There are two “Sounding Board” articles published in the September 3, 1998, issue of the New England Journal of Medicine that at first glance, do not seem to have much relationship to one another.^1,,2 The first article describes ethical guidelines for practicing physicians to prevent financial considerations from interfering with decisions about medical care. The second article reviews the process of taking basic science research and translating it for clinical purposes. The terms“ translational research” and clinical “evaluative research” are introduced to describe the important process that takes discoveries from bench to bedside.

Sisyphus,¹ the legendary king of Corinth, committed such crimes in his life that on his death he was sent to Hades for judgment and sentenced to the unattainable task of rolling a heavy stone up a hill. Each time he would near the apex of the hill, the stone would shift and roll back down to the plane. Sisyphus was condemned to repeat this cycle for eternity. As a practicing pulmonologist in a rural community in upper east Tennessee, establishing a pulmonary rehabilitation program was a Sisyphean task. Armed with vision, passion, and determination to succeed, 6 years were spent planning, marketing, and selling the idea of pulmonary rehabilitation to the community. The formidable hurdles of apathy, ignorance, and indifference were finally overcome. Within months of opening the doors of our newly established program, we had an extensive waiting list and were already outgrowing the existing facility. Obviously, there had been a strong need for pulmonary rehabilitation in this community. A need that was not being met by conventional therapies alone.

The drug therapy of asthma has remained essentially unchanged over the past 3 decades, comprising use of glucocorticoids,β ₂-agonists, and theophyllines. The antileukotrienes and particularly the leukotriene antagonists represent an important new class of drug therapy for asthma. At present, the use of the 5-lipoxygenase inhibitor zileuton is somewhat limited due to its four-times-daily dosing regimen and the need to monitor biochemical liver function tests. The advantages of the available leukotriene antagonists are the use of once-daily (montelukast) or twice-daily (zafirlukast) dosing in terms of improved compliance, as well as there being no need to routinely monitor liver function. The leukotriene antagonists seem to be effective over a wide range of asthma disease severity, although their precise role in asthma management guidelines has yet to be established due to the relatively small published database on long-term clinical efficacy.

To comply with the mandatory phase-out of chlorofluorocarbons (CFCs) that destroy ozone in the stratosphere and allow excessive ultraviolet radiation to reach the earth’s atmosphere,^1– CFC-based metered-dose therapeutic aerosols are in the process of being reformulated with more environmentally friendly alternative propellants, such as hydrofluoroalkanes (HFAs). This process has created formidable technical challenges as well as new opportunities for potentially improved aerosol delivery. Beclomethasone dipropionate (BDP), the oldest inhaled corticosteroid molecule with high topical-to-systemic activity, has been used in asthma therapy for over two decades. Reformulation of BDP with HFA-134a results in a solution preparation that delivers an aerosol with a much smaller mean particle size (mass median aerodynamic diameter [MMAD] 1.1 μm) than that of aerosols generated by conventional CFC-based metered-dose inhalers of BDP (MMAD, 3.5 to 4 μm).^2– Mathematical models that relate particle size to the site of deposition in the respiratory tract predict that extra-fine particles with an MMAD of approximately 1 μm would deposit to a greater extent in the lung periphery than less fine particles with an MMAD of 4 to 5 μm, which would tend to deposit more centrally, as well as in the oropharynx.^3– Since this theoretical model does not take into account a number of other factors that influence aerosol particle deposition in vivo, such as variations in inhalation technique (inspiratory flow, breath-holding time) and airway morphology (narrowing or occlusion caused by disease),⁴in vivo studies are required to ascertain actual sites of aerosol deposition in both healthy subjects and patients with airways disease. Using an optimized method of metered-dose inhaler use and lung imaging techniques incorporating procedures validated to ensure consistency of drug radiolabeling in the different ranges of particle size, Leach² demonstrated that a large proportion of HFA-BDP (51 to 56%) was delivered uniformly throughout the lungs (ie, presumably to peripheral, as well as large- and medium-sized airways) of both normal volunteers and patients with mild asthma with relatively little oropharyngeal deposition (28 to 30%), in contrast to CFC-BDP that deposited mainly in the oropharynx (94%) and large central airways with little peripheral penetration.

Lung volume reduction surgery (LVRS) originally proposed by Brantigan and colleagues^1– and revived by Cooper and colleagues,^2– has become a new therapeutic option for patients with end-stage emphysema, a disease that is frustratingly difficult to treat. Although LVRS has been greeted with enthusiasm by many physicians, skepticism on the safety and efficacy of this surgical intervention in comparison to conventional medical therapy has arisen.^3,,4

The first systematic assessment of whether exposure to asbestos or the fibrotic response to asbestos fiber inhalation (asbestosis) is the cause of excess lung cancer was raised in a 1949 report.^1– Lung cancer occurred in 35 of 235 (13.2%) autopsied deaths where asbestosis was identified. In 1955, the first mortality study of a cohort of asbestos-exposed workers² showed that among 105 deaths, lung cancer was found in 18 instances, 15 times in association with asbestosis. In the 3 without asbestosis, the latencies (time from first exposure to death) were 2, 12, and 11 years, respectively.

Carbon monoxide (CO) is an odorless, colorless, and tasteless product of incomplete fuel combustion, whose ubiquitous but silent presence accounts for it being the leading cause of poisoning death in the United States. CO poisoning may account for as many as 5,000 deaths each year in the United States, with an additional 10,000 patients seeking medical attention for toxic exposure.^1– CO poisoning may be deliberate (as reported in this issue of CHEST [see page 580]) or accidental; in the latter case, it may be acute,² subacute,^3– or chronic.⁴

Background: Genetic polymorphism determines agonist-induced down-regulation and desensitization ofβ ₂-adrenoceptors.

Objectives: The aim of the present study was to investigate the effects of genetic polymorphism on ex vivo (lymphocytes) and in vivo (bronchoprotection) function ofβ ₂-adrenoceptors in asthmatic patients, having been washed out of previous β₂-agonist exposure.

Methods: Sixty patients with stable mild-to-moderate asthma were evaluated, with a post hoc analysis of genotype performed at end of study. Having withheld treatment with long-actingβ ₂-agonists for ≥ 48 h and short-actingβ ₂-agonists for ≥ 12 h, measurements of lymphocyteβ ₂-adrenoceptors were made for binding density, binding affinity, basal cyclic adenosine monophosphate (cAMP), and maximal cAMP response to isoproterenol (Emax). In addition, in 48 of these patients who were methacholine responsive (PD₂₀ < 1,000 μg), the acute protective effect of formoterol as a 24-μg single dose (at 1 h) was also evaluated. Comparisons were made according to homozygous and heterozygous (Het) polymorphisms at codon 16 and codon 27.

Results: There were no significant differences in age, FEV₁ percent predicted, or inhaled corticosteroid dose, when comparing mean values for polymorphisms at either codon 16 or codon 27. There were also no significant differences between polymorphisms for any of the measured lymphocyteβ ₂-adrenoceptor parameters apart from basal cAMP between Glu-27 and Het-27. Mean values for Emax (after-before isoproterenol as pmol/10⁶ cells) were as follows: Gly-16 (3.4), Arg-16 (3.5), Het-16 (4.0), Glu-27 (3.9), Gln-27 (3.5), and Het-27 (3.7). Polymorphism had no significant effect on formoterol protection as doubling dose shift in methacholine PD₂₀ (geometric mean): Gly-16 (5.3), Arg-16 (5.4), Het-16 (4.6), Glu-27 (5.3), Gln-27 (5.3), Het-27 (4.5).

Conclusions: Our results show that genetic polymorphism at codon 16 or 27 does not influence stimulated coupling of lymphocyte β₂-adrenoceptors and similarly did not influence the degree of functional antagonism exhibited by formoterol. Thus, a single dose of β₂-agonist when used on demand affords equal protection against bronchoprotection regardless of genetic polymorphism.

Abbreviations: Arg = homozygous arginine; Bmax = receptor binding density; cAMP = cyclic adenosine monophosphate; Emax = maximal cyclic adenosine monophosphate response; Glu = homozygous glutamic acid; Gly = homozygous glycine; Het = heterozygous; Kd = receptor binding affinity; PD₂₀ = provocative dose causing a 20% fall in FEV₁

Study objective: To compare the long-term efficacy and safety of albuterol administration using a Spiros Inhalation System (Dura Pharmaceuticals; San Diego, CA) dry powder inhaler (DPI) and albuterol (Ventolin; Glaxo Wellcome; Research Triangle Park, NC) administration using a metered-dose inhaler (MDI) in patients with asthma.

Materials and methods: This was a phase III, 12-week, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter study of 283 adolescent and adult patients with mild to moderate asthma. The patients were randomized into one of three treatment groups: the Spiros group, who were given 108 μg/actuation of albuterol sulfate equivalent to 90μ g of albuterol base; the MDI group, who were given 90 μg/actuation of albuterol; and the placebo group.

