American College of Chest Physicians (ACCP): Annual International Scientific Assembly (CHEST 2011)

HONOLULU – Current interventions for chronic obstructive pulmonary disease leave many patients with unmet needs, according to Dr. Nicola A. Hanania.

"We know from large clinical trials that current pharmacotherapies do not change the natural history of COPD, and many patients remain symptomatic with current therapies," Dr. Hanania, director of the asthma clinical research center at Baylor College of Medicine, Houston, said at the annual meeting of the American College of Chest Physicians.

Inadequate adherence to therapy "is a major cause of poor clinical outcomes in the treatment of COPD," he said. The cost, compliance, and safety of certain agents are issues "that we cannot ignore."

When considering a therapy for COPD, clinicians should factor in components of COPD beyond bronchoconstriction, he advised, including mucociliary dysfunction, structural changes in the airway and the lung, systemic components, and airway inflammation. "We also have to look at outcomes other than lung function including exacerbations, activity limitation, and symptoms of dyspnea," he said. "We are no more satisfied with just a drug that improves lung function but does nothing for the patient-reported outcomes."

Dr. Hanania’s "wish list" for an ideal COPD therapeutic option in the future is one that addresses the multiple components and phenotypes of COPD. He said he would like to see drugs that blunt proinflammatory cells and molecules known to be involved in COPD. "We’d also like to see drugs that could modify the disease progression and comorbid conditions," he said. Such drugs, he continued, should be well tolerated and compatible with other therapies for COPD and comorbid conditions, be simple to administer, and have the potential to improve patient adherence, he added.

Treatment approaches being studied include novel formulations of existing medications, such as the combination of ultralong-acting beta-2 agonists and long-acting antimuscarinics. Among the agents that are the most promising on this front, he said, are indacaterol plus glycopyrronium (QVA-149) and vilanterol plus GSK-573719.

Other agents in development include bifunctional muscarinic antagonist–beta-2 agonists such as GSK-961081 and THRX-200495 as well as combinations of once-daily long-acting beta-2 agonists and inhaled corticosteroids, including formoterol and mometasone (MFF258) and vilanterol and fluticasone (Relovair).

However, perhaps the most promising pharmacotherapies will be novel agents aimed at reducing local and systemic inflammation. "We know that COPD is an inflammatory disease, so we need drugs that can target inflammation right from the very beginning," Dr. Hanania explained. "Inhaled steroids are important, but they’re not as effective in COPD as they are in asthma."

Phosphodiesterase type 4 inhibitors are currently being studied in COPD. These agents reduce the activity of neutrophils, macrophages, and CD8-positive T-lymphocytes, as well as the expression of cytokines and other inflammatory mediators. Currently, the only phosphodiesterase type 4 inhibitor approved in the United States for use in patients with COPD is roflumilast (Daliresp). Several others are in development.

"We know from large clinical trials that current pharmaco-therapies do not change the natural history of COPD."

Because they target airway inflammation, p38 mitogen-activated protein kinase inhibitors are also being studied in COPD patients. However, so far clinical trials have found potential problems related to systemic side effects and toxicity, "indicating that it is probably necessary to deliver these drugs by inhalation to reduce systemic exposure," Dr. Hanania said.

He concluded his presentation by noting that certain medications used to treat comorbidities in COPD may have beneficial effects on COPD outcomes. These include statins, ACE inhibitors, beta-blockers, peroxisome proliferator–activated receptor agonists, and macrolides. The National Heart, Lung, and Blood Institute COPD Clinical Research Network is currently conducting a prospective randomized controlled trial in 1,126 patients with severe COPD randomized to daily simvastatin (40 mg) vs. placebo for at least 1 year. The primary outcome is exacerbation of COPD. The secondary outcomes include change in forced expiratory volume in 1 second (FEV₁), St. George’s Respiratory Questionnaire responses, 6-minute walk test results, BODE Index score, a combined cardiovascular end point, and serum inflammatory biomarker levels. Furthermore, a recent study showed that daily azithromycin significantly reduced exacerbations in high-risk patients.

Dr. Hanania disclosed that he has received grant support from the National Institutes of Health, the American Lung Association, GlaxoSmithKline (GSK), Boehringer Ingelheim (BI), Sunovion, Novartis, Pfizer, and Forest Pharmaceuticals. He also serves as a consultant for GSK, Dey Pharmaceuticals, Sunovion, Pfizer, and Forest, and is a member of the speakers bureau for GSK, BI, AstraZeneca, and Forest.

HONOLULU – Current interventions for chronic obstructive pulmonary disease leave many patients with unmet needs, according to Dr. Nicola A. Hanania.

"We know from large clinical trials that current pharmacotherapies do not change the natural history of COPD, and many patients remain symptomatic with current therapies," Dr. Hanania, director of the asthma clinical research center at Baylor College of Medicine, Houston, said at the annual meeting of the American College of Chest Physicians.

Inadequate adherence to therapy "is a major cause of poor clinical outcomes in the treatment of COPD," he said. The cost, compliance, and safety of certain agents are issues "that we cannot ignore."

When considering a therapy for COPD, clinicians should factor in components of COPD beyond bronchoconstriction, he advised, including mucociliary dysfunction, structural changes in the airway and the lung, systemic components, and airway inflammation. "We also have to look at outcomes other than lung function including exacerbations, activity limitation, and symptoms of dyspnea," he said. "We are no more satisfied with just a drug that improves lung function but does nothing for the patient-reported outcomes."

Dr. Hanania’s "wish list" for an ideal COPD therapeutic option in the future is one that addresses the multiple components and phenotypes of COPD. He said he would like to see drugs that blunt proinflammatory cells and molecules known to be involved in COPD. "We’d also like to see drugs that could modify the disease progression and comorbid conditions," he said. Such drugs, he continued, should be well tolerated and compatible with other therapies for COPD and comorbid conditions, be simple to administer, and have the potential to improve patient adherence, he added.

Treatment approaches being studied include novel formulations of existing medications, such as the combination of ultralong-acting beta-2 agonists and long-acting antimuscarinics. Among the agents that are the most promising on this front, he said, are indacaterol plus glycopyrronium (QVA-149) and vilanterol plus GSK-573719.

Other agents in development include bifunctional muscarinic antagonist–beta-2 agonists such as GSK-961081 and THRX-200495 as well as combinations of once-daily long-acting beta-2 agonists and inhaled corticosteroids, including formoterol and mometasone (MFF258) and vilanterol and fluticasone (Relovair).

However, perhaps the most promising pharmacotherapies will be novel agents aimed at reducing local and systemic inflammation. "We know that COPD is an inflammatory disease, so we need drugs that can target inflammation right from the very beginning," Dr. Hanania explained. "Inhaled steroids are important, but they’re not as effective in COPD as they are in asthma."

Phosphodiesterase type 4 inhibitors are currently being studied in COPD. These agents reduce the activity of neutrophils, macrophages, and CD8-positive T-lymphocytes, as well as the expression of cytokines and other inflammatory mediators. Currently, the only phosphodiesterase type 4 inhibitor approved in the United States for use in patients with COPD is roflumilast (Daliresp). Several others are in development.

"We know from large clinical trials that current pharmaco-therapies do not change the natural history of COPD."

Because they target airway inflammation, p38 mitogen-activated protein kinase inhibitors are also being studied in COPD patients. However, so far clinical trials have found potential problems related to systemic side effects and toxicity, "indicating that it is probably necessary to deliver these drugs by inhalation to reduce systemic exposure," Dr. Hanania said.

He concluded his presentation by noting that certain medications used to treat comorbidities in COPD may have beneficial effects on COPD outcomes. These include statins, ACE inhibitors, beta-blockers, peroxisome proliferator–activated receptor agonists, and macrolides. The National Heart, Lung, and Blood Institute COPD Clinical Research Network is currently conducting a prospective randomized controlled trial in 1,126 patients with severe COPD randomized to daily simvastatin (40 mg) vs. placebo for at least 1 year. The primary outcome is exacerbation of COPD. The secondary outcomes include change in forced expiratory volume in 1 second (FEV₁), St. George’s Respiratory Questionnaire responses, 6-minute walk test results, BODE Index score, a combined cardiovascular end point, and serum inflammatory biomarker levels. Furthermore, a recent study showed that daily azithromycin significantly reduced exacerbations in high-risk patients.

Dr. Hanania disclosed that he has received grant support from the National Institutes of Health, the American Lung Association, GlaxoSmithKline (GSK), Boehringer Ingelheim (BI), Sunovion, Novartis, Pfizer, and Forest Pharmaceuticals. He also serves as a consultant for GSK, Dey Pharmaceuticals, Sunovion, Pfizer, and Forest, and is a member of the speakers bureau for GSK, BI, AstraZeneca, and Forest.

HONOLULU – Current interventions for chronic obstructive pulmonary disease leave many patients with unmet needs, according to Dr. Nicola A. Hanania.

"We know from large clinical trials that current pharmacotherapies do not change the natural history of COPD, and many patients remain symptomatic with current therapies," Dr. Hanania, director of the asthma clinical research center at Baylor College of Medicine, Houston, said at the annual meeting of the American College of Chest Physicians.

Inadequate adherence to therapy "is a major cause of poor clinical outcomes in the treatment of COPD," he said. The cost, compliance, and safety of certain agents are issues "that we cannot ignore."

When considering a therapy for COPD, clinicians should factor in components of COPD beyond bronchoconstriction, he advised, including mucociliary dysfunction, structural changes in the airway and the lung, systemic components, and airway inflammation. "We also have to look at outcomes other than lung function including exacerbations, activity limitation, and symptoms of dyspnea," he said. "We are no more satisfied with just a drug that improves lung function but does nothing for the patient-reported outcomes."

Dr. Hanania’s "wish list" for an ideal COPD therapeutic option in the future is one that addresses the multiple components and phenotypes of COPD. He said he would like to see drugs that blunt proinflammatory cells and molecules known to be involved in COPD. "We’d also like to see drugs that could modify the disease progression and comorbid conditions," he said. Such drugs, he continued, should be well tolerated and compatible with other therapies for COPD and comorbid conditions, be simple to administer, and have the potential to improve patient adherence, he added.

Treatment approaches being studied include novel formulations of existing medications, such as the combination of ultralong-acting beta-2 agonists and long-acting antimuscarinics. Among the agents that are the most promising on this front, he said, are indacaterol plus glycopyrronium (QVA-149) and vilanterol plus GSK-573719.

Other agents in development include bifunctional muscarinic antagonist–beta-2 agonists such as GSK-961081 and THRX-200495 as well as combinations of once-daily long-acting beta-2 agonists and inhaled corticosteroids, including formoterol and mometasone (MFF258) and vilanterol and fluticasone (Relovair).

However, perhaps the most promising pharmacotherapies will be novel agents aimed at reducing local and systemic inflammation. "We know that COPD is an inflammatory disease, so we need drugs that can target inflammation right from the very beginning," Dr. Hanania explained. "Inhaled steroids are important, but they’re not as effective in COPD as they are in asthma."

Phosphodiesterase type 4 inhibitors are currently being studied in COPD. These agents reduce the activity of neutrophils, macrophages, and CD8-positive T-lymphocytes, as well as the expression of cytokines and other inflammatory mediators. Currently, the only phosphodiesterase type 4 inhibitor approved in the United States for use in patients with COPD is roflumilast (Daliresp). Several others are in development.

"We know from large clinical trials that current pharmaco-therapies do not change the natural history of COPD."

Because they target airway inflammation, p38 mitogen-activated protein kinase inhibitors are also being studied in COPD patients. However, so far clinical trials have found potential problems related to systemic side effects and toxicity, "indicating that it is probably necessary to deliver these drugs by inhalation to reduce systemic exposure," Dr. Hanania said.

He concluded his presentation by noting that certain medications used to treat comorbidities in COPD may have beneficial effects on COPD outcomes. These include statins, ACE inhibitors, beta-blockers, peroxisome proliferator–activated receptor agonists, and macrolides. The National Heart, Lung, and Blood Institute COPD Clinical Research Network is currently conducting a prospective randomized controlled trial in 1,126 patients with severe COPD randomized to daily simvastatin (40 mg) vs. placebo for at least 1 year. The primary outcome is exacerbation of COPD. The secondary outcomes include change in forced expiratory volume in 1 second (FEV₁), St. George’s Respiratory Questionnaire responses, 6-minute walk test results, BODE Index score, a combined cardiovascular end point, and serum inflammatory biomarker levels. Furthermore, a recent study showed that daily azithromycin significantly reduced exacerbations in high-risk patients.

Dr. Hanania disclosed that he has received grant support from the National Institutes of Health, the American Lung Association, GlaxoSmithKline (GSK), Boehringer Ingelheim (BI), Sunovion, Novartis, Pfizer, and Forest Pharmaceuticals. He also serves as a consultant for GSK, Dey Pharmaceuticals, Sunovion, Pfizer, and Forest, and is a member of the speakers bureau for GSK, BI, AstraZeneca, and Forest.

HONOLULU – Acute worsening is an important part of the natural history of many interstitial lung diseases, especially idiopathic pulmonary fibrosis.

But the roots of acute worsening in interstitial lung disease (ILD) are not fully understood, Dr. Harold R. Collard said at the annual meeting of the American College of Chest Physicians.

"A lot of what’s known in the medical literature comes from patients with idiopathic pulmonary fibrosis [IPF]," said Dr. Collard, who directs the interstitial lung disease program at the University of California, San Francisco. "I think it’s an open question whether that can be extrapolated to patients with other forms of ILD or not. The course of many ILDs – certainly IPF – is unpredictable; it’s not always a linear decline," he continued. "This is an important shift in how we think about the disease – to recognize that this is the case for many patients."

According to a survey of academic pulmonologists, 88% of respondents reported that acute exacerbations in ILD patients occur "sometimes" or "frequently," while 92% of respondents reported that exacerbations were "sometimes" or "frequently" fatal (Respir. Med. 2007;101:2011-6).

If these are not fatal, they often leave patients significantly worse than they were before, unlike exacerbations in other forms of lung disease, said Dr. Collard, who was the survey’s lead investigator.

Potential causes of acute worsening include infection, aspiration, myocardial infarction, pulmonary embolism, pneumothorax, and heart failure, as well as idiopathic causes. Acute worsening has not been studied in all ILDs, but it has been most closely studied in IPF. In Dr. Collard’s opinion, the best data on acute worsening in IPF come from a Korean cohort study of 461 patients with IPF who were followed longitudinally (Eur. Resp. J. 2011;37:356-63). The researchers divided patients into two groups: those with respiratory deterioration (defined as acute worsening with radiographic abnormalities) and those with acute exacerbation (defined as acute worsening in the absence of an identifiable etiology).

The researchers found that the 1-year incidence of respiratory deterioration was 23%, "which is higher than a lot of us have taken from clinical trials," Dr. Collard said. Of these cases, 55% were idiopathic, while the remainder had known causes that included infection and heart failure.

"These idiopathic acute worsenings, as defined in this study, are what we call acute exacerbation," Dr. Collard noted. "In IPF, acute exacerbation has a specific connotation compared with asthma or [chronic obstructive pulmonary disease]. It’s an idiopathic acute worsening."

The median survival among patients with acute exacerbation of IPF was 2.2 months from the onset of exacerbation. "This is a highly morbid and fatal condition," he said.

