DOC-20250324-WA0008..PowerPoint presentation

Perioperative Anaphylaxis

1. PERIOPERATIVE ANAPHYLAXIS Name : Dr. V. Pavani 2 nd yr post graduate Moderator : Dr. Swetha ( Assistant professor) Dept. of Anaesthesiology

2. OBJECTIVES Hypersensitivity and it’s types. Anaphylaxis definition. Pathophysiology Clinical grading Management.

3. HYPERSENSITIVITY Hypersensitivity is an immune system dysfunction that causes an exaggerated response to a substance that wouldn’t normally trigger an immune reaction. It can also refer to the immune system attacking the body’s own cells and tissues. Hypersensitivity can lead to inflammation, damage, and immune diseases like allergies and autoimmunity.

4. Types of Hypersensitivity reactions Type 1 – Anaphylactic or immediate type Hypersensitivity reactions Type 2– Antibody dependent cell mediated cytotoxic Hypersensitivity Reactions. Type 3– Immune complex Reactions Type 4– Delayed Hypersensitivity Reactions. Anaphylaxis Definitions Defined based on clinical presentation alone or in combination with the underlying mechanism. Allergic anaphylaxis : Typically IgE -mediated . Non-allergic anaphylaxis : Resembles anaphylaxis but is not IgE -mediated . The term "anaphylactoid" is no longer used.

5. Anaphylaxis is a severe, acute allergic reaction triggered by the release of inflammatory mediators from mast cells and basophils, often involving a hypersensitivity response to an external antigen. It can affect multiple organs, such as the skin, lungs, gastrointestinal tract, and cardiovascular system, with common triggers including drugs (especially antibiotics), food, and insect stings. Despite its dramatic symptoms, the mortality rate is low, around 0.25%–0.33%. Clinical Features : Symptoms typically appear within minutes of exposure to a trigger and may include urticaria, angioedema, flushing, difficulty breathing, and hypotension. A biphasic reaction, where symptoms recur within 72 hours, is also possible. Anaphylaxis can also be associated with acute coronary syndromes, a condition known as Kounis Syndrome, resulting from coronary vasospasm or plaque rupture.

6. Anaphylactic Shock Anaphylactic shock is an acute, severe, and life-threatening allergic reaction characterized by rapid onset and rapid progression, often leading to circulatory failure and airway compromise. Treatment is primarily based on clinical experience and understanding of pathophysiology, as controlled trials are limited.

7. IgE -mediated perioperative anaphylaxis is mainly triggered by intravenous agents and usually occurs after induction of anaesthesia . Neuromuscular blocking agents (NMBAs) and antibiotics are the most common triggers. NAP6 study drug involvement: Antibiotics (48%) were the most common cause. NMBAs (25%) were the second most common. Co-amoxiclav and teicoplanin accounted for 90% of antibiotic cases. Teicoplanin use was often due to reported penicillin allergies, but many of these allergy claims were unconfirmed. French data (2011–2012) differs from UK data: NMBAs (61%) were the most common cause. Antibiotics (18%), with β-lactams making up 90% of antibiotic cases.

8. Other potential triggers of IgE -mediated anaphylaxis include: Dyes (patent blue, methylene blue). Antiseptics (chlorhexidine, povidone iodine). Colloids (gelatins). Iodinated contrast agents. Sugammadex (a neuromuscular blockade reversal agent). Chlorhexidine-induced anaphylaxis has increased over the past decade . Propofol, opioids, and amide local anaesthetics allergies are very uncommon. Latex allergy is now rare, with no cases reported in the NAP6 survey.

9. Pathophysiology of Perioperative Immediate Hypersensitivity IgE -Mediated Anaphylaxis occurs when allergens trigger an immune response involving IgE antibodies. Mast cells and basophils have high-affinity FcεRI receptors on their plasma membranes that bind IgE . Sensitization Phase : Initially, exposure to an allergen does not cause symptoms but leads to the production of specific IgE antibodies. Re-Exposure Phase : When the same allergen enters the body again, it cross-links two IgE molecules on the mast cell or basophil surface. This cross-linking triggers a signal transduction cascade, leading to immune cell activation. Preformed mediators (e.g., histamine, tryptase) are rapidly released, causing an immediate allergic response. Newly formed mediators (e.g., leukotrienes, thromboxane A2, cytokines) are synthesized, prolonging and amplifying the reaction. These mediators cause the clinical features of anaphylaxis, such as bronchospasm, hypotension, and increased vascular permeability.

