Conference Lectures
Anaphylaxis in the Operation Room
Dr. S.K.Deshpande (MD, DNB, PDCC)
Cardiac Anesthesiologist &Intensivist
Dr K G Deshpande Memorial Centre, Nagpur
Anaphylaxis is defined as a “severe systemic or generalized hypersensitivity or allergic reaction with rapid onset and can occur with or without exposure to a known allergen”. Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden release of mast cell- and basophil-derived mediators into the circulation.(1,2). The incidence of anaphylaxis during general anesthesia is 1:10,000 to 1:20,000. Anaphylaxis once started can be fatal in 5% (3%-10%) of surgical cases(4). Female to male ratio is 3:1 however in young ones the incidence is same.
Pathophysiology : Anaphylaxis is an acute, multisystem syndrome resulting from the sudden release of mast cell- and basophil-derived mediators into the circulation and if untreated may be fatal medical emergency. Anaphylaxis is basically Type I (among the 4 types) hypersensitivity reaction. Others being Types II (IgG,IgM, Complement, III (Immune complex response), and IV(T-cell mediated) reactions which do not result in anaphylaxis. Type I allergic hypersensitivity reactions can be 1) Anaphylaxis : IgE-triggered (previous antigen or allergen exposure resulting in antigen specific IgE antibodies) and 2) Anaphylactoid : non–IgE triggered hypersensitivity reactions. Peri-operative Anaphylaxis in 60% cases has IgE-dependent mechanisms. Non IgE-dependent immunologic reactions are mediated by IgG or IgM antibodies or by antigen:antibody complexes and complement.
Histamine, in combination with additional vasodilator substances, causes systemic vasodilation, pooling of the blood, resulting in severe hypotension and shock in a very short time. Further there is increased capillary permeability and tissue edema. The vascular complications are accompanied by respiratory complications swelling of the smooth muscles in the airway tract,
bronchospasm, and angioedema. Angioedema of the pharynx, larynx and trachea
produces upper airway obstruction, whereas bronchospasm and mucosal edema produce
lower airway obstruction. Histamine tends to cause constriction of the large airway tracts
and leukotrienes affect the smaller peripheral airways. The airway obstruction can be just
as life threatening as a result of the laryngeal edema and/or bronchial spasm. Death
usually occurs due to asphyxiation and/or circulatory shock.
Anaphylaxis : IgE-mediated anaphylaxis occurs on subsequent exposure after a patient is sensitized to an antigen with the production of an antigen-specific IgE. Allergen taken up by cell and T-Cell related Helper cells then come into action. The B lymphocytes develop into plasma cells that secrete immunoglobulin antibodies such as IgG or IgE or memory cells with receptors that remember antigens. The gene segments encode the formation of hundreds of allergen-specific B and T cells, thus millions of different receptors can develop with long-lasting memory.
These IgE antibodies are moving in circulation and bind to immune related cells like mast cells (Histamine) and Basophils (inflammatory mediators). On re-exposure, Multivalent allergens need to cross-link with at least 2 IgE high affinity receptor sites on the surface of the mast cell and basophils to release histamine and inflammatory mediators (previously formed or newly generated) (5).
Other Non-immunologic reactions which can have presentation similar to Type I reaction can result with the first exposure to the allergen cause direct release of histamine and other mediators by several mechanisms. The mechanisms may be idiopathic or may result from a combination of mechanisms. Non-IgE reactions may directly trigger the release of histamine, may occur in response to complement or bradykinin activation, or can be mediated by an IgG antigen. In an 8-year survey of surgical patients who experienced anaphylaxis, IgE-mediated reactions were most (n = 1,816 [72.2%]) and severe (grade 3; n = 1,092; [60%]) than non-IgE reactions, which occurred less (n = 700; [27.8%]) and were milder (grade 1; n = 372; [53%]) (4).
Mast Cells and Basophils. Although mast cells are present in all tissues, basophils circulate in the vasculature. Mast cells are found within most organs and tissues, especially in the heart, vasculature, respiratory and gastrointestinal tracts, and integument. The release of cell mediators is controlled by calcium channel receptors. Mast cells and basophils have similar receptors and functions: to respond to signals of innate and adaptive immunity and to release inflammatory mediators, but the role of basophils has not been defined in human anaphylaxis.
Late phase reaction : The early phase of an allergic reaction that induces mast cell degranulation may be followed by a late phase reaction with the release of cytokines that can interact with T-helper type 2 cells. In turn, cytokines such as interleukin 4 (IL-4) stimulate B cells to generate IgE and further stimulate mast cells and eosinophils.
