Getting the data right: information accuracy in pediatric emergency medicine.

OBJECTIVES: (1) To identify the extent to which information provided by parents in the pediatric emergency department (ED) can drive the assessment and categorization of data on allergies to medications, and (2) to identify errors related to the capture and documentation of allergy data at specific process level steps during ED care. METHODS: An observational study was conducted in a pediatric ED, combining direct observation at triage, a structured verbal interview with parents to ascertain a full allergy history related to medications, and chart abstraction. A comparative standard for the allergy history was established using parents' interview responses and existing guidelines for allergy. Errors associated with ED information management of allergy data were evaluated at five steps: (1) triage assessment, (2) treating physician's discussion with parent, (3) treating nurse's discussion with parent, (4) use of an allergy bracelet, and (5) documentation of allergy history on medication order sheets. RESULTS: 256 parent-child dyads were observed at triage; 211/256 parents (82.4%) completed the structured verbal interview that served as the basis for the comparative standard (CS). Parents reported a total of 59 medications as possible allergies; 56 (94.9%) were categorized as allergy or not based on the CS. Twenty eight of 48 patient cases were true allergies by guideline based assessment. Sensitivity of triage for detecting true medication allergy was 74.1% (95% confidence interval (CI) 53.7 to 88.9). Specificity of triage personnel for correctly determining that no allergy existed was 93.2% (95% CI 88.5 to 96.5). Physician and nursing care had performance gaps related to medication allergy in 10-25% of cases. CONCLUSIONS: There are significant gaps in the quality of information management regarding medication allergies in the pediatric ED.

Role of interferon gamma in the pathogenesis of primary respiratory syncytial virus infection in BALB/c mice.

Immunologic mechanisms are thought to contribute to the pathogenesis of respiratory syncytial virus (RSV) bronchiolitis in humans. RSV-infected BALB/c mice exhibit tachypnea and signs of outflow obstruction, similar to symptoms in humans. Interferon gamma (IFNgamma) has been found to be the predominant cytokine produced in humans and mice with RSV infection. We therefore undertook this study to evaluate the role of IFNgamma in the development of respiratory illness in RSV-infected mice. BALB/c mice were infected with RSV, and lung function was assessed by plethysmography. Bronchoalveolar lavage (BAL) fluids were analyzed for the concentration of interferon gamma (IFNgamma) and the presence of inflammatory cells, and lung tissue sections were examined for histopathologic changes. The role of IFNgamma was further addressed in studies of IFNgamma knock-out mice (IFNgamma(-/-)) and of mice depleted of IFNgamma by in vivo administration of a neutralizing antibody. After infection, mice developed respiratory symptoms that were strongly associated with the number of inflammatory cells in BAL, as well as with the concentrations of IFN-gamma. Both IFN-gamma(-/-) mice and mice treated with anti-IFNgamma developed more extensive inflammation of the airways than control mice. However mice lacking IFNgamma exhibited less severe signs of airway obstruction. Together these data suggest a protective role of IFNgamma in RSV infection in terms of limiting viral replication and inflammatory responses but also a pathogenic role in causing airway obstruction.

Primary respiratory syncytial virus infection: pathology, immune response, and evaluation of vaccine challenge strains in a new mouse model.

Respiratory syncytial virus (RSV) is the primary cause of lower respiratory tract illness in young children. Vaccine development has been hampered by the experience of the formalin-inactivated vaccine tested in the 1960's. Currently, several vaccine candidates are under development and immune response to these candidate vaccines must be evaluated closely. We introduce a novel low-dose murine model of RSV infection and a new pathologic scoring system for the resultant pulmonary disease. We have also developed new sensitive methods for measuring cytokine expression. We then used this new model to test vaccine challenge strains of RSV in order to determine their pathogenicity.

Heterotrimeric G proteins physically associated with the lipopolysaccharide receptor CD14 modulate both in vivo and in vitro responses to lipopolysaccharide.

Septic shock induced by lipopolysaccharide (LPS) triggering of cytokine production from monocytes/macrophages is a major cause of morbidity and mortality. The major monocyte/macrophage LPS receptor is the glycosylphosphatidylinositol (GPI)-anchored glycoprotein CD14. Here we demonstrate that CD14 coimmunoprecipitates with Gi/Go heterotrimeric G proteins. Furthermore, we demonstrate that heterotrimeric G proteins specifically regulate CD14-mediated, LPS-induced mitogen-activated protein kinase (MAPK) activation and cytokine production in normal human monocytes and cultured cells. We report here that a G protein binding peptide protects rats from LPS-induced mortality, suggesting a functional linkage between a GPI-anchored receptor and the intracellular signaling molecules with which it is physically associated.

