Pulmonary Health Hub

DESTIN, FLA. – A 2010 study by Dr. Anna-Luise A. Katzenstein and her colleagues was the first to show that interstitial fibrosis is remarkably common and often severe in cigarette smokers, including those with no clinical evidence of interstitial lung disease.

Pathologic specimens showed that interstitial fibrosis occurred in 12 of 20 smokers (60%) but in none of 3 nonsmokers; three of the smokers with fibrosis had well-defined smoking-related disorders such as respiratory bronchiolitis–interstitial lung disease (RB-ILD), but 9 had pathology showing more than 10% fibrosis on their lung biopsies (Hum. Pathol. 2010;41:316-25). They were considered to have smoking-related interstitial lung disease, Dr. David Moller said at the Congress of Clinical Rheumatology.

"More recently this has been described as [combined pulmonary fibrosis and emphysema, or CPFE syndrome], and it’s largely with the advent of high resolution computed tomography scanning that it has been appreciated how common fibrosis is in association with emphysema," said Dr. Moller, professor of medicine and director of the sarcoidosis clinic at Johns Hopkins University, Baltimore.

Typically, patients with CPFE syndrome have upper-lobe emphysema and lower-lobe fibrosis, he said.

"Because of that, you can get relatively normalized lung volumes and spirometry, but what characterizes these patients is a severe reduction in diffusing capacity. This is often associated with a pulmonary hypertension, which can be a major determinant of survival," he added.

CPFE syndrome is more common in males than females, and is found in 19%-51% of smokers with emphysema on chest CT who have no defined underlying interstitial lung disease. On biopsy, a number of pathological patterns may be seen, including usual interstitial pneumonitis (UIP), nonspecific interstitial pneumonia, and RB-ILD, Dr. Moller said.

Mortality is increased in patients with this syndrome, compared with those who smoke and have chronic obstructive pulmonary disease, and survival ranges from 35% to 80% at 5 years, he added, noting that the mortality rate is unclear in patients who may have underlying idiopathic pulmonary fibrosis.

The syndrome is strongly associated with smoking but is also associated with lung cancer, asbestos and mineral dust exposures, and pulmonary hypertension. A 2011 study demonstrated that CPFE is also associated with connective tissue disease.

In that retrospective study of 34 patients with both connective tissue disease and CPFE syndrome who were followed for about 8 years, 18 had rheumatoid arthritis, 10 had systemic sclerosis, 2 had mixed connective tissues disease, 2 had overlapping connective tissue disease, 1 had Sjögren’s syndrome, and 1 had polymyositis.

High resolution CT showed emphysema of the upper lobes of the lungs and pulmonary fibrosis of the lower lobes in all patients, and all experienced dyspnea during exercise. Pulmonary hypertension was present in five of the systemic sclerosis patients, and four of these patients died during follow-up (Arthritis Rheum. 2011;63:295-304).

The patients in this study were significantly younger than a historical control group of patients with idiopathic CPFE syndrome, and were more frequently female than male, Dr. Moller noted.

Compared with patients with connective tissue disease and lung fibrosis without emphysema, however, the study patients with connective tissue disease and CPFE had higher lung volumes, lower diffusion capacity, higher pulmonary pressures and were more frequently male than female.

There was also some suggestion that those with connective tissue disease and CPFE syndrome may have less severe outcomes than did those with idiopathic CPFE syndrome, but again, pulmonary hypertension is the key to the clinical course, Dr. Moller said.

The authors of this study concluded that CPFE syndrome should be included as a novel, distinct pulmonary manifestation within the spectrum of connective tissue disease–associated lung diseases in smokers and former smokers – particularly those with rheumatoid arthritis or systemic sclerosis.

Treatment for CPFE syndrome includes smoking cessation and treating the underlying cause when it is apparent, Dr. Moller said.

Dr. Moller reported having no financial disclosures.

DESTIN, FLA. – A 2010 study by Dr. Anna-Luise A. Katzenstein and her colleagues was the first to show that interstitial fibrosis is remarkably common and often severe in cigarette smokers, including those with no clinical evidence of interstitial lung disease.

Pathologic specimens showed that interstitial fibrosis occurred in 12 of 20 smokers (60%) but in none of 3 nonsmokers; three of the smokers with fibrosis had well-defined smoking-related disorders such as respiratory bronchiolitis–interstitial lung disease (RB-ILD), but 9 had pathology showing more than 10% fibrosis on their lung biopsies (Hum. Pathol. 2010;41:316-25). They were considered to have smoking-related interstitial lung disease, Dr. David Moller said at the Congress of Clinical Rheumatology.

"More recently this has been described as [combined pulmonary fibrosis and emphysema, or CPFE syndrome], and it’s largely with the advent of high resolution computed tomography scanning that it has been appreciated how common fibrosis is in association with emphysema," said Dr. Moller, professor of medicine and director of the sarcoidosis clinic at Johns Hopkins University, Baltimore.

Typically, patients with CPFE syndrome have upper-lobe emphysema and lower-lobe fibrosis, he said.

"Because of that, you can get relatively normalized lung volumes and spirometry, but what characterizes these patients is a severe reduction in diffusing capacity. This is often associated with a pulmonary hypertension, which can be a major determinant of survival," he added.

CPFE syndrome is more common in males than females, and is found in 19%-51% of smokers with emphysema on chest CT who have no defined underlying interstitial lung disease. On biopsy, a number of pathological patterns may be seen, including usual interstitial pneumonitis (UIP), nonspecific interstitial pneumonia, and RB-ILD, Dr. Moller said.

Mortality is increased in patients with this syndrome, compared with those who smoke and have chronic obstructive pulmonary disease, and survival ranges from 35% to 80% at 5 years, he added, noting that the mortality rate is unclear in patients who may have underlying idiopathic pulmonary fibrosis.

The syndrome is strongly associated with smoking but is also associated with lung cancer, asbestos and mineral dust exposures, and pulmonary hypertension. A 2011 study demonstrated that CPFE is also associated with connective tissue disease.

In that retrospective study of 34 patients with both connective tissue disease and CPFE syndrome who were followed for about 8 years, 18 had rheumatoid arthritis, 10 had systemic sclerosis, 2 had mixed connective tissues disease, 2 had overlapping connective tissue disease, 1 had Sjögren’s syndrome, and 1 had polymyositis.

High resolution CT showed emphysema of the upper lobes of the lungs and pulmonary fibrosis of the lower lobes in all patients, and all experienced dyspnea during exercise. Pulmonary hypertension was present in five of the systemic sclerosis patients, and four of these patients died during follow-up (Arthritis Rheum. 2011;63:295-304).

The patients in this study were significantly younger than a historical control group of patients with idiopathic CPFE syndrome, and were more frequently female than male, Dr. Moller noted.

Compared with patients with connective tissue disease and lung fibrosis without emphysema, however, the study patients with connective tissue disease and CPFE had higher lung volumes, lower diffusion capacity, higher pulmonary pressures and were more frequently male than female.

There was also some suggestion that those with connective tissue disease and CPFE syndrome may have less severe outcomes than did those with idiopathic CPFE syndrome, but again, pulmonary hypertension is the key to the clinical course, Dr. Moller said.

The authors of this study concluded that CPFE syndrome should be included as a novel, distinct pulmonary manifestation within the spectrum of connective tissue disease–associated lung diseases in smokers and former smokers – particularly those with rheumatoid arthritis or systemic sclerosis.

Treatment for CPFE syndrome includes smoking cessation and treating the underlying cause when it is apparent, Dr. Moller said.

Dr. Moller reported having no financial disclosures.

DESTIN, FLA. – A 2010 study by Dr. Anna-Luise A. Katzenstein and her colleagues was the first to show that interstitial fibrosis is remarkably common and often severe in cigarette smokers, including those with no clinical evidence of interstitial lung disease.

Pathologic specimens showed that interstitial fibrosis occurred in 12 of 20 smokers (60%) but in none of 3 nonsmokers; three of the smokers with fibrosis had well-defined smoking-related disorders such as respiratory bronchiolitis–interstitial lung disease (RB-ILD), but 9 had pathology showing more than 10% fibrosis on their lung biopsies (Hum. Pathol. 2010;41:316-25). They were considered to have smoking-related interstitial lung disease, Dr. David Moller said at the Congress of Clinical Rheumatology.

"More recently this has been described as [combined pulmonary fibrosis and emphysema, or CPFE syndrome], and it’s largely with the advent of high resolution computed tomography scanning that it has been appreciated how common fibrosis is in association with emphysema," said Dr. Moller, professor of medicine and director of the sarcoidosis clinic at Johns Hopkins University, Baltimore.

Typically, patients with CPFE syndrome have upper-lobe emphysema and lower-lobe fibrosis, he said.

"Because of that, you can get relatively normalized lung volumes and spirometry, but what characterizes these patients is a severe reduction in diffusing capacity. This is often associated with a pulmonary hypertension, which can be a major determinant of survival," he added.

CPFE syndrome is more common in males than females, and is found in 19%-51% of smokers with emphysema on chest CT who have no defined underlying interstitial lung disease. On biopsy, a number of pathological patterns may be seen, including usual interstitial pneumonitis (UIP), nonspecific interstitial pneumonia, and RB-ILD, Dr. Moller said.

Mortality is increased in patients with this syndrome, compared with those who smoke and have chronic obstructive pulmonary disease, and survival ranges from 35% to 80% at 5 years, he added, noting that the mortality rate is unclear in patients who may have underlying idiopathic pulmonary fibrosis.

The syndrome is strongly associated with smoking but is also associated with lung cancer, asbestos and mineral dust exposures, and pulmonary hypertension. A 2011 study demonstrated that CPFE is also associated with connective tissue disease.

In that retrospective study of 34 patients with both connective tissue disease and CPFE syndrome who were followed for about 8 years, 18 had rheumatoid arthritis, 10 had systemic sclerosis, 2 had mixed connective tissues disease, 2 had overlapping connective tissue disease, 1 had Sjögren’s syndrome, and 1 had polymyositis.

High resolution CT showed emphysema of the upper lobes of the lungs and pulmonary fibrosis of the lower lobes in all patients, and all experienced dyspnea during exercise. Pulmonary hypertension was present in five of the systemic sclerosis patients, and four of these patients died during follow-up (Arthritis Rheum. 2011;63:295-304).

The patients in this study were significantly younger than a historical control group of patients with idiopathic CPFE syndrome, and were more frequently female than male, Dr. Moller noted.

Compared with patients with connective tissue disease and lung fibrosis without emphysema, however, the study patients with connective tissue disease and CPFE had higher lung volumes, lower diffusion capacity, higher pulmonary pressures and were more frequently male than female.

There was also some suggestion that those with connective tissue disease and CPFE syndrome may have less severe outcomes than did those with idiopathic CPFE syndrome, but again, pulmonary hypertension is the key to the clinical course, Dr. Moller said.

The authors of this study concluded that CPFE syndrome should be included as a novel, distinct pulmonary manifestation within the spectrum of connective tissue disease–associated lung diseases in smokers and former smokers – particularly those with rheumatoid arthritis or systemic sclerosis.

Treatment for CPFE syndrome includes smoking cessation and treating the underlying cause when it is apparent, Dr. Moller said.

Dr. Moller reported having no financial disclosures.

SAN FRANCISCO – A phase III clinical trial ended early after preliminary results showed lower cure rates and higher death rates in patients with ventilator-associated pneumonia who were treated for 7 days with doripenem, compared with patients who received 10 days of imipenem.

With 274 patients randomized of a planned enrollment of 524 participants, the investigators conducted a modified intention-to-treat analysis of patients with qualifying bacterial organisms confirmed by bronchiolar lavage and culture. Clinical cure rates were 46% for doripenem and 57% for imipenem, and 28-day all-cause mortality rates were 22% for doripenem and 15% for imipenem, Dr. Marin H. Kollef and his associates reported in a late-breaker session at an international the conference of the American Thoracic Society.

The confidence intervals for both results crossed the threshold of no greater than a 15% difference between groups that would be required to say the doripenem regimen was noninferior to the imipenem regimen. Multiple overall and subgroup analyses showed trends favoring the safety and efficacy of the imipenem regimen, said Dr. Kollef, professor of medicine at Washington University and director of the medical ICU and of respiratory care services at Barnes-Jewish Hospital, both in St. Louis.