Results: Over the length of the study, the Spiros and MDI groups were comparable in all FEV₁ parameters. Both active treatment groups were superior to the placebo group for each FEV₁ parameter at all visits. With the exception of differences at treatment week 0 for the maximum percent change in the FEV₁, the duration of effect, and the area under the curve at baseline, there were no statistically significant differences between the Spiros and MDI groups for any FEV₁ parameters. Using a repeated-measures analysis, the FEV₁ parameters at week 0 for the Spiros group were not statistically significantly different from the parameters at weeks 4, 8, and 12. The same analysis effect at week 0 for the MDI group was greater for maximum percent change in the FEV₁ from baseline (weeks 4, 8, and 12) and duration of effect. Adverse events and changes in clinical laboratory values, vital signs, ECG results, and physical examinations were reported with similar incidence in each of the three treatment groups.

Conclusion: Both active treatments were superior to the placebo treatment. The Spiros DPI was well tolerated and was as effective as the albuterol MDI in treating patients with moderate asthma.

Abbreviations: ANCOVA = analysis of covariance; ANOVA = analysis of variance; AUCBL = area under the serial FEV₁ curve and above baseline; CFC = chlorofluorocarbon; DPI = dry powder inhaler; FDA = Food and Drug Administration; LED = light-emitting diode; MDI = metered-dose inhaler; PEF = peak expiratory flow

Study objectives: We evaluated the efficacy of the leukotriene receptor antagonist zafirlukast (Accolate^®), 20 mg twice daily, as monotherapy in patients with severe persistent asthma (defined by an FEV₁ < 60% of predicted before treatment and frequent night-time symptoms).

Design: Data were analyzed from a subgroup of 261 steroid-naive patients (zafirlukast, n = 149; placebo, n = 112) from four randomized, double-blind, placebo-controlled, 13-week trials with similar experimental designs, entry criteria, and clinical assessments.

Patients: These patients were mostly men (57%) older than 30 years (56%) with pulmonary obstruction, ie, FEV₁/FVC ratio < 0.7 (79%), and reversible airway disease demonstrated by a 15% increase in FEV₁ after inhaled bronchodilator use.

Results: At end point, patients who received zafirlukast monotherapy had significant (p < 0.05) improvements from baseline, and compared with placebo, in FEV₁, morning and evening peak expiratory flow (PEF), daytime asthma symptoms, nighttime awakenings, and β₂-agonist use. A stratified analysis based on the FEV₁/FVC ratio showed an interaction between treatment and the amount of airflow obstruction for nighttime awakenings and mornings with asthma. Moreover, 37% of patients in both treatment groups had PEF variability ≥ 20% (an indirect measure of airway inflammation). Zafirlukast patients with PEF variability≥ 20% had increases from baseline in the morning and evening PEF of approximately 40 and 11 L/min, respectively. For patients who take zafirlukast and who have a PEF variability of < 20%, the morning and evening PEF increased by 25 and 30 L/min, respectively. Regardless of the degree of PEF variability, zafirlukast significantly (p < 0.05) increased morning and evening PEF compared with placebo.

Conclusion: Patients with severe persistent asthma who received zafirlukast as monotherapy had clinically significant improvements across all efficacy measures compared with placebo and significant reductions in PEF variability.

Objective: The improved lung deposition of hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) extrafine aerosol compared with chlorofluorocarbon beclomethasone dipropionate (CFC-BDP) suggests that lower doses of HFA-BDP may be required to provide equivalent asthma control. The present study was undertaken to test this hypothesis.

Design: A 10- to 12-day run-in period confirmed that patients met established criteria of at least moderate asthma and the asthma was inadequately controlled by current therapy (inhaled β-agonist and CFC-BDP [≤ 400 μg/d]). A short course of oral prednisone, 30 mg/d for 7 to 12 days, was followed to establish the patients were steroid responsive and to provide an“ in-study” baseline of “optimal” asthma control.

Patients: A total of 347 patients were then randomized to HFA-BDP 400 μg/d, CFC-BDP 800 μg/d, or HFA-placebo for 12 weeks.

Results: Morning peak expiratory flow (am PEF) measurements showed that HFA-BDP 400 μg/d achieved equivalent control of asthma to CFC-BDP 800 μg/d at all time intervals after oral steroid treatment. All other efficacy variables supported the am PEF results and both active treatments were more effective than placebo. The safety profile of HFA-BDP compared favorably with that of CFC-BDP with no unexpected adverse events reported.

Conclusions: These findings demonstrate that HFA-BDP provides equivalent control of moderate or moderately severe asthma as CFC-BDP in the population studied, but at half the total daily dose.

Abbreviations: am PEF = morning peak expiratory flow; ANOVA = analysis of variance; BDP = beclomethasone dipropionate; CFC = chlorofluorocarbon; CI = confidence interval; HFA = hydrofluoroalkane-134a; MDI = metered-dose inhaler; pm PEF = evening peak expiratory flow

Study objectives: Endothelin (ET)-1 is a potent bronchoconstrictor, and asthmatics demonstrate bronchial hyperresponsiveness to ET-1 given by inhalation. Angiotensin II (Ang II) is increased in plasma in acute severe asthma, causes bronchoconstriction in asthmatics, and potentiates contractions induced by ET-1 in bovine bronchial smooth muscle in vitro, and contractions induced by methacholine both in vitro and in vivo. We wished to examine any potentiation of the bronchoconstrictor activity of inhaled ET-1 by infused Ang II at subbronchoconstrictor doses.

Design: Double-blind randomized placebo-controlled study.

Setting: Asthma research unit in university hospital.

Patients: Eight asthmatic subjects with baseline FEV₁ 88% predicted, bronchial hyperreactivity (geometric mean, concentration of methacholine producing 20% fall, methacholine PC₂₀ 2.5 mg/mL), and mean age 37.1 years.

Interventions: We examined the effect of subbronchoconstrictor doses of infused Ang II (1 ng/kg/min and 2 ng/kg/min) or placebo on bronchoconstrictor responses to inhaled ET-1 (dose range, 0.96 to 15.36 nmol).

Measurements: Oxygen saturation, noninvasive BP, and spirometric measurements were made throughout the study visits. Blood was sampled for plasma Ang II levels at baseline and before and after ET-1 inhalation.

Results: Ang II infusion did not produce bronchoconstriction per se at either dose prior to ET-1 challenge. Bronchial challenge with inhaled ET-1 produced dose-dependent bronchoconstriction, but there was no difference in bronchial responsiveness to ET-1 comparing infusion of placebo with Ang II at 1 ng/kg/min or 2 ng/kg/min (geometric mean, concentration of ET-1 producing 15% fall, 5.34 nmol, 4.95 nmol, and 4.96 nmol, respectively) (analysis of variance, p > 0.05). There was an increase in systolic and diastolic BP at the higher dose of Ang II compared to placebo (mean 136/86 vs 117/75 mm Hg, respectively). Plasma Ang II was elevated following infusion of both doses of Ang II compared to placebo.

Conclusions: In contrast to the potentiating effect on methacholine-induced bronchoconstriction, Ang II at subbronchoconstrictor doses does not potentiate ET-1-induced bronchoconstriction in asthma.

Abbreviations: Ang II = angiotensin II; ET-1 = endothelin-1; PC₁₅FEV₁ ET-1 = concentration of endothelin-1 producing 15% fall in FEV₁; PC₂₀FEV₁ methacholine = concentration of methacholine producing 20% fall in FEV₁; RAS = renin-angiotensin system

Study objectives: Bronchus-associated lymphoid tissue (BALT) is well defined in animals. In humans, however, BALT has been reported to be inducible under pathologic conditions, such as chronic respiratory infection, although it is not present in healthy adults. Thus, induced BALT is considered to be involved in the mucosal immunity of the human lung under these conditions. However, there have been few studies to investigate BALT development in hypersensitivity pneumonitis. The aim of this study was to examine the presence of BALT in hypersensitivity pneumonitis, especially in its chronic form.

Methods: The subjects included five patients with chronic hypersensitivity pneumonitis (CHP) diagnosed from clinical and histologic findings. We investigated histologically the development of BALT in these patients. Further, the cellular distribution of BALT was also examined by immunohistochemistry.

Results: BALT was present in three of five patients with CHP. Immunohistochemical examination revealed the follicular area of BALT to be composed mainly of B cells, while the parafollicular area comprised predominantly T cells. Centroblasts located in the germinal center of BALT expressed Ki-67 antigen, a marker of cell proliferation, suggesting that these cells were actively proliferating after antigenic stimulation. Cells expressing bcl-2, which is present primarily on memory B cells, were confined to the follicular area, devoid of any germinal centers. S-100-positive, CD1a-negative interdigitating dendritic cells were observed in the dome area of BALT.

Conclusions: These observations suggest that chronic antigenic stimulation and/or inflammation in CHP may cause BALT development, which, in turn, is likely to play an important role in the mucosal immune response of this disease.

Abbreviations:BALT = bronchus-associated lymphoid tissue; CHP = chronic hypersensitivity pneumonitis; DPB = diffuse panbronchiolitis; GALT = gut-associated lymphoid tissue

Study objectives: (1) To determine the relationship between IgE levels and the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) patients, (2) to establish the usefulness of assessing atopy as an identifying risk factor for ABPA, (3) to evaluate the clinical course of patients receiving and not receiving itraconazole as reflected in oral steroid dose requirements and number of acute episodes of ABPA, and (4) to determine the role of acute episodes of ABPA in pulmonary exacerbations of CF.

Design: Retrospective review of online clinical database and medical records.

Setting: CF clinic and inpatient services of Lucile Salter Packard Children’s Hospital at Stanford.

