Anaphylaxis in Anaesthesia

Transcription

1 Anaphylaxis in Anaesthesia Professeur Paul Michel MERTES Service d'anesthésie-réanimation chirurgicale Hôpitaux Universitaires de Strasbourg Nouvel Hôpital Civil U961 CEEA 2012 Kosice

2

3 Strasbourg - France

4 Risks in medicine compared to other technical fields According to René Amalberti Unsafe Safe systems Super safe systems Blood transfusion Anaesthesia/ASA 1-2 young patient «Surgical» risk Mountain climbing Industry Cardiac surgery ASA 3-4 patient Civil aviation Railway system Road security Nuclear Industry Mortality 10-5 risks 10-6 No system beyond Iatrogenic medical risk

5 DUR. Simone 1st anaesthesia 2sd anaesthesia Succinyl. Thiopental Heart rate/min 200 Succinyl. Thiopental 200 Systolic blood pressure mmhg Cardiac arrest 12 h 9 30 Cardiac arrest 10 h 30 erythema 11 h

6 Revised Classification Johansson SGO, Allergy 2001 Clinical Hypersensitivity Reaction Allergy Other Causes IgE-mediated Other immune mechanisms

7 Definitions according to the World Allergy Organization Anaphylaxis : A severe, life-threatening generalized or systemic hypersensitivity reaction. This might be subclassified as allergic (e.g. mediated by IgE, IgG or immune complexes) or non-allergic. Allergic anaphylaxis mediated by IgE antibodies is referred to as IgE-mediated anaphylaxis Emergency Medicine Australasia (2006) 18,

8 HOW REAL IS THE RISK OF AN ALLERGIC HYPERSENSITIVITY REACTION IN ANESTHESIA? Classification, incidence, clinical aspects (immediate and delayed), morbidity, mortality, substances responsible

9 English and French literature over 25 yrs ( ): 5644 cases of anaphylaxis occurring during anesthesia Muscle relaxants Latex Antibiotics Hypnotics Colloids Opioids Others 3509 cases

10 Immediate Hypersensitivity Reactions Australia : 1/5.000 à 1/ (Anesth Int Care, 1981) France : 1/4.600 (AFAR, 1983) New zealand : 1/1.250 à 1/5.000 (Anaesth, 1985) UK : 1/3.500 (Anaest, 1985)

11 Immediate Hypersensitivity Reactions -IgE mediated Global incidence (all drugs) France : 1 / 10,000-1 / 20,000 (NMBAs 50%) Australia : 1 / 10,000-1 / 20,000 (NMBAs 60%) UK : 1 / 10,000-1 / 20,000 (NMBAs 60%) Norway : 1 / 10,000 (NMBAs 90%) Sweden : 1 / 60,000 (NMBAs 8%) Mortality 3-9%

12 French Society of Anaesthesia Clinical Practice Guidelines 2001 Revised 2011 «Reducing the risk of anaphylaxis during anaesthesia» (French) Ann Fr Anesth Réanim 2011; in press (English) J Invest Allergol Clin Immunol 2011; in press

13 GERAP 40 diagnostic centres

14 Patients 1st January December patients Non IgE-mediated 700 (27,82 %) IgE-mediated 1816 (72,18 %)

15 Patients Female : Men n = 1760 (69,95 %) : n = 756 (30,5 %)

16 Agents involved in anaphylactic reactions during anesthesia (1816 patients, 1851 substances) between January 1, 1997 and December 31, 2004 in France Causal agents Neuromuscular blocking agents (n = 1067, %) Succinylcholine Rocuronium Atracurium Vecuronium Pancuronium Mivacurium Cisatracurium % Number of patients Latex (n = 361, %) Antibiotics (n = 236, %) Hypnotics (n = 43, 2.34 %) Penicillin Cephalosporin Others Propofol Midazolam Pentothal Ketamine