Inflammatory Mediators are released such as histamine, proteases (among which is tryptase), leukotrienes, and prostaglandins result in immediate symptoms pruritis, wheezing, or hypotension, and can induce cardiovascular collapse. The inflammatory mediators released from cardiac mast cells such as cysteinyl leukotrienes and prostaglandins decrease myocardial perfusion and contractility. Platelet-activating factor can constrict the coronary arteries, decrease coronary perfusion and contractility, and can contribute to coronary plaque rupture.
The various mechanisms leading to activation of mast cells and basophils are increasingly grouped together under the term anaphylaxis because the initial management of these reactions is the same, regardless of the trigger or mechanism involved, and the clinical severity of the reactions may be similar.
Two primary causes of true anaphylaxis in patients in OR are Muscle relaxants (MR-NMBA) and Latex allergy.Both can cause anaphylaxis through both IgE-mediated and nonimmunologic direct mast cell activation. Anaphylaxis due to MR is the most common (1 in 6,500 cases) and account for almost 70% cases. Reactions resulting from direct mast cell activation are more common; however, severe reactions are usually IgE-mediated. Histamine release may be more common with tubocurarine, mivacurium, atracurium. Commonly implicated agents include atracurium, pancuronium, rocuronium, succinylcholine, tubocurarine and vecuronium, although this may largely reflect the frequency with which these agents are used.
Allergy to MR is more common in women than men (3:1). This phenomenon is believed due to cross-reactive tertiary or quaternary ammonium groups found in MR and a variety of topical cosmetics and personal products, as well as certain over-the-counter cough remedies (ie, pholcodine). Allergic reactions to MR can occur upon initial exposure due to sensitization through exposure to quaternary ammonium groups in topical agents.
Latex — Second most common cause of Anaphylaxis. Natural rubber latex accounted for approximately 20 percent of perioperative anaphylaxis cases (8) and it is from the formation of specific-IgE against proteins from natural rubber latex. Example of latex use in Gloves, Drains, Catheters. The reactions to latex tend to occur later in surgical procedures (eg, 30 minutes or more after the start of the intervention). Repeated exposure, children with spina bifida and healthcare workers.
Antibiotics — Third most common cause. Antibiotics, administered before, during, or immediately after anesthesia, were responsible for 12 to 15 percent of identifiable triggers in the French studies (3) and in 50% in American series(5),
Beta-lactam antibiotics (specifically penicillins and cephalosporins), which cause IgE-mediated anaphylaxis, and vancomycin, which causes reactions due to direct histamine release from mast cells, are the most common offenders (7). Sulfonamide and Quinolones are infrequently incriminated, but their more common use is associated with increased reports of immediate reactions. The antibiotic commonly used for antibiotic prophylaxis in the surgical patient is
vancomycin and it is commonly associated with anaphylactoid reactions consisting of
pruritus, erythema of the head and upper torso, and arterial hypotension.
Less common — In the French studies mentioned previously, the following groups of agents were implicated in 1 to 5 percent of reactions are Hypnotic induction agents, Opioids, Colloids and plasma expanders, Other agents……
Hypnotic induction agents (2%) - Barbiturates (eg, thiopental, methohexital and are IgE mediated) and uncommon in nonbarbiturates (eg, benzodiazepines, propofol, etomidate, and ketamine). Barbiturates are responsible for the majority of reactions.
Opioids — flushing and urticaria following intravenous administration,but rarely cause life-threatening reactions. Typically, opioids cause limited cutaneous symptoms that are non IgE-mediated. Morphine or meperidine can cause degranulation of dermal mast cells, resulting in release of histamine and other mediators.
Colloids and plasma expanders (3%) — Dextran or hetastarch (hydroxyethyl starch, HES. These agents are capable of causing both IgE-mediated and non IgE-mediated immunologic reactions. Hetastarch is used in major surgeries expected to cause significant fluid shifts (eg, trauma). Dextran is less commonly used as a volume expander, but its antiplatelet effects make it useful as an adjunct to some cardiovascular procedures.
Albumin has also been implicated in rare perioperative anaphylactic reactions(9). Gelatin in the plasma expanders polygeline (eg, Haemaccel) and succinylated gelatins (Gelofusin) has caused IgE-mediated anaphylactic reactions (10).
Other agents (<5%) : Radiocontrast agents, Blood transfusion, Metabisulfites and bisulfites used as preservatives in medications, NSAID, chlorhexidine (11), Povidone in the topical antiseptic povidone-iodine (12)Bacitracin, ETO and ortho-phthalaldehyde (Cidex OPA) , Streptokinase or urokinase, Insulin, Local anesthetics (13), Heparin and other anticoagulants (14), Protamine (15), Aprotinin, Hyaluronidase,
RISK FACTORS — Asthma, female sex (for certain medications), past history of anaphylaxis, allergic drug reactions, other allergic conditions such as eczema or hay fever, multiple past surgeries or procedures (especially for latex and ethylene oxide), and mast cell disorders(mastocytosis).
