A genetic factor associated with low final bone mineral density in children after a long-term glucocorticoids treatment.

Treatment with glucocorticoids is associated with lower bone mineral density (BMD). We performed a genome-wide association study to analyze interactive effects between genotypes and cumulative dose of prednisone (PD) over 4.3 years of follow-up period on the final BMD Z-scores in 461 white children from the Childhood Asthma Management Program. No variants met the conventional criteria for genome-wide significance, and thus we looked for evidence of replication. The top 100-ranked single-nucleotide polymorphisms (SNPs) were then carried forward replication in 59 children with acute lymphoblastic leukemia (ALL) exposed to large fixed doses of PD as part of their chemotherapeutic regimen. Among them, rs6461639 (interaction P=1.88 × 10-5 in the CAMP population) showed a significant association with the final BMD Z-scores in the ALL population (P=0.016). The association of the ALL population was only present after correction for the anti-metabolite treatment arm (high vs low dose). We have identified a novel SNP, rs6461639, showing a significant effect on the final BMD Z-scores in two independent pediatric populations after long-term high-dose PD treatment.

Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma.

BACKGROUND: Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. METHODS: We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. RESULTS: Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). CONCLUSIONS: Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.).

Updates on the use of inhaled corticosteroids in asthma.

PURPOSE OF REVIEW: The purpose of this review is to compare and contrast the newer inhaled corticosteroid (ICS) ciclesonide with older ICSs in terms of pharmacodynamic and pharmacokinetic properties and how these affect comparative efficacy. In addition, clinical dosing strategies for ICSs including as-needed use will be explored. RECENT FINDINGS: Ciclesonide has demonstrated similar efficacy to that of fluticasone propionate and mometasone furoate in equipotent doses with a potentially improved therapeutic index. Once-daily administration of ICSs is generally not as effective as twice-daily. Continuous administration of ICSs does not change the natural history of asthma in either children or adults. Long-term administration of medium dose ICSs does not increase the risk of cataracts or osteopenia in children and young adults. Studies of as-needed ICSs in mild persistent asthma in adults and children have demonstrated mixed results, with some showing equal efficacy to continuous therapy and others showing superiority of continuous therapy. SUMMARY: Ciclesonide provides a newer ICS with favorable pharmacokinetics that may improve the therapeutic index, but assessment of its systemic effects such as growth await further studies. Continuous administration of ICSs in low to medium dose over many years is well tolerated. The use of as-needed ICSs in patients with mild persistent asthma is promising as a potential step-down therapy but awaits further studies.

Newness of drugs and use of HMO services by asthma patients.

OBJECTIVE: To define newness of drug technology and show associations between two measures of newness and health service utilization. METHODS: Healthcare use and changes in severity at each office visit were assessed for 1309 asthma patients from six health maintenance organizations (HMOs) during 1992. The age of each drug product, derived by subtracting its Food and Drug Administration (FDA) approval date from January 1, 1992, was used to construct two newness measures: the average age of all asthma drugs and, separately, all non-asthma drugs a patient used during the year and the percentages of a patient's asthma drugs from each of four time intervals of asthma drug breakthroughs. Service utilization variables included all primary care provider (PCP) visits, total prescription costs, emergency department (ED) visits, and hospitalizations. RESULTS: Using either measure of drug newness, multivariate analyses showed an association between greater use of newer asthma drugs and lower overall drug costs and fewer PCP visits. A trend was found between greater use of newer asthma drugs and fewer hospitalizations and ED visits. Newer non-asthma medications were associated with fewer ED visits. CONCLUSIONS: After controlling for patient and site variables, greater use of newer asthma drugs was associated with significantly lower drug costs and fewer PCP visits; associations with hospitalization rates and ED visits, although lower, were not significant.

Evaluation of particle size distribution of salmeterol administered via metered-dose inhaler with and without valved holding chambers.

