Sugammadex-Associated Delayed Laryngeal and Upper Airway Edema: A Novel Adverse Effect

Abstract

Sugammadex is a new drug that gained FDA approval in 2015 for rapid reversal of aminosteroid neuromuscular blockade as it showed faster action than the traditional drugs, neostigmine and is generally well tolerated. However, hypersensitivity reactions, including anaphylaxis, have been increasingly recognized. These reactions typically occur within minutes of administration and often involve multisystem manifestations. Isolated upper airway edema with delayed onset has not been previously described. We present an 87-year-old woman was admitted for abdominal wall cellulitis complicated by abscess requiring incision and drainage under general anesthesia. She received propofol, rocuronium, and sugammadex without immediate complications and was extubated successfully. Approximately 2.5 hours later, she developed acute tongue and lip swelling, respiratory distress, and stridor. Vital signs showed hypoxia, hypertension and tachycardia without hypotension. She was treated with epinephrine, corticosteroids, and antihistamines but required emergent intubation due to severe airway edema. Laryngoscopy revealed significant glottic swelling. She improved with supportive care in the intensive care unit and was successfully extubated after 2 days. Laboratory evaluation demonstrated normal C1 esterase inhibitor levels and complement levels, excluding hereditary and acquired C1 inhibitor deficiency. Medication review identified sugammadex as the only new exposure. The delayed onset, isolated airway involvement, and absence of systemic features distinguish this case from typical sugammadex hypersensitivity and suggest a possible alternative mechanism, including bradykinin-mediated pathways. This case expands the spectrum of sugammadex-related adverse effects and highlights the need for awareness of delayed, atypical presentations to guide perioperative monitoring and future anesthetic management.

Introduction

Sugammadex is a modified gamma-cyclodextrin that reverses neuromuscular blockade by selectively encapsulating aminosteroid neuromuscular blocking agents creating a concentration gradient that favors movement of NMB molecules from the neuromuscular junction back into plasma, where they are encapsulated in a 1:1 ratio, resulting in rapid recovery of neuromuscular function.^1-3 Since receiving FDA approval in 2015, sugammadex has demonstrated significant advantages over traditional reversal agents like neostigmine, including faster recovery times and reduced postoperative complications. Given that it has also been used alongside rocuronium for rapid sequence intubation and showed superiority to the common use of succinylcholine.^4,5

While sugammadex is generally well tolerated, hypersensitivity reactions represent a serious safety concern. Anaphylaxis has been reported with an estimated incidence of 1.6 per 10,000 patients, though individual institutional studies have reported rates ranging from 0.004% to 0.01%.^6-8 Hypersensitivity reactions can include flushing, urticaria, hypotension, tachycardia, swelling of the tongue and pharynx, bronchospasm, and pulmonary obstructive events. ⁸ However laryngeal and upper airway edema as a standalone side effect has not been reported yet in the literature.

The typical presentation of sugammadex hypersensitivity involves hypotension (83.3% of cases) and flushing/erythema (70% of cases), with a median time to recognition of 5 minutes after administration, though delayed recognition occurring 10–30 minutes post-administration has been documented. ⁷ We present a case of isolated laryngeal and upper airway edema occurring approximately 2.5 hours after sugammadex administration, representing an unusually delayed presentation of this novel adverse effect.

Case Presentation

An 87-year-old woman with significant cardiac history presented to the emergency department with abdominal wall redness, edema, and tenderness. Computed tomography confirmed cellulitis, and antibiotic therapy with vancomycin and cefepime was initiated. Cefepime was discontinued 2 days after as cultures showed positive MRSA sensitive to vancomycin. Several days post-admission, she developed an abdominal wall abscess requiring incision and drainage.

The procedure was performed under general anesthesia with endotracheal intubation and proceeded without complications. Anesthetic medications included 250 mg of propofol for induction, 40 mg of rocuronium for neuromuscular blockade, and 250 mg of sugammadex for reversal of neuromuscular blockade prior to extubation after which she was observed for 2 hours in the PACU and then transferred to the medical floor.

Thirty minutes after transfer to the floor (approximately 2.5 hours post-extubation), the patient developed acute swelling of the tongue and lips accompanied by respiratory distress and audible stridor. Vital signs at the time of presentation included blood pressure 177/122 mmHg, heart rate 113 beats per minute, respiratory rate 34 breaths per minute, and oxygen saturation 98% on a non-rebreather mask.

Emergency treatment was initiated with intravenous epinephrine 0.3 mg, methylprednisolone 125 mg, and diphenhydramine 40 mg. The anesthesia team was called for bedside intubation. After multiple unsuccessful intubation attempts at the bedside, the patient was emergently transferred to the operating room for possible tracheostomy. Successful intubation was ultimately achieved, and she was noted to have significant edema of glottis structures by anesthesia in addition to previously noted tongue and pharynx swelling. The patient was transferred to the intensive care unit for continued management. The tongue edema improved after 2 days with positive cuff leak and she was successfully extubated without further complications.

Laboratory evaluation included assessment of C1 esterase inhibitor levels and function, as well as C4, C3 levels, all of which were within normal limits. This ruled out hereditary angioedema types I and II. Even though the patient has an extensive cardiac history of hypertension, hyperlipidemia and coronary artery disease, she has not been on ACEi or ARBs during the past 2 years and her medications included diltiazem, Isosorbide mononitrate, atorvastatin, Plavix and Protonix. Inpatient medication review revealed that sugammadex was the only new medication administered on the day of the procedure as the patient had previously undergone multiple surgical procedures and had frequent admissions with exposure to propofol, rocuronium, vancomycin and betalactam antibiotics without adverse effects, making these agents unlikely culprits.