17 Agents involved in anaphylactic reactions during anesthesia (1816 patients, 1851 substances) between January 1, 1997 and December 31, 2004 in France (2) Causal agents % Number of patients Opioids (n = 31, 1.69 %) Morphine Fentanyl Sufentanil Nalbuphine Remifentanil Colloids (n = 63, 3.43 %) Gelatine Hetastarch Albumin Local anesthetics (n = 236, %) Bupivacaine Lidocaine Mepivacaine

18 Agents involved in anaphylactic reactions during anesthesia (1816 patients, 1851 substances) between January 1, 1997 and December 31, 2004 in France (3) Causal agents Other agents (n = 44, 2.40 %) Patent blue Methylene blue Propacetamol Aprotinine Protamin WSAI Papain Nefopam Ethylene oxide Steroids Hyaluronidase Metabisulfate Povidone Contrast media % Number of patients

19 Drugs responsible for HSI-IgE peranesthesic reactions (9 epidemiologic surveys of GERAP) 1989 * 1992 * 1994 * 1996 * 1998 ** * n=821 n=813 n=1030 n=734 n=486 n=518 n=502 n=406 n=602 81,0 70,2 59,2 61,6 69,2 58,2 54,0 49,6 48 0,5 12,5 19,0 16,6 12,1 16,7 22,3 26,4 20,3 Hypnotics 11,0 5,6 8,0 5,1 3,7 3,4 0,8 1,4 0,8 Opioids 3,0 1,7 3,5 2,7 1,4 1,3 2,4 1,4 1,8 Colloids 0,5 4,6 5,0 3,1 2,7 4,0 2,8 4,6 2,3 Antib 2,0 2,6 3,1 8,3 8,0 15,1 14,7 12,2 17,9 Others 2,0 2,8 8,3 2,6 2,9 1,3 3,0 4,4 7,1 NMBAs Latex * AFAR ** BJA 2001 Anesthesiology 2003 JACI 2011 Min anesth 2012

20 Estimated annual incidence of IgEmediated allergic reactions during anesthesia Causal agents Estimated annual number of case Overall 780 [ ] Estimated annual incidence in France (/million) median [5th-95th perc] Male Overall Female [ ] 55.4 [ ] NMBAs 458 [ ] [ ] [ ] [ ] Latex 155 [ ] [ ] 59.1 [ ] 32.6 [ ] 91.0 [ ] Antibiotics 101 [72-131] - Others agents 80 [57-103] -

21 Clinical Features

22 Grade of severity for quantification of anaphylaxis Grade Symptoms I Cutaneous signs : generalized erythema, urticaria, Angioedema. II Measurable but not life-threatening symptoms Cutaneous signs, hypotension, tachycardia Respiratory disturbance : cough, difficulty to inflate III Life-threatening symptoms : collapse, tachycardia or bradycardia, arrhythmias, bronchospasm IV Cardiac and/or respiratory arrest, or death

23 Clinical Features IgE/ non IgE-mediated Reactions Usually within minutes following injection of the suspected drug Similar symptoms In any case : Investigate Outcome Spontaneous recovery (Grade I) Evolution when appropriately treated Usually favorable Tachycardia and edema may persist for several hours Mortality rate : 5 to 6% Japan - 9% UK

24 Frequencies of clinical severity grade of IgE-mediated and non IgE-mediated hypersensitivity reactions between January 1, 1997 and December 31, 2004 in France. HSI non IgE HSI IgE % Grade 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Grade 4

25 Clinical symptoms (January 1, 1997Clinical and December 31, 2004, n=2516) features IgE-mediated (%) Cutaneous symptoms Erythema Urticaria Angioedema Cardiovascular symptoms hypotension cardiovascular collapse cardiac arrest Bronchospasm Non IgE-mediated (%) p < p < p < p < (n = 97) (n = 2) p < p <

26 Position Genupectorale Intervention

27 HSI IgE mediated Before induction Antibiotics : betalactamines ++ Volume expanding fluid: gélatins++ Latex : bronchospasm

