Anaphylaxis
Anaphylaxis
J Allergy Clin Immunol 2007;120:506-15
http://www.youtube.com/watch?v=VcxdqIPLyK8&list=PL7C80B961F004CBB8
Anaphylaxis Road Map
Definition
Pathophysiology
Epidemiology
Etiology
Morbidity and Mortality
Evaluation
Treatment
Dispo
Ana- -phylaxis
Ana- = again, up, back
-phylaxis = protection, immunity, guarding
1902
+
=
1902 + a few days
+
=
Definition
Clinically Meaningless: acute, severe, life-threatening, potentially
fatal, multi-organ, systemic reaction caused by the release of chemical
mediators from mast cells and basophils
Definition
Clinically Meaningful: When 1 of the following 3 criteria are fulfilled:
1. Acute onset of mucocutaneous signs AND 1 of the following: respiratory
compromise (wheezing-bronchospasm, dyspnea, stridor,
hypoxemia), hypotension (syncope), or hypotonia.
2. Rapid onset of 2 of the following after exposure to likely allergen:
mucocutaneous signs, respiratory compromise, hypotension, or
persistent gastrointestinal symptoms.
3. Hypotension after exposure to a known allergen.
Pathophysiology
Pathophysiology… for the ED doc
Pathophysiology
Type I Hypersensitivity Phases
Pathophysiology
Type I Hypersensitivity Phases
Step 1: Sensitization “fool me once…”
The allergen exposure  allergen uptake by dendritic
cells  broken down into antigenic peptides  peptides
presented on T-lymphocytes  cytokines are secreted from
the T-lymphocytes -> B lymphocytes then directly interact
with the Ts  Bs produce antigen specific IgE which is
packaged on the surface of mast cells (cell surfaces) and
basophils (circulating)
Pathophysiology
Type I Hypersensitivity Phases
Step 2: early-phase reaction
Allergen re-exposure  IgE on mast cell and basophil
surfaces “recognizes” allergen  degranulation releases
histamine, tryptase, heparin)  immediate symptoms at
target organs (vasculature, skin, smooth muscle etc.)
Step 3: late-phase reaction  about 6 hours later, allergen
stimulates T-cells to produce additional inflammatory
mediators (ie. leukotrienes) resulting in inflammatory cell
influx etc. etc. etc.
Why me?
Hypersensitivities are to substances – some people are predisposed to
make IgE when exposed to these substances whereas “normals” make IgG
(the activation of which would not result in hypersensitivity cascade)
Or…
Anaphylactoid reaction is an immediate systemic reaction that
mimics anaphylaxis in end-point (mast cell and basophil
degranulation) but lacks IgE’s involvement. Therefore, it can
happen on first exposure. Typically “dose” dependant.
Clinically indistinguishable from anaphylaxis.
Epidemiology
Very likely under-reported
1% of serious anaphylactic reactions result in death, or about
500-1000 deaths/year in the US
Foods  100 -200 fatalities / year
Beta Lactams (parenteral)  400 - 800 fatalities / year
Radiocontrast  900 fatalities / year
Insect stings  40 – 100 fatalities / year
Latex  3 fatalities / year
Desensitization injections about 3.4 fatalities / year
Allergen testing 1 fatality reported between 1990-2001
Etiology
#1: Food
#2: Drugs – allergic reactions make up somewhere between 5-25% of all
adverse drug reactions
#3: Stinging insects
Hymenoptera
Apid (honeybee, bumblebee)
Vespid (yellow jacket, hornet, wasp)
Formicid (fire ant)
#4: Latex
#5: others (ie. exercise, idiopathic etc)
Adverse Drug Reactions
WHO definition: All nontherapeutic consequences, with the
exception of treatment failures, purposeful or accidental
poisonings, and drug abuse.
All allergic reactions are ADRs, but not all ADRs (nausea,
diarrhea, malaise) are allergic reactions, so clarify with your
patient what their “allergy” really is.
Adverse Drug Reactions
Immediate hypersensitivity (IgE)
Nonimmediate allergic reactions (not IgE, typically)
SJS
TEN
Nonimmunological reactions
Anaphylactoid
Nonspecific histamine release (morphine itch, vanco red man)
Bradykinin accumulation (ACE-I angioedema)
Complement activation (radiocontrast)
Leukotrienes (NSAIDs)
DDx
Anaphylaxis / Anaphylactoid
Neurocardiac reaction (fancy pants for Vasovagal)
Other Shock classes (cardiogenic, hemorrhagic, septic)
“Flush” syndromes (carcinoid, medullary thyroid carcinoma)
“Restaurant” syndromes (Scrombroid, MSG)
Excess endogenous histamine production (things with big names)
Nonorganic (nuts, the psych kind)
Other (ACE-I, C1 esterase difficiency, pheos)
Symptoms
Definition
J Allergy Clin Immunol 2006 ;117 : 391-7
Clinically Meaningful: When 1 of the following 3 criteria are fulfilled:
1. Acute onset of mucocutaneous signs AND 1 of the following: respiratory
compromise (wheezing-bronchospasm, dyspnea, stridor,
hypoxemia), hypotension (syncope), or hypotonia.
