Bronchodilator response in patients with normal baseline spirometry.

BACKGROUND: Spirometry before and after bronchodilator is performed to assess air flow-limitation reversibility. In patients with normal baseline spirometry the frequency of a positive bronchodilator response, as defined by American Thoracic Society/European Respiratory Society criteria, has not been described. METHODS: We retrospectively analyzed adult patients tested in 2 academic pulmonary function testing laboratories over a 7-year period, with specific attention to patients who underwent bronchodilator testing after a normal baseline spirometry (FEV(1), FVC, and FEV(1)/FVC within normal limits). The frequency of a positive response to bronchodilator, defined as a 12% and 200 mL increase in either FEV(1) or FVC, was calculated and associated with demographic factors. RESULTS: Of the 1,394 patients with normal spirometry who were administered bronchodilator, 43 (3.1%) had a positive response. The percent of patients responding to bronchodilator were grouped according to pre-bronchodilator FEV(1): > lower limit of normal to 90% of predicted = 6.9%, 90-100% of predicted = 1.9%, and > 100% of predicted = 0%. An FEV(1)/FVC in the lowest 2 quartiles was associated with a higher frequency of bronchodilator response. Older patients were more likely to respond to bronchodilator, but no other demographic factors were associated with a positive bronchodilator response. CONCLUSIONS: In our study population the frequency of a positive bronchodilator response in patients with normal baseline spirometry is 3.1%. None of the patients with a pre-bronchodilator FEV(1) > 100% of predicted and only 1.9% of patients with an FEV(1) between 90% and 100% of predicted responded. Bronchodilator testing can be omitted in patients with normal spirometry and an FEV(1) above 90% of predicted, as they have a low probability of a positive response.

Long-term intersession variability for single-breath diffusing capacity.

BACKGROUND: Characterizing long-term diffusing capacity (DL(CO)) variability is important in assessing quality control for DL(CO) equipment and patient management. Long-term DL(CO) variability has not been reported. OBJECTIVES: It was the aim of this study to characterize long-term variability of DL(CO) in a cohort of biocontrols and to compare different methods of selecting a target value. METHODS: Longitudinal DL(CO) monitoring of biocontrols was performed as part of the inhaled insulin development program; 288 biocontrols were tested twice monthly for up to 5 years using a standardized technique. Variability, expressed either as percent change or DL(CO) units, was assessed using three different target values. RESULTS: The 90th percentile for mean intersession change in DL(CO) was between 10.9 and 15.8% (2.6-4.1 units) depending on the target value. Variability was lowest when the mean of all DL(CO) tests was used as the target value and highest when the baseline DL(CO) was used. The average of the first six DL(CO) tests provided an accurate estimate of the mean DL(CO) value. Using this target, the 90th percentile for mean intersession change was 12.3% and 3.0 units. Variability was stable over time and there were no meaningful associations between variability and demographic factors. CONCLUSIONS: DL(CO) biocontrol deviations >12% or >3.0 units, from the average of the first six tests, indicate that the instrument is not within quality control limits and should be carefully evaluated before further patient testing.

Respiratory physiology in pregnancy.

Pregnancy induces marked changes in the respiratory and cardiovascular systems that are essential for meeting the increased metabolic demands of the mother and fetus. Important respiratory system changes occur in the upper airway, chest wall, static lung volumes, and ventilation and gas exchange. Marked cardiovascular changes also occur during pregnancy including increased plasma volume, increased cardiac output, and reduced vascular resistance. Knowledge of these physiologic adaptations is necessary for the clinician to distinguish the common "physiologic dyspnea" from disease states that occur during pregnancy.

Spirometry guidelines influence lung function results in a longitudinal study of young adults.

