Analyzing the short-term effect of placebo therapy in pulmonary arterial hypertension: potential implications for the design of future clinical trials.

BACKGROUND: Placebo is commonly used in short-term randomized trials for pulmonary arterial hypertension (PAH). Currently, outcome data regarding placebo are lacking. We conducted a systematic review and performed a metaanalysis to assess its effect. METHODS: Articles were identified via a query of MEDLINE and EMBASE using the following terms: "pulmonary hypertension"; "clinical trial"; "six minute walk"; "pulmonary hemodynamic"; and "survival." A manual bibliography search of selected trials, reviews, and guidelines was performed. The inclusion criteria were as follows: randomized, placebo-controlled with data reported at baseline and at 12 to 18 weeks. Two reviewers independently abstracted: 6-min walk distance, pulmonary hemodynamic measures and frequency of death, clinical worsening, and change in New York Heart Association/World Health Organization functional class. The data were pooled using a random-effects model. RESULTS: Thirteen of the 688 articles identified met the inclusion criteria (a total of 868 placebo-treated patients). After 12 to 18 weeks, the 6-min walk distance decreased by 8.4 m (95% confidence interval [CI], -14.6 to -2.2) and pulmonary vascular resistance increased by 58.9 dyne (.) s (.) cm(-5) (95% CI, 27.6 to 90.1). Placebo-treated patients were 1.81 times more likely to experience a clinical worsening (95% CI, 1.30 to 2.53). Placebo treatment was not associated with a difference in mortality. CONCLUSIONS: Patients with PAH who receive placebo are more likely to experience clinical deteriorations. Further debate is needed regarding the design of future clinical trials. Research efforts should focus on evaluating existing medications against one another and comparing novel therapies with currently accepted ones.

Outcomes and safety of surgical lung biopsy for interstitial lung disease.

STUDY OBJECTIVES: To determine the safety of surgical lung biopsy (SLB) in patients with interstitial lung disease (ILD), and specifically in those with idiopathic pulmonary fibrosis (IPF). DESIGN: Retrospective cohort. SETTING: Tertiary care university-affiliated military medical center. PATIENTS: Individuals undergoing SLB for suspected ILD. MEASUREMENTS AND RESULTS: We examined outcomes for subjects with a clinical diagnosis of ILD who had been designated to undergo SLB. Mortality (assessed at 30 and 90 days) following SLB represented the primary end point. Morbidity resulting from complications from SLB served as a secondary end point. The cohort included 83 patients (mean [+/- SD] age, 57.3 +/- 14.2 years; men, 57.8%). IPF was eventually diagnosed in slightly more than half of the subjects. Overall, 30-day and 90-day mortality rates were low (4.8% and 6.0%, respectively). Subjects with IPF did well with SLB (30-day mortality rate, 7.1%) and did not face a higher risk of either death or complications relative to individuals with non-IPF forms of ILD. The only predictors of perioperative mortality were either the need for mechanical ventilation (MV) at the time of SLB or being immunosuppressed prior to undergoing SLB. Excluding persons who met either criterion yielded an overall 90-day post-SLB mortality rate of 1.5% in persons with IPF. Approximately 40% of patients in whom IPF was eventually diagnosed were initially thought to have another form of ILD. CONCLUSIONS: Persons with IPF tolerate SLB well. Requiring MV or being immunosuppressed is associated with an increased risk for death following SLB. Safety concerns should not preclude referral for SLB in patients who are clinically suspected of having IPF.

Depreotide scanning in sarcoidosis: a pilot study.

STUDY OBJECTIVES: To determine whether sarcoidosis results in uptake on (99m)Tc-labeled depreotide (DP) scintigraphy and to generate preliminary data to guide the development of future trials exploring this imaging modality in sarcoidosis patients. DESIGN: Prospective cohort trial among a convenience sample of patients with sarcoidosis. SETTING: Tertiary care medical center pulmonary clinic. PATIENTS: Subjects in whom sarcoidosis has been diagnosed based on a biopsy revealing nonnecrotizing granulomas. INTERVENTIONS: Two hours after IV administration of (99m)Tc-DP, all patients underwent whole-body anterior and posterior planar imaging, followed by thoracic single-photon emission CT scanning. Images were interpreted by two nuclear medicine physicians who were blinded to the patient's clinical status. MEASUREMENTS AND RESULTS: The study cohort included 22 subjects (mean [+/- SD] age, 41.3 +/- 9.3 years; 40% female). Approximately half of the cohort had stage I disease determined by chest radiographs (CXRs). The results of (99m)Tc-DP scintigraphy were positive for sarcoidosis in 18 individuals (81.8%; 95% confidence interval, 59.7 to 94.8%). Of the four persons lacking (99m)Tc-DP uptake, all had normalized their CXRs since the time of presentation. In the entire sample, the intraclass correlation between radiographic stage determined by CXR vs that determined by (99m)Tc-DP scintigraphy was robust (kappa = 0.79; p = 0.0005). Among patients with positive (99m)Tc-DP scan findings, the correlation was stronger (kappa = 0.94; p < 0.0001). Flow rates and lung volumes were lower in patients with parenchymal activity on (99m)Tc-DP scintigraphy (mean FEV(1), 68.6 +/- 13.9% predicted vs 84.5 +/- 10.7% predicted, respectively [p = 0.012]; mean FVC, 74.0 +/- 16.0% predicted vs 88.4 +/- 12.7% predicted [p = 0.041]). (99m)Tc-DP scintigraphy correctly identified all sites of known nonpulmonary visceral involvement with sarcoidosis. CONCLUSIONS: The results of (99m)Tc-DP imaging are often positive in sarcoidosis patients, and correlate with disease stage determined by CXR and pulmonary function. (99m)Tc-DP scintigraphy does not preclude the need for biopsy if this is indicated to confirm the diagnosis of sarcoidosis or to exclude the possibility of malignancy. (99m)Tc-DP scintigraphy merits further study in the evaluation and management of sarcoidosis.

