Approach to Anaphylaxis By: Muhamad Na’im B. Ab Razak

Universiti Sains Malaysia

Case scenario 10 years old malay boy presented to casualty after developing pruritic rash with shortness of breath. Prior to presentation, he is on oral antibiotic for skin infection. Physical examination shows urticaric rash to the arm, trunk and leg. Chest auscultation reveals generalized rhonci and fine crepitation. Recorded vital sign are as follows BP: 110/ 66 (97 – 122/ 57 – 71) PR: 136 (60 – 140) RR: 26 (18 – 30) T: 37°C He was treated with IV hydrocortisone 100mg stat, IM Piriton 5 mg stat and salbutamol nebulizer stat. after 20 minutes, the rash are settled. Chest auscultation reveals no more rhonci and crepitation. He was discharged 10 minutes later with tab. Piriton 4 mg t.d.s On the following night after discharged, he was brought again to the hospital with similar problem. Questions

1) Define anaphylaxis and anaphylactoid 2) What is the pathophysiology behind the condition? 3) What is gold standard for anaphylaxis management? 4) What is the role of steroid in treating the anaphylaxis? 5) Role of anti histamines in treating anaphylaxis. 6) Do you think that this patient should be discharged at the first place? 7) Outline your management for the second presentation and what advise would you give to

the mother?

Anaphylaxis and anaphylactoid There is no universal agreement on the definition of anaphylaxis or the criteria for establishing its diagnosis, although it has been known to the field of emergency medicine for more than 100 years.[Rohit Sharma et al] Anaphylaxis is a type I immune-a specific immunoglobulin IgE–in mast cell degranulation and basophil activation [Rohit Sharma et al] The term anaphylaxis refers to an acute, potentially life threatening, systemic allergic disorder that involves the cardiovascular or respiratory system, or both. Anyphylactoid has similar presentation with anaphylaxis but without IgE involvement. Among the proposed mechanism are; 1) Kinin production from activation of coagulation or fibrinolysis, 2) activation of complement cascade (eg by gelofusine), 3) modulation of arachidonic acid metabolism (aspirin) and 4) direct histamine release (opiods, contrast injection) Distinction between anaphylacticrecommended as the clinical picture and emergencyregardless of the patho-physiological mechanism [Aziz Sheikh et al, 2009] Clinical Diagnosis of Anaphylaxis based on

Anaphylaxis and anaphylactoid

There is no universal agreement on the definition of anaphylaxis or the criteria for establishing its diagnosis, although it has been known to the field of emergency medicine for more than 100

-mediated, lifethreatening severe systemic allergic reaction. It is –mediated, antigeninduced reaction to various allergens resulting

in mast cell degranulation and basophil activation [Rohit Sharma et al]

The term anaphylaxis refers to an acute, potentially life threatening, systemic allergic disorder ascular or respiratory system, or both. [Aziz Sheikh et al, 2005]

Anyphylactoid has similar presentation with anaphylaxis but without IgE involvement. Among the proposed mechanism are; 1) Kinin production from activation of coagulation or fibrinolysis,

activation of complement cascade (eg by gelofusine), 3) modulation of arachidonic acid metabolism (aspirin) and 4) direct histamine release (opiods, contrast injection)

Distinction between anaphylactic reactions and an anaphylactoid reaction is no longerrecommended as the clinical picture and emergency treatment of anaphylaxis are similar

physiological mechanism [Aziz Sheikh et al, 2009]

Clinical Diagnosis of Anaphylaxis based on Journal of Allergy and Clinical Immunology

There is no universal agreement on the definition of anaphylaxis or the criteria for establishing its diagnosis, although it has been known to the field of emergency medicine for more than 100

mediated, lifethreatening severe systemic allergic reaction. It is ted, antigeninduced reaction to various allergens resulting

The term anaphylaxis refers to an acute, potentially life threatening, systemic allergic disorder et al, 2005]

Anyphylactoid has similar presentation with anaphylaxis but without IgE involvement. Among the proposed mechanism are; 1) Kinin production from activation of coagulation or fibrinolysis,

activation of complement cascade (eg by gelofusine), 3) modulation of arachidonic acid

reactions and an anaphylactoid reaction is no longer treatment of anaphylaxis are similar