Patients: One hundred seventy-two patients with CF for whom serial serum total IgE levels were measured over a 5-year study period, 1992 to 1996.

Interventions: We reviewed records of patients followed up at the CF Center at Stanford who had serum total IgE measured between January 1, 1992, and December 31, 1996. Total IgE and Aspergillus fumigatus (Af) specific IgE antibodies were measured by commercial fluorometric solid-phase immunoassay. Precipitating antibodies to Af were measured by double immunodiffusion. Patients who were diagnosed as having ABPA were treated with itraconazole unless significant liver dysfunction was present. Oral steroid dosing requirements and acute episodes of ABPA for days with vs days without itraconazole were compared.

Measurements and results: Serum total IgE was elevated (> 1 SD > geometric mean for age) in 51% of patients tested. IgE > 500 IU/mL, chosen as a screening cutoff for evaluating possible ABPA, was present in 19% of patients at some time during the study period. Atopy (defined as ≥ 1 IU/mL IgE antibody to ≥ 1 allergen) was present in 61% of 104 patients tested for specific allergen sensitization. ABPA was diagnosed in 16 patients (9%). ABPA occurred in 22% of atopic CF patients but only in 2% of nonatopic patients (p = 0.001). Six percent of pulmonary exacerbations requiring hospitalization were associated with acute episodes of ABPA. Over the study period, itraconazole use was associated with a reduced average daily oral steroid dose of 47% (p = 0.05) and a reduction in the number of acute ABPA episodes by 55% (p < 0.001).

Conclusions: Screening for atopy may be a cost-effective way to select CF patients for periodic monitoring with total serum IgE levels, since there is an increased risk of ABPA developing in atopic CF patients. Itraconazole treatment of ABPA is safe and associated with fewer acute episodes of ABPA despite reduction in average daily oral steroid dose.

Abbreviations: ABPA = allergic bronchopulmonary aspergillosis; Af = Aspergillus fumigatus; ALT = alanine transaminase; AST = aspartate transaminase; CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator; LPCH = Lucile Packard Children’s Hospital; sIgE = specific IgE; tIgE = total IgE

Study objectives: The aim of this study was to examine the effect of body composition on maximal exercise performance in patients with COPD.

Methods: The study was carried out on 27 patients with COPD and was confirmed by pulmonary function testing. Body composition was measured by dual energy x-ray absorptiometry (DXA). Exercise performance was conducted on a cycle ergometer and was measured as maximal work rate (WRmax) and maximal oxygen uptake (V̇o₂max). Bone mineral content (BMC), lean mass (LEAN), and fat mass (FAT) were assessed by DXA and were expressed as a percentage of ideal body weight, BMC, LEAN, and FAT.

Results: LEAN% correlated significantly with V̇o₂max (r = 0.66, p = 0.0002) and WRmax (r = 0.70, p < 0.0001). No significant correlation was found between FAT% and exercise performance. By stepwise regression analysis, variables significantly contributing to WRmax and V̇o₂max were LEAN% and the maximal voluntary ventilation. Total variance explained in these models was 81% for WRmax and 82% for V̇o₂max.

Conclusion: Lean mass was an important determinant of maximal exercise performance in patients with COPD.

Abbreviations: BMC = bone mineral content; BMC% = percentage of BMC; Dlco = diffusing capacity of the lung for carbon monoxide; DXA = dual energy x-ray absorptiometry; FAT = fat mass; FAT% = percentage of FAT; FFM = fat-free mass; %IBW = percentage of ideal body weight; LEAN = lean mass; LEAN% = percentage of LEAN; MVV = maximal voluntary ventilation; RV = residual volume; TLC = total lung capacity; V̇o₂max = maximal oxygen uptake; WRmax = maximal work rate

Introduction: Inhaled anticholinergic drugs are often recommended for use as a first-line therapy for patients with COPD because they provide similar or more effective bronchodilating actions, as well as fewer side effects. It is not known, however, which class of bronchodilators is more advantageous for pulmonary hemodynamics, particularly during exercise.

Objectives: To compare the effects of oxitropium and fenoterol on pulmonary hemodynamics in patients with COPD at rest and during exercise.

Patients: The study participants consisted of 20 consecutive male patients with stable COPD, a mean (± SD) age of 68 ± 8 years old, and an FEV₁/FVC ratio of 47.5 ± 10.0%.

Methods: Eleven patients inhaled two puffs of oxitropium, and nine patients inhaled two puffs of fenoterol. Seven members of each group performed incremental exercise using a cycle ergometer. The hemodynamic measurements with right heart catheterization were performed by taking the average of three consecutive respiratory cycles before and after the administration of inhaled bronchodilators at rest and during exercise.

Results: At rest, despite a similar improvement of spirometric data with the two drugs, fenoterol, not oxitropium, caused significant increases in heart rate and cardiac output, a decrease in pulmonary vascular resistance, and a deteriorated Pao₂. During exercise, however, both drugs similarly attenuated elevations in the mean pulmonary arterial pressure (40 ± 12 to 38 ± 10 mm Hg by oxitropium, and 41 ± 9 to 36 ± 9 mm Hg by fenoterol), the mean pulmonary capillary wedge pressure, and the mean right atrial pressure.

Conclusion: Our findings indicate that both classes of bronchodilators are equally beneficial in the attenuation of right heart afterload during exercise in patients with COPD.

Abbreviations: BPM = beats per minute; CI = cardiac index; CO = cardiac output; HR = heart rate; PAP = pulmonary arterial pressure;Δ PAP = change in mean pulmonary arterial pressure; PCWP = pulmonary capillary wedge pressure; Pvo₂ = mixed venous oxygen tension; PVR = pulmonary vascular resistance; RAP = right atrial pressure; SBP = systemic blood pressure

Study objectives: To evaluate changes in health-related quality of life (HRQL) as assessed by the Medical Outcomes Study Short Form 36-item questionnaire (SF-36) after pulmonary rehabilitation and lung volume reduction surgery (LVRS).

Design: Prospective cohort study.

Patients: Nineteen patients with severe emphysema who underwent pulmonary rehabilitation in preparation for LVRS.

Interventions: Pulmonary rehabilitation followed by bilateral sequential LVRS.

Measurements and results: HRQL assessed by the SF-36 was measured at baseline, after pulmonary rehabilitation, and 6 months after LVRS. One-way analysis of variance with repeated measures demonstrated no significant change from baseline in any of the eight domains after pulmonary rehabilitation. Scores for only one domain, vitality, improved significantly after LVRS compared with scores after pulmonary rehabilitation. However, significant improvements over baseline scores were demonstrated after combined preoperative pulmonary rehabilitation and LVRS in the domains of physical functioning, role limitations due to physical problems, social functioning, and vitality. Pulmonary rehabilitation contributed most to the overall improvements in role limitations due to physical problems, whereas LVRS contributed mainly to the overall improvements in physical functioning, social functioning, and vitality.

Conclusions: Patients with severe emphysema experience significant improvements in both physical and social health status as assessed by the SF-36 after combined pulmonary rehabilitation and LVRS. Each intervention makes unique and complementary contributions to the overall improvements in HRQL.

Abbreviations: HRQL = health-related quality of life; LVRS = lung volume reduction surgery; r = correlation coefficient; SF-36 = Medical Outcomes Study Short Form-36

Study objectives: Despite numerous reports of short-term response to lung volume reduction surgery (LVRS) for treatment of emphysema, to our knowledge, longer-term survival has not been reported. We describe survival following LVRS in a large cohort of 256 patients treated with bilateral staple LVRS (n = 236 video-assisted thoracic surgery [VATS] approaches, n = 20 median sternotomy) by a single group of physicians over a 3 1/2-year period from April 1994 to November 1997.

Design: Prospective survival study. Overall survival, survival stratified by preoperative presentation, and acute postoperative response were investigated using Kaplan-Meier methods. The simultaneous effects of preoperative predictors and postoperative response variables on survival were examined using a Cox proportional hazards model.

Setting: Community hospital and university medical center.

Patients: We studied 256 consecutive patients with severe emphysema treated with LVRS.

Interventions: Bilateral staple LVRS by VATS.

Measurements and results: Overall survival information was known with certainty for 246 of 256 patients as of February 1, 1998. Median follow-up time was 623 days (range, 0 to 1,545 days). Mean FEV₁ was 0.635L ± 0.015 L preoperatively and rose to 1.068L ± 0.029 L postoperatively. By standard analysis methods (missing patients censored at the time of last contact), 1-year survival was 85 ± 2.3% compared with 83 ± 2.4% 1-year survival with “worst case” analytic methods (assuming all missing patients died). Two-year survival averaged 81 ± 2.7% by standard analysis vs 76 ± 2.9% by worst case evaluation. Survival was significantly better for patients who were younger (≤ 70 years old, p = 0.02) and with higher baseline FEV₁ (> 0.5, p < 0.03) and Po₂ (> 54, p < 0.001). Patients who had greatest short-term improvement in FEV₁ following surgery (> 0.56 L increase) also had significantly better longer-term survival following LVRS.

Conclusions: To our knowledge, this is the first longer-term survival analysis of a large series of patients who underwent bilateral staple LVRS for emphysema. Substantial long-term mortality is seen, particularly within identifiable high-risk subgroups. Careful comparison to comparably matched control patients will be needed to definitively assess the benefits and risks of LVRS. This study suggests that prospective, controlled trials may need to stratify patient randomization based on preoperative risk factors to obtain meaningful results.

