ANGIOEDEMA, LARYNGEAL EDEMAANGIOEDEMA, LARYNGEAL EDEMADIAGNOSIS AND MANAGEMENTDIAGNOSIS AND MANAGEMENT

Henriette Farkas Semmelweis University

3 rd Department of Internal MedicineBudapest, Hungary

farkash@kut.sote.hu

UPPER AIRWAY OBSTRUCTION (UAO)AETIOLOGY

MECHANICAL CAUSESForeign body aspirationInfections Laryngeal edema Haemorrhage and haematoma Trauma Burns Neoplasm CongenitalMiscellaneous

FUNCTIONAL CAUSESCNS depression Peripheral nervous system and neuromuscular abnormalities

LARYNGEAL EDEMA

is a life-threatening condition characterized by acute or gradual onset with swelling of the laryngeal mucosa

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

PHYSICIAN EXAMINATION

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

1. Medical history (patient or relatives)

EXAMINATION IN THE HOSPITAL

Indirect laryngoscopy

flexible fibreoptic laryngoscopy

direct laryngoscopy

Radiographic imagingAP and lateral plain neck radiographs, CT, MRI

Congenital stenosis

Infection Laryngeal oedema Tumor

Foreign bodyRecurrent paralysis

Normal larynx

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

Physical status

Neonate Child Adult

Normal

Subglottic area (mm2)

12 48 147

Effect of 1 mm edema

3 27 108

Reduction of airway area %

75 44 27

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

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.

PRINCIPLES OF AIRWAY MANAGEMENT TECHNIQUES2. Endotracheal intubation

Method of choice for the unconscious apnoeic patient

PRINCIPLES OF AIRWAY MANAGEMENT TECHNIQUES3. Surgical airway

• cricothyroidotomy • percutanous tracheotomy • emergency tracheostomy

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)

CRICOTHYROIDOTOMY

PERCUTANOUS TRACHEOSTOMY

PCT is cost-effective, safe, fast, and easy to perform

Emergency tracheotomy rarely required.

Formal surgical tracheotomy under local anaesthesiamay be a prudent approach under some controlled conditions.

TRACHEOTOMY

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

PATHOMECHANISM

IGE MEDIATED, I TYPE HYPERSENSITIVITY

Roitt

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

SYMPTOMS

• 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

May be localized or part of a systemic anaphylactic reaction

Prick test

DIAGNOSIS

Specific IgE Use specific monoclonal antibodies against allergens

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)

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

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

VasodilatationIncreased vascular permeabity

HW kininogen

bradykinin

BK metabolits

Angiotensinogen

Angiotensin I

Angiotensin II

VasoconstrictionVascular hypertrophyAldosterone release

ACE

reninkallikrein

KININ SYSTEM

VasodilatationIncreased vascular permeabity

kininogen

bradykinin

BK metabolits

angiotensinogen

Angiotensin I

Angiotensin II

VasoconstrictionVascular hypertrophyAldosterone release

ACE

reninkallikrein

EFFECT OF ACE INHIBITORS

ACE inhibitor

ATII Blocker

ACE INHIBITORS

35 - 40 million patients worldwide are treated with ACEinhibitors, ACE inhibitors are generally well tolerated.

ADVERSE EFFECTS:Significant adverse effects include hypotension, renalimpairment, cough, and angioedemaPrevalence of angioedema: 0.1-0.7%

Angiooedema can first manifest itself from a few hours to 10years after an ACE inhibitor has been first taken.Thereforephysicians fail to recognize the association.

MANAGEMENT OF ACE INHIBITOR-INDUCED ANGIOEDEMA

Avoid ACE inhibitors

Conservative treatment antihistamines with orwithout 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 antagonisthas been successfully

ACUT TREATMENT

MANAGEMENT OF ACE INHIBITOR-INDUCED ANGIOEDEMA

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.

LONG-TERM

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

Type I Type I (Donaldson, 1963)(Donaldson, 1963)

Type II Type II (Rosen, 1965)(Rosen, 1965)

Type IIIType III(Bork, (Bork, Binkley, 2000, Martin Binkley, 2000, Martin 20020011))

HEREDITARY ANGIOEDEMA (HAE)

C1-inhibitor (C1-INH) deficiency

Normal C1-INH

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 %

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?

