Jeffrey S. Eisenberg

The rate of change in forced expiratory volume in 1 second among patients with chronic obstructive pulmonary disease is highly variable, with the greatest rates of decline occurring among current smokers, patients with bronchodilator reversibility, and those with emphysema, according to an analysis of data from the ECLIPSE observational study reported online Sept. 26 in the New England Journal of Medicine.

Research in the 1970s established that patients with COPD experience an accelerated decline in FEV₁, yet few longitudinal studies have provided detailed data about this decline. Also, none have provided information about FEV₁ in specific subgroups of patients with COPD or according to levels of specific biomarkers.

Dr. Jørgen Vestbo of the University of Copenhagen and his colleagues analyzed data collected for the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, which included 2,163 patients aged 40-75 years who had a smoking history of 10 or more pack-years and 80% of the predicted value and ratio of FEV₁ to forced vital capacity (FVC) of 0.7 or less (N. Engl. J. Med. 2011 Sept. 26 [doi:10.1056/NEJMoa1105482]).

Specifically, the researchers analyzed changes in FEV₁ after bronchodilator use at baseline, 3 months, 6 months, and then every 6 months for 3 years. They defined subgroups according to the presence of emphysema and chronic bronchitis, bronchodilator reversibility, and cardiovascular disease. They also obtained serum and plasma samples for the following biomarkers: C-reactive protein, interleukin-8, interleukin-6, fibrinogen, tumor necrosis factor–alpha, surfactant protein D, and Clara cell secretory protein 16 (CC-16).

The rate of FEV₁ was highly variable during the 3-year period, the results showed. Overall, there was a mean decline of 33 mL/year. More specifically, 38% of patients had a decline of more than 40 mL/year, 31% had a decline of 21-40 mL/year, 23% had changes ranging from a decline of 20 mL/year to an increase of 20 mL/year, and 8% had an increase of more than 20 mL/year.

The researchers also found an inverse relationship between the declines in FEV₁ and stage of disease, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Mean rates of decline were 35 mL/year in patients with moderate disease (GOLD stage 2), 33 mL/year in patients with severe disease (GOLD stage 3), and 25 mL/year in patients with very severe disease (GOLD stage 4).

Smoking status was most strongly associated with the rate of decline, with current smokers experiencing a decline of 21 mL/year more than former smokers. However, cumulative exposure did not affect future decline. "This finding points to smoking cessation as the most important tool in secondary and tertiary prevention for patients at all stages of COPD," the researchers said.

Among the subgroups studied, FEV₁ declined by 17 mL more per year in patients with bronchodilator reversibility at baseline, compared with those without reversibility. Also, FEV₁ declined by an additional 13 mL/year in patients with clinically significant emphysema versus those with little or no emphysema. The presence of cardiovascular disease had no effect on FEV₁.

Although several biomarkers were associated with FEV₁ at baseline, only CC-16 levels were significantly associated with the rate of change in FEV₁, with an additional decline of 4 mL/year for each decrease of 1 standard deviation in the level of CC-16. "This association was weak, and whether it is biologically meaningful has yet to be determined," Dr. Vestbo and his colleagues said. "Without confirmation, it does not seem appropriate to speculate on the potential significance of this finding."

The study findings call into question whether COPD is invariably progressive. "In more than half the patients in our study, the rate of decline in FEV₁ over a period of 3 years was no greater than that which has been observed in people without lung disease. This finding could indicate that COPD may ‘burn out’ or at least stabilize for periods of 3 years or more, which would be good news for patients and could influence a variety of management decisions that depend on prognosis."

A limitation of the study was that it included only patients with moderate, severe, or very severe COPD, and therefore could not identify factors associated with rates of decline in early-stage COPD. Also, the study was purely observational and did not include treatment. "Moreover, the diagnosis and management of COPD in the patients in our study were carried out at specialist centers, and our results may not extend beyond this patient population for a variety of reasons, including the clinically determined care they received," the researchers said.

In an editorial accompanying the report, Dr. Peter Burney said this longitudinal analysis "did not confirm the promise of the earlier cross-sectional analysis [Eur. Respir. J. 2008;31:869-73] by these investigators." One reason is that "association studies undertaken in clinical settings are likely to provide misleading results" because participants often have "coexisting illnesses that may result in spurious associations with the condition being investigated," he said (N. Engl. J. Med. 2011 Sept. 26 [doi:10.1056/NEJMe1109130]).

In addition, "defining GOLD stage 1 disease as a ratio of FEV₁ to forced vital capacity (FVC) of less than 0.7, applied to all age groups, may lead to overreporting of abnormal ratios in older age groups and underreporting of them in younger age groups," said Dr. Burney of the National Heart and Lung Institute, Imperial College, London.

"Failure to distinguish between FEV₁ as a sign of obstruction and FEV₁ as a marker of low FVC has caused much confusion, mostly due to failure to measure or report FVC. It is almost certainly responsible for the association between ventilator function and markers of systemic inflammation in the cross-sectional data for ECLIPSE and has similarly led to inflated associations of ‘obstruction’ with increased all-cause mortality and cardiovascular events in so-called normal populations," Dr. Burney wrote.

As with other studies, he continued, this one showed that those who quit smoking have no clear loss of lung function over time, compared with nonsmokers, adding to the body of evidence that quitting smoking can reduce the rate of decline of lung function. The important message from ECLIPSE is that it is never too late to derive benefit from quitting smoking, although patients derive more benefits by doing so earlier, he noted.

The study was supported by grants from GlaxoSmithKline to Dr. Vestbo and several coauthors. Some of the coauthors are employees of and own stock in GlaxoSmithKline. All coauthors reported ties to numerous pharmaceutical companies, including AstraZeneca, Boehringer Ingelheim, Novartis, and Pfizer.

Dr. Burney disclosed receiving consulting fees from GlaxoSmithKline and lecture fees from Pfizer and Boehringer Ingelheim.

The rate of change in forced expiratory volume in 1 second among patients with chronic obstructive pulmonary disease is highly variable, with the greatest rates of decline occurring among current smokers, patients with bronchodilator reversibility, and those with emphysema, according to an analysis of data from the ECLIPSE observational study reported online Sept. 26 in the New England Journal of Medicine.

Research in the 1970s established that patients with COPD experience an accelerated decline in FEV₁, yet few longitudinal studies have provided detailed data about this decline. Also, none have provided information about FEV₁ in specific subgroups of patients with COPD or according to levels of specific biomarkers.

Dr. Jørgen Vestbo of the University of Copenhagen and his colleagues analyzed data collected for the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, which included 2,163 patients aged 40-75 years who had a smoking history of 10 or more pack-years and 80% of the predicted value and ratio of FEV₁ to forced vital capacity (FVC) of 0.7 or less (N. Engl. J. Med. 2011 Sept. 26 [doi:10.1056/NEJMoa1105482]).

Specifically, the researchers analyzed changes in FEV₁ after bronchodilator use at baseline, 3 months, 6 months, and then every 6 months for 3 years. They defined subgroups according to the presence of emphysema and chronic bronchitis, bronchodilator reversibility, and cardiovascular disease. They also obtained serum and plasma samples for the following biomarkers: C-reactive protein, interleukin-8, interleukin-6, fibrinogen, tumor necrosis factor–alpha, surfactant protein D, and Clara cell secretory protein 16 (CC-16).

The rate of FEV₁ was highly variable during the 3-year period, the results showed. Overall, there was a mean decline of 33 mL/year. More specifically, 38% of patients had a decline of more than 40 mL/year, 31% had a decline of 21-40 mL/year, 23% had changes ranging from a decline of 20 mL/year to an increase of 20 mL/year, and 8% had an increase of more than 20 mL/year.

The researchers also found an inverse relationship between the declines in FEV₁ and stage of disease, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Mean rates of decline were 35 mL/year in patients with moderate disease (GOLD stage 2), 33 mL/year in patients with severe disease (GOLD stage 3), and 25 mL/year in patients with very severe disease (GOLD stage 4).

Smoking status was most strongly associated with the rate of decline, with current smokers experiencing a decline of 21 mL/year more than former smokers. However, cumulative exposure did not affect future decline. "This finding points to smoking cessation as the most important tool in secondary and tertiary prevention for patients at all stages of COPD," the researchers said.

Among the subgroups studied, FEV₁ declined by 17 mL more per year in patients with bronchodilator reversibility at baseline, compared with those without reversibility. Also, FEV₁ declined by an additional 13 mL/year in patients with clinically significant emphysema versus those with little or no emphysema. The presence of cardiovascular disease had no effect on FEV₁.

Although several biomarkers were associated with FEV₁ at baseline, only CC-16 levels were significantly associated with the rate of change in FEV₁, with an additional decline of 4 mL/year for each decrease of 1 standard deviation in the level of CC-16. "This association was weak, and whether it is biologically meaningful has yet to be determined," Dr. Vestbo and his colleagues said. "Without confirmation, it does not seem appropriate to speculate on the potential significance of this finding."

The study findings call into question whether COPD is invariably progressive. "In more than half the patients in our study, the rate of decline in FEV₁ over a period of 3 years was no greater than that which has been observed in people without lung disease. This finding could indicate that COPD may ‘burn out’ or at least stabilize for periods of 3 years or more, which would be good news for patients and could influence a variety of management decisions that depend on prognosis."

A limitation of the study was that it included only patients with moderate, severe, or very severe COPD, and therefore could not identify factors associated with rates of decline in early-stage COPD. Also, the study was purely observational and did not include treatment. "Moreover, the diagnosis and management of COPD in the patients in our study were carried out at specialist centers, and our results may not extend beyond this patient population for a variety of reasons, including the clinically determined care they received," the researchers said.

In an editorial accompanying the report, Dr. Peter Burney said this longitudinal analysis "did not confirm the promise of the earlier cross-sectional analysis [Eur. Respir. J. 2008;31:869-73] by these investigators." One reason is that "association studies undertaken in clinical settings are likely to provide misleading results" because participants often have "coexisting illnesses that may result in spurious associations with the condition being investigated," he said (N. Engl. J. Med. 2011 Sept. 26 [doi:10.1056/NEJMe1109130]).

In addition, "defining GOLD stage 1 disease as a ratio of FEV₁ to forced vital capacity (FVC) of less than 0.7, applied to all age groups, may lead to overreporting of abnormal ratios in older age groups and underreporting of them in younger age groups," said Dr. Burney of the National Heart and Lung Institute, Imperial College, London.

"Failure to distinguish between FEV₁ as a sign of obstruction and FEV₁ as a marker of low FVC has caused much confusion, mostly due to failure to measure or report FVC. It is almost certainly responsible for the association between ventilator function and markers of systemic inflammation in the cross-sectional data for ECLIPSE and has similarly led to inflated associations of ‘obstruction’ with increased all-cause mortality and cardiovascular events in so-called normal populations," Dr. Burney wrote.

As with other studies, he continued, this one showed that those who quit smoking have no clear loss of lung function over time, compared with nonsmokers, adding to the body of evidence that quitting smoking can reduce the rate of decline of lung function. The important message from ECLIPSE is that it is never too late to derive benefit from quitting smoking, although patients derive more benefits by doing so earlier, he noted.

The study was supported by grants from GlaxoSmithKline to Dr. Vestbo and several coauthors. Some of the coauthors are employees of and own stock in GlaxoSmithKline. All coauthors reported ties to numerous pharmaceutical companies, including AstraZeneca, Boehringer Ingelheim, Novartis, and Pfizer.

Dr. Burney disclosed receiving consulting fees from GlaxoSmithKline and lecture fees from Pfizer and Boehringer Ingelheim.

The rate of change in forced expiratory volume in 1 second among patients with chronic obstructive pulmonary disease is highly variable, with the greatest rates of decline occurring among current smokers, patients with bronchodilator reversibility, and those with emphysema, according to an analysis of data from the ECLIPSE observational study reported online Sept. 26 in the New England Journal of Medicine.

Research in the 1970s established that patients with COPD experience an accelerated decline in FEV₁, yet few longitudinal studies have provided detailed data about this decline. Also, none have provided information about FEV₁ in specific subgroups of patients with COPD or according to levels of specific biomarkers.

Dr. Jørgen Vestbo of the University of Copenhagen and his colleagues analyzed data collected for the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, which included 2,163 patients aged 40-75 years who had a smoking history of 10 or more pack-years and 80% of the predicted value and ratio of FEV₁ to forced vital capacity (FVC) of 0.7 or less (N. Engl. J. Med. 2011 Sept. 26 [doi:10.1056/NEJMoa1105482]).

Specifically, the researchers analyzed changes in FEV₁ after bronchodilator use at baseline, 3 months, 6 months, and then every 6 months for 3 years. They defined subgroups according to the presence of emphysema and chronic bronchitis, bronchodilator reversibility, and cardiovascular disease. They also obtained serum and plasma samples for the following biomarkers: C-reactive protein, interleukin-8, interleukin-6, fibrinogen, tumor necrosis factor–alpha, surfactant protein D, and Clara cell secretory protein 16 (CC-16).

The rate of FEV₁ was highly variable during the 3-year period, the results showed. Overall, there was a mean decline of 33 mL/year. More specifically, 38% of patients had a decline of more than 40 mL/year, 31% had a decline of 21-40 mL/year, 23% had changes ranging from a decline of 20 mL/year to an increase of 20 mL/year, and 8% had an increase of more than 20 mL/year.

The researchers also found an inverse relationship between the declines in FEV₁ and stage of disease, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Mean rates of decline were 35 mL/year in patients with moderate disease (GOLD stage 2), 33 mL/year in patients with severe disease (GOLD stage 3), and 25 mL/year in patients with very severe disease (GOLD stage 4).

Smoking status was most strongly associated with the rate of decline, with current smokers experiencing a decline of 21 mL/year more than former smokers. However, cumulative exposure did not affect future decline. "This finding points to smoking cessation as the most important tool in secondary and tertiary prevention for patients at all stages of COPD," the researchers said.

Among the subgroups studied, FEV₁ declined by 17 mL more per year in patients with bronchodilator reversibility at baseline, compared with those without reversibility. Also, FEV₁ declined by an additional 13 mL/year in patients with clinically significant emphysema versus those with little or no emphysema. The presence of cardiovascular disease had no effect on FEV₁.

Although several biomarkers were associated with FEV₁ at baseline, only CC-16 levels were significantly associated with the rate of change in FEV₁, with an additional decline of 4 mL/year for each decrease of 1 standard deviation in the level of CC-16. "This association was weak, and whether it is biologically meaningful has yet to be determined," Dr. Vestbo and his colleagues said. "Without confirmation, it does not seem appropriate to speculate on the potential significance of this finding."

The study findings call into question whether COPD is invariably progressive. "In more than half the patients in our study, the rate of decline in FEV₁ over a period of 3 years was no greater than that which has been observed in people without lung disease. This finding could indicate that COPD may ‘burn out’ or at least stabilize for periods of 3 years or more, which would be good news for patients and could influence a variety of management decisions that depend on prognosis."

A limitation of the study was that it included only patients with moderate, severe, or very severe COPD, and therefore could not identify factors associated with rates of decline in early-stage COPD. Also, the study was purely observational and did not include treatment. "Moreover, the diagnosis and management of COPD in the patients in our study were carried out at specialist centers, and our results may not extend beyond this patient population for a variety of reasons, including the clinically determined care they received," the researchers said.

In an editorial accompanying the report, Dr. Peter Burney said this longitudinal analysis "did not confirm the promise of the earlier cross-sectional analysis [Eur. Respir. J. 2008;31:869-73] by these investigators." One reason is that "association studies undertaken in clinical settings are likely to provide misleading results" because participants often have "coexisting illnesses that may result in spurious associations with the condition being investigated," he said (N. Engl. J. Med. 2011 Sept. 26 [doi:10.1056/NEJMe1109130]).

In addition, "defining GOLD stage 1 disease as a ratio of FEV₁ to forced vital capacity (FVC) of less than 0.7, applied to all age groups, may lead to overreporting of abnormal ratios in older age groups and underreporting of them in younger age groups," said Dr. Burney of the National Heart and Lung Institute, Imperial College, London.

