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Patients with an osteoporotic hip fracture suffer from profound morbidity and are at a heightened risk of death. It is therefore essential that they receive treatment with a bisphosphonate known to modify the subsequent risk of fracture at any site—eg, alendronate (Fosamax), risedronate (Actonel), or zoledronic acid (Reclast).

However, there is concern that starting a bisphosphonate too soon after surgery could disrupt bone remodeling and delay fracture repair.

Only one clinical study addressed the timing of bisphosphonate therapy after hip fracture repair. In this study, Eriksen et al¹ performed a post hoc analysis of data from the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT)² and concluded that the optimal time to give intravenous zoledronic acid is 2 to 12 weeks after surgical repair of the fracture.

In a frail, elderly patient with comorbidities, a single intravenous 5-mg dose of zoledronic acid guarantees adequate treatment, obviating issues of poor compliance and oral absorption and loss to follow-up. Sufficient levels of vitamin D and calcium should be ensured.

THE EVIDENCE

The original HORIZON-RFT study,² published in 2007, compared intravenous zoledronic acid against placebo in elderly patients with osteoporotic hip fracture. Most of the patients were white women; their mean age was 74; 1,065 received intravenous zoledronic acid, and 1,062 received placebo. All received vitamin D and calcium.

The trial showed a clear reduction in the rate of recurrent fractures at other sites (a primary end point) and a reduction in the rate of all-cause mortality in patients treated within 90 days of fracture. A total of 424 fractures occurred in 231 patients. The risk of any new clinical fracture was 35% lower with treatment than with placebo (occurring in 8.6% vs 13.9% of patients, P = .001), and the number of deaths due to any cause was 28% lower with treatment than with placebo (occurring in 101 vs 141, P = .01).²

The mean time to fracture was 39.8 months in the treated group vs 36.4 in the placebo group. The fracture risk reduction began to be apparent by 12 months, and the reduction in mortality rate by 16 months.²

In a post hoc analysis of the trial, Eriksen et al¹ attempted to ascertain the optimal time for therapy in terms of fracture risk and mortality reduction. Analyzing the data by 2-week intervals beginning after the surgical repair of the fracture, the authors found that only 56 patients (5.3%) had received zoledronic acid within 2 weeks of surgery and only 47 had received placebo, and they saw no advantage to intravenous zoledronic acid compared with placebo in these first 2 weeks with respect to bone mineral density, fracture risk, or risk of death. However, excluding this small subset, antifracture efficacy and reduction in mortality rate were present when patients were treated with zoledronic acid in the 2 to 12 weeks after hip fracture repair, and improvement in bone mineral density at the hip was noted at 12 months in all cohorts.

Colón-Emeric et al³ performed another post hoc analysis, attempting to explain the lower mortality rate seen in patients treated with zoledronic acid. It had been an unexpected finding, and determinants of mortality rate reduction were hampered by a limited knowledge of the true cause of death or the circumstances of care after fracture. The authors concluded that only 8% of the reduction in mortality rate evident early in the second year of treatment with zoledronic acid could be attributed to a reduction in fractures.³ Other mechanisms by which the mortality rate reduction occurred remained unclear.

Curiously, in another large randomized controlled trial of zoledronic acid, in women with postmenopausal osteoporosis, Black et al⁴ reported that more patients died in the treated group (130 of 3,862) than in the placebo group (112 of 3,852). This difference was not statistically significant, but neither was it explained.

A meta-analysis by Bolland et al⁵ examined the effect of other osteoporosis treatments on mortality rate, using randomized controlled trials that lasted more than 12 months and that reported more than 10 deaths. The authors concluded the following:

• In the trials in which bisphosphonates reduced the mortality rate, the mortality rate in the placebo group was higher than 10 per 1,000 patient-years
• The effect of osteoporosis treatment on the mortality rate in a frail, elderly population is evident using agents with proven efficacy in reducing vertebral and nonvertebral fractures, eg, alendronate, risedronate, and zoledronic acid.⁵

THE SCIENCE

Osteoporotic fractures occur with minimal trauma, with the failure of bone attributed to impaired integrity of bone microarchitecture. The ultimate goal of fracture repair is to restore bone size, shape, and tissue properties. The issue of when to treat with a bisphosphonate after hip fracture arises because bisphosphonates are known to disrupt bone remodeling and so delay fracture repair.

After fracture, both anabolic and catabolic phases occur.⁶ The final outcome depends on the following:

• The type of intervention to stabilize the fracture site (eg, surgical repair)
• The inflammatory cytokines and growth factors released by the cellular elements in bloody and disrupted tissue.

Oxygen tension, angiogenesis, and osteoblasts are critical to primary bone formation, and osteoclasts are essential in remodeling this initial bone deposition. These late phases of fracture repair are most vulnerable to the bisphosphonates, through suppression of osteoclast resorption and possibly through decreased angiogenesis.⁶ Callus formation is sustained, but bone remodeling is delayed.

Amanat et al⁷ examined the timing of a single dose of zoledronic acid after fracture repair in a rat model of diaphyseal fracture and found that the callus was larger and stronger if the bisphosphonate dose had been delayed 1 or 2 weeks. The animals treated with zoledronic acid showed a remarkable trabecular network of bone between the original femoral cortex and the new cortical bone that was not present in the control group, perhaps contributing to the enhanced mechanical properties of the callus. Other studies suggest single dosing rather than continuous dosing may be advantageous in fracture healing.⁸

THE REALITY

Healthy dogs or growing rats with linear diaphyseal fractures are imperfect models for elderly osteoporotic patients with hip fracture, as Dr. Herbert Fleisch noted in his editorial, “Can bisphosphonates be given to patients with fractures?”⁹ Still, if retained primary bone can be used in the process of fracture repair to gain an early mechanical advantage, then perhaps delayed remodeling will permit early mobilization and further fracture prevention in humans.

How soon after hip fracture surgery should a patient start a bisphosphonate? The only data we have are from a single randomized controlled trial designed to measure fracture risk reduction in osteoporotic patients with hip fracture using intravenous zoledronic acid 5 mg compared with placebo.² A post hoc analysis of this study¹ generated the limited clinical data we have on the optimal timing of the treatment. Linking these study data with the laboratory data, one would intuit that delaying the infusion of zoledronic acid for at least 2 weeks after hip fracture repair would offer a clinical reduction in fracture risk and improvement (or stabilization) in bone mineral density by 12 months, and a reduction in the rate of all-cause mortality beginning at 16 months.

Patients with an osteoporotic hip fracture suffer from profound morbidity and are at a heightened risk of death. It is therefore essential that they receive treatment with a bisphosphonate known to modify the subsequent risk of fracture at any site—eg, alendronate (Fosamax), risedronate (Actonel), or zoledronic acid (Reclast).

However, there is concern that starting a bisphosphonate too soon after surgery could disrupt bone remodeling and delay fracture repair.

Only one clinical study addressed the timing of bisphosphonate therapy after hip fracture repair. In this study, Eriksen et al¹ performed a post hoc analysis of data from the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT)² and concluded that the optimal time to give intravenous zoledronic acid is 2 to 12 weeks after surgical repair of the fracture.

In a frail, elderly patient with comorbidities, a single intravenous 5-mg dose of zoledronic acid guarantees adequate treatment, obviating issues of poor compliance and oral absorption and loss to follow-up. Sufficient levels of vitamin D and calcium should be ensured.

THE EVIDENCE

The original HORIZON-RFT study,² published in 2007, compared intravenous zoledronic acid against placebo in elderly patients with osteoporotic hip fracture. Most of the patients were white women; their mean age was 74; 1,065 received intravenous zoledronic acid, and 1,062 received placebo. All received vitamin D and calcium.

The trial showed a clear reduction in the rate of recurrent fractures at other sites (a primary end point) and a reduction in the rate of all-cause mortality in patients treated within 90 days of fracture. A total of 424 fractures occurred in 231 patients. The risk of any new clinical fracture was 35% lower with treatment than with placebo (occurring in 8.6% vs 13.9% of patients, P = .001), and the number of deaths due to any cause was 28% lower with treatment than with placebo (occurring in 101 vs 141, P = .01).²

The mean time to fracture was 39.8 months in the treated group vs 36.4 in the placebo group. The fracture risk reduction began to be apparent by 12 months, and the reduction in mortality rate by 16 months.²

In a post hoc analysis of the trial, Eriksen et al¹ attempted to ascertain the optimal time for therapy in terms of fracture risk and mortality reduction. Analyzing the data by 2-week intervals beginning after the surgical repair of the fracture, the authors found that only 56 patients (5.3%) had received zoledronic acid within 2 weeks of surgery and only 47 had received placebo, and they saw no advantage to intravenous zoledronic acid compared with placebo in these first 2 weeks with respect to bone mineral density, fracture risk, or risk of death. However, excluding this small subset, antifracture efficacy and reduction in mortality rate were present when patients were treated with zoledronic acid in the 2 to 12 weeks after hip fracture repair, and improvement in bone mineral density at the hip was noted at 12 months in all cohorts.

Colón-Emeric et al³ performed another post hoc analysis, attempting to explain the lower mortality rate seen in patients treated with zoledronic acid. It had been an unexpected finding, and determinants of mortality rate reduction were hampered by a limited knowledge of the true cause of death or the circumstances of care after fracture. The authors concluded that only 8% of the reduction in mortality rate evident early in the second year of treatment with zoledronic acid could be attributed to a reduction in fractures.³ Other mechanisms by which the mortality rate reduction occurred remained unclear.

Curiously, in another large randomized controlled trial of zoledronic acid, in women with postmenopausal osteoporosis, Black et al⁴ reported that more patients died in the treated group (130 of 3,862) than in the placebo group (112 of 3,852). This difference was not statistically significant, but neither was it explained.

A meta-analysis by Bolland et al⁵ examined the effect of other osteoporosis treatments on mortality rate, using randomized controlled trials that lasted more than 12 months and that reported more than 10 deaths. The authors concluded the following:

• In the trials in which bisphosphonates reduced the mortality rate, the mortality rate in the placebo group was higher than 10 per 1,000 patient-years
• The effect of osteoporosis treatment on the mortality rate in a frail, elderly population is evident using agents with proven efficacy in reducing vertebral and nonvertebral fractures, eg, alendronate, risedronate, and zoledronic acid.⁵

THE SCIENCE

Osteoporotic fractures occur with minimal trauma, with the failure of bone attributed to impaired integrity of bone microarchitecture. The ultimate goal of fracture repair is to restore bone size, shape, and tissue properties. The issue of when to treat with a bisphosphonate after hip fracture arises because bisphosphonates are known to disrupt bone remodeling and so delay fracture repair.

After fracture, both anabolic and catabolic phases occur.⁶ The final outcome depends on the following:

• The type of intervention to stabilize the fracture site (eg, surgical repair)
• The inflammatory cytokines and growth factors released by the cellular elements in bloody and disrupted tissue.

Oxygen tension, angiogenesis, and osteoblasts are critical to primary bone formation, and osteoclasts are essential in remodeling this initial bone deposition. These late phases of fracture repair are most vulnerable to the bisphosphonates, through suppression of osteoclast resorption and possibly through decreased angiogenesis.⁶ Callus formation is sustained, but bone remodeling is delayed.

Amanat et al⁷ examined the timing of a single dose of zoledronic acid after fracture repair in a rat model of diaphyseal fracture and found that the callus was larger and stronger if the bisphosphonate dose had been delayed 1 or 2 weeks. The animals treated with zoledronic acid showed a remarkable trabecular network of bone between the original femoral cortex and the new cortical bone that was not present in the control group, perhaps contributing to the enhanced mechanical properties of the callus. Other studies suggest single dosing rather than continuous dosing may be advantageous in fracture healing.⁸

THE REALITY

Healthy dogs or growing rats with linear diaphyseal fractures are imperfect models for elderly osteoporotic patients with hip fracture, as Dr. Herbert Fleisch noted in his editorial, “Can bisphosphonates be given to patients with fractures?”⁹ Still, if retained primary bone can be used in the process of fracture repair to gain an early mechanical advantage, then perhaps delayed remodeling will permit early mobilization and further fracture prevention in humans.

How soon after hip fracture surgery should a patient start a bisphosphonate? The only data we have are from a single randomized controlled trial designed to measure fracture risk reduction in osteoporotic patients with hip fracture using intravenous zoledronic acid 5 mg compared with placebo.² A post hoc analysis of this study¹ generated the limited clinical data we have on the optimal timing of the treatment. Linking these study data with the laboratory data, one would intuit that delaying the infusion of zoledronic acid for at least 2 weeks after hip fracture repair would offer a clinical reduction in fracture risk and improvement (or stabilization) in bone mineral density by 12 months, and a reduction in the rate of all-cause mortality beginning at 16 months.

Patients with an osteoporotic hip fracture suffer from profound morbidity and are at a heightened risk of death. It is therefore essential that they receive treatment with a bisphosphonate known to modify the subsequent risk of fracture at any site—eg, alendronate (Fosamax), risedronate (Actonel), or zoledronic acid (Reclast).

However, there is concern that starting a bisphosphonate too soon after surgery could disrupt bone remodeling and delay fracture repair.

Only one clinical study addressed the timing of bisphosphonate therapy after hip fracture repair. In this study, Eriksen et al¹ performed a post hoc analysis of data from the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT)² and concluded that the optimal time to give intravenous zoledronic acid is 2 to 12 weeks after surgical repair of the fracture.

In a frail, elderly patient with comorbidities, a single intravenous 5-mg dose of zoledronic acid guarantees adequate treatment, obviating issues of poor compliance and oral absorption and loss to follow-up. Sufficient levels of vitamin D and calcium should be ensured.

THE EVIDENCE

The original HORIZON-RFT study,² published in 2007, compared intravenous zoledronic acid against placebo in elderly patients with osteoporotic hip fracture. Most of the patients were white women; their mean age was 74; 1,065 received intravenous zoledronic acid, and 1,062 received placebo. All received vitamin D and calcium.

