The effect of fixed combination of fluticasone and salmeterol on asthma drug utilization, asthma drug cost, and episodes of asthma exacerbations.

OBJECTIVE: This study evaluated the use and drug costs of inhaled corticosteroids (ICSs), long-acting beta2-agonists (LABAs), and fluticasone propionate and salmeterol in a fixed-dose combination (FSC) and their relationship to asthma exacerbations before and after the market introduction of FSC in April 2001. METHODS: This is a retrospective analysis of employer-sponsored health insurance claims filed between January 1, 1998, and December 31, 2003 to detect impact of introduction of FSC (approved by the US Food and Drug Administration in August 2000) on utilization and cost of FSC, any ICS (excluding FSC), and any LABA (excluding FSC) along with utilization of medical services related to asthma exacerbations. Asthma medications were identified using National Drug Codes and Redbook, whereas asthma exacerbations were identified using ICD-9-CM primary diagnosis code 493.x. These medical and pharmacy claims were converted to rates per 100 asthma office visits. RESULTS: For all ICSs, the average pharmacy claims per 100 office visits increased from 383 in the year before FSC was introduced to 407 (120 [29.5%] were for FSC and 287 [70.5%] were for single-entity ICSs) in 2003. LABA prescribing increased from 72 in the year before FSC to 147 (120 from FSC, 27 single-entity LABA) in 2003 (p < 0.001). An additional $13,511 per 100 asthma office visits was spent on the FSC product (p < 0.001). After the introduction of FSC, there was no significant difference in asthma admissions (p = 0.17), whereas emergency department (ED) visits increased by 0.92 visits per 100 office visits (p = 0.03). The diagnosis and severity of asthma was inferred from the pharmacy claims and patients with chronic obstructive pulmonary disease could not be excluded. In addition, the study was not designed to assess the impact of other asthma medications on the disease and/or associated costs, and patient adherence to claimed medication could not be monitored. CONCLUSIONS: The introduction of FSC was associated with increased LABAs/FSC patient exposure and expenditure with no change in asthma hospitalizations and an increase in ED visits.

Oxygen saturation in adult cystic fibrosis patients during exercise at high altitude.

The objective of this study was to determine the frequency and severity of decreased arterial oxy-hemoglobin saturation during exercise in adults with cystic fibrosis at 1,500 m above sea level. A convenience sample of 50 adults with cystic fibrosis who did not have hypoxemia (oxygen saturation, < 90%) at rest were evaluated. Spirometry was performed according to American Thoracic Society standards, and maximal exercise tests were performed on an electronically braked cycle ergometer using a ramp protocol individualized for each patient. Pulse oximetry was measured every 2 min. When exercising at high altitude, 45 of 50 patients had a decrease in arterial oxy-hemoglobin saturation from baseline to some degree. In 29 patients, oxy-hemoglobin saturation fell below 90%; in 14 patients, it fell below 85%; and in 4 patients, it fell below 80%. Oxy-hemoglobin saturation decreased to < 90% in 12 of 14 patients with severe pulmonary disease (FEV(1) < 40% predicted), in 15 of 26 patients with moderate disease (40% less than or equal to FEV(1) < 70% predicted), in 2 of 6 patients with mild disease (70% less than or equal to FEV(1) < 90% predicted), and in 0 of 4 with normal pulmonary function (FEV(1) greater than or equal to 90%). Percent predicted FEV(1) (r = 0.57; P < 0.0001) and FEV(1)/FVC ratio (r = 0.52; P < 0.0001) most highly correlated with arterial oxy-hemoglobin saturation at peak exercise. We conclude that at 1,500 m above sea level, adult CF patients with obstructive airways disease are at significant risk for decreased arterial oxy-hemoglobin saturation during exercise. A supervised exercise test should be considered prior to recommending an exercise program for such patients.

Asthma patients' satisfaction with the frequency and content of pharmacist counseling.

