Eunice Y. Huang

Early vs interval appendectomy for children with perforated appendicitis.

OBJECTIVE To compare the effectiveness and adverse event rates of early vs interval appendectomy in children with perforated appendicitis. DESIGN Nonblinded randomized trial. SETTING A tertiary-referral urban childrens hospital. PATIENTS A total of 131 patients younger than 18 years with a preoperative diagnosis of perforated appendicitis. INTERVENTIONS Early appendectomy (within 24 hours of admission) vs interval appendectomy (6-8 weeks after diagnosis). MAIN OUTCOME MEASURES Time away from normal activities (days). Secondary outcomes included the overall adverse event rates and the rate of predefined specific adverse events (eg, intra-abdominal abscess, surgical site infection, unplanned readmission). RESULTS Early appendectomy, compared with interval appendectomy, significantly reduced the time away from normal activities (mean, 13.8 vs 19.4 days; P < .001). The overall adverse event rate was 30% for early appendectomy vs 55% for interval appendectomy (relative risk with interval appendectomy, 1.86; 95% confidence interval, 1.21-2.87; P = .003). Of the patients randomized to interval appendectomy, 23 (34%) had an appendectomy earlier than planned owing to failure to improve (n = 17), recurrent appendicitis (n = 5), or other reasons (n = 1). CONCLUSIONS Early appendectomy significantly reduced the time away from normal activities. The overall adverse event rate after early appendectomy was significantly lower compared with interval appendectomy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00435032.

Plasminogen activator/plasmin system: A major player in wound healing?

The role of the plasminogen activator/plasmin system in fibrinolysis has been well established. Indeed, clinicians worldwide have successfully utilized recombinant tissue‐type plasminogen activator as first‐line treatment of acute myocardial infarction for almost 2 decades. Outside the field of cardiology, there has been increasing excitement regarding the possible contribution of this system in many other important biological processes, including cell adhesion, cell migration, cell–cell signaling, tumor invasion and metastasis, ovulation, and wound healing. In this review, we present evidence in the current literature that the plasminogen activator/plasmin system does have a role in wound healing, looking at both normal and abnormal healing. Furthermore, the invaluable insights provided by numerous transgenic animal experiments are summarized. (WOUND REP REG 2003;11:239–247)

Parenteral nutrition–associated cholestasis: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review

OBJECTIVE The aim of this study was to review evidence-based data addressing key clinical questions regarding parenteral nutrition-associated cholestasis (PNAC) and parenteral nutrition-associated liver disease (PNALD) in children. DATA SOURCE Data were obtained from PubMed, Medicine databases of the English literature (up to October 2010), and the Cochrane Database of Systematic Reviews. STUDY SELECTION The review of PNAC/PNALD has been divided into 4 areas to simplify ones understanding of the current knowledge regarding the pathogenesis and treatment of this disease: (1) nonnutrient risk factors associated with PNAC, (2) PNAC and lipid emulsions, (3) nutritional (nonlipid) considerations in the prevention of PNAC, and (4) supplemental medications in the prevention and treatment of PNAC. RESULTS The data for each topic area relevant to the clinical practice of pediatric surgery were reviewed, evaluated, graded, and summarized. CONCLUSIONS Although the conditions of PNAC and PNALD have been well recognized for more than 30 years, only a few concrete associations and treatment protocols have been established.

Treatment of necrotizing enterocolitis: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review

OBJECTIVE The optimal treatment of necrotizing enterocolitis (NEC) is a common challenge for pediatric surgeons. Although many studies have evaluated prevention and medical therapy for NEC, few guidelines for surgical care exist. The aim of this systematic review is to review and evaluate the currently available evidence for the surgical care of patients with NEC. METHODS Data were compiled from a search of PubMed, OVID, the Cochrane Library database, and Web of Science from January 1985 until December 2011. Publications were screened, and their references were hand-searched to identify additional studies. Clinicaltrials.gov was also searched to identify ongoing or unpublished trials. The American Pediatric Surgical Association Outcomes and Clinical Trials Committee proposed six questions deemed pertinent to the surgical treatment of NEC. Recent Cochrane Reviews examined three of these topics; a literature review was performed to address the additional three specific questions. RESULTS The Cochrane Reviews support the use of prophylactic probiotics in preterm infants less than 2500 grams to reduce the incidence of NEC, as well as the use of human breast milk rather than formula when possible. There is no clear evidence to support delayed initiation or slow advancement of feeds. For surgical treatment of NEC with perforation, there is no clear support of peritoneal drainage versus laparotomy. Similarly, there is a lack of evidence comparing enterostomy versus primary anastomosis after resection at laparotomy. There are little data to determine the length of treatment with antibiotics to prevent recurrence of NEC. CONCLUSION Based on available evidence, probiotics are advised to decrease the incidence of NEC, and human milk should be used when possible. The other reviewed questions are clinically relevant, but there is a lack of evidence-based data to support definitive recommendations. These areas of NEC treatment would benefit from future investigation.

