Development of predictive models for airflow obstruction in alpha-1-antitrypsin deficiency.

Alpha-1-antitrypsin deficiency is a genetic condition associated with severe, early-onset chronic obstructive pulmonary disease (COPD). However, there is significant variability in lung function impairment among persons with the protease inhibitor ZZ genotype. Early identification of persons at highest risk of developing lung disease could be beneficial in guiding monitoring and treatment decisions. Using a multicenter, family-based study sample (2002-2005) of 372 persons with the protease inhibitor ZZ genotype, the authors developed prediction models for forced expiratory volume in 1 second (FEV(1)) and the presence of severe COPD using demographic, clinical, and genetic variables. Half of the data sample was used for model development, and the other half was used for model validation. In the training sample, variables found to be predictive of both FEV(1) and severe COPD were age, sex, pack-years of smoking, bronchodilator responsiveness, chronic bronchitis symptoms, and index case status. In the validation sample, the predictive model for FEV(1) explained 50% of the variance in FEV(1), and the model for severe COPD exhibited excellent discrimination (c statistic = 0.88).

New Findings in PiZZ alpha1-antitrypsin deficiency-related panniculitis. Demonstration of skin polymers and high dosing requirements of intravenous augmentation therapy.

Panniculitis is a recognized but unusual complication of a severe deficiency of alpha1-antitrypsin (AAT), with fewer than 100 cases described to date. Like the pathogenesis of emphysema in severe PiZZ deficiency of AAT, panniculitis has been hypothesized to be an inflammatory process, possibly related to Z AAT polymer formation and to an unopposed anti-inflammatory screen in the context of deficient serum levels of AAT. The current report presents a 31-year-old woman with PiZZ AAT deficiency-associated panniculitis. Our case extends current knowledge of AAT-associated panniculitis in 2 ways: (1) we demonstrate Z-type AAT polymers in the skin, which supports the inflammatory pathogenesis of panniculitis and the potential pro-inflammatory role of polymers; (2) we show that a high dose and long-term use of intravenous augmentation therapy (90 mg/kg body weight once weekly during 3 years) can ameliorate the frequency and severity of panniculitis associated with AAT deficiency.

Heritability of lung function in severe alpha-1 antitrypsin deficiency.

Severe alpha-1 antitrypsin (AAT) deficiency is a proven genetic risk factor for COPD, but there is marked variation in the development of COPD among AAT deficient subjects. To investigate familial aggregation of lung function in subjects with AAT deficiency, we estimated heritability for forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) in 378 AAT deficient subjects from 167 families in the AAT Genetic Modifiers Study; all subjects were verified homozygous for the Z AAT deficiency allele. Heritability was evaluated for models that included and excluded an ascertainment correction, as well as for models that excluded, included and were stratified by a cigarette smoking covariate. In models without an ascertainment correction, and in all models without a covariate for smoking, no evidence for familial aggregation of lung function was observed. In models conditioned on the index proband with covariates for smoking, post-bronchodilator FEV1/FVC demonstrated significant heritability (0.26 +/- 0.14, p = 0.03). When we limited the analysis to subjects with a smoking history, post-bronchodilator FEV1 demonstrated significant heritability (0.47 +/- 0.21, p = 0.02). Severity rate phenotypes were also assessed as potential phenotypes for genetic modifier studies. Significant heritability was found with all age-of-onset threshold models that included smoking and ascertainment adjustments. Using the t-distribution, the heritability estimates ranged from 0.43 to 0.64, depending on the age-of-onset of FEV1 decline used for the severity rate calculation. Correction for ascertainment and consideration of gene-by-smoking interactions will be crucial for the identification of genes that may modify susceptibility for COPD in families with AAT deficiency.

Hepatopulmonary syndrome following portopulmonary hypertension.