Journal of Allergy and Clinical Immunology

Pathophysiology of Anaphylaxis

Picture from ABC of allergies: Anaphylaxis by Pamela W Ewan

Picture from ABC of allergies: Anaphylaxis by Pamela W Ewan

Gold standard for anaphylaxis management Epinephrine is the medication of choice in the first-aid treatment of anaphylaxis in the community. For ethical reasons, it is not possible to conduct randomized, placebo-controlled trials of epinephrine in anaphylaxis; however, continued efforts are needed towards improving the evidence base for epinephrine injection in this potentially fatal disease.[Simons KJ et al, 2010] Epinephrine is the recommended first-line treatment for anaphylaxis and moderate-to-severe croup [Walker DM, 2009] Cochrane review also found no prospective controlled trials on the benefits of adrenaline in anaphylaxis eligible for inclusion.......adrenaline as first line treatment for anaphylaxis, based on expert consensus and indirect observational data [D A Andreae et al, 2009] Key point from journal by Sarah L Johnston et al, 2003

1) Authors reported a case to show the dangers of inappropriate treatment with adrenaline for mild urticaria or angio-oedema in the absence of cardiovascular or respiratory features of anaphylaxis.

2) Intravenous adrenaline should be reserved for extreme emergencies when there is doubt about the adequacy of the circulation

3) In practice, guidelines advise careful titration of the 1 in 10 000 intravenous preparation only by experienced medical staff, with adequate cardiac monitoring.

4) In the context of life threatening shock or anaesthetic anaphylaxis where there features of systemic anaphylaxis,adrenaline was therefore not indicated

Key point from journal by Andrew P C McLean-Tooke et al, 2003

1) Adrenaline is the recommended first line treatment in anaphylaxis 2) Inappropriate use of adrenaline may be dangerous. 3) Those particularly at risk include elderly patients and patients with hypertension,

arteriopathies, or known ischaemic heart disease 4) The benefit of using appropriate doses of intramuscular adrenaline far exceeds the risk

(grade C). 5) inhaled adrenaline by way of a pressurised aerosol have given conflicting results 6) Intravenous adrenaline has been associated with the induction of fatal cardiac arrythmias

and myocardial infarction. Major adverse effects usually occur when adrenaline has been given too rapidly, inadequately diluted, or in excessive dose (grade C).

7) No comparative trials have been conducted for the difference suggested dose of adrenaline injection.

8) Anaphylaxis may be made worse by β blockers, and these drugs decrease the effectiveness of adrenaline

9) A poor outcome from anaphylaxis is associated with late administration of adrenaline. Key point from journal by A. Sheikh et al, 2009

1) Delayed injection of adrenaline in anaphylaxis is reported to be associated with mortality 2) Because of potential harm from the use of i.v. adrenaline in inexperienced hands,

guidelines generally recommend that the i.v. route is reserved for cases that do not respond to initial treatment with i.m. adrenaline and where cardiovascular collapse and cardiac arrest is considered imminent

3) As there are no controlled trials, there is no way to estimate the risk in relation to benefit. 4) Adrenaline is not contraindicated in individuals with underlying ischaemic heart disease

as the decrease in filling pressure caused by anaphylaxis is likely to result in further coronary ischaemia

5) There is a strong clinical impression that prompt injection of adrenaline is life saving in anaphylaxis

6) No relevant evidence for adrenaline use in the treatment of anaphylaxis. 7) Adrenaline administration by intramuscular injection should still be regarded as first-line

treatment for the management of anaphylaxis.

Role of steroid in treating the anaphylaxis Key point from journal by Rohit Sharma et al

1) The effectiveness of corticosteroids in anaphylaxis has never been determined in placebo-controlled trials.

2) Because the onset of action is slow, steroids are not useful in the acute management stage 3) It has been suggested that their use might prevent a protracted or biphasic reaction,

although there is no evidence to prove this 4) If given, the dosing of intravenous corticosteroids should be equivalent to 1 to 2 mg/kg

per dose of Methylprednisolone every 6 hours. Oral administration of prednisone, 1 mg/kg, up to 50 mg might be sufficient for milder attacks.