The trial showed a clear reduction in the rate of recurrent fractures at other sites (a primary end point) and a reduction in the rate of all-cause mortality in patients treated within 90 days of fracture. A total of 424 fractures occurred in 231 patients. The risk of any new clinical fracture was 35% lower with treatment than with placebo (occurring in 8.6% vs 13.9% of patients, P = .001), and the number of deaths due to any cause was 28% lower with treatment than with placebo (occurring in 101 vs 141, P = .01).²

The mean time to fracture was 39.8 months in the treated group vs 36.4 in the placebo group. The fracture risk reduction began to be apparent by 12 months, and the reduction in mortality rate by 16 months.²

In a post hoc analysis of the trial, Eriksen et al¹ attempted to ascertain the optimal time for therapy in terms of fracture risk and mortality reduction. Analyzing the data by 2-week intervals beginning after the surgical repair of the fracture, the authors found that only 56 patients (5.3%) had received zoledronic acid within 2 weeks of surgery and only 47 had received placebo, and they saw no advantage to intravenous zoledronic acid compared with placebo in these first 2 weeks with respect to bone mineral density, fracture risk, or risk of death. However, excluding this small subset, antifracture efficacy and reduction in mortality rate were present when patients were treated with zoledronic acid in the 2 to 12 weeks after hip fracture repair, and improvement in bone mineral density at the hip was noted at 12 months in all cohorts.

Colón-Emeric et al³ performed another post hoc analysis, attempting to explain the lower mortality rate seen in patients treated with zoledronic acid. It had been an unexpected finding, and determinants of mortality rate reduction were hampered by a limited knowledge of the true cause of death or the circumstances of care after fracture. The authors concluded that only 8% of the reduction in mortality rate evident early in the second year of treatment with zoledronic acid could be attributed to a reduction in fractures.³ Other mechanisms by which the mortality rate reduction occurred remained unclear.

Curiously, in another large randomized controlled trial of zoledronic acid, in women with postmenopausal osteoporosis, Black et al⁴ reported that more patients died in the treated group (130 of 3,862) than in the placebo group (112 of 3,852). This difference was not statistically significant, but neither was it explained.

A meta-analysis by Bolland et al⁵ examined the effect of other osteoporosis treatments on mortality rate, using randomized controlled trials that lasted more than 12 months and that reported more than 10 deaths. The authors concluded the following:

• In the trials in which bisphosphonates reduced the mortality rate, the mortality rate in the placebo group was higher than 10 per 1,000 patient-years
• The effect of osteoporosis treatment on the mortality rate in a frail, elderly population is evident using agents with proven efficacy in reducing vertebral and nonvertebral fractures, eg, alendronate, risedronate, and zoledronic acid.⁵

THE SCIENCE

Osteoporotic fractures occur with minimal trauma, with the failure of bone attributed to impaired integrity of bone microarchitecture. The ultimate goal of fracture repair is to restore bone size, shape, and tissue properties. The issue of when to treat with a bisphosphonate after hip fracture arises because bisphosphonates are known to disrupt bone remodeling and so delay fracture repair.

After fracture, both anabolic and catabolic phases occur.⁶ The final outcome depends on the following:

• The type of intervention to stabilize the fracture site (eg, surgical repair)
• The inflammatory cytokines and growth factors released by the cellular elements in bloody and disrupted tissue.

Oxygen tension, angiogenesis, and osteoblasts are critical to primary bone formation, and osteoclasts are essential in remodeling this initial bone deposition. These late phases of fracture repair are most vulnerable to the bisphosphonates, through suppression of osteoclast resorption and possibly through decreased angiogenesis.⁶ Callus formation is sustained, but bone remodeling is delayed.

Amanat et al⁷ examined the timing of a single dose of zoledronic acid after fracture repair in a rat model of diaphyseal fracture and found that the callus was larger and stronger if the bisphosphonate dose had been delayed 1 or 2 weeks. The animals treated with zoledronic acid showed a remarkable trabecular network of bone between the original femoral cortex and the new cortical bone that was not present in the control group, perhaps contributing to the enhanced mechanical properties of the callus. Other studies suggest single dosing rather than continuous dosing may be advantageous in fracture healing.⁸

THE REALITY

Healthy dogs or growing rats with linear diaphyseal fractures are imperfect models for elderly osteoporotic patients with hip fracture, as Dr. Herbert Fleisch noted in his editorial, “Can bisphosphonates be given to patients with fractures?”⁹ Still, if retained primary bone can be used in the process of fracture repair to gain an early mechanical advantage, then perhaps delayed remodeling will permit early mobilization and further fracture prevention in humans.

How soon after hip fracture surgery should a patient start a bisphosphonate? The only data we have are from a single randomized controlled trial designed to measure fracture risk reduction in osteoporotic patients with hip fracture using intravenous zoledronic acid 5 mg compared with placebo.² A post hoc analysis of this study¹ generated the limited clinical data we have on the optimal timing of the treatment. Linking these study data with the laboratory data, one would intuit that delaying the infusion of zoledronic acid for at least 2 weeks after hip fracture repair would offer a clinical reduction in fracture risk and improvement (or stabilization) in bone mineral density by 12 months, and a reduction in the rate of all-cause mortality beginning at 16 months.

Antibiotics are indicated for primary bacterial aspiration pneumonia and secondary bacterial infection of aspiration (chemical) pneumonitis, but not for uncomplicated chemical pneumonitis.

THREE TYPES OF ‘ASPIRATION PNEUMONIA’

Aspiration pneumonia is a broad and vague term mainly used to refer to the pulmonary consequences of abnormal entry of exogenous or endogenous substances into the lower airways. It can be classified as:

• Aspiration (chemical) pneumonitis
• Primary bacterial aspiration pneumonia
• Secondary bacterial infection of chemical pneumonitis.

These three are sometimes difficult to differentiate, as their signs and symptoms can overlap.

CHEMICAL PNEUMONITIS

Aspiration of stomach contents is relatively common, even in healthy people, and usually has no clinical consequences.¹ However, it has also been closely related to community-acquired and nosocomial pneumonia in some studies.^2,3

Chemical pneumonitis is usually a consequence of the aspiration of a large volume (≥ 4 mL/kg) of sterile acidic (pH < 2.5) gastric contents into the lower airways (Mendelson syndrome).^4,5 The clinical picture varies from asymptomatic to signs of severe dyspnea, hypoxia, cough, and low-grade fever; these signs and symptoms may develop rapidly, within minutes to hours after a witnessed or suspected episode of aspiration.^2,6,7 However, they represent an inflammatory reaction to the gastric acid rather than a reaction to bacterial infection.^8–10

Chemical pneumonitis affects the most dependent regions of the lungs

Chest radiography shows infiltrates in the most dependent regions of the lung. If aspiration occurs while the patient is supine, the posterior segments of the upper lobes and the apical segments of the lower lobes are most affected. The basal segments of the lower lobes are usually affected if aspiration occurs while the patient is standing or upright.^1,2,11,12

Clinical course varies

The clinical course varies. In almost 60% of cases, the patient’s condition improves and the lung infiltrates resolve rapidly, within 2 to 4 days. On the other hand, in about 15% of cases, the patient’s condition deteriorates quickly, within 24 to 36 hours, and progresses to hypoxic respiratory failure and acute respiratory distress syndrome.

In the other 25% of cases, the patient’s condition may improve initially but then worsen as a secondary bacterial infection sets in. The death rate in these patients is almost three times higher than the rate in patients with uncomplicated chemical pneumonitis.^11,13

Treatment of uncomplicated cases is mainly supportive

The treatment of uncomplicated chemical pneumonitis involves supportive measures such as airway clearance, oxygen supplementation, and positive pressure ventilation if needed. An obstructing foreign body may need to be removed.^12,14 Corticosteroids have been tried, without success.^11–13,15

Empiric antibiotic treatment is controversial

Chemical pneumonitis can be difficult to differentiate from bacterial aspiration pneumonia, and whether to give antibiotics is controversial. ¹⁶ A survey of current practices among intensivists showed that antimicrobial therapy was often given empirically for noninfectious chemical pneumonitis.¹⁷ This practice raises concerns of higher treatment costs and antibiotic resistance.^16,18,19 Additionally, antibiotics do not seem to alter the clinical outcome, including radiographic resolution, duration of hospitalization, or death rate, nor do they influence the subsequent development of infection.^1,11,13,20

In cases of witnessed or strongly suspected aspiration of gastric contents, antibiotics are not warranted since bacterial infection is not likely to be the cause of any signs or symptoms. ^2,7,16 However, to detect secondary infection early, the patient’s respiratory status should be monitored carefully and chest radiography should be repeated.

In less clear-cut cases, ie, if it is not clear whether the patient actually has chemical pneumonitis or primary bacterial aspiration pneumonia, it is prudent to start antibiotics empirically after obtaining lower-respiratory-tract secretions for stains and cultures, and then to reassess within 48 to 72 hours. The antibiotics can be discontinued if the patient has rapid clinical and radiographic improvement and negative cultures. Those whose condition does not improve or who have positive cultures should receive a full course of antibiotics.^21,22

PRIMARY BACTERIAL ASPIRATION PNEUMONIA

Primary bacterial aspiration pneumonia—ie, caused by bacteria residing in the upper airways and stomach gaining access to lower airways through aspiration in small or large amounts—is the most common form of aspiration pneumonia, although the actual episode of aspiration is seldom observed.

Signs of bacterial pneumonia

Primary bacterial aspiration pneumonia bears the hallmarks of bacterial pneumonia.¹² The clinical picture is more indolent than chemical pneumonitis and includes cough, fever, and putrid sputum, mainly in patients who have clinical conditions predisposing to aspiration (eg, coma, stroke, alcoholism, poor dentition, tube feedings).^1,12,20

The characteristic signs on chest radiography are infiltrates involving mainly the lung bases (the right more then the left). If untreated or inadequately treated, complications such as lung abscess, empyema, bronchiectasis, and broncopleural fistula are common.²³

Are aerobic organisms replacing anaerobic ones in the community?

The causative organisms in community-acquired aspiration pneumonia are still debated despite abundant research. Older studies^1,24,25 found mostly anaerobic organisms (pepto-streptococci, peptococci, Fusobacterium, Prevotela, Bacteroides) as the underlying pathogens, whereas more recent studies^16,26,27 found mostly aerobic organisms (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Enterobacteriaceae) and failed to recover anaerobic organisms. These discrepancies may be the result of different techniques used to isolate organisms: older studies used transtracheal sampling, and transtracheal aspirates may be easily contaminated or colonized by oropharyngeal flora; more recent studies used protected specimen brushes to collect lower-airway specimens.²

In addition, the pathogenic organisms that predominate in community-acquired aspiration pneumonia, as listed above, are different from those most often found in nosocomial cases; gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli) are most often isolated in patients with aspiration pneumonia acquired in hospitals and nursing homes.^16,27,28S aureus also is an important causative organism in nosocomial cases.^16,28

Knowing the causative organisms in bacterial aspiration pneumonia is important for guiding antimicrobial therapy.

Antibiotics are required for bacterial aspiration pneumonia

A course of antibiotics is required for bacterial aspiration pneumonia. While there are no definitive recommendations for the duration of treatment, 7 to 8 days is probably appropriate in uncomplicated cases (ie, no lung abscess, empyema, bronchopleural fistula).^22,29 Patients who have complications may need drainage of abscesses or empyema along with a longer duration of antibiotic therapy until clinical and radiographic signs improve.

For community-acquired cases of aspiration pneumonia, a number of antibiotics have proven effective:

• Clindamycin (Cleocin) is still the agent most commonly used, although it lacks gram-negative bacterial coverage.
• Beta-lactam penicillins and newer quinolones have been used successfully.^2,29–31 In addition to covering the previously mentioned bacteria, these antibiotics have the added benefit of covering anaerobic bacteria.
• Metronidazole (Flagyl) should not be used alone because it has a higher clinical failure rate.^32,33

For nosocomial aspiration pneumonia, giving a broad-spectrum antibiotic empirically is warranted. Beta-lactam penicillins with extended gram-negative coverage, carbapenems, or monobactams in combination with an anti-staphylococcal drug have been advocated for nosocomial aspiration.^2,22 A strategy of broad-spectrum coverage followed by narrowing or de-escalating coverage according to lower respiratory tract cultures is encouraged.^21,22,34

SECONDARY BACTERIAL INFECTION OF CHEMICAL PNEUMONITIS

Nearly 25% of patients with chemical pneumonitis improve initially, then show clinical deterioration secondary to superimposed bacterial infection.¹³ Chest radiographs show worsening of initial infiltrates or the development of new ones. The causative organisms and treatment depend on whether the superimposed infection is community-acquired or nosocomial, as is the case in primary bacterial aspiration pneumonia.

PREVENTING ASPIRATION

Measures should be taken to prevent aspiration pneumonia and chemical pneumonitis, especially in institutionalized patients at high risk.¹²

Elevation of the head of the bed while feeding, dental prophylaxis, and good oral hygiene are known to reduce the incidence of these problems.^35–37

A swallowing evaluation for patients with dysphagia can identify those at higher risk of aspiration. These patients may be candidates for postural adjustments, diet modification, strengthening, and other measures offered by the speech and language pathology teams to improve swallowing physiology, biomechanics, safety, and endurance.^2,35

Although percutaneous endoscopic gastrostomy tubes are often placed in patients who have aspirated or who are at high risk of aspiration, they do not protect against aspiration, nor do orogastric or nasogastric tubes.³⁸

To date, we have no evidence that prophylactic antibiotic therapy prevents bacterial aspiration pneumonia. In addition, this practice encourages the development of resistant organisms.^19,39,40

Antibiotics are indicated for primary bacterial aspiration pneumonia and secondary bacterial infection of aspiration (chemical) pneumonitis, but not for uncomplicated chemical pneumonitis.

THREE TYPES OF ‘ASPIRATION PNEUMONIA’

Aspiration pneumonia is a broad and vague term mainly used to refer to the pulmonary consequences of abnormal entry of exogenous or endogenous substances into the lower airways. It can be classified as:

• Aspiration (chemical) pneumonitis
• Primary bacterial aspiration pneumonia
• Secondary bacterial infection of chemical pneumonitis.

These three are sometimes difficult to differentiate, as their signs and symptoms can overlap.

