Long-term clinical outcome in patients with Hirschsprung's disease and associated Down's syndrome

Background/Purpose

Down's syndrome (DS) is the most common chromosomal abnormality associated with Hirschsprung's disease (HD). The purpose of this study was to review the long-term clinical outcome in patients with HD and associated DS.

Methods

Between 1975 and 2003, 39 (15%) of the 259 patients with HD had been associated with DS. Follow-up was carried out by means of examination of patient's records and personal/telephone interviews with the patient's parents or guardians.

Results

Twenty-six (67%) patients presented in the newborn period and 13 (33%) after the neonatal period. Twenty-eight (72%) patients had rectosigmoid HD, 10 long segment, and 1 total colonic aganglionosis. Thirty-two patients had other associated anomalies, 24 of these having cardiac anomalies. Definitive pull-through operation was performed in 33 patients. Parents of 1 child refused surgical intervention and parents of 2 children decided against pull-through operation after colostomy. Three children died before pull through. Thirteen patients had one or more episodes of enterocolitis after pull-through operation. At the time of follow-up (6 months to 28 years), 3 patients were found to have reverted to stoma because of poor bowel control or recurrent enterocolitis. Of the remaining 30 patients, 3 were lost to follow-up and 4 were too young to be assessed for bowel control. Assessment of bowel function in 23 patients revealed normal control in 8 (4 of these soiled for 6-17 years after definitive surgery), soiling in 8, and constipation requiring enemas or laxatives in 7.

Conclusions

The vast majority of patients with HD associated with DS continue to have disturbances of bowel function after definitive pull-through operation.     

A correlation between polyomavirus JC virus quantification and genotypes in renal transplantation

Objective

To determine whether the John Cunningham virus (JCV) viral load and the multigenotypes in viruria are correlated with transplant patients.

Methods

The urine of 60 renal transplant patients and 60 healthy controls were screened. We used quantitative real-time polymerase chain reaction and capillary electrophoresis to assess viral load and genotype respectively.

Results

The incidence of viruria and viral load were higher in transplant patients with P = .0092 and P = .0094, respectively. The incidence of different genotype in transplant patients versus controls was 8.3% versus 13.3% for single genotype, 26.7% versus 5% for 2 genotypes, and 5% versus 0% for multigenotypes (P = .0004). The incidence of more than 2 genotypes was high in people with a high viral load and closely related with the transplant patients (P = .007).

Conclusions

Not only viral load but also genotypes are important as a screening parameter to understand the immune milieu of the patients to prevent subsequent complications like polyomavirus nephropathy, infection, and malignancy.     

Fetoscopic temporary tracheal occlusion for congenital diaphragmatic hernia: prelude to a randomized,controlled trial

Objective

As previously reported, high postnatal mortality seen in fetuses with congenital diaphragmatic hernia (CDH) with liver herniation and low lung-to-head ratio (LHR) appears to be improved in fetuses who undergo fetoscopic temporary tracheal occlusion (TO). To test whether further evolution of this technique produces results that justify a randomized controlled trial comparing prenatal intervention to postnatal care, the authors analyzed 11 additional cases and the cumulative experience with 19 cases.

Methods

The authors analyzed retrospectively the outcome of 11 new and 8 previously reported cases of fetoscopic temporary tracheal occlusion. Various factors were studied including maternal morbidity, antenatal outcome, physiologic lung response, and neonatal course.

Results

Temporary TO can be accomplished using 3 5-mm radially expanding uterine ports without hysterotomy. Obstetric morbidity included mild pulmonary edema in 6 cases, chorioamniotic separation and premature rupture of membranes in 12 patients, and preterm labor and delivery in all patients. Thirteen of 19 (68%) neonates survived for 90 days after delivery; one died in utero, and 5 died after birth. Late mortality included one death caused by sepsis and 2 by complications associated with tracheostomies. Morbidity from gastroesophageal reflux requiring Nissen fundoplication, tracheal injury requiring repair or tracheostomy, and recurrent hernias after diaphragmatic repair were characteristic in longterm survivors.

Conclusions

Fetoscopic temporary TO may improve outcome in poor-prognosis fetuses with CDH. However, complications related to tracheal dissection, premature delivery and late morbidity are significant. This experience has led to simpler techniques for fetoscopic tracheal occlusion and to an National Institutes of Health-sponsored randomized controlled trial comparing fetoscopic tracheal occlusion with optimal postnatal care.     

