AnaphylaxisDifferences between countries

Anne Berit GuttormsenDepartment of Anaesthesia and Intensive Care,

Haukeland University Hospital and Section for Anaesthesiology and Intensive Care,

Department of Surgical Sciences, Medical Faculty, University of Bergen

Aetiology

• Allergy is common, but progression of an allergic

reaction to a severe life-threatening condition is

rare.

• Most common causes of the life-threatening

reactions are drugs, stinging insects and food.

European Resuscitation council Guidelines for Resuscitation 2005

Early signs

• Urticaria

• Rhinitis

• Conjunctivitis

• Abdominal pain

• Vomiting and diarrhoea

• Flushing or pallor

European Resuscitation council Guidelines for Resuscitation 2005

Diagnosis is difficult

• Due to

– Lack of consistent clinical information

– A wide range of presentations

• Always exclude anaphylaxis as the cause

of the reaction.

– Misinterpretation might be fatal!

Anaphylaxis

• An acute general

hypersensitivity reaction– That takes place seconds/minutes

after exposure with the

drug/specimen in question

– The reaction involves one or more

organ systems

– The symptoms vary

• Often dramatic, potentially

lifethreatening

– Several mechanisms

• IgE/Non IgE

• Non allergic

Classification

• Grade 1: Symptoms from the skin, only

• Grade 2: Systemic, not lifethreatening

• Grade 3: Systemic, lifethreatening

• Grade 4: Asystoli/or respiratory arrest

• Grade 5: Death

Ring J, Messmer K. Lancet 1977

IgE-mediated

allergicNon-allergic

Codeine, NMBA,

fMLP, C3a, C3b etc .

Histamine

Cytokines

Tryptase, etc

CD63

Design; Anna Nopp/SGO

Johansson

Mechanisms

Patients

Patient 1 Male born 1972 (2006)

• He developed an itchy head, dizziness, facial oedema and

hypotension 10-20 minutes after taking cough-syrup containing ethyl

morphine.

• His wife suspected anaphylaxis and took him to hospital.

• On admission; BP was 84/58 mmHg, declining to 68/40 mmHg, and

he still had the facial oedema.

• He was treated with adrenaline, i.v. fluids, steroids and

antihistamines. He stabilized.

• Observed at the hospital for one night.

• (2005) Spinal anaesthesia, Bupivacaine with

fentanyl. After 50 minutes; Urticaria, face,

thorax lower part of abdomen and groins, itching

sensation on his palms. A small decrease in

blood pressure.

• Treatment

Ephedrine 10 mg, antihistamine and steroids

Patient 2 Male born 1935 (2005)

• (2001) Had Corsodyl mouth rinse – after surgery in the

mouth performed by the dentist. Five minutes after

exposure his body felt “itchy and strange”

• He left the dentist office, went to his car, turned the

switch, and 30 minutes later he woke up in the

Emergency Department, at the local hospital

• He lost his drivers licence for 3 months because doctors

thought he had a heart problem

• Although the patient was convinced that the reaction was

due to the mouth rinse

Patient 3 Pregnant female born 1962 (2006)

1987

• Forceps delivery – performed without general

anaesthesia. She was stable during the procedure

• Cervical laceration – suture in general anaesthesia

• Induction of general anaesthesia

– Fentanyl, Thiopenthone, Suxamethonium

• After induction she became cyanotic and

hypotensive

• Treatment: Rapid infusion of dextran, iv

ephedrine. Still low BP

• Reasons: Embolus to the lungs, amniotic fluid

embolus, sepsis or allergy.

1990

• Planned caesarean in general anaesthesia. She believes

that she will die during the procedure!

• Induction: Fentanyl, Thiopentone and suxamethonium.

• Reaction: BP dropped to 48 mm/Hg systolic.

Vasoconstriction, bronchospasm, cyanosis, oedema in

the face and the tongue.

• Treatment: Adrenaline 0,1 mg/ml in increments,

Ephedrine in increments and steroids

No follow-up – no warning card!

Patient 4 Female born 1942 Breast cancer surgery (2005)

• Daycare surgery

• Premedication; paracetamol and a NSAID

• Induction; remifentanil and propofol, circulation stable.

• Subcutaneous injection of Patent Blue (sentinal node)

• 20 minutes after induction;

– BP cannot be measured,

– Sinus rhythm on ECG

– Read skin, but no urticaria,

– No bronchospasm

– Saturation 68-78% on FiO2 1.0.

