CONTINUING PROFESSIONAL DEVELOPMENT

Introduction Tujuan pemakaian beberapa obat :

untuk mendapatkan terapi yang adekuat dengan efek samping yang minimal. Pemakaian kombinasi obat-obatan ini diikuti pula dengan pemikiran adanya interaksi antar obat yang mungkin terjadi sehingga tindakan antisipasi bisa dilakukan.Rosow C, Levine WC. Drug interactions. Barash PG, Cullen BF, Stoelting RK, Clinical anesthesia. Edisi ke-5. 2001. h.1313-30.

Praktek anestesi tidak terlepas dari pemakaian beberapa

obat untuk mendapatkan kondisi anestesia yang optimal. seperti gas anestesi inhalasi, seringkali tidak dapat memberikan kondisi anestesia yang diinginkan.

Pembiusan dengan hanya menggunakan satu modalitas

Zbinden dkk, melaporkan bahwa pemakaian tunggal

isofluran dengan konsentrasi tinggi gagal menekan respons hemodinamik terhadap stimulus operasi.

Pengetahuan mengenai interaksi obat penting untuk

setiap ahli anestesi terutama dalam merencanakan dan menggunakan obat-obat anestesia agar dapat memperoleh kondisi yang optimal dengan efek samping yang minimal

Komplikasi akibat interaksi obat Interaksi sering terjadi namun tidak menyebabkan

masalah. Toksisitas interaksi obat menjadi morbiditas apabila tidak cepat dideteksi dan ditangani. Contoh : kombinasi opioid dan midazolam oleh petugas non-anestesia pada prosedur endoskopi dan radiologi efek sedasi dan ventilasi yang sangat besar mengakibatkan berbagai laporan kematian.

Interaksi dari kebanyakan obat anestesi dapat

diperkirakan secara kualitatif namun secara kuantitatif sulit diketahui dengan pasti. Contoh: kombinasi dua depresan kardiovaskular menyebabkan hipotensi yang lebih kuat, kombinasi dua depresan sistem saraf pusat menyebabkan sedasi yang lebih dalam.

Kebanyakan obat anestesi intravena (diazepam,

fentanil) memiliki batas keamanan (safety margins) yang luas, terutama bila terdapat dukungan respirasi, sehingga perubahan efek obat hanya memiliki sedikit konsekuensi. Interaksi yang berbahaya umumnya mencakup obat-obat dengan batas keamanan yang sempit, seperti warfarin, digoksin, dan teofilin.

Interaksi farmasi (pharmaceutical interaction) :

Interaksi farmasi

interaksi kimiawi atau fisik yang terjadi sebelum obat diberikan atau diabsorpsi sistemik. yang dicampur dalam suatu cairan, misalnya: Tiopental akan mengendap bila disuntikkan bersamaan dengan suksinilkolin dalam satu kateter intravena yang sama. Bikarbonat dapat menurunkan solubilitas bupivakain dan menyebabkannya mengendap.

Inkompatibilitas interaksi farmasi yang terjadi antara obat-obat

Ahli anestesi sebaiknya menghindari pencampuran obat-obat Dua obat dapat berinteraksi secara kimiawi dan membentuk

kecuali telah diketahui bahwa pencampuran tersebut kompatibel

senyawa yang toksik, misalnya: Zat anestesi halogen (desfluran, enfluran, dan isofluran) diketahui berinteraksi dengan dry soda lime atau Baralyme dan memproduksi karbon monoksida. Ini lebih berisiko apabila oksigen dibiarkan mengalir terus di pipanya semalaman

Interaksi Farmakokinetik terjadi apabila suatu obat mempengaruhi

absorpsi, distribusi, metabolisme, atau eliminasi obat lainnya

Absorpsi Perubahan absorpsi terjadi karena - interaksi kimiawi atau fisik langsung antar obat-obat dalam tubuh, atau - satu obat mengubah mekanisme fisiologis absorpsi obat yang

lain, contoh: tetrasiklin bila diberikan bersamaan dengan antasid menjadi tidak aktif.

Interaksi lain yang bermakna untuk ahli anestesi adalah pengosongan lambung yang diperlambat oleh obat-obat opioid dan antikolinergik. - Pemberian morfin dapat meningkatkan waktu paruh pengosongan lambung dari 5,5 menjadi 21 menit sehingga selanjutnya dapat mengurangi absorpsi obat-obat oral lain - Perubahan aliran darah regional akibat vasodilator atau vasokonstriktor mempengaruhi absorpsi obat-obat parenteral, contoh: pemberian adrenalin dapat mengurangi absorpsi obat anestesi lokal sehingga memperpanjang efeknya.Murphy DB, Sutton JA, Prescott LF, Murphy MB. Opioid-induced delay in gastric emptying: a peripheral mecahnism in humans. Anesthesiology. 1997; 87:765-70.

