Ultrase MT12 and Ultrase MT20 in the treatment of exocrine pancreatic insufficiency in cystic fibrosis: safety and efficacy.

BACKGROUND: Cystic fibrosis causes exocrine pancreatic insufficiency, leading to malabsorption. Supplemental pancreatic enzyme therapy alleviates the concomitant malnutrition experienced by cystic fibrosis patients. It is recognized that patients experience variations in clinical response to different brands of enzymes. This has prompted the US Food and Drug Administration to require that enzyme supplements be subjected to New Drug Applications. AIM: To investigate the safety and efficacy of supplemental pancreatic enzyme therapy in cystic fibrosis subjects. METHODS: We compared two doses of one formulation of enteric-coated pancreatic enzymes: Ultrase MT12 (12,000 lipase units per capsule) and Ultrase MT20 (20,000 lipase units per capsule), to placebo in two separate safety and efficacy studies. RESULTS: Mean total fat, protein and carbohydrate intake did not differ significantly between the groups. A significant difference in both fat and protein absorption occurred with the enzyme therapy groups. The Ultrase MT12 and Ultrase MT20 groups experienced a mean fat and protein absorption 79.4% and 83.8%, and 87.3% and 88.6%, respectively. No adverse events related to study drug were reported. CONCLUSIONS: This study further supports the use of enzymes to treat pancreatic insufficiency in cystic fibrosis. Excellent fat and protein absorption was achieved with minimal adverse events and safe doses.

Spirometric pulmonary function in healthy preschool children.

The purpose of this study was to evaluate spirometric lung function in normal children ages 3 to 6 yr. Spirometric measurements were obtained at nursery and daycare centers by experienced pediatric pulmonary function technicians. Of 307 children recruited, 259 fulfilled our criteria as normal. Of these, 82.6% (214) were able to perform technically acceptable and reproducible maneuvers during a testing session limited to 15 min. The regression model with log-transformed parameters of pulmonary function and height had the best correlations. After accounting for height in the model, other physical traits and health questionnaire items did not contribute significantly. PEFR, FVC, FEV1, and FEF25-75 all increased with increasing height; correlation coefficients were 0.73, 0.93, 0.92, and 0.67, respectively. The group mean coefficients of variation for replicate measurements of PEFR, FVC, FEV1, and FEF25-75 were 7.8%, 2.5%, 2.7%, and 8.3%, respectively. There was a significant decrease in the ratio FEV1/FVC with increasing height; the mean predicted FEV1/FVC was 0.97 at 90 cm height and 0.89 at 125 cm height. In conclusion, reproducible spirometry can be obtained in the majority of preschool children and has the potential to improve our assessment and management of pulmonary disease.

Medical care of the adolescent with asthma.

Asthma is the most common chronic disease in adolescents. Despite advances in the understanding of this disease and the availability of more specific treatment, the prevalence of asthma and its morbidity and mortality are increasing. This trend is especially prominent and worrisome in the age group that includes adolescents and young adults. Possible factors contributing to this significant problem in adolescents include a lack of knowledge about the disease, delays in seeking medical attention due to denial of symptoms or overuse of acute relief medication that mask the progression of the inflammation, and various psychological problems such as low self-esteem or depression. These factors, in addition to the typical developmental behaviors recognized in adolescence, contribute to the complexity of asthma management in this age group. This article comprehensively reviews the pathophysiology and precipitating factors of asthma as well as all aspects of medical care of affected individuals, including monitoring and self-care.

Factors associated with self-concept in children with asthma.

PURPOSE: To investigate the relationship of demographic asthma, family, and child factors with self-concept in children with asthma. METHODS: Data were collected twice approximately 4 years apart from both the affected children and their mothers (N = 134) via interviews and self-report questionnaire. FINDINGS: Children who demonstrated more negative attitudes toward their illness, had less satisfaction with family relationships, and used more negative coping behaviors had the poorest self-concepts. Over time, the greatest improvement in self-concept occurred in children whose attitudes and satisfaction with family relationships improved and whose use of negative coping behaviors decreased. CONCLUSIONS: Results suggest that some children with asthma, especially girls with severe asthma, appear to be at risk for poor self-concept.

