Click here to listen to Dr. Doctoroff

Click here to listen to Dr. Doctoroff

Click here to listen to Dr. Doctoroff

Click here to listen to Dr. Gould

Click here to listen to Dr. Kobaidze

Click here to listen to Dr. Gould

Click here to listen to Dr. Kobaidze

Click here to listen to Dr. Gould

Click here to listen to Dr. Kobaidze

Listen to Dr. Gould

At 480-bed Emory University Hospital Midtown in Atlanta, the physicians and staff seemingly are doing all the right things to foil one of hospital’s archenemies: Clostridium difficile. The bacteria, better known as C. diff, is responsible for a sharp rise in hospital-acquired infections over the past decade, rivaling even MRSA.

In 2010, Emory Midtown launched a campaign to boost awareness of the importance of hand washing before and after treating patients infected with C. diff and those likely to be infected. They also began using the polymerase-chain-reaction-based assay to detect the bacteria, a test with much higher sensitivity that helps to more efficiently identify those infected so control measures can be more prompt and targeted. They use a hypochlorite mixture to clean the rooms of those infected, which is considered a must. And a committee monitors the use of antibiotics to prevent overuse—often the scapegoat for the rise of the hard-to-kill bacteria.

Still, at Emory, the rate of C. diff is about the same as the national average, says hospitalist Ketino Kobaidze, MD, assistant professor at the Emory University School of Medicine and a member of the antimicrobial stewardship and infectious disease control committees at Midtown. While Dr. Kobaidze says her institution is doing a good job of trying to keep C. diff under control, she thinks hospitalists can do more.

“My feeling is that we are not as involved as we’re supposed to be,” she says. “I think we need to be a little bit more proactive, be involved in committees and research activities across the hospital.”

You Are Not Alone

The experience at Emory Midtown is far from unusual—healthcare facilities, and hospitalists, across the country have seen healthcare-related C. diff cases more than double since 2001 to between 400,000 and 500,000 a year, says Carolyn Gould, MD, a medical epidemiologist in the division of healthcare quality promotion at the Centers for Disease Control and Prevention (CDC) in Atlanta.

Hospitalists, whether they realize it or not, are intimately involved in how well the C. diff outbreak is controlled. Infectious-disease (ID) specialists say hospitalists are perfectly situated to make an impact in efforts to help curb the outbreak.

“Hospitalists are critical to this effort,” Dr. Gould says. “They’re in the hospital day in and day out, and they’re constantly interacting with the patients, staff, and administration. They’re often the first on the scene to see a patient who might have suddenly developed diarrhea; they’re the first to react. I think they’re in a prime position to play a leadership role to prevent C. diff infections.”

They’re also situated well to work with infection-control experts on antimicrobial stewardship programs, she says.

“I look at hospitalists just like I would have looked at internists managing their own patients 15 years ago,” says Stuart Cohen, MD, an ID expert with the University of California at Davis and a fellow with the Infectious Diseases Society of America who was lead author of the latest published IDSA guidelines on C. diff treatment. “And so they’re the first-line people.”

continued below...

 

A Tough Bug

Believed to be aided largely by the use of broad-spectrum antibiotics that knock out the colon’s natural flora, C. diff in the hospital—as well as nursing homes and acute-care facilities—has raged for much of the past decade. Its rise is tied to the emergence of a new hypervirulent strain known as BI/NAP1/027, or NAP1 for short. The strain is highly resistant to fluoroquinolones, such as ciprofloxacin and levofloxacin, which are used often in healthcare settings.

“A fluoroquinolone will wipe out a lot of your normal flora in your gut,” Dr. Gould says. “But it won’t wipe out C. diff, in particular this hypervirulent strain. And so this strain can flourish in the presence of fluoroquinolones.” The strain produces up to 15 to 20 times more toxins than other C. diff strains, according to some data, she adds.

Vancomycin (Vanconin) and metronidazole (Flagyl) are the most common antibiotics used to treat patients infected with C. diff. Mortality rates are higher among the elderly, largely because of their weaker immune system, Dr. Gould says. Studies have generally shown mortality rates of 10% or a bit lower.¹

More recent studies have shown that the number of hospital-related C. diff cases might have begun to level off in 2008 and 2009. Dr. Gould says she thinks the leveling off is for real, but there is debate over what the immediate future holds.

“There’s a lot of work and initiatives, especially state-based initiatives, that are being done in hospitals. And there’s reason to believe they’re effective,” she says, adding it’s harder to get a good picture of the problem in long-term care facilities and in the community.

Dr. Cohen with the IDSA says it’s too soon to say whether the problem is hitting a plateau. “CDC data are always a couple of years behind,” he says. “Until you see another data point, you can’t tell whether that’s just a transient flattening and whether it’s going to keep going up or not.”

Kevin Kavanagh, MD, founder of the patient advocacy group Health Watch USA and a retired otolaryngologist in Kentucky who has taken a keen interest in the C. diff problem, says he doesn’t think the end of the tunnel is within view yet.