Dr. Collard led a panel of experts that established criteria for acute exacerbations of IPF (Am. J. Respir. Crit. Care Med. 2007;176:636-43). The criteria include previous or concurrent diagnosis of IPF, unexplained worsening or development of dyspnea over a period of 30 days or less, new bilateral ground glass and/or consolidation superimposed on a usual interstitial pneumonitis pattern on high-resolution CT, no microbiologic evidence of respiratory infection by endotracheal aspirate or bronchoalveolar lavage, and exclusion of other known causes of acute worsening.

According to the Korean IPF cohort study, significant risk factors for acute exacerbation include never having smoked tobacco and having a low forced vital capacity (FVC). "The higher your FVC, the lower your risk of acute exacerbation," Dr. Collard said. "That makes sense, [but] the protective effect of smoking is hard to explain."

He acknowledged that certain aspects of acute exacerbation remain elusive. "Does exacerbation actually represent an abrupt acceleration of the underlying disease process, or is it a manifestation of an occult secondary complication such as an infection that we’re missing because of the limitations of our clinical assessment?" he asked.

Researchers who conducted a test of gene expression profiling in this patient population found no differences in the global expression pattern between patients with stable IPF and those with acute exacerbation (Am. J. Respir. Crit. Care Med. 2009;180:167-75). "They did find evidence of enhanced alveolar epithelial cell activity," Dr. Collard said. "That was the main predominant pattern."

A study of biomarkers conducted by Dr. Collard and his associates yielded similar findings (Am. J. Physiol. Lung Cell Mol. Physiol. 2010;299:L3-7).

Dr. Collard hypothesized that acute exacerbation of IPF represents a primary acceleration of IPF in the setting of acute lung stress. "This stress may be minor, at a level that would not cause clinical disease in a normal lung," he said. Potential sources of stress include infection, occult aspiration, interventions, and drugs.

Dr. Collard disclosed that he receives research funding from the National Institutes of Health, the University of California, Boehringer Ingelheim, and Genentech. He also receives consulting fees from Fibrogen, Gilead, InterMune, and Onyx.

HONOLULU – Acute worsening is an important part of the natural history of many interstitial lung diseases, especially idiopathic pulmonary fibrosis.

But the roots of acute worsening in interstitial lung disease (ILD) are not fully understood, Dr. Harold R. Collard said at the annual meeting of the American College of Chest Physicians.

"A lot of what’s known in the medical literature comes from patients with idiopathic pulmonary fibrosis [IPF]," said Dr. Collard, who directs the interstitial lung disease program at the University of California, San Francisco. "I think it’s an open question whether that can be extrapolated to patients with other forms of ILD or not. The course of many ILDs – certainly IPF – is unpredictable; it’s not always a linear decline," he continued. "This is an important shift in how we think about the disease – to recognize that this is the case for many patients."

According to a survey of academic pulmonologists, 88% of respondents reported that acute exacerbations in ILD patients occur "sometimes" or "frequently," while 92% of respondents reported that exacerbations were "sometimes" or "frequently" fatal (Respir. Med. 2007;101:2011-6).

If these are not fatal, they often leave patients significantly worse than they were before, unlike exacerbations in other forms of lung disease, said Dr. Collard, who was the survey’s lead investigator.

Potential causes of acute worsening include infection, aspiration, myocardial infarction, pulmonary embolism, pneumothorax, and heart failure, as well as idiopathic causes. Acute worsening has not been studied in all ILDs, but it has been most closely studied in IPF. In Dr. Collard’s opinion, the best data on acute worsening in IPF come from a Korean cohort study of 461 patients with IPF who were followed longitudinally (Eur. Resp. J. 2011;37:356-63). The researchers divided patients into two groups: those with respiratory deterioration (defined as acute worsening with radiographic abnormalities) and those with acute exacerbation (defined as acute worsening in the absence of an identifiable etiology).

The researchers found that the 1-year incidence of respiratory deterioration was 23%, "which is higher than a lot of us have taken from clinical trials," Dr. Collard said. Of these cases, 55% were idiopathic, while the remainder had known causes that included infection and heart failure.

"These idiopathic acute worsenings, as defined in this study, are what we call acute exacerbation," Dr. Collard noted. "In IPF, acute exacerbation has a specific connotation compared with asthma or [chronic obstructive pulmonary disease]. It’s an idiopathic acute worsening."

The median survival among patients with acute exacerbation of IPF was 2.2 months from the onset of exacerbation. "This is a highly morbid and fatal condition," he said.

Dr. Collard led a panel of experts that established criteria for acute exacerbations of IPF (Am. J. Respir. Crit. Care Med. 2007;176:636-43). The criteria include previous or concurrent diagnosis of IPF, unexplained worsening or development of dyspnea over a period of 30 days or less, new bilateral ground glass and/or consolidation superimposed on a usual interstitial pneumonitis pattern on high-resolution CT, no microbiologic evidence of respiratory infection by endotracheal aspirate or bronchoalveolar lavage, and exclusion of other known causes of acute worsening.

According to the Korean IPF cohort study, significant risk factors for acute exacerbation include never having smoked tobacco and having a low forced vital capacity (FVC). "The higher your FVC, the lower your risk of acute exacerbation," Dr. Collard said. "That makes sense, [but] the protective effect of smoking is hard to explain."

He acknowledged that certain aspects of acute exacerbation remain elusive. "Does exacerbation actually represent an abrupt acceleration of the underlying disease process, or is it a manifestation of an occult secondary complication such as an infection that we’re missing because of the limitations of our clinical assessment?" he asked.

Researchers who conducted a test of gene expression profiling in this patient population found no differences in the global expression pattern between patients with stable IPF and those with acute exacerbation (Am. J. Respir. Crit. Care Med. 2009;180:167-75). "They did find evidence of enhanced alveolar epithelial cell activity," Dr. Collard said. "That was the main predominant pattern."

A study of biomarkers conducted by Dr. Collard and his associates yielded similar findings (Am. J. Physiol. Lung Cell Mol. Physiol. 2010;299:L3-7).

Dr. Collard hypothesized that acute exacerbation of IPF represents a primary acceleration of IPF in the setting of acute lung stress. "This stress may be minor, at a level that would not cause clinical disease in a normal lung," he said. Potential sources of stress include infection, occult aspiration, interventions, and drugs.

Dr. Collard disclosed that he receives research funding from the National Institutes of Health, the University of California, Boehringer Ingelheim, and Genentech. He also receives consulting fees from Fibrogen, Gilead, InterMune, and Onyx.

HONOLULU – Acute worsening is an important part of the natural history of many interstitial lung diseases, especially idiopathic pulmonary fibrosis.

But the roots of acute worsening in interstitial lung disease (ILD) are not fully understood, Dr. Harold R. Collard said at the annual meeting of the American College of Chest Physicians.

"A lot of what’s known in the medical literature comes from patients with idiopathic pulmonary fibrosis [IPF]," said Dr. Collard, who directs the interstitial lung disease program at the University of California, San Francisco. "I think it’s an open question whether that can be extrapolated to patients with other forms of ILD or not. The course of many ILDs – certainly IPF – is unpredictable; it’s not always a linear decline," he continued. "This is an important shift in how we think about the disease – to recognize that this is the case for many patients."

According to a survey of academic pulmonologists, 88% of respondents reported that acute exacerbations in ILD patients occur "sometimes" or "frequently," while 92% of respondents reported that exacerbations were "sometimes" or "frequently" fatal (Respir. Med. 2007;101:2011-6).

If these are not fatal, they often leave patients significantly worse than they were before, unlike exacerbations in other forms of lung disease, said Dr. Collard, who was the survey’s lead investigator.

Potential causes of acute worsening include infection, aspiration, myocardial infarction, pulmonary embolism, pneumothorax, and heart failure, as well as idiopathic causes. Acute worsening has not been studied in all ILDs, but it has been most closely studied in IPF. In Dr. Collard’s opinion, the best data on acute worsening in IPF come from a Korean cohort study of 461 patients with IPF who were followed longitudinally (Eur. Resp. J. 2011;37:356-63). The researchers divided patients into two groups: those with respiratory deterioration (defined as acute worsening with radiographic abnormalities) and those with acute exacerbation (defined as acute worsening in the absence of an identifiable etiology).

The researchers found that the 1-year incidence of respiratory deterioration was 23%, "which is higher than a lot of us have taken from clinical trials," Dr. Collard said. Of these cases, 55% were idiopathic, while the remainder had known causes that included infection and heart failure.

"These idiopathic acute worsenings, as defined in this study, are what we call acute exacerbation," Dr. Collard noted. "In IPF, acute exacerbation has a specific connotation compared with asthma or [chronic obstructive pulmonary disease]. It’s an idiopathic acute worsening."

The median survival among patients with acute exacerbation of IPF was 2.2 months from the onset of exacerbation. "This is a highly morbid and fatal condition," he said.

Dr. Collard led a panel of experts that established criteria for acute exacerbations of IPF (Am. J. Respir. Crit. Care Med. 2007;176:636-43). The criteria include previous or concurrent diagnosis of IPF, unexplained worsening or development of dyspnea over a period of 30 days or less, new bilateral ground glass and/or consolidation superimposed on a usual interstitial pneumonitis pattern on high-resolution CT, no microbiologic evidence of respiratory infection by endotracheal aspirate or bronchoalveolar lavage, and exclusion of other known causes of acute worsening.

According to the Korean IPF cohort study, significant risk factors for acute exacerbation include never having smoked tobacco and having a low forced vital capacity (FVC). "The higher your FVC, the lower your risk of acute exacerbation," Dr. Collard said. "That makes sense, [but] the protective effect of smoking is hard to explain."

He acknowledged that certain aspects of acute exacerbation remain elusive. "Does exacerbation actually represent an abrupt acceleration of the underlying disease process, or is it a manifestation of an occult secondary complication such as an infection that we’re missing because of the limitations of our clinical assessment?" he asked.

Researchers who conducted a test of gene expression profiling in this patient population found no differences in the global expression pattern between patients with stable IPF and those with acute exacerbation (Am. J. Respir. Crit. Care Med. 2009;180:167-75). "They did find evidence of enhanced alveolar epithelial cell activity," Dr. Collard said. "That was the main predominant pattern."

A study of biomarkers conducted by Dr. Collard and his associates yielded similar findings (Am. J. Physiol. Lung Cell Mol. Physiol. 2010;299:L3-7).

Dr. Collard hypothesized that acute exacerbation of IPF represents a primary acceleration of IPF in the setting of acute lung stress. "This stress may be minor, at a level that would not cause clinical disease in a normal lung," he said. Potential sources of stress include infection, occult aspiration, interventions, and drugs.

Dr. Collard disclosed that he receives research funding from the National Institutes of Health, the University of California, Boehringer Ingelheim, and Genentech. He also receives consulting fees from Fibrogen, Gilead, InterMune, and Onyx.

HONOLULU – Although large numbers of patients are surviving acute lung injury/adult respiratory distress syndrome, long-term impairments are common and "striking for their relationship to neuropsychiatric dysfunction," Dr. Jesse Hall said at the annual meeting of the American College of Chest Physicians.

"The pace of recovery is protracted and likely incomplete in the current paradigm of care," said Dr. Hall, professor of medicine, anesthesia, and critical care at the University of Chicago. "Interventions including those begun at the onset of critical illness will hopefully improve these outcomes."

According to the best epidemiologic study on the topic, an estimated 191,000 cases of acute lung injury (ALI) and 141,500 cases of adult respiratory distress syndrome (ARDS) occur each year in the United States, causing a combined 133,500 deaths annually (N. Engl. J. Med 2005;353:1685-93). Implementation of low-tidal-volume ventilation over the past decade has led to an improvement in survival among this patient population, Dr. Hall said, but "we are just beginning to understand through descriptive studies what the path is for these patients down the road. We really lack many prospective trials in that arena."

One study of 109 ARDS patients who were followed for 1 year found that most developed a restrictive lung lesion that improved in the first 6-12 months (N. Engl. J. Med 2003;348:683-93). "The most consistent pulmonary function test abnormality tends to be low diffusion capacity that often resolves over time," Dr. Hall said. Some of their general functional limitation correlates to their pulmonary dysfunction, "but much of it does not," he said. "In fact, it’s not what the patients report. They start to have a very low functional status 6, 12, and more months out, and they don’t ascribe it primarily to their lung dysfunction."

Residual areas of fibrosis are not unusual on follow-up CT scans of ALI/ARDS patients, and many of these patients develop airway abnormalities such as bronchiectasis associated with their lung injury, said Dr. Hall, who is also section chief of pulmonary and critical care medicine at the University of Chicago.

The 2003 study of 109 ARDS patients found that all subjects reported poor function due to loss of muscle bulk, proximal weakness, and fatigue. Some (12%) reported persistent pain at the chest tube site, 7% reported entrapment neuropathies, 7% had tracheotomy site problems, 5% had large joint enlargement/immobility from heterotopic ossification, and 4% had immobility in the form of contracted fingers or frozen shoulders. "It can be up to a year before patients regain their body weight after this episode," Dr. Hall said.

Neuromuscular sequelae may include myopathy, peripheral neuropathy, or deconditioning. "Any given patient can have any combination of those," he said. "Some of these disorders are reasonably strongly associated with some of our therapies. Most of our patients have a combination of peripheral neuropathies and myopathies that may by themselves be modest but are attended by extreme deconditioning. The neuromuscular sequelae of critical illness are variable in terms of recovery over months and years, and some patients seem to never fully recover."

The impact of neuropsychiatric sequelae can be significant. One study of 55 ARDS patients found that 100% had cognitive and affective impairments at hospital discharge, and 30% had generalized cognitive decline 1 year later (Am. J. Respir. Crit. Care Med. 1999;160:50-6). In the 2003 study, only 49% of the ARDS patients who had been employed were back to work at 1 year. "This is an astounding economic and financial consequence for the patient and the family," Dr. Hall commented. "Scores on the Short Form-36 were below normal in all eight domains at 3-, 6-, and 12-month follow-up from ICU discharge. There were improvements in most SF-36 categories, but almost none were back to normal."

Dr. Hall said that changes in the current health care system are needed to improve outcomes for ALI/ARDS patients. Currently, "it’s difficult for those in our discipline to figure out how to become a change agent, or help our patients acquire what they need to optimize their recovery," he explained. "It’s not likely, in fact, to be done by critical care doctors down the road."

One study from the United Kingdom sought to determine if giving patients a self-help rehabilitation manual would affect their general functional status "and therefore their psychiatric axes as well, and maybe even make them more functional," Dr. Hall said. For the study, patients in the control group received ward visits, three telephone calls at home, and clinic appointments at 8 weeks and 6 months, whereas patients in the intervention group received the same plus a 6-week self-help rehabilitation manual. At the end of 6 weeks, patients in the intervention group had significantly better physical function scores, compared with controls (Crit. Care Med. 2003;31:2456-61). Unfortunately, such benefits were not seen in another recent prospective trial.

In a recent trial conducted by a group of researchers that included Dr. Hall, 104 critical care patients who required ventilation were randomized to either early physical and occupational therapy during periods of daily interruption of sedation, or to daily interruption of sedation with therapy as ordered by the primary care team (Lancet 2009;373:1874-82). Compared with controls, patients who received early physical and occupational therapy had better return to independent functional status at hospital discharge (59% vs. 35%, respectively) and less ICU delirium (2 days vs. 4 days).

Dr. Hall concluded by noting that the brain and the neurologic and musculoskeletal systems "are likely the last to recover after ALI/ARDS, and may not recover fully to the status patients had before. We don’t know what matters most for long-term recovery. It’s reasonable to think that shortening ICU and mechanical ventilation time would be beneficial."

Dr. Hall disclosed that he receives honoraria from the American College of Chest Physicians and the American Thoracic Society.

