Perioperative anaphylaxis Presented by Thitima Kantachatvanich, MD. November16, 2018

1. Perioperative
anaphylaxis
Thitima Kantachatvanich, MD.
Division of Allergy and Clinical Immunology
Faculty Medicine, Chulalongkorn University
16/11/2018

2. CASE
• Male 21 years old, no U/D
• Admit for cystoscope with laser granulation tissue and change SPC
• Acute urticaria and nasal congestion at recovery room after
cystoscope with laser granulation tissue
• PH: motorcycle accident 1 year ago  pelvic, rt.femur Fx with rectal,
urethral, prostate, bladder, rt.internal iliac a. injury

3. Case
• Status: bedridden, retain Foley catheter
• Past surgical Hx:
• Rectal repair with dilatation
• Angioembolization rt.internal iliac a.
• Repair bladder with suprapubic cystostomy(SPC)
• Explore laparotomy with 2nd bladder, prostate repair with bilateral
ureterostomy and SPC
• Bilateral retrograde pyelogram with cystogram
• ORIF pelvis and rt.femur
• RUG, cystogram, change SPC x 2times
• Combined RUG

4. Timeline & Anesthetic Chart

7. What will you do next?

8. Perioperative Anaphylaxis
• Immediate hypersensitivity during or after procedure
• Anaphylaxis: A serious, generalized or systemic, allergic or
hypersensitivity reaction that can be life-threatening or fatal1
1.Simons et al. International Consensus on Anaphylaxis,WAO Journal 2014

9. Clinical importance
• Severe anaphylaxis, high mortality
• Delayed recognition (unnoticed/draped skin/sedated patient)
• Vulnerable after physiologic disturbance
• IV drug route
• Concomittant illness/stress/medication(Betablockers)
• Difficult to find etiologies
• Multiple drug administration
• Limited Hx, PE (incomplete and difficult-to-read anesthetic chart)
• Limited way to test (unable to do DPT in some)

10. Ring and Messmer Classification in 1977
Mertes PM, Laxenaire MC. Les reactions anaphylactiques et anaphylactoides peranesthesiques en France.[Anaphylactic and anaphylactoid
reactions occurring during anaesthesia in France. Seventh epidemiologic survey (January 2001– December 2002)]. Ann Fr Anesth Reanim
2004;23(12):1133–43 [in French].

11. Incidence
• 1:3500-1:20000 (underestimated)
• Thailand: 1:5000
• Mortality: up to 9%
• The most important morbidity: brain anoxia (2%)
• 9–19% of all surgical complications
• 5–7 % of all deaths during anesthesia
• Gender
• Prepuberty: male = female
• Adult: female > male
Violeta Régnier Galvão, Pedro Giavina-Bianchi, Mariana Castells:
Perioperative Anaphylaxis, Curr Allergy Asthma Rep (2014) 14:452

12. Etiologies
• More common
• A: Antibiotic
• B: Blocking agent “NMBAs”
• C: Chlorhexidine
• D: Drain “Latex”
• Europe: pholcodine use
(cross-react to NMBAs, morphine)
Wolfgang Pfützner, Knut Brockow: Perioperative drug reactions–practical recommendations
for allergy testing and patient management, Allergo J Int (2018) 27:126–129

13. Mechanism
• Allergic (66%)1
• IgE dependent: 60-70%1
• Non-IgE dependent: IgG, complement-mediated
• Nonallergic2
• Direct MC activation
• Dysfunction of arachidonic acid metabolism
• Anaphylactoxin
1.Simons FER, Ardusso LRF, Bilò MB, et al. World Allergy Organization anaphylaxis
guidelines: summary. J Allergy Clin Immunol. 2011;127:587–593.e1–22
2. Farnam K, Chang C, Teuber S, Gershwin ME. Nonallergic drug hypersensitivity
reactions. Int Arch Allergy Immunol. 2012;159: 327–45.

14. Parenteral administration of a large quantity of an antigen: IgG-mediated
Fred D. Finkelman, et al., Human IgE-independent systemic anaphylaxis, JACI 2016

15. Agents IgE-mediated Non-IgE
mediated
Non-
immunologic
NMBAs ++ - +
Antibiotics + (bata-lactam) +/- + (vancomycin)
Chlorhexidine ++ +/- -
Latex ++ - -
Hypnotics: barbiturates ++ + +
Hypnotics:
nonbarbiturates
+/- + +
Opioids + - ++
Colloids and plasma
expanders
+ +(Dextran) +
Ethylene oxide ++ - -
Vital dyes + - +/-
Streptokinase,
chymopapain, insulin
+ - -

