1. Clinical Challenges in Recognizing, Diagnosing and Treating Anaphylaxis David Elkayam, MD Bellingham Asthma, Allergy & Immunology Bellingham, Washington SNOW Conference, 10 March 2007

2. Goals Recognize the newer definition of anaphyalxis. Recognize the difference / similarity between anaphylaxis and anaphylactoid reactions. Recognize biphasic anaphylaxis. Optimize treatment: Initiate tx early IM v. SC Epi

3. Case Presentation CK is a 10 yo male who presents to the school nurse’s office. Onset of sx: ~5-10 mins ago during recess after lunch. Sx: oropharyngeal and palmar itching  progresses to generalized itching, visible hives and a sensation of mild throat swelling, w/o wheezing, coughing, or obvious respiratory distress. Pt has Medic Alert Bracelet that identifies him as peanut allergic.

4. Case Presentation CK : is he in trouble? What else do you need to know? –VS, PE, PHx: severity of prior rxn? does he have asthma? What do you do? –Administer Benadryl? –Administer Epi? –How much? –Call 911? What are the consequences of intervention v. monitoring?

5. Anaphylaxis: Defined Anaphylaxis is a potentially life-threatening allergic or allergic-like (anaphylactoid) reaction resulting from exposure to a substance to which an individual has become sensitized Most typically, an immediate systemic reaction caused by rapid, IgE-mediated immune release of potent mediators from mast cells and peripheral blood basophils Lieberman PL. Anaphylaxis. MedGenMed 1(1), 1999 [formerly published in Medscape Pulmonary Medicine eJournal 1(4), 1997]. Available at: http://www.medscape.com/viewarticle/408706. Accessed July 8, 2005.

6. Anaphylactoid Reaction Anaphylactoid rxn: non-IgE, otherwise the same pathophysiology/ potential severity. –ASA –Radiocontrast Dye –Some drug reactions

7. Causes of Anaphylaxis www.emnet-usa.org

8. Anaphylaxis – Operational Definition n Two or more organ systems –skin (e.g., hives) –respiratory (e.g., swelling of the lips, tongue, or throat; trouble breathing or shortness of breath; stridor, wheezing) –cardiovascular (e.g., hypotension, dizziness or fainting, altered mental status) –gastrointestinal (e.g., trouble swallowing, abdominal pain) –…or… Hypotension (SBP <100 mmHg) www.emnet-usa.org

9. Definition: Anaphylactic Reactions 1.Requires two or more body systems to undergo an allergic reaction –Skin plus respiratory, gastrointestinal, cardiovascular 2. Presence of shock alone, which requires only one system 3. Wide variety of clinical signs and symptoms may be observed Symposium on the Definition and Management of Anaphylaxis: J Allergy Clin Immunol 2005;115,584-91

10. Epidemiology of Anaphylaxis 1-15% of US population (2.8 to 42.7 million people) may be at risk (Yocum et al, Neugut et al) –30/100,000 population/year (Yocum et al) Estimated annual incidence –21/100,000 (Yocum et al) 0.95% of 1.2 million individuals in a claims database were dispensed injectable epinephrine –Rates ranged from 1.44% of patients 65 years Incidence of anaphylaxis is increasing Sheikh et al, BMJ, 2000; Yocum et al, J Allergy Clin Immunol, 1999; Simons et al, J Allergy Clin Immunol, 2002, Neugut et al, Arch Int Med, 2001.

11. Incidence of Anaphylaxis Increase between 1991 and 1995 Sheikh and Alves, BMJ, 2000 Cause of anaphylaxis Year N=415 N=462 N=671 N=876 0 0 2 2 4 4 6 6 8 8 10 12 1991-2 1992-3 1993-4 1994-5 No. of discharges with diagnosis of anaphylaxis/ 100,000 discharges Other Insect venom Food Therapeutic drugs Unspecified

12. Incidence of Anaphylaxis Continues to Increase: 1995-1999 Wilson, comment on Sheikh and Alves, BMJ, 2000

13. Pathophysiology Signs and symptoms due primarily to –Sudden release of histamine and other potent mediators –Smooth muscle contraction –Increased vascular permeability –Vasodilation May include life-threatening reactions involving the airways, blood vessels, and heart Symptoms generally have onset within minutes but can rarely occur as late as several hours after exposure to the offending antigen Simons et al, J Allergy Clin Immunol, 2004

14. Anaphylactic Reaction Phil Lieberman: Anaphylaxis,a clinicians manual Mast Cell Mast cell granules Allergen IgE antibody Immediate reaction Wheeze Urticaria Hypotension Abdominal cramping Late-phase reaction Immediate reaction Wheeze Urticaria Hypotension Abdominal cramping Late-phase reaction

