Hyaluronidase for the Treatment of Mannitol Extravasation: A Case Report

Jah-Hsuan Wu, Yu-Ju Tseng

Department of Pharmacy, National Taiwan University Hospital

Abstract

Hyaluronidase is a recombinant enzyme which is indicated for absorption and dispersion of injected drugs, subcutaneous fluid administration and subcutaneous urography. The use of hyaluronidase for hyperosmotic extravasations constitutes a non-U.S. Food and Drug Administration-approved use.
Mannitol is a hyperosmolar agent that reduces intracranial pressure or cerebral edema. Mannitol has an osmolarity of 1098 mOsm/L, and its hyperosmolarity may cause severe edema or swelling. We present a case in which hyaluronidase was used to successfully treat mannitol extravasation.
A 66-year-old man was admitted to hospital for a scheduled brain tumor operation. The patient underwent craniotomy for meningioma excision on June 16, 2022. The patient received intravenous infusions of 100 mL of 20% mannitol solution every 8 hours for cerebral edema. Mannitol extravasation with progressive edema was noted at 16:00 on June 18, 2022. Symptoms included right hand redness and severe swelling with progressive edema, which influenced the bending of the wrist. The patient then received 15 units of hyaluronidase as 5 separate subcutaneous injections along the leading edge of the extravasation site at 19:30 and 21:30, separately. Right hand redness, swelling, and edema had nearly resolved the following day.
The exact dosage of hyaluronidase for extravasation is not clearly defined and ranges from 15–150 units. Our case report administered cumulative dose of 30 units of hyaluronidase. Hyaluronidase is an effective treatment for mannitol extravasation.

Keywords: Hyaluronidase; Mannitol; Extravasation

1. Background

Hyaluronidase is a recombinant enzyme that depolymerizes glycosaminoglycans such as hyaluronic acid and chondroitin sulfate. Hyaluronidase is believed to facilitate the dispersion of injected agents by increasing tissue permeability. The U.S. Food and Drug Administration (FDA) has approved hyaluronidase for the following indications: (1) subcutaneous fluid administration (hypodermoclysis); (2) as an adjuvant to accelerate the absorption and dispersion of drugs in subcutaneous tissue or to manage extravasation; and (3) as an adjunct to promote the absorption of contrast media in subcutaneous urography.¹ The use of hyaluronidase for hyperosmotic extravasations constitutes a non-FDA-approved use.¹

Mannitol is a hyperosmolar agent that reduces intracranial pressure or cerebral edema. Mannitol has an osmolarity of 1098 mOsm/L, and its hyperosmolarity may cause severe edema or swelling. The guidelines for the management of mannitol extravasation include initiating treatment with hyaluronidase, applying dry cold compresses, and elevating the extremities. We present a case in which hyaluronidase was used to successfully treat mannitol extravasation.

2. Case Report

A 66-year-old man with a medical history of hypertension, hyperlipidemia, benign prostatic hyperplasia, and chronic periodontitis was admitted to the hospital for a scheduled brain tumor operation. After the detection of a meningioma of the left anterior clinoid process, the patient underwent craniotomy for meningioma excision on June 16, 2022. The patient received intravenous infusions of 100 mL of 20% mannitol solution every 8 hours beginning on June 16, 2022, for cerebral edema. In addition, 100 mg intravenous cefazolin sodium was administered every 8 hours for postoperative prophylaxis. Mannitol extravasation with progressive edema was noted at 16:00 on June 18, 2022. Symptoms included right hand redness and severe swelling with progressive edema, which influenced the bending of the wrist. Because the application of a dry cold compress and the elevation of the right wrist did not improve circulation, a dermatologist and plastic surgeon suggested administering a total of 15 units of hyaluronidase as 5 separate subcutaneous injections into the leading edge of the extravasation site. The patient then received 15 units of hyaluronidase as 5 separate subcutaneous injections along the leading edge of the extravasation site at 19:30 and 21:30, separately. The patient's pulse rate, capillary refill time, color, and sensation were closely monitored. Symptoms of extravasation such as swelling improved 2 hours after hyaluronidase administration. The patient's heart rate ranged between 65 and 76 beats per minute. Right hand redness, swelling, and edema had nearly resolved the following day.