"Failure to distinguish between FEV₁ as a sign of obstruction and FEV₁ as a marker of low FVC has caused much confusion, mostly due to failure to measure or report FVC. It is almost certainly responsible for the association between ventilator function and markers of systemic inflammation in the cross-sectional data for ECLIPSE and has similarly led to inflated associations of ‘obstruction’ with increased all-cause mortality and cardiovascular events in so-called normal populations," Dr. Burney wrote.

As with other studies, he continued, this one showed that those who quit smoking have no clear loss of lung function over time, compared with nonsmokers, adding to the body of evidence that quitting smoking can reduce the rate of decline of lung function. The important message from ECLIPSE is that it is never too late to derive benefit from quitting smoking, although patients derive more benefits by doing so earlier, he noted.

The study was supported by grants from GlaxoSmithKline to Dr. Vestbo and several coauthors. Some of the coauthors are employees of and own stock in GlaxoSmithKline. All coauthors reported ties to numerous pharmaceutical companies, including AstraZeneca, Boehringer Ingelheim, Novartis, and Pfizer.

Dr. Burney disclosed receiving consulting fees from GlaxoSmithKline and lecture fees from Pfizer and Boehringer Ingelheim.

Oral isotretinoin may improve patient hearing at all audiometric frequencies, according to new research published in the September issue of the International Journal of Dermatology.

For the study, the researchers wanted to investigate whether oral isotretinoin could affect patients’ hearing, as measured by audiometry and tympanometry. "The adverse effects of isotretinoin are well known, but ototoxic effects have rarely been reported," wrote Dr. Hayriye Karabulut, of Ankara Kecioren Research and Training Hospital in Turkey, and his colleagues.

The researchers enrolled 47 patients with moderate to severe nodulocystic acne (Int. J. Dermatol. 2011;50:1139-43). Of the 38 patients (76 ears) who completed the study, 15 were male, and 23 were female. Female subjects of childbearing potential used two methods of birth control and had a negative pregnancy test 1 week before initiating therapy. Patients ranged in age from 15 to 34 years (mean, 20 years).

The researchers prescribed oral isotretinoin 0.5-0.75 mg/kg body weight twice daily for at least 3 months. They evaluated biochemical parameters at baseline and at 1-month follow-up, and conducted a physical examination, including otoscopy.

They also conducted audiometric tests at baseline and weeks 1, 2, and 3. These included pure-tone, speech, and high-frequency audiometry, as well as ipsi- and contralateral acoustic reflexes. They measured air conduction pure-tone averages (PTAs) at frequencies of 250 Hz (PTA1); 500, 1,000, 2,000 Hz (PTA2); 4,000, 8,000 and 10,000 Hz (PTA3); and 12,500, 16,000, 18,000 and 20,000 Hz (PTA4) for each ear.

The otoscopic exam was normal in all patients before and after initiation of treatment, the researchers reported. There were no changes in speech discrimination scores. Oral isotretinoin, which is a derivative of retinol (vitamin A), improved the hearing level of the patients in all audiometric frequencies in the short-period follow-up study.

Compared with baseline scores, the hearing thresholds of patients were increased in middle frequency (PTA2 and PTA3) during the first week of follow-up, in low frequency (PTA1) during the second week of follow-up, and in high and ultrahigh frequency (PTA4) during the third week of follow-up. Specific results included the following:

• PTA1 went from a mean 10.1 decibels (dB) at baseline to 9.5 dB at week 1, and to 9.0 dB at weeks 2 and 3.

• PTA2 went from a mean 7.1 dB at baseline to 6.3 dB at week 1, to 6.1 dB at week 2, and to 5.8 dB at week 3.

• PTA3 went from 10.1 dB at baseline to 7.7 dB at week 1, to 8.0 dB at week 2, and to 6.8 dB at week 3.

• PTA4 went from 44.4 dB at baseline to 42.2 dB at week 1, to 40.7 dB at week 2, and to 38.9 dB at week 3.

"Because oxidative stress has been suggested to be involved in hearing impairment, antioxidants are expected to play a preventive role," the researchers noted. "It is also known that retinoic acid, an active metabolite of retinol, is indispensable for normal development of the Corti organ. The association between vitamin A (retinol) and the prevention of hearing impairment in particular has been focused on because the concentration of vitamin A in the inner ear has been shown to be high."

Oral isotretinoin is used to treat extensive and nodulocystic acne, as well as moderate acne that does not respond to conventional treatment. Teratogenicity and a high risk of spontaneous abortion are known risks of treatment with the drug.

The authors did not disclose having any conflicts of interest.

Oral isotretinoin may improve patient hearing at all audiometric frequencies, according to new research published in the September issue of the International Journal of Dermatology.

For the study, the researchers wanted to investigate whether oral isotretinoin could affect patients’ hearing, as measured by audiometry and tympanometry. "The adverse effects of isotretinoin are well known, but ototoxic effects have rarely been reported," wrote Dr. Hayriye Karabulut, of Ankara Kecioren Research and Training Hospital in Turkey, and his colleagues.

The researchers enrolled 47 patients with moderate to severe nodulocystic acne (Int. J. Dermatol. 2011;50:1139-43). Of the 38 patients (76 ears) who completed the study, 15 were male, and 23 were female. Female subjects of childbearing potential used two methods of birth control and had a negative pregnancy test 1 week before initiating therapy. Patients ranged in age from 15 to 34 years (mean, 20 years).

The researchers prescribed oral isotretinoin 0.5-0.75 mg/kg body weight twice daily for at least 3 months. They evaluated biochemical parameters at baseline and at 1-month follow-up, and conducted a physical examination, including otoscopy.

They also conducted audiometric tests at baseline and weeks 1, 2, and 3. These included pure-tone, speech, and high-frequency audiometry, as well as ipsi- and contralateral acoustic reflexes. They measured air conduction pure-tone averages (PTAs) at frequencies of 250 Hz (PTA1); 500, 1,000, 2,000 Hz (PTA2); 4,000, 8,000 and 10,000 Hz (PTA3); and 12,500, 16,000, 18,000 and 20,000 Hz (PTA4) for each ear.

The otoscopic exam was normal in all patients before and after initiation of treatment, the researchers reported. There were no changes in speech discrimination scores. Oral isotretinoin, which is a derivative of retinol (vitamin A), improved the hearing level of the patients in all audiometric frequencies in the short-period follow-up study.

Compared with baseline scores, the hearing thresholds of patients were increased in middle frequency (PTA2 and PTA3) during the first week of follow-up, in low frequency (PTA1) during the second week of follow-up, and in high and ultrahigh frequency (PTA4) during the third week of follow-up. Specific results included the following:

• PTA1 went from a mean 10.1 decibels (dB) at baseline to 9.5 dB at week 1, and to 9.0 dB at weeks 2 and 3.

• PTA2 went from a mean 7.1 dB at baseline to 6.3 dB at week 1, to 6.1 dB at week 2, and to 5.8 dB at week 3.

• PTA3 went from 10.1 dB at baseline to 7.7 dB at week 1, to 8.0 dB at week 2, and to 6.8 dB at week 3.

• PTA4 went from 44.4 dB at baseline to 42.2 dB at week 1, to 40.7 dB at week 2, and to 38.9 dB at week 3.

"Because oxidative stress has been suggested to be involved in hearing impairment, antioxidants are expected to play a preventive role," the researchers noted. "It is also known that retinoic acid, an active metabolite of retinol, is indispensable for normal development of the Corti organ. The association between vitamin A (retinol) and the prevention of hearing impairment in particular has been focused on because the concentration of vitamin A in the inner ear has been shown to be high."

Oral isotretinoin is used to treat extensive and nodulocystic acne, as well as moderate acne that does not respond to conventional treatment. Teratogenicity and a high risk of spontaneous abortion are known risks of treatment with the drug.

The authors did not disclose having any conflicts of interest.

Oral isotretinoin may improve patient hearing at all audiometric frequencies, according to new research published in the September issue of the International Journal of Dermatology.

For the study, the researchers wanted to investigate whether oral isotretinoin could affect patients’ hearing, as measured by audiometry and tympanometry. "The adverse effects of isotretinoin are well known, but ototoxic effects have rarely been reported," wrote Dr. Hayriye Karabulut, of Ankara Kecioren Research and Training Hospital in Turkey, and his colleagues.

The researchers enrolled 47 patients with moderate to severe nodulocystic acne (Int. J. Dermatol. 2011;50:1139-43). Of the 38 patients (76 ears) who completed the study, 15 were male, and 23 were female. Female subjects of childbearing potential used two methods of birth control and had a negative pregnancy test 1 week before initiating therapy. Patients ranged in age from 15 to 34 years (mean, 20 years).

The researchers prescribed oral isotretinoin 0.5-0.75 mg/kg body weight twice daily for at least 3 months. They evaluated biochemical parameters at baseline and at 1-month follow-up, and conducted a physical examination, including otoscopy.

They also conducted audiometric tests at baseline and weeks 1, 2, and 3. These included pure-tone, speech, and high-frequency audiometry, as well as ipsi- and contralateral acoustic reflexes. They measured air conduction pure-tone averages (PTAs) at frequencies of 250 Hz (PTA1); 500, 1,000, 2,000 Hz (PTA2); 4,000, 8,000 and 10,000 Hz (PTA3); and 12,500, 16,000, 18,000 and 20,000 Hz (PTA4) for each ear.

The otoscopic exam was normal in all patients before and after initiation of treatment, the researchers reported. There were no changes in speech discrimination scores. Oral isotretinoin, which is a derivative of retinol (vitamin A), improved the hearing level of the patients in all audiometric frequencies in the short-period follow-up study.

Compared with baseline scores, the hearing thresholds of patients were increased in middle frequency (PTA2 and PTA3) during the first week of follow-up, in low frequency (PTA1) during the second week of follow-up, and in high and ultrahigh frequency (PTA4) during the third week of follow-up. Specific results included the following:

• PTA1 went from a mean 10.1 decibels (dB) at baseline to 9.5 dB at week 1, and to 9.0 dB at weeks 2 and 3.

• PTA2 went from a mean 7.1 dB at baseline to 6.3 dB at week 1, to 6.1 dB at week 2, and to 5.8 dB at week 3.

• PTA3 went from 10.1 dB at baseline to 7.7 dB at week 1, to 8.0 dB at week 2, and to 6.8 dB at week 3.

• PTA4 went from 44.4 dB at baseline to 42.2 dB at week 1, to 40.7 dB at week 2, and to 38.9 dB at week 3.

"Because oxidative stress has been suggested to be involved in hearing impairment, antioxidants are expected to play a preventive role," the researchers noted. "It is also known that retinoic acid, an active metabolite of retinol, is indispensable for normal development of the Corti organ. The association between vitamin A (retinol) and the prevention of hearing impairment in particular has been focused on because the concentration of vitamin A in the inner ear has been shown to be high."

Oral isotretinoin is used to treat extensive and nodulocystic acne, as well as moderate acne that does not respond to conventional treatment. Teratogenicity and a high risk of spontaneous abortion are known risks of treatment with the drug.

The authors did not disclose having any conflicts of interest.

Lifestyle modifications and pharmacotherapy to reduce the risk of cardiovascular disease can also improve sexual function in men who have erectile dysfunction, according to findings from a meta-analysis first posted online Sept. 12 in Archives of Internal Medicine.

Erectile dysfunction (ED), with a prevalence ranging from 12% of men younger than 59 years of age to 42% of men aged 40-70, shares modifiable risks factors with atherosclerosis and coronary artery disease. These factors include hypertension, diabetes, dyslipidemia, cigarette smoking, obesity, metabolic syndrome, and sedentary behavior. ED has a high prevalence in individuals with multiple risk factors for cardiovascular (CV) disease, and its presence may be an early predictor or marker for cardiovascular events.

While clinical trials have shown that modifying lifestyle risks led to improvement in ED, many are limited by a small sample size and single geographic location and have not studied both lifestyle modifications and pharmacotherapy on ED.

So, Dr. Bhanu P. Gupta and colleagues with the Mayo Clinic, Rochester, Minn., conducted a meta-analysis of six previous randomized controlled trials from four countries to evaluate the relationship between lifestyle intervention and pharmaceutical treatment of cardiovascular risk factors and the severity of ED (Arch. Intern. Med. 2011 Sept 12 [doi:10.1001/archinternmed.2011.440]). The six trials, published between 2004 and 2010 examined in the meta-analysis, included a total of 740 participants (374 who received intervention and 366 control subjects), with the number of participants per trial ranging from 12 to 372. Average age of the participants was 55.4 years, and the study duration ranged from 12 to 104 weeks. All studies included in the analysis showed lessening of ED with adoption of a more healthful lifestyle and improvement in blood lipid parameters.

The meta-analysis showed that improvement in CV risk factors was associated with statistically significant improvement in sexual function, as measured by the Internal Index of Erectile Function, or IIEF-5 score, in which a score of 22- 25 points indicates normal erectile function, 17-21 indicates mild ED, 12-16 indicates mild to moderate ED, 8-11 indicates moderate ED, and 7 and below indicates severe ED.

Meta-analysis of all six trials showed a 2.7-point improvement in mean IIEF-5 score. When excluding studies that included use of statin medications, there was a 2.4-point improvement on the IIEF-5 score. Pharmacotherapy targeting CV risk factors demonstrated improvement of 3.1 points.

Typically, a 4-point improvement in the IIEF-5 score is considered the minimal clinically important difference (MCID). However, the MCID varies significantly according to baseline ED severity, ranging from 2.0 for mild ED to 7.0 for severe ED. "Therefore, the results of this analysis regarding the pooled IIEF-5 score improvement of 2.7 points might not translate into clinically important differences for moderate and severe ED," the researchers say. "Nevertheless, the overall weighted mean difference of 2.7 in IIEF-5 score improvement is consistent with significant improvement in mild ED and lesser improvement in more advanced ED."

"The results of the present meta-analysis add to and strengthen existing knowledge that healthy dietary habits and increased physical activity are important components of health to improve quality of life in men by improving sexual health," the researchers say.

The authors had no financial disclosures to report.

Lifestyle modifications and pharmacotherapy to reduce the risk of cardiovascular disease can also improve sexual function in men who have erectile dysfunction, according to findings from a meta-analysis first posted online Sept. 12 in Archives of Internal Medicine.

Erectile dysfunction (ED), with a prevalence ranging from 12% of men younger than 59 years of age to 42% of men aged 40-70, shares modifiable risks factors with atherosclerosis and coronary artery disease. These factors include hypertension, diabetes, dyslipidemia, cigarette smoking, obesity, metabolic syndrome, and sedentary behavior. ED has a high prevalence in individuals with multiple risk factors for cardiovascular (CV) disease, and its presence may be an early predictor or marker for cardiovascular events.

While clinical trials have shown that modifying lifestyle risks led to improvement in ED, many are limited by a small sample size and single geographic location and have not studied both lifestyle modifications and pharmacotherapy on ED.

So, Dr. Bhanu P. Gupta and colleagues with the Mayo Clinic, Rochester, Minn., conducted a meta-analysis of six previous randomized controlled trials from four countries to evaluate the relationship between lifestyle intervention and pharmaceutical treatment of cardiovascular risk factors and the severity of ED (Arch. Intern. Med. 2011 Sept 12 [doi:10.1001/archinternmed.2011.440]). The six trials, published between 2004 and 2010 examined in the meta-analysis, included a total of 740 participants (374 who received intervention and 366 control subjects), with the number of participants per trial ranging from 12 to 372. Average age of the participants was 55.4 years, and the study duration ranged from 12 to 104 weeks. All studies included in the analysis showed lessening of ED with adoption of a more healthful lifestyle and improvement in blood lipid parameters.

The meta-analysis showed that improvement in CV risk factors was associated with statistically significant improvement in sexual function, as measured by the Internal Index of Erectile Function, or IIEF-5 score, in which a score of 22- 25 points indicates normal erectile function, 17-21 indicates mild ED, 12-16 indicates mild to moderate ED, 8-11 indicates moderate ED, and 7 and below indicates severe ED.