OBJECTIVE: To assess the level of expectation and satisfaction of patients with asthma regarding the counseling provided by community pharmacists, and to identify the counseling information patients consider important in helping them manage their asthma. DESIGN: Mailed survey. PARTICIPANTS: 208 patients seen in the University of Utah Asthma Clinic for at least 3 months, age 18 years or older, and on at least 1 asthma medication. MAIN OUTCOME MEASURES: Frequency of pharmacist-provided asthma medication counseling, patients' perception of the importance of counseling, and their satisfaction with counseling. RESULTS: Response rate was 55% (106 of 194 surveys returned). The majority of patients (> 90%) indicated that their community pharmacist "never" or "sometimes" discussed the management of their asthma with them. Frequency of counseling in three predefined areas of asthma education (role of medications, inhaler technique, and prevention of asthma attacks) was 1.91, 1.72, and 1.31, respectively (1 = never, 4 = always). Most patients (76%) considered these areas of counseling to be important for the management of their asthma. Most patients (62%) were "somewhat" to "pretty" satisfied with the type and amount of asthma counseling provided by their pharmacist. Counseling sessions averaged less than 3 minutes. Only 25% of patients would be willing to pay an additional amount for pharmaceutical care. CONCLUSION: Self-reported rates of patient counseling concerning asthma medications in the community pharmacy setting are low and adequately address neither the educational needs of patients nor the recommendations of the National Asthma Education and Prevention Program.

A prospective comparison of fiberoptic transbronchial needle aspiration and bronchial biopsy for bronchoscopically visible lung carcinoma.

BACKGROUND: Fiberoptic bronchoscopy is the most common modality used to diagnose endobronchial carcinoma. The authors prospectively compared the sensitivity of endobronchial needle aspiration (EBNA) and immediate cytologic assessment with bronchial biopsy and bronchial washing in the diagnosis of endobronchial malignancy. METHODS: A prospective trial comparing the sensitivity of EBNA, bronchial biopsy, and bronchial washings during fiberoptic bronchoscopy for endobronchially visible lung tumor was conducted. The authors enrolled 65 consecutive patients with endobronchial abnormalities identified during bronchoscopy. All patients in the study underwent fiberoptic bronchoscopy that included EBNA, bronchial biopsy, and bronchial wash. The sensitivities of the individual techniques were compared. The sensitivities of bronchoscopy were also prospectively compared when multiple sampling techniques were employed. RESULTS: Malignancy was present in 57 of 65 study patients. Cancer was diagnosed in 47 patients by EBNA, 42 patients by bronchial biopsy, and 36 patients by bronchial washing. The sensitivity of a strategy employing bronchial biopsy and bronchial washings was 0.82 (95% CI, 0.70-0.90). The addition of EBNA to bronchial biopsy and bronchial washings significantly increased the sensitivity to 0.95 (95% CI, 0.85-0.98; McNemar P = 0.02). Subset analysis revealed that this strategy was especially useful in cases in which lesions were submucosal or causing extrinsic compression. CONCLUSIONS: There is a modest increase in the sensitivity of fiberoptic bronchoscopy in diagnosing endobronchial cancer with the addition of EBNA to bronchial biopsy and bronchial washings, especially for patients with submucosal abnormalities. Collection of EBNA, followed by biopsy and washings only if immediate interpretation of EBNA is negative or inadequate, may be the most effective bronchoscopy strategy for evaluating visible endobronchial abnormalities.

Basic therapies in cystic fibrosis. Does standard therapy work?