16. Mechanisms Characteristics
IgE-mediated • Require prior exposure
• More severe
• Amenable to desensitization
• Premedication may helpful in mild reactions
Non-IgE mediated • May not require prior exposure
• Premedication may helpful
Direct MC, Ba
activation
• Not require prior exposure
• Rate dependent reaction
• Slow administration minimize reactions
• Premedication may helpful

17. Risk Factors for Perioperative Anaphylaxis
• History of previous periprocedural reaction
• Previous drug used in current procedure hypersensitivity
• Atopy: latex, RCM
• Poor controlled asthma
• Fruit* allergy (latex)
• Avocado, kiwi, banana, pineapple, papaya, chestnut, passion fruit
• High exposure to latex (spina bifida, HCW)
• Multiple past Sx/procedures (latex, ethylene oxide, NMBAs)
• Mast cell disorders (drugs, physiologic stimuli)
Violeta Régnier Galvão, Pedro Giavina-Bianchi, Mariana Castells:
Perioperative Anaphylaxis, Curr Allergy Asthma Rep (2014) 14:452

18. for general anesthetics (A) and radiocontrast (B)
Liccardi G et al, Hospital Radiocontrast Media and Anesthetic-Induced Anaphylaxis Prevention Working Group. Strategies for the prevention of asthmatic,
anaphylactic and anaphylactoid reactions during the administration of anesthetics and/or contrast media. J Investig Allergol Clin Immunol 2008;18:3
No evidence now

19. Risk factors for Death/Cardiac arrest from Severe
Anaphylaxis (2018 UK National Survey)
• Obesity
• High ASA score
• BBs, ACEI

20. Differences Between Perioperative
Anaphylaxis and Other Settings
Manifestations Other Settings Perioperative Settings
Upper RS/laryngeal
edema
Throat tightness, voice change • Difficulty to intubation
• Postextubation stridor
Lower
RS/bronchospasm
Shortness of breath, wheezing,
cough
• ↑Ventilatory pressure
(Difficulty to inflate lungs)
• ↑EtCO2
• ↓SaO2
CVS
Dizziness, tunnel vision
Collapse
• CVS collapse (1st detected in
50%)
• Arrhythmia, cardiac arrest
Skin
Flushing, itching, urticarial
(>90% of cases)
• Absent or present but may be
hidden by surgical drapes
Warning sign of severe anaphylaxis will not presented in sedated pt.

21. Differential Diagnosis
• RS symptoms
• Asthmatic attack
• Aspiration
• ET malposition
• Pulmonary emboli
• Pulmonary congestion
• Pneumothorax
• TRALI
• Postextubation stridor
Mertes P.M., et al. Perioperative anaphylaxis Med Clin N Am 94 (2010) 761–789
• CVS symptoms
• Arrhythmia
• Cardiac tamponade
• Overdose of
vasoactive agents
• Vasovagal reaction
• Partial
sympathectomy
(spinal anesthesia)
• Air emboli
• Angioedema
• HAE or acquired C1
inhibitor deficiency
• ACEI, NSAIDs induced
• Urticaria
• Cold urticaria

22. Acute Management
• IV bolus epinephrine (readily available IV access, V/S monitoring)
• Lab test: serum tryptase
• Serum tryptase (event and baseline): Dx, mast cell disorders
• Consider other DDx
• Decision to proceed Sx
• Safe after grade 1, 2
• Severity after grade 3: ↑risk of event but not different in risk between
continued or abandoned
(profound hypotension or severe bronchospasm)
• Allergic evaluation: 1month to 1 year
Sadleir PHM, Clarke RC, Bozic B, Platt PR. Consequences of proceeding with surgery
after resuscitation from intra-operative anaphylaxis. Anaesthesia 2018; 73:32.

23. Serum Tryptase
• Perioperative anaphylaxis: PPV 93%, NPV 54%1
• Peak at 30 minutes, return to BL at 12-14 hr
• Collect blood at 15min-1hr, 24hr (If grade3-4: recommend 30min-2hr, 2day)
• ≥ 1ml of blood in red tube
• 1.2xbaseline + 2 mcg/L :mast cell mediated event
• Elevated tryptase: severe, detectable sIgE to culprit
• ↑↑ Change >141 %; or level of >15.7 mcg/L): highly predictive of IgE-
mediated perioperative anaphylaxis in a multi-center, retrospective analysis2
1.Mertes PM, Laxenaire MC, Alla F, Groupe d'Etudes des Réactions Anaphylactoïdes Peranesthésiques. Anaphylactic and
anaphylactoid reactions occurring during anesthesia in France in 1999-2000. Anesthesiology 2003; 99:536.
2. Krishna MT, et al. Multi-centre retrospective analysis of anaphylaxis during general anaesthesia in the United Kingdom: aetiology
and diagnostic performance of acute serum tryptase. Clin Exp Immunol. 2014;178:399–404.

