Faculty Bibliography

PURPOSE: Extracorporeal Life Support Organization Registry data confirm that the number of pediatric patients being supported by extracorporeal membrane oxygenation (ECMO) is increasing. To minimize the potential neurologic effects of carotid artery ligation, the common femoral artery (CFA) is frequently being used for arterial cannulation. The cannula has the potential for obstructing flow to the lower limb, thus increasing ischemia and possible limb loss. We present a single institution's experience with CFA cannulation for venoarterial (VA) ECMO and ask whether any precannulation variables correlate with the development of significant limb ischemia. METHODS: We reviewed all pediatric patients who were supported by VA ECMO via CFA cannulation from January 2000 to February 2010. Limb ischemia was the primary variable. The ischemia group was defined as the patients requiring an intervention because of the development of lower extremity ischemia. The patients in the no-ischemia group did not develop significant ischemia. Continuous variables were reported as medians with interquartile ranges and compared using Mann-Whitney U tests. Differences in categorical variables were assessed using chi(2) testing (Fisher's Exact). Statistical significance was assumed at P < .05. RESULTS: Twenty-one patients (age, 2-22 years) were cannulated via the CFA for VA ECMO. Significant ischemia requiring intervention (ischemia group) occurred in 11 (52%) of 21. In comparing the 2 groups (ischemia vs no ischemia), no clinical variables predicted the development of ischemia (Table 1). In the ischemia group, 9 (81%) of 11 had a distal perfusion catheter (DPC) placed. Complications of DPC placement included one case of compartment syndrome requiring a fasciotomy and one patient requiring interval toe amputation. Of the 2 patients in the ischemia group who did not have a DPC placed, 1 required a vascular reconstruction of an injured superficial femoral artery and 1 underwent a below-the-knee amputation. Mortality was lower in the ischemia group (27% vs 60%). CONCLUSIONS: Limb ischemia remains a significant problem, as more than half of our patients developed it. The true incidence may not be known as a 60% mortality in the no-ischemia group could mask subsequent ischemia. Although children are at risk for developing limb ischemia/loss, no variable was predictive of the development of significant limb ischemia in our series. Because of the inability to predict who will develop limb ischemia, early routine placement of a DPC at the time of cannulation may be warranted. However, DPCs do not completely resolve issues around tissue loss and morbidity. Prevention of limb ischemia/loss because of CFA cannulation for VA ECMO continues to be a problem that could benefit from new strategies.

Hepatic pulmonary fusion is extremely rare with only 9 previous cases reported in the literature. In typical cases, the clinician should be alerted to the possibility of hepatic pulmonary fusion if the chest radiograph shows a large opacity on the right side without a contralateral mediastinal shift. The authors present a case of right-sided diaphragmatic hernia and hepatic pulmonary fusion with associated contralateral mediastinal shift discovered beyond the neonatal period. The 9 previous cases were retrospectively reviewed with special attention to mediastinal shift on preoperative chest radiograph, operative procedure, and mortality. Only one previous case demonstrated a contralateral mediastinal shift. The most common procedure performed was partial separation of the hepatic pulmonary fusion and approximation of the diaphragmatic defect. Four of the previous 9 patients died. In our case, reduction of bowel and approximation of the diaphragmatic defect around the fused liver and lung have been successful.

Clear cell sarcoma of the kidney (CCSK) is uncommon pediatric renal tumor and can present a significant therapeutic challenge in those patients whose tumors spread beyond the kidney. Thus, identifying potential novel targets for treatment may be clinically important. Clear cell sarcoma of the kidney is characterized by a unique vascular pattern, in which nests of tumor cells are separated by regularly-spaced, fine fibrovascular septa. This distinctive histopathology raises the possibility that understanding the factors which drive angiogenesis in CCSK tumors may suggest new therapeutic targets. Here, we describe a case of CCSK and present immunohistochemical studies of its vasculature.

Several short and long-term complications of esophageal replacement have been described in the literature. We report the case of a gastric tube-pericardial fistula occurring 20 years after initial repair of long gap esophageal atresia with a reversed gastric tube.

