Patients who receive rectal indomethacin after undergoing endoscopic retrograde cholangiopancreatography (ERCP) are not any less likely to develop pancreatitis than individuals who don’t, according to the findings of a recent study published in Gastroenterology (2016 Jan 9. doi: 10.1053/j.gastro.2015.12.018).

“These results are in contrast to recent studies highlighting the benefit of rectal NSAIDS to prevent PEP [post-ECRP pancreatitis] in high-risk patients [and] counter the guidelines espoused by the European Society for Gastrointestinal Endoscopy, which recently recommended giving rectal indomethacin to prevent PEP in all patients undergoing ERCP,” said the study authors, led by Dr. John M. Levenick of Penn State University in Hershey, Pa.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Dr. Levenick and his coinvestigators screened 604 consecutive patients undergoing ERCP, with and without endoscopic ultrasound, at the Dartmouth-Hitchcock Medical Center between March 2013 and December 2014, eventually enrolling and randomizing 449 subjects into two cohorts: one in which subjects were given indomethacin after undergoing ERCP (n = 223), and one in which subjects were simply given a placebo (n = 226). Randomization happened after subjects’ major papilla had been reached, and cannulation attempts were started.

Individuals were excluded if they had active acute pancreatitis or had undergone ERCP to treat or diagnose acute pancreatitis, if they had any contraindications or allergies to NSAIDs, or were younger than 18 years of age, among other factors. The mean age of the indomethacin cohort was 64.9 years, with 118 (52.9%) females; in the placebo cohort, mean age was 64.3 years and 118 (52.2%) were female.

Pancreatitis occurred in 27 subjects overall, 16 (7.2%) of whom were in the indomethacin cohort and the other 11 (4.9%) were on placebo followed ERCP (P = .33). No subjects receiving indomethacin had severe or moderately severe PEP, but one subject had severe PEP and one had moderately severe PEP in the placebo cohort (P = 1.0). There was no necrotizing pancreatitis in either cohort, nor were there any significant differences in gastrointestinal bleeding (P = .75), death (P = .25), or 30-day hospital readmission (P = .1) between the two cohorts.

“Prophylactic rectal indomethacin did not reduce the incidence or severity of PEP in consecutive patients undergoing ERCP,” Dr. Levenick and his coauthors concluded, adding that “guidelines that recommend the administration of rectal indomethacin in all patients undergoing ERCP should be reconsidered.”

This study was funded by the National Pancreas Foundation and a grant from the National Institutes of Health. Dr. Levenick and his coauthors did not report any financial disclosures.

[email protected]

Patients who receive rectal indomethacin after undergoing endoscopic retrograde cholangiopancreatography (ERCP) are not any less likely to develop pancreatitis than individuals who don’t, according to the findings of a recent study published in Gastroenterology (2016 Jan 9. doi: 10.1053/j.gastro.2015.12.018).

“These results are in contrast to recent studies highlighting the benefit of rectal NSAIDS to prevent PEP [post-ECRP pancreatitis] in high-risk patients [and] counter the guidelines espoused by the European Society for Gastrointestinal Endoscopy, which recently recommended giving rectal indomethacin to prevent PEP in all patients undergoing ERCP,” said the study authors, led by Dr. John M. Levenick of Penn State University in Hershey, Pa.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Dr. Levenick and his coinvestigators screened 604 consecutive patients undergoing ERCP, with and without endoscopic ultrasound, at the Dartmouth-Hitchcock Medical Center between March 2013 and December 2014, eventually enrolling and randomizing 449 subjects into two cohorts: one in which subjects were given indomethacin after undergoing ERCP (n = 223), and one in which subjects were simply given a placebo (n = 226). Randomization happened after subjects’ major papilla had been reached, and cannulation attempts were started.

Individuals were excluded if they had active acute pancreatitis or had undergone ERCP to treat or diagnose acute pancreatitis, if they had any contraindications or allergies to NSAIDs, or were younger than 18 years of age, among other factors. The mean age of the indomethacin cohort was 64.9 years, with 118 (52.9%) females; in the placebo cohort, mean age was 64.3 years and 118 (52.2%) were female.

Pancreatitis occurred in 27 subjects overall, 16 (7.2%) of whom were in the indomethacin cohort and the other 11 (4.9%) were on placebo followed ERCP (P = .33). No subjects receiving indomethacin had severe or moderately severe PEP, but one subject had severe PEP and one had moderately severe PEP in the placebo cohort (P = 1.0). There was no necrotizing pancreatitis in either cohort, nor were there any significant differences in gastrointestinal bleeding (P = .75), death (P = .25), or 30-day hospital readmission (P = .1) between the two cohorts.

“Prophylactic rectal indomethacin did not reduce the incidence or severity of PEP in consecutive patients undergoing ERCP,” Dr. Levenick and his coauthors concluded, adding that “guidelines that recommend the administration of rectal indomethacin in all patients undergoing ERCP should be reconsidered.”

This study was funded by the National Pancreas Foundation and a grant from the National Institutes of Health. Dr. Levenick and his coauthors did not report any financial disclosures.

[email protected]

Patients who receive rectal indomethacin after undergoing endoscopic retrograde cholangiopancreatography (ERCP) are not any less likely to develop pancreatitis than individuals who don’t, according to the findings of a recent study published in Gastroenterology (2016 Jan 9. doi: 10.1053/j.gastro.2015.12.018).

“These results are in contrast to recent studies highlighting the benefit of rectal NSAIDS to prevent PEP [post-ECRP pancreatitis] in high-risk patients [and] counter the guidelines espoused by the European Society for Gastrointestinal Endoscopy, which recently recommended giving rectal indomethacin to prevent PEP in all patients undergoing ERCP,” said the study authors, led by Dr. John M. Levenick of Penn State University in Hershey, Pa.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Dr. Levenick and his coinvestigators screened 604 consecutive patients undergoing ERCP, with and without endoscopic ultrasound, at the Dartmouth-Hitchcock Medical Center between March 2013 and December 2014, eventually enrolling and randomizing 449 subjects into two cohorts: one in which subjects were given indomethacin after undergoing ERCP (n = 223), and one in which subjects were simply given a placebo (n = 226). Randomization happened after subjects’ major papilla had been reached, and cannulation attempts were started.

Individuals were excluded if they had active acute pancreatitis or had undergone ERCP to treat or diagnose acute pancreatitis, if they had any contraindications or allergies to NSAIDs, or were younger than 18 years of age, among other factors. The mean age of the indomethacin cohort was 64.9 years, with 118 (52.9%) females; in the placebo cohort, mean age was 64.3 years and 118 (52.2%) were female.

Pancreatitis occurred in 27 subjects overall, 16 (7.2%) of whom were in the indomethacin cohort and the other 11 (4.9%) were on placebo followed ERCP (P = .33). No subjects receiving indomethacin had severe or moderately severe PEP, but one subject had severe PEP and one had moderately severe PEP in the placebo cohort (P = 1.0). There was no necrotizing pancreatitis in either cohort, nor were there any significant differences in gastrointestinal bleeding (P = .75), death (P = .25), or 30-day hospital readmission (P = .1) between the two cohorts.

“Prophylactic rectal indomethacin did not reduce the incidence or severity of PEP in consecutive patients undergoing ERCP,” Dr. Levenick and his coauthors concluded, adding that “guidelines that recommend the administration of rectal indomethacin in all patients undergoing ERCP should be reconsidered.”

This study was funded by the National Pancreas Foundation and a grant from the National Institutes of Health. Dr. Levenick and his coauthors did not report any financial disclosures.

[email protected]

As magnetic resonance imaging technology continues to advance year after year, so does MRI’s ability to accurately detect pancreatic cysts, according to a new study published in the April issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2015.08.038).

“To our knowledge, this is the first study to analyze the relationship between the technical improvements in imaging techniques (specifically, MRI) and the presence of incidentally found PCLs [pancreatic cystic lesions],” said the study authors, led by Dr. Michael B. Wallace of the Mayo Clinic in Jacksonville, Fla.

Dr. Wallace and his coinvestigators launched this retrospective descriptive study selecting the first 50 consecutive abdominal MRI patients at the Jacksonville Mayo Clinic during January and February of each year from 2005 through 2014, for a total of 500 cases who met inclusion criteria included in the study. Patients were excluded if they had preexisting symptomatic or asymptomatic pancreatitis, either acute or chronic, pancreatic masses, pancreatic cysts, pancreatic surgery, pancreatic symptoms, or any pancreas-related indications found by MRI.

The clinic underwent periodic MRI updates over the course of the 10-year study, along with requisite software updates to “take advantage of the new hardware technology,” the study explains. Major hardware improvements, provided by Siemens Medical Solutions USA, were Symphony/Sonata, Espree/Avanto, and Aera/Skyra, while software updates corresponding to each hardware update were VA, VB, and VD, respectively.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Furthermore, each software update had other, smaller upgrades, leading to a total of 20 combinations of MRI hardware and software on which MRIs were performed over the 10 years. Every MRI taken included “an axial and a coronal T2-weighted single-shot (HASTE) pulse sequence [with] TR 1400-1500 ms, TE 82-99 ms, and slice thickness 5-7 mm (gap, 0.5-0.7 mm).” Each MRI was analyzed by a pancreatic MRI specialist to find incidental cysts.

The number of patients found with pancreatic cysts increased incrementally from 2005 to 2014, with 2010 being the year with the highest number. A total of 208 subjects (41.6%) were found to have incidental cysts, but only 44 of these cases were discovered in the original MRI. The presence of cysts was associated with older age in patients who had them; only 20% of all subjects under 50 years of age had cysts, compared to 32.4% of those between 50 and 60 years, 54.9% of those between 60 and 70 years, and 61.5% of those over the age of 70 years (P less than .01).

Additionally, 56.4% of all subjects with diabetes (P less than .01), 59.0% of subjects with nonmelanoma skin cancer (P less than .03), and 58.1% of those with hepatocarcinoma (P less than .02) were also found to have cysts. Most striking, however, is that newer hardware and software permutations were able to detect cysts in 56.3% (Skyra) of patients who had them, compared with only 30.3% (Symphony) of patients who underwent MRI on older technology.

“The variable field strength” (1.5 T vs. 3 T) was not significantly related to the presence of PCLs,” Dr. Wallace and his coauthors concluded. “We believe this may be secondary to the lack of power of the analysis, because only 6% of the examinations were 3-T studies. Therefore, we speculate that this relationship may be confirmed if the number of 3-T studies increased.”

Males and females each made up roughly 50% of the study population, with a median age of 60 years and 85% being white. Additionally, 4% of subjects had a family history of pancreatic cancer, 12% had a personal history of solid organ transplant, and 53% had a personal history of smoking.

This study was funded by the Mayo Clinic. Dr. Wallace disclosed that he has received grant funding from Olympus, Boston Scientific, and Cosmo Pharmaceuticals, and travel support from Olympus. No other authors reported any financial disclosures.

[email protected]

As magnetic resonance imaging technology continues to advance year after year, so does MRI’s ability to accurately detect pancreatic cysts, according to a new study published in the April issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2015.08.038).

“To our knowledge, this is the first study to analyze the relationship between the technical improvements in imaging techniques (specifically, MRI) and the presence of incidentally found PCLs [pancreatic cystic lesions],” said the study authors, led by Dr. Michael B. Wallace of the Mayo Clinic in Jacksonville, Fla.

Dr. Wallace and his coinvestigators launched this retrospective descriptive study selecting the first 50 consecutive abdominal MRI patients at the Jacksonville Mayo Clinic during January and February of each year from 2005 through 2014, for a total of 500 cases who met inclusion criteria included in the study. Patients were excluded if they had preexisting symptomatic or asymptomatic pancreatitis, either acute or chronic, pancreatic masses, pancreatic cysts, pancreatic surgery, pancreatic symptoms, or any pancreas-related indications found by MRI.

The clinic underwent periodic MRI updates over the course of the 10-year study, along with requisite software updates to “take advantage of the new hardware technology,” the study explains. Major hardware improvements, provided by Siemens Medical Solutions USA, were Symphony/Sonata, Espree/Avanto, and Aera/Skyra, while software updates corresponding to each hardware update were VA, VB, and VD, respectively.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Furthermore, each software update had other, smaller upgrades, leading to a total of 20 combinations of MRI hardware and software on which MRIs were performed over the 10 years. Every MRI taken included “an axial and a coronal T2-weighted single-shot (HASTE) pulse sequence [with] TR 1400-1500 ms, TE 82-99 ms, and slice thickness 5-7 mm (gap, 0.5-0.7 mm).” Each MRI was analyzed by a pancreatic MRI specialist to find incidental cysts.

The number of patients found with pancreatic cysts increased incrementally from 2005 to 2014, with 2010 being the year with the highest number. A total of 208 subjects (41.6%) were found to have incidental cysts, but only 44 of these cases were discovered in the original MRI. The presence of cysts was associated with older age in patients who had them; only 20% of all subjects under 50 years of age had cysts, compared to 32.4% of those between 50 and 60 years, 54.9% of those between 60 and 70 years, and 61.5% of those over the age of 70 years (P less than .01).

Additionally, 56.4% of all subjects with diabetes (P less than .01), 59.0% of subjects with nonmelanoma skin cancer (P less than .03), and 58.1% of those with hepatocarcinoma (P less than .02) were also found to have cysts. Most striking, however, is that newer hardware and software permutations were able to detect cysts in 56.3% (Skyra) of patients who had them, compared with only 30.3% (Symphony) of patients who underwent MRI on older technology.

“The variable field strength” (1.5 T vs. 3 T) was not significantly related to the presence of PCLs,” Dr. Wallace and his coauthors concluded. “We believe this may be secondary to the lack of power of the analysis, because only 6% of the examinations were 3-T studies. Therefore, we speculate that this relationship may be confirmed if the number of 3-T studies increased.”

Males and females each made up roughly 50% of the study population, with a median age of 60 years and 85% being white. Additionally, 4% of subjects had a family history of pancreatic cancer, 12% had a personal history of solid organ transplant, and 53% had a personal history of smoking.

This study was funded by the Mayo Clinic. Dr. Wallace disclosed that he has received grant funding from Olympus, Boston Scientific, and Cosmo Pharmaceuticals, and travel support from Olympus. No other authors reported any financial disclosures.

[email protected]

As magnetic resonance imaging technology continues to advance year after year, so does MRI’s ability to accurately detect pancreatic cysts, according to a new study published in the April issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2015.08.038).

“To our knowledge, this is the first study to analyze the relationship between the technical improvements in imaging techniques (specifically, MRI) and the presence of incidentally found PCLs [pancreatic cystic lesions],” said the study authors, led by Dr. Michael B. Wallace of the Mayo Clinic in Jacksonville, Fla.

Dr. Wallace and his coinvestigators launched this retrospective descriptive study selecting the first 50 consecutive abdominal MRI patients at the Jacksonville Mayo Clinic during January and February of each year from 2005 through 2014, for a total of 500 cases who met inclusion criteria included in the study. Patients were excluded if they had preexisting symptomatic or asymptomatic pancreatitis, either acute or chronic, pancreatic masses, pancreatic cysts, pancreatic surgery, pancreatic symptoms, or any pancreas-related indications found by MRI.

The clinic underwent periodic MRI updates over the course of the 10-year study, along with requisite software updates to “take advantage of the new hardware technology,” the study explains. Major hardware improvements, provided by Siemens Medical Solutions USA, were Symphony/Sonata, Espree/Avanto, and Aera/Skyra, while software updates corresponding to each hardware update were VA, VB, and VD, respectively.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Furthermore, each software update had other, smaller upgrades, leading to a total of 20 combinations of MRI hardware and software on which MRIs were performed over the 10 years. Every MRI taken included “an axial and a coronal T2-weighted single-shot (HASTE) pulse sequence [with] TR 1400-1500 ms, TE 82-99 ms, and slice thickness 5-7 mm (gap, 0.5-0.7 mm).” Each MRI was analyzed by a pancreatic MRI specialist to find incidental cysts.

The number of patients found with pancreatic cysts increased incrementally from 2005 to 2014, with 2010 being the year with the highest number. A total of 208 subjects (41.6%) were found to have incidental cysts, but only 44 of these cases were discovered in the original MRI. The presence of cysts was associated with older age in patients who had them; only 20% of all subjects under 50 years of age had cysts, compared to 32.4% of those between 50 and 60 years, 54.9% of those between 60 and 70 years, and 61.5% of those over the age of 70 years (P less than .01).

Additionally, 56.4% of all subjects with diabetes (P less than .01), 59.0% of subjects with nonmelanoma skin cancer (P less than .03), and 58.1% of those with hepatocarcinoma (P less than .02) were also found to have cysts. Most striking, however, is that newer hardware and software permutations were able to detect cysts in 56.3% (Skyra) of patients who had them, compared with only 30.3% (Symphony) of patients who underwent MRI on older technology.

“The variable field strength” (1.5 T vs. 3 T) was not significantly related to the presence of PCLs,” Dr. Wallace and his coauthors concluded. “We believe this may be secondary to the lack of power of the analysis, because only 6% of the examinations were 3-T studies. Therefore, we speculate that this relationship may be confirmed if the number of 3-T studies increased.”

Males and females each made up roughly 50% of the study population, with a median age of 60 years and 85% being white. Additionally, 4% of subjects had a family history of pancreatic cancer, 12% had a personal history of solid organ transplant, and 53% had a personal history of smoking.

This study was funded by the Mayo Clinic. Dr. Wallace disclosed that he has received grant funding from Olympus, Boston Scientific, and Cosmo Pharmaceuticals, and travel support from Olympus. No other authors reported any financial disclosures.

[email protected]

In contrast to stable chronic obstructive pulmonary disease (COPD),¹ acute exacerbations of COPD pose special management challenges and can significantly increase the risk of morbidity and death and the cost of care.

This review addresses the definition and diagnosis of COPD exacerbations, disease burden and costs, etiology and pathogenesis, and management and prevention strategies.

DEFINITIONS ARE PROBLEMATIC

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines a COPD exacer­bation as “an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication.”² It further categorizes acute exacerbations by severity:

• Mild—treated with increased frequency of doses of existing medications
• Moderate—treated with corticosteroids or antibiotics, or both
• Severe—requires hospital utilization (either emergency room treatment or admission).

Although descriptive and useful for retrospective analyses, this current definition poses ambiguities for clinicians. Day-to-day variation in symptoms is not routinely assessed, so deviations from baseline may be difficult to detect. Although clinical tools are available for assessing symptoms in stable and exacerbated states (eg, the COPD assessment test³ and the Exacerbations of Chronic Pulmonary Disease Tool [EXACT]⁴), they have not been widely adopted in daily practice. Also, according to the current definition, the severity of an exacerbation can be classified only after the course of action is determined, so the severity is not helpful for forming a management strategy at bedside. In addition, physicians may have different thresholds for prescribing antibiotics and corticosteroids.

An earlier definition categorized a COPD exacerbation by the presence of its three cardinal symptoms (ie, increased shortness of breath, sputum volume, and purulence):

• Type I—all three symptoms present
• Type II—two symptoms present
• Type III—one symptom present, accompanied by at least one of the following: upper respiratory tract infection within the past 5 days, unexplained fever, increased wheezing or cough, or 20% increased respiratory rate or heart rate from baseline.

This older definition was successfully used in a prospective clinical trial to identify patients who benefited most from antibiotics for COPD exacerbations.⁵

COPD exacerbation: an acute worsening of respiratory symptoms

Despite these caveats regarding a definition, most clinicians agree on the clinical presentation of a patient with COPD exacerbation: ie, having some combination of shortness of breath, increased sputum volume, and purulence. By the same token, patients with COPD who present with symptoms not typical of an exacerbation should be evaluated for another diagnosis. For instance, Tillie-Leblond et al⁶ reported that 49 (25%) of 197 patients hospitalized with an “unexplained” exacerbation of COPD were eventually diagnosed with pulmonary embolism.

EXACERBATIONS ARE COSTLY

The care of patients with COPD places a great burden on the healthcare system. Using multiple national databases, Ford et al⁷ estimated that medical costs in the United States in 2010 attributable to COPD and its complications were $32.1 billion.

The largest component of direct healthcare costs of COPD is exacerbations and subsequent hospitalizations.⁸ Data from a predominantly Medicare population indicate that the annualized mean COPD-related cost for a patient with no exacerbations was $1,425, compared with $12,765 for a patient with severe exacerbations.⁹ The investigators estimated that reducing exacerbations from two or more to none could save $5,125 per patient per year.

EXACERBATIONS AFFECT HEALTH BEYOND THE EVENT

COPD exacerbations are associated with a faster decline in lung function,¹⁰ reduced quality of life,¹¹ and lost workdays.⁷ A single exacerbation may cause a decline in lung function and health status that may not return to baseline for several months, particularly if another exacerbation occurs within 6 months.^12,13 COPD exacerbations have also been linked to poor clinical outcomes, including death.

In a prospective study in 304 men with COPD followed for 5 years, those who had three or more COPD exacerbations annually were four times as likely to die than patients who did not have an exacerbation.¹⁴ Nevertheless, the relationship with mortality may not be causal: Brusselle pointed out in an editorial¹⁵ that established mortality predictors for COPD do not include exacerbations, and symptomatic patients with COPD without any history of exacerbations are at greater risk of death than those who are asymptomatic but at high risk for exacerbations.

INFECTION + INFLAMMATION = EXACERBATION

An acute COPD exacerbation can be viewed as an acute inflammatory event superimposed on chronic inflammation associated with COPD. Inflammation in the airways increases resistance to air flow with consequent air trapping. Increased resistance and elastic load due to air trapping place respiratory muscles at a mechanical disadvantage and increase the work of breathing.

Infection starts the process

Infections are thought to be the major instigators of COPD exacerbation

Infections, particularly bacterial and viral, are thought to be the major instigators of COPD exacerbation, although environmental factors such as air pollution may also play a role.¹⁶

Airway inflammation is markedly reduced when bacterial infection is eradicated. But if bacterial colonization continues, inflammatory markers remain elevated despite clinical resolution of the exacerbation.¹⁷ Desai et al¹⁸ found that patients with COPD and chronic bronchitis with bacterial colonization had a larger symptom burden than patients without colonization, even without an exacerbation.

Allergic profile increases risk

Although most studies indicate that infection is the main cause of exacerbations, clinicians should consider other mechanisms of inflammation on an individual basis. COPD exacerbations may be phenotyped by measuring inflammatory markers, perhaps as a starting point for tailored therapies.

Bafadhel et al¹⁹ studied 145 patients with COPD over the course of a year and recorded various biomarkers at baseline and during exacerbations. Exacerbations had an inflammatory profile that was predominantly bacterial in 37%, viral in 10%, and eosinophilic in 17%, and had limited changes in the inflammatory profile in 14%. The remaining episodes were combinations of categories. In another study,²⁰ multivariate analysis conducted in two cohorts with COPD found that patients who had an allergic phenotype had more respiratory symptoms and a higher likelihood of COPD exacerbations.

Frequent COPD exacerbations are increasingly recognized as being associated with an asthma-COPD overlap syndrome, consisting of symptoms of increased airflow variability and incompletely reversible airflow obstruction.²¹

Inflammation as a marker of frequent exacerbations

Evidence is accumulating that supports systemic inflammation as a marker of frequent exacerbations. The Copenhagen Heart Study tested for baseline plasma C-reactive protein, fibrinogen, and white blood cell count in 6,574 stable patients with COPD.²² After multivariable adjustment, they found a significantly higher likelihood of having a subsequent exacerbation in patients who had all three biomarkers elevated (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.9–7.4), even in patients with milder COPD and those without previous exacerbations.

Past exacerbations predict risk

A history of exacerbation is the best predictor of future exacerbation

The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study²³ found that a history of acute COPD exacerbation was the single best predictor of future exacerbations. This risk factor remained stable over 3 years and was present across the severity of COPD, ie, patients at lower GOLD stages who had a history of frequent exacerbations were likely to have exacerbations during follow-up.

EXACERBATION INCREASES CARDIOVASCULAR RISK

COPD exacerbations increase the risk of cardiovascular events, particularly myocardial infarction.²⁴ During hospitalization for acute exacerbation of COPD, markers of myocardial injury and heart failure may be elevated and are a predictor of death.²⁵

Patel et al²⁶ measured arterial stiffness (aortic pulse wave velocity, a validated measure of cardiovascular risk) and cardiac biomarkers (troponin and N-terminal B-type natriuretic peptide) at baseline in 98 patients and longitudinally during and after a COPD exacerbation. In addition to increased levels of cardiac biomarkers, they found a significant rise in arterial stiffness during the exacerbation event without return to baseline levels over 35 days of follow-up. The arterial stiffness increase was related to airway inflammation as measured by sputum interleukin 6, particularly in patients with documented lower respiratory tract infection.

Retrospective analysis suggests a reduced all-cause mortality rate in COPD patients who are treated with beta-blockers.²⁷

Recommendation. We recommend that patients already taking a selective beta-blocker continue to do so during a COPD exacerbation.

OUTPATIENT MANAGEMENT

Treatment with a combination of a corticosteroid, antibiotic, and bronchodilator addresses the underlying pathophysiologic processes of an acute exacerbation: inflammation, infection, and airway trapping.

Short course of a corticosteroid improves outcomes

A single exacerbation may worsen health status for several months

A 10-day systemic course of a corticosteroid prescribed for COPD exacerbation before discharge from the emergency department was found to offer a small advantage over placebo for reducing treatment failure (unscheduled physician visits, return to emergency room for recurrent symptoms) and improving dyspnea scores and lung function.²⁸ Even just a 3-day course improved measures of respiration (forced expiratory volume in the first second of expiration [FEV₁] and arterial oxygenation) at days 3 and 10, and reduced treatment failures compared with placebo.²⁹

Corticosteroid prescription should not be taken lightly, because adverse effects are common. In a systematic review, one adverse effect (hyperglycemia, weight gain, or insomnia) occurred for every five people treated.³⁰

Identifying subgroups of patients most likely to benefit from corticosteroid treatment may be helpful. Corticosteroids may delay improvement in patients without eosinophilic inflammation and hasten recovery in those with more than 2% peripheral eosinophils.³¹ Siva et al³² found that limiting corticosteroids to patients with sputum eosinophilia reduced corticosteroid use and reduced severe exacerbations compared with standard care.³²

Recommendation. For an acute exacerbation, we prescribe a short course of corticosteroids (eg, prednisone 40 mg daily for 5 to 7 days). Tapering dosing is probably unnecessary because adrenal insufficiency is uncommon before 2 weeks of corticosteroid exposure. Clinicians should weigh the merits of tapering (reduced corticosteroid exposure) against patient inconvenience and difficulty following complicated instructions.

Antibiotics help, but exact strategy uncertain

Although antibiotic therapy is one of the three pillars of COPD exacerbation management, the optimal antimicrobial agent, duration of therapy, and which patients will benefit remain areas of controversy and research. Thus far, large trials have been unable to definitely show the superiority of one antibiotic over another.^33,34

A 1987 randomized controlled trial⁵ of antibiotic therapy in acute exacerbation of COPD found the greatest benefit to patients who had all three cardinal symptoms (ie, increased shortness of breath, sputum volume, and purulence), with less marked but still significant improvement in patients with two symptoms. In a 2012 multicenter trial³⁵ patients with mild to moderate COPD experiencing an exacerbation were treated with either combined amoxicillin and clavulanate or placebo if they had one of the three cardinal symptoms. The antibiotic group had a significantly higher clinical cure rate at days 9 to 11 (74.1% vs 59.9%) as well as a longer time until the next exacerbation (233 vs 160 days).

Recommendation. Optimal antibiotic management of COPD exacerbations may also depend on risk factors. For patients with at least two cardinal symptoms, we favor a scheme akin to one proposed for treating community-acquired pneumonia (Table 1).^16,36

INPATIENT MANAGEMENT

Corticosteroids improve outcomes

A Department of Veterans Affairs cooperative trial³⁷ randomized 271 patients hospitalized with COPD exacerbation to receive either corticosteroids (intravenous followed by oral) or placebo for either 2 weeks or 8 weeks. Corticosteroid recipients had lower rates of treatment failure at 30 and 90 days, defined as death from any cause, need for mechanical ventilation, readmission, or intensification of pharmacologic therapy. Corticosteroid therapy also reduced hospital length of stay and improved the rate of recovery. The longer corticosteroid course was associated with a higher rate of adverse effects.

Oral corticosteroids not inferior to intravenous

Using the same end point of treatment failure as the Veterans Affairs cooperative trial, deJong et al³⁸ demonstrated that prednisone 60 mg by mouth was not inferior to intravenous prednisone. Neither trial demonstrated a difference in mortality between corticosteroid use and placebo.

Short course of a corticosteroid not inferior to a long course

In 2013, the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial³⁹ randomized 314 patients presenting with an acute COPD exacerbation (92% requiring hospital admission) to oral prednisone 40 mg daily for either 5 days or 14 days. They found that the short course was noninferior in preventing exacerbations over the ensuing 6 months in terms of death and the need for mechanical ventilation.

Recommendation. Our threshold for initiating systemic corticosteroid therapy is lower in hospitalized patients than in outpatients. We recommend the regimen of the REDUCE trial: prednisone 40 mg daily for 5 days.

Corticosteroids for patients on ventilatory support

Severe COPD exacerbations requiring admission to intensive care are a significant source of morbidity and mortality, and the strategy of corticosteroid treatment is still under investigation.

Intravenous corticosteroids are effective. A multicenter trial⁴⁰ in 354 patients requiring either invasive or noninvasive mechanical ventilation randomized them to treatment with either intravenous methylprednisolone (tapered) or placebo. Treatment was associated with fewer mechanical ventilation days and a lower rate of noninvasive ventilation failure.

Low-dose oral corticosteroids ineffective. In contrast, an open-label trial⁴¹ of patients requiring ventilatory support and randomized to either oral prednisone (1 mg/kg for up to 10 days) or usual care found no difference in intensive care length of stay or noninvasive ventilation failure. This study used the oral route and smaller doses, and its open-label design might have introduced bias.

Lower-dose steroids better than high-dose. A 2014 cohort study of 17,239 patients admitted to the ICU with acute exacerbations of COPD evaluated outcomes of treatment with high methylprednisolone dosages (> 240 mg per day) vs lower dosages, using propensity score matching.⁴² No mortality difference was found between the groups. The lower dosage group (median methylprednisolone dose 100 mg per day) had shorter hospital and intensive care unit stays, shorter duration of noninvasive positive pressure ventilation, less need for insulin therapy, and fewer fungal infections.

Antibiotics for hospitalized patients

Only scarce data are available on the use of antibiotics for patients hospitalized with COPD exacerbation. In a study of patients hospitalized with COPD exacerbations, adding doxycycline to corticosteroids led to better clinical success and cure rates at 10 days compared with placebo, but the primary end point of clinical success at 30 days was not different between the two groups.⁴³

BRONCHODILATORS: A MAINSTAY OF COPD TREATMENT

Bronchodilators are an important part of treatment of COPD exacerbations in inpatient and outpatient settings.

Nebulized beta-2 agonists are given every 1 to 4 hours. Albuterol at a 2.5-mg dose in each nebulization was found to be as effective as 5 mg for length of hospital stay and recovery of lung function in patients with an acute exacerbation of COPD.⁴⁴

Adding an anticholinergic may help. Nebulized anticholinergics can be given alone or combined with beta-2 agonists. Whether long-acting bronchodilators should be used to manage COPD patients hospitalized with an exacerbation requires further inquiry. In an observational study with historical controls, Drescher and colleagues⁴⁵ found cost savings and shorter hospital stays if tiotropium (a long-acting anticholinergic) was added to the respiratory care protocol, which also included formoterol (a long-acting beta-2 agonist).

OXYGEN: TITRATED APPROACH SAFER

Caution is needed to avoid hyperoxemic hypercapnia in patients on oxygen

Oxygen should be supplied during a COPD exacerbation to ensure adequate oxyhemoglobin saturation. Caution is needed to avoid hyperoxemic hypercapnia, particularly in patients with severe COPD and propensity to ventilatory failure. The routine administration of oxygen at high concentrations during a COPD exacerbation has been associated with a higher mortality rate than with a titrated oxygen approach.⁴⁶ Long-term oxygen treatment started at discharge or as outpatient therapy is associated with reduced hospital admissions and shorter hospital stays for acute exacerbations of COPD.⁴⁷

VENTILATION SUPPORT

Noninvasive positive-pressure ventilation is a useful adjunct to treatment of COPD exacerbations with evidence of ventilatory failure (ie, acute respiratory acidosis), helping to offset the work of breathing until respiratory system mechanics improve. Keenan et al⁴⁸ reviewed 15 randomized controlled trials, involving 636 patients, of noninvasive positive-pressure ventilation in the setting of COPD exacerbation. They concluded that noninvasive positive-pressure ventilation reduced the in-hospital mortality rate and length of stay compared with standard therapy. Noninvasive positive-pressure ventilation is most useful in patients with severe COPD exacerbations and acute respiratory acidosis (pH < 7.35).⁴⁹

Intubation and mechanical ventilation. Although no standards exist for determining which COPD exacerbations may be too severe for noninvasive positive-pressure ventilation, intubation is clearly indicated for impending respiratory failure or hemodynamic instability. Other factors to consider include the greater likelihood of noninvasive positive-pressure ventilation failure in patients with severe respiratory acidosis (pH < 7.25 is associated with a > 50% failure rate) and in those with no improvement in acidosis or respiratory rate during the first hour after initiation of noninvasive positive-pressure ventilation.⁵⁰

PREVENTING EXACERBATIONS

Recent data indicate that COPD exacerbations can often be prevented (Table 2).

Inhaled pharmacotherapy

Inhaled pharmacotherapeutic agents, singly or in combination, reduce the frequency of COPD exacerbations.

Combined long-acting beta-2 agonist and corticosteroid is better than single-agent therapy. In 2007, the Towards a Revolution in COPD Health (TORCH) trial⁵¹ evaluated outpatient therapy in more than 6,000 patients worldwide with either an inhaled long-acting beta-2 agonist (salmeterol), an inhaled corticosteroid (fluticasone), both drugs in combination, or placebo. Patients had baseline prebronchodilator FEV₁ of less than 60% and were followed for 3 years. No difference was found between the groups in the primary end point of deaths, but the annualized rate of moderate to severe exacerbations was reduced by 25% in the group that received combination therapy vs placebo. Combination therapy showed superior efficacy over individual drug therapy in preventing exacerbations. Treatment with the inhaled corticosteroid, whether alone or in combination with salmeterol, increased the risk of pneumonia.

A long-acting antimuscarinic agent is better than placebo. In 2008, the Understanding Potential Long-Term Impacts on Function With Tiotropium (UPLIFT) trial⁵² randomized nearly 6,000 patients with COPD and a postbronchodilator FEV₁ of less than 70% to placebo or tiotropium, a long-acting antimuscarinic agent. Tiotropium reduced the exacerbation rate by 14% compared with placebo and improved quality of life.

Antimuscarinics may be better than beta-2 agonists. Head-to-head comparisons suggest that long-acting antimuscarinic agents are preferable to long-acting beta-2 agonists for preventing COPD exacerbations.^53,54

Triple therapy: evidence is mixed. For patients with severe symptomatic COPD and frequent exacerbations, triple therapy with a combination of an inhaled long-acting antimuscarinic agent, an inhaled long-acting beta-2 agonist, and an inhaled corticosteroid has been suggested.

Data to support this practice are limited. In the Canadian Optimal Trial,⁵⁵ the rate of exacerbations was not different between tiotropium alone, tiotropium plus salmeterol, and triple therapy. However, the rate of hospitalization for severe exacerbation was lower with triple therapy than tiotropium alone. A large, retrospective cohort study also supported triple therapy by finding reduced mortality, hospitalizations, and need for oral corticosteroid bursts compared to combination therapy with an inhaled long-acting beta-2 agonist and an inhaled corticosteroid.⁵⁶

The drawback of triple therapy is an increased incidence of pneumonia associated with combined beta-2 agonist and corticosteroids, most likely due to the corticosteroid component.⁵¹ The risk appears to be higher for higher potency corticosteroids, eg, fluticasone.⁵⁷

In 2014, the Withdrawal of Inhaled Steroids During Optimised Bronchodilator Management (WISDOM) trial⁵⁸ randomized nearly 2,500 patients with a history of COPD exacerbation receiving triple therapy consisting of tiotropium, salmeterol, and inhaled fluticasone to either continue treatment or withdraw the corticosteroid for 3 months. The investigators defined an annualized exacerbation rate of 1.2 (ie, a 20% increase) as the upper limit of the confidence interval for an acceptable therapeutic margin of noninferiority. The study showed that the risk of moderate to severe exacerbations with combined tiotropium and salmeterol was noninferior to triple therapy.

Nevertheless, caution is advised when removing the corticosteroid component from triple therapy. The trial demonstrated a worsening in overall health status, some reduction in lung function, and a transient increase in severe exacerbations in the withdrawal group. Patients with increased symptom burden at baseline and a history of severe exacerbations may not be optimal candidates for this strategy.

Roflumilast is effective but has side effects

Roflumilast, an oral phosphodiesterase 4 inhibitor, is an anti-inflammatory drug without bronchodilator properties. In randomized controlled trials, the drug was associated with a 17% reduction in acute exacerbations compared with placebo.⁵⁹

Adding roflumilast to either a long-acting beta-2 agonist or a long-acting antimuscarinic agent resulted in a 6% to 8% further reduction in the proportion of patients with exacerbation.^60,61 Martinez et al⁶¹ found that roflumilast added to a regimen of a long-acting beta-2 agonist plus an inhaled corticosteroid reduced moderate to severe exacerbations by 14.2%, even in the presence of tiotropium. Compared with placebo, roflumilast treatment reduced exacerbations necessitating hospitalizations by 23.9%.

The FDA has approved oral roflumilast 500 µg once daily to prevent COPD exacerbations.

Roflumilast is frequently associated with side effects, including gastrointestinal symptoms (chiefly diarrhea), weight loss, and psychiatric effects. A benefit-to-harm study in 2014 concluded that using the drug is only favorable for patients who have a high risk of severe exacerbations, ie, those who have a greater than 22% baseline risk of having at least one exacerbation annually.⁶²

Recommendation. Roflumilast should be reserved for patients who have severe COPD with a chronic bronchitis phenotype (ie, with cough and sputum production) and repeated exacerbations despite an optimal regimen of an inhaled corticosteroid, long-acting beta-2 agonist, and long-acting antimuscarinic agent.

Macrolide antibiotics: Role unclear

Macrolide antibiotics have anti-inflammatory and immunomodulatory activities.

Azithromycin: fewer exacerbations but some side effects. A multicenter trial⁶³ in 1,142 COPD patients randomized to either oral azithromycin 250 mg daily or placebo found a 27% reduction in the risk of COPD exacerbation in the intervention arm. No differences were found between the groups in mortality, hospitalizations, emergency department visits, or respiratory failure. Hearing loss and increased macrolide resistance were noted in the intervention arm. In a secondary subgroup analysis,⁶⁴ no difference in efficacy was found by sex, history of chronic bronchitis, oxygen use, or concomitant COPD treatment.

The COPD: Influence of Macrolides on Exacerbation Frequency in Patients trial⁶⁵ helped refine patient selection for macrolide therapy. In this single-center study, 92 patients with COPD and at least three exacerbations during the year prior to enrollment were randomized to receive either azithromycin 500 mg three times weekly or placebo. Exacerbations in the intervention group were markedly reduced (42%) with no difference in hospitalization rate.

The place of macrolide antibiotics in the treatment strategy of COPD is unclear, and they are not currently part of the GOLD guidelines. Still unknown is the incremental benefit of adding them to existing preventive regimens, cardiovascular safety, side effects, and potential effects on the resident microbial flora. 

Other antibiotics have also been investigated for efficacy in preventing exacerbations.

Moxifloxacin: fewer exacerbations. The Pulsed Moxifloxacin Usage and Its Long-term Impact on the Reduction of Subsequent Exacerbations study⁶⁶ randomized more than 1,000 patients with stable COPD to receive either moxifloxacin 400 mg or placebo daily for 5 days repeated every 8 weeks for six courses. Frequent assessment during the treatment period and for 6 months afterward revealed a reduced exacerbation rate in the intervention group but without benefit in hospitalization rate, mortality, lung function, or health status.

