ANGIOEDEMA, LARYNGEAL EDEMA DIAGNOSIS AND MANAGEMENT

1. ANGIOEDEMA, LARYNGEAL EDEMADIAGNOSIS AND MANAGEMENT Henriette Farkas Semmelweis University 3 rd Department of Internal Medicine Budapest, Hungary farkash@kut.sote.hu

2. UPPER AIRWAY OBSTRUCTION (UAO)AETIOLOGY MECHANICAL CAUSES Foreign body aspiration Infections Laryngeal edema Haemorrhage and haematoma Trauma Burns Neoplasm Congenital Miscellaneous LARYNGEAL EDEMA is a life-threatening condition characterized by acute or gradual onset with swelling of the laryngeal mucosa FUNCTIONAL CAUSES CNS depression Peripheral nervous system and neuromuscular abnormalities

3. PATIENT’S COMPLAINTS, SIGNS • Dysphagia • Sensation of a lump in the throat • Feeling of tightness • Voice changes • Hoarseness • Roughness • Resonant barky cough • Stridor • Dyspnea • Fear of asphyxation • Aphonia • Patient is unable to breathe, speak, or cough and may hold the throat • between the thumb and index finger (the universal choking sign) • Patient is anxious and agitated

4. PHYSICIAN EXAMINATION 1. Medical history (patient or relatives) • 2. Physical examination • Voice changes • Hoarseness • Roughness • Resonant barky cough • Stridor • Dyspnea • Aphonia • Patient is anxious and agitated • Vigorous attempts at respiration with intercostal and supraclavicular retraction • Patient becomes rapidly cyanosed • Respiratory efforts diminish • Loss of consciousness • Heart rate and blood pressure raised, bradycardia • Hypotension, cardiac arrest • Death is inevitable if the obstruction is not relieved within 2-5 minutes of the onset

5. EXAMINATION IN THE HOSPITAL flexible fibreoptic laryngoscopy Indirect laryngoscopy direct laryngoscopy Radiographic imaging AP and lateral plain neck radiographs, CT, MRI

6. Congenital stenosis Foreign body Recurrent paralysis Normal larynx Infection Laryngeal oedema Tumor

7. THE EFFECT OF EDEMA ON THE CROSS SECTIONAL AREA OF THE SUBGLOTTIC LARYNX

8. MANAGEMENT • Treatment consists of • immediately ensuring an adequate airway • administration of oxygen • intravenous fluids • epinephrine, antihistamines and steroids • C1-INH concentrate, bradykinin receptor B2 antagonist, kallikrein inhibitor or FFP

9. PRINCIPLES OF AIRWAY MANAGEMENT TECHNIQUES1. Try simple manoeuvres to open airway • Jaw thrust is used when other methods have failed. • Oro- or nasopharyngeal airway is useful in the unconscious patient. • If the patient is not immediately intubated the coma position should be used.

10. PRINCIPLES OF AIRWAY MANAGEMENT TECHNIQUES2. Endotracheal intubation Method of choice for the unconscious apnoeic patient

11. PRINCIPLES OF AIRWAY MANAGEMENT TECHNIQUES3. Surgical airway • cricothyroidotomy • percutanous tracheotomy • emergency tracheostomy

12. CRICOTHYROIDOTOMY Cricothyroidotomy is an emergency procedure when intubation or tracheotomy are impossible. Relatively easy way of providing an emergency airway. (cricothyroid membrane is near the skin surface)

13. PERCUTANOUS TRACHEOSTOMY PCT is cost-effective, safe, fast, and easy to perform

14. TRACHEOTOMY Emergency tracheotomy rarely required. Formal surgical tracheotomy under local anaesthesia may be a prudent approach under some controlled conditions.

15. CLASSIFICATION OF ANGIOEDEMA • ALLERGIC • NSAID-induced • Idiopathic • Associated with idiopathic or autoimmune urticaria • Associated with urticaria vasculitis • Infections and infestations • Angioedema with eosinophilia • Associated with some physical urticarias and with cholinerg urticaria • Associated with contact urticaria • Angiotensin- converting enzyme inhibitor-induced • C1-INH deficiency • Hereditary angioedema with normal C1-INH Kaplan, Graeves 2005

16. PATHOMECHANISM • IGE MEDIATED, I TYPE HYPERSENSITIVITY Roitt

17. COMMON ALLERGENS • Foods such as peanut,milk, nuts, shellfish, fish, eggs, and other foods. • Medications including penicillin and related or unrelated antibiotics, may produce allergic reactions. • Insect sting venom • Less common causes are latex rubber in surgical gloves and enema devices

18. SYMPTOMS May be localized or part of a systemic anaphylactic reaction • in acute allergic laryngeal edema, angioedema of the lips and supraglottis, glottis, and infraglottis results in airway obstruction • systemic reaction consists of a variable combination of urticaria (79%), bronchospasm (70%), shock, cardiovascular collapse and abdominal pain

