Perioperative Anaphylaxis: Preparing for the Next Rocuronium, Chlorhexidine, or Antibiotic Reaction

Introduction

Perioperative anaphylaxis is an acute diagnostic and resuscitation challenge in an environment where hypotension, bronchospasm, flushing, tachycardia, bradycardia, and hypoxemia have many possible explanations. The patient is often sedated, draped, mechanically ventilated, and exposed to multiple drugs, antiseptics, devices, and procedural materials within minutes.

These conditions make perioperative anaphylaxis easy to miss and easy to misattribute. A reaction may initially be attributed to anesthetic depth, hemorrhage, myocardial dysfunction, pulmonary embolism, aspiration, vagal stimulation, sepsis, or equipment failure. The reverse is also true: not every episode of intraoperative cardiovascular or respiratory instability represents anaphylaxis. Clinicians need a structured response that treats suspected anaphylaxis immediately while evaluating alternative or coexisting causes of deterioration.

The issue extends beyond anesthesiology. Internists, subspecialists, pharmacists, advanced practice clinicians, surgeons, and perioperative nurses frequently influence risk before the patient reaches the operating room. They interpret allergy histories, reconcile medications, assess cardiopulmonary risk, evaluate previous procedural reactions, and help determine whether additional investigation is needed before a future procedure.

Why This Topic Matters Now

Contemporary surgical patients frequently have multiple drug-allergy labels, prior procedures, implanted devices, complex antimicrobial histories, and chronic cardiovascular or immunomodulatory therapies. Repeated procedures create additional opportunities for exposure to anesthetic agents, antibiotics, antiseptics, contrast media, blood products, and biomaterials. Repeated exposure may contribute to sensitization for selected agents, but the relationship is not uniform or reliably predictive.

Electronic health records also contain allergy entries that may be incomplete, duplicated, nonspecific, or never formally evaluated. Terms such as “rash,” “reaction,” or “intolerance” often provide insufficient information to distinguish immediate hypersensitivity from a predictable adverse effect, nonallergic reaction, or remote event of uncertain significance. Inaccurate labels may lead to unnecessary avoidance of first-line therapies and can complicate identification of the true culprit after a perioperative reaction.

Perioperative anaphylaxis remains rare, but its consequences can be severe. The Sixth National Audit Project, or NAP6, reviewed 266 reports of grade 3 to 5 perioperative reactions collected over one year from hospitals throughout the United Kingdom National Health Service. It estimated an incidence of approximately 1 case per 10,000 anesthetics, while acknowledging that the true incidence could be higher because of exclusions and incomplete capture (Harper et al., 2018a).

The rarity of perioperative anaphylaxis makes standardization and rehearsal more important, not less. Most clinicians encounter relatively few cases personally, and successful management should not depend on memory or individual improvisation.

Epidemiology and Culprit Patterns

Incidence estimates vary according to geography, case definition, reporting method, referral patterns, and denominator. NAP6 remains one of the most informative prospective datasets because it combined national participation, structured case review, and detailed analysis of severe reactions (Harper et al., 2018a, 2018b).

Culprit patterns also vary across countries and institutions. Antibiotics and neuromuscular blocking agents are consistently important, but their relative ranking depends on exposure frequency, regional anesthesia practice, antimicrobial prophylaxis patterns, and diagnostic ascertainment. Chlorhexidine, latex, dyes, gelatin-containing products, colloids, contrast media, blood products, and other procedural exposures are also identified in specialist investigations.

It is therefore more accurate to describe common culprit groups than to state that rocuronium, cefazolin, or chlorhexidine is universally the leading cause. Rocuronium is widely used and clinically important, but antibiotic-related reactions are prominent in several major datasets. Cefazolin is an important perioperative antibiotic, but a penicillin allergy label does not automatically make cefazolin unsafe. Chlorhexidine is an effective antiseptic, but its widespread and sometimes hidden use can make it an overlooked cause of serious reactions.