Current concepts on interstitial lung disease in children.

Pediatric interstitial lung disease comprises a diverse group of rare conditions characterized by an infiltrative process, abnormal gas exchange, and restrictive lung disease. Although the disorder is similar to its adult counterpart, its course is complicated by the continued need for lung growth and differentiation in infants and children. Knowledge about the pathogenesis, prognosis, and treatment of pediatric interstitial lung disease is limited. Investigators are focusing on defining the cellular mediators of the interstitial damage and describing the role of viral infections in and possible genetic predisposition to interstitial lung disease. Clinicians continue to define the various types of interstitial lung disease and to evaluate the roles of bronchoalveolar lavage, radiography, and biopsy in diagnosis. Together, investigators are working toward the development of specific, targeted therapy that will reduce the significant morbidity and mortality seen in pediatric interstitial lung disease.

Common pleural effusions in children.

The evaluation of pleural effusions in children differ from that of the adult in cause, symptom presentation, character of the fluid, techniques for diagnosis, treatment or management, and prognosis. These similarities and differences are reviewed with emphasis on the treatment of empyema.

Role strain in couples with and without a child with a chronic illness: associations with marital satisfaction, intimacy, and daily mood.

This study examined marital role strain in 33 couples caring for a child with cystic fibrosis (CF) and 33 couples with a healthy child. The relationship between role strain, marital satisfaction, and psychological distress was tested. Couples completed a structured interview, questionnaires, a card sort procedure, and 4 daily diaries assessing activities and mood. Couples in the CF versus comparison group reported greater role strain on measures of role conflict, child-care tasks, and exchanges of affection. They also spent less time in recreational activities, but no reliable group differences were found in marital satisfaction or depression. Regression analyses indicated that role strain was related to marital satisfaction and depression and that recreation time accounted for additional variance. Path analysis suggested that recreation mediated the negative relationship between role strain and distress. The importance of using a contextual, process-oriented approach is discussed.

Effect of smaller droplet size of dornase alfa on lung function in mild cystic fibrosis. Dornase Alfa Nebulizer Group.

Aerosolized recombinant human DNase (dornase alfa) reduces mucus viscoelasticity in vitro and improves pulmonary function in patients with cystic fibrosis (CF). We postulated that if dornase alfa could be delivered more peripherally to small airways in the lung in the form of smaller aerosol droplets in patients with early airway obstruction, the increase in pulmonary function from baseline might be improved. CF patients (n = 749) with mild lung disease (baseline forced vital capacity > or = 70% predicted) were randomly assigned to receive dornase alfa 2.5 mg daily for 2 weeks by one of two nebulizer systems: 1) the Medic-Aid Durable SideStream nebulizer powered by the MobilAire Compressor (SS/MA) producing a droplet size with a mass median aerodynamic diameter (MMAD) of 2.1 microm; or 2) the Hudson T Up-draft nebulizer with a DeVilbiss Pulmo-Aide compressor (HT/PA) with an MMAD of 4.9 microm. Spirometry was performed at baseline and following 14 days of treatment. Dornase alfa delivered by both nebulizer systems produced small but statistically significant improvements in pulmonary function compared with baseline. There was a trend (P = 0.06) toward greater improvement in forced expiratory flow in 1 s in the SS/MA group (4.3%) compared with the HT/PA group (2.5%). These results indicate that the short-term spirometric response to dornase alfa is influenced in part by the physical characteristics of the aerosol in patients with mild lung disease. We speculate that this may be true for other therapeutic aerosols, and it appears that localization of disease in the lung plays a role in the response to inhaled agents.

Status asthmaticus.

Despite improved understanding of the pathophysiology and treatment of asthma, significant morbidity and mortality exist for both the pediatric and adult patient. The critical care practitioner must understand the chronic as well as the acute nature of the condition in order to provide effective intervention. This article reviews the epidemiology and pathophysiology of asthma, clinical assessment, management principles, therapeutic modalities, and future approaches to the management of asthma.

