Going into surgery is stressful enough without the added worry of a sudden, severe allergic reaction on the operating table. Yet understanding and tracking down the root causes of perioperative anaphylaxis—a life-threatening allergic reaction during surgery—remains one of the trickiest puzzles in modern medicine. Earlier this year at the Eastern Allergy Conference (EAC) 2026 in Palm Beach, Florida, Kimberly Blumenthal, MD, outlined a clearer approach to navigating these high-stakes situations, from evaluating historical allergy labels to identifying the true culprits when things go wrong.
Many patients heading into the operating room arrive with at least one documented drug allergy label attached to their medical chart. These warnings can stem from a wide range of past experiences, including a forgotten childhood reaction to penicillin or an adverse effect from commonly prescribed medications such as ibuprofen or an opioid. While some of these labels represent true allergies and others do not, all warrant careful evaluation before surgery.
Preoperative teams pay closest attention to allergy labels that could directly affect anesthesia. A reported history of reactions to medications such as lidocaine, propofol, fentanyl, or midazolam (Versed) can complicate anesthetic planning and influence which medications clinicians choose. Beyond the operation itself, teams also need to think ahead to postoperative recovery, ensuring they have safe options for pain management if a patient reports an allergy to NSAIDs or opioids.
Antibiotic allergy labels are equally important because most surgical patients receive preventive antibiotics to reduce the risk of infections at the surgical site. Dr Blumenthal emphasized that collecting a thorough allergy history before surgery is essential.
“[Collecting] the allergy history for all patients with drug allergy labels before surgery is important,” Blumenthal said. “Things that have significant reactions you might want to avoid. Things that are lower risk, [or] moderate risk, we could potentially test using a combination of skin testing and drug challenge tests.”
When it comes to surgical antibiotics, cefazolin (commonly known by the brand name Ancef) is considered the preferred first-line antibiotic for many common surgical procedures, making it especially important to determine whether patients with reported antibiotic allergies can safely receive it. Because cefazolin belongs to the cephalosporin family, patients who report childhood reactions to related antibiotics such as cephalexin or cefadroxil often prompt questions about whether cefazolin can be used safely. Careful evaluation can help determine whether cefazolin remains an appropriate choice.
Fortunately, growing evidence shows there is no meaningful cross-reactivity between penicillin and cefazolin specifically. As a result, nearly all patients with a penicillin allergy label can safely receive cefazolin in the operating room after appropriate clinical evaluation. In fact, Dr Blumenthal’s own research has shown that avoiding first-line cefazolin because of an unverified penicillin allergy label can actually increase a patient’s risk of developing a surgical site infection.
However, when perioperative anaphylaxis does occur during surgery, figuring out exactly what caused it becomes a complex medical investigation. Unlike a controlled allergy challenge in a clinic—where one medication is introduced at a time—patients undergoing surgery often receive multiple drugs within just a few minutes. To untangle the sequence of events, allergists become medical detectives, reconstructing a minute-by-minute timeline from the anesthesiologist’s record to determine which medication was administered immediately before the reaction began.
Even with a detailed timeline, identifying the responsible drug remains difficult.
“We really don’t get to see what causes it in all of the patients,” Dr Blumenthal acknowledged.
In practice, comprehensive allergy testing identifies a likely causative agent in only about one-third to one-half of patients referred for postoperative evaluation by an allergist.
When a cause is identified in the United States, antibiotics—with cefazolin leading the list—are the most common trigger of perioperative anaphylaxis. Neuromuscular blocking agents, the medications used to produce temporary muscle paralysis during surgery, rank second. These drugs present a unique diagnostic challenge because many reactions appear to result from direct mast cell activation rather than the classic IgE-mediated allergic pathway, making them more difficult to confirm through standard allergy testing.
Ultimately, Dr Blumenthal emphasized that careful allergy evaluation before surgery and thorough investigation afterward go hand in hand. Identifying which drug truly caused a reaction not only helps explain what happened during a patient’s procedure but also allows clinicians to plan future surgeries more safely while preventing patients from carrying inaccurate drug allergy labels that could unnecessarily limit their treatment options for years to come.
Here is a video of Dr Blumenthal’s interview with HCP Live:
