Discussion

This case series collectively illustrates several key clinical aspects of contrast-induced anaphylaxis, including early recognition, prompt management, and institutional preparedness, which merit careful consideration by radiologists, oncologists, and emergency clinicians.

During the two-year study period, approximately 72,000 contrast-enhanced CT examinations were performed at our institution. Only three patients developed severe iodinated contrast-induced anaphylactic shock, corresponding to an institutional incidence of approximately 0.0042% (4.2 cases per 100,000 examinations, or roughly one case per 24,000 contrast-enhanced CT examinations). This figure is consistent with previously reported rates of severe immediate hypersensitivity reactions to nonionic ICM, cited in the literature at 0.01%-0.04% of administrations [1,4,5].

Despite this rarity, the unpredictability of anaphylaxis in the setting of negative screening is the most noticeable feature. All three cases had no prior history of contrast allergy. Standard preprocedural screening, including allergy history and renal function assessment, was performed in each case and yielded no contraindications. Beyond confirming these reactions are rare, our series also demonstrates that these uncommon reactions can present with markedly different clinical manifestations despite exposure to modern low-osmolar contrast agents. Two patients progressed rapidly to cardiovascular collapse requiring ICU admission, whereas one patient was stabilized without intensive care despite significant hypotension. This variability reinforces that the severity of anaphylaxis cannot be predicted solely by the type of contrast agent, previous allergy history, or initial clinical presentation, emphasizing the need for immediate recognition and preparedness in all patients receiving ICM [1,5].

Existing risk factors, such as prior ICM reactions, asthma, multiple allergies, or previous anaphylaxis, are associated with a higher relative risk for reaction recurrence, but the majority of severe reactions occur in patients without these factors. Case 2 uniquely presented a patient with a penicillin allergy and significant cardiorespiratory comorbidity (COPD, IHD), which are risk factors for worse clinical outcomes, rather than for the reaction being triggered in the first place [7]. Nonetheless, similar severe reactions were observed in Cases 1 and 3 without any such background. Paradoxically, Case 2, the only patient with significant cardiorespiratory comorbidity, had the least severe clinical course, requiring only a single dose of intramuscular epinephrine and never progressing to cardiac arrest or ICU-level care, whereas Cases 1 and 3, both without cardiovascular disease, progressed to unrecordable BP and loss of consciousness. This observation should be interpreted cautiously given the small sample size, but it illustrates that theoretical outcome-risk factors do not reliably predict comparative severity.

Furthermore, agent-specific risk data from Kim et al. [1] identified iopromide as carrying significantly higher odds of hypotension/shock (OR 3.09) compared with any other agents. None of our three patients received iopromide (two received iohexol and one iodixanol), yet all three developed severe hypotensive/hypoxic reactions. This suggests that agent-specific risk profiles derived from single-center cohorts may not generalize reliably, and that no currently available contrast agent can be considered free of anaphylaxis risk.

The pathophysiology of ICM-induced anaphylaxis is not fully characterized. Both immunologic (IgE-mediated) and nonimmunologic pathways contribute. Nonionic low-osmolar agents such as iohexol are associated with a lower incidence of adverse reactions than older high-osmolar agents, because they primarily cause less complement activation and direct mast cell degranulation [1,4]. Nevertheless, as demonstrated in all three cases, severe reactions can still occur. In Cases 1 and 3, the elevated serum tryptase of 82.7 and 40.30 mcg/L, respectively, provided important biochemical evidence of mast cell degranulation and supports a diagnosis of true anaphylaxis rather than a vasovagal or anxiety-mediated event. Measurement of serum tryptase within one to three hours of symptom onset is recommended by international guidelines for the laboratory confirmation of anaphylaxis; its availability in Cases 1 and 3 adds diagnostic value that was absent in Case 2 and should be sought whenever feasible following suspected anaphylaxis.

In the acute setting, several alternative diagnoses were considered, including vasovagal reactions, anxiety-related events, acute coronary syndromes, pulmonary embolism, and contrast extravasation. However, the rapid onset immediately following iodinated contrast administration, multisystem involvement, profound hypotension, and prompt clinical improvement following treatment with intramuscular epinephrine strongly supported the diagnosis of anaphylaxis according to established diagnostic criteria. In Cases 1 and 3, markedly elevated serum tryptase further provided biochemical confirmation of mast cell activation, supporting the clinical diagnosis of anaphylaxis and making alternative diagnoses such as vasovagal syncope or anxiety-related reactions less likely.

