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Miorilassanti e reazioni anafilattiche

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muscle relaxants ,anaphylactic shock,

muscle relaxants ,anaphylactic shock,

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  • 1. Miorilassanti e reazioni anafilattiche Claudio Melloni Libero professionista Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 2. Il caso Clinico :BGM • trauma stradale: GMB : • Motocicletta contro auto: – frattura bifocale dell’omero sinistro – – – – Frattura della scafoide mano sn frattura falange intermedia II dito sn Frattura dell’apofisi stiloidea ulna destra. Ferita ginocchio dx. – Fratture costali multiple a sn con peumotorace – Contusione epatica di notevole diametro(circa 10 cm all’inizio) con raccolta di sangue nello spazio del Morrison • • Lesione surrenalica dx (TAC dell’11/7)?
  • 3. 4 gg dopo … • Ore 8 induzione dell'anestesia : propofol,150 mg, atracurium 40 mg, fentanyl lOO microg • …. Dopo l'intubazione il paziente viene connesso al respiratore automatico e immediatamente si rileva crollo della saturazione, non rilevazione della C02 e perdita dei polsi periferici (sempre presenti i carotidei e il tracciato Ecgrafico) • miosi • rottura della cuffia del tubo-sostituzione del tubo: • comparsa di broncospasmo. • La frequenza cardiaca è balzata a da 100a 160 al minuto- La PA arteriosa' da 120/70 alle ore 8 a imprendibile alle ore 8,10, a 90/50 alle ore 8 30 quando vi e la ricomparsa dei polsi periferici con inizio di infusione della noradrenalina,bentelan,voluven . • 8.10-8.30? …
  • 4. Diagnosi differenziale Chacko T, Ledford D. Peri-anesthetic anaphylaxis. Immunol Allergy Clin N Am 2007; 27:213–230 • asthma exacerbation, • • • • • • • • arrhythmia, hemorrhage, Angioedema Mastocytosis acute myocardial infarction, drug overdose pericardial tamponade pulmonary edema, • pulmonary embolus • • • • • • • Sepsis tension pneumothorax vasovagal reaction venous air embolus Laryngospasm blood transfusion reaction malignant hyperthermia .
  • 5. Scheda originale I anestesia:14/7
  • 6. II anestesia:VI g.dall’incidente e 2 gg dopo la I anestesia • • • • • • Inizio anestesia ore 8.10. Induzione con propofol, nimbex, morfina e fentanest. Il paziente viene reintubato e broncoaspirato con sondino angolato. . Bentelan 1 fi. Mantenimento dell'anestesia con sevorane. La FC da 150 cala durante l'intervento a circa 110/100 al minuto. La PA va da 100/60 a 140/80 stabilizzandosi intorno a 120/70. Fine anestesia ore 11.50. Intervento chirurgico.: inizio 08.30, fine 11.45. Osteosintesi a cielo aperto di frattura dell'omero con fissazione interna. Frattura bifocale di omero sinistro. Via di accesso bicipitale esterna ed accesso al focolaio di frattura omerale distale. Dopo riduzione cruenta di tale lesione, sotto controllo amplioscopico si esegue osteosintesi endomidollare con chiodo omerale bloccato ad introduzione anterograda e montaggio statico (mod. T2 Stryker). Lavaggi multipli,e h12 Ritoma dalla sala operatoria, viene connesso al Respiratore in PSV con 20 cm H20 di SP e 30 di Fi02. mantenuto sedato con Diprivan 2 10 mi/ora e morfina vel 2. Si inizia infusione di NTP + 1500 mi di liquidi fino alle 24. Viene mantenuto il drenaggio toracico. h18 Paziente in PSV con 20 cm di H20 di SP. Parametri vitali stabili. Diuresi buona.
  • 7. Scheda orig II anestesia:14/7
  • 8. 15/07/05 • Ore 08 Durante la notte ha riposato con infusione di Diprivan • Paziente sveglio che segue con gli occhi, è abbastanza tranquillo ma non risponde ad ordini elementari. Ha evacuato. Rialzo termico. • Ore 08.30 persiste stato di sopore, alternato a momenti di agitazione psico-motoria. La risposta al dolore è finalistica. • Persiste modica ipertermia. Richiesta consulenza neurologica. Emocromo: Hb 7.0 ed Htc 20 per cui inizia trattamento con Eprex 4000 UVdie e Ferlixit ev. • Ore 12 Esegue eco addome e tac cerebrale.
  • 9. Es.obb.neurol. • ipovigilanza.:paziente risvegliabile con stimoli energici. Non entra in contatto. Non deficit focali. E' necessaria TC cerebrale per escludere la natura lesionale del quadro neurologico (mutismo acinetico). Ritengo tuttavia più probabile la genesi anossica. • • • • • TAC encefalo senza MDC: non alterazioni tomodensitometriche dell'encefalo. Ore 17.30 Situazione neurologica invariata. Persiste stato soporoso e la risposta allo stimolo doloroso è sempre finalistica. Diuresi abbondante. Il controllo ecografìco :riduzione del focolaio contusivo epatico.
  • 10. 16/07/05 • Ore 07.45 Discreto riposo notturno. Non esegue ordini semplici.Buona risposta a stimoli dolorosi. Emodinamica valida. Diuresi abbondante. Febbre. • ……Persiste stato di sopore. La risposta al dolore è debolmente finalistica. Apirettico. Si richiede visita fisiatrica. • Ore 17 Quadro neurologico invariato. Lieve iperpiressia trattata con paracetamolo. • Diuresi abbondante. Parametri cardiocircolatori stabili
  • 11. 18/07/05 • Ore 7.30 Apre gli occhi alla chiamata ma non esegue ordini • semplici. Risposta finalistica agli stimoli dolorosi. Durante la notte è stato a tratti agitato. T 38°. Sa02 96 con 02 2 I/min. Tosse efficace. • Emodinamica buona. Lieve tachicardia. Diuresi abbondante. elettrogenesi cerebrale con reattività del tracciato agli stimoli nocicettivi. • Consulenza neurologica: II paziente appare lievemente responsivo,non ancora in contatto, ed è presente un risparmio motorio destro in presenza di saltuari tremori parossistici che interessano gli arti di destra. Sulla base della evoluzione ritengo indicata una RMN cerebrale per escludere lesioni emisferiche sinistre. • Ore 16 EEG: Sofferenza severa della
  • 12. 23/07/05 • • Ore 8.35 nessuna variazione degna di nota. EON invariato. Crisi di agitazione motoria. Apirettico Ore 10.30 Causa crisi di agitazione motoria subentranti si procede a sedazione con Propofol; esegue EEG e visita neurologica. Lievissimo miglioramento dell'EEG (movimenti finalistici). • EEG: Tracciato diffusamente rallentato, sprovvisto di anomalie focali. • Consulenza neurologica: Fasi di agitazione psicomotoria esplosive.Attualmente modesta sedazione con propofol. Reattivo a stimoli dolorosi. Grimaces facciali e movimenti finalistici di allontanamento.Non chiari segni di lato. Consiglio sedazione solo al bisogno.. • Ore 17 Crisi di agitazione accompagnata da tachicardia e sudorazione ripetute durante il pomeriggio. Si procede a sedazione inizialmente in bolo e successivamente in infusione continua. Si protegge il paziente con imbottitura perimetrale del letto.