28 HSI IgE mediated At induction NMBAs Hypnotics (rarely) Opioids (exceptionnal)

29

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31 HSI IgE mediated During surgery Latex Volume expanding fluids Dysinfectant: chlorhexidine, povidone Iodinated contrast media Dyes : patent blue, methylene blue, fluorescein

32 Urticaire H+10

33 HSI IgE mediated After surgery NSAIDs Morphine

34 MECHANISMS OF SENSITIVITY AND HYPERSENSITIVITY ASSOCIATED WITH ANESTHESIA

35 It is not always allergy!

36 Histamine Release Benzylisoquinolinium > Aminosteroid NMBAs Atracurium Mivacurium But : Rapacuronium : histamine release Cis-atracurium : histamine release

37 A Mechanism for Rapacuronium-induced Bronchospasm M2 Muscarinic Receptor Antagonism Rapacuronium has a higher affinity for M2 muscarinic receptors as compared with M3 muscarinic receptors. Blockade of M2 muscarinic receptors on prejunctional parasympathetic nerves increased release of acetylcholine M3 muscarinic receptor mediated airway smooth muscle constriction Jooste et al. Anesthesiology 2003; 98:906 11

38 Biophysical Journal Volume 92 January

39 SENSITIZATION Ag REACTION Antigen Presenting Cell Ag Mast Cell activation CMH II peptide Fixation on RFcε T IgE IL4 plasmocyte B Mediators Preformed Synthesis Clinical Signs

40 From PM Mertes et al., Physiology of anaphylaxis 2006

41 J Allergy Clin Immunol 2007;120:506-15

42 DIVERSITY OF HYPERSENSITIVITY REACTIONS TO NMBAs

43 NMBAs, allergy and immunological dogma

44 Previous Exposure IgE-mediated reactions after exposure to a drug are generally assumed to be due to the prior sensitization of the allergic subject by the drug But : lack of previous exposure At least 17% in France Up to 75% in Australia

45 Substituted ammonium ions as allergenic determinants in drug allergy. Alcuronium-reactive antibodies were found in five drug-sensitive subjects and most of the antibodies cross-reacted with other muscle relaxants and with a variety of apparently structurally unrelated drugs Structure-activity studies designed to explore the molecular basis of the antibody binding established that quaternary and tertiary ammonium ions were the complementary allergenic sites on the reactive drugs... Sensitivity might be established by prior exposure to substituted ammonium groups on a compound that is otherwise structurally unrelated to the NMBAs. Such compounds are many, widely distributed and often contacted in everyday activities. Baldo, B A. Fisher, M M., Nature. 306(5940):262-4, 1983 Nov

46 IgE-cross linking Multivalent drug -- carrier complexes are said to be a requirement for cross-linking of mast cell-bound IgE. NMBAs did not bind to plasma proteins The substituted ammonium ions of NMBAs: are responsible for neuromuscular blocking and allergenic properties are at a distance from 1 to 1.45 nm Divalency of NMBAs could explain allergeninduced mediator release in a sensitized subject even in the absence of protein binding.

47 Are there differences between NMBAs?

48 Pancuronium OAc CH3 N+ C +N A AcO B D 2Br CH3O CH3O Vecuronium O OCH3 OCH3 CH3O N OCH3 +N CH3 CH3O - CH3O Rocuronium OAc CH2 CH3 O O CH3 CH2CH2CO(CH2)3OCCH2CH2 N+ CH2 O N Cis-Atracurium HO O CH2 - H H3CO H3CO CH2 OCH3 +N O CH3 Suxamethonium H3C H3C O + O H3C N+ OCH3 OCH3 OCH3 H3CO H3C O H3CO CH O + NCH2CH2OCCH2CH2COCH2CH2N OCH3 OCH3 OCH3 OCH3 N+ Br OCH3 OCH3 OCH3 CH3O N+ H H Atracurium OAc AcO CH3 O OCH3 CH3 N+ H (CH ) OCCH CH C = CCH CH CO(CH ) H CH2 CH2 H +N CH3 H Br Mivacurium CH3O CH3 CH3 CH3