Meta-analysis of all six trials showed a 2.7-point improvement in mean IIEF-5 score. When excluding studies that included use of statin medications, there was a 2.4-point improvement on the IIEF-5 score. Pharmacotherapy targeting CV risk factors demonstrated improvement of 3.1 points.

Typically, a 4-point improvement in the IIEF-5 score is considered the minimal clinically important difference (MCID). However, the MCID varies significantly according to baseline ED severity, ranging from 2.0 for mild ED to 7.0 for severe ED. "Therefore, the results of this analysis regarding the pooled IIEF-5 score improvement of 2.7 points might not translate into clinically important differences for moderate and severe ED," the researchers say. "Nevertheless, the overall weighted mean difference of 2.7 in IIEF-5 score improvement is consistent with significant improvement in mild ED and lesser improvement in more advanced ED."

"The results of the present meta-analysis add to and strengthen existing knowledge that healthy dietary habits and increased physical activity are important components of health to improve quality of life in men by improving sexual health," the researchers say.

The authors had no financial disclosures to report.

Lifestyle modifications and pharmacotherapy to reduce the risk of cardiovascular disease can also improve sexual function in men who have erectile dysfunction, according to findings from a meta-analysis first posted online Sept. 12 in Archives of Internal Medicine.

Erectile dysfunction (ED), with a prevalence ranging from 12% of men younger than 59 years of age to 42% of men aged 40-70, shares modifiable risks factors with atherosclerosis and coronary artery disease. These factors include hypertension, diabetes, dyslipidemia, cigarette smoking, obesity, metabolic syndrome, and sedentary behavior. ED has a high prevalence in individuals with multiple risk factors for cardiovascular (CV) disease, and its presence may be an early predictor or marker for cardiovascular events.

While clinical trials have shown that modifying lifestyle risks led to improvement in ED, many are limited by a small sample size and single geographic location and have not studied both lifestyle modifications and pharmacotherapy on ED.

So, Dr. Bhanu P. Gupta and colleagues with the Mayo Clinic, Rochester, Minn., conducted a meta-analysis of six previous randomized controlled trials from four countries to evaluate the relationship between lifestyle intervention and pharmaceutical treatment of cardiovascular risk factors and the severity of ED (Arch. Intern. Med. 2011 Sept 12 [doi:10.1001/archinternmed.2011.440]). The six trials, published between 2004 and 2010 examined in the meta-analysis, included a total of 740 participants (374 who received intervention and 366 control subjects), with the number of participants per trial ranging from 12 to 372. Average age of the participants was 55.4 years, and the study duration ranged from 12 to 104 weeks. All studies included in the analysis showed lessening of ED with adoption of a more healthful lifestyle and improvement in blood lipid parameters.

The meta-analysis showed that improvement in CV risk factors was associated with statistically significant improvement in sexual function, as measured by the Internal Index of Erectile Function, or IIEF-5 score, in which a score of 22- 25 points indicates normal erectile function, 17-21 indicates mild ED, 12-16 indicates mild to moderate ED, 8-11 indicates moderate ED, and 7 and below indicates severe ED.

Meta-analysis of all six trials showed a 2.7-point improvement in mean IIEF-5 score. When excluding studies that included use of statin medications, there was a 2.4-point improvement on the IIEF-5 score. Pharmacotherapy targeting CV risk factors demonstrated improvement of 3.1 points.

Typically, a 4-point improvement in the IIEF-5 score is considered the minimal clinically important difference (MCID). However, the MCID varies significantly according to baseline ED severity, ranging from 2.0 for mild ED to 7.0 for severe ED. "Therefore, the results of this analysis regarding the pooled IIEF-5 score improvement of 2.7 points might not translate into clinically important differences for moderate and severe ED," the researchers say. "Nevertheless, the overall weighted mean difference of 2.7 in IIEF-5 score improvement is consistent with significant improvement in mild ED and lesser improvement in more advanced ED."

"The results of the present meta-analysis add to and strengthen existing knowledge that healthy dietary habits and increased physical activity are important components of health to improve quality of life in men by improving sexual health," the researchers say.

The authors had no financial disclosures to report.

Not all dermatologists comply with recommendations for use of isotretinoin in females of childbearing potential, according to a study in the September issue of the International Journal of Dermatology. The finding was especially significant in countries with restrictions on abortion.

Dr. Khalid M. AlGhamdi of King Saud University in Riyadh, Saudi Arabia, and colleagues looked at the practices and safety concerns of dermatologists in Saudi Arabia, including whether they followed necessary precautions when prescribing isotretinoin to females of childbearing potential (FCBP) (Int. J. Dermatol. 2011;50:1094-8).

For the cross-sectional study, the investigators distributed a self-administered questionnaire to 160 dermatologists attending a national conference in Riyadh during 2008. Of the dermatologists, 134 completed the survey (82 female and 52 male), for a response rate of 84%. The physicians ranged in age from 25 to 66 (mean age 39). They were in practice for a mean of 11 years, though 32% were residents. Of the 160 dermatologists, 70% worked in government hospitals, 15% were in private practice, and 15% worked in both sectors.

Using the questionnaire, the researchers gathered the following information:

• Isotretinoin prescriptions. Respondents prescribed isotretinoin during the previous 12 months for an estimated 792 FCBP.

• Pregnancy. Of these 792 FCBP, there were 7 reported pregnancies, for an estimated rate of 8.8 per 1,000. "Such a rate of pregnancy may be an underestimate of the true rate, because there are no registries at the present time of such incidents on a local/national scale," the researchers reported.

Three women (43%) terminated their pregnancies, one miscarried, two were lost to follow-up, and one gave birth to a normal baby.

• Pregnancy tests. Of the responding dermatologists, 71% reported performing a pregnancy test for patients before initiating treatment with isotretinoin, while 22% reported asking for a monthly pregnancy test.

• Informed consent. The questionnaire asked whether the dermatologists obtained informed consent from their female patients before starting isotretinoin treatment, if they discussed the potential teratogenic risk of using the drug, and if they educated patients about how to prevent pregnancy. Of the questionnaire respondents, 79% asked patients to sign a consent form, and 99% discussed teratogenic effects.

• Instructions. Of the dermatologists, 91% advised patients to continue contraception for 1 month after the last dose, 44% provided written guidelines about teratogenic risks, and 36% provided written information about contraception. Also, 73% advised patients to use two effective contraception methods, and 72% advised patients to begin effective contraception 1 month before starting isotretinoin,

• Attitudes. About two-thirds, 63% reported generally avoiding isotretinoin therapy in FCBP. This was irrespective of the dermatologist’s gender, years of experience, or any previous incident of having a patient become pregnant while on isotretinoin, the researchers reported.

"This study was the first, to our knowledge, to examine trends and practices of dermatologists from their perspective in this significant area," Dr. AlGhamdi and his colleagues wrote. "Saudi Arabia is among the countries where there are certain limitations on abortion, which renders this study of great importance."

Contraception is easily accessible in Saudi Arabia, but Islamic law makes abortion difficult to obtain. "In view of restricted and diverse jurisprudence regarding abortion on fetal impairment grounds, one should be very vigilant in prescribing such a teratogenic drug in FCBP and take all necessary precautions to avoid the tragedy of exposing the embryo to a highly teratogenic medication such as isotretinoin."

The strengths of the study, the researchers noted, were its large sample size and that it may be the first to examine pregnancy prevention from the perspective of prescribing dermatologists rather than patients. One weakness may be recall bias as dermatologists may have been inaccurate in remembering the exact number of female isotretinoin users.

Isotretinoin, used to treat extensive and nodulocystic acne and moderate acne that is unresponsive to conventional treatment, can cause severe birth defects when used during pregnancy (even as little as one dose). In March 2006, the four drug companies in the U.S. that market isotretinoin jointly launched iPLEDGE, a computer-based risk management program, to prevent female patients from beginning therapy while pregnant or becoming pregnant during therapy. Three previous programs failed to prevent pregnancies in patients using isotretinoin.

The iPLEDGE program requires FCBP to commit to using two forms of contraception, and to have a negative urine or serum pregnancy test before receiving the initial dose and every month before receiving a new prescription. Prescribing physicians must enter pregnancy results and the two forms of contraception in the system, counsel patients about the risks of isotretinoin each month before providing a prescription, and document the counseling in the system.

The authors did not declare having any conflicts of interest.

Not all dermatologists comply with recommendations for use of isotretinoin in females of childbearing potential, according to a study in the September issue of the International Journal of Dermatology. The finding was especially significant in countries with restrictions on abortion.

Dr. Khalid M. AlGhamdi of King Saud University in Riyadh, Saudi Arabia, and colleagues looked at the practices and safety concerns of dermatologists in Saudi Arabia, including whether they followed necessary precautions when prescribing isotretinoin to females of childbearing potential (FCBP) (Int. J. Dermatol. 2011;50:1094-8).

For the cross-sectional study, the investigators distributed a self-administered questionnaire to 160 dermatologists attending a national conference in Riyadh during 2008. Of the dermatologists, 134 completed the survey (82 female and 52 male), for a response rate of 84%. The physicians ranged in age from 25 to 66 (mean age 39). They were in practice for a mean of 11 years, though 32% were residents. Of the 160 dermatologists, 70% worked in government hospitals, 15% were in private practice, and 15% worked in both sectors.

Using the questionnaire, the researchers gathered the following information:

• Isotretinoin prescriptions. Respondents prescribed isotretinoin during the previous 12 months for an estimated 792 FCBP.

• Pregnancy. Of these 792 FCBP, there were 7 reported pregnancies, for an estimated rate of 8.8 per 1,000. "Such a rate of pregnancy may be an underestimate of the true rate, because there are no registries at the present time of such incidents on a local/national scale," the researchers reported.

Three women (43%) terminated their pregnancies, one miscarried, two were lost to follow-up, and one gave birth to a normal baby.

• Pregnancy tests. Of the responding dermatologists, 71% reported performing a pregnancy test for patients before initiating treatment with isotretinoin, while 22% reported asking for a monthly pregnancy test.

• Informed consent. The questionnaire asked whether the dermatologists obtained informed consent from their female patients before starting isotretinoin treatment, if they discussed the potential teratogenic risk of using the drug, and if they educated patients about how to prevent pregnancy. Of the questionnaire respondents, 79% asked patients to sign a consent form, and 99% discussed teratogenic effects.

• Instructions. Of the dermatologists, 91% advised patients to continue contraception for 1 month after the last dose, 44% provided written guidelines about teratogenic risks, and 36% provided written information about contraception. Also, 73% advised patients to use two effective contraception methods, and 72% advised patients to begin effective contraception 1 month before starting isotretinoin,

• Attitudes. About two-thirds, 63% reported generally avoiding isotretinoin therapy in FCBP. This was irrespective of the dermatologist’s gender, years of experience, or any previous incident of having a patient become pregnant while on isotretinoin, the researchers reported.

"This study was the first, to our knowledge, to examine trends and practices of dermatologists from their perspective in this significant area," Dr. AlGhamdi and his colleagues wrote. "Saudi Arabia is among the countries where there are certain limitations on abortion, which renders this study of great importance."

Contraception is easily accessible in Saudi Arabia, but Islamic law makes abortion difficult to obtain. "In view of restricted and diverse jurisprudence regarding abortion on fetal impairment grounds, one should be very vigilant in prescribing such a teratogenic drug in FCBP and take all necessary precautions to avoid the tragedy of exposing the embryo to a highly teratogenic medication such as isotretinoin."

The strengths of the study, the researchers noted, were its large sample size and that it may be the first to examine pregnancy prevention from the perspective of prescribing dermatologists rather than patients. One weakness may be recall bias as dermatologists may have been inaccurate in remembering the exact number of female isotretinoin users.

Isotretinoin, used to treat extensive and nodulocystic acne and moderate acne that is unresponsive to conventional treatment, can cause severe birth defects when used during pregnancy (even as little as one dose). In March 2006, the four drug companies in the U.S. that market isotretinoin jointly launched iPLEDGE, a computer-based risk management program, to prevent female patients from beginning therapy while pregnant or becoming pregnant during therapy. Three previous programs failed to prevent pregnancies in patients using isotretinoin.

The iPLEDGE program requires FCBP to commit to using two forms of contraception, and to have a negative urine or serum pregnancy test before receiving the initial dose and every month before receiving a new prescription. Prescribing physicians must enter pregnancy results and the two forms of contraception in the system, counsel patients about the risks of isotretinoin each month before providing a prescription, and document the counseling in the system.

The authors did not declare having any conflicts of interest.

Not all dermatologists comply with recommendations for use of isotretinoin in females of childbearing potential, according to a study in the September issue of the International Journal of Dermatology. The finding was especially significant in countries with restrictions on abortion.

Dr. Khalid M. AlGhamdi of King Saud University in Riyadh, Saudi Arabia, and colleagues looked at the practices and safety concerns of dermatologists in Saudi Arabia, including whether they followed necessary precautions when prescribing isotretinoin to females of childbearing potential (FCBP) (Int. J. Dermatol. 2011;50:1094-8).

For the cross-sectional study, the investigators distributed a self-administered questionnaire to 160 dermatologists attending a national conference in Riyadh during 2008. Of the dermatologists, 134 completed the survey (82 female and 52 male), for a response rate of 84%. The physicians ranged in age from 25 to 66 (mean age 39). They were in practice for a mean of 11 years, though 32% were residents. Of the 160 dermatologists, 70% worked in government hospitals, 15% were in private practice, and 15% worked in both sectors.

Using the questionnaire, the researchers gathered the following information:

• Isotretinoin prescriptions. Respondents prescribed isotretinoin during the previous 12 months for an estimated 792 FCBP.

• Pregnancy. Of these 792 FCBP, there were 7 reported pregnancies, for an estimated rate of 8.8 per 1,000. "Such a rate of pregnancy may be an underestimate of the true rate, because there are no registries at the present time of such incidents on a local/national scale," the researchers reported.

Three women (43%) terminated their pregnancies, one miscarried, two were lost to follow-up, and one gave birth to a normal baby.

• Pregnancy tests. Of the responding dermatologists, 71% reported performing a pregnancy test for patients before initiating treatment with isotretinoin, while 22% reported asking for a monthly pregnancy test.

• Informed consent. The questionnaire asked whether the dermatologists obtained informed consent from their female patients before starting isotretinoin treatment, if they discussed the potential teratogenic risk of using the drug, and if they educated patients about how to prevent pregnancy. Of the questionnaire respondents, 79% asked patients to sign a consent form, and 99% discussed teratogenic effects.

• Instructions. Of the dermatologists, 91% advised patients to continue contraception for 1 month after the last dose, 44% provided written guidelines about teratogenic risks, and 36% provided written information about contraception. Also, 73% advised patients to use two effective contraception methods, and 72% advised patients to begin effective contraception 1 month before starting isotretinoin,

• Attitudes. About two-thirds, 63% reported generally avoiding isotretinoin therapy in FCBP. This was irrespective of the dermatologist’s gender, years of experience, or any previous incident of having a patient become pregnant while on isotretinoin, the researchers reported.

"This study was the first, to our knowledge, to examine trends and practices of dermatologists from their perspective in this significant area," Dr. AlGhamdi and his colleagues wrote. "Saudi Arabia is among the countries where there are certain limitations on abortion, which renders this study of great importance."

Contraception is easily accessible in Saudi Arabia, but Islamic law makes abortion difficult to obtain. "In view of restricted and diverse jurisprudence regarding abortion on fetal impairment grounds, one should be very vigilant in prescribing such a teratogenic drug in FCBP and take all necessary precautions to avoid the tragedy of exposing the embryo to a highly teratogenic medication such as isotretinoin."

The strengths of the study, the researchers noted, were its large sample size and that it may be the first to examine pregnancy prevention from the perspective of prescribing dermatologists rather than patients. One weakness may be recall bias as dermatologists may have been inaccurate in remembering the exact number of female isotretinoin users.