“I think C. diff is going to get worse before it gets better,” Dr. Kavanagh says. “And that’s not necessarily because the healthcare profession isn’t doing due diligence. This is a tough organism.—it can be tough to treat and can be very tough to kill.”

The Best Defense?

Because C. diff lives within protective spores, sound hand hygiene practices and room-cleaning practices are essential for keeping infections to a minimum. Alcohol-based hand sanitizers, effective against other organisms including MRSA, do not kill C. diff. The bacteria must be mechanically removed through hand washing.

And even hand washing might not be totally effective at getting rid of the spores, which means it’s important for healthcare workers to gown and glove in high-risk rooms.

Sodium hypochlorite solutions, or bleach mixtures, have to be used to clean rooms occupied by patients with C. diff, and the prevailing thought is to clean the rooms of patients suspected of having C. diff, even if those cases might not be confirmed.

Equally important to cleaning and hand washing is systemwide emphasis on antibiotic stewardship. A 2011 study at the State University of New York Buffalo found that the risk of a C. diff infection rose with the number of antibiotics taken.²

 

While a broad-spectrum antibiotic might be necessary at first, once the results of cultures are received, the treatment should be finely tailored to kill only the problem bacteria so that the body’s natural defenses aren’t broken down, Dr. Gould explains.

“If someone is very sick and you’re not sure what is going on, it’s very reasonable to treat them empirically with broad-spectrum antibiotics,” she says. “The important thing is that you send the appropriate cultures before so that you know what you’re treating and you can optimize those antibiotics with daily assessments.”

It’s clear why an overreliance on broad-spectrum drugs prevails in U.S. health settings, Dr. Cohen acknowledges. Recent literature suggests treating critically ill patients with wide-ranging antimicrobials as the mortality rate can be twice as high with narrower options. “I think people have gotten very quick to give broad-spectrum therapy,” he says.

continued below...

 

National Response, Localized Attention

Dr. Kavanagh of Health Watch USA says that more information about C. diff is needed, particularly publicly available numbers of infections at hospitals. Some states require those figures to be reported, but most don’t. And there is no current federal mandate on reporting of C. diff cases, although acute-care hospitals will be required to report C. diff infection rates starting in 2013.

“We really have scant data,” he says. “There is not a lot of reporting if you look at the nation on a whole. And I think that underscores one of the reasons why you need to have data for action. You need to have reporting of these organisms to the National Healthcare Safety Network so that the CDC can monitor and can make plans and can do effective interventions.

“You want to know where the areas of highest infection are,” he adds. “You want to know what interventions work and don’t work. If you don’t have a national coordinated reporting system, it really makes it difficult to address the problem. C. diff is going to be much harder to control than MRSA or other bacteria because it changes into a hard-to-kill dormant spore stage and then re-occurs at some point.”

The Centers for Medicare & Medicaid Services (CMS) has proposed adding C. diff infections to the list of hospital-acquired conditions that will not be reimbursable. It is widely hoped that such a measure will go a long way toward stamping out the problem.

Dr. Kobaidze of Emory notes that C. diff is a dynamic problem, always adapting and posing new challenges. And hospitalists should be more involved in answering these questions through research. One recent question, she points out, is whether proton pump inhibitor use is related to the rise of C. diff.

Ultimately, though, controlling C. diff in hospitals might come down to what is done day to day inside the hospital. And hospitalists can play a big role.

Danielle Scheurer, MD, MSCR, SFHM, a hospitalist and medical director of quality at the Medical University of South Carolina in Charleston, says that a full-time pharmacist on the hospital’s antimicrobial stewardship committee is always reviewing antibiotic prescriptions and is prepared to flag cases in which a broad-spectrum is used when one with a more narrow scope might be more appropriate.

The hospital has done its best, as part of its “renovation cycle,” to standardize the layouts of rooms “so that the second you open the door you know exactly where the alcohol gel is and where the soap and the sink is going to be.” The idea is to make compliance as “mindless” as possible. Such efforts can be hampered by structural limitations though, she says.

HM group leaders, she suggests, can play an important part simply by being good role models—gowning and gloving without complaint before entering high-risk rooms and reinforcing the message that such efforts have real effects on patient safety.

But she also acknowledges that “it always sounds easy....There has to be some level of redundancy built into the hospital system. This is more of a system thing than the individual hospitalist.”

One level of redundancy at MUSC that has been particularly effective, she says, are “secret shoppers” who keep an eye out for medical teams that might not be washing their hands as they go in and out of high-risk rooms. Each unit is responsible for their hand hygiene numbers—which include both self-reported figures and those obtained by the secret onlookers—and those numbers are made available to the hospital.

 

Those units with the best numbers are sometimes given a reward, such as a pizza party, but it’s colleagues’ knowledge of the numbers that matters most, she says.

“That, in and of itself, is a powerful motivator,” Dr. Scheurer says. “We bring it to all of our quality operations meetings, all the administrators, the CEO, the CMO. It’s very motivating for every unit. They don’t want to be the trailing unit.”

Tom Collins is a freelance medical writer based in Miami.