19. Prick test DIAGNOSIS Specific IgE Use specific monoclonal antibodies against allergens

20. MANAGEMENT • ACUTE TREATMENT CONSISTS OF • immediately ensuring an adequate airway • and administration of oxygen, • intravenous fluids, • epinephrine:im, iv • antihistamines and steroids NEXT STEP hyposensibilisation (bee, wasp venom)

21. INFORMATION, EMERGENCY CARE KIT • Wear a medic alert bracelet at all times • Get information from patient’s doctor and the pharmacist before taking any medication • Read all food labels carefully • Carry with the patient an emergency care kit so that it can be self-administered epinephrine

22. CLASSIFICATION OF ANGIOEDEMA • Allergic • NSAID-induced • Idiopathic • Associated with idiopathic or autoimmune urticaria • Associated with urticaria vasculitis • Infections and infestations • Angioedema with eosinophilia • Associated with some physical urticarias and with cholinerg urticaria • Associated with contact urticaria • ANGIOTENSIN- CONVERTING ENZYME INHIBITOR-INDUCED • Acquired C1-INH deficiency • Hereditary angioedema Kaplan, Graeves 2005

23. KININ SYSTEM HW kininogen Angiotensinogen kallikrein renin Vasodilatation Increased vascular permeabity Angiotensin I bradykinin ACE BK metabolits Angiotensin II Vasoconstriction Vascular hypertrophy Aldosterone release

24. EFFECT OF ACE INHIBITORS kininogen angiotensinogen kallikrein renin Vasodilatation Increased vascular permeabity bradykinin Angiotensin I ACE ACE inhibitor Angiotensin II BK metabolits ATII Blocker Vasoconstriction Vascular hypertrophy Aldosterone release

25. ACE INHIBITORS 35 - 40 million patients worldwide are treated with ACE inhibitors, ACE inhibitors are generally well tolerated. ADVERSE EFFECTS: • Significant adverse effects include hypotension, renal • impairment, cough, and angioedema • Prevalence of angioedema: 0.1-0.7% Angiooedema can first manifest itself from a few hours to 10 years after an ACE inhibitor has been first taken.Therefore physicians fail to recognize the association.

26. MANAGEMENT OF ACE INHIBITOR-INDUCED ANGIOEDEMA ACUT TREATMENT Avoid ACE inhibitors Conservative treatmentantihistamines with or without steroids Tongue and upper airway are involved, intramuscular adrenaline should be used, some patients require an artificial airway C1 inhibitor concentrate,FFP, SDP, kallikrein inhibitor or bradykinin receptor antagonist has been successfully

27. MANAGEMENT OF ACE INHIBITOR-INDUCED ANGIOEDEMA LONG-TERM Should not be switched to another ACE inhibitor. Calcium channel blockers and/or thiazides are appropriate as alternative antihypertensives. Beta blockers are contraindicated in the initial setting. Alternative medications: are AT II receptor blockers Several cases of angioedema associated with ATII receptor although the overall incidence appears lower than that with ACE inhibitors.

28. CLASSIFICATION OF ANGIOEDEMA • Allergic • NSAID-induced • Idiopathic • Associated with idiopathic or autoimmune urticaria • Associated with urticaria vasculitis • Infections and infestations • Angioedema with eosinophilia • Associated with some physical urticarias and with cholinerg urticaria • Associated with contact urticaria • Angiotensin- converting enzyme inhibitor-induced • ACQUIRED C1-INH DEFICIENCY • HEREDITARY ANGIOEDEMA Kaplan, Graeves 2005

29. HEREDITARY ANGIOEDEMA (HAE) Type I (Donaldson, 1963) Type II (Rosen, 1965) Type III (Bork, Binkley, 2000, Martin 2001) C1-inhibitor (C1-INH) deficiency NormalC1-INH

30. HEREDITARY ANGIOEDEMA (HAE) Type I. II • autosomal dominant inheritance • deficiency of C1 inhibitor • onset of symptoms: in childhood • prevalence: 1:10 000, 1:50 0000 • mortality: 20-30 %

31. HEREDITARY ANGIOEDEMA (HAE)Type III • Mainly in vomen • Percipitating factors: oral contraceptive therapy, hormone replacement treatment, pregnancy • Symptoms: similar to HAE Type I and II • Subgroup: missense mutation in factor XII gene • Normal C1-INH function • Not respond antihistamine treatment • Tranexamic acid, C1-INH concentrate?