Dermatologic toxicity induced by mannitol extravasation occurred. The patient had a Naranjo score of 7 points, indicating a probable adverse drug reaction (table 1). The patient's renal and liver functions remained normal during treatment. A serum creatinine of 1.1 mg/dL, blood urea nitrogen of 14.8 mg/dL, and an AST/ALT ratio of 22/23 U/L were reported. A total of 30 units of hyaluronidase were administered, and the extravasation symptoms were successfully relieved.

Table 1　Naranjo score

3. Discussion and Conclusion
Hyaluronidase contains the polymers D-glucuronic acid and D-N-acetylglucosamine, which are composed of disaccharides linked by β-1,4 and β-1,3 glycosidic bonds.¹ It can break down hyaluronic acid and glucosaminoglycans. Hyaluronidase decreases the viscosity of hyaluronic acid to improve the resorption rate of fluid and tissue diffusion. Two published case reports were reported of successful use of hyaluronidase in mannitol extravasation. ^{2, 3}
The exact dosage of hyaluronidase for extravasation is not clearly defined.^2,4,5 Previous studies especially for vinca alkaloid extravasation have reported that a higher dosage of 150 units/mL hyaluronidase comprises 5 separate subcutaneous or intradermal injections of 0.2 mL (30 units) along the borders of the extravasation site using a 25- or 26-gauge needle. Administration of 1 ml hyaluronidase solution for each ml of extravasated vinca alkaloid-containing solution and total dose 150-900 units of hyaluronidase are recommended. ^4-7 Alternatively, clinicians may administer a lower dosage of hyaluronidase with a diluted concentration of 15 units/mL according to the same dosing instructions.² Dosages of 15–25 units of hyaluronidase are generally administered as 5 intradermal injections or through an injection catheter along the borders of the extravasation site.⁵

A higher dosage is recommended for patients receiving treatment for chemotherapy extravasations, particularly for those who have undergone vinca alkaloid chemotherapy.^7,8 Review articles have recommended higher dosages for hyperosmolar agents, such as radiographic contrast media, 10%–50% dextrose (504–2520 mOsm/L), mannitol 20% (1098 mOsm/L), nafcillin (363 mOsm/L), and phenytoin,^4,5 whereas some case reports have reported the administration of lower dosages.² In this case report, a lower dosage of hyaluronidase was applied. Hyaluronidase is typically reconstituted with normal saline or 1% lidocaine to achieve 10–15 units/mL hyaluronidase.²

In this case report, 150 units of hyaluronidase were mixed in 10 mL of normal saline, and 10 subcutaneous injections of 0.2 mL-hyaluronidase were then administered along the leading edge of the extravasation site. After giving 30 units of hyaluronidase, swelling gradually diminished after one hour. Redness, swelling, and edema had nearly resolved by the following day. According to the guideline, if extravasation occurs, nurse should stop infusion first then local cooling or warming compress for 15-20 minutes at least 4 times per day for 1-2 days, elevate extremity and monitor extravasation site every 2-4 hours.⁹ Ideally administer hyaluronidase within 1 hour after extravasation. Hyaluronidase was limited to be prescribed by dermatology in our hospital and it was one of reasons why we delayed administrating hyaluronidase in this case. In our case, doctor took 2 hours to ensure the effects of dry cold compress and elevation of the wrist. Because non-pharmacological treatment was in vain, doctor consulted dermatologist for hyaluronidase therapy. According to Reynolds et al, 15 units hyaluronidase was given at 19:30 but no improvement was observed. Due to dosage range was hyaluronidase 15–25 units, another 15 units hyaluronidase was administered after 2 hours and extravasation site significantly improved within 1 hour.^2,5 Proper time to consider hyaluronidase to treat extravasation was less than 1 hour. Late treatment in our case was due to late observation of extravasation, evaluation of non-pharmacological treatment and limitation of hyaluronidase prescription in our hospital. Although we did not administer hyaluronidase less than 1 hour after extravasation, we reported a successful case that late hyaluronidase administration can also successfully treat mannitol extravasation.

Figures 1　Progressive edema before treatment (left). After treatment with hyaluronidase (right).

Hyaluronidase should be self-paid for extravasation management. It contains 1500 units of hyaluronidase in 1 amp and 30 units of hyaluronidase was used in this case. If the patient did not response to hyaluronidase therapy, he would receive fasciotomy. Although it seems that hyaluronidase was not cost-effective in this case, it prevented the patient from fasciotomy and saved other surgical fees.
According to Kaur1 Manbir et al, hyaluronidase improves mild to moderate compartment syndrome. It should be performed by certain protocol.3 When mannitol extravasation induce compartment syndrome, we should evaluate the injury of distal sensory and motor deficit and the compartment pressure. If compartment pressure is less than 30 mmHg and no distal sensory and motor deficit, therapy of hyaluronidase 150 units in 10 ml normal saline by multiple subcutaneous injections of 0.5-1 ml is suggested. If compartment pressure more than 30 mmHg or severe compartment syndrome occurs, immediate fasciotomy is first-line therapy.