Recommendation. Azithromycin (either 250 mg daily or 500 mg three times weekly) can be considered for patients who have repeated COPD exacerbations despite an optimal regimen of an inhaled corticosteroid, inhaled long-acting beta-2 agonist, and inhaled long-acting antimuscarinic agent. The need to continue azithromycin should be reassessed yearly.

Mucolytics

Greatest benefit to patients not taking inhaled corticosteroids. Mucolytic agents help clear airway secretions by reducing viscosity. N-acetylcysteine and carbocysteine (not available in the United States) also have antioxidant properties that may counteract oxidant stress associated with acute COPD exacerbations.

The Bronchitis Randomized on NAC Cost-Utility Study (BRONCUS)⁶⁷ randomized 523 COPD patients to N-acetylcysteine 600 mg daily or placebo. After 3 years of follow-up, no differences were found in the rate of exacerbations, lung function decline, and quality of life. Subgroup analysis suggested a reduction in exacerbations for patients who were not taking inhaled corticosteroids.

The Effect of Carbocisteine on Acute Exacerbation of Chronic Obstructive Pulmonary Disease (PEACE) study randomized more than 700 patients from multiple centers in China who had COPD and a recent history of exacerbations; they found a 25% lower exacerbation rate over 1 year with carbocysteine vs placebo.⁶⁸ Most of the patients (83%) were not on inhaled corticosteroids, which complemented findings of the BRONCUS trial.

The Effect of High Dose N-acetylcysteine on Air Trapping and Airway Resistance of COPD (HIACE) study randomized 120 patients with stable COPD in a hospital in Hong Kong to either oral N-acetylcysteine (600 mg twice daily) or placebo and found a reduced exacerbation rate of exacerbations. Patients were matched at baseline for inhaled corticosteroid use.⁶⁹

In 2014, the Twice Daily N-acetylcysteine 600 mg for Exacerbations of Chronic Obstructive Pulmonary Disease (PANTHEON) study⁷⁰ randomized 1,006 patients from multiple hospitals in China with a history of moderate to severe COPD and exacerbations to receive either N-acetylcysteine 600 mg twice daily or placebo for 1 year. They found a 22% reduction in exacerbations in the treatment group vs placebo.  

GOLD guidelines² recommend mucolytics for patients with severe COPD and exacerbations when inhaled corticosteroids are not available or affordable.

Recommendation. Mucolytics may be useful for patients with difficulty expectorating and with a history of exacerbations despite appropriate inhaled therapy.

OTHER INTERVENTIONS CAN HELP

Pulmonary rehabilitation provides multiple benefits

Pulmonary rehabilitation increases exercise tolerance and reduces symptoms

Pulmonary rehabilitation increases exercise tolerance and reduces symptom burden in patients with stable COPD. It is also a multidisciplinary effort that may help reinforce adherence to medications, enhance COPD education, and provide closer medical surveillance to patients at high risk for recurrent exacerbations.

A small randomized controlled trial⁷¹ prescribed pulmonary rehabilitation on discharge for a COPD exacerbation and found sustainable improvements in exercise capacity and health status after 3 months.

In a later study,⁷² the same group started pulmonary rehabilitation within a week of hospital discharge and found reduced hospital readmissions over a 3-month period.

Smoking cessation is always worth advocating

A large observational cohort study concluded that current smokers were at a higher risk for COPD exacerbations compared with former smokers.⁷³ Although there are no randomized controlled trials that assess the effects of smoking cessation at the time of COPD exacerbation, we recommend seizing the opportunity to implement this important intervention.

Vaccinations: Influenza and pneumococcal

Influenza vaccination is associated with reduced incidence of hospitalization among patients with cardiopulmonary disease.⁷⁴ A meta-analysis of randomized clinical trials of influenza vaccination for patients with COPD⁷⁵ reported significantly fewer exacerbations from vaccination, mostly owing to fewer episodes occurring after 3 to 4 weeks, coinciding with anticipated vaccine-induced immune protection. Furumoto and colleagues⁷⁶ reported an added benefit of combined vaccination with 23-valent pneumococcal polysaccharide vaccine and influenza vaccine in reducing hospital admissions over influenza vaccination alone. We also recommend providing the 13-valent pneumococcal conjugate vaccine to patients with COPD, particularly for those older than 65, consistent with CDC recommendations.⁷⁷

In contrast to stable chronic obstructive pulmonary disease (COPD),¹ acute exacerbations of COPD pose special management challenges and can significantly increase the risk of morbidity and death and the cost of care.

This review addresses the definition and diagnosis of COPD exacerbations, disease burden and costs, etiology and pathogenesis, and management and prevention strategies.

DEFINITIONS ARE PROBLEMATIC

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines a COPD exacer­bation as “an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication.”² It further categorizes acute exacerbations by severity:

• Mild—treated with increased frequency of doses of existing medications
• Moderate—treated with corticosteroids or antibiotics, or both
• Severe—requires hospital utilization (either emergency room treatment or admission).

Although descriptive and useful for retrospective analyses, this current definition poses ambiguities for clinicians. Day-to-day variation in symptoms is not routinely assessed, so deviations from baseline may be difficult to detect. Although clinical tools are available for assessing symptoms in stable and exacerbated states (eg, the COPD assessment test³ and the Exacerbations of Chronic Pulmonary Disease Tool [EXACT]⁴), they have not been widely adopted in daily practice. Also, according to the current definition, the severity of an exacerbation can be classified only after the course of action is determined, so the severity is not helpful for forming a management strategy at bedside. In addition, physicians may have different thresholds for prescribing antibiotics and corticosteroids.

An earlier definition categorized a COPD exacerbation by the presence of its three cardinal symptoms (ie, increased shortness of breath, sputum volume, and purulence):

• Type I—all three symptoms present
• Type II—two symptoms present
• Type III—one symptom present, accompanied by at least one of the following: upper respiratory tract infection within the past 5 days, unexplained fever, increased wheezing or cough, or 20% increased respiratory rate or heart rate from baseline.

This older definition was successfully used in a prospective clinical trial to identify patients who benefited most from antibiotics for COPD exacerbations.⁵

COPD exacerbation: an acute worsening of respiratory symptoms

Despite these caveats regarding a definition, most clinicians agree on the clinical presentation of a patient with COPD exacerbation: ie, having some combination of shortness of breath, increased sputum volume, and purulence. By the same token, patients with COPD who present with symptoms not typical of an exacerbation should be evaluated for another diagnosis. For instance, Tillie-Leblond et al⁶ reported that 49 (25%) of 197 patients hospitalized with an “unexplained” exacerbation of COPD were eventually diagnosed with pulmonary embolism.

EXACERBATIONS ARE COSTLY

The care of patients with COPD places a great burden on the healthcare system. Using multiple national databases, Ford et al⁷ estimated that medical costs in the United States in 2010 attributable to COPD and its complications were $32.1 billion.

The largest component of direct healthcare costs of COPD is exacerbations and subsequent hospitalizations.⁸ Data from a predominantly Medicare population indicate that the annualized mean COPD-related cost for a patient with no exacerbations was $1,425, compared with $12,765 for a patient with severe exacerbations.⁹ The investigators estimated that reducing exacerbations from two or more to none could save $5,125 per patient per year.

EXACERBATIONS AFFECT HEALTH BEYOND THE EVENT

COPD exacerbations are associated with a faster decline in lung function,¹⁰ reduced quality of life,¹¹ and lost workdays.⁷ A single exacerbation may cause a decline in lung function and health status that may not return to baseline for several months, particularly if another exacerbation occurs within 6 months.^12,13 COPD exacerbations have also been linked to poor clinical outcomes, including death.

In a prospective study in 304 men with COPD followed for 5 years, those who had three or more COPD exacerbations annually were four times as likely to die than patients who did not have an exacerbation.¹⁴ Nevertheless, the relationship with mortality may not be causal: Brusselle pointed out in an editorial¹⁵ that established mortality predictors for COPD do not include exacerbations, and symptomatic patients with COPD without any history of exacerbations are at greater risk of death than those who are asymptomatic but at high risk for exacerbations.

INFECTION + INFLAMMATION = EXACERBATION

An acute COPD exacerbation can be viewed as an acute inflammatory event superimposed on chronic inflammation associated with COPD. Inflammation in the airways increases resistance to air flow with consequent air trapping. Increased resistance and elastic load due to air trapping place respiratory muscles at a mechanical disadvantage and increase the work of breathing.

Infection starts the process

Infections are thought to be the major instigators of COPD exacerbation

Infections, particularly bacterial and viral, are thought to be the major instigators of COPD exacerbation, although environmental factors such as air pollution may also play a role.¹⁶

Airway inflammation is markedly reduced when bacterial infection is eradicated. But if bacterial colonization continues, inflammatory markers remain elevated despite clinical resolution of the exacerbation.¹⁷ Desai et al¹⁸ found that patients with COPD and chronic bronchitis with bacterial colonization had a larger symptom burden than patients without colonization, even without an exacerbation.

Allergic profile increases risk

Although most studies indicate that infection is the main cause of exacerbations, clinicians should consider other mechanisms of inflammation on an individual basis. COPD exacerbations may be phenotyped by measuring inflammatory markers, perhaps as a starting point for tailored therapies.

Bafadhel et al¹⁹ studied 145 patients with COPD over the course of a year and recorded various biomarkers at baseline and during exacerbations. Exacerbations had an inflammatory profile that was predominantly bacterial in 37%, viral in 10%, and eosinophilic in 17%, and had limited changes in the inflammatory profile in 14%. The remaining episodes were combinations of categories. In another study,²⁰ multivariate analysis conducted in two cohorts with COPD found that patients who had an allergic phenotype had more respiratory symptoms and a higher likelihood of COPD exacerbations.

Frequent COPD exacerbations are increasingly recognized as being associated with an asthma-COPD overlap syndrome, consisting of symptoms of increased airflow variability and incompletely reversible airflow obstruction.²¹

Inflammation as a marker of frequent exacerbations

Evidence is accumulating that supports systemic inflammation as a marker of frequent exacerbations. The Copenhagen Heart Study tested for baseline plasma C-reactive protein, fibrinogen, and white blood cell count in 6,574 stable patients with COPD.²² After multivariable adjustment, they found a significantly higher likelihood of having a subsequent exacerbation in patients who had all three biomarkers elevated (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.9–7.4), even in patients with milder COPD and those without previous exacerbations.

Past exacerbations predict risk

A history of exacerbation is the best predictor of future exacerbation

The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study²³ found that a history of acute COPD exacerbation was the single best predictor of future exacerbations. This risk factor remained stable over 3 years and was present across the severity of COPD, ie, patients at lower GOLD stages who had a history of frequent exacerbations were likely to have exacerbations during follow-up.

EXACERBATION INCREASES CARDIOVASCULAR RISK

COPD exacerbations increase the risk of cardiovascular events, particularly myocardial infarction.²⁴ During hospitalization for acute exacerbation of COPD, markers of myocardial injury and heart failure may be elevated and are a predictor of death.²⁵

Patel et al²⁶ measured arterial stiffness (aortic pulse wave velocity, a validated measure of cardiovascular risk) and cardiac biomarkers (troponin and N-terminal B-type natriuretic peptide) at baseline in 98 patients and longitudinally during and after a COPD exacerbation. In addition to increased levels of cardiac biomarkers, they found a significant rise in arterial stiffness during the exacerbation event without return to baseline levels over 35 days of follow-up. The arterial stiffness increase was related to airway inflammation as measured by sputum interleukin 6, particularly in patients with documented lower respiratory tract infection.

Retrospective analysis suggests a reduced all-cause mortality rate in COPD patients who are treated with beta-blockers.²⁷

Recommendation. We recommend that patients already taking a selective beta-blocker continue to do so during a COPD exacerbation.

OUTPATIENT MANAGEMENT

Treatment with a combination of a corticosteroid, antibiotic, and bronchodilator addresses the underlying pathophysiologic processes of an acute exacerbation: inflammation, infection, and airway trapping.

Short course of a corticosteroid improves outcomes

A single exacerbation may worsen health status for several months

A 10-day systemic course of a corticosteroid prescribed for COPD exacerbation before discharge from the emergency department was found to offer a small advantage over placebo for reducing treatment failure (unscheduled physician visits, return to emergency room for recurrent symptoms) and improving dyspnea scores and lung function.²⁸ Even just a 3-day course improved measures of respiration (forced expiratory volume in the first second of expiration [FEV₁] and arterial oxygenation) at days 3 and 10, and reduced treatment failures compared with placebo.²⁹

Corticosteroid prescription should not be taken lightly, because adverse effects are common. In a systematic review, one adverse effect (hyperglycemia, weight gain, or insomnia) occurred for every five people treated.³⁰

Identifying subgroups of patients most likely to benefit from corticosteroid treatment may be helpful. Corticosteroids may delay improvement in patients without eosinophilic inflammation and hasten recovery in those with more than 2% peripheral eosinophils.³¹ Siva et al³² found that limiting corticosteroids to patients with sputum eosinophilia reduced corticosteroid use and reduced severe exacerbations compared with standard care.³²

Recommendation. For an acute exacerbation, we prescribe a short course of corticosteroids (eg, prednisone 40 mg daily for 5 to 7 days). Tapering dosing is probably unnecessary because adrenal insufficiency is uncommon before 2 weeks of corticosteroid exposure. Clinicians should weigh the merits of tapering (reduced corticosteroid exposure) against patient inconvenience and difficulty following complicated instructions.

Antibiotics help, but exact strategy uncertain

Although antibiotic therapy is one of the three pillars of COPD exacerbation management, the optimal antimicrobial agent, duration of therapy, and which patients will benefit remain areas of controversy and research. Thus far, large trials have been unable to definitely show the superiority of one antibiotic over another.^33,34

A 1987 randomized controlled trial⁵ of antibiotic therapy in acute exacerbation of COPD found the greatest benefit to patients who had all three cardinal symptoms (ie, increased shortness of breath, sputum volume, and purulence), with less marked but still significant improvement in patients with two symptoms. In a 2012 multicenter trial³⁵ patients with mild to moderate COPD experiencing an exacerbation were treated with either combined amoxicillin and clavulanate or placebo if they had one of the three cardinal symptoms. The antibiotic group had a significantly higher clinical cure rate at days 9 to 11 (74.1% vs 59.9%) as well as a longer time until the next exacerbation (233 vs 160 days).

Recommendation. Optimal antibiotic management of COPD exacerbations may also depend on risk factors. For patients with at least two cardinal symptoms, we favor a scheme akin to one proposed for treating community-acquired pneumonia (Table 1).^16,36

INPATIENT MANAGEMENT

Corticosteroids improve outcomes

A Department of Veterans Affairs cooperative trial³⁷ randomized 271 patients hospitalized with COPD exacerbation to receive either corticosteroids (intravenous followed by oral) or placebo for either 2 weeks or 8 weeks. Corticosteroid recipients had lower rates of treatment failure at 30 and 90 days, defined as death from any cause, need for mechanical ventilation, readmission, or intensification of pharmacologic therapy. Corticosteroid therapy also reduced hospital length of stay and improved the rate of recovery. The longer corticosteroid course was associated with a higher rate of adverse effects.

Oral corticosteroids not inferior to intravenous

Using the same end point of treatment failure as the Veterans Affairs cooperative trial, deJong et al³⁸ demonstrated that prednisone 60 mg by mouth was not inferior to intravenous prednisone. Neither trial demonstrated a difference in mortality between corticosteroid use and placebo.

Short course of a corticosteroid not inferior to a long course

In 2013, the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial³⁹ randomized 314 patients presenting with an acute COPD exacerbation (92% requiring hospital admission) to oral prednisone 40 mg daily for either 5 days or 14 days. They found that the short course was noninferior in preventing exacerbations over the ensuing 6 months in terms of death and the need for mechanical ventilation.

Recommendation. Our threshold for initiating systemic corticosteroid therapy is lower in hospitalized patients than in outpatients. We recommend the regimen of the REDUCE trial: prednisone 40 mg daily for 5 days.

Corticosteroids for patients on ventilatory support

Severe COPD exacerbations requiring admission to intensive care are a significant source of morbidity and mortality, and the strategy of corticosteroid treatment is still under investigation.

Intravenous corticosteroids are effective. A multicenter trial⁴⁰ in 354 patients requiring either invasive or noninvasive mechanical ventilation randomized them to treatment with either intravenous methylprednisolone (tapered) or placebo. Treatment was associated with fewer mechanical ventilation days and a lower rate of noninvasive ventilation failure.

Low-dose oral corticosteroids ineffective. In contrast, an open-label trial⁴¹ of patients requiring ventilatory support and randomized to either oral prednisone (1 mg/kg for up to 10 days) or usual care found no difference in intensive care length of stay or noninvasive ventilation failure. This study used the oral route and smaller doses, and its open-label design might have introduced bias.

Lower-dose steroids better than high-dose. A 2014 cohort study of 17,239 patients admitted to the ICU with acute exacerbations of COPD evaluated outcomes of treatment with high methylprednisolone dosages (> 240 mg per day) vs lower dosages, using propensity score matching.⁴² No mortality difference was found between the groups. The lower dosage group (median methylprednisolone dose 100 mg per day) had shorter hospital and intensive care unit stays, shorter duration of noninvasive positive pressure ventilation, less need for insulin therapy, and fewer fungal infections.

Antibiotics for hospitalized patients

Only scarce data are available on the use of antibiotics for patients hospitalized with COPD exacerbation. In a study of patients hospitalized with COPD exacerbations, adding doxycycline to corticosteroids led to better clinical success and cure rates at 10 days compared with placebo, but the primary end point of clinical success at 30 days was not different between the two groups.⁴³

BRONCHODILATORS: A MAINSTAY OF COPD TREATMENT

Bronchodilators are an important part of treatment of COPD exacerbations in inpatient and outpatient settings.

Nebulized beta-2 agonists are given every 1 to 4 hours. Albuterol at a 2.5-mg dose in each nebulization was found to be as effective as 5 mg for length of hospital stay and recovery of lung function in patients with an acute exacerbation of COPD.⁴⁴

Adding an anticholinergic may help. Nebulized anticholinergics can be given alone or combined with beta-2 agonists. Whether long-acting bronchodilators should be used to manage COPD patients hospitalized with an exacerbation requires further inquiry. In an observational study with historical controls, Drescher and colleagues⁴⁵ found cost savings and shorter hospital stays if tiotropium (a long-acting anticholinergic) was added to the respiratory care protocol, which also included formoterol (a long-acting beta-2 agonist).

OXYGEN: TITRATED APPROACH SAFER

Caution is needed to avoid hyperoxemic hypercapnia in patients on oxygen

Oxygen should be supplied during a COPD exacerbation to ensure adequate oxyhemoglobin saturation. Caution is needed to avoid hyperoxemic hypercapnia, particularly in patients with severe COPD and propensity to ventilatory failure. The routine administration of oxygen at high concentrations during a COPD exacerbation has been associated with a higher mortality rate than with a titrated oxygen approach.⁴⁶ Long-term oxygen treatment started at discharge or as outpatient therapy is associated with reduced hospital admissions and shorter hospital stays for acute exacerbations of COPD.⁴⁷

VENTILATION SUPPORT

Noninvasive positive-pressure ventilation is a useful adjunct to treatment of COPD exacerbations with evidence of ventilatory failure (ie, acute respiratory acidosis), helping to offset the work of breathing until respiratory system mechanics improve. Keenan et al⁴⁸ reviewed 15 randomized controlled trials, involving 636 patients, of noninvasive positive-pressure ventilation in the setting of COPD exacerbation. They concluded that noninvasive positive-pressure ventilation reduced the in-hospital mortality rate and length of stay compared with standard therapy. Noninvasive positive-pressure ventilation is most useful in patients with severe COPD exacerbations and acute respiratory acidosis (pH < 7.35).⁴⁹

Intubation and mechanical ventilation. Although no standards exist for determining which COPD exacerbations may be too severe for noninvasive positive-pressure ventilation, intubation is clearly indicated for impending respiratory failure or hemodynamic instability. Other factors to consider include the greater likelihood of noninvasive positive-pressure ventilation failure in patients with severe respiratory acidosis (pH < 7.25 is associated with a > 50% failure rate) and in those with no improvement in acidosis or respiratory rate during the first hour after initiation of noninvasive positive-pressure ventilation.⁵⁰

PREVENTING EXACERBATIONS

Recent data indicate that COPD exacerbations can often be prevented (Table 2).

Inhaled pharmacotherapy

Inhaled pharmacotherapeutic agents, singly or in combination, reduce the frequency of COPD exacerbations.

Combined long-acting beta-2 agonist and corticosteroid is better than single-agent therapy. In 2007, the Towards a Revolution in COPD Health (TORCH) trial⁵¹ evaluated outpatient therapy in more than 6,000 patients worldwide with either an inhaled long-acting beta-2 agonist (salmeterol), an inhaled corticosteroid (fluticasone), both drugs in combination, or placebo. Patients had baseline prebronchodilator FEV₁ of less than 60% and were followed for 3 years. No difference was found between the groups in the primary end point of deaths, but the annualized rate of moderate to severe exacerbations was reduced by 25% in the group that received combination therapy vs placebo. Combination therapy showed superior efficacy over individual drug therapy in preventing exacerbations. Treatment with the inhaled corticosteroid, whether alone or in combination with salmeterol, increased the risk of pneumonia.

A long-acting antimuscarinic agent is better than placebo. In 2008, the Understanding Potential Long-Term Impacts on Function With Tiotropium (UPLIFT) trial⁵² randomized nearly 6,000 patients with COPD and a postbronchodilator FEV₁ of less than 70% to placebo or tiotropium, a long-acting antimuscarinic agent. Tiotropium reduced the exacerbation rate by 14% compared with placebo and improved quality of life.

Antimuscarinics may be better than beta-2 agonists. Head-to-head comparisons suggest that long-acting antimuscarinic agents are preferable to long-acting beta-2 agonists for preventing COPD exacerbations.^53,54

Triple therapy: evidence is mixed. For patients with severe symptomatic COPD and frequent exacerbations, triple therapy with a combination of an inhaled long-acting antimuscarinic agent, an inhaled long-acting beta-2 agonist, and an inhaled corticosteroid has been suggested.

Data to support this practice are limited. In the Canadian Optimal Trial,⁵⁵ the rate of exacerbations was not different between tiotropium alone, tiotropium plus salmeterol, and triple therapy. However, the rate of hospitalization for severe exacerbation was lower with triple therapy than tiotropium alone. A large, retrospective cohort study also supported triple therapy by finding reduced mortality, hospitalizations, and need for oral corticosteroid bursts compared to combination therapy with an inhaled long-acting beta-2 agonist and an inhaled corticosteroid.⁵⁶

The drawback of triple therapy is an increased incidence of pneumonia associated with combined beta-2 agonist and corticosteroids, most likely due to the corticosteroid component.⁵¹ The risk appears to be higher for higher potency corticosteroids, eg, fluticasone.⁵⁷

In 2014, the Withdrawal of Inhaled Steroids During Optimised Bronchodilator Management (WISDOM) trial⁵⁸ randomized nearly 2,500 patients with a history of COPD exacerbation receiving triple therapy consisting of tiotropium, salmeterol, and inhaled fluticasone to either continue treatment or withdraw the corticosteroid for 3 months. The investigators defined an annualized exacerbation rate of 1.2 (ie, a 20% increase) as the upper limit of the confidence interval for an acceptable therapeutic margin of noninferiority. The study showed that the risk of moderate to severe exacerbations with combined tiotropium and salmeterol was noninferior to triple therapy.

Nevertheless, caution is advised when removing the corticosteroid component from triple therapy. The trial demonstrated a worsening in overall health status, some reduction in lung function, and a transient increase in severe exacerbations in the withdrawal group. Patients with increased symptom burden at baseline and a history of severe exacerbations may not be optimal candidates for this strategy.

Roflumilast is effective but has side effects

Roflumilast, an oral phosphodiesterase 4 inhibitor, is an anti-inflammatory drug without bronchodilator properties. In randomized controlled trials, the drug was associated with a 17% reduction in acute exacerbations compared with placebo.⁵⁹

Adding roflumilast to either a long-acting beta-2 agonist or a long-acting antimuscarinic agent resulted in a 6% to 8% further reduction in the proportion of patients with exacerbation.^60,61 Martinez et al⁶¹ found that roflumilast added to a regimen of a long-acting beta-2 agonist plus an inhaled corticosteroid reduced moderate to severe exacerbations by 14.2%, even in the presence of tiotropium. Compared with placebo, roflumilast treatment reduced exacerbations necessitating hospitalizations by 23.9%.

The FDA has approved oral roflumilast 500 µg once daily to prevent COPD exacerbations.

Roflumilast is frequently associated with side effects, including gastrointestinal symptoms (chiefly diarrhea), weight loss, and psychiatric effects. A benefit-to-harm study in 2014 concluded that using the drug is only favorable for patients who have a high risk of severe exacerbations, ie, those who have a greater than 22% baseline risk of having at least one exacerbation annually.⁶²

Recommendation. Roflumilast should be reserved for patients who have severe COPD with a chronic bronchitis phenotype (ie, with cough and sputum production) and repeated exacerbations despite an optimal regimen of an inhaled corticosteroid, long-acting beta-2 agonist, and long-acting antimuscarinic agent.

Macrolide antibiotics: Role unclear

Macrolide antibiotics have anti-inflammatory and immunomodulatory activities.

Azithromycin: fewer exacerbations but some side effects. A multicenter trial⁶³ in 1,142 COPD patients randomized to either oral azithromycin 250 mg daily or placebo found a 27% reduction in the risk of COPD exacerbation in the intervention arm. No differences were found between the groups in mortality, hospitalizations, emergency department visits, or respiratory failure. Hearing loss and increased macrolide resistance were noted in the intervention arm. In a secondary subgroup analysis,⁶⁴ no difference in efficacy was found by sex, history of chronic bronchitis, oxygen use, or concomitant COPD treatment.

The COPD: Influence of Macrolides on Exacerbation Frequency in Patients trial⁶⁵ helped refine patient selection for macrolide therapy. In this single-center study, 92 patients with COPD and at least three exacerbations during the year prior to enrollment were randomized to receive either azithromycin 500 mg three times weekly or placebo. Exacerbations in the intervention group were markedly reduced (42%) with no difference in hospitalization rate.

The place of macrolide antibiotics in the treatment strategy of COPD is unclear, and they are not currently part of the GOLD guidelines. Still unknown is the incremental benefit of adding them to existing preventive regimens, cardiovascular safety, side effects, and potential effects on the resident microbial flora. 

Other antibiotics have also been investigated for efficacy in preventing exacerbations.

Moxifloxacin: fewer exacerbations. The Pulsed Moxifloxacin Usage and Its Long-term Impact on the Reduction of Subsequent Exacerbations study⁶⁶ randomized more than 1,000 patients with stable COPD to receive either moxifloxacin 400 mg or placebo daily for 5 days repeated every 8 weeks for six courses. Frequent assessment during the treatment period and for 6 months afterward revealed a reduced exacerbation rate in the intervention group but without benefit in hospitalization rate, mortality, lung function, or health status.

Recommendation. Azithromycin (either 250 mg daily or 500 mg three times weekly) can be considered for patients who have repeated COPD exacerbations despite an optimal regimen of an inhaled corticosteroid, inhaled long-acting beta-2 agonist, and inhaled long-acting antimuscarinic agent. The need to continue azithromycin should be reassessed yearly.

Mucolytics

Greatest benefit to patients not taking inhaled corticosteroids. Mucolytic agents help clear airway secretions by reducing viscosity. N-acetylcysteine and carbocysteine (not available in the United States) also have antioxidant properties that may counteract oxidant stress associated with acute COPD exacerbations.

The Bronchitis Randomized on NAC Cost-Utility Study (BRONCUS)⁶⁷ randomized 523 COPD patients to N-acetylcysteine 600 mg daily or placebo. After 3 years of follow-up, no differences were found in the rate of exacerbations, lung function decline, and quality of life. Subgroup analysis suggested a reduction in exacerbations for patients who were not taking inhaled corticosteroids.

The Effect of Carbocisteine on Acute Exacerbation of Chronic Obstructive Pulmonary Disease (PEACE) study randomized more than 700 patients from multiple centers in China who had COPD and a recent history of exacerbations; they found a 25% lower exacerbation rate over 1 year with carbocysteine vs placebo.⁶⁸ Most of the patients (83%) were not on inhaled corticosteroids, which complemented findings of the BRONCUS trial.

The Effect of High Dose N-acetylcysteine on Air Trapping and Airway Resistance of COPD (HIACE) study randomized 120 patients with stable COPD in a hospital in Hong Kong to either oral N-acetylcysteine (600 mg twice daily) or placebo and found a reduced exacerbation rate of exacerbations. Patients were matched at baseline for inhaled corticosteroid use.⁶⁹

In 2014, the Twice Daily N-acetylcysteine 600 mg for Exacerbations of Chronic Obstructive Pulmonary Disease (PANTHEON) study⁷⁰ randomized 1,006 patients from multiple hospitals in China with a history of moderate to severe COPD and exacerbations to receive either N-acetylcysteine 600 mg twice daily or placebo for 1 year. They found a 22% reduction in exacerbations in the treatment group vs placebo.  

GOLD guidelines² recommend mucolytics for patients with severe COPD and exacerbations when inhaled corticosteroids are not available or affordable.

Recommendation. Mucolytics may be useful for patients with difficulty expectorating and with a history of exacerbations despite appropriate inhaled therapy.

OTHER INTERVENTIONS CAN HELP

Pulmonary rehabilitation provides multiple benefits

Pulmonary rehabilitation increases exercise tolerance and reduces symptoms

Pulmonary rehabilitation increases exercise tolerance and reduces symptom burden in patients with stable COPD. It is also a multidisciplinary effort that may help reinforce adherence to medications, enhance COPD education, and provide closer medical surveillance to patients at high risk for recurrent exacerbations.

A small randomized controlled trial⁷¹ prescribed pulmonary rehabilitation on discharge for a COPD exacerbation and found sustainable improvements in exercise capacity and health status after 3 months.

In a later study,⁷² the same group started pulmonary rehabilitation within a week of hospital discharge and found reduced hospital readmissions over a 3-month period.

Smoking cessation is always worth advocating

A large observational cohort study concluded that current smokers were at a higher risk for COPD exacerbations compared with former smokers.⁷³ Although there are no randomized controlled trials that assess the effects of smoking cessation at the time of COPD exacerbation, we recommend seizing the opportunity to implement this important intervention.

Vaccinations: Influenza and pneumococcal

Influenza vaccination is associated with reduced incidence of hospitalization among patients with cardiopulmonary disease.⁷⁴ A meta-analysis of randomized clinical trials of influenza vaccination for patients with COPD⁷⁵ reported significantly fewer exacerbations from vaccination, mostly owing to fewer episodes occurring after 3 to 4 weeks, coinciding with anticipated vaccine-induced immune protection. Furumoto and colleagues⁷⁶ reported an added benefit of combined vaccination with 23-valent pneumococcal polysaccharide vaccine and influenza vaccine in reducing hospital admissions over influenza vaccination alone. We also recommend providing the 13-valent pneumococcal conjugate vaccine to patients with COPD, particularly for those older than 65, consistent with CDC recommendations.⁷⁷

In contrast to stable chronic obstructive pulmonary disease (COPD),¹ acute exacerbations of COPD pose special management challenges and can significantly increase the risk of morbidity and death and the cost of care.

This review addresses the definition and diagnosis of COPD exacerbations, disease burden and costs, etiology and pathogenesis, and management and prevention strategies.

DEFINITIONS ARE PROBLEMATIC

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines a COPD exacer­bation as “an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication.”² It further categorizes acute exacerbations by severity:

• Mild—treated with increased frequency of doses of existing medications
• Moderate—treated with corticosteroids or antibiotics, or both
• Severe—requires hospital utilization (either emergency room treatment or admission).

Although descriptive and useful for retrospective analyses, this current definition poses ambiguities for clinicians. Day-to-day variation in symptoms is not routinely assessed, so deviations from baseline may be difficult to detect. Although clinical tools are available for assessing symptoms in stable and exacerbated states (eg, the COPD assessment test³ and the Exacerbations of Chronic Pulmonary Disease Tool [EXACT]⁴), they have not been widely adopted in daily practice. Also, according to the current definition, the severity of an exacerbation can be classified only after the course of action is determined, so the severity is not helpful for forming a management strategy at bedside. In addition, physicians may have different thresholds for prescribing antibiotics and corticosteroids.

An earlier definition categorized a COPD exacerbation by the presence of its three cardinal symptoms (ie, increased shortness of breath, sputum volume, and purulence):

• Type I—all three symptoms present
• Type II—two symptoms present
• Type III—one symptom present, accompanied by at least one of the following: upper respiratory tract infection within the past 5 days, unexplained fever, increased wheezing or cough, or 20% increased respiratory rate or heart rate from baseline.

This older definition was successfully used in a prospective clinical trial to identify patients who benefited most from antibiotics for COPD exacerbations.⁵

COPD exacerbation: an acute worsening of respiratory symptoms

Despite these caveats regarding a definition, most clinicians agree on the clinical presentation of a patient with COPD exacerbation: ie, having some combination of shortness of breath, increased sputum volume, and purulence. By the same token, patients with COPD who present with symptoms not typical of an exacerbation should be evaluated for another diagnosis. For instance, Tillie-Leblond et al⁶ reported that 49 (25%) of 197 patients hospitalized with an “unexplained” exacerbation of COPD were eventually diagnosed with pulmonary embolism.

EXACERBATIONS ARE COSTLY

The care of patients with COPD places a great burden on the healthcare system. Using multiple national databases, Ford et al⁷ estimated that medical costs in the United States in 2010 attributable to COPD and its complications were $32.1 billion.

The largest component of direct healthcare costs of COPD is exacerbations and subsequent hospitalizations.⁸ Data from a predominantly Medicare population indicate that the annualized mean COPD-related cost for a patient with no exacerbations was $1,425, compared with $12,765 for a patient with severe exacerbations.⁹ The investigators estimated that reducing exacerbations from two or more to none could save $5,125 per patient per year.

EXACERBATIONS AFFECT HEALTH BEYOND THE EVENT

COPD exacerbations are associated with a faster decline in lung function,¹⁰ reduced quality of life,¹¹ and lost workdays.⁷ A single exacerbation may cause a decline in lung function and health status that may not return to baseline for several months, particularly if another exacerbation occurs within 6 months.^12,13 COPD exacerbations have also been linked to poor clinical outcomes, including death.

In a prospective study in 304 men with COPD followed for 5 years, those who had three or more COPD exacerbations annually were four times as likely to die than patients who did not have an exacerbation.¹⁴ Nevertheless, the relationship with mortality may not be causal: Brusselle pointed out in an editorial¹⁵ that established mortality predictors for COPD do not include exacerbations, and symptomatic patients with COPD without any history of exacerbations are at greater risk of death than those who are asymptomatic but at high risk for exacerbations.

INFECTION + INFLAMMATION = EXACERBATION

An acute COPD exacerbation can be viewed as an acute inflammatory event superimposed on chronic inflammation associated with COPD. Inflammation in the airways increases resistance to air flow with consequent air trapping. Increased resistance and elastic load due to air trapping place respiratory muscles at a mechanical disadvantage and increase the work of breathing.

Infection starts the process

Infections are thought to be the major instigators of COPD exacerbation

Infections, particularly bacterial and viral, are thought to be the major instigators of COPD exacerbation, although environmental factors such as air pollution may also play a role.¹⁶

Airway inflammation is markedly reduced when bacterial infection is eradicated. But if bacterial colonization continues, inflammatory markers remain elevated despite clinical resolution of the exacerbation.¹⁷ Desai et al¹⁸ found that patients with COPD and chronic bronchitis with bacterial colonization had a larger symptom burden than patients without colonization, even without an exacerbation.

Allergic profile increases risk

Although most studies indicate that infection is the main cause of exacerbations, clinicians should consider other mechanisms of inflammation on an individual basis. COPD exacerbations may be phenotyped by measuring inflammatory markers, perhaps as a starting point for tailored therapies.

Bafadhel et al¹⁹ studied 145 patients with COPD over the course of a year and recorded various biomarkers at baseline and during exacerbations. Exacerbations had an inflammatory profile that was predominantly bacterial in 37%, viral in 10%, and eosinophilic in 17%, and had limited changes in the inflammatory profile in 14%. The remaining episodes were combinations of categories. In another study,²⁰ multivariate analysis conducted in two cohorts with COPD found that patients who had an allergic phenotype had more respiratory symptoms and a higher likelihood of COPD exacerbations.

Frequent COPD exacerbations are increasingly recognized as being associated with an asthma-COPD overlap syndrome, consisting of symptoms of increased airflow variability and incompletely reversible airflow obstruction.²¹

Inflammation as a marker of frequent exacerbations

Evidence is accumulating that supports systemic inflammation as a marker of frequent exacerbations. The Copenhagen Heart Study tested for baseline plasma C-reactive protein, fibrinogen, and white blood cell count in 6,574 stable patients with COPD.²² After multivariable adjustment, they found a significantly higher likelihood of having a subsequent exacerbation in patients who had all three biomarkers elevated (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.9–7.4), even in patients with milder COPD and those without previous exacerbations.

Past exacerbations predict risk

A history of exacerbation is the best predictor of future exacerbation

The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study²³ found that a history of acute COPD exacerbation was the single best predictor of future exacerbations. This risk factor remained stable over 3 years and was present across the severity of COPD, ie, patients at lower GOLD stages who had a history of frequent exacerbations were likely to have exacerbations during follow-up.

EXACERBATION INCREASES CARDIOVASCULAR RISK

COPD exacerbations increase the risk of cardiovascular events, particularly myocardial infarction.²⁴ During hospitalization for acute exacerbation of COPD, markers of myocardial injury and heart failure may be elevated and are a predictor of death.²⁵

Patel et al²⁶ measured arterial stiffness (aortic pulse wave velocity, a validated measure of cardiovascular risk) and cardiac biomarkers (troponin and N-terminal B-type natriuretic peptide) at baseline in 98 patients and longitudinally during and after a COPD exacerbation. In addition to increased levels of cardiac biomarkers, they found a significant rise in arterial stiffness during the exacerbation event without return to baseline levels over 35 days of follow-up. The arterial stiffness increase was related to airway inflammation as measured by sputum interleukin 6, particularly in patients with documented lower respiratory tract infection.

Retrospective analysis suggests a reduced all-cause mortality rate in COPD patients who are treated with beta-blockers.²⁷

Recommendation. We recommend that patients already taking a selective beta-blocker continue to do so during a COPD exacerbation.

OUTPATIENT MANAGEMENT

Treatment with a combination of a corticosteroid, antibiotic, and bronchodilator addresses the underlying pathophysiologic processes of an acute exacerbation: inflammation, infection, and airway trapping.

Short course of a corticosteroid improves outcomes

A single exacerbation may worsen health status for several months

A 10-day systemic course of a corticosteroid prescribed for COPD exacerbation before discharge from the emergency department was found to offer a small advantage over placebo for reducing treatment failure (unscheduled physician visits, return to emergency room for recurrent symptoms) and improving dyspnea scores and lung function.²⁸ Even just a 3-day course improved measures of respiration (forced expiratory volume in the first second of expiration [FEV₁] and arterial oxygenation) at days 3 and 10, and reduced treatment failures compared with placebo.²⁹

Corticosteroid prescription should not be taken lightly, because adverse effects are common. In a systematic review, one adverse effect (hyperglycemia, weight gain, or insomnia) occurred for every five people treated.³⁰

Identifying subgroups of patients most likely to benefit from corticosteroid treatment may be helpful. Corticosteroids may delay improvement in patients without eosinophilic inflammation and hasten recovery in those with more than 2% peripheral eosinophils.³¹ Siva et al³² found that limiting corticosteroids to patients with sputum eosinophilia reduced corticosteroid use and reduced severe exacerbations compared with standard care.³²

Recommendation. For an acute exacerbation, we prescribe a short course of corticosteroids (eg, prednisone 40 mg daily for 5 to 7 days). Tapering dosing is probably unnecessary because adrenal insufficiency is uncommon before 2 weeks of corticosteroid exposure. Clinicians should weigh the merits of tapering (reduced corticosteroid exposure) against patient inconvenience and difficulty following complicated instructions.