HONOLULU – Although large numbers of patients are surviving acute lung injury/adult respiratory distress syndrome, long-term impairments are common and "striking for their relationship to neuropsychiatric dysfunction," Dr. Jesse Hall said at the annual meeting of the American College of Chest Physicians.

"The pace of recovery is protracted and likely incomplete in the current paradigm of care," said Dr. Hall, professor of medicine, anesthesia, and critical care at the University of Chicago. "Interventions including those begun at the onset of critical illness will hopefully improve these outcomes."

According to the best epidemiologic study on the topic, an estimated 191,000 cases of acute lung injury (ALI) and 141,500 cases of adult respiratory distress syndrome (ARDS) occur each year in the United States, causing a combined 133,500 deaths annually (N. Engl. J. Med 2005;353:1685-93). Implementation of low-tidal-volume ventilation over the past decade has led to an improvement in survival among this patient population, Dr. Hall said, but "we are just beginning to understand through descriptive studies what the path is for these patients down the road. We really lack many prospective trials in that arena."

One study of 109 ARDS patients who were followed for 1 year found that most developed a restrictive lung lesion that improved in the first 6-12 months (N. Engl. J. Med 2003;348:683-93). "The most consistent pulmonary function test abnormality tends to be low diffusion capacity that often resolves over time," Dr. Hall said. Some of their general functional limitation correlates to their pulmonary dysfunction, "but much of it does not," he said. "In fact, it’s not what the patients report. They start to have a very low functional status 6, 12, and more months out, and they don’t ascribe it primarily to their lung dysfunction."

Residual areas of fibrosis are not unusual on follow-up CT scans of ALI/ARDS patients, and many of these patients develop airway abnormalities such as bronchiectasis associated with their lung injury, said Dr. Hall, who is also section chief of pulmonary and critical care medicine at the University of Chicago.

The 2003 study of 109 ARDS patients found that all subjects reported poor function due to loss of muscle bulk, proximal weakness, and fatigue. Some (12%) reported persistent pain at the chest tube site, 7% reported entrapment neuropathies, 7% had tracheotomy site problems, 5% had large joint enlargement/immobility from heterotopic ossification, and 4% had immobility in the form of contracted fingers or frozen shoulders. "It can be up to a year before patients regain their body weight after this episode," Dr. Hall said.

Neuromuscular sequelae may include myopathy, peripheral neuropathy, or deconditioning. "Any given patient can have any combination of those," he said. "Some of these disorders are reasonably strongly associated with some of our therapies. Most of our patients have a combination of peripheral neuropathies and myopathies that may by themselves be modest but are attended by extreme deconditioning. The neuromuscular sequelae of critical illness are variable in terms of recovery over months and years, and some patients seem to never fully recover."

The impact of neuropsychiatric sequelae can be significant. One study of 55 ARDS patients found that 100% had cognitive and affective impairments at hospital discharge, and 30% had generalized cognitive decline 1 year later (Am. J. Respir. Crit. Care Med. 1999;160:50-6). In the 2003 study, only 49% of the ARDS patients who had been employed were back to work at 1 year. "This is an astounding economic and financial consequence for the patient and the family," Dr. Hall commented. "Scores on the Short Form-36 were below normal in all eight domains at 3-, 6-, and 12-month follow-up from ICU discharge. There were improvements in most SF-36 categories, but almost none were back to normal."

Dr. Hall said that changes in the current health care system are needed to improve outcomes for ALI/ARDS patients. Currently, "it’s difficult for those in our discipline to figure out how to become a change agent, or help our patients acquire what they need to optimize their recovery," he explained. "It’s not likely, in fact, to be done by critical care doctors down the road."

One study from the United Kingdom sought to determine if giving patients a self-help rehabilitation manual would affect their general functional status "and therefore their psychiatric axes as well, and maybe even make them more functional," Dr. Hall said. For the study, patients in the control group received ward visits, three telephone calls at home, and clinic appointments at 8 weeks and 6 months, whereas patients in the intervention group received the same plus a 6-week self-help rehabilitation manual. At the end of 6 weeks, patients in the intervention group had significantly better physical function scores, compared with controls (Crit. Care Med. 2003;31:2456-61). Unfortunately, such benefits were not seen in another recent prospective trial.

In a recent trial conducted by a group of researchers that included Dr. Hall, 104 critical care patients who required ventilation were randomized to either early physical and occupational therapy during periods of daily interruption of sedation, or to daily interruption of sedation with therapy as ordered by the primary care team (Lancet 2009;373:1874-82). Compared with controls, patients who received early physical and occupational therapy had better return to independent functional status at hospital discharge (59% vs. 35%, respectively) and less ICU delirium (2 days vs. 4 days).

Dr. Hall concluded by noting that the brain and the neurologic and musculoskeletal systems "are likely the last to recover after ALI/ARDS, and may not recover fully to the status patients had before. We don’t know what matters most for long-term recovery. It’s reasonable to think that shortening ICU and mechanical ventilation time would be beneficial."

Dr. Hall disclosed that he receives honoraria from the American College of Chest Physicians and the American Thoracic Society.

HONOLULU – Although large numbers of patients are surviving acute lung injury/adult respiratory distress syndrome, long-term impairments are common and "striking for their relationship to neuropsychiatric dysfunction," Dr. Jesse Hall said at the annual meeting of the American College of Chest Physicians.

"The pace of recovery is protracted and likely incomplete in the current paradigm of care," said Dr. Hall, professor of medicine, anesthesia, and critical care at the University of Chicago. "Interventions including those begun at the onset of critical illness will hopefully improve these outcomes."

According to the best epidemiologic study on the topic, an estimated 191,000 cases of acute lung injury (ALI) and 141,500 cases of adult respiratory distress syndrome (ARDS) occur each year in the United States, causing a combined 133,500 deaths annually (N. Engl. J. Med 2005;353:1685-93). Implementation of low-tidal-volume ventilation over the past decade has led to an improvement in survival among this patient population, Dr. Hall said, but "we are just beginning to understand through descriptive studies what the path is for these patients down the road. We really lack many prospective trials in that arena."

One study of 109 ARDS patients who were followed for 1 year found that most developed a restrictive lung lesion that improved in the first 6-12 months (N. Engl. J. Med 2003;348:683-93). "The most consistent pulmonary function test abnormality tends to be low diffusion capacity that often resolves over time," Dr. Hall said. Some of their general functional limitation correlates to their pulmonary dysfunction, "but much of it does not," he said. "In fact, it’s not what the patients report. They start to have a very low functional status 6, 12, and more months out, and they don’t ascribe it primarily to their lung dysfunction."

Residual areas of fibrosis are not unusual on follow-up CT scans of ALI/ARDS patients, and many of these patients develop airway abnormalities such as bronchiectasis associated with their lung injury, said Dr. Hall, who is also section chief of pulmonary and critical care medicine at the University of Chicago.

The 2003 study of 109 ARDS patients found that all subjects reported poor function due to loss of muscle bulk, proximal weakness, and fatigue. Some (12%) reported persistent pain at the chest tube site, 7% reported entrapment neuropathies, 7% had tracheotomy site problems, 5% had large joint enlargement/immobility from heterotopic ossification, and 4% had immobility in the form of contracted fingers or frozen shoulders. "It can be up to a year before patients regain their body weight after this episode," Dr. Hall said.

Neuromuscular sequelae may include myopathy, peripheral neuropathy, or deconditioning. "Any given patient can have any combination of those," he said. "Some of these disorders are reasonably strongly associated with some of our therapies. Most of our patients have a combination of peripheral neuropathies and myopathies that may by themselves be modest but are attended by extreme deconditioning. The neuromuscular sequelae of critical illness are variable in terms of recovery over months and years, and some patients seem to never fully recover."

The impact of neuropsychiatric sequelae can be significant. One study of 55 ARDS patients found that 100% had cognitive and affective impairments at hospital discharge, and 30% had generalized cognitive decline 1 year later (Am. J. Respir. Crit. Care Med. 1999;160:50-6). In the 2003 study, only 49% of the ARDS patients who had been employed were back to work at 1 year. "This is an astounding economic and financial consequence for the patient and the family," Dr. Hall commented. "Scores on the Short Form-36 were below normal in all eight domains at 3-, 6-, and 12-month follow-up from ICU discharge. There were improvements in most SF-36 categories, but almost none were back to normal."

Dr. Hall said that changes in the current health care system are needed to improve outcomes for ALI/ARDS patients. Currently, "it’s difficult for those in our discipline to figure out how to become a change agent, or help our patients acquire what they need to optimize their recovery," he explained. "It’s not likely, in fact, to be done by critical care doctors down the road."

One study from the United Kingdom sought to determine if giving patients a self-help rehabilitation manual would affect their general functional status "and therefore their psychiatric axes as well, and maybe even make them more functional," Dr. Hall said. For the study, patients in the control group received ward visits, three telephone calls at home, and clinic appointments at 8 weeks and 6 months, whereas patients in the intervention group received the same plus a 6-week self-help rehabilitation manual. At the end of 6 weeks, patients in the intervention group had significantly better physical function scores, compared with controls (Crit. Care Med. 2003;31:2456-61). Unfortunately, such benefits were not seen in another recent prospective trial.

In a recent trial conducted by a group of researchers that included Dr. Hall, 104 critical care patients who required ventilation were randomized to either early physical and occupational therapy during periods of daily interruption of sedation, or to daily interruption of sedation with therapy as ordered by the primary care team (Lancet 2009;373:1874-82). Compared with controls, patients who received early physical and occupational therapy had better return to independent functional status at hospital discharge (59% vs. 35%, respectively) and less ICU delirium (2 days vs. 4 days).

Dr. Hall concluded by noting that the brain and the neurologic and musculoskeletal systems "are likely the last to recover after ALI/ARDS, and may not recover fully to the status patients had before. We don’t know what matters most for long-term recovery. It’s reasonable to think that shortening ICU and mechanical ventilation time would be beneficial."

Dr. Hall disclosed that he receives honoraria from the American College of Chest Physicians and the American Thoracic Society.

HONOLULU – Having a higher body mass index is not significantly associated with hospital mortality among patients admitted to the surgical ICU.

While similar findings have been reported in medical ICUs, this is believed to be the largest study to investigate the relationship between BMI and mortality exclusively in a surgical ICU, Dr. Adam Khader said in an interview during a poster session at the annual meeting of the American College of Chest Physicians.

Dr. Khader, a resident in the department of surgery at Hofstra North Shore–Long Island Jewish Medical Center, Manhasset, N.Y., and his associates evaluated the records of 1,860 patients admitted to the medical center’s surgical ICU. Patients younger than age 18 years and those who did not undergo surgery were excluded from the analysis. The researchers used area under the receiver operating characteristic curves to assess the effect of BMI on mortality and categorized patients as underweight (BMI less than 20 kg/m²), normal weight (20-25 kg/m²), overweight (25-30 kg/m²), obese (30-35 kg/m²), severely obese (35-50 kg/m²), and super obese (greater than 50 kg/m²).

Overall 30-day hospital mortality was 10%. Hospital mortality was 15% for underweight patients, 11% for normal weight patients, 8% for overweight patients, 9% for obese patients, 13% for severely obese patients, and 22% for super obese patients. Area under the receiver operating characteristic curve analysis yielded no significant association between BMI and mortality, even after stratification of patients by elective vs. emergent surgery, and patients younger vs. older than age 75 years.

Dr. Khader and his associates observed a trend toward increased mortality for patients in the underweight, obese, and severely obese categories of BMI, "but nothing statistically significant," he said. "Still, there was a large number of patients [in this study]. You can’t really ignore the numbers."

Dr. Khader said that he had no relevant financial conflicts to disclose.

HONOLULU – Having a higher body mass index is not significantly associated with hospital mortality among patients admitted to the surgical ICU.

While similar findings have been reported in medical ICUs, this is believed to be the largest study to investigate the relationship between BMI and mortality exclusively in a surgical ICU, Dr. Adam Khader said in an interview during a poster session at the annual meeting of the American College of Chest Physicians.

Dr. Khader, a resident in the department of surgery at Hofstra North Shore–Long Island Jewish Medical Center, Manhasset, N.Y., and his associates evaluated the records of 1,860 patients admitted to the medical center’s surgical ICU. Patients younger than age 18 years and those who did not undergo surgery were excluded from the analysis. The researchers used area under the receiver operating characteristic curves to assess the effect of BMI on mortality and categorized patients as underweight (BMI less than 20 kg/m²), normal weight (20-25 kg/m²), overweight (25-30 kg/m²), obese (30-35 kg/m²), severely obese (35-50 kg/m²), and super obese (greater than 50 kg/m²).

Overall 30-day hospital mortality was 10%. Hospital mortality was 15% for underweight patients, 11% for normal weight patients, 8% for overweight patients, 9% for obese patients, 13% for severely obese patients, and 22% for super obese patients. Area under the receiver operating characteristic curve analysis yielded no significant association between BMI and mortality, even after stratification of patients by elective vs. emergent surgery, and patients younger vs. older than age 75 years.

Dr. Khader and his associates observed a trend toward increased mortality for patients in the underweight, obese, and severely obese categories of BMI, "but nothing statistically significant," he said. "Still, there was a large number of patients [in this study]. You can’t really ignore the numbers."

Dr. Khader said that he had no relevant financial conflicts to disclose.

HONOLULU – Having a higher body mass index is not significantly associated with hospital mortality among patients admitted to the surgical ICU.

While similar findings have been reported in medical ICUs, this is believed to be the largest study to investigate the relationship between BMI and mortality exclusively in a surgical ICU, Dr. Adam Khader said in an interview during a poster session at the annual meeting of the American College of Chest Physicians.

Dr. Khader, a resident in the department of surgery at Hofstra North Shore–Long Island Jewish Medical Center, Manhasset, N.Y., and his associates evaluated the records of 1,860 patients admitted to the medical center’s surgical ICU. Patients younger than age 18 years and those who did not undergo surgery were excluded from the analysis. The researchers used area under the receiver operating characteristic curves to assess the effect of BMI on mortality and categorized patients as underweight (BMI less than 20 kg/m²), normal weight (20-25 kg/m²), overweight (25-30 kg/m²), obese (30-35 kg/m²), severely obese (35-50 kg/m²), and super obese (greater than 50 kg/m²).

Overall 30-day hospital mortality was 10%. Hospital mortality was 15% for underweight patients, 11% for normal weight patients, 8% for overweight patients, 9% for obese patients, 13% for severely obese patients, and 22% for super obese patients. Area under the receiver operating characteristic curve analysis yielded no significant association between BMI and mortality, even after stratification of patients by elective vs. emergent surgery, and patients younger vs. older than age 75 years.

Dr. Khader and his associates observed a trend toward increased mortality for patients in the underweight, obese, and severely obese categories of BMI, "but nothing statistically significant," he said. "Still, there was a large number of patients [in this study]. You can’t really ignore the numbers."

Dr. Khader said that he had no relevant financial conflicts to disclose.

HONOLULU – Not long ago, patients older than 65 years were rarely considered candidates for lung transplantation. But that’s not quite true anymore.

Being elderly is still a relative contraindication, but according to data from the International Society for Heart and Lung Transplantation, an increasing proportion of people older than age 65 are receiving lung transplants, from about 2% in 1995-1999 to about 6% between 2000 and June of 2010.

Instead of age and the length of time spent on the list waiting for a transplant, candidacy for the procedure is now based on whether patients’ advanced respiratory disease has progressed despite medical therapy, and whether they have a 50% or less chance of survival in the next 2-3 years, Dr. Luis F. Angel explained at the annual meeting of the American College of Chest Physicians.