Mechanisms and Differential Diagnosis

Perioperative anaphylaxis may be IgE-mediated or may arise through non-IgE-mediated mast-cell activation. These mechanisms are generally indistinguishable during the acute event. Mast-cell and basophil mediator release can produce vasodilation, capillary leakage, bronchospasm, increased airway pressure, hypoxemia, tachycardia, bradycardia, and cardiovascular collapse (Garvey et al., 2019; Golden et al., 2024).

Cutaneous findings are helpful when present but may be absent, delayed, concealed by drapes, or missed during resuscitation. Their absence does not exclude anaphylaxis.

The differential diagnosis is broad and may include:

1. Hemorrhage or concealed blood loss.

2. High neuraxial block.

3. Myocardial ischemia or acute ventricular dysfunction.

4. Pulmonary or air embolism.

5. Tension pneumothorax.

6. Aspiration.

7. Severe nonallergic bronchospasm.

8. Endotracheal tube or ventilator-circuit problems.

9. Anesthetic overdose or excessive vasodilation.

10. Vagal reflexes.

11. Sepsis or another form of distributive shock.

Clinicians should not wait for diagnostic certainty when anaphylaxis is plausible. Immediate treatment and parallel evaluation for alternative or coexisting causes are both required.

The Rocuronium Problem

Rocuronium is a nondepolarizing neuromuscular blocking agent used to facilitate tracheal intubation and provide skeletal muscle relaxation during surgery or mechanical ventilation. Current labeling lists hypersensitivity to rocuronium or other neuromuscular blocking agents as a contraindication and warns that severe anaphylaxis has been reported. It also advises clinicians to consider possible cross-reactivity among neuromuscular blocking agents (DailyMed, 2019).

A patient with suspected rocuronium anaphylaxis should not simply receive a nonspecific “anesthesia allergy” label. Future planning requires a detailed record of all perioperative exposures, specialist review, and allergy investigation when appropriate. Cross-reactivity can occur, so substitution with another neuromuscular blocking agent should not be assumed safe without expert evaluation.

Sugammadex requires separate consideration. It is indicated for reversal of neuromuscular blockade induced by rocuronium or vecuronium. It is not established as first-line treatment for rocuronium-induced anaphylaxis and should not replace epinephrine, oxygenation, ventilation, discontinuation of suspected triggers, and crystalloid resuscitation.

Sugammadex itself can cause hypersensitivity and anaphylaxis. Current labeling also warns about marked bradycardia, including cases resulting in cardiac arrest, and requires continued respiratory monitoring until adequate spontaneous ventilation and airway patency are assured. Recurrent or persistent neuromuscular blockade can occur. Sugammadex is not recommended in severe renal impairment. Patients using hormonal contraception should use an additional nonhormonal contraceptive method for 7 days after administration, according to current labeling (DailyMed, 2026).

The Chlorhexidine Problem

Chlorhexidine is an effective and widely used antiseptic. Its ubiquity, however, can obscure its allergy risk. The FDA has warned that rare but serious allergic reactions, including fatal anaphylaxis, have been reported with chlorhexidine gluconate products. The agency advises clinicians to ask about previous antiseptic reactions and to consider alternative antiseptics when chlorhexidine allergy is documented or suspected (U.S. Food and Drug Administration, 2017).

In perioperative practice, chlorhexidine should be treated as a drug-like exposure. Its use should be documented and included in post-event investigation. The exposure assessment should extend beyond skin preparation and include:

• Chlorhexidine-coated vascular catheters.

• Urinary catheter lubricants and insertion products.

• Surgical dressings and drapes.

• Procedural and ultrasound gels.

• Line-care and vascular-access products.

• Oral rinses and other mucosal products.

• Bedside antiseptic supplies.

Confirmed chlorhexidine allergy requires an operational avoidance plan. A chart entry alone is insufficient. Future procedures require chlorhexidine-free skin preparation, compatible dressings, non-chlorhexidine catheter products, line-care substitutions, and clear communication among anesthesia, surgery, nursing, procedural teams, and pharmacy.

