Assessment of Plasma Cytokine Profile Changes in Bevacizumab-Treated Retinopathy of Prematurity Infants.

PURPOSE: We compared changes of plasma angiogenesis cytokine profiles in infants who were treated with intravitreal injection of bevacizumab (IVB) for type 1 retinopathy of prematurity (ROP) with age-matched preterm non-ROP infants. METHODS: Thirteen infants with type 1 ROP and 13 age-matched preterm non-ROP infants were included. Blood samples were collected prior to treatment (time 0) and 6 weeks after the treatment (time 42). Plasma levels of nine cytokines from the angiogenesis growth factor panel and seven soluble cytokine receptors were measured using a magnetic multiplex assay. RESULTS: Plasma cytokine profiles changed from time 0 to time 42 in both groups. In bevacizumab-treated ROP infants, the following plasma angiogenesis growth factor and soluble cytokine receptor levels decreased significantly: soluble VEGF-A (sVEGF-A; P = 0.0001), sVEGF-D (P = 0.04), angiopoietin-2 (Ang-2; P = 0.002), sVEGF receptor 1 (R1) and R2 (P = 0.005), soluble IL-6 receptor (sIL-6R; P = 0.002), soluble glycoprotein 130 (spg130; P = 0.0001), and soluble TNF receptor (sTNFR) I and II (P = 0.0001). The following factors and receptors increased significantly: sVEGF-C (P = 0.05), placental growth factor (PlGF; P = 0.02), endothelin-1 (ET-1; P = 0.0001), and FGF-1 (P = 0.02). At time 42, sVEGF-A, sgp130, sIL-6R, sTNFR I, and sTNFR II were lower, and ET-1 level was higher, in bevacizumab-treated ROP infants compared to age-matched non-ROP infants. CONCLUSIONS: The results suggest that bevacizumab treatment resulted in significant angiogenic cytokine profile changes in infants with severe ROP. The long-term clinical impact of these changes should be studied carefully.

Pharmacokinetics of bevacizumab and its effects on serum VEGF and IGF-1 in infants with retinopathy of prematurity.

PURPOSE: To measure serum levels of bevacizumab and to compare serum levels of free vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) in infants who were treated with either intravitreal injection of bevacizumab (IVB) or laser for type 1 retinopathy of prematurity (ROP). METHODS: Twenty-four infants with type 1 ROP were randomized into three treatment groups: IVB at 0.625 mg per eye per dose, IVB at 0.25 mg per eye per dose, and laser. Blood samples were collected prior to treatment and on posttreatment days 2, 14, 42, and 60. Weekly body weights were documented from birth until 60 days post treatment. Serum levels of bevacizumab, free VEGF, and IGF-1 were measured with enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum bevacizumab was detected 2 days after the injection, peaked at 14 days, and persisted for up to 60 days with half-life of 21 days. Area under the curve (AUC) analysis showed that systemic exposure to bevacizumab was variable among the subjects and was dose dependent. Serum free VEGF levels decreased in all three subgroups 2 days post treatment, with more significant reductions found in both IVB-treated groups, P = 0.0001. Serum IGF-1 levels were lower in both IVB-treated groups. CONCLUSIONS: Clearance of bevacizumab from the bloodstream in premature infants takes at least 2 months. Although serum free VEGF levels decreased following either laser or bevacizumab treatment, the reductions were more significant in the IVB-treated groups. Potential long-term effects of systemic exposure to bevacizumab in infants need to be studied further.

Repair of congenital diaphragmatic hernias on Extracorporeal Membrane Oxygenation (ECMO): does early repair improve patient survival?

INTRODUCTION: The optimal timing of repair for congenital diaphragmatic hernia (CDH) patients that require ECMO is controversial. Early repair on ECMO theoretically allows for restoration of normal thoracic anatomy but entails significant bleeding risks. The purpose of this study was to examine the institutional outcomes of early CDH repair on ECMO. METHODS: The records of infants with CDH placed on ECMO from 2001 to 2011 were reviewed. Since 2009, a protocol was instituted for early repair while on ECMO. For this study, three cohorts were analyzed: early repair (<72 h), late repair (>72 h), and post-decannulation. These groups were compared for outcomes regarding morbidity and survival. RESULTS: Forty-six CDH patients received ECMO support with an overall survival of 53%. Twenty-nine patients (11 early/18 late) were repaired on ECMO, while 17 patients had repair post-decannulation. Survival was 73%, 50%, and 64% for those repaired early, late, or post-decannulation, respectively. Despite significantly worse prenatal factors, patients repaired early on ECMO had a similar survival. When comparing patients repaired on ECMO, the early group patients were decannulated 6 days earlier (p-value=0.009) and had significantly lower circuit complications (p=0.03). CONCLUSION: In conclusion, early repair on ECMO was associated with decreased ECMO duration, decreased circuit complications, and a trend towards improved survival.