David A. Lloyd

Predictive value of skull radiography for intracranial injury in children with blunt head injury

BACKGROUND The value of routine skull radiography as a method of predicting intracranial injury is controversial. We aimed to assess the effectiveness of skull radiography by prospectively studying head-injured children admitted to a childrens hospital that serves an urban population. METHODS Over a 2-year period, 9269 children attended our accident and emergency department with head injury, and 6011 were referred for skull radiography. All children who were admitted to hospital or had a skull fracture (n = 883) were included in the study. Computed tomography (CT) was done in children with skull fractures on radiography and in those without fractures if there were neurological indications. FINDINGS Radiographs showed 162 fractures (2.7% of all radiographs and 18% of study group radiographs). Staff in the accident and emergency department missed 37 (23%) fractures. CT scan was done on 156 children, of whom 107 had a skull fracture. 23 children were found to have intracranial injuries on CT. The presence of neurological abnormalities had a sensitivity for identification of intracranial injury of 91% (21 of 23) and a negative predictive value of 97%. The corresponding values for skull fracture on radiography were 65% (15 of 23) and 83%. Four children died, of whom only one had a skull fracture. INTERPRETATION In children, severe intracranial injury can occur in the absence of skull fracture. Skull radiography is not a reliable predictor of intracranial injury and is indicated only to confirm or exclude a suspected depressed fracture or penetrating injury, and when non-accidental injury is suspected, including in all infants younger than 2 years. Clinical neurological abnormalities are a reliable predictor of intracranial injury. If imaging is required, it should be with CT and not skull radiography.

Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group.

The Childrens Cancer Study Group (CCSG) undertook a study (CCG-823F) to test the feasibility of administering continuous infusion doxorubicin (CI DOX) and cisplatin (CDDP) in patients with unresectable or incompletely resected hepatoblastoma (HB) or hepatocellular carcinoma (HCC). Chemotherapy consisted of CI DOX 20 mg/m2/d for days 1 to 4 and CDDP 100 mg/m2 on day 1 followed by a 21-day rest period. Second-look surgery was performed after the administration of four chemotherapy courses. Forty-seven (47) assessable patients were entered on study, 33 with HB and 14 with HCC; of these, 34 (26 HB and eight HCC) completed the initial four courses of chemotherapy. Of the 26 HB patients, 25 were evaluated as responding to chemotherapy before the scheduled second-look procedure and were considered surgically resectable at that time. Surgery was performed on 22 patients; three patients refused the second-look surgery. Nine patients had no evidence of residual malignant disease, seven underwent surgical resection of remaining tumor, four were left with microscopic residual disease, one had a partial resection with gross tumor left behind, and one remained unresectable. Nine HCC patients completed four chemotherapy courses. Eight patients achieved a partial remission and second-look surgery was attempted on seven. Only two had all malignant disease removed at the second procedure. Data from 225 courses of chemotherapy were evaluated for toxicity. Neutropenia (absolute granulocyte count less than 500/mL) was observed in 68 courses, and five of these episodes were associated with sepsis. Severe mucositis was documented in 21 courses, and hypomagnesemia (magnesium less than 1.2 mg) was noted in 30 patients. Two patients developed decreased left ventricular shortening fraction, which resolved when chemotherapy was discontinued. In summary, CI DOX plus CDDP is a well-tolerated and effective regimen in inducing surgical resectability in HB patients who are unresectable at diagnosis and significantly improves survival for this group of patients to 66.6%.

Peritoneal drainage for necrotizing enterocolitis

This study evaluates the role of primary peritoneal drainage (PPD) in the management of neonatal necrotizing enterocolitis (NEC). Of 169 patients with definite NEC, 92 (55%) underwent operation: primary laparotomy, 41 patients (45%); and PPD, 51 patients (55%). Seventeen (33%) of the PPD infants had subsequent laparotomy within seven days. Pneumoperitoneum was the indication for operation in 37% of the primary laparotomy and 67% of the PPD infants. Following PPD, 34 patients (67%) showed clinical improvement. Operative survivals were as follows: primary laparotomy, 83%; PPD, 53%. Infants who had PPD had a significantly lower mean birth weight, gestational age, preoperative pH and platelet count, and a significantly higher incidence of intraventricular hemorrhage and patent ductus arteriosus. For infants weighing less than 1,000 g at birth, the survival was similar following primary laparotomy (57%) and PPD (52%); this occurred in spite of the higher incidence of adverse risk factors in the PPD infants. For infants weighing greater than 1,000 g, the survival was 86% following primary laparotomy and 62% after PPD; in this group, all the early deaths following PPD occurred in critically ill infants who died within 48 hours of drainage. The late survival rates were as follows: primary laparotomy, 76%; PPD, 35%. More than half of the late deaths following PPD were not related to NEC, reflecting the difference between the two patient populations. Primary peritoneal drainage is a useful adjunct to resuscitation of the critically ill infant with complicated NEC, particularly prematures less than 1,000 g birth weight with intestinal perforation. Primary peritoneal drainage is not an alternative to laparotomy, which is recommended when an optimal clinical response has been achieved.

Early lung malformations in congenital diaphragmatic hernia

BACKGROUND/PURPOSE Lung hypoplasia, a leading contributor to the lethality of congenital diaphragmatic hernia (CDH), has been attributed to compression of the fetal lung by herniated abdominal viscera. Contested findings in experimental CDH suggest that lung malformation may precede diaphragmatic hernia. To address this unresolved question, we studied the pattern and progress of embryonic lung development in vivo and in vitro before diaphragmatic herniation in the nitrofen CDH model. METHODS Sprague-Dawley rats were fed nitrofen on day 9.5 of pregnancy to induce pulmonary hypoplasia and CDH in newborns (term, day 22). Control rats received olive oil. Embryonic lungs were microdissected on day 13.5 gestation, 24 hours after lung primordia bud from the foregut (normal diaphragmatic closure, day 16.5). In vivo airway branching was measured by counting terminal lung buds at this stage. Lungs were cultured for up to 78 hours and longitudinal in vitro development studied by serial measurements of terminal bud count, area, and perimeter. RESULTS At 13.5 days of gestation in vivo, nearly 99% of normal lungs (n = 130) had > or = 6 terminal lung buds. In contrast, 36% of the nitrofen-exposed lungs (n = 170) fell short of this developmental milestone with less than 6 terminal buds (P < .001). In vitro, the nitrofen lungs had reduced area compared with controls after 6, 30, and 54 hours (P = .001, P < .001, and P = .001, respectively). Bud count and epithelial perimeter were reduced in the nitrofen lungs after 6 and 30 hours in vitro (P < .001 and P = .01 v normal terminal bud count; P < .001 and P= .002 v normal perimeter). CONCLUSIONS Before diaphragmatic herniation, nitrofen-exposed embryos in vivo have a 36% frequency of reduced airway branching that strikingly parallels the 30% to 40% term incidence of CDH in this model. The authors propose that this early lung anomaly is restricted to a subset of nitrofen-exposed embryos in which it is integral to an emerging CDH phenotype. In vitro data confirm that nitrofen-induced pulmonary hypoplasia precedes visceral herniation and persists to allow experimental manipulation in culture. The developmental biology underlying lung hypoplasia in CDH may now be addressed using this organ culture system.

The surgical management of children with incompletely resected hepatic cancer is facilitated by intensive chemotherapy

This prospective study was undertaken to evaluate the efficacy of continuous-infusion doxorubicin and cisplatin (CI-DOX/CPPD) for the treatment of children with incompletely resected hepatic cancer. Of the 46 evaluable patients, 32 had hepatoblastoma (70%) and 14 had hepatocellular carcinoma. Ten children had stage II tumors (microscopic residual), 25 were defined as stage III (gross residual), and 11 had distant metastasis (stage IV). Twelve patients underwent initial incomplete resection of their hepatic lesions and in the 34 others tumor biopsy specimens were obtained. Chemotherapy was administered and the majority of the children (70%) had an excellent clinical response with a decrease in both alpha-fetoprotein levels and measured tumor dimensions. The combination of CI-DOX/CPDD clearly facilitated surgical management, allowing for delayed hepatic resections in 20 of the 34 patients (59%) whose tumors were initially biopsied and considered to be unresectable. Overall survival in this study demonstrates a significant improvement in comparison to the historical controls. Twenty-one patients (46%) remain in complete clinical remission an average of 30 months following diagnosis (range, 17 to 40 months). The outcome of the children with hepatoblastoma was much better than those with hepatocellular carcinoma (63% v 17% survival). Survival of the 20 children who underwent delayed hepatic resections was not statistically different from the 12 patients whose hepatic tumors were removed at the initial laparotomy (41% v 58% survival). Although no obvious survival advantage was observed in those patients who underwent initial hepatic resections, there did appear to be an increased risk of postoperative complications in children whose tumors were resected following chemotherapy (8% v 25%).

Glucose utilization in the surgical newborn infant receiving total parenteral nutrition.

Glucose is the main source of nonprotein calories in total parenteral nutrition (TPN). However, its use has been associated with various nutritional, metabolic, and respiratory complications. The aim of this study was to determine, in the stable surgical newborn infant, the characteristics of carbohydrate metabolism, in particular the maximum oxidative threshold for intravenous glucose and the thermogenic effect of glucose. Twenty-one studies were done on 11 infants (weight 2.82 +/- 0.19 kg) receiving TPN containing constant amounts of amino acids (2.5 g/kg/d) and fat (3.0 g/kg/d), and different amounts of glucose (range, 10 to 25 g/kg/d). Oxygen consumption (VO2), carbon-dioxide production (VCO2), and resting energy expenditure (REE) were measured by indirect calorimetry. Urinary nitrogen excretion rate was measured and substrate utilization calculated from the nonprotein respiratory quotient (NPRQ). There was a positive correlation between the predictor variable glucose intake and the dependent variables VO2 (r = .55; P < .05), VCO2 (r = .83; P < .0001), REE (r = .65; P < .005), NPRQ (r = .94; P < .0001), respiratory rate (r = .46; P = .06), and plasma triglycerides level (r = .67; P < .01). When glucose intake exceeded 18 g/kg/d the NPRQ was greater than 1.0, indicating glucose conversion to fat. Above this level of intake, the gradient of the correlation between the predictor variable glucose intake and the dependent variables VCO2 and REE increased. From this study we conclude that: (1) Glucose intake is the principal determinant of glucose utilization and exerts an influence on the metabolism of exogenous fat.(ABSTRACT TRUNCATED AT 250 WORDS)

Congenital Diaphragmatic Hernia-Does the Side of the Defect Influence the Incidence of Associated Malformations?

BACKGROUND/PURPOSE Patients with congenital diaphragmatic hernia (CDH) frequently have associated anomalies. Experiments in the nitrofen CDH model have shown differential embryonic cell death patterns in rodents suggesting unique mechanisms in the formation of right-sided (RCDH) or left-sided (LCDH) diaphragmatic hernia. These findings provide insight into the pathogenesis of CDH and may aid our understanding on the spectrum of associated anomalies commonly observed in humans. This study therefore set out to test the hypothesis that the side of the diaphragmatic defect in humans is related to the incidence and severity of coexistent organ malformations. METHODS The medical and autopsy records of 301 CDH patients presenting to two institutions over a 23-year period were examined to analyze these factors. RESULTS One hundred patients (33%) were found to have one or more associated anomalies. The incidence of multiple-RCDH (10%) versus LCDH (7.3%) and cardiac anomalies-RCDH (10%) versus LCDH (8.5%) was similar in both groups of patients. However, the hypoplastic heart syndrome was a unique feature in 5 of 22 patients (23%) with LCDH who had cardiac abnormalities. This cardiac anomaly may be related developmentally to LCDH. CONCLUSION The cellular mechanisms underlying the genesis of this spectrum of abnormalities in humans and the nitrofen CDH model warrant further study to elucidate factors governing embryonic cell fate and phenotype expression.

Evolving experience in the management of empyema thoracis

The optimal management of paediatric empyema thoracis remains controversial. The objective of the study was to analyse evolving experience in clinical presentation, management, outcome and factors contributing to adverse morbidity in thoracic empyema. Forty‐seven patients presenting to a paediatric surgical centre were studied in three consecutive 6‐y periods during 1980‐97 to compare any change in the pattern of disease influencing diagnosis and management. Patients were categorized into two treatment groups: (i) conservative management (antibiotics and/or tube thoracostomy), (ii) thoracotomy. The median duration of illness prior to hospital admission was 10 d (range 1‐42 d). Ultrasound was increasingly utilized in the diagnosis and staging of empyema and played an important role in directing definitive management. The presence of loculated pleural fluid determined the need for thoracotomy. Sixteen of 20 patients (80%) who were initially treated with thoracocentesis or tube thoracostomy eventually needed thoracotomy. There was a positive shift in management towards early thoracotomy resulting in prompt symptomatic recovery. Significant complications were noted in seven children who had delayed thoracotomy. These included recurrent empyema with lung abscess (n= 2), scoliosis (n= 2), restrictive lung disease (n= 1), bronchopleural fistula (n= 1) and sympathetic pericardial effusion (n= 1). An unfavourable experience with delayed thoracotomy during the study period has led us to adopt a more aggressive early operative approach to empyema thoracis. The decision to undertake thoracotomy has been influenced by the ultrasound findings of organized loculated pleural fluid. Delayed surgery was associated with adverse outcome.