Antibiotics help, but exact strategy uncertain

Although antibiotic therapy is one of the three pillars of COPD exacerbation management, the optimal antimicrobial agent, duration of therapy, and which patients will benefit remain areas of controversy and research. Thus far, large trials have been unable to definitely show the superiority of one antibiotic over another.^33,34

A 1987 randomized controlled trial⁵ of antibiotic therapy in acute exacerbation of COPD found the greatest benefit to patients who had all three cardinal symptoms (ie, increased shortness of breath, sputum volume, and purulence), with less marked but still significant improvement in patients with two symptoms. In a 2012 multicenter trial³⁵ patients with mild to moderate COPD experiencing an exacerbation were treated with either combined amoxicillin and clavulanate or placebo if they had one of the three cardinal symptoms. The antibiotic group had a significantly higher clinical cure rate at days 9 to 11 (74.1% vs 59.9%) as well as a longer time until the next exacerbation (233 vs 160 days).

Recommendation. Optimal antibiotic management of COPD exacerbations may also depend on risk factors. For patients with at least two cardinal symptoms, we favor a scheme akin to one proposed for treating community-acquired pneumonia (Table 1).^16,36

INPATIENT MANAGEMENT

Corticosteroids improve outcomes

A Department of Veterans Affairs cooperative trial³⁷ randomized 271 patients hospitalized with COPD exacerbation to receive either corticosteroids (intravenous followed by oral) or placebo for either 2 weeks or 8 weeks. Corticosteroid recipients had lower rates of treatment failure at 30 and 90 days, defined as death from any cause, need for mechanical ventilation, readmission, or intensification of pharmacologic therapy. Corticosteroid therapy also reduced hospital length of stay and improved the rate of recovery. The longer corticosteroid course was associated with a higher rate of adverse effects.

Oral corticosteroids not inferior to intravenous

Using the same end point of treatment failure as the Veterans Affairs cooperative trial, deJong et al³⁸ demonstrated that prednisone 60 mg by mouth was not inferior to intravenous prednisone. Neither trial demonstrated a difference in mortality between corticosteroid use and placebo.

Short course of a corticosteroid not inferior to a long course

In 2013, the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial³⁹ randomized 314 patients presenting with an acute COPD exacerbation (92% requiring hospital admission) to oral prednisone 40 mg daily for either 5 days or 14 days. They found that the short course was noninferior in preventing exacerbations over the ensuing 6 months in terms of death and the need for mechanical ventilation.

Recommendation. Our threshold for initiating systemic corticosteroid therapy is lower in hospitalized patients than in outpatients. We recommend the regimen of the REDUCE trial: prednisone 40 mg daily for 5 days.

Corticosteroids for patients on ventilatory support

Severe COPD exacerbations requiring admission to intensive care are a significant source of morbidity and mortality, and the strategy of corticosteroid treatment is still under investigation.

Intravenous corticosteroids are effective. A multicenter trial⁴⁰ in 354 patients requiring either invasive or noninvasive mechanical ventilation randomized them to treatment with either intravenous methylprednisolone (tapered) or placebo. Treatment was associated with fewer mechanical ventilation days and a lower rate of noninvasive ventilation failure.

Low-dose oral corticosteroids ineffective. In contrast, an open-label trial⁴¹ of patients requiring ventilatory support and randomized to either oral prednisone (1 mg/kg for up to 10 days) or usual care found no difference in intensive care length of stay or noninvasive ventilation failure. This study used the oral route and smaller doses, and its open-label design might have introduced bias.

Lower-dose steroids better than high-dose. A 2014 cohort study of 17,239 patients admitted to the ICU with acute exacerbations of COPD evaluated outcomes of treatment with high methylprednisolone dosages (> 240 mg per day) vs lower dosages, using propensity score matching.⁴² No mortality difference was found between the groups. The lower dosage group (median methylprednisolone dose 100 mg per day) had shorter hospital and intensive care unit stays, shorter duration of noninvasive positive pressure ventilation, less need for insulin therapy, and fewer fungal infections.

Antibiotics for hospitalized patients

Only scarce data are available on the use of antibiotics for patients hospitalized with COPD exacerbation. In a study of patients hospitalized with COPD exacerbations, adding doxycycline to corticosteroids led to better clinical success and cure rates at 10 days compared with placebo, but the primary end point of clinical success at 30 days was not different between the two groups.⁴³

BRONCHODILATORS: A MAINSTAY OF COPD TREATMENT

Bronchodilators are an important part of treatment of COPD exacerbations in inpatient and outpatient settings.

Nebulized beta-2 agonists are given every 1 to 4 hours. Albuterol at a 2.5-mg dose in each nebulization was found to be as effective as 5 mg for length of hospital stay and recovery of lung function in patients with an acute exacerbation of COPD.⁴⁴

Adding an anticholinergic may help. Nebulized anticholinergics can be given alone or combined with beta-2 agonists. Whether long-acting bronchodilators should be used to manage COPD patients hospitalized with an exacerbation requires further inquiry. In an observational study with historical controls, Drescher and colleagues⁴⁵ found cost savings and shorter hospital stays if tiotropium (a long-acting anticholinergic) was added to the respiratory care protocol, which also included formoterol (a long-acting beta-2 agonist).

OXYGEN: TITRATED APPROACH SAFER

Caution is needed to avoid hyperoxemic hypercapnia in patients on oxygen

Oxygen should be supplied during a COPD exacerbation to ensure adequate oxyhemoglobin saturation. Caution is needed to avoid hyperoxemic hypercapnia, particularly in patients with severe COPD and propensity to ventilatory failure. The routine administration of oxygen at high concentrations during a COPD exacerbation has been associated with a higher mortality rate than with a titrated oxygen approach.⁴⁶ Long-term oxygen treatment started at discharge or as outpatient therapy is associated with reduced hospital admissions and shorter hospital stays for acute exacerbations of COPD.⁴⁷

VENTILATION SUPPORT

Noninvasive positive-pressure ventilation is a useful adjunct to treatment of COPD exacerbations with evidence of ventilatory failure (ie, acute respiratory acidosis), helping to offset the work of breathing until respiratory system mechanics improve. Keenan et al⁴⁸ reviewed 15 randomized controlled trials, involving 636 patients, of noninvasive positive-pressure ventilation in the setting of COPD exacerbation. They concluded that noninvasive positive-pressure ventilation reduced the in-hospital mortality rate and length of stay compared with standard therapy. Noninvasive positive-pressure ventilation is most useful in patients with severe COPD exacerbations and acute respiratory acidosis (pH < 7.35).⁴⁹

Intubation and mechanical ventilation. Although no standards exist for determining which COPD exacerbations may be too severe for noninvasive positive-pressure ventilation, intubation is clearly indicated for impending respiratory failure or hemodynamic instability. Other factors to consider include the greater likelihood of noninvasive positive-pressure ventilation failure in patients with severe respiratory acidosis (pH < 7.25 is associated with a > 50% failure rate) and in those with no improvement in acidosis or respiratory rate during the first hour after initiation of noninvasive positive-pressure ventilation.⁵⁰

PREVENTING EXACERBATIONS

Recent data indicate that COPD exacerbations can often be prevented (Table 2).

Inhaled pharmacotherapy

Inhaled pharmacotherapeutic agents, singly or in combination, reduce the frequency of COPD exacerbations.

Combined long-acting beta-2 agonist and corticosteroid is better than single-agent therapy. In 2007, the Towards a Revolution in COPD Health (TORCH) trial⁵¹ evaluated outpatient therapy in more than 6,000 patients worldwide with either an inhaled long-acting beta-2 agonist (salmeterol), an inhaled corticosteroid (fluticasone), both drugs in combination, or placebo. Patients had baseline prebronchodilator FEV₁ of less than 60% and were followed for 3 years. No difference was found between the groups in the primary end point of deaths, but the annualized rate of moderate to severe exacerbations was reduced by 25% in the group that received combination therapy vs placebo. Combination therapy showed superior efficacy over individual drug therapy in preventing exacerbations. Treatment with the inhaled corticosteroid, whether alone or in combination with salmeterol, increased the risk of pneumonia.

A long-acting antimuscarinic agent is better than placebo. In 2008, the Understanding Potential Long-Term Impacts on Function With Tiotropium (UPLIFT) trial⁵² randomized nearly 6,000 patients with COPD and a postbronchodilator FEV₁ of less than 70% to placebo or tiotropium, a long-acting antimuscarinic agent. Tiotropium reduced the exacerbation rate by 14% compared with placebo and improved quality of life.

Antimuscarinics may be better than beta-2 agonists. Head-to-head comparisons suggest that long-acting antimuscarinic agents are preferable to long-acting beta-2 agonists for preventing COPD exacerbations.^53,54

Triple therapy: evidence is mixed. For patients with severe symptomatic COPD and frequent exacerbations, triple therapy with a combination of an inhaled long-acting antimuscarinic agent, an inhaled long-acting beta-2 agonist, and an inhaled corticosteroid has been suggested.

Data to support this practice are limited. In the Canadian Optimal Trial,⁵⁵ the rate of exacerbations was not different between tiotropium alone, tiotropium plus salmeterol, and triple therapy. However, the rate of hospitalization for severe exacerbation was lower with triple therapy than tiotropium alone. A large, retrospective cohort study also supported triple therapy by finding reduced mortality, hospitalizations, and need for oral corticosteroid bursts compared to combination therapy with an inhaled long-acting beta-2 agonist and an inhaled corticosteroid.⁵⁶

The drawback of triple therapy is an increased incidence of pneumonia associated with combined beta-2 agonist and corticosteroids, most likely due to the corticosteroid component.⁵¹ The risk appears to be higher for higher potency corticosteroids, eg, fluticasone.⁵⁷

In 2014, the Withdrawal of Inhaled Steroids During Optimised Bronchodilator Management (WISDOM) trial⁵⁸ randomized nearly 2,500 patients with a history of COPD exacerbation receiving triple therapy consisting of tiotropium, salmeterol, and inhaled fluticasone to either continue treatment or withdraw the corticosteroid for 3 months. The investigators defined an annualized exacerbation rate of 1.2 (ie, a 20% increase) as the upper limit of the confidence interval for an acceptable therapeutic margin of noninferiority. The study showed that the risk of moderate to severe exacerbations with combined tiotropium and salmeterol was noninferior to triple therapy.

Nevertheless, caution is advised when removing the corticosteroid component from triple therapy. The trial demonstrated a worsening in overall health status, some reduction in lung function, and a transient increase in severe exacerbations in the withdrawal group. Patients with increased symptom burden at baseline and a history of severe exacerbations may not be optimal candidates for this strategy.

Roflumilast is effective but has side effects

Roflumilast, an oral phosphodiesterase 4 inhibitor, is an anti-inflammatory drug without bronchodilator properties. In randomized controlled trials, the drug was associated with a 17% reduction in acute exacerbations compared with placebo.⁵⁹

Adding roflumilast to either a long-acting beta-2 agonist or a long-acting antimuscarinic agent resulted in a 6% to 8% further reduction in the proportion of patients with exacerbation.^60,61 Martinez et al⁶¹ found that roflumilast added to a regimen of a long-acting beta-2 agonist plus an inhaled corticosteroid reduced moderate to severe exacerbations by 14.2%, even in the presence of tiotropium. Compared with placebo, roflumilast treatment reduced exacerbations necessitating hospitalizations by 23.9%.

The FDA has approved oral roflumilast 500 µg once daily to prevent COPD exacerbations.

Roflumilast is frequently associated with side effects, including gastrointestinal symptoms (chiefly diarrhea), weight loss, and psychiatric effects. A benefit-to-harm study in 2014 concluded that using the drug is only favorable for patients who have a high risk of severe exacerbations, ie, those who have a greater than 22% baseline risk of having at least one exacerbation annually.⁶²

Recommendation. Roflumilast should be reserved for patients who have severe COPD with a chronic bronchitis phenotype (ie, with cough and sputum production) and repeated exacerbations despite an optimal regimen of an inhaled corticosteroid, long-acting beta-2 agonist, and long-acting antimuscarinic agent.

Macrolide antibiotics: Role unclear

Macrolide antibiotics have anti-inflammatory and immunomodulatory activities.

Azithromycin: fewer exacerbations but some side effects. A multicenter trial⁶³ in 1,142 COPD patients randomized to either oral azithromycin 250 mg daily or placebo found a 27% reduction in the risk of COPD exacerbation in the intervention arm. No differences were found between the groups in mortality, hospitalizations, emergency department visits, or respiratory failure. Hearing loss and increased macrolide resistance were noted in the intervention arm. In a secondary subgroup analysis,⁶⁴ no difference in efficacy was found by sex, history of chronic bronchitis, oxygen use, or concomitant COPD treatment.

The COPD: Influence of Macrolides on Exacerbation Frequency in Patients trial⁶⁵ helped refine patient selection for macrolide therapy. In this single-center study, 92 patients with COPD and at least three exacerbations during the year prior to enrollment were randomized to receive either azithromycin 500 mg three times weekly or placebo. Exacerbations in the intervention group were markedly reduced (42%) with no difference in hospitalization rate.

The place of macrolide antibiotics in the treatment strategy of COPD is unclear, and they are not currently part of the GOLD guidelines. Still unknown is the incremental benefit of adding them to existing preventive regimens, cardiovascular safety, side effects, and potential effects on the resident microbial flora. 

Other antibiotics have also been investigated for efficacy in preventing exacerbations.

Moxifloxacin: fewer exacerbations. The Pulsed Moxifloxacin Usage and Its Long-term Impact on the Reduction of Subsequent Exacerbations study⁶⁶ randomized more than 1,000 patients with stable COPD to receive either moxifloxacin 400 mg or placebo daily for 5 days repeated every 8 weeks for six courses. Frequent assessment during the treatment period and for 6 months afterward revealed a reduced exacerbation rate in the intervention group but without benefit in hospitalization rate, mortality, lung function, or health status.

Recommendation. Azithromycin (either 250 mg daily or 500 mg three times weekly) can be considered for patients who have repeated COPD exacerbations despite an optimal regimen of an inhaled corticosteroid, inhaled long-acting beta-2 agonist, and inhaled long-acting antimuscarinic agent. The need to continue azithromycin should be reassessed yearly.

Mucolytics

Greatest benefit to patients not taking inhaled corticosteroids. Mucolytic agents help clear airway secretions by reducing viscosity. N-acetylcysteine and carbocysteine (not available in the United States) also have antioxidant properties that may counteract oxidant stress associated with acute COPD exacerbations.

The Bronchitis Randomized on NAC Cost-Utility Study (BRONCUS)⁶⁷ randomized 523 COPD patients to N-acetylcysteine 600 mg daily or placebo. After 3 years of follow-up, no differences were found in the rate of exacerbations, lung function decline, and quality of life. Subgroup analysis suggested a reduction in exacerbations for patients who were not taking inhaled corticosteroids.

The Effect of Carbocisteine on Acute Exacerbation of Chronic Obstructive Pulmonary Disease (PEACE) study randomized more than 700 patients from multiple centers in China who had COPD and a recent history of exacerbations; they found a 25% lower exacerbation rate over 1 year with carbocysteine vs placebo.⁶⁸ Most of the patients (83%) were not on inhaled corticosteroids, which complemented findings of the BRONCUS trial.

The Effect of High Dose N-acetylcysteine on Air Trapping and Airway Resistance of COPD (HIACE) study randomized 120 patients with stable COPD in a hospital in Hong Kong to either oral N-acetylcysteine (600 mg twice daily) or placebo and found a reduced exacerbation rate of exacerbations. Patients were matched at baseline for inhaled corticosteroid use.⁶⁹

In 2014, the Twice Daily N-acetylcysteine 600 mg for Exacerbations of Chronic Obstructive Pulmonary Disease (PANTHEON) study⁷⁰ randomized 1,006 patients from multiple hospitals in China with a history of moderate to severe COPD and exacerbations to receive either N-acetylcysteine 600 mg twice daily or placebo for 1 year. They found a 22% reduction in exacerbations in the treatment group vs placebo.  

GOLD guidelines² recommend mucolytics for patients with severe COPD and exacerbations when inhaled corticosteroids are not available or affordable.

Recommendation. Mucolytics may be useful for patients with difficulty expectorating and with a history of exacerbations despite appropriate inhaled therapy.

OTHER INTERVENTIONS CAN HELP

Pulmonary rehabilitation provides multiple benefits

Pulmonary rehabilitation increases exercise tolerance and reduces symptoms

Pulmonary rehabilitation increases exercise tolerance and reduces symptom burden in patients with stable COPD. It is also a multidisciplinary effort that may help reinforce adherence to medications, enhance COPD education, and provide closer medical surveillance to patients at high risk for recurrent exacerbations.

A small randomized controlled trial⁷¹ prescribed pulmonary rehabilitation on discharge for a COPD exacerbation and found sustainable improvements in exercise capacity and health status after 3 months.

In a later study,⁷² the same group started pulmonary rehabilitation within a week of hospital discharge and found reduced hospital readmissions over a 3-month period.

Smoking cessation is always worth advocating

A large observational cohort study concluded that current smokers were at a higher risk for COPD exacerbations compared with former smokers.⁷³ Although there are no randomized controlled trials that assess the effects of smoking cessation at the time of COPD exacerbation, we recommend seizing the opportunity to implement this important intervention.

Vaccinations: Influenza and pneumococcal

Influenza vaccination is associated with reduced incidence of hospitalization among patients with cardiopulmonary disease.⁷⁴ A meta-analysis of randomized clinical trials of influenza vaccination for patients with COPD⁷⁵ reported significantly fewer exacerbations from vaccination, mostly owing to fewer episodes occurring after 3 to 4 weeks, coinciding with anticipated vaccine-induced immune protection. Furumoto and colleagues⁷⁶ reported an added benefit of combined vaccination with 23-valent pneumococcal polysaccharide vaccine and influenza vaccine in reducing hospital admissions over influenza vaccination alone. We also recommend providing the 13-valent pneumococcal conjugate vaccine to patients with COPD, particularly for those older than 65, consistent with CDC recommendations.⁷⁷

Managing glycemic control in hospitalized patients with chronic kidney disease (CKD) and diabetes mellitus is a challenge, with no published guidelines. In this setting, avoiding hypoglycemia takes precedence over meeting strict blood glucose targets. Optimal management is essential to reduce hypoglycemia and the risk of death from cardiovascular disease.¹

This article reviews the evidence to guide diabetes management in hospitalized patients with CKD, focusing on blood glucose monitoring, insulin dosing, and concerns about other diabetic agents.

FOCUS ON AVOIDING HYPOGLYCEMIA

CKD is common, estimated to affect more than 50 million people worldwide.² Diabetes mellitus is the primary cause of kidney failure in 45% of dialysis patients with CKD.

Tight control comes with a cost

Hyperglycemia in hospitalized patients is associated with a higher risk of death, a higher risk of infections, and a longer hospital stay.^3,4 In 2001, Van den Berghe et al⁵ found that intensive insulin therapy reduced the mortality rate in critically ill patients in the surgical intensive care unit. But subsequent studies^6,7 found that intensive insulin therapy to achieve tight glycemic control increased rates of morbidity and mortality without adding clinical benefit.

Randomized clinical trials in outpatients have shown that tight control of blood glucose levels reduces microvascular and macrovascular complications in patients with type 1 diabetes.^8–10 In the Diabetes Control and Complications Trial,⁹ compared with conventional therapy, intensive insulin therapy reduced the incidence of retinopathy progression (4.7 vs 1.2 cases per 100 patient-years, number needed to treat [NNT] = 3 for 10 years) and clinical neuropathy (9.8 vs 3.1 per 100 patient-years, NNT = 1.5 for 10 years). The long-term likelihood of a cardiovascular event was also significantly lower in the intensive treatment group (0.38 vs 0.80 events per 100 patient-years).⁹

Similarly, in the Epidemiology of Diabetes Interventions and Complications follow-up study, the intensive therapy group had fewer cardiovascular deaths.¹¹ On the other hand, the risk of severe hypoglycemia and subsequent coma or seizure was significantly higher in the intensive therapy group than in the conventional therapy group (16.3 vs 5.4 per 100 patient-years).⁸

CKD increases hypoglycemia risk

Moen et al¹² found that the incidence of hypoglycemia was significantly higher in patients with CKD (estimated glomerular filtration rate [GFR] < 60 mL/min) with or without diabetes, and that patients with both conditions were at greatest risk (Figure 1). Multiple factors contribute to the increased risk of hypoglycemia: patients with advanced CKD tend to have poor nutrition, resulting in reduced glycogen stores, and a smaller renal mass reduces renal gluconeogenesis and decreases the elimination of insulin and oral antidiabetic agents.

After the onset of diabetic nephropathy, progression of renal complications and overall life expectancy are influenced by earlier glycemic control.⁸ Development of diabetic nephropathy is commonly accompanied by changes in metabolic control, particularly an increased risk of hypoglycemia.¹³ In addition, episodes of severe hypoglycemia constitute an independent cardiovascular risk factor.¹⁴

Aggressive glycemic control in hospitalized patients, particularly those with advanced CKD, is associated with a risk of hypoglycemia without overall improvement in outcomes.¹⁵ Elderly patients with type 2 diabetes are similar to patients with CKD in that they have a reduced GFR and are thus more sensitive to insulin. In both groups, intensifying glycemic control, especially in the hospital, is associated with more frequent episodes of severe hypoglycemia.¹⁶ The focus should be not only on maintaining optimal blood glucose concentration, but also on preventing hypoglycemia.

‘Burnt-out’ diabetes

Paradoxically, patients with end-stage renal disease and type 2 diabetes often experience altered glucose homeostasis with markedly improved glycemic control. They may attain normoglycemia and normalization of hemoglobin A_1c, a condition known as “burnt-out” diabetes. Its precise mechanism is not understood and its significance remains unclear (Table 1).¹⁷

HEMOGLOBIN A_1c CAN BE FALSELY HIGH OR FALSELY LOW

Hemoglobin A_1c measurement is used to diagnose diabetes and to assess long-term glycemic control. It is a measure of the fraction of hemoglobin that has been glycated by exposure to glucose. Because the average lifespan of a red cell is 120 days, the hemoglobin A_1c value reflects the mean blood glucose concentration over the preceding 3 months.

But hemoglobin A_1c measurement has limitations: any condition that alters the lifespan of erythrocytes leads to higher or lower hemoglobin A_1c levels. Hemoglobin A_1c levels are also affected by kidney dysfunction, hemolysis, and acidosis.¹⁸

Falsely high hemoglobin A_1c levels are associated with conditions that prolong the lifespan of erythrocytes, such as asplenia. Iron deficiency also increases the average age of circulating red cells because of reduced red cell production. For patients in whom blood glucose measurements do not correlate with hemoglobin A_1c measurements, iron deficiency anemia should be considered before altering a treatment regimen.

Falsely low hemoglobin A_1c levels are associated with conditions of more rapid erythrocyte turnover, such as autoimmune hemolytic anemia, hereditary spherocytosis, and acute blood loss anemia. In patients with CKD, recombinant erythropoietin treatment lowers hemoglobin A_1c levels by increasing the number of immature red cells, which are less likely to glycosylate.¹⁹

Morgan et al²⁰ compared the association between hemoglobin A_1c and blood glucose levels in diabetic patients with moderate to severe CKD not requiring dialysis and in diabetic patients with normal renal function and found no difference between these two groups, suggesting that hemoglobin A_1c is reliable in this setting. But study results conflict for patients on dialysis, making the usefulness of hemoglobin A_1c testing for those patients less clear. In one study, hemoglobin A_1c testing underestimated glycemic control,²⁰ but other studies found that glycemic control was overestimated.^21,22

Alternatives to hemoglobin A_1c

Other measures of long-term glycemic control such as fructosamine and glycated albumin levels are sometimes used in conditions in which hemoglobin A_1c may not be reliable.

Albumin also undergoes glycation when exposed to glucose. Glycated albumin appears to be a better measure of glycemic control in patients with CKD and diabetes than serum fructosamine,²³ which has failed to show a significant correlation with blood glucose levels in patients with CKD.²⁴ However, because serum albumin has a short half-life, glycated albumin reflects glycemic control in only the approximately 1 to 2 weeks before sampling,²⁵ so monthly monitoring is required.

Glycated albumin levels may be reduced due to increased albumin turnover in patients with nephrotic-range proteinuria and in diabetic patients on peritoneal dialysis. Several issues remain unclear, such as the appropriate target level of glycated albumin and at what stage of CKD it should replace hemoglobin A_1c testing. If an improved assay that is unaffected by changes in serum albumin becomes available, it may be appropriate to use glycated albumin measurements to assess long-term glycemic control for patients with CKD.

In general, therapeutic decisions to achieve optimum glycemic control in patients with diabetes and CKD should be based on hemoglobin A_1c testing, multiple glucose measurements, and patient symptoms of hypoglycemia or hyperglycemia. The best measure for assessing glycemic control in hospitalized patients with CKD remains multiple blood glucose testing daily.

INSULIN THERAPY PREFERRED

Although several studies have evaluated inpatient glycemic control,^26–29 no guidelines have been published for hospitalized patients with diabetes and CKD. Insulin therapy is preferred for achieving glycemic control in acutely ill or hospitalized patients with diabetes. Oral hypoglycemic agents should be discontinued.

Regardless of the form of insulin chosen to treat diabetes, caution is needed for patients with kidney disease. During hospitalization, clinical changes are expected owing to illness and differences in caloric intake and physical activity, resulting in altered insulin sensitivity. Insulin-treated hospitalized patients require individualized care, including multiple daily blood glucose tests and insulin therapy modifications for ideal glycemic control.

For surgical or medical intensive care patients on insulin therapy, the target blood glucose level before meals should be 140 mg/dL, and the target random level should be less than 180 mg/dL.^15,26–29

Basal-bolus insulin

Sliding-scale therapy should be avoided as the only method for glycemic control. Instead, scheduled subcutaneous basal insulin once or twice daily combined with rapid- or short-acting insulin with meals is recommended.

Basal-bolus insulin therapy, one of the most advanced and flexible insulin replacement therapies, mimics endogenous insulin release and offers great advantages in diabetes care. Using mealtime bolus insulin permits variation in the amount of food eaten; more insulin can be taken with a larger meal and less with smaller meals. A bolus approach offers the flexibility of administering rapid-acting insulin immediately after meals when oral intake is variable.

Individualize insulin therapy

Optimizing glycemic control requires an understanding of the altered pharmacokinetics and pharmacodynamics of insulin in patients with diabetic nephropathy. Table 2 shows the pharmacokinetic profiles of insulin preparations in healthy people. Analogue insulins, which are manufactured by recombinant DNA technology, have conformational changes in the insulin molecule that alter their pharmacokinetics and pharmacodynamics. The rapid-acting analogue insulins are absorbed quickly, making them suitable for postprandial glucose control.

Changes in GFR are associated with altered pharmacokinetics and pharmacodynamics of insulin,^30,31 but unlike for oral antidiabetic agents, these properties are not well characterized for insulin preparations in patients with renal insufficiency.^13,32–36

CKD may reduce insulin clearance. Rave et al³² reported that the clearance of regular human insulin was reduced by 30% to 40% in patients with type 1 diabetes and a mean estimated GFR of 54 mL/min. They found that the metabolic activity of insulin lispro was more robust than that of short-acting regular human insulin in patients with diabetic nephropathy. In another study, patients with diabetes treated with insulin aspart did not show any significant change in the required insulin dosage in relation to the renal filtration rate.³⁴ Biesenbach et al³³ found a 38% reduction in insulin requirements in patients with type 1 diabetes as estimated GFR decreased from 80 mL/min to 10 mL/min. Further studies are required to better understand the safety of insulin in treating hospitalized patients with diabetes and renal insufficiency.

Few studies have compared the pharmacodynamics of long-acting insulins in relation to declining renal function. The long-acting analogue insulins have less of a peak than human insulin and thus better mimic endogenous insulin secretion. For insulin detemir, Lindholm and Jacobsen found no significant differences in the pharmacokinetics related to the stages of CKD.³⁵ When using the long-acting insulins glargine or detemir, one should consider giving much lower doses (half the initial starting dosage) and titrating the dosage until target fasting glucose concentrations are reached to prevent hypoglycemia.

Table 3 summarizes recommended insulin dosage adjustments in CKD based on the literature and our clinical experience.

Considerations for dialysis patients

Subcutaneously administered insulin is eliminated renally, unlike endogenous insulin, which undergoes first-pass metabolism in the liver.^13,37 As renal function declines, insulin clearance decreases and the insulin dosage must be reduced to prevent hypoglycemia.

Patients on hemodialysis or peritoneal dialysis pose a challenge for insulin dosing. Hemodialysis improves insulin sensitivity but also increases insulin clearance, making it difficult to determine insulin requirements. Sobngwi et al³⁸ conducted a study in diabetic patients with end-stage renal disease on hemodialysis, using a 24-hour euglycemic clamp. They found that exogenous basal insulin requirements were 25% lower on the day after hemodialysis compared with the day before, but premeal insulin requirements stayed the same.

Peritoneal dialysis exposes patients to a high glucose load via the peritoneum, which can worsen insulin resistance. Intraperitoneal administration of insulin during peritoneal dialysis provides a more physiologic effect than subcutaneous administration: it prevents fluctuations of blood glucose and the formation of insulin antibodies. But insulin requirements are higher owing to a dilutional effect and to insulin binding to the plastic surface of the dialysis fluid reservoir.³⁹

GLYCEMIC CONTROL FOR PROCEDURES

No guidelines have been established regarding the optimal blood glucose range for diabetic patients with CKD undergoing diagnostic or surgical procedures. Given the risk of hypoglycemia in such settings, less-stringent targets are reasonable, ie, premeal blood glucose levels of 140 mg/dL and random blood glucose levels of less than 180 mg/dL.

Before surgery, consideration should be given to the type of diabetes, surgical procedure, and metabolic control. Patients on insulin detemir or glargine as part of a basal-bolus regimen with rapid-acting insulin may safely be given the full dose of their basal insulin the night before or the morning of their procedure. However, patients on neutral protamine Hagedorn (NPH) insulin as a part of their basal-bolus regimen should receive half of their usual dose due to a difference in pharmacokinetic profile compared with insulin glargine or detemir.

In insulin-treated patients undergoing prolonged procedures (eg, coronary artery bypass grafting, transplant):

• Discontinue subcutaneous insulin and start an intravenous insulin infusion, titrated to maintain a blood glucose range of 140 to 180 mg/dL
• Subcutaneous insulin management may be acceptable for patients undergoing shorter outpatient procedures
• Supplemental subcutaneous doses of short- or rapid-acting insulin preparations can be given for blood glucose elevation greater than 180 mg/dL.

AVOID ORAL AGENTS AND NONINSULIN INJECTABLES

Oral antidiabetic agents and noninsulin injectables (Table 4) should generally be avoided in hospitalized patients, especially for those with decompensated heart failure, renal insufficiency, hypoperfusion, or chronic pulmonary disease, or for those given intravenous contrast. Most oral medications used to treat diabetes are affected by reduced kidney function, resulting in prolonged drug exposure and increased risk of hypoglycemia in patients with moderate to severe CKD (stages 3–5).

Metformin, a biguanide, is contraindicated in patients with high serum creatinine levels (> 1.5 mg/dL in men, > 1.4 mg/dL in women) because of the theoretical risk of lactic acidosis.⁴⁰

Sulfonylurea clearance depends on kidney function.⁴¹ Severe prolonged episodes of hypoglycemia have been reported in dialysis patients taking these drugs, except with glipizide, which carries a lower risk.^41,42

Repaglinide, a nonsulfonylurea insulin secretagogue, can be used in CKD stages 3 to 4 without any dosage adjustment.⁴³

Thiazolidinediones have been reported to slow the progression of diabetic kidney disease independent of glycemic control.⁴⁴ Adverse effects include fluid retention, edema, and congestive heart failure. Thiazolidinediones should not be used in patients with New York Heart Association class 3 or 4 heart failure,⁴⁵ and so should not be prescribed in the hospital except for patients who are clinically stable or ready for discharge.

Quick-release bromocriptine, a dopamine receptor agonist, has been shown to be effective in lowering fasting plasma glucose levels and hemoglobin A_1c, and improving glucose tolerance in obese patients with type 2 diabetes, although its usefulness in hospitalized patients with diabetes is not known.^46,47

Dipeptidyl peptidase inhibitors. Sitagliptin and saxagliptin have been shown to be safe and effective in hospitalized patients with type 2 diabetes.⁴⁸ However, except for linagliptin, dose reduction is recommended in patients with CKD stage 3 and higher.^49–52

GLP-1 receptor agonists. Drugs of this class are potent agents for the reduction of glucose in the outpatient setting but are relatively contraindicated if the GFR is less than 30 mL/min, and they are currently not used in the hospital.

BLOOD GLUCOSE MONITORING IN HOSPITALIZED PATIENTS

Bedside blood glucose monitoring is recommended for all hospitalized patients with known diabetes with or without CKD, those with newly recognized hyperglycemia, and those who receive therapy associated with high risk for hyperglycemia, such as glucocorticoid therapy and enteral and parenteral nutrition. For patients on scheduled diets, fingerstick blood glucose monitoring is recommended before meals and at bedtime. In patients with no oral intake or on continuous enteral or parenteral nutrition, blood glucose monitoring every 4 to 6 hours is recommended. More frequent monitoring (eg, adding a 3:00 am check) may be prudent in patients with CKD.

Continuous glucose monitoring systems use a sensor inserted under the skin and transmit information via radio to a wireless monitor. Such systems are more expensive than conventional glucose monitoring but may enable better glucose control by providing real-time glucose measurements, with levels displayed at 5-minute or 1-minute intervals. Marshall et al⁵³ confirmed this technology’s accuracy and precision in uremic patients on dialysis.

Considerations for peritoneal dialysis

For patients on peritoneal dialysis, glucose in the dialysate exacerbates hyperglycemia. Dialysis solutions with the glucose polymer icodextrin as the osmotic agent instead of glucose have been suggested to reduce glucose exposure.

Glucose monitoring systems measure interstitial fluid glucose by the glucose oxidase reaction and therefore are not affected by icodextrin. However, icodextrin is converted to maltose, a disaccharide composed of two glucose molecules, which can cause spuriously high readings in devices that use test strips containing the enzymes glucose dehydrogenase pyrroloquinoline quinone or glucose dye oxidoreductase. Spurious hyperglycemia may lead to giving too much insulin, in turn leading to symptomatic hypoglycemia.

Clinicians caring for patients receiving icodextrin should ensure that the glucose monitoring system uses only test strips that contain glucose oxidase, glucose dehydrogenase-nicotinamide adenine dinucleotide, or glucose dehydrogenase-flavin adenine dinucleotide, which are not affected by icodextrin.⁵⁴

IMPROVING QUALITY

Hospitalized patients face many barriers to optimal glycemic control. Less experienced practitioners tend to have insufficient knowledge of insulin preparations and appropriate insulin dosing. Also, diabetes is often listed as a secondary diagnosis and so may be overlooked by the inpatient care team.

Educational programs should be instituted to overcome these barriers and improve knowledge related to inpatient diabetes care. When necessary, the appropriate use of consultants is important in hospitalized settings to improve quality and make hospital care more efficient and cost-effective.

No national benchmarks currently exist for inpatient diabetes care, and they need to be developed to ensure best practices. Physicians should take the initiative to remedy this by collaborating with other healthcare providers, such as dedicated diabetes educators, nursing staff, pharmacists, registered dietitians, and physicians with expertise in diabetes management, with the aim of achieving optimum glycemic control and minimizing hypoglycemia. 

Managing glycemic control in hospitalized patients with chronic kidney disease (CKD) and diabetes mellitus is a challenge, with no published guidelines. In this setting, avoiding hypoglycemia takes precedence over meeting strict blood glucose targets. Optimal management is essential to reduce hypoglycemia and the risk of death from cardiovascular disease.¹

This article reviews the evidence to guide diabetes management in hospitalized patients with CKD, focusing on blood glucose monitoring, insulin dosing, and concerns about other diabetic agents.

FOCUS ON AVOIDING HYPOGLYCEMIA

CKD is common, estimated to affect more than 50 million people worldwide.² Diabetes mellitus is the primary cause of kidney failure in 45% of dialysis patients with CKD.

Tight control comes with a cost

Hyperglycemia in hospitalized patients is associated with a higher risk of death, a higher risk of infections, and a longer hospital stay.^3,4 In 2001, Van den Berghe et al⁵ found that intensive insulin therapy reduced the mortality rate in critically ill patients in the surgical intensive care unit. But subsequent studies^6,7 found that intensive insulin therapy to achieve tight glycemic control increased rates of morbidity and mortality without adding clinical benefit.

Randomized clinical trials in outpatients have shown that tight control of blood glucose levels reduces microvascular and macrovascular complications in patients with type 1 diabetes.^8–10 In the Diabetes Control and Complications Trial,⁹ compared with conventional therapy, intensive insulin therapy reduced the incidence of retinopathy progression (4.7 vs 1.2 cases per 100 patient-years, number needed to treat [NNT] = 3 for 10 years) and clinical neuropathy (9.8 vs 3.1 per 100 patient-years, NNT = 1.5 for 10 years). The long-term likelihood of a cardiovascular event was also significantly lower in the intensive treatment group (0.38 vs 0.80 events per 100 patient-years).⁹

Similarly, in the Epidemiology of Diabetes Interventions and Complications follow-up study, the intensive therapy group had fewer cardiovascular deaths.¹¹ On the other hand, the risk of severe hypoglycemia and subsequent coma or seizure was significantly higher in the intensive therapy group than in the conventional therapy group (16.3 vs 5.4 per 100 patient-years).⁸

CKD increases hypoglycemia risk

Moen et al¹² found that the incidence of hypoglycemia was significantly higher in patients with CKD (estimated glomerular filtration rate [GFR] < 60 mL/min) with or without diabetes, and that patients with both conditions were at greatest risk (Figure 1). Multiple factors contribute to the increased risk of hypoglycemia: patients with advanced CKD tend to have poor nutrition, resulting in reduced glycogen stores, and a smaller renal mass reduces renal gluconeogenesis and decreases the elimination of insulin and oral antidiabetic agents.

After the onset of diabetic nephropathy, progression of renal complications and overall life expectancy are influenced by earlier glycemic control.⁸ Development of diabetic nephropathy is commonly accompanied by changes in metabolic control, particularly an increased risk of hypoglycemia.¹³ In addition, episodes of severe hypoglycemia constitute an independent cardiovascular risk factor.¹⁴

Aggressive glycemic control in hospitalized patients, particularly those with advanced CKD, is associated with a risk of hypoglycemia without overall improvement in outcomes.¹⁵ Elderly patients with type 2 diabetes are similar to patients with CKD in that they have a reduced GFR and are thus more sensitive to insulin. In both groups, intensifying glycemic control, especially in the hospital, is associated with more frequent episodes of severe hypoglycemia.¹⁶ The focus should be not only on maintaining optimal blood glucose concentration, but also on preventing hypoglycemia.

‘Burnt-out’ diabetes

Paradoxically, patients with end-stage renal disease and type 2 diabetes often experience altered glucose homeostasis with markedly improved glycemic control. They may attain normoglycemia and normalization of hemoglobin A_1c, a condition known as “burnt-out” diabetes. Its precise mechanism is not understood and its significance remains unclear (Table 1).¹⁷

HEMOGLOBIN A_1c CAN BE FALSELY HIGH OR FALSELY LOW

Hemoglobin A_1c measurement is used to diagnose diabetes and to assess long-term glycemic control. It is a measure of the fraction of hemoglobin that has been glycated by exposure to glucose. Because the average lifespan of a red cell is 120 days, the hemoglobin A_1c value reflects the mean blood glucose concentration over the preceding 3 months.