Nitrofen-induced congenital diaphragmatic hernia in rat embryo: what model?

Purpose

The aim of this study was to investigate the natural history of congenital diaphragmatic hernia (CDH) in rat embryos with special attention to the pathomorphologic changes of diaphragm, liver, intestines, and lungs at various stages of embryonic development.

Methods

Pregnant Sprague-Dawley rats were given, via a gavage tube, 100 mg nitrofen (Wako Chemicals, Neuss, Germany) on day 10.5 of gestation. Fetuses were harvested by laparotomy on day 15.5, 16.5, 18, and 21. Anatomic study of the diaphragm, herniated viscera, and lungs was performed under stereoscope with special attention to the diaphragmatic defect.

Results

CDH occurred in 44 embryos on right, in 10 on the left, and in 34 bilateral. In the youngest embryos, the small defect was located in the dorsomedial portion of the diaphragm very close to the aortic hiatus. During pregnancy, the defect enlarged progressively to occupy more than half of the affected hemidiaphragm on day 21. In all animals, regardless of their age and side of the defect, the liver was found inside the chest. The intrathoracic mass was formed by ingrown hepatic tissue originating from the dorsal surface of the intraabdominal liver. It appeared as an accessory liver lobe. The amount of intrathoracic liver increased rapidly. From around day 18, the thoracic portion of liver, when examined in sagittal plane, was bent forward and assumed an uncinate shape. The stomach and small bowel loops were displaced into the chest in the oldest examined fetuses. The first sign of reduction of size of the lung was seen in 16, 5-day old embryos, and at further stages of embryonic development the lung growth impairment strictly paralleled the ingrowth of the liver. The natural history of the right and left CDH were very similar. In fetuses with bilateral CDH, asymmetry regarding size of the defect and volume of intrathoracic hepatic mass was noted with larger defects on the left side in more than 60% of animals.

Conclusions

Pathogenesis of nitrofen-induced diaphragmatic defect in the rat embryo and CDH in the human fetus seem to differ significantly. Nitrofen induces a complex malformation of the embryonic diaphragm and the liver. CDH in rat embryo bears more resemblance to a model of space-occupying lesion than to human CDH. The induction of localized hepatic proliferation may be a result of disturbance of as yet unknown regulatory interaction between hepatic and mesenchymal diaphragmatic cells.     

Abnormal intrinsic esophageal innervation in congenital diaphragmatic hernia: a likely cause of motor dysfunction

Purpose

Patients with congenital diaphragmatic hernia (CDH) often have dilated esophagus and gastroesophageal reflux. Sparse intrinsic esophageal innervation has been described in rats with CDH, but this issue has not been investigated in patients with CDH. The present study tests the hypothesis that innervatory anomalies could account for motor dysfunction in human CDH.

Methods

The esophagi of CDH (n = 6) and control babies dead of other causes (n = 6) were included in paraffin, transversally sectioned, and immunostained with antineurofilament and anti-S-100 antibodies. The proportion of the section surface occupied by neural structures, the ganglionar surface, and the number of neurons per ganglion were measured in 2 to 5 low-power fields from the proximal and distal esophagus with the assistance of image analysis software. Mann-Whitney tests were used for comparing the results using a threshold of significance of P < .05.

Results

The percentage of neural/muscle surface was similar in the upper esophagus in both groups, but it was significantly decreased in the lower esophagus of patients with CDH in comparison with controls. There was a relative scarcity of neural tissue in the intermuscular plexus of the lower esophagus. On the other hand, the ganglionar surface and the number of neurons per ganglion were identical in both groups. These results were similar with both immunostainings.

Conclusion

Intrinsic innervation of the lower esophagus in CDH is abnormal in terms of decreased density of neural structures in the intermuscular plexus. These neural crest-derived anomalies could explain in part the esophageal dysfunction in survivors of CDH.     

Late-presenting congenital diaphragmatic hernia

Background

Late-presenting congenital diaphragmatic hernia (CDH) is a rare subset of CDH, most of the information derived from small series or case reports. The aim of this study was to document the clinical manifestations of late-presenting CDH using a large multicenter database.