Abbreviations: Dlco = carbon monoxide diffusing capacity; LVRS = lung volume reduction surgery; NIH = National Institutes of Health; VATS = video-assisted thoracoscopic surgery

Study objective: To determine whether recipients of lung transplants have a higher risk of bleeding from fiberoptic bronchoscopy (FOB) than other patients who undergo the procedure.

Design: Prospective cohort study.

Setting: Bronchoscopy services of Johns Hopkins Hospital, a tertiary referral center and Johns Hopkins Bayview Medical Center, a community hospital.

Patients: All adult patients (18 years) who underwent FOB between July 1, 1996 and June 30, 1997 by the full-time pulmonary medicine staff were included. A total of 720 procedures were performed, including 38 in lung transplant recipients.

Measurements: Bleeding was assessed by reviewing physician reports of bloody drainage after the procedure and whether the procedure was terminated early for bleeding. Patient reports of hemoptysis were assessed using questionnaires administered pre- and post-FOB. Predictor variables included patient demographics, bleeding parameters (platelets, prothrombin time, and activated partial thromboplastin time), immunosuppressive medications, aspirin use, use of transbronchial biopsy, and the time length of the procedure.

Results: Lung transplant recipients were significantly more likely to have used aspirin prior to FOB (18.4 vs 7.2%, p < 0.05) and to undergo transbronchial biopsy (64.9 vs 26.8%, p < 0.001). Lung transplant patients were more likely to have new or worsened hemoptysis (53.8 vs 24.6%, p < 0.001), to have> 25 mL of blood loss (44.5 vs 17.5%, p < 0.001) and to have the procedure terminated early for bleeding (5.4 vs 1.0%, p < 0.05). In multivariate analysis, predictors of new or worsened hemoptysis included lung transplant, longer procedure time, and older patient age. Independent predictors of greater blood loss included lung transplant, performance of transbronchial biopsy, longer procedure time, and older patient age.

Conclusions: Lung transplant recipients are at higher risk of bleeding from bronchoscopy than are other patients. This propensity to bleed is independent of coagulation parameters, platelet count, immunosuppressive medication use, aspirin use, or performance of transbronchial biopsy. The higher risk of bleeding should be considered when assessing the risks and benefits of bronchoscopy in lung transplant recipients.

Abbreviations: aPTT = activated partial thromboplastin time; BRONCHQI = bronchoscopy quality improvement project; FOB = fiberoptic bronchoscopy; PT = prothrombin time; TBBx = transbronchial biopsy

Study objectives: To evaluate whether findings from surveillance bronchoscopy predict survival following lung transplantation.

Design: Retrospective review and analysis of 498 bronchoscopies with transbronchial biopsy (TBB) and BAL performed in 34 patients after lung transplantation.

Setting: University-based, tertiary referral medical center.

Patients: Thirty-four patients after lung transplantation. The mean age at transplantation was 49 ± 9 years; 20 (59%) were female. Twenty-four (71%) underwent single and 10 (29%) underwent bilateral lung transplantation. The most common pretransplantation diagnostic groups were emphysema/COPD without concomitant α₁-antiprotease deficiency (n = 13) and other obstructive disease processes (n = 10).

Interventions: Over follow-up, subjects underwent multiple bronchoscopies with TBB and BAL. The median number per subject was 15 (25 to 75% range 13 to 17).

Measurements and results: We calculated the overall median BAL WBCs and median percent neutrophils (polymorphonuclear leukocytes [PMNs]) among all of the BALs performed for each subject. We then calculated the mean ± SD of those median values. We used Cox proportionate hazards to assess mortality risk. The median overall follow-up observation period for the cohort was 560 days. There were 11 deaths during this period. Twenty-four subjects (71%) had acute rejection (AR) grades 2 to 4 (mild to severe), and nine (27%) had obliterative bronchiolitis (OB) diagnosed by TBB at any point. The mean value for BAL WBCs was 366 ± 145 × 10³ per milliliter; for percentage PMNs, the mean was 7 ± 10%. Adjusting for age, gender, single vs bilateral lung transplantation, pretransplantation diagnostic group, presence of AR, presence of OB, BAL WBC concentration, and lymphocyte CD4/CD8 ratio, PMN percent was a significant predictor of mortality (p = 0.02).

Conclusions: Ongoing inflammation manifested by an increased percentage PMNs over repeated bronchoscopies predicts mortality following lung transplantation. Biopsy data alone may be insufficient to identify posttransplantation patients at risk of poor outcome.

Abbreviations: AR = acute rejection; BOS = bronchiolitis obliterans syndrome; CMV = cytomegalovirus; OB = obliterative bronchiolitis; PFT = pulmonary function test; PMNs = neutrophils (polymorphonuclear leukocytes); TBB = transbronchial biopsy; UCSF = University of California, San Francisco

Background: Peak exercise oxygen consumption (peak V̇o₂), which is considered an indicator of prognosis in advanced heart failure, is currently being used as a major criterion in many centers for the selection of candidates for heart transplantation. Available studies suggest that patients with peak V̇o₂ < 14 mL/min/kg have improved survival and significant functional benefit with transplantation. Since patients may terminate symptom-limited exercise tests for a variety of reasons, peak V̇o₂ does not necessarily reflect maximal V̇o₂, leading to the possibility of inappropriate selection for transplantation. Therefore, we investigated the proportion of transplant candidates referred for exercise testing considered to have achieved maximal results from studies.

Methods: Fifty-five patients with heart failure, aged 51 ± 9 years, (mean ± SD) underwent maximum symptom-limited exercise tests on a cycle ergometer utilizing a Jones stage 1 incremental protocol. Tests were considered maximal if subjects achieved peak heart rate (HR) > 85% predicted (“cardiocirculatory limitation”) or peak minute ventilation (V̇e) > 85% predicted (“ventilatory limitation”), and achieved an anaerobic threshold (AT) by noninvasive measures.

Results: Seven tests were terminated because of chest pain, ST-segment abnormalities, or ventricular arrhythmias. Of the remaining 48 studies, the reasons for stopping exercise were leg fatigue in 52%, dyspnea in 16%, and both symptoms in 23%. Sixteen of the 48 patients (33%) had peak V̇o₂ < 14 mL/min/kg. In 8 of these 16 patients, both peak HR and V̇e were < 85% predicted. Of these eight without apparent HR or ventilatory limitation, none had oxygen desaturation below 90% or fall in BP, two were in atrial fibrillation, and only three had evidence that an AT was achieved.

Conclusions: Among the patients with peak V̇o₂ < 14 mL/min/kg, there were no objective signs of a cardiocirculatory or a respiratory limitation to exercise in half of them, and 31% did not achieve an AT either, thus not meeting any criteria to support evidence of maximal exercise. Exercise tests without objective evidence of cardiocirculatory or ventilatory limitation may not represent maximal performance. Consequently, peak V̇o₂ may misclassify an appreciable proportion of candidates if the test results are submaximal.

Clinical implications: Clinical exercise studies indicating low peak V̇o₂ must be interpreted in the context of whether a defined objective exercise limitation is evident to avoid biasing the selection of heart transplant candidates.

Abbreviations: AT = anaerobic threshold; BMI = body mass index; HR = heart rate; LVEF = left ventricular ejection fraction; MVV = maximum voluntary ventilation; RER = respiratory exchange ratio; SaO₂ = arterial oxygen saturation; V̇e = minute ventilation; V̇o₂ = oxygen consumption; V̇o₂max = maximum oxygen consumption

Study objectives: Previous studies have showed that the pericardium is frequently involved in HIV infection. However, the characteristics and etiology of the pericardial abnormalities that have been found remained poorly defined. We analyzed the features of pericardial involvement in these patients and investigated the clinical variables associated with moderate and severe effusions.

Design: Prospective, clinical, and echocardiographic study.

Setting: The service of infectious diseases of a university hospital.

Patients: 181 consecutive patients at all stages of HIV infection.

Results: Only one patient (0.55%) had acute pericarditis. Seventy-five patients (41%) had an asymptomatic pericardial effusion; in 23 patients (13% of all patients), the effusion was either moderate or severe. Ten cases (5.5% of all patients) of moderate or severe effusions resulted in right atrium diastolic compression, and three of these cases (1.6% of all patients) required pericardiocentesis for the management of tamponade. Six patients (3%) presented with echogenic pericardial masses of undetermined etiology. A moderate or severe effusion was present in a greater number of patients with symptomatic HIV infection than was present in asymptomatic HIV-infected patients, respectively: 17 vs 2% (p = 0.015). The following are variables independently associated with moderate or severe pericardial effusions: heart failure (odds ratio, 20.3; p = 0.0001); Kaposi’s sarcoma (odds ratio, 8.6; p = 0.01), tuberculosis (TB; odds ratio, 47.2; p = 0.0006); and other pulmonary infections (odds ratio,15.0; p = 0.02).

Conclusions: Most of these moderate or severe effusions are clinically unsuspected, but they can lead to life-threatening tamponade. This fact seems to justify echocardiographic surveillance in HIV-infected patients, especially in those with heart failure, Kaposi’s sarcoma, TB, or other pulmonary infections.