The difference in 28-day all-cause mortality did reach statistical significance in a subgroup of patients infected with P. aeruginosa, who were more likely to survive on imipenem therapy, he said.

Doripenem is a carbapenem antibiotic that is approved in the United States for the treatment of complicated urinary and abdominal infections caused by susceptible bacteria but is not approved for pneumonia. It is approved in many other countries for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia (VAP).

The study, known as the DORINOS3008 study, used a higher dose of doripenem than is approved in other countries for pneumonia, the thinking being that a higher dosage might allow shorter duration of treatment. Patients randomized to doripenem received 1 g of doripenem in a 4-hour infusion every 8 hours for 7 days plus a 1-hour infusion of saline placebo every 8 hours for 10 days. The imipenem group received a 4-hour infusion of placebo every 8 hours for 7 days and a 1-hour infusion of imipenem every 8 hours for 10 days.

In the doripenem group, 44% of patients reached a creatinine clearance of at least 150 mL/min, compared with 71% of patients in the imipenem group.

The findings contradict results of a previous phase III study of VAP treated for 7-10 days at the discretion of the investigator. That study, known as DORI-10, reported noninferiority between a regimen of doripenem 500 mg in 4-hour infusions every 8 hours and treatment with imipenem 500 mg in 30-minute infusions every 6 hours or 1 g in 60-minute infusions every 8 hours. In that study, more than 90% of cured patients were treated for at least 8 days, and 35% of patients were treated for at least 10 days, Dr. Kollef noted (Crit. Care Med. 2008;36:1089-96).

In countries where doripenem is approved to treat ventilator-associated pneumonia, the usual duration of treatment is 7-14 days.

"I can’t give you the absolute explanation" for the differences in results from DORI-10 and DORINOS3008, but the findings suggest that physicians should consider treating VAP for longer than 7 days, Dr. Kollef said.

The current study included adult patients who had been hospitalized for at least 5 days, who were on mechanical ventilation, and who met clinical and radiographic criteria for pneumonia.

The study was funded by Johnson & Johnson, which markets doripenem. Dr. Kollef has been a speaker for Pfizer.

SAN FRANCISCO – A phase III clinical trial ended early after preliminary results showed lower cure rates and higher death rates in patients with ventilator-associated pneumonia who were treated for 7 days with doripenem, compared with patients who received 10 days of imipenem.

With 274 patients randomized of a planned enrollment of 524 participants, the investigators conducted a modified intention-to-treat analysis of patients with qualifying bacterial organisms confirmed by bronchiolar lavage and culture. Clinical cure rates were 46% for doripenem and 57% for imipenem, and 28-day all-cause mortality rates were 22% for doripenem and 15% for imipenem, Dr. Marin H. Kollef and his associates reported in a late-breaker session at an international the conference of the American Thoracic Society.

The confidence intervals for both results crossed the threshold of no greater than a 15% difference between groups that would be required to say the doripenem regimen was noninferior to the imipenem regimen. Multiple overall and subgroup analyses showed trends favoring the safety and efficacy of the imipenem regimen, said Dr. Kollef, professor of medicine at Washington University and director of the medical ICU and of respiratory care services at Barnes-Jewish Hospital, both in St. Louis.

The difference in 28-day all-cause mortality did reach statistical significance in a subgroup of patients infected with P. aeruginosa, who were more likely to survive on imipenem therapy, he said.

Doripenem is a carbapenem antibiotic that is approved in the United States for the treatment of complicated urinary and abdominal infections caused by susceptible bacteria but is not approved for pneumonia. It is approved in many other countries for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia (VAP).

The study, known as the DORINOS3008 study, used a higher dose of doripenem than is approved in other countries for pneumonia, the thinking being that a higher dosage might allow shorter duration of treatment. Patients randomized to doripenem received 1 g of doripenem in a 4-hour infusion every 8 hours for 7 days plus a 1-hour infusion of saline placebo every 8 hours for 10 days. The imipenem group received a 4-hour infusion of placebo every 8 hours for 7 days and a 1-hour infusion of imipenem every 8 hours for 10 days.

In the doripenem group, 44% of patients reached a creatinine clearance of at least 150 mL/min, compared with 71% of patients in the imipenem group.

The findings contradict results of a previous phase III study of VAP treated for 7-10 days at the discretion of the investigator. That study, known as DORI-10, reported noninferiority between a regimen of doripenem 500 mg in 4-hour infusions every 8 hours and treatment with imipenem 500 mg in 30-minute infusions every 6 hours or 1 g in 60-minute infusions every 8 hours. In that study, more than 90% of cured patients were treated for at least 8 days, and 35% of patients were treated for at least 10 days, Dr. Kollef noted (Crit. Care Med. 2008;36:1089-96).

In countries where doripenem is approved to treat ventilator-associated pneumonia, the usual duration of treatment is 7-14 days.

"I can’t give you the absolute explanation" for the differences in results from DORI-10 and DORINOS3008, but the findings suggest that physicians should consider treating VAP for longer than 7 days, Dr. Kollef said.

The current study included adult patients who had been hospitalized for at least 5 days, who were on mechanical ventilation, and who met clinical and radiographic criteria for pneumonia.

The study was funded by Johnson & Johnson, which markets doripenem. Dr. Kollef has been a speaker for Pfizer.

SAN FRANCISCO – A phase III clinical trial ended early after preliminary results showed lower cure rates and higher death rates in patients with ventilator-associated pneumonia who were treated for 7 days with doripenem, compared with patients who received 10 days of imipenem.

With 274 patients randomized of a planned enrollment of 524 participants, the investigators conducted a modified intention-to-treat analysis of patients with qualifying bacterial organisms confirmed by bronchiolar lavage and culture. Clinical cure rates were 46% for doripenem and 57% for imipenem, and 28-day all-cause mortality rates were 22% for doripenem and 15% for imipenem, Dr. Marin H. Kollef and his associates reported in a late-breaker session at an international the conference of the American Thoracic Society.

The confidence intervals for both results crossed the threshold of no greater than a 15% difference between groups that would be required to say the doripenem regimen was noninferior to the imipenem regimen. Multiple overall and subgroup analyses showed trends favoring the safety and efficacy of the imipenem regimen, said Dr. Kollef, professor of medicine at Washington University and director of the medical ICU and of respiratory care services at Barnes-Jewish Hospital, both in St. Louis.

The difference in 28-day all-cause mortality did reach statistical significance in a subgroup of patients infected with P. aeruginosa, who were more likely to survive on imipenem therapy, he said.

Doripenem is a carbapenem antibiotic that is approved in the United States for the treatment of complicated urinary and abdominal infections caused by susceptible bacteria but is not approved for pneumonia. It is approved in many other countries for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia (VAP).

The study, known as the DORINOS3008 study, used a higher dose of doripenem than is approved in other countries for pneumonia, the thinking being that a higher dosage might allow shorter duration of treatment. Patients randomized to doripenem received 1 g of doripenem in a 4-hour infusion every 8 hours for 7 days plus a 1-hour infusion of saline placebo every 8 hours for 10 days. The imipenem group received a 4-hour infusion of placebo every 8 hours for 7 days and a 1-hour infusion of imipenem every 8 hours for 10 days.

In the doripenem group, 44% of patients reached a creatinine clearance of at least 150 mL/min, compared with 71% of patients in the imipenem group.

The findings contradict results of a previous phase III study of VAP treated for 7-10 days at the discretion of the investigator. That study, known as DORI-10, reported noninferiority between a regimen of doripenem 500 mg in 4-hour infusions every 8 hours and treatment with imipenem 500 mg in 30-minute infusions every 6 hours or 1 g in 60-minute infusions every 8 hours. In that study, more than 90% of cured patients were treated for at least 8 days, and 35% of patients were treated for at least 10 days, Dr. Kollef noted (Crit. Care Med. 2008;36:1089-96).

In countries where doripenem is approved to treat ventilator-associated pneumonia, the usual duration of treatment is 7-14 days.

"I can’t give you the absolute explanation" for the differences in results from DORI-10 and DORINOS3008, but the findings suggest that physicians should consider treating VAP for longer than 7 days, Dr. Kollef said.

The current study included adult patients who had been hospitalized for at least 5 days, who were on mechanical ventilation, and who met clinical and radiographic criteria for pneumonia.

The study was funded by Johnson & Johnson, which markets doripenem. Dr. Kollef has been a speaker for Pfizer.

Asthma prevalence in the United States rose from 7.3% in 2001 to 8.4% in 2010, an increase of 15%, according to a report from the National Center for Health Statistics.

The number of asthma-related visits to physician offices and hospital outpatient departments dropped from 61.9 per 100 persons with asthma in 2001 to 47.8 per 100 in 2009. The number of visits to emergency departments, however, remained stable: 8.2 per 100 persons with asthma in 2001 and 8.4 per 100 in 2009. Hospitalizations were also stable, going from 2.2 per 100 persons with asthma in 2001 to 2.0 per 100 in 2009, the NCHS noted.

The total number of Americans with asthma in 2010 was 25.7 million. For the period from 2008 to 2010, the average annual prevalence was higher for blacks and American Indian/Alaska Natives than for whites, Hispanics, or Asians. (See below.) Asthma prevalence among Hispanics of Puerto Rican descent was three times higher than among those of Mexican descent.

The death rate for asthma dropped from 0.21 per 1,000 persons with asthma in 2001 to 0.14 per 1,000 in 2009, according to the report.

Note: Based on data from the National Health Interview Survey.

Source: National Center for Health Statistics

Asthma prevalence in the United States rose from 7.3% in 2001 to 8.4% in 2010, an increase of 15%, according to a report from the National Center for Health Statistics.

The number of asthma-related visits to physician offices and hospital outpatient departments dropped from 61.9 per 100 persons with asthma in 2001 to 47.8 per 100 in 2009. The number of visits to emergency departments, however, remained stable: 8.2 per 100 persons with asthma in 2001 and 8.4 per 100 in 2009. Hospitalizations were also stable, going from 2.2 per 100 persons with asthma in 2001 to 2.0 per 100 in 2009, the NCHS noted.

The total number of Americans with asthma in 2010 was 25.7 million. For the period from 2008 to 2010, the average annual prevalence was higher for blacks and American Indian/Alaska Natives than for whites, Hispanics, or Asians. (See below.) Asthma prevalence among Hispanics of Puerto Rican descent was three times higher than among those of Mexican descent.

The death rate for asthma dropped from 0.21 per 1,000 persons with asthma in 2001 to 0.14 per 1,000 in 2009, according to the report.

Note: Based on data from the National Health Interview Survey.

Source: National Center for Health Statistics

Asthma prevalence in the United States rose from 7.3% in 2001 to 8.4% in 2010, an increase of 15%, according to a report from the National Center for Health Statistics.

The number of asthma-related visits to physician offices and hospital outpatient departments dropped from 61.9 per 100 persons with asthma in 2001 to 47.8 per 100 in 2009. The number of visits to emergency departments, however, remained stable: 8.2 per 100 persons with asthma in 2001 and 8.4 per 100 in 2009. Hospitalizations were also stable, going from 2.2 per 100 persons with asthma in 2001 to 2.0 per 100 in 2009, the NCHS noted.

The total number of Americans with asthma in 2010 was 25.7 million. For the period from 2008 to 2010, the average annual prevalence was higher for blacks and American Indian/Alaska Natives than for whites, Hispanics, or Asians. (See below.) Asthma prevalence among Hispanics of Puerto Rican descent was three times higher than among those of Mexican descent.

The death rate for asthma dropped from 0.21 per 1,000 persons with asthma in 2001 to 0.14 per 1,000 in 2009, according to the report.

Note: Based on data from the National Health Interview Survey.

Source: National Center for Health Statistics

SAN FRANCISCO – Inhaled hypertonic saline did not reduce the number of pulmonary exacerbations in infants and children with cystic fibrosis in a randomized trial.

The trial pitted 7% hypertonic saline in 158 pediatric patients against 0.9% isotonic saline as a control in 163 patients. The solutions were nebulized twice daily for 48 weeks, with both groups getting albuterol or levalbuterol beforehand. The patients ranged in age from 4 to 60 months. Adherence was at least 75% in each group, judging from returned study drug ampoules, reported lead investigator Dr. Margaret Rosenfeld at an international conference of the American Thoracic Society.