15. Most Frequent Signs and Symptoms of Anaphylaxis ManifestationPercent Urticaria/angioedema88 Upper airway edema56 Dyspnea/wheeze47 Flush46 Hypotension33 Gastrointestinal30 Tang AW. Am Fam Physician 2003

16. Clinical Course of Anaphylaxis

17. Patterns of Anaphylaxis Uniphasic –Symptoms resolve within hours of treatment Biphasic –Symptoms resolve after treatment but return between 1 and 72 hours later (usually 1-3 hours) Protracted –Symptoms do not resolve with treatment and may last >24 hours Lieberman, 2004

18. Uniphasic Anaphylaxis Antigen Exposure Treatment Initial Symptoms 0 Time

19. Biphasic Anaphylaxis Antigen Exposure Treatment Initial Symptoms 0 Second- Phase Symptoms Treatment 1-8 hours Classic Model New Evidence 1-72 hours Time

20. Protracted Anaphylaxis Antigen Exposure Initial Symptoms 0 Possibly >24 hours Time

21. Biphasic Anaphylaxis Biphasic reactions comprise 1-20% of attacks and are usually characterized by an initial symptomatic period followed by an asymptomatic period of 1-8 hours, but the asymptomatic phase may last longer than 24 hours No predictive characteristics (age, gender) for biphasic reactions These patients may require additional epinephrine Stark and Sullivan, J Allergy Clin Immunol, 1986; Lieberman, Allergy Clin Immunol Int, 2004; Ellis and Day, Curr Allergy Asthma Rep, 2003

22. Clinical Impact of Biphasic Reactions Regardless of the inconsistencies in reported incidence and severity of biphasic reaction, it occurs Considerations when treating the episode: –observation period –discharge instructions –prescribing epinephrine for outpatient use Slide courtesy of Phil Lieberman, MD

23. Fatal Reactions

24. Fatal Reactions Incidence Often Underestimated Negative autopsy findings –Rapid death may leave no characteristic macroscopic findings Episodes can be misclassified as asthma deaths Since coronary artery constriction is common, episodes can be misclassified as death due to acute coronary syndrome Pumphrey, 2004

25. Fatal Anaphylactic Reactions Are Often Associated With: Delay between time of symptom onset and administration of treatment Adverse therapeutic event History of asthma However, most fatal reactions are unpredictable –Appropriate management after recovery from a severe reaction may be protective against a fatal recurrence Pumphrey, Curr Opin Allergy Clin Immunol 2004; Sampson et al, N Engl J Med, 1992; Pumphrey, Clin Exp Allergy, 2000

26. Subsequent Reactions May Increase in Severity with Time % of reactions Proportion of reactions rated severe Simons et al, J Allergy Clin Immunol, 2004

27. Anaphylaxis : Acute Management Overview of the most important aspects of in-office and in-the-field treatments

28. Treatment Epinephrine is the drug of choice for all anaphylactic episodes Flexibility in dosing needed to treat effectively –Some patients require more than a single injection –Different doses for pediatrics and adults Early and aggressive use to maintain airway, blood pressure, and cardiac output

29. Medical Clinic Treatment Epinephrine –Up to 35% of patents may need a second dose Antihistamines Corticosteroids Oxygen Impair further absorption –Local epinephrine, tourniquet Supine, elevate legs ER, ICU monitor/support (fluids, pressors, etc.) Lieberman PL. Anaphylaxis. MedGenMed 1(1), 1999 [formerly published in Medscape Pulmonary Medicine eJournal 1(4), 1997]. Available at: http://www.medscape.com/viewarticle/408706. Accessed July 8, 2005.

30. Epinephrine The most important single medication in the treatment of acute systemic allergic / anaphylactic events. No strict contraindications –(including metabisulfite sensitivity). Reverses airway edema and spasm, slows/stops the release of potent vasoactive mediators –(e.g., histamine, etc.), Potent inotropic and chronotropic cardiac effects – (ie., supports / restores perfusion and BP). Frequently underutilized.