Portopulmonary hypertension (PPHTN) and hepatopulmonary syndrome (HPS) are distinct clinical entities that may accompany liver disease. While PPHTN and HPS have been infrequently described as occurring in the same patient, to the present authors' knowledge, the order of occurrence has always been the initial onset of HPS, with pulmonary hypertension developing either concurrently or subsequently. In some instances, liver transplantation has been undertaken for HPS, followed by resolution of the HPS and subsequent development of pulmonary hypertension. The current case study presents a patient with hepatitis C-related cirrhosis in whom PPTHN developed initially, followed 2 yrs later by the development of the HPS. The current authors speculate that progressive imbalance in favour of endogenous vasodilators over vasoconstrictive factors led to normalisation of the pulmonary artery pressures.

alpha1-Antitrypsin deficiency . 5: intravenous augmentation therapy: current understanding.

The biochemical and clinical efficacy of intravenous augmentation therapy in alpha(1)-antitrypsin deficiency is reviewed, adverse events experienced with this treatment are considered, and its cost effectiveness is discussed.

Right hemidiaphragmatic elevation with a right-to-left interatrial shunt through a patent foramen ovale: a case report and literature review.

A right-to-left shunt (RLS) is an uncommon complication of a patent foramen ovale (PFO) that may cause hypoxemia from venous admixture and ischemic complications from paradoxic embolization. This report presents the third described patient whose RLS through a PFO and profound hypoxemia developed in association with right hemidiaphragm dysfunction (but without a pressure gradient driving the right-to-left flow). In addition to extending the available experience with this unusual clinical event, we report on the successful closure of the PFO by a catheter-deployed double-umbrella device, after the positioning of which the patient's oxygenation normalized.

Mechanical ventilator weaning protocols driven by nonphysician health-care professionals: evidence-based clinical practice guidelines.

Health-care professionals (HCPs) can provide protocol-based care that has a measurable impact on critically ill patients beyond their liberation from mechanical ventilation (MV). Randomized controlled trials have demonstrated that protocols for liberating patients from MV driven by nonphysician HCPs can reduce the duration of MV. The structure and features of protocols should be adapted from published protocols to incorporate patient-specific needs, clinician preferences, and institutional resources. As a general approach, shortly after patients demonstrate that their condition has been stabilized on the ventilator, a spontaneous breathing trial (SBT) is safe to perform and is indicated. Ventilator management strategies for patients who fail a trial of spontaneous breathing include the following: (1) consideration of all remediable factors (such as electrolyte derangements, bronchospasm, malnutrition, patient positioning, and excess secretions) to enhance the prospects of successful liberation from MV; (2) use of a comfortable, safe, and well-monitored mode of MV (such as pressure support ventilation); and (3) repeating a trial of spontaneous breathing on the following day. For patients who pass the SBT, the decision to extubate must be guided by clinical judgment and objective data to minimize the risk of unnecessary reintubations and self-extubations. Protocols should not represent rigid rules but, rather, guides to patient care. Moreover, the protocols may evolve over time as clinical and institutional experience with them increases. Useful protocols aim to safely and efficiently liberate patients from MV, reducing unnecessary or harmful variations in approach.

The impact of turnover among respiratory care practitioners in a health care system: frequency and associated costs.

BACKGROUND: Retention of respiratory therapists (RTs) is a desired institutional goal that reflects department loyalty and RTs' satisfaction. When RTs leave a department, services are disrupted and new therapists must undergo orientation and training, which requires time and expense. Despite the widely shared goal of minimal turnover, neither the annual rate nor the associated expense of turnover for RTs has been described. STUDY PURPOSE: Determine the rate of RT turnover and the costs related to training new staff members. METHODS: The Cleveland Clinic Health System is composed of 9 participating hospitals, which range from small, community-based institutions to large, tertiary care institutions. To elicit information about annual turnover among RTs throughout the system, we conducted a survey of key personnel in each of the hospitals' respiratory therapy departments. To calculate the costs of training, we reviewed the training schedule for an RT joining the Respiratory Therapy Section at the Cleveland Clinic Hospital. Cost estimates reflect the duration of training by various supervisory RTs, their respective wages (including benefit costs), and educational materials used in training and orientation. RESULTS: Turnover rates ranged from 3% to 18% per year. Five of the 8 institutions from which rates were available reported rates greater than 8% per year. The rate of annual turnover correlated significantly with the ratio of hospital beds to RT staff (Pearson r = 0.784, r(2) = 0.61, p = 0.02). The cost of training an RT at the Cleveland Clinic Hospital totaled $3,447.11. CONCLUSIONS: Turnover among respiratory therapists poses a substantial problem because of its frequency and expense. Greater attention to issues affecting turnover and to enhancing retention of RTs is warranted.