49 NMBA anaphylaxis and market share over 6 years in France ( ) Anaphylaxis (912 cases) Rocu Succi Atrac Vecu Pancu Miva Cisatrac (301) (249) (193) (104) (37) (20) (8) 33 % Market share (17 million patients) 9%

50 Incidence of anaphylaxis according to the NMBA over 6 years in France ( ) Rocuronium 1: Succinylcholine 1 : 5,100 5,500 Vecuronium Pancuronium 1: 1: 13,000 14,700 Mivacurium Atracurium Cisatracurium 1 : 38,000 1 : 52,800 1 : 149,000

51 Anaphylactic risk in relaxant-sensitive population France* (GERAP) Australia (Fisher) High risk Intermediate Suxa Rocur Vecu Pancur Atracur Cis-atrac Rocur Atracur Cis-atrac Vecur Pancur Suxa * 5th, 6th and 7th surveys BJA 2001 Low risk

52 How can we explain these differences between drugs?

53 Results from skin-test investigations Patients may react with : All NMBAs a single overwhelmingly dominant allergenic determinant structure quaternary ammonium determinant (alcuronium) A single NMBAs or Several NMBAS with or without class effect neighboring groups of different structures on the different NMBAs, in addition to the substituted ammonium groups, form part of the allergenic determinant structure

54 Succinylcholine Terminal Trimethylammonium (not included in a cycle) Highly flexible molecule (no cycle)vs rigid nondepolarizing NMBAs 8 carbons and 2 oxygens: maximum chain length 11.6 Å In vitro assays: < 4 Å no histamine release optimal length >6 Å

55 Alcuronium - Rocuronium The propenylammonium moieties of alcuronium are chemically unrelated to the substituted ammonium or amine groups on the other NMBAs but it also occurs on rocuronium. As for alcuronium in the late 1970s, rocuronium has been claimed to be at high risk for anaphylaxis. If this is true, propenylammonium moieties present in both NMBAs may account for the apparent increased allergenicity.

56 What can be the antigenic source of NMBA-reactive IgE antibodies?

57 Environmental agents Compounds containing tertiary amine or quaternary ammonium groups occur widely in drugs, cosmetics, disinfectants, industrial materials, foods Only a small number of cases of anaphylaxis apparently provoked by environmental agents have been reported The theory of environmental sensitization remains unproven and difficult to establish.

58 The Pholcodine Hypothesis

59 The Pholcodine hypothesis Erik Florvaag MD PhD Haukeland University Hospital & University of Bergen, Bergen, Norway

60 Methyl-substituted tertiary amine group

61 The Pholcodine Hypothesis Anaphylactic reactions to NMBAs are six times more common in Norway than in Sweden IgE antibodies to pholcodine, used in cough suppressants in Norway but not in Sweden, were found in six per cent of blood donors from Norway but in none of the Swedish donors. Positive reactions to succinylcholine in 0.4 per cent and 3.7 per cent, of Norwegian blood donors and allergic subjects respectively. No serum from Sweden was positive. Florvaag et al, Allergy 2005: 60:

62

63 The Pholcodine Hypothesis Pholcodine exposure raises serum IgE in patients with previous anaphylaxis to neuromuscular blocking agent It has to be proved that pholcodine (or morphine and codeine) can act as sensitizing antigen The mechanism underlying the immunological boostering effect exhibited by pholcodine remains unclear. Harboe et al, Allergy 2007: 62:

64 Morphine and derivatives Morphine Morpholinylethyl group Pholcodine Codeine Pholcodine [3-(2-morpholinylethyl)morphine] differs in structure from morphine and codeine only at position 3 and, as with these two analogues, the methyl-substituted tertiary amine group on pholcodine is freely accessible