References

1. Orenstein R, Aronhalt KC, McManus JE Jr., Fedraw LA. A targeted strategy to wipe out Clostridium difficile. Infect Control Hosp Epidemiol. 2011;32(11):1137-1139.
2. Stevens V, Dumyati G, Fine LS, Fisher SG, van Wijngaarden E. Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. Clin Infect Dis. 2011;53(1):42-48.

 

Listen to Dr. Gould

At 480-bed Emory University Hospital Midtown in Atlanta, the physicians and staff seemingly are doing all the right things to foil one of hospital’s archenemies: Clostridium difficile. The bacteria, better known as C. diff, is responsible for a sharp rise in hospital-acquired infections over the past decade, rivaling even MRSA.

In 2010, Emory Midtown launched a campaign to boost awareness of the importance of hand washing before and after treating patients infected with C. diff and those likely to be infected. They also began using the polymerase-chain-reaction-based assay to detect the bacteria, a test with much higher sensitivity that helps to more efficiently identify those infected so control measures can be more prompt and targeted. They use a hypochlorite mixture to clean the rooms of those infected, which is considered a must. And a committee monitors the use of antibiotics to prevent overuse—often the scapegoat for the rise of the hard-to-kill bacteria.

Still, at Emory, the rate of C. diff is about the same as the national average, says hospitalist Ketino Kobaidze, MD, assistant professor at the Emory University School of Medicine and a member of the antimicrobial stewardship and infectious disease control committees at Midtown. While Dr. Kobaidze says her institution is doing a good job of trying to keep C. diff under control, she thinks hospitalists can do more.

“My feeling is that we are not as involved as we’re supposed to be,” she says. “I think we need to be a little bit more proactive, be involved in committees and research activities across the hospital.”

You Are Not Alone

The experience at Emory Midtown is far from unusual—healthcare facilities, and hospitalists, across the country have seen healthcare-related C. diff cases more than double since 2001 to between 400,000 and 500,000 a year, says Carolyn Gould, MD, a medical epidemiologist in the division of healthcare quality promotion at the Centers for Disease Control and Prevention (CDC) in Atlanta.

Hospitalists, whether they realize it or not, are intimately involved in how well the C. diff outbreak is controlled. Infectious-disease (ID) specialists say hospitalists are perfectly situated to make an impact in efforts to help curb the outbreak.

“Hospitalists are critical to this effort,” Dr. Gould says. “They’re in the hospital day in and day out, and they’re constantly interacting with the patients, staff, and administration. They’re often the first on the scene to see a patient who might have suddenly developed diarrhea; they’re the first to react. I think they’re in a prime position to play a leadership role to prevent C. diff infections.”

They’re also situated well to work with infection-control experts on antimicrobial stewardship programs, she says.

“I look at hospitalists just like I would have looked at internists managing their own patients 15 years ago,” says Stuart Cohen, MD, an ID expert with the University of California at Davis and a fellow with the Infectious Diseases Society of America who was lead author of the latest published IDSA guidelines on C. diff treatment. “And so they’re the first-line people.”

continued below...

 

A Tough Bug

Believed to be aided largely by the use of broad-spectrum antibiotics that knock out the colon’s natural flora, C. diff in the hospital—as well as nursing homes and acute-care facilities—has raged for much of the past decade. Its rise is tied to the emergence of a new hypervirulent strain known as BI/NAP1/027, or NAP1 for short. The strain is highly resistant to fluoroquinolones, such as ciprofloxacin and levofloxacin, which are used often in healthcare settings.

“A fluoroquinolone will wipe out a lot of your normal flora in your gut,” Dr. Gould says. “But it won’t wipe out C. diff, in particular this hypervirulent strain. And so this strain can flourish in the presence of fluoroquinolones.” The strain produces up to 15 to 20 times more toxins than other C. diff strains, according to some data, she adds.

Vancomycin (Vanconin) and metronidazole (Flagyl) are the most common antibiotics used to treat patients infected with C. diff. Mortality rates are higher among the elderly, largely because of their weaker immune system, Dr. Gould says. Studies have generally shown mortality rates of 10% or a bit lower.¹

More recent studies have shown that the number of hospital-related C. diff cases might have begun to level off in 2008 and 2009. Dr. Gould says she thinks the leveling off is for real, but there is debate over what the immediate future holds.

“There’s a lot of work and initiatives, especially state-based initiatives, that are being done in hospitals. And there’s reason to believe they’re effective,” she says, adding it’s harder to get a good picture of the problem in long-term care facilities and in the community.

Dr. Cohen with the IDSA says it’s too soon to say whether the problem is hitting a plateau. “CDC data are always a couple of years behind,” he says. “Until you see another data point, you can’t tell whether that’s just a transient flattening and whether it’s going to keep going up or not.”

Kevin Kavanagh, MD, founder of the patient advocacy group Health Watch USA and a retired otolaryngologist in Kentucky who has taken a keen interest in the C. diff problem, says he doesn’t think the end of the tunnel is within view yet.

