Feasibility of a clinical trial of augmentation therapy for alpha(1)-antitrypsin deficiency. The Alpha 1-Antitrypsin Deficiency Registry Study Group.

We examined the feasibility of a randomized clinical trial of intravenous augmentation therapy for individuals with alpha 1-antitrypsin (alpha1AT) deficiency, basing calculations on newly available data obtained from the NHLBI Registry of Patients with Severe Deficiency of Alpha 1-Antitrypsin. Using rate of FEV(1) decline as the primary outcome and adjusting for noncompliance, a study of subjects with Stage II chronic obstructive pulmonary disease (COPD) (initial FEV(1) 35 to 49% predicted) with biannual spirometry measures obtained over 4 yr of follow-up would require 147 subjects per treatment arm to detect a difference in FEV(1) decline of 23 ml/yr (i.e., a 28% reduction), the difference observed in the NHLBI Registry (1-sided test, alpha = 0.05, 90% power). To detect a 40% reduction in mortality in a 5-year study of subjects with baseline FEV(1) 35 to 49% predicted, recruited over the first 2 yr and then followed an additional 3 yr, 342 subjects per treatment arm would be needed. Though significant impediments to carrying out a clinical trial exist, including the cost of such a trial and the potential difficulties in recruiting patients for a placebo-controlled trial, we recommend a randomized controlled trial as the best method to evaluate the efficacy of intravenous augmentation therapy and of possible future treatments.

Quality control of spirometry testing in the registry for patients with severe alpha1-antitrypsin deficiency. alpha1-Antitrypsin Deficiency Registry Study Group.

As part of the multicenter National Heart, Lung, and Blood Institute registry of patients with severe deficiency of alpha1-antitrypsin with 1,129 enrollees, this report describes measures undertaken to achieve high-quality FEV1 measurements, the rates of satisfying reproducibility and acceptability criteria, and clinical features of participants unable to achieve reproducible FEV1 values at baseline. Spirograms were performed both before and after an inhaled bronchodilator in enrollees followed up at 37 participating clinical centers. Using a reproducibility criterion of < 100 mL or 5% (whichever greater), high reproducibility rates for FEV1 measurements at baseline were observed for both prebronchodilator (95.0% of 1,090 sessions) and postbronchodilator measurements (95.7% of 1,077 sessions). Using the more recently published reproducibility criterion of < or = 200 mL, reproducibility rates were even higher. Eighty-four percent of clinical centers submitted FEV1 values that satisfied reproducibility criteria for at least 90% of spirograms. Also, the mean coefficient of variation for prebronchodilator FEV1 values measured over serial visits separated by up to 9 months was 5.6% for participants with baseline FEV1 55 to 90% predicted. This degree of reproducibility is similar to that observed in the Lung Health Study. Rates of satisfying acceptability criteria for prebronchodilator spirograms were lower, almost universally (98% of tests) due to failure to achieve end-of-test criteria (which usually required 15 s of expiration in this population with mean FEV1 = 42.6+/-29.6% [SD] predicted). Multivariate logistic regression models show that clinical correlates of failure to achieve reproducible prebronchodilator FEV1 efforts include symptoms of chronic wheeze, chronic cough, and chronic phlegm, and the degree of airflow obstruction. We conclude that highly reproducible FEV1 measurements are achievable in a population with severe airflow obstruction despite the additional challenges posed by testing in multiple centers on a variety of spirometers. Furthermore, the difficulty of satisfying end-of-test criteria in a large cohort with severe airflow obstruction did not preclude achieving high rates of reproducibility for FEV1 measurements. Finally, our study confirms prior observations that failure to achieve reproducible efforts is associated with the presence of pulmonary symptoms and the degree of airflow obstruction. Thus, excluding patients with nonreproducible FEV1 efforts from epidemiologic studies would bias results by including only healthier participants.

Trial of oral physostigmine in amyotrophic lateral sclerosis.

We evaluated a double-blind, placebo-controlled, and double-crossover trial of oral physostigmine salicylate for a 9-month period in 13 of 25 patients with sporadic amyotrophic lateral sclerosis (ALS). A large dropout rate of 48% was secondary to eight deaths and four exclusions attributed to the incapability to swallow the tablets (physostigmine) and capsules (lecithin) or to attend the clinic. Parameters used for assessment of the drug efficacy included body weight, ALS score, Jamar grip strength, forced vital capacity, and maximum voluntary ventilation. It revealed slight benefit in reduced loss of grip strength compared with the pretrial and placebo periods. However, the rates of decline for body weight, ALS score, forced vital capacity, maximum voluntary ventilation, and megascore did not differ significantly between the pretrial, placebo, and physostigmine periods. We therefore concluded that overall no significant alteration in the clinical course was gained by oral physostigmine therapy in the 13 patients with ALS who were included in this study.

Trial of octacosanol in amyotrophic lateral sclerosis.

Octacosanol was tried in amyotrophic lateral sclerosis in a double-blind, placebo-controlled, crossover design. Neurologic and pulmonary function evaluations showed no benefit.

Collaborative study to assess risk of lung disease in Pi MZ phenotype subjects.