65 National pholcodine consumption and prevalence of IgE-sensitization: a multicentre study S. G. O. Johansson, E. Florvaag, H. man, L. K. Poulsen, P. M. Mertes, N. J. Harper, L. H. Garvey, R. Gerth van Wijk, T. Metso, A. Irgens,T. Dybendal, J. Halsey, A. B. Guttormsen, S. L. Seneviratne Allergy 2009 DOI: /j x

66 Allergy 2009 DOI: /j x

67 Allergy 2009 DOI: /j x

68 Allergy 2009 DOI: /j x

69 Pholcodine (Tussokon ) in Sweden from Reported PHO anaphylaxis consumpt (per mill) (kg/mill) (1.6) PHO % pos MOR % pos SUX % pos nt nt nt (13.5) (2.9) 77 (9.2) (1.3) 51 (6.1) (0.5) 9.5 (1.1) (0.6) 0 69 Johansson SG, Oman H, Nopp A, Florvaag E. Pholcodine caused anaphylaxis in Sweden 30 years ago. Allergy May;64(5):820-1.

70 3 years follow-up study after withdrawal of pholcodine (Tuxi ) IgE-sensitization to the cough suppressant pholcodine and the effects of its withdrawal from the Norwegian market. Florvaag E, Johansson SGO, Irgens Å, de Pater GH. Allergy 2011; 66:

71 Prevalences of IgE sensitisation ( 0.35 kua/l) to PHO, MOR and SUX in 300 allergics after withdrawal Before Years after Tuxi withdrawal Trend P-value P-value LbL PHO MOR SUX 33 (11.0) 15 (5.0) 17 (5.7) 8 (2.7) <0.001 <0.001* 30 (10.0) nt 8 (2.7) 4 (1.3) <0.001 <0.001* 11 (3.7) 2 (0.7) 1 (0.3) 1 (0.3) <0.001*

72 NARA reports on anaphylactic reactions during anaesthesia

73 O N O at present.. O H NCH3 Pholcodine a small molecule key that turns on polyclonal IgE synthesis HO Pholcodine by downregulating inhibitory mechanisms? leads to IgE sensitization in a considerable proportion of exposed individuals has a striking effect on IgE synthesis in sensitized individuals can explain the differences in prevalence of IgEsensitization and frequencies of reported NMBA anaphylaxis between Norway and Sweden and possibly also for other countries

74 DIAGNOSTIC PROCEDURES IN AN IMMEDIATE HYPERSENSITIVITY REACTION

75 Implications for clinical testing Providing advice for safe future anesthesia. Identification of the drug/agent responsible for the reaction and any cross-sensitivity with other drugs. Criteria for diagnosing anaphylaxis associated with anesthesia have been issued by the French Society of Anesthesia, and others.

76 Investigations for diagnosing IgE anaphylaxis 15 min to 1 h after reaction Plasma histamine Serum tryptase Specific IgEs Skin tests (prick and IDT) * *NMBA, thiopental, latex 6 weeks later on French Society of Anaesthesia Guidelines2001

77 Timing of sampling for histamine, tryptase and specific IgE against QA ion + : recommanded ; (+) : if not collected at the time of the reaction

78 Skin testing for diagnosing an IgE anaphylaxis skin tests must include all anesthetics listed in the anaesthesia record, as well as latex and other agents administered the criteria for positivity of an IDT are the appearance after 15 to 20 min of a wheal with a diameter of at least 8 mm and which is also at least the double diameter of the bleb produced by the injection.. In case of allergic reaction to an NMBA, investigate all NMBAs French Society of Anaesthesia Guidelines

79 Dermographism

80

81 Concentrations of anaesthetic agents normally non-reactive Available agents maximal concentration and/or dilution atracurium cis-atracurium mivacurium pancuronium rocuronium suxamethonium vecuronium Prick-tests Intradermal tests mg.ml-1 Dilution mg.ml-1 Dilution µg.ml /10 Undiluted 1/10 Undiluted Undiluted 1/5 Undiluted 1 2 0, /1000 1/100 1/1000 1/10 1/200 1/500 1/