BACKGROUND: Administration of inhaled medications to very young children is sometimes difficult. Administration of inhaled medications via metered dose inhalers (MDIs) to pediatric patients younger than 4 years of age requires use of a holding chamber/spacer with an attached facemask. OBJECTIVE: This in vitro study was conducted to determine the particle size distribution and overall dose of salmeterol delivered in conjunction with the use of various US-marketed valved holding chambers (VHCs) in comparison to the dose-delivered via MDI without VHCs. METHODS: Cascade impaction methodology with high-performance liquid chromatography was used to evaluate the fine particle mass (FPM) of salmeterol administered without and with the use of the following VHCs: Optichamber, medium and large Aerochambers, adult Aerochamber, and medium Aerochamber Plus. RESULTS: Particle size distributions for the Optichamber, various sizes of Aerochamber, and the Aerochamber Plus were very similar and the particle size distributions for all VHCs were similar to the distribution of the control. The FPM for particles ranging from 0.7 to <3.3 microm in diameter (in the range shown to provide the greatest lung dose to negotiate the small airways of infants) was similar across the various VHCs tested. Statistical comparison of the fine particle fraction for these stages shows a very similar profile when differences from the salmeterol MDI control were evaluated. CONCLUSIONS: In vitro results obtained under these test conditions demonstrate that all FPM values for the VHCs tested were within 15% of the control range, a difference that is unlikely to be clinically meaningful. These results indicate that the difference in FPM does not warrant a change in the recommended dosage of salmeterol administered when using the VHCs tested. Our results demonstrate that the use of an MDI and VHC provides a reasonable therapeutic approach for administration of salmeterol MDI to young children and other patients who have difficulties administering the MDI alone.

Correlation between reversibility of airway obstruction and exhaled nitric oxide levels in children with stable bronchial asthma.

Recent trials measuring exhaled nitric oxide (eNO) concentrations have suggested that it may be a useful measure of ongoing airway inflammation in patients with asthma. The purpose of this study was to examine the relationship between eNO levels and baseline as well as postbronchodilator spirometry, a measurement commonly used in the clinical setting to determine the severity of asthma and as a guide to therapeutic decisions. Forty-nine patients between the ages of 5-16 years with physician-diagnosed asthma who attended the pediatric pulmonary clinic for a routine asthma visit with spirometric evaluation were recruited for the study. eNO levels prior to spirometry were obtained before and after receiving inhaled beta(2) agonist. eNO samples were collected in impermeable bags (Tedlar) and assayed within 24 hr by chemiluminescence. Regression analysis was used to assess the relationships between pre- and postbronchodilator eNO and spirometric variables. eNO was also compared in patients receiving and not receiving inhaled corticosteroids (ICS), as well as those whose therapy had been increased after evaluation by a pediatric pulmonologist or allergist. We found no significant difference between the levels of eNO before and after inhalation of beta(2) agonist (P = 0.60 paired t-test). Positive correlation was found between eNO vs. percentage change in FEV(1) (r = 0.35, P = 0.01) and percentage change in FEF(25-75% )(r = 0.29, P = 0.04). A negative correlation was found between prebronchodilator FEV(1) and eNO (r = -0.29, P = 0.03). Patients on ICS had lower mean eNO levels (29.9 vs. 47.6 parts per billion (ppb), P = 0.053) than those not receiving ICS. Patients whose ICS therapy was increased had higher mean eNO levels (47.2 vs. 26.9 ppb, P = 0.018) than those not having ICS therapy increased. We suggest that eNO levels could be a clinically useful measurement of asthma severity and could be used as an adjunct to spirometry to determine appropriate treatment plans. Longitudinal clinical trials are needed to determine if eNO can enhance therapeutic decisions for asthmatic children.

Comparative potency and clinical efficacy of inhaled corticosteroids.

The inhaled corticosteroids (ICSs) are currently the most potent antiinflammatory drugs available for the long-term control of persistent asthma. Physico-chemical modifications of the basic steroid structure result in pharmacodynamic and pharmacokinetic properties that confer both enhanced topical efficacy and diminished systemic activity compared with older corticosteroids such as prednisolone. The purpose of this article is to compare the pharmacodynamic, pharmacokinetic, and lung delivery differences among the products and demonstrate how those differences translate into significant differences in the clinical effectiveness of the ICSs.

Establishing a therapeutic index for the inhaled corticosteroids: part I. Pharmacokinetic/pharmacodynamic comparison of the inhaled corticosteroids.

