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Frederick E Barr

Publications and source records attributed to Frederick E Barr.

9 recordsLinked to original sources
PubMed2006

Genetic variation in the mitochondrial enzyme carbamyl-phosphate synthetase I predisposes children to increased pulmonary artery pressure following surgical repair of congenital heart defects: a validated genetic association study.

Increased pulmonary artery pressure (PAP) can complicate the postoperative care of children undergoing surgical repair of congenital heart defects. Endogenous NO regulates PAP and is derived from arginine supplied by the urea cycle. The rate-limiting step in the urea cycle is catalyzed by a mitochondrial enzyme, carbamoyl-phosphate synthetase I (CPSI). A well-characterized polymorphism in the gene encoding CPSI (T1405N) has previously been implicated in neonatal pulmonary hypertension. A consecutive modeling cohort of children (N=131) with congenital heart defects requiring surgery was prospectively evaluated to determine key factors associated with increased postoperative PAP, defined as a mean PAP>20 mmHg for at least 1h during the 48h following surgery measured by an indwelling pulmonary artery catheter. Multiple dimensionality reduction (MDR) was used to both internally validate observations and develop optimal two-variable through five-variable models that were tested prospectively in a validation cohort (N=41). Unconditional logistic regression analysis of the modeling cohort revealed that age (OR=0.92, p=0.01), CPSI T1405N genotype (AC vs. AA: OR=4.08, p=0.04, CC vs. AA: OR=5.96, p=0.01), and Down syndrome (OR=5.25, p=0.04) were independent predictors of this complex phenotype. MDR predicted that the best two-variable model consisted of age and CPSI T1405N genotype (p<0.001). This two-variable model correctly predicted 73% of the outcomes from the validation cohort. A five-variable model that added race, gender and Down's syndrome was not significantly better than the two-variable model. In conclusion, the CPSI T1405N genotype appears to be an important new factor in predicting susceptibility to increased PAP following surgical repair of congenital cardiac defects in children.

Carbamoyl-Phosphate Synthase (Ammonia)↗
PubMed2006

Clinical trial design--effect of prone positioning on clinical outcomes in infants and children with acute respiratory distress syndrome.

PURPOSE: This paper describes the methodology of a clinical trial of prone positioning in pediatric patients with acute lung injury (ALI). Nonrandomized studies suggest that prone positioning improves oxygenation in patients with ALI/acute respiratory distress syndrome without the risk of serious iatrogenic injury. It is not known if these improvements in oxygenation result in improvements in clinical outcomes. A clinical trial was needed to answer this question. MATERIALS AND METHODS: The pediatric prone study is a multicenter, randomized, noncrossover, controlled clinical trial. The trial is designed to test the hypothesis that at the end of 28 days, children with ALI treated with prone positioning will have more ventilator-free days than children treated with supine positioning. Secondary end points include the time to recovery of lung injury, organ failure-free days, functional outcome, adverse events, and mortality from all causes. Pediatric patients, 42 weeks postconceptual age to 18 years of age, are enrolled within 48 hours of meeting ALI criteria. Patients randomized to the prone group are positioned prone within 4 hours of randomization and remain prone for 20 hours each day during the acute phase of their illness for a maximum of 7 days. Both groups are managed according to ventilator protocol, extubation readiness testing, and sedation protocols and hemodynamic, nutrition, and skin care guidelines. CONCLUSIONS: This paper describes the process, multidisciplinary input, and procedures used to support the design of the clinical trial, as well as the challenges faced by the clinical scientists during the conduct of the clinical trial.

Adolescent↗
PubMed2006

Nitric oxide precursors and congenital heart surgery: a randomized controlled trial of oral citrulline.

OBJECTIVE: The study sought to determine whether citrulline supplementation, a precursor to nitric oxide synthesis, is safe and efficacious in increasing plasma citrulline concentrations and decreasing the risk of postoperative pulmonary hypertension. STUDY DESIGN: Forty children, undergoing cardiopulmonary bypass and at risk for pulmonary hypertension, were randomized to receive 5 perioperative doses (1.9 g/m2 per dose) of either oral citrulline or placebo. Plasma citrulline and arginine concentrations were measured at 5 time points. Measurements of systemic blood pressure and presence of pulmonary hypertension were collected. RESULTS: Median citrulline concentrations were significantly higher in the citrulline group versus the placebo group immediately postoperatively (36 micromol/L vs 26 micromol/L, P = .012) and at 12 hours postoperatively (37 micromol/L vs 20 micromol/L, P = .015). Mean plasma arginine concentrations were significantly higher in the citrulline group versus the placebo group by 12 hours postoperatively (36 micromol/L vs 23 micromol/L, P = .037). Mean systemic blood pressure did not differ between groups (P = .53). Postoperative pulmonary hypertension developed in 9 patients, 6 of 20 (30%) in the placebo group and 3 of 20 (15%) in the citrulline group (P = .451), all of whom had plasma citrulline concentrations less than age-specific norms. Postoperative pulmonary hypertension did not develop in patients who demonstrated plasma citrulline concentrations in excess of 37 mumol/L (P = .036). CONCLUSIONS: Oral citrulline supplementation safely increased plasma citrulline and arginine concentrations compared with placebo after cardiopulmonary bypass. Postoperative pulmonary hypertension did not occur in children with naturally elevated citrulline levels or elevations through supplementation. Oral citrulline supplementation may be effective in reducing postoperative pulmonary hypertension.

