Jason C. Fisher

Redefining outcomes in right congenital diaphragmatic hernia

PURPOSE Available data comparing the management and outcome of right-sided (R-CDH) vs left-sided congenital diaphragmatic hernia (L-CDH) are inconsistent. Large-volume CDH studies are limited by small numbers of R-CDH or are confounded by compilations from multiple institutions with multiple treatment strategies. Consequently, they are underpowered to draw conclusions. To define the behavior and outcomes of R-CDH better, we report the largest single-institution series of R-CDH and ask if factors traditionally linked to poor prognosis in L-CDH were applicable to R-CDH. METHODS We reviewed a single institutions experience with 267 consecutive evaluable neonates with unilateral CDH repaired from 1990 to 2006, with specific focus on R-CDH. chi(2) tests were performed for disease-related categorical variables. Two-tailed unpaired t tests were used for continuous variables. Factors associated with morbidity and survival were determined by univariate regression. Statistical significance was set at P < .05. RESULTS Forty right-sided (15%) and 227 (85%) left-sided cases of CDH were identified. Prenatal diagnosis was made in 20 right-sided vs 170 left-sided defects (50% vs 75%, P < .01). Survival was 22 of 40 in R-CDH compared with 175 of 227 in L-CDH (55% vs 77%, P < .01). Extracorporeal membrane oxygenation was required in 16 right-sided and 33 left-sided cases (40% vs 15%, P < .001). A diaphragmatic patch was used in 22 of 29 right-sided compared with 82 of 199 left-sided repairs (76% vs 41%, P < .01); rates of abdominal wall prosthesis were also higher in right-sided hernias (38% vs 19%, P < .05). No differences were detected in right-sided vs left-sided recurrences (14% vs 8%, P = .38), mean time from birth to operation (5.3 vs 4.8 days, P = .80), or presence of cardiac anomalies (15% vs 12%, P = .63). Morbidity persisting beyond 6 months of age was present in 16 of 22 R-CDH survivors compared with 76 of 175 L-CDH survivors (73% vs 43%, P > .05). Among R-CDHs, prenatal diagnosis was the only factor to predict survival by univariate regression (P < .01). Use of a prosthesis in the diaphragm (P < .05) for R-CDH repair correlated with morbidity. CONCLUSION Although previous reports suggest that associated anomalies, need for extracorporeal membrane oxygenation, and time to repair can influence L-CDH survival, these data do not support extrapolation to R-CDH survival. Right-sided CDH carries a disproportionately high morbidity and mortality. Prenatal diagnosis was the only factor predictive of R-CDH survival. Morbidity may correlate with use of prosthetic material for R-CDH repair. Right-sided CDH is a unique disease that may require a modified antenatal consultation.

Limb ischemia after common femoral artery cannulation for venoarterial extracorporeal membrane oxygenation: an unresolved problem

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 institutions 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 χ² testing (Fishers 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.

Sustained VEGF blockade results in microenvironmental sequestration of VEGF by tumors and persistent VEGF receptor-2 activation.

Vascular endothelial growth factor (VEGF) blockade has been validated clinically as a treatment for human cancers, yet virtually all patients eventually develop progressive disease during therapy. In order to dissect this phenomenon, we examined the effect of sustained VEGF blockade in a model of advanced pediatric cancer. Treatment of late-stage hepatoblastoma xenografts resulted in the initial collapse of the vasculature and significant tumor regression. However, during sustained treatment, vessels recovered, concurrent with a striking increase in tumor expression of perlecan, a heparan sulfate proteoglycan. Whereas VEGF mRNA was expressed at the periphery of surviving clusters of tumor cells, both secreted VEGF and perlecan accumulated circumferential to central vessels. Vascular expression of heparanase, VEGF receptor-2 ligand binding, and receptor activation were concurrently maintained despite circulating unbound VEGF Trap. Endothelial survival signaling via Akt persisted. These findings provide a novel mechanism for vascular survival during sustained VEGF blockade and indicate a role for extracellular matrix molecules that sequester and release biologically active VEGF. (Mol Cancer Res 2008;6(1):1–9)

Early recurrence of congenital diaphragmatic hernia is higher after thoracoscopic than open repair: a single institutional study.