Abbreviations: ARC = AIDS-related complex; TB = tuberculosis

Study objective: The presence of pleural adhesions may render video-assisted thoracoscopic surgery (VATS) difficult or impossible. The aim of this study was to assess the value of chest CT in the detection of pleural adhesions prior to VATS.

Design: Prospective study of the accuracy of chest CT in detecting pleural adhesions prior to VATS.

Setting: Tertiary-referral teaching hospital and Veterans Administration hospital.

Patients: Between July 1994 and March 1995, 63 consecutive patients undergoing 64 VATS procedures were evaluated with chest CT prior to surgery.

Measurements and results: Preoperative scans were interpreted by consensus of two pulmonary radiologists prior to surgery. Suspected pleural adhesions and other findings related to the pleura were recorded on a form given to the surgeon prior to VATS. The surgeon confirmed or excluded each suspected adhesion during VATS, and documented any other lesions not identified preoperatively. Patient-by-patient and lesion-by-lesion analyses were performed. Pleural adhesions were correctly identified by CT in 28 of 39 cases (sensitivity, 71%) and excluded in 18 of 25 cases (specificity, 72%). On a lesion-by-lesion basis, 73 adhesions were identified during VATS, of which only 28 were identified prospectively at CT. There were 45 missed adhesions and 20 adhesions that were suggested falsely (sensitivity, 38%; specificity, 46%). Eighteen pleural spaces were correctly identified as being free of pleural adhesions.

Conclusions: CT is moderately sensitive and specific for preoperative identification of pleural adhesions in patients undergoing VATS but its accuracy is poorer for individual lesions.

Abbreviations: HRCT = high-resolution CT; VATS = video-assisted thoracoscopic surgery

Background: Pulmonary tuberculosis (PTB) develops by a complex combination of environmental factors with genetic susceptibility. In this context, an association between human leukocyte antigens (HLAs) and tuberculosis has been examined in several populations, but results have been controversial.

Design and measurements: A prospective evaluation of class II HLA genotypes was completed by the polymerase chain reaction (PCR) sequence-specific primer technique and PCR sequence-specific oligonucleotide hybridization in a Mexican population.

Setting: This study was conducted at the Clinical Service of Tuberculosis and the Department of Immunology, National Institute of Respiratory Diseases, México City, México.

Patients: Four groups were examined: 95 healthy subjects; 50 nonimmunosuppressed PTB patients; 15 HIV-infected patients (stage IVc in the Centers for Disease Control and Prevention [CDC] classification system for AIDS) with PTB; and 37 HIV-infected patients in the asymptomatic stage (CDC stage II).

Results: The frequencies of alleles DQA1*0101 (odds ratio [OR], 6.18; 95% confidence interval [CI], 2.38 to 16.08), DQB1*0501 (OR, 6.16; 95% CI, 2.44 to 17.71), and DRB1*1501 (OR, 7.92; 95% CI, 2.71 to 23.14) were significantly increased in nonimmunosuppressed patients with PTB when compared with healthy subjects. By contrast, frequencies of allele DQB1*0402 and antigens DR4 and DR8 were significantly decreased in patients with PTB. Additionally, a significantly higher frequency of the DRB1*1101 allele was found in HIV-positive subjects (OR, 6.67; 95% CI, 2.13 to 20.83).

Conclusion: The genetic influence associated with the HLA system appears to have an important role in the development of PTB, although this susceptibility may not be relevant in patients with severe immunodeficiency diseases such as AIDS.

Abbreviations: CI = confidence interval; CDC = Centers for Disease Control and Prevention; EDTA =ethylenediaminetetraacetic acid; HLA = human leukocyte antigen; MHC = major histocompatibility complex; OR = odds ratio; PCR = polymerase chain reaction; PTB = pulmonary tuberculosis; SSPE = sodium chloride, sodium phosphate, and EDTA; TB = tuberculosis

Study objective: Cough is a common symptom in children that is frequently encountered in general practice. However, most of the information on the prevalence of persistent cough has come from studies that use different, often ambiguous, definitions for persistent cough. It is therefore important that a validated questionnaire to accurately measure persistent cough is developed and is appropriate for use in different age groups of children and in different cultures. Such a questionnaire is essential for accurately measuring the prevalence of persistent cough and the factors associated with its occurrence.

Design: A parent-administered respiratory questionnaire was developed and administered twice during a 3-week interval pilot study to test repeatability. The questionnaire was then administered to a randomly selected cross-section of Australian children aged 5 to 7 years old and 8 to 11 years old (N = 511 and N = 654, respectively), and to 566 Nigerian children aged 8 to 11 years old.

Results: The new questionnaire was reliable, with most of the questions having a κ value of above 0.6. The prevalence of persistent cough was similar in younger and older Australian children, but significantly less in Nigerian children (p < 0.001). Also, persistent cough was more prevalent in children of high rather than low socioeconomic status among older Australian children (p = 0.04).

Conclusions: The newly developed questionnaire will be an important tool in epidemiological studies for measuring the prevalence, morbidity, and risk factors of persistent cough in childhood. Although our findings showed that persistent cough does not occur more frequently in younger than in older Australian children, it is more frequent in Australian than in Nigerian children.

Abbreviations: SES = socioeconomic status

Background: The link between travel and the risk of venous thromboembolic disease (VTED) has been widely suspected. However, only cases or series of cases have been reported in the literature.

Study objectives: By means of a case-control study, we sought to confirm this relationship and to determine the main features, if any, of these posttravel VTEDs.

Design: The history, in particular the history of recent travel, of 160 patients presenting in our department with VTED was scrupulously investigated. All journeys undertaken during the preceding 4 weeks and lasting > 4 h by whatever means of transport were considered. The same questionnaire was submitted to a control group.

Results: When the two groups of patients are compared, a history of recent travel is found almost four times more frequently in the VTED group (p < 0.0001). The odds ratio for having a VTED in patients who traveled was 3.98 (95% confidence interval, 1.9 to 8.4). Means of travel used included the train in 2 cases, airplane in 9, and car in 28. Mean duration of travel was 5.4 ± 2.1 h. These posttravel VTEDs are not confined to a specific location, seem to involve no particular predisposition, and are more often “idiopathic.” This fact supports the hypothesis that travel alone can produce vein clot formation.

Conclusions: A history of recent travel is a risk factor for VTED. Posttravel venous thrombotic events can occur after short journeys in patients with no other risk factors or concomitant disease

Abbreviations: CI = confidence interval; DVT = deep venous thrombosis; OR = odds ratio; PE = pulmonary embolism; VTED = venous thromboembolic disease

Objectives: To describe the early symptoms of pulmonary tuberculosis (TB) when the chest radiograph (CXR) is normal.

Setting: Centralized, provincial TB control program.

Subjects: Twenty-five patients with culture-positive pulmonary TB and a normal CXR were identified from a review of 518 consecutive patients with culture-positive pulmonary TB in the province of Saskatchewan from January 1, 1988 to March 31, 1997. Patients with abnormal CXRs at the time of diagnosis were excluded from the analysis.

Results: Twenty-three of the 25 patients (92%) were symptomatic at the time of diagnosis, with cough/sputum (76%) being reported most commonly. Eleven patients were identified because of contact tracing from cases of infectious pulmonary TB, while the other 14 patients were identified because of an investigation of symptoms. Twenty-four patients (96%) exhibited one or more symptoms of cough for > 1 month, fever for > 1 week, or skin-test conversion after contact with infectious TB. The sputum smear of only one patient was positive. Two patients were pregnant at the time of diagnosis, one patient was HIV-positive, and one patient demonstrated isoniazid-resistant organisms on sensitivity testing. Five patients were diagnosed as having primary TB associated with Mantoux skin-test conversion. The incidence of culture-positive pulmonary TB with a normal chest radiograph was < 1% in the period from 1988 to 1989 and steadily increased to 10% in the period from 1996 to 1997.

Conclusions: Culture-positive pulmonary TB with a normal CXR is not uncommon, and the incidence of this presentation is increasing. Patients with this presentation of TB are typically symptomatic and/or are detected by contact tracing to infectious cases of pulmonary TB. The results suggest that patients presenting with a cough for > 1 month, with a fever for > 1 week, or with documented skin-test conversion < 2 years after known exposure to infectious TB should have sputum submitted for a Mycobacterium tuberculosis smear and culture despite a normal CXR.

Abbreviations: CXR = chest radiograph; TB = tuberculosis

Objective: To evaluate the effects of increased oxygen delivery on mortality and morbidity.

Design: Randomized, controlled trial.

Setting: Medical-surgical ICU of a tertiary care hospital.

Patients: Sixty-three patients classified according to predetermined criteria as having severe sepsis or septic shock.

Interventions: The patients were randomly assigned to one of two groups: the control group (n = 32) received conventional therapy with a normal targeted value of oxygen delivery, and the treatment group (n = 31) received therapy with a targeted oxygen delivery index (Do₂i) value of> 600 mL/min/m². The therapeutic approach to maintain BP, arterial saturation, hemoglobin concentration, and pulmonary artery occlusion pressure was similar in both groups.