The inhaled corticosteroids contain physicochemical differences that alter both glucocorticoid receptor-binding characteristics and the pharmacokinetic variables of these drugs. Differences in receptor-binding affinity translate into differences in potency for different drugs. Differences in pharmacokinetics, however, determine the topical effect to systemic effect ratio, or the "pulmonary targeting" of the drug. Beneficial pharmacokinetic properties that may improve pulmonary targeting include low oral bioavailability, rapid systemic clearance, and slow absorption from the lung. Delivery devices can produce clinically significant differences in topical activity by altering the dose deposited in the lung and, for orally absorbed drugs, the amount deposited in the oropharynx and swallowed. Clinical trials have confirmed that differences in potency or drug delivery of 2-fold or more can be detected in patients with asthma. However, because of the relatively flat nature of the dose-response curve for morning peak expiratory flow and forced expiratory volume in 1 second, the trials must be adequately powered and well controlled. The use of bronchial provocation measures are problematic because of the prolonged lag time for response. Study design flaws can lead to misinterpretation of results. Clinical studies have indicated the following relative potency differences: fluticasone propionate > budesonide = beclomethasone dipropionate > triamcinolone acetonide = flunisolide. Current evidence suggests that potency differences can be overcome by giving larger doses of the less potent drug. However, because of these potency differences, studies of systemic effects should not be done in isolation of adequate topical activity studies to define the pulmonary targeting of the drugs.

Comparison of inhaled corticosteroids.

OBJECTIVE: To review the comparative studies evaluating both efficacy and safety of inhaled corticosteroids in the management of asthma. Specifically, comparative clinical trials are evaluated that allow clinicians to determine relative potencies of the various inhaled corticosteroids. METHODS: A critical review was performed of the published clinical trials, either as articles or abstracts, comparing the clinical efficacy or systemic activity of inhaled corticosteroids. No a priori criteria were applied, as this was not a meta-analysis. FINDINGS: In vitro measures of antiinflammatory activity of corticosteroids consistently demonstrate potency differences among the various corticosteroids. Traditionally, these in vitro measures have been used to develop new corticosteroids with greater topical activity. While no accepted direct measure of antiasthmatic antiinflammatory activity exists, clinical trials using surrogate measures (e.g., forced expiratory volume in 1 second, peak expiratory flow, bronchial hyperresponsiveness, symptom control) indicate that in vitro measures provide a relatively accurate assessment of antiasthmatic potency. The relative antiinflammatory potency of the inhaled corticosteroids is in the following rank order. flunisolide = triamcinolone acetonide < beclomethasone dipropionate = budesonide < fluticasone. Studies of systemic activity appear to confirm this relative order of potency. Currently, no evidence exists for greater efficacy for any of the inhaled corticosteroids when administered in their relative equipotent dosages. The preponderance of current data suggests that when administered in equipotent antiinflammatory doses as a metered-dose inhaler plus spacer or as their respective dry-powder inhaler, the existing inhaled corticosteroids have similar risks of producing systemic effects. CONCLUSIONS: Delivery systems can significantly affect both topical and systemic activity of inhaled corticosteroids. More direct comparative studies between agents are required to firmly establish comparative topical to systemic activity ratios. The preponderance of evidence suggests that the agents are not equipotent on a microgram basis.

Asthma pharmacotherapy: current practices and outlook.

Owing to its high incidence and rapidly increasing prevalence in the United States population, and to the billions of dollars in associated costs, asthma is a significant public health problem. A variety of pharmacologic agents exist to manage asthma, but their efficacies vary, as do their costs. Recently published guidelines on asthma management set forth a four-step approach that is guided by severity of disease and symptom control. These guidelines also suggest increased use of antiinflammatory agents, primarily inhaled corticosteroids, which carry a higher cost. Shifts in prescribing patterns among physicians who treat patients with asthma indicate that the guidelines are being adopted to some extent. However, some reluctance toward widespread use of corticosteroids remains, due to potential adverse effects as well as cost considerations. Alternatives to increased or high-dose corticosteroid use include combination therapy with long-acting bronchodilators. Newer medications that have more specific mechanisms of action, such as leukotriene synthesis inhibitors and leukotriene receptor antagonists, may offer another option.

Therapeutic aerosol delivery during mechanical ventilation.

