[size=6]A 6-month-old baby is being treated with sirolimus for a lymphatic malformation of the head and neck. Sirolimus levels are being maintained between 4-8 ng/mL. The child requires placement of a gastrostomy tube that is planned for the following week. In preparation for surgery, sirolimus should be

 

a stopped today and resumed 14 days after surgery

 

b stopped today and resumed 5 days after surgery

 

c administered without interruption of dosing

 

d stopped today and resumed 6 months after surgery[/size]

A

A

A

[size=6]A 6-month-old baby is being treated with sirolimus for a lymphatic malformation of the head and neck. Sirolimus levels are being maintained between 4-8 ng/mL. The child requires placement of a gastrostomy tube that is planned for the following week. In preparation for surgery, sirolimus should be

 

a stopped today and resumed 14 days after surgery

 

b stopped today and resumed 5 days after surgery

 

c administered without interruption of dosing

 

d stopped today and resumed 6 months after surgery[/size]

a

correct answer

c administered without interruption of dosing

 

This patient will undergo laparoscopic surgery with relatively low sirolimus levels. Sirolimus may be administered through the perioperative period.

 

The mammalian target of rapamycin (mTOR) inhibitors block enzymes in the cell cycle transduction pathways that play a role in the development and progression of certain cancers as well as immunosuppressants in solid organ transplantation. Sirolimus, an mTOR inhibitor, is currently used in the treatment of lymphatic malformations.

 

Mechanistically, mTOR impairs wound healing in a dose-dependent manner due to its action in decreasing angiogenesis, decreasing VEGF secretion, decreasing nitric oxide production, and smooth muscle contraction. Studies in transplant patients have noted that higher levels of mTOR as well as its combination with modifiable and non-modifiable factors lead to adverse events for wound healing. Campistol’s systematic review of the literature identified that advanced age and African-American race are risk factors for impaired wound healing and lymphoceles in transplant patients. Additive and potentially modifiable factors that contribute to poor wound healing include obesity, uncontrolled diabetes, concomitant steroids, thymoglobulin induction, anticoagulants, smoking, and alcohol use. Guidelines formulated from findings in the transplant population have recommended having sirolimus levels to be kept in the 5-10 ng/mL range if surgery is needed.

 

A comparison between pediatric patients who underwent resection for lympathic and lymphovascular malformations with or without preoperative sirolimus found no significant difference in wound complication rates (14% vs 6% respectively). The authors noted that in the 4 sirolimus patients who had complications, the serum levels were in the lower range of < 2 to 12 ng/mL and they surmised that the lower levels may help account for the lower complication rates. The authors described that some of their patients on sirolimus underwent other procedures such as G tube placement, circumcision, gastrocnemius recession, femur epiphysiodesis, arthodesis, tracheostomies, thyroid surgery, myringotomy, tonsillectomy and adenoidectomy and had no wound related problems for these procedures. Pediatric cardiac transplant patients on sirolimus who underwent surgical procedures (tonsilectomies and adenoidectomies, sternal revisions, pulmonary vein repair, pacemaker placement, posterior spinal fusion, Achilles tendon lengthening and ventriculoperitoneal shunt revision) had a low (7.6%) wound complications. In this study, average sirolimus levels were 4.8 ng/mL within 30 days of the surgical procedure. Both these studies concluded that sirolimus likely does not need to be discontinued before surgery given the low risk of wound complications. It bears noting that neither of these studies had patients that require intestinal anastomoses.

 

The extent of surgical procedure as well as serum levels of sirolimus should be considered in patients on sirolimus undergoing surgery. In adult patients, current recommendations for minor surgery or laparoscopic surgery is to have no change in sirolimus dosing provided no risk factors are present and levels are in the 5-10 ng/mL. For patients undergoing major elective surgery including cancer surgery plus chemotherapy, sirolimus should be stopped 5-10 days before planned surgery and resumed 1-3 months after surgery. For emergency major surgery, sirolimus should be stopped and resumed 5-10 days after surgery.