But hemoglobin A_1c measurement has limitations: any condition that alters the lifespan of erythrocytes leads to higher or lower hemoglobin A_1c levels. Hemoglobin A_1c levels are also affected by kidney dysfunction, hemolysis, and acidosis.¹⁸

Falsely high hemoglobin A_1c levels are associated with conditions that prolong the lifespan of erythrocytes, such as asplenia. Iron deficiency also increases the average age of circulating red cells because of reduced red cell production. For patients in whom blood glucose measurements do not correlate with hemoglobin A_1c measurements, iron deficiency anemia should be considered before altering a treatment regimen.

Falsely low hemoglobin A_1c levels are associated with conditions of more rapid erythrocyte turnover, such as autoimmune hemolytic anemia, hereditary spherocytosis, and acute blood loss anemia. In patients with CKD, recombinant erythropoietin treatment lowers hemoglobin A_1c levels by increasing the number of immature red cells, which are less likely to glycosylate.¹⁹

Morgan et al²⁰ compared the association between hemoglobin A_1c and blood glucose levels in diabetic patients with moderate to severe CKD not requiring dialysis and in diabetic patients with normal renal function and found no difference between these two groups, suggesting that hemoglobin A_1c is reliable in this setting. But study results conflict for patients on dialysis, making the usefulness of hemoglobin A_1c testing for those patients less clear. In one study, hemoglobin A_1c testing underestimated glycemic control,²⁰ but other studies found that glycemic control was overestimated.^21,22

Alternatives to hemoglobin A_1c

Other measures of long-term glycemic control such as fructosamine and glycated albumin levels are sometimes used in conditions in which hemoglobin A_1c may not be reliable.

Albumin also undergoes glycation when exposed to glucose. Glycated albumin appears to be a better measure of glycemic control in patients with CKD and diabetes than serum fructosamine,²³ which has failed to show a significant correlation with blood glucose levels in patients with CKD.²⁴ However, because serum albumin has a short half-life, glycated albumin reflects glycemic control in only the approximately 1 to 2 weeks before sampling,²⁵ so monthly monitoring is required.

Glycated albumin levels may be reduced due to increased albumin turnover in patients with nephrotic-range proteinuria and in diabetic patients on peritoneal dialysis. Several issues remain unclear, such as the appropriate target level of glycated albumin and at what stage of CKD it should replace hemoglobin A_1c testing. If an improved assay that is unaffected by changes in serum albumin becomes available, it may be appropriate to use glycated albumin measurements to assess long-term glycemic control for patients with CKD.

In general, therapeutic decisions to achieve optimum glycemic control in patients with diabetes and CKD should be based on hemoglobin A_1c testing, multiple glucose measurements, and patient symptoms of hypoglycemia or hyperglycemia. The best measure for assessing glycemic control in hospitalized patients with CKD remains multiple blood glucose testing daily.

INSULIN THERAPY PREFERRED

Although several studies have evaluated inpatient glycemic control,^26–29 no guidelines have been published for hospitalized patients with diabetes and CKD. Insulin therapy is preferred for achieving glycemic control in acutely ill or hospitalized patients with diabetes. Oral hypoglycemic agents should be discontinued.

Regardless of the form of insulin chosen to treat diabetes, caution is needed for patients with kidney disease. During hospitalization, clinical changes are expected owing to illness and differences in caloric intake and physical activity, resulting in altered insulin sensitivity. Insulin-treated hospitalized patients require individualized care, including multiple daily blood glucose tests and insulin therapy modifications for ideal glycemic control.

For surgical or medical intensive care patients on insulin therapy, the target blood glucose level before meals should be 140 mg/dL, and the target random level should be less than 180 mg/dL.^15,26–29

Basal-bolus insulin

Sliding-scale therapy should be avoided as the only method for glycemic control. Instead, scheduled subcutaneous basal insulin once or twice daily combined with rapid- or short-acting insulin with meals is recommended.

Basal-bolus insulin therapy, one of the most advanced and flexible insulin replacement therapies, mimics endogenous insulin release and offers great advantages in diabetes care. Using mealtime bolus insulin permits variation in the amount of food eaten; more insulin can be taken with a larger meal and less with smaller meals. A bolus approach offers the flexibility of administering rapid-acting insulin immediately after meals when oral intake is variable.

Individualize insulin therapy

Optimizing glycemic control requires an understanding of the altered pharmacokinetics and pharmacodynamics of insulin in patients with diabetic nephropathy. Table 2 shows the pharmacokinetic profiles of insulin preparations in healthy people. Analogue insulins, which are manufactured by recombinant DNA technology, have conformational changes in the insulin molecule that alter their pharmacokinetics and pharmacodynamics. The rapid-acting analogue insulins are absorbed quickly, making them suitable for postprandial glucose control.

Changes in GFR are associated with altered pharmacokinetics and pharmacodynamics of insulin,^30,31 but unlike for oral antidiabetic agents, these properties are not well characterized for insulin preparations in patients with renal insufficiency.^13,32–36

CKD may reduce insulin clearance. Rave et al³² reported that the clearance of regular human insulin was reduced by 30% to 40% in patients with type 1 diabetes and a mean estimated GFR of 54 mL/min. They found that the metabolic activity of insulin lispro was more robust than that of short-acting regular human insulin in patients with diabetic nephropathy. In another study, patients with diabetes treated with insulin aspart did not show any significant change in the required insulin dosage in relation to the renal filtration rate.³⁴ Biesenbach et al³³ found a 38% reduction in insulin requirements in patients with type 1 diabetes as estimated GFR decreased from 80 mL/min to 10 mL/min. Further studies are required to better understand the safety of insulin in treating hospitalized patients with diabetes and renal insufficiency.

Few studies have compared the pharmacodynamics of long-acting insulins in relation to declining renal function. The long-acting analogue insulins have less of a peak than human insulin and thus better mimic endogenous insulin secretion. For insulin detemir, Lindholm and Jacobsen found no significant differences in the pharmacokinetics related to the stages of CKD.³⁵ When using the long-acting insulins glargine or detemir, one should consider giving much lower doses (half the initial starting dosage) and titrating the dosage until target fasting glucose concentrations are reached to prevent hypoglycemia.

Table 3 summarizes recommended insulin dosage adjustments in CKD based on the literature and our clinical experience.

Considerations for dialysis patients

Subcutaneously administered insulin is eliminated renally, unlike endogenous insulin, which undergoes first-pass metabolism in the liver.^13,37 As renal function declines, insulin clearance decreases and the insulin dosage must be reduced to prevent hypoglycemia.

Patients on hemodialysis or peritoneal dialysis pose a challenge for insulin dosing. Hemodialysis improves insulin sensitivity but also increases insulin clearance, making it difficult to determine insulin requirements. Sobngwi et al³⁸ conducted a study in diabetic patients with end-stage renal disease on hemodialysis, using a 24-hour euglycemic clamp. They found that exogenous basal insulin requirements were 25% lower on the day after hemodialysis compared with the day before, but premeal insulin requirements stayed the same.

Peritoneal dialysis exposes patients to a high glucose load via the peritoneum, which can worsen insulin resistance. Intraperitoneal administration of insulin during peritoneal dialysis provides a more physiologic effect than subcutaneous administration: it prevents fluctuations of blood glucose and the formation of insulin antibodies. But insulin requirements are higher owing to a dilutional effect and to insulin binding to the plastic surface of the dialysis fluid reservoir.³⁹

GLYCEMIC CONTROL FOR PROCEDURES

No guidelines have been established regarding the optimal blood glucose range for diabetic patients with CKD undergoing diagnostic or surgical procedures. Given the risk of hypoglycemia in such settings, less-stringent targets are reasonable, ie, premeal blood glucose levels of 140 mg/dL and random blood glucose levels of less than 180 mg/dL.

Before surgery, consideration should be given to the type of diabetes, surgical procedure, and metabolic control. Patients on insulin detemir or glargine as part of a basal-bolus regimen with rapid-acting insulin may safely be given the full dose of their basal insulin the night before or the morning of their procedure. However, patients on neutral protamine Hagedorn (NPH) insulin as a part of their basal-bolus regimen should receive half of their usual dose due to a difference in pharmacokinetic profile compared with insulin glargine or detemir.

In insulin-treated patients undergoing prolonged procedures (eg, coronary artery bypass grafting, transplant):

• Discontinue subcutaneous insulin and start an intravenous insulin infusion, titrated to maintain a blood glucose range of 140 to 180 mg/dL
• Subcutaneous insulin management may be acceptable for patients undergoing shorter outpatient procedures
• Supplemental subcutaneous doses of short- or rapid-acting insulin preparations can be given for blood glucose elevation greater than 180 mg/dL.

AVOID ORAL AGENTS AND NONINSULIN INJECTABLES

Oral antidiabetic agents and noninsulin injectables (Table 4) should generally be avoided in hospitalized patients, especially for those with decompensated heart failure, renal insufficiency, hypoperfusion, or chronic pulmonary disease, or for those given intravenous contrast. Most oral medications used to treat diabetes are affected by reduced kidney function, resulting in prolonged drug exposure and increased risk of hypoglycemia in patients with moderate to severe CKD (stages 3–5).

Metformin, a biguanide, is contraindicated in patients with high serum creatinine levels (> 1.5 mg/dL in men, > 1.4 mg/dL in women) because of the theoretical risk of lactic acidosis.⁴⁰

Sulfonylurea clearance depends on kidney function.⁴¹ Severe prolonged episodes of hypoglycemia have been reported in dialysis patients taking these drugs, except with glipizide, which carries a lower risk.^41,42

Repaglinide, a nonsulfonylurea insulin secretagogue, can be used in CKD stages 3 to 4 without any dosage adjustment.⁴³

Thiazolidinediones have been reported to slow the progression of diabetic kidney disease independent of glycemic control.⁴⁴ Adverse effects include fluid retention, edema, and congestive heart failure. Thiazolidinediones should not be used in patients with New York Heart Association class 3 or 4 heart failure,⁴⁵ and so should not be prescribed in the hospital except for patients who are clinically stable or ready for discharge.

Quick-release bromocriptine, a dopamine receptor agonist, has been shown to be effective in lowering fasting plasma glucose levels and hemoglobin A_1c, and improving glucose tolerance in obese patients with type 2 diabetes, although its usefulness in hospitalized patients with diabetes is not known.^46,47

Dipeptidyl peptidase inhibitors. Sitagliptin and saxagliptin have been shown to be safe and effective in hospitalized patients with type 2 diabetes.⁴⁸ However, except for linagliptin, dose reduction is recommended in patients with CKD stage 3 and higher.^49–52

GLP-1 receptor agonists. Drugs of this class are potent agents for the reduction of glucose in the outpatient setting but are relatively contraindicated if the GFR is less than 30 mL/min, and they are currently not used in the hospital.

BLOOD GLUCOSE MONITORING IN HOSPITALIZED PATIENTS

Bedside blood glucose monitoring is recommended for all hospitalized patients with known diabetes with or without CKD, those with newly recognized hyperglycemia, and those who receive therapy associated with high risk for hyperglycemia, such as glucocorticoid therapy and enteral and parenteral nutrition. For patients on scheduled diets, fingerstick blood glucose monitoring is recommended before meals and at bedtime. In patients with no oral intake or on continuous enteral or parenteral nutrition, blood glucose monitoring every 4 to 6 hours is recommended. More frequent monitoring (eg, adding a 3:00 am check) may be prudent in patients with CKD.

Continuous glucose monitoring systems use a sensor inserted under the skin and transmit information via radio to a wireless monitor. Such systems are more expensive than conventional glucose monitoring but may enable better glucose control by providing real-time glucose measurements, with levels displayed at 5-minute or 1-minute intervals. Marshall et al⁵³ confirmed this technology’s accuracy and precision in uremic patients on dialysis.

Considerations for peritoneal dialysis

For patients on peritoneal dialysis, glucose in the dialysate exacerbates hyperglycemia. Dialysis solutions with the glucose polymer icodextrin as the osmotic agent instead of glucose have been suggested to reduce glucose exposure.

Glucose monitoring systems measure interstitial fluid glucose by the glucose oxidase reaction and therefore are not affected by icodextrin. However, icodextrin is converted to maltose, a disaccharide composed of two glucose molecules, which can cause spuriously high readings in devices that use test strips containing the enzymes glucose dehydrogenase pyrroloquinoline quinone or glucose dye oxidoreductase. Spurious hyperglycemia may lead to giving too much insulin, in turn leading to symptomatic hypoglycemia.

Clinicians caring for patients receiving icodextrin should ensure that the glucose monitoring system uses only test strips that contain glucose oxidase, glucose dehydrogenase-nicotinamide adenine dinucleotide, or glucose dehydrogenase-flavin adenine dinucleotide, which are not affected by icodextrin.⁵⁴

IMPROVING QUALITY

Hospitalized patients face many barriers to optimal glycemic control. Less experienced practitioners tend to have insufficient knowledge of insulin preparations and appropriate insulin dosing. Also, diabetes is often listed as a secondary diagnosis and so may be overlooked by the inpatient care team.

Educational programs should be instituted to overcome these barriers and improve knowledge related to inpatient diabetes care. When necessary, the appropriate use of consultants is important in hospitalized settings to improve quality and make hospital care more efficient and cost-effective.

No national benchmarks currently exist for inpatient diabetes care, and they need to be developed to ensure best practices. Physicians should take the initiative to remedy this by collaborating with other healthcare providers, such as dedicated diabetes educators, nursing staff, pharmacists, registered dietitians, and physicians with expertise in diabetes management, with the aim of achieving optimum glycemic control and minimizing hypoglycemia. 

Managing glycemic control in hospitalized patients with chronic kidney disease (CKD) and diabetes mellitus is a challenge, with no published guidelines. In this setting, avoiding hypoglycemia takes precedence over meeting strict blood glucose targets. Optimal management is essential to reduce hypoglycemia and the risk of death from cardiovascular disease.¹

This article reviews the evidence to guide diabetes management in hospitalized patients with CKD, focusing on blood glucose monitoring, insulin dosing, and concerns about other diabetic agents.

FOCUS ON AVOIDING HYPOGLYCEMIA

CKD is common, estimated to affect more than 50 million people worldwide.² Diabetes mellitus is the primary cause of kidney failure in 45% of dialysis patients with CKD.

Tight control comes with a cost

Hyperglycemia in hospitalized patients is associated with a higher risk of death, a higher risk of infections, and a longer hospital stay.^3,4 In 2001, Van den Berghe et al⁵ found that intensive insulin therapy reduced the mortality rate in critically ill patients in the surgical intensive care unit. But subsequent studies^6,7 found that intensive insulin therapy to achieve tight glycemic control increased rates of morbidity and mortality without adding clinical benefit.

Randomized clinical trials in outpatients have shown that tight control of blood glucose levels reduces microvascular and macrovascular complications in patients with type 1 diabetes.^8–10 In the Diabetes Control and Complications Trial,⁹ compared with conventional therapy, intensive insulin therapy reduced the incidence of retinopathy progression (4.7 vs 1.2 cases per 100 patient-years, number needed to treat [NNT] = 3 for 10 years) and clinical neuropathy (9.8 vs 3.1 per 100 patient-years, NNT = 1.5 for 10 years). The long-term likelihood of a cardiovascular event was also significantly lower in the intensive treatment group (0.38 vs 0.80 events per 100 patient-years).⁹

Similarly, in the Epidemiology of Diabetes Interventions and Complications follow-up study, the intensive therapy group had fewer cardiovascular deaths.¹¹ On the other hand, the risk of severe hypoglycemia and subsequent coma or seizure was significantly higher in the intensive therapy group than in the conventional therapy group (16.3 vs 5.4 per 100 patient-years).⁸

CKD increases hypoglycemia risk

Moen et al¹² found that the incidence of hypoglycemia was significantly higher in patients with CKD (estimated glomerular filtration rate [GFR] < 60 mL/min) with or without diabetes, and that patients with both conditions were at greatest risk (Figure 1). Multiple factors contribute to the increased risk of hypoglycemia: patients with advanced CKD tend to have poor nutrition, resulting in reduced glycogen stores, and a smaller renal mass reduces renal gluconeogenesis and decreases the elimination of insulin and oral antidiabetic agents.

After the onset of diabetic nephropathy, progression of renal complications and overall life expectancy are influenced by earlier glycemic control.⁸ Development of diabetic nephropathy is commonly accompanied by changes in metabolic control, particularly an increased risk of hypoglycemia.¹³ In addition, episodes of severe hypoglycemia constitute an independent cardiovascular risk factor.¹⁴

Aggressive glycemic control in hospitalized patients, particularly those with advanced CKD, is associated with a risk of hypoglycemia without overall improvement in outcomes.¹⁵ Elderly patients with type 2 diabetes are similar to patients with CKD in that they have a reduced GFR and are thus more sensitive to insulin. In both groups, intensifying glycemic control, especially in the hospital, is associated with more frequent episodes of severe hypoglycemia.¹⁶ The focus should be not only on maintaining optimal blood glucose concentration, but also on preventing hypoglycemia.

‘Burnt-out’ diabetes

Paradoxically, patients with end-stage renal disease and type 2 diabetes often experience altered glucose homeostasis with markedly improved glycemic control. They may attain normoglycemia and normalization of hemoglobin A_1c, a condition known as “burnt-out” diabetes. Its precise mechanism is not understood and its significance remains unclear (Table 1).¹⁷

HEMOGLOBIN A_1c CAN BE FALSELY HIGH OR FALSELY LOW

Hemoglobin A_1c measurement is used to diagnose diabetes and to assess long-term glycemic control. It is a measure of the fraction of hemoglobin that has been glycated by exposure to glucose. Because the average lifespan of a red cell is 120 days, the hemoglobin A_1c value reflects the mean blood glucose concentration over the preceding 3 months.

But hemoglobin A_1c measurement has limitations: any condition that alters the lifespan of erythrocytes leads to higher or lower hemoglobin A_1c levels. Hemoglobin A_1c levels are also affected by kidney dysfunction, hemolysis, and acidosis.¹⁸

Falsely high hemoglobin A_1c levels are associated with conditions that prolong the lifespan of erythrocytes, such as asplenia. Iron deficiency also increases the average age of circulating red cells because of reduced red cell production. For patients in whom blood glucose measurements do not correlate with hemoglobin A_1c measurements, iron deficiency anemia should be considered before altering a treatment regimen.

Falsely low hemoglobin A_1c levels are associated with conditions of more rapid erythrocyte turnover, such as autoimmune hemolytic anemia, hereditary spherocytosis, and acute blood loss anemia. In patients with CKD, recombinant erythropoietin treatment lowers hemoglobin A_1c levels by increasing the number of immature red cells, which are less likely to glycosylate.¹⁹

Morgan et al²⁰ compared the association between hemoglobin A_1c and blood glucose levels in diabetic patients with moderate to severe CKD not requiring dialysis and in diabetic patients with normal renal function and found no difference between these two groups, suggesting that hemoglobin A_1c is reliable in this setting. But study results conflict for patients on dialysis, making the usefulness of hemoglobin A_1c testing for those patients less clear. In one study, hemoglobin A_1c testing underestimated glycemic control,²⁰ but other studies found that glycemic control was overestimated.^21,22

Alternatives to hemoglobin A_1c

Other measures of long-term glycemic control such as fructosamine and glycated albumin levels are sometimes used in conditions in which hemoglobin A_1c may not be reliable.

Albumin also undergoes glycation when exposed to glucose. Glycated albumin appears to be a better measure of glycemic control in patients with CKD and diabetes than serum fructosamine,²³ which has failed to show a significant correlation with blood glucose levels in patients with CKD.²⁴ However, because serum albumin has a short half-life, glycated albumin reflects glycemic control in only the approximately 1 to 2 weeks before sampling,²⁵ so monthly monitoring is required.

Glycated albumin levels may be reduced due to increased albumin turnover in patients with nephrotic-range proteinuria and in diabetic patients on peritoneal dialysis. Several issues remain unclear, such as the appropriate target level of glycated albumin and at what stage of CKD it should replace hemoglobin A_1c testing. If an improved assay that is unaffected by changes in serum albumin becomes available, it may be appropriate to use glycated albumin measurements to assess long-term glycemic control for patients with CKD.

In general, therapeutic decisions to achieve optimum glycemic control in patients with diabetes and CKD should be based on hemoglobin A_1c testing, multiple glucose measurements, and patient symptoms of hypoglycemia or hyperglycemia. The best measure for assessing glycemic control in hospitalized patients with CKD remains multiple blood glucose testing daily.

INSULIN THERAPY PREFERRED

Although several studies have evaluated inpatient glycemic control,^26–29 no guidelines have been published for hospitalized patients with diabetes and CKD. Insulin therapy is preferred for achieving glycemic control in acutely ill or hospitalized patients with diabetes. Oral hypoglycemic agents should be discontinued.

Regardless of the form of insulin chosen to treat diabetes, caution is needed for patients with kidney disease. During hospitalization, clinical changes are expected owing to illness and differences in caloric intake and physical activity, resulting in altered insulin sensitivity. Insulin-treated hospitalized patients require individualized care, including multiple daily blood glucose tests and insulin therapy modifications for ideal glycemic control.

For surgical or medical intensive care patients on insulin therapy, the target blood glucose level before meals should be 140 mg/dL, and the target random level should be less than 180 mg/dL.^15,26–29

Basal-bolus insulin

Sliding-scale therapy should be avoided as the only method for glycemic control. Instead, scheduled subcutaneous basal insulin once or twice daily combined with rapid- or short-acting insulin with meals is recommended.

Basal-bolus insulin therapy, one of the most advanced and flexible insulin replacement therapies, mimics endogenous insulin release and offers great advantages in diabetes care. Using mealtime bolus insulin permits variation in the amount of food eaten; more insulin can be taken with a larger meal and less with smaller meals. A bolus approach offers the flexibility of administering rapid-acting insulin immediately after meals when oral intake is variable.

Individualize insulin therapy

Optimizing glycemic control requires an understanding of the altered pharmacokinetics and pharmacodynamics of insulin in patients with diabetic nephropathy. Table 2 shows the pharmacokinetic profiles of insulin preparations in healthy people. Analogue insulins, which are manufactured by recombinant DNA technology, have conformational changes in the insulin molecule that alter their pharmacokinetics and pharmacodynamics. The rapid-acting analogue insulins are absorbed quickly, making them suitable for postprandial glucose control.

Changes in GFR are associated with altered pharmacokinetics and pharmacodynamics of insulin,^30,31 but unlike for oral antidiabetic agents, these properties are not well characterized for insulin preparations in patients with renal insufficiency.^13,32–36

CKD may reduce insulin clearance. Rave et al³² reported that the clearance of regular human insulin was reduced by 30% to 40% in patients with type 1 diabetes and a mean estimated GFR of 54 mL/min. They found that the metabolic activity of insulin lispro was more robust than that of short-acting regular human insulin in patients with diabetic nephropathy. In another study, patients with diabetes treated with insulin aspart did not show any significant change in the required insulin dosage in relation to the renal filtration rate.³⁴ Biesenbach et al³³ found a 38% reduction in insulin requirements in patients with type 1 diabetes as estimated GFR decreased from 80 mL/min to 10 mL/min. Further studies are required to better understand the safety of insulin in treating hospitalized patients with diabetes and renal insufficiency.

Few studies have compared the pharmacodynamics of long-acting insulins in relation to declining renal function. The long-acting analogue insulins have less of a peak than human insulin and thus better mimic endogenous insulin secretion. For insulin detemir, Lindholm and Jacobsen found no significant differences in the pharmacokinetics related to the stages of CKD.³⁵ When using the long-acting insulins glargine or detemir, one should consider giving much lower doses (half the initial starting dosage) and titrating the dosage until target fasting glucose concentrations are reached to prevent hypoglycemia.

Table 3 summarizes recommended insulin dosage adjustments in CKD based on the literature and our clinical experience.

Considerations for dialysis patients

Subcutaneously administered insulin is eliminated renally, unlike endogenous insulin, which undergoes first-pass metabolism in the liver.^13,37 As renal function declines, insulin clearance decreases and the insulin dosage must be reduced to prevent hypoglycemia.

Patients on hemodialysis or peritoneal dialysis pose a challenge for insulin dosing. Hemodialysis improves insulin sensitivity but also increases insulin clearance, making it difficult to determine insulin requirements. Sobngwi et al³⁸ conducted a study in diabetic patients with end-stage renal disease on hemodialysis, using a 24-hour euglycemic clamp. They found that exogenous basal insulin requirements were 25% lower on the day after hemodialysis compared with the day before, but premeal insulin requirements stayed the same.

Peritoneal dialysis exposes patients to a high glucose load via the peritoneum, which can worsen insulin resistance. Intraperitoneal administration of insulin during peritoneal dialysis provides a more physiologic effect than subcutaneous administration: it prevents fluctuations of blood glucose and the formation of insulin antibodies. But insulin requirements are higher owing to a dilutional effect and to insulin binding to the plastic surface of the dialysis fluid reservoir.³⁹

GLYCEMIC CONTROL FOR PROCEDURES

No guidelines have been established regarding the optimal blood glucose range for diabetic patients with CKD undergoing diagnostic or surgical procedures. Given the risk of hypoglycemia in such settings, less-stringent targets are reasonable, ie, premeal blood glucose levels of 140 mg/dL and random blood glucose levels of less than 180 mg/dL.

Before surgery, consideration should be given to the type of diabetes, surgical procedure, and metabolic control. Patients on insulin detemir or glargine as part of a basal-bolus regimen with rapid-acting insulin may safely be given the full dose of their basal insulin the night before or the morning of their procedure. However, patients on neutral protamine Hagedorn (NPH) insulin as a part of their basal-bolus regimen should receive half of their usual dose due to a difference in pharmacokinetic profile compared with insulin glargine or detemir.

In insulin-treated patients undergoing prolonged procedures (eg, coronary artery bypass grafting, transplant):

• Discontinue subcutaneous insulin and start an intravenous insulin infusion, titrated to maintain a blood glucose range of 140 to 180 mg/dL
• Subcutaneous insulin management may be acceptable for patients undergoing shorter outpatient procedures
• Supplemental subcutaneous doses of short- or rapid-acting insulin preparations can be given for blood glucose elevation greater than 180 mg/dL.

AVOID ORAL AGENTS AND NONINSULIN INJECTABLES

Oral antidiabetic agents and noninsulin injectables (Table 4) should generally be avoided in hospitalized patients, especially for those with decompensated heart failure, renal insufficiency, hypoperfusion, or chronic pulmonary disease, or for those given intravenous contrast. Most oral medications used to treat diabetes are affected by reduced kidney function, resulting in prolonged drug exposure and increased risk of hypoglycemia in patients with moderate to severe CKD (stages 3–5).

Metformin, a biguanide, is contraindicated in patients with high serum creatinine levels (> 1.5 mg/dL in men, > 1.4 mg/dL in women) because of the theoretical risk of lactic acidosis.⁴⁰

Sulfonylurea clearance depends on kidney function.⁴¹ Severe prolonged episodes of hypoglycemia have been reported in dialysis patients taking these drugs, except with glipizide, which carries a lower risk.^41,42

Repaglinide, a nonsulfonylurea insulin secretagogue, can be used in CKD stages 3 to 4 without any dosage adjustment.⁴³

Thiazolidinediones have been reported to slow the progression of diabetic kidney disease independent of glycemic control.⁴⁴ Adverse effects include fluid retention, edema, and congestive heart failure. Thiazolidinediones should not be used in patients with New York Heart Association class 3 or 4 heart failure,⁴⁵ and so should not be prescribed in the hospital except for patients who are clinically stable or ready for discharge.

Quick-release bromocriptine, a dopamine receptor agonist, has been shown to be effective in lowering fasting plasma glucose levels and hemoglobin A_1c, and improving glucose tolerance in obese patients with type 2 diabetes, although its usefulness in hospitalized patients with diabetes is not known.^46,47

Dipeptidyl peptidase inhibitors. Sitagliptin and saxagliptin have been shown to be safe and effective in hospitalized patients with type 2 diabetes.⁴⁸ However, except for linagliptin, dose reduction is recommended in patients with CKD stage 3 and higher.^49–52

GLP-1 receptor agonists. Drugs of this class are potent agents for the reduction of glucose in the outpatient setting but are relatively contraindicated if the GFR is less than 30 mL/min, and they are currently not used in the hospital.

BLOOD GLUCOSE MONITORING IN HOSPITALIZED PATIENTS

Bedside blood glucose monitoring is recommended for all hospitalized patients with known diabetes with or without CKD, those with newly recognized hyperglycemia, and those who receive therapy associated with high risk for hyperglycemia, such as glucocorticoid therapy and enteral and parenteral nutrition. For patients on scheduled diets, fingerstick blood glucose monitoring is recommended before meals and at bedtime. In patients with no oral intake or on continuous enteral or parenteral nutrition, blood glucose monitoring every 4 to 6 hours is recommended. More frequent monitoring (eg, adding a 3:00 am check) may be prudent in patients with CKD.

Continuous glucose monitoring systems use a sensor inserted under the skin and transmit information via radio to a wireless monitor. Such systems are more expensive than conventional glucose monitoring but may enable better glucose control by providing real-time glucose measurements, with levels displayed at 5-minute or 1-minute intervals. Marshall et al⁵³ confirmed this technology’s accuracy and precision in uremic patients on dialysis.

Considerations for peritoneal dialysis

For patients on peritoneal dialysis, glucose in the dialysate exacerbates hyperglycemia. Dialysis solutions with the glucose polymer icodextrin as the osmotic agent instead of glucose have been suggested to reduce glucose exposure.

Glucose monitoring systems measure interstitial fluid glucose by the glucose oxidase reaction and therefore are not affected by icodextrin. However, icodextrin is converted to maltose, a disaccharide composed of two glucose molecules, which can cause spuriously high readings in devices that use test strips containing the enzymes glucose dehydrogenase pyrroloquinoline quinone or glucose dye oxidoreductase. Spurious hyperglycemia may lead to giving too much insulin, in turn leading to symptomatic hypoglycemia.

Clinicians caring for patients receiving icodextrin should ensure that the glucose monitoring system uses only test strips that contain glucose oxidase, glucose dehydrogenase-nicotinamide adenine dinucleotide, or glucose dehydrogenase-flavin adenine dinucleotide, which are not affected by icodextrin.⁵⁴

IMPROVING QUALITY

Hospitalized patients face many barriers to optimal glycemic control. Less experienced practitioners tend to have insufficient knowledge of insulin preparations and appropriate insulin dosing. Also, diabetes is often listed as a secondary diagnosis and so may be overlooked by the inpatient care team.

Educational programs should be instituted to overcome these barriers and improve knowledge related to inpatient diabetes care. When necessary, the appropriate use of consultants is important in hospitalized settings to improve quality and make hospital care more efficient and cost-effective.

No national benchmarks currently exist for inpatient diabetes care, and they need to be developed to ensure best practices. Physicians should take the initiative to remedy this by collaborating with other healthcare providers, such as dedicated diabetes educators, nursing staff, pharmacists, registered dietitians, and physicians with expertise in diabetes management, with the aim of achieving optimum glycemic control and minimizing hypoglycemia. 

The incidental finding of high systolic pulmonary artery pressure on echocardiography is common. What we should do about it varies according to clinical presentation, comorbidities, and results of other tests, including assessment of the right ventricle. Thus, the optimal approach ranges from no further investigation to right heart catheterization and, in some cases, referral to a pulmonary hypertension center.

THE TWO MEASUREMENTS COMPARED

Although it raises concern, the finding of high systolic pulmonary artery pressure is not enough to diagnose pulmonary hypertension. In fact, several other conditions are associated with high systolic pulmonary artery pressure on echocardiography (Table 1). The diagnosis must be confirmed with right heart catheterization.¹

Echocardiography provides an estimate of the systolic pulmonary artery pressure that is calculated from other values, whereas right heart catheterization gives a direct measurement of the mean pulmonary artery pressure, which is necessary for diagnosing pulmonary hypertension. The two values are correlated, but the differences are noteworthy.

WHAT IS PULMONARY HYPERTENSION?

Pulmonary hypertension is defined by a resting mean pulmonary artery pressure 25 mm Hg or greater during right heart catheterization.¹ The large number of conditions associated with pulmonary hypertension can be divided into five groups²:

• Group 1, pulmonary artery hypertension
• Group 2, pulmonary hypertension associated with left heart disease
• Group 3, pulmonary hypertension due to chronic lung disease or hypoxia
• Group 4, chronic thromboembolic pulmonary hypertension
• Group 5, pulmonary hypertension due to unclear multifactorial mechanisms.²

Pulmonary artery hypertension (group 1) is a syndrome characterized by a restricted flow of small pulmonary arteries that can be idiopathic, heritable, or induced by anorexigens, connective tissue disease, congenital heart disease, portal hypertension, human immunodeficiency virus (HIV), or schistosomiasis.^2,3 In spite of significant advances in therapy in the last 3 decades, pulmonary artery hypertension continues to lead to right heart failure and death,⁴ and the diagnosis has adverse prognostic implications. Therefore, it is essential to be attentive when reviewing the echocardiogram, since an elevated systolic pulmonary artery pressure may be an important clue to pulmonary hypertension.

ESTIMATED PRESSURE: HOW HIGH IS TOO HIGH?

There is no consensus on the optimal cutoff of echocardiographic systolic pulmonary artery pressure to trigger a further evaluation for pulmonary hypertension.

A retrospective evaluation of nearly 16,000 normal echocardiograms found that the 95% upper limit for systolic pulmonary artery pressure was 37 mm Hg.⁵

European guidelines⁶ propose that pulmonary hypertension is unlikely if the estimated systolic pulmonary artery pressure is 36 mm Hg or lower, possible if it is 37 to 50 mm Hg, and likely if it is higher than 50 mm Hg.⁶

The 2009 consensus document of the American College of Cardiology Foundation and American Heart Association³ recommends a systolic pulmonary artery pressure greater than 40 mm Hg as the threshold to suggest further evaluation in a patient with unexplained dyspnea.

Converting the systolic pulmonary artery pressure to the mean pressure

Although not validated to use with echocardiography, the most accurate estimate of mean pulmonary artery pressure was shown in one study⁷ to be obtained with the equation:

0.61 × systolic pulmonary artery pressure
+ 2 mm Hg

Using this formula, a systolic pulmonary artery pressure of 37 mm Hg would correspond to a mean pulmonary artery pressure of 24.6 mm Hg. A systolic pulmonary artery pressure of 40 mm Hg would correspond to a mean pulmonary artery pressure of 26.4 mm Hg.

Estimated systolic pulmonary artery pressure depends on several variables

Systolic pulmonary artery pressure is estimated using the simplified Bernoulli equation⁸:

4 × tricuspid regurgitation jet velocity² (m/s)
+ right atrial pressure (mm Hg)

Tricuspid regurgitation is present in over 75% of the normal population. The regurgitation velocity across the tricuspid valve must be measured to estimate the pressure gradient between the right ventricle and the right atrium. The right atrial pressure is estimated from the diameter of the inferior vena cava and the degree of inspiratory collapse with the sniff test. As the right atrial pressure increases, the inferior vena cava dilates and inspiratory collapse decreases.⁸ If there is no gradient across the right ventricular outflow tract or pulmonary valve, the right ventricular systolic pressure is equal to the systolic pulmonary artery pressure.

Since tricuspid regurgitation velocity is squared and then multiplied by 4, small deviations of this measurement lead to markedly different systolic pulmonary artery pressure values. To avoid this problem, the tricuspid regurgitation velocity needs to be looked at in multiple echocardiographic views to find the best alignment with the flow and an adequate envelope.

Many causes of high estimated systolic pulmonary artery pressure

Table 1 shows conditions associated with a high estimated systolic pulmonary artery pressure. Echocardiographic limitations, constitutional factors, and high cardiac output states can lead to an apparent elevation in systolic pulmonary artery pressure, which is not confirmed later during right heart catheterization.

Systolic pulmonary artery pressure increases with age and body mass index as a result of worsening left ventricular diastolic dysfunction.⁸ In fact, an estimated pressure greater than 40 mm Hg is found⁵ in 6% of people over age 50 and in 5% of people with a body mass index greater than 30 kg/m². It can also be high in conditions in which there is an increase in cardiac output, such as pregnancy, anemia (sickle cell disease, thalassemia), cirrhosis, and arteriovenous fistula.

The estimated systolic value often differs from the measured value

Studies have compared the systolic pulmonary artery pressure measured during right heart catheterization with the estimated value on echocardiography.^9,10 These studies noted a reasonable degree of agreement between the tests but a substantial variability.

Both underestimation and overestimation of the systolic pulmonary artery pressure by echocardiography were common, with 95% limits of agreement ranging from minus 40 mm Hg to plus 40 mm Hg.^9,10 A difference of plus or minus 10 mm Hg in systolic pulmonary artery pressure between echocardiography and catheterization was observed in 48% to 51% of patients with pulmonary hypertension, particularly in those with higher systolic pulmonary artery pressure.^9,10

An important reason for overestimation of systolic pulmonary artery pressure is the inaccurate estimation of the right atrial pressure by echocardiography.^9,10 Indeed, this factor may account for half of the cases in which the systolic pulmonary artery pressure is overestimated.¹⁰ Although the traditional methods to estimate the right atrial pressure have been revisited,^8,11 this estimation is less reliable for intermediate pressure values, for patients on mechanical ventilation, and for young athletes.⁸

Other explanations for the variability between measured and estimated systolic pulmonary artery pressure include suboptimal alignment between the Doppler beam and the regurgitant jet, severe tricuspid regurgitation, arrhythmias, and limitations inherent to the simplified Bernoulli equation.¹² The estimated value is particularly inaccurate in patients with advanced lung disease, possibly owing to lung hyperinflation and alteration in the thoracic cavity and position of the heart—all factors that limit visualization and measurement of the tricuspid regurgitant jet.¹³

OTHER SIGNS OF PULMONARY HYPERTENSION ON ECHOCARDIOGRAPHY

Echocardiography provides information that is useful in assessing the accuracy of the estimated systolic pulmonary artery pressure, particularly right ventricular size and function.

As pulmonary hypertension progresses, the right ventricle dilates, and its function is compromised. Therefore, it is important to determine the right ventricular size and function by using objective echocardiographic findings such as right ventricular diameters (basal, mid, apical) and area, right ventricular fractional area change, tricuspid annular plane systolic excursion, myocardial performance index, and the pulsed tissue Doppler tricuspid annular peak systolic excursion velocity.⁸

Other echocardiographic features that suggest pulmonary hypertension include a dilated right atrial area, flattening of the interventricular septum, notching of the right ventricular outflow tract flow, and dilation of the main pulmonary artery. Interestingly, left ventricular diastolic dysfunction of the impaired relaxation type (grade I) is commonly observed in pulmonary hypertension¹⁴; however, more advanced degrees of diastolic dysfunction, ie, pseudonormalization (grade II) or restrictive left ventricular filling (grade III),¹⁵ particularly when associated with a left atrial enlargement, suggest pulmonary hypertension associated with left heart disease and not pulmonary artery hypertension.

WHAT TO DO IF ECHOCARDIOGRAPHY INDICATES PULMONARY HYPERTENSION

Adapted in part from the diagnostic approach to pulmonary hypertension recommended by the Fifth World Symposium on Pulmonary Hypertension (reference 6).

An algorithm showing the approach to an elevated systolic pulmonary artery pressure on echocardiography is presented in Figure 1.

In the appropriate clinical setting, if the systolic pulmonary artery pressure is 40 mm Hg or greater or if other echocardiographic variables suggest pulmonary hypertension, our practice is to proceed with right heart catheterization.

Clinical variables that suggest pulmonary hypertension include progressive dyspnea, chest pain, presyncope-syncope, lower extremity edema, hepatomegaly, jugular vein distention, hepatojugular reflux, sternal heave, loud second heart sound (P2), murmur of tricuspid or pulmonary regurgitation, and right ventricular third heart sound.¹⁶ These are of particular interest when associated with conditions known to cause pulmonary hypertension,²such as connective tissue disease, portal hypertension, congenital heart disease, HIV infection, and certain drugs and toxins.

Other tests that raise suspicion of pulmonary hypertension are an electrocardiogram suggesting a dilated right atrium or ventricle, an elevated brain natriuretic peptide level, a low carbon monoxide diffusing capacity on pulmonary function testing, and an enlarged pulmonary artery diameter on imaging.