OBJECTIVE: To provide an overview of aerosol drug delivery during mechanical ventilation in the pediatric and adult populations. DATA SOURCES: Published articles and abstracts identified in a MEDLINE search (1984-July 1994) were reviewed. STUDY SELECTION: All articles and abstracts found, including review articles, in vivo and in vitro studies, case reports, and case series pertaining to issues involving aerosol delivery during mechanical ventilation, were reviewed. No predetermined selection criteria were used to exclude studies. DATA EXTRACTION: Percent delivery of the starting dose to either the patients or the various in vitro lung models, as well as each variable possibly affecting delivery for each study, were tabulated for each study reviewed. DATA SYNTHESIS: The delivery of therapeutic aerosols to endotracheally intubated and mechanically ventilated patients presents a unique challenge for healthcare providers. Delivery can be affected by the diameter of the endotracheal tube and ventilator circuitry, type of ventilator, ventilator modes, type of delivery device, and how the delivery device is operated and introduced into the ventilator circuitry. The drug being aerosolized may behave differently from one delivery system to another. The proper operation of each device requires attention to positioning in the ventilator circuit as well as the mode of ventilation. CONCLUSIONS: No apparent advantage exists for metered-dose inhalers with a large-volume adapter over jet nebulizers, as each method of delivery is capable of similar efficiency (5-15%). Sufficient attention to detail, including the use of an efficient nebulizer and/or adapter and proper placement and operating method, is required to provide optimal delivery. For bronchodilator administration, careful monitoring of outcomes will provide the most optimal dosing schedule.

Determinants of aerosolized albuterol delivery to mechanically ventilated infants.

An in-vitro lung model and a volume ventilator were used to evaluate the delivery of aerosolized albuterol through an infant ventilator circuit. We compared the following: continuous nebulization (CNA) and intermittent nebulization (INA); various nebulizer gas flows, 5.0, 6.5,and 8.0 L/min; and duty cycle of 33% and 50%. The efficiency and consistency of aerosol delivery by metered-dose inhaler (MDI) with four different spacer devices and by nebulizer positioned at the manifold and at the same position as the MDI were also evaluated. A volume ventilator (Servo 900B) was used with settings selected to reflect those of a moderately to severely ill 4-kg infant. A 3.5-mm endotracheal tube was used in all experiments. A specific type of nebulizer used (Airlife Misty Neb; Baxter; Valencia, Calif) and several spacers were studied (Aerochamber and Aerovent, Monaghan Medical Corporation in Plattsburgh, NY [corrected]; ACE, Diemolding Healthcare Division in Canastota, NY [corrected]; and an in-line MDI adapter, Instrumentation Industries Inc, Pittsburgh). CNA delivered significantly more aerosol to the lung model (4.8 +/- 0.6% of the starting dose) than INA (3.8 +/- 0.3%; p<0.01). There was a significant stepwise decrease in aerosol delivery with increasing nebulizer flow (4.8 +/- 1.3% at 5.0 L/min; 3.7 +/- 1.1% at 6.5 L/min; and 2.7 +/- 1.1% at 8.0 L/min). Increasing duty cycle did not significantly affeet delivery. Overall the spacers with MDI were more efficient than the nebulizer in either position delivering about twice the percentage of the starting dose than the nebulizers. All modes of delivery, except the Aerochamber, demonstrated a marked degree of variability. Most of the starting dose of albuterol either remained in the nebulizer (30.4 +/- 6.0% at 5.0 L/min and 25.3 +/- 4.1% at 8.0 L/min) or was deposited in the inspiratory tubing (34.7 +/- 0.7% at 5.0 L/min and 43.7+/- 4.9% at 8.0 L/min) in our system. In conclusion, we have confirmed that aerosol delivery depends on the mode of delivery and the operating conditions. Although delivery with an MDI and spacer is more efficient than a nebulizer, both methods may produce high variability depending on the method or spacer used.

Aerosolized beta 2-agonists do not induce bronchial hyperreactivity in healthy adults.

OBJECTIVE: To determine whether regular administration of beta 2-agonists could induce bronchial hyperreactivity in nonasthmatic volunteers. DESIGN: A prospective, randomized, double-blind, placebo-controlled, crossover clinical trial of 2 weeks therapy with a 2-week washout period between each treatment period. Treatments were albuterol or matching placebo as 2 inhalations 4 times daily. SUBJECTS: Ten healthy, nonsmoking women 27-37 years old. SETTING: General clinical research center of a tertiary care university hospital. MAIN OUTCOME MEASURES: Baseline spirometry and methacholine bronchoprovocation studies were performed immediately prior to, 12 hours following, and 1 and 2 weeks following each treatment period. RESULTS: No change was detected in either baseline spirometry or methacholine responsiveness. CONCLUSIONS: This suggests that if beta 2-agonists induce a rebound bronchial hyperreactivity, it is not the result of the production of tolerance or a direct effect on bronchial smooth muscle.