31. The Top 10 Reasons for NOT using epinephrine Failure to recognize sx (atypical presentations) Rationalization & denial Spontaneous recovery last time Reliance and belief in antihistamines The clinic/ER was nearby Fear re: use of epinephrine (side effects) Fear of needles 2 words: Fear and denial 1 word: Fear…

32. Treatment of Anaphylaxis

33. Epinephrine Dosing Intramuscular injection in lateral thigh produces most rapid rise in blood level –0.01mg/kg in children, 0.3-0.5mg in adults Data suggest that as many as 30-35% of patients require more than a single epinephrine injection Korenblat and Day, Allergy Asthma Proc, 1999; Webb et al, J Allergy Clin Immunol, 2004

34. Epinephrine Injection: Route and Site Do Matter Injection route Injection siteC-max: mean ± SEM (pg/mL) EpiPen IM Thigh12,222* ± 3,829 Epinephrine IM Thigh 9,722* ± 4,801 Epinephrine IM Arm 1,821 ± 426 Epinephrine SQ Arm 2,877 ± 567 Saline IM Arm 1,458† ± 444 Saline SQ Arm 1,495† ± 524 *P <.01 from all arm values. †Endogenous epinephrine Simons, et al. JACI 2001;108:871-873.

35. Epinephrine Injection: IM vs. SQ Simons et al.: Prospective, randomized, blinded study in children T-max was 8 ± 2 minutes after injection of epinephrine 0.3 mg from an EpiPen IM in the vastus lateralis vs. 34 ± 14 minutes (range, 5 to 120) after injection of epinephrine 0.01 mg/kg SQ in the deltoid region.

36. Acute Management: Epinephrine Autoinjector

37. Overview of Available Auto-Injectors Twinject™EpiPen Available Doses0.3 mg (single and 2 Pack) & 0.15 mg (single and 2 Pack) 0.3 mg (single and 2-Pak) & 0.15 mg (single and 2-Pak) Doses Per Injector2 inseparable doses in one injector 1 dose per injector Second Dose Administration Available Manual injector included inside the barrel of Twinject™ Requires availability of second auto-injector

38. Overview of Available Auto-Injectors Twinject™EpiPen PackagingPermanently attached wrap label patient instructions Crush-resistant container with clip Updated instructions attached to auto-injector New plastic sleeve case with S clip Needle SizeThin 25 gauge ½ inch exposed needle length 22 gauge ½ inch exposed needle length Noise LevelQuiet operation reduces risk of removal from injection site Slightly louder firing mechanism Cost / Formulary Position AWP Single $68.04 AWP Two-Pack $114.60 Expected 2 nd or 3 rd Tier AWP Single $54.38 AWP 2 Pack $104.16 2 nd Tier

39. Epinephrine content vs. Time past expiration

40. Case Presentation: CK Peanut Allergy –Dangerous: most common cause of food allergy related deaths in US. –Added risk factors: severity of prior event level of anti peanut sIgE Presence of asthma –In this setting, treat early, aggressively (injected Epi + other tx’s)

41. Inadequate Management Post ER for Food Anaphylaxis Clark et al, J Allergy Clin Immunol, 2004

42. Anaphylaxis Conclusions Anaphylaxis is a life-threatening acute reaction which is under-reported, frequently misdiagnosed and under- treated –More common than previously thought; increasing incidence and prevalence Rapid and proper administration of epinephrine is the standard of treatment –Many patients require a second epinephrine injection to treat anaphylaxis Patients education needed – delays in treatment, improper administration and outdated epinephrine –Written Action Plan –Medical Alert Bracelet

43. Recurrent Attacks are The Rule! Patient Challenges: Failure to carry epinephrine auto-injector (Kemp et al) –47% of patients with known cause fail to carry EpiPen –9% of patients with idiopathic fail to carry EpiPen Difficulty avoiding known allergen –75% of patients known to be allergic to peanut failed despite best effort to avoid (Bock) Delayed treatment – often associated with fear of needles and/or medication

44. Anaphylaxis: Conclusions & Questions Prior to this presentation, how aware were you –Of the new practice parameters? –Difference/similarity b/w anaphylaxis and anaphylactoid reactions. –Uniphasic, protracted & biphasic anaphylaxis? –Underutilization of epinephrine in fatal attacks? –35% of patients may need a second dose?

45. Patient Challenges Failure to carry epinephrine auto-injector –EpiPen available in 2-pack but patients may separate doses Delayed treatment – often associated with fear of needles and/or medication –Failure to administer the first dose –Multiple doses may be needed to treat all reaction types Inadequate treatment –Insufficient amount of epinephrine injected –Failure to administer second injection –Use of outdated epinephrine

46. Provider Challenges Inadequate treatment and patient education –Dependence on antihistamines Failure to prescribe epinephrine auto- injector –Infrequent post ED visit Failure to instruct patients about when and how to use epi autoinjectors –Few pts have an action plan

47. Thank You ! Questions? Please feel free to write me at: David Elkayam, MD ddelkayam@hinet.org