Distribusi Perubahan distribusi suatu obat karena obat lain

terjadi akibat perubahan hemodinamik, ionisasi obat, atau pengikatan dengan protein plasma dan jaringan. Gas anestesi dapat menurunkan curah jantung dan menyebabkan perubahan bermakna distribusi obat, yaitu meningkatkan konsentrasi arterial obat lain pada jaringan-dengan perfusi tinggi seperti otak dan miokardium.

Avram MJ, Krejcie TC, Henthorn TK, Niemann CU. Beta-adrenergic blockade affects initial drug distribution due to decreased cardiac output and altered blood flow distribution. J Pharmacol Exp Ther. 2004;311:617-24.

Metabolisme

Obat-obat anestesia yang dapat meningkatkan atau

menurunkan metabolisme obat lain. Interaksi ini terjadi intra- maupun ekstrahepatik. Obat dengan ikatan ester, mengalami hidrolisis oleh esterase spesifik dan nonspesifik dalam darah dan jaringan perifer, Contoh: obat penghambat asetilkolinesterase menghambat butirilkolinesterase dalam plasma. Sehingga pemberian neostigmin atau piridostigmin meningkatkan dan memperpanjang efek suksinilkolin dan dapat mempengaruhi anestesi lokal (prokain, kloroprocain, tetrakain, kokain).

Kuhnert BR, Philipson EH, Pimental R, Kuhnert PM. A prolonged chloroprocaine epidural block in a postpartum patient with abnormal pseudocholinesterase. Anesthesiology. 1982;56:477-8.

Monoamida oksidase (MAO) Enzim monoamida oksidase (MAO) berada di tubuh dengan jumlah

terbanyak di hati, ginjal, dan otak.

Inhibitor MAO (MAOI) digunakan dalam terapi depresi dan

kelainan mood, memiliki banyak interaksi dengan obat lain.

Interaksi MAOI dibagi menjadi dua tipe, pengaruh terhadap

neurotransmisi simpatetik dan interaksi dengan depresan sistem saraf pusat. yaitu terjadi peningkatan jumlah transmiter presinaps yang dilepaskan oleh efedrin;dapat menyebabkan krisis hipertensi berat sinaps, sehingga obat yang berpengaruh langsung pada reseptor pasca-sinaps (fenilefrin, norepinefrin, epinefrin) hanya sedikit berinteraksi dengan MAOI.

Interaksi tipe pertama adalah interaksi MAOI dengan efedrin,

Enzim MAO sedikit berperan pada metabolisme senyawa dalam

Interaksi tipe kedua, yaitu MAOI dengan

depresan sistem saraf pusat belum diketahui dengan pasti. Contoh interaksi MAOI dengan meperidin dapat menimbulkan reaksi fatal seperti eksitasi, hiperpireksia, hipertensi, keringat berlebihan, dan kekakuan, dapat berlanjut menjadi kejang, koma, dan kematian. Tapi Morfin dan fentanil dilaporkan tidak menghasilkan interaksi ini. Kontroversi adalah konsumsi MAOI harus dihentikan pemakaiannya sebelum operasi elektif. Pemberian MAOI dapat diteruskan dengan menghindari obat-obat simpatomimetik (pankuronium, kokain,petidin, ketamin).

Biotransformasi hepatik Obat-obatan seperti obat anestesi inhalasi,

meperidin, barbiturat, dan benzodiazepin mengalami biotransformasi oksidatif oleh sitokrom P450 (enzim CYP450) dalam mikrosom hati. Inhibitor maupun inducer dari enzim-enzim ini juga dapat mempengaruhi klirens obat-obatan.