“I think C. diff is going to get worse before it gets better,” Dr. Kavanagh says. “And that’s not necessarily because the healthcare profession isn’t doing due diligence. This is a tough organism.—it can be tough to treat and can be very tough to kill.”

The Best Defense?

Because C. diff lives within protective spores, sound hand hygiene practices and room-cleaning practices are essential for keeping infections to a minimum. Alcohol-based hand sanitizers, effective against other organisms including MRSA, do not kill C. diff. The bacteria must be mechanically removed through hand washing.

And even hand washing might not be totally effective at getting rid of the spores, which means it’s important for healthcare workers to gown and glove in high-risk rooms.

Sodium hypochlorite solutions, or bleach mixtures, have to be used to clean rooms occupied by patients with C. diff, and the prevailing thought is to clean the rooms of patients suspected of having C. diff, even if those cases might not be confirmed.

Equally important to cleaning and hand washing is systemwide emphasis on antibiotic stewardship. A 2011 study at the State University of New York Buffalo found that the risk of a C. diff infection rose with the number of antibiotics taken.²

 

While a broad-spectrum antibiotic might be necessary at first, once the results of cultures are received, the treatment should be finely tailored to kill only the problem bacteria so that the body’s natural defenses aren’t broken down, Dr. Gould explains.

“If someone is very sick and you’re not sure what is going on, it’s very reasonable to treat them empirically with broad-spectrum antibiotics,” she says. “The important thing is that you send the appropriate cultures before so that you know what you’re treating and you can optimize those antibiotics with daily assessments.”

It’s clear why an overreliance on broad-spectrum drugs prevails in U.S. health settings, Dr. Cohen acknowledges. Recent literature suggests treating critically ill patients with wide-ranging antimicrobials as the mortality rate can be twice as high with narrower options. “I think people have gotten very quick to give broad-spectrum therapy,” he says.

continued below...

 

National Response, Localized Attention

Dr. Kavanagh of Health Watch USA says that more information about C. diff is needed, particularly publicly available numbers of infections at hospitals. Some states require those figures to be reported, but most don’t. And there is no current federal mandate on reporting of C. diff cases, although acute-care hospitals will be required to report C. diff infection rates starting in 2013.

“We really have scant data,” he says. “There is not a lot of reporting if you look at the nation on a whole. And I think that underscores one of the reasons why you need to have data for action. You need to have reporting of these organisms to the National Healthcare Safety Network so that the CDC can monitor and can make plans and can do effective interventions.

“You want to know where the areas of highest infection are,” he adds. “You want to know what interventions work and don’t work. If you don’t have a national coordinated reporting system, it really makes it difficult to address the problem. C. diff is going to be much harder to control than MRSA or other bacteria because it changes into a hard-to-kill dormant spore stage and then re-occurs at some point.”

The Centers for Medicare & Medicaid Services (CMS) has proposed adding C. diff infections to the list of hospital-acquired conditions that will not be reimbursable. It is widely hoped that such a measure will go a long way toward stamping out the problem.

Dr. Kobaidze of Emory notes that C. diff is a dynamic problem, always adapting and posing new challenges. And hospitalists should be more involved in answering these questions through research. One recent question, she points out, is whether proton pump inhibitor use is related to the rise of C. diff.

Ultimately, though, controlling C. diff in hospitals might come down to what is done day to day inside the hospital. And hospitalists can play a big role.

Danielle Scheurer, MD, MSCR, SFHM, a hospitalist and medical director of quality at the Medical University of South Carolina in Charleston, says that a full-time pharmacist on the hospital’s antimicrobial stewardship committee is always reviewing antibiotic prescriptions and is prepared to flag cases in which a broad-spectrum is used when one with a more narrow scope might be more appropriate.

The hospital has done its best, as part of its “renovation cycle,” to standardize the layouts of rooms “so that the second you open the door you know exactly where the alcohol gel is and where the soap and the sink is going to be.” The idea is to make compliance as “mindless” as possible. Such efforts can be hampered by structural limitations though, she says.

HM group leaders, she suggests, can play an important part simply by being good role models—gowning and gloving without complaint before entering high-risk rooms and reinforcing the message that such efforts have real effects on patient safety.

But she also acknowledges that “it always sounds easy....There has to be some level of redundancy built into the hospital system. This is more of a system thing than the individual hospitalist.”

One level of redundancy at MUSC that has been particularly effective, she says, are “secret shoppers” who keep an eye out for medical teams that might not be washing their hands as they go in and out of high-risk rooms. Each unit is responsible for their hand hygiene numbers—which include both self-reported figures and those obtained by the secret onlookers—and those numbers are made available to the hospital.

 

Those units with the best numbers are sometimes given a reward, such as a pizza party, but it’s colleagues’ knowledge of the numbers that matters most, she says.

“That, in and of itself, is a powerful motivator,” Dr. Scheurer says. “We bring it to all of our quality operations meetings, all the administrators, the CEO, the CMO. It’s very motivating for every unit. They don’t want to be the trailing unit.”

Tom Collins is a freelance medical writer based in Miami.