RATIONALE: End of test criteria can influence spirometry results. Epidemiology studies initiated before adoption of the 1987 American Thoracic Society (ATS) guidelines typically used a 1 or 2 s plateau on the volume-time curve, not a minimum test duration of 6 s, to terminate a test. OBJECTIVES: To determine the effect of changing guidelines on FEV(1), FVC and FEV(1)/FVC during a longitudinal study of young adults. METHODS: Spirometry was performed on participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Values obtained at entry and 2, 5 and 10 years later using accepted procedures were re-evaluated using the 2005 ATS-ERS guidelines, which were in effect for the year 20 exam. Generalized estimating equations were used to adjust tests with short exhalations that were acceptable by then current end of test criteria. RESULTS: The percentage of participants at years 0, 2, 5, and 10 with exhalations less than 6 s but with an acceptable plateau was 33%, 29%, 9%, and 2%, respectively. Exhalations less than 6 s occurred more frequently in younger and female participants, and were associated with lower FVC and higher FEV(1)/FVC. For short exhalations the adjusted FVC was 47 ml and 110 ml higher than the measured FVC when 6 and 8 s exhalation times were used. CONCLUSIONS: In longitudinal studies of young adults, changing end of test criteria may affect lung function, especially among younger and female participants. Determining adjusted values for tests with short exhalations may better represent the lung health of participants.

The measure of treatment agreement between portable and laboratory blood gas measurements in guiding protocol-driven ventilator management.

BACKGROUND: Portable blood gas analyzer and monitor devices are increasingly being used to direct ventilator therapy. The purpose of this study was to evaluate the "measure of treatment agreement" between portable and laboratory blood gas measurements used in guiding protocol-driven ventilator management. MATERIALS AND METHODS: Using National Institutes of Health Acute Respiratory Distress Syndrome network ventilator management guidelines to manage patient care, measurements taken from the Nonin 8500 M pulse oximeter (SpO2), the Novametrix-610 end-tidal CO2 (ETCO2) detector, and the i-STAT 1 (SaO2, PO2, pH, PCO2) were compared with the recommended treatment from paired laboratory ABL-725 (SaCO2, PO2, pH, PCO2) measurements. RESULTS: Four hundred forty-six intubated adult intensive care unit patients were studied prospectively. Except for the ETCO2 (R2 = 0.460), correlation coefficients between portable and laboratory measurements were high (R2 > or = 0.755). Testing for equivalence, the Nonin-SpO2, iSTAT-PO2, iSTAT-pH, and iSTAT-PCO2 were deemed "equivalent" surrogates to paired ABL measurements. Testing for the limits of agreement found only the iSTAT-PCO2 to be an acceptable surrogate measurement. The measure of treatment agreement between the portable and paired laboratory blood gas measurements were Nonin-SpO2 (68%), iSTAT-SaO2 (73%), iSTAT-PO2 (97%), iSTAT-pH (88%), iSTAT-PCO2 (95%), and Novametrix-ETCO2 (60%). Only the iSTAT-PO2 and the iSTAT-PCO2 achieved the > or =95% treatment agreement threshold to be considered as acceptable surrogates to laboratory measurements. CONCLUSIONS: : The iSTAT-PO2 and -PCO2 were portable device measurements acceptable as surrogates to standard clinical laboratory blood gas measurements in guiding protocol-directed ventilator management. The "measure of treatment agreement," based on standardized decisions and measurement thresholds of a protocol, provides a simple method for assessing clinical validity of surrogate measurements.

Prevalence of airway obstruction in recreational SCUBA divers.