CHEMICAL PNEUMONITIS

Aspiration of stomach contents is relatively common, even in healthy people, and usually has no clinical consequences.¹ However, it has also been closely related to community-acquired and nosocomial pneumonia in some studies.^2,3

Chemical pneumonitis is usually a consequence of the aspiration of a large volume (≥ 4 mL/kg) of sterile acidic (pH < 2.5) gastric contents into the lower airways (Mendelson syndrome).^4,5 The clinical picture varies from asymptomatic to signs of severe dyspnea, hypoxia, cough, and low-grade fever; these signs and symptoms may develop rapidly, within minutes to hours after a witnessed or suspected episode of aspiration.^2,6,7 However, they represent an inflammatory reaction to the gastric acid rather than a reaction to bacterial infection.^8–10

Chemical pneumonitis affects the most dependent regions of the lungs

Chest radiography shows infiltrates in the most dependent regions of the lung. If aspiration occurs while the patient is supine, the posterior segments of the upper lobes and the apical segments of the lower lobes are most affected. The basal segments of the lower lobes are usually affected if aspiration occurs while the patient is standing or upright.^1,2,11,12

Clinical course varies

The clinical course varies. In almost 60% of cases, the patient’s condition improves and the lung infiltrates resolve rapidly, within 2 to 4 days. On the other hand, in about 15% of cases, the patient’s condition deteriorates quickly, within 24 to 36 hours, and progresses to hypoxic respiratory failure and acute respiratory distress syndrome.

In the other 25% of cases, the patient’s condition may improve initially but then worsen as a secondary bacterial infection sets in. The death rate in these patients is almost three times higher than the rate in patients with uncomplicated chemical pneumonitis.^11,13

Treatment of uncomplicated cases is mainly supportive

The treatment of uncomplicated chemical pneumonitis involves supportive measures such as airway clearance, oxygen supplementation, and positive pressure ventilation if needed. An obstructing foreign body may need to be removed.^12,14 Corticosteroids have been tried, without success.^11–13,15

Empiric antibiotic treatment is controversial

Chemical pneumonitis can be difficult to differentiate from bacterial aspiration pneumonia, and whether to give antibiotics is controversial. ¹⁶ A survey of current practices among intensivists showed that antimicrobial therapy was often given empirically for noninfectious chemical pneumonitis.¹⁷ This practice raises concerns of higher treatment costs and antibiotic resistance.^16,18,19 Additionally, antibiotics do not seem to alter the clinical outcome, including radiographic resolution, duration of hospitalization, or death rate, nor do they influence the subsequent development of infection.^1,11,13,20

In cases of witnessed or strongly suspected aspiration of gastric contents, antibiotics are not warranted since bacterial infection is not likely to be the cause of any signs or symptoms. ^2,7,16 However, to detect secondary infection early, the patient’s respiratory status should be monitored carefully and chest radiography should be repeated.

In less clear-cut cases, ie, if it is not clear whether the patient actually has chemical pneumonitis or primary bacterial aspiration pneumonia, it is prudent to start antibiotics empirically after obtaining lower-respiratory-tract secretions for stains and cultures, and then to reassess within 48 to 72 hours. The antibiotics can be discontinued if the patient has rapid clinical and radiographic improvement and negative cultures. Those whose condition does not improve or who have positive cultures should receive a full course of antibiotics.^21,22

PRIMARY BACTERIAL ASPIRATION PNEUMONIA

Primary bacterial aspiration pneumonia—ie, caused by bacteria residing in the upper airways and stomach gaining access to lower airways through aspiration in small or large amounts—is the most common form of aspiration pneumonia, although the actual episode of aspiration is seldom observed.

Signs of bacterial pneumonia

Primary bacterial aspiration pneumonia bears the hallmarks of bacterial pneumonia.¹² The clinical picture is more indolent than chemical pneumonitis and includes cough, fever, and putrid sputum, mainly in patients who have clinical conditions predisposing to aspiration (eg, coma, stroke, alcoholism, poor dentition, tube feedings).^1,12,20

The characteristic signs on chest radiography are infiltrates involving mainly the lung bases (the right more then the left). If untreated or inadequately treated, complications such as lung abscess, empyema, bronchiectasis, and broncopleural fistula are common.²³

Are aerobic organisms replacing anaerobic ones in the community?

The causative organisms in community-acquired aspiration pneumonia are still debated despite abundant research. Older studies^1,24,25 found mostly anaerobic organisms (pepto-streptococci, peptococci, Fusobacterium, Prevotela, Bacteroides) as the underlying pathogens, whereas more recent studies^16,26,27 found mostly aerobic organisms (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Enterobacteriaceae) and failed to recover anaerobic organisms. These discrepancies may be the result of different techniques used to isolate organisms: older studies used transtracheal sampling, and transtracheal aspirates may be easily contaminated or colonized by oropharyngeal flora; more recent studies used protected specimen brushes to collect lower-airway specimens.²

In addition, the pathogenic organisms that predominate in community-acquired aspiration pneumonia, as listed above, are different from those most often found in nosocomial cases; gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli) are most often isolated in patients with aspiration pneumonia acquired in hospitals and nursing homes.^16,27,28S aureus also is an important causative organism in nosocomial cases.^16,28

Knowing the causative organisms in bacterial aspiration pneumonia is important for guiding antimicrobial therapy.

Antibiotics are required for bacterial aspiration pneumonia

A course of antibiotics is required for bacterial aspiration pneumonia. While there are no definitive recommendations for the duration of treatment, 7 to 8 days is probably appropriate in uncomplicated cases (ie, no lung abscess, empyema, bronchopleural fistula).^22,29 Patients who have complications may need drainage of abscesses or empyema along with a longer duration of antibiotic therapy until clinical and radiographic signs improve.

For community-acquired cases of aspiration pneumonia, a number of antibiotics have proven effective:

• Clindamycin (Cleocin) is still the agent most commonly used, although it lacks gram-negative bacterial coverage.
• Beta-lactam penicillins and newer quinolones have been used successfully.^2,29–31 In addition to covering the previously mentioned bacteria, these antibiotics have the added benefit of covering anaerobic bacteria.
• Metronidazole (Flagyl) should not be used alone because it has a higher clinical failure rate.^32,33

For nosocomial aspiration pneumonia, giving a broad-spectrum antibiotic empirically is warranted. Beta-lactam penicillins with extended gram-negative coverage, carbapenems, or monobactams in combination with an anti-staphylococcal drug have been advocated for nosocomial aspiration.^2,22 A strategy of broad-spectrum coverage followed by narrowing or de-escalating coverage according to lower respiratory tract cultures is encouraged.^21,22,34

SECONDARY BACTERIAL INFECTION OF CHEMICAL PNEUMONITIS

Nearly 25% of patients with chemical pneumonitis improve initially, then show clinical deterioration secondary to superimposed bacterial infection.¹³ Chest radiographs show worsening of initial infiltrates or the development of new ones. The causative organisms and treatment depend on whether the superimposed infection is community-acquired or nosocomial, as is the case in primary bacterial aspiration pneumonia.

PREVENTING ASPIRATION

Measures should be taken to prevent aspiration pneumonia and chemical pneumonitis, especially in institutionalized patients at high risk.¹²

Elevation of the head of the bed while feeding, dental prophylaxis, and good oral hygiene are known to reduce the incidence of these problems.^35–37

A swallowing evaluation for patients with dysphagia can identify those at higher risk of aspiration. These patients may be candidates for postural adjustments, diet modification, strengthening, and other measures offered by the speech and language pathology teams to improve swallowing physiology, biomechanics, safety, and endurance.^2,35

Although percutaneous endoscopic gastrostomy tubes are often placed in patients who have aspirated or who are at high risk of aspiration, they do not protect against aspiration, nor do orogastric or nasogastric tubes.³⁸

To date, we have no evidence that prophylactic antibiotic therapy prevents bacterial aspiration pneumonia. In addition, this practice encourages the development of resistant organisms.^19,39,40

Antibiotics are indicated for primary bacterial aspiration pneumonia and secondary bacterial infection of aspiration (chemical) pneumonitis, but not for uncomplicated chemical pneumonitis.

THREE TYPES OF ‘ASPIRATION PNEUMONIA’

Aspiration pneumonia is a broad and vague term mainly used to refer to the pulmonary consequences of abnormal entry of exogenous or endogenous substances into the lower airways. It can be classified as:

• Aspiration (chemical) pneumonitis
• Primary bacterial aspiration pneumonia
• Secondary bacterial infection of chemical pneumonitis.

These three are sometimes difficult to differentiate, as their signs and symptoms can overlap.

CHEMICAL PNEUMONITIS

Aspiration of stomach contents is relatively common, even in healthy people, and usually has no clinical consequences.¹ However, it has also been closely related to community-acquired and nosocomial pneumonia in some studies.^2,3

Chemical pneumonitis is usually a consequence of the aspiration of a large volume (≥ 4 mL/kg) of sterile acidic (pH < 2.5) gastric contents into the lower airways (Mendelson syndrome).^4,5 The clinical picture varies from asymptomatic to signs of severe dyspnea, hypoxia, cough, and low-grade fever; these signs and symptoms may develop rapidly, within minutes to hours after a witnessed or suspected episode of aspiration.^2,6,7 However, they represent an inflammatory reaction to the gastric acid rather than a reaction to bacterial infection.^8–10

Chemical pneumonitis affects the most dependent regions of the lungs

Chest radiography shows infiltrates in the most dependent regions of the lung. If aspiration occurs while the patient is supine, the posterior segments of the upper lobes and the apical segments of the lower lobes are most affected. The basal segments of the lower lobes are usually affected if aspiration occurs while the patient is standing or upright.^1,2,11,12

Clinical course varies

The clinical course varies. In almost 60% of cases, the patient’s condition improves and the lung infiltrates resolve rapidly, within 2 to 4 days. On the other hand, in about 15% of cases, the patient’s condition deteriorates quickly, within 24 to 36 hours, and progresses to hypoxic respiratory failure and acute respiratory distress syndrome.

In the other 25% of cases, the patient’s condition may improve initially but then worsen as a secondary bacterial infection sets in. The death rate in these patients is almost three times higher than the rate in patients with uncomplicated chemical pneumonitis.^11,13

Treatment of uncomplicated cases is mainly supportive

The treatment of uncomplicated chemical pneumonitis involves supportive measures such as airway clearance, oxygen supplementation, and positive pressure ventilation if needed. An obstructing foreign body may need to be removed.^12,14 Corticosteroids have been tried, without success.^11–13,15

Empiric antibiotic treatment is controversial

Chemical pneumonitis can be difficult to differentiate from bacterial aspiration pneumonia, and whether to give antibiotics is controversial. ¹⁶ A survey of current practices among intensivists showed that antimicrobial therapy was often given empirically for noninfectious chemical pneumonitis.¹⁷ This practice raises concerns of higher treatment costs and antibiotic resistance.^16,18,19 Additionally, antibiotics do not seem to alter the clinical outcome, including radiographic resolution, duration of hospitalization, or death rate, nor do they influence the subsequent development of infection.^1,11,13,20

In cases of witnessed or strongly suspected aspiration of gastric contents, antibiotics are not warranted since bacterial infection is not likely to be the cause of any signs or symptoms. ^2,7,16 However, to detect secondary infection early, the patient’s respiratory status should be monitored carefully and chest radiography should be repeated.

In less clear-cut cases, ie, if it is not clear whether the patient actually has chemical pneumonitis or primary bacterial aspiration pneumonia, it is prudent to start antibiotics empirically after obtaining lower-respiratory-tract secretions for stains and cultures, and then to reassess within 48 to 72 hours. The antibiotics can be discontinued if the patient has rapid clinical and radiographic improvement and negative cultures. Those whose condition does not improve or who have positive cultures should receive a full course of antibiotics.^21,22

PRIMARY BACTERIAL ASPIRATION PNEUMONIA

Primary bacterial aspiration pneumonia—ie, caused by bacteria residing in the upper airways and stomach gaining access to lower airways through aspiration in small or large amounts—is the most common form of aspiration pneumonia, although the actual episode of aspiration is seldom observed.

Signs of bacterial pneumonia

Primary bacterial aspiration pneumonia bears the hallmarks of bacterial pneumonia.¹² The clinical picture is more indolent than chemical pneumonitis and includes cough, fever, and putrid sputum, mainly in patients who have clinical conditions predisposing to aspiration (eg, coma, stroke, alcoholism, poor dentition, tube feedings).^1,12,20

The characteristic signs on chest radiography are infiltrates involving mainly the lung bases (the right more then the left). If untreated or inadequately treated, complications such as lung abscess, empyema, bronchiectasis, and broncopleural fistula are common.²³

Are aerobic organisms replacing anaerobic ones in the community?

The causative organisms in community-acquired aspiration pneumonia are still debated despite abundant research. Older studies^1,24,25 found mostly anaerobic organisms (pepto-streptococci, peptococci, Fusobacterium, Prevotela, Bacteroides) as the underlying pathogens, whereas more recent studies^16,26,27 found mostly aerobic organisms (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Enterobacteriaceae) and failed to recover anaerobic organisms. These discrepancies may be the result of different techniques used to isolate organisms: older studies used transtracheal sampling, and transtracheal aspirates may be easily contaminated or colonized by oropharyngeal flora; more recent studies used protected specimen brushes to collect lower-airway specimens.²

In addition, the pathogenic organisms that predominate in community-acquired aspiration pneumonia, as listed above, are different from those most often found in nosocomial cases; gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli) are most often isolated in patients with aspiration pneumonia acquired in hospitals and nursing homes.^16,27,28S aureus also is an important causative organism in nosocomial cases.^16,28

Knowing the causative organisms in bacterial aspiration pneumonia is important for guiding antimicrobial therapy.

Antibiotics are required for bacterial aspiration pneumonia

A course of antibiotics is required for bacterial aspiration pneumonia. While there are no definitive recommendations for the duration of treatment, 7 to 8 days is probably appropriate in uncomplicated cases (ie, no lung abscess, empyema, bronchopleural fistula).^22,29 Patients who have complications may need drainage of abscesses or empyema along with a longer duration of antibiotic therapy until clinical and radiographic signs improve.

For community-acquired cases of aspiration pneumonia, a number of antibiotics have proven effective:

• Clindamycin (Cleocin) is still the agent most commonly used, although it lacks gram-negative bacterial coverage.
• Beta-lactam penicillins and newer quinolones have been used successfully.^2,29–31 In addition to covering the previously mentioned bacteria, these antibiotics have the added benefit of covering anaerobic bacteria.
• Metronidazole (Flagyl) should not be used alone because it has a higher clinical failure rate.^32,33

For nosocomial aspiration pneumonia, giving a broad-spectrum antibiotic empirically is warranted. Beta-lactam penicillins with extended gram-negative coverage, carbapenems, or monobactams in combination with an anti-staphylococcal drug have been advocated for nosocomial aspiration.^2,22 A strategy of broad-spectrum coverage followed by narrowing or de-escalating coverage according to lower respiratory tract cultures is encouraged.^21,22,34

SECONDARY BACTERIAL INFECTION OF CHEMICAL PNEUMONITIS

Nearly 25% of patients with chemical pneumonitis improve initially, then show clinical deterioration secondary to superimposed bacterial infection.¹³ Chest radiographs show worsening of initial infiltrates or the development of new ones. The causative organisms and treatment depend on whether the superimposed infection is community-acquired or nosocomial, as is the case in primary bacterial aspiration pneumonia.

