In vivo detection of acinar microstructural changes in early emphysema with (3)He lung morphometry.

PURPOSE: To quantitatively characterize early emphysematous changes in the lung microstructure of current and former smokers with noninvasive helium 3 ((3)He) lung morphometry and to compare these results with the clinical standards, pulmonary function testing (PFT) and low-dose computed tomography (CT). MATERIALS AND METHODS: This study was approved by the local institutional review board, and all subjects provided informed consent. Thirty current and former smokers, each with a minimum 30-pack-year smoking history and mild or no abnormalities at PFT, underwent (3)He lung morphometry. This technique is based on diffusion MR imaging with hyperpolarized (3)He gas and yields quantitative localized in vivo measurements of acinar airway geometric parameters, such as airway radii, alveolar depth, and number of alveoli per unit lung volume. These measurements enable calculation of standard morphometric characteristics, such as mean linear intercept and surface-to-volume ratio. RESULTS: Noninvasive (3)He lung morphometry was used to detect alterations in acinar structure in smokers with normal PFT findings. When compared with smokers with the largest forced expiratory volume in 1 second (FEV(1)) to forced vital capacity (FVC) ratio, those with chronic obstructive pulmonary disease had significantly reduced alveolar depth (0.07 mm vs 0.13 mm) and enlarged acinar ducts (0.36 mm vs 0.3 mm). The mean alveolar geometry measurements in the healthiest subjects were in excellent quantitative agreement with literature values obtained by using invasive techniques (acinar duct radius, 0.3 mm; alveolar depth, 0.14 mm at 1 L above functional residual capacity). (3)He lung morphometry depicted greater abnormalities than did PFT and CT. No adverse events were associated with inhalation of (3)He gas. CONCLUSION: (3)He lung morphometry yields valuable noninvasive insight into early emphysematous changes in alveolar geometry with increased sensitivity compared with conventional techniques.

Accuracy of emphysema quantification performed with reduced numbers of CT sections.

OBJECTIVE: The purpose of this study was to assess the accuracy of emphysema measurements obtained from systematic samples of evenly spaced CT images compared with measurements obtained from the entire scan. MATERIALS AND METHODS: Evenly spaced transverse sections from the CT studies of 136 heavy smokers who underwent screening for lung cancer in the National Lung Screening Trial and of 112 subjects who underwent imaging before lung volume reduction surgery were sampled retrospectively. The samples were acquired both by selection of specific numbers of evenly spaced images and by selection of images at specific distance intervals. The percentage of lung pixels with attenuation below specific thresholds was used as an emphysema index. The image sample error was determined as the difference in emphysema index between the image samples and the entire scan. RESULTS: The largest absolute image sample errors in the National Lung Screening Trial cohort with image sample sizes of five, 10, and 20 were 2.2, 0.8, and 0.5 index percentage points, respectively, at 1-mm section thickness (-960 HU threshold), and 2.6, 1.1, and 0.5 index percentage points at 5-mm section thickness (-930 HU threshold). The largest errors in the lung volume reduction surgery cohort for image sample sizes of five and 10 were 5.6 and 2.3 index percentage points at 8- to 10-mm section thickness (-900 HU threshold). Image sample errors were equivalent for the two sampling methods. CONCLUSION: Systematic sampling resulted in very small errors in emphysema quantification and may be useful for decreasing radiation exposure in clinical research studies of emphysema.

Hyperpolarized 3He MR imaging: physiologic monitoring observations and safety considerations in 100 consecutive subjects.