In the hypertonic saline group, the mean pulmonary exacerbation rate was 2.3 events/person-year (95% confidence interval [CI], 2.0-2.5), and the mean number of total antibiotic treatment days for pulmonary exacerbations was 60 (95% CI, 49-70). In the control group, the mean pulmonary exacerbation rate was 2.3 events/person-year (95% CI, 2.1-2.6), and the mean total number of antibiotic treatment days was 52 (95% CI, 43-61).

No significant differences were seen in secondary end points, including height, weight, respiratory rate, oxygen saturation, cough, or respiratory symptom scores. Adverse event profiles were similar, with cough the most common adverse event in about 40% of each group (JAMA 2012 May 20 [doi:10.1001/jama.2012.5214]).

"There is great interest in the CF [cystic fibrosis] community about developing early intervention strategies to delay or prevent CF lung disease before the bronchiectasis becomes irreversible. From our current evidence, hypertonic saline does not fulfill that role. Based on its inability to reduce the rate of pulmonary exacerbations, we would not recommend that it be used in this age range," said Dr. Rosenfeld, a pediatric pulmonologist and associate professor of pediatrics at the University of Washington in Seattle.

The finding was a surprise because hypertonic saline is known to prevent exacerbations in older children and adults, perhaps by helping the lungs cough out bacteria. There has been hope it would also help very young children, and its use in that population has increased substantially in recent years, Dr. Rosenfeld noted (N. Engl. J. Med. 2006;354:229-40).

"We’ve been scratching our heads about" why that hope didn’t pan out in the trial. "We have a number of hypotheses. The first one is that pulmonary exacerbations may be really different beasts in infants and young children. [Perhaps] they are mostly triggered by viral respiratory infections. Hypertonic saline can’t prevent people from getting respiratory viruses," she said at the conference.

Exacerbations might have been too blunt a primary outcome measure, according to an editorial that accompanied the published study in JAMA.

Very young children with CF have not yet developed the outright lung damage that makes older patients particularly susceptible to exacerbations. Perhaps more subtle markers of early disease onset and progression were needed in the trial, wrote Dr. Elliott Dasenbrook, associate director of the Adult Cystic Fibrosis Program at Case Western Reserve University, Cleveland, and Dr. Michael Konstan, director of the school’s Cystic Fibrosis Center and chairman of its pediatrics department.

"Although the results of the study suggest that inhaled hypertonic saline should not be used routinely in young children, the final verdict on its use for infants and young children has not been rendered. It would be disheartening if a viable therapeutic option was discarded because of negative study results when more sensitive end points might have detected benefit from the intervention. Testing therapeutic agents in infants and young children may require different end points capable of assessing onset and progression of disease," they wrote (JAMA 2012 May 20 [doi: 10.1001/jama.2012.5853]).

There was one "tantalizing" hint in the trial that hypertonic saline may delay structural damage, Dr. Rosenfeld said. Among the 22 children aged 4-16 months in the hypertonic saline group who had pulmonary function tests, forced expiratory volume in 0.5 seconds (FEV_0.5) was a mean of 38 mL greater (95% CI, 1-76) than among the 23 children tested in the control group, the only significant pulmonary function difference.

Perhaps that could be a marker in future trials, but "statistically significant difference does not necessarily imply clinical significance," Dr. Dasenbrook and Dr. Konstan noted. "Even though the results of infant pulmonary function testing appear encouraging, ... these exploratory end points should be viewed as hypothesis generating, and research exploring the clinical effects of these differences is needed."

That research is likely to happen. "We would like to study [hypertonic saline] further and see if we get a signal if we choose more physiologic end points," Dr. Rosenfeld said.

Dr. Rosenfeld disclosed that she is an adviser to Genentech and Vertex Pharmaceuticals, and receives research grants from Vertex. Dr. Dasenbrook is a consultant for Savara and Gilead. Dr. Konstan is an adviser to Aradigm and a consultant for Boehringer Ingelheim, Genentech, Novartis, PARI Respiratory Equipment, Vertex, and several other companies. He receives grants or has grants pending from several companies, and receives speaker’s fees from Genentech and Novartis.

SAN FRANCISCO – Inhaled hypertonic saline did not reduce the number of pulmonary exacerbations in infants and children with cystic fibrosis in a randomized trial.

The trial pitted 7% hypertonic saline in 158 pediatric patients against 0.9% isotonic saline as a control in 163 patients. The solutions were nebulized twice daily for 48 weeks, with both groups getting albuterol or levalbuterol beforehand. The patients ranged in age from 4 to 60 months. Adherence was at least 75% in each group, judging from returned study drug ampoules, reported lead investigator Dr. Margaret Rosenfeld at an international conference of the American Thoracic Society.

In the hypertonic saline group, the mean pulmonary exacerbation rate was 2.3 events/person-year (95% confidence interval [CI], 2.0-2.5), and the mean number of total antibiotic treatment days for pulmonary exacerbations was 60 (95% CI, 49-70). In the control group, the mean pulmonary exacerbation rate was 2.3 events/person-year (95% CI, 2.1-2.6), and the mean total number of antibiotic treatment days was 52 (95% CI, 43-61).

No significant differences were seen in secondary end points, including height, weight, respiratory rate, oxygen saturation, cough, or respiratory symptom scores. Adverse event profiles were similar, with cough the most common adverse event in about 40% of each group (JAMA 2012 May 20 [doi:10.1001/jama.2012.5214]).

"There is great interest in the CF [cystic fibrosis] community about developing early intervention strategies to delay or prevent CF lung disease before the bronchiectasis becomes irreversible. From our current evidence, hypertonic saline does not fulfill that role. Based on its inability to reduce the rate of pulmonary exacerbations, we would not recommend that it be used in this age range," said Dr. Rosenfeld, a pediatric pulmonologist and associate professor of pediatrics at the University of Washington in Seattle.

The finding was a surprise because hypertonic saline is known to prevent exacerbations in older children and adults, perhaps by helping the lungs cough out bacteria. There has been hope it would also help very young children, and its use in that population has increased substantially in recent years, Dr. Rosenfeld noted (N. Engl. J. Med. 2006;354:229-40).

"We’ve been scratching our heads about" why that hope didn’t pan out in the trial. "We have a number of hypotheses. The first one is that pulmonary exacerbations may be really different beasts in infants and young children. [Perhaps] they are mostly triggered by viral respiratory infections. Hypertonic saline can’t prevent people from getting respiratory viruses," she said at the conference.

Exacerbations might have been too blunt a primary outcome measure, according to an editorial that accompanied the published study in JAMA.

Very young children with CF have not yet developed the outright lung damage that makes older patients particularly susceptible to exacerbations. Perhaps more subtle markers of early disease onset and progression were needed in the trial, wrote Dr. Elliott Dasenbrook, associate director of the Adult Cystic Fibrosis Program at Case Western Reserve University, Cleveland, and Dr. Michael Konstan, director of the school’s Cystic Fibrosis Center and chairman of its pediatrics department.

"Although the results of the study suggest that inhaled hypertonic saline should not be used routinely in young children, the final verdict on its use for infants and young children has not been rendered. It would be disheartening if a viable therapeutic option was discarded because of negative study results when more sensitive end points might have detected benefit from the intervention. Testing therapeutic agents in infants and young children may require different end points capable of assessing onset and progression of disease," they wrote (JAMA 2012 May 20 [doi: 10.1001/jama.2012.5853]).

There was one "tantalizing" hint in the trial that hypertonic saline may delay structural damage, Dr. Rosenfeld said. Among the 22 children aged 4-16 months in the hypertonic saline group who had pulmonary function tests, forced expiratory volume in 0.5 seconds (FEV_0.5) was a mean of 38 mL greater (95% CI, 1-76) than among the 23 children tested in the control group, the only significant pulmonary function difference.

Perhaps that could be a marker in future trials, but "statistically significant difference does not necessarily imply clinical significance," Dr. Dasenbrook and Dr. Konstan noted. "Even though the results of infant pulmonary function testing appear encouraging, ... these exploratory end points should be viewed as hypothesis generating, and research exploring the clinical effects of these differences is needed."

That research is likely to happen. "We would like to study [hypertonic saline] further and see if we get a signal if we choose more physiologic end points," Dr. Rosenfeld said.

Dr. Rosenfeld disclosed that she is an adviser to Genentech and Vertex Pharmaceuticals, and receives research grants from Vertex. Dr. Dasenbrook is a consultant for Savara and Gilead. Dr. Konstan is an adviser to Aradigm and a consultant for Boehringer Ingelheim, Genentech, Novartis, PARI Respiratory Equipment, Vertex, and several other companies. He receives grants or has grants pending from several companies, and receives speaker’s fees from Genentech and Novartis.

SAN FRANCISCO – Inhaled hypertonic saline did not reduce the number of pulmonary exacerbations in infants and children with cystic fibrosis in a randomized trial.

The trial pitted 7% hypertonic saline in 158 pediatric patients against 0.9% isotonic saline as a control in 163 patients. The solutions were nebulized twice daily for 48 weeks, with both groups getting albuterol or levalbuterol beforehand. The patients ranged in age from 4 to 60 months. Adherence was at least 75% in each group, judging from returned study drug ampoules, reported lead investigator Dr. Margaret Rosenfeld at an international conference of the American Thoracic Society.

In the hypertonic saline group, the mean pulmonary exacerbation rate was 2.3 events/person-year (95% confidence interval [CI], 2.0-2.5), and the mean number of total antibiotic treatment days for pulmonary exacerbations was 60 (95% CI, 49-70). In the control group, the mean pulmonary exacerbation rate was 2.3 events/person-year (95% CI, 2.1-2.6), and the mean total number of antibiotic treatment days was 52 (95% CI, 43-61).

No significant differences were seen in secondary end points, including height, weight, respiratory rate, oxygen saturation, cough, or respiratory symptom scores. Adverse event profiles were similar, with cough the most common adverse event in about 40% of each group (JAMA 2012 May 20 [doi:10.1001/jama.2012.5214]).

"There is great interest in the CF [cystic fibrosis] community about developing early intervention strategies to delay or prevent CF lung disease before the bronchiectasis becomes irreversible. From our current evidence, hypertonic saline does not fulfill that role. Based on its inability to reduce the rate of pulmonary exacerbations, we would not recommend that it be used in this age range," said Dr. Rosenfeld, a pediatric pulmonologist and associate professor of pediatrics at the University of Washington in Seattle.

The finding was a surprise because hypertonic saline is known to prevent exacerbations in older children and adults, perhaps by helping the lungs cough out bacteria. There has been hope it would also help very young children, and its use in that population has increased substantially in recent years, Dr. Rosenfeld noted (N. Engl. J. Med. 2006;354:229-40).

"We’ve been scratching our heads about" why that hope didn’t pan out in the trial. "We have a number of hypotheses. The first one is that pulmonary exacerbations may be really different beasts in infants and young children. [Perhaps] they are mostly triggered by viral respiratory infections. Hypertonic saline can’t prevent people from getting respiratory viruses," she said at the conference.

Exacerbations might have been too blunt a primary outcome measure, according to an editorial that accompanied the published study in JAMA.

Very young children with CF have not yet developed the outright lung damage that makes older patients particularly susceptible to exacerbations. Perhaps more subtle markers of early disease onset and progression were needed in the trial, wrote Dr. Elliott Dasenbrook, associate director of the Adult Cystic Fibrosis Program at Case Western Reserve University, Cleveland, and Dr. Michael Konstan, director of the school’s Cystic Fibrosis Center and chairman of its pediatrics department.

"Although the results of the study suggest that inhaled hypertonic saline should not be used routinely in young children, the final verdict on its use for infants and young children has not been rendered. It would be disheartening if a viable therapeutic option was discarded because of negative study results when more sensitive end points might have detected benefit from the intervention. Testing therapeutic agents in infants and young children may require different end points capable of assessing onset and progression of disease," they wrote (JAMA 2012 May 20 [doi: 10.1001/jama.2012.5853]).

There was one "tantalizing" hint in the trial that hypertonic saline may delay structural damage, Dr. Rosenfeld said. Among the 22 children aged 4-16 months in the hypertonic saline group who had pulmonary function tests, forced expiratory volume in 0.5 seconds (FEV_0.5) was a mean of 38 mL greater (95% CI, 1-76) than among the 23 children tested in the control group, the only significant pulmonary function difference.

Perhaps that could be a marker in future trials, but "statistically significant difference does not necessarily imply clinical significance," Dr. Dasenbrook and Dr. Konstan noted. "Even though the results of infant pulmonary function testing appear encouraging, ... these exploratory end points should be viewed as hypothesis generating, and research exploring the clinical effects of these differences is needed."