Eliminasi Interaksi obat dalam fase ini berhubungan

dengan perubahan klirens renal, dan ekskresi pulmonal. Anion dan kation organik disekresikan oleh transporter yang berbeda di tubulus ginjal. Sistem kation mempengaruhi eliminasi atropin, isoproterenol, dan meperidin. Sistem anion berperan dalam ekskresi salisilat, penisilin, dan diuretik

Interaksi farmakodinamik Terjadi ketika suatu obat mengubah sensitivitas

reseptor atau jaringan target pada efek obat kedua. Hal ini berarti kurva dosis-respons atau konsentrasi-respons suatu obat diubah oleh obat lain. Klasifikasi yang untuk jenis interaksi ini adalah aditif, antagonistik, atau supraaditif (sinergistik)

Interaksi aditif Interaksi aditif terjadi pada kombinasi dua

obat dengan mekanisme serupa, Misalnya pada kombinasi dua jenis benzodiazepin, dua analog fentanil, dua gas anestesi.

Interaksi antagonistik Interaksi antagonis yang digunakan secara

sengaja dalam anestesi adalah reversi efek oleh antagonis kompetitif (antidot) seperti neostigmin, nalokson, atau flumazenil. Antagonisme yang tidak disengaja jarang terjadi, contohnya: interaksi suksinilkolin dan relaksan non-depolarisasi. Blok oleh 2-kloroprokain sebelum epidural dengan morfin atau fentanil menghasilkan penurunan durasi dan intensitas analgesia opioid tersebut.

Interaksi sinergistik Adalah ketika dosis kecil dari dua obat dapat

menghasilkan efek yang besar. Sinergi terjadi pada dua macam obat yang berasal dari kelas yang berbeda atau yang memiliki mekanisme berbeda digunakan untuk menghasilkan efek yang sama, contoh: - Potensiasi opioid oleh obat NSAID adalah contoh interaksi dua obat analgesik. - Potensiasi relaksan non-depolarisasi oleh gas anestesi - Interaksi aminosteroid dan benzilkuinolin (kombinasi pankuronium dan d-tubokurarin) menghasilkan efek relaksan sinergis.

Interaksi farmakodinamik yang mempengaruhi hemodinamik Interaksi obat-obat kardiovaskular umumnya

merupakan perluasan farmakologi obat-obat itu sendiri Dengan kata lain, efek hipotensi dari anestesi umum atau regional dapat meningkat akibat konsumsi obat-obat antihipertensi. Hal ini juga menjelaskan pengaruh obat antidisritmia seperti amiodaron atau prokainamid dalam meningkatkan kemungkinan bradikardi, hipotensi dan penurunan curah jantung.

Efek obat antihipertensi selama anesthesiaKelas Penyekat alfa Obat Fenoksibenzamin Fentolamin Prazosin Propranolol Metoprolol Atenolol Labetalol Efek Hipotensi/vasodilatasi Takikardia refleks Hipotensi Penurunan kontraktilitas Bradikardia Blok atrioventrikular Hipotensi/vasodilatasi Bradikardia Blok atrioventrikular Hipotensi/vasodilatasi Penurunan kontraktilitas Bradikardia Blok atrioventrikular Hipotensi/vasodilatasi Takikardia refleks Hipotensi/vasodilatasi Hiperkalemia Hipotensi/vasodilatasi Hiperkalemia Hipovolemia Hipokalemia Kemungkinan vasodilatasi Penyekat beta

Campuran alfa/beta blocker

Penyekat kanal kalsium

Verapamil Diltiazem Nifedipin Nikardipin Nitrogliserin Isosorbid Hidralazin Captopril Enalapril Lisinopril Losartan Valsartan Tiazid Furosemid Bumetanid

Vasodilator langsung

ACE-inhibitor

Penyekat angiotensin II Diuretik

Interaksi farmakodinamik yang mempengaruhi analgesia dan hipnosis Kombinasi depresan sistem saraf pusat hampir selalu menghasilkan

peningkatan efek SSP secara aditif atau sinergistik. Interaksi ini umumnya bermanfaat dan dapat diprediksi. Interaksi opioid-hipnotik: Fentanil dan alfentanil dapat mengurangi dosis tiopental Pengurangan dosis tiopental mempercepat pemulihan dan orientasi. Opioid juga meningkatkan potensiasi propofol. Alfentanil dosis kecil dapat mengurangi dosis induksi propofol sebanyak 50%. Interaksi opioid-benzodiazepin: Opioid merupakan depresan SSP selektif; menghasilkan sedasi namun hipnotik lemah tapi alfentanil dosis sangat kecil (3 ug/kg) dapat mengurangi dosis midazolam sampai 50%. Apabila fentanil atau alfentanil dikombinasikan dengan midazolam,dapat menyebabkan tidur dan analgesia.