PURPOSE: To evaluate the safety of hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging. MATERIALS AND METHODS: Local institutional review board approval and informed consent were obtained. Physiologic monitoring data were obtained before, during, and after hyperpolarized (3)He MR imaging in 100 consecutive subjects (57 men, 43 women; mean age, 52 years +/- 14 [standard deviation]). The subjects inhaled 1-3 L of a gas mixture containing 300-500 mL (3)He and 0-2700 mL N(2) and held their breath for up to 15 seconds during MR imaging. Heart rate and rhythm and oxygen saturation of hemoglobin as measured by pulse oximetry (Spo(2)) were monitored continuously throughout each study. The effects of (3)He MR imaging on vital signs and Spo(2) and the relationship between pulmonary function, number of doses, and clinical classification (healthy volunteers, patients with asthma, heavy smokers, patients undergoing lung volume reduction surgery for severe emphysema, and patients with lung cancer) and the lowest observed Spo(2) were assessed. Any subjective symptoms were noted. RESULTS: Except for a small postimaging decrease in mean heart rate (from 78 beats per minute +/- 13 to 73 beats per minute +/- 11, P < .001), there was no effect on vital signs. A mean transient decrease in Spo(2) of 4% +/- 3 was observed during the first minute after gas inhalation (P < .001) in 77 subjects who inhaled a dose of 1 L for 10 seconds or less, reaching a nadir of less than 90% at least once in 20 subjects and of less than 85% in four subjects. There was no correlation between the lowest Spo(2) and pulmonary function parameters other than baseline Spo(2) (r = 0.36, P = .001). The lowest mean Spo(2) varied by 1% between the first and second and second and third doses (P < .001) and was unrelated to clinical classification (P = .40). Minor subjective symptoms were noted by 10 subjects. No serious adverse events occurred. CONCLUSION: Hyperpolarized (3)He MR imaging can be safely performed in healthy subjects, heavy smokers, and those with severe obstructive airflow limitation, although unpredictable transient desaturation suggests that potential subjects should be carefully screened for comorbidities.

Outcomes after unilateral lung volume reduction.

BACKGROUND: For patients with end-stage emphysema undergoing lung volume reduction surgery (LVRS), we have preferred a bilateral (BLVRS) approach to achieve maximum benefit with a single procedure. A unilateral (ULVRS) approach has been used in certain patients in whom BLVRS is contraindicated. METHODS: Between January 1993 and December 2006, 43 consecutive patients underwent ULVRS. The study excluded patients undergoing giant bullectomy. Relative contraindications for BLVRS were unilateral emphysema, 21; unilateral emphysema plus other factors, 2; and other factors alone, 10. Preoperative pulmonary rehabilitation was required. Postrehabilitation data were used as the baseline for analyses. Outcome measurements for ULVRS were compared with BLVRS results. RESULTS: After ULVRS, the mean increase in forced expiratory volume in 1 second (FEV(1)) from postrehabilitation values was 32% at 6 months (p

Transpleural ventilation of explanted human lungs.

BACKGROUND: The hypothesis that ventilation of emphysematous lungs would be enhanced by communication with the parenchyma through holes in the pleural surface was tested. METHODS: Fresh human lungs were obtained from patients with emphysema undergoing lung transplantation. Control human lungs were obtained from organ donors whose lungs, for technical reasons, were not considered suitable for implantation. Lungs were ventilated through the bronchial tree or transpleurally via a small hole communicating with the underlying parenchyma over which a flanged silicone tube had been cemented to the surface of the lung (spiracle). Measurements included flow-volume-time curves during passive deflation via each pathway; volume of trapped gas recovered from lungs via spiracles when no additional gas was obtainable passively from the airways; and magnetic resonance imaging assessment of spatial distribution of hyperpolarised helium ((3)He) administered through either the airways or spiracles. RESULTS: In emphysematous lungs, passively expelled volumes at 20 s were 94% greater through spiracles than via the airways. Following passive deflation from the airways, an average of 1.07 litres of trapped gas volume was recoverable via spiracles. Regions were ventilated by spiracles that were less well ventilated via bronchi. CONCLUSIONS: Because of the extensive collateral ventilation present in emphysematous lungs, direct communication with the lung parenchyma through non-anatomical pathways has the potential to improve the mechanics of breathing and hence ventilation.

3He diffusion MRI of the lung.

RATIONALE AND OBJECTIVES: MR imaging of the restricted diffusion of laser-polarized 3He gas provides unique insights into the changes in lung microstructure in emphysema. RESULTS: We discuss measurements of ventilation (spin density), mean diffusivity, and the anisotropy of diffusion, which yields the mean acinar airway radius. In addition, the use of spatially modulated longitudinal magnetization allows diffusion to be measured over longer distances and times, with sensitivity to collateral ventilation paths. Early results are also presented for spin density and diffusivity maps made with a perfluorinated inert gas, C3F8. METHODS: Techniques for purging and imaging excised lungs are discussed.

