ALLERGIC REACTIONS TO THE MEDICATIONS ADMINISTRATED DURING ANAESTHESIA ALERGIJSKE REAKCIJE NA LEKOVE KOJI SE KORISTE ZA IZVOĐENJE ANESTEZIJE
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1 ALERGIJSKE REAKCIJE TOKOM ANESTEZIJE Četvti kurs Evropskog komiteta za edukaciju u anesteziji (CEEA 4), Beograd, godine (Pedijatrijska i akušerska anestezija) ALERGIJSKE REAKCIJE NA LEKOVE KOJI SE KORISTE ZA IZVOĐENJE ANESTEZIJE Ana Mimić 1 ALLERGIC REACTIONS TO THE MEDICATIONS ADMINISTRATED DURING ANAESTHESIA Ana Mimić 1 1 Centar za anesteziju i reanimaciju, Klinički centar Srbije, Beograd 1 Center for Anesthesiology and reanimatology, Clinical Center of Serbia, Belgrade Sažetak. Anafilaksa je promptna sistemska hipersenzitivna reakcija na određenu supstancu na koju je pacijent senzibilisan, praćena potencijalno po život opasnim komplikacijama.alergijske reakcije na lekove koji se koriste u anesteziji predstavljaju relativno retku ali veoma ozbiljnu komplikaciju. Učestalost ovih reakcija, prema navodima različitih epidemioloških studija, varira od 1:950 do 1: ,2. Anafilalktičke reakcije u anesteziji mogu biti fatalne, čak i u slučajevima kada su prepoznate na vreme i kada je primenjena adekvatna terapijasa mortalitetom od 3 do 6%. Prema revidiranoj nomenklaturi sve reakcije se dele na alergijsku anafilaksu i ne-alergijsku anafilaksu. Mehanizam nastanka anafilaktičkih reakcija je degranulacija mastocita i bazofila sa posledičnim oslobadjanjem histamina i drugih inflamatornih medijatora koji su odgovorni za nastanak kliničkih simptoma i znakova. Iako kontroverzni, podaci iz literature ukazuju da su mišićni relaksanti lekovi koji najčešće dovode do anafilaktičkih reakcija. Najvažniji faktor rizika je prethodna anafilaktička reakcija tokom anestezije. Klinički simptomi variraju od blagih kao što je crvenilo do teške hipotenzije i šoka. Ne postoji test koji bi bio zlatni standard za dijagnozu anafilakse. Najbolja prevencija je vigilni anesteziolog. Ključne reči: alergije, anafilaksa, anestezija, mišićni relaksanti Summary. Anaphylaxis is a rapid, systemic hypersensitivity reaction to a substance in a sensitised individual with potentially life-threatening consequences. Although the exact incidence of anaphylaxis during general anaesthesia is unknown, estimates from epidemiological studies have reported a varying rate from 1 in 950 to 1 in 20,000 anaesthetics. These reactions may be fatal, even when adequate treatment is given. The mortality rate is estimated to be between 3 and 6% of those who have an anaphylactic reaction. According to revised nomenclature, all reactions are subdivided into allergic anaphylaxis and non-allergic anaphylaxis. The most common mechanism for an anaphylactic reaction is the degranulation of mast cells and basophils, release of histamine and other inflammatory mediators, which are responsible for the symptoms and signs. Although conflicting, data suggests that the most common cause of anaphylaxis are muscular blocking agents. The most important risk factor is the previous allergic reaction during anaesthesia. The clinical symptoms vary from flushing to severe hypotension and shock. There is no gold standard test for anaphylaxis. The best prevention for anaphylaxis is the vigilant anaethetist. Key words: allergy, anaphylaxis, anaesthesia, muscular blocking agents Adresa autora: Ana Mimić, Centar za anesteziologiju i reanimatologiju Klinički centar Srbije, Koste Todorovića 26, Beograd tel.: , anamimic@gmail.com