Other patients relapse after an apparent complete resolution of all their initial symptoms and signs, known as biphasic anaphylaxis, which is reported in 1-5% of cases. It is unknown if more severe presenting features, delayed or inadequate doses of adrenaline, or the non-use of steroids predispose to, or predict the biphasic response [Anthony Ft Brown] The reported time intervals between the initial reaction and the onset of the second phase ranged from 1 to 72 hours. Unfortunately, no reliable clinical predictors have been identified to enable the identification of patients at increased risk of a biphasic reaction, although some studies have suggested that patients requiring higher doses of epinephrine to control initial symptoms or delayed administration of epinephrine might be associated with increased risk of a biphasic reaction [Sampson et al]

Should antihistamines be used to treat anaphylaxis?

Key point from journal by D A Andreae et al (2009) 1) No randomised controlled clinical trials or observational studies exist 2) Only one prospective trial was identified but was excluded as it lacked a control group

and did not study patients with anaphylaxis 3) Comparison of important international guidelines found conflicting advice about

antihistamines, reflecting the uncertainty in international clinical practice 4) US guideline recommends the use of diphenhydramine as second line treatment in

anaphylaxis (Expert opinion) 5) Australian guideline advises against the use of antihistamines in anaphylaxis (except in

special circumstances) 6) The Resuscitation Council of the United Kingdom still recommends chlorphenamine as

second line treatment after initial resuscitation 7) Antihistamines have no proved clinical effect on the immediate and life threatening

symptoms of anaphylaxis 8) In conventional doses, antihistamines fail to prevent the massive release of histamine

observed in anaphylaxis 9) Slower in onset than adrenaline and have little effect on blood pressure 10) Play a negligible role in relieving bronchospasm or gastrointestinal symptoms, relegating

them to second tier treatment 11) May just be useful for relief of mild symptoms, such as allergic reactions limited to the

skin or the mucous membranes and flushing, itching, urticaria, and rhinorrhea 12) Treatment with both H1-antagonists (antihistamines) and H2-antagonists (such as

cimetidine and ranitidine) combined is more effective in alleviating the cutaneous manifestations of anaphylaxis than H1-antagonists alone

13) In susceptible patients (genetic predisposition, drug overdose, electrolyte imbalance, those taking certain medications, or those with coronary artery disease), the risk of potentially fatal cardiac arrhythmias such as QT prolongation and torsade de pointes argues against the administration of older, first generation intravenous H1 antihistamines

14) Anticholinergic properties of these older drugs may lead to tachycardia and sedation, potentially confusing the picture in anaphylaxis

In anaphylaxis, universal consensus is to give adrenaline intramuscularly. International guidelines recommend 0.01 mg/kg and/or a maximum of 0.3-0.5 mg for adults. Antihistamines should never be given alone or instead of adrenaline in anaphylaxis. [D A Andreae et al, 2009]