24. Serum Tryptase
• Collection before death
• Stable in frozen serum up to 1 year
• Non-specific release immediately after death
• The cut-off of tryptase 7.35 mcg/L(ng/ml) & of histamine 6.35
nmol/L
• Sensitivity & specificity 90-92% for Dx perioperative “allergic”
cardiopulmonary arrest
Laroche D, Gomis P, Gallimidi E, et al. Diagnostic value of histamine and tryptase concentrations
in severe anaphylaxis with shock or cardiac arrest during anesthesia. Anesthesiology 2014; 121:272.

25. History Taking for Allergist
• Description of anaphylactic event: S&S
• Type of procedure
• Anesthesia, procedural records
• Timeline of agent
• Instrument, disinfectant
• Prior anesthesia, previous exposure
• Alternative agents available in the facility

26. Etiologies
• More common
• A: Antibiotic
• B: Blocking agent “NMBAs”
• C: Chlorhexidine
• D: Drain “Latex”
• Europe: pholcodine use
(cross-react to NMBAs, morphine)
Wolfgang Pfützner, Knut Brockow: Perioperative drug reactions–practical recommendations
for allergy testing and patient management, Allergo J Int (2018) 27:126–129

27. Timing of Onset vs Etiologies
• Depend on time of used agent, route
• Within minutes after induction: NMBA, ATB
• During maintenance: Volume expanders
• After manipulation:
Dyes, contrast, Latex (glove contact with mucosa, irrigation), topical hemostatic agents
• Sudden shift in blood/fluid
• Remove tourniquet, unclamp vvs, uterine manipulation after oxytocin
Mertes P.M., et al. Perioperative anaphylaxis Med Clin N Am 94 (2010) 761–789

28. NMBAs
• 50-70%1
• Female > male1
• Most common identifiable cause in French surveys1
• IgE-mediated: to QAI, complementary structure
• Rocuronium, pancuronium, vecuronium, succinylcholine
• Direct MC activation via MRGPRX22 (20-50%)
• Tubocurarine, mivacurium, atracurium, rapacuronium
• Rapacuronium: withdrawn from US (high rate of bronchospasm w/o other
symptoms)
1.Mertes PM, Laxenaire MC, Alla F, Groupe Anaphylactic and anaphylactoid reactions occurring
during anesthesia in France in 1999-2000. Anesthesiology 2003; 99:536.
2.McNeil BD, Pundir P, Meeker S, et al. Identification of a mast-cell-specific receptor crucial for
pseudo-allergic drug reactions. Nature 2015; 519:237.

29. NMBAs
• Succinylcholine: most cause among NMBAs
• Reversing agent
• In 14 of 15 patients with perioperative anaphylaxis due to sugammadex,
symptoms began within 4 minutes of injection2
• Monosensitized frequent with succinylcholine
• More commonly causes bronchospasm1
• Atracurium
• More commonly causes hypotension1
1. Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: epidemiology and
clinical features of perioperative anaphylaxis in the 6th National Audit Project (NAP6). Br J Anaesth 2018; 121:159.
2.Tsur A, Kalansky A. Hypersensitivity associated with sugammadex administration: a systematic review. Anaesthesia.
2014;69:1251–7.

30. NMBAs
• Cross-react: not depend on the pharmacological class, but rather on
the distance between the two substituted ammonium2
• STs are so far the only mean to predict clinical cross-reactivity
1.Violeta Régnier Galvão, Pedro Giavina-Bianchi, Mariana Castells: Perioperative Anaphylaxis, Curr Allergy Asthma Rep (2014) 14:452
2.Didier CA, Cador D, Bougrand P. Role of quaternary ammonium ion determinants in allergy to muscle relaxants. J Allergy Clin Immunol 1987;79:578–584.
Cross-react to QAI(Quaternary ammonium ions) epitope
• Pholcodine hypothesis
• Among all NMBAs subclasses (65% by ST, 80% by RAI)
• Most reports: pancuronium vs vecuronium,
succinylcholine vs gallamine
• Topical cosmetics and personal products
sIgE to QAI: sen 65-88%, FP rate 5-10%
- If high suspicious but negative ST
• Divalency allow 1 molecule of NMBA to bridge IgE
• Longer molecule: flexible backbone ↑Mediator release

31. Excellent NPV of NMBA ST
L. F. Ramirez, A. Pereira, A. M. Chiriac, M.-C. Bonnet-Boyer & P. Demoly, et al. Negative predictive
value of skin tests to neuromuscular blocking agents Allergy (2012) 439–441 John Wiley & Sons A/S
Not standardized
But useful for find safe alternatives