32. HEREDITARYANGIOEDEMA (HAE) TYPE I & II Autosomal dominant inheritance Deficiency of C1-inhibitor (C1-INH) Two phenotype HAE I and II Prevalence: 1/50 000 Mortality: 20-30% Osler Am J Med Sci 1888; DonaldsonAm J Med 1963; Rosen J Clin Invest 1971

33. C1-INH FXII FXIIa Prekallikrein C1 C42 HWK Kallikrein C1rs Plasminogén C2 kinin Bradykinin Plasmin PATHOMECHANISM edema

34. DIAGNOSIS OF HAE • pedigree analysis • genetic testing in HAE • Family history • Clinical symptoms • Measurement of complement asymptomatic • Confirm the diagnosis • in uncertain cases • Prenatal diagnostics AgostoniA Medicine 1992

35. SUBCUTANEOUS SYMPTOMS Farkas HActa Dermato-Venereol 2001

36. SUBCUTANEOUS SYMPTOMS Bork K Am J Med 2006

37. SUBMUCOSAL SYMPTOMSUpper airway mucosa Laryngeal edema Pharyngeal edema Bork K Transfus Apher Sci 2003; Tsunoda Laryngoscope 2000

38. SUBMUCOSAL SYMPTOMSIntestinal mucosa • intense, colicky abdominal pain • nausea and vomiting • postattack (watery) diarrhea • can mimic an „acute abdomen” Unnecessary surgical intervention Bork K Am J Gastroenterol 2006

39. ABDOMINAL ULTRASOUND Nonspecific but extremely sensitive method ascites edematous intestinal wall • In patients with known HAE • Differential diagnosis Recurrent abdominal complaints with ascites • HAE should be considered if all other differential diagnostic options have been ruled out. Farkas H Eur J Gastroenterol Hepatol 2001; Acta Paediatr 2002

40. COMPLEMENT PROFILES IN C1-INH DEFICIENCIES Agostoni A J Allergy Clin Immunol. 2004

41. MANAGEMENT COUNSELING & EDUCATION TREATMENT FOLLOW-UP Bowen J Allergy Clin Immunol 2004

42. COUNSELING & EDUCATION Individualized information to patient and parents Written information to school, pediatrician, &family practitioner Multilanguage infocard, hne service, hospitalfor emergencies Patient diary Drug for emergency Patient organizations, websites Farkas HTransfus Apher Sci 2003

43. TREATMENT stress minor trauma infection Elimination of precipitating factors drugs hormons (estrogens) Prophylaxis with drugs Management of attack Farkas HLancet 2001; Bouillet LDermatology 2003

44. PROPHYLAXIS WITH DRUGS Long-term antifibrinolytic agents (tranexamic acid) • ≥1 attack per monthor• history of life-threatening attacks attenuated androgens C1-INH concentrate Short-term attenuated androgens 5 days before the intervention and for 2 days after Before surgery and instrumentation on the oropharynx, head and neck C1-INH concentrate, SDP, FFP Cicardi M J Allergy Clin Immunol 1991;Farkas HJ Oral Maxillofac Surg 1999

45. SIDE EFFECTS ATTENUATED ANDROGENS ANTIFIBRINOLYTIC AGENTS Tranexamic acid Epsilon-amino-caproic acid Danazol, stanozolol, oxandrolone -seborrhoea, acne, hirsutism, weight gain, hair loss, deeping of the voice, menstrual irregularities,decrease breast size, myalgia, fatigue, headaches, SHBG ↓ -inzulin resistance↑, plasma glucagon↑, LDL, cholesterol↑, a HDL-cholesterol↓, Apo-AI and Apo-AII↓, TBG↓ -erythrocytosis, polycythaemia, thrombocytosis, eosinophylia, leukopenia, Prot. C, S ↑, antithrombin III ↑, haematuria -transaminase↑, hepatocellular adenomaand liver carcinoma thrombosis postural hypotension muscular pain and weekness creatine kinase ↑ aldolase ↑ rhabdomyolysis myositis fatigue Cicardi MJ Allergy Clin Immunol. 1997; Széplaki GJ Allergy Clin Immunol. 2005

46. FOLLOW-UP SIDE EFFECTS MINIMAL EFFECTIVE DOSE blood cell count liver & renal function, lipid profile,CK urinalysis abdominal ultrasound HIV, Hepatitis A,B,C, serology vaccination to Hepatitis B ADJUSTMENT OF THERAPY ALTERATION IN STATUS Gompels MClin Exp Immunol 2005; Farkas HLancet 1999

47. MANAGEMENT OF ATTACK pharyngeal/laryngeal face, lips edema abdominal attack severe edema of extremities, trunk neck& genitals SEVERE C1-INH concentrate, FFP,SDF Edema of the extremities, Mild abdominal attack tranexamic acid or danazol for 2-3 days MILD Corticosteroids, antihistamines, and epinephrine are INEFFECTIVE Farkas HJACI 2007; Prematta MAnn Allergy Asthma Immunol 2007; Bork KTransfusion 2005

48. FUTURE TREATMENT OPTIONS Trauma Prekallikrein Kallikrein inhibitor, DX88 XIIa Faktor ACE hC1-INH, rhC1-INH Kallikrein Bradykinin Des-Arg9-Bradykinin HMW-Kininogen Bradykinin receptor antagonist Icatibant edema Bork KJ Allergy Clin Immunol 2007; Van Doom MJ Allergy Clin Immunol 2005; Levy JExpert Opin Investig Drugs 2006

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