That research is likely to happen. "We would like to study [hypertonic saline] further and see if we get a signal if we choose more physiologic end points," Dr. Rosenfeld said.

Dr. Rosenfeld disclosed that she is an adviser to Genentech and Vertex Pharmaceuticals, and receives research grants from Vertex. Dr. Dasenbrook is a consultant for Savara and Gilead. Dr. Konstan is an adviser to Aradigm and a consultant for Boehringer Ingelheim, Genentech, Novartis, PARI Respiratory Equipment, Vertex, and several other companies. He receives grants or has grants pending from several companies, and receives speaker’s fees from Genentech and Novartis.

NEW ORLEANS – A reformulated version of the previously withdrawn Neupro rotigotine patch had favorable results in separate studies of patients with advanced idiopathic Parkinson’s disease and restless legs syndrome, according to reports given prior to the planned return of the patch to the U.S. market in July.

The dopamine agonist patch was originally approved by the Food and Drug Administration in 2007 for early-stage idiopathic Parkinson’s disease, but UCB Pharma withdrew it from the U.S. market in 2008 because rotigotine was crystallizing out of the delivery matrix. The agency approved a reformulated version in April along with revised labeling that now indicates Neupro for all stages of idiopathic Parkinson’s, plus moderate to severe primary restless legs syndrome (RLS).

The return of the patch is "terrific news for the Parkinson’s disease community. ... Because Parkinson’s disease patients typically have to take many doses of medications each day, the re-approval of the patch will hopefully help a lot of sufferers," by cutting pill burden, among other things, said Dr. Michael Okun, medical director of the National Parkinson Foundation, in a written statement.

In a 16-week, randomized trial involving 514 advanced idiopathic Parkinson’s disease (PD) patients, 8 mg/24 hours reduced off-time by 2.4 hours per day after 12 weeks of maintenance therapy, a statistically significant benefit over placebo, which reduced off-time by 1.5 hours. Lower patch doses reduced off-time as well, but not significantly better than did placebo. All patients in the trial were on levodopa; other medications were allowed. Off-time was assessed by home diaries.

The benefit of 8 mg/24 hour is in line with the new label, which recommends that dosage for advanced Parkinson’s, and 6 mg/24 hours for early-stage disease. The recommended RLS dosage is up to 3 mg/24 hours.

The label details two clinical trials for RLS. In one involving 505 patients, scores on the 40-point IRLS (International RLS) rating scale improved by 14.2 points in patients who were randomized to 3 mg/24 hours for 6 months, whereas placebo improved scores by 9 points. That difference was statistically significant, as were lower Neupro doses. UCB fleshed out the results at the annual meeting of the American Academy of Neurology, noting the magnitude of statistically significant improvements, compared with placebo, in individual components of the IRLS, such as sleep disturbances (0.4-point improvement over placebo on a 5-point scale), impact on daily activities (0.3-point improvement over placebo on a 5-point scale), and frequency of symptoms (0.9-point improvement over placebo on a 5-point scale).

The company also presented post hoc analyses of previous trials that showed that Neupro may help fatigue, apathy, anhedonia, anxiety, and depression in PD. Another post hoc analysis of a 287-patient trial suggested that it might also help with pain; PD patients with a score equal to 1 (any pain) on a 10-point Likert pain scale had a 0.54-point improvement over placebo after being maintained at 2-16 mg/24 hours for 4 weeks.

The patch’s new labeling adds advice on discontinuing the drug, as well as information about the risk of augmentation and rebound in RLS, plus additional detail on somnolence, hypotension, hallucination, impulse control disorder, and other possible side effects.

In the recent randomized trial of 514 patients with PD, "the most common adverse events included application site reactions [15% vs. 7% placebo], nausea [12% vs. 7% placebo], and dyskinesias [8% vs. 3% placebo]. The remainder of the safety profile was similar to previous studies of rotigotine in patients with advanced Parkinson’s," said Dr. Lawrence Elmer, medical director of the center for neurological disorders at the University of Toledo (Ohio), who presented the findings at the meeting.

Dr. Elmer disclosed unrestricted educational grants and payments for consulting, advisory, and speaking services from UCB Pharma and other pharmaceutical companies. Dr. Okun had no current, relevant disclosures.

NEW ORLEANS – A reformulated version of the previously withdrawn Neupro rotigotine patch had favorable results in separate studies of patients with advanced idiopathic Parkinson’s disease and restless legs syndrome, according to reports given prior to the planned return of the patch to the U.S. market in July.

The dopamine agonist patch was originally approved by the Food and Drug Administration in 2007 for early-stage idiopathic Parkinson’s disease, but UCB Pharma withdrew it from the U.S. market in 2008 because rotigotine was crystallizing out of the delivery matrix. The agency approved a reformulated version in April along with revised labeling that now indicates Neupro for all stages of idiopathic Parkinson’s, plus moderate to severe primary restless legs syndrome (RLS).

The return of the patch is "terrific news for the Parkinson’s disease community. ... Because Parkinson’s disease patients typically have to take many doses of medications each day, the re-approval of the patch will hopefully help a lot of sufferers," by cutting pill burden, among other things, said Dr. Michael Okun, medical director of the National Parkinson Foundation, in a written statement.

In a 16-week, randomized trial involving 514 advanced idiopathic Parkinson’s disease (PD) patients, 8 mg/24 hours reduced off-time by 2.4 hours per day after 12 weeks of maintenance therapy, a statistically significant benefit over placebo, which reduced off-time by 1.5 hours. Lower patch doses reduced off-time as well, but not significantly better than did placebo. All patients in the trial were on levodopa; other medications were allowed. Off-time was assessed by home diaries.

The benefit of 8 mg/24 hour is in line with the new label, which recommends that dosage for advanced Parkinson’s, and 6 mg/24 hours for early-stage disease. The recommended RLS dosage is up to 3 mg/24 hours.

The label details two clinical trials for RLS. In one involving 505 patients, scores on the 40-point IRLS (International RLS) rating scale improved by 14.2 points in patients who were randomized to 3 mg/24 hours for 6 months, whereas placebo improved scores by 9 points. That difference was statistically significant, as were lower Neupro doses. UCB fleshed out the results at the annual meeting of the American Academy of Neurology, noting the magnitude of statistically significant improvements, compared with placebo, in individual components of the IRLS, such as sleep disturbances (0.4-point improvement over placebo on a 5-point scale), impact on daily activities (0.3-point improvement over placebo on a 5-point scale), and frequency of symptoms (0.9-point improvement over placebo on a 5-point scale).

The company also presented post hoc analyses of previous trials that showed that Neupro may help fatigue, apathy, anhedonia, anxiety, and depression in PD. Another post hoc analysis of a 287-patient trial suggested that it might also help with pain; PD patients with a score equal to 1 (any pain) on a 10-point Likert pain scale had a 0.54-point improvement over placebo after being maintained at 2-16 mg/24 hours for 4 weeks.

The patch’s new labeling adds advice on discontinuing the drug, as well as information about the risk of augmentation and rebound in RLS, plus additional detail on somnolence, hypotension, hallucination, impulse control disorder, and other possible side effects.

In the recent randomized trial of 514 patients with PD, "the most common adverse events included application site reactions [15% vs. 7% placebo], nausea [12% vs. 7% placebo], and dyskinesias [8% vs. 3% placebo]. The remainder of the safety profile was similar to previous studies of rotigotine in patients with advanced Parkinson’s," said Dr. Lawrence Elmer, medical director of the center for neurological disorders at the University of Toledo (Ohio), who presented the findings at the meeting.

Dr. Elmer disclosed unrestricted educational grants and payments for consulting, advisory, and speaking services from UCB Pharma and other pharmaceutical companies. Dr. Okun had no current, relevant disclosures.

NEW ORLEANS – A reformulated version of the previously withdrawn Neupro rotigotine patch had favorable results in separate studies of patients with advanced idiopathic Parkinson’s disease and restless legs syndrome, according to reports given prior to the planned return of the patch to the U.S. market in July.

The dopamine agonist patch was originally approved by the Food and Drug Administration in 2007 for early-stage idiopathic Parkinson’s disease, but UCB Pharma withdrew it from the U.S. market in 2008 because rotigotine was crystallizing out of the delivery matrix. The agency approved a reformulated version in April along with revised labeling that now indicates Neupro for all stages of idiopathic Parkinson’s, plus moderate to severe primary restless legs syndrome (RLS).

The return of the patch is "terrific news for the Parkinson’s disease community. ... Because Parkinson’s disease patients typically have to take many doses of medications each day, the re-approval of the patch will hopefully help a lot of sufferers," by cutting pill burden, among other things, said Dr. Michael Okun, medical director of the National Parkinson Foundation, in a written statement.

In a 16-week, randomized trial involving 514 advanced idiopathic Parkinson’s disease (PD) patients, 8 mg/24 hours reduced off-time by 2.4 hours per day after 12 weeks of maintenance therapy, a statistically significant benefit over placebo, which reduced off-time by 1.5 hours. Lower patch doses reduced off-time as well, but not significantly better than did placebo. All patients in the trial were on levodopa; other medications were allowed. Off-time was assessed by home diaries.

The benefit of 8 mg/24 hour is in line with the new label, which recommends that dosage for advanced Parkinson’s, and 6 mg/24 hours for early-stage disease. The recommended RLS dosage is up to 3 mg/24 hours.

The label details two clinical trials for RLS. In one involving 505 patients, scores on the 40-point IRLS (International RLS) rating scale improved by 14.2 points in patients who were randomized to 3 mg/24 hours for 6 months, whereas placebo improved scores by 9 points. That difference was statistically significant, as were lower Neupro doses. UCB fleshed out the results at the annual meeting of the American Academy of Neurology, noting the magnitude of statistically significant improvements, compared with placebo, in individual components of the IRLS, such as sleep disturbances (0.4-point improvement over placebo on a 5-point scale), impact on daily activities (0.3-point improvement over placebo on a 5-point scale), and frequency of symptoms (0.9-point improvement over placebo on a 5-point scale).

The company also presented post hoc analyses of previous trials that showed that Neupro may help fatigue, apathy, anhedonia, anxiety, and depression in PD. Another post hoc analysis of a 287-patient trial suggested that it might also help with pain; PD patients with a score equal to 1 (any pain) on a 10-point Likert pain scale had a 0.54-point improvement over placebo after being maintained at 2-16 mg/24 hours for 4 weeks.

The patch’s new labeling adds advice on discontinuing the drug, as well as information about the risk of augmentation and rebound in RLS, plus additional detail on somnolence, hypotension, hallucination, impulse control disorder, and other possible side effects.

In the recent randomized trial of 514 patients with PD, "the most common adverse events included application site reactions [15% vs. 7% placebo], nausea [12% vs. 7% placebo], and dyskinesias [8% vs. 3% placebo]. The remainder of the safety profile was similar to previous studies of rotigotine in patients with advanced Parkinson’s," said Dr. Lawrence Elmer, medical director of the center for neurological disorders at the University of Toledo (Ohio), who presented the findings at the meeting.

Dr. Elmer disclosed unrestricted educational grants and payments for consulting, advisory, and speaking services from UCB Pharma and other pharmaceutical companies. Dr. Okun had no current, relevant disclosures.

Continuous positive airway pressure therapy was linked to a lower rate of incident hypertension in one study but not in another, separate study reported online in the May 23/30 issue of JAMA.

However, the investigators in the second study discovered methodologic flaws that called their conclusion into question. They performed a post hoc analysis, and the results were similar to those of the first study: CPAP therapy, when adhered to, is associated with a lower rate of incident hypertension.

© David Cannings-Bushell/iStockphoto

Neither study could definitively establish that CPAP itself decreases hypertension; both could only note the strong association between the treatment and a decreased rate of the disorder.

CPAP therapy is known to decrease overall cardiovascular risk and to lower blood pressure in certain groups of patients, but its efficacy in preventing the onset of hypertension has not been adequately studied to date, both groups of researchers noted.

In the first study, Dr. Jose M. Marin of Miguel Servet University Hospital, Zaragoza (Spain), and his associates used data from the observational Zaragoza Sleep Cohort Study to assess whether patients on long-term CPAP were less likely to develop hypertension. The cohort study involved more than 5,000 patients referred by their primary care physicians to a sleep center for assessment of sleep-disordered breathing in 1994-2000.

