Core outcome set for perinatal interventions for congenital diaphragmatic hernia.

OBJECTIVE: To develop a core set of prenatal and neonatal outcomes for clinical studies evaluating perinatal interventions for congenital diaphragmatic hernia, using a validated consensus-building method. METHODS: An international steering group comprising 13 leading maternal-fetal medicine specialists, neonatologists, pediatric surgeons, patient representatives, researchers and methodologists guided the development of this core outcome set. Potential outcomes were collected through a systematic review of the literature and entered into a two-round online Delphi survey. A call was made for stakeholders with experience of congenital diaphragmatic hernia to review the list and score outcomes based on their perceived relevance. Outcomes that fulfilled the consensus criteria defined a priori were discussed subsequently in online breakout meetings. Results were reviewed in a consensus meeting, during which the core outcome set was defined. Finally, the definitions, measurement methods and aspirational outcomes were defined in online and in-person definition meetings by a selection of 45 stakeholders. RESULTS: Overall, 221 stakeholders participated in the Delphi survey and 198 completed both rounds. Fifty outcomes met the consensus criteria and were discussed and rescored by 78 stakeholders in the breakout meetings. During the consensus meeting, 93 stakeholders agreed eventually on eight outcomes, which constituted the core outcome set. Maternal and obstetric outcomes included maternal morbidity related to the intervention and gestational age at delivery. Fetal outcomes included intrauterine demise, interval between intervention and delivery and change in lung size in utero around the time of the intervention. Neonatal outcomes included neonatal mortality, pulmonary hypertension and use of extracorporeal membrane oxygenation. Definitions and measurement methods were formulated by 45 stakeholders, who also added three aspirational outcomes: duration of invasive ventilation, duration of oxygen supplementation and use of pulmonary vasodilators at discharge. CONCLUSIONS: We developed with relevant stakeholders a core outcome set for studies evaluating perinatal interventions in congenital diaphragmatic hernia. Its implementation should facilitate the comparison and combination of trial results, enabling future research to better guide clinical practice. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Association of timing of congenital diaphragmatic hernia repair with survival and morbidity for patients not requiring extra-corporeal life support.

BACKGROUND: While physiologic stabilization followed by repair has become the accepted paradigm for management of congenital diaphragmatic hernia (CDH), few studies have examined the effect of incremental changes in operative timing on patient outcomes. We hypothesized that later repair would be associated with higher morbidity and mortality. METHODS: Data were queried from the CDH Study Group (CDHSG) from 2007-2020. Patients with chromosomal or cardiac abnormalities and those who were never repaired or required pre-repair extra-corporeal life support (ECLS) were excluded. Time to repair was analyzed both as a continuous variable and by splitting the cohort into top/bottom percentiles. The primary outcome of interest was in-hospital mortality. Secondary outcomes included need for and duration of post-repair ventilatory and nutritional support. RESULTS: A total of 4,104 CDH infants were included. Median time to repair was 4 days (IQR 2-6). On multivariable analysis, high-risk (CDHSG stage C/D) defects and lower birthweight predicted later repair. Overall, in-hospital mortality was 6%. On univariate analysis, there was no difference in the number of days to repair between survivors and non-survivors. On risk-adjusted analysis, single-day changes in day of repair were not associated with increased mortality. Later repair was associated with longer time to reach full oral feeds, increased post-repair ventilator days, and increased need for tube feeds and supplementary oxygen at discharge. CONCLUSIONS: For infants with isolated CDH not requiring pre-operative ECLS, there is no difference in mortality based on timing of repair, but single-day delays in repair are associated with increased post-repair duration of ventilatory and nutritional support.

Tissue Engineering to Repair Diaphragmatic Defect in a Rat Model.

Tissue engineering is an emerging strategy for repairing damaged tissues or organs. The current study explored using decellularized rat diaphragm scaffolds combined with human amniotic fluid-derived multipotent stromal cells (hAFMSC) to provide a scaffold, stem cell construct that would allow structural barrier function during tissue ingrowth/regeneration. We created an innovative cell infusion system that allowed hAFMSC to embed into scaffolds and then implanted the composite tissues into rats with surgically created left-sided diaphragmatic defects. Control rats received decellularized diaphragm scaffolds alone. We found that the composite tissues that combined hAFMSCs demonstrated improved physiological function as well as the muscular-tendon structure, compared with the native contralateral hemidiaphragm of the same rat. Our results indicate that the decellularized diaphragm scaffolds are a potential support material for diaphragmatic hernia repair and the composite grafts with hAFMSC are able to accelerate the functional recovery of diaphragmatic hernia.

