tryptase sub-type of total tryptase that is released into the blood during anaphylactic reactions.

One puzzling aspect you described is the limitation of symptoms to areas below the waist. From what I know of EIA, this would be an unusual finding. It does not sound as if the cause is a primary vascular problem Prominent pruritis is not seen in usual vascular insufficiency disorders such as Raynaud¹s Syndrome. There is an unusual vascular disorder called erythromelalgia in which regional skin redness and swelling occur in response to cold temperature exposures. Mild itching may occur, but a burning sensation is more common. This disorder is not usually related to exercise.

7/2/03 re: Prevention of cold-induced anaphylaxis

Are there any new therapies or ideas to prevent severe cold induced anaphylaxis- in someone who has tried most allergy treatments--long acting antihistamines--without success?

It is not clear to me from your description whether your patient has severe cold-induced urticaria (presumably of the acquired, not the familial type) or true anaphylaxis with systemic manifestations (e.g.,-hypotension, laryngeal and/or bronchial obstruction). As far as I know, the reported cases of true anaphylactic episodes associated with cold temperature exposure have occurred in concert with exercise (see enclosed abstract). I am assuming that you have investigated the possibility that prior ingestion of certain foods might play a pathogenic role.

If there is no other triggering factors other than unavoidable exposures to cold temperatures, the choices of preventive treatments are quite limited when the usual H1 antihistamines of several types have been tried as pre-treatment without success. Concomitant use of H1 and H2 antihistamines may be worth trying as pre-treatment since the increased vasodilation in anaphylaxis is partially due to histamine binding to the H2 receptor.

If your patient has an extreme form of acquired cold urticaria this may be due to an IgE-mediated mechanism (as suggested by some studies of such cases years ago). If that were the case, a trial of the recently released anti-IgE monoclonal antibody (Xolair) might be worth considering. Xolair has been approved by the FDA for the treatment of allergic asthma, not controlled by other means. A recent report by Leung et al has described reduction of marked systemic sensitivity to peanuts by this anti-IgE therapy (see enclosed abstract). Xolair treatment appears to be well tolerated but requires monthly injections at sizable expense (probably about $10,000 per year for an average-sized adult). Since your clinical indication is not an FDA-approved one for Xolair, insurance carriers may be resistant to paying for it. It would also be advisable to obtain written informed consent of the patient in advance since I am not mentioning this as established therapy.
__________________________________________________________

Br J Dermatol. 2002 Aug;147(2):368-70.
A case of cold-dependent exercise-induced anaphylaxis.
Ii M, Sayama K, Tohyama M, Hashimoto K.
Department of Dermatology, Ehime University School of Medicine, Shigenobucho, Ehime 791-0295, Japan.

Exercise-induced anaphylaxis (EIA) is a form of physical urticaria that is induced by exercise. A 16-year-old Japanese boy had a 4-year history of recurrent wealing and dyspnoea after physical exercise such as jogging, playing handball or riding a bicycle in winter. The episodes were not associated with ingestion of foods including wheat or soya bean. A provocation test, with 15 min of exercise and 2 min of cold stimulation immediately before or immediately after the exercise, elicited a weal that was localized to the test area. A challenge test with ingestion of boiled soya beans and exercise did not elicit a weal. Therefore, in this case, cold exposure, but not food ingestion, was essential for inducing EIA. Cold-dependent EIA is different from cold urticaria, food-dependent EIA, cholinergic urticaria and cold-induced cholinergic urticaria, and may be a distinct entity.
______________________________________

N Engl J Med. 2003 Mar 13;348(11):986-93. Epub 2003 Mar 10.
Effect of anti-IgE therapy in patients with peanut allergy.
Leung DY, Sampson HA, Yunginger JW, Burks AW Jr, Schneider LC, Wortel CH, Davis FM, Hyun JD, Shanahan WR Jr; Avon Longitudinal Study of Parents and Children Study Team.
National Jewish Medical and Research Center, Denver, USA.

