Sirolimus for Congenital Vascular Anomalies in the First Year of Life: A Systematic Review

Background: Congenital vascular anomalies (VA) include vascular malformations (developmental anomaly) and vascular tumors (endothelial proliferation). In cases of surgical failure, or in cases where the anatomy makes surgical resection impossible, pharmacological therapy with sirolimus, a mTOR inhibitor, is an option. Sirolimus inhibits angiogenesis and lymphangiogenesis and decreases the production and leakage of lymph by decreasing lymphatic endothelial cell activity. Previously published studies have demonstrated its efficacy and safety in adults and older children in solid organ transplant rejection and cancer, and in others as an immunosuppressant. Physicians in the intensive care unit may be unfamiliar with the indications for use, dosing, length, and outcomes related to sirolimus use. We aimed to systematically review the efficacy and safety of sirolimus in treating congenital vascular anomalies (tumors and malformations) in the first year of life.

Methods: We used the standard methods of performing a systematic review. We included all studies irrespective of study design including case studies evaluating the use of sirolimus (at any dose or route of administration or duration) for VA in the first year of life. The primary outcome was efficacy (as measured by resolution, improvement or no improvement of the VA related to 4 domains: overall, clinical status, quality of life and radiological imaging) and the secondary outcome was safety. We searched literature with the help of a librarian in December 2020, using Medline through the OVID platform (Medline on OVIDSP) as the primary database, and extended to Embase, Scopus and Cochrane CENTRAL.

Results: We identified and included 62 case series and reports. We classified vascular malformations as blood vessel disorder, lymphatic disorder or both, efficacy measured by decrease in size of the mass (50-75% decreased volume), hematological parameters and clinical functionality (Figure 1). When participants were categorized by age ( < 1 month, 1-6 months and 7-12 months), the efficacy was similar in all age groups. Adverse effects included mucositis, dyslipidemia, transaminitis, infection, fever, neutropenia, skin rashes, GI symptoms, pain among others (Figure 2). More than 50% of participants did not experience any adverse effects.

Conclusion: Sirolimus used to treat vascular anomalies in the first year of life, was well tolerated and effective in decreasing the size of the VA in more than 50% of the participants. No adverse effects were reported in more than 50% of the participants. There is an urgent need to evaluate the effectiveness of sirolimus in randomized or controlled observational studies.