Prenatally diagnosed congenital diaphragmatic hernia: optimal mode of delivery?

OBJECTIVE: To evaluate if the delivery mode of infants with prenatally diagnosed congenital diaphragmatic hernia (CDH) affects the outcome. STUDY DESIGN: Data from the CDH Study Group database of infants with prenatal diagnosis between 2001-2015 were divided into four delivery mode groups: vaginal spontaneous, vaginal induced, elective caesarean section, and emergent caesarean section. Outcomes were analyzed in relation to the time of day of delivery and the gestational age at birth. RESULTS: A total of 3906 cases of prenatally diagnosed CDH were assessed, with an overall survival of 64%. There were no differences in patient characteristics, requirement for extracorporeal membrane oxygenation, length of hospital stay or intubation, requirement for O2 at 30 days or overall survival. The time of day at birth did not affect the outcome. There was no difference in outcome between the different delivery modes at similar gestational age (GA) at birth, with worse outcomes at lower GA. CONCLUSIONS: Neither the mode nor time of delivery seems to affect the overall outcome for patients with prenatally diagnosed CDH. Outcome is strongly associated with the GA at birth.

Does a highest pre-ductal O(2) saturation <85% predict non-survival for congenital diaphragmatic hernia?

OBJECTIVE: To analyze operative repair, extracorporeal membrane oxygenation (ECMO) and survival rates based on highest pre-ductal oxygen saturation (Pre-O(2)SAT) in a large infant cohort reported to Congenital Diaphragmatic Hernia Study Group Registry between 2000 and 2010. STUDY DESIGN: Analyzed data included gestational age, birth weight, defect side and size, repair, ECMO use, survival and highest reported PaO(2) and Pre-O(2)SAT in first 24 h of life. We excluded 614 infants due to severe anomaly. Pre-O(2)SAT data were available for 1672 infants. RESULT: Among infants with highest Pre-O(2)SAT value <85%, survival (24/105=23%) and repair (55/105=52%) rates were significantly decreased compared with infants with higher values. Survival increased to 44% for infants with highest Pre-O(2)SAT<85% who underwent operative repair. Of these, 83% (20/24) required ECMO support compared with 15% (144/961) of survivors with Pre-O(2)SAT>99% (P<0.001). The lowest reported Pre-O(2)SAT with survival was 32% and for survival without ECMO was 52%. CONCLUSION: A reported highest Pre-O(2)SAT<85% in the first 24 h of life was not uniformly fatal; but survival of infants with Pre-O(2)SAT<85% was associated with high ECMO use and prolonged hospitalization.

Hyperglycemia and morbidity and mortality in extremely low birth weight infants.

OBJECTIVE: The purpose of this study was to determine the association between hyperglycemia and mortality and late-onset infections (>72 h) in extremely low birth weight (ELBW) infants. STUDY DESIGN: Retrospective analysis of a prospective cohort study of 201 ELBW infants who survived greater than 3 days after birth. Mean morning glucose levels were categorized as normoglycemia (<120 mg/dl), mild-moderate hyperglycemia (120 to 179 mg/dl) and severe hyperglycemia (> or =180 mg/dl). Hyperglycemia was further divided into early (first 3 days of age) and persistent (first week of age). Logistic regression was performed to assess whether hyperglycemia was associated with either mortality or late-onset culture-proven infection, measured after 3 and 7 days of age. RESULTS: Adjusting for age, the odds ratio (OR) for either dying or developing a late infection was 5.07 (95% confidence interval (CI): 1.06 to 24.3) for infants with early severe hyperglycemia and 6.26 (95% CI: 0.73 to 54.0) for infants with persistent severe hyperglycemia. Adjusting for age, both severe early and persistent hyperglycemia were associated with increased mortality. Among survivors, there was no significant association between hyperglycemia and length of mechanical ventilation or length of hospital stay. Persistent severe hyperglycemia was associated with the development of Stage II/III necrotizing enterocolitis, after adjusting for age and male gender (OR: 9.49, 95% CI: 1.52 to 59.3). CONCLUSION: Severe hyperglycemia in the first few days after birth is associated with increased odds of death and sepsis in ELBW infants.

Late versus early surgical correction for congenital diaphragmatic hernia in newborn infants.