Isotretinoin, used to treat extensive and nodulocystic acne and moderate acne that is unresponsive to conventional treatment, can cause severe birth defects when used during pregnancy (even as little as one dose). In March 2006, the four drug companies in the U.S. that market isotretinoin jointly launched iPLEDGE, a computer-based risk management program, to prevent female patients from beginning therapy while pregnant or becoming pregnant during therapy. Three previous programs failed to prevent pregnancies in patients using isotretinoin.

The iPLEDGE program requires FCBP to commit to using two forms of contraception, and to have a negative urine or serum pregnancy test before receiving the initial dose and every month before receiving a new prescription. Prescribing physicians must enter pregnancy results and the two forms of contraception in the system, counsel patients about the risks of isotretinoin each month before providing a prescription, and document the counseling in the system.

The authors did not declare having any conflicts of interest.

ATLANTA – Community-based weight loss programs for individuals ages 60 years or older who are at risk for diabetes or heart disease could save Medicare between $7 billion and $15 billion over the lifetimes of one cohort of baby boomers, according to a study in the September Health Affairs.

Obesity, defined as body mass index (BMI) of 30 kg/m², more than doubled from 18% to 37% of adults ages 65 years and older between 1980 and 2008, according to data from the Centers for Disease Control and Prevention. At the same time, obese adults spent about 40% more on health care than adults whose weight was normal, due to higher rates of diabetes and other chronic illnesses.

"It seems to me that Medicare has an incentive to reach out earlier and improve the health of people who will be coming into the program," study author, Kenneth E. Thorpe, Ph.D., of Emory University, Atlanta, said in a statement.

Dr. Thorpe and his colleague, Zhou Yang, Ph.D., proposed an evidence-based weight loss program for individuals ages 60 to 64 who are not yet eligible for Medicare, but who are overweight (BMI higher than 24) or obese and at risk for diabetes, cardiovascular disease, or both (Health Affairs 2011 [doi:10.1377/hlthaff.2010.0944]).

Specifically, they suggested expanding an existing community-based weight loss program developed by the CDC, the YMCA of the USA, and UnitedHealth Group, in which trained lifestyle coaches help overweight individuals select healthier foods and increase physical activity. The program is provided by 50 YMCAs and is available at more than 116 sites in 24 states. Studies of this and similar programs show that participants ages 60 years and older lose weight and reduce their risk of developing diabetes by up to 71%.

For the current study, the investigators used 2009 census data to estimate net savings to Medicare over a 10-year period over the lifetime of a single cohort of eligible individuals. Their findings were based on the assumption of participation rates of 70% and 55% of eligible individuals using two enrollment scenarios.

The first scenario would limit enrollment to individuals ages 60 to 64 who have prediabetes and whose BMI is higher than 24. The cost to enroll 70% of that target group would be about $590 million ($240 per person for 2.6 million participants) but would result in a net savings of $2.3 billion over 10 years and $9.3 billion in net lifetime savings. If 55% of those eligible participated, estimated savings would exceed $1.8 billion over 10 years and $7.3 billion in net lifetime savings.

The second scenario would broaden eligibility to individuals with the same BMI who were at risk for cardiovascular complications (high blood pressure or elevated cholesterol) regardless of whether they had prediabetes. If 70% of eligible patients participate, Medicare would achieve an estimated net savings of $1.4 billion over 10 years and $5.8 billion in net lifetime savings. If 55% of eligible patients participate, the estimated additional net savings to Medicare would be $1.2 billion over 10 years and $4.6 billion over participants’ lifetimes.

By extending eligibility to both at-risk groups, the authors estimate that Medicare would see net savings of $3 billion to $3.7 billion over the next 10 years and $11.9 to $15.1 billion over participants’ lifetimes, depending on the participation rate.

"Our results show the potential savings to Medicare if a proven community-based approach to reducing obesity and related chronic disease were to be made available, nationwide, to high-risk individuals soon to become Medicare beneficiaries," the researchers said. "In doing so, they also present a potential business case for the federal government to partner with the private sector in order to encourage broad enrollment in effective weight loss programs."

Estimated lifetime Medicare savings of $7 billion to $15 billion depend on several factors, such as how broad eligibility and participation are, the researchers say. They used a 4.2% weight loss impact to avoid overestimation, so the program might have larger effects than expected. The proposed program could result in even greater long-term reductions in federal health care spending by extending the program to additional individuals.

The investigators proposed funding the expanded program through the CDC’s National Diabetes Prevention Program and the Prevention and Public Health Fund. Both were established as part of the Patient Protection and Affordable Care Act of 2010 to identify approaches for improving the quality of health care and reducing costs.

The authors had no financial disclosures. The Peter G. Peterson Foundation provided assistance for the research.

ATLANTA – Community-based weight loss programs for individuals ages 60 years or older who are at risk for diabetes or heart disease could save Medicare between $7 billion and $15 billion over the lifetimes of one cohort of baby boomers, according to a study in the September Health Affairs.

Obesity, defined as body mass index (BMI) of 30 kg/m², more than doubled from 18% to 37% of adults ages 65 years and older between 1980 and 2008, according to data from the Centers for Disease Control and Prevention. At the same time, obese adults spent about 40% more on health care than adults whose weight was normal, due to higher rates of diabetes and other chronic illnesses.

"It seems to me that Medicare has an incentive to reach out earlier and improve the health of people who will be coming into the program," study author, Kenneth E. Thorpe, Ph.D., of Emory University, Atlanta, said in a statement.

Dr. Thorpe and his colleague, Zhou Yang, Ph.D., proposed an evidence-based weight loss program for individuals ages 60 to 64 who are not yet eligible for Medicare, but who are overweight (BMI higher than 24) or obese and at risk for diabetes, cardiovascular disease, or both (Health Affairs 2011 [doi:10.1377/hlthaff.2010.0944]).

Specifically, they suggested expanding an existing community-based weight loss program developed by the CDC, the YMCA of the USA, and UnitedHealth Group, in which trained lifestyle coaches help overweight individuals select healthier foods and increase physical activity. The program is provided by 50 YMCAs and is available at more than 116 sites in 24 states. Studies of this and similar programs show that participants ages 60 years and older lose weight and reduce their risk of developing diabetes by up to 71%.

For the current study, the investigators used 2009 census data to estimate net savings to Medicare over a 10-year period over the lifetime of a single cohort of eligible individuals. Their findings were based on the assumption of participation rates of 70% and 55% of eligible individuals using two enrollment scenarios.

The first scenario would limit enrollment to individuals ages 60 to 64 who have prediabetes and whose BMI is higher than 24. The cost to enroll 70% of that target group would be about $590 million ($240 per person for 2.6 million participants) but would result in a net savings of $2.3 billion over 10 years and $9.3 billion in net lifetime savings. If 55% of those eligible participated, estimated savings would exceed $1.8 billion over 10 years and $7.3 billion in net lifetime savings.

The second scenario would broaden eligibility to individuals with the same BMI who were at risk for cardiovascular complications (high blood pressure or elevated cholesterol) regardless of whether they had prediabetes. If 70% of eligible patients participate, Medicare would achieve an estimated net savings of $1.4 billion over 10 years and $5.8 billion in net lifetime savings. If 55% of eligible patients participate, the estimated additional net savings to Medicare would be $1.2 billion over 10 years and $4.6 billion over participants’ lifetimes.

By extending eligibility to both at-risk groups, the authors estimate that Medicare would see net savings of $3 billion to $3.7 billion over the next 10 years and $11.9 to $15.1 billion over participants’ lifetimes, depending on the participation rate.

"Our results show the potential savings to Medicare if a proven community-based approach to reducing obesity and related chronic disease were to be made available, nationwide, to high-risk individuals soon to become Medicare beneficiaries," the researchers said. "In doing so, they also present a potential business case for the federal government to partner with the private sector in order to encourage broad enrollment in effective weight loss programs."

Estimated lifetime Medicare savings of $7 billion to $15 billion depend on several factors, such as how broad eligibility and participation are, the researchers say. They used a 4.2% weight loss impact to avoid overestimation, so the program might have larger effects than expected. The proposed program could result in even greater long-term reductions in federal health care spending by extending the program to additional individuals.

The investigators proposed funding the expanded program through the CDC’s National Diabetes Prevention Program and the Prevention and Public Health Fund. Both were established as part of the Patient Protection and Affordable Care Act of 2010 to identify approaches for improving the quality of health care and reducing costs.

The authors had no financial disclosures. The Peter G. Peterson Foundation provided assistance for the research.

ATLANTA – Community-based weight loss programs for individuals ages 60 years or older who are at risk for diabetes or heart disease could save Medicare between $7 billion and $15 billion over the lifetimes of one cohort of baby boomers, according to a study in the September Health Affairs.

Obesity, defined as body mass index (BMI) of 30 kg/m², more than doubled from 18% to 37% of adults ages 65 years and older between 1980 and 2008, according to data from the Centers for Disease Control and Prevention. At the same time, obese adults spent about 40% more on health care than adults whose weight was normal, due to higher rates of diabetes and other chronic illnesses.

"It seems to me that Medicare has an incentive to reach out earlier and improve the health of people who will be coming into the program," study author, Kenneth E. Thorpe, Ph.D., of Emory University, Atlanta, said in a statement.

Dr. Thorpe and his colleague, Zhou Yang, Ph.D., proposed an evidence-based weight loss program for individuals ages 60 to 64 who are not yet eligible for Medicare, but who are overweight (BMI higher than 24) or obese and at risk for diabetes, cardiovascular disease, or both (Health Affairs 2011 [doi:10.1377/hlthaff.2010.0944]).

Specifically, they suggested expanding an existing community-based weight loss program developed by the CDC, the YMCA of the USA, and UnitedHealth Group, in which trained lifestyle coaches help overweight individuals select healthier foods and increase physical activity. The program is provided by 50 YMCAs and is available at more than 116 sites in 24 states. Studies of this and similar programs show that participants ages 60 years and older lose weight and reduce their risk of developing diabetes by up to 71%.

For the current study, the investigators used 2009 census data to estimate net savings to Medicare over a 10-year period over the lifetime of a single cohort of eligible individuals. Their findings were based on the assumption of participation rates of 70% and 55% of eligible individuals using two enrollment scenarios.

The first scenario would limit enrollment to individuals ages 60 to 64 who have prediabetes and whose BMI is higher than 24. The cost to enroll 70% of that target group would be about $590 million ($240 per person for 2.6 million participants) but would result in a net savings of $2.3 billion over 10 years and $9.3 billion in net lifetime savings. If 55% of those eligible participated, estimated savings would exceed $1.8 billion over 10 years and $7.3 billion in net lifetime savings.

The second scenario would broaden eligibility to individuals with the same BMI who were at risk for cardiovascular complications (high blood pressure or elevated cholesterol) regardless of whether they had prediabetes. If 70% of eligible patients participate, Medicare would achieve an estimated net savings of $1.4 billion over 10 years and $5.8 billion in net lifetime savings. If 55% of eligible patients participate, the estimated additional net savings to Medicare would be $1.2 billion over 10 years and $4.6 billion over participants’ lifetimes.

By extending eligibility to both at-risk groups, the authors estimate that Medicare would see net savings of $3 billion to $3.7 billion over the next 10 years and $11.9 to $15.1 billion over participants’ lifetimes, depending on the participation rate.

"Our results show the potential savings to Medicare if a proven community-based approach to reducing obesity and related chronic disease were to be made available, nationwide, to high-risk individuals soon to become Medicare beneficiaries," the researchers said. "In doing so, they also present a potential business case for the federal government to partner with the private sector in order to encourage broad enrollment in effective weight loss programs."

Estimated lifetime Medicare savings of $7 billion to $15 billion depend on several factors, such as how broad eligibility and participation are, the researchers say. They used a 4.2% weight loss impact to avoid overestimation, so the program might have larger effects than expected. The proposed program could result in even greater long-term reductions in federal health care spending by extending the program to additional individuals.

The investigators proposed funding the expanded program through the CDC’s National Diabetes Prevention Program and the Prevention and Public Health Fund. Both were established as part of the Patient Protection and Affordable Care Act of 2010 to identify approaches for improving the quality of health care and reducing costs.

The authors had no financial disclosures. The Peter G. Peterson Foundation provided assistance for the research.

Fifty-five percent of preteens had at least one vaccination visit at ages 11-12 years in a 2009 Centers for Disease Control and Prevention survey, but they often did not receive all vaccines indicated for this age group.

In 1996, the Centers for Disease Control and Prevention (CDC) recommended that physicians administer tetanus-diphtheria (Td) vaccine to 11- and 12-year-olds. Between 2005 and 2008, the CDC recommendations for this population also include meningococcal conjugate vaccine (MCV4), a booster dose of tetanus and diphtheria toxoids with acellular pertussis (Tdap) vaccine, quadrivalent human papillomavirus (HPV) vaccine for girls, influenza vaccine, and, for some adolescents, a second dose of varicella vaccine.

So Shannon Stokley, M.P.H., of the CDC Immunization Services Division, and her colleagues examined data from the 2009 National Immunization Survey–Teen (NIS-Teen) telephone interview to estimate vaccination coverage rates for adolescents aged 13-17 years. Although significantly more preteens and adolescents are being vaccinated than indicated in previous studies, estimates from previous studies did not reflect the specific ages at which the individuals received the vaccines.

©Micah Young/istockphoto.com

NIS-Teen, conducted between Jan. 6, 2009, and Feb. 10, 2010, used random-digit dialing to survey households with age-eligible adolescents and, with consent, mailed an Immunization History Questionnaire to providers. The researchers completed interviews with 35,004 households and obtained information from vaccine providers for 20,066 children and adolescents, Ms. Stokley and her coauthors reported in the September issue of Archives of Pediatric and Adolescent Medicine (2011;165:813-8).

The investigators assessed the immunization rates for measles, hepatitis B, and varicella, as well as Td/Tdap and meningococcal-containing vaccines, for all children and adolescents and for specific age groups, and they also assessed HPV vaccination for girls. They determined the age at which each child or adolescent received each dose of vaccine, and the percentage of adolescents aged 11-12 years who made at least one vaccination visit.

Outcome measures included being up-to-date with recommended vaccines by age 11 years, by age 13 years, and at the time of the interview (ages 13 and older).

Analysis of the data showed the following:

• Td/Tdap vaccine. The researchers found that 6.1% of preteens received Td/Tdap vaccine by age 11. Vaccination with Td/Tdap during ages 11-12 years increased with each birth cohort; receipt of a Td and/or Tdap vaccine at ages 11-12 years more than doubled, from 33.8% among those born in 1991 to 68.2% for those born in 1996. Coverage increased an additional 42.1% by age 13 years and an additional 28.9% by the time of the interview.

• MCV4: The number of patients who received MCV4 increased from 8.4% in the 1993 birth cohort (the first cohort for whom it was available) to 50.0% in 1996 birth cohort. Overall, 18.6% of the sample received the vaccine by age 13.

• HPV: The number of girls who received the HPV vaccine at ages 11-12 years increased significantly, from 11.1% of those born in 1994 (the first birth cohort for whom it was available) to 30.5% of those born in 1996. By age 13, 10.9% of the population studied had received the vaccine.

Although 55% of preteen patients had at least one vaccination visit at ages 11-12 years, 19.5% of the preteens who made a vaccination visit at this age and were eligible for vaccination did not receive Td and/or Tdap vaccines, 60.9% did not receive meningococcal-containing vaccines, and 62.4% of girls did not receive HPV vaccines. Recent surveys have shown that physicians are reluctant to administer the HPV and MCV4 at these ages, but the data in this analysis show that vaccination rates at this age may be increasing, Ms. Stokley and her associates reported.

"Our analysis of the early stages of adolescent vaccine implementation show encouraging progress with implementing the new recommendations, but also indicate that more can be done to increase the frequency with which adolescents receive all necessary vaccines during a visit," the researchers said.

Some suggestions they offer:

• Educate parents about recommended vaccines and the diseases they prevent, as well as the benefits of preventive health care visits.