Methods

Information about late-presenting CDH (diagnosed at later than 30 days of age) was identified from the database of the CDH Study Group (3098 cases collected during 1995-2004) and reviewed retrospectively.

Results

Seventy-nine cases (2.6%) from 30 centers met the inclusion criteria. Seven cases had a Morgagni hernia. There were 50 males (65%) and 27 females (35%). The mean age at diagnosis was 372 days (32 days to 15 years). Major associated anomalies (10 cardiac and 7 chromosomal abnormalities) were identified in 12 cases (15%). Presenting symptoms were respiratory in 20 (43%), gastrointestinal in 15 (33%), both in 6 (13%), and none (asymptomatic) in 5 (11%). The hernia was left-sided in 53 (69%), right-sided in 21 (27%), and central or bilateral in 3 (4%). Patients with gastrointestinal symptoms invariably had left-sided hernias (n = 19), whereas patients with respiratory symptoms (n = 24) seemed equally likely to have right- or left-sided lesions. A primary repair without patch was done in all cases with 100% survival.

Conclusions

Presenting symptoms of late-onset CDH can be respiratory or gastrointestinal, but presentation with gastrointestinal problems was more common in left-sided hernias, whereas respiratory symptoms predominated in right-sided lesions. The prognosis is excellent once the correct diagnosis is made.     

Apparent truth about congenital diaphragmatic hernia: a population-based database is needed to establish benchmarking for clinical outcomes for CDH

Background

The authors hypothesize that recent single or multiinstitution-based reports of improved survival of congenital diaphragmatic hernia (CDH) patients are biased by patient selection, practice, and referral patterns. Here the authors report a population-based analysis of the clinical outcomes of CDH in the province of Ontario for 1996.

Methods

A retrospective analysis of cross-sectional data from the Bureau of Vital Statistics of Ontario and all 5 pediatric surgical institutions in Ontario for 1996 was performed.

Results

Twenty-four CDH-associated deaths were registered in Canada in 1996. Fourteen of 24 occurred in Ontario (58.3%). Of 30 institutionally identified CDH in Ontario, 8 patients died (26.7%). CDH-associated infant mortality rate was 6.6 of 100,000 live births in Canada compared with 10 of 100,000 live births for Ontario (Relative risk, 1.4; confidence interval, 0.5, 3.7; P > .01). Neonatal death (<28 postnatal days) accounted for the majority, 13 of 14 (92.8%) of deaths. Six of 14 (42.9%) CDH-associated deaths, however, were not accounted by the institutional-based reporting. In addition, institutional-based survival rates for CDH varied from 62.5% to 100%.

Conclusions

Our results indicate the existing bias associated with institution-based reporting and database of CDH. The “hidden mortality” associated with CDH is still present. A population-based database is needed to establish the benchmarking for management of CDH.     

Predicting the need for fundoplication at the time of congenital diaphragmatic hernia repair

Purpose

This study was conducted to examine the preoperative factors predictive of subsequent intervention for gastroesophageal reflux (GER) in children with congenital diaphragmatic hernia (CDH).

Methods

We conducted a retrospective cohort study on children who underwent repair of a CDH between January 1, 1995, and December 31, 2002 with follow-up continuing to September 1, 2005. Excluded in the study were children who died during their first admission, or who underwent fundoplication at the time of CDH repair. Univariate and multivariate logistic regressions were performed to examine preoperative factors predictive of subsequent intervention (fundoplication or gastrojejunal tube placement).

Results

Of 86 children, 13 underwent intervention (fundoplication, 10; gastrojejunal tube, 3) for GER. Univariate predictors included the following: right-sided CDH, use of nonconventional ventilation, liver within the chest, and patch closure of the CDH. However, only liver within the chest and patch closure of the CDH were significant predictors in a multiple variable analysis. The positive and negative predictive values of the multivariate model were 69.2% and 87.7%, respectively.

Conclusions

Infants with CDH who have liver within the chest or require patch closure of their hernia are at increased risk for subsequent intervention for GER. These children may represent a subpopulation that would benefit from fundoplication at the time of CDH repair.     