PREVENTING ASPIRATION

Measures should be taken to prevent aspiration pneumonia and chemical pneumonitis, especially in institutionalized patients at high risk.¹²

Elevation of the head of the bed while feeding, dental prophylaxis, and good oral hygiene are known to reduce the incidence of these problems.^35–37

A swallowing evaluation for patients with dysphagia can identify those at higher risk of aspiration. These patients may be candidates for postural adjustments, diet modification, strengthening, and other measures offered by the speech and language pathology teams to improve swallowing physiology, biomechanics, safety, and endurance.^2,35

Although percutaneous endoscopic gastrostomy tubes are often placed in patients who have aspirated or who are at high risk of aspiration, they do not protect against aspiration, nor do orogastric or nasogastric tubes.³⁸

To date, we have no evidence that prophylactic antibiotic therapy prevents bacterial aspiration pneumonia. In addition, this practice encourages the development of resistant organisms.^19,39,40

Yes. Treatment with beta-adrenergic receptor blockers decreases the mortality rate in patients with coronary artery disease or heart failure, as well as during the perioperative period in selected patients (eg, those with a history of myocardial infarction, a positive stress test, or current chest pain due to myocardial ischemia). The current evidence supports giving beta-blockers to patients with coronary artery disease and chronic obstructive pulmonary disease (COPD) or asthma, which lowers the 1-year mortality rate to a degree similar to that in patients without COPD or asthma, and without worsening respiratory function.¹ However, many clinicians still hesitate to start patients with COPD or asthma on a beta-blocker due to the fear of bronchoconstriction.²

THE RISKS

In patients with reversible airway disease, beta-blockers may increase airway reactivity and bronchospasm, as well as decrease the response to inhaled or oral beta-receptor agonists.³ Even topical ophthalmic nonselective beta-blockers for glaucoma can cause a worsening of pulmonary function.⁴ However, these data are from small trials in the 1970s and 1980s.

On the other hand, not giving beta-blockers can pose a risk of death. In a retrospective study of more than 200,000 patients with myocardial infarction, Gottlieb et al⁵ found that beta-blockers were associated with a 40% reduction in mortality rates in patients with conditions often considered a contraindication to beta-blocker therapy, such as congestive heart failure, pulmonary disease, and older age.⁵

CARDIOSELECTIVE BETA-BLOCKERS

Cardioselective beta-blockers with an affinity for the beta-1 receptor theoretically result in fewer adverse effects on the lungs. They competitively block the response to beta-adrenergic stimulation and selectively block beta-1 receptors with little or no effect on beta-2 receptors, except perhaps at high doses. However, this possible high-dose effect requires further study.

The effect of cardioselective beta-blockers on respiratory function was evaluated in two meta-analyses,^6,7 one in patients with mild to moderate reactive airway disease, the other in patients with mild to severe COPD. Patients with reactive airway disease who received a single dose of a beta-blocker had a 7.46% reduction in forced expiratory volume in the first second of expiration (FEV₁), an effect that was completely reversed by treatment with a beta-agonist inhaler. The FEV₁ increased by a statistically significantly greater amount in response to beta-agonists in patients who received beta-blockers (a single dose or continuous therapy) than in those who did not receive beta-blockers. Patients who received continuous cardioselective beta-blockers experienced no significant drop in FEV₁, and no new symptoms developed. These results led the authors to conclude that cardioselective beta-blockers do not cause a significant reduction in pulmonary function in patients with mild to moderate reactive airway disease and COPD and are therefore safe to use. A single dose of a cardioselective beta-blocker may produce a small decrease in FEV₁, especially in patients with reactive airway disease, but as therapy is continued over days to weeks, there is no significant change in symptoms or FEV₁ and no increase in the need for beta-agonist inhalers.

A major limitation of the two meta-analyses was that the patients were younger than most patients who require beta-blockers: the average age was 40 in patients with reactive airway disease, and 54 in patients with COPD. Also important to consider is that only patients with mild to moderate reactive airway disease were included. Patients with severe asthma, especially those with active bronchospasm, may react differently to even cardioselective beta-blockers.

NONSELECTIVE BETA-BLOCKERS

Recent studies suggest that nonselective beta-blockers can affect respiratory function in patients with COPD, but they have failed to show any harm. For example, propranolol (Inderal) was shown to worsen pulmonary function and to decrease the sensitivity of the airway to the effects of long-acting beta-2-agonists, but the 15 patients included in this study had no increase in respiratory symptoms.⁸

It has also been suggested that combined nonselective beta- and alpha-receptor blockade—eg, with labetalol (Trandate) or carvedilol (Coreg)—might be better tolerated than nonselective beta-blockers in patients with COPD.⁹ However, from limited data, Kotlyar et al¹⁰ suggested that carvedilol may be less well tolerated in patients with asthma than with COPD. All current evidence on combined nonselective beta-and alpha-blockade is observational, and it is not yet clear whether this class of beta-blockers is better tolerated due to alpha-blockade or merely because nonselective beta-blockers themselves are well tolerated.

OUR RECOMMENDATIONS

Yes. Treatment with beta-adrenergic receptor blockers decreases the mortality rate in patients with coronary artery disease or heart failure, as well as during the perioperative period in selected patients (eg, those with a history of myocardial infarction, a positive stress test, or current chest pain due to myocardial ischemia). The current evidence supports giving beta-blockers to patients with coronary artery disease and chronic obstructive pulmonary disease (COPD) or asthma, which lowers the 1-year mortality rate to a degree similar to that in patients without COPD or asthma, and without worsening respiratory function.¹ However, many clinicians still hesitate to start patients with COPD or asthma on a beta-blocker due to the fear of bronchoconstriction.²

THE RISKS

In patients with reversible airway disease, beta-blockers may increase airway reactivity and bronchospasm, as well as decrease the response to inhaled or oral beta-receptor agonists.³ Even topical ophthalmic nonselective beta-blockers for glaucoma can cause a worsening of pulmonary function.⁴ However, these data are from small trials in the 1970s and 1980s.

On the other hand, not giving beta-blockers can pose a risk of death. In a retrospective study of more than 200,000 patients with myocardial infarction, Gottlieb et al⁵ found that beta-blockers were associated with a 40% reduction in mortality rates in patients with conditions often considered a contraindication to beta-blocker therapy, such as congestive heart failure, pulmonary disease, and older age.⁵

CARDIOSELECTIVE BETA-BLOCKERS

Cardioselective beta-blockers with an affinity for the beta-1 receptor theoretically result in fewer adverse effects on the lungs. They competitively block the response to beta-adrenergic stimulation and selectively block beta-1 receptors with little or no effect on beta-2 receptors, except perhaps at high doses. However, this possible high-dose effect requires further study.

The effect of cardioselective beta-blockers on respiratory function was evaluated in two meta-analyses,^6,7 one in patients with mild to moderate reactive airway disease, the other in patients with mild to severe COPD. Patients with reactive airway disease who received a single dose of a beta-blocker had a 7.46% reduction in forced expiratory volume in the first second of expiration (FEV₁), an effect that was completely reversed by treatment with a beta-agonist inhaler. The FEV₁ increased by a statistically significantly greater amount in response to beta-agonists in patients who received beta-blockers (a single dose or continuous therapy) than in those who did not receive beta-blockers. Patients who received continuous cardioselective beta-blockers experienced no significant drop in FEV₁, and no new symptoms developed. These results led the authors to conclude that cardioselective beta-blockers do not cause a significant reduction in pulmonary function in patients with mild to moderate reactive airway disease and COPD and are therefore safe to use. A single dose of a cardioselective beta-blocker may produce a small decrease in FEV₁, especially in patients with reactive airway disease, but as therapy is continued over days to weeks, there is no significant change in symptoms or FEV₁ and no increase in the need for beta-agonist inhalers.

A major limitation of the two meta-analyses was that the patients were younger than most patients who require beta-blockers: the average age was 40 in patients with reactive airway disease, and 54 in patients with COPD. Also important to consider is that only patients with mild to moderate reactive airway disease were included. Patients with severe asthma, especially those with active bronchospasm, may react differently to even cardioselective beta-blockers.

NONSELECTIVE BETA-BLOCKERS

Recent studies suggest that nonselective beta-blockers can affect respiratory function in patients with COPD, but they have failed to show any harm. For example, propranolol (Inderal) was shown to worsen pulmonary function and to decrease the sensitivity of the airway to the effects of long-acting beta-2-agonists, but the 15 patients included in this study had no increase in respiratory symptoms.⁸

It has also been suggested that combined nonselective beta- and alpha-receptor blockade—eg, with labetalol (Trandate) or carvedilol (Coreg)—might be better tolerated than nonselective beta-blockers in patients with COPD.⁹ However, from limited data, Kotlyar et al¹⁰ suggested that carvedilol may be less well tolerated in patients with asthma than with COPD. All current evidence on combined nonselective beta-and alpha-blockade is observational, and it is not yet clear whether this class of beta-blockers is better tolerated due to alpha-blockade or merely because nonselective beta-blockers themselves are well tolerated.

OUR RECOMMENDATIONS

Yes. Treatment with beta-adrenergic receptor blockers decreases the mortality rate in patients with coronary artery disease or heart failure, as well as during the perioperative period in selected patients (eg, those with a history of myocardial infarction, a positive stress test, or current chest pain due to myocardial ischemia). The current evidence supports giving beta-blockers to patients with coronary artery disease and chronic obstructive pulmonary disease (COPD) or asthma, which lowers the 1-year mortality rate to a degree similar to that in patients without COPD or asthma, and without worsening respiratory function.¹ However, many clinicians still hesitate to start patients with COPD or asthma on a beta-blocker due to the fear of bronchoconstriction.²

THE RISKS

In patients with reversible airway disease, beta-blockers may increase airway reactivity and bronchospasm, as well as decrease the response to inhaled or oral beta-receptor agonists.³ Even topical ophthalmic nonselective beta-blockers for glaucoma can cause a worsening of pulmonary function.⁴ However, these data are from small trials in the 1970s and 1980s.

On the other hand, not giving beta-blockers can pose a risk of death. In a retrospective study of more than 200,000 patients with myocardial infarction, Gottlieb et al⁵ found that beta-blockers were associated with a 40% reduction in mortality rates in patients with conditions often considered a contraindication to beta-blocker therapy, such as congestive heart failure, pulmonary disease, and older age.⁵

CARDIOSELECTIVE BETA-BLOCKERS

Cardioselective beta-blockers with an affinity for the beta-1 receptor theoretically result in fewer adverse effects on the lungs. They competitively block the response to beta-adrenergic stimulation and selectively block beta-1 receptors with little or no effect on beta-2 receptors, except perhaps at high doses. However, this possible high-dose effect requires further study.

The effect of cardioselective beta-blockers on respiratory function was evaluated in two meta-analyses,^6,7 one in patients with mild to moderate reactive airway disease, the other in patients with mild to severe COPD. Patients with reactive airway disease who received a single dose of a beta-blocker had a 7.46% reduction in forced expiratory volume in the first second of expiration (FEV₁), an effect that was completely reversed by treatment with a beta-agonist inhaler. The FEV₁ increased by a statistically significantly greater amount in response to beta-agonists in patients who received beta-blockers (a single dose or continuous therapy) than in those who did not receive beta-blockers. Patients who received continuous cardioselective beta-blockers experienced no significant drop in FEV₁, and no new symptoms developed. These results led the authors to conclude that cardioselective beta-blockers do not cause a significant reduction in pulmonary function in patients with mild to moderate reactive airway disease and COPD and are therefore safe to use. A single dose of a cardioselective beta-blocker may produce a small decrease in FEV₁, especially in patients with reactive airway disease, but as therapy is continued over days to weeks, there is no significant change in symptoms or FEV₁ and no increase in the need for beta-agonist inhalers.

A major limitation of the two meta-analyses was that the patients were younger than most patients who require beta-blockers: the average age was 40 in patients with reactive airway disease, and 54 in patients with COPD. Also important to consider is that only patients with mild to moderate reactive airway disease were included. Patients with severe asthma, especially those with active bronchospasm, may react differently to even cardioselective beta-blockers.

NONSELECTIVE BETA-BLOCKERS

Recent studies suggest that nonselective beta-blockers can affect respiratory function in patients with COPD, but they have failed to show any harm. For example, propranolol (Inderal) was shown to worsen pulmonary function and to decrease the sensitivity of the airway to the effects of long-acting beta-2-agonists, but the 15 patients included in this study had no increase in respiratory symptoms.⁸

It has also been suggested that combined nonselective beta- and alpha-receptor blockade—eg, with labetalol (Trandate) or carvedilol (Coreg)—might be better tolerated than nonselective beta-blockers in patients with COPD.⁹ However, from limited data, Kotlyar et al¹⁰ suggested that carvedilol may be less well tolerated in patients with asthma than with COPD. All current evidence on combined nonselective beta-and alpha-blockade is observational, and it is not yet clear whether this class of beta-blockers is better tolerated due to alpha-blockade or merely because nonselective beta-blockers themselves are well tolerated.

OUR RECOMMENDATIONS

Yes. A number of large randomized controlled trials have shown inhaled corticosteroids to be beneficial in low doses for patients who have mild persistent asthma, and therefore these drugs are strongly recommended in this situation.¹

Asthma care providers should, however, consider this “yes” in the context of asthma severity, the goals of therapy, and the benefits and risks associated with inhaled corticosteroids.

CLASSIFICATION OF ASTHMA SEVERITY

Although the studies of asthma prevalence had methodologic limitations and therefore the true prevalence of mild persistent asthma cannot be determined, it is common. Fuhlbrigge et al² reported that most asthma patients have some form of persistent asthma. In contrast, Dusser et al³ reviewed available studies and concluded that most patients with asthma have either intermittent or mild persistent asthma.