82 Concentrations of anaesthetic agents normally non-reactive Available agents maximal concentration and/or dilution Prick-tests Intradermal tests mg.ml-1 Dilution mg.ml-1 Dilution µg.ml-1 etomidate 2 Undiluted 2 1/ midazolam propofol thiopental Undiluted Undiluted Undiluted /10 1/10 1/ ketamine 100 1/ / alfentanil fentanyl morphine remifentanil sufentanil Undiluted Undiluted 1/10 Undiluted Undiluted /10 1/10 1/1000 1/10 1/ bupivacain lidocain mepivacain ropivacain Undiluted Undiluted Undiluted Undiluted /10 1/10 1/10 1/

83 Concentrations of antiseptic and dyes normally nonreactive in practice of skin tests Available agents maximal concentrations or dilutions chlorhexidin povidone iodine patent blue methylene blue Prick tests mg.ml-1 Dilution mg.ml-1 Intradermal tests Dilution µ.ml Undilute d 0,5 1/ Undilute d 10 1/ Undilute d 25 1/ Undilute d 10 1/

84 Ebo D et al., Allergy 2006: 61:

85 Flow Cytometry -Technical Issues Whole blood / isolated basophils Pre-activation with IL-3 Allergen selection Dose-response experiments Positive and negative control stimulation (anti-ige antibody, anti-fcεri Non-responders (5 10%)

86 Flow Cytometry -Technical Issues Basophil characterization Anti-IgE Anti-CD123+/HLA DR- Activation marker Anti-CD63 (lysosyme-associated membrane protein) Anti-CD203 (neural cell surface differentiation antigen) cut-offs value : 4%, 10%

87 Flow cytometry Latex : se 80-93%, sp % Beta-lactam antibiotics : se 50%, sp 94% NMBAs : se 54-79%, sp % diagnosis/cross-sensitisation investigation Ongoing research protocol (J Sainte-Laudy and ENDA) For review see Ebo et al Allergy 2006

88 FACTORS FAVORING A HYPERSENSITIVITY REACTION AND THE ROLE OF THE ANESTHETIC ALLERGY WORKUP

89 History of patients with immediate IgE-mediated hypersensitivity reactions between January 1, 1997 and December 31, 2004 in France (n = 2516) Atopy Asthma Drug intolerance Food intolerance p < p < p < p < Neuromuscular blocking agents Latex Antibiotics

90 Patients who do need preanesthesia allergy investigations reaction suggesting allergy during a previous anesthesia spina bifida, multiple surgery in children clinical manifestations of allergy when exposed latex, avocado, banana, chestnut to

91 Patients who do not need preanesthesia allergy investigations Atopic patients (asthma, hay fever ) Patients allergic to drugs not likely to be used during anasthesia Population in general without risk factors

92 TREATMENT OF IMMEDIATE HYPERSENSITIVITY REACTIONS WITH EMPHASIS ON ANAPHYLACTIC SHOCK OCCURRING DURING ANESTHESIA

93 TREATMENT OF ANAPHYLACTIC SHOCK: WHERE IS THE EVIDENCE? Dünser et al. Anesth Analg.2008; 107:

94 Primary Treatment General measures Inform the surgeon Request immediate assistance Cease all drugs, colloids, blood products (and latex if suspected) Maintain airway with 100%oxygen Elevated the legs, if practical

95 Primary Treatment Epinephrine Adults Titrate dose according symptoms severity Grade 2: 10 to 20 µg and clinical response Grade 3: 100 to 200 µg Grade 4: 1mg i.v. infusion starting dose: 0,050,1 µg/kg/min Repeat doses every 1 to 2 min as necessary If large doses are needed, use i.v. infusion Children Grade 2 to 3 : 1 to 5 µg/kg Grade 4 :10 µg/kg Fluid Therapy Nacl 9mg/L or colloids according to clinical response Crystalloid : ml/kg over 20 min, more may be needed Colloid: 10 ml/kg over 20 min,

