ANAPHYLAXIS THE EXTREME HYPERSENSITIVITY!

A 5 year old female child was admitted in the ER with h/o wasp sting. She is drowsy and has facial and lip edema.She is also in respiratory distress with stridor. She has a rapid thready pulse with urticarial rashes all over the body. An attempt for endotracheal intubation under suxamethonium and sedation failed due to extensive edema of the tongue and oropharynx and the vocal cords were not visualised. Emergency airway access obtained by a classic LMA with positive pressure ventilation but desaturation persisted and the ENT surgeon was called in for emergency tracheostomy

Anaphylaxis is an acute, severe, potentially life threatening allergic reaction (type 1 hypersensitivity) characterised by severe bronchospasm, angio neurotic edema and cardiovascular collapse following repeated exposure to an allergen to which the individual is already sensitised. Anaphylaxis can be caused by a variety of allergens.  

• Food, (Peanuts Tree nuts (walnuts, pecans, pistachios, filberts, cashews, almonds, etc.)
• Shellfish (crab, crayfish, prawns, shrimp, lobster, etc.)
• Proteins in  Fish Milk, Soyabean, Wheat, Eggs
• Medications(Penicillin, Sulfa antibiotics, Allopurinol, IV contrast material )
• Insect venom (including bees, wasps, ants )
• Latex.

Pathophysiology
At the time of first exposure to the antigen,allergen or drug the immunoglobulin IgE(antibody) is sensitised by the allergen.The IgE antibody is now fixed to its receptors on tissue mast cells or circulating basophils.Re exposure to the same antigen causes direct bridging of cell surface Ig E receptors.This causes activation of membrane associated enzymes causing complex biochemical cascades that lead to efflux of Ca++ ion with release of granule associated mediators and generations of new mediators from cell membrane phospho lipids.The important mediator is Histamine which dilate terminal arterioles and increase the permeability of venules, causing extravasation of fluid, increased airway resistance,cutaneous vasodilatation, resulting in pruritus and urticaria. Other mediators are Prostaglandins,ECF - A [ Eosinophil Chemotactic Factor - A]NCF [ Neutrophil Chemotactic Factor ],Slow Reacting Substance of Anaphylaxis ( SRS – A ), Leukotriens and Platelet Activating Factor ( PAF ). These chemical mediators are responsible for the systemic manifestations of anaphylaxis including vasidilatation and flushing, bronchospasm, itching, urticaria angioedema and hypotension.

Clinical manifestations:
General : The patient will be apprehensive, anxious and may c/o dizziness, loss of consciousness, tightness of chest, dysphagea,throat pain,abdominal pain, nausea or vomiting. There may be tachycardia, numbness of tongue sneezing or muscle cramps.

The major systemic manifestations are
Cutaneous

• The classic skin manifestation is itching and urticaria, commonly called as hives. These lesions are red and raised, and they sometimes have central blanching. Intense pruritus is associated with the lesions. This can be generalised or localised. Localised lesions are common in insect bites, where the involved area is erythematous, edematous, and pruritic.Angioedema is also often asociated with anaphylaxis manifesrted as cutaneous nonpruritic edematous lesions in the skin and mucosa typically seen around the eyes, lips, palms, soles, and genitalia.

Pulmonary.

• Mucosal edema of the upper airway including oropharynx, tongue and larynx can occur.This may lead on to stridor,severe airway obstruction and hypoxia. Lower airway involvement is manifested as severe boronchospasm (wheezes). Angioedema alone can cause severe edema of the tongue and lips causing severe airway obstruction.