GOALS: REDUCE IMPAIRMENT AND RISK

The goals of asthma management are to:

Reduce impairment by controlling symptoms so that normal activity levels can be maintained, by minimizing the need for short-acting bronchodilator use, and by maintaining normal pulmonary function; and to

Reduce risk by preventing progressive loss of lung function and recurrent exacerbations, and by optimizing pharmacotherapy while minimizing potential adverse effects.¹

EVIDENCE OF BENEFIT

The OPTIMA trial⁴ (Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma) was a double-blind, randomized trial carried out in 198 centers in 17 countries. Compared with those randomized to receive placebo, patients who were randomized to receive an inhaled corticosteroid, ie, budesonide (Pulmicort) 100 μg twice daily, had 60% fewer severe exacerbations (relative risk [RR] 0.4, 95% confidence interval [CI] 0.27–0.59) and 48% fewer days when their asthma was poorly controlled (RR 0.52, 95% CI 0.4–0.67). Adding a long-acting beta-agonist did not change this outcome.

The START study⁵ (Inhaled Steroid Treatment as Regular Therapy in Early Asthma) showed that, compared with placebo, starting inhaled budesonide within the first 2 years of asthma symptoms in patients with mild persistent asthma was associated with better asthma control and less need for additional asthma medication.

The IMPACT study⁶ (Improving Asthma Control Trial) showed that inhaled steroids need to be taken daily, on a regular schedule, rather than intermittently as needed. Patients received either inhaled budesonide as needed, budesonide 200 μg twice daily every day, or zafirlukast (Accolate) 20 mg twice daily. Daily budesonide therapy resulted in better asthma control, less bronchial hyperresponsiveness, and less airway inflammation compared with intermittent use, zafirlukast therapy, or placebo. Daily zafirlukast and intermittent steroid treatment produced similar results for all outcomes measured.

Despite this strong evidence supporting regular use of inhaled corticosteroids in patients with mild persistent asthma, many patients choose to take them intermittently.

Suissa et al⁷ found, in a large observational cohort study, that fewer patients died of asthma if they were receiving low-dose inhaled corticosteroids than if they were not. The rate of death due to asthma was lower in patients who had used more inhaled corticosteroids over the previous year, and the death rate was higher in those who had discontinued inhaled corticosteroids in the previous 3 months than in those who continued using them.

STEROIDS DO NOT SLOW THE LOSS OF LUNG FUNCTION

Compared with people without asthma, asthma patients have substantially lower values of forced expiratory volume in the first second of expiration (FEV₁). They also have a faster rate of functional decline: the average decrease in FEV₁ in asthma patients is 38 mL per year, compared with 22 mL per year in nonasthmatic people.⁹

Although inhaled corticosteroids have been shown to increase lung function in asthma patients in the short term, there is little convincing evidence to suggest that they affect the rate of decline in the long term.¹⁰ In fact, airway inflammation and bronchial hyperresponsiveness return to baseline within 2 weeks after inhaled corticosteroids are discontinued.¹⁰

DO INHALED CORTICOSTEROIDS STUNT CHILDREN’S GROWTH?

The safety of long-term low-dose inhaled corticosteroids is well established in adults. However, two large randomized controlled trials found that children treated with low-dose inhaled steroids (budesonide 200–400 μg per day) grew 1 to 1.5 cm less over 3 to 5 years of treatment than children receiving placebo.¹¹ However, this effect was primarily evident within the first year of therapy, and growth velocity was similar to that with placebo at the end of the treatment period (4 to 6 years).¹²

Agertoft and Pedersen¹³ found that taking inhaled corticosteroids long-term is unlikely to have an effect on final height. Children who took inhaled budesonide (up to an average daily dose of 500 μg) into adulthood ended up no shorter than those who did not.

Based on these and other data, inhaled corticosteroids are generally considered safe at recommended doses. However, the decision to prescribe them for long-term therapy should be based on the risks and benefits to the individual patient.¹

ALTERNATIVE DRUGS FOR MILD PERSISTENT ASTHMA

Leukotriene-modifying drugs include the leukotriene receptor antagonists montelukast (Singulair) and zafirlukast and the 5-lipoxygenase inhibitor zileuton (Zyflo CR). These drugs have been associated with statistically significant improvement in FEV₁ compared with placebo in patients with mild to moderate asthma, reductions in both blood and sputum eosinophils,¹⁴ and attenuation of bronchoconstriction with exercise.¹¹

Large randomized trials comparing leukotriene modifier therapy with low-dose inhaled steroids in adults and children with mild persistent asthma have found that although outcomes improve with either therapy, the improvement is statistically superior with inhaled steroids for most asthma-control measures. ^6,8 Low-dose inhaled steroid therapy in patients with mild persistent and moderate persistent asthma has been associated with superior clinical outcomes as well as greater improvement in pulmonary function than treatment with antileukotriene drugs (Table 2).⁸

Asthma is heterogeneous, and properly selected patients with mild persistent asthma may achieve good control with leukotrienemodifier monotherapy.¹⁵ Alternatives for patients with mild persistent asthma include the methylxanthine theophylline, but this drug is less desirable due to its narrow therapeutic index. ¹ The inhaled cromones nedocromil (Tilade) and cromolyn (Intal) were other options in this patient population, but their short half-lives made them less practical, and US production has been discontinued.

THE BOTTOM LINE

Though leukotriene receptor antagonists can be effective, the daily use of inhaled corticosteroids results in higher asthma control test scores, more symptom-free days, greater pre-bronchodilator FEV₁, and decreased percentage of sputum eosinophils⁶ in patients with mild persistent asthma, and the addition of a long-acting beta agonist does not provide additional benefit.⁴ Furthermore, daily use of inhaled corticosteroids in these patients has also been associated with a lower rate of asthma-related deaths and with less need for systemic corticosteroid therapy,^7,8 even though inhaled corticosteroids have not yet been shown to alter the progressive loss of lung function.¹⁰

Yes. A number of large randomized controlled trials have shown inhaled corticosteroids to be beneficial in low doses for patients who have mild persistent asthma, and therefore these drugs are strongly recommended in this situation.¹

Asthma care providers should, however, consider this “yes” in the context of asthma severity, the goals of therapy, and the benefits and risks associated with inhaled corticosteroids.

CLASSIFICATION OF ASTHMA SEVERITY

Although the studies of asthma prevalence had methodologic limitations and therefore the true prevalence of mild persistent asthma cannot be determined, it is common. Fuhlbrigge et al² reported that most asthma patients have some form of persistent asthma. In contrast, Dusser et al³ reviewed available studies and concluded that most patients with asthma have either intermittent or mild persistent asthma.

GOALS: REDUCE IMPAIRMENT AND RISK

The goals of asthma management are to:

Reduce impairment by controlling symptoms so that normal activity levels can be maintained, by minimizing the need for short-acting bronchodilator use, and by maintaining normal pulmonary function; and to

Reduce risk by preventing progressive loss of lung function and recurrent exacerbations, and by optimizing pharmacotherapy while minimizing potential adverse effects.¹

EVIDENCE OF BENEFIT

The OPTIMA trial⁴ (Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma) was a double-blind, randomized trial carried out in 198 centers in 17 countries. Compared with those randomized to receive placebo, patients who were randomized to receive an inhaled corticosteroid, ie, budesonide (Pulmicort) 100 μg twice daily, had 60% fewer severe exacerbations (relative risk [RR] 0.4, 95% confidence interval [CI] 0.27–0.59) and 48% fewer days when their asthma was poorly controlled (RR 0.52, 95% CI 0.4–0.67). Adding a long-acting beta-agonist did not change this outcome.

The START study⁵ (Inhaled Steroid Treatment as Regular Therapy in Early Asthma) showed that, compared with placebo, starting inhaled budesonide within the first 2 years of asthma symptoms in patients with mild persistent asthma was associated with better asthma control and less need for additional asthma medication.

The IMPACT study⁶ (Improving Asthma Control Trial) showed that inhaled steroids need to be taken daily, on a regular schedule, rather than intermittently as needed. Patients received either inhaled budesonide as needed, budesonide 200 μg twice daily every day, or zafirlukast (Accolate) 20 mg twice daily. Daily budesonide therapy resulted in better asthma control, less bronchial hyperresponsiveness, and less airway inflammation compared with intermittent use, zafirlukast therapy, or placebo. Daily zafirlukast and intermittent steroid treatment produced similar results for all outcomes measured.

Despite this strong evidence supporting regular use of inhaled corticosteroids in patients with mild persistent asthma, many patients choose to take them intermittently.

Suissa et al⁷ found, in a large observational cohort study, that fewer patients died of asthma if they were receiving low-dose inhaled corticosteroids than if they were not. The rate of death due to asthma was lower in patients who had used more inhaled corticosteroids over the previous year, and the death rate was higher in those who had discontinued inhaled corticosteroids in the previous 3 months than in those who continued using them.

STEROIDS DO NOT SLOW THE LOSS OF LUNG FUNCTION

Compared with people without asthma, asthma patients have substantially lower values of forced expiratory volume in the first second of expiration (FEV₁). They also have a faster rate of functional decline: the average decrease in FEV₁ in asthma patients is 38 mL per year, compared with 22 mL per year in nonasthmatic people.⁹

Although inhaled corticosteroids have been shown to increase lung function in asthma patients in the short term, there is little convincing evidence to suggest that they affect the rate of decline in the long term.¹⁰ In fact, airway inflammation and bronchial hyperresponsiveness return to baseline within 2 weeks after inhaled corticosteroids are discontinued.¹⁰

DO INHALED CORTICOSTEROIDS STUNT CHILDREN’S GROWTH?

The safety of long-term low-dose inhaled corticosteroids is well established in adults. However, two large randomized controlled trials found that children treated with low-dose inhaled steroids (budesonide 200–400 μg per day) grew 1 to 1.5 cm less over 3 to 5 years of treatment than children receiving placebo.¹¹ However, this effect was primarily evident within the first year of therapy, and growth velocity was similar to that with placebo at the end of the treatment period (4 to 6 years).¹²

Agertoft and Pedersen¹³ found that taking inhaled corticosteroids long-term is unlikely to have an effect on final height. Children who took inhaled budesonide (up to an average daily dose of 500 μg) into adulthood ended up no shorter than those who did not.

Based on these and other data, inhaled corticosteroids are generally considered safe at recommended doses. However, the decision to prescribe them for long-term therapy should be based on the risks and benefits to the individual patient.¹

ALTERNATIVE DRUGS FOR MILD PERSISTENT ASTHMA

Leukotriene-modifying drugs include the leukotriene receptor antagonists montelukast (Singulair) and zafirlukast and the 5-lipoxygenase inhibitor zileuton (Zyflo CR). These drugs have been associated with statistically significant improvement in FEV₁ compared with placebo in patients with mild to moderate asthma, reductions in both blood and sputum eosinophils,¹⁴ and attenuation of bronchoconstriction with exercise.¹¹

Large randomized trials comparing leukotriene modifier therapy with low-dose inhaled steroids in adults and children with mild persistent asthma have found that although outcomes improve with either therapy, the improvement is statistically superior with inhaled steroids for most asthma-control measures. ^6,8 Low-dose inhaled steroid therapy in patients with mild persistent and moderate persistent asthma has been associated with superior clinical outcomes as well as greater improvement in pulmonary function than treatment with antileukotriene drugs (Table 2).⁸

Asthma is heterogeneous, and properly selected patients with mild persistent asthma may achieve good control with leukotrienemodifier monotherapy.¹⁵ Alternatives for patients with mild persistent asthma include the methylxanthine theophylline, but this drug is less desirable due to its narrow therapeutic index. ¹ The inhaled cromones nedocromil (Tilade) and cromolyn (Intal) were other options in this patient population, but their short half-lives made them less practical, and US production has been discontinued.

THE BOTTOM LINE

Though leukotriene receptor antagonists can be effective, the daily use of inhaled corticosteroids results in higher asthma control test scores, more symptom-free days, greater pre-bronchodilator FEV₁, and decreased percentage of sputum eosinophils⁶ in patients with mild persistent asthma, and the addition of a long-acting beta agonist does not provide additional benefit.⁴ Furthermore, daily use of inhaled corticosteroids in these patients has also been associated with a lower rate of asthma-related deaths and with less need for systemic corticosteroid therapy,^7,8 even though inhaled corticosteroids have not yet been shown to alter the progressive loss of lung function.¹⁰

Yes. A number of large randomized controlled trials have shown inhaled corticosteroids to be beneficial in low doses for patients who have mild persistent asthma, and therefore these drugs are strongly recommended in this situation.¹

Asthma care providers should, however, consider this “yes” in the context of asthma severity, the goals of therapy, and the benefits and risks associated with inhaled corticosteroids.

CLASSIFICATION OF ASTHMA SEVERITY

Although the studies of asthma prevalence had methodologic limitations and therefore the true prevalence of mild persistent asthma cannot be determined, it is common. Fuhlbrigge et al² reported that most asthma patients have some form of persistent asthma. In contrast, Dusser et al³ reviewed available studies and concluded that most patients with asthma have either intermittent or mild persistent asthma.

GOALS: REDUCE IMPAIRMENT AND RISK

The goals of asthma management are to:

Reduce impairment by controlling symptoms so that normal activity levels can be maintained, by minimizing the need for short-acting bronchodilator use, and by maintaining normal pulmonary function; and to

Reduce risk by preventing progressive loss of lung function and recurrent exacerbations, and by optimizing pharmacotherapy while minimizing potential adverse effects.¹

EVIDENCE OF BENEFIT

The OPTIMA trial⁴ (Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma) was a double-blind, randomized trial carried out in 198 centers in 17 countries. Compared with those randomized to receive placebo, patients who were randomized to receive an inhaled corticosteroid, ie, budesonide (Pulmicort) 100 μg twice daily, had 60% fewer severe exacerbations (relative risk [RR] 0.4, 95% confidence interval [CI] 0.27–0.59) and 48% fewer days when their asthma was poorly controlled (RR 0.52, 95% CI 0.4–0.67). Adding a long-acting beta-agonist did not change this outcome.

The START study⁵ (Inhaled Steroid Treatment as Regular Therapy in Early Asthma) showed that, compared with placebo, starting inhaled budesonide within the first 2 years of asthma symptoms in patients with mild persistent asthma was associated with better asthma control and less need for additional asthma medication.

The IMPACT study⁶ (Improving Asthma Control Trial) showed that inhaled steroids need to be taken daily, on a regular schedule, rather than intermittently as needed. Patients received either inhaled budesonide as needed, budesonide 200 μg twice daily every day, or zafirlukast (Accolate) 20 mg twice daily. Daily budesonide therapy resulted in better asthma control, less bronchial hyperresponsiveness, and less airway inflammation compared with intermittent use, zafirlukast therapy, or placebo. Daily zafirlukast and intermittent steroid treatment produced similar results for all outcomes measured.