PURPOSE: Risk factors that predispose children with congenital diaphragmatic hernia (CDH) to recurrence remain poorly defined. We report a large series of recurrent CDH and ask whether prenatal patient factors or postnatal treatment variables better predict recurrence. METHODS: Two hundred thirty-eight neonates with unilateral CDH underwent repair from 1990 to 2006. Data were assessed by chi(2) and Mann-Whitney U tests. Multivariate regression identified independent predictors of recurrence. Statistical significance was set at P < .05. RESULTS: We identified 24 recurrences (10%). Median time from repair to recurrence diagnosis was 4.9 months. Patients with recurrence were older (P = .02) and more often required abdominal wall patches at initial repair (P = .01) compared to nonrecurrence patients. Postoperative length of stay (LOS) after initial repair (P < .01) and morbidity (P = .01) were greater in recurrence patients. Use of diaphragm patch at initial repair was greater in patients with recurrence but only approached statistical significance (P = .05). Only 2 variables independently predicted recurrence by multivariate regression as follows: abdominal (not diaphragm) wall patch during initial repair (odds ratio [OR] 3.50; P = .04) and postoperative LOS (OR, 1.012; P = .01). CONCLUSION: Neonates at risk for CDH recurrence are better identified by postnatal treatment variables than by prenatal patient factors. Although age at repair and diaphragm patch use are greater in recurrence patients, the only factors to independently predict recurrence were postoperative LOS and abdominal wall patch use. These data can help optimize follow-up regimens.

BACKGROUND: Rapamycin can inhibit tumor growth and angiogenesis in various human cancers. Cyclooxygenase 2 (COX-2) is involved in the angiogenic process. We hypothesized that the antiangiogenic effect of rapamycin may be mediated by suppression of COX-2. METHODS: Ewing sarcoma (ES) cells were implanted in athymic mice. Selected animals were treated with rapamycin for 5 weeks. Tumor vascularity was assessed by lectin perfusion angiography and immunohistochemistry. Phosphorylation of mammalian target of rapamycin pathway proteins was determined by Western blot analysis. Staining of COX-2 protein was determined by immunohistochemistry, and expression of COX-2 messenger RNA levels was assessed with quantitative real-time (RT) polymerase chain reaction. RESULTS: Mean tumor weights were significantly reduced in the treated group (5.43 g +/- 1.43 SEM vs 0.49 g +/- 0.15 SEM, P < .003). There was abundant vasculature in the control group and blunted vascularity in the treated xenografts. The phosphorylation of p70s6k and Akt was not inhibited in the rapamycin-treated tumors. Cyclooxygenase 2 was suppressed in the treated xenografts at both the protein and messenger RNA levels. CONCLUSION: Low-dose rapamycin inhibits tumor growth and angiogenesis in human ES without inhibiting the phosphorylation of p70s6k and Akt. Cyclooxygenase 2 levels are inhibited by low-dose treatment of ES with rapamycin. Cyclooxygenase 2 suppression may mediate the antiangiogenic effect of rapamycin in Ewing sarcoma.

Femoral cannulation in pediatric patients requiring extracorporeal membrane oxygenation (ECMO) is commonly associated with distal limb ischemia. Authors have previously reported successful lower limb perfusion using various open techniques to cannulate a distal lower extremity artery at the time of initial ECMO cannulation. These procedures include open femoral artery antegrade cannulation and distal posterior tibial artery retrograde cannulation in older children and adults. Such approaches require ample vessel diameters to accommodate an arteriotomy and catheter insertion and, therefore, are of limited use in smaller children. We hypothesized that after femoral artery cannulation for ECMO, a percutaneous technique of distal limb perfusion might offer unique advantages when treating lower extremity ischemia in small pediatric patients. We report a technique for percutaneous antegrade cannulation in a 4-year-old patient shortly after her primary cannulation for venoarterial ECMO via the femoral artery.

Most children with neuroblastoma presenting after infancy have metastatic, chemoresistant disease. Amplification of the MYCN proto-oncogene is a significant marker of these poor-prognosis neuroblastoma tumors. Recent studies suggest that MYCN may function in part by promoting angiogenesis via vascular endothelial growth factor (VEGF). VEGF blockade has been validated as a therapeutic strategy in adult cancers. In these studies, we asked whether inhibition of VEGF signaling via VEGFR2 blockade in established MYCN-amplified neuroblastoma xenografts would: 1) restrict tumor growth; 2) induce hypoxia; and 3) alter tumor vasculature. The MYCN-amplified neuroblastoma human cell line NGP was implanted intrarenally in athymic female mice. After 5 weeks, mice with established tumors were selected, a cohort euthanized to provide day 0 controls, and the rest assigned to receive biweekly injections of DC101 (anti-murine VEGFR2 antibody) or vehicle. DC101 treatment did not inhibit progressive tumor growth in established NGP xenografts. Although tumor vasculature was not significantly disrupted, a modest increase in tumor hypoxia was demonstrated by pimonidazole staining, and expression of a previously described hypoxia metagene was increased by gene set enrichment analysis (GSEA) in DC101-treated tumors. DC101 treatment elicited increased: 1) expression of VEGFR1 and its ligand placental growth factor; and 2) increased Notch activation in tumor vasculature concurrent with expression of the Notch ligand Jagged1. This result suggests that established MYCN-amplified neuroblastoma tumors are relatively VEGF-independent, and display the ability to rapidly up-regulate hypoxia-responsive alternative proangiogenic mechanisms that may stabilize vasculature when VEGF is deficient.

