Diphenhydramine prophylaxis before using indocyanine green during flap surgery in patients with iodine allergies: a two-case report

Introduction

Local flap surgery is a fundamental aspect of reconstructive plastic surgery involving the transfer of a tissue flap directly adjacent to the defect (1-3). The design of flaps is crucial, as they rely on adequate blood supply to ensure ideal aesthetic and functional outcomes (1-4). Local flaps largely rely on random pattern blood supply and are predominantly used for smaller defects (3). Thus, visualizing the perfusion of subdermal vascular plexus is an imperative step in local flap design (1,5-7). Several methods have been employed by physicians for the evaluation of flap vascularization, including magnetic resonance imaging (MRI), computed tomographic angiography (CTA), and Doppler sonography (1). However, these methods are often unreliable at detecting the degree of perfusion in flaps (1). Thus, the field of reconstructive plastic surgery is still vying for a reliable and effective process to assess flap perfusion. In recent years, a near-infrared fluorescence imaging device has been used with indocyanine green (ICG) during flap surgery (1,8). A digital camera allows for physicians to see the absorption of ICG fluorescence and assess tissue perfusion in real time. This procedure has proven to be effective in both the preoperative identification of flap perforators and in observing refill of flaps after closure (1,4,9,10).

It has been widely accepted that ICG is a safe contrast agent with a low rate of allergy and research has shown that it does not alter blood composition and coagulation systems (1,11-13). As previously published, any potential adverse reactions to ICG are categorized into three arbitrary levels: mild, moderate, and severe. A mild reaction is any temporary effect that resolved promptly without any need for intervention, such as nausea, vomiting, sneezing, or itching. Moderate reactions are those might require a medical intervention, such as urticaria, syncope, fever, local tissue necrosis, and nerve palsy. Severe reactions are defined as prolonged consequences that necessitate intense treatment, which involve the cardiac, respiratory, and neurologic systems (14,15). Patients who are allergic to iodine are the most probable to experience adverse allergic reactions to ICG because it contains up to 5% sodium iodide (1,16). Thus, ICG must be used with caution in patients with iodine allergies. Recently, Zammarrelli et al. demonstrated that premedication of corticosteroids with or without diphenhydramine prior to sentinel lymph node biopsy with ICG is a reasonable approach (17). However, researchers have yet to explore a premedication of solely diphenhydramine before ICG administration in patients with iodine allergies.

In this article, we aim to introduce a method for premedication of diphenhydramine before the administration of ICG in local flap surgery in patients that have mild to moderate allergies to iodine or shellfish. This technique offers a procedure for surgeons to use ICG in patients with mild to moderate iodine or shellfish allergies in combination with a reduced dose of ICG, with the two patients in this report experiencing no surgical adverse events while still retaining the effectiveness of ICG. We present this article in accordance with the CARE reporting checklist (available at https://asj.amegroups.com/article/view/10.21037/asj-25-9/rc).

Case presentation

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study protocol was approved by the University of Alabama at Birmingham Institutional Review Board for Human Use (IRB) (IRB-300003998) and written informed consent was obtained from all participants or their authorized representatives for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. The first patient presented with melanoma of the left preauricular and melanoma in situ of the left forehead, whereas the second patient presented with basal cell carcinoma of the right lateral ala and a small erythematous area of the mid forehead. Both received wide local excisions with negative margins prior to reconstruction. The first patient underwent surgery in reconstruction in two stages due to the defect size, while surgical excision was followed by reconstruction in one stage in the second patient. Additionally, both patients were determined to have an allergy to shellfish or iodine preoperatively and received an intravenous injection of 12.5 mg diphenhydramine (Benadryl) before reconstruction. Both patients received an injection of 1 mL ICG or 0.03 mg ICG/kg body weight (BW), which was prepared by reconstituting 25 mg ICG in 10 mL sterile water. On the contrary, retrospective analysis was conducted on 16 patients lacking iodine allergies from the University of Alabama at Birmingham from 2022 to 2024 who received ICG during flap surgery. It was determined that the average standard dose was 3.25±0.58 mL or 0.10±0.02 mg ICG/kg BW, with the standard doses ranging from 0.06 to 0.14 mg/kg.

Case 1

An 84-year-old White male weighing 85.28 kg presented with melanoma of the left preauricular and melanoma in situ of the left forehead. Tumor resection and reconstruction were planned in two stages due to the size of the tumor. During the first stage, a wide local excision was performed on the tumors of both the left preauricular and the left forehead. Final pathological sections were analyzed to verify negative margins before proceeding to the second portion of the procedure.

