1. OBJECTIVE OF DOCUMENT

No definitive clinical trials have been performed to provide an

unequivocal evidence base: moreover such evidence is

unlikely to be forthcoming. A wealth of experience does,

however, exist. This has been integrated through the wide

membership of the Project Team which was convened under

the aegis of the Resuscitation Council of the United Kingdom

with representation from four Royal Colleges and three

specialist associations: other members were coopted

because of their individual expertise. Consensus was

achieved after two meetings and multiple circulation of

working papers. An earlier document from broadly the same

group (but at that time representing the Joint Royal Colleges

and Ambulance Liaison Committee) has dealt with the

management of anaphylaxis by paramedics--who are often

the first to attend out of hospital emergencies.^[2] This

complementary document offers guidance to general

practitioners and A&E staff who are usually the first

physicians to become involved. Anaphylactic reactions may

occur within hospital as a result of attempted

hyposensitisation, the administration of drugs including

anaesthetic agents, or contrast materials. Some specialist

groups have issued recommendations for the management of

emergencies that occur under these specific

circumstances.^[3-5] The present guidance is not intended to

replace existing advice for defined groups in hospital nor to

influence the essential individual advice and management

provided in specialist clinics.

2. RECOGNITION OF ANAPHYLACTIC AND ANAPHYLACTOID REACTIONS>

2.1. There are no universally accepted definitions of

anaphylactic and anaphylactoid reactions. Disparate

mechanisms can lead to serious symptoms and signs due to

sudden activation of mast cells and basophils. The term

anaphylaxis is usually used for hypersensitivity reactions

typically mediated by immunoglobulin E (IgE). Anaphylactoid

reactions are similar, but do not depend upon

hypersensitivity. For simplicity the term anaphylaxis will be

used here for both types of reactions unless there is an

important distinction to be made. Their manifestations and

management are similar so that the distinction becomes

important only when considering the follow up management.

Both may present clinically with angio-oedema, urticaria,

dyspnoea, and hypotension. But some patients may die from

acute irreversible asthma or laryngeal oedema with few more

generalised manifestations. Other symptoms include rhinitis,

conjunctivitis, abdominal pain, vomiting, diarrhoea, and a

sense of impending doom. There is also usually a colour

change: the patient may appear either flushed or pale.

Cardiovascular collapse is a common manifestation ^[6]

especially in response to intravenous drugs or stings, and is

caused by vasodilatation and loss of plasma from the blood

compartment. Cardiac dysfunction or arrhythmias are due

principally to hypotension, or rarely to underlying disease,^{[7 8]}

or to epinephrine (adrenaline) that has been administered

intravenously.^[9] Anaphylactic reactions vary in severity and

progress may be rapid, slow, or (unusually) biphasic.^[10]

Rarely manifestations may be delayed by a few hours (adding

to diagnostic difficulty), or persist for more than 24 hours.^[7]

Reactions may follow exposure to a variety of agents--with

insect stings, drugs or contrast media, and some foods being

the most common. Peanut and tree nut allergy has recently

been recognised as particularly dangerous.^[11] Muscle

relaxants may cause anaphylaxis while anaesthetic agents

are important causes of anaphylactoid reactions.^{[3 12]}

Betablockers may increase the severity of an anaphylactic

reaction and antagonise the response to epinephrine

(adrenaline).^[13] They may also increase the incidence of anaphylaxis, but the data are limited and inconsistent. ^{[13 14]}

The complex nature of anaphylaxis has been described in

reviews.^[15-17]

2.2. The lack of any consistent clinical manifestation and a

wide range of possible presentations may cause diagnostic

difficulty. Clinical experience has shown that many patients

with genuine anaphylaxis do not always receive appropriate

medication. Rarely, patients have been given injections of

epinephrine (adrenaline) inappropriately for vasovagal

reactions or panic attacks. Diagnostic problems have arisen

particularly in children. Guidelines for the management of

shock from anaphylaxis must therefore take into account the

inevitability of some diagnostic errors, with an emphasis on

the need for safety of any recommended measures.

2.3. In each case, a full history and examination should be

undertaken as soon as circumstances permit. The history of

previous allergic reactions is important as well as that of the

recent incident. Special attention should be paid to the

condition of the skin, the pulse rate, the blood pressure, the

upper airways, and auscultation of the chest. Peak flow

should be measured where possible, and recorded.

2.4. No investigations can prove anaphylactic sensitivity to an

allergen other than giving a challenge with the suspect agent.