Lower respiratory illness in infants and young children with cystic fibrosis: evaluation of treatment with intravenous hydrocortisone.

The purpose of our study was to assess the effect on pulmonary function of adding intravenous hydrocortisone to the standard treatment of infants with cystic fibrosis (CF) hospitalized for lower respiratory illnesses (LRI). Twenty CF infants were randomized and received 10 days of hydrocortisone (10 mg/kg/day) or placebo in addition to standard treatment with intravenous antibiotics, chest physiotherapy, and an aerosolized beta-agonist with cromolyn. Functional residual capacity (FRC) and forced expiratory flows (V'mak,FRC) were measured on admission, on Day 10 of hospitalization, and as outpatients 1-2 months following hospital discharge. Pulmonary function values were adjusted for differences in body length and expressed as Z-scores. Upon admission flows were decreased, and FRC was increased in both groups; there were no differences between the groups. The change in pulmonary function from admission to Day 10 of hospitalization was not different for the two groups. From admission to outpatient follow-up after hospitalization, there was a significant increase in flows for the steroid group, but not for the placebo group. In addition, the direction of change in FRC was significantly different for the two groups; the steroid group had a small decrease in FRC, while the placebo group had a small increase in FRC. These findings suggest that the addition of intravenous hydrocortisone to the standard treatment of CF infants hospitalized for a LRI may produce a greater or a more sustained improvement in lung function following hospitalization.

Aerosolized recombinant human DNase in hospitalized cystic fibrosis patients with acute pulmonary exacerbations.

The goal of this study was to evaluate the safety and efficacy of recombinant human DNase (rhDNase) in hospitalized patients with cystic fibrosis (CF) experiencing acute pulmonary exacerbations. Eighty patients with documented CF were enrolled at 11 CF centers when admitted for antibiotic therapy. Patients were at least 5 yr old with a forced vital capacity (FVC) > or = 35% of predicted and an oxygen saturation > or = 90% on a fraction of inspired oxygen (FIO2) < 0.5. Patients were randomized to receive rhDNase 2.5 mg in 2.5 ml excipient twice a day (n = 43) or 2.5 ml excipient alone twice daily (n = 37) along with conventional treatment for exacerbations. Administration of rhDNase was not associated with acute adverse events or deaths, and no patients experienced allergic or anaphylactic reactions. Although forced expiratory volume in one second (FEV1) and FVC improved in both treatment groups during the double-blind period, there were no statistically significant differences in the mean change from baseline in FEV1 or FVC between the two groups. rhDNase therapy is safe and well tolerated in CF patients with acute exacerbations requiring hospitalization, but the study did not demonstrate a statistically significant therapeutic effect of rhDNase when added to a regimen of antibiotics and chest physical therapy.

Development of the role-play inventory of situations and coping strategies for parents of children with cystic fibrosis.

Critiqued previous conceptual and methodological approaches to the measurement of stress and coping. Applied Goldfried and D'Zurilla's behavior-analytic model to create a context-specific measure of problematic situations and coping strategies for parents of school-age children with cystic fibrosis (CF). The sample was stratified by child's gender and illness severity. Forty-seven families (46 mothers, 32 fathers) and 8 health care professionals completed structured interviews or daily diaries to obtain the widest range of problematic situations; 1,725 situations were elicited across all participants and then content-analyzed into 97 nonredundant categories in 11 domains (e.g., Discipline, Medical Care). Few differences were found in problem frequency or difficulty as a function of either gender or illness severity. Using empirical criteria, the most frequent and difficult problem situations were selected and developed into role-play vignettes that include relevant contextual, developmental, and interactional details. The Role-Play Inventory of Situations and Coping Strategies (RISCS) consists of 31 audiotaped vignettes designed to elicit and evaluate the coping strategies used by parents of children with CF.