Cardiovascular

• Intravascular volume depletion may take place as a consequence of capillary leakage. There will be associated tachycardia and severe hypotension, termed as anaphylactic shock.Various arrhythmias are also reported and may be worsened by treatment with adrenaline

Emergency management

• Progression to severe bronchospasm or laryngeal edema can occur within few minutes to hours in sensitised individuals and so early treatment is advised. Adrenaline injection 0.3 to 0.5 mg should be given deep intramuscular immediately on diagnosis. IM route preferred as absorption will be better and reliable.
• In case of severe laryngeal edema; nebulised adrenaline is administered (0.25 ml 1:100 epinephrine added to 2 ml saline)
• Glucagon 5-15 mic/mt intravenous is also tried in refractory hypotension or in patients already on treatment with beta blockers.
• Histamine blockers like diphenhydramine 25-50 mg PO/IM/orIV may be given to block the effects of histamine.
• Ranitidine 50 mg IV or 150 mg orally may be given for blocking H2 receptors
• Steroids; Prednisolone 50 mg PO or Methyl prednisolone 125mg IV sixth hourly may be administered
• Albuterol 2.5 ml 0.5% solution nebulised, is useful for relieving severe bronchospasm

Anaphylactic shock

• Epinephrine 0.3 to 0.5 mg intravenous followed by infusion 2-8 mic/mt
• Volume resuscitation as massive fluid shifts are common. Colloids like hetastarch are preferred.
• Persistent hypotension is managed with infusion of dopamine 5-15 mic/kg/mt or nor epinephrine 2-8 mic/mt

Prevention

• Identify the cause of allergy and avoid exposure, Food, Dust, Drugs etc.
• Epi Pen: It is essential that anyone with a history of anaphylaxis or allergy should keep epinephrine auto-injectors, such as EpiPen® with them at all times and be prepared to use them whenever a reaction occurs.These are available in 0.15mg and 0.3 mg doses for subcutaneous injections by using a pen device

Anaphylaxis during Anaesthesia:

Evaluation and management of anaphylaxis is difficult and challenging in OT set up as multiple drugs are given repeatedly and that the general warning symptoms are absent under anaesthesia.Patients are unconscious  and in deep levels of anaesthesia masking the symptoms and signs of anaphylaxis. The anaesthetist has to look for cardiovascular and respiratory signs like unexplained hypotension and increase in airway resistance with desaturation. Increased or decreased ETCO2 is observed and there will be hemoconcentration. CVS collapse is the most common manifestation under anaesthesia and is seen in around 80% of cases with the reported incidence of cardiac arrest in 10% cases.On table management is the same as described above.Stop all anaesthetic agents keeping the minimum of inhalational agents.Unintubated patients should be intubated, airway pressures are monitored, and nebulised adrenaline or albuterol administered via T piece attached to the breahting circuit.CPCR should be activated as per ACLS protocols If you notice facial swelling and lip edema with the above findings extubation is deferred and patient may be ventilated until systemic manifestations like laryngeal edema bronchospasm and hypotension are treated.A simple test to find residual airway edema on table is absence of leak following deflation of ETT cuff.
Lab findings intra op

• Serum histamine and mast cell tryptase lavel within ten minutes of onset of signs and symptoms.
• Detection of N methyl histamine a breakdown product of histamine in urine is also helpful

Differential Diagnoses intra op:

• Myocardial infarction
• Exacerbation of bronchospasm in asthmatics
• Pulmonary embolism
• Pulmonary aspiration
• Acute pulmonary edema
• Pneumothorax

Some Anaphylaxis situations encountered by anaesthesiologists:

• Opioid administration for acute  painful conditions like trauma: due to histamine release mild anaphylactic reactions are  observed.  Manifested as itching and hypotension and are treated with antihistamines and IV fluids.
• Barbiturates due to non immunologically mediated mechanisms
• Local anaesthetics mainly ester linked local anaesthetics are involved
• Radiocontrast media. In radiology suite anaesthetists are called to treat patients with anaphylactic reactions.Reactions to radiocontrast usually are mild (most commonly urticarial), and rarely serious reactions can occur. Risk of a fatal reaction has been estimated at 0.9 cases per 100,000 exposures and the incidence is 5-8%.The reaction is said to be anaphylactoid and may be due to complement activation.Pretreatment with antihistamines or corticosteroids and use of LMW agents can significantly reduce the incidence. A suggested protocol for prevention of reactions to IV contrast is given below.