Epidemiologic data demonstrate a dramatic improvement in survival for cystic fibrosis (CF) over the last few decades and projections suggest that trend will continue. Standard therapy works and should be aggressively applied to this patient population. Although the specific therapies have evolved over the years, the basic tenets of CF care remain unchanged and include antibiotics to control infection, airway clearance, and adequate nutrition. This article focuses on treatment of the pulmonary disease and includes a discussion of the following specific components of a standard therapeutic approach to CF: (1) antibiotics, (2) airway clearance and exercise, (3) mucolytics, (4) bronchodilators, (5) oxygen, (6) anti-inflammatory therapies, and (7) nutritional support. Judicious application of these therapies coupled with careful monitoring of pulmonary, nutritional, and metabolic parameters results in most CF patients surviving into adulthood with an acceptable quality of life.

Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS.

A randomized, controlled clinical trial was performed with patients with acute respiratory distress syndrome (ARDS) to compare the effect of conventional therapy or inhaled nitric oxide (iNO) on oxygenation. Patients were randomized to either conventional therapy or conventional therapy plus iNO for 72 h. We tested the following hypotheses: (1) that iNO would improve oxygenation during the 72 h after randomization, as compared with conventional therapy; and (2) that iNO would increase the likelihood that patients would improve to the extent that the FI(O2) could be decreased by > or = 0.15 within 72 h after randomization. There were two major findings. First, That iNO as compared with conventional therapy increased Pa(O2)/FI(O2) at 1 h, 12 h, and possibly 24 h. Beyond 24 h, the two groups had an equivalent improvement in Pa(O2)/FI(O2). Second, that patients treated with iNO therapy were no more likely to improve so that they could be managed with a persistent decrease in FI(O2) > or = 0.15 during the 72 h following randomization (11 of 20 patients with iNO versus 9 of 20 patients with conventional therapy, p = 0.55). In patients with severe ARDS, our results indicate that iNO does not lead to a sustained improvement in oxygenation as compared with conventional therapy.

Gastroesophageal reflux: a common exacerbating factor in adult asthma.

There is a unique yet common relationship between gastroesophageal reflux (GER) and asthma. This paper's discussion covers the lower esophageal sphincter (LES) and other components that form the anti-reflux barrier and how the barrier can be breached. There are three predominant theories on the asthma/GER connection; (1) the inhalation of microaspirate into the lungs causes an inflammatory response, (2) a vagally mediated reflex pathway occurring when acid is present in the esophagus, and (3) a combination of the first two theories. Available diagnostic tests for GER include the "gold standard," the 24-hour ambulatory pH monitor. Adult asthmatic patients with GER can present with atypical symptoms such as worsening nocturnal asthma or hoarseness and not have a single classic symptom like heartburn. Treatment is implemented in a step-wise approach first using education to introduce conservative anti-reflux measures, progressing to pharmacotherapy (acid suppressive agents and promotility agents) and finally surgical correction like the Nissen fundoplication to create a competent anti-reflux barrier, thus achieving improved asthma management.

Cost-effectiveness of collecting routine cytologic specimens during fiberoptic bronchoscopy for endoscopically visible lung tumor.

STUDY OBJECTIVE: Fiberoptic bronchoscopy is the most common modality used to diagnose endobronchial carcinoma. Collection of brushing and washing specimens for cytology is common during bronchoscopy for endobronchial abnormality, but it is unknown if collection of these specimens is cost-effective. DESIGN: Retrospective review of a computerized database with cost-effectiveness analysis. SETTING: Tertiary care medical center. PATIENTS: Two hundred one patients undergoing bronchoscopy for endobronchial lung tumor. INTERVENTION: All patients in the study underwent fiberoptic bronchoscopy that included forceps biopsies, washings, and brushings. In addition to analyzing the sensitivity of forceps-biopsy, washings, and brushings at diagnosing malignancy, we analyzed the cost-effectiveness of three potential specimen collection strategies. These strategies were (1) collection of both washings and brushings in addition to forceps biopsy specimen, (2) collection of either washings or brushings in addition to forceps biopsy specimen, and (3) collection of forceps biopsy specimen only. MEASUREMENTS AND RESULTS: The sensitivity of bronchoscopy, including biopsy, washing, and brushing is 85.3% (95% confidence interval [CI], 80.1 to 90.5%). The sensitivity of forceps biopsy is 80.8% (95% CI, 75.0 to 86.6%). The addition of washings and brushings increases the sensitivity of bronchoscopy from 80.8 to 85.3% (McNemar's p = 0.01). Cost-effectiveness analysis reveals that forceps biopsy plus washing or brushing has a marginal cost-effectiveness ratio of $308 per reduced-quality day avoided compared with forceps alone. Adding an additional cytology specimen has a marginal cost-effectiveness ratio of $5,500 per reduced-quality day avoided. CONCLUSIONS: There is a modest but definite increase in the sensitivity of bronchoscopy in diagnosing endobronchial cancer with the addition of washings and brushings for cytology. Cost-effectiveness analysis reveals that collection of either washings or brushings is probably the best strategy.