Delivery of glucocorticoids by jet nebulization: aerosol characteristics and output.

BACKGROUND: Since inflammation has been identified as a critical factor in the pathogenesis of asthma, use of inhaled glucocorticoids has increased. Because young children are often unable to coordinate properly the use of metered-dose inhalers and no glucocorticoids preparations for nebulization have been approved in the United States, parenteral and intranasal glucocorticoids preparations are occasionally administered by nebulization. METHODS: We examined whether a parenteral preparation (triamcinolone acetonide [TAA]; Kenalog) could be delivered by nebulization. TAA, 1000 micrograms (0.1 ml), was placed in the nebulizer bowl (MB5 [MeFar, Brescia, Italy] or Pari-Jet [Dura Pharmaceuticals, San Diego, Calif.]), then diluted with 2.9 ml normal saline solution for a total volume fill of 3 ml. Using a laser particle analyzer, high-performance liquid chromatography, and cascade impactor, we examined the percentage of aerosol volume produced with particles in the respirable range of 1 to 5 microns in diameter, actual TAA output (in micrograms) and concentration of TAA contained in the particles within the respirable range. RESULTS: Laser particle analysis indicated that 34% +/- 3% (mean +/- SEM) (MB5) and 47 +/- 3% (Pari-Jet) of the total aerosol volume produced were within the respirable range of 1 to 5 microns in diameter, and this remained consistent throughout nebulization. The nebulizer was stopped serially for determination of TAA output with high-performance liquid chromatography. TAA output (1000 micrograms less the amount in micrograms remaining after nebulization) was essentially complete after 2 minutes with the Pari-Jet and within 4 minutes with the MB5 and totaled 352 +/- 19 micrograms and 367 +/- 9 micrograms, respectively. Finally, cascade impactor studies confirmed that 33.4% of the TAA aerosol generated by the MB5 nebulizer was contained in particles in the respirable range. CONCLUSION: Approximately 35% (Pari-Jet) and 37% (MB5) of the initial 1000 micrograms of TAA was delivered with the two nebulizers tested. The particles generated within the respirable range were limited to 34% (MB5) and 47% (Pari-Jet) of the amount delivered. TAA was equally distributed in the particles generated. The theoretic amount delivered in the respirable range was approximately 12.5% for the MB5 nebulizer on the basis of the cascade impactor and 16.5% for the Pari-Jet (assuming TAA distribution equivalence) of the TAA placed in each of the nebulizers. Additional clinical studies are needed to define efficacy and safety in view of the excipients used in preparing the parenteral preparation.

Prospective study on the occurrence of withdrawal in critically ill children who receive fentanyl by continuous infusion.

OBJECTIVE: To determine the occurrence of narcotic withdrawal in critically ill children who receive continuous infusions of fentanyl. DESIGN: Prospective case series. SETTING: A university hospital pediatric intensive care unit. PATIENTS: Twenty-three children, aged 1 wk to 22 months (mean 6 months), who required assisted mechanical ventilation and who received continuous infusions of fentanyl for > 24 hrs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total fentanyl dose received, length of infusion, and peak infusion rate were recorded. Patients were evaluated for narcotic withdrawal by the Neonatal Abstinence Scoring System of Finnegan. Children with scores of > or = 8 were considered to have narcotic withdrawal. Withdrawal was observed in 13 (57%) of 23 infants. Total fentanyl dose (2.96 +/- 4.10 vs. 0.53 +/- 0.37 mg/kg, p < .005) and length of fentanyl infusion (13.1 +/- 11.3 vs. 3.8 +/- 1.5 days, p < .0001) were significantly greater in those infants with narcotic withdrawal than in those infants with no withdrawal, respectively. Peak fentanyl infusion rate (9.9 +/- 7.8 vs. 9.2 +/- 4.4 micrograms/kg/hr) did not differ significantly between the two groups. A total fentanyl dose of > 2.5 mg/kg or a duration of infusion of > 9 days was 100% predictive of withdrawal. CONCLUSIONS: Continuous infusions of fentanyl produce a high occurrence rate of narcotic withdrawal when administered to critically ill children. This effect is both dose- and duration-dependent.