Administration, Oral↗
PubMed2005

Effect of prone positioning on clinical outcomes in children with acute lung injury: a randomized controlled trial.

CONTEXT: In uncontrolled clinical studies, prone positioning appeared to be safe and to improve oxygenation in pediatric patients with acute lung injury. However, the effect of prone positioning on clinical outcomes in children is not known. OBJECTIVE: To test the hypothesis that at the end of 28 days infants and children with acute lung injury treated with prone positioning would have more ventilator-free days than those treated with supine positioning. DESIGN, SETTING, AND PATIENTS: Multicenter, randomized, controlled clinical trial conducted from August 28, 2001, to April 23, 2004, of 102 pediatric patients from 7 US pediatric intensive care units aged 2 weeks to 18 years who were treated with supine vs prone positioning. Randomization was concealed and group assignment was not blinded. INTERVENTION: Patients were randomized to either supine or prone positioning within 48 hours of meeting acute lung injury criteria, with those patients in the prone group being positioned within 4 hours of randomization and remaining prone for 20 hours each day during the acute phase of their illness for a maximum of 7 days, after which they were positioned supine. Both groups were treated using lung protective ventilator and sedation protocols, extubation readiness testing, and hemodynamic, nutrition, and skin care guidelines. MAIN OUTCOME MEASURE: Ventilator-free days to day 28. RESULTS: The trial was stopped at the planned interim analysis on the basis of the prespecified futility stopping rule. There were no differences in the number of ventilator-free days between the 2 groups (mean [SD], 15.8 [8.5] supine vs 15.6 [8.6] prone; mean difference, -0.2 days; 95% CI, -3.6 to 3.2; P = .91). After controlling for age, Pediatric Risk of Mortality III score, direct vs indirect acute lung injury, and mode of mechanical ventilation at enrollment, the adjusted difference in ventilator-free days was 0.3 days (95% CI, -3.0 to 3.5; P = .87). There were no differences in the secondary end points, including proportion alive and ventilator-free on day 28 (P = .45), mortality from all causes (P>.99), the time to recovery of lung injury (P = .78), organ-failure-free days (P = .88), and cognitive impairment (P = .16) or overall functional health (P = .12) at hospital discharge or on day 28. CONCLUSION: Prone positioning does not significantly reduce ventilator-free days or improve other clinical outcomes in pediatric patients with acute lung injury.

Adolescent↗
PubMed2004

Computerized physician order entry and medication errors in a pediatric critical care unit.

OBJECTIVE: Medication errors are a major concern of health care professionals and medical institutions, especially errors involving children. Studies in adults have shown that computerized physician order entry (CPOE) systems reduce medication errors and adverse drug events (ADEs). The effect of CPOE implementation in a pediatric population has not been reported. The objective of this study was to evaluate the impact of CPOE on the frequency of errors in the medication ordering process in a pediatric critical care unit (PCCU). METHODS: A prospective trial was conducted of 514 pediatric patients who were admitted to a 20-bed PCCU in a tertiary-care children's hospital before and after implementation of CPOE. Medication errors were identified after review of all orders during the study period and then further classified as potential ADEs, medication prescribing errors (MPE), and rule violations (RV). RESULTS: A total of 13 828 medication orders were reviewed. Before implementation, potential ADEs occurred at a rate of 2.2 per 100 orders, MPEs at a rate of 30.1 per 100 orders, and RVs at a rate of 6.8 per 100 orders. After implementation, the rate of potential ADEs was reduced to 1.3 per 100 orders, MPEs to 0.2 per 100 orders, and RVs to 0.1 per 100 orders. The overall error reduction was 95.9%. Potential ADEs were reduced by 40.9%, and MPEs and RVs were reduced by 99.4% and 97.9%, respectively. CONCLUSIONS: The implementation of CPOE resulted in almost a complete elimination of MPEs and RVs and a significant but less dramatic effect on potential ADEs.

Child↗
PubMed2003

Ethnic diversity in a critical gene responsible for glutathione synthesis.