  • 13. RMN (altro ospedale):03/08 • Giunti a …i trasferiva il paziente alla RMN mantenendo per il tragitto la ventilazione con AMBU (SaO2 97). Qui giunti, siccome il paziente cominciava ad alleggerirsi si somministravano 50 mg di propofol e 50 mg di Atracurium e lo si portava in sede RMN dove veniva collegato al ventilatore automatico. • • • • • Monitoraggio subito instaurato evidenziava un ET C02 estremamente basso (10 12 cm H20) poi si aveva la comparsa di sudorazione profusa e di marcato pallore. Si continuavano a percepire i polsi carotidei, la sat 02 continuava ad essere di 99 con una frequenza cardiaca di 70/min. Dopo la somministrazione di un 1 mg di atropina e.v. si portava il paziente fuori dalla RMN e si notava ancor più marcata la sudorazione e il pallore con comparsa di anisocoria e successivamente di midriasi bilaterale. 2 fiale di atropina e 3 fiale di adrenalina a dosi refratte, una fiala di dopamina in infusione continua e un flacone di Voluven 6. Dopo la somministrazione di tali tarmaci si aveva la ripresa della circolazione con colorito roseo e marcata riduzione della Sai. 02. Data la gravita del caso il paziente veniva ricoverato in Rianimazione a …
  • 14. A questo punto che cosa pensate? • Siete stati aiutati molto ……………….
  • 15. La reazione anafilattica è difficile da diagnosticare? • Anesthesiology 1992 ,76:495 Anesthesiologist’ Management of simulated critical incidents di Howard A. ,D. O’Dnell • Acta Anaesthesiol. Scand. 2001;45,315 Management of anaphylactic shock evaluated using simulator .J.Jacobson et al • N Z Med J. 2007 ;120(1252):U2492.Treatment of anaphylaxis in adults: results of a survey of doctors at Dunedin Hospital, New Zealand.Thain S, Rubython J.
  • 16. Schwid HA, O'Donnell D Anesthesiologists' Management of Simulated Critical Incidents Anesthesiology 76:495-501, 1992 • Simulazione su programma di computer IBM(1992…..) • 10 specializzandi,10 professori,10 privati • Solo il 40% diagnostica correttamente una reazione anafilattica • • Many errors were observed in the management of these emergency situations, and even anesthesiologists with years of experience made serious errors. Although all experienced anesthesiologists correctly diagnosed simulated esophageal intubation, two residents misinterpreted the lack of end-tidal carbon dioxide. Only 40% of subjects correctly diagnosed simulated anaphylactic reaction; 27% adequately treated simulated myocardial ischemia; and 30% managed a simulated cardiac arrest according to Advanced Cardiac Life Support (ACLS) guidelines. Problems with continuous infusions of vasoactive agents were common. Fixation errors or failure to revise a plan in the presence of inconsistent cues were made by 63% of subjects. The subjects that gathered more information during simulated anaphylaxis made the correct diagnosis more often and made fewer treatment errors. The time since the last ACLS training was found to be an important predictor of correct management of simulated cardiac arrest. Whereas 71% of those trained within the last 6 months managed simulated resuscitations successfully, successful management was decreased to about 30% by those whose ACLS training occurred from 6 months to 2 yr earlier, and no subject who had trained in ACLS longer than 2 yr prior to evaluation successfully followed ACLS guidelines. Based on the retention of ACLS protocols during the management of simulated cardiac arrest, anesthesiologists should review the management of emergency situations such as cardiac arrest, anaphylaxis, myocardial ischemia, and malignant hyperthermia every 6 months to maintain the appropriate skill level.
  • 17. K, Ostergaard D,Laub M,Jensen PF,Johannesen N.Management of anaphlylactic shock evaluated using a full scale anestehsia simulator.Acta Anesthesiol.Scand.2001;45:315-19. • Simulazione su manichino totale di Shock anafilattico a nmb(tachicardia ,ipotensione , pressione vie aeree elevate 1 min dopo la iniez del nmb), • 42 anestesisti(21 medici e 21 nurse anest) • Nessuno fa diagnosi iniziale! • Solo 6/21 considerano la diagnosi dopo suggerimenti ulteriori(apparizione di pomfi e espirazione prolungata) • Di questi 6 ,pochi usano la sequenza completa consigliata per il trattamento dell’anafilassi: – – – – – – – – Head down 100% O2 Close anesthetic gases I v adrenaline Increase volume infusion Beta 2 agonist I.v corticosteroids Iv antihistamines
  • 18. N Z Med J. 2007 ;120(1252):U2492.Treatment of anaphylaxis in adults: results of a survey of doctors at Dunedin Hospital, New Zealand.Thain S, Rubython J. • 91 MD in dept per acuti at Dunedin Public Hosp • Questionario anonimo con 2 casi di anafilassi • 92% somministrano adr;ma solo 20% dosaggio corretto • 43% adr iv,ma 20% > 1 mg!
  • 19. TRiptasi • H 9.30:16.8 (v n.<13 mcg/lt) • H 16.30 :161
  • 20. Rianimazione di …….. • Diagnosi di ammissione: Shock anafilattico in politrauma. • Paziente ricoverato nella Rianimazione di …. ha riportato un importante episodio di ipotensione e desaturazione mentre era in attesa di essere sottoposto ad esame RMN nella nostra Radiologia. Anamnesi patologica remota: Non riferite allergie. Assumeva …… Riferita osteomielite piede sn trattata con antibiotici nel 1994. • • Ore 12.30 Entra in reparto. Viene connesso a RA in SIMV-ASB. • • Ore 15.35 PA 120/66. Fc 135/min. Ridotta Nora e DOPA. T. 37.3° Contattato cardiologo. Eseguito ECO ed ECG. Non segni di sovraccarico atriale da EPA. Contattato allergologo. Richiesti esami. Richiesta visita angiologia per ricerca di TVP. Il paziente tende a svegliarsi, si procede a sedazione con ipnovel. EGA buona. Diuresi al momento ancora contratta. Visita cardiologica: Arresto e.e. di n.d.d. ECG: tachicardia sinusale;turbe aspecifiche della ripolarizzazione ventricolare. Ecocardio: cavità non dilatate, ventricoli ipercinetici, non ostacoli valvolari, non versamento pericardico. Presenta arteria polmonare non calcolabile per l'assenza di rigurgito tricuspidale. Ecodoppler tronchi sopraortici: nulla di patologico. Ecodoppler venoso arti inferiori: non flehitLsupeFficiali, non TVP. 04/08/05 Ore 07.45 Ha sempre ventilato in CPAP/ASB Mantiene sedazione con Midazolam in pompa e noradrenalina. Nel corso della notte eseguito carico idrico extra (2000 cc) per diuresi contratta. Risposta modesta. La PA è stabile intorno ai 140. Presenti crisi tonico-cloniche. Apertura spontanea degli occhi. Difficile valutare il grado di coscienza del paziente. • • • • • •
  • 21. • Ore 9: consulenza allergologica: Paziente con due recenti shock anafilattici dopo somministrazione di miorilassanti (Atracurium?). Utile ovviamente prima di ulteriori anestesie generali screeening allergologico per escludere sensibilizzazione a tali molecole. Nel frattempo Triptase (già eseguita alla quarta ora durante l'episodio anafìlattico) + Phadiatop - RAST tarmaci - PRIST. A disposizione. • RMN: Si evidenziano multiple aree di alterazione della intensità di segnale a livello corticale, bilateralmente e spicularmente distribuite, ed aspetto tumefatto della corticale interessata. (...) Reperti da riferire a lesioni corticali multiple da verosimile ipoperfusione tissutale
  • 22. •Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death .”[
  • 23. Incidenza e gravità delle reazioni anafilattiche • l’esatta incidenza è sicuramente sottostimata…………………………. • Francia:il 3% della mortalità che riguarda totalmente o parzialmente l’anestesia coinvolge l’anafilassi: • IN UK 10% (United Kingdom Medicines Control Agency ) • Australia: Fisher and Moore, in 1981,: 1 / 5000 - 1 / 25,000 ; mortality 3.4%. – Fisher and Baldo 1993: 1 / 10,000-1/20,000 • Thailandia:1/5500 – – – ] Lienhart A, Auroy Y, Pequignot F, Benhamou D, Warszaws ki J, Bovet M, Jougla E: Survey of anesthesia-related mortality in France. Anesthesiology 105. 1087-1097.2006 Harper NJ, Dixon T, Dugue P, Edgar DM, Fay A, Gooi HC, Herriot R, Hopkins P, Hunter JM, Mirakian Fisher MM, Baldo BA. The incidence and clinical features of anaphylactic reactions during anesthesia in Australia. Ann Fr Anesth Reanim 1993;12:97-104. J Med Assoc Thai. 2005 Nov;88 Suppl 7:S128-33..The Thai Anesthesia Incidents Study (THAI Study) of perioperative allergic reactions.Thienthong S, Hintong T, Pulnitiporn A. R, Pumphrey RS, Seneviratne SL, Walls AF, Williams P, Wildsmith JA, Wood P, Nasser AS, Powell RK, Mirakhur R, Soar J: Suspected anaphylactic reactions associated with anaesthesia. Anaesthesia 64. 199-211.2009;
  • 24. Malinovsky JM,Decagny,S.,Wessel,F.,Guilloux L,Mertes PM.Systematic follow up increases incidence of anaphylaxis during adverse reactions in anesthetized patients.Acta Anesthesiol. Scand.2008;52:175-181. • University Hospital di Nantes:70.000 interventi ,3 anni. • Inclusi tutti i casi di ipersensibilità o di reazioni inspiegabili durante anestesia • Ricerca sistematica di istamina e triptasi a 1 e 24 h • Skin tests 6 settimane dopo. • 39 casi: 8 non eseguiti,22 gudicati da ipersensibilità:9 inspiegati • 22/70.000 = 1:3180 anestesie • Latex in 12(55%),NMBA in 6(27%,3 succi,1 ciascuno per cis,atrac,rocu),gelatina in 3,14%),antibiotici 1
  • 25. per stimare la vera incidenza: • Se è 1/5000 occorre un campione di 7.000.000 per una possibilità del 95% di essere entro il 5% del vero valore
  • 26. PERCHE’?