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; Donaldson Am J Med 1963; Rosen J Clin Invest 1971

HEREDITARY ANGIOEDEMA (HAE) TYPE I & IIHEREDITARY ANGIOEDEMA (HAE) TYPE I & II

PATHOMECHANISM

FXII FXIIa

Prekallikrein

Kallikrein

HWK

BradBradyykininkinin

Plasminogén

Plasmin

C1

C1rs

C42

C2 kininC2 kinin

C1C1--INHINHC1C1--INHINH

edema

Family historyFamily history

CClinicallinical symptoms symptoms

Measurement of Measurement of complement complement

• pedigree analysis

• genetic testing in HAE

DIAGNOSIS OF HAE

asymptomatic

Confirm the diagnosisin uncertain casesPrenatal diagnostics

Agostoni A Medicine 1992

Farkas H Acta Dermato-Venereol 2001

SUBCUTANEOUS SYMPTOMS

SUBCUTANEOUS SYMPTOMS

Bork K Am J Med 2006

SUBMUCOSAL SYMPTOMS

Upper airway mucosa

Pharyngeal edema Laryngeal edema

Bork K Transfus Apher Sci 2003; Tsunoda Laryngoscope 2000

SUBMUCOSAL SYMPTOMS Intestinal mucosa

intense, colicky abdominal pain nausea and vomiting postattack (watery) diarrhea can mimic an „acute abdomen”

Unnecessary surgicalintervention

Bork K Am J Gastroenterol 2006

ABDOMINAL ULTRASOUNDNonspecific but extremely sensitive method

ascites edematous intestinal wall

Farkas H Eur J Gastroenterol Hepatol 2001; Acta Paediatr 2002

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.

COMPLEMENT PROFILES IN C1-INH DEFICIENCIES

TypeType C1qC1qC1-INHC1-INH

antigenantigenC1-INH C1-INH

functionfunction C4C4 Anti-Anti-C1-INHC1-INH

HAE-IHAE-I NN LL LL LL --

HAE-IIHAE-II NN N/HN/H LL LL --

AAE-IAAE-I LL LL LL LL --

AAE-II AAE-II

(autoimm.)(autoimm.)LL N/LN/L LL LL ++++++

Agostoni A J Allergy Clin Immunol. 2004

COUNSELING & EDUCATION

FOLLOW-UP

TREATMENT

MANAGEMENT

Bowen J Allergy Clin Immunol 2004

Individualized information to patient and parents

Written information to school, pediatrician, & family practitioner

Multilanguage infocard, hne service, hospital for emergencies

Drug for emergency

Patient diary

Patient organizations, websites

Farkas H Transfus Apher Sci 2003

COUNSELING & EDUCATION

TREATMENT

Elimination of precipitating factors

Prophylaxis with drugs

Management of attack

minor trauma

stress

drugs hormons

(estrogens)

infection

Farkas H Lancet 2001; Bouillet L Dermatology 2003

Long-term antifibrinolytic agents (tranexamic acid)

attenuated androgens

attenuated androgens5 days before the intervention and for2 days after

Short-term

Before surgery and

instrumentation on the

oropharynx, head and neck

C1-INH concentrate

C1-INH concentrate, SDP, FFP

• ≥1 attack per month or• history of life-threatening attacks

PROPHYLAXIS WITH DRUGS

Cicardi M J Allergy Clin Immunol 1991; Farkas H J Oral Maxillofac Surg 1999

SIDE EFFECTS

-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 adenoma and liver carcinoma

ATTENUATED ANDROGENS ANTIFIBRINOLYTIC AGENTS

thrombosispostural hypotensionmuscular pain and weeknesscreatine kinase ↑aldolase ↑rhabdomyolysis myositisfatigue

Tranexamic acidEpsilon-amino-caproic acid

Danazol, stanozolol, oxandrolone

Cicardi M J Allergy Clin Immunol. 1997; Széplaki G J Allergy Clin Immunol. 2005

SIDE EFFECTS MINIMAL EFFECTIVE DOSE

FOLLOW-UP

blood cell count liver & renal function, lipid profile, CK urinalysis abdominal ultrasound HIV, Hepatitis A,B,C, serology vaccination to Hepatitis B

ADJUSTMENT OF THERAPYALTERATION IN STATUS

Gompels M Clin Exp Immunol 2005; Farkas H Lancet 1999

MANAGEMENT OF ATTACK

pharyngeal/laryngealface, lips edemaabdominal attacksevere edema ofextremities, trunkneck & genitals

Edema of theextremities,Mild abdominal attack

tranexamic acid or danazol for 2-3 days

MILD

C1-INH concentrate, FFP,SDFSEVERE

Corticosteroids, antihistamines, and epinephrine are INEFFECTIVE

Farkas H JACI 2007; Prematta M Ann Allergy Asthma Immunol 2007; Bork K Transfusion 2005

XIIa Faktor

Trauma

Kallikrein

Prekallikrein

HMW-KininogenBradykinin

hC1-INH, rhC1-INH

ACE

Des-Arg9-Bradykinin

Bradykinin receptor Bradykinin receptor antagonist antagonist IcatibantIcatibant

Kallikrein inhibitor, DX88

edema

Bork K J Allergy Clin Immunol 2007; Van Doom M J Allergy Clin Immunol 2005; Levy J Expert Opin Investig Drugs 2006

FUTURE TREATMENT OPTIONS

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