10. Alternative Mechanisms of Perioperative Immediate Hypersensitivity Non-allergic perioperative hypersensitivity occurs without an immune-mediated ( IgE ) response. Mast cell activation mechanisms: Direct non-specific activation: Triggered by drugs like atracurium, mivacurium, suxamethonium , propofol. Calcium- and phospholipase-dependent activation: Seen with vancomycin. MRGPRX2 receptor activation: Suspected in NMBAs-induced reactions but not yet confirmed in humans. Cyclooxygenase-1 (COX-1) inhibition (e.g., NSAIDs) can trigger mast cell-independent reactions.

11. Complement Activation : Complement activation occurs through immunologic (antibody-mediated/classic pathway) or nonimmunologic (alternative) pathways. The activation releases C3 and C5 fragments, with C3a and C5a acting as anaphylatoxins . These fragments release histamine from mast cells and basophils, causing smooth muscle contraction, increased capillary permeability, and interleukin synthesis. C5a : Specifically interacts with high-affinity receptors on polymorphonuclear leukocytes (PMNs) and platelets, leading to chemotaxis, aggregation, and activation. This can result in leukocyte embolization to organs and the release of inflammatory products, contributing to conditions like transfusion reactions, pulmonary vasoconstriction, adult respiratory distress syndrome (ARDS), and septic shock.

12. Molecular Mediators of Anaphylaxis Histamine: Stimulates H1, H2, and H3 receptors. H1 receptor activation causes nitric oxide release, increased capillary permeability, and smooth muscle contraction (airway and vascular). H2 receptor activation leads to gastric secretion, inhibits mast cell activation, and causes vasodilation. Histamine metabolism is rapid in humans by enzymes like histamine N-methyltransferase and diamine oxidase. Injections of histamine cause wheal ( edema ) and flare (vasodilation) reactions.

13. Peptide Mediators : Eosinophilic Chemotactic Factor of Anaphylaxis (ECF-A) : A peptide that attracts eosinophils, which may help inactivate histamine and leukotrienes. Neutrophilic Chemotactic Factor : Stimulates neutrophil migration and activation, potentially contributing to recurring anaphylaxis symptoms . Arachidonic Acid Metabolites : Leukotrienes : Derived from mast cells, they cause bronchoconstriction, increased capillary permeability, vasodilation, coronary vasoconstriction, and myocardial depression. Prostaglandins : Cause vasodilation, bronchospasm, pulmonary hypertension, and increased capillary permeability. Prostaglandin D2 causes bronchospasm and vasodilation. Thromboxane B2 : A prostaglandin linked to pulmonary hypertension during reactions, like protamine reactions.

14. Kinins : Small peptides produced by mast cells and basophils, which increase capillary permeability and cause bronchoconstriction. They also stimulate the release of vasoactive factors like nitric oxide. Platelet-Activating Factor (PAF) : A lipid released from activated mast cells, it aggregates platelets and possibly leukocytes, leading to the release of inflammatory products. Elevated PAF levels correlate with the severity of anaphylaxis.

15. Nonimmunologic Release of Histamine : Histamine Release : Many substances administered during the perioperative period can release histamine in a dose-dependent, nonimmunologic manner, selectively activating mast cells, not basophils. The exact mechanisms are not well understood but may involve specific cell signaling pathways in mast cells. Histamine Release Agents : Different drugs, including muscle relaxants like atracurium (as potent as d-tubocurarine or metocurine) and some neuropeptides, can trigger histamine release. While newer muscle relaxants like rocuronium and pancuronium are less potent in this regard, certain agents still degranulate mast cells. Antihistamines : Pretreatment with antihistamines does not prevent histamine release but may reduce effects on vascular resistance by competing with histamine at the receptor. The overall effect on vascular resistance can also depend on other factors beyond histamine release.