Clinical Manifestations :
Signs and symptoms — Peri-operative anaphylaxis most commonly presents with cardiovascular, cutaneous, and respiratory signs and symptoms (if the patient is conscious), with variable involvement of other organ systems. Cardiovascular collapse is the first detected manifestation in up to 50 percent of cases. Tachycardia is a classic sign of anaphylaxis with Bronchospasm may present as a sudden increase in the ventilatory pressure required to inflate the lungs, an increase in end-tidal carbon dioxide, or a decrease in arterial oxygen saturation. Rapidly developing laryngeal edema : stridor postoperatively.
Difficulties of Intra-operative Anaphylaxis :
Early or mild symptoms itching or shortness of breath, may go unnoticed under anesthesis while flushing, urticaria, and angioedema, may be missed because the patient is draped for surgery. As a result of these factors, the reaction may be detected only when dramatic respiratory and hemodynamic changes develop. Time period to develop Anaphylaxis : IgE-mediated reaction usually develops within a few seconds to one hour of exposure to the trigger. Intravenous medications typically cause symptoms more rapidly than exposures through tissues or skin (eg, latex).
First 30 minutes :Allergic reactions due to antibiotics, neuromuscular blocking agents (NMBAs) or hypnotic induction agents because these agents are given at the start of the procedure.
After 30 minutes : more likely due to latex, or miscellaneous agents, such as protamine, plasma expanders, or supravital dyes.
Severity of Anaphylaxis in OR — Perioperative anaphylaxis tends to be severe and has a higher mortality rate than anaphylaxis occurring in other settings. Severity of IgE mediated anaphylaxis > Non IgE type. Mortality ranges from 1.4 to 6 (5%) percent. IV route used in OR and late detection may be responsible for the higher mortality. IgE-mediated anaphylaxis is generally more severe than non IgE-mediated anaphylaxis although both types can be fatal.
ACUTE DIAGNOSIS AND TREATMENT — Clinical signs like Urticaria or rash (direct histamine release) hypotension, tachycardia, bronchospasm (histamine release) guide us to suspect intra-operative anaphylaxis however absence of tachycardia or cutaneous signs does not rule out the anaphylaxis. The signs are
Integumentary : Urticaria, pruritis, facial edema,CVS : Tachycardia, hypotension
RS : Bronchospasm, dyspnea, pulmonary edema, hypoxia
Anaphylaxis in OR is graded as :
Grade 1 : Generalised mucocutaneous signs: Erythema, Urticaria+/- Angioedema
Grade 2 : Moderately severe - Multi-organ manifestations including: Mucocutaneous signsHypotension, Tachycardia, Evidence of Bronchospasm, cough, difficult ventilation.
Grade 3 : Severe-Life Threatening and requiring immediate and specific treatment: Cardiovascular collapse, Bradycardia or Tachycardia, Arrhythmias, Bronchospasm. Cutaneous signs may be absent, or present only after correction of hypotension
Grade 4: Cardiopulmonary arrest
Laboratory tests - Blood for Tryptase and Histamine : Mast Cells and Basophils release tryptase and histamine which can help to distinguish anaphylaxis from or rash other perioperative events, such as cardiogenic shock. Tryptase was elevated in 68 percent of IgE-mediated reactions and 4 percent of non IgE-mediated reactions in the largest French study (3). The Serum tryptase has a half-life of approximately 2 hours. Blood for serum tryptase should be (in plain, serum or EDTA tube) collected immediately, 1 hr, 6 hrs and 24 hrs after the anaphylaxis. ABG, electrolytes, coagulation screen.
Histamine is another mediator released from mast cells but has a short half life and sample should be immediately drawn. Urinary histamine metabolites is N-methylhistamine which has a longer half-life than histamine.
DIFFERENTIAL DIAGNOSIS — Several causes which are not anaphylactic but can produce acute CVS collapse like shock; hypovolemia, myocardial depression, MI, haemorrhage, cardiac tamponade, arrhythmia etc), respiratory causes (asthma; ETT related; pnumothorax, pulmonary edema, hypoxia), vasoplegia due to drug overdose,drug interaction, Sepsis. The serum Tryptase or histamine levels help to differentiate.
Management of Anaphylaxis in OR : The Australian and New Zealand Anesthetic Allergy group has published the guidelines (16).