Integrating social and ethics-based aspects of medicine into physician education.

Ethics plays an important, formative role in medical education, stimulating the transformation of a physiologist-scientist into a compassionate and competent clinician. Our clinical ethics program challenges students to observe and recognize inherent value conflicts and understand how such issues must be resolved in their day-to-day work. Advances in biomedical research that hold potential to enhance human health and treat disease are provoking controversial questions of current practices in medical ethics and spawning new, unprecedented ethical dilemmas.

Results of lung volume reduction surgery in patients meeting a national emphysema treatment trial high-risk criterion.

OBJECTIVES: A report from the National Emphysema Treatment Trial indicated that lung volume reduction candidates with a forced expiratory volume in 1 second and a diffusing capacity of carbon monoxide of 20% or less of predicted value were at high risk for mortality and were unlikely to benefit from surgical intervention. This article examines the applicability of the National Emphysema Treatment Trial findings to our own patients. METHODS: We reviewed 280 patients who underwent bilateral lung volume reduction surgery at our institution between January 1993 and December 2001. All patients met our selection criteria, including heterogeneous distribution of emphysema. Of these 280 patients, 20 patients had both a preoperative forced expiratory volume in 1 second and a diffusing capacity of carbon monoxide of less than or equal to 20% of the predicted normal values, thus meeting one National Emphysema Treatment Trial criterion for high risk. Outcomes of the 20 patients were assessed through 5 years after the operation. The survival of the 20 patient cohort was compared with that of the 260 patients not meeting the National Emphysema Treatment Trial high-risk criterion. RESULTS: Ninety-day operative mortality included 1 (5%) patient. In all patients the forced expiratory volume in 1 second increased from 0.46 L (17%) to 0.78 L (32%), a 73% change; the diffusing capacity of carbon monoxide increased from 16% to 27%, a 70% improvement; residual volume decreased from 6.33 L (305%) to 4.26 L (205%), a 33% improvement; and room air arterial partial pressure of oxygen increased from 55 mm Hg to 64 mm Hg. Kaplan-Meier 5-year survivals did not differ between the high-risk and non-high-risk groups. CONCLUSIONS: Patients with a forced expiratory volume in 1 second and a diffusing capacity of carbon monoxide of 20% or less of predicted value might experience improvements in lung function, exercise tolerance, and quality of life with acceptable morbidity and mortality after lung volume reduction surgery.

A prospective evaluation of lung volume reduction surgery in 200 consecutive patients.

OBJECTIVES: Though numerous studies have demonstrated the short-term efficacy of lung volume reduction surgery (LVRS) in select patients with emphysema, the longer-term follow-up studies are just being reported. The primary objectives of this study were to assess long-term health-related quality of life, satisfaction, physiologic status, and survival of patients following LVRS. DESIGN: We used a prospective cohort study design to assess the first 200 patients undergoing bilateral LVRS (from 1993 to 1998), with follow-up through the year 2000. Each patient served as his own control, initially receiving optimal medical management including exercise rehabilitation before undergoing surgery. Preoperative postrehabilitation data were used as the baseline for comparisons with postoperative data. The primary end points were the effects of LVRS on dyspnea (modified Medical Research Council dyspnea sale), general health-related quality of life (Medical Outcomes Study 36-Item Short-Form Health Survey [SF-36]), patient satisfaction, and survival. The secondary end points were the effects of LVRS on pulmonary function, exercise capacity, and supplemental oxygen requirements. SETTING: A tertiary care urban university-based referral center. PATIENTS: Eligibility requirements for LVRS included disabling dyspnea due to marked airflow obstruction, thoracic hyperinflation, and heterogeneously distributed emphysema that provided target areas for resection. Patients were assessed at 6 months, 3 years, and 5 years after surgery. INTERVENTIONS: Preoperative pulmonary rehabilitation and bilateral stapling LVRS. MEASUREMENTS AND RESULTS: The 200 patients accrued 735 person-years (mean +/- SD, 3.7 +/- 1.6 years; median, 4.0 years) of follow-up. Over the three follow-up periods, an average of > 90% of evaluable patients completed testing. Six months, 3 years, and 5 years after surgery, dyspnea scores were improved in 81%, 52%, and 40% of patients, respectively. Dyspnea scores were the same or improved in 96% (6 months), 82% (3 years), and 74% (5 years) of patients. Improvements in SF-36 physical functioning were demonstrated in 93% (6 months), 78% (3 years), and 69% (5 years) of patients. Good-to-excellent satisfaction with the outcomes was reported by 96% (6 months), 89% (3 years), and 77% (5 years) of patients. The FEV(1) was improved in 92% (6 months), 72% (3 years), and 58% (5 years) of patients. Changes in dyspnea and general health-related quality-of-life scores, and patient satisfaction scores were all significantly correlated with changes in FEV(1). Following surgery, the median length of hospital stay in survivors was 9 days. The 90-day postoperative mortality was 4.5%. Annual Kaplan-Meier survival through 5 years after surgery was 93%, 88%, 83%, 74%, and 63%, respectively. During follow-up, 15 patients underwent subsequent lung transplantation. CONCLUSIONS: In stringently selected patients, LVRS resulted in substantial beneficial effects over and above those achieved with optimized medical therapy. The duration of improvement was at least 5 years in the majority of survivors.