For his analysis, Dr. Marin and his colleagues studied 1,889 such patients who had no hypertension at baseline and who underwent overnight sleep studies to ascertain the cause of their snoring, daytime fatigue, or daytime sleepiness. A total of 824 subjects were found to have obstructive sleep apnea and then adhered to CPAP therapy; another 462 were found to have obstructive sleep apnea but were ineligible for CPAP, 195 declined to try CPAP, and 98 were nonadherent with CPAP therapy. Another 310 patients who were not found to have obstructive sleep apnea served as control subjects.

During a mean follow-up of 11 years, 705 patients developed incident hypertension.

In unadjusted analyses, the rate of new-onset HT was 3.06 per 100 person-years among patients who adhered to CPAP therapy. It was significantly higher in patients who were ineligible for CPAP (3.34 per 100 person-years), and dramatically higher those who declined CPAP (5.84 per 100 person-years) and those who were nonadherent (5.12 per 100 person-years).

After the data were adjusted to account for several confounders, the risk of new-onset HT was the same between patients who adhered to CPAP and control subjects, but was significantly higher in all other groups (JAMA 2012;307:2169-76).

These findings were independent of the severity of obstructive sleep apnea and of patients’ body mass index. Since almost all the subjects gained weight during follow-up, this suggests that weight gain does not diminish the protective association of CPAP therapy and the development of HT, Dr. Marin and his associates said.

Overall, the study results suggest that obstructive sleep apnea is a modifiable risk factor for new-onset HT. This is highly relevant to clinicians "considering that obstructive sleep apnea, despite a high prevalence in Western populations, remains overwhelmingly unrecognized and untreated," they added.

In the second study, Dr. Ferran Barbe of Arnau de Vilanova University Hospital, Lleida (Spain), and his associates assessed CPAP’s effect on incident hypertension among subjects who had obstructive sleep apnea but did not have symptoms of daytime sleepiness or fatigue. This is a subgroup of apnea patients who have not been shown to benefit from the treatment, with the caveat that research in this patient population has been inadequate.

Dr. Barbe and his colleagues assessed 723 such patients who were randomly assigned to receive CPAP (357 subjects) or no CPAP (366 control subjects). During a median follow-up of 4 years, 147 patients developed incident hypertension and 59 had cardiovascular events.

In the CPAP group there were 68 cases of HT and 28 CV events, and in the control group there were 79 cases of HT and 31 CV events – a nonsignificant difference.

The rate of combined HT/CV events was 11.02 per 100 person-years with CPAP and 9.20 per 100 person-years without CPAP, also a nonsignificant difference. Apnea severity did not affect these findings.

The researchers noted that they had assessed patients who had been prescribed CPAP but not patients who had adhered to CPAP therapy, and that adherence – use of the treatment for at least 4 hours per night – is critical to CPAP’s effectiveness. They therefore performed a post hoc analysis based on a cutoff of 4 hours of actual adherence to CPAP, which they substantiated by examining oxygen saturation data.

This analysis showed that CPAP was associated with a significantly reduced rate of incident HT and CV events as long as patients received 4 hours or more of the treatment each night (JAMA 2012;307:2161-8).

However, as the conclusion of a post hoc analysis, this result must be considered "hypothesis-generating" rather than definitive, they noted.

In addition, Dr. Barbe and his associates realized that they had erred in designing the study and that it likely had insufficient statistical power to detect a significant difference in the rate of HT. "A larger study or longer follow-up might have been able to identify a significant association between treatment and outcome," they said.

Dr. Marin’s study was supported by Instituto Carlos III; the Ministry of Health, Madrid; and the Spanish Society of Respiratory Medicine. Dr. Barbe’s study was funded by Instituto de Salud Carlos III, the Spanish Respiratory Society, Resmed, Air Products-Carburos Metalicos, Respironics, and Breas Medical. Dr. Marin, Dr. Barbe, and their associates reported no financial conflicts of interest.

Continuous positive airway pressure therapy was linked to a lower rate of incident hypertension in one study but not in another, separate study reported online in the May 23/30 issue of JAMA.

However, the investigators in the second study discovered methodologic flaws that called their conclusion into question. They performed a post hoc analysis, and the results were similar to those of the first study: CPAP therapy, when adhered to, is associated with a lower rate of incident hypertension.

© David Cannings-Bushell/iStockphoto

Neither study could definitively establish that CPAP itself decreases hypertension; both could only note the strong association between the treatment and a decreased rate of the disorder.

CPAP therapy is known to decrease overall cardiovascular risk and to lower blood pressure in certain groups of patients, but its efficacy in preventing the onset of hypertension has not been adequately studied to date, both groups of researchers noted.

In the first study, Dr. Jose M. Marin of Miguel Servet University Hospital, Zaragoza (Spain), and his associates used data from the observational Zaragoza Sleep Cohort Study to assess whether patients on long-term CPAP were less likely to develop hypertension. The cohort study involved more than 5,000 patients referred by their primary care physicians to a sleep center for assessment of sleep-disordered breathing in 1994-2000.

For his analysis, Dr. Marin and his colleagues studied 1,889 such patients who had no hypertension at baseline and who underwent overnight sleep studies to ascertain the cause of their snoring, daytime fatigue, or daytime sleepiness. A total of 824 subjects were found to have obstructive sleep apnea and then adhered to CPAP therapy; another 462 were found to have obstructive sleep apnea but were ineligible for CPAP, 195 declined to try CPAP, and 98 were nonadherent with CPAP therapy. Another 310 patients who were not found to have obstructive sleep apnea served as control subjects.

During a mean follow-up of 11 years, 705 patients developed incident hypertension.

In unadjusted analyses, the rate of new-onset HT was 3.06 per 100 person-years among patients who adhered to CPAP therapy. It was significantly higher in patients who were ineligible for CPAP (3.34 per 100 person-years), and dramatically higher those who declined CPAP (5.84 per 100 person-years) and those who were nonadherent (5.12 per 100 person-years).

After the data were adjusted to account for several confounders, the risk of new-onset HT was the same between patients who adhered to CPAP and control subjects, but was significantly higher in all other groups (JAMA 2012;307:2169-76).

These findings were independent of the severity of obstructive sleep apnea and of patients’ body mass index. Since almost all the subjects gained weight during follow-up, this suggests that weight gain does not diminish the protective association of CPAP therapy and the development of HT, Dr. Marin and his associates said.

Overall, the study results suggest that obstructive sleep apnea is a modifiable risk factor for new-onset HT. This is highly relevant to clinicians "considering that obstructive sleep apnea, despite a high prevalence in Western populations, remains overwhelmingly unrecognized and untreated," they added.

In the second study, Dr. Ferran Barbe of Arnau de Vilanova University Hospital, Lleida (Spain), and his associates assessed CPAP’s effect on incident hypertension among subjects who had obstructive sleep apnea but did not have symptoms of daytime sleepiness or fatigue. This is a subgroup of apnea patients who have not been shown to benefit from the treatment, with the caveat that research in this patient population has been inadequate.

Dr. Barbe and his colleagues assessed 723 such patients who were randomly assigned to receive CPAP (357 subjects) or no CPAP (366 control subjects). During a median follow-up of 4 years, 147 patients developed incident hypertension and 59 had cardiovascular events.

In the CPAP group there were 68 cases of HT and 28 CV events, and in the control group there were 79 cases of HT and 31 CV events – a nonsignificant difference.

The rate of combined HT/CV events was 11.02 per 100 person-years with CPAP and 9.20 per 100 person-years without CPAP, also a nonsignificant difference. Apnea severity did not affect these findings.

The researchers noted that they had assessed patients who had been prescribed CPAP but not patients who had adhered to CPAP therapy, and that adherence – use of the treatment for at least 4 hours per night – is critical to CPAP’s effectiveness. They therefore performed a post hoc analysis based on a cutoff of 4 hours of actual adherence to CPAP, which they substantiated by examining oxygen saturation data.

This analysis showed that CPAP was associated with a significantly reduced rate of incident HT and CV events as long as patients received 4 hours or more of the treatment each night (JAMA 2012;307:2161-8).

However, as the conclusion of a post hoc analysis, this result must be considered "hypothesis-generating" rather than definitive, they noted.

In addition, Dr. Barbe and his associates realized that they had erred in designing the study and that it likely had insufficient statistical power to detect a significant difference in the rate of HT. "A larger study or longer follow-up might have been able to identify a significant association between treatment and outcome," they said.

Dr. Marin’s study was supported by Instituto Carlos III; the Ministry of Health, Madrid; and the Spanish Society of Respiratory Medicine. Dr. Barbe’s study was funded by Instituto de Salud Carlos III, the Spanish Respiratory Society, Resmed, Air Products-Carburos Metalicos, Respironics, and Breas Medical. Dr. Marin, Dr. Barbe, and their associates reported no financial conflicts of interest.

Continuous positive airway pressure therapy was linked to a lower rate of incident hypertension in one study but not in another, separate study reported online in the May 23/30 issue of JAMA.

However, the investigators in the second study discovered methodologic flaws that called their conclusion into question. They performed a post hoc analysis, and the results were similar to those of the first study: CPAP therapy, when adhered to, is associated with a lower rate of incident hypertension.

© David Cannings-Bushell/iStockphoto

Neither study could definitively establish that CPAP itself decreases hypertension; both could only note the strong association between the treatment and a decreased rate of the disorder.

CPAP therapy is known to decrease overall cardiovascular risk and to lower blood pressure in certain groups of patients, but its efficacy in preventing the onset of hypertension has not been adequately studied to date, both groups of researchers noted.

In the first study, Dr. Jose M. Marin of Miguel Servet University Hospital, Zaragoza (Spain), and his associates used data from the observational Zaragoza Sleep Cohort Study to assess whether patients on long-term CPAP were less likely to develop hypertension. The cohort study involved more than 5,000 patients referred by their primary care physicians to a sleep center for assessment of sleep-disordered breathing in 1994-2000.

For his analysis, Dr. Marin and his colleagues studied 1,889 such patients who had no hypertension at baseline and who underwent overnight sleep studies to ascertain the cause of their snoring, daytime fatigue, or daytime sleepiness. A total of 824 subjects were found to have obstructive sleep apnea and then adhered to CPAP therapy; another 462 were found to have obstructive sleep apnea but were ineligible for CPAP, 195 declined to try CPAP, and 98 were nonadherent with CPAP therapy. Another 310 patients who were not found to have obstructive sleep apnea served as control subjects.

During a mean follow-up of 11 years, 705 patients developed incident hypertension.

In unadjusted analyses, the rate of new-onset HT was 3.06 per 100 person-years among patients who adhered to CPAP therapy. It was significantly higher in patients who were ineligible for CPAP (3.34 per 100 person-years), and dramatically higher those who declined CPAP (5.84 per 100 person-years) and those who were nonadherent (5.12 per 100 person-years).

After the data were adjusted to account for several confounders, the risk of new-onset HT was the same between patients who adhered to CPAP and control subjects, but was significantly higher in all other groups (JAMA 2012;307:2169-76).

These findings were independent of the severity of obstructive sleep apnea and of patients’ body mass index. Since almost all the subjects gained weight during follow-up, this suggests that weight gain does not diminish the protective association of CPAP therapy and the development of HT, Dr. Marin and his associates said.

Overall, the study results suggest that obstructive sleep apnea is a modifiable risk factor for new-onset HT. This is highly relevant to clinicians "considering that obstructive sleep apnea, despite a high prevalence in Western populations, remains overwhelmingly unrecognized and untreated," they added.

In the second study, Dr. Ferran Barbe of Arnau de Vilanova University Hospital, Lleida (Spain), and his associates assessed CPAP’s effect on incident hypertension among subjects who had obstructive sleep apnea but did not have symptoms of daytime sleepiness or fatigue. This is a subgroup of apnea patients who have not been shown to benefit from the treatment, with the caveat that research in this patient population has been inadequate.

Dr. Barbe and his colleagues assessed 723 such patients who were randomly assigned to receive CPAP (357 subjects) or no CPAP (366 control subjects). During a median follow-up of 4 years, 147 patients developed incident hypertension and 59 had cardiovascular events.

In the CPAP group there were 68 cases of HT and 28 CV events, and in the control group there were 79 cases of HT and 31 CV events – a nonsignificant difference.