2. Rapid onset of 2 of the following after exposure to likely allergen:
mucocutaneous signs, respiratory compromise, hypotension, or
persistent gastrointestinal symptoms.
3. Hypotension after exposure to a known allergen.
Criteria 1 : skin lesions and/or mucosa lesions (urticaria, itching or
erythema, lip edema or tongue-uvula edema). With one or more or
following signs :
Respiratory troubles (dyspnea, bronchospasm, stridor, decreased of
peak flow, hypoxia)
Systolic BP<90 mmHg) or organ dysfunction (hypotonia, syncope,
incontinence)
Criteria 2 : 2 or more signs after exposition to a probable allergen:
skin lesions and/or mucosa lesions (urticaria, itching or erythema, lips
edema or tongue-uvula edema). With one or more of the following signs :
Respiratory troubles (dyspnea, bronchospasm, stridor, decreased of peak
flow, hypoxia)
Systolic BP<90 mmHg) or organ dysfunction (hypotonia, syncope,
incontinence)
Persistent gastrointestinal troubles (abdominal pain, vomiting)
Criteria 3: hypotension, know exposure
Decrease of SBP< 90mmHg or more than 30% compared to basal in
adults* after exposition to known allergen.
*In child decrease of SBP is defined as: SBP < 70 mmHg from 1
month to 1 year, below (70 mmHg + [2 x age]) from 1 to 10 years,
<90mmHg from 11 to 17 years.
Symptoms
Up to 35% of circulating volume can be displaced extravascularly
within just 10 MINUTES of symptom onset
Most cases have cutaneous findings
A few cases do not
Cutaneous 90%
Respiratory 50% +/- 10%
Cardiovascular (dizzy, syncope, low BP) 33%
GI 25-30%
Other Sxs (HA, chest pain, Sz) <8%
Diagnostic Tests
Yeaaaaah…
For the inpatient team, you could send serum tryptase levels
(which obviously peak between 60-90 minutes)
Treatment
Which of the following are first line agents for
the treatment of anaphylaxis (select all that
apply)?
a. IV Corticosteroids
b. PO Corticosteroids
c. Parenteral Epinephrine
d. Nebulized Beta agonists
e. Oral Antihistamines
f. IV Antihistamines
Treatment
Treatment
Treatment
AIRWAY
Control it early (waaaaay easier to explain to an alive patient why they
maybe didn’t need it then to explain to the family why the deceased,
in retrospect, did)
Standard of care is NOT to call ENT to look at larynx. You either look at
the larynx yourself or you make a call based on symptoms (Voice
change, respiratory distress, etc. One day, ultrasound)
Many difficult airway devices will not work
LMA – nope
Combitube – eh eh
Things to have:
Bougie
Tubes many sizes smaller than you typically use
Fiberoptics (but Bougie + Glidescope pretty good too)
½ dose Etomidate without paralytic for “awake” intubation
Crich tray or kit (seldinger)
ENT, Anesthesiology (time permitting, don’t be proud, be
smart)
Treatment
CIRCULATION (and A and B)
Be vigilant for tachycardia (brady and other dysrhythmias can
sometimes also happen), hypotension, etc.
IV fluids – lots of them
Epinephrine – Dr. House says, “Don’t be a….”
Treatment - Epinephrine
Study #1: 13 fatal or near-fatal cases of anaphylaxis
of 6 who died, only 2 received epi within 1 hour of sx onset
of 7 who survived, 6 received epi within 30 minutes
Study #2: there were others, but I lost them, so here we are….
Delay in epi administration also associated with higher rate of biphasic
reactions
No placebo controlled allowed, so keep all your snooty journal club
whining to yourselves
Treatment - Epinephrine
Treatment - Epinephrine
BEST ROUTE = IM to the anterolateral middle third of the thigh
with a needle long enough to reach MUSCLE
SubQ  unreliable absorption
IV  unless you need it, that sh$&% will kill you (virtually ALL
adverse outcomes resulted from IV administration)
Epi Dosing
Adults
IM 0.2 – 0.5mg
Literature suggests that you go big (0.5 -1mg) or go home
Peds
IM 0.01mg / kg up to a max of 0.3mg
IM solution is the 1:1000 one (which means
1gm /1000mL
1000mg / 1000mL
1mg in 1mL
0.5mg = 0.5mL
Do this once. In five minutes, if necessary, do it again.
Then draw up a third and mix up the IV epi for when the third fails.
IV dosing is not well established
Want to hear something scary?
Multicenter study found:
fewer than 25% of “serious reactions” received epi
fewer than 16% discharged with Rx for epi-pens
but..
72% received antihistamines
48% systemic steroids
33% Nebs
Another study:
only 5% of housestaff new appropriate route and dosage
Who SHOULDN’T get Epi?
ABSOLUTELY NO ABSOLUTE CONTRAINDICATIONS!
It IS safe (IM, anyway)….
