# Anaphylaxis in the Operating Room

## Introduction

Perioperative anaphylaxis is a life-threatening hypersensitivity reaction that occurs in approximately 1 in 10,000 to 20,000 anesthetics. The operating room is a uniquely challenging environment for this emergency because multiple drugs and substances are administered simultaneously, making identification of the trigger difficult. Rapid recognition and treatment with epinephrine are the cornerstones of survival.

## Pathophysiology

### Immunologic (IgE-Mediated) Anaphylaxis

True anaphylaxis is a type I hypersensitivity reaction in which prior sensitization produces allergen-specific IgE antibodies bound to mast cells and basophils. Re-exposure causes cross-linking of IgE receptors, triggering degranulation and the release of histamine, tryptase, leukotrienes, prostaglandins, and platelet-activating factor. The resulting effects include vasodilation, increased vascular permeability, bronchospasm, and myocardial depression.

### Non-Immunologic (Anaphylactoid) Reactions

Non-immunologic reactions involve direct mast cell activation without prior sensitization or IgE involvement. They are clinically indistinguishable from true anaphylaxis and can occur on first exposure to the offending agent. Examples include reactions to radiocontrast media, vancomycin ("Red Man Syndrome"), and some neuromuscular blocking agents.

## Common Perioperative Triggers

### Neuromuscular Blocking Agents (NMBAs)

NMBAs are the most common cause of perioperative anaphylaxis, accounting for 50 to 70% of cases in some series. Rocuronium and succinylcholine are the most frequently implicated agents. Cross-reactivity between NMBAs is approximately 60 to 70%. The ammonium group in NMBAs is the allergenic epitope, which is also found in cosmetics and household products, providing a potential source of prior sensitization.

### Antibiotics

Antibiotics are the second most common trigger, accounting for 15 to 25% of cases. Beta-lactams (penicillins and cephalosporins) are the most frequently implicated antibiotics. Prophylactic antibiotics should be administered early enough before incision to allow time to observe for reactions.

### Latex

Latex was historically a major trigger, though its incidence has declined due to latex-free OR environments. High-risk populations include healthcare workers, patients with spina bifida, those with multiple prior surgeries, and atopic individuals. Cross-reactivity exists with banana, avocado, kiwi, and chestnut (the "latex-fruit syndrome").

### Other Triggers

Chlorhexidine is increasingly recognized as a trigger and is found in skin prep, coated central lines, and lubricants. Sugammadex, whose cyclodextrin ring can form allergenic complexes, has an incidence of approximately 1 in 2,500. Colloids such as gelatin, dextran, and hydroxyethyl starch can cause reactions. Blood products may trigger reactions to plasma proteins or in patients with IgA deficiency. Dyes including patent blue, methylene blue, and indocyanine green are also potential triggers.

![Diagram of IgE-mediated mast cell degranulation and mediator release](images/anaphylaxis-pathophysiology.png)

## Clinical Presentation

### Grading System (Ring and Messmer Classification)

| Grade | Clinical Features |
|-------|-------------------|
| **I** | Cutaneous signs only: urticaria, erythema, angioedema |
| **II** | Moderate multisystem: hypotension, tachycardia, bronchospasm (mild) |
| **III** | Severe, life-threatening: cardiovascular collapse, severe bronchospasm |
| **IV** | Cardiac arrest |

### Intraoperative Recognition Challenges

Cutaneous signs such as urticaria and flushing may be hidden under surgical drapes and are absent in up to 20% of severe reactions. The first sign is often unexplained hypotension or tachycardia. Bronchospasm may be the predominant feature, especially in asthmatic patients, presenting with elevated peak airway pressures and desaturation. Cardiovascular collapse may be the presenting sign in Grade III to IV reactions. The differential diagnosis includes hypovolemia, vasovagal reaction, tension pneumothorax, myocardial ischemia, drug error, and pulmonary embolism.

## Immediate Management

### ABCDE Approach

The first step is to stop the likely trigger by discontinuing all recently administered agents and removing latex if suspected. Help should be called and an anaphylaxis emergency declared. The airway is secured with endotracheal intubation if not already done, with anticipation of angioedema. Breathing is managed with 100% FiO2, and bronchospasm is treated with inhaled albuterol and deepened anesthesia.