Despite this strong evidence supporting regular use of inhaled corticosteroids in patients with mild persistent asthma, many patients choose to take them intermittently.

Suissa et al⁷ found, in a large observational cohort study, that fewer patients died of asthma if they were receiving low-dose inhaled corticosteroids than if they were not. The rate of death due to asthma was lower in patients who had used more inhaled corticosteroids over the previous year, and the death rate was higher in those who had discontinued inhaled corticosteroids in the previous 3 months than in those who continued using them.

STEROIDS DO NOT SLOW THE LOSS OF LUNG FUNCTION

Compared with people without asthma, asthma patients have substantially lower values of forced expiratory volume in the first second of expiration (FEV₁). They also have a faster rate of functional decline: the average decrease in FEV₁ in asthma patients is 38 mL per year, compared with 22 mL per year in nonasthmatic people.⁹

Although inhaled corticosteroids have been shown to increase lung function in asthma patients in the short term, there is little convincing evidence to suggest that they affect the rate of decline in the long term.¹⁰ In fact, airway inflammation and bronchial hyperresponsiveness return to baseline within 2 weeks after inhaled corticosteroids are discontinued.¹⁰

DO INHALED CORTICOSTEROIDS STUNT CHILDREN’S GROWTH?

The safety of long-term low-dose inhaled corticosteroids is well established in adults. However, two large randomized controlled trials found that children treated with low-dose inhaled steroids (budesonide 200–400 μg per day) grew 1 to 1.5 cm less over 3 to 5 years of treatment than children receiving placebo.¹¹ However, this effect was primarily evident within the first year of therapy, and growth velocity was similar to that with placebo at the end of the treatment period (4 to 6 years).¹²

Agertoft and Pedersen¹³ found that taking inhaled corticosteroids long-term is unlikely to have an effect on final height. Children who took inhaled budesonide (up to an average daily dose of 500 μg) into adulthood ended up no shorter than those who did not.

Based on these and other data, inhaled corticosteroids are generally considered safe at recommended doses. However, the decision to prescribe them for long-term therapy should be based on the risks and benefits to the individual patient.¹

ALTERNATIVE DRUGS FOR MILD PERSISTENT ASTHMA

Leukotriene-modifying drugs include the leukotriene receptor antagonists montelukast (Singulair) and zafirlukast and the 5-lipoxygenase inhibitor zileuton (Zyflo CR). These drugs have been associated with statistically significant improvement in FEV₁ compared with placebo in patients with mild to moderate asthma, reductions in both blood and sputum eosinophils,¹⁴ and attenuation of bronchoconstriction with exercise.¹¹

Large randomized trials comparing leukotriene modifier therapy with low-dose inhaled steroids in adults and children with mild persistent asthma have found that although outcomes improve with either therapy, the improvement is statistically superior with inhaled steroids for most asthma-control measures. ^6,8 Low-dose inhaled steroid therapy in patients with mild persistent and moderate persistent asthma has been associated with superior clinical outcomes as well as greater improvement in pulmonary function than treatment with antileukotriene drugs (Table 2).⁸

Asthma is heterogeneous, and properly selected patients with mild persistent asthma may achieve good control with leukotrienemodifier monotherapy.¹⁵ Alternatives for patients with mild persistent asthma include the methylxanthine theophylline, but this drug is less desirable due to its narrow therapeutic index. ¹ The inhaled cromones nedocromil (Tilade) and cromolyn (Intal) were other options in this patient population, but their short half-lives made them less practical, and US production has been discontinued.

THE BOTTOM LINE

Though leukotriene receptor antagonists can be effective, the daily use of inhaled corticosteroids results in higher asthma control test scores, more symptom-free days, greater pre-bronchodilator FEV₁, and decreased percentage of sputum eosinophils⁶ in patients with mild persistent asthma, and the addition of a long-acting beta agonist does not provide additional benefit.⁴ Furthermore, daily use of inhaled corticosteroids in these patients has also been associated with a lower rate of asthma-related deaths and with less need for systemic corticosteroid therapy,^7,8 even though inhaled corticosteroids have not yet been shown to alter the progressive loss of lung function.¹⁰

Vitamin D deficiency may play a role in the pathogenesis of chronic heart failure, but whether giving patients supplements to raise their vitamin D levels into the normal range improves their survival is not clear.

ASSOCIATION BETWEEN VITAMIN D DEFICIENCY AND OTHER DISORDERS

In the mid-17th century, Whistler and Glisson independently described rickets as a severe bone-deforming disease characterized by growth retardation, bending of the spine, deformities of the legs, and weak and toneless muscles. Histologically, rickets is characterized by impaired mineralization of the cartilage in the epiphyseal growth plates in children. In 1919, Sir Edward Mellanby identified vitamin D deficiency as the cause.

Osteomalacia, another disease caused by vitamin D deficiency, is a disorder of mineralization of newly formed bone matrix in adults. Vitamin D, therefore, has well-known roles in maintaining bone health and calcium and phosphorus homeostasis.

In addition, vitamin D deficiency has been shown in recent years to be associated with myocardial dysfunction.^1,2

VITAMIN D METABOLISM IS COMPLEX

In skin exposed to ultraviolet B light, the provitamin 7-dehydrocholesterol is converted to vitamin D₃ (cholecalciferol). Vitamin D₃ is also obtained from dietary sources. However, many scientists consider vitamin D more a hormone than a classic vitamin, as adequate exposure to sunlight may negate the need for dietary supplements.

The active form of vitamin D is synthesized by hydroxylation in the liver and kidney. In the liver, hepatic enzymes add a hydroxyl (OH) group to vitamin D₃, changing it to 25-hydroxyvitamin D₃. In the kidney, 25-hydroxyvitamin D₃ receives another hydroxyl group, converting it to the biologically active metabolite 1,25-dihydroxyvitamin D₃ (calcitriol). This renal hydroxylation is via 1-alpha-hydroxylase activity and is directly under control of parathyroid hormone (PTH), and indirectly under control of the serum concentrations of calcium.

Interestingly, a number of different organ cells, including cardiomyocytes, also express 1-alpha-hydroxylase and therefore also convert 25-hydroxyvitamin D₃ to 1,25-dihydroxyvitamin D₃. Unlike the renal hydroxylation, this extrarenal process depends on cytokine activation and on serum levels of 25-hydroxyvitamin D₃.³ Low levels of 25-hydroxyvitamin D₃ lead to alterations in cellular control over growth, differentiation, and function.

The active form of vitamin D is transported protein-bound in the blood to various target organs, where it is delivered in free form to cells. Specific nuclear receptor proteins are found in many organs not classically considered target organs for vitamin D, including the skin, brain, skeletal muscles, cardiomyocytes, vascular endothelial cells, circulating monocytes, and activated B and T lymphocytes. Vitamin D plays a significant role in the autocrine and paracrine regulation of cellular function, growth, and differentiation in various organs.³

MOST HEART FAILURE PATIENTS HAVE LOW VITAMIN D LEVELS

More than 40% of men and 50% of women in the United States have low vitamin D levels (< 30 ng/mL [75 nmol/L])—and low levels in adults are associated with both coronary artery disease and heart failure.⁴ Most patients with heart failure have low levels.^5,6 Therefore, screening for vitamin D deficiency in patients with heart failure is appropriate and encouraged.

Low vitamin D levels carry a poor prognosis. Pilz et al⁵ measured baseline 25-hydroxyvitamin D₃ levels in 3,299 patients referred for elective coronary angiography and followed them prospectively for a median of 7.7 years. Even after adjustment for cardiac risk factors, patients who had low 25-hydroxyvitamin D₃ levels were more likely to die of heart failure or sudden cardiac death than patients with normal levels.

Boxer et al⁷ found an association between low 25-hydroxyvitamin D₃ levels and low exercise capacity and frailty in patients with systolic heart failure.

LOW VITAMIN D CONTRIBUTES TO THE PATHOGENESIS OF HEART FAILURE

In recent years, ideas about the pathophysiology of heart failure have expanded from a purely hemodynamic view to a more complex concept involving inflammatory cytokines and neurohormonal overactivation.⁸

Animal studies first showed vitamin D to inhibit the renin-angiotensin-aldosterone system, activation of which contributes to the salt and water retention seen in heart failure.^4,9

In addition, vitamin D has a number of effects that should help prevent hypertension, an important risk factor for heart failure. It protects the kidney by suppressing the reninangiotensin-aldosterone system, prevents secondary hyperparathyroidism and its effects on vascular stiffness, prevents insulin resistance, and suppresses inflammation, which protects vascular endothelial cells.¹⁰

The first studies to show a connection between cardiovascular homeostasis and vitamin D status were in animal models more than 20 years ago. These studies showed that 1,25-dihydroxyvitamin D₃ acts directly on cardiomyocyte vitamin D receptors, which are widely distributed throughout the body in several tissue types.¹¹

Excess PTH levels associated with low vitamin D levels may play a role in cardiovascular disease by leading to cardiomyocyte hypertrophy and interstitial fibrosis of the heart.¹² Animal studies have found that vitamin D suppresses cardiac hypertrophy.¹³ Vitamin D also plays a role in cardiomyocyte relaxation and may abrogate the hypercontractility associated with diastolic heart failure.^2,14

Currently, it is unclear whether vitamin D deficiency is a causative risk factor for heart failure or simply a reflection of the poor functional status of patients with heart failure that leads to decreased exposure to sunlight. This debate will continue until further randomized clinical trials address this association.

VITAMIN D AND HEART TRANSPLANTATION

One would expect that patients with endstage organ failure would be at high risk of vitamin D deficiency because of limited sunlight exposure. However, few studies have evaluated the role of this vitamin in heart transplant recipients.

Stein and colleagues¹⁵ measured serum 25-hydroxyvitamin D₃ immediately after transplantation in 46 heart and 23 liver transplant recipients. Levels were low in both types of transplant recipients, but liver transplant recipients had significantly lower levels than heart transplant patients. This could be explained by malabsorption and impaired synthesis of 25-hydroxyvitamin D₃ in end-stage liver disease.

Also, an important point is that osteoporosis is prevalent in postcardiac transplant patients and likely related to the immunosuppressive agents these patients must take.¹⁶ In theory, increasing the body’s stores of vitamin D during the pretransplant period could lower the rate of bone loss and osteoporosis after cardiac transplantation.

Further investigation is needed to determine whether restoring adequate levels of vitamin D at the time of or after transplantation prevents graft rejection or improves survival.

VITAMIN D SUPPLEMENTATION AND SURVIVAL IN HEART FAILURE

The best laboratory test to assess vitamin D levels is the serum 25-hydroxyvitamin D₃ concentration. A level between 20 and 30 ng/mL (50–75 nmol/L) is considered insufficient, and a level below 20 ng/mL (50 nmol/L) represents vitamin D deficiency.^4,5,11

Vitamin D insufficiency is typically treated with 800 to 1,000 IU of vitamin D₃ daily, whereas deficiency requires 50,000 IU of vitamin D₃ weekly for 6 to 8 weeks, followed by 800 to 1,000 IU daily.¹⁹ The goal of therapy is to increase the serum 25-hydroxyvitamin D₃ level above 30 ng/mL.¹⁹

Currently, it is unknown if vitamin D supplementation improves survival in heart failure. We recommend testing for vitamin D deficiency in all patients with heart failure and treating them as described above. For heart failure patients that are not deficient, daily intake of 800 to 1,000 IU of vitamin D is reasonable. Our review underscores the need for more studies to evaluate the efficacy of vitamin D replacement in improving survival in patients with heart failure.

KEY POINTS

• Screening for vitamin D deficiency in patients with heart failure is appropriate and encouraged.
• Vitamin D deficiency is common in patients with heart failure and in heart transplant recipients.
• In theory, achieving adequate levels of vitamin D would have a beneficial effect on patients with heart failure.
• Randomized controlled trials are needed to determine if vitamin D supplementation confers a survival benefit in patients with heart failure who have deficient vitamin D levels.

Vitamin D deficiency may play a role in the pathogenesis of chronic heart failure, but whether giving patients supplements to raise their vitamin D levels into the normal range improves their survival is not clear.

ASSOCIATION BETWEEN VITAMIN D DEFICIENCY AND OTHER DISORDERS

In the mid-17th century, Whistler and Glisson independently described rickets as a severe bone-deforming disease characterized by growth retardation, bending of the spine, deformities of the legs, and weak and toneless muscles. Histologically, rickets is characterized by impaired mineralization of the cartilage in the epiphyseal growth plates in children. In 1919, Sir Edward Mellanby identified vitamin D deficiency as the cause.

Osteomalacia, another disease caused by vitamin D deficiency, is a disorder of mineralization of newly formed bone matrix in adults. Vitamin D, therefore, has well-known roles in maintaining bone health and calcium and phosphorus homeostasis.

In addition, vitamin D deficiency has been shown in recent years to be associated with myocardial dysfunction.^1,2

VITAMIN D METABOLISM IS COMPLEX

In skin exposed to ultraviolet B light, the provitamin 7-dehydrocholesterol is converted to vitamin D₃ (cholecalciferol). Vitamin D₃ is also obtained from dietary sources. However, many scientists consider vitamin D more a hormone than a classic vitamin, as adequate exposure to sunlight may negate the need for dietary supplements.

The active form of vitamin D is synthesized by hydroxylation in the liver and kidney. In the liver, hepatic enzymes add a hydroxyl (OH) group to vitamin D₃, changing it to 25-hydroxyvitamin D₃. In the kidney, 25-hydroxyvitamin D₃ receives another hydroxyl group, converting it to the biologically active metabolite 1,25-dihydroxyvitamin D₃ (calcitriol). This renal hydroxylation is via 1-alpha-hydroxylase activity and is directly under control of parathyroid hormone (PTH), and indirectly under control of the serum concentrations of calcium.

Interestingly, a number of different organ cells, including cardiomyocytes, also express 1-alpha-hydroxylase and therefore also convert 25-hydroxyvitamin D₃ to 1,25-dihydroxyvitamin D₃. Unlike the renal hydroxylation, this extrarenal process depends on cytokine activation and on serum levels of 25-hydroxyvitamin D₃.³ Low levels of 25-hydroxyvitamin D₃ lead to alterations in cellular control over growth, differentiation, and function.