Interaksi farmakodinamik yang mempengaruhi analgesia dan hipnosis Interaksi benzodiazepin-hipnotik

obat masing-masing. Efek hipnotik propofol makin kuat bila kombinasi dengan midazolam Interaksi gas anestesi opioid Opioid menurunkan konsentrasi MAC gas inhalasi secara dose-dependent dan

Kombinasi tiopental-midazolam

efek 1,8 kali lebih kuat daripada efek

concentration-dependent

Interaksi agonis-2

sedasi dan analgesik kuat. Deksmedetomidin dapat menurunkan MAC halotan sampai hampir 100% melalui mekanisme pasca-sinaps -2 spesifik. Interaksi 3-obat Pemberian kombinasi > 2 obat dengan efek sedatif-hipnotik : Kombinasi propofol, midazolam, dan alfentanil; dosis propofol dapat dikurangi sampai 86% dengan kombinasi-3-obat Kombinasi enfluran, deksmedetomidin, dan fentanil; didapatkan MAC yang lebih rendah namun bradikardia yang lebih hebat

Obat Agonis-2 klonidin atau deksmedetomidin menekan simpatis sekaligus

Key points Kombinasi obat merupakan bagian dari praktek

anestesia, namun dapat menjadi sumber morbiditas. Interaksi dari kebanyakan obat anestesi dapat diperkirakan secara kualitatif namun secara kuantitatif sulit diketahui dengan pasti. Kebanyakan interaksi obat-obat kardiovaskular merupakan perluasan farmakologi obat-obat itu sendiri. Kombinasi depresan sistem saraf pusat hampir selalu menghasilkan peningkatan efek SSP secara aditif atau sinergistik. Pengetahuan mengenai interaksi obat penting untuk sahli anestesi dalam merencanakan dan menggunakan obat-obat anestesia agar dapat memperoleh kondisi yang optimal dengan efek samping yang minimal.

OBJECTIVES: Describe the incidence and classification of

adverse drug effects. Explain the use and limitation of animal testing for drug toxicity. Describe the approach to minimizing adverse drug reactions. Explain the mechanisms underlying clinically important drug-drug interactions.

TOXICOLOGY?Toxicology is the science that defines the limits of safety of chemical agents. Overlap with pharmacology and pathology Types: Classical toxicology Industrial hygiene Environmental toxicology Forensic toxicology Clinical toxicology Mechanistic (molecular) toxicology

ADVERSE DRUG REACTIONS ?ADVERSE DRUG REACTIONS is all undesired consequences of drug administration Usually >10 drugs/hospitalization Small groups responsible for disproportionate number of reactions (analgesics, digoxin, anticoagulants, antineoplastics, hypoglycemics) Types: 1. Excess primary pharmacologic activity (mechanism-based) - Receptor mediated - Non-receptor mediated 2. Excess side-effects - behavioral changes, - drug dependence/addiction 3. Drug-drug interactions - Pharmacokinetic (delay drug clearance) - Pharmacodynamic

Incidence (in US) 18-30% of patients in hospital have an adverse

drug reaction Account for 3-5% of hospital admissions About 30% of adverse reactions are severe; can be fatal

IDIOSYNCRATIC DRUG REACTIONS Unexpected, individual reaction to a drug, Hyper-

reactivity Genetically-controlled abnormal responses (adverse reactions with known genetic basis) : Genetic basis for abnormal response has been established Mechanism may or may not be known, reactions may not related to known pharmacology of the drug Ethnic variability - Low incidence, often not detected during clinical trials e.g Atypical pseudocholinesterase Malignant hyperthermia

Atypical pseudocholinesterase Neuromuscular block by succinylcholine terminated by plasmacholinesterase, Patients have atypical pseudocholinesterase which metabolizes succinylcholine very slowly, resulting in prolonged apneaMalignant hyperthermia Inhalation anesthetics, succinylcholine Rapidly developing muscular rigidity and extreme hyperthermia Low incidence (1 in 20,000) but frequently fatal (60%) Treatment: dantrolene (ryanodine receptor antagonist)

Approach to Minimizing Adverse Drug Reactions Benefit vs. risk: Is the drug really necessary? Assessment of therapeutic effect: patient should only

continue to receive the drug if benefit is established. Assessment of toxicity: be aware of the toxicity of the drug (package insert) and alert for signs of toxicity. Avoid polypharmacy and therapeutic heroics. Apply pharmacokinetic principles (e.g. toxicity may develop gradually as steady state is reached over 4 half-lives). Individualize therapy where possible (age, body weight, disease state) Know patient drug history Be aware of idiosyncratic reactions, especially those with a known genetic basis (family history).