Measurements and main results: The hemodynamic, oxygen transport, and gastric intramucosal pH measurements were recorded at the time of admission to the study and every 6 h for the next 96 h. The outcome measures were the rate of patient mortality and the number of organ dysfunctions occurring during the ICU stay. The study groups were similar with respect to demographics and admission hemodynamic variables, but the percentage of patients with positive blood cultures was significantly higher in the control group than in the treatment group, respectively: 34 vs 13% (p = 0.04). The average cardiac index was significantly higher in the treatment group than in the control group, respectively: 3.96 vs 3.05 L/min/m² (p = 0.01). This factor did not significantly affect the Do₂i. Nine of the 31 treatment group patients reached an average Do₂i value of > 600 mL/min/m². The rate of mortality in the control group patients up to the time of ICU discharge (66%) was similar to that seen in the treatment group (74%), respectively: 21 of 32 vs 23 of 31 (p = 0.46). The number of dysfunctional organs per patient was also similar in the control and treatment groups, respectively: 2.1 ± 1.1 vs 2.6 ± 1.2 (p = 0.12).

Conclusion: Treatment aimed at maximizing oxygen delivery in patients with severe sepsis or septic shock does not reduce mortality or morbidity.

Abbreviations: CI = cardiac index; Do₂i = oxygen delivery index; Fio₂ = fraction of inspired oxygen; Hb = hemoglobin; PAOP = pulmonary artery occlusion pressure; pHi = gastric intramucosal pH; RR = relative risk; Sao₂ = arterial oxygen saturation; Svo₂ = mixed venous saturation; V̇o₂i = oxygen consumption index

Study objective: To evaluate the relationship between inadequate antimicrobial treatment of infections (both community-acquired and nosocomial infections) and hospital mortality for patients requiring ICU admission.

Design: Prospective cohort study.

Setting: Barnes-Jewish Hospital, a university-affiliated urban teaching hospital.

Patients: Two thousand consecutive patients requiring admission to the medical or surgical ICU.

Interventions: Prospective patient surveillance and data collection.

Measurements and results: One hundred sixty-nine (8.5%) infected patients received inadequate antimicrobial treatment of their infections. This represented 25.8% of the 655 patients assessed to have either community-acquired or nosocomial infections. The occurrence of inadequate antimicrobial treatment of infection was most common among patients with nosocomial infections, which developed after treatment of a community-acquired infection (45.2%), followed by patients with nosocomial infections alone (34.3%) and patients with community-acquired infections alone (17.1%) (p < 0.001). Multiple logistic regression analysis, using only the cohort of infected patients (n = 655), demonstrated that the prior administration of antibiotics (adjusted odds ratio [OR], 3.39; 95% confidence interval [CI], 2.88 to 4.23; p < 0.001), presence of a bloodstream infection (adjusted OR, 1.88; 95% CI, 1.52 to 2.32; p = 0.003), increasing acute physiology and chronic health evaluation (APACHE) II scores (adjusted OR, 1.04; 95% CI, 1.03 to 1.05; p = 0.002), and decreasing patient age (adjusted OR, 1.01; 95% CI, 1.01 to 1.02; p = 0.012) were independently associated with the administration of inadequate antimicrobial treatment. The hospital mortality rate of infected patients receiving inadequate antimicrobial treatment (52.1%) was statistically greater than the hospital mortality rate of the remaining patients in the cohort (n = 1,831) without this risk factor (12.2%) (relative risk [RR], 4.26; 95% CI, 3.52 to 5.15; p < 0.001). Similarly, the infection-related mortality rate for infected patients receiving inadequate antimicrobial treatment (42.0%) was significantly greater than the infection-related mortality rate of infected patients receiving adequate antimicrobial treatment (17.7%) (RR, 2.37; 95% CI, 1.83 to 3.08; p < 0.001). Using a logistic regression model, inadequate antimicrobial treatment of infection was found to be the most important independent determinant of hospital mortality for the entire patient cohort (adjusted OR, 4.27; 95% CI, 3.35 to 5.44; p < 0.001). The other identified independent determinants of hospital mortality included the number of acquired organ system derangements, use of vasopressor agents, the presence of an underlying malignancy, increasing APACHE II scores, increasing age, and having a nonsurgical diagnosis at the time of ICU admission.

Conclusions: Inadequate treatment of infections among patients requiring ICU admission appears to be an important determinant of hospital mortality. These data suggest that clinical efforts aimed at reducing the occurrence of inadequate antimicrobial treatment could improve the outcomes of critically ill patients. Additionally, prior antimicrobial therapy should be recognized as an important risk factor for the administration of inadequate antimicrobial treatment among ICU patients with clinically suspected infections.

Abbreviations: APACHE = acute physiology and chronic health evaluation; CI = confidence interval; OR = odds ratio; ORSA = oxacillin-resistant Staphylococcus aureus; RR = relative risk; VAP = ventilator-associated pneumonia; VRE = vancomycin-resistant enterococci

Study objectives: The purpose of this cross-sectional study was to confirm the observation that pulse oximetry tracing correlates with pulsus paradoxus, and is therefore a measure of the severity of air trapping in obstructive airway disease.

Design: Cross-sectional survey.

Setting: The ICU in a tertiary care academic hospital.

Patients: Twenty-six patients consecutively admitted to the ICU with obstructive airway disease, either asthma or COPD.

Measurements and results: Forty-six percent of the study patients required mechanical ventilation, and 69% had an elevated pulsus paradoxus. We defined the altered pulse oximetry baseline tracing as the respiratory waveform variation (RWV). The RWV was measured in numerical form as the change in millimeters from the baseline. Pulsus paradoxus was significantly correlated with the RWV of the pulse oximetry tracing (p < 0.0001). An analysis of the respiratory variations in the pulse oximetry waveforms in obstructive lung disease patients reflects the presence and degree of auto-positive end-expiratory pressure (auto-PEEP; p < 0.0001).

Conclusions: We describe the characteristic alterations in the pulse oximetry tracings that occur in the presence of pulsus paradoxus and auto-PEEP. Since pulse oximetry is available universally in ICUs and emergency departments, it may be a useful noninvasive means of continually assessing pulsus paradoxus and air trapping severity in obstructive airway disease patients.

Abbreviations: AC = alternating current; auto-PEEP = auto-positive end-expiratory pressure; DC = direct current; RWV = respiratory waveform variation; VMICU = Vanderbilt Medical Intensive Care Unit; WOB = work of breathing

Study objectives: To ascertain whether inspiratory pressure support (IPS) can be triggered reliably from and targeted at esophageal pressures (Pes), and to compare the work of breathing and time delay to initiation of inspiratory flow between conventional pressure support and esophageal-directed pressure support (EDPS).

Design: Prospective laboratory study.

Setting: University medical school.

Patients or participants: Five normal volunteers.

Interventions: IPS at a level to achieve tidal volume of 10 mL/kg, and EDPS with a target Pes of 0 cm H₂O via full facemask.

Measurements and results: Pes, airway pressure, and inspiratory flow were measured during spontaneous breathing. Peak Pes and pressure time product (PTP) of Pes were calculated during spontaneous breathing and through linear resistances. Measurements were repeated during IPS and EDPS ventilation. At rest, PTP was 7.56 (± 3.6) and peak Pes was −5.8 cm H₂O (± 1.44). When subjects were breathing through the resistors, PTP increased to 12.4 (± 8.1) and 30.3 (± 8.9) and peak Pes decreased to −7.2 and −15.3 cm H₂O respectively. With facemask IPS, unloaded PTP fell to 1.7 (± 1.3) and peak Pes fell to −3.3 cm H₂O (± 1.3). When ventilated through the highest resistance with IPS, mean PTP increased to 21.9 and peak Pes increased to −11.9 (± 4.2) cm H₂O relative to baseline. During EDPS with the resistor, PTP fell to 1.5 ± 1.1 (p < 0.007) and peak Pes fell to −1.9 ± 1.1 cm H₂O (p < 0.0001).

Conclusions: It was possible to initiate supported breathing from Pes values. The work performed, as measured by PTP, was lower during EDPS than during either unsupported breathing or conventional IPS.

Abbreviations: EDPS = esophageal-directed pressure support; IPS = inspiratory pressure support; PEEP = positive end-expiratory pressure; Pes = esophageal pressure; PTP = pressure time product

The aim of the present study was to compare, in rabbits, the biocompatibility and suitability of a bioabsorbable spiral stent made of self-reinforced poly-l-lactide (SR-PLLA) in the management of experimental tracheal stenosis with stents made of metal and silicone. Tracheobronchial stenosis, and its management, is still problematic because stenoses are not always amenable to surgical resection and reconstruction, especially concerning anastomotic problems and stenosis after lung transplantation. Stenosis can be handled with stenting, although the ideal stent has yet to be developed; all the stents available have their disadvantages. Because stenting of the airways can be only temporary, stents made of bioabsorbable materials, theoretically, offer benefits. Tracheal stenosis was created in rabbits by the extramucosal resection of cartilaginous arches of the cervical trachea. After a few weeks, the animals were operated on again, and those stenoses that had developed were dilated with a balloon. Stents then were implanted in the area of stenosis to keep the dilated trachea open. All the animals in the group with silicone stents had to be killed because of respiratory difficulties: their stents had a tendency to occlude because of internal encrustation, and they developed a hyperplastic polyp at the ends of the stents. The SR-PLLA and metallic stents were tolerated well, and after follow-up ended the animals were put to death. This experimental study showed that silicone stents had a tendency to occlude and that stents made of metal and of SR-PLLA were well tolerated and can be used in the management of airway stenosis.