Pharmacokinetics of vancomycin in adult cystic fibrosis patients.

Although the depositions of many antibiotics are altered in cystic fibrosis patients, that of vancomycin has not been studied. To assess vancomycin pharmacokinetics, 10 adult cystic fibrosis patients were given a parenteral dose of vancomycin (15 mg/kg) during the first 72 h of hospitalization for acute bronchopulmonary exacerbation. Blood samples were obtained at 0, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 15, and 24 h. The mean (standard deviation) weight, measured creatinine clearance, and Taussig clinical score were 51 (13) kg, 130 (39) ml/min/1.73 m2, and 64 (13), respectively. Multicompartmental pharmacokinetic parameters were best described by a two-compartment model. The mean (standard deviation) volume of distribution, total body clearance, and terminal elimination rate constant were 0.58 (0.15) liter/kg, 91 (19) ml/min/1.73 m2, and 0.123 (0.05) h-1, respectively. These values were consistent with vancomycin pharmacokinetic parameters obtained in previous studies of healthy adult volunteers. Vancomycin dosages predicted by using a two-compartment Bayesian model were approximately 15 mg/kg every 8 to 12 h. There were poor correlations between clinical score or creatinine clearance and any pharmacokinetic parameter (r values of < 0.32). The coefficient of correlation between urine flow rate and total body clearance was 0.7 (P < 0.05). Adult cystic fibrosis patients exhibit a disposition of vancomycin similar to that exhibited by healthy adults, and thus cystic fibrosis does not alter vancomycin pharmacokinetics.

Management of the difficult asthmatic. Gastroesophageal reflux, sinusitis, and pregnancy.

The frustration of treating the difficult asthmatic can be minimized by recognizing that interactions of disease processes can complicate therapy. At the same time, therapy of asthma can be simplified by the awareness that control of allied conditions can improve the response to treatment directed at the airways. The future likely will bring more challenges as our ability to cope with complicated asthma patients improves.

Allergic reactions to parenteral beta-lactam antibiotics in patients with cystic fibrosis.

Certain antibiotics, particularly piperacillin, have been reported to be associated with a high incidence of allergic reactions in patients with cystic fibrosis. We initiated a study to determine the relative frequency of allergic reactions, ie, drug-induced fever and rash, to parenteral beta-lactam antibiotics in adult patients with cystic fibrosis. Charts of 111 patients were reviewed for each hospitalization to assess allergic reactions. Of 90 evaluable patients, 26 patients developed one or more allergic reactions to beta-lactam antibiotics. The number of allergic reactions per number of patients receiving specific antibiotics were carbenicillin (4/56), mezlocillin (7/42), piperacillin (11/31), ticarcillin (1/20), cefazolin (0/24), ceftazidime (1/35), imipenem/cilastatin (4/16), and nafcillin (3/36). The mean time to onset of drug-induced fever or of rash was 9.1 days. As a group penicillins had a higher frequency of allergic reactions than cephalosporins. The frequency of reactions was greatest with acylaminopenicillins (mezlocillin and piperacillin) and imipenem/cilastatin. The results of this study indicate that in addition to piperacillin, mezlocillin and imipenem/cilastatin may be associated with a high incidence of allergic reactions in patients with CF.