Hyaluronidase can be used to treat extravasation injuries from drugs such as mannitol, vinca alkaloids, paclitaxel, phenytoin, 10%–50% dextrose, total parenteral nutrition (TPN), calcium salts (in the early stage), and docetaxel.⁴ The early administration of hyaluronidase in patients with extravasation of hyperosmolar fluids such as mannitol, TPN, 10% dextrose, and 30% urea prevents the need for fasciotomy.² For reducing swelling due to extravasation, the effects of hyaluronidase are onset approximately 15–30 minutes.⁵ Certain patient characteristics may influence the effect of hyaluronidase. Older adults may be less responsive to hyaluronidase due to their inelastic skin; this treatment is more effective in areas with a lower subcutaneous fat content. Patients receiving large doses of antihistamines, corticosteroids, salicylates, or estrogens may also require higher doses of hyaluronidase because such agents may cause resistance to hyaluronidase.⁵ The patient in this case report did not have any characteristics that could diminish the effect of hyaluronidase.

Mannitol extravasation was successfully treated with 30 units of hyaluronidase.

 Hyaluronidase is an effective therapy for mannitol extravasation to prevent surgical intervention.

玻尿酸分解酶於甘露醇外滲之案例報告

吳佳璇、曾郁茹

臺大醫院藥劑部

摘要

玻尿酸分解酶為一種合成酵素用於注射藥物的吸收和分佈、皮下注射輸液和皮下尿路造影。藥品仿單標示外也使用於高滲透藥物的外滲。

甘露醇藉由高滲透壓性質可用於降低腦內壓與減緩腦水腫，滲透壓為1098 mOsm/L，高滲透壓可能導致嚴重的水腫與腫脹。此篇描述一位成功藉由玻尿酸分解酶緩解甘露醇外滲的案例。

一位66歲的男性由於腦瘤安排住院開刀，2022年6月16日進行顱骨切開術，並且開始輸注每8時100毫升 20%甘露醇以治療腦水腫。自6月18日16:00發生甘露醇外滲與水腫，症狀包含右手紅腫與漸進式的腫脹，並且影響手腕的彎曲。病人接受玻尿酸分解酶治療，共15單位分五次皮下注射於外滲部位的邊緣，並於當天19:30與21:30各執行兩次，完成共30單位注射療程，右手紅腫與脹痛於隔天幾乎緩解。
玻尿酸分解酶使用於外滲的劑量為15至150單位，此案例使用累積劑量30單位玻尿酸分解酶，證實玻尿酸分解酶對於甘露醇的外滲為有效的治療藥物。

關鍵字： 玻尿酸分解酶、甘露醇、外滲

References：

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3. Kaur M, Balakrishnan N, Gosal JS, et al. Efficacy of Hyaluronidase in the Mannitol Extravasation Induced Compartment Syndrome-A Case Report and Review of Literature. Turk J Anaesthesiol Reanim 2021; 49 : 329-33.
4. Le A, Patel S. Extravasation of Noncytotoxic Drugs: A Review of the Literature. Ann Pharmacother 2014; 48 : 870-86.
5. Reynolds PM, MacLaren R, Mueller SW, et al. Management of extravasation injuries: a focused evaluation of noncytotoxic medications. Pharmacotherapy 2014; 34 : 617-32.
6. Boulanger J, Ducharme A, Dufour A, et al. Management of the extravasation of anti-neoplastic agents. Support Care Cancer 2015; 23 : 1459-71.
7. Pérez Fidalgo JA, García Fabregat L, Cervantes A, et al. Management of chemotherapy extravasation: ESMO--EONS clinical practice guidelines. Eur J Oncol Nurs 2012; 16 : 528-34.
8. Hanrahan K. Hyaluronidase for treatment of intravenous extravasations: implementation of an evidence-based guideline in a pediatric population. J Spec Pediatr Nurs 2013; 18 : 253-62.
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通訊作者：吳佳璇／電子信箱：111104@ntuh.gov.tw