Long-term outcome of bilateral lung volume reduction in 250 consecutive patients with emphysema.

OBJECTIVE: Numerous reports have confirmed the early benefits of lung volume reduction surgery for selected patients with emphysema. This report documents the long-term survival and functional results after lung volume reduction surgery. METHODS: Between January 1993 and June 2000, a total of 250 consecutive patients underwent bilateral lung volume reduction surgery through median sternotomy at our institution. All patients had disabling dyspnea, thoracic hyperinflation, and a heterogeneous pattern of emphysema with suitable target areas for resection. Preoperative pulmonary rehabilitation was required and post-rehabilitation data were used as the baseline for data analysis. Follow-up ranged from 1.8 to 9.1 years (median 4.4 years). RESULTS: Prolonged air leaks (>7 days) were the most common complication (45.2%, n = 113). Reexploration rates for air leak and bleeding were 3.2% (n = 8) and 1.2% (n = 3), respectively. Eighteen patients (7.2%) required reintubation and mechanical ventilation. The in-hospital mortality in this series was 4.8% (n = 12). The median length of hospitalization was 9 days (range 4-168 days). Kaplan-Meier survivals after lung volume reduction surgery were 93.6%, 84.4%, and 67.7% at 1, 3, and 5 years, respectively. Eighteen patients (7.2%) have subsequently undergone lung transplantation after a median interval of 4.3 years (range 2.1-6.4 years). Spirometric values, lung volumes, and gas exchange parameters improved after surgery. The forced expiratory volume in 1 second and the residual volume showed statistically significant improvements between preoperative values and each time point of follow-up. Health-related quality of life showed significant postoperative improvement and with time correlated well with the improvement in forced expiratory volume in 1 second. CONCLUSIONS: Lung volume reduction surgery produces significant functional improvement for selected patients with emphysema. For most of these patients, benefits appear to last at least 5 years.

Quantitative in vivo assessment of lung microstructure at the alveolar level with hyperpolarized 3He diffusion MRI.

The study of lung emphysema dates back to the beginning of the 17th century. Nevertheless, a number of important questions remain unanswered because a quantitative localized characterization of emphysema requires knowledge of lung structure at the alveolar level in the intact living lung. This information is not available from traditional imaging modalities and pulmonary function tests. Herein, we report the first in vivo measurements of lung geometrical parameters at the alveolar level obtained with 3He diffusion MRI in healthy human subjects and patients with severe emphysema. We also provide the first experimental data demonstrating that 3He gas diffusivity in the acinus of human lung is highly anisotropic. A theory of anisotropic diffusion is presented. Our results clearly demonstrate substantial differences between healthy and emphysematous lung at the acinar level and may provide new insights into emphysema progression. The technique offers promise as a clinical tool for early diagnosis of emphysema.