Anticapsular polysaccharide antibodies and nasopharyngeal colonization with Streptococcus pneumoniae in infant rats.

To evaluate the effect of passive immunization with anticapsular antibodies on nasopharyngeal carriage, two models of Streptococcus pneumoniae colonization were developed in infant rats. In a direct inoculation model, 3- to 4-day-old infant rats were intranasally inoculated with 2 x 10(5) cfu of S. pneumoniae type 3 or 6 x 10(3) cfu of S. pneumoniae type 23F. In an intralitter transmission model, 2 infant rats were intranasally inoculated with 10(3) cfu of pneumococcus type 3 or type 19F and placed in a cage containing 10 infant rats. Pretreatment with bacterial polysaccharide immune globulin led to a significant reduction in colonization of contact animals with S. pneumoniae type 3 or 19F in the intralitter transmission model (P < .05). No effect of immune globulin could be demonstrated in the direct inoculation model. These results indicate that systemic anticapsular antibodies conferred significant protection against nasopharyngeal acquisition by intralitter spread of S. pneumoniae type 3 and 19F.

Minimum protective serum concentrations of pneumococcal anti-capsular antibodies in infant rats.

Infant rats were passively immunized to determine the protective capacity of pneumococcal anticapsular antibodies. Animal-passaged strains of Streptococcus pneumoniae serotypes 1, 4, 5, 6b, 7f, 9v, 14, 18c, 19f, and 23f were used as challenge inocula (1-1500 cfu) in a model of pulmonary infection that resulted in bacteremia, meningitis, and death. From untreated control animals, histologic sections of lung demonstrated infiltrative pneumonia and lung homogenate cultures grew S. pneumoniae at concentrations of 10(3)-10(8) cfu per gram of lung tissue. A type-specific anti-capsular antibody serum concentration of 0.1-1.15 microg/mL resulted in a statistically significant reduction in mortality compared with the reduction in untreated controls, except for serotype 14, which required 2.32 microg/mL for a significant reduction in mortality. The serum antibody level that provided 50% reduction in mortality ranged from 0.1-3.5 microg/mL for all serotypes.

Activated protein C concentrate for the treatment of meningococcal endotoxin shock in rabbits.

To evaluate the effects of activated protein C therapy in a rabbit model of meningococcal endotoxin-induced shock, we performed a prospective, blinded, placebo-controlled animal trial. Forty New Zealand White rabbits were challenged with intravenous meningococcal endotoxin (lipooligosaccharide) 100 microg/kg. Ten minutes before endotoxin challenge, animals were administered either activated protein C 1600 microg/mL (n = 20) or an equal volume of saline (n = 20) as an initial bolus. After endotoxin challenge, activated protein C treated animals were administered a continuous infusion of activated protein C 160 microg/kg/h and saline-treated animals were administered an equal volume infusion of saline. Both activated protein C treated and saline control animals demonstrated evidence of shock after endotoxin challenge; mean arterial pressure and serum bicarbonate significantly (p < .01) declined, and heart rate significantly (p < .01) increased from baseline. In activated protein C treated animals, mean plasma activated protein C activity was 5.69 microg/mL (+/- 3.2) 1 h after challenge, whereas plasma protein C activity was not detected in controls. Mean prothrombin and activated partial thromboplastin times were significantly (p < or = .01) prolonged compared with saline-treated controls. Other hematologic and chemical measurements did not differ between groups. Fifteen of 20 (75%) animals treated with activated protein C concentrate survived to 24 h, while 9 of 20 (45%) control animals survived to 24 h (p = .05). Those animals treated with activated protein C had improved survival, which corroborates the findings of early clinical studies in which replacement of protein C improved outcome.

Development of a model of low-inoculum Streptococcus pneumoniae intrapulmonary infection in infant rats.

We have developed a model of low-inoculum Streptococcus pneumoniae infection in infant rats. We challenged 4-day-old Sprague-Dawley pups via intraperitoneal or intrapulmonary injection of S. pneumoniae serotypes 1, 3, 4, 5, 6b, 7f, 9v, 14, 19f, and 23f. To achieve bacteremia with low inocula, it was necessary to passage the isolates in rats. Inocula of the 10 S. pneumoniae serotypes producing bacteremia in 50% or more animals ranged from 1 to 400 CFU. Virulence was similar by intraperitoneal and intrapulmonary routes. Lung specimens from animals challenged by the intrapulmonary route grew S. pneumoniae and demonstrated histologic evidence of focal infection. Meningitis was detected in 20 to 50% of bacteremic animals, and mortality invariably followed bacteremia within 24 to 48 h. This model of intrapulmonary infection uses low inocula of S. pneumoniae and results in bacteremia, meningitis, and death in infant rats.