The direct medical costs of alpha(1)-antitrypsin deficiency.

BACKGROUND: For individuals with emphysema because of severe alpha(1)-antitrypsin deficiency, specific therapy called IV augmentation therapy has been available since 1989. Such therapy consists of IV infusion of pooled human plasma alpha(1)-antiprotease. METHODS: To assess the direct medical costs of having alpha(1)-antitrypsin deficiency, the current study surveyed members of the Alpha One Foundation Registry for Individuals With alpha(1)-Antitrypsin Deficiency regarding their annual expenditures for treatment of this disease. Data regarding demographic features, alpha(1)-antitrypsin status, and health-resource utilization were collected from a self-administered questionnaire. Respondents were asked to provide total health-care expenditures, but costs by specific items of care (eg, drugs, physician visits, etc) were not available. RESULTS: Mean annual cost estimates were higher for PI*ZZ-phenotype individuals ($30,948, n = 292) than for non-PI*ZZ-phenotype individuals ($20,673, n = 53; p = 0.049). Among PI*ZZ-phenotype individuals, self-reported costs of health-care services were further analyzed for those 288 individuals whose alpha(1)-antiprotease use status was reported. For the 185 current alpha(1)-antiprotease users, the mean annual cost was $40,123 (median, $36,000). CONCLUSIONS: Annual health-care expenditures by individuals with alpha(1)-antitrypsin deficiency are very high, whether or not they are currently receiving augmentation therapy. Augmentation therapy adds substantial costs, especially for heavier individuals who are receiving weekly infusions.

2000 Donald F. Egan Scientific Lecture. Are respiratory therapists effective? Assessing the evidence.

In the current cost-attentive health care climate, the effectiveness of various providers in delivering care is being examined closely. To evaluate the effectiveness of respiratory therapists (RTs) in delivering respiratory care in the intensive care unit (ICU), in adult non-ICU inpatient care, and in ambulatory care, this 27th Egan Lecture presents a systematic review of the available literature examining RTs' effectiveness in these settings. Overall, available studies support the effectiveness of RTs in providing care in various roles in all clinical venues, with the strongest evidence based on the results of concordant randomized controlled clinical trials. Indeed, 5 randomized clinical trials show that RTs are effective in implementing respiratory care protocols to wean patients from mechanical ventilation and in appropriately allocating respiratory care services to adult non-ICU inpatients. Lower levels of evidence support RTs' roles in performing intubation, placing indwelling arterial lines, performing mini-bronchoalveolar lavage, allocating arterial blood gases, and in various counseling and teaching roles. Notwithstanding the considerable body of available evidence that buttresses RTs' effectiveness in delivering care, additional rigorously designed studies are needed to examine RTs' effectiveness in new roles (eg, geriatric care, pediatric care), in new venues (eg, extended care facilities), and to assure the generalizability of available findings to the broad spectrum of health care facilities (eg, academic and community-based facilities alike). Finally, the respiratory therapy community must continue to cultivate and suppport investigative expertise to assure continued inquiry.

Respiratory care protocols in the Cleveland Clinic Health System.

Although respiratory care protocols have been proven efficacious in several academic medical centers, little attention has been given to their use and effect in community-based hospitals. To evaluate the use and effect of respiratory care protocols in community hospitals in the Cleveland Clinic Health System (CCHS) in Cleveland, OH, an observational study was conducted based on a survey of respiratory therapists from 9 of the 10 CCHS hospitals. Study results showed that respiratory care protocols had been implemented in most of the CCHS hospitals in a variety of formats and that use of a full respiratory therapy consult service was common. Over-ordering of respiratory care services was reported far more frequently than was under-ordering and was often the impetus to adopt respiratory care protocols. Larger hospitals were more likely to implement protocols, but protocol use was not associated with having a residency training program. Furthermore, in the three hospitals in which the issue was examined, use of respiratory care protocols did not appear to discourage pulmonary consultation. As was the case in academic medical centers, which have generated most studies to date, the use of respiratory care protocols was reported to be beneficial in community-based hospitals.