• Work with immunization providers to encourage them to take advantage of all health care encounters to administer all vaccines for which an adolescent is eligible during the same visit.

Potential limitations of this study include bias due to household nonresponse and households not having landlines, exclusion of adolescents for whom there was not adequate immunization data, and possible misclassification of adolescents as not having received all vaccines if all providers were not identified.

The CDC offers information for parents (www.cdc.gov/vaccines/who/teens/index.html) and for health care providers (www.cdc.gov/vaccines/who/teens/for-hcp.html).

Ms. Stokley and her associates had no relevant financial disclosures.

Fifty-five percent of preteens had at least one vaccination visit at ages 11-12 years in a 2009 Centers for Disease Control and Prevention survey, but they often did not receive all vaccines indicated for this age group.

In 1996, the Centers for Disease Control and Prevention (CDC) recommended that physicians administer tetanus-diphtheria (Td) vaccine to 11- and 12-year-olds. Between 2005 and 2008, the CDC recommendations for this population also include meningococcal conjugate vaccine (MCV4), a booster dose of tetanus and diphtheria toxoids with acellular pertussis (Tdap) vaccine, quadrivalent human papillomavirus (HPV) vaccine for girls, influenza vaccine, and, for some adolescents, a second dose of varicella vaccine.

So Shannon Stokley, M.P.H., of the CDC Immunization Services Division, and her colleagues examined data from the 2009 National Immunization Survey–Teen (NIS-Teen) telephone interview to estimate vaccination coverage rates for adolescents aged 13-17 years. Although significantly more preteens and adolescents are being vaccinated than indicated in previous studies, estimates from previous studies did not reflect the specific ages at which the individuals received the vaccines.

©Micah Young/istockphoto.com

NIS-Teen, conducted between Jan. 6, 2009, and Feb. 10, 2010, used random-digit dialing to survey households with age-eligible adolescents and, with consent, mailed an Immunization History Questionnaire to providers. The researchers completed interviews with 35,004 households and obtained information from vaccine providers for 20,066 children and adolescents, Ms. Stokley and her coauthors reported in the September issue of Archives of Pediatric and Adolescent Medicine (2011;165:813-8).

The investigators assessed the immunization rates for measles, hepatitis B, and varicella, as well as Td/Tdap and meningococcal-containing vaccines, for all children and adolescents and for specific age groups, and they also assessed HPV vaccination for girls. They determined the age at which each child or adolescent received each dose of vaccine, and the percentage of adolescents aged 11-12 years who made at least one vaccination visit.

Outcome measures included being up-to-date with recommended vaccines by age 11 years, by age 13 years, and at the time of the interview (ages 13 and older).

Analysis of the data showed the following:

• Td/Tdap vaccine. The researchers found that 6.1% of preteens received Td/Tdap vaccine by age 11. Vaccination with Td/Tdap during ages 11-12 years increased with each birth cohort; receipt of a Td and/or Tdap vaccine at ages 11-12 years more than doubled, from 33.8% among those born in 1991 to 68.2% for those born in 1996. Coverage increased an additional 42.1% by age 13 years and an additional 28.9% by the time of the interview.

• MCV4: The number of patients who received MCV4 increased from 8.4% in the 1993 birth cohort (the first cohort for whom it was available) to 50.0% in 1996 birth cohort. Overall, 18.6% of the sample received the vaccine by age 13.

• HPV: The number of girls who received the HPV vaccine at ages 11-12 years increased significantly, from 11.1% of those born in 1994 (the first birth cohort for whom it was available) to 30.5% of those born in 1996. By age 13, 10.9% of the population studied had received the vaccine.

Although 55% of preteen patients had at least one vaccination visit at ages 11-12 years, 19.5% of the preteens who made a vaccination visit at this age and were eligible for vaccination did not receive Td and/or Tdap vaccines, 60.9% did not receive meningococcal-containing vaccines, and 62.4% of girls did not receive HPV vaccines. Recent surveys have shown that physicians are reluctant to administer the HPV and MCV4 at these ages, but the data in this analysis show that vaccination rates at this age may be increasing, Ms. Stokley and her associates reported.

"Our analysis of the early stages of adolescent vaccine implementation show encouraging progress with implementing the new recommendations, but also indicate that more can be done to increase the frequency with which adolescents receive all necessary vaccines during a visit," the researchers said.

Some suggestions they offer:

• Educate parents about recommended vaccines and the diseases they prevent, as well as the benefits of preventive health care visits.

• Work with immunization providers to encourage them to take advantage of all health care encounters to administer all vaccines for which an adolescent is eligible during the same visit.

Potential limitations of this study include bias due to household nonresponse and households not having landlines, exclusion of adolescents for whom there was not adequate immunization data, and possible misclassification of adolescents as not having received all vaccines if all providers were not identified.

The CDC offers information for parents (www.cdc.gov/vaccines/who/teens/index.html) and for health care providers (www.cdc.gov/vaccines/who/teens/for-hcp.html).

Ms. Stokley and her associates had no relevant financial disclosures.

Fifty-five percent of preteens had at least one vaccination visit at ages 11-12 years in a 2009 Centers for Disease Control and Prevention survey, but they often did not receive all vaccines indicated for this age group.

In 1996, the Centers for Disease Control and Prevention (CDC) recommended that physicians administer tetanus-diphtheria (Td) vaccine to 11- and 12-year-olds. Between 2005 and 2008, the CDC recommendations for this population also include meningococcal conjugate vaccine (MCV4), a booster dose of tetanus and diphtheria toxoids with acellular pertussis (Tdap) vaccine, quadrivalent human papillomavirus (HPV) vaccine for girls, influenza vaccine, and, for some adolescents, a second dose of varicella vaccine.

So Shannon Stokley, M.P.H., of the CDC Immunization Services Division, and her colleagues examined data from the 2009 National Immunization Survey–Teen (NIS-Teen) telephone interview to estimate vaccination coverage rates for adolescents aged 13-17 years. Although significantly more preteens and adolescents are being vaccinated than indicated in previous studies, estimates from previous studies did not reflect the specific ages at which the individuals received the vaccines.

©Micah Young/istockphoto.com

NIS-Teen, conducted between Jan. 6, 2009, and Feb. 10, 2010, used random-digit dialing to survey households with age-eligible adolescents and, with consent, mailed an Immunization History Questionnaire to providers. The researchers completed interviews with 35,004 households and obtained information from vaccine providers for 20,066 children and adolescents, Ms. Stokley and her coauthors reported in the September issue of Archives of Pediatric and Adolescent Medicine (2011;165:813-8).

The investigators assessed the immunization rates for measles, hepatitis B, and varicella, as well as Td/Tdap and meningococcal-containing vaccines, for all children and adolescents and for specific age groups, and they also assessed HPV vaccination for girls. They determined the age at which each child or adolescent received each dose of vaccine, and the percentage of adolescents aged 11-12 years who made at least one vaccination visit.

Outcome measures included being up-to-date with recommended vaccines by age 11 years, by age 13 years, and at the time of the interview (ages 13 and older).

Analysis of the data showed the following:

• Td/Tdap vaccine. The researchers found that 6.1% of preteens received Td/Tdap vaccine by age 11. Vaccination with Td/Tdap during ages 11-12 years increased with each birth cohort; receipt of a Td and/or Tdap vaccine at ages 11-12 years more than doubled, from 33.8% among those born in 1991 to 68.2% for those born in 1996. Coverage increased an additional 42.1% by age 13 years and an additional 28.9% by the time of the interview.

• MCV4: The number of patients who received MCV4 increased from 8.4% in the 1993 birth cohort (the first cohort for whom it was available) to 50.0% in 1996 birth cohort. Overall, 18.6% of the sample received the vaccine by age 13.

• HPV: The number of girls who received the HPV vaccine at ages 11-12 years increased significantly, from 11.1% of those born in 1994 (the first birth cohort for whom it was available) to 30.5% of those born in 1996. By age 13, 10.9% of the population studied had received the vaccine.

Although 55% of preteen patients had at least one vaccination visit at ages 11-12 years, 19.5% of the preteens who made a vaccination visit at this age and were eligible for vaccination did not receive Td and/or Tdap vaccines, 60.9% did not receive meningococcal-containing vaccines, and 62.4% of girls did not receive HPV vaccines. Recent surveys have shown that physicians are reluctant to administer the HPV and MCV4 at these ages, but the data in this analysis show that vaccination rates at this age may be increasing, Ms. Stokley and her associates reported.

"Our analysis of the early stages of adolescent vaccine implementation show encouraging progress with implementing the new recommendations, but also indicate that more can be done to increase the frequency with which adolescents receive all necessary vaccines during a visit," the researchers said.

Some suggestions they offer:

• Educate parents about recommended vaccines and the diseases they prevent, as well as the benefits of preventive health care visits.

• Work with immunization providers to encourage them to take advantage of all health care encounters to administer all vaccines for which an adolescent is eligible during the same visit.

Potential limitations of this study include bias due to household nonresponse and households not having landlines, exclusion of adolescents for whom there was not adequate immunization data, and possible misclassification of adolescents as not having received all vaccines if all providers were not identified.

The CDC offers information for parents (www.cdc.gov/vaccines/who/teens/index.html) and for health care providers (www.cdc.gov/vaccines/who/teens/for-hcp.html).

Ms. Stokley and her associates had no relevant financial disclosures.

The average cost to treat a patient with postoperative sepsis is 2.28-3.6 times higher than the cost of treating a patient without sepsis, results from a large database analysis demonstrate.

Postoperative sepsis can lead to complications such as kidney failure or depressed heart rate, and an estimated 30% of patients with severe sepsis die within 1 month. Cost estimates for treating postoperative sepsis have ranged from $10,000 to $40,000 per case (Arch. Surg. 2011;146:944-51).

In this study, Mary S. Vaughan-Sarrazin, Ph.D., of the University of Iowa and her colleagues sought to determine the incremental cost associated with sepsis as a complication of general surgery, drawing on data from 118 acute care Veterans Affairs hospitals and the VA Surgical Quality Improvement Program (VASQIP) to identify patient risk factors and postoperative complications. They looked at results for 16,360 patients who underwent surgery performed by a general surgeon between Oct. 1, 2005, and Sept. 30, 2006, including total costs associated with the index admission and all subsequent readmissions within 30 days after surgery.

Of 13,878 patients included in the final analysis, 564 (4.1%) developed postoperative sepsis. A total of 365 had severe sepsis, and 199 had septic shock. The overall rates of sepsis, however, varied by the following criteria:

• Age. Older patients had a greater likelihood of developing sepsis, which occurred in 2.3% of patients younger than age 55 and in 6.1% of patients aged 85 and older.

• Type of surgery. Sepsis was more likely to occur in patients who had surgery involving the stomach (8.0% of patients), pancreas (13.5%), and rectum (8.6%), as well as total colon removal (8.3%) and other intestinal procedures (10.2%).

• Preexisting conditions. Patients with preexisting conditions before the surgery were more likely to develop postoperative sepsis. The largest occurrence was in 24.6% of patients who were ventilator dependent within 48 hours of surgery. There also were high rates of sepsis in patients with dyspnea (7.2%-13.7% of patients), diabetes mellitus (6.0%), loss of more than 10% of body weight preoperatively (8.8%), bleeding disorders (8.9%), open wound or wound infection (5.6%), blood transfusion (14.6%), pneumonia (10.9%), severe chronic obstructive pulmonary disease (6.6%), and acute renal failure (11.2%).

• Laboratory results. Postoperative sepsis occurred in 3.0% of patients whose serum urea nitrogen (SUN) levels were 15 mg/dL or less, and in 9.4% of those whose SUN levels were greater than 30 mg/dL. Sepsis also occurred in 9.3% of patients whose WBC was 20 mcL or greater, and in 13.8% of patients whose albumen level was less than 2.0 mg/dL or higher.

• Other complications. Sepsis often occurred along with other complications, including failure to wean the patient from a mechanical ventilator after 48 hours (35.8% of patients), postoperative pneumonia (30.9%), reintubation for respiratory or cardiac failure (28.7%), and urinary tract infection (18.8%).

Assuming a 4.1% rate of sepsis, as in this study, an average hospital spends $230,000 annually to treat postoperative sepsis in general surgery patients. The average unadjusted cost per patient went from $24,923 for patients with no sepsis to $88,747 for patients with sepsis, the researchers found. The cost increased further to $92,829 for patients with septic shock. Unadjusted costs when sepsis occurred with other conditions were highest in patients with deep vein thrombosis ($134,162), wound dehiscence ($121,801), and pneumonia ($115,182). Sepsis resulting from failure to wean the patient from mechanical ventilation after 48 hours resulted in an estimated cost of $124,895.

In risk-adjusted analysis, the costs for patients with sepsis were 2.28 times higher than for those without ($48,017 per patient vs. $21,045 per patient, respectively), a difference of $26,972.

The mortality rate, quality of life considerations, and costs make a case for hospitals to adopt initiatives to avoid postoperative sepsis and to identify and treat earlier those cases that do occur. Across the VA hospital system, a 10%-15% drop in sepsis rates after general surgery would save $2.8-$4 million, the researchers said.

"Achieving meaningful reductions in complications of surgery requires sustained institutional commitment to encourage quality improvement efforts that bring together surgeons, anesthesiologists, nurses, and other individuals in the surgical process. This study documents that, although time consuming and often expensive, successful efforts to reduce postoperative sepsis may result in substantial cost savings," they concluded.

Potential limitations of the study include the variance in cost estimates among hospitals and the reliance on observational data, they noted.

This study was supported by Merit Review grant IIR-07-151 from the VA Health Services Research and Development Service. The authors had no financial disclosures.

The average cost to treat a patient with postoperative sepsis is 2.28-3.6 times higher than the cost of treating a patient without sepsis, results from a large database analysis demonstrate.

Postoperative sepsis can lead to complications such as kidney failure or depressed heart rate, and an estimated 30% of patients with severe sepsis die within 1 month. Cost estimates for treating postoperative sepsis have ranged from $10,000 to $40,000 per case (Arch. Surg. 2011;146:944-51).

In this study, Mary S. Vaughan-Sarrazin, Ph.D., of the University of Iowa and her colleagues sought to determine the incremental cost associated with sepsis as a complication of general surgery, drawing on data from 118 acute care Veterans Affairs hospitals and the VA Surgical Quality Improvement Program (VASQIP) to identify patient risk factors and postoperative complications. They looked at results for 16,360 patients who underwent surgery performed by a general surgeon between Oct. 1, 2005, and Sept. 30, 2006, including total costs associated with the index admission and all subsequent readmissions within 30 days after surgery.

Of 13,878 patients included in the final analysis, 564 (4.1%) developed postoperative sepsis. A total of 365 had severe sepsis, and 199 had septic shock. The overall rates of sepsis, however, varied by the following criteria:

• Age. Older patients had a greater likelihood of developing sepsis, which occurred in 2.3% of patients younger than age 55 and in 6.1% of patients aged 85 and older.

• Type of surgery. Sepsis was more likely to occur in patients who had surgery involving the stomach (8.0% of patients), pancreas (13.5%), and rectum (8.6%), as well as total colon removal (8.3%) and other intestinal procedures (10.2%).

• Preexisting conditions. Patients with preexisting conditions before the surgery were more likely to develop postoperative sepsis. The largest occurrence was in 24.6% of patients who were ventilator dependent within 48 hours of surgery. There also were high rates of sepsis in patients with dyspnea (7.2%-13.7% of patients), diabetes mellitus (6.0%), loss of more than 10% of body weight preoperatively (8.8%), bleeding disorders (8.9%), open wound or wound infection (5.6%), blood transfusion (14.6%), pneumonia (10.9%), severe chronic obstructive pulmonary disease (6.6%), and acute renal failure (11.2%).