          Use low osmolality contrast media
          Administer hydrocortisone (200 mg IV), wait 1-2 hours
          if time permits.
          Administer diphenhydramine (25-50 mg IM) immediately
          before the procedure.

• Protamine used for heparine reversal in CPB cardiac catheterisation or hemodialysis and can cause fatal anaphylactic reactions sometimes.The patients who are more prone are diabetics on subcutaneous insulin,vasectomised patients or those allergic to fish. In this situation it is better to reverse the effect with hexadimethrine
• Methyl methacrylate is another agent commonly implicated in allergic reactions and anaphylaxis.Methyl methacrylate otherwise known as bone cement is used to attach a prosthetic joint to raw bone and is widely used in hip and knee replacement surgeries. Hypotension hypoxemia and pulmonary edema are observed during implant fixation.Prior corticosteroids rae found to be useful to prevent this reaction.
• Mannitol is known to cause release of histamine from basophil degranulation due to a direct reaction
• Streptokinase and Eurokinase are also responsible for rare anaphylactic reactions
• Neuromuscular blocking agents are also involved in anaphylaxis due to non immunologic mechanisms eg pancuronium and vecuronium.Cross sensitivity is also noted

Sensitivity testing

Pre op diagnosis of allergic drugs or antigens in susceptible individuals: Intradermal skin tests using 0.01 -0.02 ml  of the allergen. An intradermal weal of more than 8 mm is considered postive. Obtain informed consent and all necessary precautions are taken to deal wth an emergency situation as even test dose can precipitate severe allergic reactions.Testing for sensitivity to penicillin antibiotics may be useful when a penicillin or cephalosporin antibiotic is the drug of choice for a serious infection in a patient who has a history of severe reaction.Here Incremental doses of intradermal doses of the drug are administered while observing the patient for pruritus, flushing, urticaria, dyspnea, hypotension, or other manifestations of anaphylaxis. If no reactions are observed a full dose can be given safely As per, Richard S Krause, MD, Ref (4) A suggested protocol for IV testing begins with 0.001 mg of the chosen drug. At 10-min intervals, incrementally increase the dose (eg, 0.001 mg, 0.005 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 10 mg, 50 mg, 100 mg, full dose), while observing the patient. Sensitivity testing along with desensitisation occurs here but can be rarely fatal.

Desensitization regimens

Desensitization regimens for certain antibiotic allergy have been shown effective. A typical desensitization regimen involves administering the antibiotic of choice at an initial dose of 0.01 mg. While observing the patient, double the dose every 10-15 minutes until a full dose has been administered.This is the basis of administering immunotherapy to sensitised individuals where an allergist or other physician who has been trained in the therapy administers immunotherapy by injecting a small, precisely calibrated amount of purified extract of the identified allergen under the skin of a patient's arm. Patients then are given injections of gradually increasing doses of the allergen at intervals that typically range from 1 to 8 weeks over the course of 3 to 5 years. The dosage, regimen intervals, and duration of therapy vary depending on the type and severity of the person's allergy.
The other useful tests used to detrmine the hypersensitivity are Radioallergosorbent test (RAST) which determines antigen specific IgE antibodies in serum and Basophil Activation test,by flow cytometric analysis of basophil membranes following activation

Anaphylactoid reactionsSome drugs (Non steroidal anti inflammatory drugs,polymyxin, morphine, x-ray dye, and others) may cause an anaphylactic-like reaction (anaphylactoid reaction) when people are first exposed to them. This is usually due to a non immunologically mediated toxic reaction(directly causing the release of mediators from mast cells and basophils )rather than the immune system response that occurs with "true" anaphylaxis.
The Anaphylaxis Algorithm:

Ref:
acta anaesthesia belgica 2004;55,229-237
http://www.wikipedia.org/
http://www.anaphylaxis.org/
http://emedicine.medscape.com/article/756150-overview
Paul Marino the icu book 3rd edition
Tinkers anaesthesiology
http://www.resuscitation.org.uk/
image
http://www.naturfoto-cz.de/
Thanks to Mr.Nisar Abdulla, Nisar Manzil  Ponkunnam for technical assistance