Immediate management : Unresponsive hypotension or bronchospasm : Stop triggering agents like chlorhexidine, colloids; maintain patient on minimum inhalational anesthesia. Consider other differential diagnosis.
Adrenaline is life saving in anaphylaxis and should be immediately given as described below.
It maintains haemodynamics, antagonizes effects of mediators and prevents further release of mediators. Anaphylactic related deaths were directly correlated with delayed administration of adrenaline.
Call for help, inform surgeon. Intubate and give 100% Oxygen. If no pulse; give IV 1 mg Adrenaline in adults (Paediatric pt. @ 10 microgm/Kg),
Up to 50% blood volume can extravasate in first 10 minutes so reasonable to give upto 1.5-2.0 litres IV fluidsGive IV fluid bolus @20 ml/kg and repeat if needed. CPR if no response. Repeat adrenaline and start infusion of adrenaline. If moderate hypotension and bronchospam give adrenaline 50-100 microgm bolus.
If there is no IV access give Adrenaline by IM route : Adult = 0.5ml (500mcg), <12 years = 0.3ml (300mcg), <6 years = 0.15ml (150mcg) in the lateral thigh (Vastus lateralis muscle)
Adrenaline infusion : Add 3 mg (1:1000) i.e. 3,000 micrograms adrenaline in 50 ml to get concentration as 60 mcg/ml, So 1ml/Hr= 1mcg/minute. Dose in adults is 0.05-0.4 microgram/Kg/min. In children 0.1- 5 microgram/Kg/min.
Monitoring : Arterial line insertion, CVP, TTE,
If no response to Adrenaline infusion and fluid therapy, Noradrenaline infusion @ 0.1mcg/kg/min, Vasopressin bolus 1-2 units (0.03units/kg) then infusion 2 units per hour. Glucagon 1-5mg over 5 min (βblocker reversal) (Child 20-30mcg/kg to max 1mg)
Consider cardiac bypass where available.
Severe Bronchospam : Salbutamol IV bolus 100-200mcg, +/- Salbutamol infusion 5-25mcg/min (Child 5mcg/kg/min for 1 hour then run infusion at 1-2mcg/kg/min). Consider: Auto PEEP (disconnect from ventilator), Tension pneumothorax.
Post Crisis management : Steroids : Hydrocortisone 2-4 mg/Kg, Dexamethasone 0.1-0.4 mg/Kg. Consider oral antihistaminics. Parenteral antihistaminics are not recommended. Monitor closely for 6 hrs. Admit in ICU for 24 hrs. Anaphylaxis may last upto 32 hrs.
After discharge : Reaction description and agents used.
References:
- Lieberman P. – Definition and criteria for the diagnosis of Anaphylaxis : Anaphylaxis and Hypersensitivity Reaction,New York: Springer; 2011:1-12.
- Perioperative anaphylaxis: Clinical manifestations, etiology, and diagnosis; Dennis K Ledford in online article in UpToDate 2014.
- Anaphylaxis during anesthesia in France: an 8-year national survey : J Allergy Clin Immunol. 2011;128(2):366
- Schummer C etal:The Pivotal role of Vasopressin in refractory anaphylactic shock. Anesth. Analg. 2008:107(2):620-624
- Stone KD, Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol. 2010;125
- Gurrieri C. etal: Allergic reactions during Anesthesia at a large US referral Centre : Anesth.analg. 2011:113:1202
- Mertes PM et al : Peri-operative anaphylaxis, Med. Clin. North Am.2010:94:761 in UpToDate online
- Mertes PM et al : Reducing the risks of anaphylaxis during anesthesia- 2011 updated guidelines for clinical practice. J investing. Allergol Clin Immunology in UpToDate 2014 online
- Fujita A. et al : Anaphylactoid shock in a patient following 5%human serum albumin infusion during OPCAB: J.anesth, 2007:21:396
- Russell WJ: anaphylaxis to Haemaccel and cross reactivity to Gelofusine: Anesth. Intensive Care 2002; 30:481.
- Parkes AW et al : anaphylaxis to the Chlorhexidine component of Instillagel; A Case series: BJA 2009;102;65.
- Gray PE et al : Recurrent anaphylaxis caused by topical Povidone- iodine (Betadine):J Paediatr Child Health:2013;49;506.
- Ring J et al :Anaphylactic reactions to local anesthetics: Chem Immunol. Allergy:2010;95;190.
- Berkun Y et al: Heparin-induced recurrent anaphylaxis> Clin Exp allergy 2004;34;1916
- Park KW : protamine and protamine reactions. Int Anestheiol. Clin. 2004;42:135
- ANZAAG-ANZCA Anaphylaxis Management Guidelines Version 1.1 June 2013
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