2 402 SJAIT 2013/7-8 Uvod Alergijske reakcije na lekove koji se koriste u anesteziji predstavljaju relativno retku ali veoma ozbiljnu komplikaciju. Učestalost ovih reakcija, prema navodima različitih epidemioloških studija, varira od 1:950 do 1: ,2. Anafilalktičke reakcije u anesteziji mogu biti fatalne, čak i u slučajevima kada su prepoznate na vreme i kada je primenjena adekvatna terapija. Mortalitet od anafilaktičkih reakcija u anesteziji se procenjuje na 3% do 6%. Svaki lek koji se koristi u anesteziji, osim inhalacionih anestetika predstavlja potencijalni alergen. Nespecifična klinička slika, nepostojanje testa koji bi bio zlatni standard za detektovanje alergije, mali broj validnih kliničkih studija iz ove oblasti čini problem anafilaktičkih reakcija u anesteziji i dalje veoma aktuelnim 3. Definicija i nomenklatura Anafilaksa je promptna sistemska hipersenzitivna reakcija na određenu supstancu na koju je pacijent senzibilisan, praćena potencijalno po život opasnim komplikacijama. Prema novoj nomenklaturi Radne grupe evropskog udruženja alergologa i kliničkih imunologa, ranija podela na anafilaktičke i anafilaktoidne reakcije, nije više aktuelna. Prema novim preporukama termin anafilaksa se koristi i za imunološki posredovane i ne-imunološki posredovane reakcije, odnosno sve reakcije se dele na alergijsku anafilaksu i ne-alergijsku anafilaksu 4 Patofizologija anafilakse Kod senzibilisanih individua IgE antitela su vezana za membranu tkivnih mastocita i bazofila iz periferne krvi. Lek (potencijalni antigen) se vezuje za IgE antitela, dolazi do aktivacije mastocita, momentalnog oslobađanja histamina sa maksimalnom koncentracijom nakon 5 minuta. Nakon minuta posle inicijalnog stimulus, mastociti počinju da luče prostaglandine i leukotrijene koji dalje pogoršavaju simptomatologiju. Oslobodjeni histamin takodje dovodi do aktivacije i drugih inflamatornih ćelija. Mehanizam ne-imunološke degranulacije mastocita i bazofila i posledične histaminoliberacije još uvek nije objašnjen. Predpostavlja se da ključnu ulogu igra aktivacija membranskih enzima fosfolipaze A2 i fosfolipaze C. Anafilaksa na lekove koji se koriste u anesteziji Postoji disproporcija u prijavljivanju najčešćih uzročnika alergijskih reakcija na lekove koji se koriste za izvodjenje anestezije u različitim zemljama. Prema podacima velike francuske studije 2 koja je obuhvatila sve prijavljene anafilaktičke reakcije na lekove koji se koriste u anesteziji tokom 1999 i 2000 godine, u 58% slučajeva uzročnici su bili mišićni relaksanti (Grafikon 1). Medju mišićnim relaksantima, najviše anafilaktičkih reakcija je bilo uzrokovano rokuronijumom (Tabela 1). Sa druge strane, prema američkim podacima, do sada je prijavljeno samo nekoliko pojedinačnih anafilaktičkih reakcija na rokuronijum, koji je u toj zemlji najčešće primenjivani mišićni relaksant i do sada ga je dobilo više od 45 miliona pacijenata. Najčešći uzročnici anafilakse kod hospitalizovanih pacijenata u SAD su latex, penicillin i radiokontrastna sredstva. Od lekova koji se koriste u anesteziji, najviše je prijavljenih alergijskih reakcija na lokalne anestetike 5. Nespecifična klinička slika anafilakse, nepostojanje adekvatnog testa, korišćenje različitih mišićnih relaksanata u različitim zemljama, predstavljaju neke od razloga heterogenosti uzročnika anafilakse. Klinička slika Klinička prezentacija anafilakse u anesteziji varira od blagih simptoma do šoka. Anafilaksa se može dogoditi u bilo kom trenutku anestezije i može nastati sporo ili brzo. Što brže nastane ozbiljnija je reakcija. Simptomi i znaci nastaju najčešće 5-30 minuta nakon davanja antigena. Kada se pojave znaci i simptomi anafilakse nakon što je dato nekoliko lekova, kao što je slučaj prilikom uvoda u anesteziju, to ne znači da je poslednji primenjeni lek izazvao reakciju! Anafilaktičke reakcije uglavnom počinju promenama na koži, crvenilom i/ili urtikarijom, mada je jedan od prvih znakova anafilaktičke reakcije u anesteziji nemogućnost inflacije pluća pre intubacije. Respiratorna simptomatologija obuhvata edem gornjih disajnih puteva, što može dovesti do asfiksije, ali i spazam donjih disajnih puteva koji se manifestuje vizingom i otežanom ventilacijom.