16. Clinical Presentation of Perioperative Anaphylaxis Timing of Onset : Perioperative anaphylaxis typically occurs within minutes of anesthesia induction, with reactions depending on the drugs administered. Non-intravascular routes (e.g., patent blue injection during sentinel node biopsy) may cause a delayed onset of hypersensitivity. Ring and Messmer Scale : This four-step grading scale (I-IV) classifies the severity of anaphylactic reactions, although it does not address the underlying pathophysiology. Grades I and II are generally not life-threatening, while Grades III and IV are considered life-threatening (anaphylaxis).

17. Grade I Reaction : Mild reaction with mucocutaneous signs, such as generalized erythema and extensive urticaria,possibly with angioedema. These reactions are typically non-life-threatening. Grade II Reaction : Moderate reactions involving mucocutaneous signs, moderate hypotension, tachycardia, and possibly bronchospasm or gastrointestinal symptoms.

18. Grade III Reaction : Life-threatening : Characterized by cardiovascular compromise (hypotension, tachycardia), cutaneous signs (erythema, urticaria), and potential severe bronchospasm or gastrointestinal symptoms. Swelling of eyelids, lips, or tongue may occur. Tachycardia can progress to bradycardia or cardiac arrhythmias, especially due to massive hypovolemia and mediator release. Paradoxical Bradycardia : A sudden drop in peripheral resistance can cause paradoxical bradycardia, a reflex response to hypovolemia that aims to maintain diastolic filling of the heart. Cutaneous Features : Erythema and urticaria may appear due to cutaneous vasodilation. In severe cases, vasoconstriction (e.g., sweating, goosebumps) may occur, possibly due to extreme sympathetic nervous system activation.

19. Grade IV Reaction : Circulatory Arrest : The most severe reaction, defined as circulatory arrest, often presenting as pulseless electrical activity (PEA), likely due to severe hypovolemia. This is a medical emergency requiring immediate intervention. Bronchospasm and Comorbidities : Bronchospasm is more common in patients with uncontrolled airway conditions like asthma,COPD , or obesity. These factors, along with mechanical issues (e.g., obstructive sleep apnea),can complicate management. Hypotension and Treatment : In cases of unexplained perioperative hypotension, especially when vasopressors have limited effect, anaphylaxis should be suspected and treated immediately to prevent progression to circulatory arrest.

20. Management of Perioperative Anaphylaxis General Measures: Withdrawal of Culprit Drug: Discontinue the suspected causative agent, such as antibiotics or other infusions. Adjust Anesthesia: Temporarily lighten anesthesia depth or wake the patient, if necessary, as general anesthetics may worsen cardiovascular issues. Positioning: Consider using the Trendelenburg position or leg-raising maneuvers, depending on the clinical setting. Call for Help: Early assistance is critical to manage the situation effectively.

21. Initial Therapy : If stopping antigen exposure is not possible, minimize further exposure to prevent additional mast cell and basophil activation. Airway Maintenance and Oxygen : Anaphylaxis can lead to ventilation-perfusion abnormalities, resulting in hypoxemia. Always administer 100% oxygen and provide ventilatory support as needed. Arterial blood gas values should be monitored to track progress during resuscitation. Discontinue Anesthetic Drugs : Inhalational anesthetic agents are not effective for treating bronchospasm during anaphylaxis, especially under hypotension. These drugs can interfere with compensatory mechanisms during cardiovascular collapse.

22. Volume Expansion : Anaphylaxis leads to rapid fluid loss (up to 40% of intravascular fluid into interstitial spaces), resulting in hypovolemia. Volume expansion is critical for correcting hypotension. Crystalloids are recommended as the first-line treatment. Fluid volumes may range from 20 mL/kg (UK) to 30 mL/kg (France), with more fluids if necessary. Fluid administration should continue until hemodynamic stability is achieved Initial infusion of 2 to 4 liters of lactated Ringer’s solution or normal saline is recommended. If hypotension persists, additional fluid (25–50 mL/kg) may be necessary. Transesophageal echocardiography can be used for rapid assessment of intraventricular volume and cardiac function. Intravascular Volume Repletion : Fulminant noncardiogenic pulmonary edema may occur, requiring cautious volume resuscitation and careful monitoring of hemodynamic status.