"Potential candidates must be capable of comprehending the procedure, undergoing the selection process, and waiting the time necessary on the waiting list," said Dr. Angel, director of lung transplantation for the University of Texas Health Science Center at San Antonio.

In a review of the latest criteria, he explained that patients "must also be free of significant medical comorbidities and be sufficiently fit to handle this major surgical procedure and multiple medications post procedure."

The list of absolute contraindications for lung transplantation is lengthy, and includes recent malignancy (other than nonmelanoma skin cancer); infection with HIV; infection with hepatitis B or C with histologic evidence of cirrhosis; active cigarette smoking or substance abuse; severe and untreated psychiatric illness; documented noncompliance with medical care; and absence of a reliable social network.

Relative contraindications, Dr. Angel said, include the clinical state at the moment of notification or referral, such as the presence of hemodynamic instability, excessive physical deterioration, or severe muscle atrophy that impedes performing outpatient rehabilitation. Also taken into account is the need for invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) support.

"Colonization by multiresistant or panresistant bacteria, fungus, or mycobacteria is another contraindication," Dr. Angel said, "as are other medical conditions such as coronary artery disease, liver and renal disease, gastroesophageal reflux, or symptomatic osteoporosis, and having a body mass index higher than 30 kg/m²."

Regarding the following specific indication for transplantation, the success rates vary according to the condition:

• COPD/emphysema. In a select group of patients with COPD/emphysema, transplantation provides both survival and quality of life benefits.

Referral criteria include a BODE index of 7-10 points, or at least one of the following: a history of hospitalization for exacerbation associated with acute hypercapnia; pulmonary hypertension or cor pulmonale, or both, despite oxygen therapy; and an FEV₁ (forced expiratory volume in 1 second) of less than 20% and either a DLCO (diffusing capacity of the lungs for carbon monoxide) finding of less than 20% or homogenous distribution of emphysema.

• Pulmonary fibrosis. "The natural history of the disease is more predictable, and there are major limitations in effective therapy for this diagnosis," said Dr. Angel of the department of pulmonary and critical care medicine at the university.

Referral criteria, he said, include histologic or radiographic evidence of interstitial pneumonia, and any of the following: a DLCO of less than 39% predicted; a 10% or greater decrement in forced vital capacity during 6 months of follow-up; a decrease in pulse oximetry less than 88% during a 6-minute walk test; honeycombing on high-resolution CT; or development of secondary pulmonary hypertension.

• Cystic fibrosis. Patients with this condition "can get the most significant benefit and prolonged survival with lung transplantation," Dr. Angel said. "Referrals are often delayed, as there is [a] high emotional aspect in the management of these patients and their families."

Referral criteria, he said, include a FEV₁ of less than 30% of predicted, or rapidly declining lung function if FEV₁ is greater than 30% of predicted, and/or any of the following: increasing oxygen requirements, hypercapnia, and pulmonary hypertension.

• Idiopathic PAH (pulmonary arterial hypertension). "This is one of the most difficult conditions [in which] to determine the right time for transplantation," Dr. Angel said. "Significant improvements with medical therapy and increased awareness of the disease have decreased the number of lung transplants for this indication."

Referral criteria, he said, include persistent New York Heart Association class III or IV on maximal medical therapy; low or declining 6-minute walk test findings; failing therapy with intravenous epoprostenol or equivalent; a cardiac index of less than 2 L/min per square meter, or a right atrial pressure exceeding 15 mm Hg.

Dr. Angel said that he had no relevant financial conflicts to disclose.

HONOLULU – Not long ago, patients older than 65 years were rarely considered candidates for lung transplantation. But that’s not quite true anymore.

Being elderly is still a relative contraindication, but according to data from the International Society for Heart and Lung Transplantation, an increasing proportion of people older than age 65 are receiving lung transplants, from about 2% in 1995-1999 to about 6% between 2000 and June of 2010.

Instead of age and the length of time spent on the list waiting for a transplant, candidacy for the procedure is now based on whether patients’ advanced respiratory disease has progressed despite medical therapy, and whether they have a 50% or less chance of survival in the next 2-3 years, Dr. Luis F. Angel explained at the annual meeting of the American College of Chest Physicians.

"Potential candidates must be capable of comprehending the procedure, undergoing the selection process, and waiting the time necessary on the waiting list," said Dr. Angel, director of lung transplantation for the University of Texas Health Science Center at San Antonio.

In a review of the latest criteria, he explained that patients "must also be free of significant medical comorbidities and be sufficiently fit to handle this major surgical procedure and multiple medications post procedure."

The list of absolute contraindications for lung transplantation is lengthy, and includes recent malignancy (other than nonmelanoma skin cancer); infection with HIV; infection with hepatitis B or C with histologic evidence of cirrhosis; active cigarette smoking or substance abuse; severe and untreated psychiatric illness; documented noncompliance with medical care; and absence of a reliable social network.

Relative contraindications, Dr. Angel said, include the clinical state at the moment of notification or referral, such as the presence of hemodynamic instability, excessive physical deterioration, or severe muscle atrophy that impedes performing outpatient rehabilitation. Also taken into account is the need for invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) support.

"Colonization by multiresistant or panresistant bacteria, fungus, or mycobacteria is another contraindication," Dr. Angel said, "as are other medical conditions such as coronary artery disease, liver and renal disease, gastroesophageal reflux, or symptomatic osteoporosis, and having a body mass index higher than 30 kg/m²."

Regarding the following specific indication for transplantation, the success rates vary according to the condition:

• COPD/emphysema. In a select group of patients with COPD/emphysema, transplantation provides both survival and quality of life benefits.

Referral criteria include a BODE index of 7-10 points, or at least one of the following: a history of hospitalization for exacerbation associated with acute hypercapnia; pulmonary hypertension or cor pulmonale, or both, despite oxygen therapy; and an FEV₁ (forced expiratory volume in 1 second) of less than 20% and either a DLCO (diffusing capacity of the lungs for carbon monoxide) finding of less than 20% or homogenous distribution of emphysema.

• Pulmonary fibrosis. "The natural history of the disease is more predictable, and there are major limitations in effective therapy for this diagnosis," said Dr. Angel of the department of pulmonary and critical care medicine at the university.

Referral criteria, he said, include histologic or radiographic evidence of interstitial pneumonia, and any of the following: a DLCO of less than 39% predicted; a 10% or greater decrement in forced vital capacity during 6 months of follow-up; a decrease in pulse oximetry less than 88% during a 6-minute walk test; honeycombing on high-resolution CT; or development of secondary pulmonary hypertension.

• Cystic fibrosis. Patients with this condition "can get the most significant benefit and prolonged survival with lung transplantation," Dr. Angel said. "Referrals are often delayed, as there is [a] high emotional aspect in the management of these patients and their families."

Referral criteria, he said, include a FEV₁ of less than 30% of predicted, or rapidly declining lung function if FEV₁ is greater than 30% of predicted, and/or any of the following: increasing oxygen requirements, hypercapnia, and pulmonary hypertension.

• Idiopathic PAH (pulmonary arterial hypertension). "This is one of the most difficult conditions [in which] to determine the right time for transplantation," Dr. Angel said. "Significant improvements with medical therapy and increased awareness of the disease have decreased the number of lung transplants for this indication."

Referral criteria, he said, include persistent New York Heart Association class III or IV on maximal medical therapy; low or declining 6-minute walk test findings; failing therapy with intravenous epoprostenol or equivalent; a cardiac index of less than 2 L/min per square meter, or a right atrial pressure exceeding 15 mm Hg.

Dr. Angel said that he had no relevant financial conflicts to disclose.

HONOLULU – Not long ago, patients older than 65 years were rarely considered candidates for lung transplantation. But that’s not quite true anymore.

Being elderly is still a relative contraindication, but according to data from the International Society for Heart and Lung Transplantation, an increasing proportion of people older than age 65 are receiving lung transplants, from about 2% in 1995-1999 to about 6% between 2000 and June of 2010.

Instead of age and the length of time spent on the list waiting for a transplant, candidacy for the procedure is now based on whether patients’ advanced respiratory disease has progressed despite medical therapy, and whether they have a 50% or less chance of survival in the next 2-3 years, Dr. Luis F. Angel explained at the annual meeting of the American College of Chest Physicians.

"Potential candidates must be capable of comprehending the procedure, undergoing the selection process, and waiting the time necessary on the waiting list," said Dr. Angel, director of lung transplantation for the University of Texas Health Science Center at San Antonio.

In a review of the latest criteria, he explained that patients "must also be free of significant medical comorbidities and be sufficiently fit to handle this major surgical procedure and multiple medications post procedure."

The list of absolute contraindications for lung transplantation is lengthy, and includes recent malignancy (other than nonmelanoma skin cancer); infection with HIV; infection with hepatitis B or C with histologic evidence of cirrhosis; active cigarette smoking or substance abuse; severe and untreated psychiatric illness; documented noncompliance with medical care; and absence of a reliable social network.

Relative contraindications, Dr. Angel said, include the clinical state at the moment of notification or referral, such as the presence of hemodynamic instability, excessive physical deterioration, or severe muscle atrophy that impedes performing outpatient rehabilitation. Also taken into account is the need for invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) support.

"Colonization by multiresistant or panresistant bacteria, fungus, or mycobacteria is another contraindication," Dr. Angel said, "as are other medical conditions such as coronary artery disease, liver and renal disease, gastroesophageal reflux, or symptomatic osteoporosis, and having a body mass index higher than 30 kg/m²."

Regarding the following specific indication for transplantation, the success rates vary according to the condition:

• COPD/emphysema. In a select group of patients with COPD/emphysema, transplantation provides both survival and quality of life benefits.

Referral criteria include a BODE index of 7-10 points, or at least one of the following: a history of hospitalization for exacerbation associated with acute hypercapnia; pulmonary hypertension or cor pulmonale, or both, despite oxygen therapy; and an FEV₁ (forced expiratory volume in 1 second) of less than 20% and either a DLCO (diffusing capacity of the lungs for carbon monoxide) finding of less than 20% or homogenous distribution of emphysema.

• Pulmonary fibrosis. "The natural history of the disease is more predictable, and there are major limitations in effective therapy for this diagnosis," said Dr. Angel of the department of pulmonary and critical care medicine at the university.

Referral criteria, he said, include histologic or radiographic evidence of interstitial pneumonia, and any of the following: a DLCO of less than 39% predicted; a 10% or greater decrement in forced vital capacity during 6 months of follow-up; a decrease in pulse oximetry less than 88% during a 6-minute walk test; honeycombing on high-resolution CT; or development of secondary pulmonary hypertension.

• Cystic fibrosis. Patients with this condition "can get the most significant benefit and prolonged survival with lung transplantation," Dr. Angel said. "Referrals are often delayed, as there is [a] high emotional aspect in the management of these patients and their families."

Referral criteria, he said, include a FEV₁ of less than 30% of predicted, or rapidly declining lung function if FEV₁ is greater than 30% of predicted, and/or any of the following: increasing oxygen requirements, hypercapnia, and pulmonary hypertension.

• Idiopathic PAH (pulmonary arterial hypertension). "This is one of the most difficult conditions [in which] to determine the right time for transplantation," Dr. Angel said. "Significant improvements with medical therapy and increased awareness of the disease have decreased the number of lung transplants for this indication."

Referral criteria, he said, include persistent New York Heart Association class III or IV on maximal medical therapy; low or declining 6-minute walk test findings; failing therapy with intravenous epoprostenol or equivalent; a cardiac index of less than 2 L/min per square meter, or a right atrial pressure exceeding 15 mm Hg.

Dr. Angel said that he had no relevant financial conflicts to disclose.

HONOLULU – What do patients in the ICU want at the end of life?

Research has shown that pain control typically ranks at the top of the list, "but they also want to avoid inappropriate prolongation of dying," Dr. Richard Mularski said at the annual meeting of the American College of Chest Physicians.

Patients "want to achieve a sense of control at the end of life," continued Dr. Mularski, a pulmonologist who is a clinical investigator with the Center for Health Research at Kaiser Permanente Northwest, Portland, Ore. "They don’t want to be a burden on their family. We have to offer professional help, which primarily comes from talking with our patients and providing opportunities to strengthen relationships with loved ones. This might mean backing off on sedatives and pain medications so that patients and loved ones can interact before withdrawal of life support."

Dr. Mularski highlighted four key points from a 2009 consensus statement he helped to create on pain management during the palliative and end-of-life experience in the ICU (Chest 2009;135:1360-9). The first point reads that all ICU patients "experience opportunities for discomfort and suffering regardless of prognosis or goals, thus palliative therapy is a requisite approach for every patient, of which pain management is a principal component."

According to the second, third, and fourth key points, "for those dying in the ICU, an explicit shift in management to comfort-oriented care is often warranted and may be the most beneficial treatment the health-care team can offer; communication and cultural sensitivity with the patient-family unit is a principal approach for optimizing palliative and pain management as part of comprehensive ICU care, [and] ethical and legal misconceptions about the escalation of opiates and other palliative therapies should not be barriers to appropriate care, provided the intention of treatment is alleviation of pain and suffering."

Communicating effectively with the patient and family about prognosis in the critical care setting can be difficult "because we’re often limited by what treatments or interventions we can make," Dr. Mularski said. "This creates a certain tension: Patients have a widespread and deeply held desire not to be dead. We have to try to focus on that desire and acknowledge our limitations. Data show we don’t really prognosticate when death will occur very well."

"For those dying in the ICU, an explicit shift in management to comfort-oriented care ... may be the most beneficial treatment the health-care team can offer."

The potential for limited treatment options is only part of the problem. A trial conducted in a university-affiliated ICU found that 54% of families fail to comprehend a diagnosis, a prognosis, or treatment options (Crit. Care Med. 2000;28:3044-9). "We also know that family members experience a fair amount of moderate to severe posttraumatic stress," Dr. Mularski added. "This stress is increased when we provide inadequate information. We have to be careful not to use phrases that suggest abandonment or a failure of medicine to care, such as ‘there’s nothing more we can do,’ or ‘we have nothing to offer.’ We have plenty to offer. Palliative care may be the most important thing we have to offer at the end of life."

Key factors in shared decision making between clinicians and families about end-of-life care include prognosis, level of certainty "which may not be there," and family preferences. "The role of the patient and family is to help us understand patient values and preferences, and for us as clinicians to indicate which treatments might be concurrent with those values and preferences," Dr. Mularski said.

In a 2008 article, "Practical Guidance for Evidence-Based ICU Family Conferences," Dr. J. Randall Curtis and Dr. Douglas B. White offered a five-step approach to improving communication in the ICU with families (Chest 2008;134:835-43). It centers on the mnemonic "VALUE," which stands for value family statements, acknowledge family emotions, listen to the family, understand the patient as a person, and elicit family questions.

At Kaiser Permanente Northwest, Dr. Mularski and his colleagues created pocket cards for critical care staff that contain the VALUE mnemonic to remind them of how to best interact with families of patients in the ICU. He also recommends the book by Dr. Anthony L. Back and colleagues, "Mastering Communication with Seriously Ill Patients: Balancing Honesty with Empathy and Hope" (New York: Cambridge University Press, 2009).

Dr. Mularski disclosed that he has received research funding from several agencies including the Agency for Healthcare Research and Quality, National Cancer Institute, National Quality Forum, and Robert Wood Johnson Foundation. He also has received research support from Novartis and Spiration for unrelated work in chronic obstructive pulmonary disorder.

HONOLULU – What do patients in the ICU want at the end of life?