The rate of combined HT/CV events was 11.02 per 100 person-years with CPAP and 9.20 per 100 person-years without CPAP, also a nonsignificant difference. Apnea severity did not affect these findings.

The researchers noted that they had assessed patients who had been prescribed CPAP but not patients who had adhered to CPAP therapy, and that adherence – use of the treatment for at least 4 hours per night – is critical to CPAP’s effectiveness. They therefore performed a post hoc analysis based on a cutoff of 4 hours of actual adherence to CPAP, which they substantiated by examining oxygen saturation data.

This analysis showed that CPAP was associated with a significantly reduced rate of incident HT and CV events as long as patients received 4 hours or more of the treatment each night (JAMA 2012;307:2161-8).

However, as the conclusion of a post hoc analysis, this result must be considered "hypothesis-generating" rather than definitive, they noted.

In addition, Dr. Barbe and his associates realized that they had erred in designing the study and that it likely had insufficient statistical power to detect a significant difference in the rate of HT. "A larger study or longer follow-up might have been able to identify a significant association between treatment and outcome," they said.

Dr. Marin’s study was supported by Instituto Carlos III; the Ministry of Health, Madrid; and the Spanish Society of Respiratory Medicine. Dr. Barbe’s study was funded by Instituto de Salud Carlos III, the Spanish Respiratory Society, Resmed, Air Products-Carburos Metalicos, Respironics, and Breas Medical. Dr. Marin, Dr. Barbe, and their associates reported no financial conflicts of interest.

SAN FRANCISCO – A proposed new definition of acute respiratory distress syndrome describes categories based on mild, moderate, or severe hypoxemia that correlate increasing severity with significantly increased mortality or increased time on mechanical ventilation among survivors.

The draft definition, created under consensus process by an international panel of experts, was refined by empirical testing in a meta-analysis of data on 4,457 patients in two large data sets from seven centers. The risk of mortality from acute respiratory distress syndrome (ARDS) was 27% with mild disease, 32% with moderate ARDS, and 45% with severe ARDS, Dr. Niall D. Ferguson and Dr. Gordon D. Rubenfeld reported at an international conference of the American Thoracic Society.

Sherry Boschert/IMNG Medical Media

The median duration of mechanical ventilation in survivors was 5 days in patients with mild ARDS, 7 days with moderate ARDS, and 9 days with severe ARDS, said Dr. Ferguson, director of critical care medicine at the University of Toronto. The study was published online May 21 in JAMA (doi: 10.1001/jama.2012.5669).

The European Society of Intensive Care Medicine convened the panel of experts in Berlin in 2011 to draft a new definition of ARDS in hopes of improving upon the 1994 definition from the American-European Consensus Conference (AECC), said Dr. Rubenfeld, professor of medicine at the University of Toronto and chief of the program in trauma/emergency and critical care at Sunnybrook Health Sciences Center, Toronto. Since the AECC definition was adopted widely, issues of reliability and validity have emerged. The American Thoracic Society and the Society of Critical Care Medicine endorsed the 2011 consensus effort.

Under the new Berlin Definition, patients with mild ARDS have mild hypoxemia, defined as a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen of 201-300 mm Hg (PaO₂/FIO₂ = 201-300 mm Hg). Moderate hypoxia (PaO₂/FIO₂ = 101-200 mm Hg) defines moderate ARDS, and severe hypoxia (PaO₂/FIO₂ = 100 mm Hg or less) defines severe ARDS.

The initial draft of the Berlin Definition included four ancillary variables for severe ARDS that were dropped after the meta-analysis found that they did not improve the predictive value for mortality, the speakers and their associates in the study reported. The abandoned variables were radiographic severity, respiratory system compliance, positive end-expiratory pressure, and corrected expired volume per minute.

Dr. Rubenfeld stressed that these variables still are important for clinicians to measure and for understanding ARDS, but they were not included in the definition of severe ARDS because they made the definition more complex while not adding anything to the predictive value of the definition.

He also cautioned that neither the Berlin Definition nor the AECC definition is designed to be a prognostic model; the end point of mortality was used to hone the Berlin Definition.

The Berlin Definition had better predictive validity for mortality than the AECC definition in an analysis using the area under the receiver operating curve (AUROC) in logistic regression models. The Berlin Definition had an AUROC of 0.577, compared with 0.536 for the AECC definition, a statistically significant improvement.

The data for the meta-analysis came from four multicenter clinical studies and three single-center physiological studies, the investigators reported.

Twenty-two percent of patients met the Berlin Definition criteria for mild ARDS, 50% had moderate ARDS, and 28% had severe ARDS. Median ventilator-free days declined with severity of disease, from 20 days with mild ARDS to 16 days with moderate ARDS and 1 day with severe ARDS.

Among patients with mild ARDS at baseline under the Berlin Definition, 29% progressed to moderate disease and 4% progressed to severe disease within 7 days. Among patients with moderate ARDS at baseline, 13% progressed to severe disease within 7 days.

Sherry Boschert/IMNG Medical Media

The investigators suggested that this approach of combining consensus discussions with empirical evaluation might be a model for creating more accurate, evidence-based definitions for critical illness syndromes. Previous ARDS definitions relied on expert consensus alone.

Without the empirical evaluation that led to deleting the ancillary variables, a needlessly complex ARDS definition would have been proposed, Dr. Rubenfeld said.

The study was sponsored by the European Society of Intensive Care Medicine, the National Institutes of Health, and the Canadian Institutes of Health Research (CIHR). CareFusion provided in-kind support for the study. Dr. Ferguson was supported by a CIHR New Investigator Award. Dr. Rubenfeld reported having financial relationships with Ikaria, Faron, and Cerus. Some of his associates in the study reported financial relationships with Maquet Medical, Hemodec, Faron, AstraZeneca, U.S. Biotest, Sirius Genetics, Sanofi-Aventis, Immunetrics, Abbott, Eli Lilly, Ikaria, GlaxoSmithKline, Tarix, Apeiron, and/or Novalung.

The Berlin Definition of ARDS

• Timing: Within 1 week of a known clinical insult or new or worsening respiratory symptoms.

• Chest imaging: Bilateral opacities on x-ray or CT scan not fully explained by effusions, lobar/lung collapse, or nodules.

• Origin of edema: Respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present.

• Oxygenation:

Mild: PaO₂/FIO₂ of 201-300 mm Hg with positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) of 5 cm H₂O or greater.

Moderate: PaO₂/FIO₂ of 101-200 mm Hg with PEEP of 5 cm H₂O or greater.

Severe: PaO₂/FIO₂ of 100 mm Hg or less with PEEP of 5 cm H₂O or greater.

If the altitude is higher than 1,000 m, the correction factor should be calculated as PaO₂/RO₂ × (barometric pressure/760).

SAN FRANCISCO – A proposed new definition of acute respiratory distress syndrome describes categories based on mild, moderate, or severe hypoxemia that correlate increasing severity with significantly increased mortality or increased time on mechanical ventilation among survivors.

The draft definition, created under consensus process by an international panel of experts, was refined by empirical testing in a meta-analysis of data on 4,457 patients in two large data sets from seven centers. The risk of mortality from acute respiratory distress syndrome (ARDS) was 27% with mild disease, 32% with moderate ARDS, and 45% with severe ARDS, Dr. Niall D. Ferguson and Dr. Gordon D. Rubenfeld reported at an international conference of the American Thoracic Society.

Sherry Boschert/IMNG Medical Media

The median duration of mechanical ventilation in survivors was 5 days in patients with mild ARDS, 7 days with moderate ARDS, and 9 days with severe ARDS, said Dr. Ferguson, director of critical care medicine at the University of Toronto. The study was published online May 21 in JAMA (doi: 10.1001/jama.2012.5669).

The European Society of Intensive Care Medicine convened the panel of experts in Berlin in 2011 to draft a new definition of ARDS in hopes of improving upon the 1994 definition from the American-European Consensus Conference (AECC), said Dr. Rubenfeld, professor of medicine at the University of Toronto and chief of the program in trauma/emergency and critical care at Sunnybrook Health Sciences Center, Toronto. Since the AECC definition was adopted widely, issues of reliability and validity have emerged. The American Thoracic Society and the Society of Critical Care Medicine endorsed the 2011 consensus effort.

Under the new Berlin Definition, patients with mild ARDS have mild hypoxemia, defined as a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen of 201-300 mm Hg (PaO₂/FIO₂ = 201-300 mm Hg). Moderate hypoxia (PaO₂/FIO₂ = 101-200 mm Hg) defines moderate ARDS, and severe hypoxia (PaO₂/FIO₂ = 100 mm Hg or less) defines severe ARDS.

The initial draft of the Berlin Definition included four ancillary variables for severe ARDS that were dropped after the meta-analysis found that they did not improve the predictive value for mortality, the speakers and their associates in the study reported. The abandoned variables were radiographic severity, respiratory system compliance, positive end-expiratory pressure, and corrected expired volume per minute.

Dr. Rubenfeld stressed that these variables still are important for clinicians to measure and for understanding ARDS, but they were not included in the definition of severe ARDS because they made the definition more complex while not adding anything to the predictive value of the definition.

He also cautioned that neither the Berlin Definition nor the AECC definition is designed to be a prognostic model; the end point of mortality was used to hone the Berlin Definition.

The Berlin Definition had better predictive validity for mortality than the AECC definition in an analysis using the area under the receiver operating curve (AUROC) in logistic regression models. The Berlin Definition had an AUROC of 0.577, compared with 0.536 for the AECC definition, a statistically significant improvement.

The data for the meta-analysis came from four multicenter clinical studies and three single-center physiological studies, the investigators reported.

Twenty-two percent of patients met the Berlin Definition criteria for mild ARDS, 50% had moderate ARDS, and 28% had severe ARDS. Median ventilator-free days declined with severity of disease, from 20 days with mild ARDS to 16 days with moderate ARDS and 1 day with severe ARDS.

Among patients with mild ARDS at baseline under the Berlin Definition, 29% progressed to moderate disease and 4% progressed to severe disease within 7 days. Among patients with moderate ARDS at baseline, 13% progressed to severe disease within 7 days.

Sherry Boschert/IMNG Medical Media

The investigators suggested that this approach of combining consensus discussions with empirical evaluation might be a model for creating more accurate, evidence-based definitions for critical illness syndromes. Previous ARDS definitions relied on expert consensus alone.

Without the empirical evaluation that led to deleting the ancillary variables, a needlessly complex ARDS definition would have been proposed, Dr. Rubenfeld said.

The study was sponsored by the European Society of Intensive Care Medicine, the National Institutes of Health, and the Canadian Institutes of Health Research (CIHR). CareFusion provided in-kind support for the study. Dr. Ferguson was supported by a CIHR New Investigator Award. Dr. Rubenfeld reported having financial relationships with Ikaria, Faron, and Cerus. Some of his associates in the study reported financial relationships with Maquet Medical, Hemodec, Faron, AstraZeneca, U.S. Biotest, Sirius Genetics, Sanofi-Aventis, Immunetrics, Abbott, Eli Lilly, Ikaria, GlaxoSmithKline, Tarix, Apeiron, and/or Novalung.

The Berlin Definition of ARDS

• Timing: Within 1 week of a known clinical insult or new or worsening respiratory symptoms.

• Chest imaging: Bilateral opacities on x-ray or CT scan not fully explained by effusions, lobar/lung collapse, or nodules.

• Origin of edema: Respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present.

• Oxygenation:

Mild: PaO₂/FIO₂ of 201-300 mm Hg with positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) of 5 cm H₂O or greater.

Moderate: PaO₂/FIO₂ of 101-200 mm Hg with PEEP of 5 cm H₂O or greater.

Severe: PaO₂/FIO₂ of 100 mm Hg or less with PEEP of 5 cm H₂O or greater.

If the altitude is higher than 1,000 m, the correction factor should be calculated as PaO₂/RO₂ × (barometric pressure/760).

SAN FRANCISCO – A proposed new definition of acute respiratory distress syndrome describes categories based on mild, moderate, or severe hypoxemia that correlate increasing severity with significantly increased mortality or increased time on mechanical ventilation among survivors.

The draft definition, created under consensus process by an international panel of experts, was refined by empirical testing in a meta-analysis of data on 4,457 patients in two large data sets from seven centers. The risk of mortality from acute respiratory distress syndrome (ARDS) was 27% with mild disease, 32% with moderate ARDS, and 45% with severe ARDS, Dr. Niall D. Ferguson and Dr. Gordon D. Rubenfeld reported at an international conference of the American Thoracic Society.