The tripeptide glutathione is an important biomolecule that acts as a scavenger of free radicals and plays a role in a number of other cellular processes. A number of diseases, including Parkinson's disease, cancer, sickle cell anemia, and HIV infection, are thought to involve oxidative stress and depletion of glutathione. The heterodimeric enzyme glutamate cysteine ligase catalyzes the first, rate-limiting step in the de novo synthesis of glutathione. Functional polymorphisms within the gene encoding the subunits of glutamate cysteine ligase have the potential to affect the body's capacity to synthesize glutathione and thus, may affect those diseases in which oxidative stress and glutathione have roles. We undertook systematic screening for polymorphisms within the exons and intronic flanking sequences of the gene encoding the catalytic subunit of glutamate cysteine ligase (GCLC). We identified 11 polymorphisms in GCLC and established allele frequencies for those polymorphisms in a population fitting the demographics of the middle Tennessee area. The nonsynonymous polymorphism C1384T was found only in individuals of African descent. In addition, allele frequencies for three other polymorphisms differ between Caucasians and African-Americans. Understanding these polymorphisms may lead to better understanding of diseases where glutathione is important so that better treatments may be developed.

Ethnicity↗
PubMed2003

Effect of cardiopulmonary bypass on urea cycle intermediates and nitric oxide levels after congenital heart surgery.

OBJECTIVE: To test the hypothesis that cardiopulmonary bypass used for repair of ventricular septal defects and atrioventricular septal defects would decrease availability of urea cycle intermediates including arginine and subsequent nitric oxide availability. STUDY DESIGN: Consecutive infants (n = 26) undergoing cardiopulmonary bypass for repair of an unrestrictive ventricular septal defect or atrioventricular septal defect were studied. Blood samples were collected immediately before surgery, immediately after surgery, and 12 hours, 24 hours, and 48 hours after surgery. Urea cycle intermediates, including citrulline, arginine, and ornithine, were measured by amino acid analysis. Nitric oxide metabolites were measured by means of the modified Griess reaction. RESULTS: Cardiopulmonary bypass caused a significant decrease in the urea cycle intermediates arginine, citrulline, and ornithine at all postoperative time points compared with preoperative levels. The ratio of ornithine to citrulline, a marker of urea cycle function, was elevated at all postoperative time points compared with preoperative values, indicating decreased urea cycle function. Nitric oxide metabolites were significantly decreased at all postoperative time points except for 48 hours, compared with preoperative levels. CONCLUSIONS: Cardiopulmonary bypass significantly decreases availability of arginine, citrulline, and nitric oxide metabolites in the postoperative period. Decreased availability of nitric oxide precursors may contribute to the increased risk of postoperative pulmonary hypertension.

Arginine↗
PubMed2003

Fatal pulmonary hypertension associated with pertussis in infants: does extracorporeal membrane oxygenation have a role?

OBJECTIVE: The deaths of 4 infants who had confirmed pertussis infection at our hospital during the past year motivated us to review their cases as well as the use of extracorporeal membrane oxygenation (ECMO) in respiratory failure caused by pertussis. METHODS: Retrospective chart reviews of the 4 infants who had pertussis and died at Vanderbilt University Medical Center (VUMC) from May 2001 to May 2002 were conducted. The Extracorporeal Life Support Organization (ELSO) database is an international voluntary registry established in 1986 to compile passive reports of adult and pediatric patients placed on ECMO. We searched this database for pertussis cases and analyzed the clinical outcomes by age, ventilatory management, and measurements of cardiopulmonary status. RESULTS: All 4 infants who died from pertussis infection at VUMC were younger than 3 months and had severe pulmonary hypertension, and ECMO therapy was considered for respiratory failure. Review of the international ELSO database, focusing only on children from 1986 to July 2002, revealed a total of 23,970 patients placed on ECMO. Since the first pertussis case treated with ECMO in 1990, a total of 61 children with pertussis have been treated with ECMO, representing an increase from 0.09% to 1% of the total cases. Mean age of the pertussis patients placed on ECMO was 88 days (1 day-2.7 years). The overall mortality was 70.5% (43 of 61) but was significantly higher for infants who were younger than 6 weeks (84%) compared with infants who were older than 6 weeks (61%). When evaluating pre-ECMO management, survivors had received significantly higher mean positive end expiratory pressures than nonsurvivors (11.1 +/- 4.5 vs 7.3 +/- 3.1 cmH(2)O) and had significantly higher serum pH than nonsurvivors (7.31 +/- 0.14 vs 7.14 +/- 0.19). There was no effect of duration of ECMO, positive inspiratory pressure, mean arterial pressure, ECMO mode (venoarterial vs venovenous mode), or sex on mortality. CONCLUSIONS: Although the ECMO registry is not an active surveillance system, it suggests that the numbers of children who require ECMO for pertussis have significantly increased. The high fatality rates of pertussis patients who have placed on ECMO are alarming and should stimulate reevaluation of whether this high-risk intervention is beneficial to patients with pertussis. This review, coupled with the 4 infants who died of pertussis at VUMC, suggests that improved measures are needed to prevent pertussis in infants.

Extracorporeal Membrane Oxygenation↗