At the time of reconstruction, the size of the defect of the left preauricular cheek was 3.5 cm × 3.5 cm and the defect of the left forehead was 2.0 cm × 1.5 cm (Figure 1). Before surgery it was determined that the patient had a mild allergy to shellfish, due to previous reactions of an upset stomach and vomiting after eating shellfish. A premedication of 12.5 mg diphenhydramine was administered to the patient. After waiting 15 minutes, the patient was then injected with 1 mL (2.5 mg) of ICG to visualize the vasculature of the flap and plan the closure of the two defects, which was quickly visible and marked with a standard marking pen. The defects were then debrided, and skin edges were excised from the upper, lower, and periphery of the defects. A cheek advancement flap was employed for the defect of the preauricular cheek, resulting in a closure that was 6 cm in length. Alternatively, a rotation flap was designed medially with the base superiorly for the left forehead defect. For both flaps, Vicryl sutures were used for the deep tissue, with Prolene and nylon sutures being used for the skin. Following closure, 1 mL of ICG was again injected, showing good filling in both flaps in the closed defect areas. The patient did not experience any complications related to the use of ICG. After surgery, eosinophils and basophils made up 3% and 1% of the patient’s total white blood cell count, respectively, indicating no allergic reaction. At the 3-week follow-up appointment, physical examination revealed well-healing flaps without surrounding erythema (Figure 2). The patient was highly satisfied with the outcome of the procedure.

Figure 1 Left preauricular and left forehead defects 1 week following surgical excision.

Figure 2 Cheek advancement flap and rotation flap two and a half weeks following local flap surgery.

Case 2

A 63-year-old White female weighing 80.56 kg presented with basal cell carcinoma of the right lateral ala and an erythematous area of the mid forehead (Figure 3). The patient was determined to possess moderate iodine and shellfish allergies due to previous rash and itching in response to iodine and urticaria in response to shellfish. 12.5 mg diphenhydramine was given intravenously prior to timeout. After 15 minutes, 1 mL (2.5 mg) of ICG was administered intravenously, showing the angular vessel at the junction of the nose and cheek (Figure 4). This vessel was lateral to the defect and was included in the V to Y advancement flap for improved blood supply. Following the marking of the vessel, the lesion was also marked in the periphery with a standard marking pen. A wide local incision of the right lateral ala with negative margins was performed to remove the basal cell carcinoma, resulting in a 1 cm × 9 mm defect. Following excision, a V-Y advancement flap was used to close the defect of the right lateral nose. Vicryl sutures were used for the deep tissue, with Prolene and nylon sutures for the skin (Figure 5). Upon closure, the flap showed good refill. Finally, a punch biopsy was then performed on the erythematous area of the mid forehead. There were no surgical adverse events experienced by the patient during the procedure. Following surgery, eosinophils made up 3% of the patient’s total white blood cell count. Additionally, basophils were not detected, indicating the patient did not have an allergic reaction to ICG. At the 3-week follow-up appointment, the right lateral ala incision was healing well without erythema, purulence, or drainage upon physical examination, and the patient reported satisfaction with the procedure’s outcome (Figure 6).

Figure 3 Basal cell carcinoma of the right lateral ala (as denoted by the purple arrow).

Figure 4 Fluorescence image of the flap site perforator (as denoted by the black arrow) on the right lateral nose cheek junction visualized by ICG intraoperatively. ICG, indocyanine green.

Figure 5 Closure of the V-Y advancement flap (containing the perforator) of the right lateral ala. Patient consent for publication of this image has been obtained.

Figure 6 V-Y Advancement flap 1 week following local flap surgery.

Discussion

In this study, we describe two cases in which a premedication of 12.5 mg diphenhydramine in combination with a reduced dose of ICG was successful in preventing any adverse reactions in patients with mild to moderate iodine allergies. Neither patient experienced any surgical adverse events. Additionally, both patients had well-healing flaps at least three weeks following local flap surgery. Both patients expressed satisfaction with the outcomes of the procedure as well. One patient in this study had a mild allergy to shellfish, while another patient had a moderate allergy to iodine and shellfish, so we suggest that this strategy may work in patients with mild to moderate allergies iodine and shellfish.