Formation and current results of a patient-organized registry for alpha(1)-antitrypsin deficiency.

BACKGROUND: Significant challenges exist to investigating uncommon illnesses because too few patients are seen at any single clinical center to permit appropriate research studies. Recognizing this impediment to clinical research in alpha(1)-antitrypsin deficiency, the Alpha One Foundation, a patient-organized research foundation, has collaborated with clinician-scientists to organize a voluntary registry of individuals with alpha(1)-antitrypsin deficiency. PURPOSE: To facilitate clinical research in alpha(1)-antitrypsin deficiency by organizing a registry of affected individuals willing to be approached to participate in clinical studies. METHODS: Elements of the Alpha One Foundation Research Network Registry include a Medical and Scientific Advisory Committee, composed of physician-investigators and patient advocates, designated clinical resource centers at medical institutions with expertise in the management of individuals with alpha(1)-antitrypsin deficiency, and a data coordinating center with responsibility for database management and analysis. Questionnaires requesting information about demographic features, alpha(1)-antitrypsin phenotype, smoking history, and health-care utilization were distributed to prospective registrants through the following channels: mailings from the Alpha One Foundation; mailings from the clinical resource centers; and distribution by home-care and pharmaceutical companies. Information from this questionnaire formed the basis of the initial registry database. RESULTS: Between May 1997 and June 1999, 7,789 forms were distributed, and forms were returned by 712 unique registrants. Registrants have the following characteristics: mean (+/- SD) age, 49.3+/-13.2 years; women, 47.7%; white, 96.2%; PI*ZZ phenotype, 70.7%; ex-smokers, 73.3%; COPD patients, 87.2% (emphysema patients, 54.2%; chronic bronchitis patients, 33%); and self-reported liver disease, 6.4%. The mean number of physician visits reported by registrants in the preceding 12 months was 7.8+/-9.4, 59% reported currently receiving IV augmentation therapy, and 35% reported using supplemental oxygen at home. Examples of ongoing research studies using this unique database include: (1) a case-control study to evaluate occupational risk factors for obstructive lung disease in individuals with alpha(1)-antitrypsin deficiency and (2) a study to evaluate the health-care costs for affected individuals. CONCLUSIONS: A registry currently including 712 individuals with alpha(1)-antitrypsin deficiency has been organized through a collaboration between physician-investigators and a patient-organized research foundation. Use of the registry has already facilitated studies that were previously difficult because of the paucity of identifiable study subjects. The registry cohort promises to provide an important resource for future clinical and epidemiologic studies.

Occupational exposure risks in individuals with PI*Z alpha(1)-antitrypsin deficiency.

We obtained questionnaire and spirometry data from 128 alpha(1)-antitrypsin (alpha(1)AT)-deficient individuals with phenotype PI*Z to examine the relationship between chronic respiratory symptoms, airflow limitation, treatment requirements, and semiquantitative estimates of occupational exposure to dust, fumes, smoke, and gas. After adjusting for age, smoking, and prior lower respiratory tract infections, increased prevalence of chronic cough (OR = 4.69, 95% CI = 1.57-13.74, p = 0.006) and having left a job due to breathlessness (OR = 2.72, 95% CI = 1.07-6.92, p = 0.036) were seen in individuals reporting high mineral dust exposure compared with those with no exposure. Subjects reporting high mineral dust exposure also had significantly lower FEV(1) (31% predicted for high exposure versus 36% for low and 40% for unexposed, p = 0.032). The excess risk of chronic cough seen with occupational fumes or smoke exposure disappeared after adjusting for mineral dust exposure, but the association with lower FEV(1)/FVC ratio persisted (p = 0.022). Personal tobacco use was a significant risk factor for most outcome measures, but no interaction with occupational exposure was seen. These results suggest that occupational inhalational exposures are independently associated with respiratory symptoms and airflow limitation in severely alpha(1)AT-deficient individuals.

