Author + information
- Claire Lawley, MBBS(Hons)a,b,∗ (, )
- Himanshu Popat, MDa,c,
- Melanie Wong, PhDa,d,
- Nadia Badawi, PhDa,c,e and
- Julian Ayer, PhDa,b
- aDiscipline of Child and Adolescent Health, The Children’s Hospital at Westmead Clinical School, Sydney Medical School, Sydney, New South Wales, Australia
- bThe Heart Centre for Children, The Children’s Hospital at Westmead, Sydney Children’s Hospital Network, Sydney, New South Wales, Australia
- cGrace Centre for Newborn Intensive Care, The Children’s Hospital at Westmead, Westmead, New South Wales, Australia
- dDepartment of Immunology, The Children’s Hospital at Westmead, Sydney Children’s Hospital Network, Westmead, New South Wales, Australia
- eCerebral Palsy Alliance Research Institute, Allambie Heights, New South Wales, Australia
- ↵∗Address for correspondence:
Dr. Claire Lawley, Discipline of Child and Adolescent Health, The Children's Hospital at Westmead Clinical School, Sydney Medical School, Corner Hawkesbury Road and Hainsworth Street, Westmead, New South Wales 2145, Australia.
Cardiac rhabdomyomas in neonates may cause significant cardiac risk. Recently, sirolimus has been used to treat these lesions. The dose, duration, and monitoring for therapy are unknown. A case of sirolimus use in a premature neonate is presented. No significant adverse effects were seen. Review of published cases is included. (Level of Difficulty: Advanced.)
Cardiac rhabdomyomas in neonates are almost exclusively associated with tuberous sclerosis and carry significant cardiac risk, particularly when causing ventricular outflow tract obstruction due to mass effect. Recently, mammalian target of rapamycin (mTOR) inhibitors including sirolimus and everolimus have been used to treat these lesions in individual cases when surgical resection is inappropriate. The exact dose, duration, and monitoring of these medications remain unknown. This case report presents a case of sirolimus use in a premature neonate resulting in a dramatic decrease in cardiac rhabdomyoma size, although with a supratherapeutic sirolimus level. No significant adverse effects were seen. Review of other published cases is included.
• With appropriate monitoring, sirolimus can be used safely in premature infants to treat cardiac rhabdomyoma.
• Exact dosing, duration, and long-term safety profile of sirolimus in the neonatal and early infant setting remain unknown.
• Where rapid reductions in rhabdomyoma size are needed, particularly in the newborn with hemodynamic compromise, supratherapeutic sirolimus levels may be justified.
mTOR inhibitors including sirolimus and everolimus are increasingly included in the management of tuberous sclerosis complex (TSC) manifestations, including for subependymal giant-cell astrocytomas and renal angiomyolipomas. Everolimus has been approved for use in managing these conditions. Both sirolimus and everolimus have also been used “off-label” in infants with cardiac rhabdomyomas (1,2). Published data on dosing, duration, and safety profile for sirolimus in this setting is limited to a few case reports (3–6).
This case report presents a case of sirolimus use in a premature neonate with significant cardiac rhabdomyomas. Review of other published cases is included. Ethics approval and informed consent were obtained (SCHN-CCR 2018/04).
History of Presentation
A 32-year-old female gravida 4 para 4 (now) gave birth to a female infant at 33 + 4 weeks gestational age, birth weight 2.25 kg (81st centile). The infant had been diagnosed antenatally with significant cardiac rhabdomyomas with potential for left ventricular outflow tract (LVOT) obstruction and impact on both ventricular cavities (Figure 1A). The family history was significant for TSC in the mother, maternal uncle, maternal grandfather, and 2 of the infant’s siblings. Various options for postnatal management including single ventricle palliation, debulking surgery, medical therapy with an mTOR inhibitor, and comfort care were discussed antenatally.
The infant was born with Apgar scores of 3, 5, and 6 at 1, 5, and 10 min, respectively. She required intubation and ventilation at birth in view of poor respiratory effort. Prostaglandin E1 was commenced due to concerns for potential significant LVOT obstruction.
Postnatal echocardiography demonstrated large cardiac rhabdomyomas in the intraventricular septum encroaching on both ventricular cavities and causing LVOT obstruction (Figure 1B), although with sufficient left ventricular output for prostaglandin E1 to be ceased. Significant cardiomegaly was noted on the chest x-ray (Figure 1D).
Ultrasound of the kidneys revealed bilateral mild increased cortical echogenicity with no evidence of angiomyolipoma. Ophthalmological review identified a right supratemporal hamartoma. Cranial ultrasonography and magnetic resonance imaging of the brain were unremarkable. In the context of the clinical findings and family history, a presumptive diagnosis of TSC was made.
The infant was commenced on sirolimus 0.25-mg dose once daily via a nasogastric tube on day 3 of life. The infant was having minimal trophic enteral intake at this time. Feeds were gradually graded up, and she was taking full enteral feeds by day 10. The target sirolimus trough level was 5 to 15 μg/l. The initial trough level 8 days after drug commencement (day 11 of life) was significantly higher at 69.7 μg/l. Transthoracic echocardiogram on day 11 of life demonstrated significant regression of the cardiac rhabdomyoma (Figure 1C). On the chest x-ray, the cardiac silhouette was also seen to decrease in size (Figure 1E). Following a period of dose omission until the serum sirolimus level reached 16.2 μg/l, sirolimus was recommenced at 0.125-mg dose once daily, one-half the previous dose. Sirolimus serum trough levels remained within normal limits (6.8 to 9.9 μg/l).