32. NMBAs
• sIgE to QAI: available in some countries (e.g. US)
• sIgE to suxamethonium: poor sensitivity
• ST: only way to prove, find alternatives
• DPT: not feasible
• Premedication: may help in direct MC activation
• Cisatracurium: appear to be lowest risk NMBAs
Violeta Régnier Galvão, Pedro Giavina-Bianchi, Mariana Castells: Perioperative Anaphylaxis, Curr Allergy Asthma Rep (2014) 14:452

33. Antibiotic
• 12-15% in French studies
• 50% of IgE mediated reactions in an American series
• 45% of identifiable causes in German series
• 47% of identifiable causes in a prospective UK registry
• Betalactam (penicillin, cephalosporin): frequently by IgE-mediated
anaphylaxis  Only standardized ST
• Quinolone
• Direct MC activation via MRGPRX22
• Some reports of IgE-mediated
• Vancomycin: the most cause of direct MC activation(red man syndrome)
• IgE-mediated: rare (SPT 50mg/ml)
1.Mertes PM, Laxenaire MC, Alla F, Groupe Anaphylactic and anaphylactoid reactions occurring
during anesthesia in France in 1999-2000. Anesthesiology 2003; 99:536.
2.McNeil BD, Pundir P, Meeker S, et al. Identification of a mast-cell-specific receptor crucial for
pseudo-allergic drug reactions. Nature 2015; 519:237.

34. Chlorhexidine
• 9% in prospective UK registry 2018
• Postoperative urticarial to severe anaphylaxis
• *High index of suspicion: routinely test
• Specific IgE: high sensitivity, specificity
• ST: SPT 0.5mg/ml, IDT 0.05mg/ml
• BAT: not routine lab
Opstrup MS, Malling HJ, Kroigaard M, Mosbech H, Skov PS, Poulsen LK, et al. Standardized testing with
chlorhexidine in perioperative allergy – a large single-centre evaluation. Allergy. 2014;69:1390–6.

35. Chlorhexidine
• Applied to surgical fields esp. mucosa, urethral lubricants, CVC tips,
disrupted surface
• Found in toothpastes, mouthwashes, bath solutions, lozenges
• ↑Risk if alcoholic solvent > other solvents
• No cross-reactivity with povidone iodine
• Povidone iodine: able to induce anaphylaxis also
Violeta Régnier Galvão, Pedro Giavina-Bianchi, Mariana Castells: Perioperative Anaphylaxis, Curr Allergy Asthma Rep (2014) 14:452

36. Latex
• ↓Incidence (↑Awareness of HCWs and patients): 12-16.7%
• IgE mediated (to Hev b protein allergen)
• Sensitized by contact, aeroparticle, ingestion
• Risk: multiple Sx (esp. ≥5 Sx), spina bifida, atopy
• ≥ 30 minutes after manipulation skin, mucosa (during maintenance)
• 10-290 minutes
• Faster if contact with peritoneum, mucosa
Violeta Régnier Galvão, Pedro Giavina-Bianchi, Mariana Castells: Perioperative Anaphylaxis, Curr Allergy Asthma Rep (2014) 14:452

37. Latex
• Serum specific IgE
• Sensitivity: 92%
• CRD: rHev b1  sen 81.6%, spe 97.3%
• SPT with standardized commercial natural rubber extracts
• Sensitivity, specificity near 100%
• SPT with latex glove: variable allergen content
• Glove use test: if clinical highly suggestive but negative/inconclusive
sIgE, SPT
• Patch test is for latex allergic contact dermatitis
Violeta Régnier Galvão, Pedro Giavina-Bianchi, Mariana Castells: Perioperative Anaphylaxis, Curr Allergy Asthma Rep (2014) 14:452

38. High Risk of Latex Allergy
Vargas A, Foncea C, Astorga P. Latex Allergy: Overview and Recommendations for the
Perioperative Management of High-Risk Patients. J Head Neck Spine Surg. 2017

39. Questionnaire for Screening pt to Test
• In Israel, 9-item written screening questionnaire before elective
Caesarean delivery identified potential clinical reactivity to latex in
14.6 % of 453 women, compared with only 2.6 % of 460 women by
standard verbal inquiry2
Péer L, et al. Evaluation of a prospectively administered written questionnaire to reduce the incidence
of suspected latex anaphylaxis during elective cesarean delivery. Int J Obstet Anesth. 2014;23:335–40.

