This single-center retrospective cohort study of children with PVS receiving SS demonstrated a reasonable time to reach therapeutic levels, with most levels not requiring dose adjustments over the course of therapy. Additionally, transitioning SS oversight to a dedicated PVS team corresponded with improvements in toxicity surveillance compliance and TTR, though differences between care eras did not reach statistical significance. Lastly, SS discontinuation because of AEs potentially related to SS was uncommon.

These findings provide practical guidance for the implementation of SS in a vulnerable, high-risk population. Clinicians initiating SS in infants with PVS may face uncertainty around dosing, monitoring frequency, and risk of adverse events. Our data help fill this gap by characterizing the timeline to therapeutic levels, frequency of dose adjustments, duration, and typical monitoring burden, particularly during the first 6 months of therapy. Importantly, a structured, multidisciplinary monitoring approach may improve compliance with safety labs and may help maintain patients in therapeutic range. However, there are key areas for institutional quality improvement given that TTR and compliance remain imperfect, and challenges such as communication with families, non-adherence to recommended testing, and difficulties in coordinating timed lab draws persist.

Multiple factors, including the timing of blood draws, can affect the trough level of SS. Young children have individual variability in drug metabolism and higher clearance rates of SS as compared to adults [8, 9]. Additionally, drug–drug interactions, particularly with CYP3A and p-glycoprotein inhibitors or inducers, and dietary factors can influence SS levels [8, 9]. These factors are considered during drug initiation, ideally under the consultation of a clinical pharmacist. The specific timing required for trough level measurement poses a significant challenge for both medical providers and families, necessitating education and logistical planning. While it was not feasible to determine the timing of all blood draws in this study, nearly half of subtherapeutic or supratherapeutic levels did not result in a dose adjustment, suggesting that many may have been inappropriately timed and not true trough levels. Inpatient settings accounted for more blood draws and dose adjustments than outpatient assessments, likely due to increased exposure to factors that influence SS levels. Acute illness, dietary changes, and new drug–drug interactions are more common in inpatients and require closer monitoring. Notably, most supratherapeutic levels in this cohort were observed in inpatient samples. An additional consideration is the placement of a limus drug-eluting stent, a type of catheter-based pulmonary vein intervention, which may lead to measurable SS levels, as seen in infants undergoing ductal stenting. [10, 11] Interestingly, in our cohort, among patients who had SS levels within seven days following stent placement, only one required a dose change for a supratherapeutic level.

SS was well tolerated overall with few serious AEs necessitating dose reduction or discontinuation. This is consistent with the previous publications of SS use in PVS and in other pathologies [1, 4, 5, 12]. For example, a prospective trial of SS for the treatment of vascular anomalies reported 23 AEs in 60 patients, most of which were myelosuppression (16) and only 4 patients required dose reduction or discontinuation [12]. It is noteworthy that one of our patients acquired PJP and is now on antibiotic prophylaxis. Despite this occurrence, and because PJP with mTOR inhibitors is rare (prevalence 0.4% to 0.9%), we discuss prophylaxis on a case-by-case basis with consideration of the duration of therapy, lymphocyte count, and concurrent treatment with additional immunosuppressive medications including systemic corticosteroids [13,14,15]. For serious AE prevention, SS may be temporarily lowered or held for significant infections to optimize the immune response or prior to surgery to optimize wound healing, although this is debated [16, 17]. In practice, preferences on holding SS and timing of reinitiation for surgical procedures are at the discretion of the operator. Typically, for open heart surgery, SS is held two weeks prior to surgery and initiated at least seven days after chest closure.

SS is one of the medical therapies in the management of PVS and is used in addition to interventions to treat stenosis, surveillance testing, and removal of possible PVS triggers [18]. At the time of PVS diagnosis, workup and treatment for aspiration or other lung insult was performed, and normalizing pulmonary blood flow is considered to minimize the flow disturbance in the pulmonary veins [19,20,21,22]. Following transcatheter or surgical relief of PVS, medical therapy is initiated.