The active form of vitamin D is transported protein-bound in the blood to various target organs, where it is delivered in free form to cells. Specific nuclear receptor proteins are found in many organs not classically considered target organs for vitamin D, including the skin, brain, skeletal muscles, cardiomyocytes, vascular endothelial cells, circulating monocytes, and activated B and T lymphocytes. Vitamin D plays a significant role in the autocrine and paracrine regulation of cellular function, growth, and differentiation in various organs.³

MOST HEART FAILURE PATIENTS HAVE LOW VITAMIN D LEVELS

More than 40% of men and 50% of women in the United States have low vitamin D levels (< 30 ng/mL [75 nmol/L])—and low levels in adults are associated with both coronary artery disease and heart failure.⁴ Most patients with heart failure have low levels.^5,6 Therefore, screening for vitamin D deficiency in patients with heart failure is appropriate and encouraged.

Low vitamin D levels carry a poor prognosis. Pilz et al⁵ measured baseline 25-hydroxyvitamin D₃ levels in 3,299 patients referred for elective coronary angiography and followed them prospectively for a median of 7.7 years. Even after adjustment for cardiac risk factors, patients who had low 25-hydroxyvitamin D₃ levels were more likely to die of heart failure or sudden cardiac death than patients with normal levels.

Boxer et al⁷ found an association between low 25-hydroxyvitamin D₃ levels and low exercise capacity and frailty in patients with systolic heart failure.

LOW VITAMIN D CONTRIBUTES TO THE PATHOGENESIS OF HEART FAILURE

In recent years, ideas about the pathophysiology of heart failure have expanded from a purely hemodynamic view to a more complex concept involving inflammatory cytokines and neurohormonal overactivation.⁸

Animal studies first showed vitamin D to inhibit the renin-angiotensin-aldosterone system, activation of which contributes to the salt and water retention seen in heart failure.^4,9

In addition, vitamin D has a number of effects that should help prevent hypertension, an important risk factor for heart failure. It protects the kidney by suppressing the reninangiotensin-aldosterone system, prevents secondary hyperparathyroidism and its effects on vascular stiffness, prevents insulin resistance, and suppresses inflammation, which protects vascular endothelial cells.¹⁰

The first studies to show a connection between cardiovascular homeostasis and vitamin D status were in animal models more than 20 years ago. These studies showed that 1,25-dihydroxyvitamin D₃ acts directly on cardiomyocyte vitamin D receptors, which are widely distributed throughout the body in several tissue types.¹¹

Excess PTH levels associated with low vitamin D levels may play a role in cardiovascular disease by leading to cardiomyocyte hypertrophy and interstitial fibrosis of the heart.¹² Animal studies have found that vitamin D suppresses cardiac hypertrophy.¹³ Vitamin D also plays a role in cardiomyocyte relaxation and may abrogate the hypercontractility associated with diastolic heart failure.^2,14

Currently, it is unclear whether vitamin D deficiency is a causative risk factor for heart failure or simply a reflection of the poor functional status of patients with heart failure that leads to decreased exposure to sunlight. This debate will continue until further randomized clinical trials address this association.

VITAMIN D AND HEART TRANSPLANTATION

One would expect that patients with endstage organ failure would be at high risk of vitamin D deficiency because of limited sunlight exposure. However, few studies have evaluated the role of this vitamin in heart transplant recipients.

Stein and colleagues¹⁵ measured serum 25-hydroxyvitamin D₃ immediately after transplantation in 46 heart and 23 liver transplant recipients. Levels were low in both types of transplant recipients, but liver transplant recipients had significantly lower levels than heart transplant patients. This could be explained by malabsorption and impaired synthesis of 25-hydroxyvitamin D₃ in end-stage liver disease.

Also, an important point is that osteoporosis is prevalent in postcardiac transplant patients and likely related to the immunosuppressive agents these patients must take.¹⁶ In theory, increasing the body’s stores of vitamin D during the pretransplant period could lower the rate of bone loss and osteoporosis after cardiac transplantation.

Further investigation is needed to determine whether restoring adequate levels of vitamin D at the time of or after transplantation prevents graft rejection or improves survival.

VITAMIN D SUPPLEMENTATION AND SURVIVAL IN HEART FAILURE

The best laboratory test to assess vitamin D levels is the serum 25-hydroxyvitamin D₃ concentration. A level between 20 and 30 ng/mL (50–75 nmol/L) is considered insufficient, and a level below 20 ng/mL (50 nmol/L) represents vitamin D deficiency.^4,5,11

Vitamin D insufficiency is typically treated with 800 to 1,000 IU of vitamin D₃ daily, whereas deficiency requires 50,000 IU of vitamin D₃ weekly for 6 to 8 weeks, followed by 800 to 1,000 IU daily.¹⁹ The goal of therapy is to increase the serum 25-hydroxyvitamin D₃ level above 30 ng/mL.¹⁹

Currently, it is unknown if vitamin D supplementation improves survival in heart failure. We recommend testing for vitamin D deficiency in all patients with heart failure and treating them as described above. For heart failure patients that are not deficient, daily intake of 800 to 1,000 IU of vitamin D is reasonable. Our review underscores the need for more studies to evaluate the efficacy of vitamin D replacement in improving survival in patients with heart failure.

KEY POINTS

• Screening for vitamin D deficiency in patients with heart failure is appropriate and encouraged.
• Vitamin D deficiency is common in patients with heart failure and in heart transplant recipients.
• In theory, achieving adequate levels of vitamin D would have a beneficial effect on patients with heart failure.
• Randomized controlled trials are needed to determine if vitamin D supplementation confers a survival benefit in patients with heart failure who have deficient vitamin D levels.

Vitamin D deficiency may play a role in the pathogenesis of chronic heart failure, but whether giving patients supplements to raise their vitamin D levels into the normal range improves their survival is not clear.

ASSOCIATION BETWEEN VITAMIN D DEFICIENCY AND OTHER DISORDERS

In the mid-17th century, Whistler and Glisson independently described rickets as a severe bone-deforming disease characterized by growth retardation, bending of the spine, deformities of the legs, and weak and toneless muscles. Histologically, rickets is characterized by impaired mineralization of the cartilage in the epiphyseal growth plates in children. In 1919, Sir Edward Mellanby identified vitamin D deficiency as the cause.

Osteomalacia, another disease caused by vitamin D deficiency, is a disorder of mineralization of newly formed bone matrix in adults. Vitamin D, therefore, has well-known roles in maintaining bone health and calcium and phosphorus homeostasis.

In addition, vitamin D deficiency has been shown in recent years to be associated with myocardial dysfunction.^1,2

VITAMIN D METABOLISM IS COMPLEX

In skin exposed to ultraviolet B light, the provitamin 7-dehydrocholesterol is converted to vitamin D₃ (cholecalciferol). Vitamin D₃ is also obtained from dietary sources. However, many scientists consider vitamin D more a hormone than a classic vitamin, as adequate exposure to sunlight may negate the need for dietary supplements.

The active form of vitamin D is synthesized by hydroxylation in the liver and kidney. In the liver, hepatic enzymes add a hydroxyl (OH) group to vitamin D₃, changing it to 25-hydroxyvitamin D₃. In the kidney, 25-hydroxyvitamin D₃ receives another hydroxyl group, converting it to the biologically active metabolite 1,25-dihydroxyvitamin D₃ (calcitriol). This renal hydroxylation is via 1-alpha-hydroxylase activity and is directly under control of parathyroid hormone (PTH), and indirectly under control of the serum concentrations of calcium.

Interestingly, a number of different organ cells, including cardiomyocytes, also express 1-alpha-hydroxylase and therefore also convert 25-hydroxyvitamin D₃ to 1,25-dihydroxyvitamin D₃. Unlike the renal hydroxylation, this extrarenal process depends on cytokine activation and on serum levels of 25-hydroxyvitamin D₃.³ Low levels of 25-hydroxyvitamin D₃ lead to alterations in cellular control over growth, differentiation, and function.

The active form of vitamin D is transported protein-bound in the blood to various target organs, where it is delivered in free form to cells. Specific nuclear receptor proteins are found in many organs not classically considered target organs for vitamin D, including the skin, brain, skeletal muscles, cardiomyocytes, vascular endothelial cells, circulating monocytes, and activated B and T lymphocytes. Vitamin D plays a significant role in the autocrine and paracrine regulation of cellular function, growth, and differentiation in various organs.³

MOST HEART FAILURE PATIENTS HAVE LOW VITAMIN D LEVELS

More than 40% of men and 50% of women in the United States have low vitamin D levels (< 30 ng/mL [75 nmol/L])—and low levels in adults are associated with both coronary artery disease and heart failure.⁴ Most patients with heart failure have low levels.^5,6 Therefore, screening for vitamin D deficiency in patients with heart failure is appropriate and encouraged.

Low vitamin D levels carry a poor prognosis. Pilz et al⁵ measured baseline 25-hydroxyvitamin D₃ levels in 3,299 patients referred for elective coronary angiography and followed them prospectively for a median of 7.7 years. Even after adjustment for cardiac risk factors, patients who had low 25-hydroxyvitamin D₃ levels were more likely to die of heart failure or sudden cardiac death than patients with normal levels.

Boxer et al⁷ found an association between low 25-hydroxyvitamin D₃ levels and low exercise capacity and frailty in patients with systolic heart failure.

LOW VITAMIN D CONTRIBUTES TO THE PATHOGENESIS OF HEART FAILURE

In recent years, ideas about the pathophysiology of heart failure have expanded from a purely hemodynamic view to a more complex concept involving inflammatory cytokines and neurohormonal overactivation.⁸

Animal studies first showed vitamin D to inhibit the renin-angiotensin-aldosterone system, activation of which contributes to the salt and water retention seen in heart failure.^4,9

In addition, vitamin D has a number of effects that should help prevent hypertension, an important risk factor for heart failure. It protects the kidney by suppressing the reninangiotensin-aldosterone system, prevents secondary hyperparathyroidism and its effects on vascular stiffness, prevents insulin resistance, and suppresses inflammation, which protects vascular endothelial cells.¹⁰

The first studies to show a connection between cardiovascular homeostasis and vitamin D status were in animal models more than 20 years ago. These studies showed that 1,25-dihydroxyvitamin D₃ acts directly on cardiomyocyte vitamin D receptors, which are widely distributed throughout the body in several tissue types.¹¹

Excess PTH levels associated with low vitamin D levels may play a role in cardiovascular disease by leading to cardiomyocyte hypertrophy and interstitial fibrosis of the heart.¹² Animal studies have found that vitamin D suppresses cardiac hypertrophy.¹³ Vitamin D also plays a role in cardiomyocyte relaxation and may abrogate the hypercontractility associated with diastolic heart failure.^2,14

Currently, it is unclear whether vitamin D deficiency is a causative risk factor for heart failure or simply a reflection of the poor functional status of patients with heart failure that leads to decreased exposure to sunlight. This debate will continue until further randomized clinical trials address this association.

VITAMIN D AND HEART TRANSPLANTATION

One would expect that patients with endstage organ failure would be at high risk of vitamin D deficiency because of limited sunlight exposure. However, few studies have evaluated the role of this vitamin in heart transplant recipients.

Stein and colleagues¹⁵ measured serum 25-hydroxyvitamin D₃ immediately after transplantation in 46 heart and 23 liver transplant recipients. Levels were low in both types of transplant recipients, but liver transplant recipients had significantly lower levels than heart transplant patients. This could be explained by malabsorption and impaired synthesis of 25-hydroxyvitamin D₃ in end-stage liver disease.

Also, an important point is that osteoporosis is prevalent in postcardiac transplant patients and likely related to the immunosuppressive agents these patients must take.¹⁶ In theory, increasing the body’s stores of vitamin D during the pretransplant period could lower the rate of bone loss and osteoporosis after cardiac transplantation.

Further investigation is needed to determine whether restoring adequate levels of vitamin D at the time of or after transplantation prevents graft rejection or improves survival.

VITAMIN D SUPPLEMENTATION AND SURVIVAL IN HEART FAILURE

The best laboratory test to assess vitamin D levels is the serum 25-hydroxyvitamin D₃ concentration. A level between 20 and 30 ng/mL (50–75 nmol/L) is considered insufficient, and a level below 20 ng/mL (50 nmol/L) represents vitamin D deficiency.^4,5,11

Vitamin D insufficiency is typically treated with 800 to 1,000 IU of vitamin D₃ daily, whereas deficiency requires 50,000 IU of vitamin D₃ weekly for 6 to 8 weeks, followed by 800 to 1,000 IU daily.¹⁹ The goal of therapy is to increase the serum 25-hydroxyvitamin D₃ level above 30 ng/mL.¹⁹

Currently, it is unknown if vitamin D supplementation improves survival in heart failure. We recommend testing for vitamin D deficiency in all patients with heart failure and treating them as described above. For heart failure patients that are not deficient, daily intake of 800 to 1,000 IU of vitamin D is reasonable. Our review underscores the need for more studies to evaluate the efficacy of vitamin D replacement in improving survival in patients with heart failure.

KEY POINTS

• Screening for vitamin D deficiency in patients with heart failure is appropriate and encouraged.
• Vitamin D deficiency is common in patients with heart failure and in heart transplant recipients.
• In theory, achieving adequate levels of vitamin D would have a beneficial effect on patients with heart failure.
• Randomized controlled trials are needed to determine if vitamin D supplementation confers a survival benefit in patients with heart failure who have deficient vitamin D levels.

Yes. Obesity hypoventilation syndrome (OHS) is often undiagnosed and greatly increases perioperative risk. Therefore, we recommend trying to detect OHS in a timely manner. Treatment should begin without delay to avoid adverse perioperative outcomes, which can include acute-on-chronic respiratory failure requiring intensive-care monitoring and invasive mechanical ventilation, or death.

ALSO CALLED PICKWICKIAN SYNDROME

OHS is also known as Pickwickian syndrome, named for a character—a “fat boy” who is constantly falling asleep—in The Posthumous Papers of the Pickwick Club by Charles Dickens.

Salient features of OHS are:

• Obesity (body mass index ≥ 30 kg/m²)
• Sleep-disordered breathing (most patients with OHS are morbidly obese and have severe obstructive sleep apnea1)
• Chronic daytime alveolar hypoventilation: ie, Paco₂ ≥ 45 mm Hg (normal range 35–45 mm Hg) and Pao₂ < 70 mm Hg1 (normal range 85–95 mm Hg)
• No other identifiable cause of hypoventilation such as pulmonary disease (severe obstructive or restrictive), chest wall deformities, severe hypothyroidism, or neuromuscular disease.