For circulation, epinephrine is the first-line drug. IV bolus dosing is 10 to 20 mcg for mild reactions, 100 to 200 mcg for moderate reactions, and 0.5 to 1 mg for cardiac arrest. If no IV access is available, IM epinephrine at 0.3 to 0.5 mg is administered into the anterolateral thigh. An epinephrine infusion at 0.05 to 0.5 mcg/kg/min is used for refractory hypotension. Volume resuscitation with rapid infusion of crystalloid (2 to 4 L may be required) is essential, and colloids may be used if available (avoiding gelatin). Trendelenburg position augments venous return, and preparation for CPR should be made if cardiac arrest occurs.

### Second-Line Agents

Vasopressin at 1 to 2 units IV bolus is used for refractory hypotension in catecholamine-resistant shock. Glucagon at 1 to 5 mg IV is given for patients on beta-blockers because it enhances cardiac contractility independent of beta receptors. Corticosteroids such as hydrocortisone 200 mg IV or methylprednisolone 1 to 2 mg/kg IV prevent biphasic reactions, though onset takes 4 to 6 hours. Antihistamines including diphenhydramine 25 to 50 mg IV (H1 blocker) and ranitidine 50 mg IV (H2 blocker) are adjuncts only and are not substitutes for epinephrine. Bronchodilators including inhaled albuterol and IV magnesium 2 g are used for refractory bronchospasm.

![Acute management algorithm for perioperative anaphylaxis](images/anaphylaxis-management-algorithm.png)

## Diagnostic Workup

### Immediate Testing

Serum tryptase should be drawn at 30 minutes, 1 to 2 hours, and 24 hours after the event. A tryptase level greater than 11.4 ng/mL or greater than twice baseline plus 2 supports mast cell degranulation. Beta-tryptase is specific to mast cell degranulation, while alpha-tryptase is constitutive. Tryptase may be normal in food-related anaphylaxis or anaphylactoid reactions.

### Delayed Testing (6-8 Weeks Post-Event)

Skin prick testing and intradermal testing with suspected agents should be performed. Referral to an allergist or immunologist with experience in perioperative anaphylaxis is essential. Specific IgE testing (ImmunoCAP) is available for some agents including penicillin, latex, chlorhexidine, and suxamethonium. The basophil activation test (BAT), a flow cytometry-based assay, is emerging as a complementary diagnostic tool.

### Documentation and Reporting

All drugs, their timing, and the temporal relationship to the reaction should be documented. The patient should receive a written summary and allergy alert documentation. The medical record and allergy list should be updated with the confirmed or suspected trigger. The event should be reported to the institutional adverse event system and national anaphylaxis registries if available.

![Timeline for tryptase sampling and subsequent allergy testing after anaphylaxis](images/anaphylaxis-testing-timeline.png)

## Key Clinical Pearls

Epinephrine is the only first-line treatment for anaphylaxis, and delays in administration are the most common cause of anaphylaxis-related death. Antihistamines and steroids should never be substituted for epinephrine. The absence of cutaneous signs does not rule out anaphylaxis; unexplained cardiovascular collapse under anesthesia should prompt consideration of anaphylaxis in the differential. Serial tryptase levels should always be drawn (especially at 1 to 2 hours post-event) and the patient referred for allergy testing at 6 to 8 weeks, as identifying the trigger is essential for future safe anesthesia. NMBAs are the most common trigger of perioperative anaphylaxis, but chlorhexidine is an increasingly recognized and under-diagnosed cause.

## References

1. Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). *Br J Anaesth*. 2018;121(1):172-188.
2. Dewachter P, Mouton-Faivre C, Emala CW. Anaphylaxis and anesthesia: controversies and new insights. *Anesthesiology*. 2009;111(5):1141-1150.
3. Kolawole H, Marshall SD, Crilly H, Kerridge R, Roessler P. Australian and New Zealand Anaesthetic Allergy Group/Australian New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. *Anaesth Intensive Care*. 2017;45(2):151-158.
4. Mertes PM, Volcheck GW, Garvey LH, et al. Epidemiology of perioperative anaphylaxis. *Presse Med*. 2016;45(9):758-767.