BACKGROUND: Peanut-induced anaphylaxis is an IgE-mediated condition that is estimated to affect 1.5 million people and cause 50 to 100 deaths per year in the United States. TNX-901 is a humanized IgG1 monoclonal antibody against IgE that recognizes and masks an epitope in the CH3 region of IgE responsible for binding to the high-affinity Fc(epsilon) receptor on mast cells and basophils. METHODS: We conducted a double-blind, randomized, dose-ranging trial in 84 patients with a history of immediate hypersensitivity to peanut. Hypersensitivity was confirmed and the threshold dose of encapsulated peanut flour established by a double-blind, placebo-controlled oral food challenge at screening. Patients were randomly assigned in a 3:1 ratio to receive either TNX-901 (150, 300, or 450 mg) or placebo subcutaneously every four weeks for four doses. The patients underwent a final oral food challenge within two to four weeks after the fourth dose. RESULTS: From a mean base-line threshold of sensitivity of 178 to 436 mg of peanut flour in the various groups, the mean increases in the oral-food-challenge threshold were 710 mg in the placebo group, 913 mg in the group given 150 mg of TNX-901, 1650 mg in the group given 300 mg of TNX-901, and 2627 mg in the group given 450 mg of TNX-901 (P<0.001 for the comparison of the 450-mg dose with placebo, and P for trend with increasing dose <0.001). TNX-901 was well tolerated. CONCLUSIONS: A 450-mg dose of TNX-901 significantly and substantially increased the threshold of sensitivity to peanut on oral food challenge from a level equal to approximately half a peanut (178 mg) to one equal to almost nine peanuts (2805 mg), an effect that should translate into protection against most unintended ingestions of peanut.

1/28/03 re: Urokinase-induced anaphylaxis

I am researching any information about urokinase and anaphylactic shock. Do you have any information related to the administration of urokinase in hemodialysis catheters that are clotted and nay reported anaphylactic reactions.

My understanding is that true anaphylactic reactions (on a proven allergic basis) are rare (see enclosed abstract). Anaphylactoid reactions, which mimic anaphylactic reactions on a non-allergic basis, may occur more commonly during urokinase administration but are still quite unusual, reported only as occasional case reports (see enclosed abstract). Some investigators report that such reactions can be treated successfully with sizable doses of traditional H1-antihistamines such as diphenhydramine (see enclosed abstract- the more recently developed non-sedating antihistamines are unfortunately not generally available in forms for parenteral use). Other investigators recommend use of both H1 and H2 antihistamines ( e.g.,- famotidine) for urokinase-induced reactions. I know of no controlled study of the effect of pre-treatment with H1 antihistamines on the subsequent incidence of anaphylactoid reactions to urokinase. I think that it would be difficult to obtain definitive findings in such a study because of the very low incidence of anaphylactoid reactions to urokinase when no pre-treatment is used.

Blood Coagul Fibrinolysis 2001 Sep;12(6):491-4
Hypersensitivity reactions associated with recombinant tissue-type plasminogen activator and urokinase.
Pechlaner C, Knapp E, Wiedermann CJ.
Department of Internal Medicine, Innsbruck University Hospital, Innsbruck, Austria.

Anaphylaxis or angioedema in response to recombinant tissue-type plasminogen activator or urokinase have been reported in only a few isolated cases. Both agents are endogenous proteins and thus considered non-antigenic. Activation of fibrinolysis may per se facilitate anaphylactoid reactions by pathophysiologic pathways that are not well understood. We report a unique case, review the literature and discuss implication for the clinician. The 25-year-old patient underwent thrombolytic treatment for extensive thrombosis of pelvic and deep lower extremity veins. The patient developed protracted anaphylactoid reactions
during recombinant tissue-type plasminogen activator continuous intravenous infusion. After changing treatment to urokinase, the same symptoms recurred with more severe intensity, despite corticosteroid premedication. Symptoms resolved within hours after treatment with histamine receptor blockers. This unique observation, i.e. sequential occurrence of anaphylactoid reactions during recombinant tissue plasminogen activator and urokinase treatments, adds to existing evidence for an unspecific non-antigenic pathomechanism, and for a class effect of thrombolytics. Steroids do not prevent, but histamine receptor blockers seem to be an effective treatment of this unusual complication of thrombolytic therapy.

Ann Pharmacother 1992 Jun;26(6):782-3
Treatment of urokinase-related anaphylactoid reaction with intravenous
famotidine.
Vidovich RR, Heiselman DE, Hudock D.
Critical Care Medicine, Akron General Medical Center, OH 44307.