40. Questionnaire
Vargas A, Foncea C, Astorga P. Latex Allergy: Overview and Recommendations for the
Perioperative Management of High-Risk Patients. J Head Neck Spine Surg. 2017

41. Buss, et al. Screening for latex sensitization by questionnaire: diagnostic performance in health care workers. JACI 2008; 18: 12–16
Combination III+IV:
sen100%, spe100%
:To detect HCW
positive SPT to NRL

42. How to Deal With Latex Sensitization
• Prevention is GOLD
• General measures: safe for some pt., ↓HCW exposure
• Label allergic patient
• Label latex containing products
• Latex free gloves
• Specific protocol for high risk of latex allergy: ideal situation
• Preoperative
• Intraoperative
• Postoperative
Vargas A, Foncea C, Astorga P. Latex Allergy: Overview and Recommendations for the
Perioperative Management of High-Risk Patients. J Head Neck Spine Surg. 2017

43. Latex Free Equipments
Vargas A, Foncea C, Astorga P. Latex Allergy: Overview and Recommendations for the
Perioperative Management of High-Risk Patients. J Head Neck Spine Surg. 2017

44. Preoperative Period in Latex Allergy
• Scheduled 1st case of the day (↓aeroallergens)
• Label on the door  allergic pt, latex-free room
• The day before surgery, remove all products containing latex
• Cleaning staff should not wear latex gloves
• Aeroparticles from dust stay for up to 5 hr, undetectable after
removal 24 hr
• Availability of epinephrine and resuscitation set in room
Vargas A, Foncea C, Astorga P. Latex Allergy: Overview and Recommendations for the
Perioperative Management of High-Risk Patients. J Head Neck Spine Surg. 2017

45. Preoperative Period in Latex Allergy
• The day of the surgery, cleaned again to remove the suspended
powder
• Cover all monitoring devices: avoid direct contact with the skin
• Rinsed Products sterilized in ethylene oxide before use
• May cause an allergic response in a patient allergic to latex
(Cosensitization in multiple Sx)
Vargas A, Foncea C, Astorga P. Latex Allergy: Overview and Recommendations for the
Perioperative Management of High-Risk Patients. J Head Neck Spine Surg. 2017

46. Preoperative Period in Latex Allergy
• Identified pt. by bracelet and note in the sheets of nursing
• Before BP measurement
• Cover arm with a cotton mesh
(Avoiding contact stetoscope with the skin)
Vargas A, Foncea C, Astorga P. Latex Allergy: Overview and Recommendations for the
Perioperative Management of High-Risk Patients. J Head Neck Spine Surg. 2017

47. Intraoperative Period in Latex Allergy
• Wear latex-free gloves
• Minimize traffic inside OR
• Do not use penrose drains, latex bands, latex irrigation elements
• Latex-free or glass syringes
• Preferred glass ampoules medications
• If not available, remove the rubber stoppers before preparing the medication
• Prepared immediately prior their administration (↓contact with plunger)
Vargas A, Foncea C, Astorga P. Latex Allergy: Overview and Recommendations for the
Perioperative Management of High-Risk Patients. J Head Neck Spine Surg. 2017

48. Postoperative Period in Latex Allergy
• Room prepared for the patient
• Informed all involved departments
Vargas A, Foncea C, Astorga P. Latex Allergy: Overview and Recommendations for the
Perioperative Management of High-Risk Patients. J Head Neck Spine Surg. 2017

49. May Contain NRL
• Gloves
• Drains (Penrose, others)
• Catheters (Indwelling, straight,
and condom)
• Ambu-bag
• Airway masks
• Endotracheal tubes
• Suction catheter
• Intravenous bags, ports
• Infusion sets
• Elastic bandages
• Self-adhesive bandages, adhesive tape
• Electrode pads
Now Latex Free

50. Colloids, Plasma Expanders
• 3% of identifiable causes
• Gelatins > Dextran > Albumin > Starch (0.06-0.35%)
• Non-IgE > IgE-mediated mechanisms
• DDx to non-allergic reaction
• TRALI, fluid overload, hemolytic reaction
• TRALI: dyspnea, hypoxemia, hypotension within 1-6 hr
Violeta Régnier Galvão, Pedro Giavina-Bianchi, Mariana Castells: Perioperative Anaphylaxis, Curr Allergy Asthma Rep (2014) 14:452

51. Colloids, Plasma Expanders
• High MW polysaccharides: incidence of each agent < 0.1%
• Dextran: IgG-mediated  Immune complex  anaphylatoxin
• Hydroxyethyl starch (HES): pruritus over months, refractory to Tx
• Albumin: rare
• Gelatin: IgE-mediated
• Avoid gelatin based colloid in whom had gelatin allergy
• Polygeline (Haemaccel)
• Gelofusine: succinylated
• ST, gelatin specific IgE is helpful
Violeta Régnier Galvão, Pedro Giavina-Bianchi, Mariana Castells: Perioperative Anaphylaxis, Curr Allergy Asthma Rep (2014) 14:452