OBJECTIVE: The prevalence of airflow obstruction in recreational self-contained underwater breathing apparatus (SCUBA) divers is unknown. Since airflow obstruction is a relative contraindication for diving, we conducted a study to determine its prevalence and magnitude in a cohort of recreational divers in Saba, Netherlands Antilles. METHODS: Prior to diving, divers were asked to complete a diving/health questionnaire and then to perform spirometry administered by trained dive store personnel. Spirometry instrumentation provided immediate feedback regarding test quality. RESULTS: Of 8365 eligible divers during the study period (November 1997-March 1999), 668 enrolled and completed questionnaires. Of those completing questionnaires, 46% reported a history of smoking, 13% were current smokers, 15% wheezed, 6% had asthma, 4% used bronchodilators, and 3% took oral steroids. Of 654 completing spirometry, 231 had acceptable spirometry quality and complete questionnaires. By forced expiratory volume in 1 second/forced vital capacity, 10% had mild, 1.7% had moderate, and 0.4% had severe airflow obstruction. CONCLUSIONS: The prevalence of airflow obstruction was 6% to 15% by report and 12% by spirometry, approximating the combined prevalence of asthma and chronic obstructive pulmonary disease in the general population. Study limitations include possible self-selection and low enrollment rate. Prospective lung function testing can be conducted at remote sites using nonmedical personnel as "testers." This study could guide future investigations to determine if asthma is a risk factor for decompression illness.

Reference values for lung volumes in an Iranian population: introducing a new equation model.

BACKGROUND: Measurement of lung volumes, especially residual volume and total lung capacity are essential for assessment of restrictive lung disorders. Information regarding normative prediction values for lung volumes as measured by body plethysmography is scarce, and plethysmographic parameters are believed to be poorly reproducible. In this study, we report a comprehensive set of predictive equations for static lung volumes from a general population sample of urban Iranians as measured by body plethysmography. METHODS: Standardized measurements were carried out on 1487 healthy nonsmoking volunteers (845 men and 642 women), aged six to 85 years, living in Isfahan, Iran. Nonlinear multiple regression analysis was used to calculate prediction equations based on subjects' ages and heights for the subdivisions of lung volumes [total lung capacity, functional residual capacity, residual volume, and residual volume/total lung capacity (%)], separately for the two genders. The derived equations were used to calculate prediction values for the subjects. The two sets of predicted and measured values were compared by paired sample t-test. RESULTS: Prediction equations based on a new nonlinear model, (alpha(1) x age + alpha(2) x age(n) + beta x height + c) which best fitted our data are presented. The measured and predicted values closely resemble and there is no significant difference between the two sets. Since increments in total lung capacity, functional residual capacity, and residual volume disclose air trapping within the lungs, their upper limits of normal are as important as the lower limits. So, we have presented both for the equations. CONCLUSION: Despite the usual beliefs we found rather reproducible prediction equations with high coefficient of determination (r2) and low standard error of estimate (SEE) in Iranian population.

The impact of diabetes and age on pulmonary function: data from the National Health and Nutrition Examination Survey.

Using data from NHANES III, we evaluated the effect of diabetes on the age-related decline in lung function. The Diabetes group (n=471) had significantly lower mean FEV(1) and FVC values than the No Diabetes group (n=4317), but pulmonary function declined with increasing age at a similar rate for both groups.

Significant evidence for linkage to chromosome 5q13 in a genome-wide scan for asthma in an extended pedigree resource.

Asthma is a multifactorial disease with undetermined genetic factors. We performed a genome-wide scan to identify predisposition loci for asthma. The asthma phenotype consisted of physician-confirmed presence or absence of asthma symptoms. We analyzed 81 extended Utah pedigrees ranging from three to six generations, including 742 affected individuals, ranging from 2 to 40 per pedigree. We performed parametric multipoint linkage analyses with dominant and recessive models. Our analysis revealed genome-wide significant evidence of linkage to region 5q13 (log of the odds ratio (LOD)=3.8, recessive model), and suggestive evidence for linkage to region 6p21 (LOD=2.1, dominant model). Both the 5q13 and 6p21 regions indicated in these analyses have been previously identified as regions of interest in other genome-wide scans for asthma-related phenotypes. The evidence of linkage at the 5q13 region represents the first significant evidence for linkage on a genome-wide basis for this locus. Linked pedigrees localize the region to approximately between 92.3-105.5 Mb.

Intersession variability in single-breath diffusing capacity in diabetics without overt lung disease.