BACKGROUND: Congenital diaphragmatic hernia, although rare (1 per 2-4,000 births), is associated with high mortality and cost. Opinion regarding the timing of surgical repair has gradually shifted from emergent repair to a policy of stabilization using a variety of ventilatory strategies prior to operation. Whether delayed surgery is beneficial remains controversial. OBJECTIVES: To summarize the available data regarding whether surgical repair in the first 24 hours after birth rather than later than 24 hours of age improves survival to hospital discharge in infants with congenital diaphragmatic hernia who are symptomatic at or immediately after birth. SEARCH STRATEGY: Search of MEDLINE (1966-2002), EMBASE (1978-2002) and the Cochrane databases using the terms "congenital diaphragmatic hernia" and "surg*"; citations search, and contact with experts in the field to locate other published and unpublished studies. SELECTION CRITERIA: Studies were eligible for inclusion if they were randomized or quasi-randomized trials that addressed infants with CDH who were symptomatic at or shortly after birth, comparing early (<24 hours) vs late (>24 hours) surgical intervention, and evaluated mortality as the primary outcome. DATA COLLECTION AND ANALYSIS: Data were collected regarding study methods and outcomes including mortality, need for ECMO and duration of ventilation, both from the study reports and from personal communication with investigators. Analysis was performed in accordance with the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Two trials met the pre-specified inclusion criteria for this review. Both were small trials (total n<90) and neither showed any significant difference between groups in mortality. Meta-analysis was not performed because of significant clinical heterogeneity between the trials. REVIEWER'S CONCLUSIONS: There is no clear evidence which favors delayed (when stabilized) as compared with immediate (within 24 hours of birth) timing of surgical repair of congenital diaphragmatic hernia, but a substantial advantage to either one cannot be ruled out. A large, multicenter randomized trial would be needed to answer this question.

Surgery-associated complications in necrotizing enterocolitis: A multiinstitutional study.

PURPOSE: This study was designed to evaluate the wound and stomal complication rate associated with surgical intervention in infants with necrotizing enterocolitis (NEC). METHODS: Comprehensive demographic and perioperative data were collected prospectively from 4 separate university hospitals on 51 infants with surgically treated NEC. The postoperative complication rate included wound (infection, dehiscence) and stomal (prolapse, retraction, necrosis, stricture) problems. For analysis, patients were grouped based on gestational age less than 28 weeks (group I, n = 30) and >/=28 weeks (group II, n = 21). Z-score analysis was used for intergroup evaluation. RESULTS: Significantly more infants in group I (21 of 30 [70%] versus group II, 6 of 21 [29%]; P <.001) were treated initially with Penrose drainage alone, but most eventually underwent laparotomy (group I, 28 of 30 [93%] versus group II, 19 of 21 [91%]; P value, not significant). The combined stomal/wound complication rate was significantly higher in group I (14 of 30 [47%]) versus group II (6 of 21 [29%]; P <.025). Of 51 patients, one operation was required in 23 (45%), 2 in 18 (35%), 3 in 8 (16%), and 4 in 2 (4%). CONCLUSIONS: Although the stomal/wound complication rate was significantly higher in group I, both groups had very substantial complication rates, emphasizing the vulnerability of this infant population. Parents, especially of very premature babies, should be advised that multiple operations are likely and that complications should be expected.

Usefulness of surveillance cultures in neonatal extracorporeal membrane oxygenation.

Sepsis is difficult to identify in patients treated with extracorporeal membrane oxygenation (ECMO). This study evaluates the usefulness of surveillance cultures obtained during ECMO. We retrospectively reviewed the records of 187 patients from four ECMO centers with birth weights 1,574 to 4,900 gm and gestational ages 33-43 weeks, over a 4 year interval. Most patients had surveillance blood cultures daily, and tracheal aspirates and urine culture every other day. Charts were reviewed for culture results before, during, and for the 7 days after ECMO, and clinical response to the culture results. A total of 2,423 cultures were obtained during 1,487 days of ECMO, of which 155 were positive (6.4%): 13 of 1,370 blood cultures (0.9%), 137 of 850 tracheal aspirate cultures (16%), and 5 of 203 urine cultures (2.3%). After 72 hours, tracheal aspirate cultures became positive with nosocomial organisms in 33 of 131 patients. None of 153 bacterial urine cultures were positive, and only one of 34 viral urine cultures were positive (CMV). We conclude that routine daily blood cultures are not useful in neonatal ECMO. Tracheal aspirate cultures may be helpful in the management of antibiotic therapy in patients on ECMO for more than 5 days. Routine bacterial urine cultures did not provide useful information.

The role of surgery in children with neurofibromatosis.