The diagnosis and management of empyema in children: a comprehensive review from the APSA Outcomes and Clinical Trials Committee.

The aim of this study is to review the current evidence on the diagnosis and management of empyema. The American Pediatric Surgical Association Outcomes and Clinical Trials Committee compiled 8 questions to address. A comprehensive review was performed on each topic. Topics included the distinction between parapneumonic effusion and empyema, the optimal imaging modality in evaluating pleural space disease, when and how pleural fluid should be managed, the first treatment option and optimal timing in the management of empyema, the optimal chemical debridement agent for empyema, therapeutic options if chemical debridement fails, therapy for parenchymal abscess or necrotizing pneumonia and duration of antibiotic therapy after an intervention. The evidence was graded for each topic to provide grade of recommendation where appropriate.

Increased Plasminogen Activator Inhibitor-1 in Keloid Fibroblasts May Account for their Elevated Collagen Accumulation in Fibrin Gel Cultures

Proteolytic degradation of the provisional fibrin matrix and subsequent substitution by fibroblast-produced collagen are essential features of injury repair. Immunohistochemical studies revealed that although dermal fibroblasts of normal scars and keloids expressed both urokinase type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1), keloid fibroblasts had a much higher PAI-1 expression. In long-term three-dimensional fibrin gel cultures (the in vitro fibroplasia model), normal fibroblasts expressed moderate and modulated activity levels of uPA and PAI-1. In contrast, keloid fibroblasts expressed a persistently high level of PAI-1 and a low level of uPA. The high PAI-1 activity of keloid fibroblasts correlated with their elevated collagen accumulation in fibrin gel cultures. Substituting collagen for fibrin in the gel matrix resulted in increased uPA activity and reduced collagen accumulation of keloid fibroblasts. Furthermore, decreasing PAI-1 activity of keloid fibroblasts in fibrin gel cultures with anti-PAI-1-neutralizing antibodies also resulted in a reduction in collagen accumulation by keloid fibroblasts. Cumulatively, these results suggest that PAI-1 overexpression is a consistent feature of keloid fibroblasts both in vitro and in vivo, and PAI-1 may play a causative role in elevated collagen accumulation of keloid fibroblasts.

Indomethacin promotes germinal matrix microvessel maturation in the newborn beagle pup.

Background and Purpose Although indomethacin has been demonstrated to prevent germinal matrix and intraventricular hemorrhage in clinical and animal studies, the mechanism of action of this agent to prevent hemorrhage remains unclear. Previous studies have demonstrated both that the microvessels in the germinal matrix of newborn beagle pups undergo basement membrane maturation during the first 4 postnatal days and that indomethacin may promote laminin deposition in tumor cell culture systems. Methods We employed the newborn beagle pup model to test the hypothesis that indomethacin may stimulate laminin deposition in germinal matrix microvessels. Newborn pups were randomized to receive either 0.1 mg/ kg/dose i.p. indomethacin or an equal volume of saline diluent. Pups received doses of study medication once a day for 1, 2, or 3 days and were studied on postnatal days 1, 2, 3, or 4. Pups were anesthetized and systemically perfused with buffered formalin; the brains were removed and prepared for immunohistochemical study. Results Sections stained with Bandeiraea lectin demonstrated that there was no difference in germinal matrix vessel density among the postnatal ages studied; similarly, there were no differences in vessel density between saline- and indomethacin-treated animals at any postnatal age. Quantification of germinal matrix stained intensity by confocal microscopy demonstrated significant increases in indomethacin- treated pups for both laminin staining at postnatal days 2 (p=0.05) and 3 (p=0.0009) and type V collagen staining at postnatal day 2 (p=0.011). Although staining for β1 integrins increased across postnatal ages, there were no differences between saline- and indomethacin-treated animals. Conclusions These data suggest that indomethacin may stimulate basement membrane deposition in the germinal matrix microvessels of newborn beagle pups to prevent germinal matrix and/or intraventricular hemorrhage.