WHY SCREEN FOR OHS?

Both obstructive sleep apnea and OHS worsen quality of life and increase the risk of serious disease and death.^2–3 Patients with severe sleep apnea, particularly those with hypercapnia (ie, OHS) are at higher risk of cardiopulmonary complications in the perioperative period.

Compared with eucapnic patients with obstructive sleep apnea, patients with OHS have higher health care expenses, are at higher risk of developing serious cardiovascular diseases such as pulmonary hypertension and congestive heart failure, and are more likely to die sooner.^4,5

Nowbar et al⁵ prospectively followed a group of severely obese patients after hospital discharge. At 18 months, 23% of those with OHS had died, compared with 9% of those without OHS. The groups were well matched for body mass index, age, and a number of comorbid conditions. Most of the deaths occurred in the first 3 months after hospital discharge. During the hospital stay, more patients with OHS were admitted to the intensive care unit and needed endotracheal intubation and mechanical ventilation, and more were discharged to a long-term facility.

A high level of suspicion can lead to early recognition and treatment, which may reduce the rate of adverse outcomes associated with undiagnosed and untreated OHS. Routine screening for hypercapnia in patients with sleep apnea might help to identify patients with OHS and allow for modifications in surgical approach, anesthetic technique, and postoperative monitoring, increasing patient safety.

HOW PREVALENT IS OHS?

Obstructive sleep apnea affects up to 20% of US adults and is undiagnosed and untreated in up to 90% of cases.⁶ Simple screening questionnaires have been shown to reliably identify patients at risk.^7,8

To date, no population-based prevalence studies of OHS have been done.

The overall prevalence of OHS in patients with obstructive sleep apnea is better studied: multiple prospective and retrospective studies across various geographic regions with a variety of racial or ethnic populations have shown it to be between 10% and 20%.^1,9 This range is very consistent among studies performed in Europe, the United States, and Japan, whether retrospective or prospective, and whether large or small.

The prevalence of OHS in the general adult population in the United States can, however, be estimated. If approximately 5% of the general US population has severe obesity (body mass index ≤ 40 kg/m²), if half of patients with severe obesity have obstructive sleep apnea,¹⁰ and if 15% of severely obese patients with sleep apnea have OHS, then a conservative estimated prevalence of OHS in the general adult US population is 0.37% (1 in 270 adults).

WHAT CAN BE DONE BEFORE ELECTIVE SURGERY?

Patients with OHS have an elevated serum bicarbonate level due to metabolic compensation for chronic respiratory acidosis. Moreover, they may have mild hypoxemia during wakefulness as measured by finger pulse oximetry.

The serum venous bicarbonate level is an easy and reasonable test to screen for hypercapnia in obese patients with obstructive sleep apnea because it is readily available, physiologically sensible, and less invasive than arterial puncture to measure blood gases.⁹

Arterial blood gas measurements, however, should be obtained to confirm the presence and severity of daytime hypercapnia in obese patients with hypoxemia during wakefulness or an elevated serum bicarbonate level.

Pulmonary function testing and chest imaging can exclude other causes of hypercapnia if hypercapnia is confirmed.

An overnight, attended polysomnographic study in a sleep laboratory is ultimately needed to establish the diagnosis and severity of obstructive sleep apnea and to titrate continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BPAP) therapy. Since most patients with OHS have severe obstructive sleep apnea, in-laboratory attended polysomnography allows the clinician to both diagnose and intervene with PAP therapy (a “split-night” study). Home titration with an auto-CPAP device is not recommended because it does not have the ability to titrate PAP pressures in response to hypoxemia or hypoventilation. Patients with OHS require attended, laboratory-based PAP titration with or without supplemental oxygen.

CPAP or BPAP therapy should be started during the few days or weeks before surgery, and adherence should be emphasized. Anesthesiologists might reconsider the choice of anesthetic technique in favor of regional anesthesia and modify postoperative pain management to reduce opioid requirements. Reinstituting CPAP or BPAP therapy upon extubation or arrival in the postoperative recovery unit can further reduce the risk of respiratory complications. Additional monitoring such as continuous pulse oximetry when the patient is on the general ward should be considered.

Yes. Obesity hypoventilation syndrome (OHS) is often undiagnosed and greatly increases perioperative risk. Therefore, we recommend trying to detect OHS in a timely manner. Treatment should begin without delay to avoid adverse perioperative outcomes, which can include acute-on-chronic respiratory failure requiring intensive-care monitoring and invasive mechanical ventilation, or death.

ALSO CALLED PICKWICKIAN SYNDROME

OHS is also known as Pickwickian syndrome, named for a character—a “fat boy” who is constantly falling asleep—in The Posthumous Papers of the Pickwick Club by Charles Dickens.

Salient features of OHS are:

• Obesity (body mass index ≥ 30 kg/m²)
• Sleep-disordered breathing (most patients with OHS are morbidly obese and have severe obstructive sleep apnea1)
• Chronic daytime alveolar hypoventilation: ie, Paco₂ ≥ 45 mm Hg (normal range 35–45 mm Hg) and Pao₂ < 70 mm Hg1 (normal range 85–95 mm Hg)
• No other identifiable cause of hypoventilation such as pulmonary disease (severe obstructive or restrictive), chest wall deformities, severe hypothyroidism, or neuromuscular disease.

WHY SCREEN FOR OHS?

Both obstructive sleep apnea and OHS worsen quality of life and increase the risk of serious disease and death.^2–3 Patients with severe sleep apnea, particularly those with hypercapnia (ie, OHS) are at higher risk of cardiopulmonary complications in the perioperative period.

Compared with eucapnic patients with obstructive sleep apnea, patients with OHS have higher health care expenses, are at higher risk of developing serious cardiovascular diseases such as pulmonary hypertension and congestive heart failure, and are more likely to die sooner.^4,5

Nowbar et al⁵ prospectively followed a group of severely obese patients after hospital discharge. At 18 months, 23% of those with OHS had died, compared with 9% of those without OHS. The groups were well matched for body mass index, age, and a number of comorbid conditions. Most of the deaths occurred in the first 3 months after hospital discharge. During the hospital stay, more patients with OHS were admitted to the intensive care unit and needed endotracheal intubation and mechanical ventilation, and more were discharged to a long-term facility.

A high level of suspicion can lead to early recognition and treatment, which may reduce the rate of adverse outcomes associated with undiagnosed and untreated OHS. Routine screening for hypercapnia in patients with sleep apnea might help to identify patients with OHS and allow for modifications in surgical approach, anesthetic technique, and postoperative monitoring, increasing patient safety.

HOW PREVALENT IS OHS?

Obstructive sleep apnea affects up to 20% of US adults and is undiagnosed and untreated in up to 90% of cases.⁶ Simple screening questionnaires have been shown to reliably identify patients at risk.^7,8

To date, no population-based prevalence studies of OHS have been done.

The overall prevalence of OHS in patients with obstructive sleep apnea is better studied: multiple prospective and retrospective studies across various geographic regions with a variety of racial or ethnic populations have shown it to be between 10% and 20%.^1,9 This range is very consistent among studies performed in Europe, the United States, and Japan, whether retrospective or prospective, and whether large or small.

The prevalence of OHS in the general adult population in the United States can, however, be estimated. If approximately 5% of the general US population has severe obesity (body mass index ≤ 40 kg/m²), if half of patients with severe obesity have obstructive sleep apnea,¹⁰ and if 15% of severely obese patients with sleep apnea have OHS, then a conservative estimated prevalence of OHS in the general adult US population is 0.37% (1 in 270 adults).

WHAT CAN BE DONE BEFORE ELECTIVE SURGERY?

Patients with OHS have an elevated serum bicarbonate level due to metabolic compensation for chronic respiratory acidosis. Moreover, they may have mild hypoxemia during wakefulness as measured by finger pulse oximetry.

The serum venous bicarbonate level is an easy and reasonable test to screen for hypercapnia in obese patients with obstructive sleep apnea because it is readily available, physiologically sensible, and less invasive than arterial puncture to measure blood gases.⁹

Arterial blood gas measurements, however, should be obtained to confirm the presence and severity of daytime hypercapnia in obese patients with hypoxemia during wakefulness or an elevated serum bicarbonate level.

Pulmonary function testing and chest imaging can exclude other causes of hypercapnia if hypercapnia is confirmed.

An overnight, attended polysomnographic study in a sleep laboratory is ultimately needed to establish the diagnosis and severity of obstructive sleep apnea and to titrate continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BPAP) therapy. Since most patients with OHS have severe obstructive sleep apnea, in-laboratory attended polysomnography allows the clinician to both diagnose and intervene with PAP therapy (a “split-night” study). Home titration with an auto-CPAP device is not recommended because it does not have the ability to titrate PAP pressures in response to hypoxemia or hypoventilation. Patients with OHS require attended, laboratory-based PAP titration with or without supplemental oxygen.

CPAP or BPAP therapy should be started during the few days or weeks before surgery, and adherence should be emphasized. Anesthesiologists might reconsider the choice of anesthetic technique in favor of regional anesthesia and modify postoperative pain management to reduce opioid requirements. Reinstituting CPAP or BPAP therapy upon extubation or arrival in the postoperative recovery unit can further reduce the risk of respiratory complications. Additional monitoring such as continuous pulse oximetry when the patient is on the general ward should be considered.

Yes. Obesity hypoventilation syndrome (OHS) is often undiagnosed and greatly increases perioperative risk. Therefore, we recommend trying to detect OHS in a timely manner. Treatment should begin without delay to avoid adverse perioperative outcomes, which can include acute-on-chronic respiratory failure requiring intensive-care monitoring and invasive mechanical ventilation, or death.

ALSO CALLED PICKWICKIAN SYNDROME

OHS is also known as Pickwickian syndrome, named for a character—a “fat boy” who is constantly falling asleep—in The Posthumous Papers of the Pickwick Club by Charles Dickens.

Salient features of OHS are:

• Obesity (body mass index ≥ 30 kg/m²)
• Sleep-disordered breathing (most patients with OHS are morbidly obese and have severe obstructive sleep apnea1)
• Chronic daytime alveolar hypoventilation: ie, Paco₂ ≥ 45 mm Hg (normal range 35–45 mm Hg) and Pao₂ < 70 mm Hg1 (normal range 85–95 mm Hg)
• No other identifiable cause of hypoventilation such as pulmonary disease (severe obstructive or restrictive), chest wall deformities, severe hypothyroidism, or neuromuscular disease.

WHY SCREEN FOR OHS?

Both obstructive sleep apnea and OHS worsen quality of life and increase the risk of serious disease and death.^2–3 Patients with severe sleep apnea, particularly those with hypercapnia (ie, OHS) are at higher risk of cardiopulmonary complications in the perioperative period.

Compared with eucapnic patients with obstructive sleep apnea, patients with OHS have higher health care expenses, are at higher risk of developing serious cardiovascular diseases such as pulmonary hypertension and congestive heart failure, and are more likely to die sooner.^4,5

Nowbar et al⁵ prospectively followed a group of severely obese patients after hospital discharge. At 18 months, 23% of those with OHS had died, compared with 9% of those without OHS. The groups were well matched for body mass index, age, and a number of comorbid conditions. Most of the deaths occurred in the first 3 months after hospital discharge. During the hospital stay, more patients with OHS were admitted to the intensive care unit and needed endotracheal intubation and mechanical ventilation, and more were discharged to a long-term facility.

A high level of suspicion can lead to early recognition and treatment, which may reduce the rate of adverse outcomes associated with undiagnosed and untreated OHS. Routine screening for hypercapnia in patients with sleep apnea might help to identify patients with OHS and allow for modifications in surgical approach, anesthetic technique, and postoperative monitoring, increasing patient safety.

HOW PREVALENT IS OHS?

Obstructive sleep apnea affects up to 20% of US adults and is undiagnosed and untreated in up to 90% of cases.⁶ Simple screening questionnaires have been shown to reliably identify patients at risk.^7,8

To date, no population-based prevalence studies of OHS have been done.

The overall prevalence of OHS in patients with obstructive sleep apnea is better studied: multiple prospective and retrospective studies across various geographic regions with a variety of racial or ethnic populations have shown it to be between 10% and 20%.^1,9 This range is very consistent among studies performed in Europe, the United States, and Japan, whether retrospective or prospective, and whether large or small.

The prevalence of OHS in the general adult population in the United States can, however, be estimated. If approximately 5% of the general US population has severe obesity (body mass index ≤ 40 kg/m²), if half of patients with severe obesity have obstructive sleep apnea,¹⁰ and if 15% of severely obese patients with sleep apnea have OHS, then a conservative estimated prevalence of OHS in the general adult US population is 0.37% (1 in 270 adults).

WHAT CAN BE DONE BEFORE ELECTIVE SURGERY?

Patients with OHS have an elevated serum bicarbonate level due to metabolic compensation for chronic respiratory acidosis. Moreover, they may have mild hypoxemia during wakefulness as measured by finger pulse oximetry.

The serum venous bicarbonate level is an easy and reasonable test to screen for hypercapnia in obese patients with obstructive sleep apnea because it is readily available, physiologically sensible, and less invasive than arterial puncture to measure blood gases.⁹

Arterial blood gas measurements, however, should be obtained to confirm the presence and severity of daytime hypercapnia in obese patients with hypoxemia during wakefulness or an elevated serum bicarbonate level.

Pulmonary function testing and chest imaging can exclude other causes of hypercapnia if hypercapnia is confirmed.

An overnight, attended polysomnographic study in a sleep laboratory is ultimately needed to establish the diagnosis and severity of obstructive sleep apnea and to titrate continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BPAP) therapy. Since most patients with OHS have severe obstructive sleep apnea, in-laboratory attended polysomnography allows the clinician to both diagnose and intervene with PAP therapy (a “split-night” study). Home titration with an auto-CPAP device is not recommended because it does not have the ability to titrate PAP pressures in response to hypoxemia or hypoventilation. Patients with OHS require attended, laboratory-based PAP titration with or without supplemental oxygen.

CPAP or BPAP therapy should be started during the few days or weeks before surgery, and adherence should be emphasized. Anesthesiologists might reconsider the choice of anesthetic technique in favor of regional anesthesia and modify postoperative pain management to reduce opioid requirements. Reinstituting CPAP or BPAP therapy upon extubation or arrival in the postoperative recovery unit can further reduce the risk of respiratory complications. Additional monitoring such as continuous pulse oximetry when the patient is on the general ward should be considered.