23. Epinephrine Administration : Epinephrine is the primary drug for anaphylactic shock. α-adrenergic effects (vasoconstriction) reverse hypotension. β2-receptor stimulation (bronchodilation) inhibits mediator release from mast cells and basophils. Epinephrine should be administered rapidly and at the correct dose for the patient's condition. For hypotensive patients, 5–10 μg boluses of epinephrine can be given intravenously, titrated to restore blood pressure. If needed, increase epinephrine doses incrementally until hypotension is corrected. In cases of laryngeal edema without hypotension, subcutaneous epinephrine should be used. IV epinephrine is not recommended for patients with normal blood pressure .

24. Dosing varies depending on the severity of the reaction. For Grade III reactions, initial doses can be 50-100 µg, while higher doses (e.g., 200 µg) might be required in severe cases. Careful titration is essential due to adrenaline's narrow therapeutic window. Additional Considerations: Cardiopulmonary Resuscitation (CPR) : If systolic BP drops below 50 mmHg, CPR should be initiated along with adrenaline and fluid therapy, even in the absence of cardiac arrest.

25. Secondary Treatment : Antihistamines : Histamine release is managed by H1 blockers like diphenhydramine (0.5-1 mg/kg) intravenously. Antihistamines do not prevent anaphylactic reactions but can alleviate symptoms like pruritus and rhinorrhea . H2 blockers have unclear indications. Catecholamines : Epinephrine infusions may be used for persistent hypotension or bronchospasm. Epinephrine infusion should start at 0.05–0.1 μ g/kg/min and be titrated to correct hypotension. Norepinephrine may be necessary for patients with refractory hypotension due to decreased vascular resistance.

26. Bronchodilators : Inhaled β-adrenergic agents (albuterol, terbutaline) for bronchospasm. Inhaled ipratropium is useful in patients on β-blockers. Corticosteroids : High-dose corticosteroids may be considered, particularly if there is refractory bronchospasm or shock. Steroids help by modifying the inflammatory response, although their effects are delayed (4–6 hours). Recommended doses: Hydrocortisone: 0.25–1 g intravenously. Methylprednisolone: 1–2 g intravenously (for complement-mediated reactions). Corticosteroids help in preventing late-phase reactions (12–24 hours post-event).

27. Airway Evaluation : Evaluate for laryngeal edema, especially if persistent facial swelling suggests airway involvement. Tracheal Intubation : If there's any doubt about airway patency, intubation should remain until edema subsides. An air leak after endotracheal tube cuff deflation is a useful sign for assessing airway status. Refractory Hypotension : Vasopressin can be effective for treating refractory shock. Initial dose: 0.01 units/min via infusion. Vasopressin helps mitigate vasodilation and can be used in patients with vasoplegia from anaphylaxis. Additional hemodynamic monitoring, including echocardiography, should be considered to assess cardiac function and volume status.

28. Perioperative Management of Allergic Reactions : Allergic Drug Reactions : Occur in 6-10% of all adverse drug reactions. Drugs can cause reactions either predictably or unpredictably. Predictable Reactions : Often dose-dependent (e.g., opioids causing hypotension by histamine release or venous dilation). Unpredictable Reactions : These are immunologic, unrelated to the drug's pharmacological actions, and occur in susceptible individuals (e.g., anaphylaxis). Differentiating Reactions : Clinicians must identify if symptoms result from an allergic reaction or from other drug side effects. Management of Adverse Reactions : Symptoms typically resolve after discontinuation of the drug. However, anaphylaxis requires urgent intervention as outlined above.

29. SUMMARY Perioperative anaphylaxis is a life-threatening immediate hypersensitivity reaction that is usually IgE -mediated. Antibiotics and neuromuscular blocking agents are the most common triggers. The Ring and Messmer four step (I-IV) grading scale is the most widely accepted tool for describing the clinical severity. The most common clinical presentation includes cardiovascular collapse, tachycardia and cutaneous features (Grade III). The cornerstones of management are adrenaline (epinephrine) and i.v. fluids. Diagnosis is based on the clinical presentation, in conjunction with mast cell tryptase concentrations and the results of skin testing.

30. REFERENCES : BARASH CLINICAL ANAESTHESIA 8 TH EDITION THE ICU BOOK PAUL MARINO 5 TH EDITION PERIOPERATIVE ANAPHYLAXIS : PATHOPHYSIOLOGY, CLINICAL PRESENTATION, AND MANAGEMENT – ARTICLE BY P.DEWACHTER AND L. SAVIC.