Absolute vs relative improvements in congenital diaphragmatic hernia survival: what happened to “hidden mortality”

Purpose

The aim of this study is to determine if there has been a true, absolute, or apparent relative increase in congenital diaphragmatic hernia (CDH) survival for the last 2 decades.

Method

All neonatal Bochdalek CDH patients admitted to an Ontario pediatric surgical hospital during the period when significant improvements in CDH survival was reported (from January 1, 1992, to December 31, 1999) were analyzed. Patient characteristics were assessed for CDH population homogeneity and differences between institutional and vital statistics-based population survival outcomes. SAS 9.1 (SAS Institute, Cary, NC) was used for analysis.

Result

Of 198 cohorts, demographic parameters including birth weight, gestational age, Apgar scores, sex, and associated congenital anomalies did not change significantly. Preoperative survival was 149 (75.2%) of 198, whereas postoperative survival was 133 (89.3%) of 149, and overall institutional survival was 133 (67.2%) of 198. Comparison of institution and population-based mortality (n = 65 vs 96) during the period yielded 32% of CDH deaths unaccounted for by institutions. Yearly analysis of hidden mortality consistently showed a significantly lower mortality in institution-based reporting than population.

Conclusion

A hidden mortality exists for institutionally reported CDH survival rates. Careful interpretation of research findings and more comprehensive population-based tools are needed for reliable counseling and evaluation of current and future treatments.     

Surfactant does not improve survival rate in preterm infants with congenital diaphragmatic hernia

Background

Use of exogenous surfactant in congenital diaphragmatic hernia (CDH) patients is routine in many centers. The authors sought to determine the impact of surfactant use in the premature infant with CDH.

Methods

Data on liveborn infants with CDH from participating institutions were collected prospectively. Surfactant use and timing and outcome data were analyzed retrospectively. The authors evaluated the prenatal diagnosis patients as well. The outcome variable was survival to discharge. Odds ratios with confidence intervals were calculated.

Results

Five hundred ten infants less than 37 weeks’ gestation were entered in the CDH registry. Infants with severe anomalies (n = 80) were excluded. Information on surfactant use was available for 424 patients. Infants receiving surfactant (n = 209) had a greater odds of death than infants not receiving surfactant (n = 215, odds ratio, 2.17, 95% CI: 1.5 to 3.2; P < .01). In prenatally diagnosed infants with immediate distress, there was a trend toward worse survival rates among those receiving surfactant at 1 hour (52 patients) versus those that did not (93 patients; odds ratio, 1.93, 95% CI: 0.96 to 3.9; P < .07).

Conclusions

Surfactant, as currently used, is associated with a lower survival rate in preterm infants with CDH. The use of surfactant replacement in premature infants with CDH can be recommended only within the context of a randomized clinical trial.     

Endoscopic gastrostomy placement in the child with gastroesophageal reflux: is concomitant antireflux surgery indicated?

Background/Purpose

Previously, we performed concomitant antireflux surgery in patients with abnormal pH study undergoing gastrostomy. This increased complications without always alleviating the troublesome symptom of vomiting. In contrast, vomiting with normal preoperative pH study generally disappeared after gastrostomy placement. Therefore, we changed policy to perform only gastrostomy, regardless of pH study results. Subsequent antireflux surgery is performed only as necessary. We report here our results.

Methods

We retrospectively reviewed patients undergoing gastrostomy from April 1997 to January 2004. For patients with abnormal preoperative pH studies, detailed data were recorded including medical history, indication for gastrostomy, operative technique, symptoms of gastroesophageal reflux (GER), and use of antireflux medication. Symptomatic GER postgastrostomy was managed pharmacotherapeutically. If this proved inadequate, patients underwent antireflux surgery.

Results

Twenty-eight patients with abnormal pregastrostomy pH study entered the study. Median age was 3 years and 2 months. Seventy-five percent were neurologically impaired. Indication for gastrostomy was inadequate oral nutrition in 26 of 28 patients. Only 3 of 28 patients were asymptomatic for GER. Of the 25 symptomatic patients 19 improved postgastrostomy (6 did not). Antireflux surgery ultimately proved indicated in 2 patients (7% [2/28]). The asymptomatic patients remained asymptomatic.

Conclusions

For patients with abnormal pH study presenting primarily for gastrostomy placement, concomitant antireflux surgery is not indicated.     