Given the high prevalence of pulmonary hypertension, the Fifth World Symposium on Pulmonary Hypertension recommended first considering heart or parenchymal lung disease when an echocardiogram suggests pulmonary hypertension.⁶ If there are signs of severe pulmonary hypertension or right ventricular dysfunction, referral to a center specializing in pulmonary hypertension is recommended. Referral is also appropriate when there is no major heart or lung disease and the echocardiogram shows an elevated systolic pulmonary artery pressure, particularly when the clinical presentation or results of other testing suggest pulmonary hypertension.

TAKE-HOME POINTS

In the appropriate context, a high systolic pulmonary artery pressure on echocardiography suggests pulmonary hypertension, but right heart catheterization is needed to confirm the diagnosis. Estimating the systolic pulmonary artery pressure with echocardiography has limitations, including false-positive results, predominantly when the pretest probability of pulmonary hypertension is low.

The incidental finding of high systolic pulmonary artery pressure on echocardiography is common. What we should do about it varies according to clinical presentation, comorbidities, and results of other tests, including assessment of the right ventricle. Thus, the optimal approach ranges from no further investigation to right heart catheterization and, in some cases, referral to a pulmonary hypertension center.

THE TWO MEASUREMENTS COMPARED

Although it raises concern, the finding of high systolic pulmonary artery pressure is not enough to diagnose pulmonary hypertension. In fact, several other conditions are associated with high systolic pulmonary artery pressure on echocardiography (Table 1). The diagnosis must be confirmed with right heart catheterization.¹

Echocardiography provides an estimate of the systolic pulmonary artery pressure that is calculated from other values, whereas right heart catheterization gives a direct measurement of the mean pulmonary artery pressure, which is necessary for diagnosing pulmonary hypertension. The two values are correlated, but the differences are noteworthy.

WHAT IS PULMONARY HYPERTENSION?

Pulmonary hypertension is defined by a resting mean pulmonary artery pressure 25 mm Hg or greater during right heart catheterization.¹ The large number of conditions associated with pulmonary hypertension can be divided into five groups²:

• Group 1, pulmonary artery hypertension
• Group 2, pulmonary hypertension associated with left heart disease
• Group 3, pulmonary hypertension due to chronic lung disease or hypoxia
• Group 4, chronic thromboembolic pulmonary hypertension
• Group 5, pulmonary hypertension due to unclear multifactorial mechanisms.²

Pulmonary artery hypertension (group 1) is a syndrome characterized by a restricted flow of small pulmonary arteries that can be idiopathic, heritable, or induced by anorexigens, connective tissue disease, congenital heart disease, portal hypertension, human immunodeficiency virus (HIV), or schistosomiasis.^2,3 In spite of significant advances in therapy in the last 3 decades, pulmonary artery hypertension continues to lead to right heart failure and death,⁴ and the diagnosis has adverse prognostic implications. Therefore, it is essential to be attentive when reviewing the echocardiogram, since an elevated systolic pulmonary artery pressure may be an important clue to pulmonary hypertension.

ESTIMATED PRESSURE: HOW HIGH IS TOO HIGH?

There is no consensus on the optimal cutoff of echocardiographic systolic pulmonary artery pressure to trigger a further evaluation for pulmonary hypertension.

A retrospective evaluation of nearly 16,000 normal echocardiograms found that the 95% upper limit for systolic pulmonary artery pressure was 37 mm Hg.⁵

European guidelines⁶ propose that pulmonary hypertension is unlikely if the estimated systolic pulmonary artery pressure is 36 mm Hg or lower, possible if it is 37 to 50 mm Hg, and likely if it is higher than 50 mm Hg.⁶

The 2009 consensus document of the American College of Cardiology Foundation and American Heart Association³ recommends a systolic pulmonary artery pressure greater than 40 mm Hg as the threshold to suggest further evaluation in a patient with unexplained dyspnea.

Converting the systolic pulmonary artery pressure to the mean pressure

Although not validated to use with echocardiography, the most accurate estimate of mean pulmonary artery pressure was shown in one study⁷ to be obtained with the equation:

0.61 × systolic pulmonary artery pressure
+ 2 mm Hg

Using this formula, a systolic pulmonary artery pressure of 37 mm Hg would correspond to a mean pulmonary artery pressure of 24.6 mm Hg. A systolic pulmonary artery pressure of 40 mm Hg would correspond to a mean pulmonary artery pressure of 26.4 mm Hg.

Estimated systolic pulmonary artery pressure depends on several variables

Systolic pulmonary artery pressure is estimated using the simplified Bernoulli equation⁸:

4 × tricuspid regurgitation jet velocity² (m/s)
+ right atrial pressure (mm Hg)

Tricuspid regurgitation is present in over 75% of the normal population. The regurgitation velocity across the tricuspid valve must be measured to estimate the pressure gradient between the right ventricle and the right atrium. The right atrial pressure is estimated from the diameter of the inferior vena cava and the degree of inspiratory collapse with the sniff test. As the right atrial pressure increases, the inferior vena cava dilates and inspiratory collapse decreases.⁸ If there is no gradient across the right ventricular outflow tract or pulmonary valve, the right ventricular systolic pressure is equal to the systolic pulmonary artery pressure.

Since tricuspid regurgitation velocity is squared and then multiplied by 4, small deviations of this measurement lead to markedly different systolic pulmonary artery pressure values. To avoid this problem, the tricuspid regurgitation velocity needs to be looked at in multiple echocardiographic views to find the best alignment with the flow and an adequate envelope.

Many causes of high estimated systolic pulmonary artery pressure

Table 1 shows conditions associated with a high estimated systolic pulmonary artery pressure. Echocardiographic limitations, constitutional factors, and high cardiac output states can lead to an apparent elevation in systolic pulmonary artery pressure, which is not confirmed later during right heart catheterization.

Systolic pulmonary artery pressure increases with age and body mass index as a result of worsening left ventricular diastolic dysfunction.⁸ In fact, an estimated pressure greater than 40 mm Hg is found⁵ in 6% of people over age 50 and in 5% of people with a body mass index greater than 30 kg/m². It can also be high in conditions in which there is an increase in cardiac output, such as pregnancy, anemia (sickle cell disease, thalassemia), cirrhosis, and arteriovenous fistula.

The estimated systolic value often differs from the measured value

Studies have compared the systolic pulmonary artery pressure measured during right heart catheterization with the estimated value on echocardiography.^9,10 These studies noted a reasonable degree of agreement between the tests but a substantial variability.

Both underestimation and overestimation of the systolic pulmonary artery pressure by echocardiography were common, with 95% limits of agreement ranging from minus 40 mm Hg to plus 40 mm Hg.^9,10 A difference of plus or minus 10 mm Hg in systolic pulmonary artery pressure between echocardiography and catheterization was observed in 48% to 51% of patients with pulmonary hypertension, particularly in those with higher systolic pulmonary artery pressure.^9,10

An important reason for overestimation of systolic pulmonary artery pressure is the inaccurate estimation of the right atrial pressure by echocardiography.^9,10 Indeed, this factor may account for half of the cases in which the systolic pulmonary artery pressure is overestimated.¹⁰ Although the traditional methods to estimate the right atrial pressure have been revisited,^8,11 this estimation is less reliable for intermediate pressure values, for patients on mechanical ventilation, and for young athletes.⁸

Other explanations for the variability between measured and estimated systolic pulmonary artery pressure include suboptimal alignment between the Doppler beam and the regurgitant jet, severe tricuspid regurgitation, arrhythmias, and limitations inherent to the simplified Bernoulli equation.¹² The estimated value is particularly inaccurate in patients with advanced lung disease, possibly owing to lung hyperinflation and alteration in the thoracic cavity and position of the heart—all factors that limit visualization and measurement of the tricuspid regurgitant jet.¹³

OTHER SIGNS OF PULMONARY HYPERTENSION ON ECHOCARDIOGRAPHY

Echocardiography provides information that is useful in assessing the accuracy of the estimated systolic pulmonary artery pressure, particularly right ventricular size and function.

As pulmonary hypertension progresses, the right ventricle dilates, and its function is compromised. Therefore, it is important to determine the right ventricular size and function by using objective echocardiographic findings such as right ventricular diameters (basal, mid, apical) and area, right ventricular fractional area change, tricuspid annular plane systolic excursion, myocardial performance index, and the pulsed tissue Doppler tricuspid annular peak systolic excursion velocity.⁸

Other echocardiographic features that suggest pulmonary hypertension include a dilated right atrial area, flattening of the interventricular septum, notching of the right ventricular outflow tract flow, and dilation of the main pulmonary artery. Interestingly, left ventricular diastolic dysfunction of the impaired relaxation type (grade I) is commonly observed in pulmonary hypertension¹⁴; however, more advanced degrees of diastolic dysfunction, ie, pseudonormalization (grade II) or restrictive left ventricular filling (grade III),¹⁵ particularly when associated with a left atrial enlargement, suggest pulmonary hypertension associated with left heart disease and not pulmonary artery hypertension.

WHAT TO DO IF ECHOCARDIOGRAPHY INDICATES PULMONARY HYPERTENSION

Adapted in part from the diagnostic approach to pulmonary hypertension recommended by the Fifth World Symposium on Pulmonary Hypertension (reference 6).

An algorithm showing the approach to an elevated systolic pulmonary artery pressure on echocardiography is presented in Figure 1.

In the appropriate clinical setting, if the systolic pulmonary artery pressure is 40 mm Hg or greater or if other echocardiographic variables suggest pulmonary hypertension, our practice is to proceed with right heart catheterization.

Clinical variables that suggest pulmonary hypertension include progressive dyspnea, chest pain, presyncope-syncope, lower extremity edema, hepatomegaly, jugular vein distention, hepatojugular reflux, sternal heave, loud second heart sound (P2), murmur of tricuspid or pulmonary regurgitation, and right ventricular third heart sound.¹⁶ These are of particular interest when associated with conditions known to cause pulmonary hypertension,²such as connective tissue disease, portal hypertension, congenital heart disease, HIV infection, and certain drugs and toxins.

Other tests that raise suspicion of pulmonary hypertension are an electrocardiogram suggesting a dilated right atrium or ventricle, an elevated brain natriuretic peptide level, a low carbon monoxide diffusing capacity on pulmonary function testing, and an enlarged pulmonary artery diameter on imaging.

Given the high prevalence of pulmonary hypertension, the Fifth World Symposium on Pulmonary Hypertension recommended first considering heart or parenchymal lung disease when an echocardiogram suggests pulmonary hypertension.⁶ If there are signs of severe pulmonary hypertension or right ventricular dysfunction, referral to a center specializing in pulmonary hypertension is recommended. Referral is also appropriate when there is no major heart or lung disease and the echocardiogram shows an elevated systolic pulmonary artery pressure, particularly when the clinical presentation or results of other testing suggest pulmonary hypertension.

TAKE-HOME POINTS

In the appropriate context, a high systolic pulmonary artery pressure on echocardiography suggests pulmonary hypertension, but right heart catheterization is needed to confirm the diagnosis. Estimating the systolic pulmonary artery pressure with echocardiography has limitations, including false-positive results, predominantly when the pretest probability of pulmonary hypertension is low.

The incidental finding of high systolic pulmonary artery pressure on echocardiography is common. What we should do about it varies according to clinical presentation, comorbidities, and results of other tests, including assessment of the right ventricle. Thus, the optimal approach ranges from no further investigation to right heart catheterization and, in some cases, referral to a pulmonary hypertension center.

THE TWO MEASUREMENTS COMPARED

Although it raises concern, the finding of high systolic pulmonary artery pressure is not enough to diagnose pulmonary hypertension. In fact, several other conditions are associated with high systolic pulmonary artery pressure on echocardiography (Table 1). The diagnosis must be confirmed with right heart catheterization.¹

Echocardiography provides an estimate of the systolic pulmonary artery pressure that is calculated from other values, whereas right heart catheterization gives a direct measurement of the mean pulmonary artery pressure, which is necessary for diagnosing pulmonary hypertension. The two values are correlated, but the differences are noteworthy.

WHAT IS PULMONARY HYPERTENSION?

Pulmonary hypertension is defined by a resting mean pulmonary artery pressure 25 mm Hg or greater during right heart catheterization.¹ The large number of conditions associated with pulmonary hypertension can be divided into five groups²:

• Group 1, pulmonary artery hypertension
• Group 2, pulmonary hypertension associated with left heart disease
• Group 3, pulmonary hypertension due to chronic lung disease or hypoxia
• Group 4, chronic thromboembolic pulmonary hypertension
• Group 5, pulmonary hypertension due to unclear multifactorial mechanisms.²

Pulmonary artery hypertension (group 1) is a syndrome characterized by a restricted flow of small pulmonary arteries that can be idiopathic, heritable, or induced by anorexigens, connective tissue disease, congenital heart disease, portal hypertension, human immunodeficiency virus (HIV), or schistosomiasis.^2,3 In spite of significant advances in therapy in the last 3 decades, pulmonary artery hypertension continues to lead to right heart failure and death,⁴ and the diagnosis has adverse prognostic implications. Therefore, it is essential to be attentive when reviewing the echocardiogram, since an elevated systolic pulmonary artery pressure may be an important clue to pulmonary hypertension.

ESTIMATED PRESSURE: HOW HIGH IS TOO HIGH?

There is no consensus on the optimal cutoff of echocardiographic systolic pulmonary artery pressure to trigger a further evaluation for pulmonary hypertension.

A retrospective evaluation of nearly 16,000 normal echocardiograms found that the 95% upper limit for systolic pulmonary artery pressure was 37 mm Hg.⁵

European guidelines⁶ propose that pulmonary hypertension is unlikely if the estimated systolic pulmonary artery pressure is 36 mm Hg or lower, possible if it is 37 to 50 mm Hg, and likely if it is higher than 50 mm Hg.⁶

The 2009 consensus document of the American College of Cardiology Foundation and American Heart Association³ recommends a systolic pulmonary artery pressure greater than 40 mm Hg as the threshold to suggest further evaluation in a patient with unexplained dyspnea.

Converting the systolic pulmonary artery pressure to the mean pressure

Although not validated to use with echocardiography, the most accurate estimate of mean pulmonary artery pressure was shown in one study⁷ to be obtained with the equation:

0.61 × systolic pulmonary artery pressure
+ 2 mm Hg

Using this formula, a systolic pulmonary artery pressure of 37 mm Hg would correspond to a mean pulmonary artery pressure of 24.6 mm Hg. A systolic pulmonary artery pressure of 40 mm Hg would correspond to a mean pulmonary artery pressure of 26.4 mm Hg.

Estimated systolic pulmonary artery pressure depends on several variables

Systolic pulmonary artery pressure is estimated using the simplified Bernoulli equation⁸:

4 × tricuspid regurgitation jet velocity² (m/s)
+ right atrial pressure (mm Hg)

Tricuspid regurgitation is present in over 75% of the normal population. The regurgitation velocity across the tricuspid valve must be measured to estimate the pressure gradient between the right ventricle and the right atrium. The right atrial pressure is estimated from the diameter of the inferior vena cava and the degree of inspiratory collapse with the sniff test. As the right atrial pressure increases, the inferior vena cava dilates and inspiratory collapse decreases.⁸ If there is no gradient across the right ventricular outflow tract or pulmonary valve, the right ventricular systolic pressure is equal to the systolic pulmonary artery pressure.

Since tricuspid regurgitation velocity is squared and then multiplied by 4, small deviations of this measurement lead to markedly different systolic pulmonary artery pressure values. To avoid this problem, the tricuspid regurgitation velocity needs to be looked at in multiple echocardiographic views to find the best alignment with the flow and an adequate envelope.

Many causes of high estimated systolic pulmonary artery pressure

Table 1 shows conditions associated with a high estimated systolic pulmonary artery pressure. Echocardiographic limitations, constitutional factors, and high cardiac output states can lead to an apparent elevation in systolic pulmonary artery pressure, which is not confirmed later during right heart catheterization.

Systolic pulmonary artery pressure increases with age and body mass index as a result of worsening left ventricular diastolic dysfunction.⁸ In fact, an estimated pressure greater than 40 mm Hg is found⁵ in 6% of people over age 50 and in 5% of people with a body mass index greater than 30 kg/m². It can also be high in conditions in which there is an increase in cardiac output, such as pregnancy, anemia (sickle cell disease, thalassemia), cirrhosis, and arteriovenous fistula.

The estimated systolic value often differs from the measured value

Studies have compared the systolic pulmonary artery pressure measured during right heart catheterization with the estimated value on echocardiography.^9,10 These studies noted a reasonable degree of agreement between the tests but a substantial variability.

Both underestimation and overestimation of the systolic pulmonary artery pressure by echocardiography were common, with 95% limits of agreement ranging from minus 40 mm Hg to plus 40 mm Hg.^9,10 A difference of plus or minus 10 mm Hg in systolic pulmonary artery pressure between echocardiography and catheterization was observed in 48% to 51% of patients with pulmonary hypertension, particularly in those with higher systolic pulmonary artery pressure.^9,10

An important reason for overestimation of systolic pulmonary artery pressure is the inaccurate estimation of the right atrial pressure by echocardiography.^9,10 Indeed, this factor may account for half of the cases in which the systolic pulmonary artery pressure is overestimated.¹⁰ Although the traditional methods to estimate the right atrial pressure have been revisited,^8,11 this estimation is less reliable for intermediate pressure values, for patients on mechanical ventilation, and for young athletes.⁸

Other explanations for the variability between measured and estimated systolic pulmonary artery pressure include suboptimal alignment between the Doppler beam and the regurgitant jet, severe tricuspid regurgitation, arrhythmias, and limitations inherent to the simplified Bernoulli equation.¹² The estimated value is particularly inaccurate in patients with advanced lung disease, possibly owing to lung hyperinflation and alteration in the thoracic cavity and position of the heart—all factors that limit visualization and measurement of the tricuspid regurgitant jet.¹³

OTHER SIGNS OF PULMONARY HYPERTENSION ON ECHOCARDIOGRAPHY

Echocardiography provides information that is useful in assessing the accuracy of the estimated systolic pulmonary artery pressure, particularly right ventricular size and function.

As pulmonary hypertension progresses, the right ventricle dilates, and its function is compromised. Therefore, it is important to determine the right ventricular size and function by using objective echocardiographic findings such as right ventricular diameters (basal, mid, apical) and area, right ventricular fractional area change, tricuspid annular plane systolic excursion, myocardial performance index, and the pulsed tissue Doppler tricuspid annular peak systolic excursion velocity.⁸

Other echocardiographic features that suggest pulmonary hypertension include a dilated right atrial area, flattening of the interventricular septum, notching of the right ventricular outflow tract flow, and dilation of the main pulmonary artery. Interestingly, left ventricular diastolic dysfunction of the impaired relaxation type (grade I) is commonly observed in pulmonary hypertension¹⁴; however, more advanced degrees of diastolic dysfunction, ie, pseudonormalization (grade II) or restrictive left ventricular filling (grade III),¹⁵ particularly when associated with a left atrial enlargement, suggest pulmonary hypertension associated with left heart disease and not pulmonary artery hypertension.

WHAT TO DO IF ECHOCARDIOGRAPHY INDICATES PULMONARY HYPERTENSION

Adapted in part from the diagnostic approach to pulmonary hypertension recommended by the Fifth World Symposium on Pulmonary Hypertension (reference 6).

An algorithm showing the approach to an elevated systolic pulmonary artery pressure on echocardiography is presented in Figure 1.

In the appropriate clinical setting, if the systolic pulmonary artery pressure is 40 mm Hg or greater or if other echocardiographic variables suggest pulmonary hypertension, our practice is to proceed with right heart catheterization.

Clinical variables that suggest pulmonary hypertension include progressive dyspnea, chest pain, presyncope-syncope, lower extremity edema, hepatomegaly, jugular vein distention, hepatojugular reflux, sternal heave, loud second heart sound (P2), murmur of tricuspid or pulmonary regurgitation, and right ventricular third heart sound.¹⁶ These are of particular interest when associated with conditions known to cause pulmonary hypertension,²such as connective tissue disease, portal hypertension, congenital heart disease, HIV infection, and certain drugs and toxins.

Other tests that raise suspicion of pulmonary hypertension are an electrocardiogram suggesting a dilated right atrium or ventricle, an elevated brain natriuretic peptide level, a low carbon monoxide diffusing capacity on pulmonary function testing, and an enlarged pulmonary artery diameter on imaging.

Given the high prevalence of pulmonary hypertension, the Fifth World Symposium on Pulmonary Hypertension recommended first considering heart or parenchymal lung disease when an echocardiogram suggests pulmonary hypertension.⁶ If there are signs of severe pulmonary hypertension or right ventricular dysfunction, referral to a center specializing in pulmonary hypertension is recommended. Referral is also appropriate when there is no major heart or lung disease and the echocardiogram shows an elevated systolic pulmonary artery pressure, particularly when the clinical presentation or results of other testing suggest pulmonary hypertension.

TAKE-HOME POINTS

In the appropriate context, a high systolic pulmonary artery pressure on echocardiography suggests pulmonary hypertension, but right heart catheterization is needed to confirm the diagnosis. Estimating the systolic pulmonary artery pressure with echocardiography has limitations, including false-positive results, predominantly when the pretest probability of pulmonary hypertension is low.

Drug-induced osteoporosis is common, and the list of drugs that can harm bone continues to grow. As part of routine health maintenance, practitioners should recognize the drugs that increase bone loss and take measures to mitigate these effects to help avoid osteopenia and osteoporosis.

Osteoporosis, a silent systemic disease defined by low bone mineral density and changes in skeletal microstructure, leads to a higher risk of fragility fractures. Some of the risk factors are well described, but less well known is the role of pharmacologic therapy. The implicated drugs (Table 1) have important therapeutic roles, so the benefits of using them must be weighed against their risks, including their potential effects on bone.

This review focuses on a few drugs known to increase fracture risk, their mechanisms of bone loss, and management considerations (Table 2).

GLUCOCORTICOIDS

Glucocorticoids are used to treat many medical conditions, including allergic, rheumatic, and other inflammatory diseases, and as immunosuppressive therapy after solid organ and bone marrow transplant. They are the most common cause of drug-induced bone loss and related secondary osteoporosis.

Multiple effects on bone

Glucocorticoids both increase bone resorption and decrease bone formation by a variety of mechanisms.¹ They reduce intestinal calcium absorption, increase urinary excretion of calcium, and enhance osteocyte apoptosis, leading to deterioration of the bone microarchitecture and bone mineral density.² They also affect sex hormones, decreasing testosterone production in men and estrogen in women, leading to increased bone resorption, altered bone architecture, and poorer bone quality.^3,4 The bone loss is greater in trabecular bone (eg, the femoral neck and vertebral bodies) than in cortical bone (eg, the forearm).⁵

Glucocorticoids have other systemic effects that increase fracture risk. For example, they cause muscle weakness and atrophy, increasing the risk of falls.⁴ Additionally, many of the inflammatory conditions for which they are prescribed (eg, rheumatoid arthritis) also increase the risk of osteoporosis by means of proinflammatory cytokine production, which may contribute to systemic and local effects on bone.^4,6

Bone mineral density declines quickly

Bone mineral density declines within the first 3 months after starting oral glucocorticoids, with the rate of bone loss peaking at 6 months. Up to 12% of bone mass is lost in the first year. In subsequent years of continued use, bone loss progresses at a slower, steadier rate, averaging 2% to 3% annually.^5,7,8

Oral therapy increases fracture risk

Kanis et al⁹ performed a meta-analysis of seven prospective cohort studies in 40,000 patients and found that the current or previous use of an oral glucocorticoid increased the risk of fragility fractures, and that men and women were  affected about equally.⁹

Van Staa et al^10,11 reported that daily doses of glucocorticoids equivalent to more than 2.5 mg of prednisone were associated with an increased risk of vertebral and hip fractures; fracture risk was related mainly to daily dosage rather than cumulative dose.

Van Staa et al,¹² in a retrospective cohort study, compared nearly 250,000 adult users of oral glucocorticoids from general medical practice settings with the same number of controls matched for sex, age, and medical practice. The relative risks for fractures and 95% confidence intervals (CIs) during oral glucocorticoid treatment were as follows:

• Forearm fracture 1.09 (1.01–1.17)
• Nonvertebral fracture 1.33 (1.29–1.38)
• Hip fracture 1.61 (1.47–1.76)
• Vertebral fracture 2.60 (2.31–2.92).

The risk was dose-dependent. For a low daily dose (< 2.5 mg/day of prednisolone), the relative risks were:

• Hip fracture 0.99 (0.82–1.20)
• Vertebral fracture 1.55 (1.20–2.01) .

For a medium daily dose (2.5–7.5 mg/day), the relative risks were: 

• Hip fracture 1.77 (1.55–2.02)
• Vertebral fracture 2.59 (2.16–3.10) .

For a high daily dose (> 7.5 mg/day), the relative risks were:

• Hip fracture 2.27 (1.94–2.66)
• Vertebral fracture 5.18 (4.25–6.31).

Fracture risk rapidly declined toward baseline after the patients stopped taking oral glucocorticoids but did not return to baseline levels. The lessening of excess fracture risk occurred mainly within the first year after stopping therapy.

Other studies^5,9,13 have suggested that the increased fracture risk is mostly independent of bone mineral density, and that other mechanisms are at play. One study¹⁴ found that oral glucocorticoid users with a prevalent vertebral fracture actually had higher bone mineral density than patients with a fracture not taking glucocorticoids, although this finding was not confirmed in a subsequent study.¹⁵

Inhaled glucocorticoids have less effect on bone

Inhaled glucocorticoids are commonly used to treat chronic obstructive pulmonary disease and asthma. They do not have the same systemic bioavailability as oral glucocorticoids, so the risk of adverse effects is lower.

Data are inconsistent among several studies that evaluated the relationship between inhaled glucocorticoids, bone mineral density, osteoporosis, and fragility fracture. The inconsistencies may be due to heterogeneity of the study populations, self-reporting of fractures, and different methods of assessing chronic obstructive pulmonary disease severity.¹⁶

A Cochrane review¹⁷ in 2002 evaluated seven randomized controlled trials that compared the use of inhaled glucocorticoids vs placebo in nearly 2,000 patients with mild asthma or chronic obstructive pulmonary disease and found no evidence for decreased bone mineral density, increased bone turnover, or increased vertebral fracture incidence in the glucocorticoid users at 2 to 3 years of follow-up (odds ratio for fracture 1.87, 95% CI 0.5–7.0).

The Evaluation of Obstructive Lung Disease and Osteoporosis study,¹⁶ a multicenter Italian observational epidemiologic study, reported that patients taking the highest daily doses of inhaled glucocorticoids (> 1,500 μg of beclomethasone or its equivalent) had a significantly higher risk of vertebral fracture (odds ratio 1.4, 95% CI 1.04–1.89).¹⁶

A meta-analysis¹⁸ of five case-control studies (43,783 cases and 259,936 controls) identified a possible dose-dependent relationship, with a relative risk for nonvertebral fracture of 1.12 (95% CI 1.0–1.26) for each 1,000-μg increase in beclomethasone-equivalent inhaled glucocorticoid per day.

In summary, the effects of inhaled glucocorticoids in adults are uncertain, although trends toward increased fracture risk and decreased bone mineral density are evident with chronic therapy at moderate to high dosages. The risks and benefits of treatment should be carefully considered in patients with osteoporosis and baseline elevated fracture risk.¹⁹

Managing the risk of glucocorticoid-induced osteoporosis

In 2010, the American College of Rheumatology published recommendations for preventing and treating glucocorticoid-induced osteoporosis, which were endorsed by the American Society for Bone and Mineral Research.²⁰ To lessen the risk of osteoporosis, the recommendations are as follows:

Limit exposure. Patients receiving glucocorticoids should be given the smallest dosage for the shortest duration possible.

Advise lifestyle changes. Patients should be counseled to limit their alcohol intake to no more than two drinks per day, to quit smoking, to engage in weight-bearing exercise, and to ingest enough calcium (1,200–1,500 mg/day, through diet and supplements) and vitamin D.

Monitor bone mineral density. Patients starting glucocorticoids at any dosage for an expected duration of at least 3 months should have their bone mineral density measured at baseline. The frequency of subsequent measurements should be based on the presence of other risk factors for fracture, results of previous bone density testing, glucocorticoid dosage, whether therapy for bone health has been initiated, and the rate of change in bone mineral density. If warranted and if the results would lead to a change in management, patients can undergo dual-energy x-ray absorptiometry more often than usual, ie, more often than every 2 years. Prevalent and incident fragility fractures, height measurements, fall risk assessments, laboratory measurements of 25-hydroxyvitamin D, and consideration of vertebral fracture assessment or other imaging of the spine, as necessary, should be part of counseling and monitoring.

Osteoporosis treatment. For patients who will be taking glucocorticoids for at least 3 months, alendronate, risedronate, zoledronic acid, or teriparatide can be initiated to prevent or treat osteoporosis in the following groups: 

• Postmenopausal women and men over age 50 if the daily glucocorticoid dosage is at least 7.5 mg/day or if the World Health Organization Fracture Risk Assessment Tool (FRAX) score is more than 10% (the threshold for medium fracture risk)
• Premenopausal women and men younger than 50 if they have a history of fragility fracture, the FRAX score is more than 20% (the threshold for high fracture risk), or the T score is less than –2.5.

Certain clinical factors can also put a patient into a higher-risk category. These include current tobacco use, low body mass index, parental history of hip fracture, consuming more than three alcoholic drinks daily, higher daily or cumulative glucocorticoid dosage, intravenous pulse glucocorticoid usage, or a decline in central bone mineral density that exceeds the least significant change according to the scanner used.²⁰

The FRAX tool accounts for bone density only at the femoral neck, and while useful, it cannot replace clinical judgment in stratifying risk. Moreover, it does not apply to premenopausal women or men under age 40.

The implicated medications have important roles, so weigh their risks and benefits

The long-term risks of medications to treat glucocorticoid-induced osteoporosis are not well defined for premenopausal women (or their unborn children) or in men younger than 40, so treatment is recommended in those groups only for those with prevalent fragility fractures who are clearly at higher risk of additional fractures.²⁰

PROTON PUMP INHIBITORS

Proton pump inhibitors are available by prescription and over the counter for gastric acid-related conditions. Concerns have been raised that these highly effective drugs are overused.²¹ Several of their adverse effects are self-limited and minor, but long-term use may entail serious risks, including propensity to bone fracture.²²

Low acid leads to poor calcium absorption

Why fracture risk increases with proton pump inhibitors is controversial and may relate to their desired effect of suppressing gastric acid production: calcium salts, including carbonate and chloride, are poorly soluble and require an acidic environment to increase calcium ionization and thus absorption.²³ For this reason, if patients taking a proton pump inhibitor take a calcium supplement, it should be calcium citrate, which unlike calcium carbonate does not require an acid environment for absorption.

Higher risk in older patients, with longer use, and with higher dosage

Since the first reports on proton pump inhibitors and fracture risk were published in 2006,^24,25 a number of studies have reported this association, including several systematic reviews.

In 2011, the US Food and Drug Administration (FDA) updated a 2010 safety communication based on seven epidemiologic studies reporting an increased risk of fractures of the spine, hip, and wrist with proton pump inhibitors.^24–31 Time of exposure to a proton pump inhibitor in these studies varied from 1 to 12 years. Fracture risk was higher in older patients,²⁶ with higher doses,^24,29 and with longer duration of drug use.^24,27 On the other hand, one study that included only patients without other major fracture risk factors failed to find an association between the use of proton pump inhibitors and fractures.²⁸

Is evidence sufficient for changing use?

The FDA report included a disclaimer that they had no access to study data or protocols and so could not verify the findings.²⁶ Moreover, the studies used claims data from computerized databases to evaluate the risk of fractures in patients treated with proton pump inhibitors compared with those not using these drugs.^24–31 Information was often incomplete regarding potentially important factors (eg, falls, family history of osteoporosis, calcium and vitamin D intake, smoking, alcohol use, reason for medication use), as well as the timing of drug use related to the onset or worsening of osteoporosis.²⁶

Although 34 published studies evaluated the association of fracture risk and proton pump inhibitors, Leontiadis and Moayyedi³² argued that insufficient evidence exists to change our prescribing habits for these drugs based on fracture risk, as the studies varied considerably in their designs and results, a clear dose-response relationship is lacking, and the modest association is likely related to multiple confounders.

Bottom line: Use with caution

Although the increased fracture risk associated with proton pump inhibitors is likely multifactorial and is not fully delineated, it appears to be real. These drugs should be used only if there is a clear indication for them and if their benefits likely outweigh their risks. The lowest effective dose should be used, and the need for continuing use should be frequently reassessed.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

Depression affects 1 in 10 people in the United States, is especially common in the elderly, and leads to significant morbidity and reduced quality of life.³³ Selective serotonin reuptake inhibitors (SSRIs) are often prescribed and are generally considered first-line agents for treating depression.

Complex bone effects

Use proton pump inhibitors only if there is a clear indication for them and their benefits likely outweigh the risks

SSRIs antagonize the serotonin transporter, which normally assists serotonin uptake from the extracellular space. The serotonin transporter is found in all main types of bone cells, including osteoclasts, osteoblasts, and osteocytes.³³ Serotonin is made by different genes in the brain than in the periphery, causing opposing effects on bone biology: when generated peripherally, it acts as a hormone to inhibit bone formation, while when generated in the brain, it acts as a neurotransmitter to create a major and positive effect on bone mass accrual by enhancing bone formation and limiting bone resorption.^34,35

Potential confounders complicate the effect of SSRIs on bone health, as depression itself may be a risk factor for fracture. Patients with depression tend to have increased inflammation and cortisol, decreased gonadal steroids, more behavioral risk factors such as tobacco and increased alcohol use, and less physical activity, all of which can contribute to low bone density and risk of falls and fractures.³³

Daily use of SSRIs increases fracture risk

A 2012 meta-analysis³⁶ of 12 studies (seven case-control and five cohort), showed that SSRI users had a higher overall risk of fracture (adjusted odds ratio 1.69, 95% CI 1.51–1.90). By anatomic site, pooled odds ratios and 95% CIs were:

• Vertebral fractures 1.34 (1.13–1.59)
• Wrist or forearm fractures 1.51 (1.26–1.82)
• Hip or femur fractures 2.06 (1.84–2.30). 

A 2013 meta-analysis³⁷ of 34 studies with more than 1 million patients found that the random-effects pooled relative risk of all fracture types in users of antidepressants (including but not limited to SSRIs) was 1.39 (95% CI 1.32–1.47) compared with nonusers. Relative risks and 95% CIs in antidepressant users were:

• Vertebral fractures 1.38 (1.19–1.61)
• Nonvertebral fractures 1.42 (1.34–1.51)
• Hip fractures 1.47 (1.36–1.58).

A population-based, prospective cohort study³⁸ of 5,008 community-dwelling adults age 50 and older, followed for 5 years, found that the daily use of SSRIs was associated with a twofold increased risk of clinical fragility fractures (defined as minimal trauma fractures that were clinically reported and radiographically confirmed) after adjusting for potential covariates. Daily SSRI use was also associated with an increased risk of falling (odds ratio 2.2, 95% CI 1.4–3.5), lower bone mineral density at the hip, and a trend toward lower bone mineral density at the spine. These effects were dose-dependent and were similar for those who reported taking SSRIs at baseline and at 5 years.

Bottom line: Counsel bone health

Although no guidelines exist for preventing or treating SSRI-induced bone loss, providers should discuss with patients the potential effect of these medications on bone health, taking into account patient age, severity of depression, sex, duration of use, length of SSRI treatment, and other clinical risk factors for osteoporosis.³⁴ Given the widespread use of these medications for treating depression, more study into this association is needed to further guide providers.

ANTIEPILEPTIC DRUGS

Antiepileptic drugs are used to treat not only seizure disorders but also migraine headaches, neuropathy, and psychiatric and pain disorders. Many studies have linked their use to an increased risk of fractures.

The mechanism of this effect remains controversial. Early studies reported that inducers of cytochrome P450 enzymes (eg, phenobarbital, phenytoin) lead to increased vitamin D degradation, causing osteomalacia.³⁹ Another study suggested that changes in calcium metabolism and reduced bone mineral density occur without vitamin D deficiency and that drugs such as valproate that do not induce cytochrome P450 enzymes may also affect bone health.⁴⁰ Other bone effects may include direct inhibition of intestinal calcium absorption (seen in animal studies) and the induction of a high remodeling state leading to osteomalacia.^41,42

Epilepsy itself increases risk of fractures

Patients with seizure disorders may also have an increased risk of fractures because of falls, trauma, impaired balance, use of glucocorticoids and benzodiazepines, and comorbid conditions (eg, mental retardation, cerebral palsy, and brain neoplasm).⁴³

A 2005 meta-analysis⁴³ of 11 studies of epilepsy and fracture risk and 12 studies of epilepsy and bone mineral density found that the risks of fractures were increased. The following relative risks and 95% CIs were noted:

The benefit of preventing seizures outweighs the risks of fractures

• Any fracture 2.2 (1.9–2.5), in five studies
• Forearm 1.7 (1.2–2.3), in six studies
• Hip 5.3 (3.2–8.8), six studies
• Spine 6.2 (2.5–15.5), in three studies.

A large proportion of fractures (35%) seemed related to seizures.

Certain drugs increase risk

A large 2004 population-based, case-control, study⁴⁴ (124,655 fracture cases and 373,962 controls) found an association between the use of antiepileptic drugs and increased fracture risk. After adjusting for current or prior use of glucocorticoids, prior fracture, social variables, comorbid conditions, and epilepsy diagnosis, excess fracture risk was found to be associated with the following drugs (odds ratios and 95% CIs):

• Oxcarbazepine 1.14 (1.03–1.26)
• Valproate 1.15 (1.05–1.26)
• Carbamazepine 1.18 (1.10-1.26)
• Phenobarbital 1.79 (1.64–1.95).

The risk was higher with higher doses. Fracture risk was higher with cytochrome P450 enzyme-inducing drugs (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, and primidone; odds ratio 1.38, 95% CI 1.31–1.45) than for noninducing drugs (clonazepam, ethosuximide, lamotrigine, tiagabine, topiramate, valproate, and vigabatrin; odds ratio 1.19, 95% CI 1.11–1.27). No significant increased risk of fracture was found with use of phenytoin, tiagabine, topiramate, ethosuximide, lamotrigine, vigabatrin, or primidone after adjusting for confounders. 

Bottom line: Monitor bone health

With antiepileptic drugs, the benefit of preventing seizures outweighs the risks of fractures. Patients on long-term antiepileptic drug therapy should be monitored for bone mineral density and vitamin D levels and receive counseling on lifestyle measures including tobacco cessation, alcohol moderation, and fall prevention.⁴⁵ As there are no evidence-based guidelines for bone health in patients on antiepileptic drugs, management should be based on current guidelines for treating osteoporosis.

AROMATASE INHIBITORS

Depression itself may be a risk factor for fracture

Breast cancer is the most common cancer in women and is the second-leading cause of cancer-associated deaths in women after lung cancer. Aromatase inhibitors, such as anastrozole, letrozole, and exemestane, are the standard of care in adjuvant treatment for hormone-receptor-positive breast cancer, leading to longer disease-free survival.

However, aromatase inhibitors increase bone loss and fracture risk, and only partial recovery of bone mineral density occurs after treatment is stopped. The drugs deter the aromatization of androgens and their conversion to estrogens in peripheral tissue, leading to reduced estrogen levels and resulting bone loss.⁴⁶ Anastrozole and letrozole have been found to reduce bone mineral density, increase bone turnover, and increase the relative risk for nonvertebral and vertebral fractures in postmenopausal women by 40% compared with tamoxifen.^47,48

Base osteoporosis treatment on risk

Several groups have issued guidelines for preventing and treating bone loss in postmenopausal women being treated with an aromatase inhibitor. When initiating treatment, women should be counseled about modifiable risk factors, exercise, and calcium and vitamin D supplementation.

Baseline bone mineral testing should also be obtained when starting treatment. Hadji et al,⁴⁹ in a review article, recommend starting bone-directed therapy if the patient’s T score is less than –2.0 (using the lowest score from three sites) or if she has any of at least two of the following fracture risk factors:

• T score less than –1.5
• Age over 65
• Family history of hip fracture
• Personal history of fragility fracture after age 50
• Low body mass index (< 20 kg/m²)
• Current or prior history of tobacco use
• Oral glucocorticoid use for longer than 6 months.