– 10 minutes with BP < 65 mmHg systolic

• The Emergency team was alarmed

• Treatment

• Chest compressions

• Intubation

• Extra iv lines

• Arterial line

• Ephedrine and phenylephrine

• Increments i.v with adrenaline, total 4 mg,

• Adrenaline infusion 0,1 µg/kg/min - 0,02 µg/kg/min

• Fluids

Follow-up

• Patient 1 Patient drinking cough syrup

– He refused re-challenge - but the most probable cause to the

reaction was ethyl-morphine –no other exposure

– He had antibodies towards morphine and pholcodine in serum

– Incremental challenge up to 5 mg showed tolerance to morphine.

• Patient 2 Patient with mouth rinse and spinal anaesthesia

– IgE mediated reaction towards Chlorhexidine – specific IgE and

positive skin test.

– Chlorhexidine in the mouth rinse and in the disinfectant used to

wash the operation field

• Patient 3 Pregnant female

– Suxamethonuim – identified 19 years after the

first reaction – the GP referred her

• Patient 4 Patient with breast cancer

– Patent blue

Urticaria in a patient with a suspected reaction on

patent blue

Photo: ABGuttormsen

There was a complete match between the

suspected cause and the result of

follow-up in only 7% of the cases

Challenges

• Early diagnosis

• Early and adequate treatment– Adrenaline and fluids are the cornerstones in treatment

Diagnosis and treatment are difficult!

91doctors from different specialties answered questionnaire about treatment of anaphylaxis:

92 % would give adrenaline as first line treatment

20% knew correct dose and route of administration

43% would give iv, 20% of these in doses of 1mg or greater!

Thain S, Rubython. N. Z. Med. J. April 2007

42 anaesthetists in anaphylaxis simulation:

0 made the diagnosis within 10 minutes

6 teams considered anaphylaxis after 15 minutes and heavy hints from

instructor

0 teams had a plan for treating anaphylaxis

Jacobsen Jet al. AAS 2001 45: 315-319

Study of fatal anaphylaxis

124 fatal reactions in Great Britain 1992-1998

• 47 in hospital, 31 of these in operating theatre

• Incidence 1:10.000.000 population

• Most reactions to drugs happen within 5 minutes of administration, mainly circulatory symptoms

Reasons for death:

• 48 cases no administration of adrenaline

•

• 60 cases late administration of adrenaline

• 1 case lack of clinical response to adrenaline

• 3 cases too high doses of adrenaline for mild reactions

RSH Pumphrey, Clin exp allergy 2000; 30: 1144-1150

• Identify risk patients

– Patients who have suffered severe

anaphylaxis

• A standardized follow-up to identify the

cause of anaphylaxis in risk patients

Key to success

”Anaphylaxis kit”

Reporting

Hud

Ventrikkeltachycardi

Ventrikkelfl immer

Asystoli

Annet.......................

Ingen endring

Endring av rytme

Bronkospasme

Luftveisødem

Ingen reaksjon

Ventilasjon

Kramper

Annet .............................

Ingen reaksjon

CNS

Brekning

Annet ............................

Ingen reaksjon

GI

Andre manifestasjoner

AnnetTekstReaksjonsbilde

Reaksjonsbilde

Høyeste målte

luftveistrykk

Laveste målte BT

Tid hypotensiv -

SAP<80 mmHg

Hjertefrekvens

Laveste

målte

metning

Rubor

Urticaria

Angioødem

Ingen reaksjon

/ mmHg

minutter

/min

cmH2O

%

Design Torkel Harboe

Differences between countries

• Prevalence of anaphylaxis caused by

NMBAs

– High in Norway, France, New Zealand

– Low in Denmark, Sweden, USA

History• NMBA introduced to clinical practice in the early

1950ies

• Rocuronium (Esmeron) – 1996, Market share ~50%

• 2001 – Advice from Legemiddelverket – to use only on indication

• 2003 – Not enough evidence to claim that Rocuronium (Esmeron) causes anaphylaxis more often than the other NMBAs