OBJECTIVE: We describe our experience with an anaphylactoid reaction to urokinase and the treatment used. We also discuss the use of histamine H1- and H2- blockers in combination for the treatment of allergic anaphylactoid reactions.
DESIGN: Case report.
SETTING: Hospital.
PARTICIPANTS: Observation of a patient who had a pulmonary embolism.
INTERVENTION: During the use of urokinase, in treatment of a pulmonary embolism, the patient developed an anaphylactoid reaction that did not respond to diphenhydramine or hydrocortisone. Famotidine was administered.
RESULTS: Abatement of urticaria and normalization of vital signs were obtained soon after famotidine was given. Completion of thrombolysis took place.
CONCLUSIONS: Further investigation of the use of H1- and H2-blocking agents in the presence of anaphylactoid reactions to thrombolytic agents should be performed. Consideration of intravenous famotidine for the treatment of anaphylactoid-type reactions to urokinase is suggested.

10/7/02 re: Test dose of IV Iron-dextran

The PDR recommends a test dose of 25 mg of IMFed (iron dextran) IV prior to a therapeutic dose. How was this dosage arrived at, and what are the implications of giving 50 mg as the test dose? It is my understanding that an anaphylaxis type reaction that might occur as a result of the test dose would more properly be on the basis of an anaphyactoid reaction meaning without evidence of an IgE trigger mechanism. If a person were to have experienced such a reaction to 50 mg IV would it have made any difference had he/she been given 25 mg? That is, is there any greater risk from giving 50 mg as compared to 25 mg.?

I agree with you that the systemic reactions occurring during IV administration of iron-dextran products such as InFed sound more like anaphylactoid reactions than true anaphylaxis. The manufacturers of InFed have provided no literature reference for evidence that the reactions are truly anaphylactic (due to either IgE antibody or complement-mediated) despite their use of this term in their PDR description. Systemic reactions to IV iron-dextran are very unusual, particularly when the InFed product is used (see enclosed abstracts). Individuals at increased risk appear to be those with histories of drug reactions, particularly reactions to several drugs of different chemical types (see enclosed abstract).

My personal opinion is that use of the test dose of 25 mg described by the manufacturer is not particularly reliable for these reasons:1) some of the anaphylactoid reactions described in the literature have occurred to the 25 mg test dose (see enclosed abstract); 2) by the manufacturers' own statement, there have been systemic reactions to the full recommended therapeutic dose (up to 100 mg at a time) in individuals who previously tolerated the test dose of 25 mg. Therefore, if one is concerned about the potentially increased risk for a systemic reaction, my personal approach would be this (assuming that there is a valid indication for IV iron-dextran when other approaches are not feasible or successful):

1) Get advanced informed consent

2) Put in a hep-lock intravenous needle. This will allow a very slow InFed infusion and ready access for IV fluids, etc. if needed to treat any systemic reaction. Have emergency equipment and epinephrine (and individuals trained to use them) immediately available.

3) Infuse the InFed very slowly, preferably using a 1.0 ml tuberculin-type syringe. Although there is no "carved in stone" schedule for a rate of infusion available, a reasonable approach would be to give 5 mg (0.1 ml) over 30 seconds, wait 15 minutes to see how tolerated, then give another 5 mg, wait 15-30 minutes, give another dose, etc. In this way a 50 mg dose could be give in about 2 hours. If a larger total dose is required, perhaps the subsequent doses could be 10 mg every 15 minutes.

Although the approach suggested above cannot be guaranteed to avoid all adverse reactions, I believe that the risk of a severe systemic reaction would be reduced considerably.

Am J Kidney Dis 2001 Apr;37(4):743-9
Comment in: Am J Kidney Dis. 2001 Apr;37(4):859-61.
Suspected iron dextran-related adverse drug events in hemodialysis patients.
Fletes R, Lazarus JM, Gage J, Chertow GM.
Division of Nephrology, Moffitt-Long Hospitals, University of California, San Francisco, 94143-0532, USA.

