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Anaphylaxis - PowerPoint

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									Anaphylaxis

 IWAA 2008
            TERMINOLOGY

 CLASSIC            SUGGESTED
   Anaphylaxis vs    CHANGE
 anaphylactoid         Anaphylaxis
                     immunologic
                           IgE
                           Non IgE
                       Anaphylaxis non-
                     immunologic
                 OUTLINE

 Epidemiology
 Idiopathic anaphylaxis
 Mediators, mechanisms, pathophysiology
 Clinical manifestations
 The laboratory in diagnosis
 Management and Mortality
EPIDEMIOLOGY
Working Group on Anaphylaxis
           ACAAI

 Incidence 0.05 to 2%
 Highest in children and adolescents
 Best data from outpatient Rx for epi
 Under diagnosis




Lieberman P et al: Ann Allergy, Asthma and Immunol, 97: 596, 2006
    Incidence based on epi Rx

 From Canada and Wales
 1.0% of population in Manitoba
 0.2 per 1000 in Wales
 Incidence increased in Wales
  between1994 & 1999

 Simons:J Allergy Clin Immunol 108; 2002
 Rangaraj: J Allergy Clin Immunol 109; 2002
EPI-PEN SALES INCREASING
Poulos LM et al: J Allergy Clin Immunol
2007; 120:878
Factors Affecting the Incidence
        of Anaphylaxis

Risk factors          Not risk factor
 Atopy                Race
                       Chronobiology
 Gender
                       Geography
 Econonomic status



                        Clin Exp Allergy31:2001
                      J Allergy Clin Immunol105;2001
       The North/South Gradient




Camargo et al: JACCI 120:131, 2007
Webb et al:J Allergy Clin Immunol 113:s241,2004
     The Role of Atopy as a
   Risk Factor for Anaphylaxis

 Risk factor
  Idiopathic
  Exercise
  Latex
  Radiocontrast




J Allergy Clin Immunol 113:536,2004
MEDIATORS, MECHANISMS,

 and PATHOPHYSIOLOGY
      HISTAMINE

works through three receptors
Mast cell mediators shown to be
            elevated

 Histamine
 Tryptase
 Paf
 LTE
 PGD2
 IL10
 Carboxypeptidase
H1,2,3 RECEPTOR ACTIVITIES

      H1 ONLY
Coronary artery                   H1 & H2
  vasoconstriction        Pulse
Bronchial constriction    Pulse pressure
                          Fall in diastoic pressure
                          Headache

      H2 ONLY                   H3
Coronary vasodilation     Autonomic
Ventricular ionotropy      receptor
Ventricular chronotropy
Atrial chronotropy
 Effects of Pretreatment with Histamine Receptor
  Antagonists on Widening of Pulse Pressure in
Response to Increasing Concentrations of Plasma
                    Histamine
                                                 130
                    Pulse pressure, % increase   120                             No pretreatment
                                                 110
                                                                                 Cimetidine
                                                 100
                                                  90                             Hydroxyzine
                                                  80
                                                                                 Cimetidine +
                                                  70                             hydroxyzine
                                                  60
                                                  50
                                                  40
                                                  30
                                                  20
                                                                      **
                                                  10       * **
                                                   0
                                                       0 1 2 3 4 5 6 7
                                                       Plasma histamine, ng/mL
 *P<0.05; **P<0.01
 Kaliner M, et al. J Allergy Clin Immunol. 1982;69:287.
Requirement for Pressor Support
  During Morphine Induction
                                                  No. of patients
                                                    requiring
  Group                                           neosynephrine
   Placebo                                             8/10
   Cimetidine, 4 mg/kg                                 6/10
   Diphenhydramine, 1 mg/kg                            5/10
   Cimetidine + diphenhydramine                        0/10
  Morphine administration at 1 mg/kg followed dosing
  with cimetidine and/or diphenhydramine (or administration
  of placebo).