Potential limitations of clinical criteria for the diagnosis of idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis.

BACKGROUND: The need to perform surgical lung biopsy (SLB) in all cases of suspected idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis (IPF/CFA) is controversial. The American Thoracic Society (ATS) and the European Respiratory Society (ERS) recently endorsed explicit clinical criteria for the diagnosis of IPF/CFA in the absence of SLB. Prior studies evaluating clinical criteria for the diagnosis of IPF/CFA have been limited in that either they were performed by clinicians with expertise in the diagnosis of IPF/CFA or they did not utilize explicit diagnostic criteria. We investigated the accuracy of the ATS/ERS criteria when applied in a general pulmonary medicine setting. OBJECTIVES: To determine the interobserver variability of clinical criteria for the diagnosis of IPF/CFA. METHODS: This was a retrospective, blinded evaluation by three board certified pulmonary physicians without extensive experience in the evaluation of IPF/CFA performed at a United States Army tertiary care academic medical center. Patients referred for surgical lung biopsy as part of a diagnostic evaluation of interstitial lung disease (ILD) were evaluated. The physicians reviewed high-resolution computed tomography scans of the chest (HRCT) and clinical data for each patient. The physicians were blinded to all other data and to the opinions of other study participants. Employing the histologic presence of usual interstitial pneumonia (UIP) coupled with appropriate clinical findings as the gold standard for a diagnosis of IPF/CFA we determined the accuracy and interobserver variability for a diagnosis of IPF/CFA based on HRCT alone and based on the ATS/ERS clinical criteria. RESULTS: The sensitivity and positive predictive value for a HRCT diagnosis of IPF/CFA were 71% each while specificity and negative predictive value were 67% each. For the ATS/ERS criteria sensitivity, specificity, positive predictive value and negative predictive value were 71, 75, 77 and 69%, respectively. The interobserver variability, expressed as a kappa coefficient, for HRCT and the ATS/ERS criteria were 0.59 and 0.53, respectively. CONCLUSIONS: Both HRCT and the ATS/ERS clinical criteria may lead to misdiagnosis of patients with ILD. Further studies are needed to fully characterize the accuracy of these tests when applied in a routine pulmonary medicine practice setting.

Sarcoidosis, race, and short-term outcomes following lung transplantation.

BACKGROUND: Patients with sarcoidosis, many of whom are African American, may require lung transplantation (LT). Little is known about survival following LT for sarcoidosis. OBJECTIVE: To determine short-term mortality following LT for sarcoidosis, to evaluate if survival after LT for sarcoidosis is similar to outcomes after LT for other diseases, and to investigate the impact of race on the results of LT. DESIGN: Retrospective review. PATIENTS: All patients who underwent LT, irrespective of diagnosis, in the United States between January 1995 and December 2000. MEASUREMENTS: Vital status at 30 days after LT and cause of death. RESULTS: During the study period, 4,721 LTs were performed; of these 133 LTs (2.8%) were for sarcoidosis. Approximately 83% of patients with sarcoidosis survived following LT compared to 91% of persons undergoing transplantation for other reasons (p = 0.002). In multivariate analysis controlling both for health insurance status and other factors known to affect survival after LT, patients with sarcoidosis were no more likely to die than persons undergoing transplantation for other conditions (adjusted odds ratio for death, 1.45; 95% confidence interval [CI], 0.84 to 2.48). Significant predictors of mortality included the following: undergoing combined heart-lung transplant, need for mechanical ventilation, treatment in an ICU at time of LT, pre-LT FEV(1), need for supplemental oxygen, and donor age. Both recipient race and donor race significantly affected short-term survival. African-American patients were nearly 50% more likely to die (adjusted odds ratio, 1.49; 95% CI, 1.01 to 2.20). This difference based on race persisted after excluding heart-lung recipients and after controlling for recipient-donor racial mismatch. The most frequent cause of death for patients with sarcoidosis was graft failure, while infection was the primary cause of death among other LT patients. CONCLUSIONS: Patients with sarcoidosis do as well as patients undergoing LT for other diseases. Race is an important factor affecting survival after LT.