BACKGROUND/PURPOSE: Neurofibromatosis frequently is complicated by the development of symptomatic lesions such as optic gliomas and plexiform neurofibromas that require operative resection. Although characteristically benign, these neoplasms have often devastating functional and cosmetic effects and must be monitored for malignant transformation. The purpose of this study is to identify and describe the surgical considerations in the care of children with neurofibromatosis. METHODS: The authors reviewed the charts of all children (<21) at our institution with neurofibromatosis who underwent an operative procedure from 1979 to 1999. Patient demographics, symptomatic lesions, malignant transformation, form of surgical intervention, type of anesthesia, and outcome were collected. RESULTS: A total of 249 patients with either neurofibromatosis 1 or 2 were identified. Of these, 50 (20%) underwent a total of 93 operations. The average age at operation was 9.4 years (1.2 to 21 years). There were 40 soft tissue procedures, 21 intracranial, and 32 miscellaneous. The soft tissue masses typically were treated with wide local excision, and in 8 of these procedures multiple resections were performed. Fourteen of the 50 patients had malignancies. Five of the tumors were soft tissue sarcomas, and 9 were intracranial malignancies. Three patients died, 2 from malignancy and 1 from acute, obstructive hydrocephalus after operation. There were 3 patients alive with malignancy and 8 others living with varying levels of disability. CONCLUSIONS: Neurofibromatosis in the pediatric patient frequently requires surgical intervention, often because of symptoms such as pain or cosmetic deformity, or for malignancy. Children should be watched carefully for signs of malignant transformation and undergo biopsy for neurofibromas that exhibit rapid growth. Management of sarcomas should be aggressive with consideration given to re-excision, placement of brachytherapy catheters, metastectomy, and limb salvage with adjuvant therapy when possible. Preoperatively, children should receive clinical and radiographic (computed tomography or magnetic resonance imaging) evaluation for hydrocephalus.

Late versus early surgical correction for congenital diaphragmatic hernia in newborn infants.

BACKGROUND: Congenital diaphragmatic hernia, although rare (1 per 2-4,000 births), is associated with high mortality and cost. Opinion regarding the timing of surgical repair has gradually shifted from emergent repair to a policy of stabilization using a variety of ventilatory strategies prior to operation. Whether delayed surgery is beneficial remains controversial. OBJECTIVES: To summarize the available data regarding whether surgical repair in the first 24 hours after birth rather than later than 24 hours of age improves survival to hospital discharge in infants with congenital diaphragmatic hernia who are symptomatic at or immediately after birth. SEARCH STRATEGY: Search of Medline (1966-1999), Embase (1978-1999) and the Cochrane databases using the terms "congenital diaphragmatic hernia" and "surg*"; citations search, and contact with experts in the field to locate other published and unpublished studies. SELECTION CRITERIA: Studies were eligible for inclusion if they were randomized or quasi-randomized trials that addressed infants with CDH who were symptomatic at or shortly after birth, comparing early (<24 hours) vs late (>24 hours) surgical intervention, and evaluated mortality as the primary outcome. DATA COLLECTION AND ANALYSIS: Data were collected regarding study methods and outcomes including mortality, need for ECMO and duration of ventilation, both from the study reports and from personal communication with investigators. Analysis was performed in accordance with the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Two trials met the pre-specified inclusion criteria for this review. Both were small trials (total n<90) and neither showed any significant difference between groups in mortality. Meta-analysis was not performed because of significant clinical heterogeneity between the trials. REVIEWER'S CONCLUSIONS: There is no clear support for either immediate (within 24 hours of birth) or delayed (until stabilized) repair of congenital diaphragmatic hernia, but a substantial advantage to either one cannot be ruled out. A large, multicenter randomized trial would be needed to answer this question.

The role of anti-tumor necrosis factor-alpha and interleukin-10 in protecting murine neonates from Escherichia coli sepsis.