• Still little use of Rocuronium (Esmeron) in Norway

HO

H

O

HO

N

Morphine

OO

H OH

H

N

Ethyl morphine

O

HO

N

H

H

H

N

O

O

+Rocur onium

H

(H3 C)3 N

+

Suxamethonium

O

O

O

ON(CH

3)3

+

O

NCH3

H

HO

HO

Morphine

O

NCH3

H

O

HO

N

O

Pholcodine

Morphine and pholcodine (PHO) are monovalent for two,

noncross reacting allergenic epitopes

QAI MOR/PHO Mo+

SGO Johansson

HO

H

O

HO

N

Morphine

OO

H OH

H

N

Ethyl morphine

O

HO

N

H

H

H

N

O

O

+Rocur onium

H

(H3 C)3 N

+

Suxamethonium

O

O

O

ON(CH

3)3

+

O

NCH3

H

HO

HO

Morphine

O

NCH3

H

O

HO

N

O

Pholcodine

IgE-mediated

allergicNon-allergic

Codeine, NMBA,

fMLP, C3a, C3b etc .

Histamine

Cytokines

Tryptase, etc

CD63

Design; Anna Nopp/SGO

Johansson

Mechanisms

“Morphine RIA is the most appropriate in vitro test for the

detection of IgE antibodies that cross-react with substituted

ammonium ions and hence for the in vitro diagnosis of NMBD-

induced anaphylaxis”.

M.Rose and M. Fisher, Brit J Anaest 2001;86:678-82

IgE antibodies to suxamethonium, morphine and

pholcodine in serum of Norwegian “nonallergics” (blood donors)

• Suxamethonium

2/500 (0.4 %)

• Morphine

25/500 (5.0 %)

• Pholcodine

30/500 (6.0 %)

Sales figures for pholcodine

• DDD per million inhabitants (1994-1998)

– Norway: 2773

– France: 2936

– United kingdom: 1522

– Ireland 3837

– New Zealand: 1458

– Finland: 944

– Denmark: 2

– Sweden 0

– USA 0

Pholcodine stimulates a dramatic increase of

IgE in IgE-sensitized individuals. A pilot study.

E. Florvaag, S.G.O. Johansson, H. Öman,

T. Harboe, A. Nopp

Haukeland University Hospital, Bergen, Norway,

Karolinska University Hospital, Stockholm, Sweden

Allergy 2006, 61:49-55

Cough syrup exposure test

Two PHO-sensitized and two non-sensitized,

healthy individuals were taking codeine alt.

noscapine (negative control) for one week

followed by one week of an OTC cough syrup

containing pholcodine.

Serum levels of IgE and IgE antibodies to

PHO, MOR and SUX were followed before

and after exposure.

Close this WindowFlorvaag, E., Johansson, S. G. O., Öman, H., Harboe, T. & Nopp, A.

Pholcodine stimulates a dramatic increase of IgE in IgE-sensitized individuals. A pilot study.

Allergy 2005: 61 (1), 49-55.

• IgE increases 60-105

times

• Ig-ab to PHO, MOR,

SUX increase 30-80

times

t1/2: 40 dager

t1/2: 10 dager

Further studies

• The ISPHO study; International study of

pholcodine

• Animal experiments to elucidate how

pholcodine triggers IgE synthesis

How do we become better?• To train

– Patients

– Relatives

– Paramedics

– Nurses

– Doctors

• Anaphylaxis drill among hospital employees

• Focus on– How to recognize anaphylaxis?

– How to treat – appropriate doses and correct administration of adrenaline

– How to prevent new anaphylactic episodes – to perform follow-up

Guideline

Limited knowledge

Adrenaline - adults

Moderate reaction 10 - 50 µg i.v

Circulatory collapse 0,1 -1 mg i.v.

Titrate

Fluids

Crystalloid 20 ml/kg

In conclusion• Be Alert

• Be Aggressive in your approach

• To give Adrenaline and Fluids

Strategy for secondary follow-up• All patients surviving an anaphylactic shock must have a

follow-up

• Testing all drugs/substances encountered beforereaction

• Risk assessment• Which drugs/specimens should be avoided?

• Patients with in-hospital anaphylaxis are tested with latex and chlorhexidine

Garvey LH et al Acta Anaesthesiol Scand 2001

Harboe T et al, Anaesthesiology 2005

HO

H

O

HO

N

Morphine

OO

H OH

H

N

Ethyl morphine

O

HO

N

H

H

H

N

O

O

+Rocur onium

H

(H3 C)3 N

+

Suxamethonium

O

O

O

ON(CH

3)3

+