Despite the use of recombinant erythropoietin, anemia remains a significant
problem for patients with end-stage renal disease, in part related to chronic dialysis-related blood loss and resultant iron deficiency. Because oral iron preparations have been relatively ineffective and poorly tolerated in this population, intravenous (IV) iron dextran has been widely prescribed, despite a finite risk for adverse effects associated with its use. We analyzed data from Fresenius Medical Care North America (FMCNA) clinical variance reports to determine the incidence of suspected iron dextran-related adverse drug events (ADEs) and associated patient characteristics, dialysis practice patterns, and outcomes. We used a case-cohort study design, comparing individuals who experienced suspected ADEs with the overall FMCNA population. Among 841,252 IV iron dextran administrations from October 1998 through March 1999, there were 165 reported suspected ADEs, corresponding to an overall rate of 0.000196%, or approximately 20 per 100,000 doses. Forty-three patients (26%) required an independent emergency department evaluation, 18 patients (11%) required hospitalization, and 1 patient (0.6%) died. Dyspnea (43%), hypotension (23%), and neurological symptoms (23%) were the most common major ADEs; nausea (34%), vomiting (23%), flushing (27%), and pruritus (25%) were the most common other ADEs. ADEs were 8.1-fold more common among patients administered Dexferrum (American Regent Laboratories, Inc, Shirley, NY) compared with those administered InFed (Watson Pharmaceuticals, Phoenix, AZ). In summary, serious adverse reactions to IV iron dextran are rare in clinical practice. The risk appears to depend on the specific formulation of IV iron dextran. Otherwise, iron dextran-related ADEs are difficult to predict

Am J Nephrol 2000 Nov-Dec;20(6):455-62
Adverse events in chronic hemodialysis patients receiving intravenous iron dextran--a comparison of two products.
McCarthy JT, Regnier CE, Loebertmann CL, Bergstralh EJ.
Division of Nephrology and Mayo Clinic Dialysis Services, Mayo Clinic and Mayo Foundation, Rochester, Minn. 55905, USA.

BACKGROUND: Parenteral iron therapy is required in a majority of chronic
dialysis patients who are receiving recombinant human erythropoietin (r-HuEPO) in order to provide adequate iron for erythropoiesis. At this time, there are only two formulations of parenteral iron dextran available for clinical use in the USA. These two preparations of iron dextran have different physical and chemical characteristics that might affect the adverse events experienced by dialysis patients receiving iron dextran.
METHODS: We performed a retrospective analysis of all 665 courses of parenteral iron dextran which were administered in our hemodialysis unit from June 1992 through July 1997. An adverse event (AE) was defined as any event which led to interruption of the prescribed course of iron therapy or precluded subsequent administration of parenteral iron in the presence of documented iron deficiency. Database elements included patient age, gender, cause of renal failure, and prior history of drug allergy. The average hemoglobin value and serum iron parameters (iron, total iron binding capacity (TIBC), percent saturation of TIBC, and ferritin) were recorded both pre- and post-iron administration, when available. A course of parenteral iron dextran consisted of a 25-mg test dose, followed by four or five doses of 300 mg each. Iron dextran was infused into the venous limb of the hemodialysis blood circuit over the last 30-60 min of a dialysis treatment. The two forms of iron dextran were designated as Iron A (molecular weight = 165,000) and Iron B (molecular weight = 267,000).
RESULTS: Fifty-seven percent of our patients were male, 92% were of white race, and diabetes was the most common cause of renal failure (34%). Sixty-four percent of the patients were 60 years of age or older, and 39% had a history of allergy to one or more drugs. We observed 33 AEs during the administration of parenteral iron dextran, and these AEs occurred in 21 courses of parenteral iron dextran administration. Eighteen of the AEs were gastrointestinal in nature; 7 AEs were cutaneous in nature, 6 AEs had systemic manifestations, while only 2 AEs caused respiratory problems. Two of the AEs were felt to be anaphylactoid in nature. Female gender (p = 0.06) and iron dextran product (p = 0.02) were identified as potential risk factors for the development of an AE. There were 468 courses of Iron A administered, 10 of these courses were complicated by 15 AEs (one or more AE per course). One hundred and ninety-seven courses of Iron B were administered and 11 (5.6%) courses were complicated by the development of 18 AEs (9.1 AEs per 100 courses). Serum iron rose by 22 microg/dl and TIBC saturation increased by 14% after the administration of parenteral iron. The average serum ferritin level rose by 430 microg/l and hemoglobin values rose by an average of 0.8 g/dl. There were no significant differences in the changes of iron parameters or hemoglobin levels between the two iron dextran preparations.
CONCLUSIONS: The administration of parenteral iron dextran to chronic hemodialysis patients has a relatively high degree of safety. Both iron products were equally efficacious in increasing serum iron parameters and hemoglobin levels. Even when corrected for other factors, there was a significant difference in the observed AEs between the two formulations of parenteral iron dextran. Our observations, if true, may have important implications for the management of anemia in chronic hemodialysis patients. If a significant number of AEs prohibit the administration of a specific iron dextran product to a large number of chronic hemodialysis patients, then anemia management may become suboptimal. In the future, newer iron products may provide even safer alternatives for the administration of parenteral iron to chronic hemodialysis patients.