Hypersensitivity (drug allergy) Drug as hapten (covalent binding to protein can

form an immunogen) Antibodies raised against drug-protein adduct in subsequent drug Exposure elicits immune response (e.g., halothane hepatitis) Dose-response relationships unclear

Incidence Allergic reactions represent 10% of all

complications occurring during anesthesia Overall incidence is low 1 : 10,000 - 1 : 20,000 Unpredictable Life-threatening Mortality rate of 3 to 10% even when treated appropriately Often resistant to treatment

Allergic reactions 78% occur immediately following induction

16% occur during maintenance 6% occur during recovery 69% of patients experienced IgE anaphylaxis

31% of patients experienced non-IgE

(anaphylactoid) reactions

Anaphylactic vs Anaphylactoid Distinguishing between an anaphylactic and

anaphylactoid reaction is difficult Diagnosis based on patient evaluation and outcome long after the reaction has occurred Key distinction Immunoglobulin E (IgE) is present in anaphylactic reactions, and absent in anaphylactoid reactions

Particularly difficult to diagnose during Anesthesia Multiple drugs are administered in rapid succession

Onset can occur at any time Usually within minutes after injection Direct result of an allergy to a specific drug

Late onset indicates sensitivity to latex or volume

expanding fluids Drug preservatives can also be a contributing factor Severity and progression of symptoms vary widely between patients Reactions are dose INdependent

Anaphylactic vs Anaphylactoid Anaphylactic - an immediate systemic reaction

caused by rapid, IgE-mediated immune release of potent mediators from tissue mast cells and peripheral blood basophils

Anaphylactoid - immediate systemic reactions

that mimic anaphylaxis but are caused by nonimmune-mediated release of mediators or complement activation

Clinical features

coughing wheezing stridor tachypnea cyanosis facial swelling flare of histamine release diaphoresis periorbital edema vomiting Awake patients may exhibit: Loss of consciousness or a convulsive episode may be the initial sign of anaphylaxis

More severe clinical features

hypotension tachycardia bronchospasm pulmonary edema difficulty ventilating circulatory collapse decreasing O2 saturation rapid increase ETCO2 facial edema and perioral edema

Patients under anesthesia may exhibit:

hypotension, bronchospasm and cutaneous signs are usually the first manifestations of reaction flushing always affects the entire body, but edema mainly appears in the face, draping may prevent early detection of urticaria or angioedema

Four point severity scaleGrade I Cutaneous signs generalized erythema urticaria angioedema Grade II Significant but not life threatening symptoms cutaneous signs hypotension tachycardia respiratory difficulty Grade III Life threatening symptoms arrhythmias bronchospasm cardiovascular collapse Grade IV cardiac and/or respiratory arrest Death

Anaphylactic vs Anaphylactoid ReactionsAnaphylactoid less severe reactions 60% of patients have Grade I reactions 26% of patients have Grade II reactions 15% of patients have Grade III reactions Anaphylaxis - as clinical severity increases 13% of patients have Grade I reactions 22% of patients have Grade II reactions 60% of patients have Grade III reactions 2% of patients have Grade IV reactions

Anaphylaxis 70% are women Average age ~ 44 years 18% of patients have previous history of

systemic reaction to drugs 6% of patients report a history of food allergies The earlier the onset of symptoms = more severe the reaction

Anaphylactic reactions Profound vasodilatation, decreased venous return,

cardiac output falls significant hypotension increased heart rate Acute changes in vascular permeability, fluid moves into interstitial spaces Bronchial hyperactivity, bronchial edema, bronchospasm Alveolar hypoventilation, hypoxemia Respiratory & metabolic acidosis Decreased mixed venous O2 saturation Acute respiratory distress Most frequent causes of death -laryngeal edema -cardiovascular collapse

Clinically Important Mediators Histamine Leukotrienes Tryptase IgE antibodies

Histamine direct activation of H2

receptors indirectly by catecholamine release

Cardiovascular effects: Tachycardia Marked reduction SVR from vasodilation Coronary vasoconstriction Increased capillary permeability

Mast cell Main physiologic

source of Histamine Abundant in airways and skin Make & release many mediators Release triggered by antigens, drugs

Leukotrienes Breakdown product of

arachidonic acid Plays an important role in immunologically mediated anaphylaxis Effects : -Bronchoconstriction -Increased vascular permeability