INTRODUCTION Experience in thoracoscopic congenital diaphragmatic hernia (CDH) repair has expanded, yet efficacy equal to that of open repair has not been demonstrated. In spite of reports suggesting higher recurrent hernia rates after thoracoscopic repair, this approach has widely been adopted into practice. We report a large, single institutional experience with thoracoscopic CDH repair with special attention to recurrent hernia rates. METHODS We reviewed the records of neonates with unilateral CDH repaired between January 2006 and February 2010 at Morgan Stanley Childrens Hospital. Completely thoracoscopic repairs were compared to open repairs of the same period. In addition, successful thoracoscopic repairs were compared with thoracoscopic repairs that developed recurrence. Data were analyzed by Mann-Whitney U and Fisher exact tests. RESULTS Thirty-five neonates underwent attempted thoracoscopic repair, with 26 completed. Concurrently, 19 initially open CDH repairs were performed. Preoperatively, patients in the open repair group required more ventilatory support than the thoracoscopic group. Recurrence was higher after thoracoscopic repair (23% vs 0%; P = .032). In comparing successful thoracoscopic repairs to those with recurrence, none of the factors analyzed were predictive of recurrence. CONCLUSIONS Early recurrence of hernia is higher in thoracoscopic CDH repairs than in open repairs. Technical factors and a steep learning curve for thoracoscopy may account for the higher recurrence rates, but not patient severity of illness. In an already-tenuous patient population, performing the repair thoracoscopically with a higher risk of recurrence may not be advantageous.

Recurrence after laparoscopic excision of nonparasitic splenic cysts

BACKGROUND Minimally invasive treatments for nonparasitic splenic cysts are well described. Recent evidence suggests that laparoscopic splenic cystectomy is associated with high recurrence rates in children. Because these cysts are uncommon, no large series is available. We reviewed our clinical data focusing on cyst recurrences and their management. METHODS All children who underwent laparoscopic excision of a nonparasitic splenic cyst from January 2002 to December 2006 were identified. Medical and surgical records were reviewed for perioperative details, hospital course, and outcome. RESULTS Eight children (median age, 13 years; range, 7-16 years) who underwent laparoscopic splenic cystectomy were identified. The most common presenting complaint was left upper quadrant pain or mass (n = 6; 75%). Median cyst size was 13 cm (range, 4-20 cm). There were no conversions to an open technique, completion splenectomies, or perioperative complications. Cysts were identified pathologically as epidermoid (n = 6) or posttraumatic (n = 2). Median hospital stay was 1.5 days. One child required partial splenectomy because of cyst anatomy and remains recurrence-free at 12 months. Cyst recurrence occurred in 7 patients (88%) at a median of 9.4 months (range, 3-18 months) after initial surgery. Median recurrent cyst size was 5.6 cm (range, 3-11 cm). Of 7 recurrences, 4 (57%) were symptomatic. Percutaneous ultrasound-guided cyst drainage and sclerosis were performed in 2 children with symptomatic recurrences, one of whom required 4 separate interventions. There were no complications during management of cyst recurrences. Five children with recurrence (71%) have been followed conservatively and are free of morbidity at a median of 23 months (range, 8-55 months). CONCLUSIONS Laparoscopic excision of nonparasitic splenic cysts in children is associated with a high recurrence rate and may be insufficient treatment. Partial splenectomy may decrease recurrence rates. Conservative management of splenic cyst recurrence after laparoscopic excision is associated with good short-term outcomes. If necessary, image-guided management of symptomatic recurrences can be performed safely.

Percutaneous distal perfusion of the lower extremity after femoral cannulation for venoarterial extracorporeal membrane oxygenation in a small child.

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.