Am J Kidney Dis 1996 Oct;28(4):529-34
Comment in: Am J Kidney Dis. 2000 Feb;35(2):360-1.
The safety of intravenous iron dextran in hemodialysis patients.
Fishbane S, Ungureanu VD, Maesaka JK, Kaupke CJ, Lim V, Wish J.
Department of Medicine, Winthrop-University Hospital, Mineola, NY, USA.

The treatment of anemia in hemodialysis patients is frequently hindered by the presence of suboptimal iron stores. Intravenous iron dextran is in common use to maintain iron stores in this population, but there are little published data regarding the incidence and type of adverse events. The purpose of this study was to evaluate the safety of this medication. Charts from four hemodialysis centers of all 573 patients treated with intravenous iron dextran (INFeD; Schein Pharmaceutical, Inc, Florham Park, NJ) between July 1, 1993, and June 30, 1995, were studied. Twenty-seven patients (4.7%) had adverse reactions that were related to iron dextran. Four patients (0.7%) had reactions classified as serious (one cardiac arrest; three others required hospitalization). Ten patients (1.7%) had reactions classified as anaphylactoid. No patients died or developed permanent disability as a result of reactions. The most common adverse reactions included itching (1.5% of patients) and dyspnea or wheezing (1.5%); others included chest pain (1.0%), nausea (0.5%), hypotension (0.5%), swelling (0.5%), dyspepsia (0.5%), diarrhea (0.5%), skin flushing (0.3%), headache (0.3%), cardiac arrest (0.2%), and myalgias (0.2%). Five of all the reactions occurred during a test dose; four of these were anaphylactoid. Several factors were studied as possible predictors of adverse reactions. A positive history of drug allergy (odds ratio, 2.4; P = 0.03) and history of multiple drug allergy (odds ratio, 5.5; P = 0.0004) were significant predictors of reactions. In summary, we found serious adverse reactions to be uncommon in hemodialysis patients treated with intravenous iron dextran. Future prospective studies will help confirm this finding.

10/4/02 re: Reaction during blood drawing

I am an infectious disease Pediatrician, and the reason I am writing is because I can not find any literature about allergy or anaphylaxis due to the use of needle. Is that possible? I have read about latex, food allergies and so on. The case is regarding my husband who had in three occasions episodes of diarrhea, collapse (unconsciousness, pale skin and cyanosis) after having his blood taken for routine blood exams. The symptoms start about one minute after the procedure and last for about 3 minutes or so. He is not afraid of injections, and as I was there for the three episodes the symptoms did not look like an normal reaction of a person who is scared or something. I am very concerned because the symptoms are becoming worse each episode. Could you be so kind to help me out with this matter?

Although you did not mention certain aspects of your husband's case, I will make certain assumptions: 1) He did not experience similar reactions in childhood/adolescence; 2) He has not had similar reactions when receiving medication injections subcutaneously or intramuscularly; 3) The venesection for blood drawing had been carried out using a vacuum-based collection tube system such as the Vacutainer system (B-D) used in the USA.

The reactions you described do not sound like vaso-vagal reactions. However, was his pulse examined during such reactions? A slow bounding pulse would suggest a vaso-vagal reaction whereas a rapid, more thready pulse would be compatible with an anaphylactic/anaphylactoid (or similar) reaction. Diarrhea can be a manifestation of anaphylaxis, though the onset is generally not as rapid as within 1 minute of the inciting event. Is it possible that your husband is reacting to something in the antiseptic solution swabbed on the site before needle entry and then absorbed intravascularly when the needle enters the vein? Tolerance of the same antiseptic swabbed on the skin before subQ or IM injections does not rule out intravscular transfer of small amount so the antiseptic during venesection.

