Effect of ABCC2 (MRP2) transport function on erythromycin metabolism.

The macrolide antiobiotic erythromycin undergoes extensive hepatic metabolism and is commonly used as a probe for cytochrome P450 (CYP) 3A4 activity. By means of a transporter screen, erythromycin was identified as a substrate for the transporter ABCC2 (MRP2) and its murine ortholog, Abcc2. Because these proteins are highly expressed on the biliary surface of hepatocytes, we hypothesized that impaired Abcc2 function may influence the rate of hepatobiliary excretion and thereby enhance erythromycin metabolism. Using Abcc2 knockout mice, we found that Abcc2 deficiency was associated with a significant increase in erythromycin metabolism, whereas murine Cyp3a protein expression and microsomal Cyp3a activity were not affected. Next, in a cohort of 108 human subjects, we observed that homozygosity for a common reduced-function variant in ABCC2 (rs717620) was also linked to an increase in erythromycin metabolism but was not correlated with the clearance of midazolam. These results suggest that impaired ABCC2 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.

Necrotizing fasciitis in children: prompt recognition and aggressive therapy improve survival.

UNLABELLED: Necrotizing fasciitis (NF) is a bacterial infection of the soft tissues with a fulminant course and a high mortality rate. The authors performed a review to define the diagnosis, bacteriology, and management of NF in the pediatric population. This report of 20 cases treated over 18 years represents the largest reported pediatric experience. These infections were attributable to secondary infection of varicella lesions (5), omphalitis (4), extremity lesions (4), perineal infections (3), head and neck lesions (2), inguinal herniorrhapy (1), and breast abscess (1). Nineteen of the 20 children were healthy, without chronic disease or immunosuppression. All patients presented with an altered sensorium and signs of systemic toxicity. Fever (40%), tachycardia (70%), and abnormal white blood cell count (50%) were not uniformly present. There was marked tissue edema in all patients, with a characteristic peau d'orange appearance in 18. Seven infections were caused by streptococcus; the remainder were polymicrobial, involving multiple aerobes and anaerobes. Initial gram stain was of limited utility; in 14 of 19 cases the result was negative or showed only one of many organisms present. Fifteen patients survived and five died. All survivors underwent aggressive surgical debridement within 3 hours of admission. The survivors required of a mean of 3.8 operations. Fascial excision of up to 35% of total body surface area was required. One patient required amputation, two had colostomies, and six required extensive skin grafting for reconstruction. All five patients who died had delayed initial management. CONCLUSION: NF is a serious cause of death in previously healthy children. The diagnosis should be considered in the presence of any soft tissue infection presenting with signs of toxicity and marked wound edema, even in the absence of fever or abnormal white blood cell count. Immediate surgical debridement and coverage with penicillin, an aminoglycoside, and metronidazole are essential. Subsequent changes in antibiotics should be based on culture data because gram stain results are not reliable. More than one operation is required in almost all cases.

Surgical infections in children.

Infection remains a major cause of death and complication in pediatric surgery today. Impaired host resistance from such circumstances as immaturity, cancer chemotherapy, or AIDS predisposes to opportunistic infection by fungi, viruses, mycobacteria, and even protozoa. This review considers recent advances in five areas: 1) sepsis, 2) soft-tissue and wound infections, 3) chest infections, 4) abdominal infections, and 5) miscellaneous (including nosocomial) infections. Of particular importance are the new concepts of sepsis. The new terminology distinguishes stages in the septic process and a complex interaction of inflammatory mediators. The systemic inflammatory response syndrome may progress independently of the original infection to multiorgan dysfunction syndrome, and death. The reports cited herein are, for the most part, retrospective observational studies. There is a great need for prospective, randomized trials to answer questions about the optimal management of, and prevention of, pediatric surgical infections.

Indications for operation in necrotizing enterocolitis revisited.