52. Dextran 1
• Hapten inhibition by Dextran 1
• Dextran 1: small fraction (1kDa) of entire dextran complex to bind IgG but not
form immune complex
• Dextran 1 use in Sweden between 1983-1985 (compared to 1975-
1979 period)
• ↓Severe reactions: 22  1.2 per 100000 units
• ↓Fatal reaction from 23  1
Ljungstrom, et al. Hapten inhibition and dextran anaphylaxis Anesthesia, 1988, Vol 43 (729-732)

53. Hypnotic Induction Agents
• After Cremophor ER (polyethoxylated castor oil; solvent) removal
• Significantly ↓incidence of anaphylaxis from hypnotic agents
• Barbiturates >> Non-barbiturates
• No report of immune mediated reaction from inhalational agents
Violeta Régnier Galvão, Pedro Giavina-Bianchi, Mariana Castells: Perioperative Anaphylaxis, Curr Allergy Asthma Rep (2014) 14:452

54. Barbiturates
• Thiopental: most common
• Methohexital
Non-barbiturates
• Benzodiazepine
• Propofol
• Etomidate
• Ketamine
• Inhale
IgE > Direct MC activation Direct MC activation > IgE
Not cross-react between barbiturates and non-barbiturates
Violeta Régnier Galvão, Pedro Giavina-Bianchi, Mariana Castells: Perioperative Anaphylaxis, Curr Allergy Asthma Rep (2014) 14:452

55. Hypnotic Induction Agents
• Barbiturates
• IgE > Non-IgE mediated anaphylaxis (Direct MC activation)
• Cross-reactive among barbiturate, NMBAs
• Share quaternary amine structure
• Female > Male
Violeta Régnier Galvão, Pedro Giavina-Bianchi, Mariana Castells: Perioperative Anaphylaxis, Curr Allergy Asthma Rep (2014) 14:452

56. Hypnotic Induction Agents
• Non-barbiturates
• Very rare cause of anaphylaxis
• Benzodiazepines: hypotension from ADR, rare cause of anaphylaxis
• Midazolam is the main causative agent
• In vitro MC activation by BZDs
• No report of cross-reactivity among non-barbiturates
Violeta Régnier Galvão, Pedro Giavina-Bianchi, Mariana Castells: Perioperative Anaphylaxis, Curr Allergy Asthma Rep (2014) 14:452

57. Propofol and Egg/Soy Allergy
• Vehicle for propofol: soybean oil emulsion with egg lecithin
• Allergies to egg/soybean: contraindications in the package insert
• Most reports of anaphylaxis to propofol: no egg allergy
• Most patients with egg allergy receive propofol without reaction
• Few case reports: suspected propofol allergic pt. in egg allergic pt.
• Egg lecithin has residual egg yolk, <5 mcg egg white
• Most Allergy due to propofol itself (isopropyl groups)
https://www.aaaai.org/conditions-and-treatments/library/allergy-library/soy-egg-anesthesia

58. Propofol and Egg/Soy Allergy
• Soy/egg allergy: allergic to proteins in the foods (not to the oils or fats)
• Soybean oil and egg lecithin may contain trace amounts of residual protein
• AAAAI: Patients with soy or egg allergy can receive propofol without any special
precautions
• Retrospective stusy in 32 egg allergic children (by Murphy A ,et al)2
:Only 1 child with Hx of egg anaphylaxis had erythema, urticaria after 2nd dose of
propofol 15 min  Author recommend avoidance of propofol in egg anaphylactic pt.
• Peanuts and soybeans: legume family
• Majority of peanut-allergic patients are not clinically allergic to soy
• Even if they were  not expected to react to soybean oil
1.https://www.aaaai.org/conditions-and-treatments/library/allergy-library/soy-egg-anesthesia
2.Murphy A, et al. Allergic reactions to propofol in egg-allergic children, Anesth Analg 2011 Jul;113(1):140-4.

59. Opioids
• Non-IgE > IgE mediated
• Direct MC activation
• Placebo controlled challenge
• IgE-mediated: pholcodine sensitization
• Cross react to morphine, NMBAs (QAI epitope)
• Fentanyl: lack of mast cell-/basophil-stimulating properties
• good option in cutaneous reactions with other narcotics
• IgE-mediated: ST is helpful
Johansson SG, Florvaag E, Oman H, et al. National pholcodine consumption and
prevalence of IgE-sensitization: a multicentre study. Allergy 2010; 65:498.