After the initial significant decrease in size, serial echocardiography demonstrated sustained decrease in rhabdomyoma size. The blood count, liver and renal function, and lipid profile remained normal. Prophylactic co-trimoxazole was commenced after neonatal jaundice had resolved. The infant was transferred from our institution at 4 weeks of age with outpatient follow-up arranged.
The infant’s postnatal course was complicated by respiratory distress requiring surfactant, mechanical ventilation for 12 days, and noninvasive respiratory support until day 35. There were concerns about possible seizures on day 3 of life that were not evident on the electroencephalogram. Given the presumptive diagnosis of TSC, levitiracetam was prophylactically commenced.
The infant continued on sirolimus therapy until 2 months of age at which time, in the context of persistent neutropenia 0.3 to 0.6 × 109/l and with sustained decrease in rhabdomyoma size, a decision was made to cease sirolimus therapy. Levitiracetam therapy was also weaned and ceased as an additional possible cause for neutropenia. No further seizure activity was seen.
Subsequent transthoracic echocardiography at 3 months of age (Figure 1F) demonstrated an increase in rhabdomyoma size with no change to the neutrophil count. The sirolimus was recommenced at 0.125 mg daily, resulting once again in reduction of the rhabdomyoma (Figure 1G).
In this case, treatment with sirolimus was associated with a substantial decrease in the size of a massive cardiac rhabdomyoma in a premature neonate with TSC. Of note, with cessation of treatment for 1 month, the rhabdomyomas demonstrated a substantial increase in size with regression again upon recommencement of sirolimus, suggesting an effect of treatment rather than just natural history as the cause for regression.
Initial treatment with sirolimus resulted in trough levels well above the recommended maximum adult range (5 to 15 μg/l). Although speculative, it is possible that the rapid reduction in rhabdomyoma size in this case is related to the high blood levels of sirolimus. These unanticipated high levels were not associated with significant adverse effects. Neonatal dosing of mTOR inhibitors is not well established. Sirolimus’ liquid formulation provides a distinct advantage for use in neonates, although everolimus is now available in a dispersible tablet form. Everolimus is known to have greater oral bioavailability and, due to differences in systemic clearance time, reaches steady-state levels sooner after initiation. Limited pharmacokinetic data from pediatric dialysis patients suggests that the time to maximum concentration is slightly longer in younger children and clearance adjusted for weight is higher (2). The systemic absorption of both sirolimus and everolimus is significantly decreased when taken with a meal high in fat (2). The initial fasting status of the neonate in the current case may have contributed to the supratherapeutic sirolimus.
Safety data for sirolimus use in pediatric patients, particularly in neonates, is not well established. Safety data in pediatric renal transplant patients showed an increased risk of renal impairment, elevated lipid profile, and infection in children when receiving sirolimus in combination with calcineurin inhibitors and steroids (2).
A total of 5 cases of sirolimus use in neonates with cardiac rhabdomyomas were found in published reports and are summarized in Table 1. Variation in dose, duration, and magnitude of effect were noted. A similar supratherapeutic level (42.1 μg/l) was reported in a premature neonate weighing 2.2 kg at time of drug initiation. The dose of 0.25 mg once daily was also used in this infant, and similarly no adverse effects were seen (3). A report of use in a term neonate who received 0.5 mg oral daily resulted in a slightly elevated trough level 26 μg/l and a “dramatic reduction” in LVOT tumor was once again seen by day 5 of treatment (4).
There remains a paucity of data regarding optimal duration of therapy once the desired regression of cardiac rhabdomyoma is achieved. Our case demonstrates that regrowth of rhabdomyomas may occur with sirolimus cessation and that drug recommencement may result in a further response.
Inadequate information exists on the safety of sirolimus and everolimus in pregnancy, although both are capable of crossing the placenta and in rat models have been shown toxic to the fetus (1). However, there is a single published case report of successful antenatal use of sirolimus for the treatment of fetal rhabdomyoma (7).
The infant continues on sirolimus at 0.125 mg daily at 12 months of age. Repeat imaging at 8 (Figure 1H) and 12 months of age (Figure 1I) demonstrated a sustained reduction in rhabdomyoma size. No further adverse side effects have been noted.
This case highlights the efficacy of sirolimus in the treatment of massive cardiac rhabdomyoma in TSC. The authors speculate that rapid reductions in the size of the rhabdomyoma were the result of unanticipated supratherapeutic sirolimus blood levels. Nonetheless these levels were well tolerated and not associated with side effects. Exact dosing, duration, and long-term safety profile of sirolimus in the neonatal and early infant setting remain unknown. However, where rapid reductions in rhabdomyoma size are needed, particularly in the newborn with hemodynamic compromise, supratherapeutic levels may be justified. This case report adds to the evidence that, with careful monitoring, sirolimus should be considered when managing infants with significant cardiac rhabdomyomas.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- left ventricular outflow tract
- mammalian target of rapamycin
- tuberous sclerosis complex
- Received April 25, 2019.
- Accepted July 7, 2019.
- ↵Therapeutic Goods Administration. Therapeutic Goods Administration Product and Consumer Medicine Information 2018. Available at:. ebs.tga.gov.au, Accessed March 27, 2019. January 15, 2018.
- Lee S.J.,
- Song E.S.,
- Cho H.J.,
- Choi Y.Y.,
- Ma J.S.,
- Cho Y.K.
- Breathnach C.,
- Pears J.,
- Franklin O.,
- Webb D.,
- McMahon C.J.
- Pendse A.,
- Wagh D.
- Weiland M.D.,
- Bonello K.,
- Hill K.D.
- Barnes B.T.,
- Procaccini D.,
- Crino J.,
- et al.