In the two reported cases in this article, a reduced dose of ICG was employed to help prevent any adverse reactions. Upon analysis of previous cases in patients without an iodine or shellfish allergy, it was determined that the average dose used was 3.25 mL (0.10 mg ICG/kg BW). The dose given in the two cases of interest was considerably reduced (1 mL; 0.03 mg ICG/kg BW). The reduced dose was utilized in this study to aid in the prevention of adverse reactions, and it is likely that this lower dose contributed to the absence of adverse events in the two patients of interest. The decreased dose of ICG resulted in slightly reduced image clarity compared to the typical average dose of 3.25 mL. However, the smaller dose had a minimal effect on the usefulness of ICG, as it was still helpful in the preoperative identification of flap perforators and refill of the flap after closure.

To the best of the authors’ knowledge, this article is the first to report giving simply diphenhydramine as a premedication for ICG use in patients with mild to moderate iodine or shellfish allergies. Zammarrelli et al. reported success using premedication of corticosteroids with or without diphenhydramine prior to ICG administration in patients with an iodine allergy (17). However, there was no premedication of simply diphenhydramine. However, there are several limitations of this study. Mainly, this strategy was only utilized in two patients and may lack generalizability to a larger patient population. Similarly, there was no control group in this study, making it difficult to determine causality. Additionally, ICG skin testing was not performed in this study, presenting a lack of baseline comparison for the patients’ reactions to ICG as opposed to iodine or shellfish. Future studies are needed to validate the findings in the cases described in this study.

It is important to recognize that other methods that lack the use of iodinated contrast agents have been explored. Recently, a fingerstall-type tissue oximetry system was explored as an alternative to ICG imaging for assessing flap viability and showed promising results (18,19). Similarly, in recent years a low-cost thermal camera has shown to be successful as a method to evaluate tissue perfusion in free flaps (20,21). It is important these alternative imaging methods continue to be explored and enhanced to aid in the evaluation of perfusion in patients with iodine allergies, especially those with more severe allergies than the patients described in this study.

Although it has been widely accepted that ICG is a non-toxic contrast dye with a low rate of allergy (1:42,000–1:60,000), iodine allergies still pose the prime source to any adverse effects (1,15,22). Because prior research has shown ICG to be advantageous in all steps of flap surgery—preoperative, intraoperative, and postoperative (1)—finding a strategy for administration in patients with iodine allergies would be beneficial. The two cases reported in this article demonstrate that a lower dose of ICG in combination with diphenhydramine allowed for sufficient visualization of flap perfusion and resulted in no complications, demonstrating a promising solution for administering ICG to patients who have mild to moderate iodine and shellfish allergies. Future studies with larger patient cohorts are needed to validate these findings and ensure the efficacy of a diphenhydramine premedication in patients with mild to moderate iodine allergies.

Conclusions

In this case study, two patients presented with melanoma of the left preauricular and forehead and basal cell carcinoma of the right lateral ala, respectively. Both patients possessed mild to moderate allergies to shellfish or iodine. The administration of a reduced dose of ICG had no effect on the identification of perforators or the outcome of flap surgery. Additionally, the premedication of diphenhydramine prevented any adverse reactions in patients with mild to moderate allergies to iodine or shellfish. The reduced dose in combination with the premedication of diphenhydramine demonstrates a promising solution for administering ICG to patients who have mild to moderate iodine or shellfish allergies.

Acknowledgments

This study was presented at the Academic Surgical Congress 02/12/2025 by Nolan McKibben.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://asj.amegroups.com/article/view/10.21037/asj-25-9/rc

Peer Review File: Available at https://asj.amegroups.com/article/view/10.21037/asj-25-9/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://asj.amegroups.com/article/view/10.21037/asj-25-9/coif). S.S.C. received a University of Alabama at Birmingham (UAB) faculty development grant entitled: Indocyanine green fluorescent dye for the evaluation of skin cancer margins. S.S.C. is also a current paid medical consultant for Avita and also serves as an unpaid co-chair of the American Society of Plastic Surgeons (ASPS) Panniculectomy committee. She received payment for her lecture at the meeting of Avita and payment as an expert witness on a patient who sustained burns. S.S.C. also received the support from UAB faculty expense account. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Helsinki Declaration (as revised in 2013). The study protocol was approved by the University of Alabama at Birmingham Institutional Review Board for Human Use (IRB-300003998) and written informed consent was obtained from all participants or their authorized representatives prior to participation for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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