PURPOSE: Intestinal abnormalities are sometimes seen during antenatal testing; however, the postnatal importance of these findings has not been well established. We evaluated whether abnormal intestinal appearance on fetal ultrasound (US) was ultimately related to neonatal outcome. METHODS: Fetal US examinations from 2003 to 2006 were evaluated. Hyperechogenic bowel was defined as having the echogenicity comparable to bone, and dilated bowel was identified based on the sonographer's assessment. Persistence or resolution of US findings on subsequent US examinations and eventual outcomes were assessed. Cases were categorized as hyperechogenic or dilated and then subgrouped based on whether the US finding resolved. RESULTS: Sixty-eight fetuses had either hyperechogenic (n = 48) or dilated bowel (n = 20) on antenatal US. In 56 cases, complete data were available for analysis. Of 44 liveborn infants, 11 (25.0%) had an abdominal abnormality, and 33 (75.0%) were normal at birth. Compared to those with dilated bowel, fetuses with hyperechogenic bowel had a higher rate of prenatal demise (20.8% vs 10%) but a lower rate of abnormality at birth (10.3% vs 53.3%). Hyperechogenic bowel resolved on subsequent US more frequently than dilated bowel (65.5% vs 20.0%). In both groups, all fetuses with sonographic resolution were normal at birth. Of 9 fetuses that had persistently hyperechogenic bowel, 3 (33.3%) were born with an abnormality, and all were found to have meconium peritonitis or meconium ileus. In the 12 cases where dilated bowel did not resolve, 8 (66.7%) were eventually born with an abnormality, most commonly intestinal atresia. CONCLUSIONS: Hyperechogenic and dilated bowel are associated with a significant rate of fetal demise. Hyperechogenicity is more common than dilation and is more likely to be transient. Dilated bowel is more often associated with neonatal abnormality than hyperechogenic bowel. Persistence of fetal US findings predicts a higher likelihood of abnormality in the neonate.

PURPOSE: After a successful course of extracorporeal membrane oxygenation (ECMO), patients can deteriorate and a second ECMO course may be contemplated. When a second ECMO course becomes necessary in pediatric patients, survival rates comparable to the first ECMO course are possible. The perceived difficulties involved in recannulation after an initial ECMO course can prevent clinicians from reliably offering a second ECMO run to an eligible pediatric patient. We hypothesized that national ECMO registry data could provide cannulation templates for pediatric patients requiring a second ECMO course. METHODS: We obtained data from the Extracorporeal Life Support Organization registry (1981-2007) on patients 1 to 18 years old who required single-run ECMO (SRE) or multiple-run ECMO (MRE). Primary outcome measures were complications and survival. Cannulation-specific variables were compared using chi(2) methods (Fisher exact, McNemar's). Statistical significance was assumed at P < .05. RESULTS: A total of 3810 (96.8%) children underwent SRE and 127 (3.2%) required MRE. Survival was similar in both groups (49% vs 44%; P = .28). Cannulation data were available in 2539 SRE (67%) and 88 MRE (69%) cases. Compared with SRE, first ECMO courses in MRE patients consisted of fewer cervical (52.3% vs 71.7%; P < .001) but more femoral (20.5% vs 10.7%; P = .01) and central (27.3% vs 17.6%; P = .02) cannulations. In MRE patients, central cannulation was more frequent in second vs first ECMO courses (43.0% vs 27.3%; P = .03). Multiple-run ECMO survival was unaffected by cannulation strategy. Multiple-run ECMO patients with unchanged cannulation sites between first and second ECMO courses had fewer total complications than those requiring new cannulation sites (3.7 vs 5.1; P = .04). CONCLUSIONS: Second ECMO courses in pediatric patients can achieve survival comparable to the first course, but more often require central cannulation. Reusing cannulation sites for a second ECMO course is associated with fewer total complications than cannulating at new sites. These data provide guidance when considering cannulation strategies for second ECMO courses in pediatric patients.