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Miorilassanti e reazioni anafilattiche
1. Servizio di Anestesia e
Rianimazione Ospedale di
Faenza(RA)
Miorilassanti e reazioni
anafilattiche
Claudio Melloni
Libero professionista
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? …
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.
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.
• Ore 16 EEG: Sofferenza severa della 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.
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. Jacobsen J,Lindekaer,HT,Ostergaard HT, Nielsen 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!
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
24. 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, Warszawski 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 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;
– 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.
]
25. 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
26. 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
28. 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?)
29. 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
30. 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
31. 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.
32. Servizio di Anestesia e
Rianimazione Ospedale di
Faenza(RA)
Struttura chimica del besilato di
cisatracurium(Nimbex)
38. 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
39. 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.
40. 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 IgE-
sensitization 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
41. 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 NMBD-
based 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
42. 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.
45. Distribuzione % delle reazioni anafilattiche in Francia nel
corso dei vari studi pubblicati da Laxenaire e coll.
0
10
20
30
40
50
60
70
80
90
%
NMBA Hypnotics Colloids Others
Ist
IInd
IIIrd
IV
V
VI
46. 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.
69%
12%
8%
4% 3% 2%2%
miorilass
latex
antibiotici
ipnotici
colloidi
oppioidi
altri
47. 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.
0,00
5,00
10,00
15,00
20,00
25,00
30,00
%
reaz allergiche
cisatracurium
atracurium
mivacurium
pancuronium
vecuronium
rocuronium
succinilcolina
69.2% delle 477 reazioni
allergiche
durante anestesia in Francia
succi
Rocu
vecu
48. Casi di shock anafilattico attribuiti ai curari in
Francia tra gennaio 1999 e dicembre 2000 (306)
65% dei casi di anafilassi
succi
rocu
vecu
atrac
11%
10%
53%
7%
4% 9%
6%
succinilcolina rocuronio vecuronio p
atracurio mivacurio cisatracurio
22,6%
43,1%
8,5%
3,3%
19%
2,6% 0,6%
atrac
succi
rocu
vecu
Quote di mercato Francia
49. 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
50. 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.
51. 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%).
52. 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.
53.
54. 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).
55. Rose, M.; Fisher, M. Rocuronium: high risk for
anaphylaxis? Br. J. Anaesth. 2001; 86:678-682
56. Rose, M.; Fisher, M. Rocuronium: high risk for
anaphylaxis? Br. J. Anaesth. 2001; 86:678-682
57. Dubbi e critica
• Test falsi positivi:concentrazione del reagente?
• Aum dell’utilizzo
• Problemi statistici
• Differenze nel genotipo
• Biasimo dell’osservatore
58. Servizio di Anestesia e Rianimazione
Ospedale di Faenza(RA)
Risk of allergic reactions caused by NMB’s
(ratio)
succi rocu panc vecu miva atrac cisatr
Laxenaire 1999
Laxenaire 2000
Laxenaire 2001
Mertes 2003
%
59. 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.
60. 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
61. Diagnosi:
• Caratteristiche della reazione
• Gravità dei sintomi
• Temporizzazione;immediato/acuto
• Il dosaggio per resuscitazione indica la
severità della reazione
62. 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
63. Segni e sintomi della reazione
anafilattica ai miorilassanti;%
Autore e anno Collasso
cardiovsc/arres
to
Broncospasmo
severo
Segni cutanei altro
Mertens 2003 51/6 40 72
Krombach
2001
66 50 16
Harboe 64/6 78 54 Ipossiemia 49
64. 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§
65. 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
66. • 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.
67. 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
68. Sensibilità crociata
• Legata al NH4+???
Anafilassi
Test al nmba
sospetto
Skin prick test
+
Evita!!!
Anest senza
mioril!!
Skin prick test
neg
Non
garantisce
Test a tutti i
nmba
69. 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
70. 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
71. 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
73. 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).
76. Letture consigliate:5
• Dewachter P, Mouton-Faivre C: What
investigation after an anaphylactic reaction
during anaesthesia?. Curr Opin
Anaesthesiol 21. 363-368.2008
77. 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!
78. 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)
80. • 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.
81. • 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.
82. • 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 first-
line 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
83. • 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 self-
treatment had proved unhelpful for a variety of reasons; its success depends on selection of appropriate
medication, ease of use and good training.
84. 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.
85. • 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 P-
aminophenyl-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 IgE-
sensitization towards NMBAs
86. • 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
87. • 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: Twenty-
five 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. Cross-
reactivity 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.
88. • 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.
90. Quote di mercato in Francia tra
gennaio 1999 e dicembre 2000 (306)
11%
10%
53%
7%
4% 9%
6%
succinilcolina rocuronio vecuronio
atracurio mivacurio cisatracurio
91. Anaphylaxis during anesthesia in Norway.drugs
administered before the reaction
Sux
Rocu
other NMBA
Tps
Propofol
Midaz
Ket
fent
other opioids
Atropine
Loc anesth
antib
others
Vecu 7,2,
panc e atrac 1,2
each
92.
93. Frequency of anaphylactic reactions at Hakeland Univesity Hospital
1996-2001 e market share dei miorilassanti in Norvegia
Hinweis der Redaktion
Laxenaire MC et Groupe d’Etudes des Réactions Anaphylactoïdes Peranesthesiques Epidemiology of anesthetic anaphylactoid reactions. Fourth multicenter survey (July 1994-Dec 1996). Ann Fr Anesth Reanim 1999 Aug;18(7):796-809.
Laxenaire MC, Mertes PM and Groupe d’Etudes des Réactions Anaphylactoïdes Peranesthesiques Anaphylaxis during anaesthesia. Results of a two-year survey in France Br J Anaesthesia 2001;87(4):549-58.
Laake JH, Rottingen JA. Rocuronium and anaphylaxis--a statistical challenge Acta Anaesthesiol Scand 2001 Nov;45(10):1196-203.
Mertes PM, Laxenaire MC, Alla, F et Groupe d’Etudes des Réactions Anaphylactoïdes Peranesthesiques. Anaphylactic and anaphylactoid reactions occurring in France in 1999-2000 Anesthesiology 2003;99(3):536-45
RATIO % reacties / % patients exposed
NMB Laxenaire 1999 Laxenaire 2001 Laake 2001 Mertes 2003
succinylcholine 4,02 3,05 1,23 2,88
rocuronium 1,89 2,92 1,89 4,21
pancuronium 1,29 1,78 0,10 0,74
vecuronium 1,57 1,53 0,45 1,14
atracurium 0,49 0,35 0,25 0,30
mivacurium 0,86 0,5 1,18 0,61
cisatracurium N/A 0,17 0,00 0,12