Incidence of bacteremia in infants and children with fever and petechiae.

OBJECTIVE: We determined the incidence of serious invasive bacteremia caused by Neisseria meningitidis and other organisms in febrile infants and children with a petechial rash. Further, we studied the diagnostic value of laboratory and clinical finding in these patients. STUDY DESIGN: We conducted this prospective cohort study in the emergency department of an urban pediatric teaching hospital, during an 18-month period, and enrolled consecutive patients with temperature of 38 degrees C or higher and petechiae. Our measures included (1) laboratory tests (leukocyte count, coagulation profile, blood culture, and cerebrospinal fluid bacterial culture); (2) a questionnaire requesting clinical data including general appearance, number and location of petechiae, and presence or absence of purpura; and (3) a follow-up telephone survey documenting health status. RESULTS: A total of 411 patients were enrolled, with 57.7% between 3 and 36 months of age. Eight patients (1.9%) had bacteremia or clinical sepsis. Six had serious invasive bacteremia: N. meningitidis (two patients), group A streptococcus (one), or sepsis with negative culture results (three). Two had occult bacteremia caused by Streptococcus pneumoniae and no evidence of sepsis. No patient had a positive cerebrospinal fluid culture result. None of the 357 well-appearing patients (95% confidence interval: 0.0%, 1.0%) had serious invasive bacteremia. Fifty-three patients appeared ill, including all six with serious invasive bacteremia. Ill appearance of the child had a sensitivity of 1.00 (95% confidence interval: 0.60, 1.00), and a leukocyte count of 15,000 or greater, or of less than 5000, had a sensitivity of 1.0 (95% confidence interval: 0.53, 1.00) for detecting serious invasive bacteremia. All children with meningococcemia had purpura. CONCLUSIONS: Invasive bacteremia occurred less frequently in our study than in previous series and was identified by clinical criteria. Our data support the treatment of selected well-appearing children with fever and petechiae as outpatients.

A comparison of bactericidal/permeability-increasing protein variant versus recombinant endotoxin-neutralizing protein for the treatment of Escherichia coli sepsis in rats .

OBJECTIVE: To compare a recombinant bactericidal/permeability-increasing protein variant and a recombinant endotoxin-neutralizing protein. DESIGN: Randomized, blinded, controlled study, using a rat model of sepsis. SETTING: Animal research facility. SUBJECTS: Male Wistar rats. INTERVENTIONS: An inoculum of 1.5 x 10(7) to 1.8 x 10(8) Escherichia coli O18ac K1, implanted in the peritoneum, produced bacteremia in 95% of animals after 1 hr. One hour after E. coli challenge, animals received recombinant bactericidal/permeability-increasing protein variant, recombinant endotoxin-neutralizing protein, or saline intravenously, followed by ceftriaxone and gentamicin intramuscularly. MEASUREMENTS AND MAIN RESULTS: Twenty-four (85.7%) of 28 animals receiving recombinant endotoxin-neutralizing protein (p < .001 vs. control) survived 7 days compared with nine (33.3%) of 27 recombinant bactericidal/permeability-increasing protein variant-treated (p < .001 vs. control) and two (6.5%) of 31 control animals. CONCLUSIONS: Both recombinant endotoxin-neutralizing protein and recombinant bactericidal/permeability-increasing protein variant improved survival. Recombinant endotoxin-neutralizing protein was superior to recombinant bactericidal/permeability-increasing protein variant in its protective effect at the doses tested. Our results suggest that both proteins may be useful in the treatment of human Gram-negative sepsis.

High-dose recombinant endotoxin neutralizing protein improves survival in rabbits, with Escherichia coli sepsis.

OBJECTIVE: To assess the benefit of a recombinant endotoxin neutralizing protein from Limulus polyphemus in treating Gram-negative bacterial sepsis in rabbits. DESIGN: Prospective, blinded, controlled, laboratory trial. SETTING: Animal research laboratory. SUBJECTS: New Zealand White rabbits. INTERVENTIONS: We established a rabbit model of Escherichia coli peritonitis and bacteremia, with high mortality rate, despite treatment with gentamicin and ceftriaxone. Twenty-five pairs of male New Zealand White rabbits were challenged intraperitoneally with E. coli O18ac K1 in 5% porcine mucin (mean 7 x 10(1) colony-forming units). All animals were treated with intravenous gentamicin (2.5 mg/kg) and ceftriaxone (100 mg/kg), and with either intravenous endotoxin neutralizing protein (50 mg/kg) or saline 1 hr after E. coli challenge. MEASUREMENTS AND MAIN RESULTS: All animals were bacteremic 1 hr after challenge (mean 3.6 x 10(5) colony-forming units/mL). Animals in both groups developed tachycardia, hypotension, and acidosis (NS). Geometric mean serum endotoxin and tumor necrosis factor (TNF) concentrations were significantly ( p < .001) higher 1 hr after challenge compared with baseline prechallenge concentrations in both groups. From 1 to 2 hrs after challenge, endotoxin concentrations increased 2.5-fold in control animals (95% confidence interval = 13.1 to 32.9 endotoxin units/mL, p = .024), whereas endotoxin concentrations increased only 1.2-fold in endotoxin neutralizing protein-treated animals (95% confidence interval = 20.4 to 23.6 endotoxin units/mL, NS). TNF concentrations increased significantly (p < .001) in both groups from 1 to 2 hrs after challenge. Eighteen (72%) of 25 endotoxin neutralizing protein-treated animals vs. 11 (44%) of 25 controls survived 24 hrs (p = .032). CONCLUSIONS: Treatment with endotoxin neutralizing protein had the following effects: a) the increase in serum endotoxin was blunted, but not TNF concentrations measured 1 hr after antibiotic treatment; and b) survival in rabbits with E. Coli sepsis was improved.