  • 27. Gruppo ammonio quaternario QUATS: I cationi di ammonio quaternario sono carichi sempre indipendentemente dal pH della soluzione I Sali di ammonio quaternario (amine quaternarie) sono Sali di cationi di ammonio quaternari con un anione Sono usati come:disinfettanti,surfattanti,ammorbidenti,anitstatici(shampoo),crème spermicide, paste dentifrice,detergenti,medicinali per la tosse…(folcodina?)
  • 28. Da Wikipedia • Antimicrobici • Composti di ammonio quaternari con lunghe catene alkiliche :benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, cetalkonium chloride, cetylpyridinium chloride, cetrimonium, cetrimide, dofanium chloride, tetraethylammonium bromide, didecyldimethylammonium chloride , domiphen bromide. • Agiscono distruggendo la membrana cellulare e le proteine (funghi, amoeba, virus )Uccidono quasi tutto eccetto : – endospore,, Mycobacterium tuberculosis, non-enveloped viruses, Pseudomonas spp. (. • Non sono molto efficaci in presenza di composti organici (aggiungere fenoli) • Quats disattivati dai saponi,altri detergenti anionici,fibre di cotone.Non raccomandati per acque dure .Livello efficace:200 ppm.;efficaci fino a 212ºF.[ • insieme con sodium hypochlorite, quats sono principalmente usati nell’industri dei servizi alimentair come agenti sanitizzanti
  • 29. Disinfettanti ed antisettici • Benzalconio:Bemonalcol,Cerosteril,Citrosil,Disintil,Disteril,Esoalcoli co,Disinfet,Esosan,EsoformCitromed(+clorexidina)sanitas pronto:addizionato a molti colliri Didecilammonio:Farmasept • • Cetrimide:Farvicet(+clorexidina),panseptil(+clorexidina),sonica Cl(+clorexidina) • Cetilpiridinio:golacetin,neocepacol,neoformitrol,batzeta,boroca ina gola,cetilsan,faringola,golacetin,golafair,neocepacol • :Germozero ALCHILBENZILOLEILAMMONIO ClORUR+/DIIDROSSIDIFENILE/ALCHILISOCHINOLINA BROMURO • Disinfettanti per ambienti;citromedics, sanitas beta 3,esosan casa • Disinfettanti per ferri chir:esoferri,sanisteril neo ferri
  • 30. Sensib crociata studiata da tests allergologici • Moneret-Vautrin DA, Gueant JL, Kamel L, et al. Anaphylaxis to muscle relaxants: cross-sensitivity studied by radioimmunoassays compared to intradermal tests in 34 cases. J Allergy Clin Immunol 1988; 82:745–752. • 60% cross-reactivity rate per test cutanei • 80% per in-vitro testing • Cross-reactivity può variare da paziente a paz. • Riferita 1 reaz in un paz che era risultato negativo al NMB. Fraser BA, Smart JA. Anaphylaxis to cisatracurium following negative skin testing. Anaesth Intensive Care 2005; 33:816–819.
  • 31. Struttura chimica del besilato di cisatracurium(Nimbex) Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
  • 32. atracurium
  • 33. vecuronium
  • 34. rocuronium
  • 35. pancuronium CH3
  • 36. succinilcolina
  • 37. Ipersensibilità IgE mediata da folcodina? • Harboe T, Johansson SG, Florvaag E, Oman H.. • Pholcodine exposure raises serum IgE in patients with previous anaphylaxis to neuromuscular blocking agents. Allergy. 2007 Dec;62(12):1445-50 • Department of Anaesthesia and Intensive Care, Haukeland University Hospital, Bergen, Norway. • Folcodina induce aumento nelle Ige in individui sensibilizzati • • • • 17 pazienti trattati per una settimana con uno sciroppo antitosse contenenente folcodina o guaifenesin. Quelli esposti alla folcodina hanno avuti un drastico incremento agli anticorpi igE anti folcodina(39 volte),morfina(39 volte) e sux(93 volte) No modificazione nel gruppo guaifenesin In conclusione :I livelli plasmatici degli anticorpi IgE associati all’allergia verso I NMBA aumentano considerevolmente nei pazienti sensibilizzati dopo esposizione alla folcodina. • individuals who have suffered anaphylaxis during general anesthesia and are IgE-sensitized to an NMBA respond with a remarkable and statistically highly significant increase in IgE production when exposed to small doses of cough syrup containing pholcodine
  • 38. Florvaag E, Johansson SGO, Oman H, et al. Pholcodine stimulates a dramatic increase of IgE in IgE-sensitized individuals. A pilot study. Allergy 2006;61:49–55. • Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway. • BACKGROUND: A previous study showed a relation between pholcodine (PHO) consumption, prevalence of IgE-sensitization to PHO, morphine (MOR) and suxamethonium (SUX) and anaphylaxis to neuromuscular blocking agents (NMBA). The purpose of this pilot study was to explore the effect on IgE production, in IgE-sensitized and nonsensitized individuals, of exposure to cough syrup and environmental chemicals containing PHO, MOR and SUX related allergenic structures. METHODS: Serum concentrations of IgE and IgE antibodies to PHO, MOR and SUX allergens measured by ImmunoCAP (Pharmacia Diagnostics, Uppsala, Sweden) were followed after intake of cough syrup, or exposure to confectionary and other household chemicals containing various amounts of substances cross-reacting with PHO, MOR and SUX. RESULTS: Cough syrup containing PHO gave, in sensitized individuals, within 1-2 weeks, an increase of IgE of 60-105 times and of IgE antibodies to PHO, MOR and SUX in the order of 30-80 times. The tested confectionary did not have any similar stimulating effect but seemed to counteract the expected decrease of IgE. No effect was seen in nonsensitized individuals. The PHO stimulated IgE showed a nonspecific binding to ImmunoCAP with common allergens and glycine background ImmunoCAP that was up to 10-fold higher than that of monomeric myeloma-IgE at twice the concentration. CONCLUSIONS: It seems as cough syrups containing PHO have a most remarkable IgE boostering effect in persons IgE-sensitized to PHO, MOR and SUX related allergens. Household chemicals containing such allergenic epitopes seem capable of some, minor, stimulation.
