Clinical Challenges in Recognizing, Diagnosing and Treating Anaphylaxis

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
  nurses 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

• 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 lt100 mmHg)

www.emnet-usa.org
9
Definition Anaphylactic Reactions

• 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
2005115,584-91
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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 lt17 years old
  to 0.32 of patients gt65 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.
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Incidence of Anaphylaxis Increase between 1991
and 1995
Cause of anaphylaxis
12
Other
N876
Insect venom
Food
10
Therapeutic drugs
N671
Unspecified
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No. of discharges with diagnosis of anaphylaxis/
N462
100,000 discharges
N415
6
4
2
0
1991-2
1992-3
1993-4
1994-5
Year
Sheikh and Alves, BMJ, 2000
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Incidence of Anaphylaxis Continues to Increase
1995-1999
Wilson, comment on Sheikh and Alves, BMJ, 2000
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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
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Anaphylactic Reaction
Allergen
IgE antibody
Mast cell granules
Mast Cell
Immediate reaction Wheeze Urticaria Hypotension Ab
dominal cramping Late-phase reaction
Phil Lieberman Anaphylaxis,a clinicians manual
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Most Frequent Signs and Symptoms of Anaphylaxis

• Manifestation Percent
• Urticaria/angioedema 88
• Upper airway edema 56
• Dyspnea/wheeze 47
• Flush 46
• Hypotension 33
• Gastrointestinal 30

Tang AW. Am Fam Physician 2003
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Clinical Course of Anaphylaxis
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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 gt24 hours

Lieberman, 2004
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Uniphasic Anaphylaxis
Treatment
Initial Symptoms
Time
0
Antigen Exposure
19
Biphasic Anaphylaxis
Treatment
Treatment
Second-Phase Symptoms
Initial Symptoms
1-8 hours
Time
0
Classic Model
1-72 hours
Antigen Exposure
New Evidence
20
Protracted Anaphylaxis
Initial Symptoms
0
Time
Possibly gt24 hours
Antigen Exposure
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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
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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
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Fatal Reactions
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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
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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
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Subsequent Reactions May Increase in Severity
with Time
of reactions
Proportion of reactions rated severe
Simons et al, J Allergy Clin Immunol, 2004
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Anaphylaxis Acute Management

• Overview of the most important aspects of
  in-office and in-the-field treatments

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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

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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.

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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

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Treatment of Anaphylaxis
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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
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Epinephrine Injection Route and Site Do Matter

• Injection route Injection site C-max mean
  SEM (pg/mL)
• EpiPen IM Thigh 12,222 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 lt .01 from all arm values. Endogenous
  epinephrine
• Simons, et al. JACI 2001108871-873.

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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
38
Overview of Available Auto-Injectors
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 txs)

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

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Thank You !

• Questions?
• Please feel free to write me at
• David Elkayam, MD
• ddelkayam_at_hinet.org