But an attempt should always be made retrospectively to

assess the likelihood that a severe reaction was genuinely of

an anaphylactic nature. While this is a matter for a specialist

clinic rather than part of emergency management, a possible

anaphylactic emergency provides an opportunity for specific

blood tests. Some rely on measurements of specific IgE

antibody: these are useful but must be interpreted carefully.

Measurement of mast cell tryptase can also assist with

retrospective diagnosis.^[18] Both of these tests can be

performed on 10 ml of clotted blood which hospitals can send

to a reference laboratory. Ideally blood should be taken 45 to

60 minutes after the reaction, but in any case not later than

six hours after the event. The use of blood tests is to be

encouraged because future management can be helped by

increased diagnostic certainty.

2.5. No reliable epidemiological data are available on the

incidence of anaphylaxis partly because of the difficulty

defining anaphylactic reactions, but one study found an

incidence of 1:2300 attendees at an A&E department

(equivalent to one episode per

15 000 of the population per annum) and fourfold more (approximately one in 3500 per

annum) in the second part of the study the following year.^[19]

Even the mortality is unknown. Some allergens may cause

short lived sensitivity. Second attacks are by no means

invariable in response to penicillin^[20] or contrast agents, and

approximately half remain vulnerable after insect stings.^[21]

Peanuts on the other hand, may leave patients with a

persistent predisposition to anaphylaxis after a first attack,

but eventual resolution occurs in some.

3. CONSIDERATIONS IN RELATION TO TREATMENT

3.1. Epinephrine (adrenaline) is generally agreed to be the

most important drug for any severe anaphylactic reaction,^{[6 22]}

although there has been no standard recommendation for

dose or route. As an alpha receptor agonist, it reverses

peripheral vasodilation and reduces oedema. Its beta

receptor activity dilates the airways, increases the force of

myocardial contraction, and suppresses histamine and

leukotriene release. Epinephrine (adrenaline) works best

when given early after the onset of the reaction^[22] but it is

not without risk, particularly when given intravenously.^[9]

Epinephrine (adrenaline) when given intramuscularly is very

safe. Adverse effects are extremely rare, and the only case of

myocardial infarction reported after its intramuscular

administration had numerous risk factors for coronary

disease.^[23] Sometimes there has been uncertainty as to

whether complications (for example myocardial ischaemia)

have been due to the effects of the allergen itself or to

epinephrine (adrenaline) given as treatment for it.

3.2. Epinephrine (adrenaline) may rarely fail to reverse the

clinical manifestations of anaphylaxis, especially in late

reactions or in patients treated with betablockers. Other

measures then assume greater importance, particularly volume

replacement.

3.3. Antihistamines (H₁ blockers) should be used routinely in

the management of all anaphylactic reactions to help counter

histamine mediated vasodilatation. They may be unhelpful for

at least some anaphylactoid reactions that depend in part on

other mediators but have the virtue of safety. Their use alone

is, however, unlikely to be lifesaving.

3.4. Corticosteroids are considered as slow acting drugs and

may take up to 4-6 hours to have an effect even if given

intravenously. They may, however, help in the emergency

treatment of an acute attack, and they also have a role in

preventing or shortening protracted reactions. They form an

essential part of management in recurrent idiopathic

anaphylaxis^{[24 25]} and are also of special importance to

asthmatics especially those who have been treated recently

with corticosteroids. Although some authors have expressed

cautions about steroids,^[25] and the contribution of individual

drugs when several are given is difficult to prove, clinical

experience shows that parenteral hydrocortisone is of value

in anaphylaxis. The safest practice is to use corticosteroids

for all victims likely to be suffering from a severe

anaphylactic reaction.

4. RECOMMENDATION FOR MANAGEMENT

4.1. The recommendations are summarised in algorithms

shown in fig 1 (for adults) and fig 2 (for children).

4.2. All victims should recline in a position of comfort. Lying

flat with or without leg elevation may be helpful for

hypotension but unhelpful for breathing difficulties. If

available, oxygen should be administered at high flow rates

(10-15 litres/min). Cardiopulmonary resuscitation must be

performed if the need arises.