Should This Patient be discharged at the first place? Over half the people who die of anaphylaxis succumb within the first hour. The deaths are related to asphyxia from severe bronchospasm or upper airway obstruction and from refractory hypotension [Arv Sadana et al, 2000] Among children (0-4 years old), hospitalization because of food-induced anaphylaxis is a growing concern [Leanne M. Poulos et al] Many cases of anaphylaxis are likely to have been managed in accident and emergency departments without resulting in admission [Aziz Sheikh, 2000] Risk factors for food anaphylaxis were age 10 to 35 years, active asthma, peanut allergy, ingestion of food prepared outside of the subject’s residence, and delayed administration of adrenaline. Risk factors for drug-induced anaphylaxis fatalities were age 55 to 85 years, presence of respiratory or cardiovascular comorbidities, and antibiotics or anesthetic agents. Risk factors for insect sting–induced anaphylaxis deaths were age 35 to 84 years and male sex.[Woei Kang Liew et al, 2009] Based on available evidence, observation periods after complete resolution of uniphasic anaphylaxis should be individualized, particularly because there are no reliable predictors of biphasic anaphylaxis. A 10-hour observation period appears sufficient, but some investigators recommend 24 hours. [Stephen F. Kemp] Patients with systemic anaphylactic reactions, including all those who received adrenaline, should be kept under observation. However, it is not known how long a patient should be observed for after recovering from an episode of anaphylaxis, as there is no evidence or consensus on factors that may predict a late phase recurrence, or biphasic anaphylaxis. Expert opinion varies from at least four to six hours after apparent full recovery, up to 10 hours or longer. Keep patients with reactive airways disease a little longer, because most deaths from anaphylaxis occur in this group. Observation is safely performed in the Emergency Department if a suitable holding area exists, and does not mandate ECG monitoring [Anthony Ft Brown] Patients who have had a suspected anaphylactic reaction should be treated and then observed for at least 6 h in a clinical area with facilities for treating life-threatening ABC problems. [J. Soar et al] A reasonable length of time to consider observing the postanaphylactic patient is 4 to 6 hours in most patients, with prolonged observation times or hospital admission for patients with severe or refractory symptoms [Rohit Sharma et al]

Most patients with anaphylaxis may be treated successfully in the ED and then discharged. Treatment success operationally may be defined as complete resolution of symptoms followed by a short period of observation. The purpose of observation is to monitor for recurrence of symptoms (ie, biphasic anaphylaxis) [Richard S Krause] Hospital admission is required for patients who (1) fail to respond fully, (2) have a recurrent reaction or a secondary complication (eg, myocardial ischemia), (3) experience a significant injury from syncope, or (4) need intubation. As with many other conditions, consider a lower admission threshold when patients are at age extremes or when they have significant comorbid illness. [Richard S Krause] Key point from journal by Andrew P C McLean-Tooke et al, 2003

1) The severity of previous reactions does not determine the severity of future reactions, and subsequent reactions could be the same, better, or worse.

2) The unpredictability depends on the degree of allergy and the dose of allergen. 3) Two of the three fatal reactions and five of the six near fatal reactions, the previous

allergic event had not required urgent hospital intervention (grade C). 4) A significant increased risk of near fatal and fatal reactions in patients with coexistent

asthma 5) The subsequent need for adrenaline and admission to hospital was reduced in those

patients who did receive the appropriate dose by auto-injector (grade C)

Should this patient be discharged?

Based on evidence, discharging the patient should be individualized. The practice of

discharging the patient after symptom resolve in District Hospital should be re-consider. It is

safe to keep patient for observation of minimum 4 hours.

However, since there is no evidence or guide on when the biphasic phase will occur and how

severe it is, therefore it is safe to discharge the patient with few strict condition. 1) Patient

stay near the hospital and with easy access to come to the hospital. 2) Advise the family

member to identify the recurrence of anaphylaxis. 3) patient receiving IM adrenaline 1:1000,

0.3-0.5 mg.

Management of patient with anaphylaxis

1) Positioning the patient in supine position with elevation of the leg. 2) Monitoring of vital sign 3) Give oxygen based on patient condition (choose nasal prong or high flow mas) 4) IM adrenaline 1:1000, 0.3-0.5 mg stat. 5) IV hydrocortisone 2mg/kg stat. 6) IM piriton 5-10mg IM 7) Neb. Salbutamol if evidence of bronchospasm. (0.03 to 0.05 ml/kg in 2.5 ml of 0.9% NS) 8) Admit patient for observation. 9) Stop the offensive medication 10) IM or IV glucagon, 1 mg if not responsive to adrenaline.

Other Recommendation

1) Stop the offensive medication Early identification of those at risk of drug induced anaphylaxis and improved management of this condition, similar to recent efforts in food allergy management, are urgently needed to reverse this trend. Possible strategies include improvement of drug allergy diagnostics, use of pharmacogenetics to identify at-risk subjects, specific clinics for assessment and management of drug allergy, and integration of national drug allergy alert systems. [Woei Kang Liew et al, 2009]

2) Referral to allergy clinic

All patients presenting with anaphylaxis should be referred to an allergy clinic to identify the cause, and thereby reduce the risk of future reactions and prepare the patient to manage future episodes themselves [J. Soar et al]

3) Council the patient.

