Hypersensitivity reaction to injection hyaluronidase after multiple eye surgery: Presentation, management, and preventive strategies

Allergic reaction to local anesthetic agent is rare.[1] On literature review of cases scheduled for eye surgery under regional anesthesia, a total of four cases have been reported to have allergic reaction to lignocaine, whereas around 40 cases have been reported for allergic reaction to hyaluronidase.[2-5] The incidence of local allergic reaction to hyaluronidase ranges from 0.05% to 0.69%.[5-8] Most of the cases were caused by the IgE-mediated Type I hypersensitivity reactions (HSRs), while some of them were caused by Type IV T-cell–mediated reactions. Type I–mediated HSR requires pre.-sensitization to the allergen. Thus, in these HSR patients, following an uneventful first eye surgery under regional anesthesia, during the second eye surgery, they might present with either localized or systemic reactions. Also, in these patients, history of environmental, food, or tablet allergy might be present. At our institution, between July 2021 and November 2023, a total of nine patients developed HSR following multiple injections of hyaluronidase. None of these patients had any previous history of allergy to medicine, food, or environmental agents. All of them had undergone uneventful eye surgery under regional anesthesia previously. The demographic details of these nine patients, details of the surgery, signs and symptoms developed, and the treatment given are shown in Table 1. Local anesthetic solution used was either 0.5% bupivacaine with methylparaben as a preservative (Anawin, Neon Laboratories Ltd.) or 0.75% ropivacaine without preservative (Ropizuva, Abbott Ltd) along with freshly reconstituted Inj. hyaluronidase (Hynidase) at a dose of around 15 IU/ml. Hyaluronidase was stored inside the operation theater at a temperature of less than 25°C. In all the above patients, following HSR, intradermal skin test was performed separately both for the local anesthetic solution used and for the Inj. hyaluronidase. The skin test result was found to be positive for Inj. hyaluronidase, while it was negative for the local anesthetic solution used. It was caused mainly by the multiple exposure to per se Inj. hyaluronidase.Table 1: Details of demography, surgery, signs and symptoms that occurred, and treatment given to the nine patientsFollowing second, third, and fourth eye surgery, three patients in each developed HSR to Inj. hyaluronidase. The incidence rate was calculated based on the number of incidences that occurred and the percentage of third, fourth, and fifth time eye surgery. Within the above time period, total number of patients who underwent third, fourth, and fifth time eye surgery was 871, 222, and 56, respectively. The incidence rate for hyaluronidase HSR occurring for the third, fourth, and fifth time eye surgery was 0.34%, 1.35%, and 5.36%, respectively. For the third time eye surgery, symptoms were detected at the end of surgery and the time of onset of reaction was between 90 and 150 min. Mostly, it was an unilateral swelling involving the conjunctiva, periorbital region, and forehead, but no systemic manifestations occurred. Symptoms were controlled with Inj. hydrocortisone and tablet pheniramine. For the fourth time eye surgery, reaction occurred immediately in one patient and for the other two patients, it occurred between 90 and 110 min. Swelling involved both the periorbital region, cheek, and face, but without any systemic manifestations. It was treated with Inj. hydrocortisone and tablet pheniramine. In the fifth eye time surgery, for two patients, reactions occurred between 80 and 150 min and for one patient, it occurred at his residence around 6 h later. Apart from the localized symptoms, systemic manifestations like itching involving the face and palms occurred and rashes were seen over both the arms and forearms. In two patients, swelling was seen over the lips and tongue. One patient even required oxygen supplementation via face mask and his vitals were constantly monitored in the postoperative care area for nearly 3 h. All of them were managed with Inj. hydrocortisone and Inj. pheniramine. The incidence rate of HSR for both third and fourth time exposure was found to be less than 1.35%, but for the fifth time exposure, the incidence rate increased to around 5.5%. This is somewhat similar to HSR that has been reported to occur following multiple cycles of intravenous (IV) infusion of chemotherapeutic agents like asparaginases, taxanes, platinum compounds, and epipodophyllotoxins.