Interferon gamma-1b as therapy for idiopathic pulmonary fibrosis. An intrapatient analysis.

BACKGROUND: The only proven therapeutic option for idiopathic pulmonary fibrosis (IPF) is lung transplantation. It is biologically plausible that interferon gamma-1b (G-IFN) may halt or even reverse the disease process and therefore prove to be an effective medical therapy. We report our results using this medication in a cohort of patients with a wide range of severity of IPF. OBJECTIVES: To determine the impact of G-IFN therapy on the progression of disease in patients with IPF. METHODS: We performed a retrospective analysis of patients' pulmonary function tests (PFTs), specifically the forced vital capacity (FVC) and the single breath diffusing capacity for carbon dioxide (DLCO). Comparisons of these parameters prior to and after the implementation of therapy were made by generating regression slopes by least-squares equations. RESULTS: Twenty-two patients qualified for the analysis. For the FVC, comparison of pre- and post-therapy best-fit regression lines demonstrated a significant difference in favor of G-IFN (p<0.015). For the DLCO, a significant difference in favor of gamma interferon therapy was detected in the advanced group (p<0.03). Seventy percent of the patients showed either stabilization or regression of disease in both their FVCs and their DLCO. CONCLUSION: G-IFN appears to be an effective new therapy for patients with IPF. Salutary effects on the rate of change in the FVC and DLCO were most apparent in patients with advanced disease. With slowing or reversal in loss of lung function, G-IFN may improve longevity and may have utility as a bridge to lung transplantation in those patients who are appropriate candidates.

Management of idiopathic pulmonary haemosiderosis in pregnancy: report of two cases.

Idiopathic pulmonary haemosiderosis (IPH) is a rare cause of alveolar haemorrhage. Its management in pregnancy is complicated and little clinical data exist on outcomes or treatment. Two patients with IPH, one with a known diagnosis prior to pregnancy (patient A) and one presenting de novo during pregnancy (patient B) are reported. Both subjects became maximally symptomatic in the third trimester and were treated with corticosteroids. Despite steroid treatment patient A had continued symptoms and was treated with azathioprine. Both patients delivered healthy female infants at 32 weeks and 38 weeks gestation, respectively. Patient B's course was complicated by the development of fatal invasive pulmonary aspergillosis 4 weeks postpartum. With improved care, more patients with IPH survive to childbearing age. Patients become most symptomatic late in pregnancy, underscoring the need for careful third trimester monitoring. These cases demonstrate that steroids are safe and that azathioprine can be used as additional therapy. When considering treatment options it is important to weigh the benefits of these medications against the potential for maternal and foetal harm.

Effect of standardized orders and provider education on head-of-bed positioning in mechanically ventilated patients.

OBJECTIVE: Semirecumbent head-of-bed positioning in mechanically ventilated patients decreases the risk of developing ventilator-associated pneumonia (VAP). The purpose of this study was to determine whether the addition of a standardized order followed by the initiation of a provider education program would increase the frequency with which our patients were maintained in the semirecumbent position. DESIGN: Prospective, pre-, and postintervention observational study. SETTING: A tertiary care, U.S. Army teaching hospital. PATIENTS: Mechanically ventilated medical and surgical intensive care unit patients. INTERVENTIONS: The first intervention involved the addition of an order for semirecumbent head-of-bed positioning to our intensive care unit order sets. This was followed 2 months later with a second intervention, which was a nurse and physician education program emphasizing semirecumbent positioning. MEASUREMENTS AND MAIN RESULTS: Data regarding head-of-bed positioning were collected on 100 patient observations at baseline and at 1 and 2 months after each of our interventions. The mean angle of head of bed increased from 24 +/- 9 degrees at baseline to 35 +/- 9 degrees (p <.05) 2 months after the addition of the standard order. The percentage of observations with head of bed >45 degrees increased from 3% to 16% 2 months after the standardized order (p <.05). Two months after our provider education program, the mean angle of the head of bed was 34 +/- 11 degrees and the percentage of patients with head of bed >45 degrees was 29% (p = NS compared with values after the first intervention). Data collected 6 months after completion of our education programs showed that these improvements were maintained. CONCLUSIONS: Standardizing the process of care via the addition of an order specifying head-of-bed position significantly increased the number of patients who were placed in the semirecumbent position. In an era of cost-conscious medicine, interventions that utilize protocols and education programs should be emphasized.