Abbreviations: SEM = scanning electron microscope; SR-PLLA = self-reinforced poly-l-lactide

Study objectives: To assess the usefulness of an animal model for testing new tracheobronchial stents.

Setting: Animal laboratory of a university hospital.

Animals and interventions: In a series with 12 mini-pigs, we induced a stable fibromalacic tracheal stenosis that was 50% to 70% of the normal tracheal diameter. After dilation we inserted a 16 × 40-mm self-expandable silicone stent into the stenotic part of the trachea in 10 of the mini-pigs. Five of the stents had a smooth outer surface, and five had additional silicone retaining spikes. Because of a long stenosis in two of the mini-pigs, two overlapping stents (one smooth and one with spikes) were inserted.

Measurements and results: Stent deployment was successful and resulted in the disappearance of the slight to moderate stridor in all of the mini-pigs. Over a mean (± SD) observation period of 24 days (range, 10 to 41 days), all of the mini-pigs redeveloped stridor. Three of them died unexpectedly of suffocation: in all three a smooth stent had migrated, leading to total obstruction of the stenosis. In total, five of the six smooth stents migrated, and only one of the six spiked stents migrated. There was considerable granulation tissue formation at the ends of all of the stents. In the two control mini-pigs, a 12 × 35-mm Dumon stent was inserted. Both Dumon stents migrated, and one of them had considerable granuloma formation at its ends. At the end of the observation period, all stents were removed endoscopically and were found not to have deteriorated over time.

Conclusions: Our model proved to be suitable for the evaluation of the technical aspects of the Polyflex stent. Spikes on the outer stent surface are more effective in preventing migration than smooth-surface stents. Long-term compatibility, however, seems to be difficult to test with our model because both the Polyflex and the Dumon stents had excessive granulation tissue formation at both ends, a factor which—in the case of the Dumon stent—does not occur to such a degree in benign human airway stenoses. Our results indicate a need for prospective long-term studies in benign human airway stenoses.

Study objective: To look at the effect of interstitial photodynamic therapy (PDT) in normal lung parenchyma to assess its potential for treating localized, peripheral lung tumors.

Design: Studies were performed on normal Wistar rats using the photosensitizer meso-tetrahydroxyphenyl chlorine. Drug distribution was measured by fluorescence microscopy on tissue sections. Light was delivered to the lungs via a single fiber inserted percutaneously under x-ray control and the PDT effect studied in animals killed at times up to 6 months later.

Results: Fluorescence studies showed that the drug was initially distributed throughout the lung, but was later predominantly in the vasculature, bronchi, and macrophages. PDT produced sharply defined zones of hemorrhagic necrosis up to 12 mm in diameter that healed with regeneration of bronchial epithelium and local fibrosis. Different histologic effects were seen between drug light intervals of 1 and 3 days. Treatment was well tolerated, there was a low incidence of pneumothorax, and as long as the fiber tip was within the lung parenchyma, there was no damage to adjacent tissues.

Conclusion: Interstitial PDT produces zones of necrosis in normal lung that heal safely by a percutaneous technique without affecting adjacent areas of untreated lung. If the lesion size can be increased by using multiple fibers, this could be a promising new technique for treating localized, peripheral lung cancers in patients who are unfit for surgery.

Abbreviations: CCD = charge coupled device; H & E = hematoxylin-eosin; mTHPC = meso-tetrahydorxyphenyl chlorin; PDT = photodynamic therapy

Pulmonary manifestations of pheochromocytoma are infrequent and are not well documented. A MEDLINE search in the English language revealed no cases of endobronchial involvement from a pheochromocytoma. We report a case of endobronchial metastases in a 37-year-old woman known to have a recurrent extra-adrenal pheochromocytoma. She presented with symptoms of wheezing and a nonproductive cough for 8 months and was being treated for asthma. A flexible bronchoscopy with endobronchial biopsy established the diagnosis. The patient underwent a Nd-YAG laser photoresection (LPR) to ablate the tumor, which was followed by placement of a Wallstent (Pfizer Medical Technology Group; Rutherford, NJ). She remains well 18 months later, having required multiple palliative LPRs. To our knowledge, this is the first reported case of endobronchial pheochromocytoma. The pulmonary manifestations of this rare disease and their management are reviewed.

Abbreviations: BI = bronchus intermedius; FB = flexible bronchoscopy; LPR = laser photoresection; MIBG-I¹³¹ = metiodobenzyl-guanidine-iodine 131; RML = right middle lobe; SCLC = small cell lung carcinoma

To define the epidemiology, pathogenesis, pathology, presentation, and management of tuberculous mycotic aneurysm of the aorta (TBAA) in the therapeutic era, we reviewed all of the cases reported in the English language literature from 1945 to the present. To the 39 cases in the published literature, we add two cases of our own. Although it is exceedingly rare, the prevalence of this lesion has remained relatively constant. In 75% of the cases, TBAA appeared to result from erosion of the aortic wall by a contiguous focus; 25% from direct seeding of the aortic intima or of the adventitia or media (via the vasa vasorum). Most of the aneurysms were saccular (90%) and false (88%). The thoracic and abdominal aortas were affected with equal frequency. The mean (± SD) age of the patients was 50 ± 16 years. Twenty-two were men, and 19 were women. In 63% of the cases, tuberculosis (TB) was diagnosed at presentation. Disseminated TB was present in 46% of the cases. One or more of three clinical scenarios suggested TBAA: persistent pain, major bleeding, and a palpable or radiographically visible para-aortic mass, especially if it is expanding or pulsatile. In turn, each of these findings suggested a complication of TBAA that may be an indication for surgical intervention. Among the patients who were offered both medical and surgical treatment, 20 of 23 (87%) survived. Among those who were offered only one form of treatment or were offered no treatment at all there were no survivors. Both in situ reconstruction with a prosthetic graft, and extra-anatomic bypass appeared to offer excellent results, provided that an effective regimen of antituberculous drugs was delivered postoperatively. We offer our conclusions: (1) symptomatic TBAA is a rare but uniformly fatal lesion if not diagnosed promptly, (2) in the context of active TB, and especially miliary TB, TBAA should be suspected whenever one or more of the three clinical scenarios are present, and (3) combined medical and surgical therapy appears to offer the best chance of a cure.

Abbreviations: TB = tuberculosis; TBAA = tuberculous mycotic aneurysm of the aorta

Study objectives: A frequent complication of the widely used Dumon silicone stent is its tendency to migrate when used in tracheal stenosis. We compared the clinical efficacy and complications (including migration) of the Dumon stent with a screw-thread stent, a device with an increased stent-to-wall contact surface and, theoretically, less tendency to migrate.

Design: Retrospective case analysis.

Setting: Academic hospital.

Materials and methods: Forty-six patients with tracheal stenoses (23 benign and 23 malignant) requiring the placement of 50 stents (29 Dumon and 21 screw-thread) were studied. In 26 patients Dumon stents were used, and in 20 patients screw-thread stents were used. Both patient groups had comparable clinical and stenosis-related characteristics.

Results: Stent insertion and follow-up were uneventful in both the Dumon and the screw-thread insertions, respectively: 62% vs 67% (not significant). There were seven migrations in the Dumon group, compared to only one migration in the screw-thread group, respectively: 24% vs 5%. This difference did not reach statistical significance (p = 0.1). All of the migrations occurred in the benign stenosis group, and none occurred in the malignant-stenosis group, respectively: 8 of 23 vs 0 of 23, p = 0.004. Within the benign-stenosis group, the Dumon stent had a significantly increased risk for migration when compared to the screw-thread stent, respectively: 7 of 13 vs 1 of 11, p = 0.033.

Conclusions:The screw-thread stent and the Dumon stent are equally effective in the management of tracheal stenosis. There is a general trend toward a decreased migration rate, and a significantly lower risk for migration in patients with benign tracheal stenosis. The (less expensive) screw-thread stent may represent an attractive alternative in the management of tracheal stenosis in general, and may be preferable to the Dumon stent in treating benign tracheal stenosis.

This review examines the hypothesis that excess lung cancer risk in worker cohorts exposed to asbestos occurs only among those with asbestosis. The adequately designed studies in the literature support this hypothesis. The summary relative risk for lung cancer was 1.00 in seven cohorts with no deaths from asbestosis. In addition, there is a high correlation between asbestosis rates and lung cancer rates in 38 cohorts in contrast to a poor correlation between cumulative exposure data and lung cancer relative risks in eight cohorts with adequate data. The evidence indicates that asbestosis is a much better predictor of excess lung cancer risk than measures of exposure and serves as a marker for attributable cases.

Abbreviations: CI = confidence interval; f/mL = fibers per milliliter; mppcf = million particles (dust) per cubic foot; RR = relative risk; SIO = small irregular opacities; SMR = standardized mortality (or morbidity) ratio; SMSA = standard metropolitan statistical area

Abbreviations: BHR = bronchial hyperresponsiveness; EAHR =extrathoracic airway hyperresponsiveness; IL = interleukin

Study objective: To evaluate if direct substitution of arm span for height during interpretation of spirometry data leads to any significant statistical or clinical differences in Indian adults, and to compare this method with the use of height estimated indirectly from arm span.

Design: Cross-sectional.