TNF-alpha, IL-8, soluble ICAM-1, and neutrophils in sputum of cystic fibrosis patients.

The cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8), and intercellular adhesion molecule-1 (ICAM-1) have important roles in regulating neutrophil migration and the inflammatory response. To determine whether the concentration of these cytokines and soluble ICAM-1 (sICAM-1) in sputum was increased in patients with cystic fibrosis during acute exacerbations, we conducted (1) a cross-sectional study of 40 patients, 22 who were clinically well and 18 with acute pulmonary exacerbations; and (2) an 11 months longitudinal study of 16 patients. Significant differences in clinical scores, pulmonary function, and sputum neutrophil density were found between the acutely ill and the well group. There was a strong linear relationship (P < 0.0005) between TNF-alpha and IL-8 concentrations in sputum, but no association between clinical status and cytokine concentrations. The concentration of sICAM-1 was lower in acutely ill compared with well patients in the cross-sectional study. Recovery of exogenous IL-8 added to sputum was complete, while recovery of TNF-alpha averaged 70%. Recovery of exogenous sICAM-1 was only 43%, and the recoveries were lower in sputum samples from acutely ill patients than those from stable patients (P = 0.018). These data indicate that in cystic fibrosis patients, sputum concentrations of TNF-alpha and IL-8 are not increased during acute exacerbations of pulmonary inflammation.

The effect of nedocromil sodium on childhood asthma during the viral season.

Viral-induced symptomatic respiratory infections (SRI) frequently cause exacerbations of asthma in children. This study investigated the protective effects of 0.5% nedocromil sodium nebulizer solution given three times a day in preventing asthma exacerbations associated with SRI. Ninety-three mild-moderate asthmatic children (6 to 12 yr of age) received either 0.5% nedocromil sodium or placebo for 24 wk during the viral season. The nedocromil sodium group was symptom-free 58% of the days, and the placebo-treated patients were symptom-free 45% of the days (p = 0.027). During Weeks 1-12, significant differences favored nedocromil sodium for asthma summary score (means: nedocromil sodium = 0.61, placebo = 0.92; p = 0.026), and daytime asthma (nedocromil sodium = 0.78, placebo = 1.22; p = 0.03). Significant differences were noted during monthly intervals for cough (Weeks 1-4: nedocromil sodium = 0.61, placebo = 0.92, p = 0.027) and peak expiratory flow rate (PEFR) (nedocromil sodium 262, placebo = 254 L/min, p = 0.041 Weeks 9-12). Patients in the active treatment group reduced their need for rescue inhaled beta 2-agonist by 10%, whereas patients treated with placebo demonstrated a 24% increase. There was a strong correlation between asthma symptoms and SRI symptoms (r = 0.47; p < 0.001). During SRIs, patients in the nedocromil sodium group demonstrated more rapid resolution of asthma symptoms immediately following infection (p = 0.033 summary score, p = 0.039 sleep difficulty). No serious adverse events were noted. Nedocromil sodium did not prevent the infection or exacerbation of asthma symptoms during SRI.(ABSTRACT TRUNCATED AT 250 WORDS)

A multicenter study of alternate-day prednisone therapy in patients with cystic fibrosis. Cystic Fibrosis Foundation Prednisone Trial Group.