Patients with a T score at or above –2.0 and no risk factors should have bone mineral density reassessed after 1 to 2 years. Antiresorptive therapy with intravenous zoledronic acid and evaluation for other secondary causes of bone loss should be initiated for either:

• An annual decrease of at least 10% or
• An annual decrease of at least 4% in patients with osteopenia at baseline.⁴⁹

In 2003, the American Society of Clinical Oncology updated its recommendations on the role of bisphosphonates and bone health in women with breast cancer.⁵⁰ They recommend the following:

• If the T score is –2.5 or less, prescribe a bisphosphonate (alendronate, risedronate, or zoledronic acid)
• If the T score is –1.0 to –2.5, tailor treatment individually and monitor bone mineral density annually
• If the T score is greater than –1.0, monitor bone mineral density annually.

All patients should receive lifestyle counseling, calcium and vitamin D supplementation, and monitoring of additional risk factors for osteoporosis as appropriate.⁵⁰

Drug-induced osteoporosis is common, and the list of drugs that can harm bone continues to grow. As part of routine health maintenance, practitioners should recognize the drugs that increase bone loss and take measures to mitigate these effects to help avoid osteopenia and osteoporosis.

Osteoporosis, a silent systemic disease defined by low bone mineral density and changes in skeletal microstructure, leads to a higher risk of fragility fractures. Some of the risk factors are well described, but less well known is the role of pharmacologic therapy. The implicated drugs (Table 1) have important therapeutic roles, so the benefits of using them must be weighed against their risks, including their potential effects on bone.

This review focuses on a few drugs known to increase fracture risk, their mechanisms of bone loss, and management considerations (Table 2).

GLUCOCORTICOIDS

Glucocorticoids are used to treat many medical conditions, including allergic, rheumatic, and other inflammatory diseases, and as immunosuppressive therapy after solid organ and bone marrow transplant. They are the most common cause of drug-induced bone loss and related secondary osteoporosis.

Multiple effects on bone

Glucocorticoids both increase bone resorption and decrease bone formation by a variety of mechanisms.¹ They reduce intestinal calcium absorption, increase urinary excretion of calcium, and enhance osteocyte apoptosis, leading to deterioration of the bone microarchitecture and bone mineral density.² They also affect sex hormones, decreasing testosterone production in men and estrogen in women, leading to increased bone resorption, altered bone architecture, and poorer bone quality.^3,4 The bone loss is greater in trabecular bone (eg, the femoral neck and vertebral bodies) than in cortical bone (eg, the forearm).⁵

Glucocorticoids have other systemic effects that increase fracture risk. For example, they cause muscle weakness and atrophy, increasing the risk of falls.⁴ Additionally, many of the inflammatory conditions for which they are prescribed (eg, rheumatoid arthritis) also increase the risk of osteoporosis by means of proinflammatory cytokine production, which may contribute to systemic and local effects on bone.^4,6

Bone mineral density declines quickly

Bone mineral density declines within the first 3 months after starting oral glucocorticoids, with the rate of bone loss peaking at 6 months. Up to 12% of bone mass is lost in the first year. In subsequent years of continued use, bone loss progresses at a slower, steadier rate, averaging 2% to 3% annually.^5,7,8

Oral therapy increases fracture risk

Kanis et al⁹ performed a meta-analysis of seven prospective cohort studies in 40,000 patients and found that the current or previous use of an oral glucocorticoid increased the risk of fragility fractures, and that men and women were  affected about equally.⁹

Van Staa et al^10,11 reported that daily doses of glucocorticoids equivalent to more than 2.5 mg of prednisone were associated with an increased risk of vertebral and hip fractures; fracture risk was related mainly to daily dosage rather than cumulative dose.

Van Staa et al,¹² in a retrospective cohort study, compared nearly 250,000 adult users of oral glucocorticoids from general medical practice settings with the same number of controls matched for sex, age, and medical practice. The relative risks for fractures and 95% confidence intervals (CIs) during oral glucocorticoid treatment were as follows:

• Forearm fracture 1.09 (1.01–1.17)
• Nonvertebral fracture 1.33 (1.29–1.38)
• Hip fracture 1.61 (1.47–1.76)
• Vertebral fracture 2.60 (2.31–2.92).

The risk was dose-dependent. For a low daily dose (< 2.5 mg/day of prednisolone), the relative risks were:

• Hip fracture 0.99 (0.82–1.20)
• Vertebral fracture 1.55 (1.20–2.01) .

For a medium daily dose (2.5–7.5 mg/day), the relative risks were: 

• Hip fracture 1.77 (1.55–2.02)
• Vertebral fracture 2.59 (2.16–3.10) .

For a high daily dose (> 7.5 mg/day), the relative risks were:

• Hip fracture 2.27 (1.94–2.66)
• Vertebral fracture 5.18 (4.25–6.31).

Fracture risk rapidly declined toward baseline after the patients stopped taking oral glucocorticoids but did not return to baseline levels. The lessening of excess fracture risk occurred mainly within the first year after stopping therapy.

Other studies^5,9,13 have suggested that the increased fracture risk is mostly independent of bone mineral density, and that other mechanisms are at play. One study¹⁴ found that oral glucocorticoid users with a prevalent vertebral fracture actually had higher bone mineral density than patients with a fracture not taking glucocorticoids, although this finding was not confirmed in a subsequent study.¹⁵

Inhaled glucocorticoids have less effect on bone

Inhaled glucocorticoids are commonly used to treat chronic obstructive pulmonary disease and asthma. They do not have the same systemic bioavailability as oral glucocorticoids, so the risk of adverse effects is lower.

Data are inconsistent among several studies that evaluated the relationship between inhaled glucocorticoids, bone mineral density, osteoporosis, and fragility fracture. The inconsistencies may be due to heterogeneity of the study populations, self-reporting of fractures, and different methods of assessing chronic obstructive pulmonary disease severity.¹⁶

A Cochrane review¹⁷ in 2002 evaluated seven randomized controlled trials that compared the use of inhaled glucocorticoids vs placebo in nearly 2,000 patients with mild asthma or chronic obstructive pulmonary disease and found no evidence for decreased bone mineral density, increased bone turnover, or increased vertebral fracture incidence in the glucocorticoid users at 2 to 3 years of follow-up (odds ratio for fracture 1.87, 95% CI 0.5–7.0).

The Evaluation of Obstructive Lung Disease and Osteoporosis study,¹⁶ a multicenter Italian observational epidemiologic study, reported that patients taking the highest daily doses of inhaled glucocorticoids (> 1,500 μg of beclomethasone or its equivalent) had a significantly higher risk of vertebral fracture (odds ratio 1.4, 95% CI 1.04–1.89).¹⁶

A meta-analysis¹⁸ of five case-control studies (43,783 cases and 259,936 controls) identified a possible dose-dependent relationship, with a relative risk for nonvertebral fracture of 1.12 (95% CI 1.0–1.26) for each 1,000-μg increase in beclomethasone-equivalent inhaled glucocorticoid per day.

In summary, the effects of inhaled glucocorticoids in adults are uncertain, although trends toward increased fracture risk and decreased bone mineral density are evident with chronic therapy at moderate to high dosages. The risks and benefits of treatment should be carefully considered in patients with osteoporosis and baseline elevated fracture risk.¹⁹

Managing the risk of glucocorticoid-induced osteoporosis

In 2010, the American College of Rheumatology published recommendations for preventing and treating glucocorticoid-induced osteoporosis, which were endorsed by the American Society for Bone and Mineral Research.²⁰ To lessen the risk of osteoporosis, the recommendations are as follows:

Limit exposure. Patients receiving glucocorticoids should be given the smallest dosage for the shortest duration possible.

Advise lifestyle changes. Patients should be counseled to limit their alcohol intake to no more than two drinks per day, to quit smoking, to engage in weight-bearing exercise, and to ingest enough calcium (1,200–1,500 mg/day, through diet and supplements) and vitamin D.

Monitor bone mineral density. Patients starting glucocorticoids at any dosage for an expected duration of at least 3 months should have their bone mineral density measured at baseline. The frequency of subsequent measurements should be based on the presence of other risk factors for fracture, results of previous bone density testing, glucocorticoid dosage, whether therapy for bone health has been initiated, and the rate of change in bone mineral density. If warranted and if the results would lead to a change in management, patients can undergo dual-energy x-ray absorptiometry more often than usual, ie, more often than every 2 years. Prevalent and incident fragility fractures, height measurements, fall risk assessments, laboratory measurements of 25-hydroxyvitamin D, and consideration of vertebral fracture assessment or other imaging of the spine, as necessary, should be part of counseling and monitoring.

Osteoporosis treatment. For patients who will be taking glucocorticoids for at least 3 months, alendronate, risedronate, zoledronic acid, or teriparatide can be initiated to prevent or treat osteoporosis in the following groups: 

• Postmenopausal women and men over age 50 if the daily glucocorticoid dosage is at least 7.5 mg/day or if the World Health Organization Fracture Risk Assessment Tool (FRAX) score is more than 10% (the threshold for medium fracture risk)
• Premenopausal women and men younger than 50 if they have a history of fragility fracture, the FRAX score is more than 20% (the threshold for high fracture risk), or the T score is less than –2.5.

Certain clinical factors can also put a patient into a higher-risk category. These include current tobacco use, low body mass index, parental history of hip fracture, consuming more than three alcoholic drinks daily, higher daily or cumulative glucocorticoid dosage, intravenous pulse glucocorticoid usage, or a decline in central bone mineral density that exceeds the least significant change according to the scanner used.²⁰

The FRAX tool accounts for bone density only at the femoral neck, and while useful, it cannot replace clinical judgment in stratifying risk. Moreover, it does not apply to premenopausal women or men under age 40.

The implicated medications have important roles, so weigh their risks and benefits

The long-term risks of medications to treat glucocorticoid-induced osteoporosis are not well defined for premenopausal women (or their unborn children) or in men younger than 40, so treatment is recommended in those groups only for those with prevalent fragility fractures who are clearly at higher risk of additional fractures.²⁰

PROTON PUMP INHIBITORS

Proton pump inhibitors are available by prescription and over the counter for gastric acid-related conditions. Concerns have been raised that these highly effective drugs are overused.²¹ Several of their adverse effects are self-limited and minor, but long-term use may entail serious risks, including propensity to bone fracture.²²

Low acid leads to poor calcium absorption

Why fracture risk increases with proton pump inhibitors is controversial and may relate to their desired effect of suppressing gastric acid production: calcium salts, including carbonate and chloride, are poorly soluble and require an acidic environment to increase calcium ionization and thus absorption.²³ For this reason, if patients taking a proton pump inhibitor take a calcium supplement, it should be calcium citrate, which unlike calcium carbonate does not require an acid environment for absorption.

Higher risk in older patients, with longer use, and with higher dosage

Since the first reports on proton pump inhibitors and fracture risk were published in 2006,^24,25 a number of studies have reported this association, including several systematic reviews.

In 2011, the US Food and Drug Administration (FDA) updated a 2010 safety communication based on seven epidemiologic studies reporting an increased risk of fractures of the spine, hip, and wrist with proton pump inhibitors.^24–31 Time of exposure to a proton pump inhibitor in these studies varied from 1 to 12 years. Fracture risk was higher in older patients,²⁶ with higher doses,^24,29 and with longer duration of drug use.^24,27 On the other hand, one study that included only patients without other major fracture risk factors failed to find an association between the use of proton pump inhibitors and fractures.²⁸

Is evidence sufficient for changing use?

The FDA report included a disclaimer that they had no access to study data or protocols and so could not verify the findings.²⁶ Moreover, the studies used claims data from computerized databases to evaluate the risk of fractures in patients treated with proton pump inhibitors compared with those not using these drugs.^24–31 Information was often incomplete regarding potentially important factors (eg, falls, family history of osteoporosis, calcium and vitamin D intake, smoking, alcohol use, reason for medication use), as well as the timing of drug use related to the onset or worsening of osteoporosis.²⁶

Although 34 published studies evaluated the association of fracture risk and proton pump inhibitors, Leontiadis and Moayyedi³² argued that insufficient evidence exists to change our prescribing habits for these drugs based on fracture risk, as the studies varied considerably in their designs and results, a clear dose-response relationship is lacking, and the modest association is likely related to multiple confounders.

Bottom line: Use with caution

Although the increased fracture risk associated with proton pump inhibitors is likely multifactorial and is not fully delineated, it appears to be real. These drugs should be used only if there is a clear indication for them and if their benefits likely outweigh their risks. The lowest effective dose should be used, and the need for continuing use should be frequently reassessed.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

Depression affects 1 in 10 people in the United States, is especially common in the elderly, and leads to significant morbidity and reduced quality of life.³³ Selective serotonin reuptake inhibitors (SSRIs) are often prescribed and are generally considered first-line agents for treating depression.

Complex bone effects

Use proton pump inhibitors only if there is a clear indication for them and their benefits likely outweigh the risks

SSRIs antagonize the serotonin transporter, which normally assists serotonin uptake from the extracellular space. The serotonin transporter is found in all main types of bone cells, including osteoclasts, osteoblasts, and osteocytes.³³ Serotonin is made by different genes in the brain than in the periphery, causing opposing effects on bone biology: when generated peripherally, it acts as a hormone to inhibit bone formation, while when generated in the brain, it acts as a neurotransmitter to create a major and positive effect on bone mass accrual by enhancing bone formation and limiting bone resorption.^34,35

Potential confounders complicate the effect of SSRIs on bone health, as depression itself may be a risk factor for fracture. Patients with depression tend to have increased inflammation and cortisol, decreased gonadal steroids, more behavioral risk factors such as tobacco and increased alcohol use, and less physical activity, all of which can contribute to low bone density and risk of falls and fractures.³³

Daily use of SSRIs increases fracture risk

A 2012 meta-analysis³⁶ of 12 studies (seven case-control and five cohort), showed that SSRI users had a higher overall risk of fracture (adjusted odds ratio 1.69, 95% CI 1.51–1.90). By anatomic site, pooled odds ratios and 95% CIs were:

• Vertebral fractures 1.34 (1.13–1.59)
• Wrist or forearm fractures 1.51 (1.26–1.82)
• Hip or femur fractures 2.06 (1.84–2.30). 

A 2013 meta-analysis³⁷ of 34 studies with more than 1 million patients found that the random-effects pooled relative risk of all fracture types in users of antidepressants (including but not limited to SSRIs) was 1.39 (95% CI 1.32–1.47) compared with nonusers. Relative risks and 95% CIs in antidepressant users were:

• Vertebral fractures 1.38 (1.19–1.61)
• Nonvertebral fractures 1.42 (1.34–1.51)
• Hip fractures 1.47 (1.36–1.58).

A population-based, prospective cohort study³⁸ of 5,008 community-dwelling adults age 50 and older, followed for 5 years, found that the daily use of SSRIs was associated with a twofold increased risk of clinical fragility fractures (defined as minimal trauma fractures that were clinically reported and radiographically confirmed) after adjusting for potential covariates. Daily SSRI use was also associated with an increased risk of falling (odds ratio 2.2, 95% CI 1.4–3.5), lower bone mineral density at the hip, and a trend toward lower bone mineral density at the spine. These effects were dose-dependent and were similar for those who reported taking SSRIs at baseline and at 5 years.

Bottom line: Counsel bone health

Although no guidelines exist for preventing or treating SSRI-induced bone loss, providers should discuss with patients the potential effect of these medications on bone health, taking into account patient age, severity of depression, sex, duration of use, length of SSRI treatment, and other clinical risk factors for osteoporosis.³⁴ Given the widespread use of these medications for treating depression, more study into this association is needed to further guide providers.

ANTIEPILEPTIC DRUGS

Antiepileptic drugs are used to treat not only seizure disorders but also migraine headaches, neuropathy, and psychiatric and pain disorders. Many studies have linked their use to an increased risk of fractures.

The mechanism of this effect remains controversial. Early studies reported that inducers of cytochrome P450 enzymes (eg, phenobarbital, phenytoin) lead to increased vitamin D degradation, causing osteomalacia.³⁹ Another study suggested that changes in calcium metabolism and reduced bone mineral density occur without vitamin D deficiency and that drugs such as valproate that do not induce cytochrome P450 enzymes may also affect bone health.⁴⁰ Other bone effects may include direct inhibition of intestinal calcium absorption (seen in animal studies) and the induction of a high remodeling state leading to osteomalacia.^41,42

Epilepsy itself increases risk of fractures

Patients with seizure disorders may also have an increased risk of fractures because of falls, trauma, impaired balance, use of glucocorticoids and benzodiazepines, and comorbid conditions (eg, mental retardation, cerebral palsy, and brain neoplasm).⁴³

A 2005 meta-analysis⁴³ of 11 studies of epilepsy and fracture risk and 12 studies of epilepsy and bone mineral density found that the risks of fractures were increased. The following relative risks and 95% CIs were noted:

The benefit of preventing seizures outweighs the risks of fractures

• Any fracture 2.2 (1.9–2.5), in five studies
• Forearm 1.7 (1.2–2.3), in six studies
• Hip 5.3 (3.2–8.8), six studies
• Spine 6.2 (2.5–15.5), in three studies.

A large proportion of fractures (35%) seemed related to seizures.

Certain drugs increase risk

A large 2004 population-based, case-control, study⁴⁴ (124,655 fracture cases and 373,962 controls) found an association between the use of antiepileptic drugs and increased fracture risk. After adjusting for current or prior use of glucocorticoids, prior fracture, social variables, comorbid conditions, and epilepsy diagnosis, excess fracture risk was found to be associated with the following drugs (odds ratios and 95% CIs):

• Oxcarbazepine 1.14 (1.03–1.26)
• Valproate 1.15 (1.05–1.26)
• Carbamazepine 1.18 (1.10-1.26)
• Phenobarbital 1.79 (1.64–1.95).

The risk was higher with higher doses. Fracture risk was higher with cytochrome P450 enzyme-inducing drugs (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, and primidone; odds ratio 1.38, 95% CI 1.31–1.45) than for noninducing drugs (clonazepam, ethosuximide, lamotrigine, tiagabine, topiramate, valproate, and vigabatrin; odds ratio 1.19, 95% CI 1.11–1.27). No significant increased risk of fracture was found with use of phenytoin, tiagabine, topiramate, ethosuximide, lamotrigine, vigabatrin, or primidone after adjusting for confounders. 

Bottom line: Monitor bone health

With antiepileptic drugs, the benefit of preventing seizures outweighs the risks of fractures. Patients on long-term antiepileptic drug therapy should be monitored for bone mineral density and vitamin D levels and receive counseling on lifestyle measures including tobacco cessation, alcohol moderation, and fall prevention.⁴⁵ As there are no evidence-based guidelines for bone health in patients on antiepileptic drugs, management should be based on current guidelines for treating osteoporosis.

AROMATASE INHIBITORS

Depression itself may be a risk factor for fracture

Breast cancer is the most common cancer in women and is the second-leading cause of cancer-associated deaths in women after lung cancer. Aromatase inhibitors, such as anastrozole, letrozole, and exemestane, are the standard of care in adjuvant treatment for hormone-receptor-positive breast cancer, leading to longer disease-free survival.

However, aromatase inhibitors increase bone loss and fracture risk, and only partial recovery of bone mineral density occurs after treatment is stopped. The drugs deter the aromatization of androgens and their conversion to estrogens in peripheral tissue, leading to reduced estrogen levels and resulting bone loss.⁴⁶ Anastrozole and letrozole have been found to reduce bone mineral density, increase bone turnover, and increase the relative risk for nonvertebral and vertebral fractures in postmenopausal women by 40% compared with tamoxifen.^47,48

Base osteoporosis treatment on risk

Several groups have issued guidelines for preventing and treating bone loss in postmenopausal women being treated with an aromatase inhibitor. When initiating treatment, women should be counseled about modifiable risk factors, exercise, and calcium and vitamin D supplementation.

Baseline bone mineral testing should also be obtained when starting treatment. Hadji et al,⁴⁹ in a review article, recommend starting bone-directed therapy if the patient’s T score is less than –2.0 (using the lowest score from three sites) or if she has any of at least two of the following fracture risk factors:

• T score less than –1.5
• Age over 65
• Family history of hip fracture
• Personal history of fragility fracture after age 50
• Low body mass index (< 20 kg/m²)
• Current or prior history of tobacco use
• Oral glucocorticoid use for longer than 6 months.

Patients with a T score at or above –2.0 and no risk factors should have bone mineral density reassessed after 1 to 2 years. Antiresorptive therapy with intravenous zoledronic acid and evaluation for other secondary causes of bone loss should be initiated for either:

• An annual decrease of at least 10% or
• An annual decrease of at least 4% in patients with osteopenia at baseline.⁴⁹

In 2003, the American Society of Clinical Oncology updated its recommendations on the role of bisphosphonates and bone health in women with breast cancer.⁵⁰ They recommend the following:

• If the T score is –2.5 or less, prescribe a bisphosphonate (alendronate, risedronate, or zoledronic acid)
• If the T score is –1.0 to –2.5, tailor treatment individually and monitor bone mineral density annually
• If the T score is greater than –1.0, monitor bone mineral density annually.

All patients should receive lifestyle counseling, calcium and vitamin D supplementation, and monitoring of additional risk factors for osteoporosis as appropriate.⁵⁰

Drug-induced osteoporosis is common, and the list of drugs that can harm bone continues to grow. As part of routine health maintenance, practitioners should recognize the drugs that increase bone loss and take measures to mitigate these effects to help avoid osteopenia and osteoporosis.

Osteoporosis, a silent systemic disease defined by low bone mineral density and changes in skeletal microstructure, leads to a higher risk of fragility fractures. Some of the risk factors are well described, but less well known is the role of pharmacologic therapy. The implicated drugs (Table 1) have important therapeutic roles, so the benefits of using them must be weighed against their risks, including their potential effects on bone.

This review focuses on a few drugs known to increase fracture risk, their mechanisms of bone loss, and management considerations (Table 2).

GLUCOCORTICOIDS

Glucocorticoids are used to treat many medical conditions, including allergic, rheumatic, and other inflammatory diseases, and as immunosuppressive therapy after solid organ and bone marrow transplant. They are the most common cause of drug-induced bone loss and related secondary osteoporosis.

Multiple effects on bone

Glucocorticoids both increase bone resorption and decrease bone formation by a variety of mechanisms.¹ They reduce intestinal calcium absorption, increase urinary excretion of calcium, and enhance osteocyte apoptosis, leading to deterioration of the bone microarchitecture and bone mineral density.² They also affect sex hormones, decreasing testosterone production in men and estrogen in women, leading to increased bone resorption, altered bone architecture, and poorer bone quality.^3,4 The bone loss is greater in trabecular bone (eg, the femoral neck and vertebral bodies) than in cortical bone (eg, the forearm).⁵

Glucocorticoids have other systemic effects that increase fracture risk. For example, they cause muscle weakness and atrophy, increasing the risk of falls.⁴ Additionally, many of the inflammatory conditions for which they are prescribed (eg, rheumatoid arthritis) also increase the risk of osteoporosis by means of proinflammatory cytokine production, which may contribute to systemic and local effects on bone.^4,6

Bone mineral density declines quickly

Bone mineral density declines within the first 3 months after starting oral glucocorticoids, with the rate of bone loss peaking at 6 months. Up to 12% of bone mass is lost in the first year. In subsequent years of continued use, bone loss progresses at a slower, steadier rate, averaging 2% to 3% annually.^5,7,8

Oral therapy increases fracture risk

Kanis et al⁹ performed a meta-analysis of seven prospective cohort studies in 40,000 patients and found that the current or previous use of an oral glucocorticoid increased the risk of fragility fractures, and that men and women were  affected about equally.⁹

Van Staa et al^10,11 reported that daily doses of glucocorticoids equivalent to more than 2.5 mg of prednisone were associated with an increased risk of vertebral and hip fractures; fracture risk was related mainly to daily dosage rather than cumulative dose.

Van Staa et al,¹² in a retrospective cohort study, compared nearly 250,000 adult users of oral glucocorticoids from general medical practice settings with the same number of controls matched for sex, age, and medical practice. The relative risks for fractures and 95% confidence intervals (CIs) during oral glucocorticoid treatment were as follows:

• Forearm fracture 1.09 (1.01–1.17)
• Nonvertebral fracture 1.33 (1.29–1.38)
• Hip fracture 1.61 (1.47–1.76)
• Vertebral fracture 2.60 (2.31–2.92).

The risk was dose-dependent. For a low daily dose (< 2.5 mg/day of prednisolone), the relative risks were:

• Hip fracture 0.99 (0.82–1.20)
• Vertebral fracture 1.55 (1.20–2.01) .

For a medium daily dose (2.5–7.5 mg/day), the relative risks were: 

• Hip fracture 1.77 (1.55–2.02)
• Vertebral fracture 2.59 (2.16–3.10) .

For a high daily dose (> 7.5 mg/day), the relative risks were:

• Hip fracture 2.27 (1.94–2.66)
• Vertebral fracture 5.18 (4.25–6.31).

Fracture risk rapidly declined toward baseline after the patients stopped taking oral glucocorticoids but did not return to baseline levels. The lessening of excess fracture risk occurred mainly within the first year after stopping therapy.

Other studies^5,9,13 have suggested that the increased fracture risk is mostly independent of bone mineral density, and that other mechanisms are at play. One study¹⁴ found that oral glucocorticoid users with a prevalent vertebral fracture actually had higher bone mineral density than patients with a fracture not taking glucocorticoids, although this finding was not confirmed in a subsequent study.¹⁵

Inhaled glucocorticoids have less effect on bone

Inhaled glucocorticoids are commonly used to treat chronic obstructive pulmonary disease and asthma. They do not have the same systemic bioavailability as oral glucocorticoids, so the risk of adverse effects is lower.

Data are inconsistent among several studies that evaluated the relationship between inhaled glucocorticoids, bone mineral density, osteoporosis, and fragility fracture. The inconsistencies may be due to heterogeneity of the study populations, self-reporting of fractures, and different methods of assessing chronic obstructive pulmonary disease severity.¹⁶

A Cochrane review¹⁷ in 2002 evaluated seven randomized controlled trials that compared the use of inhaled glucocorticoids vs placebo in nearly 2,000 patients with mild asthma or chronic obstructive pulmonary disease and found no evidence for decreased bone mineral density, increased bone turnover, or increased vertebral fracture incidence in the glucocorticoid users at 2 to 3 years of follow-up (odds ratio for fracture 1.87, 95% CI 0.5–7.0).

The Evaluation of Obstructive Lung Disease and Osteoporosis study,¹⁶ a multicenter Italian observational epidemiologic study, reported that patients taking the highest daily doses of inhaled glucocorticoids (> 1,500 μg of beclomethasone or its equivalent) had a significantly higher risk of vertebral fracture (odds ratio 1.4, 95% CI 1.04–1.89).¹⁶

A meta-analysis¹⁸ of five case-control studies (43,783 cases and 259,936 controls) identified a possible dose-dependent relationship, with a relative risk for nonvertebral fracture of 1.12 (95% CI 1.0–1.26) for each 1,000-μg increase in beclomethasone-equivalent inhaled glucocorticoid per day.

In summary, the effects of inhaled glucocorticoids in adults are uncertain, although trends toward increased fracture risk and decreased bone mineral density are evident with chronic therapy at moderate to high dosages. The risks and benefits of treatment should be carefully considered in patients with osteoporosis and baseline elevated fracture risk.¹⁹

Managing the risk of glucocorticoid-induced osteoporosis

In 2010, the American College of Rheumatology published recommendations for preventing and treating glucocorticoid-induced osteoporosis, which were endorsed by the American Society for Bone and Mineral Research.²⁰ To lessen the risk of osteoporosis, the recommendations are as follows:

Limit exposure. Patients receiving glucocorticoids should be given the smallest dosage for the shortest duration possible.

Advise lifestyle changes. Patients should be counseled to limit their alcohol intake to no more than two drinks per day, to quit smoking, to engage in weight-bearing exercise, and to ingest enough calcium (1,200–1,500 mg/day, through diet and supplements) and vitamin D.

Monitor bone mineral density. Patients starting glucocorticoids at any dosage for an expected duration of at least 3 months should have their bone mineral density measured at baseline. The frequency of subsequent measurements should be based on the presence of other risk factors for fracture, results of previous bone density testing, glucocorticoid dosage, whether therapy for bone health has been initiated, and the rate of change in bone mineral density. If warranted and if the results would lead to a change in management, patients can undergo dual-energy x-ray absorptiometry more often than usual, ie, more often than every 2 years. Prevalent and incident fragility fractures, height measurements, fall risk assessments, laboratory measurements of 25-hydroxyvitamin D, and consideration of vertebral fracture assessment or other imaging of the spine, as necessary, should be part of counseling and monitoring.

Osteoporosis treatment. For patients who will be taking glucocorticoids for at least 3 months, alendronate, risedronate, zoledronic acid, or teriparatide can be initiated to prevent or treat osteoporosis in the following groups: 

• Postmenopausal women and men over age 50 if the daily glucocorticoid dosage is at least 7.5 mg/day or if the World Health Organization Fracture Risk Assessment Tool (FRAX) score is more than 10% (the threshold for medium fracture risk)
• Premenopausal women and men younger than 50 if they have a history of fragility fracture, the FRAX score is more than 20% (the threshold for high fracture risk), or the T score is less than –2.5.

Certain clinical factors can also put a patient into a higher-risk category. These include current tobacco use, low body mass index, parental history of hip fracture, consuming more than three alcoholic drinks daily, higher daily or cumulative glucocorticoid dosage, intravenous pulse glucocorticoid usage, or a decline in central bone mineral density that exceeds the least significant change according to the scanner used.²⁰

The FRAX tool accounts for bone density only at the femoral neck, and while useful, it cannot replace clinical judgment in stratifying risk. Moreover, it does not apply to premenopausal women or men under age 40.

The implicated medications have important roles, so weigh their risks and benefits

The long-term risks of medications to treat glucocorticoid-induced osteoporosis are not well defined for premenopausal women (or their unborn children) or in men younger than 40, so treatment is recommended in those groups only for those with prevalent fragility fractures who are clearly at higher risk of additional fractures.²⁰

PROTON PUMP INHIBITORS

Proton pump inhibitors are available by prescription and over the counter for gastric acid-related conditions. Concerns have been raised that these highly effective drugs are overused.²¹ Several of their adverse effects are self-limited and minor, but long-term use may entail serious risks, including propensity to bone fracture.²²

Low acid leads to poor calcium absorption

Why fracture risk increases with proton pump inhibitors is controversial and may relate to their desired effect of suppressing gastric acid production: calcium salts, including carbonate and chloride, are poorly soluble and require an acidic environment to increase calcium ionization and thus absorption.²³ For this reason, if patients taking a proton pump inhibitor take a calcium supplement, it should be calcium citrate, which unlike calcium carbonate does not require an acid environment for absorption.

Higher risk in older patients, with longer use, and with higher dosage

Since the first reports on proton pump inhibitors and fracture risk were published in 2006,^24,25 a number of studies have reported this association, including several systematic reviews.

In 2011, the US Food and Drug Administration (FDA) updated a 2010 safety communication based on seven epidemiologic studies reporting an increased risk of fractures of the spine, hip, and wrist with proton pump inhibitors.^24–31 Time of exposure to a proton pump inhibitor in these studies varied from 1 to 12 years. Fracture risk was higher in older patients,²⁶ with higher doses,^24,29 and with longer duration of drug use.^24,27 On the other hand, one study that included only patients without other major fracture risk factors failed to find an association between the use of proton pump inhibitors and fractures.²⁸

Is evidence sufficient for changing use?

The FDA report included a disclaimer that they had no access to study data or protocols and so could not verify the findings.²⁶ Moreover, the studies used claims data from computerized databases to evaluate the risk of fractures in patients treated with proton pump inhibitors compared with those not using these drugs.^24–31 Information was often incomplete regarding potentially important factors (eg, falls, family history of osteoporosis, calcium and vitamin D intake, smoking, alcohol use, reason for medication use), as well as the timing of drug use related to the onset or worsening of osteoporosis.²⁶

Although 34 published studies evaluated the association of fracture risk and proton pump inhibitors, Leontiadis and Moayyedi³² argued that insufficient evidence exists to change our prescribing habits for these drugs based on fracture risk, as the studies varied considerably in their designs and results, a clear dose-response relationship is lacking, and the modest association is likely related to multiple confounders.

Bottom line: Use with caution

Although the increased fracture risk associated with proton pump inhibitors is likely multifactorial and is not fully delineated, it appears to be real. These drugs should be used only if there is a clear indication for them and if their benefits likely outweigh their risks. The lowest effective dose should be used, and the need for continuing use should be frequently reassessed.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

Depression affects 1 in 10 people in the United States, is especially common in the elderly, and leads to significant morbidity and reduced quality of life.³³ Selective serotonin reuptake inhibitors (SSRIs) are often prescribed and are generally considered first-line agents for treating depression.

Complex bone effects

Use proton pump inhibitors only if there is a clear indication for them and their benefits likely outweigh the risks

SSRIs antagonize the serotonin transporter, which normally assists serotonin uptake from the extracellular space. The serotonin transporter is found in all main types of bone cells, including osteoclasts, osteoblasts, and osteocytes.³³ Serotonin is made by different genes in the brain than in the periphery, causing opposing effects on bone biology: when generated peripherally, it acts as a hormone to inhibit bone formation, while when generated in the brain, it acts as a neurotransmitter to create a major and positive effect on bone mass accrual by enhancing bone formation and limiting bone resorption.^34,35

Potential confounders complicate the effect of SSRIs on bone health, as depression itself may be a risk factor for fracture. Patients with depression tend to have increased inflammation and cortisol, decreased gonadal steroids, more behavioral risk factors such as tobacco and increased alcohol use, and less physical activity, all of which can contribute to low bone density and risk of falls and fractures.³³

Daily use of SSRIs increases fracture risk

A 2012 meta-analysis³⁶ of 12 studies (seven case-control and five cohort), showed that SSRI users had a higher overall risk of fracture (adjusted odds ratio 1.69, 95% CI 1.51–1.90). By anatomic site, pooled odds ratios and 95% CIs were:

• Vertebral fractures 1.34 (1.13–1.59)
• Wrist or forearm fractures 1.51 (1.26–1.82)
• Hip or femur fractures 2.06 (1.84–2.30). 

A 2013 meta-analysis³⁷ of 34 studies with more than 1 million patients found that the random-effects pooled relative risk of all fracture types in users of antidepressants (including but not limited to SSRIs) was 1.39 (95% CI 1.32–1.47) compared with nonusers. Relative risks and 95% CIs in antidepressant users were:

• Vertebral fractures 1.38 (1.19–1.61)
• Nonvertebral fractures 1.42 (1.34–1.51)
• Hip fractures 1.47 (1.36–1.58).

A population-based, prospective cohort study³⁸ of 5,008 community-dwelling adults age 50 and older, followed for 5 years, found that the daily use of SSRIs was associated with a twofold increased risk of clinical fragility fractures (defined as minimal trauma fractures that were clinically reported and radiographically confirmed) after adjusting for potential covariates. Daily SSRI use was also associated with an increased risk of falling (odds ratio 2.2, 95% CI 1.4–3.5), lower bone mineral density at the hip, and a trend toward lower bone mineral density at the spine. These effects were dose-dependent and were similar for those who reported taking SSRIs at baseline and at 5 years.

Bottom line: Counsel bone health

Although no guidelines exist for preventing or treating SSRI-induced bone loss, providers should discuss with patients the potential effect of these medications on bone health, taking into account patient age, severity of depression, sex, duration of use, length of SSRI treatment, and other clinical risk factors for osteoporosis.³⁴ Given the widespread use of these medications for treating depression, more study into this association is needed to further guide providers.

ANTIEPILEPTIC DRUGS

Antiepileptic drugs are used to treat not only seizure disorders but also migraine headaches, neuropathy, and psychiatric and pain disorders. Many studies have linked their use to an increased risk of fractures.

The mechanism of this effect remains controversial. Early studies reported that inducers of cytochrome P450 enzymes (eg, phenobarbital, phenytoin) lead to increased vitamin D degradation, causing osteomalacia.³⁹ Another study suggested that changes in calcium metabolism and reduced bone mineral density occur without vitamin D deficiency and that drugs such as valproate that do not induce cytochrome P450 enzymes may also affect bone health.⁴⁰ Other bone effects may include direct inhibition of intestinal calcium absorption (seen in animal studies) and the induction of a high remodeling state leading to osteomalacia.^41,42

Epilepsy itself increases risk of fractures

Patients with seizure disorders may also have an increased risk of fractures because of falls, trauma, impaired balance, use of glucocorticoids and benzodiazepines, and comorbid conditions (eg, mental retardation, cerebral palsy, and brain neoplasm).⁴³

A 2005 meta-analysis⁴³ of 11 studies of epilepsy and fracture risk and 12 studies of epilepsy and bone mineral density found that the risks of fractures were increased. The following relative risks and 95% CIs were noted:

The benefit of preventing seizures outweighs the risks of fractures

• Any fracture 2.2 (1.9–2.5), in five studies
• Forearm 1.7 (1.2–2.3), in six studies
• Hip 5.3 (3.2–8.8), six studies
• Spine 6.2 (2.5–15.5), in three studies.

A large proportion of fractures (35%) seemed related to seizures.

Certain drugs increase risk

A large 2004 population-based, case-control, study⁴⁴ (124,655 fracture cases and 373,962 controls) found an association between the use of antiepileptic drugs and increased fracture risk. After adjusting for current or prior use of glucocorticoids, prior fracture, social variables, comorbid conditions, and epilepsy diagnosis, excess fracture risk was found to be associated with the following drugs (odds ratios and 95% CIs):

• Oxcarbazepine 1.14 (1.03–1.26)
• Valproate 1.15 (1.05–1.26)
• Carbamazepine 1.18 (1.10-1.26)
• Phenobarbital 1.79 (1.64–1.95).

The risk was higher with higher doses. Fracture risk was higher with cytochrome P450 enzyme-inducing drugs (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, and primidone; odds ratio 1.38, 95% CI 1.31–1.45) than for noninducing drugs (clonazepam, ethosuximide, lamotrigine, tiagabine, topiramate, valproate, and vigabatrin; odds ratio 1.19, 95% CI 1.11–1.27). No significant increased risk of fracture was found with use of phenytoin, tiagabine, topiramate, ethosuximide, lamotrigine, vigabatrin, or primidone after adjusting for confounders. 

Bottom line: Monitor bone health

With antiepileptic drugs, the benefit of preventing seizures outweighs the risks of fractures. Patients on long-term antiepileptic drug therapy should be monitored for bone mineral density and vitamin D levels and receive counseling on lifestyle measures including tobacco cessation, alcohol moderation, and fall prevention.⁴⁵ As there are no evidence-based guidelines for bone health in patients on antiepileptic drugs, management should be based on current guidelines for treating osteoporosis.

AROMATASE INHIBITORS

Depression itself may be a risk factor for fracture

Breast cancer is the most common cancer in women and is the second-leading cause of cancer-associated deaths in women after lung cancer. Aromatase inhibitors, such as anastrozole, letrozole, and exemestane, are the standard of care in adjuvant treatment for hormone-receptor-positive breast cancer, leading to longer disease-free survival.

However, aromatase inhibitors increase bone loss and fracture risk, and only partial recovery of bone mineral density occurs after treatment is stopped. The drugs deter the aromatization of androgens and their conversion to estrogens in peripheral tissue, leading to reduced estrogen levels and resulting bone loss.⁴⁶ Anastrozole and letrozole have been found to reduce bone mineral density, increase bone turnover, and increase the relative risk for nonvertebral and vertebral fractures in postmenopausal women by 40% compared with tamoxifen.^47,48

Base osteoporosis treatment on risk

Several groups have issued guidelines for preventing and treating bone loss in postmenopausal women being treated with an aromatase inhibitor. When initiating treatment, women should be counseled about modifiable risk factors, exercise, and calcium and vitamin D supplementation.