60. RCM
• 34.6-49.5% developed it on their first RCM exposure1,2
• Skin test positive rate was 64.7 %1 (multicenter study in Europe: up to
50%)
• In those with shock, it was 81.8 %1
• Direct MC activation or IgE-mediated
• Mx: Premed + Change to nonionic,iso-osmolar agents (practice
parameter 2010)
• 50 mg prednisolone 13,7,1 hour before and 50 mg diphenhydramine 1 hour
before
1. Kim MH, et al. Anaphylaxis to iodinated contrast media: clinical characteristics related with development of anaphylactic shock. PLoS One. 2014;9:e100154.
2. Morales-Cabeza C, et al. Immediate reactions to iodinated contrast media. Annals of allergy, asthma & immunology : official publication of the American College of Allergy,
Asthma, & Immunology.2017;119(6):553-7

61. Fluorescein and Dye
• IV fluorescein: the most common presentation was hypotension,
typically within 3 minutes of infusion
• Supravital dye: isosulfan blue, methylene blue
• Identify sentinel LN
• Risk: patent blue V ≈ Isosulfan blue > methylene blue
• IgE-mediated
• Most reaction are 1st exposure
• Cross-react: cosmetics, paints, inks, detergents, antifreeze, laxatives, cold remedies
• Potential cross-react between each dye (data from positiveST)
• Alternative: radioactive colloid
1.Ha SO, et al. Anaphylaxis caused by intravenous fluorescein: clinical characteristics and review of literature. Intern
Emerg Med. 2014;9:325–30.
2. Mertes PM, Malinovsky JM, Mouton-Faivre C, et al. Anaphylaxis to dyes during the perioperative period: Reports of 14
clinical cases. J Allergy Clin Immunol. 2008;122:348–352.

62. Blue Hive
(IgE-Mediated Reaction to Isosulfan Blue)
Martin J. O'Sullivan, F.R.C.S.I., and Monica Morrow, M.D.
IMAGES IN CLINICAL MEDICINE: Blue Hives, N Engl J Med 2008; 358:e6
Timothy S. Sadiq, et al. Blue Urticaria; A Previously Unreported Adverse
Event Associated With Isosulfan Blue, Arch Surg. 2001;136(12):1433-1435

63. Protamine
• Incidence 0.19-0.69%
• IgE, IgG, complement mediated
• Prepared from sperm of salmon or related spp.
• Risk: NPH insulin use, fish allergy, vasectomized male
• Case reports of fish allergy and protamine anaphylaxis
• In vitro study by Greenberger PA, et al.: no cross reactivity between
IgE to salmon and protamine
• Prospective study in 6 fish allergic pts.: no reaction to protamine
• Alternatives: Bivalirudin

64. Complement activation-related pseudoallergy: a stress reaction in
blood triggered by nanomedicines andbiologicals. Mol Immunol 2014
Protamine: solubilized in liposomes and lipid based excipients

65. Ethylene Oxide
• Sterile gas, dialysis membrane, angiocatheter
• Heat-intolerable medical equipment
• Haptenate with human albumin  IgE-mediated
• Risk: spina bifida, multiple surgeries
• No FDA approved for SPT reagent of EtO
• EtO-specific IgE, BAT
• Mx:
• Alternatives: stream-, gamma-irradiated, hydrogen peroxide gas plasma-sterilized
devices
• Extensively rinsed equipment(but may ↑microbial colonize)
• PreTx with omalizumab* case report
Bache S, Petersen JT, Garvey LH. Anaphylaxis to ethylene oxide—a rare and
overlooked phenomenon? Acta Anaesthesiol Scand 2011;55:1279-82.

66. Omalizumab in EtO Allergy
• Because EtO-safe Sx is very difficult (unlike latex)
• Case reports
• 2 month preoperative dose (base on BW, total IgE)1
• Single dose 600mg SC plus antihistamine, steroid before Sx 2 hr (emergency
setting)2
1.Listyo A, Hofmeier KS, Bandschapp O, Erb T, Hasler CC, Bircher AJ. Severe anaphylactic shock due to ethylene oxide in a patient
with myelomeningocele: successful exposure prevention and pretreatment with omalizumab. A A Case Rep 2014;2:3-6.
2. Bilò MB, et al., Efficacy of a single dose of omalizumab for the prevention of ethylene oxide intraoperative anaphylaxis, Ann
Allergy Asthma Immunol 2018 Aug;121(2):249-250

67. Other Agents
• < 5%
• NSAIDs: pseudoallergy, direct MC activation > IgE
• IgE-mediated: Ibuprofen, Diclofenac
• Selective COX-2 inhibitors rarely cause anaphylaxis
• ST: not standardized
• DPT: Gold standard
• Local anesthesia and preservatives: extremely rare causative agents
• Mostly caused by accidental IV injection  arrhythmia
• Skin test and DPT (SC challenge 0.5-2 ml)
Mertes P.M., et al. Perioperative anaphylaxis Med Clin N Am 94 (2010) 761–789

68. Skin Test
• 4-8 weeks after reaction, including alternatives
• Performed sooner if repeat anesthesia is necessary
• Positive tests are still meaningful
• Study2 1st : within 4 days of the reaction, 2nd : 4-8 weeks after the
reaction
• 15 had positive results at the 1st testing
• 22 at the 2nd testing
• 12 at both
• 3 at only the first testing
• 10 at only the second testing
1. Violeta Régnier Galvão, Pedro Giavina-Bianchi, Mariana Castells: Perioperative Anaphylaxis, Curr Allergy Asthma Rep (2014) 14:452
2.Lafuente A, Javaloyes G, Berroa F, et al. Early skin testing is effective for diagnosis of hypersensitivity reactions occurring during anesthesia.
Allergy 2013; 68:820.