Sherry Boschert/IMNG Medical Media

The median duration of mechanical ventilation in survivors was 5 days in patients with mild ARDS, 7 days with moderate ARDS, and 9 days with severe ARDS, said Dr. Ferguson, director of critical care medicine at the University of Toronto. The study was published online May 21 in JAMA (doi: 10.1001/jama.2012.5669).

The European Society of Intensive Care Medicine convened the panel of experts in Berlin in 2011 to draft a new definition of ARDS in hopes of improving upon the 1994 definition from the American-European Consensus Conference (AECC), said Dr. Rubenfeld, professor of medicine at the University of Toronto and chief of the program in trauma/emergency and critical care at Sunnybrook Health Sciences Center, Toronto. Since the AECC definition was adopted widely, issues of reliability and validity have emerged. The American Thoracic Society and the Society of Critical Care Medicine endorsed the 2011 consensus effort.

Under the new Berlin Definition, patients with mild ARDS have mild hypoxemia, defined as a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen of 201-300 mm Hg (PaO₂/FIO₂ = 201-300 mm Hg). Moderate hypoxia (PaO₂/FIO₂ = 101-200 mm Hg) defines moderate ARDS, and severe hypoxia (PaO₂/FIO₂ = 100 mm Hg or less) defines severe ARDS.

The initial draft of the Berlin Definition included four ancillary variables for severe ARDS that were dropped after the meta-analysis found that they did not improve the predictive value for mortality, the speakers and their associates in the study reported. The abandoned variables were radiographic severity, respiratory system compliance, positive end-expiratory pressure, and corrected expired volume per minute.

Dr. Rubenfeld stressed that these variables still are important for clinicians to measure and for understanding ARDS, but they were not included in the definition of severe ARDS because they made the definition more complex while not adding anything to the predictive value of the definition.

He also cautioned that neither the Berlin Definition nor the AECC definition is designed to be a prognostic model; the end point of mortality was used to hone the Berlin Definition.

The Berlin Definition had better predictive validity for mortality than the AECC definition in an analysis using the area under the receiver operating curve (AUROC) in logistic regression models. The Berlin Definition had an AUROC of 0.577, compared with 0.536 for the AECC definition, a statistically significant improvement.

The data for the meta-analysis came from four multicenter clinical studies and three single-center physiological studies, the investigators reported.

Twenty-two percent of patients met the Berlin Definition criteria for mild ARDS, 50% had moderate ARDS, and 28% had severe ARDS. Median ventilator-free days declined with severity of disease, from 20 days with mild ARDS to 16 days with moderate ARDS and 1 day with severe ARDS.

Among patients with mild ARDS at baseline under the Berlin Definition, 29% progressed to moderate disease and 4% progressed to severe disease within 7 days. Among patients with moderate ARDS at baseline, 13% progressed to severe disease within 7 days.

Sherry Boschert/IMNG Medical Media

The investigators suggested that this approach of combining consensus discussions with empirical evaluation might be a model for creating more accurate, evidence-based definitions for critical illness syndromes. Previous ARDS definitions relied on expert consensus alone.

Without the empirical evaluation that led to deleting the ancillary variables, a needlessly complex ARDS definition would have been proposed, Dr. Rubenfeld said.

The study was sponsored by the European Society of Intensive Care Medicine, the National Institutes of Health, and the Canadian Institutes of Health Research (CIHR). CareFusion provided in-kind support for the study. Dr. Ferguson was supported by a CIHR New Investigator Award. Dr. Rubenfeld reported having financial relationships with Ikaria, Faron, and Cerus. Some of his associates in the study reported financial relationships with Maquet Medical, Hemodec, Faron, AstraZeneca, U.S. Biotest, Sirius Genetics, Sanofi-Aventis, Immunetrics, Abbott, Eli Lilly, Ikaria, GlaxoSmithKline, Tarix, Apeiron, and/or Novalung.

The Berlin Definition of ARDS

• Timing: Within 1 week of a known clinical insult or new or worsening respiratory symptoms.

• Chest imaging: Bilateral opacities on x-ray or CT scan not fully explained by effusions, lobar/lung collapse, or nodules.

• Origin of edema: Respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present.

• Oxygenation:

Mild: PaO₂/FIO₂ of 201-300 mm Hg with positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) of 5 cm H₂O or greater.

Moderate: PaO₂/FIO₂ of 101-200 mm Hg with PEEP of 5 cm H₂O or greater.

Severe: PaO₂/FIO₂ of 100 mm Hg or less with PEEP of 5 cm H₂O or greater.

If the altitude is higher than 1,000 m, the correction factor should be calculated as PaO₂/RO₂ × (barometric pressure/760).

SAN FRANCISCO – Patients aged 55-74 years who have at least a 30 pack-year smoking history should be offered annual low-dose CT lung cancer screening, even if they have quit within the past 15 years, according to a systematic review published online May 20 in JAMA.

The review forms the basis of the new lung cancer screening clinical practice guidelines from the American College of Chest Physicians and the American Society of Clinical Oncology. The recommendations are based largely on the 53,454-patient, randomized NLST (National Lung Screening Trial), which found that for every 1,000 high-risk smokers, three rounds of annual CT screening saved approximately three lives over about 7 years, which is comparable, at least, to the absolute benefit of screening mammographies in older women (N. Engl. J. Med. 2011;365:395-409).

The risks – including misdiagnosis and unnecessary surgery – and potential benefits should be explained to patients before they opt for screening. "People need to know" that "19 out of 20 positive results are going to be false positive. A positive screen does not equal a diagnosis of lung cancer," said coauthor Dr. Michael K. Gould, assistant director for health services research at Kaiser Permanente of Southern California, Pasadena.

In addition, "CT screening should not be performed" in smokers and ex-smokers who fall outside of the high-risk group, or in those with severe comorbidities that limit life expectancy or preclude treatment, according to the guidelines (JAMA 2012 May 20 [doi:10.1001/jama.2012.5521]).

The risks and benefits of screening are just "too close to call" for those patients, said lead author Dr. Peter Bach, director of the center for health policy and outcomes at Memorial Sloan-Kettering Cancer Center in New York.

After an extensive literature review, the researchers included eight randomized trials and 13 cohort studies in its final analysis. Although they are confident that screening benefits high-risk patients – based mostly on the NLST, with some added input from smaller trials – they are also concerned about the lack of data on the potential harms of screening, which led to the recommendation to offer screening only to high-risk patients, Dr. Bach said.

Overall, the lack of additional research led both recommendations to be characterized as "weak" under the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system.

The impact of screening even high-risk patients "on smoking cessation, quality of life, and cost-effectiveness is really quite unclear. We don’t know in any sense what the frequency should be or the duration," Dr. Bach said.

Also unclear is how screening will play out in settings less rigorous than the academic centers where the NLST was conducted. Patient compliance with screening at those centers was 90%, adverse events were rare, and subsequent diagnostic work-ups and interventions were available.

To mitigate potential problems, the guidelines recommend that screening be done in similar multidisciplinary settings.

The authors also call for a screening registry "that records each patient’s experience [to] help us develop a quality measurement system similar to mammography screening that could maximize the benefits and minimize the harm for individuals who undergo screening," Dr. Bach said.

A supplement to the JAMA article includes a section entitled "Components of a Conversation About CT Screening," which addresses how to talk with patients about these issues.

The American Thoracic Society has endorsed the guidelines.

Dr. Bach reported that he has received speaking fees from Genentech. Coauthors reported ties to pharmaceutical companies such as Oncimmune and governmental agencies such as the National Cancer Institute. Dr. Gould and Dr. Bauchner said they have no relevant disclosures.

SAN FRANCISCO – Patients aged 55-74 years who have at least a 30 pack-year smoking history should be offered annual low-dose CT lung cancer screening, even if they have quit within the past 15 years, according to a systematic review published online May 20 in JAMA.

The review forms the basis of the new lung cancer screening clinical practice guidelines from the American College of Chest Physicians and the American Society of Clinical Oncology. The recommendations are based largely on the 53,454-patient, randomized NLST (National Lung Screening Trial), which found that for every 1,000 high-risk smokers, three rounds of annual CT screening saved approximately three lives over about 7 years, which is comparable, at least, to the absolute benefit of screening mammographies in older women (N. Engl. J. Med. 2011;365:395-409).

The risks – including misdiagnosis and unnecessary surgery – and potential benefits should be explained to patients before they opt for screening. "People need to know" that "19 out of 20 positive results are going to be false positive. A positive screen does not equal a diagnosis of lung cancer," said coauthor Dr. Michael K. Gould, assistant director for health services research at Kaiser Permanente of Southern California, Pasadena.

In addition, "CT screening should not be performed" in smokers and ex-smokers who fall outside of the high-risk group, or in those with severe comorbidities that limit life expectancy or preclude treatment, according to the guidelines (JAMA 2012 May 20 [doi:10.1001/jama.2012.5521]).

The risks and benefits of screening are just "too close to call" for those patients, said lead author Dr. Peter Bach, director of the center for health policy and outcomes at Memorial Sloan-Kettering Cancer Center in New York.

After an extensive literature review, the researchers included eight randomized trials and 13 cohort studies in its final analysis. Although they are confident that screening benefits high-risk patients – based mostly on the NLST, with some added input from smaller trials – they are also concerned about the lack of data on the potential harms of screening, which led to the recommendation to offer screening only to high-risk patients, Dr. Bach said.

Overall, the lack of additional research led both recommendations to be characterized as "weak" under the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system.

The impact of screening even high-risk patients "on smoking cessation, quality of life, and cost-effectiveness is really quite unclear. We don’t know in any sense what the frequency should be or the duration," Dr. Bach said.

Also unclear is how screening will play out in settings less rigorous than the academic centers where the NLST was conducted. Patient compliance with screening at those centers was 90%, adverse events were rare, and subsequent diagnostic work-ups and interventions were available.

To mitigate potential problems, the guidelines recommend that screening be done in similar multidisciplinary settings.

The authors also call for a screening registry "that records each patient’s experience [to] help us develop a quality measurement system similar to mammography screening that could maximize the benefits and minimize the harm for individuals who undergo screening," Dr. Bach said.

A supplement to the JAMA article includes a section entitled "Components of a Conversation About CT Screening," which addresses how to talk with patients about these issues.

The American Thoracic Society has endorsed the guidelines.

Dr. Bach reported that he has received speaking fees from Genentech. Coauthors reported ties to pharmaceutical companies such as Oncimmune and governmental agencies such as the National Cancer Institute. Dr. Gould and Dr. Bauchner said they have no relevant disclosures.

SAN FRANCISCO – Patients aged 55-74 years who have at least a 30 pack-year smoking history should be offered annual low-dose CT lung cancer screening, even if they have quit within the past 15 years, according to a systematic review published online May 20 in JAMA.

The review forms the basis of the new lung cancer screening clinical practice guidelines from the American College of Chest Physicians and the American Society of Clinical Oncology. The recommendations are based largely on the 53,454-patient, randomized NLST (National Lung Screening Trial), which found that for every 1,000 high-risk smokers, three rounds of annual CT screening saved approximately three lives over about 7 years, which is comparable, at least, to the absolute benefit of screening mammographies in older women (N. Engl. J. Med. 2011;365:395-409).

The risks – including misdiagnosis and unnecessary surgery – and potential benefits should be explained to patients before they opt for screening. "People need to know" that "19 out of 20 positive results are going to be false positive. A positive screen does not equal a diagnosis of lung cancer," said coauthor Dr. Michael K. Gould, assistant director for health services research at Kaiser Permanente of Southern California, Pasadena.

In addition, "CT screening should not be performed" in smokers and ex-smokers who fall outside of the high-risk group, or in those with severe comorbidities that limit life expectancy or preclude treatment, according to the guidelines (JAMA 2012 May 20 [doi:10.1001/jama.2012.5521]).

The risks and benefits of screening are just "too close to call" for those patients, said lead author Dr. Peter Bach, director of the center for health policy and outcomes at Memorial Sloan-Kettering Cancer Center in New York.

After an extensive literature review, the researchers included eight randomized trials and 13 cohort studies in its final analysis. Although they are confident that screening benefits high-risk patients – based mostly on the NLST, with some added input from smaller trials – they are also concerned about the lack of data on the potential harms of screening, which led to the recommendation to offer screening only to high-risk patients, Dr. Bach said.