Strategies for the prevention of central venous catheter infections: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review

PURPOSE The aim of this study is to review the current evidence-based data regarding strategies for prevention of central venous catheter (CVC) infections at the time of catheter insertion and as a part of routine care. METHODS We conducted a PubMed search from January 1990 to November 2010 using the following keywords: central venous catheter, clinical trials, pediatric, infection, prevention, antibiotic, chlorhexidine, dressing, antiseptic impregnated catheters, ethanol lock, impregnated cuff, insertion site infection, and Cochrane systematic review. Seven questions, selected by the American Pediatric Surgical Association Outcomes and Clinical Trials Committee, were addressed. RESULTS Thirty-six studies were selected for detailed review based on the strength of their study design and relevance to our 7 questions. These studies provide evidence that (1) chlorhexidine skin prep and chlorhexidine-impregnated dressing can decrease CVC colonization and bloodstream infection, (2) use of heparin and antibiotic-impregnated CVCs can decrease CVC colonization and bloodstream infection, and (3) ethanol and vancomycin lock therapy can reduce the incidence of catheter-associated bloodstream infections. CONCLUSION Grade A and B recommendations can be made based on available evidence in adult and limited pediatric studies for multiple components of proper CVC insertion practices and subsequent management. These strategies can minimize the risk of CVC infections in pediatric patients.

Diagnosing ruptured appendicitis preoperatively in pediatric patients.

BACKGROUND Over the past decade, pediatric patients with ruptured appendicitis (RA) have been successfully treated with IV antibiotics and an interval appendectomy. Because the treatment of acute appendicitis (AA) and RA in children is now diverging, distinguishing between these two conditions preoperatively is critical. STUDY DESIGN A prospective cohort study was conducted. Clinical data were collected, and the attending surgeons preoperative diagnosis was recorded. Accuracy of the pediatric surgeons diagnosis was determined. Univariable and multivariable logistic regression were then used to determine independent clinical predictors of RA. Using the relative beta coefficients of these predictors, a scoring system was constructed to aid in the diagnosis of RA. RESULTS Two hundred forty-seven patients were evaluated: 98 AA (40%), 53 RA (21%), and 97 not appendicitis (39%). Median age was 10 years old. The overall accuracy of the pediatric surgeons preoperative diagnosis was 92%. Sensitivity and specificity for the diagnosis of RA were 96% and 83%, respectively. Multivariable regression analysis identified generalized tenderness on examination, duration of symptoms longer than 48 hours, WBC>19,400 cells/microL, abscess, and fecalith on CT scan as independent predictors for RA. A novel scoring system was developed with these variables, and, when applied to the study population, the specificity for the diagnosis of RA improved to 98%. CONCLUSIONS Pediatric surgeons differentiate AA from RA and not appendicitis preoperatively with high accuracy and sensitivity, but the specificity for diagnosing ruptured appendicitis is lower. The scoring system improved the specificity of the preoperative diagnosis. The validity and utility of this scoring system should be examined in future studies in larger patient populations.

Transforming growth factor‐β3 affects plasminogen activator inhibitor‐1 expression in fetal mice and modulates fibroblast‐mediated collagen gel contraction

For over two decades, the precise role of transforming growth factor‐β (TGF‐β) isoforms in scarless healing of mammalian fetal skin wounds has generated much interest. Although their exact role remains to be established, it has been suggested that high TGF‐β3 activity may correlate with a scarless phenotype. Previously, we showed that plasminogen activator inhibitor‐1 (PAI‐1), a known TGF‐β downstream molecule and marker of fibrosis, is also developmentally regulated during fetal skin development. In this study, the relationship between TGF‐β3 and PAI‐1 was investigated using embryonic day 14.5 TGF‐β3 knockout (ko) mice. The results showed increased PAI‐1 expression in the epidermis and dermis of ko mice, using an ex vivo limb‐wounding study. Furthermore, increased PAI‐1 expression and activity was seen in embryo extracts and conditioned media of ko dermal fibroblasts. When TGF‐β3 knockout fibroblasts were placed into three‐dimensional collagen matrices, they were found to have decreased collagen gel contraction, suggesting altered cell–matrix interaction. These findings provide a further avenue for the interactive role of TGF‐β3 and PAI‐1 during fetal scarless repair.