We studied 143 Pi MZ heterozygous (MZ) subjects from random populations that had been examined previously for alpha 1-antitrypsin phenotype. Each Pi MZ subject was closely matched with a Pi M control subject from the same population at each of 6 centers. An expanded National Heart, Lung and Blood Institute (NHLBI) respiratory symptom questionnaire was completed by each subject. Pulmonary function tests designed to detect established as well as early obstructive airway abnormalities were administered. Multivariate analysis of the variance of data from the questionnaire and pulmonary function tests corrected for age, race, sex, and smoking history showed no significant difference (p less than 0.05) between subjects of Pi MZ and Pi M phenotype. The size of the populations studied and number of observations made for each variable were sufficient to assure that small differences could be detected with 95% power. We conclude that MZ phenotype alone carries no greater risk of developing lung disease than M phenotype.

PUFF: an expert system for interpretation of pulmonary function data.

The application of artificial intelligence techniques to real-world problems has produced promising research results, but seldom has a system become a useful tool in its domain of expertise. Notable exceptions are the DENDRAL (1) and MOLGEN (2) systems. This paper describes PUFF, a program that interprets lung function test data and has become a working tool in the pulmonary physiology lab of a large hospital. Elements of the problem that paved the way for its success are examined, as are significant limitations of the solution that warrant further study.

The effects of underrecorded forced expirations on spirometric lung function indexes.

A problem with short recorded lengths of expiration, encountered in a large heart attack intervention trial, illustrates the importance of standardization and training in spirometric lung function testing. At baseline, half of the trial's clinical centers had mean FVC values that were between 500 and 1,100 ml below those predicted for these centers. To quantify the effects of underrecorded forced expirations on the FVC, the FEV1/FVC%, the FEF70-80%, the FEF 25-75%, and the FEF45-55%, a study of 80 complete spirograms of good quality was undertaken. The findings were that short lengths of expiration cause underrecording of the FVC, inflating all of the examined FVC-dependent spirometric indexes. The inflation was fairly uniform across all obstructions for the forced expiratory flow rates, but it increased markedly with level of obstruction for the FEV1/FVC%. Virtually no subjects exhibited low values of these spirometric indexes after 3 s of expiration, and the number of subjects with low values was still substantially underestimated after 6 s of expiration. Whereas 18 (23%) of the subjects had FEV1/FVC% greater than or equal to 80% and 21 (26%) had ratios less than or equal to 69% based on complete expiration, 60 (75%) of the subjects had ratios greater than or equal to 80% and only 2 (3%) had ratios less than or equal to 69%, after 3 s of expiration. Even after 6 s, 26 subjects (33%) had ratios greater than or equal to 80%, and only 10 (13%) had ratios less than or equal to 69%. Therefore, completely recorded expirations are essential for accurate measurement of the FVC-dependent spirometric indexes.

Managing the data from respiratory measurements.

Clinical decisionmaking depends upon properly interpreting the significance of physiological and other clinical data. Our experience, summarized in six case studies, suggests that no one variable is sufficient for making clinical decisions. Rather, different parameters are relevant in different situations. This article summarizes two techniques for improving the effectiveness of clinical decisionmaking in the ICU using quantitative physiological monitoring data. First, mathematical modeling has been used for measuring the volume of gas in the lungs of patients receiving mechanical ventilation. The technique analyzes the transient response to oxygen change; thus it is suitable for routine use in the ICU. Second, symbolic processing has been used for interpreting the clinical significance of measured data. This symbolic processing is used for recognizing artifact in measured data, determining expected physiological meaning of measured data in different clinical situations, identifying physiological status, and identifying therapy that may be appropriate for meeting therapeutic goals or correcting physiological problems in patients in the intensive care unit.

Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study.

Nine medical centers collaborated in a prospective randomized study to evaluate prolonged extracorporeal membrane oxygenation (ECMO) as a therapy for severe acute respiratory failure (ARF). Ninety adult patients were selected by common criteria of arterial hypoxemia and treated with either conventional mechanical ventilation (48 patients) or mechanical ventilation supplemented with partial venoarterial bypass (42 patients). Four patients in each group survived. The majority of patients suffered acute bacterial or viral pneumonia (57%). All nine patients with pulmonary embolism and six patients with posttraumatic acute respiratory failure died. The majority of patients died of progressive reduction of transpulmonary gas exchange and decreased compliance due to diffuse pulmonary inflammation, necrosis, and fibrosis. We conclude that ECMO can support respiratory gas exchange but did not increase the probability of long-term survival in patients with severe ARF.

Spirometry in amyotrophic lateral sclerosis.

Clinical evaluation and pulmonary function tests were performed in 218 patients with motor neuron disease, mainly amyotrophic lateral sclerosis (ALS). Serial studies were obtained in 103 patients, in 31 until death from ALS. Most patients, regardless of the pattern of motor neuron involvement, had characteristic abnormalities in pulmonary function, including reduced forced vital capacity (FVC) and maximum voluntary ventilation (MVV). Reductions in the FVC and MVV to as low as 50% were commonly missed by clinical evaluators. Spirometry is therefore of value in detecting early involvement of respiratory neurons. Progressively greater reductions in the FVC and MVV in all the fatal cases indicate that serial spirometry has prognostic value in ALS.