Pneumomediastinum in childhood asthma.

The objective of this study was to examine the presentation and clinical course of patients with asthma and pneumomediastinum (PNMD). A retrospective chart review was performed from a computer-generated list of all patients discharged from an urban children's hospital between 1981 and 1991 with the diagnoses of asthma and PNMD. Thirty cases and 30 controls with asthma, matched for age and sex, were identified. The incidence of PNMD and asthma was 0.3%. Mean age was 11.8 years with a male:female ratio of 1.15:1. Chest pain was reported in 27% of patients and 13% of controls (P = 0.17). There was no difference in presenting respiratory rate, heart rate, or systolic blood pressure between cases and controls, nor was there a difference in respiratory distress by modified Wood-Downes scale. Fifty percent of patients had room air oxygen saturation measured at presentation. There was a significant difference in mean oxygen saturation between those with PNMD and those without (90.4 vs 94.1 %; P = 0.03). Subcutaneous emphysema was detected in 73% of cases versus none in controls (P < 0.001; positive predictive value (PPV) = 100%). Sixty-seven percent of patients with PNMD had repeat radiographs during hospitalization. Of these x-rays, 85% showed no change in, improvement, or complete resolution of the PNMD. Three patients (15%) developed a small increase in the PNMD. No patient developed pneumothorax, pneumopericardium, or deterioration in cardiovascular status. PNMD is a rare complication of asthma. Subcutaneous emphysema was the most useful predictor of PNMD in asthma. Chest pain and diminished oxygen saturation should heighten suspicion. Further complications of PNMD were exceedingly rare, and all patients recovered uneventfully, suggesting that attention to excellent treatment for the acute exacerbation may be sufficient in most instances of PNMD.

Failure of prophylactic and therapeutic use of a murine anti-tumor necrosis factor monoclonal antibody in Escherichia coli sepsis in the rabbit.

OBJECTIVE: To determine the efficacy of a murine anti-tumor necrosis factor (TNF) monoclonal antibody in the treatment of Escherichia coli peritonitis and sepsis in the rabbit. DESIGN: Prospective, paired, randomized, blinded, controlled animal trial. SETTING: Animal research laboratory. SUBJECTS: Male New Zealand white rabbits. INTERVENTIONS: Anesthetized rabbits were cannulated with indwelling femoral arterial and venous catheters. Peritonitis and sepsis were induced by intraperitoneal challenge using live E. coli O18ac bacteria. All animals were treated with gentamicin and ceftriaxone 1 hr after challenge. One group (prophylaxis experiment) consisting of ten rabbit pairs (the prophylaxis group), was treated with either murine anti-TNF monoclonal antibody or an equivalent volume of 5% albumin 3 hrs before E. coli challenge. A second group (therapeutic experiment) of 17 rabbit pairs, the treatment group, was also treated with murine anti-TNF monoclonal antibody or albumin control 1 hr after E. coli challenge. MEASUREMENTS AND MAIN RESULTS: All animals were bacteremic 1 hr after challenge. Physiologic measures of sepsis (heart rate, mean arterial pressure, serum bicarbonate, and arterial pH) did not differ between control, prophylaxis, and treatment groups. Peak serum TNF concentration was significantly (p < .01) lower in animals receiving anti-TNF monoclonal antibody, in both the prophylaxis and treatment groups, than in control animals. The survival rate was not improved significantly in either the prophylaxis or treatment group. CONCLUSIONS: Prophylactic and therapeutic use of anti-TNF monoclonal antibody in a rabbit model of E. coli peritonitis and sepsis significantly lowers TNF concentrations but does not ameliorate the physiologic effects of sepsis and does not significantly improve survival.