[9] During the first five cycles of carboplatin IV infusions, the risk is around 1%.[10] It rises to 6.5% with the sixth cycle[11] and increases sharply to 27% in patients receiving more than seven cycles of treatment, although the previous infusions were uneventful.[12,13] Thus, the incidence rate of hyaluronidase HSR for the fourth time exposure was found to be similar to the incidence rate of HSR for chemotherapeutic agents exposed for the fifth time (both around 1.35%). Also, the incidence rate of hyaluronidase HSR for the fifth time exposure was found to be similar to the incidence rate of sixth time exposure to the chemotherapeutic agent, that is, around 5.5% and 6.5%, respectively. The number of eye surgery cases done for more than five times was very small to report for any HSR to occur. Hence, there is no data available to compare the same with the incidence rate of seventh time exposure to the chemotherapeutic agents. Signs and symptoms of HSR for the initial infusion of chemotherapeutic agents were mild, such as skin rash, urticaria, itching over the palms, edema of the face and hands, diarrhea, and pruritus.[13-15] They usually get resolved with steroids and antihistamines. In our study too, it was found that mild, localized reactions occurred for the third and fourth time exposure and they were treated with Inj. hydrocortisone and tablet pheniramine. With subsequent IV infusions of the chemotherapeutic drugs, more severe reactions like tachycardia, hypotension or hypertension, bronchospasm, seizures, chest pain, and life-threatening anaphylaxis reactions have been reported.[14-16] In hyaluronidase exposure for the fifth time, apart from the localized symptoms, systemic reactions occurred; all of them required Inj. hydrocortisone and Inj. pheniramine. One patient even required oxygen supplementation via face mask and monitoring in the postoperative care unit for nearly 3 h. Hence, it is very important for the surgeons to be aware of this Inj. hyaluronidase HSR following multiple injections, especially for the fifth time exposure or above, and to take adequate preventive measures to prevent this from happening. Some successful preventive strategies are adopted to prevent HSR from occurring in multiple time IV infusions of chemotherapeutic agents. First and foremost is the identification of high-risk group of patients who can develop such reactions. Hence, a thorough detailed history of any reactions that occurred during the previous exposure to the drug and history of any allergy to food and environment is taken.[9] If there is any positive history, then they are subjected to allergic intradermal skin test to the drug. At our institution, we administer preoperative intradermal skin test with Inj. lignocaine along with Inj. hyaluronidase for patients with history of allergy to medicine, allergic rhinitis, bronchial asthma, food allergy, insect bite allergies, or skin allergic conditions. For the above patients requiring multiple surgeries, we repeat the skin test before every surgery, even if the skin test result was negative for earlier eye surgery. In many studies, authors have predicted the occurrence of HSR using the intradermal skin tests.[17] Skin tests are reported to have a 99% negative predictive value, and they have been recommended for every patient before administration of eight cycle of platinum compounds.[18] But performance of intradermal skin test requires certain special skills, and reactions have occurred in spite of negative skin tests results.[19] So, another additional preventive strategy method was followed with the use of premedicants like corticosteroids and histamine 1 antagonist (pheniramine).[9] But no standard premedication regimens have been developed so far.[9] Often, patients are able to tolerate a rechallenge of a taxane if they are pretreated with a corticosteroid and an antihistamine, even if they have previously experienced HSRs.[20] As practiced in IV infusions of chemotherapeutic agents, it would be a wise and safe practice to adopt such preventive method strategies for multiple exposure to Inj. hyaluronidase. Hence, identification of high-risk group of patients through a detailed history, subjecting them to intradermal skin test, and administering premedicants like steroids and/or pheniramine, especially for the fifth time exposure, can be considered. Apart from this, emergency preparedness like crash cart with necessary medicines, airway equipment, and adequately trained staff in basic and advanced cardiac life support care must be looked upon.