3 ALERGIJSKE REAKCIJE TOKOM ANESTEZIJE 403 Grafikon 1. Najčeći uzročnici anafilakse u anesteziji u Francuskoj Tabela 1. Distribucija mišićnih relaksanata prema učestalosti izazivanja anafilakse (n=306) Mišićni relaksant Broj % Rokuronijum ,1 Succynilcholine 69 22,6 Atracurium 58 19,0 Vecuronium 26 8,5 Pancuronium 10 3,3 Mivacurium 8 2,6 Cisatracurium 2 0,6 Najprominentniji klinički znak je hipotenzija koja nastaje usled povećane kapilarne propustljivosti nastale pod dejstvom histamina i drugih medijatora. Gubitak intravaskularnog volumena može biti dramatičan i do 50% u prvih 10 minuta, što dovodi do nastajanja anafilaktičkog šoka. Nekada mogu biti prisutni i gastrointestinalni simptomi, u vidu mučnine, povraćanja i abdominalnih bolova. Prema težini kliničke slike anafilaktičke reakcije se mogu podeliti na blage i životno ugrožavajuće (Tabela 2). Blage reakcije Diferencijalno dijagnostički treba isključiti druge forme šoka (kardiogeni, endotoksični, itd), druga stanja koja mogu dovesti do crvenila (karcinoidni sindrom, medularni karcinom štitaste žlezde), ali i ne-imunološki posredovanu histaminoliberaciju, koja se dešava prilikom primene nekih lekova kao što je fentanyl i atracurium. Takodje, neka stanja koja nisu tako retka u svakodnevnoj anesteziološkoj praksi, kao što je hipotenzivni odgovor na indukcioni agens, bronhospazam kod senzibilnih osoba kao reakcija na intubaciju, eg- Tabela 2. Klasifikacija anafilakse prema težini kliničke slike Koža Respiratorni sistem Kardiovaskularni sistem I x x II Povećana plućna rezistencija Značajna tahikardija Pad SAP za 20 mmhg Životno ugrožavajuće reakcije III IV Bronhospazam Cijanoza Respiratorni arrest Značajna hipotenzija (pad SAP za 60 mmhg) Šok Šok Cardiac arrest
4 404 SJAIT 2013/7-8 zarcebacija postojeće astme i sl., mogu izgledati kao anafilaksa. Faktori rizika za nastanak anafilakse Anafilaksa u anesteziji je generalno češća kod pacijenata sa atopijskom konstitucijom 6,7, iako se smatra da je ona važniji faktor rizika kada se antigen administrira oralno ili preko kože. Najčešće se javlja kod osoba u četvrtoj deceniji. Kod dece su anafilaktičke reakcije na anestetike redje. Izuzetak čine deca koja su zbog urodjenih malformacija imala višestruke operacije u najranijem uzrastu. Dokazana je povezanost spine bifide i alergije na latex 8. Pol takodje predstavlja faktor rizika, pošto su anafilaktičke reakcije na latex i mišićne relaksante tri puta češće kod žena. Najznačajniji rizik su svakako prethodne alergijske ili druge neobjašnjene reakcije tokom prethodnih anestezija 9. Dijagnostikovanje anafilakse Dijagnoza anafilaktičke reakcije nije nimalo laka. Još uvek ne postoji test koji bi nam sa većom sigurnošću mogao ukazati da se dogodila anafilaktička reakcija. U kliničkoj praksi dijagnozu postavljamo na osnovu: Kliničke slike Nivoa enzima triptaza mastocita. Triptaza se uvek oslobadja kada se mastociti aktiviraju, ali nije specifična za anafilaksu. Poluživot enzima je 90 minuta i može se odredjivati i na post-mortem uzorcima. Nivoa IgE antitela-optimalno 4 do 6 nedelja nakon suspektne reakcije Kožnim testovima u specijalizovanim centrima, 6 nedelja nakon suspektne reakcije. Potrebno je uraditi kožne probe na sve lekove koji su bili primenjivani kada se suspektna reakcija dogodila. Problem pacijenta sa multiplim alergijama i unakrsne alergijske reakcije Sve češće tokom pre-anestetičke vizite pacijenti navode multiple alergije na lekove i hranu koje nisu validno dokazane. I dalje su kontroverzni dokazi da li su takvi pacijenti pod povećanim rizikom od nastanka anafilaktičke reakcije tokom anestezije 10. Ukoliko postoji sumnja na mogućnost anafilakse u anesteziji, neophodno je uraditi alergološke testove na lekove koji će se koristiti tokom anestezije. Povezanost alergija na hranu i alergija na odredjene anestetike nije klinički dokazana. Ne postoje čvrsti dokazi da treba izbegavati primenu propofola kod pacijnata