• Laboratory results. Postoperative sepsis occurred in 3.0% of patients whose serum urea nitrogen (SUN) levels were 15 mg/dL or less, and in 9.4% of those whose SUN levels were greater than 30 mg/dL. Sepsis also occurred in 9.3% of patients whose WBC was 20 mcL or greater, and in 13.8% of patients whose albumen level was less than 2.0 mg/dL or higher.

• Other complications. Sepsis often occurred along with other complications, including failure to wean the patient from a mechanical ventilator after 48 hours (35.8% of patients), postoperative pneumonia (30.9%), reintubation for respiratory or cardiac failure (28.7%), and urinary tract infection (18.8%).

Assuming a 4.1% rate of sepsis, as in this study, an average hospital spends $230,000 annually to treat postoperative sepsis in general surgery patients. The average unadjusted cost per patient went from $24,923 for patients with no sepsis to $88,747 for patients with sepsis, the researchers found. The cost increased further to $92,829 for patients with septic shock. Unadjusted costs when sepsis occurred with other conditions were highest in patients with deep vein thrombosis ($134,162), wound dehiscence ($121,801), and pneumonia ($115,182). Sepsis resulting from failure to wean the patient from mechanical ventilation after 48 hours resulted in an estimated cost of $124,895.

In risk-adjusted analysis, the costs for patients with sepsis were 2.28 times higher than for those without ($48,017 per patient vs. $21,045 per patient, respectively), a difference of $26,972.

The mortality rate, quality of life considerations, and costs make a case for hospitals to adopt initiatives to avoid postoperative sepsis and to identify and treat earlier those cases that do occur. Across the VA hospital system, a 10%-15% drop in sepsis rates after general surgery would save $2.8-$4 million, the researchers said.

"Achieving meaningful reductions in complications of surgery requires sustained institutional commitment to encourage quality improvement efforts that bring together surgeons, anesthesiologists, nurses, and other individuals in the surgical process. This study documents that, although time consuming and often expensive, successful efforts to reduce postoperative sepsis may result in substantial cost savings," they concluded.

Potential limitations of the study include the variance in cost estimates among hospitals and the reliance on observational data, they noted.

This study was supported by Merit Review grant IIR-07-151 from the VA Health Services Research and Development Service. The authors had no financial disclosures.

The average cost to treat a patient with postoperative sepsis is 2.28-3.6 times higher than the cost of treating a patient without sepsis, results from a large database analysis demonstrate.

Postoperative sepsis can lead to complications such as kidney failure or depressed heart rate, and an estimated 30% of patients with severe sepsis die within 1 month. Cost estimates for treating postoperative sepsis have ranged from $10,000 to $40,000 per case (Arch. Surg. 2011;146:944-51).

In this study, Mary S. Vaughan-Sarrazin, Ph.D., of the University of Iowa and her colleagues sought to determine the incremental cost associated with sepsis as a complication of general surgery, drawing on data from 118 acute care Veterans Affairs hospitals and the VA Surgical Quality Improvement Program (VASQIP) to identify patient risk factors and postoperative complications. They looked at results for 16,360 patients who underwent surgery performed by a general surgeon between Oct. 1, 2005, and Sept. 30, 2006, including total costs associated with the index admission and all subsequent readmissions within 30 days after surgery.

Of 13,878 patients included in the final analysis, 564 (4.1%) developed postoperative sepsis. A total of 365 had severe sepsis, and 199 had septic shock. The overall rates of sepsis, however, varied by the following criteria:

• Age. Older patients had a greater likelihood of developing sepsis, which occurred in 2.3% of patients younger than age 55 and in 6.1% of patients aged 85 and older.

• Type of surgery. Sepsis was more likely to occur in patients who had surgery involving the stomach (8.0% of patients), pancreas (13.5%), and rectum (8.6%), as well as total colon removal (8.3%) and other intestinal procedures (10.2%).

• Preexisting conditions. Patients with preexisting conditions before the surgery were more likely to develop postoperative sepsis. The largest occurrence was in 24.6% of patients who were ventilator dependent within 48 hours of surgery. There also were high rates of sepsis in patients with dyspnea (7.2%-13.7% of patients), diabetes mellitus (6.0%), loss of more than 10% of body weight preoperatively (8.8%), bleeding disorders (8.9%), open wound or wound infection (5.6%), blood transfusion (14.6%), pneumonia (10.9%), severe chronic obstructive pulmonary disease (6.6%), and acute renal failure (11.2%).

• Laboratory results. Postoperative sepsis occurred in 3.0% of patients whose serum urea nitrogen (SUN) levels were 15 mg/dL or less, and in 9.4% of those whose SUN levels were greater than 30 mg/dL. Sepsis also occurred in 9.3% of patients whose WBC was 20 mcL or greater, and in 13.8% of patients whose albumen level was less than 2.0 mg/dL or higher.

• Other complications. Sepsis often occurred along with other complications, including failure to wean the patient from a mechanical ventilator after 48 hours (35.8% of patients), postoperative pneumonia (30.9%), reintubation for respiratory or cardiac failure (28.7%), and urinary tract infection (18.8%).

Assuming a 4.1% rate of sepsis, as in this study, an average hospital spends $230,000 annually to treat postoperative sepsis in general surgery patients. The average unadjusted cost per patient went from $24,923 for patients with no sepsis to $88,747 for patients with sepsis, the researchers found. The cost increased further to $92,829 for patients with septic shock. Unadjusted costs when sepsis occurred with other conditions were highest in patients with deep vein thrombosis ($134,162), wound dehiscence ($121,801), and pneumonia ($115,182). Sepsis resulting from failure to wean the patient from mechanical ventilation after 48 hours resulted in an estimated cost of $124,895.

In risk-adjusted analysis, the costs for patients with sepsis were 2.28 times higher than for those without ($48,017 per patient vs. $21,045 per patient, respectively), a difference of $26,972.

The mortality rate, quality of life considerations, and costs make a case for hospitals to adopt initiatives to avoid postoperative sepsis and to identify and treat earlier those cases that do occur. Across the VA hospital system, a 10%-15% drop in sepsis rates after general surgery would save $2.8-$4 million, the researchers said.

"Achieving meaningful reductions in complications of surgery requires sustained institutional commitment to encourage quality improvement efforts that bring together surgeons, anesthesiologists, nurses, and other individuals in the surgical process. This study documents that, although time consuming and often expensive, successful efforts to reduce postoperative sepsis may result in substantial cost savings," they concluded.

Potential limitations of the study include the variance in cost estimates among hospitals and the reliance on observational data, they noted.

This study was supported by Merit Review grant IIR-07-151 from the VA Health Services Research and Development Service. The authors had no financial disclosures.

The decision to use vaccines in children with rheumatic diseases must be guided by what ongoing therapy they are on, with an eye to timing the vaccination before initiation of particularly immunosuppressive treatments when possible. Follow-up titers should be assessed in some cases to document that the child has mounted a protective response, according to guidelines issued by a task force convened by the European League Against Rheumatism.

These are among the recommendations on use of vaccines in children with rheumatic diseases that the panel made after a systematic literature review of MEDLINE in December 2009, MEDLINE and EMBASE in November 2010, and abstracts from EULAR and American College of Rheumatology meetings in 2008 and 2009 (Ann. Rheum. Dis. 2011 Aug. 3 [doi:10.1136/ard.2011.150193]).

Lead by Dr. M.W. Heijstek of Wilhelmina Children’s Hospital, University Medical Center, Utrecht, the task force reviewed 67 papers, combining the search terms "vaccinations" with "immunosuppressive drugs" and 147 papers using "vaccinations" and "pediatric autoinflammatory or rheumatic disease."

Their first set of guidelines address vaccination in children on immunosuppressive medications:

• Pediatric patients who use glucocorticosteroids, disease-modifying antirheumatic drugs (DMARDs), and/or anti–tumor necrosis factor-alpha (anti-TNF-alpha) therapy can receive nonlive vaccines, when indicated according to national guidelines.

• Clinicians should determine pathogen-specific antibody concentrations after vaccination in patients who are taking either high-dose glucocorticosteroids (daily dose of 2 mg/kg higher or a total dose of at least 20 mg/day for 2 weeks or more) or rituximab and possibly in patients using an anti–TNF-alpha agent.

• The pneumococcal or influenza vaccine should be given before patients initiate treatment with rituximab.

• Tetanus immunoglobulin is indicated when patients who have been taking rituximab within the past 6 months develop a contaminated wound.

• Physicians should determine pneumococcal serotype–specific antibody concentrations after pneumococcal polysaccharide vaccine 23 vaccination in patients on methotrexate at the time of vaccination.

The panel also developed recommendations for use of live attenuated and nonlive composite vaccines in pediatric patients with rheumatic disease. For live attenuated vaccines, the panel recommends that clinicians:

• Withhold them in patients using high-doses of DMARDs or glucocorticosteroids or biological agents.

• Adhere to national vaccination guidelines for live-attenuated vaccines in patients unless they are are on high-dose DMARD, high-dose glucocorticosteroids or biological agents.

• Consider booster vaccinations against varicella zoster virus (VZV); measles, mumps and rubella (MMR); and yellow fever in patients using less than 15mg/m2 methotrexate per week or low-dose glucocorticosteroids.

• Withhold bacillus Calmette-Guerin (BCG) vaccination during active Kawasaki disease.

• Assess VZV infection and vaccination history, especially in those patients likely to use high-dose immunosuppressive therapy or biological agents. In history is negative for VZV infection or vaccination, consider using the vaccine before initiating immunosuppressive therapy.

In the case of non-live composite vaccines, the guidelines recommend that clinicians:

• Administer the tetanus toxoid (TT) vaccine to patients with juvenile systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA) according to national vaccination guidelines.

• Adhere to national vaccination guidelines for vaccination against the following: hepatitis A and B viruses, tetanus, diphtheria, pertussis, Haemophilus influenzae type B (Hib), pneumococci and meningococci, cholera, Japanese and tickborne encephalitis, poliovirus, rabies, encephalitis, typhoid fever, and human papillomavirus (HPV).

• If vaccinations against Hib, pneumococci, and meningococci are not included in the national vaccination programs, these vaccinations are recommended for children with rheumatic diseases who have low complement levels or functional asplenia. These vaccinations can be considered in patients on high-dose immunosuppressive drugs or biologic agents before therapy.

• Vaccinate female patients with SLE against HPV during adolescence, as they are at higher risk for HPV, but remain vigilant for potential thromboembolic events.

• Consider annual influenza vaccination in all pediatric patients with rheumatic disease.

The recommendations often refer to national vaccination guidelines, which consider local epidemiology, programmatic issues, resources, and policies, the authors say.

"Generally, the immunogenicity of vaccines is good in [children with rheumatic diseases]," they added. "There are some exceptions, depending on the type of dose of immunosuppressive treatment and type of vaccine."

The researchers also studied disease activity and adverse events. Most studies were underpowered to assess safety, they say, meaning that additional safety studies are warranted.

Finally, the authors recommend that these guidelines be updated regularly as new evidence on vaccinating pediatric patients on immunomodulating drugs becomes available.

The authors have no conflicts to disclose. The study was funded by EULAR.

The decision to use vaccines in children with rheumatic diseases must be guided by what ongoing therapy they are on, with an eye to timing the vaccination before initiation of particularly immunosuppressive treatments when possible. Follow-up titers should be assessed in some cases to document that the child has mounted a protective response, according to guidelines issued by a task force convened by the European League Against Rheumatism.

These are among the recommendations on use of vaccines in children with rheumatic diseases that the panel made after a systematic literature review of MEDLINE in December 2009, MEDLINE and EMBASE in November 2010, and abstracts from EULAR and American College of Rheumatology meetings in 2008 and 2009 (Ann. Rheum. Dis. 2011 Aug. 3 [doi:10.1136/ard.2011.150193]).

Lead by Dr. M.W. Heijstek of Wilhelmina Children’s Hospital, University Medical Center, Utrecht, the task force reviewed 67 papers, combining the search terms "vaccinations" with "immunosuppressive drugs" and 147 papers using "vaccinations" and "pediatric autoinflammatory or rheumatic disease."

Their first set of guidelines address vaccination in children on immunosuppressive medications:

• Pediatric patients who use glucocorticosteroids, disease-modifying antirheumatic drugs (DMARDs), and/or anti–tumor necrosis factor-alpha (anti-TNF-alpha) therapy can receive nonlive vaccines, when indicated according to national guidelines.

• Clinicians should determine pathogen-specific antibody concentrations after vaccination in patients who are taking either high-dose glucocorticosteroids (daily dose of 2 mg/kg higher or a total dose of at least 20 mg/day for 2 weeks or more) or rituximab and possibly in patients using an anti–TNF-alpha agent.

• The pneumococcal or influenza vaccine should be given before patients initiate treatment with rituximab.

• Tetanus immunoglobulin is indicated when patients who have been taking rituximab within the past 6 months develop a contaminated wound.

• Physicians should determine pneumococcal serotype–specific antibody concentrations after pneumococcal polysaccharide vaccine 23 vaccination in patients on methotrexate at the time of vaccination.

The panel also developed recommendations for use of live attenuated and nonlive composite vaccines in pediatric patients with rheumatic disease. For live attenuated vaccines, the panel recommends that clinicians:

• Withhold them in patients using high-doses of DMARDs or glucocorticosteroids or biological agents.

• Adhere to national vaccination guidelines for live-attenuated vaccines in patients unless they are are on high-dose DMARD, high-dose glucocorticosteroids or biological agents.

• Consider booster vaccinations against varicella zoster virus (VZV); measles, mumps and rubella (MMR); and yellow fever in patients using less than 15mg/m2 methotrexate per week or low-dose glucocorticosteroids.

• Withhold bacillus Calmette-Guerin (BCG) vaccination during active Kawasaki disease.

• Assess VZV infection and vaccination history, especially in those patients likely to use high-dose immunosuppressive therapy or biological agents. In history is negative for VZV infection or vaccination, consider using the vaccine before initiating immunosuppressive therapy.

In the case of non-live composite vaccines, the guidelines recommend that clinicians:

• Administer the tetanus toxoid (TT) vaccine to patients with juvenile systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA) according to national vaccination guidelines.

• Adhere to national vaccination guidelines for vaccination against the following: hepatitis A and B viruses, tetanus, diphtheria, pertussis, Haemophilus influenzae type B (Hib), pneumococci and meningococci, cholera, Japanese and tickborne encephalitis, poliovirus, rabies, encephalitis, typhoid fever, and human papillomavirus (HPV).

• If vaccinations against Hib, pneumococci, and meningococci are not included in the national vaccination programs, these vaccinations are recommended for children with rheumatic diseases who have low complement levels or functional asplenia. These vaccinations can be considered in patients on high-dose immunosuppressive drugs or biologic agents before therapy.

• Vaccinate female patients with SLE against HPV during adolescence, as they are at higher risk for HPV, but remain vigilant for potential thromboembolic events.

• Consider annual influenza vaccination in all pediatric patients with rheumatic disease.

The recommendations often refer to national vaccination guidelines, which consider local epidemiology, programmatic issues, resources, and policies, the authors say.

"Generally, the immunogenicity of vaccines is good in [children with rheumatic diseases]," they added. "There are some exceptions, depending on the type of dose of immunosuppressive treatment and type of vaccine."

The researchers also studied disease activity and adverse events. Most studies were underpowered to assess safety, they say, meaning that additional safety studies are warranted.

Finally, the authors recommend that these guidelines be updated regularly as new evidence on vaccinating pediatric patients on immunomodulating drugs becomes available.

The authors have no conflicts to disclose. The study was funded by EULAR.

The decision to use vaccines in children with rheumatic diseases must be guided by what ongoing therapy they are on, with an eye to timing the vaccination before initiation of particularly immunosuppressive treatments when possible. Follow-up titers should be assessed in some cases to document that the child has mounted a protective response, according to guidelines issued by a task force convened by the European League Against Rheumatism.

These are among the recommendations on use of vaccines in children with rheumatic diseases that the panel made after a systematic literature review of MEDLINE in December 2009, MEDLINE and EMBASE in November 2010, and abstracts from EULAR and American College of Rheumatology meetings in 2008 and 2009 (Ann. Rheum. Dis. 2011 Aug. 3 [doi:10.1136/ard.2011.150193]).