BACKGROUND/PURPOSE: The neonate is at much higher risk for septic complications and death than the adult. Although some aspects of the infant's immune response are immature, others are fully functional. Many models of septic death are caused by an overexpression of proinflammatory cytokines. If there were inadequate down regulatory mechanisms, this could lead to an overexpression of proinflammatory cytokines. The authors hypothesized that the high mortality rate of the newborn was caused by overexpression of tumor necrosis factor (TNF-alpha) and that interleukin-10 (IL-10) would attenuate this response. The aim of this study was to determine if TNF-alpha plays an important role in early death from Escherichia coli sepsis in the newborn animal and if blocking TNF improves survival. METHODS: A dose response curve was determined for 1 day old C3H/HEN mice using 10(5) intraperitoneal E coli resulting in a 30% to 50% mortality rate. Litters of newborn (1 day old) C3H/HEN mice received a subcutaneous injection of either 25 or 50 ng of murine IL-10 or 20 microL of anti-TNF-alpha 4 hours before a bacterial challenge. Control animals received nothing. Animals were observed for 5 to 7 days. At least 6 litters (18 pups per group) were used for each regimen. RESULTS: Anti-TNF-alpha resulted in a significant improvement in survival rate compared with controls (100% v 53%, P < .001). In separate experiments, IL-10 at a dose of 25 ng failed to produce any improvement in survival; however, a 50-ng dose resulted in a significant improvement in treated animals compared with controls (95% v 65%, P < .01). CONCLUSIONS: TNF-alpha plays an important role in neonatal sepsis, suggesting that the newborn mouse is capable of mounting a significant proinflammatory response to gram-negative bacteria. Newborn mice may respond to bacterial challenge with an overexpression of proinflammatory cytokines or an underproduction of downregulating cytokines. Future attempts at immunomodulation in human infants must be undertaken with caution until the inflammatory response is better defined.

Lymphatic mapping with sentinel node biopsy in pediatric patients.

BACKGROUND/PURPOSE: Lymphatic mapping with sentinel node biopsy is used widely in adult melanoma and breast cancer to determine nodal status without the morbidity associated with elective lymph node dissection. This technique can be used in children to determine lymph node status with limited dissection and accurate interpretation. The authors report their initial experience. METHODS: The charts of patients who underwent lymphatic mapping with sentinel node biopsy were reviewed retrospectively. Lymphoscintigraphy was performed in patients with truncal lesions 24 hours before surgery to determine the draining nodal basin (for surgical mapping). The tumors were injected 1 hour preoperatively with technetium sulfur colloid and in the operating room with Lymphazurin blue. The draining basin was examined using a radioisotope detector. The blue nodes with high counts were localized and removed. If nodal metastases were identified, lymph node dissection was recommended. Four patients were injected only with Lymphazurin blue. RESULTS: Thirteen children (7 girls, 6 boys; mean age, 7 years) underwent lymphatic mapping with sentinel node biopsy. The tumor types were as follows: 8 malignant melanoma (6 extremity, 2 truncal), 1 malignant peripheral nerve sheath tumor, 1 alveolar soft part sarcoma, and 3 rhabdomyosarcoma. A mean of 2.4 nodes (range, 1 to 6) were removed from each patient. Six patients had a positive sentinel node. Formal lymph node dissection was performed on 4 of the 6 patients, 1 of whom had further nodal disease with 2 of 13 nodes containing micrometastases. One of the 6 patients refused lymph node dissection and adjuvant therapy; the final patient had rhabdomyosarcoma, a malignancy for which lymph node dissection is not indicated. Pulmonary metastasis developed 26 months after diagnoses in the patient with alveolar soft part sarcoma and a negative sentinel node. This patient was injected only with Lymphazurin blue at the time of sentinel node biopsy and refused adjuvant therapy. There have been no other recurrences. There were no complications related to lymphatic mapping or sentinel node biopsy. CONCLUSIONS: Lymphatic mapping with sentinel node biopsy, using both technetium-labeled sulfur colloid and Lymphazurin blue, can be performed safely in pediatric skin and soft tissue malignancies. Further study with long-term follow-up will determine the utility and accuracy of this technique in pediatric malignancies.

Emergent abdominal decompression with patch abdominoplasty in the pediatric patient.

BACKGROUND/PURPOSE: Abdominal compartment syndrome (ACS) is the cardiac, pulmonary, and renal dysfunction that occurs as a result of elevated intraabdominal pressure. The authors present their experience with patch abdominoplasty (PA) in pediatric patients as a means to treat and prevent ACS. METHODS: The charts of patients who underwent PA were reviewed retrospectively. ACS was defined as the increased oxygen requirements and elevation of peak inspiratory pressures (PIP) associated with abdominal distension and worsening renal and or cardiac function. RESULTS: A total of 23 patients (13 boys) were treated (average age, 23 months). Diagnoses included necrotizing enterocolitis (NEC, n = 13), trauma (n = 3), Hirschsprung's enterocolitis (n = 2), perforated bowel (n = 4), and bilateral Wilms' tumor with bowel obstruction (n = 1). Oxygen requirements decreased after patch abdominoplasty (mean preoperative FIO2, 0.87 +/- 24, mean postoperative, 0.67 +/- 24 [P = .01]). The PIP decreased significantly in the 13 patients who survived (mean preoperative PIP, 33 +/- 8, mean postoperative PIP, 27 +/- 7 [P = .01]). These PIPs failed to respond in the 8 nonsurvivors (mean preoperative PIP, 35 +/- 10, mean postoperative PIP, 33 +/- 14 [P value not significant]). Six of the 8 nonsurvivors had NEC. Complications of intraabdominal abscess and enterocutaneous fistula were seen in 5 patients, all of who had NEC. CONCLUSIONS: Patch abdominoplasty effectively decreases airway pressures and oxygen requirements associated with ACS. Complications with PA occur primarily in patients with NEC. Failure to respond with a decrease in PIP and FIO2 requirements is an ominous sign.