Tryptase

Serves as an excellent marker of histamine release Normally blood levels are undetectable Elevated serum levels indicate that mast cell

activation with mediator release has occurred triggered by anaphylactic or anaphylactoid reactions 2 hour plasma half-life Maximum level of 25 mcg/L will capture the majority of anaphylactoid reactions, and also~ 60% of all anaphylactic reactions

Tryptase May not be readily available in smaller hospitals, but

can send to a reference lab Once a serum sample has been drawn, tryptase is fairly stable Tryptase levels should be measured whenever anaphylactoid or anaphylactic reactions are suspected Subsequent levels to show that tryptase has decreased are equally important Not only in evaluation and treatment but also medico-legally

Tryptase Increases capillary permeability Even very low doses results in airway edema the most fatal component of anaphylaxis No tryptase inhibitors available

Immunoglobulin E Antibody that binds to mast cells and causes

mediator release Anti IgE antibodies were first introduced in 2002 : - Very expensive - Only approved for the use in allergic asthma - Administered parenterally

What causes reaction? 5,644 cases of anaphylaxis during anesthesia

over last 25 years (1980-2004) 1. Muscle relaxants 3,509 (62%) 2. Latex 955 (17%) 3. Antibiotics 365 (6.4%) 4. Hypnotics 349 (6.1%) 5. Colloids 194 (3.4%) 6. Opioids 112 (1.9%) 7. Others 160 (2.8%)

NMBA 3,509 cases Succinylcholine 1,437 (41%) Vecuronium 905 (25%) Atracurium 475 (13%)

Rocuronium 387 (11%) Pancuronium 251 ( 7%) Mivacurium 40 ( 1%) Cisatracurium 11 (0.3%) Others 3 (0.08%)

NMBA Can produce dose-dependent, nonimmunologic

histamine release related to the rate of administration Quaternary ammonium ion in muscle relaxants is responsible for allergic reaction Cross sensitivity with one or more muscle relaxants is seen in 63% of cases

NMBA Muscle relaxants cross-react with compounds

containing quaternary and tertiary ammonium ions found in many drugs, foods, cosmetics, disinfectants, and industrial materials Because 90% to 95% of anaphylactic reactions to muscle relaxants occur in women, exposure to ammonium ion epitopes in cosmetics may elicit sensitization

Latex hypersensitivity 3 groups are at higher risk of reactions:

- health care workers - children with spina bifida and genitourinary abnormalities - workers with occupational exposure to latex should be considered as a possible cause of any reaction that occurs during anesthesia Most cases of latex-induced anaphylaxis occur about

30 minutes after induction Patients who have a prior history of contact urticaria or angioedema from rubber gloves, balloons, or condoms

Penicillin Most frequent cause of anaphylaxis among antibiotics Responsible for 75% of anaphylactic deaths in the US > 80% of patients with a history of allergy to penicillin do not have penicillinspecific IgE antibodies as detected by skintest Cephalosporins Common beta-lactam ring structure Varying degrees of cross-reactivity Risk of allergic reactions to cephalosporins in patients allergic to penicillin appears < 10% 1st generation cephalosporins allergic risk > 2nd or 3rd generation

Antibiotics

Colloids Incidence of allergic reactions

seems to be increasing Dextran more likely to cause a reaction than albumin or hetastarch More common in males than females Egg allergy not a contraindication to use of albumin (different protein)

Opioids Reactions to opioids are usually caused by

direct mast cell mediator release rather than IgE-dependent mechanisms Demerol produces greatest histamine release Most opioid-induced reactions are not lifethreatening include hives, pruritus, or mild hypotension

Aspirin and NSAIDs Non-IgE-mediated adverse effects Systemic reactions Bronchospasm, urticaria, angioedema, and

laryngeal edema No definitive skin or in vitro test to identify patients who are intolerant to Aspirin or NSAIDs

Protamine Both nonimmune and immune (IgE) mechanisms

have been reported Diabetics who have had treatment with protamine-containing insulin are 40 to 50 times more likely to have a life-threatening adverse reaction to intravenous protamine

Local anesthetics IgE-mediated systemic anaphylaxis is rare Usually due to paraaminobenzoic acid

metabolite from esters or the preservative methylparaben In patients who have had reactions to an ester-type local anesthetic, an amide should be considered for dose testing If the patient had a reaction to an amide, another amide may be used because crossreactivity among amides is rare