Low recurrence rate after Gore-Tex/Marlex composite patch repair for posterolateral congenital diaphragmatic hernia

Purpose

Many different prosthetic materials have been used for repair of large posterolateral congenital diaphragmatic hernias (CDH), with high recurrence rates for hernias that cannot be primarily repaired. Since 1993, we have used a composite patch of Gore-Tex/Marlex to repair large CDHs and hypothesized that this repair leads to fewer recurrences.

Methods

This is a retrospective review of 137 consecutive patients with CDH cared for at a single institution from 1993 to 2004. Data collected include timing and method of repair and use of extracorporeal membrane oxygenation. Outcomes include hernia recurrence, complications, and death.

Results

One hundred thirty-seven patients with CDH were analyzed. Repair was not attempted in 12 because of disease severity. Primary repair was accomplished in 79 and 46 required patch repair. Of the 46 patients with patch repairs, 32 required extracorporeal membrane oxygenation, and 18 died before discharge. Of the 28 patch repair survivors, 1 (3.57%) developed a recurrence over a median follow-up of 47 months (range, 2-115 months). Overall survival was 77%.

Conclusions

Gore-Tex/Marlex composite patch repair of large CDHs in this complex patient population results in a lower recurrence rate than has been reported for other types of prosthetic diaphragm repair.     

Early experience with minimally invasive repair of congenital diaphragmatic hernias: results and lessons learned

Background:

Minimally invasive surgery (MIS) for the repair of congenital diaphragmatic hernias (CDH) had been described. This report reviews the authors’ experience with MIS repairs of CDH and discusses the technical development of this approach.

Methods:

From 1999 until now, the authors collected data on children who underwent an MIS approach for CDH repair.

Results:

Seventeen children (11 Morgagni and 7 Bochdalek) had undergone an attempt at MIS repair. All Morgagni defects were treated successfully using laparoscopy (mean age, 28 ± 31 months). Mean follow-up was 22 ± 9 months. There was 1 recurrence. Four children with Bochdalek CDH were treated as newborns (range, 3 to 21 days), and 3 had operations later (4, 11, and 32 months). The first repair was attempted initially transabdominally and was converted to a thoracoscopic approach. The rest of the Bochdalek repairs were performed thoracoscopically. Bochdalek repairs via MIS were successful in 3 children (2 older children and 1 neonate). No child had pulmonary hypertension. Two of the 3 Bochdalek patients did well postoperatively (follow-up, 18 +/− 7 months); the last patient experienced recurrence 11 months after repair.

Conclusions:

MIS for CDH is ideal for Morgagni defects. It should be considered for nonnewborns with a Bochdalek CDH. The MIS approach for a newborn with a CDH cannot be recommended because of the high failure rate and frequent rise in Pco₂ levels.     

Effect of hospital case volume on outcome in congenital diaphragmatic hernia: the experience of the Canadian Pediatric Surgery Network

Purpose

Despite advances in neonatal care of congenital diaphragmatic hernia (CDH), a significant variation exists in the mortality rates reported by individual centers. Center experience (reflected by case volume) may contribute to this variation in outcome. The aim of the study was to determine whether CDH mortality is affected by hospital case volume.

Methods

The CDH cases were abstracted from a disease-specific, 16-hospital, national network. Thirteen hospitals participated in this study. Anonymized hospitals were categorized as either high (>6 cases) or low-volume (≤6 cases) centers (HVC, n = 6; LVC, n = 7) according to the median case number per center. Risk-adjusted (Score for Neonatal Acute Physiology, version II [SNAP-II] score) mortality rates were compared between HVC and LVC.

Results

One hundred twenty-one CDH cases were identified. Overall in-hospital survival was 81%. No significant difference in SNAP-II score was observed between HVC and LVC. Of 97 (15%) infants treated in 6 HVC, 15 (15%) died compared to 8 (33%) of 24 in 7 LVC (P < .05).

Conclusion

Hospital case volume may be partially responsible for mortality rate variation in CDH. This result requires careful analysis, as case volume may merely be a surrogate for other predictive variables.     