96 Primary Treatment Anaphylaxis resistant to Epinephrine Glucagon (failure of large doses of epinephrine in patients on βblockers) initial dose 1-5 mg, followed by mg/h infusion Norepinephrine Initial dose mg/kg/min Vasopressin Increments of 2 10 IU i.v. until response

97 Secondary Treatment Bronchospasm β2-agonist may be used, but is not first-line inhaled β2-agonists (salbutamol or treatment. IV administration may be albuterol) considered but following hemodynamic iv : 5-25 µg/min recovery Antihistamines H1 antagonist: diphenhydramine 0,5-1 mg.kg-1 IV) H2 antagonist: ranitidine 50 mg IV Corticosteroids Adults: Hydrocortisone 250 mg i.v. or Methylprednisolone 80 mg i.v. Children: Hydrocortisone mg i.v. or Methylprednisolone 2 mg/kg i.v. Further care Patient may relapse, admit to ICU in grade 3 or 4 reactions

98 Anaphylactic shock: a form of distributive shock without inhibition of cellular respiration P Dewachter, PM Mertes et al., Anesthesiology 2005

99 P Dewachter, PM Mertes et al., Anesthesiology 2005

100 Brain Perfusion Davidson J, et al Shock 2012

101 Dewachter Anetshesiology 2010

102 Dewachter Anetshesiology 2010

103 Brain Perfusion Adrenaline or vasopressine? Feng Zeng, submitted

104 Volume Expansion Tajima et al, submitted

105 Feng Zeng, Crit care med, in press Adrenaline / BM * 75 6 DSCa (ml.min-1) PAM (mmhg) 100 * * * A Temps (minutes) 1 2,5 5 7, , , Temps (minutes) * 50 * cptio2 (mmhg) DSC (PU) A 0 B 0 # # # # # # # # # # # # # # # # # 20 # # # # # # # # # # # # # # # # # # # # # # # 0 1 2,5 5 7, , , Temps (minutes) 40 0 B 1 2,5 5 7, , , Temps (minutes)

106 B Temps (minutes) Expression de Caspase 3 et HIF Cortex Cérébral 250 * M -B AD B M 0 Groupes Temps(minutes) AD O N A 0-10 C Glutamate interstitiel cérébral ( µm) 0.4 DO Glucose interstitiel Cérébral (mm)

107 Rocuronium / Sugammadex Two-dimensional structure of sugammadex, 6-perdeoxy-6-per(2carboxyethyl)thio-γ-cyclodextrin sodium salt showing the thio(2carboxyethyl) sodium group linked at position 6 of each of the eight glucopyranose units.

108 Sugammadex and rocuronium-induced anaphylaxis (Br J Anaesth 2011 Jun;106(6):911-2)

109 Sugammadex in the management of rocuronium-induced anaphylaxis 33 ans, laparoscopie, rocuronium 0,39 mg/kg, adrénaline 4 mg, m+19 sugammadex 6,5 mg/kg, puis adrénaline 0,65 et metaraminol 1 mg McDonnell et al, BJA 106 (2): (2011) 66 ans, cimentoplastie, rocuronium 0,6 mg/kg, grade III, adrénaline 0,2 mg, PA remonte à 75 mmhg, sugammadex 4 mg/kg reversion du bloc, PA 100 mmhg. Motamed et al, JACP ans, cholecystectomie, 78 kg, rocuronium 50mg, grade III, adrénaline 0,17 mcg/kg/min, transfert en ICU. Après 1 h, sugammadex 400mg, réduction des doses d adrénaline de moitié. Funnel et al, BJA, doi: /bja/aer ans, hernie ombilicale, 112 kg, rocuronium 0,45 mg/kg, grade III, adrénaline 0,5 mg en 15 min, 18 min : adrénaline 0,2 mg et sugammadex 2000 mg (18 mg/kg), amélioration, SE adrénaline 0,5 mg/h sevrée en 60 min. Raft et al, AFAR 31 (2012) ans, mastectomie, 45 kg, Rocuronium 20 mg, grade II, pas adrénaline,, 30 min : sugammadex 200mg, regression erytheme, Kawano et al., Journal of Clinical Anesthesia (2012) 24, 62 64