Having a child with anaphylaxis can have a significant long-term psychologic effect on parents, and this anxiety might, in some cases, be transferred from parents onto their children. Parents and adolescents might benefit from tailored information.[Akeson et al,2007]

Families had poor knowledge of allergen avoidance and managing reactions. After intervention, there was a significant increase in knowledge of allergen avoidance measures, managing reactions, and use of epinephrine autoinjectors [Kapoor et al,2004]

4) Correct education and training on the use of self injected adrenaline.

Prescribed epinephrine might have initially increased parental anxiety, but when combined with training and education, it reduced feelings of helplessness and provided reassurance [Rae et al, 2007]

Summary of international management for anaphylaxis from analytical study by M. Alrasbi et al. Results: 1) Agreement on the broad principles of management, 2) Important variations in relation to the treatments to be used and the dose and route of administration of the preparations, 3) Most guidelines failed to make clear the strength of evidence underpinning the recommendations being made. Conclusions: 1) There are important international differences in the recommended emergency management of anaphylaxis, 2) need for development of agreed core evidence-based guideline for the management of anaphylaxis which can then be adapted for national/local use., 3) Clinicians need to be aware of the limitations of existing guidelines.

Country and

publication year Posture Oxygen Adrenaline Antihistamines Steroid

Australia (2006) Supine or left lateral (vomiting) *elevate leg if tolerated

High flow 1:1000 solution, 0.01 mg/kg (max 0.5 mg), IM

- -

Canada (2003) - Supplemental O2 1:1000 solution (child 0.01 ml/kg, max 0.3 ml/kg) (adult 0.3 0.5 ml)

Diphenhydramine I.v. ,i.m. or p.o. Adults: 25–50 mg Child: 1.25 mg/kg + Ranitidine I.v. or p.o. Adults: 50 mg i.v. or 150 mg p.o. Child: 1.25 mg/kg i.v. or 2 mg/kg p.o

Methylprednisolone I.v. or Prednisone P.o. Adults: 125 mg i.v. or 50 mg p.o. Child: 1 mg/kg i.v. or 1 mg/kg p.o.

Russia (2004) Supine position Lift the chin upwards and turn the head to the left side

Supplemental 02 + ethanol as an antifroth agent

1 : 1000 solution S.c. or i.m. adults: 0.3–0.5 ml (0.3–0.5 mg) Child: 0.01 mg/kg

Diphenhydramine Adults: 25–50 mg Child: 1–2 mg/kg I.v. or i.m. Promethazine 2.5% – 2–4 ml i.v. or i.m. chlorphenamine 2% – 2–4 ml i.v. or i.m.

Prednisolone 1–2 mg/kg i.v. Hydrocortisone 100–300 mg i.m. or I.v. Dexametasone 4–20 mg i.v.

UK, 1999 (revised 2002 & 2005)

Lie flat with legs raised (unless respiratory distress increased)

High flow O2 (10–15 l/min)

1 : 1000 solution Adults: 0.5 ml (0.5 mg) i.m. children > 12 years up to 0.5 mg i.m. 6–12 years 0.25 I.m. > 6 month–6 years 0.12 mg I.m. < 6 month 0.05 mg i.m.

Chlorphenamine >12 years 10–20 mg i.m. or slow i.v. 6–12 years 5–10 mg i.m. 1–6 years 2.5–5 mg i.m.

Hydrocortisone 12 years >100–500 mg i.m. or slow i.v. 6–12 years 100 mg i.m. 1–6 years 50 mg i.m.

Ukraine (2002) Supine position Supplemental 02 + ethanol as an antifroth agent

1 : 1000 solution S.c. or i.m. adults: 0.3–0.5 ml (0.3–0.5 mg) child: 0.01 mg/kg

Diphenhydramine Adults 25–50 mg Child: 1–2 mg/kg I.v. or i.m. Promethazine 2.5% – 2–4 ml i.v. or i.m

Prednisolone 1–2 mg/kg i.v. Hydrocortisone 100–300 mg i.m. or I.v. dexametasone 4–20 mg i.v.