Prenatal lung-head ratio: threshold to predict outcome for congenital diaphragmatic hernia

Objective: The literature suggests that lung-head ratio (LHR) and liver position may inconsistently predict outcome for congenital diaphragmatic hernia (CDH). We reviewed our inborn neonates with isolated left-sided CDH to determine whether these variables predicted survival and to estimate the optimal LHR threshold. Methods: Prenatal LHR and liver position were obtained from 2002 to 2009. The primary endpoint was survival. Results: LHR was greater in survivors after adjusting for gestational age (median 1.40 versus 0.81; p < 0.001). LHR demonstrated excellent diagnostic discrimination, with area under receiver operating characteristic (ROC) curve 0.93 (95% CI 0.86–0.99). LHR threshold of 1.0 was 83% sensitive and 91% specific in predicting survival. An optimal LHR threshold of 0.85 predicted survival with 95% sensitivity and 64% specificity, reducing false negatives (survivors with low LHR). LHR > 0.85 predicted survival after adjustment for gestational age (OR = 33.6, 95% CI = 5.4–209.5). Liver position did not predict survival. Conclusions: Prenatal LHR >0.85 predicts survival for infants with isolated left-sided CDH without compromising discrimination of survivors from non-survivors. The diagnostic utility of LHR may be confounded by gestational age at measurement. Stringent LHR threshold may minimize false-negative attribution and improve utility of this measurement as predictor of survival.

Multivariate model for predicting recurrence in congenital diaphragmatic hernia

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.

Neonatal outcomes associated with intestinal abnormalities diagnosed by fetal ultrasound

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 sonographers 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.

Extracorporeal Membrane Oxygenation for Cardiopulmonary Failure in Pediatric Patients: Is a Second Course Justified?

BACKGROUND Extracorporeal membrane oxygenation (ECMO) is accepted therapy for cardiorespiratory failure. Even after a successful ECMO course, patient deterioration may occur and a second course of ECMO may be contemplated. Although data regarding second ECMO courses exist in neonates, there are no reports describing second ECMO courses in pediatric patients. We hypothesized that data from a national ECMO registry would be useful in identifying which pediatric patients would be optimal candidates for a second course of ECMO. METHODS We obtained data from the national Extracorporeal Life Support Organization registry from 1981 to 2007 on all patients 1-18 years old who required single-run ECMO (SRE) or multiple-run ECMO (MRE). Primary outcome measures were complications and survival. Continuous variables were assessed for distribution normality by using a Shaprio-Wilk statistic to guide nonparametric testing. SRE and MRE patients were compared by using chi2 tests (Fishers exact and McNemars) to assess differences in categorical variables; continuous data were assessed by using Mann-Whitney U or Wilcoxon signed-rank testing. Two multivariate regression models were constructed to identify independent predictors of survival and complications in MRE patients. Statistical significance was assumed at P < 0.05. RESULTS A total of 3937 pediatric patients received ECMO for cardiac or respiratory failure. Of them, 3810 (96.8%) children underwent a single course of ECMO, whereas 127 (3.2%) required multiple ECMO runs. Compared with SRE patients, the first ECMO course in MRE patients was notable for higher rates of cardiac ECMO (61% versus 44%, P < 0.001), venoarterial ECMO (88% versus 78%, P = 0.04), and central cannulation (28% versus 17%, P = 0.007). There was no survival difference between MRE and SRE patients (44% versus 49%, P = 0.28). Median time between MRE courses was 9.0 days (interquartile range = 5-20 days). The mean number of complications per MRE patient was higher in the second ECMO run compared with the first (3.93 versus 3.12, P = 0.008). Multivariate regression identified 2 variables as independent predictors of survival in MRE patients: (1) renal complications during first ECMO run (P = 0.04); and (2) total number of complications during second ECMO run (P = 0.005). A separate multivariate analysis identified 3 variables independently predictive of complications in MRE patients: (1) age (P < 0.001); (2) duration of second run (P < 0.001); and (3) total number of complications during first ECMO run (P < 0.001). CONCLUSIONS ECMO therapy achieves 49% survival in children 1-18 years of age. When a second ECMO course becomes necessary, survival rates comparable to the first ECMO course are possible. Patients developing renal complications during their first ECMO course have worse outcome with a second ECMO course. Patients are at greater risk for complications during a second ECMO course if they experience a high number of first-run complications, are >3 years old, or undergo a prolonged second ECMO course. These data are useful when deciding whether to offer a second ECMO course to an eligible pediatric patient.