RATIONALE: American Thoracic Society guidelines state that a 10% or greater intersession change in diffusing capacity of the lung (DL(CO)) should be considered clinically significant. However, little is known about the short-term intersession variability in DL(CO) in untrained subjects or how variability is affected by rigorous external quality control. OBJECTIVES: To characterize the intersession variability of DL(CO) and the effect of different quality control methods in untrained individuals without significant lung disease. METHODS: Data were pooled from the comparator arms of 14 preregistration trials of inhaled insulin that included nonsmoking diabetic patients without significant lung disease. A total of 699 participants performed repeated DL(CO) measurements using a highly standardized technique. A total of 948 participants performed repeated measurements using routine clinical testing. MEASUREMENTS AND MAIN RESULTS: The mean intersession absolute change in DL(CO) using the highly standardized method was 1.45 ml/minute/mm Hg (5.64%) compared with 2.49 ml/minute/mm Hg (9.52%) in the routine testing group (P < 0.0001 for both absolute and percent difference). The variability in absolute intersession change in DL(CO) increased with increasing baseline DL(CO) values, whereas the absolute percentage of intersession change was stable across baseline values. Depending on the method, 15.5 to 35.5% of participants had an intersession change of 10% or greater. A 20% or greater threshold would reduce this percentage of patients to 1 to 10%. CONCLUSIONS: Intersession variability in DL(CO) measurement is dependent on the method of testing used and baseline DL(CO). Using a more liberal threshold to define meaningful intersession change may reduce the misclassification of normal variation as abnormal change.

Longitudinal association of body mass index with lung function: the CARDIA study.

BACKGROUND: Lung function at the end of life depends on its peak and subsequent decline. Because obesity is epidemic in young adulthood, we quantified age-related changes in lung function relative to body mass index (BMI). METHODS: The Coronary Artery Risk Development in Young Adults (CARDIA) study in 1985-86 (year 0) recruited 5,115 black and white men and women, aged 18-30. Spirometry testing was conducted at years 0, 2, 5 and 10. We estimated 10 year change in FVC, FEV1 and FEV1/FVC according to baseline BMI and change in BMI within birth cohorts with initial average ages 20, 24, and 28 years, controlling for race, sex, smoking, asthma, physical activity, and alcohol consumption. MEASUREMENTS AND MAIN RESULTS: Participants with baseline BMI < 21.3 kg/m2 experienced 10 year increases of 71 ml in FVC and 60 ml in FEV1 and neither measure declined through age 38. In contrast, participants with baseline BMI > or = 26.4 kg/m2 experienced 10 year decreases of 185 ml in FVC and 64 ml in FEV1. FEV1/FVC increased with increasing BMI. Weight gain was also associated with lung function. Those who gained the most weight over 10 years had the largest decrease in FVC, but FVC increased with weight gain in those initially thinnest. In contrast, FEV1 decreased with increasing weight gain in all participants, with maximum decline in obese individuals who gained the most weight during the study. CONCLUSION: Among healthy young adults, increasing BMI in the initially thin participants was associated with increasing then stable lung function through age 38, but there were substantial lung function losses with higher and increasing fatness. These results suggest that the obesity epidemic threatens the lung health of the general population.

Socioeconomic status and lung function.

Poverty is a major social problem in the United States and throughout much of the world. Poverty and the broader term socioeconomic status (SES) are important determinants of overall health status and many pulmonary diseases. The purpose of this study was to review the medical literature from the past 20 years addressing the relationship between SES and lung function in both children and adults. There is a significant negative correlation between lung function (primarily FEV1 and FVC) and SES. This relationship exists even after adjusting for smoking status, occupational exposures, and race. The magnitude of the effect of low SES on lung function is variable, but FEV1 reductions of >300 mL in men and >200 mL in women have been reported. SES is an important determinant of lung function and an underrecognized contributor to pulmonary disease.