The impact of a respiratory therapy consult service on house officers' knowledge of respiratory care ordering.

BACKGROUND: Although available studies show that implementation of respiratory care protocols by respiratory therapists can enhance the allocation of respiratory care services, concern has been expressed that respiratory therapists' involvement in assessing patients and in determining treatment plans may detract from medical trainees' education and experience in ordering respiratory care services. OBJECTIVE: Compare the rates of correct responses to case-based questions about respiratory care ordering in two groups of internal medicine house officers at academic medical centers: one group training at an institution using respiratory care protocols (The Cleveland Clinic Foundation) and the other group training in an institution at which respiratory care protocols have not been used (University of Nebraska). DESIGN: Prospective cohort study. SETTING: Two academic medical centers, one using respiratory protocols and the other not using respiratory care protocols. MEASUREMENTS: Percent of correct responses to questions regarding respiratory care management posed in 5 case studies administered to both groups. RESULTS: Responses were available from 41 and 17 internal medicine house officers at The Cleveland Clinic Foundation and University of Nebraska, respectively. Respondents represented postgraduate years one, two, and three, and constituted a similar percentage of all internal medicine house officers at each institution (33%). The rate of correct responses to the 20 questions posed in the 5 case studies was high overall (76.8%) and similar in the two house staff groups (77.2 +/- 11.6% at The Cleveland Clinic Foundation and 75.8 +/- 12.0% at University of Nebraska, p = 0.69). The 95% confidence interval for the difference straddled zero (-5.4%, 8.1%), making it very unlikely that any important difference exists between the two groups in rate of correct responses. Analysis of covariance also showed no difference between groups, suggesting that postgraduate training level did not affect this conclusion. In one of the 5 case studies, the percent of correct responses was higher among trainees where respiratory care protocols were in use (86.8 +/- 18% at The Cleveland Clinic Foundation vs 69.1 +/- 14% at University of Nebraska, p = 0.0001). CONCLUSIONS: In this comparison of internal medicine house officers' knowledge regarding respiratory care ordering at institutions using versus not using respiratory care protocols, the rates of correct responses by both groups were similar and unlikely to differ significantly. For one of the 5 case studies, respondents from the institution using respiratory care protocols scored significantly higher. Taken together, these results suggest that use of respiratory care protocols implemented by respiratory therapists does not detract from internal medicine trainees' expertise in respiratory care management. Whether these results generalize to other institutions or reflect expertise in actual practice remains uncertain.

Successful lecturing: a prospective study to validate attributes of the effective medical lecture.

OBJECTIVE: In a study conducted over 3 large symposia on intensive review of internal medicine, we previously assessed the features that were most important to course participants in evaluating the quality of a lecture. In this study, we attempt to validate these observations by assessing prospectively the extent to which ratings of specific lecture features would predict the overall evaluation of lectures. MEASUREMENTS AND MAIN RESULTS: After each lecture, 143 to 355 course participants rated the overall lecture quality of 69 speakers involved in a large symposium on intensive review of internal medicine. In addition, 7 selected participants and the course directors rated specific lecture features and overall quality for each speaker. The relations among the variables were assessed through Pearson correlation coefficients and cluster analysis. Regression analysis was performed to determine which features would predict the overall lecture quality ratings. The features that most highly correlated with ratings of overall lecture quality were the speaker's abilities to identify key points (r =.797) and be engaging (r =.782), the lecture clarity (r =.754), and the slide comprehensibility (r =.691) and format (r =.660). The three lecture features of engaging the audience, lecture clarity, and using a case-based format were identified through regression as the strongest predictors of overall lecture quality ratings (R2 = 0.67, P = 0.0001). CONCLUSIONS: We have identified core lecture features that positively affect the success of the lecture. We believe our findings are useful for lecturers wanting to improve their effectiveness and for educators who design continuing medical education curricula.