alergičnih na jaja, soju ili kikiriki. Takodje nije dokazana unakrsna reaktivnost izmedju povidon joda, jodnih kontrastnih sredstava i morskih školjki. Postoji visok procenat unakrsne alergije na mišićne relaksante (60-70%) zbog njihove karakteristične strukture-kvatenerne amonijumske grupe 10. Kod pacijenata sa prethodno dokumentovanom anafilaksom na odredjeni mišićni relaksant bezbedno se može dati drugi, ukoliko je kožna proba negativna 11. Alergije na antibiotike Predstavljaju najčešće alergijske reakcije na lekove. U većini slučajeva uzročnici su penicilini I cefalosporini. Pacijenti alergični na penicilin imaju veću incidenciju alergija na cefalosporine prve generacije (8 do 10%), ali ne i na cefalosporine druge i treće generacije 10. Terapija anafilakse 1. Odmah pozvati pomoć! 2. Obustaviti davanje leka za koji sumnjamo da je doveo do anafilaktičke reakcije. Najbolje je obustaviti davanje svih lekova ukoliko je to moguće. 3. Obezbediti disajni put. Ventilirati sa 100% kiseonikom. 4. Pacijenta staviti da leži na ravnom, na leđima, sa podignutim nogama. 5. Administrirati adrenalin mg (0.5-1 ml 1:1000). Kod pacijenata sa teškim kardiovaskularnim kolapsom ponavljati dozu adrenalina na 10 minuta ili titrirati sa adrenalinom 1: brzinom 0.1 mg/min. 6. Započeti intenzivnu nadoknadu volumena kristaloidnim i/ili koloidnim rastvorima. Ukoliko je koloidni rastvor ordiniran pre reakcije - ne davati koloide. 7. Sačuvati sve uzorke krvi uzete pre operacije, i uzeti nove uzorke. Sekundarne terapijske mere: Antihistaminici, kortikosteroidi, bronhodilatatori. Obezbediti intenzivan nadzor i monitoring u Jedinici intenzivnog lečenja.
5 ALERGIJSKE REAKCIJE TOKOM ANESTEZIJE 405 Prijavljivanje alergijskih reakcija na lekove koji se koriste u anesteziji: Nacionalni centar za farmakovigilancu, Agencija za lekove i medicinska sredstva Srbije gov.rs Obrazac NRL poslati na nezeljene. reakcije@alims.gov.rs ili Poštom na adresu: Vojvode Stepe 458, Beograd. Zaključak Radi prevencije anafilaktičkih reakcija u anesteziji, potrebna je posebna pažnja anesteziologa. Preoperativna identifikacija, blagovremeno prepoznavanje kliničke slike i terapijski pristup prema savremenim preporukama i vodičima, najvažniji su preduslovi za sprečavanje i kupiranje po život opasnih komplikacija anafilakse. Literatura 1. Garvey LH, Roed-Petersen J, Menné T, Husum B. Danish Anesthesia Allergy Centre preliminary results. Acta Anaesthesiol Scand 2001;45: Mertes PM, Laxenaire M-C. Allergic reactions occurring during anaesthesia.eur J Anaesthesiol 2002;19: Mirakhur RK, Harper Nigel JN, Benoit P,Aalberse RC. Clinical Guidelines for allergy in anaesthesia. Royal College of Anaesthetist Johansson SG, Hourihane JO, Bousquet J, et al. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy 2001;56: Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States, an investigation into its epidemiology. Arch Intern Med 2001;161: Kemp SF, Lockey RF, Wolf BL, Lieberman, P. Anaphylaxis. A review of 266 cases. Arch Intern Med 1995;155: Charpin D, Benzarti M, Hemon Y, Senft M, Alazia M, Arnaud A, Vervloet D,Charpin J. Atopy and anaphylactic reactions to suxamethonium. J Allergy Clin Immunol 1988;82: Cremer R, Lorbacher M, Hering F, Engelskirchen R. Natural rubber latex sensitization and allergy in patients with spina bifida, urogenital disorders and oesophageal atresia compared with a normal paediatric population. Eur J Pediatr Surg 2007;17(3): Dewachter P. et al. Anesthesia in the patient with multiple drug allergies: are all allergies the same? Cur Opin Anaesth 2011,24: Harper NJ, Dixon T, Dugue P, et al. Suspected anaphylactic reactions associated with anaesthesia. Anaesthesia 2009; 64: French Society of Anesthesiology and Intensive Care Medicine. Reducing the risk of anaphylaxis during anaesthesia: abbreviated text. Ann Fr Anesth Reanim 2002; 21 (Suppl 1):7 23.
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