Different pattern of matrix metalloproteinases expression in alveolar versus embryonal rhabdomyosarcoma

Background/purpose

The matrix metalloproteinases (MMPs), a family of enzymes that degrade the extracellular matrix (ECM), are important in neoplastic cell invasion and metastasis. Data for rhabdomyosarcoma (RMS), the most frequent soft tissue sarcoma of childhood, are lacking. The aim of this study was to assess their expression in this tumor and to evaluate the correlation with clinicopathologic parameters.

Methods

Immunohistochemical expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, TIMP-1, and TIMP-2 was investigated in 33 human RMSs, 12 alveolar, and 21 embryonal histologic subtypes (12 high risk and 9 low/standard risk). Evaluation of the results was based on the percent of positive neoplastic cells and on staining intensity (negative, moderate, and strong). In situ zymography was carried out on 4 frozen RMS samples (2 alveolar and 2 high-risk embryonal).

Results

Alveolar type showed a stronger MMP-1, -2 and -9 expression in comparison with embryonal (P = .006, P <.001, and P <.001, respectively). Intratumoral vessels and perivascular ECM were positive for MMP-9 in the majority of RMSs. Both TIMPs had negative results.

Conclusions

Gelatinases MMP-2 and MMP-9 and collagenase MMP-1 overexpression seem to contribute to the more aggressive phenotype of alveolar rhabdomyoblastic cells. Further characterization of the expression of MMPs and consequent utilization of their inhibitors in aggressive alveolar RMSs might lead to the development of novel anticancer therapies.     

Chylothorax after congenital diaphragmatic hernia repair

Purpose

Chylothorax after congenital diaphragmatic hernia (CDH) repair contributes significantly to morbidity. Our aim was to identify factors contributing to chylothorax and effective treatment strategies.

Methods

We reviewed 171 patients with CDH from 1997 to 2008 and analyzed hernia characteristics, extracorporeal membrane oxygenation (ECMO) use, operative details, and treatment approaches for chylothorax.

Results

Ten (7%) patients developed chylothorax; all were left sided. Using univariate analysis, prenatal diagnosis, ECMO use, and patch repair were associated with development of chylothorax. Logistic regression analysis showed that patch repair was the only variable predictive of chylothorax (P = .028; confidence interval, 0.032-0.823). Although survival was not affected, patients with chylothorax had a significant increase in ventilator days and length of stay (t = 3.57; P = .000; t = 2.74; P = .007). All received thoracostomy and total parenteral nutrition. Six patients received octreotide, 5 of whom required pleurectomy because of failed medical management; the remaining patient died of overwhelming sepsis.

Conclusions

The incidence of chylothorax at our institution was relatively low. Patch repair was associated with the formation of chylothorax. Morbidity was substantial, but survival was not significantly affected. Total parenteral nutrition and thoracostomy were appropriate initial treatments. Octreotide was not an effective adjunct. Refractory cases were successfully treated with pleurectomy.     

Fetal lung-head ratio is not related to outcome for antenatal diagnosed congenital diaphragmatic hernia

We asked if fetal lung-to-head ratio (LHR) of 1.0 or lower or liver herniation had a statistical effect on survival or need for extracorporeal membrane oxygenation (ECMO), compared with LHR above 1.0 in patients with congenital diaphragmatic hernia (CDH).

Methods

Antenatal records of all patients diagnosed with CDH from January of 2002 to June of 2005 were examined. Inclusion criteria were isolated left-sided CDH and absence of significant cardiac or other anomalies/syndromes, treated solely at this institution. Lung-to-head ratio values were compared based on the value currently proposed for fetal intervention: LHR of 1.0 or lower vs LHR above 1.0. Outcome was assessed as survival (discharge to home) or need for ECMO.

Results

Twenty-eight patients met inclusion criteria. Overall survival was 86% (24/28). Postnatal survival in fetuses with LHR of 1.0 or lower (8/11) was not statistically different from LHR above 1.0 (16/17) (73% vs 94%, P = .114). The need for ECMO in the group with LHR of 1.0 or lower (3/11) was not significantly different from those with LHR above 1.0 (1/17) (27% vs 6%, P = .114). Herniation of the fetal liver into the chest did not affect survival or need for ECMO (P = .228).

Conclusion

Neither LHR of 1.0 or lower nor liver herniation identified a risk factor significant enough to warrant fetal intervention. Multicenter studies may be more appropriate to investigate this clinical problem.