A vague history of “prep allergy,” recurrent rash after procedures, unexplained reactions after catheterization, or repeated perioperative urticaria should prompt a more detailed history. These findings do not establish chlorhexidine allergy, but they may identify a previously overlooked exposure that warrants investigation (Rose et al., 2019).

The Antibiotic Problem

Perioperative antibiotic prophylaxis is commonly administered shortly before incision, often near the time of anesthetic induction. Cefazolin remains a key prophylactic agent for many surgical procedures because of its activity against common surgical-site pathogens, favorable pharmacokinetics, extensive clinical experience, and guideline-supported role (Bratzler et al., 2013).

The clinical challenge is that many patients carry penicillin allergy labels that are remote, vague, inaccurate, or never formally evaluated. Reflexive avoidance of cefazolin in every patient with a penicillin allergy label may lead to greater use of alternatives such as vancomycin or clindamycin. These agents are appropriate in selected circumstances, but unnecessary substitution may create concerns regarding antimicrobial spectrum, timing, toxicity, and surgical-site infection prevention.

Current drug-allergy guidance supports risk stratification rather than automatic avoidance. Cefazolin has side chains that are structurally distinct from those of most penicillins, and dual allergy to penicillins and cefazolin is uncommon. Many patients with unverified penicillin allergy histories can receive cefazolin under appropriate institutional protocols (Khan et al., 2022; Sousa-Pinto et al., 2021).

This does not mean that cefazolin is risk-free. Patients with confirmed immediate hypersensitivity to cefazolin, a clinically relevant cephalosporin allergy, or a severe delayed beta-lactam reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or another severe cutaneous adverse reaction require avoidance and specialist-guided planning. Unclear high-risk histories should be managed according to allergy expertise, current product-specific labeling, and institutional policy (DailyMed, n.d.).

A large U.S. health-system study found that cefazolin-associated perioperative anaphylaxis was very uncommon and did not identify a statistically supported difference based on the presence or absence of a penicillin allergy label. As a cross-sectional observational study, it does not establish that cefazolin presents no risk. It supports the narrower conclusion that a penicillin allergy label alone should not automatically exclude cefazolin (Murphy et al., 2024).

A useful antibiotic-allergy history should identify:

• The index drug.

• The reaction phenotype.

• Time from exposure to symptoms.

• Severity and treatment required.

• Time elapsed since the event.

• Beta-lactams tolerated since the event.

• Whether formal allergy evaluation or delabeling has occurred.

A chart entry that only states “penicillin allergy” is not adequate perioperative risk information.

Recognition and Immediate Management

Perioperative anaphylaxis should be considered whenever unexpected and clinically significant cardiovascular or respiratory compromise occurs during anesthesia or procedural sedation. Findings may include otherwise unexplained hypotension, bronchospasm, increased airway pressure, oxygen desaturation, difficulty ventilating, tachycardia, bradycardia, reduced end-tidal carbon dioxide, circulatory collapse, or cardiac arrest (Dodd et al., 2024).

Management begins before the culprit is known:

1. Stop suspected infusions or remove likely exposures when feasible.

2. Call for help and clearly announce that perioperative anaphylaxis is suspected.

3. Increase inspired oxygen and support ventilation.

4. Confirm airway position and ventilator-circuit integrity.

5. Begin hemodynamic resuscitation.

6. Evaluate concurrently for hemorrhage, mechanical complications, and other causes of collapse.

Epinephrine is first-line pharmacologic treatment. In a monitored operating room, experienced anesthesia clinicians generally use carefully titrated intravenous epinephrine, followed by an infusion when necessary, according to a perioperative algorithm and institutional protocol. Intramuscular epinephrine remains appropriate when immediate intravenous administration by a clinician experienced with titrated intravenous epinephrine is not feasible.

Rapid, repeated crystalloid boluses should be titrated to the patient’s hemodynamic response. Large fluid volumes may be required because vasodilation and capillary leakage can be profound. The need for substantial resuscitation should be balanced against the patient’s response and relevant cardiac, renal, or pulmonary comorbidities.