A study of epi used in asthma exacerbations
demonstrated safety in patients ages 15-96 years
HOWEVER…
… in patients using beta blocker, may get unopposed
alpha, so some advise half-dose epi
Take away the beta…
Antihistamines
H1 Blockers
SECOND LINE, NEVER THE SOLE TX OF ANAPHYLAXIS
SLOW ONSET (effects take 30 – 45 min to start)
WORK TO PROHIBIT FURTHER DEGRANULATIONS, NOT TREAT
THAT WHICH HAS ALREADY OCCURRED!
H2 Blockers
SECOND LINE
Sound data to support use (randomized, double blind, placebo
controlled)
Corticosteroids
SECOND LINE
JOINT TASK FORCE IN ALLERGY blah blah and blah says,
“systemic corticosteroids have no role in the acute management
of anaphylaxis because they might have no effect for 4 to 6
hours, even when administered intravenously.”
Never validated in placebo controlled trials, nor have standard
dose, route, or type been proven superior
But, duh
European recs: 200 mg hydrocortisone IM or IV “following the
initial resuscitation of the patient”
Glucagon
For either refractory or Beta-blocked patients
Stimulate cAMP production (like Epi does) but via a different nonbeta-blocked receptor
1 – 5 mg IV over 5 minutes (peds = 20-30 microg / kg, max 1mg),
then IV infusion of 5 – 15 microg / min titrated to response
Other
Nebs
Terbutaline
Vasopressin – evidence supports
Other vasopressors
Disposition
DISPO
Observe for at least 6 hours (8 appears better) from the time of
symptom IMPROVEMENT, not onset
Biphasic reactions occur in 5 – 20% of cases
Latency period highly variable but nearly always within 72 hours
Retrospective study of 164 cases of fatal anaphylaxis showed that vast
majority of deaths occurred within 4 hours, all within 6
Dispo
Extend observation and consider admission for:
Asthmatic component of reaction
History of biphasic reactions
Continuing absorption of allergen
Poor access to emergency care
Overnight or alone at home
Severe reactions with slow onset
Unable to use epi-pen
Admit
Anyone not cardiorespitorily perfect after 8 hours
BEFORE DISCHARGE, ALWAYS
Clear instructions to return PRN and what constitutes PRN
Rx for 3 days (72 hours for a reason) of antihistamine and steroids
EPI-PEN x2 (either in their hand or RX able to be filled immediately
Instructions how to use the epi-pen
Follow up appointment / plan
Among MDs who commonly rx epi-pens, only 25% correctly
demonstrated the proper technique for use, only 24% knew it was
available in 2 dosage forms
ACE-Inhibitor Angioedema
0.1%- 0.5% of users (more so in A-As, ACE-I cough more so in Asians)
Likely inhibition of ACE breakdown of bradykinin, a potent vasodilator
Usually localized to head, neck
Lacks cutaneous features of true allergy
Anaphylaxis Tx never proven effective (epi, roids, H1&2s), but airway
control has
FFP replenishes ACE levels (class II)
Icatibant (not likely available) specific bradykinin B2 receptor inhibitor
(Class II, off-label use)
ACE-Inhibitor Angioedema
In one retrospective study of angioedema, ACE-I were responsible for 1/3
of events. Of those:
Nearly half warranted ICU admission
One-third required definitive airway
So, they recommended
outpt or obs for sxs limited to face, lips, soft palate
Inpt for lingual edema, ICU for posterior lingual or laryngeal edema
(whether visualized or based on sxs of stridor, dyspnea, voice
change)
C1 Esterase Inhibitor Deficiency
2 Forms
Autosomal dominant
Acquired (often associated with lymphoproliferative and autoimmune dzs)
also De Novo mutations
C1EI modulates complement activation, but it also helps regulate bradykinin
formation
Lack of Inhibitor means more bradykinin
(ACE-I = inability to breakdown brady)
(C1EI def = inability to slow creation)
Recurrent episodes of well-circumscribed, nonpruritic angioedema
May involve Gi and respiratory tracts (unexplained, recurrent abd pain)
FFP, C1EI concentrate (both Class II)
Penicillin and Cephs
Shared beta-lactam structure
“10% cross-reactivity” = from 1970s, 1st gen cephs which later were found
to have trace amounts of PCN in them! (derived from same mold)
New data suggest side chains may be more important than beta-lactam
ring
AAP recently endorsed use of 2nd gen and 3rd gen Cephs for otitis in PCN
allergic peds as long as prior reaction was not hypersensitivity type 1
(fewer than 10% of those claiming PCN allergy have Type 1)
All in all, risks of serious reaction to 2nd or 3rd Ceph in a pt with a selfreported / non-skin tested PCN allergy are low (perhaps <1% but
realistically type 1 reaction to any given abx is 1-3%
Radiographic Contrast Materials
ANAPHYLACTOID (and therefore dose dependent, no IgE)
Maybe some IgE cases
Related to the osmolarity of the solution, now everyone uses safer “low
osmolarity” (3.1% adverse rx, 0.04% severe) some using even safer “isoosmolar”
No absolute contraindication
History of Iodine-containing food allergy is NOT predictive (another 1970s
study gone awry)
RFs = hx of one, atopy / asthma, Beta blockade, CAD
Tx Sxs like any other allergic / anaphylactic reaction
Pretreatment appears to reduce event likelihood by 10-fold