4.3. Epinephrine (adrenaline) should be administered

intramuscularly to all patients with clinical signs of shock,

airway swelling, or definite breathing difficulty,^[6] and will be

rapidly absorbed. Manifestations such as inspiratory stridor,

wheeze, cyanosis, pronounced tachycardia, and decreased capillary

filling alerts the physician to the likelihood of a

severe reaction. For adults, a dose of 0.5 ml epinephrine

(adrenaline) 1:1000 solution (500 micrograms) should be

administered intramuscularly, and repeated after about five minutes

in the absence of clinical improvement or if

deterioration occurs after the initial treatment especially if

consciousness becomes--or remains--impaired as a result of

hypotension. In some cases several doses may be needed,

particularly if improvement is transient.

The doses of epinephrine (adrenaline) recommended for

children are as follows:
>11 years, up to 500 micrograms intramuscularly

(0.5 ml 1:1000 solution);

6-11 years, 250 micrograms intramuscularly

(0.25 ml 1:1000 solution);

2-5 years, 125 micrograms intramuscularly

(0.125 ml 1:1000 solution);

< 2 years: 62.5 micrograms intrascularly

(by additional dilution 1:1000 solution).


As for adults, doses may be repeated after five minutes if

necessary.

Devices for home use currently known as the EpiPen or

Anapen and the EpiPen Jr or Anapen Junior that can inject

300 micrograms or 150 micrograms respectively are

available. The drug may therefore have been administered by

parents before medical help is available. The doses can be

regarded as equivalent to the 250 micrograms and 125

micrograms more generally recommended. Other self

administration devices include Min-I-Jet Adrenaline which

contains 1 mg (1000 micrograms) of epinephrine (adrenaline).

This allows incremental dose selection, but it should not be

used in children because of the risk of overdose.

4.4. Intravenous epinephrine (adrenaline) in a dilution of at

least 1:10 000 (never 1:1000) is hazardous and must be

reserved for patients with profound shock that is immediately

life threatening and for special indications, for example

during anaesthesia. The injection should be given as slowly

as seems reasonable while monitoring heart rate and the

electrocardiogram. Electrocardiographic monitoring is

mandatory if epinephrine (adrenaline) is given intravenously. Note also that a further ten-fold dilution to 1:100 000

epinephrine (adrenaline) allows finer titration of the dose and

increases its safety by reducing the risk of unwanted adverse

effects and dangerous complications.^{[9 25]}

4.5. An antihistamine (chlorpheniramine) should be

administered. Caution is needed to avoid drug induced

hypotension: administer either by slow intravenous injection

or by intramuscular injection. Its use may be helpful and is

unlikely to be harmful. The dose for children and adults is

determined by age as follows:

• >11 years , 10-20 mg intramuscularly;
  
  
• 6-11 years, 5-10 mg intramuscularly;
  
  
• 1-5 years: 2.5-5 mg intramuscularly.

   

   

  4.6. Hydrocortisone (as sodium succinate) should be
  
  administered after severe attacks to help avert late sequelae.
  
  This is of particular importance for asthmatics (who are at
  
  increased risk of severe or fatal anaphylaxis) if they have
  
  been treated with corticosteroids previously. The dose of
  
  hydrocortisone should be given by slow intravenous or
  
  intramuscular injection--care being taken to avoid inducing
  
  further hypotension. The dose for adults and children is
  
  determined by age as follows^[4]
  
  :

   

• >11 years, 100-500 mg;
  
  
• 6-11 years, 100 mg;
  
  
• 1-5 years, 50 mg.

   

  4.7. If severe hypotension does not respond rapidly to drug
  
  treatment, fluid should be infused. A crystalloid may be safer
  
  than a colloid.^[26] A rapid infusion of 1-2 litres may be needed.
  
  Children should receive 20 ml/kg rapidly, followed by another
  
  similar dose if there is no clinical response.
  
  

  4.8. Patients with even moderately severe attacks should be
  
  warned of the possibility of an early recurrence of symptoms
  
  and in some circumstances should be kept under observation
  
  for 8-24 hours. This caution is particularly applicable to:
  
  

• Severe reactions with slow onset due to idiopathic
  
  anaphylaxis.
• Reactions in severe asthmatics or with a severe asthmatic
  
  component.
• Reactions with the possibility of continuing absorption of
  
  allergen.
• Patients with a previous history of biphasic reactions.

   

  4.9. An inhaled beta ₂ agonist such as salbutamol is useful^[27]
  
  as an adjunctive measure if bronchospasm is a major feature
  
  that does not respond rapidly to other treatment.

  4.10. All sufferers from anaphylaxis should be advised of the
  
  benefits of wearing some device such as a bracelet that will
  
  inform bystanders at the time of any future attack.
  