Lead by Dr. M.W. Heijstek of Wilhelmina Children’s Hospital, University Medical Center, Utrecht, the task force reviewed 67 papers, combining the search terms "vaccinations" with "immunosuppressive drugs" and 147 papers using "vaccinations" and "pediatric autoinflammatory or rheumatic disease."

Their first set of guidelines address vaccination in children on immunosuppressive medications:

• Pediatric patients who use glucocorticosteroids, disease-modifying antirheumatic drugs (DMARDs), and/or anti–tumor necrosis factor-alpha (anti-TNF-alpha) therapy can receive nonlive vaccines, when indicated according to national guidelines.

• Clinicians should determine pathogen-specific antibody concentrations after vaccination in patients who are taking either high-dose glucocorticosteroids (daily dose of 2 mg/kg higher or a total dose of at least 20 mg/day for 2 weeks or more) or rituximab and possibly in patients using an anti–TNF-alpha agent.

• The pneumococcal or influenza vaccine should be given before patients initiate treatment with rituximab.

• Tetanus immunoglobulin is indicated when patients who have been taking rituximab within the past 6 months develop a contaminated wound.

• Physicians should determine pneumococcal serotype–specific antibody concentrations after pneumococcal polysaccharide vaccine 23 vaccination in patients on methotrexate at the time of vaccination.

The panel also developed recommendations for use of live attenuated and nonlive composite vaccines in pediatric patients with rheumatic disease. For live attenuated vaccines, the panel recommends that clinicians:

• Withhold them in patients using high-doses of DMARDs or glucocorticosteroids or biological agents.

• Adhere to national vaccination guidelines for live-attenuated vaccines in patients unless they are are on high-dose DMARD, high-dose glucocorticosteroids or biological agents.

• Consider booster vaccinations against varicella zoster virus (VZV); measles, mumps and rubella (MMR); and yellow fever in patients using less than 15mg/m2 methotrexate per week or low-dose glucocorticosteroids.

• Withhold bacillus Calmette-Guerin (BCG) vaccination during active Kawasaki disease.

• Assess VZV infection and vaccination history, especially in those patients likely to use high-dose immunosuppressive therapy or biological agents. In history is negative for VZV infection or vaccination, consider using the vaccine before initiating immunosuppressive therapy.

In the case of non-live composite vaccines, the guidelines recommend that clinicians:

• Administer the tetanus toxoid (TT) vaccine to patients with juvenile systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA) according to national vaccination guidelines.

• Adhere to national vaccination guidelines for vaccination against the following: hepatitis A and B viruses, tetanus, diphtheria, pertussis, Haemophilus influenzae type B (Hib), pneumococci and meningococci, cholera, Japanese and tickborne encephalitis, poliovirus, rabies, encephalitis, typhoid fever, and human papillomavirus (HPV).

• If vaccinations against Hib, pneumococci, and meningococci are not included in the national vaccination programs, these vaccinations are recommended for children with rheumatic diseases who have low complement levels or functional asplenia. These vaccinations can be considered in patients on high-dose immunosuppressive drugs or biologic agents before therapy.

• Vaccinate female patients with SLE against HPV during adolescence, as they are at higher risk for HPV, but remain vigilant for potential thromboembolic events.

• Consider annual influenza vaccination in all pediatric patients with rheumatic disease.

The recommendations often refer to national vaccination guidelines, which consider local epidemiology, programmatic issues, resources, and policies, the authors say.

"Generally, the immunogenicity of vaccines is good in [children with rheumatic diseases]," they added. "There are some exceptions, depending on the type of dose of immunosuppressive treatment and type of vaccine."

The researchers also studied disease activity and adverse events. Most studies were underpowered to assess safety, they say, meaning that additional safety studies are warranted.

Finally, the authors recommend that these guidelines be updated regularly as new evidence on vaccinating pediatric patients on immunomodulating drugs becomes available.

The authors have no conflicts to disclose. The study was funded by EULAR.

Intrapleural therapy with combined recombinant tissue plasminogen activator (TPA) and DNase improved fluid drainage in patients with pleural infection, led to fewer surgical referrals and reduced the length of hospital stays, according to results of the second Multicenter Intrapleural Sepsis Trial (MIST 2) reported in the Aug. 11, 2011, issue of the New England Journal of Medicine. However, neither agent when used alone was more effective than placebo.

Pleural infection affects more than 65,000 patients annually in the United States and United Kingdom, with a mortality rate between 10% and 20%. Standard therapy typically consists of antibiotics and tube drainage of the infected fluid and surgery when sepsis and infected fluid are not effectively controlled; more than 30% of patients either die or require surgery.

Although the large first Multicenter Intrapleural Sepsis Trial (MIST1) showed no benefit of intrapleural streptokinase, the strong clinical and observational support for the use of fibrinolytic agents inspired the MIST2 trial using a different direct-acting fibrinolytic agent – recombinant TPA – coupled to the use of recombinant DNase (used in order to decrease viscosity due to extracellular bacterial DNA and to inhibit biofilm formation), which has shown use in animal studies.

In order to test these purported benefits, Dr. Najib M. Rahiman of the University of Oxford, and colleagues, conducted a double-blind, double-dummy factorial randomized trial of 210 patients with pleural infection at 11 centers in the United Kingdom between December 2005 and November 2008 (N. Engl. J. Med. 2011;365:518-26). They randomized patients to receive one of four treatments: TPA plus DNase, DNase plus placebo, TPA plus placebo, and double placebo. The primary analysis included 193 patients, with 51 receiving double placebo, 48 receiving TPA only, 46 receiving DNase only and 48 receiving both agents.

The dose of DNase (Pulmozyme, Roche) was 5 mg and the dose of TPA (Actilyse, Boehringer Ingelheim) was 10 mg. Intrapleural medications were given twice daily for 3 days and each administration was followed by drain-clamping to permit the study drug to remain in the pleural space for 1 hr. Pulmozyme is approved by the U.S. Food and Drug Administration for the treatment of cystic fibrosis. Actilyse (marketed as Activase in the United States) is FDA-approved for use in acute ischemic stroke.

Baseline characteristics, including age, sex, percent of hemothorax occupied with pleural fluid, and characteristics of the infection and physiological status of the pleural fluid were not significantly different between the four groups.

The mean decrease in pleural opacity, the primary endpoint, was 29.5% in the TPA-DNase group between days 1 and 7. This was clinically and statistically significant, compared with 17.2% in the placebo group. There was no significant improvement in the primary outcome compared with the placebo when using TPA alone (17.2% decrease) or DNase alone (14.7%).

Researchers also looked at several secondary endpoints and found that:

• The frequency of referral for surgery at 3 months was 2 out of 48 patients (4%) in the TPA-DNase group vs. 8 out of 51 patients (16%) in the placebo group, 18 of 46 patients (39%) in the DNase only group and 3 out of 48 patients (6%) in the TPA group. All referrals were due to clinical evidence of worsening infection.

• Hospital stays on average were 11.8 days for the TPA-DNase group vs. 16.5 days, 28.2 days and 24.8 days for the TPA, DNase and placebo groups, respectively.

• Mortality rates were not significantly different for all four study groups at 3 months and 12 months. At 3 months , mortality rates were 2 out of 50 patients (4%) in the placebo group, 4 out of 48 patients (8%) in the TPA-DNase group, 4 out of 48 patients (8%) in the TPA group and 6 out of 46 (13%) in the DNase group. At 12 months, mortality rates were 4 out of 48 (8%) patients in the placebo group, 5 out of 47 patients (11%) in the combination group, 5 out of 46 patients (11%) in the TPA group and 9 out of 45 patients (20%) in the DNase groups alone.

• By day 7, average C-reactive protein levels were nonsignificantly lower in the combination group than the placebo group, but were nonsignificantly greater in the TPA and DNase groups.

• By day 7, The average white cell count was nonsignificantly higher with TPA alone and nonsignificantly lower with DNase alone versus the placebo group, while the average count was significantly lower in the placebo group (a difference of 3.4x109 per liter).

• Thoracic surgery and deaths due to pleural infection were evenly distributed across all four groups.

These results show that combined intrapleural TPA and DNase therapy improves the drainage of pleural fluid in patients with pleural infection and may improve the natural history of infection, including reduced hospital stays and the need for thoracic surgery.

"This combined treatment may therefore be useful in patients in whom standard medical management has failed and thoracic surgery is not a treatment option," the researchers say. "However, appropriate trials are needed to accurately define the treatment effects. If confirmed in further studies, our results will inform the choice of intrapleural adjuvant therapy for pleural infection and improve the management of this disorder," according to the researchers.

The study was funded by an unrestricted educational grant from Roche UK to the University of Oxford and by grants from the Oxford Biomedical Research Centre Programme, through the United Kingdom National Institute for Health Research) and the United Kingdom Medical Research Council. Dr. Chris W.H. Davies and Dr. John M. Wrightston disclosed receiving lecture fees from ResMed UK and Boehringer Ingelheim UK, respectively.

Intrapleural therapy with combined recombinant tissue plasminogen activator (TPA) and DNase improved fluid drainage in patients with pleural infection, led to fewer surgical referrals and reduced the length of hospital stays, according to results of the second Multicenter Intrapleural Sepsis Trial (MIST 2) reported in the Aug. 11, 2011, issue of the New England Journal of Medicine. However, neither agent when used alone was more effective than placebo.

Pleural infection affects more than 65,000 patients annually in the United States and United Kingdom, with a mortality rate between 10% and 20%. Standard therapy typically consists of antibiotics and tube drainage of the infected fluid and surgery when sepsis and infected fluid are not effectively controlled; more than 30% of patients either die or require surgery.

Although the large first Multicenter Intrapleural Sepsis Trial (MIST1) showed no benefit of intrapleural streptokinase, the strong clinical and observational support for the use of fibrinolytic agents inspired the MIST2 trial using a different direct-acting fibrinolytic agent – recombinant TPA – coupled to the use of recombinant DNase (used in order to decrease viscosity due to extracellular bacterial DNA and to inhibit biofilm formation), which has shown use in animal studies.

In order to test these purported benefits, Dr. Najib M. Rahiman of the University of Oxford, and colleagues, conducted a double-blind, double-dummy factorial randomized trial of 210 patients with pleural infection at 11 centers in the United Kingdom between December 2005 and November 2008 (N. Engl. J. Med. 2011;365:518-26). They randomized patients to receive one of four treatments: TPA plus DNase, DNase plus placebo, TPA plus placebo, and double placebo. The primary analysis included 193 patients, with 51 receiving double placebo, 48 receiving TPA only, 46 receiving DNase only and 48 receiving both agents.

The dose of DNase (Pulmozyme, Roche) was 5 mg and the dose of TPA (Actilyse, Boehringer Ingelheim) was 10 mg. Intrapleural medications were given twice daily for 3 days and each administration was followed by drain-clamping to permit the study drug to remain in the pleural space for 1 hr. Pulmozyme is approved by the U.S. Food and Drug Administration for the treatment of cystic fibrosis. Actilyse (marketed as Activase in the United States) is FDA-approved for use in acute ischemic stroke.

Baseline characteristics, including age, sex, percent of hemothorax occupied with pleural fluid, and characteristics of the infection and physiological status of the pleural fluid were not significantly different between the four groups.

The mean decrease in pleural opacity, the primary endpoint, was 29.5% in the TPA-DNase group between days 1 and 7. This was clinically and statistically significant, compared with 17.2% in the placebo group. There was no significant improvement in the primary outcome compared with the placebo when using TPA alone (17.2% decrease) or DNase alone (14.7%).

Researchers also looked at several secondary endpoints and found that:

• The frequency of referral for surgery at 3 months was 2 out of 48 patients (4%) in the TPA-DNase group vs. 8 out of 51 patients (16%) in the placebo group, 18 of 46 patients (39%) in the DNase only group and 3 out of 48 patients (6%) in the TPA group. All referrals were due to clinical evidence of worsening infection.

• Hospital stays on average were 11.8 days for the TPA-DNase group vs. 16.5 days, 28.2 days and 24.8 days for the TPA, DNase and placebo groups, respectively.

• Mortality rates were not significantly different for all four study groups at 3 months and 12 months. At 3 months , mortality rates were 2 out of 50 patients (4%) in the placebo group, 4 out of 48 patients (8%) in the TPA-DNase group, 4 out of 48 patients (8%) in the TPA group and 6 out of 46 (13%) in the DNase group. At 12 months, mortality rates were 4 out of 48 (8%) patients in the placebo group, 5 out of 47 patients (11%) in the combination group, 5 out of 46 patients (11%) in the TPA group and 9 out of 45 patients (20%) in the DNase groups alone.

• By day 7, average C-reactive protein levels were nonsignificantly lower in the combination group than the placebo group, but were nonsignificantly greater in the TPA and DNase groups.

• By day 7, The average white cell count was nonsignificantly higher with TPA alone and nonsignificantly lower with DNase alone versus the placebo group, while the average count was significantly lower in the placebo group (a difference of 3.4x109 per liter).

• Thoracic surgery and deaths due to pleural infection were evenly distributed across all four groups.

These results show that combined intrapleural TPA and DNase therapy improves the drainage of pleural fluid in patients with pleural infection and may improve the natural history of infection, including reduced hospital stays and the need for thoracic surgery.

"This combined treatment may therefore be useful in patients in whom standard medical management has failed and thoracic surgery is not a treatment option," the researchers say. "However, appropriate trials are needed to accurately define the treatment effects. If confirmed in further studies, our results will inform the choice of intrapleural adjuvant therapy for pleural infection and improve the management of this disorder," according to the researchers.

The study was funded by an unrestricted educational grant from Roche UK to the University of Oxford and by grants from the Oxford Biomedical Research Centre Programme, through the United Kingdom National Institute for Health Research) and the United Kingdom Medical Research Council. Dr. Chris W.H. Davies and Dr. John M. Wrightston disclosed receiving lecture fees from ResMed UK and Boehringer Ingelheim UK, respectively.

Intrapleural therapy with combined recombinant tissue plasminogen activator (TPA) and DNase improved fluid drainage in patients with pleural infection, led to fewer surgical referrals and reduced the length of hospital stays, according to results of the second Multicenter Intrapleural Sepsis Trial (MIST 2) reported in the Aug. 11, 2011, issue of the New England Journal of Medicine. However, neither agent when used alone was more effective than placebo.

Pleural infection affects more than 65,000 patients annually in the United States and United Kingdom, with a mortality rate between 10% and 20%. Standard therapy typically consists of antibiotics and tube drainage of the infected fluid and surgery when sepsis and infected fluid are not effectively controlled; more than 30% of patients either die or require surgery.

Although the large first Multicenter Intrapleural Sepsis Trial (MIST1) showed no benefit of intrapleural streptokinase, the strong clinical and observational support for the use of fibrinolytic agents inspired the MIST2 trial using a different direct-acting fibrinolytic agent – recombinant TPA – coupled to the use of recombinant DNase (used in order to decrease viscosity due to extracellular bacterial DNA and to inhibit biofilm formation), which has shown use in animal studies.

In order to test these purported benefits, Dr. Najib M. Rahiman of the University of Oxford, and colleagues, conducted a double-blind, double-dummy factorial randomized trial of 210 patients with pleural infection at 11 centers in the United Kingdom between December 2005 and November 2008 (N. Engl. J. Med. 2011;365:518-26). They randomized patients to receive one of four treatments: TPA plus DNase, DNase plus placebo, TPA plus placebo, and double placebo. The primary analysis included 193 patients, with 51 receiving double placebo, 48 receiving TPA only, 46 receiving DNase only and 48 receiving both agents.

The dose of DNase (Pulmozyme, Roche) was 5 mg and the dose of TPA (Actilyse, Boehringer Ingelheim) was 10 mg. Intrapleural medications were given twice daily for 3 days and each administration was followed by drain-clamping to permit the study drug to remain in the pleural space for 1 hr. Pulmozyme is approved by the U.S. Food and Drug Administration for the treatment of cystic fibrosis. Actilyse (marketed as Activase in the United States) is FDA-approved for use in acute ischemic stroke.