Effects of dexamethasone on meconium aspiration syndrome in newborn piglets.

We examined the effects of dexamethasone on lung function in a piglet model of meconium aspiration syndrome. We induced lung injury in 10 newborn piglets (age 5 +/- 0.2 d) with 4 mL/kg body weight of 20% sterile human meconium in normal saline given via tracheostomy. Ventilator management was aimed at maintaining comparable values of end tidal carbon dioxide, Hb saturation, and arterial blood gases. Lung function was assessed using a BICORE CP100 neonatal monitor. Five piglets received 0.5 mg/kg of dexamethasone 2 and 8 h after meconium administration, whereas control piglets received normal saline at similar times. Ventilator settings, oxygen requirements, and lung compliance were similar between groups at the start of the study. Two hours after the instillation of meconium, there was marked lung dysfunction in both groups as evidenced by increased oxygen requirements [fraction of inspired oxygen (FiO2) 0.98 +/- 0.01 versus FiO2 0.21 +/- 0, p < 0.0001] and reduced lung compliance (0.35 +/- 0.03 versus 0.8 +/- 0.03 mL x kg(-1) x cm(-1) H2O, p < 0.0001). Administration of dexamethasone resulted in lower oxygen requirements (FiO2 0.27 +/- 0.01 versus FiO2 1.0 +/- 0.0, p < 0.00001), lower oxygenation index (2.17 +/- 0.17 versus 22.64 +/- 3.39, p < 0.0001), ventilatory efficiency index (0.30 +/- 0.01 versus 0.07 +/- 0.01, p < 0.0001), and improved lung compliance (0.68 +/- 0.04 versus 0.34 +/- 0.05 mL x kg(-1) x cm(-1) H2O, p < 0.001) compared with the control group. In summary, a two-dose course of 0.5 mg/kg of dexamethasone improved blood gases and lung function in a piglet model of meconium aspiration syndrome.

Evidence-based practice in pediatric surgery.

BACKGROUND/PURPOSE: The current medical environment demands the provision of quality healthcare at an affordable cost. Both payors and regulators are committed to lowering cost through initiation of best practice strategies that include practice guidelines, clinical pathways, and standards of care. The only practical way to join this debate is through the use of objective, unbiased clinical data. This study was undertaken to review the current state of the pediatric surgery literature and its value in determining best clinical practice. METHODS: The National Library of Medicine Medline database was accessed using the Ovid Internet client software. All references, abstracts, and keyword indexes from the core pediatric surgery literature, the Journal of Pediatric Surgery, the European Journal of Pediatric Surgery, Pediatric Surgery International, Zeitschrift fur Kinderchirurgie, and Seminars in Pediatric Surgery were downloaded and reviewed. Search criteria were defined to identify prospective, randomized, controlled studies. References were then categorized as case reports; retrospective case series; prospective case series; randomized, controlled studies; laboratory studies; review articles; or miscellaneous studies. RESULTS: As of March 1, 1998, there are 9,373 references, excluding citations of letters or comments, contained in the core pediatric surgery literature, as provided through Medline. Of these, 485 were identified as studies for review, possible prospective case series or prospective, randomized, controlled studies. After review, 34 studies (0.3%) were classified as prospective, randomized, controlled studies, whereas 139 (1.48%) were classified as prospective studies. There were 3,241 (34.6%) case reports, 5,619 (59.9%) retrospective case series, 1,109 (11.8%) laboratory studies, 195 (2.1%) review articles, and 36 (0.3%) miscellaneous studies that did not fit into other categories. When analyzed by decade of publication, prospective studies and prospective, randomized, controlled studies (n = 173) numbered 103 in the 1990s, 63 in the 1980s, and seven in the 1970s. CONCLUSIONS: There is a paucity of scientifically rigorous data on which to base clinical practice in pediatric surgery. The increasing numbers of prospective, case-controlled studies or the more sound prospective, randomized, controlled trials in the 1990s suggests that pediatric surgeons are aware of the need to generate unbiased data to support current clinical practice and the development of practice guidelines. Limitations exist in conducting prospective, randomized, controlled trials because of the rare nature of many pediatric surgical conditions and the lack of clinical "equipoise" over available treatment options. The authors encourage the use of multiinstitutional trials and the prospective, randomized, controlled study methodology to develop data that can be used to guide clinical practice in our evolving healthcare environment.