  • 39. Acta Anaesthesiol Scand. 2005 ;49(4):437-44. Prevalence of IgE antibodies to morphine. Relation to the high and low incidences of NMBA anaphylaxis in Norway and Sweden, respectively. Florvaag E, Johansson SG, Oman H, Venemalm L, Degerbeck F, Dybendal T, Lundberg M. • • • • Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway. Comment in: Acta Anaesthesiol Scand. 2005 Apr;49(4):431-3. BACKGROUND: Anaphylactic reactions to a neuromuscular blocking agent (NMBA) is more than six times as common in Norway as in Sweden, probably due to differences in preoperative sensitization. The prevalence of IgEsensitization to morphine (MOR) and suxamethonium (SUX) in comparable populations in Bergen, Norway, and Stockholm, Sweden, was studied and related to possible sensitizing agents. METHODS: Three hundred sera of 'allergics' and 500 blood donors in Bergen and Stockholm were tested for IgE antibodies to MOR and SUX using Pharmacia Diagnostics ImmunoCAP(Uppsala, Sweden) assay and the results compared to those of 65 patients from Bergen with documented anaphylaxis to NMBA. In addition, 84 different household chemicals were tested, by IgE antibody inhibition, for SUX and MOR. RESULTS: In Norway 0.4% of blood donors, 3.7% of allergics and 38.5% of anaphylactics were IgE-sensitized to SUX, and 5.0, 10.0 and 66.7%, respectively, to MOR. No serum from Sweden was positive. The majority of those sensitized (69%) were women. Several household chemicals contained SUX and/or MOR activity, but the only difference between Norway and Sweden was cough mixtures containing pholcodine (PHO). IgE antibodies to PHO were present in 6.0% of blood donors from Norway and in no serum from Sweden. Of the anaphylactics, 65-68% were sensitized to MOR or PHO but only 39% to SUX. CONCLUSIONS: IgE-sensitization to SUX, MOR and PHO was detected in Norway but not in Sweden. One possible explanation is the unrestricted use of cough mixtures containing MOR derivatives in Norway
  • 40. Clin Exp Allergy. 2009 Mar;39(3):325-44. On the origin and specificity of antibodies to neuromuscular blocking (muscle relaxant) drugs: an immunochemical perspective. Baldo BA, Fisher MM, Pham NH. • Intensive Care Unit, Royal North Shore Hospital of Sydney, St Leonards, NSW, Australia. babaldo@iinet.net.au • ipotesi alternative…………….. • Following the demonstration 25 years ago that substituted ammonium groups on neuromuscular blocking drugs (NMBDs) are the main allergenic structures recognized by IgE antibodies in the sera of some patients who experience anaphylaxis during anaesthesia, immunoassays for these drugs were quickly applied to supplement skin tests in the diagnostic assessment of suspected adverse reactions to anaesthetic agents. Many subjects who react to an NMBD do so on first exposure and this led to the speculation that the origin of allergic sensitization is an environmental agent(s) or another drug containing an ammonium ion. Direct antibody binding and hapten inhibition studies revealed that morphine, which contains a tertiary amino group, was strongly recognized by IgE in sera from anaphylactic patients and a morphine-solid phase immunoassay was found to be superior to NMBDbased assays for the detection of NMBD-reactive IgE antibodies. Extensive inhibition experiments indicate the likelihood of antibody combining site heterogeneity with recognition at the fine structural level of features additional, and adjacent to, ammonium ions. Further quantitative investigations are needed to identify these neighbouring groups on different NMBDs. Recent work has implicated the morphine analogue pholcodine as the sensitizing agent in Norway where, unlike Sweden, anaphylactic reactions to NMBDs are not uncommon and the medicament is available over-the-counter. This has led to the suggestion that allergenic sensitization to the ammonium group of pholcodine may account for the different incidences of anaphylaxis during anaesthesia in the two countries. This work is subjected to critical review and some alternative speculations on the nature and origin of the sensitizing agent(s) are presented
  • 41. Allergy. 2009 Oct 1. [Epub ahead of print] National pholcodine consumption and prevalence of IgE-sensitization: a multicentre study.Johansson SG, Florvaag E, Oman H, Poulsen LK, Mertes PM, Harper NJ, Garvey LH, Gerth van Wijk R, Metso T, Irgens A, Dybendal T, Halsey J, Seneviratne SL, Guttormsen AB. • Esiste una correlazione positiva fra consumo di folcodina e sensibilizzazione delle IgE alla folcodina e morfina;probabilmente anche a Succi • Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
  • 42. Farmaco ANARCOINA OS GTT 10 ML CODETILINA EUCAL.HE T. AD10SUP CODETILINA EUCAL.HE T. AD10SUP CODETILINA EUCAL.HE T. BB10SUP CODETILINA EUCAL.HE T. BB10SUP CODETILINA EUCAL.HOUDE AD10SUP CODETILINA EUCAL.HOUDE AD10SUP CODETILINA EUCAL.HOUDE BB10SUP CODETILINA EUCAL.HOUDE BB10SUP CODETILINA HOUDE' 20GRAN 5MG CODETILINA HOUDE' 20GRAN 5MG CODETILINA HOUDE' 60GRAN.5MG CODETILINA HOUDE' 60GRAN.5MG SCIROPPO ROBIN 200G Principio attivo etilmorfina canfosulfonato papaverina cloridrato atropina solfato etilmorfina cloridrato eucaliptolo etilmorfina cloridrato eucaliptolo etilmorfina cloridrato eucaliptolo etilmorfina cloridrato eucaliptolo etilmorfina cloridrato eucaliptolo etilmorfina cloridrato eucaliptolo etilmorfina cloridrato eucaliptolo etilmorfina cloridrato eucaliptolo etilmorfina cloridrato terpina idrata etilmorfina cloridrato terpina idrata etilmorfina cloridrato terpina idrata etilmorfina cloridrato terpina idrata etilmorfina cloridrato bromoformio fitoterapici Cl. Ditta 0 IST.CHIM.INTERNAZ. RENDE Srl TEOFARMA Srl TEOFARMA Srl C TEOFARMA Srl C TEOFARMA Srl TEOFARMA Srl TEOFARMA Srl TEOFARMA Srl TEOFARMA Srl 0 SYNTHELABO SpA 0 SYNTHELABO SpA SYNTHELABO SpA SYNTHELABO SpA BOEHRINGER MANNHEIM ITALIA Sp
  • 43. Pholcodine (morpholinylethylmorphine) 7,8-didehydro- 4,5α-epoxy- 17-methyl- 3- [2- (morpholin- 4- yl) ethoxy] morphinan- 6α-ol Codeina 5α,6α)-7,8-didehydro-4,5epoxy-3-methoxy-17methylmorphinan-6-ol
  • 44. Distribuzione % delle reazioni anafilattiche in Francia nel corso dei vari studi pubblicati da Laxenaire e coll. 90 80 Ist IInd IIIrd IV V VI 70 60 50 % 40 30 20 10 0 NMBA Hypnotics Colloids Others
  • 45. Laxenaire MC, Mertes PM, Benabes B, et al. Anaphylaxis during anaesthesia: results of a two-year survey in France. Br J Anaesth 2001; 87:549-58. 8% 3% 2% 2% 4% miorilass latex 69% antibiotici ipnotici colloidi 12% oppioidi altri
  • 46. Reazioni allergiche attribuite ai miorilassanti in %;da Laxenaire MCEpidemiology of anesthetic anaphylactoid reactions. Fourth multicenter survey (July 1994-December 1996)Ann Fr Anesth Reanim. 1999 Aug;18(7):796-809. 30,00 25,00 % 15,00 10,00 69.2% delle 477 reazioni allergiche durante anestesia in Francia Rocu vecu 5,00 0,00 reaz allergiche succi 20,00 cisatracurium atracurium mivacurium pancuronium vecuronium rocuronium succinilcolina
  • 47. Casi di shock anafilattico attribuiti ai curari in Francia tra gennaio 1999 e dicembre 2000 (306) 2,6% 0,6% Quote di mercato Francia 6% 4% 7% 9% 11% succi atrac 22,6% 19% atrac 10% succi 53% 3,3% succinilcolina atracurio vecu vecu 8,5% rocu 43,1% 65% dei casi di anafilassi rocu rocuronio mivacurio vecuronio cisatracurio p
  • 48. Lobera T, Audicana MT, Pozo MD, Blasco A, Fernández E, Cañada P, Gastaminza G, Martinez-Albelda I, González-Mahave I, Muñoz D.Study of hypersensitivity reactions and anaphylaxis during anesthesia in Spain. J Investig Allergol Clin Immunol. 2008;18(5):350-6. • 1998-2002 • Tutte le reazioni anafilattiche in 2 centri allergologici investigate con un protocollo standard(anamnesi,triptasi,tests cutanei,immunoassay specifici) • 48 pazienti • Femm/maschi 3:2 • IgE-mediate :56%. • Antibiotici 12 casi (44%) (10 betalactams, 1 vancomycin, and 1 ciprofloxacin), miorilassanti 10 casi (37%), pyrazoloni 2 casi, latex 2 casi, Echinococcus 1
  • 49. Harboe Torkel,Guttormsen A B, Irgens A,Dybendal T,Florvaag E. Anaphylaxis during Anesthesia in Norway. A 6-Year Single-center Follow-up Study.Anesthesiology 102:897-903, 2005 • standardized allergy follow-up examination of 83 anaphylactic reactions related to general anesthesia performed at one allergy center in Bergen, Norway • 1996–2001 • diagnostic protocol : case history, serum tryptase measurements, specific immunoassays , skin tests.