USA (2005) Recumbent position and elevate lower extremities

6–8 l/min guided by arterial blood gasses or oxymetry

1 : 1000 solution 0.2–0.5 ml (0.01 mg/kg in children, maximum 0.3 mg) i.m. or S.c. lateral thigh

Diphenhydramine Adults 25–50 mg I.v. child 1 mg/kg up to 50 mg. Oral might be sufficient for milder attacks + ranitidine Adults: 1 mg/kg Child: 12.5–50 mg infused over 10–15 min

Not recommended for use as part of acute management

Reference:

1) Andrew P C McLean-Tooke, Claire A Bethune, Ann C Fay & Gavin P Spickett", “Adrenaline in the treatment of anaphylaxis: what is the evidence?", BMJ 2003;327:1332–5

2) Anthony Ft Brown, "Current management of anaphylaxis", Emergencias 2009;21:213-223 3) Aziz Sheikh, Bernadette Alves, "Hospital admissions for acute anaphylaxis: time trend study",

BMJ 2000;320:1441 4) Aziz Sheikh, Samantha Walker, "10-minute consultation Anaphylaxis", BMJ 2005;331:330 5) A. Sheikh, Y. A. Shehata, S. G. A. Brown & F. E. R. Simons, "Adrenaline for the treatment of

anaphylaxis: cochrane systematic review", Allergy 2009: 64: 204–212, Blackwell Munksgaard 6) D A Andreae & M H Andreae, "Should antihistamines be used to treat anaphylaxis?", BMJ 2009;

339 7) J Soar et al, "Emergency treatment of anaphylactic reactions—–Guidelines for healthcare

providers", Resuscitation (2008) 77, 157—169, Elsevier. 8) Leanne M. Poulos, Anne-Marie Waters, Grad Dip Pop Hlth et al, "Trends in hospitalizations for

anaphylaxis, angioedema, and urticaria in Australia, 1993-1994 to 2004-2005", J Allergy Clin Immunol Volume 120, Number 4, 2007.

9) M. Alrasbi & A. Sheikh, "Comparison of international guidelines for the emergency medical management of anaphylaxis", Allergy 2007: 62: 838–841, Blackwell Munksgaard

10) Pamela W Ewan, "ABC of allergies: Anaphylaxis "BMJ VOLUME 316,1998 11) Richard S Krause, "Anaphylaxis", eMedicine 2010

http://emedicine.medscape.com/article/756150 12) Rohit Sharma, Ramen Sinha, P.S. Menon & Deepika Sirohi, "Management Protocol for

Anaphylaxis", J Oral Maxillofac Surg 68:855-862, 2010, American Association of Oral and Maxillofacial Surgeons

13) Sampson et al, "Second symposium on the definition and management of anaphylaxis: Summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium", J Allergy Clin Immunol 2006;117:391-7

14) Sarah L Johnston, Joe Unsworth, Mark M Gompels, "Adrenaline given outside the context of life threatening allergic reactions", BMJ 2003;326:589–90

15) Simons KJ & Simons FE, "Epinephrine and its use in anaphylaxis: current issues.", Curr Opin Allergy Clin Immunol. 2010 Aug;10(4):354-61.

16) Stephen F. Kemp, "The post-anaphylaxis dilemma: How long is long enough to observe a patient after resolution of symptoms?", Current Allergy and Asthma Reports, Volume 8, Number 1, 45-48, 2008, SpringerLink

17) Ulugbek Nurmatov, Allison Worth & Aziz Sheikh, "Anaphylaxis management plans for the acute and long-term management of anaphylaxis: A systematic review", J Allergy Clin Immunol Volume 122, Number 2, 2008.

18) Walker DM, "Update on epinephrine (adrenaline) for pediatric emergencies.", Curr Opin Pediatr. 2009 Jun;21(3):313-9.

19) Woei Kang Liew, Elizabeth Williamson & Mimi L. K. Tang, "Anaphylaxis fatalities and admissions in Australia", J Allergy Clin Immunol 2009;123:434-42