Moss J, et al. Anesthesiology. 1983;59:331-339.
PAF acetylhydrolase deficiency(paf-h)
  predisposes to fatal anaphylaxis


  Fatal anaphylactic deaths vs healthy
   adults and children, peanut allergic
   children, non fatal anaphylaxis
  Paf-h was lower in fatal anaphylaxis than
   other groups, and there was no
   differences between other groups




  Vadas et al: J Allergy Clin Immunol 2003; 111:S206
PAF
PAF and Severity
    Paf vs Paf acetylhydrolase




Vadas P et al. N Engl J Med 2008;358:28-35
PAF-ah in patient groups




Vadas P et al. N Engl J Med 2008;358:28-35
           Pathway Activation
           During Anaphylaxis


                 Factor                     Contact
Clotting
                   XII                      system
                             Kallikrein

       Plasmin
                                     Mast
                          Tryptase   cell
    Complement
   Multimediator Recruitment
         in Anaphylaxis

 Complement
  – Decreased C4, C3
  – Formation C3a

 Contact system
  – Decreased high molecular weight kininogen
  – Formation of activation complexes

 Coagulation pathway
  – Decreased factor V, VII
  – Decreased fibrinogen
      Formation of Nitric Oxide


Bradykinin
                     L-arginine
Histamine

Leukotriene                         NO

PAF
                     L citrulline
Substance P
        Effects of Nitric Oxide

 Potentially detrimental
   – Smooth muscle vasodilation in vascular bed
   – Vascular permeability increased

   – Decreases catecholamine release

 Potentially beneficial
   – Smooth muscle dilatation bronchi
   – Vasodilation coronaries
   – Decreased mast cell degranulation
  L-arginine



Guanylate
 cyclase




 ↑cGMP         NO
              L-arginine
Methylene
  blue

            Guanylate
             cyclase




             ↑cGMP         NO
IL10 is increased
PATHOPHYSIOLOGY
                                            Sys
                                      100
               Arterial blood               Dias
                                       50
            pressure (TORR)
                                    0
                                    6
              Cardiac output
                                    4
                      L min-1
                                    2
                                  100
                    Heart rate
                                   75
                   beats min-1     50
                                   30
           Plasma histamine        20
                     ng ml-1       10
                                    0
    Plasma epinephrine ()     2000
    And norepinephrine ()     1000
                   pg ml-1          0
            System vascular      2000
                 resistance      1000
             dynes•sec•cm-5             0
                                              Before 2   4   10 15 20
                                             morphine
Famy NR :Anesthesiology 55:330,1981         Minutes after morphine
         125
         100
 BP       75
          50
          25
           0
           6
 CO        4
L Min      2
           0
          30
  H       20
ng/ml     10
           0
        2000

SVR     1000
d/s/c
                   Epi        Epi        Expander
           0

               0         10         20      30      40

                          Minutes
NORMAL VESSEL
ANAPHYLAXIS UNTREATED
ANAPHYLAXIS TREATED WITH VASOCONSTRICTOR ONLY
      Compensatory mechanisms


 ganglion      Nor epinephrine

               adrenal   Epinephrine




                kidney     Angiotensin
endothelium


              Endothelin
IL10 is increased
J Allergy Clin Immunol 117:169, 2006
Bradycardia may be more common
        than appreciated

  Sting challenge
  19 subjects
  All 8 subjects who experienced
  hypotension had an initial tachycardia
  followed by bradycardia



    Brown et al:Emerg Med J 12:149,2004
Anaphylaxis vs anaphylactoid
         reactions
          Clinical Sign According to
                 Mechanism*

                                                                      Nonspecific
                                         Anaphylaxis               histamine release
Clinical signs                           n = 151 (%)                   n = 57 (%)

Low blood pressure                             62.0                           25.1**
Cardiac arrest                                   9.0                           3.5**
Generalized erythema                           60.3                           75.4**
Bronchospasm                                   37.1                           42.0 NS


*Personal results:cases observed between 1995 and 1988
**P<0.01
NS = not significant
Moreret-Vautrin DA and Laxenaire MC. Clin Rev Allergy. 1991;9(3-4):249-258.
           Severity of
anaphylaxis/anaphylactoid events
                   60
                                                          Anaphylaxis
                   50                                     n = 396