Meconium stimulates a pro-inflammatory response in peritoneal macrophages: implications for meconium peritonitis.

BACKGROUND/PURPOSE: Although meconium peritonitis is a rare condition, the mortality rate can be as high as 40%. Meconium peritonitis is a result of intestinal perforation in utero, which leads to dense inflammation in the peritoneal cavity. The fetus has relatively immature peritoneal defense mechanisms, so the cause of this dense inflammation is unclear. The peritoneal macrophage is a key cell in the peritoneal inflammatory response in adults. The purpose of this investigation was to determine if sterile meconium had a direct stimulatory effect on the peritoneal macrophage. METHODS: Peritoneal macrophages were harvested from adult C3H/HEN mice. The cells were placed in microtiter wells at 10(5) cells per well. Sterile human meconium was diluted in media and placed in the wells at varying concentrations for 8 hours. Lipopolysaccharide (LPS) (10 microg/mL) served as a positive control. Supernatants were harvested and assayed for tumor necrosis factor alpha (TNF-alpha) using a commercial ELISA kit. Separate cells were assayed for TNF-alpha message using polymerase chain reaction (PCR). In another series of experiments, procoagulant activity (PCA) was determined on freeze-thawed cells using a two-stage amidolytic assay. To test for the role of protein kinase C (PKC) in the PCA response H7, a PKC inhibitor, was used as well. RESULTS: Meconium stimulation resulted in a significant increase in TNF-alpha compared with negative controls with a peak at 0.1% meconium (121 pg/mL v 11 pg/mL, P<.05). There was a significant increase in PCA, with a 10-fold increase with 1% meconium compared with controls (P<.05). This response was limited to less than 5% by PKC inhibition. CONCLUSIONS: Sterile meconium results in a marked proinflammatory response in the peritoneal macrophage with elevations of both PCA and TNF-alpha. The TNF response is likely mediated at a pretranscriptional level because there is a marked increase in TNF mRNA. These data suggest that the PCA response is regulated by a PKC mechanism similar to LPS. Stimulation of the peritoneal macrophage by meconium is a possible cause of the marked inflammation seen in meconium peritonitis.

A multicenter trial of 6-aminocaproic acid (Amicar) in the prevention of bleeding in infants on ECMO.

BACKGROUND/PURPOSE: Intracranial hemorrhage (ICH), is a major source of morbidity and the leading cause of death in neonates treated with extracorporeal membrane oxygenation (ECMO). Anecdotal reports have suggested that epsilon-aminocaproic acid (EACA) can decrease the risk of ICH. The purpose of this study was to evaluate, in a multiinstitutional, prospective, randomized, blinded fashion, the effect of EACA on the incidence of hemorrhagic complications in neonates receiving ECMO. METHODS: All neonates (except congenital diaphragmatic hernia) who met criteria for ECMO at three institutions were eligible for enrollment. EACA (100 mg/kg) or placebo was given at the time of cannulation followed by 25 mg/kg/h for 72 hours. Bleeding complications, transfusion requirements, and thrombotic complications were recorded. Post-ECMO imaging included head ultrasound scan computed tomography (CT) scan, and duplex ultrasound scan of the inferior vena cava and renal vessels. RESULTS: Twenty-nine neonates were enrolled (EACA, 13 and placebo, 16). Five (17.2%) patients had a significant (grade 3 or larger) ICH. There was no statistical difference in the incidence of significant ICH in patients who received EACA (23%) versus placebo (12.5%). Septic patients accounted for all of the ICH in the EACA group. Thrombotic complications (aortic thrombus and SVC syndrome) developed in two patients from the placebo group. There was no difference in thrombotic circuit complications between groups. CONCLUSIONS: Our results suggest that the use of EACA in neonates receiving ECMO is safe but may not decrease the overall incidence of hemorrhagic complications.

Postoperative respiratory complications in ex-premature infants after inguinal herniorrhaphy.