Operation for necrotizing enterocolitis (NEC) is reserved for infants with intestinal gangrene or perforation. It should not be undertaken until gangrene is present, but ideally should be performed before intestinal perforation occurs. To characterize the onset of intestinal gangrene, data were analyzed for 147 infants with documented NEC, 94 of whom had gangrene. Twelve criteria were evaluated as predictors of intestinal gangrene, using standard epidemiological measures for diagnostic tests. Sensitivity, specificity, positive predictive value, negative predictive value, and prevalence were calculated for each of the proposed operative criteria. The best indications were those whose specificity and positive predictive value approached 100%, and whose prevalence was greater than 10%. These were pneumoperitoneum, positive paracentesis, and portal venous gas. Good indications were those whose specificity and positive predictive value approached 100%, but whose prevalence was less than 10%. These were fixed intestinal loop noted on x-ray, erythema of the abdominal wall, and a palpable abdominal mass. A fair indication for operation--with 91% specificity, 94% positive predictive value, and prevalence of 20%--was "severe" pneumatosis intestinalis, graded by a radiographic system. Poorer indications for operation (and their predictive value for the presence of gangrene) were clinical deterioration (78%), platelet count below 100,000/mm3 (73%), abdominal tenderness (58%), severe gastrointestinal hemorrhage (50%), and gasless abdomen with ascites (0%). No test had a high sensitivity for intestinal gangrene. Portal venous gas should be acknowledged as an indication for operation. Probability analysis may provide a more scientific basis for clinical decision-making.

A bacteriologic basis for the evolution and severity of empyema.

The management of pediatric empyema remains controversial. An experimental study was undertaken to evaluate the role of bacteria in the evolution and severity of empyema, using specific bacteria that are pathogens of empyema in children. A rabbit model was used. The groups were Haemophilus influenzae (n = 9), Bacteroides fragilis (n = 8), the combination (n = 12), Staphylococcus aureus (n = 6), and control (n = 6). The total bacterial inoculum (10(8)) was constant. Diagnostic thoracentesis was performed at regular intervals. Characteristics of the empyema were evaluated when the rabbits were killed (at 4, 7, and 10 days). Most rabbits other than those of the mixed-bacteria group cleared the bacteria from their pleural cavities. Eleven of 12 mixed-bacteria animals had multiloculated empyemas; only one resolved spontaneously. In the other groups, the tendency was toward unilocular empyemas, which resolved by the 10th day in one third of the H influenzae animals, two thirds of the Bacteroides fragilis animals, and half the S aureus animals. The empyemas that persisted until the 10th day were in the exudative or fibrinopurulent stage, except for those of the mixed-bacteria group, all of which were in the advanced organizing stage. The amount of pleural debris and the degree of organization were significantly greater for the mixed bacteria group (P > .01). These findings support the clinical management of monobacterial empyema by simple drainage, whereas mixed aerobic-anaerobic empyemas may require more aggressive drainage procedures.

Epidemiology of necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a worldwide problem that has emerged in the past 25 years as the most common gastrointestinal emergency in neonatal intensive care units (NICU). In the United States the incidence ranges from 1 to 7.7% of NICU admissions. Ninety percent of the patients are premature infants. Mucosal injury, bacterial colonization and formula feeding are the three major pathogenetic factors that have been documented in most infants who have developed NEC. However, NEC may develop only if a threshold of injury, imposed by the coincidence of at least two of three events (intestinal ischemia, pathogenic bacteria, and excess of protein substrate) is exceeded. Immunological immaturity of the gut in premature babies may represent the crucial risk factor.

Intralobar pulmonary sequestration: a clinical and pathological spectrum.

