sirolimus and Ductus-Arteriosus--Patent

Sirolimus-eluting stents may have clinical advantages over bare-metal stents in the extremely proliferative environment of the neonatal arterial duct. However, sirolimus has immunosuppressive actions and little is known regarding sirolimus pharmacokinetics in the newborn.. This is a retrospective review of sirolimus pharmacokinetics in neonates who underwent sirolimus-eluting stent implantation in the arterial duct for pulmonary blood flow augmentation. Pharmacokinetic parameters were obtained by noncompartmental analysis and by a Bayesian one-compartment nonlinear mixed model. Nine neonates received a single sirolimus-eluting stent with a total sirolimus dose of 245 μg (n = 1), 194 μg (n = 5), or 143 μg (n = 3). Peak sirolimus concentrations were 13.6 ± 4.5 μg/L (24.8 μg/L highest) and clearance was 0.042 ± 0.03 L/hour (noncompartmental analysis) and 0.051 L/hour (95% credible intervals 0.037-0.069, nonlinear mixed model). Sirolimus remained > 5 μg/L, the trough level used in oral immunosuppressive therapy, for (95% credible interval) 15.9 (11.4, 22.8), 12.9 (7.6, 19.0), and 8.4 (2.3, 14.5) days for the 245, 194, and 143 μg sirolimus dose stents, respectively. Estimates of the duration of systemic immunosuppression are provided for combinations of 2 stents.. In neonates after sirolimus-eluting stent implantation, peak sirolimus levels were 20 × higher and clearance 30 × lower than previously reported in older children and adults. Sirolimus levels were within the immunosuppressive range for a prolonged period, but with no observable clinically significant adverse outcomes.

Topics: Chromatography, Liquid; Drug-Eluting Stents; Ductus Arteriosus, Patent; Humans; Immunosuppressive Agents; Infant, Newborn; Pulmonary Artery; Pulmonary Circulation; Retrospective Studies; Sirolimus; Tandem Mass Spectrometry

The primary objective was to evaluate the trend of blood sirolimus concentrations in neonates following ductal stenting. The long-term outcomes and incidence of infections were also evaluated.. Prospective open-label observational study in a tertiary referral centre over a 1-year period. Serum sirolimus levels were estimated at 1 hour and 24hrs post-stent insertion followed by 7 days in neonates who underwent ductal stenting. The trend in sirolimus levels, incidence of infections, complications and outcomes following ductal stenting were studied.. Seven neonates with duct-dependent pulmonary circulation underwent ductal stenting at median age of 8.5 days and weight of 2.83kg. The average stent size was 3.5±0.4 mm, and average stent length was 16.3±5.1 mm. The mean sirolimus concentrations at 1 hour, 24 hours and 7 days were 41.3±6.9ng/ml, 15.4±7.1ng/ml and 3.1±0.85ng/ml respectively. Levels fell below therapeutic range for all patients by 7 days. Three patients had sepsis or necrotising enterocolitis, but responded well to antibiotics; 1 patient had aspiration related sudden death. There were no further events at a mean follow-up of 207 days, and 4 patients underwent elective surgery at 238 ± 81 days after ductal stenting.. This study demonstrates applicability of drug-eluting stents for ductal stenting in newborns. Drug-eluting stents with abluminal drug delivery are associated with high sirolimus levels in initial hours but rapidly taper to negligible levels within a week of implantation. Neonates with high pre-procedure likelihood of infection developed sepsis but responded well to conservative management. The patency of drug-eluting ductal stents is preserved over long-term follow-up.

Topics: Drug-Eluting Stents; Ductus Arteriosus, Patent; Humans; Infant, Newborn; Prospective Studies; Sirolimus; Stents; Treatment Outcome

Ductal stenting (DS) palliates duct-dependent lesions using coronary stents. Sirolimus-eluting stents have replaced bare-metal stents in coronary interventions. Concerns exist about sirolimus levels in neonates. Therapeutic immunosuppressive sirolimus level is 5-15 ng/ml. After neonatal DS, drug levels were assessed at 24 h, 7 days and monthly thereafter till they were undetectable. Clinical course, ductal patency till their final corrective surgery was analyzed. The exact quantity of sirolimus in each stent was known. Twelve neonates with median age of 5.5 days received sirolimus-eluting stents, one stent in nine and two in the rest. The lesions were pulmonary atresia intact ventricular septum(PAIVS) in four, univentricular lesions with pulmonary atresia in four, biventricular lesions with pulmonary atresia in three and right ventricular rhabdomyoma in one neonate. If single stents up to 22 mm length, 24-h drug levels were less than 5 ng/ml. Even though 24-h levels were above 5 ng/ml in patients with single longer stent or two stents, it reduced to very low levels by seventh day. Two hospital deaths included rhabdomyoma with complete heart block and post-valvotomy cardiac failure for PAIVS. Stent patency after valvotomy for PAIVS exceeded three years. Patency was retained for 8-27 months till their elective corrective surgery in others. Sirolimus levels were acceptable at 24 h in all neonates receiving single stent under 22 mm length. In patients needing two stents, drug levels were in immunosuppressive range at 24 h but reduced rapidly within 7 days. The palliation provided by sirolimus-eluting DS was sufficiently long to provide clinical benefit.

Topics: Chromium; Cobalt; Drug-Eluting Stents; Ductus Arteriosus, Patent; Female; Heart Ventricles; Humans; Immunosuppressive Agents; Infant, Newborn; Male; Prospective Studies; Prosthesis Implantation; Pulmonary Atresia; Pulmonary Circulation; Sirolimus; Treatment Outcome; Ventricular Septum