69. IDT IDT
Mertes P.M., et al. Perioperative anaphylaxis Med Clin N Am 94 (2011)
Povidone Iodine 100 Undiluted 100 1/10

70. Skin Test Concentrations
Brockow K,Garvey LH,Aberer W,Atanaskovic-Markovic M, Barbaud A,Bilò MB,et al. Skin test concentrations for
systemically administered drugs—an ENDA/EAACI drug allergyinterestgrouppositionpaper.Allergy.2013;68:702–12.

71. In Vitro Test
• RAST
• Skin test: more sensitive, reliable
• Best results on QAI, latex, thiopental
• Different performance between commercial available and tests in studies
• Not validated, only few drugs specific IgE are available (e.g. IgE to latex)
• BAT
• Few studies on NMBAs, Beta-lactam
• Specific but not highly sensitive
(complimentary test after inconclusive skin test)

72. DPT
• Limited to
• LA
• Antibiotic
• Latex
• Confirm Dx

73. Repeat Anesthesia After Allergy Evaluation
• 1-4% recurrent perioperative anaphylaxis
• Misdiagnosis or Mast cell disorders
• Identified culprit  avoidance
• Use non cross-reactive alternative agents
• Unidentified culprit  avoid high risk/potential cross reactive agents,
general precaution
Mertes P.M., et al. Perioperative anaphylaxis Med Clin N Am 94 (2010) 761–789

74. Approach to Future Anesthesia
• Well controlled asthma
• BBs, ACEI: avoid if possible esp. unidentified culprit agent/severe
previous reaction
• Slow rate of drug induced MC/Ba activation
• Esp. if use in close temporal proximity to each other
Mertes P.M., et al. Perioperative anaphylaxis Med Clin N Am 94 (2010) 761–789

75. Approach to Future Anesthesia
• Intraoperative antibiotic timing
• If possible, initial dose prior induction of anesthesia (awake patient, not
concomitantly with anesthetic agents)
• Slowly drip
• Baseline tryptase
• Additional precaution for mast cell disorders
Mertes P.M., et al. Perioperative anaphylaxis Med Clin N Am 94 (2010) 761–789

76. Perioperative Bronchospasm in Asthma
• Most important risk factor = uncontrolled asthma
• Severe asthma: ↑perioperative anaphylaxis
• Incidence: 0.17-4.2% of all GA in asthma pt.
• 7% of anesthetic related death in French
• *Control asthma at least 1 wk preoperation
• Monitor spirometry in…
• Poor control symptom
• Limit perception of symptom
• Require lung resection
Gennaro Liccardi, et al., Bronchial asthma, Curr Opin Anesthesiol 2012, 25:30–37

77. Gennaro Liccardi, et al., Bronchial asthma, Curr Opin Anesthesiol 2012, 25:30–37

78. Gennaro Liccardi, et al., Bronchial asthma, Curr Opin Anesthesiol 2012, 25:30–37

79. Gennaro Liccardi, et al., Bronchial asthma, Curr Opin Anesthesiol 2012, 25:30–37

80. Case: Timeline & Anesthetic Chart

81. Case
• Come for skin test at 6 weeks later …

82. SPT: Positive to latex, Neostigmine
IDT: Positive to Pancuronium

83. Additional Test?
What will you manage for further procedure?

84. Take Home Message
• Identified cause: avoid specific and possible cross-reactive agents
• Unidentified cause: general precautions, avoid high risk agents, LA,
nerve block if possible
• Don’t forget antiseptics
• Positive skin test > 1 agents
• DDx: false positive, cross-reactivity, multiple sensitization
• Future use of alternative agents which are negative skin test
Mertes P.M., et al. Perioperative anaphylaxis Med Clin N Am 94 (2010) 761–789

85. Take Home Messages:General Precautions
• Asthma: optimal control
• Beta-blockers: avoid if possible esp. if unidentified culprit drugs
• ACEI: depend on severity of previous reaction
• MC activator: avoid if possible, slow rate esp. if infused in close
proximity to each other
• ATB: loading/initial dose prior to operation (awake pt, not
concomitant with others)
• Avoid latex exposure
• Mast cell disorders: evaluate baseline tryptase

86. Thank you for your attention