The purpose of this study was to evaluate the efficacy and safety of alternate-day prednisone therapy in treating patients with mild-to-moderate cystic fibrosis during a 4-year period. In 15 North American cystic fibrosis centers, we screened 320 patients and enrolled 285 patients from April 1986 to December 1987. Patients were randomly assigned to take prednisone, 1 mg/kg per dose or 2 mg/kg per dose, or a matching placebo given on alternate days. Lung function, clinical status, hospitalizations, growth, and steroid side effects were monitored. During the first 24 months the percentage of the predicted forced vital capacity was greater in the 1 mg/kg group (p < 0.0001) and the 2 mg/kg group (p < 0.01) when each was compared with placebo. Patients in the 1 mg/kg group had a higher percentage of predicted forced vital capacity than placebo patients during the entire 48 months (p < 0.0025), but only in the group of patients who were colonized with Pseudomonas aeruginosa at baseline. For 48 months, the 1 mg/kg group had a higher percentage of predicted forced expiratory volume in 1 second than patients given placebo (p < 0.02). The prednisone-treated groups had a reduction in serum IgG concentrations (1 mg/kg vs placebo, p < 0.007; 2 mg/kg vs placebo, p < 0.003). From 6 months onward, height z scores fell in the 2 mg/kg group compared with those given placebo (p < 0.001). For the 1 mg/kg group, height z scores were lower from 24 months. An excess of abnormalities in glucose metabolism was seen in the 2 mg/kg group compared with the placebo group (p < 0.005). Our findings suggest a role for alternate-day prednisone therapy at a dose of 1 mg/kg in patients with mild to moderate cystic fibrosis. The benefit of improved lung function appears to outweigh the potential for adverse effects when the treatment period is less than 24 months.

Heightened airway responsiveness in normal female children compared with adults.

Studies have suggested that airway responsiveness declines with maturation; however, studies comparing infants, children, and adults are confounded by differences in size as well as maturation. Therefore, to determine whether maturation has a significant affect on airway responsiveness, we compared normal female children (n = 9; mean age = 13.6 yr) and adults (n = 7; mean age = 42.4 yr) who were matched for body size. Bronchial challenge tests were performed with increasing methacholine concentrations to a maximum of 30 mg/ml. At baseline, there were no significant differences between the two groups in lung volumes (TGV, RV, TLC) or flow-volume curves (FEV1, average forced expiratory flow rate between 25% and 75% of the vital capacity [FEF25-75], FVC). All subjects but one adolescent completed the challenge (30 mg/ml). The children had a greater percentage decline from baseline in FEV1 than the adults (17 versus 7%, p < 0.03). The percentage decline in FEF25-75 was greater for the children than for the adults, but the difference was not statistically significant (35 versus 20%, p < 0.10). Compared with the children, the adults more often demonstrated a plateau in their dose-response curves for FEV1 (22 versus 86%) and for FEF25-75 (33 versus 100%). We conclude that normal female children have a greater airway responsiveness to inhaled methacholine than do adults, and that this difference is not related to baseline lung size, airway caliber, or delivered methacholine dose.

Bronchodilator responsiveness in infants with bronchiolitis.

We evaluated 34 infants with bronchiolitis, (17 of both genders; mean age, 4.6 mos; ranges, 0.7-14.5 mos). The 20 inpatients were significantly younger than the 14 outpatients (2.6 vs. 8.2 months, P < 0.05), and more females were inpatients. Forced expiratory flows at functional residual capacity (VmaxFRC) were obtained at baseline, after aerosolized normal saline (NS), and metaproterenol (0.025 mL/kg in 2 mL NS). Flows were expressed as Z-scores, the difference between the measured and predicted flows, divided by the standard deviation for the predicted value. At baseline, outpatients were more obstructed than inpatients (-1.64 vs. -0.95, P < 0.05), infants > 2 months old were more obstructed than infants < or = 2 months old (-1.54 vs. -0.80, P < 0.05), and males more than females (-1.45 vs. -1.02, P < 0.05). Following NS the whole group had a small but significant decrease in Z-scores (-1.23 to -1.31, P < 0.05). Following metaproterenol, the younger infants had significantly (P < 0.05) higher Z-scores compared to baseline and NS (-0.80 vs. -0.86 vs. -0.59). However, no significant changes occurred in older infants. Females also had an increased flow after metaproterenol and were less obstructed than after NS (-1.11 vs. -0.86, P < 0.015). In males no increased flows occurred after metaproterenol (-1.45 vs. -1.48). Bronchodilator responsiveness did not relate to severity of airway obstruction, history of family asthma, allergy, or passive smoke exposure. We conclude that inhaled metaproterenol improves airway function in a subgroup of infants with bronchiolitis, but the subgroup could not clearly be identified because age and gender were confounding factors.