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Original Investigation
July 2018

Effectiveness of Low Doses of Hyaluronidase to Remove Hyaluronic Acid Filler Nodules: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
  • 2Department of Otolaryngology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
  • 3Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
  • 4Center for Research and Grants, Baptist Health South Florida, Coral Gables
  • 5Rollins School of Public Health, Department of Epidemiology, Emory University, Atlanta, Georgia
  • 6School of Medicine, Department of Medicine, Emory University, Atlanta, Georgia
  • 7Robert Stempel College of Public Health and Social Work, Department of Biostatistics, Florida International University, Miami
JAMA Dermatol. 2018;154(7):765-772. doi:10.1001/jamadermatol.2018.0515
Key Points

Question  Can low doses of hyaluronidase safely and effectively dissolve hyaluronic acid filler nodules?

Findings  In this randomized clinical trial of 9 women and 72 injection sites, small unit doses of hyaluronidase allowed removal of minute quantities of filler without removing the entire implant.

Meaning  Minor asymmetries after filler can be corrected by the injector in a manner convenient for patients.


Importance  Although hyaluronidase is known to remove hyaluronic acid fillers, use of low doses has not been well studied.

Objective  To assess the effectiveness and dose-related effect of small quantities of hyaluronidase to treat hyaluronic acid filler nodules.

Design, Setting, and Participants  Split-arm, parallel-group, randomized clinical trial at an urban academic center. Participants were 9 healthy women. Recruitment and follow-up occurred from February 2013 to March 2014; data analysis occurred from February to July 2016.

Interventions  Each participant received aliquots (buttons) of either of 2 types of hyaluronic acid fillers into bilateral upper inner arms, respectively. At 1, 2, and 3 weeks each button was treated with a constant volume (0.1 mL) of variable-dose hyaluronidase (1.5, 3.0, or 9.0 U per 0.1 mL) or saline control.

Main Outcomes and Measures  Both a blinded dermatologist and the participant independently assessed detectability.

Results  Seventy-two treatment sites on 9 women (mean [SD] age, 45.8 [15.7] years) received all interventions and were analyzed. There was a significant difference in physician rater assessment between saline and hyaluronidase at 4 weeks (visual detection: mean difference = 1.15; 95% CI, 0.46-1.80; P < .001; palpability: mean difference = 1.22; 95% CI, 0.61-1.83; P < .001) and 4 months (visual detection: mean difference = 0.77; 95% CI, 0.33-1.26; P = .001; palpability: mean difference = 0.82; 95% CI, 0.38-1.25; P < .001) that was mirrored by participant self-assessment at 4 weeks (visual detection: mean difference = 0.87; 95% CI, 0.26-1.48; P = .006; palpability: mean difference = 1.59; 95% CI, 1.41-1.77; P < .001) and 4 months (visual detection: mean difference = 1.31; 95% CI, 1.09-1.53; P < .001; palpability: mean difference = 1.52; 95% CI, 1.03-2.01; P < .001), and hyaluronidase was associated with greater resolution of buttons compared with normal saline. The 9.0-unit hyaluronidase injection sites were significantly less palpable than the 1.5-unit sites at both 4 weeks (mean difference = 0.50; 95% CI, 0.01-.99; P = .045) and 4 months (mean difference = 0.47; 95% CI, 0.14-0.81; P = .007). Dose dependence was more notable for Restylane-L.

Conclusions and Relevance  Although very small doses of hyaluronidase can remove hyaluronic acid fillers from patient skin, slightly higher doses often result in more rapid resolution.

Trial Registration  clinicaltrials.gov Identifier: NCT01722916