DiagnosisHistamine levels peak 5 to 15 minutes after onset decrease within 30 to 60 minutes in Grade I or II reactions levels remain high 1 to 2 hours after Grade III or IV reactions blood specimens must be processed immediately to prevent spontaneous basophil histamine release results in false positive elevated histamine levels urinary histamine is elevated for a longer duration Tryptase best marker of mast cell degranulation peak levels ~ 1 to 2 hours after onset levels decrease 11 to 12 hours later in most severe cases, levels remain detectable 24 hours after onset

DiagnosisIgE antibodies Serum assays NMBA, Thiopental, Latex Intradermal testing GOLD standard for detection of IgE dependent anaphylaxis must include all agents listed in the anesthesia record include latex perform 6 to 8 weeks after reaction

Intradermal testing 4-6 wks following event by a properly trained allergist + test is appearance of skin wheal at least 8 mm 20

Diagnosis

minutes following injection diluted solutions skin tests with general anesthesia agents are difficult to interpret many of these agents cause direct histamine release Maximal concentration in dilution is different among different muscle relaxants depends on histamine releasing : benzylisoquinoline > aminosteroid direct histamine release by muscle relaxants not sufficient to cause anaphylactic/anaphylactoid reactions

Anesthetic drugs with low histamine release capacityHypnotics Propofol Etomidate Ketamine Anesthetic gases Benzodiazepines Analgesics Fentanyl Alfentanil

Local anesthetics Lidocaine Bupivicaine Neuroleptics Droperidol Muscle Relaxants Vecuronium Pancuronium

Differential diagnosis Vasovagal reaction Ischemic heart disease Cardiac arrhythmia

Seizure disorder Carcinoid syndrome Mastocytosis Acute urticaria

Angioedema Asthma/ bronchospasm Aspiration Pulmonary embolis

Kinked ETT Surgical hypothermia in cold urticaria patients Hypoglycemia Hyperventilation syndrome

Panic attack

Prevention Identify those at risk

- History of allergic reaction to anesthesia - Children with multiple surgeries - Females in their 40s - Males in their 50s - Latex sensitivity (F>M) Slow administration of drugs Combined use of H1 and H2 blockers preoperatively can reduce tachycardia/bradycardia, hypotension, skin response, and even gastric pH changes induced by histamine release No specific treatment has been shown to reliably prevent the occurrence of anaphylaxis Allergy assessment must be performed in all highrisk patients

Prevention Strict avoidance of the causative agent in the anesthetic

technique is mandatory Reliance on potent inhalation agent for muscle relaxation Consider pretreatment with corticosteroids and antihistamines (H1 and H2 blockers) Prophylaxis should begin 24 to 36 hours prior to surgery Histamine blockers should be maintained for 24 to 72 hours after surgery Continue corticosteroids for one week In preoperative interview,be careful about possible predisposing factors, including known allergy or intolerance to drugs and/or foods Any past history of reactions during anesthesia, reactions to contrast media or latex should be elicited,also other predisposing conditions,such as mastocytosis or hereditary angioedema

Treatment of Anaphylaxis During AnesthesiaPrimary treatment : stop antigen administration maintain airway, administer 100% oxygen discontinue all anesthetic agents obtain additional IV access Fluids and vasopressor for hypotension Up to 40 percent loss of intravascular fluid into the interstitial space 20-50 ml/kg of lactated Ringer's solution, normal saline, or colloid solutions Additional volume may be necessary with persistent hypotension

Primary treatmentEpinephrine : Alpha1 effects to reverse hypotension, Beta2 effects for bronchodilation Inhibits mediator release by increasing cyclic AMP in mast cells and basophils rapid onset but short duration, doses repeated as necessary Dosage : 5 - 10 mcg IV, titrated doses for hypotension 0.1-1mg IV, titrated doses for cardiovascular collapse Use subcutaneous epinephrine in patients with laryngeal edema without hypotension Hypersensitive to Epinephrine Patients taking: tricyclic antidepressants MAO inhibitors cocaine or other stimulants

Secondary treatmentAnti histamine (Benadryl) 25 to 50 mg IV (up to 1.0 mg/kg) antihistamines compete with histamine at receptor sites but do not inhibit histamine release H1 and H2 antagonists will attenuate systemic effects in chemically mediated reactions May help reverse hypotension refractory to epinephrine and volume replacement H1 antagonists do not block H2 receptors H2 antagonists do not block H1 receptors H1 Benadryl (diphenhydramine) H2 (cimetidine) 400 mg IV Zantac (ranitidine) 150 mg IV Pepcid (famotidine) 20 mg IV