I think that an allergic reaction to latex is a very unlikely cause of the reactions you described. One group has reported that repeated puncture by an injection needle of a latex-containing top vial closure will transfer small amounts of latex allergen into the fluid vial contents. However, even that remote possibility would not be operative with use of needles for venesection since such needles should not have been exposed to any vial closures. I have not heard of any proven anaphylactic reactions to the needles themselves. However, I suggest that you contact the manufacturer of the needle set used when your husband manifested his reaction to see if they have any reports of similar events in other patients.

In the meantime, I think it advisable to have epinephrine solution 1:1000 dilution and a syringe/needle for IM injection available for immediate use if needed at any future venesection. Recent studies by Dr. Estelle Simons and colleagues have shown that IM injection of epinephrine leads to faster absorption than the traditional subQ injection.

6/18/02 re: Immunotherapy

Are ACE inhibitors now considered contraindicated in patients with asthma or in patients receiving allergy vaccinations?

A. ACE inhibitors and asthma
As you likely know, about 10% of those taking therapeutic doses of ACE inhibitors will manifest a recurrent cough with associated increase in bronchial reactivity. However, as recently reviewed , there is no convincing evidence that asthmatics are at increased risk for such adverse effects of ACE inhibitors (see enclosed abstract).

Ann Pharmacother 2002 Jun;36(6):1058-67
ACE Inhibitor-Induced Bronchial Reactivity in Patients with Respiratory Dysfunction.
Packard KA, Wurdeman RL, Arouni AJ.
Kathleen A Packard PharmD, Clinical Research Fellow, Creighton Cardiac Center, Creighton University, Omaha, NE.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are often associated with an increased incidence of cough and bronchial responsiveness
that may cause further deterioration of patients with impaired pulmonary function.
OBJECTIVE: To review the available literature on the incidence of cough and bronchial responsiveness associated with ACE-inhibitor therapy in patients with asthma, chronic obstructive pulmonary disease (COPD), and congestive heart failure (CHF).
DATA SOURCES: Literature was accessed through MEDLINE (1985-September 2001). Key search terms included cough, bronchospasm, asthma, congestive heart failure, chronic obstructive pulmonary disease, ACE inhibitors, and angiotensin II receptor blockers.
DATA SYNTHESIS: The literature reports several cases of increased bronchial responsiveness associated with ACE inhibitors. Larger, controlled studies evaluating the increased risk in patients with pulmonary dysfunction are limited. Data from these trials are summarized in this article.
CONCLUSIONS: The literature shows that patients with primary airway disease such as asthma and COPD are not at an increased risk of developing cough or bronchoconstriction as a result of ACE-inhibitor therapy. Despite the ability of ACE inhibitors to improve exercise tolerance, perfusion, and gas transfer, patients with CHF may be at higher risk of developing cough than the general population. Whether this cough is attributed to ACE inhibition or increased left-ventricular dysfunction remains uncertain. If increased bronchial responsiveness does occur, angiotensin II receptor antagonists are another reasonable option.

B. ACE inhibitors and immunotherapy
I am enclosing my responses to a recent similar question about the use of immunotherapy in someone taking ACE inhibitors. To help answer your question, I consulted Dr. Richard Lockey of the University of S. Florida who has edited monographs about immunotherapy and who has a special investigative interest in the occurrence of systemic adverse reactions to allergy immunotherapy (IT). Dr. Lockey's kind response is enclosed below.

"I do not believe there is an increased risk during ACE inhibitor therapy but I think Phil Lieberman does. It is a controversial question. We do not require our patients to stop these drugs for immunotherapy. I have copied to Phil and would like his input also. In any event, there has been no "official warning" issued by a position statement from the Academy and I am not aware of any from any other organization. Perhaps Phil can help."

I then consulted Dr. Phil Lieberman of the University of Tennessee, an expert in the area of the occurrence of anaphylaxis. His response is enclosed below:

"I am enclosing for you a preprint of the section from the upcoming chapter on "Anaphylaxis" for Allergy Principles and Practice that deals with ACE inhibitors. The only true case reports were related to venom immunotherapy. There has been no data to support an increased risk for anaphylaxis other than for these venom immunotherapy articles.