New choices for central venous catheters: potential financial implications.

OBJECTIVE: To determine the cost-effectiveness of the newer antiseptic and antibiotic-impregnated central venous catheters (CVCs) relative to uncoated CVCs and to each other. DESIGN: Decision model analysis of the cost and efficacy of CVCs coated with either chlorhexidine silver sulfadiazine (CSS) or rifampin-minocycline (RM) at preventing catheter-related bloodstream infections (CRBSIs). The primary outcome is the incremental cost (or savings) to prevent one additional CRBSI. Model estimates are derived from prospective trials of the CSS and RM CVCs and from other studies describing the costs of CRBSIs. SETTING AND PATIENTS: Hypothetical cohort of 1,000 patients requiring placement of a CVC. INTERVENTIONS: In the model, patients were managed with either an uncoated CVC, CSS CVC, or RM CVC. MEASUREMENTS AND MAIN RESULTS: The incremental cost-effectiveness of the treated CVCs was calculated as the savings resulting from CRBSIs averted less the additional costs of the newer devices. Sensitivity analysis of the effect of the major clinical inputs was performed. For the base case analysis, we assumed the incidence of CRBSIs was 3.3% with traditional catheters and that the CSS and RM CVC conferred a relative risk reduction for the development of CRBSIs of 60% and 85%, respectively. Despite their significantly higher cost than older catheters, both novel CVCs yield significant savings. Employing either of the treated CVCs saves approximately $10,000 per CRBSI prevented (relative to standard catheters). Comparing the RM CVC to the CSS CVC revealed the RM product to be economically superior, saving nearly $9,600 per CRBSI averted and $81 per patient in the cohort. For sensitivity analysis, we adjusted all model variables by 50% individually and then simultaneously. This demonstrated the model to be most sensitive to the cost of a CRBSI; however, with all inputs skewed by 50% against both the CSS CVC and the RM CVC, these devices remained economically attractive. Under this scenario, use of either treated device was less costly. CONCLUSIONS: Utilization of antiseptic and antibiotic-impregnated CVCs represent an attractive alternative for the prevention of CRBSIs and may lead to significant savings. Of the two newer, coated devices, the RM CVC performs better financially. These observations hold over a range of estimates for our model inputs.

Fludarabine-related pulmonary toxicity: a distinct clinical entity in chronic lymphoproliferative syndromes.

BACKGROUND: Little is known about lung injury caused by fludarabine therapy. OBJECTIVES: To establish a case definition, to describe management, and to identify risk factors for fludarabine-related pulmonary toxicity. DESIGN: Case-control study. SETTING: Tertiary-care US Army teaching hospital. PATIENTS: Individuals treated with fludarabine at our institution between January 1989 and June 2000. MEASUREMENTS: Cases of fludarabine-related pulmonary toxicity were defined as follows: dyspnea, fever, hypoxemia, and radiographic infiltrates seen in a patient treated with fludarabine; cases were excluded if there was evidence of pulmonary infection or progression of underlying lymphoproliferative disease affecting the lungs. For each case, demographic data, medical history, radiographic information, available bronchoscopy and pathology data, and details of treatment were reviewed. Cases were compared with fludarabine-treated control subjects to identify potential risk factors. Comparisons were made with regard to age, gender, history of underlying lung disease, lymphoproliferative diagnosis, prior chemotherapy, fludarabine treatment regimen, and pretreatment chest radiograph. RESULTS: During the study period, 105 patients were treated with fludarabine. The incidence of fludarabine-related pulmonary toxicity using our definition was 8.6% (95% confidence interval [CI], 3.2 to 13.9%). One patient died before this entity was suspected; the remainder of the patients underwent bronchoscopy to exclude infection. Patients were treated with corticosteroids with subjective and objective benefits. One patient later died of apparent infection during steroid therapy. One patient was retreated with fludarabine and symptoms of lung toxicity developed again. Patients (n = 9) were similar to control subjects (n = 96) with respect to age, gender, history of underlying lung disease, previous chemotherapy, and fludarabine regimen. Patients with chronic lymphocytic leukemia were 13.3 (95% CI, 1.6 to 300.6) times more likely to have toxicity develop than patients treated with fludarabine for other diagnoses. There was a trend toward an increased incidence in patients with interstitial infiltrates apparent on prefludarabine chest radiographs. CONCLUSIONS: A variety of lung conditions arise in patients treated with fludarabine; however, this agent seems to cause direct pulmonary toxicity. After performing an appropriate evaluation to exclude infection, corticosteroids are an effective therapy. The relative frequency of this condition and potential for mortality underscore the need for increased clinician awareness of fludarabine-related pulmonary toxicity and its risk factors.