References

1. Orenstein R, Aronhalt KC, McManus JE Jr., Fedraw LA. A targeted strategy to wipe out Clostridium difficile. Infect Control Hosp Epidemiol. 2011;32(11):1137-1139.
2. Stevens V, Dumyati G, Fine LS, Fisher SG, van Wijngaarden E. Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. Clin Infect Dis. 2011;53(1):42-48.

 

Listen to Dr. Gould

At 480-bed Emory University Hospital Midtown in Atlanta, the physicians and staff seemingly are doing all the right things to foil one of hospital’s archenemies: Clostridium difficile. The bacteria, better known as C. diff, is responsible for a sharp rise in hospital-acquired infections over the past decade, rivaling even MRSA.

In 2010, Emory Midtown launched a campaign to boost awareness of the importance of hand washing before and after treating patients infected with C. diff and those likely to be infected. They also began using the polymerase-chain-reaction-based assay to detect the bacteria, a test with much higher sensitivity that helps to more efficiently identify those infected so control measures can be more prompt and targeted. They use a hypochlorite mixture to clean the rooms of those infected, which is considered a must. And a committee monitors the use of antibiotics to prevent overuse—often the scapegoat for the rise of the hard-to-kill bacteria.

Still, at Emory, the rate of C. diff is about the same as the national average, says hospitalist Ketino Kobaidze, MD, assistant professor at the Emory University School of Medicine and a member of the antimicrobial stewardship and infectious disease control committees at Midtown. While Dr. Kobaidze says her institution is doing a good job of trying to keep C. diff under control, she thinks hospitalists can do more.

“My feeling is that we are not as involved as we’re supposed to be,” she says. “I think we need to be a little bit more proactive, be involved in committees and research activities across the hospital.”

You Are Not Alone

The experience at Emory Midtown is far from unusual—healthcare facilities, and hospitalists, across the country have seen healthcare-related C. diff cases more than double since 2001 to between 400,000 and 500,000 a year, says Carolyn Gould, MD, a medical epidemiologist in the division of healthcare quality promotion at the Centers for Disease Control and Prevention (CDC) in Atlanta.

Hospitalists, whether they realize it or not, are intimately involved in how well the C. diff outbreak is controlled. Infectious-disease (ID) specialists say hospitalists are perfectly situated to make an impact in efforts to help curb the outbreak.

“Hospitalists are critical to this effort,” Dr. Gould says. “They’re in the hospital day in and day out, and they’re constantly interacting with the patients, staff, and administration. They’re often the first on the scene to see a patient who might have suddenly developed diarrhea; they’re the first to react. I think they’re in a prime position to play a leadership role to prevent C. diff infections.”

They’re also situated well to work with infection-control experts on antimicrobial stewardship programs, she says.

“I look at hospitalists just like I would have looked at internists managing their own patients 15 years ago,” says Stuart Cohen, MD, an ID expert with the University of California at Davis and a fellow with the Infectious Diseases Society of America who was lead author of the latest published IDSA guidelines on C. diff treatment. “And so they’re the first-line people.”

continued below...

 

A Tough Bug

Believed to be aided largely by the use of broad-spectrum antibiotics that knock out the colon’s natural flora, C. diff in the hospital—as well as nursing homes and acute-care facilities—has raged for much of the past decade. Its rise is tied to the emergence of a new hypervirulent strain known as BI/NAP1/027, or NAP1 for short. The strain is highly resistant to fluoroquinolones, such as ciprofloxacin and levofloxacin, which are used often in healthcare settings.

“A fluoroquinolone will wipe out a lot of your normal flora in your gut,” Dr. Gould says. “But it won’t wipe out C. diff, in particular this hypervirulent strain. And so this strain can flourish in the presence of fluoroquinolones.” The strain produces up to 15 to 20 times more toxins than other C. diff strains, according to some data, she adds.

Vancomycin (Vanconin) and metronidazole (Flagyl) are the most common antibiotics used to treat patients infected with C. diff. Mortality rates are higher among the elderly, largely because of their weaker immune system, Dr. Gould says. Studies have generally shown mortality rates of 10% or a bit lower.¹

More recent studies have shown that the number of hospital-related C. diff cases might have begun to level off in 2008 and 2009. Dr. Gould says she thinks the leveling off is for real, but there is debate over what the immediate future holds.

“There’s a lot of work and initiatives, especially state-based initiatives, that are being done in hospitals. And there’s reason to believe they’re effective,” she says, adding it’s harder to get a good picture of the problem in long-term care facilities and in the community.

Dr. Cohen with the IDSA says it’s too soon to say whether the problem is hitting a plateau. “CDC data are always a couple of years behind,” he says. “Until you see another data point, you can’t tell whether that’s just a transient flattening and whether it’s going to keep going up or not.”

Kevin Kavanagh, MD, founder of the patient advocacy group Health Watch USA and a retired otolaryngologist in Kentucky who has taken a keen interest in the C. diff problem, says he doesn’t think the end of the tunnel is within view yet.