110 Sugammadex and rocuronium-induced anaphylaxis Anaphylaxis grade III Boluses of epinephrine and steroids / 18 min after induction the patient suddenly and dramatically improved. Arterial pressure and the heart rate normalized airway pressures decreased rapidly. patient was extubated after a further 15 min of normal ventilation. Skin tests + rocuronium, cross-reactivity with steroid and benzyliso Wordsworth et al doi: /bja/aer138

111 Rocuronium-induced anaphylaxis is probably not mitigated by sugammadex: evidence from an in vitro experiment Leysen et al, Anaesthesia, 2011, 66, pages

112 The role of sugammadex in the development and modification of an allergic response to rocuronium: evidence from a cutaneous model Clarck et al, Anaesthesia 2012, 67,

113 Allergie aux cyclodextrines Allergy to low dose sugammadex. Homme 17 ans, grade II, prick +; Menéndez-Ozcoidi Anaesthesia Mar;66(3): Three cases of suspected sugammadexinduced hypersensitivity reactions. Grade I prick +, Grade III prick +, Grade II no test. Godai et al, Br J Anaesth Aug;109(2):216-8

114 Conclusion IgE-mediated reactions: Rare event Clinical diagnosis Emergency treatment Immediate and delayed investigation Vigilance is essential, and anaesthesiologists should be prepared to identify and treat without delay

115 Conclusion NMBAs are the leading incriminated drugs, followed by latex and antibiotics Differences may exist between NMBAs, Crossreactivity must be investigated Differences may exist between countries for NMBAs Cooperation between anesthesiologists and allergologists is mandatory

116 Conclusion Tryptase and Histamine measurements will help you in mechanism identification Skin tests and Immunoassays - help you in causal agent identification - are not screening tests No possible prevention investigate unexplained reactions

117 Angers : C. Cottineau, M. Drouet. Besançon : M. Neidhardt, P. Girardin, M. Vigan. Bordeaux - Pellegrin Tripode : S. Guez. Brest : J.C. Rakatoseheno. Caen : D. Laroche, M.C. Vergnault. Châlons-sur-Saône : Ph. Scherer. Colmar : O. TheissenLaval. Dieppe : B. Deschamps. Dijon : E. Collet, N. Louvier. Dreux : J.B. Duffin. Epinal : F. Jacson. Grasse : P. Dugué. Grenoble : C. Jacquot, P. Zambelli, D. Coperan. Lille catho : Ch. Castelain-Hacquet. Lille CHU : A. Facon. Limoges : I. Orsel. Lorient : F. Le Pabic. Lyon : Y. Benoît, J. Motin, L. Guilloux. Marseille : J. Birnbaum, D. Vervloet. Montpellier : M.C. Bonnet, T. Ryckwaert. Nancy : M.C. Laxenaire, C. Mouton, D.A. Moneret-Vautrin, S. Widmer, J.L. Guéant, I. Gastin. Nantes : F. Wessel. Nice : G. Occelli, J. Amédéo. Nîmes : M. Joncourt. Paris-Pitié : A.M. Korinek. ParisNecker : D. Brunet-Langot, J. Labbez. Paris-Créteil : M. Bellanger. Paris-Tenon : F. Leynadier. Paris (privé) : C. Sauvan. Poitiers : K. Breuil. Reims : A. Gallet, F. Lavaud,JM. Malinovsky. Remiremont : Dr Beaudouin. Rennes : M.M. Lucas, Y. Delaval. Saint-Etienne : C. Dzviga. Saint-Nazaire : Dr Mallet. Strasbourg : J. Valfrey. Tarbes : J. Gayraud. Toulouse-Purpan : D. Giamarchi, M. Migueres, H. Perelroizen. Toulouse-Rangueil : A. Didier. Tours : Ph. Carré.

118 Thank You For Your Attention