STUDY OBJECTIVES:To describe asthma features in a cohort with alpha(1)-antitrypsin (AAT) deficiency, and determine the impact of asthma on FEV(1) decline.BACKGROUND:Asthma may be common in those with AAT deficiency, and may lead to accelerated airflow obstruction.DESIGN:Analysis of data obtained from a 5-year, prospective National Heart, Lung, and Blood Institute registry.SETTING:A multicenter registry consisting of 37 clinical centers, a central phenotyping laboratory, and a data analysis center.PARTICIPANTS:A cohort of 1,052 subjects with AAT deficiency.MEASUREMENTS AND RESULTS:Asthma was defined as reversible airflow obstruction, recurrent attacks of wheezing, and a reported diagnosis of asthma or allergy with or without an elevated serum IgE level. FEV(1) decline was calculated by least-square means with adjustments for covariables. Asthma was present in 21% of the cohort and in 12.5% of those with a normal FEV(1). Attacks of wheezing were reported in 66%, the first attack occurring at a mean +/- SD age of 31 +/- 16 years. Allergy and asthma was reported in 29% and 38%, respectively. An elevated IgE level occurred in 17% and was significantly associated with signs and symptoms of asthma and an allergy history. Unadjusted FEV(1) decline was less in the group without asthma and a normal IgE level (- 48.5 mL/yr) vs the groups with asthma features (> or = 64 mL/yr) [p = 0.002]. Multivariable analysis showed that bronchodilator response, age, and smoking were significant predictors for FEV(1) decline but not asthma.CONCLUSIONS:Symptoms and signs of asthma are common in AAT deficiency and may start at the age of most rapid FEV(1) loss. Adjusting for other risk factors such as bronchodilator response, asthma as defined does not lead to an accelerated FEV(1) decline. In AAT deficiency, augmentation therapy is not more effective in preventing the loss of lung function in those with asthma compared to those without.

We examined the feasibility of a randomized clinical trial of intravenous augmentation therapy for individuals with alpha 1-antitrypsin (alpha 1AT) deficiency, basing calculations on newly available data obtained from the NHLBI Registry of Patients with Severe Deficiency of Alpha 1-Antitrypsin. Using rate of FEV1 decline as the primary outcome and adjusting for noncompliance, a study of subjects with Stage II chronic obstructive pulmonary disease (COPD) (initial FEV1 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 FEV1 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 FEV1 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.

Subjects greater than or equal to 18 yr of age with serum alpha(1)-antitrypsin (alpha(1)-AT) levels less than or equal to 11 mu M or a ZZ genotype were followed for 3.5 to 7 yr with spirometry measurements every 6 to 12 mo as part of a National Heart, Lung, and Blood Institute Registry of Patients with Severe Deficiency of Alpha-1-Antitrypsin. Among all 1,129 enrollees, 5-yr mortality was 19% (95% CI: 16 to 21%). In multivariate analyses of 1,048 subjects who had been contacted greater than or equal to 6 mo after enrolling, age and baseline FEV1% predicted were significant predictors of mortality. Results also showed that those subjects receiving augmentation therapy had decreased mortality (risk ratio [RR] = 0.64, 95% CI: 0.43 to 0.94, p = 0.02) as compared with those not receiving therapy. Among 927 subjects with two or more FEV1 measurements greater than or equal to 1 yr apart, the mean FEV1 decline was 54 ml/yr, with more rapid decline in males, those aged 30 to 44 yr, current smokers, those with FEV1 35 to 79% predicted, and those who ever had a bronchodilator response. Among all subjects, FEV1 decline was not different between augmentation-therapy groups (p = 0.40). However, among subjects with a mean FEV1 35 to 49% predicted, FEV1 decline was significantly slower for subjects receiving than for those not receiving augmentation therapy (mean difference = 27 ml/yr, 95% CI: 3 to 51 ml/yr; p = 0.03). Because this was not a randomized trial, we cannot exclude the possibility that these differences may have been due to other factors for which we could not control.

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.

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.

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

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.

The article by Kaplan et al in the August issue of theArchives(139:867-869,1979) shows that adult respiratory distress syndrome (ARDS) not infrequently follows sepsis, as in 20 of 86 cases of Gram-negative septicemia, hypoxemia developed; ventilator support was required and other findings were consistent with ARDS. This retrospective study showed that the association of ARDS and sepsis has a dismal prognosis, with a mortality of 90%. The authors further report that 11 of the 16 patients with ARDS had thrombocytopenia, suggesting that platelets participate in the pathogenesis of ARDS. Sepsis has long been recognized as a factor in association with ARDS, but the frequency, mortality, and particularly the pathogenetic mechanisms remain unclear. The high frequency noted by Kaplan and co-workers is confirmed by the recently completed prospective study of extracorporeal membrane oxygenation (ECMO) in the treatment of ARDS.1In this nine-center collaborative study, 59 of the 90 patients

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.

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.

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.

This paper describes an algorithm for on-line detection and quantitation of respiratory muscle usage during episodes of patient-ventilator fighting. Respiratory pressure and gas flow are measured at the mouth of patients receiving ventilatory assist and these data are processed by a computer to produce the FITE index. The mechanical properties of the pulmonary system are described by a mathematical model which assumes the respiratory muscles to be relaxed. Two model parameters, lung plus thoracic compliance and airway resistance, are estimated using a least squares approach, and the model predicted mouth pressure is computed. The fighting index is then defined as the root mean square difference of the measured and computed mouth pressure. Application of the algorithm to patients in the intensive care unit shows that (1) the FITE index is a sensitive indicator for early detection of fighting and (2) a significant arterial blood pressure increase occurs with ventilator fighting.

In Reply.— We agree with Dr Bensam that the vast majority of reduced flow rates in amyotrophic lateral sclerosis (ALS) are caused by the neuromuscular disease. Airway obstruction was only diagnosed when there were other objective findings to indicate airway obstruction, eg, curvature of the flow volume loop or a delayed helium mixing time. Thus, 19% of our patients were considered to suffer from airway obstructionin additionto neuromuscular impairment. This is not surprising since more than 50% of those studied were cigarette smokers. We disagree that tracheostomy would always be needed when the vital capacity falls below 1,200 cc. Some patients maintain adequate gas exchange with vital capacities much less than 1 L or less than 20% predicted. Conversely, some patients with larger vital capacities have frequent respiratory difficulties due to bulbar involvement, causing recurrent aspiration, pneumonia, or atelectasis. When such clinical problems arise, we generally try to avoid tracheostomy