“I think C. diff is going to get worse before it gets better,” Dr. Kavanagh says. “And that’s not necessarily because the healthcare profession isn’t doing due diligence. This is a tough organism.—it can be tough to treat and can be very tough to kill.”

The Best Defense?

Because C. diff lives within protective spores, sound hand hygiene practices and room-cleaning practices are essential for keeping infections to a minimum. Alcohol-based hand sanitizers, effective against other organisms including MRSA, do not kill C. diff. The bacteria must be mechanically removed through hand washing.

And even hand washing might not be totally effective at getting rid of the spores, which means it’s important for healthcare workers to gown and glove in high-risk rooms.

Sodium hypochlorite solutions, or bleach mixtures, have to be used to clean rooms occupied by patients with C. diff, and the prevailing thought is to clean the rooms of patients suspected of having C. diff, even if those cases might not be confirmed.

Equally important to cleaning and hand washing is systemwide emphasis on antibiotic stewardship. A 2011 study at the State University of New York Buffalo found that the risk of a C. diff infection rose with the number of antibiotics taken.²

 

While a broad-spectrum antibiotic might be necessary at first, once the results of cultures are received, the treatment should be finely tailored to kill only the problem bacteria so that the body’s natural defenses aren’t broken down, Dr. Gould explains.

“If someone is very sick and you’re not sure what is going on, it’s very reasonable to treat them empirically with broad-spectrum antibiotics,” she says. “The important thing is that you send the appropriate cultures before so that you know what you’re treating and you can optimize those antibiotics with daily assessments.”

It’s clear why an overreliance on broad-spectrum drugs prevails in U.S. health settings, Dr. Cohen acknowledges. Recent literature suggests treating critically ill patients with wide-ranging antimicrobials as the mortality rate can be twice as high with narrower options. “I think people have gotten very quick to give broad-spectrum therapy,” he says.

continued below...

 

National Response, Localized Attention

Dr. Kavanagh of Health Watch USA says that more information about C. diff is needed, particularly publicly available numbers of infections at hospitals. Some states require those figures to be reported, but most don’t. And there is no current federal mandate on reporting of C. diff cases, although acute-care hospitals will be required to report C. diff infection rates starting in 2013.

“We really have scant data,” he says. “There is not a lot of reporting if you look at the nation on a whole. And I think that underscores one of the reasons why you need to have data for action. You need to have reporting of these organisms to the National Healthcare Safety Network so that the CDC can monitor and can make plans and can do effective interventions.

“You want to know where the areas of highest infection are,” he adds. “You want to know what interventions work and don’t work. If you don’t have a national coordinated reporting system, it really makes it difficult to address the problem. C. diff is going to be much harder to control than MRSA or other bacteria because it changes into a hard-to-kill dormant spore stage and then re-occurs at some point.”

The Centers for Medicare & Medicaid Services (CMS) has proposed adding C. diff infections to the list of hospital-acquired conditions that will not be reimbursable. It is widely hoped that such a measure will go a long way toward stamping out the problem.

Dr. Kobaidze of Emory notes that C. diff is a dynamic problem, always adapting and posing new challenges. And hospitalists should be more involved in answering these questions through research. One recent question, she points out, is whether proton pump inhibitor use is related to the rise of C. diff.

Ultimately, though, controlling C. diff in hospitals might come down to what is done day to day inside the hospital. And hospitalists can play a big role.

Danielle Scheurer, MD, MSCR, SFHM, a hospitalist and medical director of quality at the Medical University of South Carolina in Charleston, says that a full-time pharmacist on the hospital’s antimicrobial stewardship committee is always reviewing antibiotic prescriptions and is prepared to flag cases in which a broad-spectrum is used when one with a more narrow scope might be more appropriate.

The hospital has done its best, as part of its “renovation cycle,” to standardize the layouts of rooms “so that the second you open the door you know exactly where the alcohol gel is and where the soap and the sink is going to be.” The idea is to make compliance as “mindless” as possible. Such efforts can be hampered by structural limitations though, she says.

HM group leaders, she suggests, can play an important part simply by being good role models—gowning and gloving without complaint before entering high-risk rooms and reinforcing the message that such efforts have real effects on patient safety.

But she also acknowledges that “it always sounds easy....There has to be some level of redundancy built into the hospital system. This is more of a system thing than the individual hospitalist.”

One level of redundancy at MUSC that has been particularly effective, she says, are “secret shoppers” who keep an eye out for medical teams that might not be washing their hands as they go in and out of high-risk rooms. Each unit is responsible for their hand hygiene numbers—which include both self-reported figures and those obtained by the secret onlookers—and those numbers are made available to the hospital.

 

Those units with the best numbers are sometimes given a reward, such as a pizza party, but it’s colleagues’ knowledge of the numbers that matters most, she says.

“That, in and of itself, is a powerful motivator,” Dr. Scheurer says. “We bring it to all of our quality operations meetings, all the administrators, the CEO, the CMO. It’s very motivating for every unit. They don’t want to be the trailing unit.”

Tom Collins is a freelance medical writer based in Miami.