Arthropathy secondary to ciprofloxacin in an adult cystic fibrosis patient.

OBJECTIVE: To report a case of possible ciprofloxacin-induced arthropathy in an adult patient with cystic fibrosis (CF). CASE SUMMARY: A 25-year-old man with CF received three separate courses of ciprofloxacin therapy at usual doses for acute pulmonary exacerbations of his disease. During the second and third courses, the patient experienced bilateral swelling of his knees between two to three weeks after initiation of each course. Both times symptoms markedly decreased after discontinuation of the drug. The patient had no prior history of arthropathy. Furthermore, during the last two acute exacerbations of his CF, he did not receive ciprofloxacin and did not experience any symptoms of arthropathy. DISCUSSION: Prior cases of quinolone-induced arthropathy involving pediatric CF patients or adult patients without CF have been reported in the literature. We report the first case of such an arthropathy in an adult patient with CF. The findings are supported by a rechallenge with the drug. CONCLUSIONS: It is likely that ciprofloxacin may produce arthropathy in adult as well as pediatric patients with CF. Quinolones should be considered as a possible cause of arthropathy in adult CF patients.

Sensitive and specific detection of the 4B5 antigen in bronchial lavage specimens from patients with primary bronchogenic carcinoma.

The monoclonal antibody 4B5 binds to a mucin-like antigen elaborated by respiratory epithelium of patients with non-small cell bronchogenic carcinoma. Several immunoassay formats were used to determine the presence of the antigen in lavage specimens. A qualitative immunodrop binding assay showed immunoreactivity in 37 (64%) of 58 specimens from patients with non-small cell lung cancer. In contrast, only 11 (12%) of 93 specimens from patients with either metastatic carcinoma or benign pulmonary diseases exhibited 4B5 immunoreactivity. A quantitative radioimmunoassay using standardized amounts of mucin exhibited similar sensitivity and specificity. Positive immunoreactivity was associated significantly with tobacco use and the cytopathologic diagnoses of squamous metaplasia, atypia, or dysplasia. Conversely, no significant association was found between 4B5 immunoreactivity and age, gender, race, benign cytologic findings, frankly malignant cytologic findings, or stage of disease. The expression of 4B5 antigen in bronchial secretions from patients with bronchogenic carcinoma deserves additional evaluation as a potential marker of pulmonary carcinogenesis.

Pulmonary embolism and splenic infarction in a patient with sickle cell trait.

A 43 year-old black man with sickle cell trait documented by hemoglobin electrophoresis presented with severe pleuritic chest pain and hypoxemia three weeks after discharge following abdominal surgery. A pulmonary embolus was diagnosed by angiography and he was treated with heparin; the minimum arterial pO2 was 55 torr while O2 was being administered at a rate of 3 L/min. During this therapy, he developed abdominal pain. Computerized tomography suggested splenic infarction, which was documented by radionuclide liver-spleen scan and magnetic resonance imaging (MRI); the patient's spleen had been normal at exploratory laparotomy three weeks previously. No source for emboli was identified in the deep venous system by MRI. Although splenic infarction has been reported in patients with sickle cell trait at high altitude, this is the first reported case of splenic infarction secondary to the hypoxemia of pulmonary embolism in a patient with sickle cell trait. The spleen is subject to infarction in sickle cell trait because blood flow is slow through a hypoxemic and acidemic environment. The additional hypoxemia due to pulmonary embolism is presumed, in our patient, to have created a local splenic environment which permitted infarction to occur.

Nonequilibrium of two redox couplets in human plasma: lactate-pyruvate and beta-hydroxybutyrate-acetoacetate.