Baseline characteristics, including age, sex, percent of hemothorax occupied with pleural fluid, and characteristics of the infection and physiological status of the pleural fluid were not significantly different between the four groups.

The mean decrease in pleural opacity, the primary endpoint, was 29.5% in the TPA-DNase group between days 1 and 7. This was clinically and statistically significant, compared with 17.2% in the placebo group. There was no significant improvement in the primary outcome compared with the placebo when using TPA alone (17.2% decrease) or DNase alone (14.7%).

Researchers also looked at several secondary endpoints and found that:

• The frequency of referral for surgery at 3 months was 2 out of 48 patients (4%) in the TPA-DNase group vs. 8 out of 51 patients (16%) in the placebo group, 18 of 46 patients (39%) in the DNase only group and 3 out of 48 patients (6%) in the TPA group. All referrals were due to clinical evidence of worsening infection.

• Hospital stays on average were 11.8 days for the TPA-DNase group vs. 16.5 days, 28.2 days and 24.8 days for the TPA, DNase and placebo groups, respectively.

• Mortality rates were not significantly different for all four study groups at 3 months and 12 months. At 3 months , mortality rates were 2 out of 50 patients (4%) in the placebo group, 4 out of 48 patients (8%) in the TPA-DNase group, 4 out of 48 patients (8%) in the TPA group and 6 out of 46 (13%) in the DNase group. At 12 months, mortality rates were 4 out of 48 (8%) patients in the placebo group, 5 out of 47 patients (11%) in the combination group, 5 out of 46 patients (11%) in the TPA group and 9 out of 45 patients (20%) in the DNase groups alone.

• By day 7, average C-reactive protein levels were nonsignificantly lower in the combination group than the placebo group, but were nonsignificantly greater in the TPA and DNase groups.

• By day 7, The average white cell count was nonsignificantly higher with TPA alone and nonsignificantly lower with DNase alone versus the placebo group, while the average count was significantly lower in the placebo group (a difference of 3.4x109 per liter).

• Thoracic surgery and deaths due to pleural infection were evenly distributed across all four groups.

These results show that combined intrapleural TPA and DNase therapy improves the drainage of pleural fluid in patients with pleural infection and may improve the natural history of infection, including reduced hospital stays and the need for thoracic surgery.

"This combined treatment may therefore be useful in patients in whom standard medical management has failed and thoracic surgery is not a treatment option," the researchers say. "However, appropriate trials are needed to accurately define the treatment effects. If confirmed in further studies, our results will inform the choice of intrapleural adjuvant therapy for pleural infection and improve the management of this disorder," according to the researchers.

The study was funded by an unrestricted educational grant from Roche UK to the University of Oxford and by grants from the Oxford Biomedical Research Centre Programme, through the United Kingdom National Institute for Health Research) and the United Kingdom Medical Research Council. Dr. Chris W.H. Davies and Dr. John M. Wrightston disclosed receiving lecture fees from ResMed UK and Boehringer Ingelheim UK, respectively.

Major Finding: Joint distraction can induce tissue structure modification in knee osteoarthritis, as shown on radiography, MRI, and blood work, possibly delaying the need for endoprosthesis.

Data Source: An open, 1-year pilot study of 20 patients with tibiofemoral osteoarthritis who were treated surgically with joint distraction.

Disclosures: The authors had no relationships to disclose. The Dutch Arthritis Foundation provided financial support for this study.

Joint distraction can induce tissue structure modification in knee osteoarthritis, possibly reversing structural damage to cartilage tissue and delaying the need for knee replacement surgery

Endoprosthesis currently is the accepted method for treating pain caused by end-stage knee OA. However, the growing number of procedures carries a high price tag, and there is a higher risk of failure in patients aged younger than 65 years.

With that in mind, Dr. Femke Intema of the University Medical Center Utrecht (the Netherlands) and colleagues wanted to determine whether joint distraction could halt and possibly reverse joint degeneration in knee OA (Ann. Rheum. Dis. 2011;70:1441-6).

The study included 11 men and 9 women who had knee OA and in whom knee replacement surgery was indicated in 2006-2008. Patients were an average of 48 years old; 18 of them had predominant OA in the medial compartment; the remaining two had OA in the lateral compartment. Patients had a score of 60 mm or higher on the Visual Analogue Scale (VAS) of pain, as well as radiographic signs of joint damage, and primarily tibiofemoral OA.

Joint distraction was applied for 2 months via an external fixation frame. At the 1-year follow-up, researchers evaluated tissue structure modification according to the following:

▸ Radiographic analysis. This showed that the mean joint space width (JSW) of the most affected compartment increased from 2.7 mm to 3.6 mm between baseline and 12 months, whereas the minimum JSW increased from 1 mm to 1.9 mm.

▸ Quantitative MRI analysis. At 1 year, this showed an increase in the mean thickness of cartilage over total area of bone (ThCtAB) from 2.4 mm to 3 mm in the most affected compartment, and a decrease in mean percentage area of denuded bone (dABp) from 22% to 5%. The thickness of cartilage over area of bone covered with cartilage (ThCcAB), a secondary structural outcome parameter, showed a borderline increase from 2.9 mm to 3.1 mm.

▸ Biomarker analysis on serum and urine samples. These showed an 11% decrease of CTXII (a collagen type II breakdown marker), and a 103% increase in PILANP/CTXII (a collage type II synthesis marker), between 6 and 12 months. These findings suggest a net increase in collagen synthesis, the researchers said.

The primary outcome parameter of this study was the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index questionnaire, which decreased from 55 points at baseline to 23 points at 1 year. In all, 18 of the 20 patients showed a greater-than-10% improvement, and 16 showed a greater-than-25% improvement. There were significant improvements in the individual components of the WOMAC index, namely pain, stiffness, and function.

One secondary measure, the VAS pain score, decreased from 73 mm at baseline to 31 mm at 1 year. Physical examination of the joint, which assessed crepitus, pain on palpation, pain with flexion, and joint effusion, showed improvement from 46% to 75%.

“This study is the first to demonstrate intrinsic tissue structure repair in OA,” the researchers said. “Historically, the regenerative capacity of cartilage has been questioned owing to the slow turnover rate of cartilage matrix, especially of collagen. However, this study shows that a significant amount of cartilage tissue is formed within 1 year after the distraction, demonstrating that under certain conditions, cartilage has regenerative capacity.”

There is uncertainty as to the underlying mechanism of the structural repair that was seen in this study. One possibility is that temporary distraction prevents mechanical stress on the cartilage, prevents further wear and tear, and allows tissue repair to begin, the researchers said.

For now, the researchers are unsure which patients may benefit from this procedure, as the study included only those patients who were younger than 50 years, had severe OA, and were likely candidates for joint replacement surgery. Referrals from peripheral hospitals may have led to selection bias, the researchers said.

Safety concerns exist as well. Two patients developed lung emboli and required hospitalization and anticoagulative treatment. Also, 17 patients developed single or multiple pin-tract infections, all of which were successfully treated with antibiotics.

Larger and longer trials in a variety of OA populations are needed to optimize treatment, to determine which patients would benefit the most and for the longest period of time, and to pay attention to reducing the number of complications, according to Dr. Intema and associates.

Knee distraction was applied for 2 months via an external fixation frame.

Source Courtesy Dr. Floris P.J.G. Lafeber

Major Finding: Joint distraction can induce tissue structure modification in knee osteoarthritis, as shown on radiography, MRI, and blood work, possibly delaying the need for endoprosthesis.

Data Source: An open, 1-year pilot study of 20 patients with tibiofemoral osteoarthritis who were treated surgically with joint distraction.

Disclosures: The authors had no relationships to disclose. The Dutch Arthritis Foundation provided financial support for this study.

Joint distraction can induce tissue structure modification in knee osteoarthritis, possibly reversing structural damage to cartilage tissue and delaying the need for knee replacement surgery

Endoprosthesis currently is the accepted method for treating pain caused by end-stage knee OA. However, the growing number of procedures carries a high price tag, and there is a higher risk of failure in patients aged younger than 65 years.

With that in mind, Dr. Femke Intema of the University Medical Center Utrecht (the Netherlands) and colleagues wanted to determine whether joint distraction could halt and possibly reverse joint degeneration in knee OA (Ann. Rheum. Dis. 2011;70:1441-6).

The study included 11 men and 9 women who had knee OA and in whom knee replacement surgery was indicated in 2006-2008. Patients were an average of 48 years old; 18 of them had predominant OA in the medial compartment; the remaining two had OA in the lateral compartment. Patients had a score of 60 mm or higher on the Visual Analogue Scale (VAS) of pain, as well as radiographic signs of joint damage, and primarily tibiofemoral OA.

Joint distraction was applied for 2 months via an external fixation frame. At the 1-year follow-up, researchers evaluated tissue structure modification according to the following:

▸ Radiographic analysis. This showed that the mean joint space width (JSW) of the most affected compartment increased from 2.7 mm to 3.6 mm between baseline and 12 months, whereas the minimum JSW increased from 1 mm to 1.9 mm.

▸ Quantitative MRI analysis. At 1 year, this showed an increase in the mean thickness of cartilage over total area of bone (ThCtAB) from 2.4 mm to 3 mm in the most affected compartment, and a decrease in mean percentage area of denuded bone (dABp) from 22% to 5%. The thickness of cartilage over area of bone covered with cartilage (ThCcAB), a secondary structural outcome parameter, showed a borderline increase from 2.9 mm to 3.1 mm.

▸ Biomarker analysis on serum and urine samples. These showed an 11% decrease of CTXII (a collagen type II breakdown marker), and a 103% increase in PILANP/CTXII (a collage type II synthesis marker), between 6 and 12 months. These findings suggest a net increase in collagen synthesis, the researchers said.

The primary outcome parameter of this study was the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index questionnaire, which decreased from 55 points at baseline to 23 points at 1 year. In all, 18 of the 20 patients showed a greater-than-10% improvement, and 16 showed a greater-than-25% improvement. There were significant improvements in the individual components of the WOMAC index, namely pain, stiffness, and function.

One secondary measure, the VAS pain score, decreased from 73 mm at baseline to 31 mm at 1 year. Physical examination of the joint, which assessed crepitus, pain on palpation, pain with flexion, and joint effusion, showed improvement from 46% to 75%.

“This study is the first to demonstrate intrinsic tissue structure repair in OA,” the researchers said. “Historically, the regenerative capacity of cartilage has been questioned owing to the slow turnover rate of cartilage matrix, especially of collagen. However, this study shows that a significant amount of cartilage tissue is formed within 1 year after the distraction, demonstrating that under certain conditions, cartilage has regenerative capacity.”

There is uncertainty as to the underlying mechanism of the structural repair that was seen in this study. One possibility is that temporary distraction prevents mechanical stress on the cartilage, prevents further wear and tear, and allows tissue repair to begin, the researchers said.

For now, the researchers are unsure which patients may benefit from this procedure, as the study included only those patients who were younger than 50 years, had severe OA, and were likely candidates for joint replacement surgery. Referrals from peripheral hospitals may have led to selection bias, the researchers said.

Safety concerns exist as well. Two patients developed lung emboli and required hospitalization and anticoagulative treatment. Also, 17 patients developed single or multiple pin-tract infections, all of which were successfully treated with antibiotics.

Larger and longer trials in a variety of OA populations are needed to optimize treatment, to determine which patients would benefit the most and for the longest period of time, and to pay attention to reducing the number of complications, according to Dr. Intema and associates.

Knee distraction was applied for 2 months via an external fixation frame.

Source Courtesy Dr. Floris P.J.G. Lafeber

Major Finding: Joint distraction can induce tissue structure modification in knee osteoarthritis, as shown on radiography, MRI, and blood work, possibly delaying the need for endoprosthesis.

Data Source: An open, 1-year pilot study of 20 patients with tibiofemoral osteoarthritis who were treated surgically with joint distraction.

Disclosures: The authors had no relationships to disclose. The Dutch Arthritis Foundation provided financial support for this study.

Joint distraction can induce tissue structure modification in knee osteoarthritis, possibly reversing structural damage to cartilage tissue and delaying the need for knee replacement surgery

Endoprosthesis currently is the accepted method for treating pain caused by end-stage knee OA. However, the growing number of procedures carries a high price tag, and there is a higher risk of failure in patients aged younger than 65 years.

With that in mind, Dr. Femke Intema of the University Medical Center Utrecht (the Netherlands) and colleagues wanted to determine whether joint distraction could halt and possibly reverse joint degeneration in knee OA (Ann. Rheum. Dis. 2011;70:1441-6).

The study included 11 men and 9 women who had knee OA and in whom knee replacement surgery was indicated in 2006-2008. Patients were an average of 48 years old; 18 of them had predominant OA in the medial compartment; the remaining two had OA in the lateral compartment. Patients had a score of 60 mm or higher on the Visual Analogue Scale (VAS) of pain, as well as radiographic signs of joint damage, and primarily tibiofemoral OA.

Joint distraction was applied for 2 months via an external fixation frame. At the 1-year follow-up, researchers evaluated tissue structure modification according to the following:

▸ Radiographic analysis. This showed that the mean joint space width (JSW) of the most affected compartment increased from 2.7 mm to 3.6 mm between baseline and 12 months, whereas the minimum JSW increased from 1 mm to 1.9 mm.

▸ Quantitative MRI analysis. At 1 year, this showed an increase in the mean thickness of cartilage over total area of bone (ThCtAB) from 2.4 mm to 3 mm in the most affected compartment, and a decrease in mean percentage area of denuded bone (dABp) from 22% to 5%. The thickness of cartilage over area of bone covered with cartilage (ThCcAB), a secondary structural outcome parameter, showed a borderline increase from 2.9 mm to 3.1 mm.

▸ Biomarker analysis on serum and urine samples. These showed an 11% decrease of CTXII (a collagen type II breakdown marker), and a 103% increase in PILANP/CTXII (a collage type II synthesis marker), between 6 and 12 months. These findings suggest a net increase in collagen synthesis, the researchers said.

The primary outcome parameter of this study was the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index questionnaire, which decreased from 55 points at baseline to 23 points at 1 year. In all, 18 of the 20 patients showed a greater-than-10% improvement, and 16 showed a greater-than-25% improvement. There were significant improvements in the individual components of the WOMAC index, namely pain, stiffness, and function.

One secondary measure, the VAS pain score, decreased from 73 mm at baseline to 31 mm at 1 year. Physical examination of the joint, which assessed crepitus, pain on palpation, pain with flexion, and joint effusion, showed improvement from 46% to 75%.

“This study is the first to demonstrate intrinsic tissue structure repair in OA,” the researchers said. “Historically, the regenerative capacity of cartilage has been questioned owing to the slow turnover rate of cartilage matrix, especially of collagen. However, this study shows that a significant amount of cartilage tissue is formed within 1 year after the distraction, demonstrating that under certain conditions, cartilage has regenerative capacity.”

There is uncertainty as to the underlying mechanism of the structural repair that was seen in this study. One possibility is that temporary distraction prevents mechanical stress on the cartilage, prevents further wear and tear, and allows tissue repair to begin, the researchers said.

For now, the researchers are unsure which patients may benefit from this procedure, as the study included only those patients who were younger than 50 years, had severe OA, and were likely candidates for joint replacement surgery. Referrals from peripheral hospitals may have led to selection bias, the researchers said.

Safety concerns exist as well. Two patients developed lung emboli and required hospitalization and anticoagulative treatment. Also, 17 patients developed single or multiple pin-tract infections, all of which were successfully treated with antibiotics.

Larger and longer trials in a variety of OA populations are needed to optimize treatment, to determine which patients would benefit the most and for the longest period of time, and to pay attention to reducing the number of complications, according to Dr. Intema and associates.

Knee distraction was applied for 2 months via an external fixation frame.

Source Courtesy Dr. Floris P.J.G. Lafeber