However, ACE inhibitors do prevent the compensatory response to hypotension that occurs with the conversion of I and II to angiotensin per se. In addition there are some articles that speak to this issue.

I think that the section on ACE inhibitors from this chapter plus an editorial (also enclosed) which Stephen Kemp and I wrote might be of some help.

From a practical standpoint we do not alter our allergen immunotherapy procedures (as we do with beta blockers), but I tend to take patients subject to anaphylaxis (insect sting, idiopathic, etc.) off ACE inhibitors and ACE blockers if at all possible."

SECTION OF DR. LIEBERMAN'S CHAPTER ENCLOSED BELOW:

Increased vascular permeability can produce a rapid and dramatic loss of intravascular volume. Fluid shifted to the extravascular space can result in a loss of 50% of vascular volume within 10 minutes.197, 198 This loss of blood volume results in compensatory mechanisms that involve both the secretion of catecholamines, such as norepinephrine and epinephrine,199, 200 as well as activation of the angiotensin system with conversion of angiotensin I to angiotensin II and increased production of these agents,201-205 and the production of endothelin-1, a potent vasoconstrictor peptide which has previously been found elevated in heart failure, strokes, and hypotension .206 Elevated levels of endothelin-1indicate that that the endothelium responds to hypotension with increased production of this agent.206 On the other hand, attempts to correlate elevations of vasopressin and oxytocin with anaphylactic episodes have shown inconsistent results.201, 204 These internal compensatory vasopressor responses can produce variable results. In some patients with anaphylactic and anaphylactoid episodes the peripheral resistance can be abnormally elevated (indicating maximal vasoconstriction) because of this response.195 Whereas, in other subjects, despite elevation of catecholamines, systemic vascular resistance falls.199 It has been suggested that failure to mobilize these compensatory mechanisms may predispose patients to anaphylaxis.203, 207 In a study comparing baseline plasma angiotensin I and angiotensin II levels in Hymenoptera-sensitive patients and normal controls, the former group had significantly lower amounts. An inverse correlation between angiotensin levels and the severity of the anaphylactic episodes was noted: the lower the levels, the more severe the symptoms. In addition, patients with a history of anaphylaxis to Hymenoptera stings have significantly lower angiotensin II levels in leukocytes than do controls.208 It is of interest that successful immunotherapy induced an increase in leukocyte angiotensin II levels in these patients.208

Patients subject to anaphylaxis should wear a MedicAlert bracelet or necklace and should keep an identification card in their wallet or purse. Such patients should be supplied with kits for the self-injection of epinephrine and should be told to keep the kit with them at all times. Beta-blockers, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor blockers, monoamine oxidase inhibitors, and some tricyclic antidepressants should not be taken by patients at risk for anaphylaxis or anaphylactoid episodes if other agents will suffice. These drugs decrease the effectiveness of epinephrine (Beta-blockers), interfere with endogenous compensatory hypotensive responses (ACE inhibitors and angiotensin II blockers),272 or prohibit the use of epinephrine by making the patient subject to side effects upon its administration (monamine oxidase inhibitors and some tricyclics). If patients are required to take medications or diagnostic agents or undergo procedures that are known to place them at risk for an anaphylactic episode, specific preventive measures, such as pretreatment, provocative challenges, or desensitization, should be instituted when appropriate. There are specific instances where published preventive regimens are helpful.

REFERENCES:
195. Hanashiro PK, Weil MH: Anaphylactic shock in man: report of two cases with detailed hemodynamic and metabolic studies, Arch Intern Med 119:129, 1967.

197. Fisher M: Clinical observations on the pathophysiology and implications for treatment. In Vincent JL, editor: Update in Intensive Care and Emergency Medicine, New York, 1989, Springer-Verlag, pp 309-316.

4/15/02 re: Allergy to epinephrine

I recently saw a child with a vague history of allergy to epinephrine that manifested with decrease level of consciousness and decrease in blood pressure several hours after epi was administered in a dental office. She was later given epi at the hospital for sob and still had no classic signs of anaphylaxis. She was skin tested by an allergist with serial dilution and had increase heart rate and nervousness with challenge at a dilute dose of epi and told sh