Research has shown that pain control typically ranks at the top of the list, "but they also want to avoid inappropriate prolongation of dying," Dr. Richard Mularski said at the annual meeting of the American College of Chest Physicians.

Patients "want to achieve a sense of control at the end of life," continued Dr. Mularski, a pulmonologist who is a clinical investigator with the Center for Health Research at Kaiser Permanente Northwest, Portland, Ore. "They don’t want to be a burden on their family. We have to offer professional help, which primarily comes from talking with our patients and providing opportunities to strengthen relationships with loved ones. This might mean backing off on sedatives and pain medications so that patients and loved ones can interact before withdrawal of life support."

Dr. Mularski highlighted four key points from a 2009 consensus statement he helped to create on pain management during the palliative and end-of-life experience in the ICU (Chest 2009;135:1360-9). The first point reads that all ICU patients "experience opportunities for discomfort and suffering regardless of prognosis or goals, thus palliative therapy is a requisite approach for every patient, of which pain management is a principal component."

According to the second, third, and fourth key points, "for those dying in the ICU, an explicit shift in management to comfort-oriented care is often warranted and may be the most beneficial treatment the health-care team can offer; communication and cultural sensitivity with the patient-family unit is a principal approach for optimizing palliative and pain management as part of comprehensive ICU care, [and] ethical and legal misconceptions about the escalation of opiates and other palliative therapies should not be barriers to appropriate care, provided the intention of treatment is alleviation of pain and suffering."

Communicating effectively with the patient and family about prognosis in the critical care setting can be difficult "because we’re often limited by what treatments or interventions we can make," Dr. Mularski said. "This creates a certain tension: Patients have a widespread and deeply held desire not to be dead. We have to try to focus on that desire and acknowledge our limitations. Data show we don’t really prognosticate when death will occur very well."

"For those dying in the ICU, an explicit shift in management to comfort-oriented care ... may be the most beneficial treatment the health-care team can offer."

The potential for limited treatment options is only part of the problem. A trial conducted in a university-affiliated ICU found that 54% of families fail to comprehend a diagnosis, a prognosis, or treatment options (Crit. Care Med. 2000;28:3044-9). "We also know that family members experience a fair amount of moderate to severe posttraumatic stress," Dr. Mularski added. "This stress is increased when we provide inadequate information. We have to be careful not to use phrases that suggest abandonment or a failure of medicine to care, such as ‘there’s nothing more we can do,’ or ‘we have nothing to offer.’ We have plenty to offer. Palliative care may be the most important thing we have to offer at the end of life."

Key factors in shared decision making between clinicians and families about end-of-life care include prognosis, level of certainty "which may not be there," and family preferences. "The role of the patient and family is to help us understand patient values and preferences, and for us as clinicians to indicate which treatments might be concurrent with those values and preferences," Dr. Mularski said.

In a 2008 article, "Practical Guidance for Evidence-Based ICU Family Conferences," Dr. J. Randall Curtis and Dr. Douglas B. White offered a five-step approach to improving communication in the ICU with families (Chest 2008;134:835-43). It centers on the mnemonic "VALUE," which stands for value family statements, acknowledge family emotions, listen to the family, understand the patient as a person, and elicit family questions.

At Kaiser Permanente Northwest, Dr. Mularski and his colleagues created pocket cards for critical care staff that contain the VALUE mnemonic to remind them of how to best interact with families of patients in the ICU. He also recommends the book by Dr. Anthony L. Back and colleagues, "Mastering Communication with Seriously Ill Patients: Balancing Honesty with Empathy and Hope" (New York: Cambridge University Press, 2009).

Dr. Mularski disclosed that he has received research funding from several agencies including the Agency for Healthcare Research and Quality, National Cancer Institute, National Quality Forum, and Robert Wood Johnson Foundation. He also has received research support from Novartis and Spiration for unrelated work in chronic obstructive pulmonary disorder.

HONOLULU – What do patients in the ICU want at the end of life?

Research has shown that pain control typically ranks at the top of the list, "but they also want to avoid inappropriate prolongation of dying," Dr. Richard Mularski said at the annual meeting of the American College of Chest Physicians.

Patients "want to achieve a sense of control at the end of life," continued Dr. Mularski, a pulmonologist who is a clinical investigator with the Center for Health Research at Kaiser Permanente Northwest, Portland, Ore. "They don’t want to be a burden on their family. We have to offer professional help, which primarily comes from talking with our patients and providing opportunities to strengthen relationships with loved ones. This might mean backing off on sedatives and pain medications so that patients and loved ones can interact before withdrawal of life support."

Dr. Mularski highlighted four key points from a 2009 consensus statement he helped to create on pain management during the palliative and end-of-life experience in the ICU (Chest 2009;135:1360-9). The first point reads that all ICU patients "experience opportunities for discomfort and suffering regardless of prognosis or goals, thus palliative therapy is a requisite approach for every patient, of which pain management is a principal component."

According to the second, third, and fourth key points, "for those dying in the ICU, an explicit shift in management to comfort-oriented care is often warranted and may be the most beneficial treatment the health-care team can offer; communication and cultural sensitivity with the patient-family unit is a principal approach for optimizing palliative and pain management as part of comprehensive ICU care, [and] ethical and legal misconceptions about the escalation of opiates and other palliative therapies should not be barriers to appropriate care, provided the intention of treatment is alleviation of pain and suffering."

Communicating effectively with the patient and family about prognosis in the critical care setting can be difficult "because we’re often limited by what treatments or interventions we can make," Dr. Mularski said. "This creates a certain tension: Patients have a widespread and deeply held desire not to be dead. We have to try to focus on that desire and acknowledge our limitations. Data show we don’t really prognosticate when death will occur very well."

"For those dying in the ICU, an explicit shift in management to comfort-oriented care ... may be the most beneficial treatment the health-care team can offer."

The potential for limited treatment options is only part of the problem. A trial conducted in a university-affiliated ICU found that 54% of families fail to comprehend a diagnosis, a prognosis, or treatment options (Crit. Care Med. 2000;28:3044-9). "We also know that family members experience a fair amount of moderate to severe posttraumatic stress," Dr. Mularski added. "This stress is increased when we provide inadequate information. We have to be careful not to use phrases that suggest abandonment or a failure of medicine to care, such as ‘there’s nothing more we can do,’ or ‘we have nothing to offer.’ We have plenty to offer. Palliative care may be the most important thing we have to offer at the end of life."

Key factors in shared decision making between clinicians and families about end-of-life care include prognosis, level of certainty "which may not be there," and family preferences. "The role of the patient and family is to help us understand patient values and preferences, and for us as clinicians to indicate which treatments might be concurrent with those values and preferences," Dr. Mularski said.

In a 2008 article, "Practical Guidance for Evidence-Based ICU Family Conferences," Dr. J. Randall Curtis and Dr. Douglas B. White offered a five-step approach to improving communication in the ICU with families (Chest 2008;134:835-43). It centers on the mnemonic "VALUE," which stands for value family statements, acknowledge family emotions, listen to the family, understand the patient as a person, and elicit family questions.

At Kaiser Permanente Northwest, Dr. Mularski and his colleagues created pocket cards for critical care staff that contain the VALUE mnemonic to remind them of how to best interact with families of patients in the ICU. He also recommends the book by Dr. Anthony L. Back and colleagues, "Mastering Communication with Seriously Ill Patients: Balancing Honesty with Empathy and Hope" (New York: Cambridge University Press, 2009).

Dr. Mularski disclosed that he has received research funding from several agencies including the Agency for Healthcare Research and Quality, National Cancer Institute, National Quality Forum, and Robert Wood Johnson Foundation. He also has received research support from Novartis and Spiration for unrelated work in chronic obstructive pulmonary disorder.

HONOLULU – The use of oral sildenafil helped improve oxygen delivery and exercise capacity in children with pulmonary arterial hypertension, results from a randomized, multicenter trial showed.

The study, which employed cardiopulmonary exercise testing – including assessment of ventilation to carbon dioxide (VE/VCO₂) slope – "confirmed our suspicion that ventilatory efficiency, as measured by VE/VCO₂, appears to be a sensitive measurement to assess exercise ability in pediatric pulmonary arterial hypertension as long as the children are old enough and developmentally able to exercise reliably," lead investigator Dr. Robyn J. Barst said in an interview in advance of the annual meeting of the American College of Chest Physicians, where the study was presented. Using such measures may allow future trials to determine drug effectiveness and safety with fewer study participants, thus shortening time to approval for new drugs, she said.

The STARTS-1 study included 234 treatment-naive children with pulmonary arterial hypertension (PAH), who were aged 1-17 years and weighed 8 kg or more. Participants were randomized to receive placebo or low, medium, or high doses of oral sildenafil three times a day at 1 of 32 centers in 16 countries, including the United States. Doses were based on weight groups – 8-20 kg, 20-45 kg, and more than 45 kg – with the doses ranging from 10 to 80 mg t.i.d. Sildenafil is approved in the European Union for the treatment of PAH in children at a dose of 10 mg t.i.d. for children who weigh less than 20 kg and a dose of 20 mg t.i.d. for children who weigh more than 20 kg, but is not currently approved in the United States for this population.

The researchers measured peak oxygen consumption (VO₂) and VE/VCO₂ levels at the beginning of the study and again at 16 weeks in 106 children who could reliably exercise on a bicycle. The primary outcome was percent change in peak VO₂. Cardiopulmonary exercise testing, rather than the more frequently used 6-minute walk test, was used to assess exercise capacity, because cardiopulmonary exercise testing is "considered a more sensitive exercise test than the 6-minute walk test; many patients have a fairly good 6-minute walk test despite significant pulmonary arterial hypertension," explained Dr. Barst, professor emeritus of pediatrics at Columbia University, New York.

Although the primary end point of percent change in peak VO₂ comparing the combined three sildenafil dose groups with placebo did not meet predefined criteria (P = .056), children in the medium- and high-dose sildenafil groups did have significantly greater improvements in peak VO₂ and VE/VCO₂ slope, compared with those on placebo, whether the pulmonary arterial hypertension was idiopathic/heritable or associated with congenital heart disease. Upper respiratory tract infections, pyrexia, and vomiting occurred more often with sildenafil than placebo. The majority of adverse events were mild or moderate.

The study demonstrated that cardiopulmonary exercise testing "is a relatively simple exercise test that can be carried out safely in an exercise lab experienced in caring for children and adults with PAH," Dr. Barst said. "Further, measurement of ventilatory efficiency does not require the patient to exercise to maximal exertion. And there now is a more simplified gas analysis system available than what was used in this study to assess these same parameters. It is a miniaturized, simplified, and portable system that has been designed for submaximal exercise testing. Utilizing the [Shape-HF Cardiopulmonary Testing System, Shape Medical Systems] should be useful to clinicians for long-term follow-up assessments to determine if their patients are responding adequately to their current treatments."

Dr. Barst acknowledged certain limitations of the study, including the fact that not all children were old enough or able to perform cardiopulmonary exercise testing. "However, all enrolled patients did have safety assessments, functional capacity evaluations, and pulmonary hemodynamic parameters obtained by invasive right heart catheterization at both baseline and at the end of the 16-week study, to obtain objective parameters of disease severity known to be prognostic for long-term outcomes," she said.

An additional limitation of most controlled studies performed in PAH, she added, is the relatively short study duration – 16 weeks in this case. "When the data from STARTS-1 [were] combined with interim data – more than 2 years – from the ongoing extension STARTS-2 study, in which all patients received active drug, the overall profile [favored] the medium dose," she said. "Further investigation is warranted to determine optimal dosing based on age and body weight."

Pfizer funded the study. Dr. Barst served as a consultant for the company during the July 2010 Food and Drug Administration advisory committee meeting on sildenafil treatment for pediatric pulmonary arterial hypertension. Dr. Barst also has received honoraria from Actelion, Eli Lilly, Gilead, GlaxoSmithKline, Ikaria, Merck, and Novartis for consulting work.

HONOLULU – The use of oral sildenafil helped improve oxygen delivery and exercise capacity in children with pulmonary arterial hypertension, results from a randomized, multicenter trial showed.

The study, which employed cardiopulmonary exercise testing – including assessment of ventilation to carbon dioxide (VE/VCO₂) slope – "confirmed our suspicion that ventilatory efficiency, as measured by VE/VCO₂, appears to be a sensitive measurement to assess exercise ability in pediatric pulmonary arterial hypertension as long as the children are old enough and developmentally able to exercise reliably," lead investigator Dr. Robyn J. Barst said in an interview in advance of the annual meeting of the American College of Chest Physicians, where the study was presented. Using such measures may allow future trials to determine drug effectiveness and safety with fewer study participants, thus shortening time to approval for new drugs, she said.

The STARTS-1 study included 234 treatment-naive children with pulmonary arterial hypertension (PAH), who were aged 1-17 years and weighed 8 kg or more. Participants were randomized to receive placebo or low, medium, or high doses of oral sildenafil three times a day at 1 of 32 centers in 16 countries, including the United States. Doses were based on weight groups – 8-20 kg, 20-45 kg, and more than 45 kg – with the doses ranging from 10 to 80 mg t.i.d. Sildenafil is approved in the European Union for the treatment of PAH in children at a dose of 10 mg t.i.d. for children who weigh less than 20 kg and a dose of 20 mg t.i.d. for children who weigh more than 20 kg, but is not currently approved in the United States for this population.

The researchers measured peak oxygen consumption (VO₂) and VE/VCO₂ levels at the beginning of the study and again at 16 weeks in 106 children who could reliably exercise on a bicycle. The primary outcome was percent change in peak VO₂. Cardiopulmonary exercise testing, rather than the more frequently used 6-minute walk test, was used to assess exercise capacity, because cardiopulmonary exercise testing is "considered a more sensitive exercise test than the 6-minute walk test; many patients have a fairly good 6-minute walk test despite significant pulmonary arterial hypertension," explained Dr. Barst, professor emeritus of pediatrics at Columbia University, New York.

Although the primary end point of percent change in peak VO₂ comparing the combined three sildenafil dose groups with placebo did not meet predefined criteria (P = .056), children in the medium- and high-dose sildenafil groups did have significantly greater improvements in peak VO₂ and VE/VCO₂ slope, compared with those on placebo, whether the pulmonary arterial hypertension was idiopathic/heritable or associated with congenital heart disease. Upper respiratory tract infections, pyrexia, and vomiting occurred more often with sildenafil than placebo. The majority of adverse events were mild or moderate.

The study demonstrated that cardiopulmonary exercise testing "is a relatively simple exercise test that can be carried out safely in an exercise lab experienced in caring for children and adults with PAH," Dr. Barst said. "Further, measurement of ventilatory efficiency does not require the patient to exercise to maximal exertion. And there now is a more simplified gas analysis system available than what was used in this study to assess these same parameters. It is a miniaturized, simplified, and portable system that has been designed for submaximal exercise testing. Utilizing the [Shape-HF Cardiopulmonary Testing System, Shape Medical Systems] should be useful to clinicians for long-term follow-up assessments to determine if their patients are responding adequately to their current treatments."

Dr. Barst acknowledged certain limitations of the study, including the fact that not all children were old enough or able to perform cardiopulmonary exercise testing. "However, all enrolled patients did have safety assessments, functional capacity evaluations, and pulmonary hemodynamic parameters obtained by invasive right heart catheterization at both baseline and at the end of the 16-week study, to obtain objective parameters of disease severity known to be prognostic for long-term outcomes," she said.