Standardization of the single-breath diffusing capacity in a multicenter clinical trial.

BACKGROUND: Standardization of the measurement of single-breath diffusing capacity of the lung for carbon monoxide (DLCO) is difficult to implement in multicenter trials as differences in equipment, training, and performance guidelines have led to high variability between and within centers. The safety assessment of inhalable insulin required the standardization of measurement of single-breath DLCO in multicenter clinical trials to optimize test precision. METHODS: This was an open-label, 24-week, parallel-group, outpatient study of inhaled human insulin in participants with type 1 diabetes who were randomly assigned to receive treatment with daily premeal inhaled or subcutaneous (SC) insulin for 12 weeks, followed by SC insulin for 12 weeks. Monitoring of single-breath DLCO using standardized methodology was performed. Standardization included uniform instrumentation, centrally trained study coordinators, and centralized data monitoring and review of quality control. Sites received feedback within 24 h for any tests of unacceptable quality with recommendations for improvement. RESULTS: A total of 226 study participants at 33 sites completed 11,335 DLCO efforts during 4,797 test sessions; 3,607 (75.2%) and 4,581 (95.5%) of all testing sessions yielded two American Thoracic Society-acceptable efforts that varied by < 1 and 2 mL/min/mm Hg, respectively. Only 65 sessions produced one or fewer acceptable efforts. The root mean square intrasubject coefficient of variation in DLCO at the end of the comparative dosing phase was 6.01%. CONCLUSIONS: The standardized methodology employed in this study demonstrates the feasibility of collecting high-quality single-breath DLCO data in the setting of a multicenter clinical trial with reliability that is comparable to spirometry.

Pulmonary function changes related to acute and chronic administration of inhaled insulin.

The need for frequent insulin injections to achieve optimal glycemic control remains a major barrier to initiating and maintaining insulin therapy in diabetes. The inhaled route of insulin administration offers many potential advantages. However, there are ongoing concerns regarding the pulmonary safety of inhaled insulin. Published studies reporting pulmonary safety and data submitted to the Food and Drug Administration were reviewed. All studies were open-label, included adult subjects with type 1 and 2 diabetes, and excluded patients with underlying lung disease. Inhaled insulin was compared with subcutaneous insulin and oral agents. Inhaled insulin is associated with small, consistent reductions in lung function, primarily forced expiratory volume in 1 s (FEV(1)) and diffusion capacity for carbon monoxide (DL(CO)). The small reductions in lung function occurred early (within 12 weeks) and did not progress over time. The magnitudes of the reductions were 30-50 mL for FEV(1) and 0.5-1.0 standard units for DL(CO). Collectively, the data indicate that inhaled insulin is safe in studies with duration up to 4 years. The Food and Drug Administration requires monitoring of lung function on a regular basis.

Arm span as an independent predictor of pulmonary function parameters: validation and reference values.

BACKGROUND AND OBJECTIVES: To determine if arm span can be used as a measure of body length in developing prediction equations for lung function and to compare these equations with height-derived equations. METHODS: Standing height and arm span were measured for all study subjects. Spirometry measurements included FVC, FEV(1), FEV(1)/FVC ratio, PEFR, FEF(25), FEF(50), FEF(75) and FEF(25-75). These data were used to develop prediction equations using multiple regression analysis based on age, gender and arm span. An independent group (225 subjects) was used to evaluate the accuracy of the equations. Predicted values for each parameter were calculated separately for arm span and height and compared with the measured values. RESULTS: Study subjects comprised 1865 healthy non-smoking Persian volunteers. Arm span-based equations accurately predicted all of the spirometric parameters. The standard errors of the estimate for prediction equations based on arm span were slightly smaller than those based on standing height. Average predicted values based on height predicted from arm span did not consistently agree with the measured values. CONCLUSIONS: Predicting pulmonary parameters using equations based on arm span is as reliable as using equations based on standing height and are more accurate for patients in whom height cannot be measured reliably.