  • 50. Results Harboe Torkel,Guttormsen A B, Irgens A,Dybendal T,Florvaag E. Anaphylaxis during Anesthesia in Norway. A 6-Year Single-center Follow-up Study.Anesthesiology 102:897-903, 2005 • Immunoglobulin E-mediated anaphylaxis was established in 71.1% of the cases • nmb were by far the most frequent allergen (93.2%). • Sux was the most frequently involved substance, followed by rocuronium and vecuronium. • The few reactions in which other allergies could be detected were mainly linked to latex (3.6%).
  • 51. Rocuronium? • Guttormsen AB. Allergic reactions during anaesthesia: increased attention to the problem in Denmark and Norway. Acta Anaesthesiol Scand 2001; 45:1189-90. – 55 reazioni al rocuronium con 3 decessi: • ”Dear Doctor letter” con raccomandazioni per evitarne l’uso eccetto le intubazioni d’urgenza!! § • http://www.legemiddelverket.no/templates/InterPage____160 57.aspx. Accessed July 13, 2009.
  • 52. Rose, M.; Fisher, M. Rocuronium: high risk for anaphylaxis? Br. J. Anaesth. 2001; 86:678-682 • 24 pazienti con anafilassi al rocuronium:diagnosi con clinica e laboratorio (intradermal, mast cell tryptase and morphine radioimmunoassay) • L’incidenza delle reaz.allergiche al rocu è salita parallelamente alle vendite,con caduta delle reazioni agli altri miorilassanti • Data from intradermal testing suggested that rocuronium is intermediate in its propensity to cause allergy in known relaxant reactors compared with low-risk agents (e.g. pancuronium, vecuronium) and higher-risk agents (e.g. alcuronium, succinylcholine).
  • 53. Rose, M.; Fisher, M. Rocuronium: high risk for anaphylaxis? Br. J. Anaesth. 2001; 86:678-682
  • 54. Rose, M.; Fisher, M. Rocuronium: high risk for anaphylaxis? Br. J. Anaesth. 2001; 86:678-682
  • 55. Dubbi e critica • • • • • Test falsi positivi:concentrazione del reagente? Aum dell’utilizzo Problemi statistici Differenze nel genotipo Biasimo dell’osservatore
  • 56. Risk of allergic reactions caused by NMB’s (ratio) Mertes 2003 Laxenaire 2001 Laxenaire 2000 Laxenaire 1999 succi rocu panc vecu miva atrac Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA) cisatr %
  • 57. Bhananker SM., O'Donnell JT,Salemi J,Bishop MJ.The risk of anaphylactic reactions to rocuronium in the USA is comparable to that of vecuronium:an analysis of FDA reporting on adverse events.Anesthesia Analgesia 2005,101,819-822 • The incidence of the reports containing anaphylaxis terms did not differ between vecuronium and rocuronium in the U.S. but were significantly different for foreign reports (P < 0.001). These data confirm that U.S. anesthesia providers have not observed a significant difference in anaphylactic reactions between the two commonly used intermediate-acting muscle relaxants and suggest that frequency of reports of anaphylaxis may be significantly influenced by the area from which the reports originate.
  • 58. Confronto su citazioni della letteratura????? • Food and Drug Administration Adverse Event Reporting System for 1999 through the first quarter of 2002 for all adverse events for the drugs rocuronium and vecuronium and then searched on the terms considered to represent possible anaphylaxis using proprietary software. We compared the frequency of these terms in data both for rocuronium and vecuronium. We then assessed the occurrence of reports of anaphylaxis-related terms in reports from the U.S. compared with reports originating outside of the U.S
  • 59. Diagnosi: • • • • Caratteristiche della reazione Gravità dei sintomi Temporizzazione;immediato/acuto Il dosaggio per resuscitazione indica la severità della reazione
  • 60. Criteri predittivi? • Tanto + è rapida,tanto più è severa: – Reaz immediata;agenti ev – Reazione > 15 min;agenti cutanei,mucosi(latex,disinfettanti) • I segni cutanei possono essere assenti all’inizio …e presentarsi a normalizzazione della pressione • Bradicardia paradossa:riflesso di Bezold–Jarisch ; – è un rifglesso cardioninibitorio originato dal ventricolo sn e trasmesso da fibre non mieliniche C ;meccanismo adattativo che permette ai ventricoli di riempirsi prima che si contraggano ancora a dispetto di ipovolemia massiva – Deve essere riconosciuto perchè la somministrazione di atropina può portare all’arresto -… – In questa situazione il trattamento razionale è riempimento volemico prima e poi adrenalina
  • 61. Segni e sintomi della reazione anafilattica ai miorilassanti;% Autore e anno Collasso Broncospasmo cardiovsc/arres severo to Segni cutanei Mertens 2003 51/6 40 72 Krombach 2001 66 50 16 Harboe 64/6 78 54 altro Ipossiemia 49
  • 62. Anesthesiology 2003; 99:536–45 Anaphylactic and Anaphylactoid Reactions Occurring during Anesthesia in France in 1999–2000 Paul Michel Mertes, M.D., Ph.D.,* Marie-Claire Laxenaire, M.D.,† François Alla, M.D., Ph.D.,‡ Groupe d’Etudes des Réactions Anaphylactoïdes Peranesthésiques§
  • 63. Anaphylactoid Reactions After Cisatracurium Administration in Six Patients Jens Krombach, MD*, Nicolas Hunzelmann, MD†, Friedrich Ko¨ ster, MD‡, Albrecht Bischoff, MD§, Helmut Hoffmann-Menzel, MD, and Walter Buzello, MD*Anesth Analg 2001;93:1257–9
  • 64. • Anaphylaxis in the operating room • William R. Reisacher • Harboe T, Guttormsen AB, Irgens A, et al. Anaphylaxis during anesthesia in • Norway: a 6-year single-center follow-up study. Anesthesiology 2005; 102: • 897–903.