Effect of prenatal glucocorticoids on pulmonary vascular muscularisation in nitrofen-induced congenital diaphragmatic hernia☆☆☆

BACKGROUND/PURPOSE Pulmonary hypertension (PH) contributes significantly to the mortality of congenital diaphragmatic hernia (CDH). Pulmonary vascular changes in CDH include a reduced vascular bed with increased arterial medial wall thickness and peripheral extension of muscle into intraacinar vessels. Antenatal steroids improve biochemical immaturity, lung compliance, and morphology in experimental CDH animals. The aim of this study was to examine the effects of prenatal glucocorticoid therapy on pulmonary artery muscularisation in CDH rats. METHODS CDH was induced in fetal rats by the maternal administration of 100 mg of nitrofen by gavage on day 9.5 of gestation (term, day 22). Control animals received olive oil (OO). Dexamethasone (Dex, 0.25 mg/kg) or normal saline (NS) was given by intraperitoneal injection on days 18.5 and 19.5, and fetuses were delivered by caesarean section on day 21.5. Lung sections from five fetuses in each of four experimental groups were studied by a blinded investigator- OO-NS controls, CDH-NS, CDH-Dex, and non-CDH-NS. The external diameter (ED), medial wall thickness (MT), percent of medial wall thickness, and wall structure were evaluated from preacinar arteries accompanying conducting airways, and the intraacinar arterioles associated with the respiratory bronchi and saccules. RESULTS In the preacinar arteries, CDH-NS animals had a significantly increased MT percentage compared with OO-NS controls (21.2+/-8.8 v 17.8+/-10.3, P = .0001). CDH-Dex rats had a lower MT percentage than CDH-NS rats (15.5+/-6.7 v 21.2+/-8.8, P = .0001). In the intraacinar region, CDH-Dex fetuses had a reduced percentage of muscularised intraacinar blood vessels compared with CDH-NS and OO-NS controls (10% v 24% and 28%, respectively, P = .01). Dexamethasone-treated CDH pups also displayed a significantly lower MT percentage of the intraacinar arteries compared with CDH-NS and OO-NS animals (15.7+/-13 v 23.4+/-9 and 25.4+/-12, P = .003). CONCLUSIONS Medial hypertrophy is present in the preacinar but not the intraacinar blood vessels of CDH rats before birth. Dexamethasone inhibits medial hypertrophy and reduces the number of muscularised intraacinar vessels. Antenatal glucocorticoids may reduce the risk of PH developing in human newborns with antenatally diagnosed CDH.

Time-dependent effects of endothelin-3 on enteric nervous system development in an organ culture model of Hirschsprung's disease.

BACKGROUND/PURPOSE Terminal colonic aganglionosis (Hirschsprung disease) results from incomplete rostrocaudal colonisation of the embryonic gut by neural crest cells (NCC). Mutations in the genes encoding endothelin-3 (EDN3) or its receptor (EDNRB) have been shown to result in a similar aganglionosis. This article describes the development of an organ culture model using embryonic murine gut to determine how endothelin-3 regulates development of the enteric nervous system. METHODS Gut explants from mice of different gestational ages were cultured for up to 3 days in the presence or absence of 5 micromol/L of the specific endothelin-B receptor antagonist BQ788. EDN3 and EDNRB mRNA expression were analysed by reverse-transcription polymerase chain reaction (RT-PCR) and whole-mount in situ hybridisation. NCC were localised using immunoreactivity for PGP 9.5, a specific neuronal marker. RESULTS EDN3 mRNA continued to be expressed by caecal mesenchymal cells and EDNRB mRNA by the migrating NCC in culture. Embryonic day (E)11.5 explants were already colonised by NCC up to the terminal ileum. Complete colonisation occurred in organ culture over the next 72 hours (equivalent to E 14.5). Explants of E 12.5 and E 13.5 showed complete colonisation after 48 and 24 hours culture, respectively. Terminal aganglionosis resulted from treatment of E 11.5 and E 12.5 gut explants with 5 micromol/L BQ788, whereas there was no inhibitory effect on E 13.5 explants. CONCLUSIONS An organ culture model has been developed in which NCC colonisation of embryonic gut mirrors that described in vivo. Blockade of the EDN3/EDNRB receptor pathway shows that the interaction of endothelin-3 with its receptor is only necessary for NCC colonisation at early time-points, despite the continued expression of endothelin-3 mRNA in the gut.