An additional limitation of most controlled studies performed in PAH, she added, is the relatively short study duration – 16 weeks in this case. "When the data from STARTS-1 [were] combined with interim data – more than 2 years – from the ongoing extension STARTS-2 study, in which all patients received active drug, the overall profile [favored] the medium dose," she said. "Further investigation is warranted to determine optimal dosing based on age and body weight."

Pfizer funded the study. Dr. Barst served as a consultant for the company during the July 2010 Food and Drug Administration advisory committee meeting on sildenafil treatment for pediatric pulmonary arterial hypertension. Dr. Barst also has received honoraria from Actelion, Eli Lilly, Gilead, GlaxoSmithKline, Ikaria, Merck, and Novartis for consulting work.

HONOLULU – The use of oral sildenafil helped improve oxygen delivery and exercise capacity in children with pulmonary arterial hypertension, results from a randomized, multicenter trial showed.

The study, which employed cardiopulmonary exercise testing – including assessment of ventilation to carbon dioxide (VE/VCO₂) slope – "confirmed our suspicion that ventilatory efficiency, as measured by VE/VCO₂, appears to be a sensitive measurement to assess exercise ability in pediatric pulmonary arterial hypertension as long as the children are old enough and developmentally able to exercise reliably," lead investigator Dr. Robyn J. Barst said in an interview in advance of the annual meeting of the American College of Chest Physicians, where the study was presented. Using such measures may allow future trials to determine drug effectiveness and safety with fewer study participants, thus shortening time to approval for new drugs, she said.

The STARTS-1 study included 234 treatment-naive children with pulmonary arterial hypertension (PAH), who were aged 1-17 years and weighed 8 kg or more. Participants were randomized to receive placebo or low, medium, or high doses of oral sildenafil three times a day at 1 of 32 centers in 16 countries, including the United States. Doses were based on weight groups – 8-20 kg, 20-45 kg, and more than 45 kg – with the doses ranging from 10 to 80 mg t.i.d. Sildenafil is approved in the European Union for the treatment of PAH in children at a dose of 10 mg t.i.d. for children who weigh less than 20 kg and a dose of 20 mg t.i.d. for children who weigh more than 20 kg, but is not currently approved in the United States for this population.

The researchers measured peak oxygen consumption (VO₂) and VE/VCO₂ levels at the beginning of the study and again at 16 weeks in 106 children who could reliably exercise on a bicycle. The primary outcome was percent change in peak VO₂. Cardiopulmonary exercise testing, rather than the more frequently used 6-minute walk test, was used to assess exercise capacity, because cardiopulmonary exercise testing is "considered a more sensitive exercise test than the 6-minute walk test; many patients have a fairly good 6-minute walk test despite significant pulmonary arterial hypertension," explained Dr. Barst, professor emeritus of pediatrics at Columbia University, New York.

Although the primary end point of percent change in peak VO₂ comparing the combined three sildenafil dose groups with placebo did not meet predefined criteria (P = .056), children in the medium- and high-dose sildenafil groups did have significantly greater improvements in peak VO₂ and VE/VCO₂ slope, compared with those on placebo, whether the pulmonary arterial hypertension was idiopathic/heritable or associated with congenital heart disease. Upper respiratory tract infections, pyrexia, and vomiting occurred more often with sildenafil than placebo. The majority of adverse events were mild or moderate.

The study demonstrated that cardiopulmonary exercise testing "is a relatively simple exercise test that can be carried out safely in an exercise lab experienced in caring for children and adults with PAH," Dr. Barst said. "Further, measurement of ventilatory efficiency does not require the patient to exercise to maximal exertion. And there now is a more simplified gas analysis system available than what was used in this study to assess these same parameters. It is a miniaturized, simplified, and portable system that has been designed for submaximal exercise testing. Utilizing the [Shape-HF Cardiopulmonary Testing System, Shape Medical Systems] should be useful to clinicians for long-term follow-up assessments to determine if their patients are responding adequately to their current treatments."

Dr. Barst acknowledged certain limitations of the study, including the fact that not all children were old enough or able to perform cardiopulmonary exercise testing. "However, all enrolled patients did have safety assessments, functional capacity evaluations, and pulmonary hemodynamic parameters obtained by invasive right heart catheterization at both baseline and at the end of the 16-week study, to obtain objective parameters of disease severity known to be prognostic for long-term outcomes," she said.

An additional limitation of most controlled studies performed in PAH, she added, is the relatively short study duration – 16 weeks in this case. "When the data from STARTS-1 [were] combined with interim data – more than 2 years – from the ongoing extension STARTS-2 study, in which all patients received active drug, the overall profile [favored] the medium dose," she said. "Further investigation is warranted to determine optimal dosing based on age and body weight."

Pfizer funded the study. Dr. Barst served as a consultant for the company during the July 2010 Food and Drug Administration advisory committee meeting on sildenafil treatment for pediatric pulmonary arterial hypertension. Dr. Barst also has received honoraria from Actelion, Eli Lilly, Gilead, GlaxoSmithKline, Ikaria, Merck, and Novartis for consulting work.

HONOLULU – The jury is still out on whether patients with acute lung injury and adult respiratory distress syndrome derive any benefit from the use of corticosteroids, according to Dr. Stephen M. Pastores.

"This is probably the most controversial topic in acute lung injury and ARDS," Dr. Pastores of the department of anesthesiology and critical care medicine at Memorial Sloan-Kettering Cancer Center, New York, said at the annual meeting of the American College of Chest Physicians. "For those of us who might believe in the use of corticosteroids, we base that on the pretty good evidence that they are effective anti-inflammatory agents. There have been a few positive trials for the use of prolonged corticosteroid treatment in ALI [acute lung injury]-ARDS, with significantly less side effects in comparison to older trials investigating massive doses," such as methylprednisolone 120 mg/kg per day.

Renewed interest in this topic came about 4 years ago, he said, after publication of a study that evaluated the effects of low-dose methylprednisolone infusion on lung function in 91 patients with early ARDS (within 72 hours). About two-thirds of the patients (66%) had sepsis (Chest 2007;131:954-63). Patients were randomized to receive methylprednisolone infusion (1 mg/kg per day) or placebo for up to 28 days. The primary end point was a 1-point reduction in the lung injury score or successful extubation by day 7.

"An important piece of this study was that [the researchers] did regular infection surveillance with regular bronchoscopies, and they avoided the use of neuromuscular blockers," said Dr. Pastores, who is also professor of medicine and anesthesiology at Cornell University in New York.

The researchers found that patients in the treatment arm had a greater than 1-point drop in their lung injury score. The researchers also found no significant increase in complications such as infection, "and because they avoided neuromuscular blockers, there was hardly any incidence of neuromuscular weakness or neuropathy," Dr. Pastores said.

In a subsequent review of five trials on the use of steroids for the treatment of ARDS that enrolled a total of 518 patients, Dr. Pastores and his associates observed that the steroid dosing and treatment duration were different across the trials, and that infection surveillance was not routine (Intensive Care Med. 2008;34:61-9). However, three of the trials in which patients received steroids before day 14 of ARDS found a slight benefit to this approach, with a number needed to treat of six.

"If you look at the patients who were randomized to the methylprednisolone arm, the mortality rate was 24%, which is about 16% less than the control arm that did not receive steroids," Dr. Pastores said of the 245 patients in these three trials. "From this review, we concluded that prolonged glucocorticoid treatment substantially and significantly improves meaningful patient-centered outcomes in terms of less ventilator days, less days in the ICU, and perhaps a distinct survival benefit – only in patients who have steroids early in the course of acute lung injury, however."

A more recent systematic review that factored in additional trials concluded that prolonged glucocorticoid treatment has a "distinct survival benefit" when initiated before day 14 of ARDS, with a number needed to treat of four (Crit. Care Med. 2009;37:1594-603). No significant differences in the rate of neuromyopathy or other major events were seen between the treatment and control groups. "However, we have to be cautious," Dr. Pastores said of the findings. "There are limitations in all of the systematic reviews on this topic. There are marked differences in study designs, patient characteristics, varying doses of steroids that were used, dosing strategies, and duration of therapy."

In 2008, a task force convened by the American College of Critical Care Medicine concluded that moderate-dose glucocorticoids should be considered in patients with early severe ARDS (PaO₂/FiO₂ of less than 200) and before day 14 in patients with unresolving ARDS (Crit. Care Med. 2008;36:1937-49). "We could not come to a definitive conclusion or recommendation on patients with less-severe ALI," said Dr. Pastores, who was a member of the task force. "Keep in mind that the recommendation is based on level 2B evidence for a mortality benefit. It’s a weak recommendation because the quality of the evidence was moderate; it wasn’t very strong because we didn’t have enough good randomized, controlled trials. For reduction in duration of mechanical ventilation, however, the evidence is strong (1B), with the aggregate of data showing a doubling of extubation, in comparison to controls, by day 7 and 14."

"Prolonged glucocorticoid treatment substantially and significantly improves meaningful patient-centered outcomes."

He went on to note that physicians should give steroids in conjunction with infection surveillance, "avoiding neuromuscular blockers if you can, and being concerned about the phenomenon of rebound inflammation if you stop steroids abruptly."

Inhaled nitric oxide has also been studied as a nonventilatory strategy in ALI/ARDS. A Cochrane review of 13 randomized, controlled trials involving 1,303 patients found no significant effect with this approach in overall mortality, but did show a transient improvement in oxygenation in the first 24 hours. The review also found that inhaled nitric oxide had no significant effect on duration of ventilation, ventilator-free days, and ICU and hospital length of stay. An increased risk of renal impairment among adults was also noted (Cochrane Database Syst. Rev. 2010 Oct. 23 [doi:10.1002/14651858.CD002787.pub2]).

"The conclusion from this meta-analysis was that there was no mortality benefit, and in fact [nitric oxide] might even be harmful," Dr. Pastores said.

Intriguing findings on the use of neuromuscular blockers in severe, early ARDS were presented in 2010 by French researchers after a multicenter trial of 340 patients who were randomized to IV cisatracurium infusion or placebo for 48 hours (N. Engl. J. Med. 2010;363:1107-16). The primary outcome was 90-day mortality and ventilator-free days.

Patients in the treatment group had lower 90-day mortality and more ventilator-free days, compared with those in the placebo group.

"Neuromuscular blockers may facilitate lung-protective ventilation in this patient population by improving patient-ventilator synchrony," Dr. Pastores said. "They may also improve chest wall compliance and reduce oxygen consumption, and possibly cause a decrease in lung or systemic inflammation."

The study’s limitations were that "it only involved cisatracurium and therefore may not apply to other neuromuscular blockers. There were also no data on conditions known to antagonize or potentiate neuromuscular blockers," he added.

Another treatment strategy for ALI/ARDS – the routine use of aerosolized beta₂-agonists – cannot be recommended at this time because of the results of a recent trial in which patients were randomized to 5-mg aerosolized albuterol or saline placebo every 4 hours for up to 10 days. The primary outcome was ventilator-free days. "The trial had to be stopped for futility because there was no improvement in ventilator-free days," Dr. Pastores said. "In fact, there was a suggestion of a slight trend of increasing morbidity among patients in the treatment group. The investigators theorized that the lung-protective ventilation and conservative fluid management reduced lung injury and water to the extent that additional lung fluid clearance with beta₂-agonists had no additional beneficial effect."

"This is probably the most controversial topic in acute lung injury and ARDS."

The role of pharmaconutrition has also been studied in this patient population. According to Dr. Pastores, three previous trials of continuous omega-3 enteral feeds showed improved PaO₂/FiO₂ ratio, shorter ventilator time and ICU stay, and fewer organ failures and lower mortality. However, a more recent randomized, controlled trial of 272 adults found that twice-daily administration of omega-3 fatty acids plus antioxidant supplementation did not improve ventilator-free days or other clinical outcomes (JAMA 2011;306:1574-81). "There was some suggestion that perhaps it was harmful to these patients," Dr. Pastores said. For example, 60-day hospital mortality was higher among the patients in the treatment group, compared with those in the placebo group (27% vs. 16%, respectively; P = .054).

Future nonventilatory therapies that might hold promise for patients with ALI/ARDS, he said, include inhaled protein C, tissue factor inhibition, statins, and the extended use of steroids in severe community-acquired pneumonia.

Dr. Pastores disclosed that he has received grant support from Altor Bioscience Corp. and from Spectral Diagnostics Inc.

HONOLULU – The jury is still out on whether patients with acute lung injury and adult respiratory distress syndrome derive any benefit from the use of corticosteroids, according to Dr. Stephen M. Pastores.

"This is probably the most controversial topic in acute lung injury and ARDS," Dr. Pastores of the department of anesthesiology and critical care medicine at Memorial Sloan-Kettering Cancer Center, New York, said at the annual meeting of the American College of Chest Physicians. "For those of us who might believe in the use of corticosteroids, we base that on the pretty good evidence that they are effective anti-inflammatory agents. There have been a few positive trials for the use of prolonged corticosteroid treatment in ALI [acute lung injury]-ARDS, with significantly less side effects in comparison to older trials investigating massive doses," such as methylprednisolone 120 mg/kg per day.

Renewed interest in this topic came about 4 years ago, he said, after publication of a study that evaluated the effects of low-dose methylprednisolone infusion on lung function in 91 patients with early ARDS (within 72 hours). About two-thirds of the patients (66%) had sepsis (Chest 2007;131:954-63). Patients were randomized to receive methylprednisolone infusion (1 mg/kg per day) or placebo for up to 28 days. The primary end point was a 1-point reduction in the lung injury score or successful extubation by day 7.

"An important piece of this study was that [the researchers] did regular infection surveillance with regular bronchoscopies, and they avoided the use of neuromuscular blockers," said Dr. Pastores, who is also professor of medicine and anesthesiology at Cornell University in New York.

The researchers found that patients in the treatment arm had a greater than 1-point drop in their lung injury score. The researchers also found no significant increase in complications such as infection, "and because they avoided neuromuscular blockers, there was hardly any incidence of neuromuscular weakness or neuropathy," Dr. Pastores said.

In a subsequent review of five trials on the use of steroids for the treatment of ARDS that enrolled a total of 518 patients, Dr. Pastores and his associates observed that the steroid dosing and treatment duration were different across the trials, and that infection surveillance was not routine (Intensive Care Med. 2008;34:61-9). However, three of the trials in which patients received steroids before day 14 of ARDS found a slight benefit to this approach, with a number needed to treat of six.

"If you look at the patients who were randomized to the methylprednisolone arm, the mortality rate was 24%, which is about 16% less than the control arm that did not receive steroids," Dr. Pastores said of the 245 patients in these three trials. "From this review, we concluded that prolonged glucocorticoid treatment substantially and significantly improves meaningful patient-centered outcomes in terms of less ventilator days, less days in the ICU, and perhaps a distinct survival benefit – only in patients who have steroids early in the course of acute lung injury, however."

A more recent systematic review that factored in additional trials concluded that prolonged glucocorticoid treatment has a "distinct survival benefit" when initiated before day 14 of ARDS, with a number needed to treat of four (Crit. Care Med. 2009;37:1594-603). No significant differences in the rate of neuromyopathy or other major events were seen between the treatment and control groups. "However, we have to be cautious," Dr. Pastores said of the findings. "There are limitations in all of the systematic reviews on this topic. There are marked differences in study designs, patient characteristics, varying doses of steroids that were used, dosing strategies, and duration of therapy."