BACKGROUND/PURPOSE: The duration of postoperative cardiorespiratory monitoring of premature infants after inguinal herniorrhaphy is uncertain. Prolonged observation requiring hospital admission may be unnecessary and increases costs. METHODS: This study was a retrospective review of 191 inguinal herniorrhaphies performed between 1993 and 1996 at the Hermann Children's Hospital. The authors reviewed their experience to identify factors associated with postoperative apnea and bradycardia and determine a safe period of observation. RESULTS: Among 191 elective inguinal herniorrhaphies performed, 57 (29.8%) were in expremature infants (< or =60 weeks postconception). Five (8.8%) infants either failed extubation or were unable to extubate (group 1). The average age for this group was 41.0 +/- 1.2 weeks compared with 47.2 +/- 1.0 (P = .06) for those who were successfully extubated (group II). Preoperative apnea-bradycardia was found in four (80%) infants in group I compared with 32 (61.5%) in group II (P = 0.67). All group I and 21 (40.4%, P = .09) group II infants with a history of preoperative apnea required intubation for an average of 24.4 +/- 7.8 days and 8.2 +/- 2.4 days, respectively (P = .04). American Society of Anesthesia (ASA) scores were 2.6 +/- 0.4 for group I compared with 1.8 +/- 0.1 for group 11 (P = .01). The use of both intraoperative narcotics (three [60%] in group I v six [12%] in group II, P = .01]) and vecuronium (four [80%] in group I v 16 [31%] in group II, P = .03) were significantly more common in group I infants. Operating room time was 46.4 +/- 4.1 minutes for group I compared with 60.6 +/- 3.9 minutes for group II (P = .27). Postoperative apnea-bradycardia occurred in all five group I infants and two (3.8%, P = .001) group II infants. Group II infants were treated successfully with supplemental oxygen. CONCLUSIONS: All instances of postoperative apnea-bradycardia and laryngospasm occurred within 4 hours after operation without significant differences between groups. The risk of postoperative cardiorespiratory distress requiring reintubation in premature infants who undergo inguinal herniorrhaphy is not insignificant (8.8%). The judicious use of narcotics and vecuronium, and limiting patient selection to those with ASA score of less than 3 may lessen the need for reintubation. When present cardiorespiratory distress occurs early; therefore we recommend outpatient inguinal herniorrhaphy as a safe and cost-effective choice.

Utility of daily head ultrasonography for infants on extracorporeal membrane oxygenation.

BACKGROUND/PURPOSE: Intracranial hemorrhage (ICH) is a major concern during extracorporeal membrane oxygenation (ECMO). Daily cranial ultrasonography has been used by many ECMO centers as a diagnostic tool for both detecting and following ICH while infants are on bypass. The purpose of this patient review was to look at the usefulness of performing daily cranial ultrasonography (HUS) in infants on ECMO in detecting intraventricular hemorrhage of a magnitude sufficient to alter patient treatment. METHODS: The authors reviewed retrospectively all of the records of all neonates treated with ECMO at the Hermann Children's Hospital, Wilford Hall USAF Medical Center, Cincinnati Children's Hospital, The University of Texas Medical Branch at Galveston, and Texas Children's Hospital between February 1986 to March 1995. Two hundred ninety-eight patients were placed on ECMO during this period. All patients had HUS before, and daily while on ECMO, and all were reviewed by the staff radiologists. A total of 2,518 HUS examinations were performed. RESULTS: Fifty-two of 298 patients (17.5%) had an intraventricular hemorrhage seen on ultrasound scan. Nine of 52 patients (17.3%) had an ICH seen on the initial HUS examination before ECMO, all of which were grade I, and 43 of 52 patients (82.7%) had ICH while on ECMO. Of these ICH, 15 were grade I, 10 were grade II, 10 were grade III, and eight were grade IV. Forty of these ICH (93%) were diagnosed by HUS during the first 5 days of the ECMO course. Seven hundred eighty-six HUS were performed after day 5, at an estimated cost of $300,000 to $450,000 (charges), demonstrating three new intraventricular hemorrhages, one grade I, and one grade IV on day 7 and one grade I on day 8. Eight patients were taken off ECMO because of ICH diagnosed within the first 5 days. One patient was taken off ECMO because of ICH diagnosed after 5 days. This patient had clinical symptoms suggestive of ICH. CONCLUSIONS: Almost all ICH occur during the first 5 days of an ECMO course. Unless there is a clinical suspicion, it is not cost effective to perform HUS after the fifth day on ECMO, because subsequent HUS examinations are unlikely to yield information significant enough to alter management.