Setting: Respiratory laboratory of a tertiary referral hospital in North India.

Participants: Two hundred twenty-eight subjects referred for spirometry.

Measurements and results: Standing height and arm span were measured for all subjects. Spirometry measurements included FVC, FEV₁, FEV₁/FVC, peak expiratory flow, and maximal midexpiratory flow. Predicted values for each parameter were calculated separately for height, arm span, and height estimated from fixed height:arm span ratio. Results were classified into normal, obstructive, and restrictive defects for each height, arm span, and estimated height measurement, and any abnormality was categorized as mild, moderate, or severe. Arm span exceeded height in 182 (79.82%) subjects. Thirty-seven (16.2%) and 32 (14.0%) results were classified or categorized incorrectly when arm span and estimated height were substituted respectively, for actual height, with a kappa estimate of agreement 0.779 and 0.808, respectively; 17.4% and 11.0% normal results were classified, respectively, as restrictive defects using arm span and estimated height. Limits of agreement, which were almost equally wide for both sets of data, were more than the permissible intraindividual variability for FVC and FEV₁.

Conclusions: The substitution of arm span for height introduces statistically significant changes in spirometry results. Use of height estimated from arm span using fixed ratio also leads to misclassification of data, though less than that caused by use of arm span alone. Height estimated from arm span can be substituted for actual height in patients in whom height cannot be measured reliably. Where racial/ethnic norms for height and arm span correlation are not available, arm span is a reasonable surrogate for standing height.

Abbreviations: FEF_25–75% = maximal midexpiratory flow; PEF = peak expiratory flow

Study objective: To determine the indications for preoperative localization of a small indeterminate pulmonary nodule.

Design: In this retrospective study, univariate and multivariate analyses were performed by the logistic regression procedure.

Setting: A single National Cancer Center Hospital in Japan.

Patients: A series of 92 consecutive patients who underwent video-assisted thoracoscopic surgery (VATS) at our institute between 1993 and 1996.

Interventions: The frequency and reasons for conversion to thoracotomy were assessed retrospectively. All preoperative CT scans were reviewed for eight radiologic features by two of the authors. These data were entered into univariate and multivariate analyses to identify the significant risk factors for a failure to detect a pulmonary nodule.

Measurements and results: Fifty patients (54%) needed conversion to a thoracotomy. The most common reason for the conversion was failure to localize nodules (46%). Univariate and multivariate analyses of 11 variables revealed one significant risk factor in the failure to detect nodules: distance to the nearest pleural surface (p < 0.05). Tumor size on radiograph remained marginally significant (p = 0.065) in multivariate analyses. If the distance to the pleural surface was > 5 mm in cases of nodules ≤ 10 mm in size, the probability of failure to detect a nodule was 63%.

Conclusions: Our results suggested the indications for preoperative localization of a peripheral pulmonary nodule. Preoperative marking for a small indeterminate pulmonary nodule should be considered when the distance to the nearest pleural surface is > 5 mm in cases of lung nodules of≤ 10 mm in size.

Abbreviations: LBAC = localized bronchioloalveolar carcinoma; VATS = video-assisted thoracoscopic surgery

Abbreviations: EMB = endomyocardial biopsy; IDC =idiopathic dilated cardiomyopathy; LV = left ventricular

A 54-year-old man was referred for an abnormality detected on a routine preoperative chest radiograph (for ophthalmological surgery). He had a history notable for a myocardial infarction that occurred 18 years ago, followed 1 year later by a four-vessel coronary artery bypass graft (CABG). The patient was symptom-free until 1 year ago, when mild angina symptoms recurred. He was a smoker known to have arterial hypertension, hyperlipidemia, and peptic ulcer disease, which were well controlled with appropriate medication. There was no history of trauma. The physical examination was not contributory.

A 78-year-old woman was referred for evaluation of a chest mass. She described progressive dyspnea on exertion over the past several years that she attributed to deconditioning. She had an occasional cough productive of a minimal amount of clear to yellow sputum. She denied wheezing, paroxysmal nocturnal dyspnea, hemoptysis, fever, chills, or weight loss. She also denied chest pain and had no history of coronary artery disease. She had been admitted to the hospital in March 1996 for cataract surgery and was noted to be hypoxemic. She had normal findings from an evaluation for coronary artery disease, including an echocardiogram, which did not show an intracardiac shunt. In January 1997, she was admitted to the hospital for evaluation and management of an embolic cerebrovascular accident. She did not have carotid artery disease. She was a former smoker but quit 30 years ago.

Inhaling motor vehicle exhaust fumes is a common method used by people attempting to commit suicide; however, the decreased carbon monoxide concentrations found in the exhaust of late-model automobiles equipped with catalytic converters are changing the clinical presentation of exhaust inhalation.

Abbreviations: CO = carbon monoxide; CO₂ = carbon dioxide; HbCO = carboxyhemoglobin; HBO = hyperbaric oxygen; MVEGE = motor vehicle exhaust gas emission; O₂ = oxygen

Background: Dumon stent placement requires use of a technically difficult rigid bronchoscope. A recently developed technique for placing a Dumon stent introduced via a conventional endotracheal tube is detailed herein.

Methods: The conventional endotracheal tube is inserted beyond the stenosis site; this procedure is observed with the use of a flexible bronchoscope with the patient undergoing general anesthesia. The Dumon stent is folded and inserted into the endotracheal tube and is introduced into the stenosis site with the use of a cylindrical-tipped stainless steel wire as a pusher. The endotracheal tube is withdrawn while the pusher is positioned to expand the stent at the stenosis site. Dumon stents of 12 to 16 mm in diameter were put in place using the present method in 5 cases of tracheobronchial stenosis.

Results: The mean time from endotracheal tube insertion to stent placement was 181 s. The present method positioned the Dumon stent more easily and safely than the original rigid bronchoscope because the endotracheal tube used was flexible. One patient, however, required a tracheostomy and surgical forceps to remove the stent 3 months after placement.

Conclusion: While Dumon stent removal may require a rigid bronchoscope or tracheostomy, stents can be introduced without difficulty via a conventional endotracheal tube.

A healthy 34-year-old man had a mediastinal cyst on the imaging study. Surgical treatment was performed. The cyst was diagnosed as a thoracic duct cyst from its anatomic location and contents. Pathologic examination found it to be consistent with thoracic duct cyst. Endothelial cells on its luminal surface were identified by an immunohistologic stain with the factor VIII-related antigen. Twenty-six cases of thoracic duct cysts have been reported. We report an additional case and review the previously reported cases. We found that the ligation of the inferior pedicle of the cyst is essential to prevent postoperative chylothorax.

This report describes the case of a 27-year-old man who survived a high-voltage chest injury that resulted in acute biventricular dysfunction. Although the prognosis is generally poor, complete recovery of cardiac function over days to weeks has been documented. This case is unique because the patient regained complete recovery of left ventricular function over 3 months, but had persistent right heart dysfunction on serial echocardiographic evaluations.

Intravenous leiomyomatosis is a histologically benign smooth-muscle tumor arising from either a uterine myoma or the walls of a uterine vessel with extension into veins. Echocardiographic features of two cases of intravenous leiomyomatosis with extensive spread into the right-sided cardiac chambers and pulmonary arteries are described. Both patients were middle-aged women, with prior history of hysterectomy 12 and 10 years earlier who presented with cardiac symptoms and signs. Distinctive echocardiographic features include 1) elongated mobile masses extending from the veins of the lower body, including inferior vena cava and azygos vein; 2) multiple venous attachments or metastases; and 3) filling of venous vessels and right-heart chambers. Intracardiac leiomyomatosis should be considered in a female patient presenting with an extensive mass in the right-sided cardiac chambers.

A 64-year-old man presented with an asymptomatic left lower lobe mass. At bronchoscopy there was a tumor in the superior segment. Biopsy revealed an acinic cell carcinoma. There was no evidence of salivary gland or other site of origin. Lobectomy and lymph node staging showed involvement of interlobar (N1) nodes, while higher stations were benign. The patient remains well 20 months postoperatively. This is the only instance of primary pulmonary acinic cell carcinoma with lymph node metastasis among 15 cases in the literature. We review the clinical features, histology, and treatment of the reported cases.

Abbreviations: ACC = acinic cell carcinoma; LLL = left lower lobe; PAS = periodic acid-Schiff

Typical pulmonary carcinoid tumors often present as proximal endobronchial masses discovered during the evaluation of cough and/or hemoptysis. We present a case of a carcinoid tumor that presented with spontaneous partial expectoration. A review of the literature revealed 16 cases of expectoration of fragments from various primary and metastatic tumors. Our case appears to be the first report of the expectoration of a carcinoid tumor.

Bronchoscopic manipulation of an endobronchial carcinoid can precipitate a carcinoid crisis. Coronary artery spasm is an uncommon manifestation of carcinoid crisis, and has never been reported as a complication of flexible bronchoscopy. We report a case of a 10-year-old girl who developed coronary artery spasm and cardiac arrest during neodymium-yttrium aluminum garnet (Nd-YAG) laser photoresection of an endobronchial carcinoid. Recognition of this unusual presentation of a carcinoid crisis is important as the treatment approach differs from standard resuscitation protocols.

Abbreviations: FB = flexible bronchoscope; RMB = right mainstem bronchus; RUL = right upper lobe

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