  • 65. Raccomandazioni: • • • • • • • • Anaesth Intensive Care. 1999 Apr;27(2):190-3. Subsequent general anaesthesia in patients with a history of previous anaphylactoid/anaphylactic reaction to muscle relaxant. Thacker MA, Davis FM. Department of Anaesthesia, Christchurch Hospital, New Zealand. 151 patients with a possible anaphylactoid/anaphylactic reaction to a muscle relaxant investigated over a 20-year period follow-up for any subsequent general anaesthesia was complete in 145 (96%). 122anaesthetics in 72 patients were documented. There were no anaesthetic-related deaths. • No subsequent reactions were seen if muscle relaxants were not used in the subsequent anaesthetic, nor were they in patients with severe reactions if the original intradermal test had been equivocal or negative. • • In the patients with a severe reaction and a positive intradermal test to one or more muscle relaxants, 6/40 later anaesthetics using muscle relaxants were associated with clinical problems, 3 being probable anaphylactic reactions, whilst three were minor. Intradermal testing should be performed prior to surgery in this group of patients for the muscle relaxant(s) planned, or an anaesthetic technique which avoids relaxants should be used. This review should encourage other centres to undertake similar follow-up
  • 66. Sensibilità crociata • Legata al NH4+??? Anafilassi Test al nmba sospetto Test a tutti i nmba Skin prick test + Skin prick test neg Evita!!! Non garantisce Anest senza mioril!!
  • 67. Dobbiamo testare la popolazione per allergia ai miorilassanti? • • • • • Clin Exp Allergy. 1999 Jan;29(1):72-5. Prevalence of muscle relaxant sensitivity in a general population: implications for a preoperative screening. Porri F, Lemiere C, Birnbaum J, Guilloux L, Lanteaume A, Didelot R, Charpin D, Vervloet D. UPRES no. 2050, Hôpital Sainte Marguerite, Université de la Méditerranée, Marseille, France. BACKGROUND: Muscle relaxants (MR) are responsible for 59% of peroperative anaphylactic reactions. A major issue would be to determine whether a systematic preoperative screening in the general population should be recommended. OBJECTIVE: The purpose of the study was to evaluate the prevalence of muscle relaxant sensitivity in a sample of the general population and to assess the role of possible risk factors. METHODS: Two hundred and fifty-eight subjects, aged 20-40 years, visiting a health care centre for a check-up were evaluated. Protocol included a questionnaire (occupation, symptoms of atopy, previous surgery, history of drug allergy), skin-prick tests to four commercial muscle relaxants and measurement of specific IgE against quaternary ammonium ions. Atopy was evaluated by skin-prick tests to common inhalant allergens and by a Phadiatop test. RESULTS: Of the study group, 9.3% had either a positive skin test to one or more muscle relaxant or a presence of specific IgE to quaternary ammonium ions. No risk factor was identified in the studied group. CONCLUSION: Since the rate of MR sensitivity is much higher than the anticipated rate of peroperative reactions due to allergy, a systematic preoperative screening for MR allergy should not be recommended for adults in a general population
  • 68. Clin Exp Allergy. 2000 Aug;30(8):1144-50. Lessons for management of anaphylaxis from a study of fatal reactions.Pumphrey RS. • Immunology Unit, Central Manchester Healthcare NHS Trust Hospitals, St Mary's Hospital, Hathersage Road, Manchester M13 0JH, UK. • Registrp UK 1992-1998 • • • • 124 reazioni fatali 47 in ospedale,31 in S,Op. Incidenza:1/10 milioni! La maggior parte delle reazioni ai farmaci avvengono entro 5 min;30 min per reaz al cibo,15 min per veleni esterni(insetti….) • Cause di morte: – 48 casi:no somministraz di Adr – 60 casi:somministrazione tardiva di adr. – 1 caso di mancata risposta all’adr – 3 casi eccessiva adr per reazione mite! – 28% resuscitati ma deceduti in 3-30 gg per danno cerebrale ipossico
  • 69. Conclusioni: • Alzare la soglia per sospette reazioni anafilattiche in generale e specialmente dopo nmb • Applicazione immediata del protocollo di trattamento anafilassi;no ritardi ! • Dosaggi seriati istamina/triptasi • Prick test e intradermal tests dopo consulto allergologico secondo le tabelle della letteratura
  • 70. Letture consigliate :1
  • 71. Letture consigliate:2 • Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson , Jr , JrNF, Bock SA, Branum A, Brown SG, Camargo , Jr , JrCA, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor , Jr , JrAD, Hepner DL, Lewis LM, Lieberman PL, Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW: Second symposium on the definition and management of anaphylaxis: Summary Report-Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 117. 391-397.2006. • overall incidence of perioperative anaphylaxis is estimated at 1 in 10,000–20,000 anesthetic procedures, whereas it is estimated at 1 in 6,500 administrations of neuromuscular blocking agents (NMBAs).
  • 72. Letture consigliate :3
  • 73. Letture consigliate:4 • Hepner,DL,Castells,MC.Anaphylaxis during the perioperative period.Anesthesia Analgesia 2003;97:1381-95.
  • 74. Letture consigliate:5 • Dewachter P, Mouton-Faivre C: What investigation after an anaphylactic reaction during anaesthesia?. Curr Opin Anaesthesiol 21. 363-368.2008
  • 75. British Journal of Anaesthesia 95 (4): 468–71 (2005) Allergic reactions in anaesthesia: are suspected causes confirmed on subsequent testing? M. Krøigaard, L. H. Garvey, T. Menne , B. Husum • …Correctly identifying the causative substance in a suspected allergic reaction during anaesthesia is obviously very difficult, as 73% of the suggestions made were not confirmed on subsequent testing at the DAAC(Danish Anaesthesia Allergy Centre),, and only 5/ 67 suggestions were completely correct… • Corrispondenza completa fra sospetto e tests nel 7% solamente!
  • 76. Come possiamo migliorare ? • Identificare pazienti a rischio;quelli che hanno sofferto reazioni severe? • Follow up standardizzato per i paz. che hanno sofferto reazioni severe • Educazione:pazienti,parenti,infermieri,medici,anestesis ti… • Esercitazioni intraospedaliere…sala op…:simulazione. • Focalizzare: – Riconoscimento – trattamento(dosaggi adrenalina) – prevenzione(follow up)
  • 77. FINE
  • 78. • • • • • Br J Anaesth. 2005 Oct;95(4):468-71. Epub 2005 Aug 12. Allergic reactions in anaesthesia: are suspected causes confirmed on subsequent testing? Krøigaard M, Garvey LH, Menné T, Husum B. Danish Anaesthesia Allergy Centre, Department of Anaesthesia, Centre of Head and Orthopaedics, Rigshospitalet, Copenhagen University Hospital, Gentofte University Hospital, Copenhagen. daac@rh.dk BACKGROUND: The aim of this retrospective survey of possible allergic reactions during anaesthesia was to investigate whether the cause suspected by anaesthetists involved corresponded with the cause found on subsequent investigation in the Danish Anaesthesia Allergy Centre (DAAC). METHODS: Case notes and anaesthetic charts from 111 reactions in 107 patients investigated in the DAAC were scrutinized for either suspicions of or warnings against specific substances stated to be the cause of the supposed allergic reaction. RESULTS: In 67 cases, one or more substances were suspected. In 49 of these (73%) the suspected cause did not match the results of subsequent investigation, either a different substance being the cause or no cause being found. Only five cases (7%) showed a complete match between suspected cause and investigation result. In the remaining 13 cases (19%) there was a partial match, the right substance being suspected, but investigations showed an additional allergen or several substances, including the right substance being suspected. CONCLUSIONS: An informed guess is not a reliable way of determining the cause of a supposed allergic reaction during anaesthesia and may put a significant number of patients at unnecessary risk. Some patients may be labelled with a wrong allergy, leading to unnecessary warnings against harmless substances, and some patients may be put at risk of subsequent re-exposure to the real allergen. Patients with suspected allergic reactions during anaesthesia should be referred for investigation in specialist centres whenever possible.