Baseline bone mineral testing should also be obtained when starting treatment. Hadji et al,⁴⁹ in a review article, recommend starting bone-directed therapy if the patient’s T score is less than –2.0 (using the lowest score from three sites) or if she has any of at least two of the following fracture risk factors:

• T score less than –1.5
• Age over 65
• Family history of hip fracture
• Personal history of fragility fracture after age 50
• Low body mass index (< 20 kg/m²)
• Current or prior history of tobacco use
• Oral glucocorticoid use for longer than 6 months.

Patients with a T score at or above –2.0 and no risk factors should have bone mineral density reassessed after 1 to 2 years. Antiresorptive therapy with intravenous zoledronic acid and evaluation for other secondary causes of bone loss should be initiated for either:

• An annual decrease of at least 10% or
• An annual decrease of at least 4% in patients with osteopenia at baseline.⁴⁹

In 2003, the American Society of Clinical Oncology updated its recommendations on the role of bisphosphonates and bone health in women with breast cancer.⁵⁰ They recommend the following:

• If the T score is –2.5 or less, prescribe a bisphosphonate (alendronate, risedronate, or zoledronic acid)
• If the T score is –1.0 to –2.5, tailor treatment individually and monitor bone mineral density annually
• If the T score is greater than –1.0, monitor bone mineral density annually.

All patients should receive lifestyle counseling, calcium and vitamin D supplementation, and monitoring of additional risk factors for osteoporosis as appropriate.⁵⁰

A 50-year-old man presented with a painful rash over his extremities for the past 2 days (Figure 1). He said he had been in his usual state of health until the day he woke up with the rash. The rash was initially limited to his upper and lower extremities, but the next day he noticed similar lesions over his cheek and hard palate. He was a smoker and was known to have hepatitis C virus infection. He denied recent trauma, fever, or chills. He said he had snorted cocaine about 24 hours before the rash first appeared.

On examination, his vital signs were normal. He had an extensive retiform rash involving the upper and lower extremities, earlobes, right cheek, and hard palate. Otherwise, the physical examination was normal.

Initial laboratory evaluation showed:

• Hemoglobin 11.5 g/dL (reference range 14.0–17.5)
• White blood cell count 2.1 × 10⁹/L (4.5–11.0)
• Platelet count 168 × 10⁹/L (150–350)
• Absolute neutrophil count 0.9 × 10⁹/L (≥ 1.5)
• Urine toxicology screen positive for cocaine.

He was admitted to the hospital and was started on intravenous vancomycin and piperacillin-sulbactam for a presumed infectious cause of the rash.

One day later, testing for myeloperoxidase-specific antineutrophil cytoplasmic antibodies (p-ANCA) was strongly positive. Skin biopsy revealed leukocytoclastic vasculitis with small-vessel thrombosis. These findings, along with the timing of the appearance of the rash after his cocaine use,  led to a diagnosis of levamisole-adulterated cocaine-induced vasculitis.

LEVAMISOLE AND VASCULITIS

Levamisole used to be used as an antihelminthic and as an adjuvant chemotherapeutic agent, but it is also added to cocaine to increase its euphoric and psychotropic effects.¹ It has been withdrawn from the market for human use because of toxic side effects including agranulocytosis, vasculitis, and autoantibody positivity.

Levamisole-adulterated cocaine has been known to induce ANCA-associated vasculitis.² Symptoms of levamisole-induced vasculitis usually start a few hours to a few days after the last dose of cocaine. Almost all patients with this condition present with a characteristic retiform purpuric rash, which has a predilection for the ears, nose, cheeks, and extremities. It also causes neutropenia and agranulocytosis (as well as autoantibodies, including antinuclear antibodies and antiphospholipid antibodies).

The characteristic lesions tend to be in a stellate pattern with erythematous borders. They often but not always have a central necrotic area. The location of the rash and the fact that it resolves after discontinuation of the offending agent help distinguish this condition from other types of vasculitis. Usually, antibodies against myeloperoxidase are present.³

Leukopenia does not typically occur in patients with primary vasculitis syndromes. The literature is mixed on the presence or absence of specific ANCAs.

Inflammatory and noninflammatory vasculopathic disorders that can present similarly include disseminated intravascular coagulation, antiphospholipid syndrome, warfarin-induced skin necrosis, paroxysmal nocturnal hemoglobinuria, cryoglobulinemia, vasculitis, and calciphylaxis.

Treatment is mainly supportive, but emollients and steroids⁴ have been reported to alleviate the symptoms. Surgical debridement is rarely needed unless skin necrosis is extensive.

Levamisole-induced vasculitis is a diagnosis of exclusion but should be strongly considered when the rash is associated with recent cocaine use, retiform purpura, or bullae with skin involvement, leukopenia, and positive ANCA in high titers.³ If cocaine use is discontinued, the syndrome is expected to resolve.

A 50-year-old man presented with a painful rash over his extremities for the past 2 days (Figure 1). He said he had been in his usual state of health until the day he woke up with the rash. The rash was initially limited to his upper and lower extremities, but the next day he noticed similar lesions over his cheek and hard palate. He was a smoker and was known to have hepatitis C virus infection. He denied recent trauma, fever, or chills. He said he had snorted cocaine about 24 hours before the rash first appeared.

On examination, his vital signs were normal. He had an extensive retiform rash involving the upper and lower extremities, earlobes, right cheek, and hard palate. Otherwise, the physical examination was normal.

Initial laboratory evaluation showed:

• Hemoglobin 11.5 g/dL (reference range 14.0–17.5)
• White blood cell count 2.1 × 10⁹/L (4.5–11.0)
• Platelet count 168 × 10⁹/L (150–350)
• Absolute neutrophil count 0.9 × 10⁹/L (≥ 1.5)
• Urine toxicology screen positive for cocaine.

He was admitted to the hospital and was started on intravenous vancomycin and piperacillin-sulbactam for a presumed infectious cause of the rash.

One day later, testing for myeloperoxidase-specific antineutrophil cytoplasmic antibodies (p-ANCA) was strongly positive. Skin biopsy revealed leukocytoclastic vasculitis with small-vessel thrombosis. These findings, along with the timing of the appearance of the rash after his cocaine use,  led to a diagnosis of levamisole-adulterated cocaine-induced vasculitis.

LEVAMISOLE AND VASCULITIS

Levamisole used to be used as an antihelminthic and as an adjuvant chemotherapeutic agent, but it is also added to cocaine to increase its euphoric and psychotropic effects.¹ It has been withdrawn from the market for human use because of toxic side effects including agranulocytosis, vasculitis, and autoantibody positivity.

Levamisole-adulterated cocaine has been known to induce ANCA-associated vasculitis.² Symptoms of levamisole-induced vasculitis usually start a few hours to a few days after the last dose of cocaine. Almost all patients with this condition present with a characteristic retiform purpuric rash, which has a predilection for the ears, nose, cheeks, and extremities. It also causes neutropenia and agranulocytosis (as well as autoantibodies, including antinuclear antibodies and antiphospholipid antibodies).

The characteristic lesions tend to be in a stellate pattern with erythematous borders. They often but not always have a central necrotic area. The location of the rash and the fact that it resolves after discontinuation of the offending agent help distinguish this condition from other types of vasculitis. Usually, antibodies against myeloperoxidase are present.³

Leukopenia does not typically occur in patients with primary vasculitis syndromes. The literature is mixed on the presence or absence of specific ANCAs.

Inflammatory and noninflammatory vasculopathic disorders that can present similarly include disseminated intravascular coagulation, antiphospholipid syndrome, warfarin-induced skin necrosis, paroxysmal nocturnal hemoglobinuria, cryoglobulinemia, vasculitis, and calciphylaxis.

Treatment is mainly supportive, but emollients and steroids⁴ have been reported to alleviate the symptoms. Surgical debridement is rarely needed unless skin necrosis is extensive.

Levamisole-induced vasculitis is a diagnosis of exclusion but should be strongly considered when the rash is associated with recent cocaine use, retiform purpura, or bullae with skin involvement, leukopenia, and positive ANCA in high titers.³ If cocaine use is discontinued, the syndrome is expected to resolve.

A 50-year-old man presented with a painful rash over his extremities for the past 2 days (Figure 1). He said he had been in his usual state of health until the day he woke up with the rash. The rash was initially limited to his upper and lower extremities, but the next day he noticed similar lesions over his cheek and hard palate. He was a smoker and was known to have hepatitis C virus infection. He denied recent trauma, fever, or chills. He said he had snorted cocaine about 24 hours before the rash first appeared.

On examination, his vital signs were normal. He had an extensive retiform rash involving the upper and lower extremities, earlobes, right cheek, and hard palate. Otherwise, the physical examination was normal.

Initial laboratory evaluation showed:

• Hemoglobin 11.5 g/dL (reference range 14.0–17.5)
• White blood cell count 2.1 × 10⁹/L (4.5–11.0)
• Platelet count 168 × 10⁹/L (150–350)
• Absolute neutrophil count 0.9 × 10⁹/L (≥ 1.5)
• Urine toxicology screen positive for cocaine.

He was admitted to the hospital and was started on intravenous vancomycin and piperacillin-sulbactam for a presumed infectious cause of the rash.

One day later, testing for myeloperoxidase-specific antineutrophil cytoplasmic antibodies (p-ANCA) was strongly positive. Skin biopsy revealed leukocytoclastic vasculitis with small-vessel thrombosis. These findings, along with the timing of the appearance of the rash after his cocaine use,  led to a diagnosis of levamisole-adulterated cocaine-induced vasculitis.

LEVAMISOLE AND VASCULITIS

Levamisole used to be used as an antihelminthic and as an adjuvant chemotherapeutic agent, but it is also added to cocaine to increase its euphoric and psychotropic effects.¹ It has been withdrawn from the market for human use because of toxic side effects including agranulocytosis, vasculitis, and autoantibody positivity.

Levamisole-adulterated cocaine has been known to induce ANCA-associated vasculitis.² Symptoms of levamisole-induced vasculitis usually start a few hours to a few days after the last dose of cocaine. Almost all patients with this condition present with a characteristic retiform purpuric rash, which has a predilection for the ears, nose, cheeks, and extremities. It also causes neutropenia and agranulocytosis (as well as autoantibodies, including antinuclear antibodies and antiphospholipid antibodies).

The characteristic lesions tend to be in a stellate pattern with erythematous borders. They often but not always have a central necrotic area. The location of the rash and the fact that it resolves after discontinuation of the offending agent help distinguish this condition from other types of vasculitis. Usually, antibodies against myeloperoxidase are present.³

Leukopenia does not typically occur in patients with primary vasculitis syndromes. The literature is mixed on the presence or absence of specific ANCAs.

Inflammatory and noninflammatory vasculopathic disorders that can present similarly include disseminated intravascular coagulation, antiphospholipid syndrome, warfarin-induced skin necrosis, paroxysmal nocturnal hemoglobinuria, cryoglobulinemia, vasculitis, and calciphylaxis.

Treatment is mainly supportive, but emollients and steroids⁴ have been reported to alleviate the symptoms. Surgical debridement is rarely needed unless skin necrosis is extensive.

Levamisole-induced vasculitis is a diagnosis of exclusion but should be strongly considered when the rash is associated with recent cocaine use, retiform purpura, or bullae with skin involvement, leukopenia, and positive ANCA in high titers.³ If cocaine use is discontinued, the syndrome is expected to resolve.

Aortic stenosis is the most common valvular heart condition in the developed world, affecting 3% of people between ages 75 and 85¹ and 4% of people over age 85.² Aortic valve replacement remains the only treatment proven to reduce the rates of mortality and morbidity in this condition.³ Under current guidelines,^4,5 the onset of symptoms of exertional angina, syncope, or dyspnea in a patient who has severe aortic stenosis is a class I indication for surgery—ie, surgery should be performed.

However, high-gradient, severe aortic stenosis that is asymptomatic often poses a dilemma. The annual rate of sudden death in patients with this condition is estimated at 1% to 3%,^6–9 but the surgical mortality rate in aortic valve replacement has been as high as 6% in Medicare patients (varying by center and comorbidities).¹⁰ Therefore, the traditional teaching was to not surgically replace the valve in asymptomatic patients, based on an adverse risk-benefit ratio. But with improvements in surgical techniques and prostheses, these rates have been reduced to 2.41% at high-volume centers¹¹ (and to less than 1% at some hospitals),¹² arguing in favor of earlier intervention.

Complicating the issue, transcatheter aortic valve replacement has become widely available, but further investigation into its use in this patient cohort is warranted.

Furthermore, many patients with severe but apparently asymptomatic aortic stenosis and normal left ventricular ejection fraction may actually have impaired exercise capacity, or they may have structural left ventricular changes such as severe hypertrophy or reduction in global strain, which may worsen the long-term survival rate.^13,14

A prospective trial in patients with severe aortic stenosis found that mortality rates were significantly lower in those who underwent surgery early than in those who received conventional treatment, ie, watchful waiting (no specific medical treatment for aortic stenosis is available).¹⁵

Patients with asymptomatic severe aortic stenosis are a diverse group; some have a far worse prognosis than others, with or without surgery.

This paper reviews the guidelines for valve replacement in this patient group and the factors useful in establishing who should be considered for early intervention even if they have no classic symptoms (Figure 1).

SIGNS AND SYMPTOMS OF STENOSIS

Aortic stenosis is often first suspected when a patient presents with angina, dyspnea, and syncope, or when an ejection systolic murmur is heard incidentally on physical examination—typically a high-pitched, crescendo-decrescendo, midsystolic ejection murmur that is best heard at the right upper sternal border and that radiates to the carotid arteries.

Several physical findings may help in assessing the severity of aortic stenosis. In mild stenosis, the murmur peaks in early systole, but as the disease progresses the peak moves later into systole. The corollary of this phenomenon is a weak and delayed carotid upstroke known as “pulsus parvus et tardus.” This can be assessed by palpating the carotid artery while auscultating the heart.

Aortic stenosis is often first suspected when a patient has angina, dyspnea, and syncope or an ejection systolic murmur

The second heart sound becomes progressively softer as the stenosis advances until it is no longer audible. If a fourth heart sound is present, it may be due to concentric left ventricular hypertrophy with reduced left ventricular compliance, and a third heart sound indicates severe left ventricular dysfunction. Both of these findings suggest severe aortic stenosis.

ECHOCARDIOGRAPHIC MEASURES OF SEVERITY

Echocardiography is the best established and most important initial investigation in the assessment of a patient with suspected aortic stenosis. It usually provides accurate information on the severity and the mechanism of stenosis. The following findings indicate severe aortic stenosis:

• Mean pressure gradient > 40 mm Hg
• Peak aortic jet velocity > 4.0 m/s
• Aortic valve area < 1 cm².

RECOMMENDATIONS FOR SURGERY BASED ON SEVERITY AND SYMPTOMS

The American College of Cardiology and American Heart Association (ACC/AHA)⁴ have issued the following recommendations for aortic valve replacement, based on the severity of stenosis and on whether the patient has symptoms (Figure 2):

Severe stenosis, with symptoms: class I recommendation (surgery should be done). Without surgery, these patients have a very poor prognosis, with an overall mortality rate of 75% at 3 years.³

Severe stenosis, no symptoms, in patients undergoing cardiac surgery for another indication (eg, coronary artery bypass grafting, ascending aortic surgery, or surgery on other valves): class I recommendation for concomitant aortic valve replacement.

Moderate stenosis, no symptoms, in patients undergoing cardiac surgery for another indication: class IIa recommendation (ie, aortic valve replacement “is reasonable”).

Very severe stenosis (aortic peak velocity > 5.0 m/s or mean pressure gradient ≥ 60 mm Hg), no symptoms, and low risk of death during surgery: class IIa recommendation.

Severe stenosis, no symptoms, and an increase in transaortic velocity of 0.3 m/s or more per year on serial testing or in patients considered to be at high risk for rapid disease progression, such as elderly patients with severe calcification: class IIb recommendation (surgery “can be considered”). The threshold to replace the valve is lower for patients who cannot make serial follow-up appointments because they live far away or lack transportation, or because they have problems with compliance.

Surgery for those with left ventricular dysfunction

Echocardiography also provides information on left ventricular function, and patients with left ventricular dysfunction have significantly worse outcomes. Studies have shown substantial differences in survival in patients who had an ejection fraction of less than 50% before valve replacement compared with those with a normal ejection fraction.³

Thus, the ACC/AHA guidelines recommend immediate referral for aortic valve replacement in asymptomatic patients whose left ventricular ejection fraction is less than 50% (class I recommendation, level of evidence B) in the hope of preventing irreversible ventricular dysfunction.⁴

TREADMILL EXERCISE TESTING UNMASKS SYMPTOMS

Treadmill testing is absolutely contraindicated in patients with severe symptomatic aortic stenosis

In the past, severe aortic stenosis was considered a contraindication to stress testing because of concerns of precipitating severe, life-threatening complications. However, studies over the past 10 years have shown that a supervised modified Bruce protocol is safe in patients with severe asymptomatic aortic stenosis.^16,17

However, treadmill exercise testing clearly is absolutely contraindicated in patients with severe symptomatic aortic stenosis because of the risk of syncope or of precipitating a malignant arrhythmia. Nevertheless, it may play an essential role in the workup of a physically active patient with no symptoms.

Symptoms can develop insidiously in patients with chronic valve disease and may often go unrecognized by patients and their physicians. Many patients who state they have no symptoms may actually be subconsciously limiting their exercise to avoid symptoms.

Amato et al¹³ examined the exercise capacity of 66 patients reported to have severe asymptomatic aortic stenosis. Treadmill exercise testing was considered positive in this study if the patient developed symptoms or complex ventricular arrhythmias, had blood pressure that failed to rise by 20 mm Hg, or developed horizontal or down-sloping ST depression (≥ 1 mm in men, ≥ 2 mm in women). Twenty (30.3%) of the 66 patients developed symptoms during exercise testing, and they had a significantly worse prognosis: the 2-year event-free survival rate was only 19% in those with a positive test compared with 85% in those with a negative test.¹³ This study highlights the problem of patients subconsciously reducing their level of activity, thereby masking their true symptoms.

A meta-analysis by Rafique et al¹⁸ found that asymptomatic patients with abnormal results on exercise testing had a risk of cardiac events during follow-up that was eight times higher than normal, and a risk of sudden death 5.5 times higher.

With trials demonstrating that exercise testing is safe and prognostically useful in patients with aortic stenosis, the ACC/AHA guidelines emphasize its role, giving a class I recommendation for aortic valve replacement in patients who develop symptoms on exercise testing, and a class IIa recommendation in asymp­tomatic patients with decreased exercise tolerance or an exercise-related fall in blood pressure (Figure 2).⁴

STRESS ECHOCARDIOGRAPHY

Stress echocardiography has been used since the 1980s to assess the hemodynamic consequences of valvular heart disease, and many studies highlight its prognostic usefulness in patients with asymptomatic aortic stenosis.

In a 2005 study by Lancellotti et al,¹⁹ 69 patients with severe asymptomatic aortic stenosis underwent a symptom-limited bicycle exercise stress test using quantitative Doppler echocardiography both at rest and at peak exercise, and a number of independent predictors of poor outcome (ie, symptoms, aortic valve replacement, death) were identified. These predictors included an abnormal test result, defined as any of the following: angina, dyspnea, ST-segment depression of 2 mm Hg or more, a fall or a small (< 20 mm Hg) rise in systolic blood pressure during the test, an aortic valve area of 0.75 cm² or less, or a mean increase in valve gradient of 18 mm Hg or more.

Subsequently, a multicenter prospective trial assessed the value of exercise stress echocardiography in 186 patients with asymptomatic moderate or severe aortic stenosis.²⁰ A mean increase in the aortic valve gradient of 20 mm Hg or more after exercise was associated with a rate of cardiovascular events (death, aortic valve replacement) 3.8 times higher, independent of other risk factors and whether moderate or severe stenosis was present (Table 1).²⁰

Exercise-induced changes in systolic pulmonary artery pressure, which can be assessed using stress echocardiography, also have prognostic utility. Elevated systolic pulmonary artery pressure (> 50 mm Hg) seems to portend a poorer prognosis^21,22 and a higher mortality rate after valve replacement,²³ making it an independent predictor of hospital mortality and postoperative major adverse cardiovascular and cerebrovascular events (Table 1).

Exercise echocardiography also can be used to assess the patient’s contractile reserve. Left ventricular contractile reserve can be defined as an exercise-induced increase in left ventricular ejection fraction. In a study by Maréchaux et al²⁴ in 50 patients with asymptomatic aortic stenosis and a normal resting left ventricular ejection fraction (> 50%), 40% of patients did not have left ventricular contractile reserve. In fact, their left ventricular ejection fraction decreased with exercise (from 64 ± 10% to 53 ± 12%). The subgroup of patients without contractile reserve developed symptoms more frequently during exercise and had lower event-free survival (Table 1).

Stress echocardiography has recently been introduced into the European Society of Cardiology guidelines, which give a class IIb indication for aortic valve replacement in asymp­tomatic patients who have severe aortic stenosis, a normal ejection fraction, and a greater than 20-mm Hg increase in mean gradient on exercise.⁵ But it has yet to be introduced into the ACC/AHA guidelines as a consideration for surgery.

LEFT VENTRICULAR FUNCTION: BEYOND EJECTION FRACTION

Left ventricular dysfunction is a bad sign for patients with aortic stenosis. Struggling to empty its contents through the narrowed aortic valve, the left ventricle is subjected to increased wall stress and eventually develops hypertrophy. The hypertrophied heart muscle requires more oxygen but receives less perfusion. Eventually, myocardial fibrosis develops, leading to systolic dysfunction and a reduction in the ejection fraction. As described above, patients with asymptomatic aortic stenosis and a left ventricular ejection fraction less than 50% have a poor prognosis,¹⁴ and therefore the ACC/AHA guidelines give this condition a class I recommendation for surgery.⁴

The ejection fraction has limitations as a marker of left ventricular function

However, the ejection fraction has limitations as a marker of left ventricular function. It reflects changes in left ventricular cavity volume but not in the complex structure of the left ventricle. Several studies show that up to one-third of patients with severe aortic stenosis have considerable impairment of intrinsic myocardial systolic function despite a preserved ejection fraction.^8,25,26

Thus, other variables such as left atrial size, left ventricular hypertrophy, myocardial deformation (assessed using strain imaging), and B-type natriuretic peptide (BNP) level may also be considered in assessing the effect of severe aortic stenosis on left ventricular function in the context of a normal ejection fraction (Table 2).

Left ventricular hypertrophy

The development of left ventricular hypertrophy is one of the earliest compensatory responses of the ventricle to the increase in afterload. This leads to impaired myocardial relaxation and reduced myocardial compliance, with resultant diastolic dysfunction with increased filling pressures.

Cioffi et al,²⁷ in a study in 209 patients with severe but asymptomatic aortic stenosis, found that inappropriately high left ventricular mass (> 110% of that expected for body size, sex, and wall stress) portended a 4.5-times higher risk of death, independent of other risk factors.

Severe left ventricular hypertrophy may have a long-term effect on prognosis irrespective of valve replacement. An observational study¹⁴ of 3,049 patients who underwent aortic valve replacement for severe aortic stenosis showed that the 10-year survival rate was 45% in those whose left ventricular mass was greater than 185 g/m², compared with 65% in patients whose left ventricular mass was less than 100 g/m².

Thus, as surgical mortality and morbidity rates decrease, the impact of these structural changes in left ventricular wall thickness may affect the decision to intervene earlier in order to improve longer-term outcomes in select asymptomatic patients with high-risk features.

Left atrial size

Diastolic dysfunction is caused by increased afterload and results in elevated left ventricular end-diastolic pressure and elevated left atrial pressure. The left atrium responds by dilating, which increases the risk of atrial fibrillation.

Lancellotti et al⁸ investigated the negative prognostic implications of a large indexed left atrial area in asymptomatic patients with severe aortic stenosis. They found that patients with an indexed left atrial area greater than 12.2 cm²/m² had a 77% 2-year probability of aortic valve replacement or death.

Beach et al²⁸ examined cardiac remodeling after surgery and found that the left atrial diameter did not decrease after aortic valve replacement, even after left ventricular hypertrophy reversed. This observation has major prognostic implications. Patients with a severely enlarged left atrium (> 5.0 cm in diameter) had considerably lower survival rates than patients with a diameter less than 3.55 cm at 5 years (61% vs 85%) and at 10 years (28% vs 62%) after aortic valve replacement.

Therefore, left atrial size appears to have an important long-term impact on prognosis in patients with aortic stenosis even after aortic valve replacement and adds valuable information when assessing the effect of aortic stenosis on myocardial function.

B-type natriuretic peptide

Natriuretic peptides are cardiac hormones released in response to myocyte stretch. In aortic stenosis, increased afterload induces significant expression of BNP, N-terminal proBNP,²⁹ and atrial natriuretic peptide,³⁰ with numerous studies showing a good correlation between plasma natriuretic peptide levels and severity of aortic stenosis.^31–34

Natriuretic peptides, though not specific, are an easy and low-cost way to assess left ventricular function

Bergler-Klein et al³³ showed that patients with asymptomatic aortic stenosis who developed symptoms during follow-up had higher levels of these biomarkers than patients who remained asymptomatic. Of note, patients with BNP levels lower than 130 pg/mL had significantly better symptom-free survival than those with higher levels, 66% vs 34% at 12 months.

However, these biomarkers are not specific to aortic stenosis and can be elevated in any condition that increases left ventricular stress. Nevertheless, they offer an easy and low-cost way to assess left ventricular function and may give an indication of the total burden of disease on the left ventricle.

Global left ventricular longitudinal strain

In view of the limitations of the left ventricular ejection fraction in identifying changes in the structure of the heart and in early detection of myocardial dysfunction, assessment of myocardial deformation using strain imaging is proving an attractive alternative.

Strain is the normalized, dimensionless measure of deformation of a solid object (such as a segment of myocardium) in response to an applied force or stress.³⁵ A novel echocardiographic technique allows assessment of segmental myocardial deformation and thereby overcomes the limitation of tethering, which limits other echocardiographic techniques in the assessment of systolic function. Strain can be circumferential, longitudinal, or radial and is generally assessed using either tissue Doppler velocities or 2D echocardiographic speckle-tracking techniques. Longitudinal strain has proven to be a more sensitive method than left ventricular ejection fraction in detecting subclinical myocardial dysfunction and is a superior prognosticator in a variety of clinical conditions.^36,37

Abnormal strain develops very early in the disease process and can even be seen in patients with mild aortic stenosis.

A study by Kearney et al³⁸ in 146 patients with various degrees of aortic stenosis (26% mild, 21% moderate, and 53% severe) and preserved left ventricular ejection fraction demonstrated that global longitudinal strain worsened with increasing severity of aortic stenosis. Furthermore, global longitudinal strain was a strong independent predictor of all-cause mortality (hazard ratio 1.38, P < .001).

Similarly, in a study by Lancellotti et al⁸ in 163 patients with at least moderate to severe asymptomatic aortic stenosis, impaired longitudinal myocardial strain was an independent predictor of survival. Patients with longitudinal strain greater than 15.9% had significantly better outcomes than patients with strain of 15.9% or less (4-year survival 63% vs 22%, P < .001).

Hence, left ventricular global longitudinal strain offers an alternative—perhaps a superior alternative—to left ventricular ejection fraction in detecting and quantifying left ventricular dysfunction in asymptomatic aortic stenosis. It is an exciting new marker for the future in aortic stenosis, with a threshold of strain below 15.9% as a possible cutoff for those at higher risk of poorer outcomes.

WHERE ARE WE NOW? WHERE ARE WE GOING?

Aortic valve replacement in patients with severe but asymptomatic aortic stenosis remains a topic of debate, but support is growing for earlier intervention.

Now that concerns over the safety of exercise stress testing in patients with severe asymptomatic aortic stenosis have subsided following multiple studies,^16,17 exercise testing should be performed in patients with asymp­tomatic severe aortic stenosis suspected of having reduced exercise capacity, with stress echocardiography providing added prognostic information through its assessment of exercise-induced changes in mean pressure gradient¹⁹ and systolic pulmonary artery pressure.^21–23

Further study of the newer evaluation techniques is needed to evaluate long-term

Assessing left ventricular function provides important information about prognosis, with left ventricular ejection fraction, left ventricular diameter, left atrial size, BNP, and global longitudinal strain all helping identify asymptomatic patients at higher risk of death. Surgical intervention in asymptomatic patients with severe aortic stenosis may be considered when there is evidence of higher longer-term mortality risk based on reduced functional capacity, excess left ventricular hypertrophy, and abnormal left ventricular function as detected by ancillary methods such as global longitudinal strain and BNP elevation despite a normal left ventricular ejection fraction.

Figure 3 shows a possible algorithm to define which patients would benefit from earlier intervention. However, left ventricular hypertrophy, left atrial diameter, BNP, left ventricular longitudinal strain, and changes in systolic pulmonary artery pressure are not included in the current ACC/AHA guidelines for the management of asymptomatic patients with severe aortic stenosis. Further study is needed to determine whether earlier intervention in those with adverse risk profiles based on the newer evaluation techniques described above leads to better long-term outcomes.

Intervention should especially be considered in those in whom the measured surgical risk is low and in surgical centers at which the mortality rate is low.

Aortic stenosis is the most common valvular heart condition in the developed world, affecting 3% of people between ages 75 and 85¹ and 4% of people over age 85.² Aortic valve replacement remains the only treatment proven to reduce the rates of mortality and morbidity in this condition.³ Under current guidelines,^4,5 the onset of symptoms of exertional angina, syncope, or dyspnea in a patient who has severe aortic stenosis is a class I indication for surgery—ie, surgery should be performed.

However, high-gradient, severe aortic stenosis that is asymptomatic often poses a dilemma. The annual rate of sudden death in patients with this condition is estimated at 1% to 3%,^6–9 but the surgical mortality rate in aortic valve replacement has been as high as 6% in Medicare patients (varying by center and comorbidities).¹⁰ Therefore, the traditional teaching was to not surgically replace the valve in asymptomatic patients, based on an adverse risk-benefit ratio. But with improvements in surgical techniques and prostheses, these rates have been reduced to 2.41% at high-volume centers¹¹ (and to less than 1% at some hospitals),¹² arguing in favor of earlier intervention.

Complicating the issue, transcatheter aortic valve replacement has become widely available, but further investigation into its use in this patient cohort is warranted.

Furthermore, many patients with severe but apparently asymptomatic aortic stenosis and normal left ventricular ejection fraction may actually have impaired exercise capacity, or they may have structural left ventricular changes such as severe hypertrophy or reduction in global strain, which may worsen the long-term survival rate.^13,14

A prospective trial in patients with severe aortic stenosis found that mortality rates were significantly lower in those who underwent surgery early than in those who received conventional treatment, ie, watchful waiting (no specific medical treatment for aortic stenosis is available).¹⁵

Patients with asymptomatic severe aortic stenosis are a diverse group; some have a far worse prognosis than others, with or without surgery.

This paper reviews the guidelines for valve replacement in this patient group and the factors useful in establishing who should be considered for early intervention even if they have no classic symptoms (Figure 1).

SIGNS AND SYMPTOMS OF STENOSIS

Aortic stenosis is often first suspected when a patient presents with angina, dyspnea, and syncope, or when an ejection systolic murmur is heard incidentally on physical examination—typically a high-pitched, crescendo-decrescendo, midsystolic ejection murmur that is best heard at the right upper sternal border and that radiates to the carotid arteries.

Several physical findings may help in assessing the severity of aortic stenosis. In mild stenosis, the murmur peaks in early systole, but as the disease progresses the peak moves later into systole. The corollary of this phenomenon is a weak and delayed carotid upstroke known as “pulsus parvus et tardus.” This can be assessed by palpating the carotid artery while auscultating the heart.

Aortic stenosis is often first suspected when a patient has angina, dyspnea, and syncope or an ejection systolic murmur

The second heart sound becomes progressively softer as the stenosis advances until it is no longer audible. If a fourth heart sound is present, it may be due to concentric left ventricular hypertrophy with reduced left ventricular compliance, and a third heart sound indicates severe left ventricular dysfunction. Both of these findings suggest severe aortic stenosis.

ECHOCARDIOGRAPHIC MEASURES OF SEVERITY

Echocardiography is the best established and most important initial investigation in the assessment of a patient with suspected aortic stenosis. It usually provides accurate information on the severity and the mechanism of stenosis. The following findings indicate severe aortic stenosis:

• Mean pressure gradient > 40 mm Hg
• Peak aortic jet velocity > 4.0 m/s
• Aortic valve area < 1 cm².

RECOMMENDATIONS FOR SURGERY BASED ON SEVERITY AND SYMPTOMS

The American College of Cardiology and American Heart Association (ACC/AHA)⁴ have issued the following recommendations for aortic valve replacement, based on the severity of stenosis and on whether the patient has symptoms (Figure 2):

Severe stenosis, with symptoms: class I recommendation (surgery should be done). Without surgery, these patients have a very poor prognosis, with an overall mortality rate of 75% at 3 years.³

Severe stenosis, no symptoms, in patients undergoing cardiac surgery for another indication (eg, coronary artery bypass grafting, ascending aortic surgery, or surgery on other valves): class I recommendation for concomitant aortic valve replacement.

Moderate stenosis, no symptoms, in patients undergoing cardiac surgery for another indication: class IIa recommendation (ie, aortic valve replacement “is reasonable”).

Very severe stenosis (aortic peak velocity > 5.0 m/s or mean pressure gradient ≥ 60 mm Hg), no symptoms, and low risk of death during surgery: class IIa recommendation.

Severe stenosis, no symptoms, and an increase in transaortic velocity of 0.3 m/s or more per year on serial testing or in patients considered to be at high risk for rapid disease progression, such as elderly patients with severe calcification: class IIb recommendation (surgery “can be considered”). The threshold to replace the valve is lower for patients who cannot make serial follow-up appointments because they live far away or lack transportation, or because they have problems with compliance.

Surgery for those with left ventricular dysfunction

Echocardiography also provides information on left ventricular function, and patients with left ventricular dysfunction have significantly worse outcomes. Studies have shown substantial differences in survival in patients who had an ejection fraction of less than 50% before valve replacement compared with those with a normal ejection fraction.³

Thus, the ACC/AHA guidelines recommend immediate referral for aortic valve replacement in asymptomatic patients whose left ventricular ejection fraction is less than 50% (class I recommendation, level of evidence B) in the hope of preventing irreversible ventricular dysfunction.⁴

TREADMILL EXERCISE TESTING UNMASKS SYMPTOMS

Treadmill testing is absolutely contraindicated in patients with severe symptomatic aortic stenosis

In the past, severe aortic stenosis was considered a contraindication to stress testing because of concerns of precipitating severe, life-threatening complications. However, studies over the past 10 years have shown that a supervised modified Bruce protocol is safe in patients with severe asymptomatic aortic stenosis.^16,17

However, treadmill exercise testing clearly is absolutely contraindicated in patients with severe symptomatic aortic stenosis because of the risk of syncope or of precipitating a malignant arrhythmia. Nevertheless, it may play an essential role in the workup of a physically active patient with no symptoms.

Symptoms can develop insidiously in patients with chronic valve disease and may often go unrecognized by patients and their physicians. Many patients who state they have no symptoms may actually be subconsciously limiting their exercise to avoid symptoms.

Amato et al¹³ examined the exercise capacity of 66 patients reported to have severe asymptomatic aortic stenosis. Treadmill exercise testing was considered positive in this study if the patient developed symptoms or complex ventricular arrhythmias, had blood pressure that failed to rise by 20 mm Hg, or developed horizontal or down-sloping ST depression (≥ 1 mm in men, ≥ 2 mm in women). Twenty (30.3%) of the 66 patients developed symptoms during exercise testing, and they had a significantly worse prognosis: the 2-year event-free survival rate was only 19% in those with a positive test compared with 85% in those with a negative test.¹³ This study highlights the problem of patients subconsciously reducing their level of activity, thereby masking their true symptoms.

A meta-analysis by Rafique et al¹⁸ found that asymptomatic patients with abnormal results on exercise testing had a risk of cardiac events during follow-up that was eight times higher than normal, and a risk of sudden death 5.5 times higher.

With trials demonstrating that exercise testing is safe and prognostically useful in patients with aortic stenosis, the ACC/AHA guidelines emphasize its role, giving a class I recommendation for aortic valve replacement in patients who develop symptoms on exercise testing, and a class IIa recommendation in asymp­tomatic patients with decreased exercise tolerance or an exercise-related fall in blood pressure (Figure 2).⁴

STRESS ECHOCARDIOGRAPHY

Stress echocardiography has been used since the 1980s to assess the hemodynamic consequences of valvular heart disease, and many studies highlight its prognostic usefulness in patients with asymptomatic aortic stenosis.

In a 2005 study by Lancellotti et al,¹⁹ 69 patients with severe asymptomatic aortic stenosis underwent a symptom-limited bicycle exercise stress test using quantitative Doppler echocardiography both at rest and at peak exercise, and a number of independent predictors of poor outcome (ie, symptoms, aortic valve replacement, death) were identified. These predictors included an abnormal test result, defined as any of the following: angina, dyspnea, ST-segment depression of 2 mm Hg or more, a fall or a small (< 20 mm Hg) rise in systolic blood pressure during the test, an aortic valve area of 0.75 cm² or less, or a mean increase in valve gradient of 18 mm Hg or more.

Subsequently, a multicenter prospective trial assessed the value of exercise stress echocardiography in 186 patients with asymptomatic moderate or severe aortic stenosis.²⁰ A mean increase in the aortic valve gradient of 20 mm Hg or more after exercise was associated with a rate of cardiovascular events (death, aortic valve replacement) 3.8 times higher, independent of other risk factors and whether moderate or severe stenosis was present (Table 1).²⁰

Exercise-induced changes in systolic pulmonary artery pressure, which can be assessed using stress echocardiography, also have prognostic utility. Elevated systolic pulmonary artery pressure (> 50 mm Hg) seems to portend a poorer prognosis^21,22 and a higher mortality rate after valve replacement,²³ making it an independent predictor of hospital mortality and postoperative major adverse cardiovascular and cerebrovascular events (Table 1).

Exercise echocardiography also can be used to assess the patient’s contractile reserve. Left ventricular contractile reserve can be defined as an exercise-induced increase in left ventricular ejection fraction. In a study by Maréchaux et al²⁴ in 50 patients with asymptomatic aortic stenosis and a normal resting left ventricular ejection fraction (> 50%), 40% of patients did not have left ventricular contractile reserve. In fact, their left ventricular ejection fraction decreased with exercise (from 64 ± 10% to 53 ± 12%). The subgroup of patients without contractile reserve developed symptoms more frequently during exercise and had lower event-free survival (Table 1).

Stress echocardiography has recently been introduced into the European Society of Cardiology guidelines, which give a class IIb indication for aortic valve replacement in asymp­tomatic patients who have severe aortic stenosis, a normal ejection fraction, and a greater than 20-mm Hg increase in mean gradient on exercise.⁵ But it has yet to be introduced into the ACC/AHA guidelines as a consideration for surgery.

LEFT VENTRICULAR FUNCTION: BEYOND EJECTION FRACTION

Left ventricular dysfunction is a bad sign for patients with aortic stenosis. Struggling to empty its contents through the narrowed aortic valve, the left ventricle is subjected to increased wall stress and eventually develops hypertrophy. The hypertrophied heart muscle requires more oxygen but receives less perfusion. Eventually, myocardial fibrosis develops, leading to systolic dysfunction and a reduction in the ejection fraction. As described above, patients with asymptomatic aortic stenosis and a left ventricular ejection fraction less than 50% have a poor prognosis,¹⁴ and therefore the ACC/AHA guidelines give this condition a class I recommendation for surgery.⁴

The ejection fraction has limitations as a marker of left ventricular function

However, the ejection fraction has limitations as a marker of left ventricular function. It reflects changes in left ventricular cavity volume but not in the complex structure of the left ventricle. Several studies show that up to one-third of patients with severe aortic stenosis have considerable impairment of intrinsic myocardial systolic function despite a preserved ejection fraction.^8,25,26

Thus, other variables such as left atrial size, left ventricular hypertrophy, myocardial deformation (assessed using strain imaging), and B-type natriuretic peptide (BNP) level may also be considered in assessing the effect of severe aortic stenosis on left ventricular function in the context of a normal ejection fraction (Table 2).