Refractory shock may require an epinephrine infusion and additional vasopressors such as norepinephrine or vasopressin. Glucagon may be considered in selected beta-blocked patients with shock that responds inadequately to epinephrine. Escalation should occur while clinicians continue to evaluate alternative or coexisting causes of cardiovascular collapse.

Bronchodilators may be used for persistent bronchospasm after epinephrine and ventilation have been addressed. Antihistamines and corticosteroids may be used as adjuncts, but they do not reverse life-threatening airway obstruction or circulatory collapse rapidly enough to serve as initial therapy. They must not delay epinephrine or fluid resuscitation.

Diagnostic Confirmation and Post-Event Investigation

The diagnosis is clinical during the event and investigative afterward. Serum tryptase can provide supportive evidence of mast-cell activation but is not independently diagnostic. A normal tryptase concentration does not fully exclude perioperative anaphylaxis, particularly when sampling is delayed, mistimed, or the reaction produces a limited tryptase response.

The 2025 ANZCA guideline recommends serial serum tryptase collection:

• As soon as practical after the event.

• At approximately 1 hour.

• At approximately 4 hours.

• More than 24 hours after the event to establish a baseline.

Local protocols may use different collection schedules, but the central principle is to obtain both acute and baseline samples and document the timing. Treatment should never be delayed to collect laboratory specimens. Referral remains appropriate when the clinical presentation supports perioperative anaphylaxis even if tryptase does not rise (Australian and New Zealand College of Anaesthetists, 2025).

The patient should not leave the healthcare system with only a nonspecific “anesthesia allergy” label. A high-quality referral should include:

• The complete anesthetic record.

• Medication administration and infusion times.

• Timing and sequence of clinical signs.

• Airway pressures, oxygenation, and ventilatory data.

• Hemodynamic data.

• Resuscitation medications and fluids.

• Tryptase values and collection times.

• All antiseptics, dressings, gels, catheters, and devices used.

• Latex, dyes, contrast media, blood products, implants, and hemostatic materials.

• The patient’s previous allergy and procedural history.

Specialist evaluation may include skin testing, specific IgE testing when available, basophil activation testing in specialized centers, and supervised drug challenge in selected circumstances. Testing should be interpreted by clinicians experienced in perioperative drug allergy because false-positive, false-negative, irritant, and clinically irrelevant results can occur. The culprit may remain uncertain even after a comprehensive investigation (Garvey et al., 2019; Golden et al., 2024).

What Internists and Subspecialists Can Do Before Surgery

Preparedness begins before the patient reaches the operating room. Allergy histories should be treated as clinical risk-stratification data, not administrative clutter. Particular attention is warranted for patients with prior perioperative reactions, unexplained intraoperative hypotension, mast-cell disorders, severe asthma, multiple complex drug-allergy labels, or repeated reactions following antiseptic, line, catheter, or procedural exposures.

The most useful preoperative allergy history answers six questions:

1. What exact drug, antiseptic, device, or product was suspected?

2. What occurred, and how soon after exposure?

3. Was there hypotension, bronchospasm, airway swelling, generalized urticaria, syncope, or epinephrine treatment?

4. Has the patient tolerated related drugs or products since?

5. Was serum tryptase measured?

6. Was a formal allergy evaluation completed?

The history may also include latex sensitivity, previous anesthetic reactions, chlorhexidine exposure, contrast media, blood products, and clinically relevant food allergies when they raise a defined question about a perioperative product, such as a gelatin-containing material. General food allergy alone does not establish allergy to unrelated anesthetic drugs or justify blanket medication avoidance.

Medication management also requires nuance. Beta-blockers and angiotensin-converting enzyme inhibitors have been discussed as potential modifiers of anaphylaxis severity or treatment response, but they should not be discontinued solely because of theoretical allergy concerns. For many indications, the risks of stopping or changing therapy may exceed the potential anaphylaxis-related risk. Decisions should be individualized according to the cardiovascular indication, anesthetic plan, hemodynamic risk, and institutional practice (Golden et al., 2024).

Systems Preparedness

Perioperative anaphylaxis should not be managed by memory alone. Institutions should have:

• A visible perioperative anaphylaxis algorithm.