References

1. Orenstein R, Aronhalt KC, McManus JE Jr., Fedraw LA. A targeted strategy to wipe out Clostridium difficile. Infect Control Hosp Epidemiol. 2011;32(11):1137-1139.
2. Stevens V, Dumyati G, Fine LS, Fisher SG, van Wijngaarden E. Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. Clin Infect Dis. 2011;53(1):42-48.

 

The hospitalist concept was established on the foundation of timely, informative handoffs to primary-care physicians (PCPs) once a patient’s hospital stay is complete. With sicker patients and shorter hospital stays, pending test results, and complex post-discharge medication regimens to sort out, this handoff is crucial to successful discharges. But what if a discharged patient can’t get in to see the PCP, or has no established PCP?

Recent research on hospital readmissions by the Dartmouth Atlas Project found that only 42% of hospitalized Medicare patients had any contact with a primary-care clinician within 14 days of discharge.¹ For patients with ongoing medical needs, such missed connections are a major contributor to hospital readmissions, and thus a target for hospitals and HM groups wanting to control their readmission rates before Medicare imposes reimbursement penalties starting in October 2012 (see “Value-Based Purchasing Raises the Stakes,” May 2011, p. 1).

One proposed solution is the post-discharge clinic, typically located on or near a hospital’s campus and staffed by hospitalists, PCPs, or advanced-practice nurses. The patient can be seen once or a few times in the post-discharge clinic to make sure that health education started in the hospital is understood and followed, and that prescriptions ordered in the hospital are being taken on schedule.

Mark V. Williams, MD, FACP, FHM, professor and chief of the division of hospital medicine at Northwestern University’s Feinberg School of Medicine in Chicago, describes hospitalist-led post-discharge clinics as “Band-Aids for an inadequate primary-care system.” What would be better, he says, is focusing on the underlying problem and working to improve post-discharge access to primary care. Dr. Williams acknowledges, however, that sometimes a patch is needed to stanch the blood flow—e.g., to better manage care transitions—while waiting on healthcare reform and medical homes to improve care coordination throughout the system.

Working in a post-discharge clinic might seem like “a stretch for many hospitalists, especially those who chose this field because they didn’t want to do outpatient medicine,” says Lauren Doctoroff, MD, a hospitalist who directs a post-discharge clinic at Beth Israel Deaconess Medical Center (BIDMC) in Boston. “But there are times when it may be appropriate for hospital-based doctors to extend their responsibility out of the hospital.”

Dr. Doctoroff also says that working in such a clinic can be practice-changing for hospitalists. “All of a sudden, you have a different view of your hospitalized patients, and you start to ask different questions while they’re in the hospital than you ever did before,” she explains.

What is a Post-Discharge Clinic?

click for large version

The post-discharge clinic, also known as a transitional-care clinic or after-care clinic, is intended to bridge medical coverage between the hospital and primary care. The clinic at BIDMC is for patients affiliated with its Health Care Associates faculty practice “discharged from either our hospital or another hospital, who need care that their PCP or specialist, because of scheduling conflicts, cannot provide within the needed time frame,” Dr. Doctoroff says.

Four hospitalists from BIDMC’s large HM group were selected to staff the clinic. The hospitalists work in one-month rotations (a total of three months on service per year), and are relieved of other responsibilities during their month in clinic. They provide five half-day clinic sessions per week, with a 40-minute-per-patient visit schedule. Thirty minutes are allotted for patients referred from the hospital’s ED who did not get admitted to the hospital but need clinical follow-up.

 

The clinic is based in a BIDMC-affiliated primary-care practice, “which allows us to use its administrative structure and logistical support,” Dr. Doctoroff explains. “A hospital-based administrative service helps set up outpatient visits prior to discharge using computerized physician order entry and a scheduling algorhythm.” (See Figure 1) Patients who can be seen by their PCP in a timely fashion are referred to the PCP office; if not, they are scheduled in the post-discharge clinic. “That helps preserve the PCP relationship, which I think is paramount,” she says.

The first two years were spent getting the clinic established, but in the near future, BIDMC will start measuring such outcomes as access to care and quality. “But not necessarily readmission rates,” Dr. Doctoroff adds. “I know many people think of post-discharge clinics in the context of preventing readmissions, although we don’t have the data yet to fully support that. In fact, some readmissions may result from seeing a doctor. If you get a closer look at some patients after discharge and they are doing badly, they are more likely to be readmitted than if they had just stayed home.” In such cases, readmission could actually be a better outcome for the patient, she notes.

Dr. Doctoroff describes a typical user of her post-discharge clinic as a non-English-speaking patient who was discharged from the hospital with severe back pain from a herniated disk. “He came back to see me 10 days later, still barely able to walk. He hadn’t been able to fill any of the prescriptions from his hospital stay. Within two hours after I saw him, we got his meds filled and outpatient services set up,” she says. “We take care of many patients like him in the hospital with acute pain issues, whom we discharge as soon as they can walk, and later we see them limping into outpatient clinics. It makes me think differently now about how I plan their discharges.”