Pulmonary sequestration is a mass of abnormal pulmonary tissue that does not communicate with the tracheobronchial tree and is supplied by an anomalous systemic artery. Whereas extralobar sequestration is clearly congenital, intralobar sequestration, which frequently presents in older children with pathological findings showing acute and chronic inflammation, may have an acquired origin secondary to frequent infections. Several large autopsy series support an acquired etiology of intralobar sequestration. Four cases of intralobar sequestration are presented that demonstrate a spectrum of inflammatory change that support its congenital, rather than acquired origin. Case 1 was a newborn who presented with tachypnea and a right lower lobe density. Resection at 3 weeks of age showed no inflammation in the sequestration specimen. Case 2 presented as a newborn infant with congestive heart failure. Pulmonary sequestration was confirmed by arteriogram. Resection at 3 months of age showed chronic inflammation. Case 3 presented at 7 months of age with chronic pneumonia. The resected specimen demonstrated moderately severe acute and chronic inflammation. Case 4 presented as a 6 year old. The operative specimen showed extensive bronchiectatic changes with marked acute and chronic inflammation. These cases support the congenital origin of intralobar sequestration and suggest a temporal progression from no inflammation to severe acute and chronic inflammation.

Nosocomial infection in pediatric surgical patients: a study of 608 infants and children.

We studied nosocomial infection in a group of 608 pediatric surgical patients over a 14-month period. All inpatients and outpatients who received an operation with an incision by the pediatric general surgical service were entered into the study. Demographic, nutritional, clinical, and laboratory data were collected. Surveillance was conducted for wound infection, septicemia, infections of the respiratory tract, urinary tract, and abdomen, and infectious diarrhea. A total of 676 operative procedures was performed. Nosocomial infection occurred in 38 of the 608 patients (6.2%). A total of 53 infectious complications was tabulated. The number and percent risk per operation were wound 17 (2.5%), septicemia 14 (2.1%), pulmonary 10 (1.5%), urinary tract 5 (0.7%), abdominal 5 (0.7%), diarrhea 2 (0.3%). Broviac catheter sepsis occurred in 7 of 61 lines (11.5%). The highest overall occurrence of infection was in the infant group (1 mo to 1 yr), (13/161, 8.1%). The probability of septicemia was highest in neonates (4.2%) compared with infants (3.1%) or older children (1.2%) (P < .05). The most common isolates were Staphylococcus epidermidis (10/17) from septic patients, and gram-negative enteric bacteria (27/50) from organ and wound infections. Infection was associated with impaired nutrition, multiple disease processes, and multiple operations. The risk of nosocomial infection in this population was comparable to that reported in adult surgical patients. These baseline data may aid the development of strategies to lower infection risk in children.

An expandable prosthesis for stabilization of the infant mediastinum following pneumonectomy.

One possible complication in infant pneumonectomy is mediastinal shift that can fatally kink or compress airways and vessels. Rigid prostheses have been used to prevent these problems; however, they cannot be adjusted as the child grows. We report a case of expandable prosthesis implantation in a 24-day-old infant. During the 18 months postimplantation, the prosthesis was periodically injected with a saline/contrast solution to maintain the mediastinum in a midline position as the child grew. At 24-month follow-up the prosthesis was still in place, and midline position of the mediastinum maintained.

Debridement of periumbilical necrotizing fasciitis: importance of excision of the umbilical vessels and urachal remnant.

The operation of a neonate with periumbilical necrotizing fasciitis consisted of (1) excision of infected skin, fat, and fascia (including the umbilicus); (2) a limited laparotomy, with ligation and excision of the umbilical vessels and urachal remnant; and (3) placement of a temporary silastic patch over the central abdominal defect. Pathological sections confirmed the spread of infection along the vessels and urachal remnant. Excision of the vessels and urachal remnant may be crucial to survival from periumbilical necrotizing fasciitis.

Left mainstem bronchopexy for severe bronchomalacia.

Severe bronchomalacia occurred in a 14-month-old boy, as a result of compression of the left mainstem bronchus by a bronchogenic cyst. After resection of the cyst, the bronchomalacia was corrected by suspension of the posterolateral bronchial wall to the ligamentum arteriosum. This method of bronchopexy may be of value for severe left mainstem bronchomalacia.

Prediction and prevention of anastomotic complications of esophageal atresia and tracheoesophageal fistula.