• Standardized epinephrine concentrations and labeling.

• Clear role assignment during resuscitation.

• Ready access to vasopressor infusions.

• A defined tryptase collection process.

• A structured documentation template.

• A written discharge warning and specialist-referral pathway.

Pharmacy and informatics should be incorporated into preparedness. Electronic allergy records should distinguish confirmed allergy from intolerance, predictable adverse effects, family history, and an unknown reaction. Vague penicillin allergy labels should not automatically block cefazolin unless defined high-risk features or local protocols justify avoidance.

Chlorhexidine allergy should be searchable in the electronic record and should trigger product-level substitutions. A warning in the allergy field is insufficient if chlorhexidine-containing dressings, catheters, gels, line-care products, and bedside antiseptics remain available for the patient.

Simulation is valuable because the event is rare and time-critical. Teams should rehearse the first several minutes: recognize the pattern, call for assistance, stop likely triggers, administer epinephrine, provide oxygen and ventilation, give titrated fluids, assign documentation, and obtain tryptase after initial resuscitation is underway.

Practical Approach for Clinicians

Patients with no previous reaction require routine readiness, guideline-concordant antimicrobial prophylaxis, precise exposure documentation, and immediate access to emergency treatment.

Patients with a vague penicillin allergy label require a more detailed history, not automatic substitution with a broader or less suitable prophylactic agent. Many can receive cefazolin under current allergy guidance and institutional protocols.

Patients with previous cefazolin anaphylaxis, a confirmed clinically relevant cephalosporin allergy, or a severe cutaneous adverse reaction to a beta-lactam require avoidance and specialist input. Uncertain high-risk histories should be addressed before elective surgery whenever feasible.

Patients with previous perioperative anaphylaxis require formal review before elective surgery whenever possible. If surgery is urgent, anesthesia, surgery, pharmacy, and allergy or immunology should develop a risk-minimized plan based on the timing and plausibility of previous exposures.

Patients with confirmed chlorhexidine allergy require a chlorhexidine-free procedural plan that covers skin preparation, dressings, catheter products, procedural gels, line care, oral products, and bedside antiseptic supplies.

Patients with confirmed neuromuscular blocking agent allergy require specialist-guided anesthesia planning. Cross-reactivity can occur, and an alternative neuromuscular blocking agent should not be assumed safe without evaluation.

Limitations of the Evidence

Evidence concerning perioperative anaphylaxis is constrained by the rarity of the condition, underreporting, regional variation, changing anesthesia practice, and imperfect diagnostic testing. Many management recommendations are based on expert consensus, pharmacology, observational studies, national audits, and emergency-care principles rather than randomized trials. Randomized trials of first-line treatment during life-threatening anaphylaxis would be difficult or unethical.

Culprit attribution can also remain uncertain. Multiple agents are administered close together, and temporal proximity alone may be misleading. Skin testing and in vitro testing support diagnosis but do not replace expert interpretation. After a severe event, conclusions should remain provisional until the available perioperative exposures have been systematically investigated.

Observational findings should not be interpreted as proof of no risk. For example, the absence of a statistically supported difference in cefazolin-associated anaphylaxis between patients with and without a penicillin allergy label does not establish universal cefazolin safety. It supports risk stratification rather than automatic exclusion.

Future Directions

The field needs stronger perioperative allergy registries, standardized electronic exposure documentation, improved access to specialized perioperative allergy services, and more reliable in vitro diagnostic tools. Antimicrobial stewardship and allergy-delabeling programs should be integrated into surgical pathways rather than isolated from perioperative decision-making.

Chlorhexidine allergy requires particular informatics attention because avoidance depends on substituting multiple products across operating rooms, procedural areas, inpatient units, and outpatient settings.

Preparedness is most effective when perioperative anaphylaxis is treated as a system event. The emergency occurs in the operating room, but prevention, investigation, and safe future planning involve preoperative medicine, anesthesia, surgery, pharmacy, nursing, allergy, and the electronic health record.

Table 1. Common Perioperative Triggers and Practical Clues

Trigger group	Practical clues and documentation	Safety implication
Neuromuscular blocking agents	Reaction may occur near induction. Record the exact agent, dose, time, and all other induction drugs.	Cross-reactivity may occur. Specialist evaluation is needed before re-exposure.
Cefazolin and other beta-lactams	Often administered near induction. Record infusion timing, reaction phenotype, and previous beta-lactam tolerance.	Risk-stratify allergy labels. Respect confirmed culprit allergy and severe delayed reactions.
Chlorhexidine	May be hidden in skin preparation, coated lines, dressings, gels, and catheter products.	Confirmed allergy requires product-level avoidance.
Latex	Consider previous latex reactions and the complete device and equipment exposure history.	Use a latex-safe environment when allergy is confirmed or strongly suspected.
Dyes, gelatin-containing products, contrast media, and blood products	Timing may be procedure-specific or delayed. Reconstruct the full procedural exposure record.	Include these products in the referral rather than focusing only on induction drugs.

Table 2. Immediate Response Priorities

Step	Action	Clinical rationale
Suspect	Consider anaphylaxis with otherwise unexplained cardiovascular or respiratory compromise.	Cutaneous findings may be absent or concealed.
Stop exposures	Stop suspected infusions and remove likely triggers when feasible.	Limits continued exposure while evaluation proceeds.
Treat	Give epinephrine promptly according to the perioperative algorithm and clinician expertise.	Epinephrine is first-line therapy for airway and circulatory compromise.
Resuscitate	Provide high inspired oxygen, ventilatory support, and rapid titrated crystalloid boluses.	Vasodilation and capillary leakage can be profound.
Escalate	Use epinephrine infusion and additional vasopressors when shock remains refractory.	Severe reactions may require prolonged hemodynamic support.
Preserve evidence	Obtain serial tryptase without delaying treatment and document all exposures.	Supports later diagnostic evaluation and safer future planning.

Table 3. Post-Event Investigation Timeline

Time point	Action	Purpose
During the event	Record signs, timing, medications, antiseptics, devices, fluids, and treatments.	Prevents loss of critical exposure data.
As soon as practical	Obtain the first serum tryptase specimen after resuscitation is underway.	Provides evidence of acute mast-cell activation.
Approximately 1 and 4 hours	Obtain additional tryptase specimens according to protocol.	Helps characterize the acute tryptase response.
More than 24 hours later	Obtain a baseline tryptase concentration.	Allows comparison with acute values.
Before discharge	Provide a written warning, exposure summary, and referral plan.	Reduces the risk of uninformed re-exposure.
Specialist follow-up	Complete perioperative allergy evaluation and selected testing.	Identifies the likely culprit and potentially safer alternatives.
Before the next procedure	Communicate the anesthesia, antibiotic, antiseptic, and device plan.	Converts investigation findings into safer care.

Table 4. Key Definitions for Clinicians

Term	Practical definition	Why it matters
Perioperative anaphylaxis	Acute, potentially life-threatening systemic hypersensitivity during anesthesia, surgery, sedation, or the immediate procedural period.	Cardiovascular or respiratory compromise may dominate the presentation.
NMBA	Neuromuscular blocking agent, such as rocuronium, vecuronium, succinylcholine, or cisatracurium.	NMBAs are an important culprit group, and cross-reactivity may occur.
Tryptase	Mast-cell mediator measured during the acute event and after recovery.	A rise above baseline supports mast-cell activation; a normal result does not fully exclude anaphylaxis.
PAL	Penicillin allergy label.	Many labels are unverified, and appropriate risk stratification may preserve cefazolin use.
SCAR	Severe cutaneous adverse reaction, such as Stevens-Johnson syndrome or toxic epidermal necrolysis.	The culprit drug should be avoided, and future beta-lactam decisions require specialist input.
Kounis syndrome	Acute coronary syndrome occurring in association with an allergic or hypersensitivity reaction.	Consider when anaphylaxis is accompanied by ischemic symptoms or electrocardiographic changes.

References