Discussion

This case presents several unique features that distinguish it from typical presentations of both post-intubation laryngeal edema and sugammadex-induced hypersensitivity reactions. The delayed onset of symptoms (2.5 hours post-extubation), isolated involvement of the upper airway without systemic manifestations of anaphylaxis, and normal C1 esterase inhibitor function suggest a novel mechanism of reaction.

Laryngeal edema following endotracheal intubation is a well-recognized complication typically caused by direct trauma to the laryngeal structures or by prolonged intubation. ⁹ However, postextubation stridor caused by laryngeal edema characteristically occurs early after extubation, usually within the first 30 minutes. ⁹ In this case, the 2.5-hour delay between extubation and symptom onset, combined with involvement of the tongue and lips in addition to the larynx, as well as short intubation duration during the procedure makes mechanical trauma and post intubation stridor an unlikely primary etiology.

The most common cause of angioedema in a patient not taking an ACE inhibitor is usually histaminergic angioedema (allergic or idiopathic, more commonly allergic related to medication).^10,11 Even though tryptase levels were not obtained during the episode, The absence of other aspects of anaphylaxis like hypotension, bronchospasm, urticaria and pruritus, along with non-response to gold standard treatment along with the delayed reaction argues against histaminergic mechanisms.^10,11

The normal C1 esterase inhibitor levels and function effectively exclude hereditary angioedema types I and II as well as acquired C1 inhibitor deficiency which are part of the bradykinin mediated angioedema.^12,13 However, hereditary angioedema type III (now termed HAE with normal C1-INH or HAE-nl-C1-INH) represents a distinct entity characterized by normal C1 inhibitor levels and function. ¹⁴ This condition demonstrates autosomal dominant inheritance with incomplete penetrance and predominantly affects women and has been linked to estrogen (pregnancy or exogenous use) even though other medications, stress, infection has been reported to trigger it.^14,15

While HAE type III remains a diagnostic consideration in this case, several features are atypical. The patient’s advanced age at first presentation (87 years) with no family history is unusual, as HAE-nl-C1-INH typically manifests earlier in life, and very rarely adult onset has been reported.^14-16

Sugammadex hypersensitivity reactions have been increasingly recognized since the drug’s introduction. The proposed mechanisms include both IgE-mediated and non-IgE-mediated pathways.^7,17 The gamma-cyclodextrin structure with eight thiopropionate side chains may be responsible for triggering hypersensitivity reactions. Evidence from skin testing and serum tryptase measurements suggests that many reactions involve IgE-mediated mechanisms, though the exact pathophysiology remains incompletely understood.^7,17

Most documented cases of sugammadex hypersensitivity present within 5 minutes of administration, with the majority occurring within 30 minutes. ⁷ However, delayed presentations occurring 10-30 minutes after administration have been reported. ⁷ This case extends the recognized time frame for sugammadex-related reactions to 2.5 hours post-administration, representing an unusually delayed presentation.

The patient’s advanced age (87 years) warrants consideration of age-related pharmacokinetic changes that may have contributed to the delayed presentation. While this patient maintained normal renal function throughout hospitalization, which reduces the likelihood of significantly impaired clearance, age-related pharmacokinetic variability—including changes in volume of distribution and body composition—cannot be entirely excluded as a factor that may have prolonged drug exposure and contributed to the delayed onset of symptoms.

The isolated nature of the angioedema in this case—affecting the upper airway without systemic manifestations such as hypotension, bronchospasm or widespread urticaria—is also atypical for sugammadex hypersensitivity. Most reported cases present with multisystem involvement, particularly cardiovascular manifestations.^7,18,19 This isolated presentation raises questions about the mechanism that probably differs from the typical IgE-mediated anaphylaxis which is the most described in literature.

It is important to note that cyclodextrins are widely used as pharmaceutical excipients to enhance drug solubility and bioavailability, and are also found in various food products and dietary supplements and prior sensitization to cyclodextrins through dietary or pharmaceutical exposure could theoretically predispose patients to hypersensitivity reactions upon sugammadex administration. ²⁰ In this case, the patient had no documented history of prior hypersensitivity reactions to medications or food products that might suggest prior sensitization to cyclodextrins. Additionally, she had been nil per os (NPO) for more than 12 hours prior to sugammadex administration in preparation for elective surgery and a review of her home and inpatient medications did not identify any agents known to contain cyclodextrin derivatives or to cause a cross-reactivity reactions with sugammadex. While this does not entirely exclude the possibility of remote prior sensitization, the absence of identifiable cyclodextrin exposure in the patient’s recent history makes cross-reactivity a less likely contributing factor in this case.

The patient presented in a way similar to what we see in Bradykinin-mediated angioedema related to ACE inhibitor consistent with the isolated angioedema without urticaria and the delayed time course, suggests that Sugammadex might trigger bradykinin generation through mechanisms independent of C1 inhibitor deficiency (given normal levels). Even though less likely, the patient may have Bradykinin-mediated angioedema related to underlying HAE type III that was unmasked by sugammadex administration requiring further genetic testing.

Conclusion

We report a novel case of laryngeal and upper airway edema occurring 2.5 hours after sugammadex administration in an elderly patient undergoing incision and drainage of an abdominal wall abscess. The delayed presentation, isolated nature of the angioedema, and normal C1 esterase inhibitor function distinguish this case from typical presentations of both sugammadex hypersensitivity and hereditary angioedema.

This case expands the recognized spectrum of sugammadex-related adverse effects and highlights the need for extended post-operative monitoring, comprehensive diagnostic evaluation, and consideration of alternative mechanisms beyond typical IgE-mediated anaphylaxis. Physicians should maintain a high index of suspicion for sugammadex-related reactions even when presentations are atypical or delayed, and patients experiencing such reactions should undergo thorough evaluation to guide future anesthetic management.