Differential effects of hyperoxia on the inducible and constitutive isoforms of nitric oxide synthase in the lung.

Hyperoxia is commonly used in the treatment of newborn respiratory distress. Although essential and life saving, oxygen therapy can result in the development of lung injury. Oxygen toxicity is associated with the production of reactive oxidant species. Nitric oxide (NO) is an oxidant formed by the catalysis of L-arginine when acted upon by the enzyme nitric oxide synthase (NOS). We studied the differential effects of prolonged normobaric hyperoxia (FIO2 = .95, for 3, 4, and 5 days) on the two major NOS enzymes, constitutive endothelial cell NOS (ecNOS) and inducible NOS (iNOS). Hyperoxia led to a significant lung injury, as measured by pulmonary compliance studies. Hyperoxia did not increase serum NO production, measured as the concentration of nitrite and nitrate. However, hyperoxia did result in a small but significant increase in NO production in the bronchoalveolar lavage fluid, as measured by the products of nitrite and nitrate concentration. This increase in NO was not associated with an induction of whole lung iNOS, as measured by the conversion of L-[3H]arginine to L-[3H]citrulline or by Northern blot analysis. Hyperoxia significantly decreased ecNOS activity as measured by the conversion of L-[3H]arginine to L-[3H]citrulline. In addition, administration of the NOS inhibitor NG-nitro-L-arginine methyl ester worsened the injury, as measured by lung compliance and survival. Further studies need to be performed to determine whether this decrease in ecNOS activity during hyperoxia plays a role in the pathogenesis of hyperoxia-related lung injury.

Low-level expression and limited role for the inducible isoform of nitric oxide synthase in the vascular hyporeactivity and mortality associated with cecal ligation and puncture in the rat.

Expression of the inducible isoform of nitric oxide synthase (iNOS) contributes to the hypotension and vascular hyporeactivity in various models of shock induced by bacterial lipopolysaccharide (LPS). However, the role of iNOS in response to shock caused by live bacteria is more controversial. In the present study, we investigated the role of iNOS in a rat model of cecal ligation and puncture (CLP). CLP resulted in increased plasma nitrite/nitrate levels (up to 59 microM at 24 h) and increased pulmonary iNOS activity (up to 71 fmoles/mg/min at 12 h) and caused a significant vascular hyporeactivity at 18 h. The degree of NO production and iNOS induction was approximately 30% of that observed several hours after administration of LPS in the same species, and the degree of vascular hyporeactivity was less than that observed after LPS injection. Selective inhibition of iNOS with mercaptoethylguanidine (MEG) reduced plasma nitrite/nitrate levels, but did not prevent the development of vascular hyporeactivity, and did not improve survival in this model of CLP. Thus, CLP-induced sepsis causes low-level induction of iNOS, but factors other than iNOS are the crucial determinants of the vascular failure and mortality in this model.

Nitric oxide: an overview.

Nitric oxide (NO), a paracrine-acting gas enzymatically synthesized from L-arginine, is a unique biologic mediator that has been implicated in a myriad of physiologic and pathophysiologic states. It is an important regulator of vascular tone and may be the mediator of the hemodynamic changes involved in sepsis and cirrhosis. In addition, there is increasing evidence that NO is involved in coagulation, immune function, inhibitory innervation of the gastrointestinal tract, protection of gastrointestinal mucosa, and the hepatotoxicity of cirrhosis. It has already been speculated that NO may represent a point of control or intervention in a number of disease states. The purpose of this paper is to provide the surgeon with a broad overview of the scientific and clinical aspects of this important molecule.

Reconstruction of congenital chest-wall deformities.

Pectus deformities and Poland's syndrome are two relatively common congenital deformities of the chest wall that are amenable to reconstruction. The extent of the structural deformity in pectus deformity and the degree of associated cardiopulmonary dysfunction are critical variables in preoperative assessment. The operative approaches range from more extensive sternal eversion to the more popular subperichondrial cartilage resection with or without internal fixation. In Poland's syndrome, the options for reconstruction include anterior transfer of the ipsilateral latissimus dorsi muscle through a transaxillary tunnel and attachment to the clavicle and sternum. Submuscular insertion of a mammary prosthesis can be added in the female patient.