  • 79. • • • • • Curr Pharm Des. 2008;14(27):2809-25. Hypersensitivity reactions to neuromuscular blocking agents. Mertes PM, Aimone-Gastin I, Guéant-Rodriguez RM, Mouton-Faivre C, Audibert G, O'Brien J, Frendt D, Brezeanu M, Bouaziz H, Guéant JL. Département d'Anesthésie-réanimation, CHU de Nancy, Hôpital Central, 29 Avenue de Lattre de Tassigny, 54035 Nancy Cedex, France. pm.mertes@chu-nancy.fr Neuromuscular blocking agents are the leading drugs responsible for immediate hypersensitivity reactions during anaesthesia. Most hypersensitivity reactions represent IgE-mediated allergic reactions. Their incidence is estimated to be between 1 in 3,000 to 1 in 110,000 general anaesthetics. However striking variations have been reported among countries. The mechanism of sensitisation seems to implicate the presence of a substituted ammonium ion in the molecule. Due to lack of exposure prior to the reaction in a large number of reactors, it has been hypothesised that sensitisation may involve other, as yet undefined, substituted (quaternary and tertiary) ammonium ion containing compounds such as pholcodine, present in the environment of the patient. This hypothesis is still under investigation. The mechanism of non-IgE mediated hypersensitivity reactions is less well known. Identified mechanisms correspond to direct histamine release or interactions with muscarinic and nicotinic receptors. Allergic reactions cannot be clinically distinguished from non-IgE-mediated reactions. Therefore, any suspected hypersensitivity reaction must be investigated using combined pre and postoperative testing. Because of the frequent but not systematic cross-reactivity observed with muscle relaxants, every available neuromuscular blocking agent should be tested, using intradermal tests to confirm the responsibility of the suspected drug which should be definitely excluded. Cross-sensitivity investigation will also try to identify the safety of drugs that can be potentially used in future anaesthesia. The determination of basophil activation investigations using direct leukocyte histamine release test or flow cytometry would be of particular interest to investigate cross sensitisation in complement to skin tests. There is no demonstrated evidence supporting systematic pre-operative screening in the general population at this time. However, since no specific treatment has been shown to reliably prevent anaphylaxis, allergy assessment must be performed in all high-risk patients. In view of the relative complexity of allergy investigation, and of the differences between countries, an active policy to identify patients at risk and to provide any necessary support from expert advice to anaesthetists and allergologists through the constitution of allergo-anaesthesia centres in every country should be promoted.
  • 80. • • • • • N Z Med J. 2007 Apr 13;120(1252):U2492. Treatment of anaphylaxis in adults: results of a survey of doctors at Dunedin Hospital, New Zealand. Thain S, Rubython J. Dunedin Public Hospital, Dunedin. suzythain@hotmail.com AIMS: To identify which medications doctors would prescribe when treating an adult patient with anaphylaxis, and to ascertain the dose and route of administration of adrenaline they would use. METHOD: Doctors of various grades working in a range of acute specialties at Dunedin Public Hospital (n=91) were asked to anonymously complete a questionnaire detailing two hypothetical cases of anaphylaxis. RESULTS: 92% of participants would give adrenaline as first-line treatment to a patient with anaphylaxis, but only 20% knew the correct dose and route of administration according to the New Zealand Resuscitation Council (NZRC) or local hospital formulary guidelines. 43% of doctors surveyed stated they would give adrenaline by the intravenous (IV) route as firstline treatment with 20% proposing a dose of 1 milligram or greater. CONCLUSION: Most doctors surveyed were not clear about current anaphylaxis treatment guidelines. In particular, they were unsure of the recommended dose and route of administration of adrenaline. To ensure that the first-line treatment of anaphylaxis is safe, we recommend that intramuscular (IM) adrenaline should be used in the majority of situations in accordance with both NZRC and local hospital guidelines. We recommend that all doctors should receive regular education concerning the treatment of anaphylaxis
  • 81. • • • • • Clin Exp Allergy. 2000 Aug;30(8):1144-50. Lessons for management of anaphylaxis from a study of fatal reactions. Pumphrey RS. Immunology Unit, Central Manchester Healthcare NHS Trust Hospitals, St Mary's Hospital, Hathersage Road, Manchester M13 0JH, UK. BACKGROUND: The unpredictability of anaphylactic reactions and the need for immediate, often improvised treatment will make controlled trials impracticable; other means must therefore be used to determine optimal management. OBJECTIVES: This study aimed to investigate the circumstances leading to fatal anaphylaxis. METHODS: A register was established including all fatal anaphylactic reactions in the UK since 1992 that could be traced from the certified cause of death. Data obtained from other sources suggested that deaths certified as due to anaphylaxis underestimate the true incidence. Details of the previous medical history, the reaction and necropsy were sought for all cases. RESULTS: Approximately half the 20 fatal reactions recorded each year in the UK were iatrogenic, and a quarter each due to food or insect venom. All fatal reactions thought to have been due to food caused difficulty breathing that in 86% led to respiratory arrest; shock was more common in iatrogenic and venom reactions. The median time to respiratory or cardiac arrest was 30 min for foods, 15 min for venom and 5 min for iatrogenic reactions. Twenty-eight per cent of fatal cases were resuscitated but died 3 h-30 days later, mostly from hypoxic brain damage. Adrenaline (epinephrine) was used in treatment of 62% of fatal reactions but before arrest in only 14%. CONCLUSIONS: Immediate recognition of anaphylaxis, early use of adrenaline, inhaled beta agonists and other measures are crucial for successful treatment. Nevertheless, a few reactions will be fatal whatever treatment is given; optimal management of anaphylaxis is therefore avoidance of the cause whenever this is possible. Predictable cross-reactivity between the cause of the fatal reaction and that of previous reactions had been overlooked. Adrenaline overdose caused at least three deaths and must be avoided. Kit for selftreatment had proved unhelpful for a variety of reasons; its success depends on selection of appropriate medication, ease of use and good training.
  • 82. Altra biblio – Francia 1983:Hatton et al1/4500 – • • • • • • • • • • operative procedures and a mortality rate of 6%. Clark et al11 found that drugs were implicated in 4.3% of deaths that occurred during anesthesia in the United Kingdom and were reported in 1975. More recent but smaller studies have been published from New Zealand,4 the United Kingdom,5 and the United States6,7 that show similar incidences. Oulieu S, Olivier J, Bourget P, et al. Strategic thérapetique du choc anaphylactoide en anesthésie generale. Therapie 1995;50:59-66. 2. 3. Laxenaire M-C. Epidémiologic des réactions anaphylactoides peranesthésiques: quatriéme enquéte multicentrique (juillet 1994-décembre 1996). Ann Fr Anesth Reanim 1999;18:796-809. 4. Sage D, Guarino R, Sage DD. Intradermal drug testing following anaphylactoid reactions during anaesthesia. Anaesth Intensive Care 1981;9:381-6. 5. Pepys J, Pepys EO, Baldo BA, et al. Anaphylactic/anaphylactoid reactions to anaesthetic and associated agents: skin prick tests in aetiological diagnosis. Anaesthesia 1994;49:470-5. 6. Moscicki RA, Sockin SM, Corsello BF, et al. Anaphylaxis during induction of general anesthesia: subsequent evaluation and management (see comments). J Allergy Clin Immunol 1990;86:325-32. 7. Knowles SR,Weber E, Shear NH. Allergic reactions during general anesthesia (GA) [abstract]. J Allergy Clin Immunol 1996;97:344.