  Precautions should be taken, where practicable, to avoid
  
  exposure to the suspected allergen.

  4.11. Investigation and assessment at a specialist allergy
  
  clinic is recommended for all patients who have suffered a
  
  severe reaction.

  5. CAUTIONS

  5.1. In patients who are taking tricyclic antidepressants or
  
  monoamine oxidase inhibitors the dose of epinephrine
  
  (adrenaline) should be much reduced because of an
  
  interaction which is potentially dangerous. Some
  
  fluorohydrocarbons used as refrigerants as well as cocaine
  
  sensitise^[28] the heart to epinephrine (adrenaline) and are
  
  contraindications to its use.

  5.2. The use of epinephrine (adrenaline) by the intravenous
  
  route in the special circumstances given in paragraph 4.4
  
  should usually be reserved for medically qualified personnel
  
  who have experience of it, who know that it must be
  
  administered with extreme care, and who are aware of the
  
  hazards associated with its use.

  5.3. The subcutaneous route for epinephrine (adrenaline),
  
  sometimes recommended for children on anecdotal evidence
  
  only, has no role in anaphylaxis because its absorption is
  
  appreciably slower.^[29] Unnecessary delay in achieving
  
  adequate plasma concentrations is inappropriate when
  
  dealing with this emergency.

  5.4. Warnings must be given, when appropriate, in relation to
  
  the two strengths of epinephrine (adrenaline) that are
  
  available for injection. For anaphylaxis, epinephrine
  
  (adrenaline) is used in a dilution of 1:1000 intramuscularly
  
  whereas a dilution of 1:10 000 is used intravenously
  
  principally for cardiac arrest (with the rare additional
  
  indications outlined in paragraphs 4.4 and 5.2).

  5.5. All who treat anaphylaxis should be aware of the
  
  potential for confusion between anaphylaxis and a panic
  
  attack. Victims of previous anaphylaxis may be particularly
  
  prone to panic attacks if they think they have been
  
  re-exposed to the allergen that caused a previous problem. The
  
  sense of anxiety and breathlessness leading to
  
  hyperventilation are symptoms that resemble anaphylaxis in
  
  some ways. While there is no hypotension, pallor, wheeze, or
  
  urticarial rash/swelling, there may sometimes be an
  
  erythematous rash associated with anxiety which adds to the
  
  diagnostic difficulty.
  
  A mild anaphylactic reaction that
  
  triggers panic causes particular diagnostic difficulty. Problems can also arise with vasovagal attacks after
  
  immunisation procedures, but the absence of rash, breathing
  
  difficulties, and swelling is a useful distinguishing feature as
  
  is the slow pulse of a vasovagal attack compared with the
  
  rapid pulse of a severe anaphylactic episode.

  REFERENCES

  1 Ewan PW. Treatment of anaphylactic reactions. Prescribers' Journal 1997;37:125-32.
  
  2 Statement from the Resuscitation Council (UK) and the Joint Royal Colleges Ambulance Service Liaison Committee. The use of adrenaline for anaphylactic shock (for ambulance paramedics). Ambulance UK 1997;12:16.
  
  3 Association of Anaesthetists of Great Britain and Ireland and British Society of Allergy and Clinical Immunology. Suspected anaphylactic reactions associated with anaesthesia. Revised edition. London: 1995.
  
  4 Board of Faculty of Clinical Radiology, Royal College of Radiologists. Advice on the management of reactions to intravenous contrast media. London: Royal College of Radiologists, 1996.
  
  5 Department of Health, Welsh Office, Scottish Office Department of Health, DHSS (Northern Ireland). Immunisation against infectious disease. London: HMSO, 1996.
  
  6 Fisher M. Treatment of acute anaphylaxis. BMJ 1995;311:731-3.
  
  7 Fisher M McD. Clinical observations on the pathophysiology and treatment of anaphylactic cardiovascular collapse. Anaesth Intensive Care 1986;14:17-21.
  
  8 Jones E, Joy M. Acute myocardial infarction after a wasp sting. Br Heart J 1988;59:506-8.
  
  9 Barach EM, Nowak RM, Lee TG, et al. Epinephrine for treatment of anaphylactic shock. JAMA 1984;251:2118-22.
  
  10 Douglas DM, Sukenick E, Andrade WP, et al. Biphasic systemic anaphylaxis: an inpatient and outpatient study. J Allergy Clin Immunol 1994;93:977-85.
  