In 2008, a task force convened by the American College of Critical Care Medicine concluded that moderate-dose glucocorticoids should be considered in patients with early severe ARDS (PaO₂/FiO₂ of less than 200) and before day 14 in patients with unresolving ARDS (Crit. Care Med. 2008;36:1937-49). "We could not come to a definitive conclusion or recommendation on patients with less-severe ALI," said Dr. Pastores, who was a member of the task force. "Keep in mind that the recommendation is based on level 2B evidence for a mortality benefit. It’s a weak recommendation because the quality of the evidence was moderate; it wasn’t very strong because we didn’t have enough good randomized, controlled trials. For reduction in duration of mechanical ventilation, however, the evidence is strong (1B), with the aggregate of data showing a doubling of extubation, in comparison to controls, by day 7 and 14."

"Prolonged glucocorticoid treatment substantially and significantly improves meaningful patient-centered outcomes."

He went on to note that physicians should give steroids in conjunction with infection surveillance, "avoiding neuromuscular blockers if you can, and being concerned about the phenomenon of rebound inflammation if you stop steroids abruptly."

Inhaled nitric oxide has also been studied as a nonventilatory strategy in ALI/ARDS. A Cochrane review of 13 randomized, controlled trials involving 1,303 patients found no significant effect with this approach in overall mortality, but did show a transient improvement in oxygenation in the first 24 hours. The review also found that inhaled nitric oxide had no significant effect on duration of ventilation, ventilator-free days, and ICU and hospital length of stay. An increased risk of renal impairment among adults was also noted (Cochrane Database Syst. Rev. 2010 Oct. 23 [doi:10.1002/14651858.CD002787.pub2]).

"The conclusion from this meta-analysis was that there was no mortality benefit, and in fact [nitric oxide] might even be harmful," Dr. Pastores said.

Intriguing findings on the use of neuromuscular blockers in severe, early ARDS were presented in 2010 by French researchers after a multicenter trial of 340 patients who were randomized to IV cisatracurium infusion or placebo for 48 hours (N. Engl. J. Med. 2010;363:1107-16). The primary outcome was 90-day mortality and ventilator-free days.

Patients in the treatment group had lower 90-day mortality and more ventilator-free days, compared with those in the placebo group.

"Neuromuscular blockers may facilitate lung-protective ventilation in this patient population by improving patient-ventilator synchrony," Dr. Pastores said. "They may also improve chest wall compliance and reduce oxygen consumption, and possibly cause a decrease in lung or systemic inflammation."

The study’s limitations were that "it only involved cisatracurium and therefore may not apply to other neuromuscular blockers. There were also no data on conditions known to antagonize or potentiate neuromuscular blockers," he added.

Another treatment strategy for ALI/ARDS – the routine use of aerosolized beta₂-agonists – cannot be recommended at this time because of the results of a recent trial in which patients were randomized to 5-mg aerosolized albuterol or saline placebo every 4 hours for up to 10 days. The primary outcome was ventilator-free days. "The trial had to be stopped for futility because there was no improvement in ventilator-free days," Dr. Pastores said. "In fact, there was a suggestion of a slight trend of increasing morbidity among patients in the treatment group. The investigators theorized that the lung-protective ventilation and conservative fluid management reduced lung injury and water to the extent that additional lung fluid clearance with beta₂-agonists had no additional beneficial effect."

"This is probably the most controversial topic in acute lung injury and ARDS."

The role of pharmaconutrition has also been studied in this patient population. According to Dr. Pastores, three previous trials of continuous omega-3 enteral feeds showed improved PaO₂/FiO₂ ratio, shorter ventilator time and ICU stay, and fewer organ failures and lower mortality. However, a more recent randomized, controlled trial of 272 adults found that twice-daily administration of omega-3 fatty acids plus antioxidant supplementation did not improve ventilator-free days or other clinical outcomes (JAMA 2011;306:1574-81). "There was some suggestion that perhaps it was harmful to these patients," Dr. Pastores said. For example, 60-day hospital mortality was higher among the patients in the treatment group, compared with those in the placebo group (27% vs. 16%, respectively; P = .054).

Future nonventilatory therapies that might hold promise for patients with ALI/ARDS, he said, include inhaled protein C, tissue factor inhibition, statins, and the extended use of steroids in severe community-acquired pneumonia.

Dr. Pastores disclosed that he has received grant support from Altor Bioscience Corp. and from Spectral Diagnostics Inc.

HONOLULU – The jury is still out on whether patients with acute lung injury and adult respiratory distress syndrome derive any benefit from the use of corticosteroids, according to Dr. Stephen M. Pastores.

"This is probably the most controversial topic in acute lung injury and ARDS," Dr. Pastores of the department of anesthesiology and critical care medicine at Memorial Sloan-Kettering Cancer Center, New York, said at the annual meeting of the American College of Chest Physicians. "For those of us who might believe in the use of corticosteroids, we base that on the pretty good evidence that they are effective anti-inflammatory agents. There have been a few positive trials for the use of prolonged corticosteroid treatment in ALI [acute lung injury]-ARDS, with significantly less side effects in comparison to older trials investigating massive doses," such as methylprednisolone 120 mg/kg per day.

Renewed interest in this topic came about 4 years ago, he said, after publication of a study that evaluated the effects of low-dose methylprednisolone infusion on lung function in 91 patients with early ARDS (within 72 hours). About two-thirds of the patients (66%) had sepsis (Chest 2007;131:954-63). Patients were randomized to receive methylprednisolone infusion (1 mg/kg per day) or placebo for up to 28 days. The primary end point was a 1-point reduction in the lung injury score or successful extubation by day 7.

"An important piece of this study was that [the researchers] did regular infection surveillance with regular bronchoscopies, and they avoided the use of neuromuscular blockers," said Dr. Pastores, who is also professor of medicine and anesthesiology at Cornell University in New York.

The researchers found that patients in the treatment arm had a greater than 1-point drop in their lung injury score. The researchers also found no significant increase in complications such as infection, "and because they avoided neuromuscular blockers, there was hardly any incidence of neuromuscular weakness or neuropathy," Dr. Pastores said.

In a subsequent review of five trials on the use of steroids for the treatment of ARDS that enrolled a total of 518 patients, Dr. Pastores and his associates observed that the steroid dosing and treatment duration were different across the trials, and that infection surveillance was not routine (Intensive Care Med. 2008;34:61-9). However, three of the trials in which patients received steroids before day 14 of ARDS found a slight benefit to this approach, with a number needed to treat of six.

"If you look at the patients who were randomized to the methylprednisolone arm, the mortality rate was 24%, which is about 16% less than the control arm that did not receive steroids," Dr. Pastores said of the 245 patients in these three trials. "From this review, we concluded that prolonged glucocorticoid treatment substantially and significantly improves meaningful patient-centered outcomes in terms of less ventilator days, less days in the ICU, and perhaps a distinct survival benefit – only in patients who have steroids early in the course of acute lung injury, however."

A more recent systematic review that factored in additional trials concluded that prolonged glucocorticoid treatment has a "distinct survival benefit" when initiated before day 14 of ARDS, with a number needed to treat of four (Crit. Care Med. 2009;37:1594-603). No significant differences in the rate of neuromyopathy or other major events were seen between the treatment and control groups. "However, we have to be cautious," Dr. Pastores said of the findings. "There are limitations in all of the systematic reviews on this topic. There are marked differences in study designs, patient characteristics, varying doses of steroids that were used, dosing strategies, and duration of therapy."

In 2008, a task force convened by the American College of Critical Care Medicine concluded that moderate-dose glucocorticoids should be considered in patients with early severe ARDS (PaO₂/FiO₂ of less than 200) and before day 14 in patients with unresolving ARDS (Crit. Care Med. 2008;36:1937-49). "We could not come to a definitive conclusion or recommendation on patients with less-severe ALI," said Dr. Pastores, who was a member of the task force. "Keep in mind that the recommendation is based on level 2B evidence for a mortality benefit. It’s a weak recommendation because the quality of the evidence was moderate; it wasn’t very strong because we didn’t have enough good randomized, controlled trials. For reduction in duration of mechanical ventilation, however, the evidence is strong (1B), with the aggregate of data showing a doubling of extubation, in comparison to controls, by day 7 and 14."

"Prolonged glucocorticoid treatment substantially and significantly improves meaningful patient-centered outcomes."

He went on to note that physicians should give steroids in conjunction with infection surveillance, "avoiding neuromuscular blockers if you can, and being concerned about the phenomenon of rebound inflammation if you stop steroids abruptly."

Inhaled nitric oxide has also been studied as a nonventilatory strategy in ALI/ARDS. A Cochrane review of 13 randomized, controlled trials involving 1,303 patients found no significant effect with this approach in overall mortality, but did show a transient improvement in oxygenation in the first 24 hours. The review also found that inhaled nitric oxide had no significant effect on duration of ventilation, ventilator-free days, and ICU and hospital length of stay. An increased risk of renal impairment among adults was also noted (Cochrane Database Syst. Rev. 2010 Oct. 23 [doi:10.1002/14651858.CD002787.pub2]).

"The conclusion from this meta-analysis was that there was no mortality benefit, and in fact [nitric oxide] might even be harmful," Dr. Pastores said.

Intriguing findings on the use of neuromuscular blockers in severe, early ARDS were presented in 2010 by French researchers after a multicenter trial of 340 patients who were randomized to IV cisatracurium infusion or placebo for 48 hours (N. Engl. J. Med. 2010;363:1107-16). The primary outcome was 90-day mortality and ventilator-free days.

Patients in the treatment group had lower 90-day mortality and more ventilator-free days, compared with those in the placebo group.

"Neuromuscular blockers may facilitate lung-protective ventilation in this patient population by improving patient-ventilator synchrony," Dr. Pastores said. "They may also improve chest wall compliance and reduce oxygen consumption, and possibly cause a decrease in lung or systemic inflammation."

The study’s limitations were that "it only involved cisatracurium and therefore may not apply to other neuromuscular blockers. There were also no data on conditions known to antagonize or potentiate neuromuscular blockers," he added.

Another treatment strategy for ALI/ARDS – the routine use of aerosolized beta₂-agonists – cannot be recommended at this time because of the results of a recent trial in which patients were randomized to 5-mg aerosolized albuterol or saline placebo every 4 hours for up to 10 days. The primary outcome was ventilator-free days. "The trial had to be stopped for futility because there was no improvement in ventilator-free days," Dr. Pastores said. "In fact, there was a suggestion of a slight trend of increasing morbidity among patients in the treatment group. The investigators theorized that the lung-protective ventilation and conservative fluid management reduced lung injury and water to the extent that additional lung fluid clearance with beta₂-agonists had no additional beneficial effect."

"This is probably the most controversial topic in acute lung injury and ARDS."

The role of pharmaconutrition has also been studied in this patient population. According to Dr. Pastores, three previous trials of continuous omega-3 enteral feeds showed improved PaO₂/FiO₂ ratio, shorter ventilator time and ICU stay, and fewer organ failures and lower mortality. However, a more recent randomized, controlled trial of 272 adults found that twice-daily administration of omega-3 fatty acids plus antioxidant supplementation did not improve ventilator-free days or other clinical outcomes (JAMA 2011;306:1574-81). "There was some suggestion that perhaps it was harmful to these patients," Dr. Pastores said. For example, 60-day hospital mortality was higher among the patients in the treatment group, compared with those in the placebo group (27% vs. 16%, respectively; P = .054).

Future nonventilatory therapies that might hold promise for patients with ALI/ARDS, he said, include inhaled protein C, tissue factor inhibition, statins, and the extended use of steroids in severe community-acquired pneumonia.

Dr. Pastores disclosed that he has received grant support from Altor Bioscience Corp. and from Spectral Diagnostics Inc.

HONOLULU – Both active smoking and secondhand smoke exposure are associated with increased susceptibility to acute lung injury in patients following blunt trauma, results from an ongoing cohort study demonstrated.

The researchers, led by Dr. Carolyn S. Calfee of the pulmonary and critical care division at the University of California, San Francisco, measured serum cotinine to quantify exposure to cigarette smoke, an approach that "transforms the field, because it’s now possible to quantify cigarette smoke exposure," coinvestigator Dr. Michael A. Matthay said at the annual meeting of the American College of Chest Physicians.

The researchers set out to investigate if exposure to cigarette smoke increases susceptibility to acute lung injury among trauma patients. They used serum cotinine testing because obtaining a reliable smoking history in the ICU "is difficult," said Dr. Matthay, professor of medicine and anesthesia at UCSF. "The patients are ventilated and there is a high mortality rate, and the family may not be able to give you a good smoking history. Therefore, Dr. Calfee is using biomarkers to measure both active and passive cigarette smoke exposure."

Serum cotinine has been shown in several studies to accurately identify both active and passive exposure to cigarette smoke. "These levels are very well validated, so now you can not only know if they’ve been exposed to cigarette smoke but you can put them in the category of secondhand or primary smoke exposure," Dr. Matthay said.

Earlier this year, researchers including Dr. Calfee reported that serum cotinine levels reflect active smoking and secondhand smoke exposure in nonsmokers in the ICU (Crit. Care Med. 2011;39:40-5). "We also found that if you use the urine for NNAL, a metabolite of nitrosamines produced in the tobacco-curing process, you can quantify the amount of cigarette smoke exposure in patients over several weeks," Dr. Matthay said.

For the ongoing cohort study, the researchers collected blood from 144 patients who presented to emergency department of San Francisco General Hospital with severe trauma caused by events that included motor vehicle accidents, falls, and assaults. They had blood drawn via waiver of consent within 5 minutes of arrival to the ED. Serum cotinine was measured from this sample. Follow-up consent was obtained from the patient or surrogate.

Active smokers were defined as those having a serum cotinine level of 3.08 ng/mL or greater, whereas passive smokers were defined as those with a cotinine level greater than zero but less than 3.08 ng/mL.

Of the 144 patients, 62 had acute lung injury (43%) and 82 (57%) did not. Patients in the acute lung injury group were significantly younger than their counterparts in the nonacute lung injury group (mean age, 44 vs. 52 years) but otherwise shared similar characteristics, including injury severity and history of alcohol abuse.

According to results from the serum cotinine testing, 44% of patients were categorized as active smokers, 37% were categorized as passive smokers, and only 19% were categorized as unexposed to smoke. "Imagine this in San Francisco, where only about 15%" of the population smoke, Dr. Matthay commented. In the ED, however, "in patients with blunt trauma, it’s the reverse: We have 81% who are exposed to some level of smoke."

"Now you can not only know if [patients] have been exposed to cigarette smoke but you can put them in the category of secondhand or primary smoke exposure."

The researchers observed that increased serum cotinine levels were associated with the development of acute lung injury. "This includes the patients with passive secondhand smoke exposure above the median level in the cohort, not just active exposure," Dr. Matthay said. "The relationship between cotinine levels and acute lung injury persisted after multivariate analysis."

He noted that the patients’ serum cotinine levels showed the inadequacy of the chart history. For example, 53 patients were defined as nonsmokers based on chart history, but many "had plasma cotinine levels that were elevated."

Dr. Matthay emphasized that many questions about the relationship between serum cotinine levels and acute lung injury remain. "The mechanism of association between exposure and acute lung injury in blunt trauma is still unknown," he said.

Dr. Calfee is currently carrying out an analysis of cigarette smoke exposure and acute lung injury in mixed medical-surgical patients in collaboration with Dr. Lorraine Ware at Vanderbilt University in Nashville, Tenn., he said. In addition, Dr. Calfee and colleagues are measuring NNAL in 489 patients enrolled in trials being conducted by the National Heart, Lung, and Blood Institute’s Acute Respiratory Distress Syndrome Network.