                   40                                     Anaphylactoid
         Percent




                                                          (non-immune)
                   30                                     n = 175)

                   20

                   10

                   0
                         I           II         III        IV      V
                                   Grades of severity
Laxenaire MC. Ann Fr Anesth Reanim. 1999;18(8):796-809.
        LABORATORY TESTS IN THE
        DIAGNOSIS OF ANAPHYLAXIS

                                                Plasma histamine
A
                                                Serum tryptase
M
                                                24-hr Urinary histamine metabolite
O
U
N
T




    0   30   60   90   120   150   180   210   240   270   300   330

                  MINUTES
Pro-tryptase & mature beta tryptase

   Pro-beta tryptase is secreted
    constitutively
   Mature Beta tryptase is secreted during
    degranulation
   The ratio of total tryptase (pro-beta+
    mature beta) to mature beta is helpful in
    distinguishing anaphylaxis in
    mastocytosis from other forms
   A ratio of >20=mastocytosis; <10 other
    cause
         Dysjunction can occur

   Elevations of histamine & tryptase may
     not correlate
   Elevated histamine was observed in 42 of
     97 pts in ER whereas only 20 exhibited
     increased tryptase
   Histamine also correlated better with
     symtoms and signs:urticaria,wheeze,flush


JAACI106:65,2000
MANAGEMENT
                                        Growing Evidence on the Need for
                                        Two Doses
   % of Patients Requiring a 2nd Dose




  Percent of Patients Requiring > 1 Dose of Epinephrine During Anaphylactic Reaction
Korenblat et al. Allergy Asthma Proc. 1999;20:383-6; Webb L, et al. J Allergy Clin Immunol. 2004;S240;
Varghese et al. AAAAI 2006; Haymore et al. Allergy Asthma Proc. 2005;26:361-5.
                        IM vs SQ Epinephrine

Intramuscular
epinephrine
(Epipen®)



Subcutaneous                                                         34 ± 14(5-120) minutes
epinephrine                                                          p<0.05




                          5           10             15        20         25         30       35
                                                 Time to Cmax after injection (minutes)
Simons. J Allergy Clin Immunol. 2004; 113:838.
 The importance of lying down

 In Pumphrey’s series of deaths the
  postural history at the time of death was
  known in 10 cases who died out of
  hospital
 In 4 of these death was associated with
  assuming the upright or sitting posture
 These findings were consistent with death
  due to an “empty heart” with pulseless
  electrical activity
 Pumphrey RSH: J Allergy Clin Immunol:2003;112:451,2
        Major causes of death

  214 deaths reported by Pumphrey in
   which the cause was determined in 196
  88 shock
  96 asphyxia (49 lower airway, 22 upper, 25
   both or unspecified)
  7 DIC
  5 Epinephrine overdose
  Severity previous reaction not predictive

Pumphrey RSH:Novartis Found Symp. 2004;257:116-28
Further Studies of Fatal Anaphylactic Reactions
              to Food, 2001-2006

  Continuing observations by AAAAI Registry
  31 deaths between 2001 and 2006
  Peanut (17), tree nuts (8), milk (4), shrimp (2)
  All had asthma
  Only 4 had epinephrine
  Adolescents and young adults most common



 Bock A et al J Allergy Clin Immunol 119:1018, 2007
        Epinephrine Not Always Effective
  • Ongoing series of anaphylaxis deaths in UK
  • 48 deaths between 1999 and 2006
  • EPI injectors given to 19 (40%) including 11 of the 13
    with previous severe reactions
  • Over one-half of deaths occurred in patients with
    previous mild reactions
  • Most deaths due to respiratory arrest (asthma a risk
    factor)



Pumphrey RSH, Gowland M. J Allergy Clin Immunol 119:1018, 2007
       Death is associated with co-
                morbidities

     25 cases of fatalities, chart review
     At least 1 significant comorbid disease
       was identified in 22 of 25
     Urticaria occurred in only 1 of 25 cases




Greenberger P et al:Ann Allergy, Asthma and Immunology, 2007, 98 ; pp. 252 - 257

								
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