We analyzed our experience with 64 infants with esophageal atresia (EA) and tracheoesophageal fistula (TEF), to determine the possibility of prediction and prevention of anastomotic complications (leak, stricture, and recurrent TEF). In most of the infants, the anatomical level of the fistula was documented preoperatively by bronchoscopy. The level of the fistula, in turn, correlated with the esophageal anatomy at thoracotomy, ie, carinal fistulas had a wide gap between esophageal pouches, whereas midtracheal or cervical fistulas had a minimal gap. Major anastomotic complications were defined as leak requiring reoperation, symptomatic strictures requiring four or more dilatations, or a recurrent TEF. The complication rates wre: leak (major and minor), 21%; major stricture, 15%; and recurrent TEF, 5%. Major complications occurred in 42% (11/26) of infants with wide gaps, compared with 8% (3/36) of infants with minimal gaps. Route of repair (transpleural or retropleural) made no difference in incidence of anastomotic complications. No infant died of an anastomotic complication. Survival was 100% for Waterston A and B infants, 83% for Waterston C, and 90% overall. Severe gastroesophageal reflux, requiring Nissen fundoplication, was more common among infants with wide gaps than those with minimal gaps (32% v 3%). The most important pathogenetic factor, present in 79% (11/14) of major anastomotic complications, was anastomotic tension, determined by the gap between esophageal pouches, and predicted by preoperative bronchoscopy. Thus the bronchoscopic finding of a carinal fistula signals the need for technical measures that may limit anastomotic morbidity, such as myotomy, patching the anastomosis, retropleural approach, or delayed repair. Assuming precise technique and gentle handling of tissues, the anatomy of the anomaly determines the anastomotic morbidity of EA and TEF.

Azygous flap technique for reinforcement of esophageal closure.

A tissue flap of azygous vein was successfully used for reinforcement of the esophageal anastomosis in two infants with wide-gap esophageal atresia and carinal tracheoesophageal fistula. In spite of anastomotic tension, both esophagi healed without leak or stricture. This technique may be of value in the surgical correction of esophageal anomalies.

Postoperative wound infection in pediatric surgical patients: a study of 676 infants and children.

We conducted an epidemiologic study of postoperative wound infection in pediatric patients. Over a 14-month period, 676 patients who received an operative incision on the Pediatric Surgical service were entered. Demographic, nutritional, clinical, and laboratory data were collected. The patients were followed for development of postoperative wound infection. Cultures were taken from wounds to identify the offending organisms. Of the 676 patients, 137 were neonates, 197 infants, and 342 older children. Wound infection occurred in 17 patients (2.5%): 1 neonate (0.7%), 8 infants (4.1%), and 8 older children (2.3%). Infection rates according to wound classification were: clean 1.0%, clean-contaminated 2.9%, contaminated 7.9%, and dirty 6.3%. Heavily contaminated or dirty wounds were packed open in one third of cases, and allowed to heal by granulation. The largest group of wound infections followed operations on the gastrointestinal tract (10 patients, 267 operations, 3.7%). Staphylococcus aureus, Escherichia coli, and alpha hemolytic streptococcus were the most common wound pathogens. An increased rate of wound infection was associated with operative procedures longer than 1 hour, with the presence of an associated illness, and with emergency operations. Age, sex, nutritional status, and duration of preoperative hospital stay did not significantly alter the wound infection rate. It could be concluded that the incidence of wound infection was lower among pediatric surgical patients than the reported incidence in adult surgical patients. The greatest risk factors were those associated with local contamination of the surgical wound.

A technique for preservation of the ileocecal valve in the neonatal short intestine.

We report a technique, appendiceal interposition, which permitted preservation of the ileocecal valve in an infant with a congenitally short intestine (jejunum, 12 cm; ileum, 1 cm). The procedure was performed on the first day of life in conjunction with jejunal lengthening by the Bianchi technique. The result was a small intestine of 21 cm in length with an intact ileocecal valve.

Giant cystic hygroma of the posterior mediastinum.

The case of a 5-year-old girl with a giant cystic hygroma of the posterior mediastinum is reported. Although the tumor was bilateral, it was excised by unilateral thoractomy. The unique anatomical features of this tumor suggested an embryologic origin from the cisterna chyli or the primitive paired thoracic ducts.