Secondary treatmentCorticosteroids (0.25-1.0g hydrocortisone) May alter the activation of other inflammatory cells following an acute reaction Onset 12 to 24 hours, which may attenuate recurring or late-phase reactions Useful in refractory bronchospasm or shock 1 to 2 g of methylprednisolone (30 to 35mg/kg) particularly useful in protamine reaction Bronchospasm refractory to epinephrine inhaled 2-adrenergic agents (albuterol or terbutaline) 4 to 12 metered dose inhaler puffs via ETT when nebulized, 0.25 to 1mL of albuterol in 2.5mL of normal saline

Secondary treatmentCatecholamine infusions Epinephrine 4-8 mcg/min for persistent hypotension or bronchospasm Norepinephrine 4-8 mcg/min use in patients with refractory hypotension due to decreased systemic vascular resistance Isoproterenol 0.5-1.0 mcg/min 1, 2 selective properties produce tachydysrhythmias, systemic vasodilatation used in patients with refractory bronchospasm, pulmonary hypertension or right ventricular dysfunction Profound 2 effects can produce systemic vasodilatation, use cautiously in hypotensive or hypovolemic patients Dopamine 3-20 mcg/kg/min Dobutamine 5-20 mcg/kg/min

Secondary treatment Sodium bicarbonate 0.5 to 1 mEq/kg

- acidosis diminishes the effect of epinephrine - for refractory hypotension or acidemia Phosphodiesterase Inhibitors- Aminophylline

- loading dose of 5 to 6 mg/kg - given over 20 minutes followed by an infusion of 0.5-0.9 mg/kg/hr - useful in patients with persistent bronchospasm and hemodynamic stability

Refractory cases not responding to epinephrine and volume replacemente.g. Patients on alpha or beta blockers Vasopressin 2 5 units Glucagon 1 mg IV -polypeptide hormone with potent chronotropic and inotropic effects (increases cAMP) - continuous infusion of 1 to 5 mg/hr may be required - monitor for hyperglycemia e.g. Patients receiving ACE inhibitors consider angiotensinamide

Life threateningFulminant non-cardiogenic pulmonary edema with hypovolemia following acute reaction intravascular volume repletion with careful hemodynamic monitoring colloids may produce a better response than crystalloids refractory hypotension, Monitor trans-esophageal echocardiography Evaluation of airway profound laryngeal edema persistent facial edema suggests airway edema may continue for 24 hours delay extubation before extubation : development of a significant air leak after endotracheal tube cuff deflation leakage test + direct laryngoscopy may be performed before extubation of the trachea

Patients under general anesthesia

- altered sympathetic responses, inhalational anesthetics interfere with compensatory response to shock - and cardiovascular dysfunction bronchodilators not of choice in treating bronchospasm following anaphylaxis, especially during hypotension Patients under spinal or epidural anesthesia

- partial sympathectomy, requiring even larger doses of Catecholamines

Early treatment with administration of

medications is recommended Patients who do not appear to have life threatening symptoms on initial presentation may progress to life threatening anaphylaxis Mediator release may be prolonged, producing biphasic anaphylaxis Some patients have a late or second phase of anaphylaxis, even after complete resolution of the first response Patients who receive epinephrine for the treatment of anaphylaxis may not improve sufficiently or may improve and then relapse

Laboratory analysis 1 to 2 hours - CBC with diff - Electrolytes, blood glucose, blood gases - PT, PTT, fibrinogen, platelets, FDP - Complement levels (C3, C4, C3a) - C1 esterase inhibitor - Total IgE - Serum tryptase - Urinary methylhistamine 6 hours - CBC with diff - Electrolytes, blood glucose, blood gases - PT, PTT, fibrinogen, platelets, FDP - Serum tryptase 24 hours - CBC with diff - Electrolytes, blood glucose, blood gases - PTT, PT, fibrinogen, platelets, FDP - Urinary methylhistamine

Be prepared Identify those at risk Training in recognition Posters in operating room Guidelines in treatment Guidelines for investigation Drugs for the immediate treatment of an

anaphylactic reaction should always easily available Kits for blood sampling readily available

Be prepared Inform the patient Document details in anesthetic record Refer patient to allergist familiar with testing

for anesthesia agents Patient must carry an allergy card to be shown for any subsequent anesthesia exposure Causative agent and drugs that cross react must be eliminated for life