  11 Ewan PW. Clinical study of peanut and nut allergy in 62 consecutive patients; new features and associations. BMJ 1996;312:1074-8.
  
  12 Fisher M McD, Baldo BA. Anaphylactoid reactions during anaesthesia. Clinics in Anaesthesiology 1984;2:677-92.
  
  13 Toogood JH. Risk of anaphylaxis in patients receiving beta-blocker drugs. J Allergy Clin Immunol 1988;81:1-5.
  
  14 Hepner MJ, Ownby DR, Anderson JA, et al. Risk of systemic reactions in patients taking beta-blocker drugs receiving allergen immunotherapy injections. J Allergy Clin Immunol 1990;86:407-11.
  
  15 Bochner BS, Lichtenstein LM. Anaphylaxis. N Engl J Med 1991;324:1785-90.
  
  16 Brown AFT. Anaphylactic shock: mechanisms and treatment. J Accid Emerg Med 1995;12:89-100.
  
  17 Ewan PW. Anaphylaxis. BMJ 1998; 316:1442-5.
  
  18 Schwartz LB, Bradford TR, Rouse C, et al. Development of a new, more sensitive immunoassay for human tryptase: use in systemic anaphylaxis. J Clin Immunol 1994;14:190-204.
  
  19 Stewart AG, Ewan PW. The incidence, aetiology and management of anaphylaxis presenting to an accident and emergency department. Q J Med 1996;89:859-64.
  
  20 Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy 1988;18:515-40.
  
  21 Hunt KJ, Valentine MD, Sobotka AK, et al. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978;299:157-61.
  
  22 Patel L, Radivan FS, David TJ. Management of anaphylactic reactions to food. Arch Dis Child 1994;71:370-5.
  
  23 Saff R, Nahhas A, Fink JN. Myocardial infarction induced by coronary vasospasm after self-administration of epinephrine. Ann Allergy 1993;70:396-8.
  
  24 Wiggins CA, Dykewicz MS, Patterson R. Idiopathic anaphylaxis: a review. Ann Allergy 1989;62:1-5.
  
  25 Brown AFT. Therapeutic controversies in the management of acute anaphylaxis. J Accid Emerg Med 1998;15:89-95.
  
  26 Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: a systematic review of randomised trials. BMJ 1998;316:961-4.
  
  27 Turpeinen M, Kuokkanen J, Backman A. Adrenaline and nebulised salbutamol in acute asthma. Arch Dis Child 1984;59:666-8.
  
  28 Cregler LL. Cocaine: the newest risk factor for cardiovascular disease. Clin Cardiol 1991;14:449-56.
  
  29 Simons FE, Roberts JR, Gu X, et al. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol 1998;101:33-7.

   

  MEMBERS OF THE PROJECT TEAM

  
  Professor Douglas Chamberlain (Chairman)
  
  Dr Judith Fisher (also for the Royal College of General Practitioners)
  
  Dr Michael Ward (also for The Association of Anaethetists)
  
  

  CO-OPTED
  Dr Andrew Cant (for the Royal College of Paediatrics & Child Health
  
  Dr Peter Dawson (for the Royal College of Radiologists)
  
  Dr Pamela Ewan (for the Anaphylaxis Campaign)
  
  Mrs Angela Fritz (for the Anaphylaxis Campaign)
  
  Dr Gideon Lack (for the British Society for Allergy & Clinical Immunology
  
  Professor Tak Lee (for the British Society for Allergy & Clinical Immunology
  
  Dr John Martin (for the British National Formulary)
  
  Dr Barbara Phillips (for the Royal College of Paediatrics & Child Health)
  
  Dr Richard Pumphrey (for the Royal College of Pathologists)
  
  Dr George Rylance (for the Royal College of Paediatrics and Child Health)
  
  Mr Howard Sherriff (for the British Association of Emeregency Medicine)
  
  Professor David Warrell (for the Royal College of Physicians)
  
  

  This report was written by a Project Team which was
  
  convened under the aegis of the Resuscitation Council (UK)
  
  with representation from four Royal Colleges and three
  
  specialist associations. It is available in booklet form and
  
  may be obtained from the Council office at a price of £3.00.
  

   

  The Resuscitation Council (UK) would like to thank the BMJ
  
  Publishing Group for permission to reproduce these
  
  guidelines from the Journal of Accident & Emergency
  
  Medicine 1999: 16(4)243-247.