We examined the extracellular equilibrium status of two redox couplets normally found in plasma (lactate-pyruvate [L-P], beta-hydroxybutyrate, and acetoacetate) during acute metabolic acidosis produced by muscle exertion. Both pre- and postexertion plasma spontaneously underwent loss of acetoacetate and gain of L when compared to the baseline values. Exercise further induced a 332% rise in L (p less than .001) and a 102% rise in P (p less than .001). The empirically derived ratio of equilibrium constants, KLP/KBA, fell 50% (p less than .001), and the calculated change in free energy (delta F) fell from 3.6 to 3.1 kcal/mol (p less than .001) after exercise. The changes induced by exertion were simulated closely by an in vitro model of a reduced state. Thus, the triad of inconstant metabolite concentrations, inconstant KLP/KBA, and delta F both inconstant and non-zero, indicates that there is no state of equilibrium for these metabolite couplets in human plasma. The KLP/KBA ratio appeared to reflect the degree of deviation from equilibrium and may therefore be useful when investigating altered redox states such as metabolic acidosis.

Assessing redox status in human plasma: experience in critically ill patients.

Clinical evaluation of metabolic acidosis has involved measurement of lactate (L), pyruvate (P), beta-hydroxybutyrate (BOHB), and acetoacetate (AcAc). We previously demonstrated that these metabolites are not at equilibrium in plasma. Their degree of disequilibrium is reflected in the ratio of apparent equilibrium constants (KLP/KBA) for the two redox couplets, L-P and BOHB-AcAc. The purpose of the study was to examine how well this ratio reflects disequilibrium in patients with metabolic acidosis. Measurements of the four metabolites were obtained in 23 critically ill patients. Disequilibrium was again observed, as manifested in an inconstant ratio (p less than .01). The ratio increased with clinical improvement. Patients were more likely to die during their ICU stay if the estimated ratio was low, particularly if metabolic acidosis was present. Patients with respiratory acidosis had both intermediate probabilities of death and intermediate ratios when compared to inpatient controls (ICU patients without acidosis). Our data indicate that changes in the L-P-BOHB-AcAc cycle reflect the degree of metabolic derangement in critically ill patients.

Opportunistic lung infection caused by Rhodococcus (Corynebacterium) equi.

Rhodococcus (formerly Corynebacterium) equi, a common animal pathogen, can cause a slowly evolving pneumonia in humans, particularly immunocompromised people. The authors describe two patients; one with acquired immunodeficiency syndrome. On chest radiographs, R. equi produces chronic, localized pulmonary opacities that can cavitate. The main differential diagnoses are tuberculosis and fungal infection.

Hydrocortisone-induced reversal of beta-adrenergic receptor uncoupling.

Prolonged exposure to adrenal-steroid hormones or adrenergic agonists results in opposing physiologic effects on beta-adrenergic receptors. These physiologic events have biochemical correlates that can be evaluated in the laboratory setting. The ability of hydrocortisone in vitro to reverse prior uncoupling of the receptor induced by terbutaline in vivo was examined. Healthy human volunteers received terbutaline sulfate, 2.5 mg orally every 8 h for 3 days, for a total of 9 doses. Neutrophils obtained from these volunteers were then incubated for 3 h in vitro in the presence of either hydrocortisone or saline placebo. Two types of receptor alterations were observed. Receptor density was reduced by 28% in terbutaline-treated subjects as compared with that in untreated control subjects (p less than 0.016). The receptors also appeared to be relatively uncoupled. This was assessed by examining the ability of the agonist isoproterenol to stabilize a high affinity form of the receptor detected by computer modeling of competition curves for [125I]cyanopindolol binding. The reduction in receptor density was not affected by incubation in hydrocortisone. The ability of isoproterenol to stabilize the high affinity form of the receptor in cells incubated with hydrocortisone was statistically indistinguishable from that of the control state. We conclude that hydrocortisone can reverse prior agonist-induced uncoupling in vitro without affecting prior homologous down regulation.