Left ventricular hypertrophy

The development of left ventricular hypertrophy is one of the earliest compensatory responses of the ventricle to the increase in afterload. This leads to impaired myocardial relaxation and reduced myocardial compliance, with resultant diastolic dysfunction with increased filling pressures.

Cioffi et al,²⁷ in a study in 209 patients with severe but asymptomatic aortic stenosis, found that inappropriately high left ventricular mass (> 110% of that expected for body size, sex, and wall stress) portended a 4.5-times higher risk of death, independent of other risk factors.

Severe left ventricular hypertrophy may have a long-term effect on prognosis irrespective of valve replacement. An observational study¹⁴ of 3,049 patients who underwent aortic valve replacement for severe aortic stenosis showed that the 10-year survival rate was 45% in those whose left ventricular mass was greater than 185 g/m², compared with 65% in patients whose left ventricular mass was less than 100 g/m².

Thus, as surgical mortality and morbidity rates decrease, the impact of these structural changes in left ventricular wall thickness may affect the decision to intervene earlier in order to improve longer-term outcomes in select asymptomatic patients with high-risk features.

Left atrial size

Diastolic dysfunction is caused by increased afterload and results in elevated left ventricular end-diastolic pressure and elevated left atrial pressure. The left atrium responds by dilating, which increases the risk of atrial fibrillation.

Lancellotti et al⁸ investigated the negative prognostic implications of a large indexed left atrial area in asymptomatic patients with severe aortic stenosis. They found that patients with an indexed left atrial area greater than 12.2 cm²/m² had a 77% 2-year probability of aortic valve replacement or death.

Beach et al²⁸ examined cardiac remodeling after surgery and found that the left atrial diameter did not decrease after aortic valve replacement, even after left ventricular hypertrophy reversed. This observation has major prognostic implications. Patients with a severely enlarged left atrium (> 5.0 cm in diameter) had considerably lower survival rates than patients with a diameter less than 3.55 cm at 5 years (61% vs 85%) and at 10 years (28% vs 62%) after aortic valve replacement.

Therefore, left atrial size appears to have an important long-term impact on prognosis in patients with aortic stenosis even after aortic valve replacement and adds valuable information when assessing the effect of aortic stenosis on myocardial function.

B-type natriuretic peptide

Natriuretic peptides are cardiac hormones released in response to myocyte stretch. In aortic stenosis, increased afterload induces significant expression of BNP, N-terminal proBNP,²⁹ and atrial natriuretic peptide,³⁰ with numerous studies showing a good correlation between plasma natriuretic peptide levels and severity of aortic stenosis.^31–34

Natriuretic peptides, though not specific, are an easy and low-cost way to assess left ventricular function

Bergler-Klein et al³³ showed that patients with asymptomatic aortic stenosis who developed symptoms during follow-up had higher levels of these biomarkers than patients who remained asymptomatic. Of note, patients with BNP levels lower than 130 pg/mL had significantly better symptom-free survival than those with higher levels, 66% vs 34% at 12 months.

However, these biomarkers are not specific to aortic stenosis and can be elevated in any condition that increases left ventricular stress. Nevertheless, they offer an easy and low-cost way to assess left ventricular function and may give an indication of the total burden of disease on the left ventricle.

Global left ventricular longitudinal strain

In view of the limitations of the left ventricular ejection fraction in identifying changes in the structure of the heart and in early detection of myocardial dysfunction, assessment of myocardial deformation using strain imaging is proving an attractive alternative.

Strain is the normalized, dimensionless measure of deformation of a solid object (such as a segment of myocardium) in response to an applied force or stress.³⁵ A novel echocardiographic technique allows assessment of segmental myocardial deformation and thereby overcomes the limitation of tethering, which limits other echocardiographic techniques in the assessment of systolic function. Strain can be circumferential, longitudinal, or radial and is generally assessed using either tissue Doppler velocities or 2D echocardiographic speckle-tracking techniques. Longitudinal strain has proven to be a more sensitive method than left ventricular ejection fraction in detecting subclinical myocardial dysfunction and is a superior prognosticator in a variety of clinical conditions.^36,37

Abnormal strain develops very early in the disease process and can even be seen in patients with mild aortic stenosis.

A study by Kearney et al³⁸ in 146 patients with various degrees of aortic stenosis (26% mild, 21% moderate, and 53% severe) and preserved left ventricular ejection fraction demonstrated that global longitudinal strain worsened with increasing severity of aortic stenosis. Furthermore, global longitudinal strain was a strong independent predictor of all-cause mortality (hazard ratio 1.38, P < .001).

Similarly, in a study by Lancellotti et al⁸ in 163 patients with at least moderate to severe asymptomatic aortic stenosis, impaired longitudinal myocardial strain was an independent predictor of survival. Patients with longitudinal strain greater than 15.9% had significantly better outcomes than patients with strain of 15.9% or less (4-year survival 63% vs 22%, P < .001).

Hence, left ventricular global longitudinal strain offers an alternative—perhaps a superior alternative—to left ventricular ejection fraction in detecting and quantifying left ventricular dysfunction in asymptomatic aortic stenosis. It is an exciting new marker for the future in aortic stenosis, with a threshold of strain below 15.9% as a possible cutoff for those at higher risk of poorer outcomes.

WHERE ARE WE NOW? WHERE ARE WE GOING?

Aortic valve replacement in patients with severe but asymptomatic aortic stenosis remains a topic of debate, but support is growing for earlier intervention.

Now that concerns over the safety of exercise stress testing in patients with severe asymptomatic aortic stenosis have subsided following multiple studies,^16,17 exercise testing should be performed in patients with asymp­tomatic severe aortic stenosis suspected of having reduced exercise capacity, with stress echocardiography providing added prognostic information through its assessment of exercise-induced changes in mean pressure gradient¹⁹ and systolic pulmonary artery pressure.^21–23

Further study of the newer evaluation techniques is needed to evaluate long-term

Assessing left ventricular function provides important information about prognosis, with left ventricular ejection fraction, left ventricular diameter, left atrial size, BNP, and global longitudinal strain all helping identify asymptomatic patients at higher risk of death. Surgical intervention in asymptomatic patients with severe aortic stenosis may be considered when there is evidence of higher longer-term mortality risk based on reduced functional capacity, excess left ventricular hypertrophy, and abnormal left ventricular function as detected by ancillary methods such as global longitudinal strain and BNP elevation despite a normal left ventricular ejection fraction.

Figure 3 shows a possible algorithm to define which patients would benefit from earlier intervention. However, left ventricular hypertrophy, left atrial diameter, BNP, left ventricular longitudinal strain, and changes in systolic pulmonary artery pressure are not included in the current ACC/AHA guidelines for the management of asymptomatic patients with severe aortic stenosis. Further study is needed to determine whether earlier intervention in those with adverse risk profiles based on the newer evaluation techniques described above leads to better long-term outcomes.

Intervention should especially be considered in those in whom the measured surgical risk is low and in surgical centers at which the mortality rate is low.

Aortic stenosis is the most common valvular heart condition in the developed world, affecting 3% of people between ages 75 and 85¹ and 4% of people over age 85.² Aortic valve replacement remains the only treatment proven to reduce the rates of mortality and morbidity in this condition.³ Under current guidelines,^4,5 the onset of symptoms of exertional angina, syncope, or dyspnea in a patient who has severe aortic stenosis is a class I indication for surgery—ie, surgery should be performed.

However, high-gradient, severe aortic stenosis that is asymptomatic often poses a dilemma. The annual rate of sudden death in patients with this condition is estimated at 1% to 3%,^6–9 but the surgical mortality rate in aortic valve replacement has been as high as 6% in Medicare patients (varying by center and comorbidities).¹⁰ Therefore, the traditional teaching was to not surgically replace the valve in asymptomatic patients, based on an adverse risk-benefit ratio. But with improvements in surgical techniques and prostheses, these rates have been reduced to 2.41% at high-volume centers¹¹ (and to less than 1% at some hospitals),¹² arguing in favor of earlier intervention.

Complicating the issue, transcatheter aortic valve replacement has become widely available, but further investigation into its use in this patient cohort is warranted.

Furthermore, many patients with severe but apparently asymptomatic aortic stenosis and normal left ventricular ejection fraction may actually have impaired exercise capacity, or they may have structural left ventricular changes such as severe hypertrophy or reduction in global strain, which may worsen the long-term survival rate.^13,14

A prospective trial in patients with severe aortic stenosis found that mortality rates were significantly lower in those who underwent surgery early than in those who received conventional treatment, ie, watchful waiting (no specific medical treatment for aortic stenosis is available).¹⁵

Patients with asymptomatic severe aortic stenosis are a diverse group; some have a far worse prognosis than others, with or without surgery.

This paper reviews the guidelines for valve replacement in this patient group and the factors useful in establishing who should be considered for early intervention even if they have no classic symptoms (Figure 1).

SIGNS AND SYMPTOMS OF STENOSIS

Aortic stenosis is often first suspected when a patient presents with angina, dyspnea, and syncope, or when an ejection systolic murmur is heard incidentally on physical examination—typically a high-pitched, crescendo-decrescendo, midsystolic ejection murmur that is best heard at the right upper sternal border and that radiates to the carotid arteries.

Several physical findings may help in assessing the severity of aortic stenosis. In mild stenosis, the murmur peaks in early systole, but as the disease progresses the peak moves later into systole. The corollary of this phenomenon is a weak and delayed carotid upstroke known as “pulsus parvus et tardus.” This can be assessed by palpating the carotid artery while auscultating the heart.

Aortic stenosis is often first suspected when a patient has angina, dyspnea, and syncope or an ejection systolic murmur

The second heart sound becomes progressively softer as the stenosis advances until it is no longer audible. If a fourth heart sound is present, it may be due to concentric left ventricular hypertrophy with reduced left ventricular compliance, and a third heart sound indicates severe left ventricular dysfunction. Both of these findings suggest severe aortic stenosis.

ECHOCARDIOGRAPHIC MEASURES OF SEVERITY

Echocardiography is the best established and most important initial investigation in the assessment of a patient with suspected aortic stenosis. It usually provides accurate information on the severity and the mechanism of stenosis. The following findings indicate severe aortic stenosis:

• Mean pressure gradient > 40 mm Hg
• Peak aortic jet velocity > 4.0 m/s
• Aortic valve area < 1 cm².

RECOMMENDATIONS FOR SURGERY BASED ON SEVERITY AND SYMPTOMS

The American College of Cardiology and American Heart Association (ACC/AHA)⁴ have issued the following recommendations for aortic valve replacement, based on the severity of stenosis and on whether the patient has symptoms (Figure 2):

Severe stenosis, with symptoms: class I recommendation (surgery should be done). Without surgery, these patients have a very poor prognosis, with an overall mortality rate of 75% at 3 years.³

Severe stenosis, no symptoms, in patients undergoing cardiac surgery for another indication (eg, coronary artery bypass grafting, ascending aortic surgery, or surgery on other valves): class I recommendation for concomitant aortic valve replacement.

Moderate stenosis, no symptoms, in patients undergoing cardiac surgery for another indication: class IIa recommendation (ie, aortic valve replacement “is reasonable”).

Very severe stenosis (aortic peak velocity > 5.0 m/s or mean pressure gradient ≥ 60 mm Hg), no symptoms, and low risk of death during surgery: class IIa recommendation.

Severe stenosis, no symptoms, and an increase in transaortic velocity of 0.3 m/s or more per year on serial testing or in patients considered to be at high risk for rapid disease progression, such as elderly patients with severe calcification: class IIb recommendation (surgery “can be considered”). The threshold to replace the valve is lower for patients who cannot make serial follow-up appointments because they live far away or lack transportation, or because they have problems with compliance.

Surgery for those with left ventricular dysfunction

Echocardiography also provides information on left ventricular function, and patients with left ventricular dysfunction have significantly worse outcomes. Studies have shown substantial differences in survival in patients who had an ejection fraction of less than 50% before valve replacement compared with those with a normal ejection fraction.³

Thus, the ACC/AHA guidelines recommend immediate referral for aortic valve replacement in asymptomatic patients whose left ventricular ejection fraction is less than 50% (class I recommendation, level of evidence B) in the hope of preventing irreversible ventricular dysfunction.⁴

TREADMILL EXERCISE TESTING UNMASKS SYMPTOMS

Treadmill testing is absolutely contraindicated in patients with severe symptomatic aortic stenosis

In the past, severe aortic stenosis was considered a contraindication to stress testing because of concerns of precipitating severe, life-threatening complications. However, studies over the past 10 years have shown that a supervised modified Bruce protocol is safe in patients with severe asymptomatic aortic stenosis.^16,17

However, treadmill exercise testing clearly is absolutely contraindicated in patients with severe symptomatic aortic stenosis because of the risk of syncope or of precipitating a malignant arrhythmia. Nevertheless, it may play an essential role in the workup of a physically active patient with no symptoms.

Symptoms can develop insidiously in patients with chronic valve disease and may often go unrecognized by patients and their physicians. Many patients who state they have no symptoms may actually be subconsciously limiting their exercise to avoid symptoms.

Amato et al¹³ examined the exercise capacity of 66 patients reported to have severe asymptomatic aortic stenosis. Treadmill exercise testing was considered positive in this study if the patient developed symptoms or complex ventricular arrhythmias, had blood pressure that failed to rise by 20 mm Hg, or developed horizontal or down-sloping ST depression (≥ 1 mm in men, ≥ 2 mm in women). Twenty (30.3%) of the 66 patients developed symptoms during exercise testing, and they had a significantly worse prognosis: the 2-year event-free survival rate was only 19% in those with a positive test compared with 85% in those with a negative test.¹³ This study highlights the problem of patients subconsciously reducing their level of activity, thereby masking their true symptoms.

A meta-analysis by Rafique et al¹⁸ found that asymptomatic patients with abnormal results on exercise testing had a risk of cardiac events during follow-up that was eight times higher than normal, and a risk of sudden death 5.5 times higher.

With trials demonstrating that exercise testing is safe and prognostically useful in patients with aortic stenosis, the ACC/AHA guidelines emphasize its role, giving a class I recommendation for aortic valve replacement in patients who develop symptoms on exercise testing, and a class IIa recommendation in asymp­tomatic patients with decreased exercise tolerance or an exercise-related fall in blood pressure (Figure 2).⁴

STRESS ECHOCARDIOGRAPHY

Stress echocardiography has been used since the 1980s to assess the hemodynamic consequences of valvular heart disease, and many studies highlight its prognostic usefulness in patients with asymptomatic aortic stenosis.

In a 2005 study by Lancellotti et al,¹⁹ 69 patients with severe asymptomatic aortic stenosis underwent a symptom-limited bicycle exercise stress test using quantitative Doppler echocardiography both at rest and at peak exercise, and a number of independent predictors of poor outcome (ie, symptoms, aortic valve replacement, death) were identified. These predictors included an abnormal test result, defined as any of the following: angina, dyspnea, ST-segment depression of 2 mm Hg or more, a fall or a small (< 20 mm Hg) rise in systolic blood pressure during the test, an aortic valve area of 0.75 cm² or less, or a mean increase in valve gradient of 18 mm Hg or more.

Subsequently, a multicenter prospective trial assessed the value of exercise stress echocardiography in 186 patients with asymptomatic moderate or severe aortic stenosis.²⁰ A mean increase in the aortic valve gradient of 20 mm Hg or more after exercise was associated with a rate of cardiovascular events (death, aortic valve replacement) 3.8 times higher, independent of other risk factors and whether moderate or severe stenosis was present (Table 1).²⁰

Exercise-induced changes in systolic pulmonary artery pressure, which can be assessed using stress echocardiography, also have prognostic utility. Elevated systolic pulmonary artery pressure (> 50 mm Hg) seems to portend a poorer prognosis^21,22 and a higher mortality rate after valve replacement,²³ making it an independent predictor of hospital mortality and postoperative major adverse cardiovascular and cerebrovascular events (Table 1).

Exercise echocardiography also can be used to assess the patient’s contractile reserve. Left ventricular contractile reserve can be defined as an exercise-induced increase in left ventricular ejection fraction. In a study by Maréchaux et al²⁴ in 50 patients with asymptomatic aortic stenosis and a normal resting left ventricular ejection fraction (> 50%), 40% of patients did not have left ventricular contractile reserve. In fact, their left ventricular ejection fraction decreased with exercise (from 64 ± 10% to 53 ± 12%). The subgroup of patients without contractile reserve developed symptoms more frequently during exercise and had lower event-free survival (Table 1).

Stress echocardiography has recently been introduced into the European Society of Cardiology guidelines, which give a class IIb indication for aortic valve replacement in asymp­tomatic patients who have severe aortic stenosis, a normal ejection fraction, and a greater than 20-mm Hg increase in mean gradient on exercise.⁵ But it has yet to be introduced into the ACC/AHA guidelines as a consideration for surgery.

LEFT VENTRICULAR FUNCTION: BEYOND EJECTION FRACTION

Left ventricular dysfunction is a bad sign for patients with aortic stenosis. Struggling to empty its contents through the narrowed aortic valve, the left ventricle is subjected to increased wall stress and eventually develops hypertrophy. The hypertrophied heart muscle requires more oxygen but receives less perfusion. Eventually, myocardial fibrosis develops, leading to systolic dysfunction and a reduction in the ejection fraction. As described above, patients with asymptomatic aortic stenosis and a left ventricular ejection fraction less than 50% have a poor prognosis,¹⁴ and therefore the ACC/AHA guidelines give this condition a class I recommendation for surgery.⁴

The ejection fraction has limitations as a marker of left ventricular function

However, the ejection fraction has limitations as a marker of left ventricular function. It reflects changes in left ventricular cavity volume but not in the complex structure of the left ventricle. Several studies show that up to one-third of patients with severe aortic stenosis have considerable impairment of intrinsic myocardial systolic function despite a preserved ejection fraction.^8,25,26

Thus, other variables such as left atrial size, left ventricular hypertrophy, myocardial deformation (assessed using strain imaging), and B-type natriuretic peptide (BNP) level may also be considered in assessing the effect of severe aortic stenosis on left ventricular function in the context of a normal ejection fraction (Table 2).

Left ventricular hypertrophy

The development of left ventricular hypertrophy is one of the earliest compensatory responses of the ventricle to the increase in afterload. This leads to impaired myocardial relaxation and reduced myocardial compliance, with resultant diastolic dysfunction with increased filling pressures.

Cioffi et al,²⁷ in a study in 209 patients with severe but asymptomatic aortic stenosis, found that inappropriately high left ventricular mass (> 110% of that expected for body size, sex, and wall stress) portended a 4.5-times higher risk of death, independent of other risk factors.

Severe left ventricular hypertrophy may have a long-term effect on prognosis irrespective of valve replacement. An observational study¹⁴ of 3,049 patients who underwent aortic valve replacement for severe aortic stenosis showed that the 10-year survival rate was 45% in those whose left ventricular mass was greater than 185 g/m², compared with 65% in patients whose left ventricular mass was less than 100 g/m².

Thus, as surgical mortality and morbidity rates decrease, the impact of these structural changes in left ventricular wall thickness may affect the decision to intervene earlier in order to improve longer-term outcomes in select asymptomatic patients with high-risk features.

Left atrial size

Diastolic dysfunction is caused by increased afterload and results in elevated left ventricular end-diastolic pressure and elevated left atrial pressure. The left atrium responds by dilating, which increases the risk of atrial fibrillation.

Lancellotti et al⁸ investigated the negative prognostic implications of a large indexed left atrial area in asymptomatic patients with severe aortic stenosis. They found that patients with an indexed left atrial area greater than 12.2 cm²/m² had a 77% 2-year probability of aortic valve replacement or death.

Beach et al²⁸ examined cardiac remodeling after surgery and found that the left atrial diameter did not decrease after aortic valve replacement, even after left ventricular hypertrophy reversed. This observation has major prognostic implications. Patients with a severely enlarged left atrium (> 5.0 cm in diameter) had considerably lower survival rates than patients with a diameter less than 3.55 cm at 5 years (61% vs 85%) and at 10 years (28% vs 62%) after aortic valve replacement.

Therefore, left atrial size appears to have an important long-term impact on prognosis in patients with aortic stenosis even after aortic valve replacement and adds valuable information when assessing the effect of aortic stenosis on myocardial function.

B-type natriuretic peptide

Natriuretic peptides are cardiac hormones released in response to myocyte stretch. In aortic stenosis, increased afterload induces significant expression of BNP, N-terminal proBNP,²⁹ and atrial natriuretic peptide,³⁰ with numerous studies showing a good correlation between plasma natriuretic peptide levels and severity of aortic stenosis.^31–34

Natriuretic peptides, though not specific, are an easy and low-cost way to assess left ventricular function

Bergler-Klein et al³³ showed that patients with asymptomatic aortic stenosis who developed symptoms during follow-up had higher levels of these biomarkers than patients who remained asymptomatic. Of note, patients with BNP levels lower than 130 pg/mL had significantly better symptom-free survival than those with higher levels, 66% vs 34% at 12 months.

However, these biomarkers are not specific to aortic stenosis and can be elevated in any condition that increases left ventricular stress. Nevertheless, they offer an easy and low-cost way to assess left ventricular function and may give an indication of the total burden of disease on the left ventricle.

Global left ventricular longitudinal strain

In view of the limitations of the left ventricular ejection fraction in identifying changes in the structure of the heart and in early detection of myocardial dysfunction, assessment of myocardial deformation using strain imaging is proving an attractive alternative.

Strain is the normalized, dimensionless measure of deformation of a solid object (such as a segment of myocardium) in response to an applied force or stress.³⁵ A novel echocardiographic technique allows assessment of segmental myocardial deformation and thereby overcomes the limitation of tethering, which limits other echocardiographic techniques in the assessment of systolic function. Strain can be circumferential, longitudinal, or radial and is generally assessed using either tissue Doppler velocities or 2D echocardiographic speckle-tracking techniques. Longitudinal strain has proven to be a more sensitive method than left ventricular ejection fraction in detecting subclinical myocardial dysfunction and is a superior prognosticator in a variety of clinical conditions.^36,37

Abnormal strain develops very early in the disease process and can even be seen in patients with mild aortic stenosis.

A study by Kearney et al³⁸ in 146 patients with various degrees of aortic stenosis (26% mild, 21% moderate, and 53% severe) and preserved left ventricular ejection fraction demonstrated that global longitudinal strain worsened with increasing severity of aortic stenosis. Furthermore, global longitudinal strain was a strong independent predictor of all-cause mortality (hazard ratio 1.38, P < .001).

Similarly, in a study by Lancellotti et al⁸ in 163 patients with at least moderate to severe asymptomatic aortic stenosis, impaired longitudinal myocardial strain was an independent predictor of survival. Patients with longitudinal strain greater than 15.9% had significantly better outcomes than patients with strain of 15.9% or less (4-year survival 63% vs 22%, P < .001).

Hence, left ventricular global longitudinal strain offers an alternative—perhaps a superior alternative—to left ventricular ejection fraction in detecting and quantifying left ventricular dysfunction in asymptomatic aortic stenosis. It is an exciting new marker for the future in aortic stenosis, with a threshold of strain below 15.9% as a possible cutoff for those at higher risk of poorer outcomes.

WHERE ARE WE NOW? WHERE ARE WE GOING?

Aortic valve replacement in patients with severe but asymptomatic aortic stenosis remains a topic of debate, but support is growing for earlier intervention.

Now that concerns over the safety of exercise stress testing in patients with severe asymptomatic aortic stenosis have subsided following multiple studies,^16,17 exercise testing should be performed in patients with asymp­tomatic severe aortic stenosis suspected of having reduced exercise capacity, with stress echocardiography providing added prognostic information through its assessment of exercise-induced changes in mean pressure gradient¹⁹ and systolic pulmonary artery pressure.^21–23

Further study of the newer evaluation techniques is needed to evaluate long-term

Assessing left ventricular function provides important information about prognosis, with left ventricular ejection fraction, left ventricular diameter, left atrial size, BNP, and global longitudinal strain all helping identify asymptomatic patients at higher risk of death. Surgical intervention in asymptomatic patients with severe aortic stenosis may be considered when there is evidence of higher longer-term mortality risk based on reduced functional capacity, excess left ventricular hypertrophy, and abnormal left ventricular function as detected by ancillary methods such as global longitudinal strain and BNP elevation despite a normal left ventricular ejection fraction.

Figure 3 shows a possible algorithm to define which patients would benefit from earlier intervention. However, left ventricular hypertrophy, left atrial diameter, BNP, left ventricular longitudinal strain, and changes in systolic pulmonary artery pressure are not included in the current ACC/AHA guidelines for the management of asymptomatic patients with severe aortic stenosis. Further study is needed to determine whether earlier intervention in those with adverse risk profiles based on the newer evaluation techniques described above leads to better long-term outcomes.

Intervention should especially be considered in those in whom the measured surgical risk is low and in surgical centers at which the mortality rate is low.

A 72-year-old man underwent elective ambulatory arthroscopic repair of the right shoulder rotator cuff. To manage postoperative pain, a supraclavicular catheter was placed for brachial plexus block, and he was sent home with a ropivacaine infusion pump.

The next day, he presented to the emergency department with right-sided chest pain and mild shortness of breath. He had normal vital signs and adequate oxygen saturation on room air. On physical examination, breath sounds were decreased at the right lung base, and chest radiography (Figure 1) revealed an isolated elevated right hemidiaphragm, a clear indication of phrenic nerve paralysis from local infiltration of the infusion.

The ropivacaine infusion was stopped, and the supraclavicular catheter was removed under anesthesia. He was admitted to the hospital for observation, and over the course of 8 to 12 hours his shortness of breath resolved, and his findings on lung examination normalized. Repeat chest radiography 24 hours after his emergency room presentation showed regular positioning of his diaphragm (Figure 2).

RECOGNIZING AND MANAGING PHRENIC NERVE PARALYSIS

The scenario described here illustrates the importance of recognizing symptomatic phrenic nerve paralysis as a result of local infiltration of anesthetic from supraclavicular brachial plexus block. Regional anesthesia is commonly used for perioperative analgesia for minor shoulder surgeries. Because these blocks anesthetize the trunks formed by the C5–T1 nerve roots, infiltration of the anesthetic agent to the proximal nerve roots resulting in phrenic nerve paralysis is a common complication.

Although phrenic nerve paralysis has been reported to some degree in nearly all patients, reports of significant shortness of breath and radiographic evidence of hemidiaphragm are few.^1–4 When it occurs, the analgesic regimen must be changed from regional anesthesia to oral or parenteral pain medications. Resolution of symptoms and radiographic abnormalities usually occurs spontaneously.

When available, an ultrasonographically guided approach for supraclavicular brachial plexus blocks is preferred over a blind approach and is associated with a higher success rate and a lower rate of complications.^5,6

A potentially life-threatening complication of brachial plexus block is pneumothorax.

Contraindications to brachial plexus block include severe lung disease and previous surgery or interventions with the potential for phrenic nerve injury that could result in bilateral paralysis of the diaphragm. Ultimately, preprocedural chest radiography in selected patients at high risk should be considered to mitigate this risk.

A 72-year-old man underwent elective ambulatory arthroscopic repair of the right shoulder rotator cuff. To manage postoperative pain, a supraclavicular catheter was placed for brachial plexus block, and he was sent home with a ropivacaine infusion pump.

The next day, he presented to the emergency department with right-sided chest pain and mild shortness of breath. He had normal vital signs and adequate oxygen saturation on room air. On physical examination, breath sounds were decreased at the right lung base, and chest radiography (Figure 1) revealed an isolated elevated right hemidiaphragm, a clear indication of phrenic nerve paralysis from local infiltration of the infusion.

The ropivacaine infusion was stopped, and the supraclavicular catheter was removed under anesthesia. He was admitted to the hospital for observation, and over the course of 8 to 12 hours his shortness of breath resolved, and his findings on lung examination normalized. Repeat chest radiography 24 hours after his emergency room presentation showed regular positioning of his diaphragm (Figure 2).

RECOGNIZING AND MANAGING PHRENIC NERVE PARALYSIS

The scenario described here illustrates the importance of recognizing symptomatic phrenic nerve paralysis as a result of local infiltration of anesthetic from supraclavicular brachial plexus block. Regional anesthesia is commonly used for perioperative analgesia for minor shoulder surgeries. Because these blocks anesthetize the trunks formed by the C5–T1 nerve roots, infiltration of the anesthetic agent to the proximal nerve roots resulting in phrenic nerve paralysis is a common complication.

Although phrenic nerve paralysis has been reported to some degree in nearly all patients, reports of significant shortness of breath and radiographic evidence of hemidiaphragm are few.^1–4 When it occurs, the analgesic regimen must be changed from regional anesthesia to oral or parenteral pain medications. Resolution of symptoms and radiographic abnormalities usually occurs spontaneously.

When available, an ultrasonographically guided approach for supraclavicular brachial plexus blocks is preferred over a blind approach and is associated with a higher success rate and a lower rate of complications.^5,6

A potentially life-threatening complication of brachial plexus block is pneumothorax.

Contraindications to brachial plexus block include severe lung disease and previous surgery or interventions with the potential for phrenic nerve injury that could result in bilateral paralysis of the diaphragm. Ultimately, preprocedural chest radiography in selected patients at high risk should be considered to mitigate this risk.

A 72-year-old man underwent elective ambulatory arthroscopic repair of the right shoulder rotator cuff. To manage postoperative pain, a supraclavicular catheter was placed for brachial plexus block, and he was sent home with a ropivacaine infusion pump.

The next day, he presented to the emergency department with right-sided chest pain and mild shortness of breath. He had normal vital signs and adequate oxygen saturation on room air. On physical examination, breath sounds were decreased at the right lung base, and chest radiography (Figure 1) revealed an isolated elevated right hemidiaphragm, a clear indication of phrenic nerve paralysis from local infiltration of the infusion.

The ropivacaine infusion was stopped, and the supraclavicular catheter was removed under anesthesia. He was admitted to the hospital for observation, and over the course of 8 to 12 hours his shortness of breath resolved, and his findings on lung examination normalized. Repeat chest radiography 24 hours after his emergency room presentation showed regular positioning of his diaphragm (Figure 2).

RECOGNIZING AND MANAGING PHRENIC NERVE PARALYSIS

The scenario described here illustrates the importance of recognizing symptomatic phrenic nerve paralysis as a result of local infiltration of anesthetic from supraclavicular brachial plexus block. Regional anesthesia is commonly used for perioperative analgesia for minor shoulder surgeries. Because these blocks anesthetize the trunks formed by the C5–T1 nerve roots, infiltration of the anesthetic agent to the proximal nerve roots resulting in phrenic nerve paralysis is a common complication.

Although phrenic nerve paralysis has been reported to some degree in nearly all patients, reports of significant shortness of breath and radiographic evidence of hemidiaphragm are few.^1–4 When it occurs, the analgesic regimen must be changed from regional anesthesia to oral or parenteral pain medications. Resolution of symptoms and radiographic abnormalities usually occurs spontaneously.

When available, an ultrasonographically guided approach for supraclavicular brachial plexus blocks is preferred over a blind approach and is associated with a higher success rate and a lower rate of complications.^5,6

A potentially life-threatening complication of brachial plexus block is pneumothorax.

Contraindications to brachial plexus block include severe lung disease and previous surgery or interventions with the potential for phrenic nerve injury that could result in bilateral paralysis of the diaphragm. Ultimately, preprocedural chest radiography in selected patients at high risk should be considered to mitigate this risk.

Receiving anesthesia services while undergoing a colonoscopy may not be in your patients’ best interest, as doing so could significantly increase the likelihood of patients experiencing serious complications within 30 days of the procedure.

This is according to a new study published in the April issue of Gastroenterology, in which Dr. Karen J. Wernli and her coinvestigators analyzed claims data, collected from the Truven Health MarketScan Research Database, related to 3,168,228 colonoscopy procedures that took place between 2008 and 2011, to determine whether patients who received anesthesia were at a higher risk of developing complications after the procedure (doi: 10.1053/j.gastro.2015.12.018).

Source: American Gastroenterological Association

“The involvement of anesthesia services for colonoscopy sedation, mainly to administer propofol, has increased accordingly, from 11.0% of colonoscopies in 2001 to 23.4% in 2006, with projections of more than 50% in 2015,” wrote Dr. Wernli of the Group Health Research Institute in Seattle, and her coauthors. “Whether the use of propofol is associated with higher rates of short-term complications compared with standard sedation is not well understood.”

Men and women whose data was included in the study were between 40 and 64 years of age; men accounted for 46.8% of those receiving standard sedation (53.2% women) and 46.5% of those receiving anesthesia services (53.5% women). A total of 4,939,993 individuals were initially screened for enrollment, with 39,784 excluded because of a previous colorectal cancer diagnosis, 240,038 for “noncancer exclusions,” and 1,491,943 for being enrolled in the study less than 1 year.

Standard sedation was done in 2,079,784 (65.6%) of the procedures included in the study, while the other 1,088,444 (34.4%) colonoscopies involved anesthesia services. Use of anesthesia services resulted in a 13% increase in likelihood for patients to experience some kind of complication within 30 days of colonoscopy (95% confidence interval, 1.12-1.14). The most common complications were perforation (odds ratio, 1.07; 95% CI, 1.00-1.15), hemorrhage (OR, 1.28; 95% CI, 1.27-1.30), abdominal pain (OR, 1.07; 95% CI, 1.05-1.08), complications secondary to anesthesia (OR, 1.15; 95% CI, 1.05-1.28), and “stroke and other central nervous system events” (OR, 1.04; 95% CI, 1.00-1.08).

Analysis of geographic distribution of colonoscopies performed with and without anesthesia services showed that all areas of the United States had a higher likelihood of postcolonoscopy complications associated with anesthesia except in the Southeast, where there was no association between the two. Additionally, in the western U.S., use of anesthesia services was less common than in any other geographic area, but was associated with a staggering 60% higher chance of complication within 30 days for patients who did opt for it.

“Although the use of anesthesia agents can directly impact colonoscopy outcomes, it is not solely the anesthesia agent that could lead to additional complications,” the study authors wrote. “In the absence of patient feedback, increased colonic-wall tension from colonoscopy pressure may not be identified by the endoscopist, and, consistent with our results, could lead to increased risks of colonic complications, such as perforation and abdominal pain.”

Dr. Wernli and her coauthors did not report any relevant financial disclosures.

[email protected]

Receiving anesthesia services while undergoing a colonoscopy may not be in your patients’ best interest, as doing so could significantly increase the likelihood of patients experiencing serious complications within 30 days of the procedure.

This is according to a new study published in the April issue of Gastroenterology, in which Dr. Karen J. Wernli and her coinvestigators analyzed claims data, collected from the Truven Health MarketScan Research Database, related to 3,168,228 colonoscopy procedures that took place between 2008 and 2011, to determine whether patients who received anesthesia were at a higher risk of developing complications after the procedure (doi: 10.1053/j.gastro.2015.12.018).

Source: American Gastroenterological Association

“The involvement of anesthesia services for colonoscopy sedation, mainly to administer propofol, has increased accordingly, from 11.0% of colonoscopies in 2001 to 23.4% in 2006, with projections of more than 50% in 2015,” wrote Dr. Wernli of the Group Health Research Institute in Seattle, and her coauthors. “Whether the use of propofol is associated with higher rates of short-term complications compared with standard sedation is not well understood.”

Men and women whose data was included in the study were between 40 and 64 years of age; men accounted for 46.8% of those receiving standard sedation (53.2% women) and 46.5% of those receiving anesthesia services (53.5% women). A total of 4,939,993 individuals were initially screened for enrollment, with 39,784 excluded because of a previous colorectal cancer diagnosis, 240,038 for “noncancer exclusions,” and 1,491,943 for being enrolled in the study less than 1 year.

Standard sedation was done in 2,079,784 (65.6%) of the procedures included in the study, while the other 1,088,444 (34.4%) colonoscopies involved anesthesia services. Use of anesthesia services resulted in a 13% increase in likelihood for patients to experience some kind of complication within 30 days of colonoscopy (95% confidence interval, 1.12-1.14). The most common complications were perforation (odds ratio, 1.07; 95% CI, 1.00-1.15), hemorrhage (OR, 1.28; 95% CI, 1.27-1.30), abdominal pain (OR, 1.07; 95% CI, 1.05-1.08), complications secondary to anesthesia (OR, 1.15; 95% CI, 1.05-1.28), and “stroke and other central nervous system events” (OR, 1.04; 95% CI, 1.00-1.08).

Analysis of geographic distribution of colonoscopies performed with and without anesthesia services showed that all areas of the United States had a higher likelihood of postcolonoscopy complications associated with anesthesia except in the Southeast, where there was no association between the two. Additionally, in the western U.S., use of anesthesia services was less common than in any other geographic area, but was associated with a staggering 60% higher chance of complication within 30 days for patients who did opt for it.

“Although the use of anesthesia agents can directly impact colonoscopy outcomes, it is not solely the anesthesia agent that could lead to additional complications,” the study authors wrote. “In the absence of patient feedback, increased colonic-wall tension from colonoscopy pressure may not be identified by the endoscopist, and, consistent with our results, could lead to increased risks of colonic complications, such as perforation and abdominal pain.”

Dr. Wernli and her coauthors did not report any relevant financial disclosures.

[email protected]

Receiving anesthesia services while undergoing a colonoscopy may not be in your patients’ best interest, as doing so could significantly increase the likelihood of patients experiencing serious complications within 30 days of the procedure.

This is according to a new study published in the April issue of Gastroenterology, in which Dr. Karen J. Wernli and her coinvestigators analyzed claims data, collected from the Truven Health MarketScan Research Database, related to 3,168,228 colonoscopy procedures that took place between 2008 and 2011, to determine whether patients who received anesthesia were at a higher risk of developing complications after the procedure (doi: 10.1053/j.gastro.2015.12.018).

Source: American Gastroenterological Association

“The involvement of anesthesia services for colonoscopy sedation, mainly to administer propofol, has increased accordingly, from 11.0% of colonoscopies in 2001 to 23.4% in 2006, with projections of more than 50% in 2015,” wrote Dr. Wernli of the Group Health Research Institute in Seattle, and her coauthors. “Whether the use of propofol is associated with higher rates of short-term complications compared with standard sedation is not well understood.”

Men and women whose data was included in the study were between 40 and 64 years of age; men accounted for 46.8% of those receiving standard sedation (53.2% women) and 46.5% of those receiving anesthesia services (53.5% women). A total of 4,939,993 individuals were initially screened for enrollment, with 39,784 excluded because of a previous colorectal cancer diagnosis, 240,038 for “noncancer exclusions,” and 1,491,943 for being enrolled in the study less than 1 year.

Standard sedation was done in 2,079,784 (65.6%) of the procedures included in the study, while the other 1,088,444 (34.4%) colonoscopies involved anesthesia services. Use of anesthesia services resulted in a 13% increase in likelihood for patients to experience some kind of complication within 30 days of colonoscopy (95% confidence interval, 1.12-1.14). The most common complications were perforation (odds ratio, 1.07; 95% CI, 1.00-1.15), hemorrhage (OR, 1.28; 95% CI, 1.27-1.30), abdominal pain (OR, 1.07; 95% CI, 1.05-1.08), complications secondary to anesthesia (OR, 1.15; 95% CI, 1.05-1.28), and “stroke and other central nervous system events” (OR, 1.04; 95% CI, 1.00-1.08).

Analysis of geographic distribution of colonoscopies performed with and without anesthesia services showed that all areas of the United States had a higher likelihood of postcolonoscopy complications associated with anesthesia except in the Southeast, where there was no association between the two. Additionally, in the western U.S., use of anesthesia services was less common than in any other geographic area, but was associated with a staggering 60% higher chance of complication within 30 days for patients who did opt for it.

“Although the use of anesthesia agents can directly impact colonoscopy outcomes, it is not solely the anesthesia agent that could lead to additional complications,” the study authors wrote. “In the absence of patient feedback, increased colonic-wall tension from colonoscopy pressure may not be identified by the endoscopist, and, consistent with our results, could lead to increased risks of colonic complications, such as perforation and abdominal pain.”

Dr. Wernli and her coauthors did not report any relevant financial disclosures.

[email protected]