  • 83. • • • • • Allergy. 2009 Oct 1. [Epub ahead of print] National pholcodine consumption and prevalence of IgE-sensitization: a multicentre study. Johansson SG, Florvaag E, Oman H, Poulsen LK, Mertes PM, Harper NJ, Garvey LH, Gerth van Wijk R, Metso T, Irgens A, Dybendal T, Halsey J, Seneviratne SL, Guttormsen AB. Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden. Background: The aim of this study was to test, on a multinational level, the pholcodine (PHO) hypothesis, i.e. that the consumption of PHO-containing cough mixtures could cause higher prevalence of IgE antibodies to PHO, morphine (MOR) and suxamethonium (SUX). As a consequence the risk of anaphylaxis to neuromuscular blocking agents (NMBA) will be increased. Methods: National PHO consumptions were derived from the United Nations International Narcotics Control Board (INCB) database. IgE and IgE antibodies to PHO, MOR, SUX and Paminophenyl-phosphoryl choline (PAPPC) were measured in sera from atopic individuals, defined by a positive Phadiatop((R)) test (>0.35 kU(A)/l), collected in nine countries representing high and low PHO-consuming nations. Results: There was a significant positive association between PHO consumption and prevalences of IgE-sensitization to PHO and MOR, but not to SUX and PAPPC, as calculated both by exposure group comparisons and linear regression analysis. The Netherlands and the USA, did not have PHO-containing drugs on the markets, although the former had a considerable PHO consumption. Both countries had high figures of IgE-sensitization. Conclusion: This international prevalence study lends additional support to the PHO hypothesis and, consequently, that continued use of drugs containing this substance should be seriously questioned. The results also indicate that other, yet unknown, substances may lead to IgEsensitization towards NMBAs
  • 84. • • • • • Curr Pharm Des. 2008;14(27):2809-25. Hypersensitivity reactions to neuromuscular blocking agents. Mertes PM, Aimone-Gastin I, Guéant-Rodriguez RM, Mouton-Faivre C, Audibert G, O'Brien J, Frendt D, Brezeanu M, Bouaziz H, Guéant JL. Département d'Anesthésie-réanimation, CHU de Nancy, Hôpital Central, 29 Avenue de Lattre de Tassigny, 54035 Nancy Cedex, France. pm.mertes@chu-nancy.fr Neuromuscular blocking agents are the leading drugs responsible for immediate hypersensitivity reactions during anaesthesia. Most hypersensitivity reactions represent IgE-mediated allergic reactions. Their incidence is estimated to be between 1 in 3,000 to 1 in 110,000 general anaesthetics. However striking variations have been reported among countries. The mechanism of sensitisation seems to implicate the presence of a substituted ammonium ion in the molecule. Due to lack of exposure prior to the reaction in a large number of reactors, it has been hypothesised that sensitisation may involve other, as yet undefined, substituted (quaternary and tertiary) ammonium ion containing compounds such as pholcodine, present in the environment of the patient. This hypothesis is still under investigation. The mechanism of non-IgE mediated hypersensitivity reactions is less well known. Identified mechanisms correspond to direct histamine release or interactions with muscarinic and nicotinic receptors. Allergic reactions cannot be clinically distinguished from non-IgE-mediated reactions. Therefore, any suspected hypersensitivity reaction must be investigated using combined pre and postoperative testing. Because of the frequent but not systematic cross-reactivity observed with muscle relaxants, every available neuromuscular blocking agent should be tested, using intradermal tests to confirm the responsibility of the suspected drug which should be definitely excluded. Cross-sensitivity investigation will also try to identify the safety of drugs that can be potentially used in future anaesthesia. The determination of basophil activation investigations using direct leukocyte histamine release test or flow cytometry would be of particular interest to investigate cross sensitisation in complement to skin tests. There is no demonstrated evidence supporting systematic pre-operative screening in the general population at this time. However, since no specific treatment has been shown to reliably prevent anaphylaxis, allergy assessment must be performed in all high-risk patients. In view of the relative complexity of allergy investigation, and of the differences between countries, an active policy to identify patients at risk and to provide any necessary support from expert advice to anaesthetists and allergologists through the constitution of allergo-anaesthesia centres in every country should be promoted
  • 85. • • • • • Anesthesiology. 2007 Aug;107(2):253-9. Immunoglobulin E antibodies to rocuronium: a new diagnostic tool. Ebo DG, Venemalm L, Bridts CH, Degerbeck F, Hagberg H, De Clerck LS, Stevens WJ. Department of Immunology-Allergology, University of Antwerp, Belgium. immuno@ua.ac.be BACKGROUND: Diagnosis of allergy from neuromuscular blocking agents is not always straightforward. The objectives of the current study were to investigate the value of quantification of immunoglobulin E (IgE) by ImmunoCAP (Phadia AB, Uppsala, Sweden) in the diagnosis of rocuronium allergy and to study whether IgE inhibition tests can predict clinical cross-reactivity between neuromuscular blocking agents. METHODS: Twentyfive rocuronium-allergic patients and 30 control individuals exposed to rocuronium during uneventful anesthesia were included. Thirty-two sera (total IgE > 1,500 kU/l) were analyzed for potential interference of elevated total IgE titers. Results were compared with quantification of IgE for suxamethonium, morphine, and pholcodine. Crossreactivity between drugs was assessed by IgE inhibition and skin tests. RESULTS: Sensitivity of IgE for rocuronium, suxamethonium, morphine, and pholcodine was 68, 60, 88, and 86%, respectively. Specificity was 100% for suxamethonium, morphine, and pholcodine IgE and 93% for rocuronium IgE. ROC analysis between patients and control individuals changed the threshold to 0.13 kUa/l for rocuronium, 0.11 kUa/l for suxamethonium, 0.36 kUa/l for morphine, and 0.43 kUa/l for pholcodine. Corresponding sensitivity was 92, 72, 88, and 86%, respectively. Specificity was unaltered. Interference of elevated total IgE with quantification of IgE was demonstrated by the analysis in sera with a total IgE greater than 1,500 kU/l. IgE inhibition did not predict clinical relevant cross-reactivity. CONCLUSIONS: The rocuronium ImmunoCAP constitutes a reliable technique to diagnose rocuronium allergy, provided an assay-specific decision threshold is applied. IgE assays based on compounds bearing ammonium epitopes are confirmed to represent reliable tools to diagnose rocuronium allergy. High total IgE titers were observed to affect specificity of the assays.
  • 86. • • • • • • • • • • • • • • Results: 14 1. [Anaphylaxis during anaesthesia] Guttormsen AB, Harboe T, Pater G, Florvaag E. Tidsskr Nor Laegeforen. 2010 Mar 11;130(5):503-6. Review. Norwegian. PMID: 20224620 [PubMed - indexed for MEDLINE]Related articlesFree article 2. National pholcodine consumption and prevalence of IgE-sensitization: a multicentre study. Johansson SG, Florvaag E, Oman H, Poulsen LK, Mertes PM, Harper NJ, Garvey LH, Gerth van Wijk R, Metso T, Irgens A, Dybendal T, Halsey J, Seneviratne SL, Guttormsen AB. Allergy. 2009 Oct 1. [Epub ahead of print]PMID: 19796197 [PubMed - as supplied by publisher]Related articles 3. The pholcodine story. Florvaag E, Johansson SG. Immunol Allergy Clin North Am. 2009 Aug;29(3):419-27.PMID: 19563989 [PubMed - indexed for MEDLINE]Related articles 4.
  • 87. Casi di shock anafilattico attribuiti ai curari in Francia tra gennaio 1999 e dicembre 2000 (306) 2,6% 19% 0,6% 22,6% succinilcolina rocuronio vecuronio 3,3% pancuronio atracurio 8,5% mivacurio cisatracurio 65% dei casi di anafilassi 43,1%
  • 88. Quote di mercato in Francia tra gennaio 1999 e dicembre 2000 (306) 6% 4% 7% 9% 11% 10% 53% succinilcolina atracurio rocuronio mivacurio vecuronio cisatracurio
  • 89. Anaphylaxis during anesthesia in Norway.drugs administered before the reaction Vecu 7,2, panc e atrac 1,2 each Sux Rocu other NMBA Tps Propofol Midaz Ket fent other opioids Atropine Loc anesth antib others
  • 90. Frequency of anaphylactic reactions at Hakeland Univesity Hospital 1996-2001 e market share dei miorilassanti in Norvegia

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