Overall, the lack of additional research led both recommendations to be characterized as "weak" under the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system.

The impact of screening even high-risk patients "on smoking cessation, quality of life, and cost-effectiveness is really quite unclear. We don’t know in any sense what the frequency should be or the duration," Dr. Bach said.

Also unclear is how screening will play out in settings less rigorous than the academic centers where the NLST was conducted. Patient compliance with screening at those centers was 90%, adverse events were rare, and subsequent diagnostic work-ups and interventions were available.

To mitigate potential problems, the guidelines recommend that screening be done in similar multidisciplinary settings.

The authors also call for a screening registry "that records each patient’s experience [to] help us develop a quality measurement system similar to mammography screening that could maximize the benefits and minimize the harm for individuals who undergo screening," Dr. Bach said.

A supplement to the JAMA article includes a section entitled "Components of a Conversation About CT Screening," which addresses how to talk with patients about these issues.

The American Thoracic Society has endorsed the guidelines.

Dr. Bach reported that he has received speaking fees from Genentech. Coauthors reported ties to pharmaceutical companies such as Oncimmune and governmental agencies such as the National Cancer Institute. Dr. Gould and Dr. Bauchner said they have no relevant disclosures.

SAN FRANCISCO – Indwelling pleural catheters did not provide greater relief of dyspnea, cause less chest pain, or improve quality of life compared with chest tube and talc pleurodesis in patients with symptomatic malignant pleural effusion, an unblinded, randomized study of 106 patients found.

Patients receiving indwelling pleural catheters (IPCs) had a shorter initial hospitalization (0 days vs. 4 days) but were five times more likely to develop adverse events, Najib M. Rahman, D.Phil., reported at an international conference of the American Thoracic Society.

The study was published online May 20, 2012 (JAMA 2012;307 [doi:10.1001/jama.2012.5535]). The lead investigator of the Second Therapeutic Intervention in Malignant Effusion Trial (TIME2) was Dr. Helen E. Davies of University Hospital of Wales, Cardiff.

The patients from seven UK centers had undergone no prior pleurodesis. In the IPC group, outpatients had the IPC inserted, had a large volume drained, and were educated to do subsequent drainage at home. In the talc group, patients were admitted for chest tube insertion and talc for slurry pleurodesis. All patients were asked to assess their dyspnea daily at the same time each day using a 100-mm visual analog scale (VAS), with 0 mm indicating no dyspnea and 100 mm representing maximum dyspnea.

Dyspnea improved in both groups. Overall, mean VAS scores decreased by 37 mm from baseline with IPC and by 30 mm with talc, which was not significantly different. Dyspnea scores did not differ significantly between groups in the first 42 days, the primary outcome measured. At 6 months, however, there was a statistically significantly greater improvement in dyspnea in the IPC group, with a mean 14-mm lower score than the talc group.

"IPC may be better than talc at 6 months" of follow-up, said Dr. Rahman of the University of Oxford (England).

In the talc group, 22% of patients required further pleural procedures, compared with 6% in the IPC group, a significant difference. Five patients in the IPC group developed pleural infection, compared with one patient in the talc group.

"A lot of chest physicians think talc pleurodesis is more painful, but it turns out that IPC is painful too," he said. Scores for chest pain and for quality of life did not differ significantly between groups.

The study was not powered to assess mortality risk, but no significant differences were seen between groups out to 12 months of follow-up.

"We must not conclude that IPCs and talc are the same" or equivalent, Dr. Rahman said. The investigators are assessing the cost implications of the results, including costs for procedures and complications after the initial treatment.

The results should be interpreted with caution because the study was powered to assess superiority, not equivalence between treatments, Dr. Nick A. Maskell said in an editorial in the same issue (JAMA 2012;307 [doi:10.1001/jama.2012.5543]).

Clinicians for years have debated the best management of malignant pleural effusions. Talc is recommended as first-line treatment of symptomatic patients by international guidelines, said Dr. Maskell of the University of Bristol (England).

Based on the TIME2 study findings, physicians should feel comfortable discussing the advantages and disadvantages of both treatments with patients to help them pick the strategy that best suits them, he said.

Combining the best of both strategies may be the way of the future, Dr. Maskell added. Some preliminary studies suggest it may be feasible and beneficial to deliver pleurodesis agents via an IPC in the outpatient setting.

The only other randomized controlled trial comparing IPCs with pleurodesis for malignant pleural effusion used doxycycline, which is not as effective as talc, and found similar improvements in dyspnea and quality of life between groups, he said (Cancer 1999;86:1992-9).

The study was funded by the British Lung Foundation and the Robert Luff Foundation. Dr. Rahman reported being a consultant to Rocket Medical, which supplied the IPCs and drainage bottles for the trial. Some of his associates reported financial associations with Boehringer Ingelheim, Medico, AstraZeneca, GlaxoSmithKline, Chiese, CareFusion, Sequana Medical, Merck, and Gilead. Dr. Maskell disclosed receiving honoraria and grants from Carefusion.

SAN FRANCISCO – Indwelling pleural catheters did not provide greater relief of dyspnea, cause less chest pain, or improve quality of life compared with chest tube and talc pleurodesis in patients with symptomatic malignant pleural effusion, an unblinded, randomized study of 106 patients found.

Patients receiving indwelling pleural catheters (IPCs) had a shorter initial hospitalization (0 days vs. 4 days) but were five times more likely to develop adverse events, Najib M. Rahman, D.Phil., reported at an international conference of the American Thoracic Society.

The study was published online May 20, 2012 (JAMA 2012;307 [doi:10.1001/jama.2012.5535]). The lead investigator of the Second Therapeutic Intervention in Malignant Effusion Trial (TIME2) was Dr. Helen E. Davies of University Hospital of Wales, Cardiff.

The patients from seven UK centers had undergone no prior pleurodesis. In the IPC group, outpatients had the IPC inserted, had a large volume drained, and were educated to do subsequent drainage at home. In the talc group, patients were admitted for chest tube insertion and talc for slurry pleurodesis. All patients were asked to assess their dyspnea daily at the same time each day using a 100-mm visual analog scale (VAS), with 0 mm indicating no dyspnea and 100 mm representing maximum dyspnea.

Dyspnea improved in both groups. Overall, mean VAS scores decreased by 37 mm from baseline with IPC and by 30 mm with talc, which was not significantly different. Dyspnea scores did not differ significantly between groups in the first 42 days, the primary outcome measured. At 6 months, however, there was a statistically significantly greater improvement in dyspnea in the IPC group, with a mean 14-mm lower score than the talc group.

"IPC may be better than talc at 6 months" of follow-up, said Dr. Rahman of the University of Oxford (England).

In the talc group, 22% of patients required further pleural procedures, compared with 6% in the IPC group, a significant difference. Five patients in the IPC group developed pleural infection, compared with one patient in the talc group.

"A lot of chest physicians think talc pleurodesis is more painful, but it turns out that IPC is painful too," he said. Scores for chest pain and for quality of life did not differ significantly between groups.

The study was not powered to assess mortality risk, but no significant differences were seen between groups out to 12 months of follow-up.

"We must not conclude that IPCs and talc are the same" or equivalent, Dr. Rahman said. The investigators are assessing the cost implications of the results, including costs for procedures and complications after the initial treatment.

The results should be interpreted with caution because the study was powered to assess superiority, not equivalence between treatments, Dr. Nick A. Maskell said in an editorial in the same issue (JAMA 2012;307 [doi:10.1001/jama.2012.5543]).

Clinicians for years have debated the best management of malignant pleural effusions. Talc is recommended as first-line treatment of symptomatic patients by international guidelines, said Dr. Maskell of the University of Bristol (England).

Based on the TIME2 study findings, physicians should feel comfortable discussing the advantages and disadvantages of both treatments with patients to help them pick the strategy that best suits them, he said.

Combining the best of both strategies may be the way of the future, Dr. Maskell added. Some preliminary studies suggest it may be feasible and beneficial to deliver pleurodesis agents via an IPC in the outpatient setting.

The only other randomized controlled trial comparing IPCs with pleurodesis for malignant pleural effusion used doxycycline, which is not as effective as talc, and found similar improvements in dyspnea and quality of life between groups, he said (Cancer 1999;86:1992-9).

The study was funded by the British Lung Foundation and the Robert Luff Foundation. Dr. Rahman reported being a consultant to Rocket Medical, which supplied the IPCs and drainage bottles for the trial. Some of his associates reported financial associations with Boehringer Ingelheim, Medico, AstraZeneca, GlaxoSmithKline, Chiese, CareFusion, Sequana Medical, Merck, and Gilead. Dr. Maskell disclosed receiving honoraria and grants from Carefusion.

SAN FRANCISCO – Indwelling pleural catheters did not provide greater relief of dyspnea, cause less chest pain, or improve quality of life compared with chest tube and talc pleurodesis in patients with symptomatic malignant pleural effusion, an unblinded, randomized study of 106 patients found.

Patients receiving indwelling pleural catheters (IPCs) had a shorter initial hospitalization (0 days vs. 4 days) but were five times more likely to develop adverse events, Najib M. Rahman, D.Phil., reported at an international conference of the American Thoracic Society.

The study was published online May 20, 2012 (JAMA 2012;307 [doi:10.1001/jama.2012.5535]). The lead investigator of the Second Therapeutic Intervention in Malignant Effusion Trial (TIME2) was Dr. Helen E. Davies of University Hospital of Wales, Cardiff.

The patients from seven UK centers had undergone no prior pleurodesis. In the IPC group, outpatients had the IPC inserted, had a large volume drained, and were educated to do subsequent drainage at home. In the talc group, patients were admitted for chest tube insertion and talc for slurry pleurodesis. All patients were asked to assess their dyspnea daily at the same time each day using a 100-mm visual analog scale (VAS), with 0 mm indicating no dyspnea and 100 mm representing maximum dyspnea.

Dyspnea improved in both groups. Overall, mean VAS scores decreased by 37 mm from baseline with IPC and by 30 mm with talc, which was not significantly different. Dyspnea scores did not differ significantly between groups in the first 42 days, the primary outcome measured. At 6 months, however, there was a statistically significantly greater improvement in dyspnea in the IPC group, with a mean 14-mm lower score than the talc group.

"IPC may be better than talc at 6 months" of follow-up, said Dr. Rahman of the University of Oxford (England).

In the talc group, 22% of patients required further pleural procedures, compared with 6% in the IPC group, a significant difference. Five patients in the IPC group developed pleural infection, compared with one patient in the talc group.

"A lot of chest physicians think talc pleurodesis is more painful, but it turns out that IPC is painful too," he said. Scores for chest pain and for quality of life did not differ significantly between groups.

The study was not powered to assess mortality risk, but no significant differences were seen between groups out to 12 months of follow-up.

"We must not conclude that IPCs and talc are the same" or equivalent, Dr. Rahman said. The investigators are assessing the cost implications of the results, including costs for procedures and complications after the initial treatment.

The results should be interpreted with caution because the study was powered to assess superiority, not equivalence between treatments, Dr. Nick A. Maskell said in an editorial in the same issue (JAMA 2012;307 [doi:10.1001/jama.2012.5543]).

Clinicians for years have debated the best management of malignant pleural effusions. Talc is recommended as first-line treatment of symptomatic patients by international guidelines, said Dr. Maskell of the University of Bristol (England).

Based on the TIME2 study findings, physicians should feel comfortable discussing the advantages and disadvantages of both treatments with patients to help them pick the strategy that best suits them, he said.

Combining the best of both strategies may be the way of the future, Dr. Maskell added. Some preliminary studies suggest it may be feasible and beneficial to deliver pleurodesis agents via an IPC in the outpatient setting.

The only other randomized controlled trial comparing IPCs with pleurodesis for malignant pleural effusion used doxycycline, which is not as effective as talc, and found similar improvements in dyspnea and quality of life between groups, he said (Cancer 1999;86:1992-9).

The study was funded by the British Lung Foundation and the Robert Luff Foundation. Dr. Rahman reported being a consultant to Rocket Medical, which supplied the IPCs and drainage bottles for the trial. Some of his associates reported financial associations with Boehringer Ingelheim, Medico, AstraZeneca, GlaxoSmithKline, Chiese, CareFusion, Sequana Medical, Merck, and Gilead. Dr. Maskell disclosed receiving honoraria and grants from Carefusion.