Overall, management in our cases was largely consistent with current ACR recommendations, particularly with respect to rapid discontinuation of contrast administration, oxygen supplementation, IV fluid resuscitation, and administration of intramuscular epinephrine [7]. However, our cases also highlight an important learning point. In Cases 1 and 3, corticosteroids and antihistamines were administered before epinephrine during the initial response. Although epinephrine was subsequently administered promptly following hemodynamic deterioration, current guidelines recommend intramuscular epinephrine as the first-line treatment and advise against delaying its administration in favor of adjunctive medications [7,8]. Initial administration of IV hydrocortisone and diphenhydramine alone, before epinephrine, in the earlier phase of Cases 1 and 3 highlights a common pitfall: corticosteroids have a delayed onset of action and should never replace or precede epinephrine in anaphylaxis management. Departments must ensure that all staff are trained to recognize when corticosteroids alone are insufficient and to escalate to epinephrine without any delays [8,9]. These cases, therefore, illustrate a common real-world challenge and reinforce the importance of regular staff education and protocol adherence.

Structured RRT response contributed to the rapid stabilization in Cases 1 and 3, with activation within minutes of symptom onset and arrival within three to four minutes. While RRT activation and arrival times were rapid in Cases 1 and 3 (within three to four minutes), response speed alone is an incomplete measure of system effectiveness. In both cases, the patient progressed to cardiovascular collapse after RRT arrival, coinciding with an initial treatment sequence that prioritized corticosteroids and antihistamines over epinephrine. Furthermore, Case 2 demonstrates that severe reactions may also occur in settings where ICU-level care is not immediately adjacent, reinforcing the requirement that all contrast-administering environments, not only radiology departments, maintain emergency medications and trained personnel capable of managing anaphylaxis to the point of transfer.

Clinical severity varied considerably between cases. Patients in Cases 1 and 3 required ICU admission because of cardiovascular collapse, repeated epinephrine administration, and the need for close hemodynamic monitoring, whereas Case 2 stabilized after a single dose of intramuscular epinephrine and supportive treatment without requiring intensive care. This highlights that escalation of care should be guided by the patient's hemodynamic status rather than the presence of cutaneous manifestations alone. Following stabilization, all three patients were discharged on a short course of oral corticosteroids and antihistamines. None developed a delayed or biphasic reaction during the observation period. Patients in Cases 1 and 3 were referred for allergy/immunology follow-up, whereas for Case 2, referral to an allergy/immunology specialist was not documented, representing a deviation from current recommendations. All patients with suspected iodinated contrast-induced anaphylaxis should undergo specialist evaluation to guide future imaging and reduce the risk of recurrent reactions.

For patients requiring future contrast-enhanced imaging, management should involve a multidisciplinary team including radiologists, oncologists, and immunologists. Premedication may reduce the risk or severity of recurrent reactions but does not eliminate the possibility of breakthrough anaphylaxis. When appropriate, alternative imaging modalities should be considered, while patients who require iodinated contrast may benefit from evaluation for alternative contrast agents or desensitization in specialized centers.

These three cases, occurring in the same institution over a relatively short period, highlight the importance of system-level preparedness. Emergency anaphylaxis kits containing epinephrine (both intramuscular and IV formulations), corticosteroids, antihistamines, and IV fluids should be immediately accessible in all areas where contrast is administered. Staff competency in anaphylaxis recognition and management should be formally assessed and refreshed regularly. Incident reporting and case review, as undertaken here, are essential quality improvement mechanisms that facilitate learning and protocol refinement.

Limitations

This study has several limitations. It is a retrospective case series from a single institution, and only three patients developed contrast-induced anaphylaxis during the study period. Consequently, the findings may not be generalizable to other institutions or populations. Laboratory confirmation with serum tryptase was available in only two of the patients; long-term allergy follow-up was incomplete for one patient. Nevertheless, detailed chronological documentation and comprehensive clinical management provide valuable educational insights into the recognition and treatment of severe iodinated contrast-induced anaphylaxis.