"Biomarkers of endothelial and epithelial injury are also being studied in patients with acute lung injury, to determine if differences exist between smokers and nonsmokers," Dr. Matthay said.

Dr. Matthay disclosed that this research, led by Dr. Calfee, is supported by the NHLBI and the Flight Attendant Medical Research Institute.

HONOLULU – Both active smoking and secondhand smoke exposure are associated with increased susceptibility to acute lung injury in patients following blunt trauma, results from an ongoing cohort study demonstrated.

The researchers, led by Dr. Carolyn S. Calfee of the pulmonary and critical care division at the University of California, San Francisco, measured serum cotinine to quantify exposure to cigarette smoke, an approach that "transforms the field, because it’s now possible to quantify cigarette smoke exposure," coinvestigator Dr. Michael A. Matthay said at the annual meeting of the American College of Chest Physicians.

The researchers set out to investigate if exposure to cigarette smoke increases susceptibility to acute lung injury among trauma patients. They used serum cotinine testing because obtaining a reliable smoking history in the ICU "is difficult," said Dr. Matthay, professor of medicine and anesthesia at UCSF. "The patients are ventilated and there is a high mortality rate, and the family may not be able to give you a good smoking history. Therefore, Dr. Calfee is using biomarkers to measure both active and passive cigarette smoke exposure."

Serum cotinine has been shown in several studies to accurately identify both active and passive exposure to cigarette smoke. "These levels are very well validated, so now you can not only know if they’ve been exposed to cigarette smoke but you can put them in the category of secondhand or primary smoke exposure," Dr. Matthay said.

Earlier this year, researchers including Dr. Calfee reported that serum cotinine levels reflect active smoking and secondhand smoke exposure in nonsmokers in the ICU (Crit. Care Med. 2011;39:40-5). "We also found that if you use the urine for NNAL, a metabolite of nitrosamines produced in the tobacco-curing process, you can quantify the amount of cigarette smoke exposure in patients over several weeks," Dr. Matthay said.

For the ongoing cohort study, the researchers collected blood from 144 patients who presented to emergency department of San Francisco General Hospital with severe trauma caused by events that included motor vehicle accidents, falls, and assaults. They had blood drawn via waiver of consent within 5 minutes of arrival to the ED. Serum cotinine was measured from this sample. Follow-up consent was obtained from the patient or surrogate.

Active smokers were defined as those having a serum cotinine level of 3.08 ng/mL or greater, whereas passive smokers were defined as those with a cotinine level greater than zero but less than 3.08 ng/mL.

Of the 144 patients, 62 had acute lung injury (43%) and 82 (57%) did not. Patients in the acute lung injury group were significantly younger than their counterparts in the nonacute lung injury group (mean age, 44 vs. 52 years) but otherwise shared similar characteristics, including injury severity and history of alcohol abuse.

According to results from the serum cotinine testing, 44% of patients were categorized as active smokers, 37% were categorized as passive smokers, and only 19% were categorized as unexposed to smoke. "Imagine this in San Francisco, where only about 15%" of the population smoke, Dr. Matthay commented. In the ED, however, "in patients with blunt trauma, it’s the reverse: We have 81% who are exposed to some level of smoke."

"Now you can not only know if [patients] have been exposed to cigarette smoke but you can put them in the category of secondhand or primary smoke exposure."

The researchers observed that increased serum cotinine levels were associated with the development of acute lung injury. "This includes the patients with passive secondhand smoke exposure above the median level in the cohort, not just active exposure," Dr. Matthay said. "The relationship between cotinine levels and acute lung injury persisted after multivariate analysis."

He noted that the patients’ serum cotinine levels showed the inadequacy of the chart history. For example, 53 patients were defined as nonsmokers based on chart history, but many "had plasma cotinine levels that were elevated."

Dr. Matthay emphasized that many questions about the relationship between serum cotinine levels and acute lung injury remain. "The mechanism of association between exposure and acute lung injury in blunt trauma is still unknown," he said.

Dr. Calfee is currently carrying out an analysis of cigarette smoke exposure and acute lung injury in mixed medical-surgical patients in collaboration with Dr. Lorraine Ware at Vanderbilt University in Nashville, Tenn., he said. In addition, Dr. Calfee and colleagues are measuring NNAL in 489 patients enrolled in trials being conducted by the National Heart, Lung, and Blood Institute’s Acute Respiratory Distress Syndrome Network.

"Biomarkers of endothelial and epithelial injury are also being studied in patients with acute lung injury, to determine if differences exist between smokers and nonsmokers," Dr. Matthay said.

Dr. Matthay disclosed that this research, led by Dr. Calfee, is supported by the NHLBI and the Flight Attendant Medical Research Institute.

HONOLULU – Both active smoking and secondhand smoke exposure are associated with increased susceptibility to acute lung injury in patients following blunt trauma, results from an ongoing cohort study demonstrated.

The researchers, led by Dr. Carolyn S. Calfee of the pulmonary and critical care division at the University of California, San Francisco, measured serum cotinine to quantify exposure to cigarette smoke, an approach that "transforms the field, because it’s now possible to quantify cigarette smoke exposure," coinvestigator Dr. Michael A. Matthay said at the annual meeting of the American College of Chest Physicians.

The researchers set out to investigate if exposure to cigarette smoke increases susceptibility to acute lung injury among trauma patients. They used serum cotinine testing because obtaining a reliable smoking history in the ICU "is difficult," said Dr. Matthay, professor of medicine and anesthesia at UCSF. "The patients are ventilated and there is a high mortality rate, and the family may not be able to give you a good smoking history. Therefore, Dr. Calfee is using biomarkers to measure both active and passive cigarette smoke exposure."

Serum cotinine has been shown in several studies to accurately identify both active and passive exposure to cigarette smoke. "These levels are very well validated, so now you can not only know if they’ve been exposed to cigarette smoke but you can put them in the category of secondhand or primary smoke exposure," Dr. Matthay said.

Earlier this year, researchers including Dr. Calfee reported that serum cotinine levels reflect active smoking and secondhand smoke exposure in nonsmokers in the ICU (Crit. Care Med. 2011;39:40-5). "We also found that if you use the urine for NNAL, a metabolite of nitrosamines produced in the tobacco-curing process, you can quantify the amount of cigarette smoke exposure in patients over several weeks," Dr. Matthay said.

For the ongoing cohort study, the researchers collected blood from 144 patients who presented to emergency department of San Francisco General Hospital with severe trauma caused by events that included motor vehicle accidents, falls, and assaults. They had blood drawn via waiver of consent within 5 minutes of arrival to the ED. Serum cotinine was measured from this sample. Follow-up consent was obtained from the patient or surrogate.

Active smokers were defined as those having a serum cotinine level of 3.08 ng/mL or greater, whereas passive smokers were defined as those with a cotinine level greater than zero but less than 3.08 ng/mL.

Of the 144 patients, 62 had acute lung injury (43%) and 82 (57%) did not. Patients in the acute lung injury group were significantly younger than their counterparts in the nonacute lung injury group (mean age, 44 vs. 52 years) but otherwise shared similar characteristics, including injury severity and history of alcohol abuse.

According to results from the serum cotinine testing, 44% of patients were categorized as active smokers, 37% were categorized as passive smokers, and only 19% were categorized as unexposed to smoke. "Imagine this in San Francisco, where only about 15%" of the population smoke, Dr. Matthay commented. In the ED, however, "in patients with blunt trauma, it’s the reverse: We have 81% who are exposed to some level of smoke."

"Now you can not only know if [patients] have been exposed to cigarette smoke but you can put them in the category of secondhand or primary smoke exposure."

The researchers observed that increased serum cotinine levels were associated with the development of acute lung injury. "This includes the patients with passive secondhand smoke exposure above the median level in the cohort, not just active exposure," Dr. Matthay said. "The relationship between cotinine levels and acute lung injury persisted after multivariate analysis."

He noted that the patients’ serum cotinine levels showed the inadequacy of the chart history. For example, 53 patients were defined as nonsmokers based on chart history, but many "had plasma cotinine levels that were elevated."

Dr. Matthay emphasized that many questions about the relationship between serum cotinine levels and acute lung injury remain. "The mechanism of association between exposure and acute lung injury in blunt trauma is still unknown," he said.

Dr. Calfee is currently carrying out an analysis of cigarette smoke exposure and acute lung injury in mixed medical-surgical patients in collaboration with Dr. Lorraine Ware at Vanderbilt University in Nashville, Tenn., he said. In addition, Dr. Calfee and colleagues are measuring NNAL in 489 patients enrolled in trials being conducted by the National Heart, Lung, and Blood Institute’s Acute Respiratory Distress Syndrome Network.

"Biomarkers of endothelial and epithelial injury are also being studied in patients with acute lung injury, to determine if differences exist between smokers and nonsmokers," Dr. Matthay said.

Dr. Matthay disclosed that this research, led by Dr. Calfee, is supported by the NHLBI and the Flight Attendant Medical Research Institute.

HONOLULU – A large, long-term study suggests that obesity is significantly associated with airway hyperresponsiveness, and therefore it might be a risk factor for asthma.

"There is definitely a relationship between obesity and the risk of having airway hyperresponsiveness, and maybe asthma," lead investigator Dr. Manon Labrecque said during an interview in advance of annual meeting of the American College of Chest Physicians, where the study was presented during a poster session.

"But how is it mediated? What is the explanation? It seems to be related to the mechanical effect of obesity on the volume of the lungs, [but] some other analysis of the data will permit us to better understand," Dr. Labrecque said.

The investigators reviewed the medical records of 17,195 patients with a mean age of 48 years who were referred to the Hôpital du Sacré-Coeur de Montréal, Canada, for confirmation of an asthma diagnosis between 1980 and 2000.

They then analyzed the data in order to classify patients as having obesity class 1 (body mass index of 30-34.9 kg/m²), class 2 (BMI of 35-39.9 kg/m²), or class 3 (BMI more than 40 kg/m²), and compared them with normal-weight patients (those with a BMI between 18.5 and 25 kg/m²). To define airway hyperresponsiveness, the study used a standard criterion: methacholine challenge cutoff of less than 8 mg/mL for causing a 20% fall in FEV₁ (forced expiratory volume in 1 second).

Of the 17,195 patients, 5,623 (33%) demonstrated airway hyperresponsiveness. The relationship between BMI and airway hyperresponsiveness increased in stepwise fashion, from an odds ratio (OR) of 1.15 for obesity class 1 to an OR of 1.46 for obesity class 2 and an OR of 1.50 for obesity class 3.

"We need more analysis to see if the effect of obesity on airway hyperresponsiveness is still there when we correct for lung volume [measures] like the FEV₁," said Dr. Labrecque, a pulmonologist at the hospital who is also affiliated with the department of medicine at the University of Montreal. "If the relation between BMI and airway hyperresponsiveness disappears after this correction, that could mean that it is not the fat itself that is responsible for the risk of asthma, but its mechanical effect on the lung’s volume."

In their poster, the researchers stated that if asthma is added to the list of conditions related to obesity, "then reducing the prevalence of obesity could be expected to produce even greater public health benefits than are currently estimated."

Dr. Labrecque said that she had no relevant financial conflicts to disclose.

HONOLULU – A large, long-term study suggests that obesity is significantly associated with airway hyperresponsiveness, and therefore it might be a risk factor for asthma.

"There is definitely a relationship between obesity and the risk of having airway hyperresponsiveness, and maybe asthma," lead investigator Dr. Manon Labrecque said during an interview in advance of annual meeting of the American College of Chest Physicians, where the study was presented during a poster session.

"But how is it mediated? What is the explanation? It seems to be related to the mechanical effect of obesity on the volume of the lungs, [but] some other analysis of the data will permit us to better understand," Dr. Labrecque said.

The investigators reviewed the medical records of 17,195 patients with a mean age of 48 years who were referred to the Hôpital du Sacré-Coeur de Montréal, Canada, for confirmation of an asthma diagnosis between 1980 and 2000.

They then analyzed the data in order to classify patients as having obesity class 1 (body mass index of 30-34.9 kg/m²), class 2 (BMI of 35-39.9 kg/m²), or class 3 (BMI more than 40 kg/m²), and compared them with normal-weight patients (those with a BMI between 18.5 and 25 kg/m²). To define airway hyperresponsiveness, the study used a standard criterion: methacholine challenge cutoff of less than 8 mg/mL for causing a 20% fall in FEV₁ (forced expiratory volume in 1 second).

Of the 17,195 patients, 5,623 (33%) demonstrated airway hyperresponsiveness. The relationship between BMI and airway hyperresponsiveness increased in stepwise fashion, from an odds ratio (OR) of 1.15 for obesity class 1 to an OR of 1.46 for obesity class 2 and an OR of 1.50 for obesity class 3.

"We need more analysis to see if the effect of obesity on airway hyperresponsiveness is still there when we correct for lung volume [measures] like the FEV₁," said Dr. Labrecque, a pulmonologist at the hospital who is also affiliated with the department of medicine at the University of Montreal. "If the relation between BMI and airway hyperresponsiveness disappears after this correction, that could mean that it is not the fat itself that is responsible for the risk of asthma, but its mechanical effect on the lung’s volume."

In their poster, the researchers stated that if asthma is added to the list of conditions related to obesity, "then reducing the prevalence of obesity could be expected to produce even greater public health benefits than are currently estimated."

Dr. Labrecque said that she had no relevant financial conflicts to disclose.

HONOLULU – A large, long-term study suggests that obesity is significantly associated with airway hyperresponsiveness, and therefore it might be a risk factor for asthma.

"There is definitely a relationship between obesity and the risk of having airway hyperresponsiveness, and maybe asthma," lead investigator Dr. Manon Labrecque said during an interview in advance of annual meeting of the American College of Chest Physicians, where the study was presented during a poster session.

"But how is it mediated? What is the explanation? It seems to be related to the mechanical effect of obesity on the volume of the lungs, [but] some other analysis of the data will permit us to better understand," Dr. Labrecque said.

The investigators reviewed the medical records of 17,195 patients with a mean age of 48 years who were referred to the Hôpital du Sacré-Coeur de Montréal, Canada, for confirmation of an asthma diagnosis between 1980 and 2000.

They then analyzed the data in order to classify patients as having obesity class 1 (body mass index of 30-34.9 kg/m²), class 2 (BMI of 35-39.9 kg/m²), or class 3 (BMI more than 40 kg/m²), and compared them with normal-weight patients (those with a BMI between 18.5 and 25 kg/m²). To define airway hyperresponsiveness, the study used a standard criterion: methacholine challenge cutoff of less than 8 mg/mL for causing a 20% fall in FEV₁ (forced expiratory volume in 1 second).

Of the 17,195 patients, 5,623 (33%) demonstrated airway hyperresponsiveness. The relationship between BMI and airway hyperresponsiveness increased in stepwise fashion, from an odds ratio (OR) of 1.15 for obesity class 1 to an OR of 1.46 for obesity class 2 and an OR of 1.50 for obesity class 3.

"We need more analysis to see if the effect of obesity on airway hyperresponsiveness is still there when we correct for lung volume [measures] like the FEV₁," said Dr. Labrecque, a pulmonologist at the hospital who is also affiliated with the department of medicine at the University of Montreal. "If the relation between BMI and airway hyperresponsiveness disappears after this correction, that could mean that it is not the fat itself that is responsible for the risk of asthma, but its mechanical effect on the lung’s volume."

In their poster, the researchers stated that if asthma is added to the list of conditions related to obesity, "then reducing the prevalence of obesity could be expected to produce even greater public health benefits than are currently estimated."

Dr. Labrecque said that she had no relevant financial conflicts to disclose.