Long-chain predominant lipid emulsions inhibit in vitro macrophage tumor necrosis factor production.

Intravenous lipid emulsions are an important component of parenteral nutrition. Despite their benefits, lipid emulsions have been associated with higher rates of bacteremia in neonates. Therefore we investigated the effect of lipid emulsions on the inflammatory response by examining their effect on in vitro macrophage tumor necrosis factor (TNF) production of two distinct macrophage populations. Through the use of endotoxin-free phosphate buffered saline, peritoneal (PER) and alveolar (ALV) macrophages were isolated from male Sprague-Dawley rats (weighing 125 to 150 g) with endotoxin-free phosphate buffered saline. Cell counts were adjusted to 2 x 10(6) cells/mL in RPMI with 2% fetal calf serum. Three hundred microliters of the cells were incubated in a 24-well culture dish with media or media with intralipid (100 micrograms/dL) for 16 hours. After washing each well three times, the cells were stimulated for 2 or 16 hours with Escherichia coli lipopolysaccharide (150 microL of 1 microgram/mL). The supernatants were assayed for TNF using the WEHI 164:13 bioassay and TNF levels were expressed as picograms per milliliter. Student's unpaired t test was used for data analysis. Lipid-exposed PER and ALV macrophages in vitro TNF levels were significantly lower-after 2 hours (12,591 pg/mL +/- 3837 vs 20,591 pg/mL +/- 6344 for PER, 3894 pg/mL +/- 1258 vs 13,177 pg/mL +/- 3266 for ALV) and 16 hours (6427 pg/mL +/- 3050 vs 12,353 pg/mL +/- 4877 for PER; 131,6000 pg/mL +/- 7317 vs 354,680 pg/mL +/- 31,605 for ALV) of endotoxin stimulation. TNF production seems to be impaired in macrophages exposed to a .1% lipid emulsion for 16 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastroduodenal polyps in familial polyposis coli.

This endoscopic evaluation of 25 patients with familial polyposis coli (FPC) further establishes gastro-duodenal polyps as a significant extracolonic manifestation of the condition. Ten patients had polyps, distributed as follows: stomach (2), duodenum (4), stomach and duodenum (4). Altogether, there were six gastric and seven duodenal lesions. Half of the gastric tumors were hyperplastic and half were adenomatous. All the duodenal tumors were adenomatous, four being ampullary. The one symptomatic patient had intra-polypoid adenocarcinoma. There were no significant correlations between the endoscopic findings and patient age, sex, presence of colon cancer, or other extracolonic abnormalities. The authors affirm that gastroduodenal polyps are an important component of FPC and recommend that all patients with this condition undergo initial and follow-up gastroduodenoscopy. Multiple small lesions may be carefully monitored, but larger ones, particularly those in the region of the ampulla, must be excised.

Selective nonoperative management of pediatric blunt splenic trauma: risk for missed associated injuries.

The spleen is the most commonly injured organ in children sustaining blunt abdominal trauma. Although accepted in pediatric patients, nonoperative management of blunt splenic trauma in adults remains controversial. A principal concern of advocates of early operation is the possibility of overlooking a second injury. To evaluate this question in a pediatric population, we reviewed the charts of 120 children who had traumatic splenic injuries and were admitted to Children's Hospital Medical Center in Cincinnati between 1982 and 1990. Splenic injuries were documented by computed tomography scans, liver/spleen scintigraphy, or during laparotomy. One hundred twelve patients (93.3%) were initially managed nonoperatively; this regimen failed in 2 patients (1.8%), in whom a late splenectomy was required for bleeding. Of 8 patients (6.7%) for whom emergency surgery was required, 4 underwent splenectomy (2 had major associated injuries), 2 underwent splenorrhaphy, and 2 required no splenic repair. Fifty-nine patients (49.2%) had associated injuries, 22 of which (18.3%) were intraabdominal. In this study, there were no missed injuries and no morbidity or mortality associated with delayed treatment. These data confirm that the majority of children with blunt splenic injury can be successfully treated without surgery, and demonstrate that selective nonoperative management of splenic injuries in children does not increase the risk of missed associated injuries.

The interval between a septic stimulus and hypoxia/reoxygenation affects cytokine elaboration by murine peritoneal macrophages.

The critically ill patient is commonly exposed to various physiological insults. The authors have previously shown that in vivo hypoxia/reoxygenation (H/R) alters the pattern of cytokines elaborated by murine peritoneal macrophages given a septic stimulus. In this study they sought to determine whether the interval between a septic stimulus and H/R affected the release of inflammatory mediators by macrophages. Adult CBA-strain mice were injected intraperitoneally with 10 micrograms of lipopolysaccharide (LPS). On day 0, 1, 2, 3, 4, or 5 after LPS injection, animals were exposed to 16 hours of hypoxia followed by 2 hours of reoxygenation. Harvested peritoneal macrophages were restimulated in vitro with 2.5 micrograms/mL LPS or left unstimulated. Culture supernatants collected at 2, 4, 6, 8, 10, and 12 hours after LPS injection were assayed for tumor necrosis factor (TNF), prostaglandin E2 (PGE2), and nitric oxide (NO) production. Macrophage-derived mediator production peaked when H/R occurred 3 days following LPS injection (P < .05). These data suggest that the interval between sepsis and subsequent H/R influences the pattern of cytokines elaborated by peritoneal macrophages given a septic stimulus.

Selective inhibition of the inducible isoform of nitric oxide synthase prevents pulmonary transvascular flux during acute endotoxemia.

The inducible isoform of nitric oxide synthase (iNOS) is expressed in various organs, including the lung, during systemic endotoxemia. Overproduction of nitric oxide (NO) by iNOS contributes significantly to the vascular failure and end-organ damage in endotoxemia. Using selective pharmacological inhibitors of iNOS, the purpose of this study was to define the role of iNOS in a rat model of endotoxin-induced pulmonary transvascular flux (TVF). Lung TVF was assessed by a method of Evans Blue permeability index (PI). Bacterial lipopolysaccharide (LPS) (15 mg/kg intraperitoneally [IP]) significantly increased pulmonary iNOS activity and serum levels of nitrite/nitrate (NO2/NO3). This was accompanied by a significant elevation of the PI 5 hours after injection. Selective iNOS inhibition with either S-methyl isothiourea (SMT; 5 mg/kg IP) or aminoguanidine (AG; 20 mg/kg IP), administered 2 hours after LPS injection, significantly prevented the increase in PI associated with LPS injection. Similarly, inhibition of the induction of iNOS with dexamethasone (10 mg/kg IP), given 3 hours before LPS, also inhibited the increase in PI. All three treatments significantly prevented the increase in both lung iNOS activity and serum NO2/NO3 associated with endotoxemia. In conclusion, the overproduction of NO generated by iNOS during systemic endotoxemia causes a vascular leak in the lung. Thus, it is speculated that selective inhibition of iNOS may be beneficial in preventing the development of acute respiratory failure in sepsis.

Prostaglandin and tumor necrosis factor levels in early wound inflammatory fluid: effects of parenteral omega-3 and omega-6 fatty acid administration.

Monokines are important mediators of wound healing. Specifically, the proportions of proinflammatory (tumor necrosis factor and PGE2) and antiinflammatory (PGF2 alpha) monokines may modulate its early phases. Using a polyvinyl alcohol sponge model of rat wounding, the authors determined the temporal changes in the levels of monokines in wound inflammatory fluid, and examined whether dietary manipulation for 6 days with the precursors (omega 6 fatty acids) and inhibitors (fish oil omega 3 fatty acids) of the prostaglandin-2 series influenced monokine composition of wound fluid. For 3 days before the wounding, adult rats received isocaloric, isovolemic, and isonitrogenous total parenteral nutrition (TPN), in which lipids supplied either 35% (Intralipid [IL] or fish oil emulsion [FO]) or 8% (minimal essential fatty acid; EFA) of the total calories. Control rats received isocaloric enteral chow. The controls were studied at 24, 48, 72, and 96 hours, and the experimentals at 72 hours after wounding. Cell counts were performed, and cell-free fluid was analyzed for PGE2, PGF2 alpha, and TNF. In control rats, the total WBC count was highest at 24 to 48 hours, and decreased significantly by 96 hours. The percentage of mononuclear cells progressively increased throughout the 96 hours, and the total mononuclear cell count peaked at 72 hours. The TNF and prostaglandin levels were highest at 24 hours; these decreased rapidly by 72 hours. At all time-points, the levels of PGE2 remained higher than those of PGF2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Cervical spine injuries in children: a review of 103 patients treated consecutively at a level 1 pediatric trauma center.

PURPOSE: Cervical spine (C-spine) injuries occur infrequently in children but may be associated with significant disability and mortality. The purpose of this study was to review the experience of a level 1 pediatric trauma center to determine the epidemiology, risk factors, mechanisms, levels, types of injury, comorbid factors, and outcomes associated with these potentially devastating injuries. METHODS: A retrospective analysis of 103 consecutive C-spine injuries treated at a level 1 pediatric trauma center over a 9(1/2)-year period (January 1991 through August 2000) was performed. RESULTS: The mean age was 10.3 +/- 5.2 years, and the male-to-female ratio was 1.6:1. The most common mechanism of injury was motor vehicle related (52%), followed by sporting injuries (27%). Football injuries accounted for 29% of all sports-related injuries. Sixty-eight percent of all children sustained injuries to C1 to C4; 25% to C5 to C7; and 7% to both. Spinal cord injury without radiographic abnormality (SCIWORA) occurred in 38%. Five patients had complete cord lesions involving the lower C-spine (C4 to C7); 4 of these were motor vehicle related, and all 4 patients died. Isolated C-spine injuries occurred in 43%, whereas 38% had associated closed head injuries (CHI). The overall mortality rate was 18.5%, most commonly motor vehicle related (95%), occurring in younger children (mean and median age 5 years) and associated with upper C-spine injuries (74%) and CHI (89%). C1 dislocations occurred in younger children (mean age, 6.6 years), most often as a result of motor vehicle-related trauma (especially pedestrians) and were associated with the highest injury severity score (ISS), longest length of stay (LOS), most CHIs, and the highest mortality rate (50%). C-spine fractures with or without SCI occurred most commonly as a result of falls and dives. Sporting injuries occurred almost exclusively in adolescent boys (mean age, 13.8 years) and were isolated injuries associated with a relatively low ISS and shorter LOS. Interestingly, 75% of sporting injuries showed SCIWORA, and all infants suffering from child abuse had SCIWORA. CONCLUSIONS: Mechanisms of injury are age related, with younger children sustaining C-spine injuries as a result of motor vehicle-related trauma and older adolescents commonly injured during sporting activities. C-spine injuries in children most commonly involve the upper C-spine, but complete lesions of the cord are associated more frequently with lower C-spine injuries. The type of C-spine injury is related to the mechanism of injury: SCIWORA is associated with sporting activities and child abuse, C-spine dislocations most commonly result from motor vehicle-related trauma (especially among pedestrians), and C-spine fractures occur most commonly as a result of falls and dives. Predictors of mortality include younger age, motor vehicle-related mechanism, C1 dislocations, high ISS greater than 25, and associated CHI. A high index of suspicion for SCIWORA is essential when evaluating adolescents with neck trauma associated with sporting injuries or victims of child abuse.

Colon interposition for the short bowel syndrome.

A 5-mo-old male had disabling diarrhea and malabsorption following massive small bowel resection. His transit time was 10 min. After 9 mo of conservative treatment, a 24-cm isoperistaltic segment of colon was interposed 6.5 cm from the ligament of Treitz. Transit time was increased to 105 min, and he was eventually able to be maintained on an enteric diet without significant diarrhea. Colon interposition requires little manipulation of the remaining small intestine and does not rely on active intestinal obstruction to effect an increased transit time.

Acute pancreatitis and increased intracranial pressure.

A retrospective review of 41 patients with post-mortem evidence of acute pancreatitis revealed that 19 patients (46%) showed concomitant evidence of increased intracranial pressure (ICP). A prospective analysis of five patients with increased ICP demonstrated two patients with evidence of acute pancreatitis. The pathogenesis of acute pancreatitis in these patients appears to be dependent on the following risk factors: increased intracranial pressure, steroids, hypovolemia, morphine infusion and hypothermia. These factors increase vagal stimulation, predispose to pancreatic duct obstruction and enhance cellular hypoperfusion. Acute pancreatitis occurring in Reye's Syndrome is probably a consequence of increased ICP and the therapy instituted.

Percutaneous subclavian venous catheters in neonates and children.

There were 191 central venous catheters placed through the subclavian vein in 135 neonates and children over a 20-mo period, providing central venous access for a total of 4525 patient days. There were 132 (69.2%) catheters inserted in patients who were in their first year of life and 60 (31.4%) weighed less than 2.5 kg. The procedure was associated with a low technical complication rate. The greatest potential intermediate or long-term complication was the development of primary catheter sepsis that occurred in 11 (5.8%) of the catheters placed.

Antimicrobial therapy of Broviac catheter infections in pediatric hematology oncology patients.

Long-term therapy of pediatric oncology patients has been facilitated by permanent indwelling venous catheters. Over a 3-year period, 54 Broviac catheters were placed in 43 oncology patients and two hemophiliacs. There were 20 episodes of sepsis in 14 patients and the most common bacteria were S epidermidis (4), S aureus (4), and K pneumoniae (3). Catheter exit site infections occurred ten times in six patients; S aureus eight of ten. Antibiotic therapy without catheter removal was successful in 18 of 20 children with catheter sepsis and 8 of 10 patients with exit site infections. These data strongly suggest that although catheter-related infections are common, removal of Broviac catheters is not required for successful treatment of the infection.

Thoracic trauma in children: an indicator of increased mortality.

This study was undertaken to assess the significance of thoracic trauma as a marker of morbidity and mortality in children. During a 34-month period, 2,086 children younger than 15 years old were consecutively admitted to a Level I pediatric trauma center with blunt or penetrating trauma. For each child we prospectively recorded Trauma Score (TS), Injury Severity Score, (ISS), medical, and etiologic data. One hundred four children (4.4%) presented with thoracic trauma. The most common mechanisms of injury were pedestrian injury (36%), motor vehicle crashes (32%), and armed assault (12%). The most common injuries were pulmonary contusion (48%), pneumothorax, hemothorax, or pneumohemothorax (39%), and rib fractures (32%). Multisystem injury was present in 82% of the children. The mean TS and ISS were 11 and 27, respectively, significantly worse than scores for children without thoracic injury (15 and 7; P less than .0001). Seventy-one percent of the children were admitted to the intensive care unit, where they stayed an average of 6 days; 20% required surgery. The mortality rate was 26%. Injuries to the heart or great vessels had the highest mortality rate (75%), followed by hemothorax (53%), lung laceration (43%), and rib fracture (42%). Mortality for children with isolated chest injury was 5%, compared with rates of 20% for abdominal and chest trauma, 35% for head and chest trauma, and 39% for trauma to the head, chest, and abdomen. Less than 5% of the admissions to a pediatric trauma center incurred thoracic injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Absent peritoneal fluid on screening trauma ultrasonography in children: a prospective comparison with computed tomography.

BACKGROUND: Although the accuracy of focused abdominal sonography for trauma (FAST) in adults has been demonstrated, results of this technique in children have been conflicting with few comparisons against computed tomography (CT), the imaging gold standard. METHODS: A total of 160 hemodynamically stable pediatric trauma victims referred for abdominal CT initially underwent rapid screening sonography looking for free fluid. Both studies were interpreted in blinded fashion. RESULTS: Forty-four of the 160 patients had an intraabdominal injury on CT, 24 (55%) of which had normal screening sonography. Fifteen of the 44 (34%) had no free fluid on either modality. Accuracy of sonography compared with CT was 76% with a negative predictive value 81%. CONCLUSIONS: Sonography for free fluid alone is not reliable to exclude blunt intraabdominal injury in hemodynamically stable children given the considerable percentage of injured patients without free fluid. J Pediatr Surg 36:565-569.

Weanling and adult rats differ in fatty acid and carnitine metabolism during sepsis.

Increased oxidation of fat is an important host response to sepsis, and carnitine is essential for long-chain fatty acid oxidation. Because neonates have low levels of carnitine, their ability to respond to a septic insult may be impaired. The purpose of this study was to compare fatty acid and carnitine metabolism in septic weanling (60 to 85 g) and septic adult (285 to 310 g) rats. Sepsis was induced in weanling and adult male Sprague-Dawley rats by cecal ligation and puncture (CLP). The rats were killed 16 hours after CLP or sham operation, and serum glucose, lactate, beta-hydroxybutyrate, fatty acid, carnitine, liver fatty acid, and tissue carnitine levels were measured. The data suggest that during sepsis weanling rats may be more dependent on fatty acid oxidation than adult rats are, as evidenced by their elevated serum fatty acid and acylcarnitine levels, and relative hypoglycemia and hyperketonemia. In addition, although total serum carnitine levels were increased in both adult and weanling septic rats, tissue carnitine levels of weanling rats became significantly depleted during sepsis, unlike in adult rats. This study supports further investigation regarding the role of exogenous carnitine in newborn sepsis.

Patterns of injury in children.

Trauma is the leading cause of death for children over 1 year of age. This study was undertaken to identify the patterns of injury among children admitted to a regional pediatric trauma center. During a 34-month period, 3,472 injured children were consecutively admitted to a regional pediatric trauma center. Data were collected on medical, etiological, and financial aspects of injury. Eight subgroups were defined by mechanism of injury: motor-vehicle crash occupants, pedestrian and cycle injuries, falls, child abuse, gunshot and stab wounds, burns, poisonings, and foreign body ingestions or aspirations. Analysis of variance, Duncan's multiple range test, and contingency table analysis were used to determine differences among subgroups of children. Blunt and penetrating trauma accounted for 64.3% of all admissions. The mean age of injured children was 5.5 years; 64% of the children were boys. Sixty-seven percent of the children were admitted directly from the scene of injury. One-way analysis of variance yielded significant differences in mean age, mean hospital length of stay (LOS), mean intensive care LOS, mean trauma score, mean injury severity, and mean hospital charges by mechanism of injury (P less than .01). The overall mortality rate was 2.4%. Child abuse, gunshot/stab wounds, and drowning had the highest mortality rates, but injuries to motor-vehicle crash occupants and pedestrians accounted for the greatest number of deaths.

Complications of gastroesophageal antireflux surgery in neurologically impaired versus neurologically normal children.

Antireflux surgery was performed in 234 children over a 5-year period; 153 were neurologically impaired (NI) and 81 were neurologically normal (NN). Initial presentation, demographic data, and type of antireflux operation were similar in the two groups. Eighty-six percent of the NI group versus 30% of the NN group had gastrostomy tubes placed. The incidence of late postoperative complications was 26% in the NI group and 12% in the NN group (P less than .01). During the late postoperative period, NI children underwent reoperation four times as frequently as NN children (19% v 5%, respectively; P less than .01). Wrap herniation accounted for 38% of complications and 59% of reoperations in the late postoperative period. Mortality due to aspiration occurred in 9% of the NI group versus 1% of the NN group. Combined failure rate (reoperation plus aspiration-induced deaths) was 28% in NI and 6% in NN (P less than .01). We conclude that neurological status is the major predictor of operative success and that wrap herniation due to crural disruption is the most common cause of operative failure.