Who else needs these clinics? Dr. Doctoroff suggests two ways of looking at the question.

“Even for a simple patient admitted to the hospital, that can represent a significant change in the medical picture—a sort of sentinel event. In the discharge clinic, we give them an opportunity to review the hospitalization and answer their questions,” she says. “A lot of information presented to patients in the hospital is not well heard, and the initial visit may be their first time to really talk about what happened.” For other patients with conditions such as congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), or poorly controlled diabetes, treatment guidelines might dictate a pattern for post-discharge follow-up—for example, medical visits in seven or 10 days.

In Seattle, Harborview Medical Center established its After Care Clinic, staffed by hospitalists and nurse practitioners, to provide transitional care for patients discharged from inpatient wards or the ED in need of follow-up, says medical director and hospitalist Shay Martinez, MD. A second priority is to see any CHF patient within 48 hours of discharge.

“We try to limit patients to a maximum of three visits in our clinic,” she says. “At that point, we help them get established in a medical home, either here in one of our primary-care clinics, or in one of the many excellent community clinics in the area.

 

“This model works well with our patient population. We actually try to do primary care on the inpatient side as well. Our hospitalists are specialized in that approach, given our patient population. We see a lot of immigrants, non-English speakers, people with low health literacy, and the homeless, many of whom lack primary care,” Dr. Martinez says. “We do medication reconciliation, reassessments, and follow-ups with lab tests. We also try to assess who is more likely to be a no-show, and who needs more help with scheduling follow-up appointments.”

Clinical coverage of post-discharge clinics varies by setting, staffing, and scope. If demand is low, hospitalists or ED physicians can be called off the floor to see patients who return to the clinic, or they could staff the clinic after their hospitalist shift ends. Post-discharge clinic staff whose schedules are light can flex into providing primary-care visits in the clinic. Post-discharge can also could be provided in conjunction with—or as an alternative to—physician house calls to patients’ homes. Some post-discharge clinics work with medical call centers or telephonic case managers; some even use telemedicine.

It also could be a growth opportunity for hospitalist practices. “It is an exciting potential role for hospitalists interested in doing a little outpatient care,” Dr. Martinez says. “This is also a good way to be a safety net for your safety-net hospital.”

continued below...

Partner with Community

Tallahassee (Fla.) Memorial Hospital (TMH) in February launched a transitional-care clinic in collaboration with faculty from Florida State University, community-based health providers, and the local Capital Health Plan. Hospitalists don’t staff the clinic, but the HM group is its major source of referrals, says Dean Watson, MD, chief medical officer at TMH. Patients can be followed for up to eight weeks, during which time they get comprehensive assessments, medication review and optimization, and referral by the clinic social worker to a PCP and to available community services.

 

“Three years ago, we came up with the idea for a patient population we know is at high risk for readmission. Why don’t we partner with organizations in the community, form a clinic, teach students and residents, and learn together?” Dr. Watson says. “In addition to the usual patients, TMH targets those who have been readmitted to the hospital three times or more in the past year.”

The clinic, open five days a week, is staffed by a physician, nurse practitioner, telephonic nurse, and social worker, and also has a geriatric assessment clinic.

“We set up a system to identify patients through our electronic health record, and when they come to the clinic, we focus on their social environment and other non-medical issues that might cause readmissions,” he says. The clinic has a pharmacy and funds to support medications for patients without insurance. “In our first six months, we reduced emergency room visits and readmissions for these patients by 68 percent.”

One key partner, Capital Health Plan, bought and refurbished a building, and made it available for the clinic at no cost. Capital’s motivation, says Tom Glennon, a senior vice president for the plan, is its commitment to the community and to community service.

“We’re a nonprofit HMO. We’re focused on what we can do to serve the community, and we’re looking at this as a way for the hospital to have fewer costly, unreimbursed bouncebacks,” Glennon says. “That’s a win-win for all of us.”

Most of the patients who use the clinic are not members of Capital Health Plan, Glennon adds. “If we see CHP members turning up at the transitions clinic, then we have a problem—a breakdown in our case management,” he explains. “Our goal is to have our members taken care of by primary-care providers.”

Hard Data? Not So Fast

How many post-discharge clinics are in operation today is not known. Fundamental financial data, too, are limited, but some say it is unlikely a post-discharge clinic will cover operating expenses from billing revenues alone.

Thus, such clinics will require funding from the hospital, HM group, health system, or health plans, based on the benefits the clinic provides to discharged patients and the impact on 30-day readmissions (for more about the logistical challenges post-discharge clinics present, see “What Do PCPs Think?”).

Some also suggest that many of the post-discharge clinics now in operation are too new to have demonstrated financial impact or return on investment. “We have not yet been asked to show our financial viability,” Dr. Doctoroff says. “I think the clinic leadership thinks we are fulfilling other goals for now, such as creating easier access for their patients after discharge.”

 

Amy Boutwell, MD, MPP, a hospitalist at Newton Wellesley Hospital in Massachusetts and founder of Collaborative Healthcare Strategies, is among the post-discharge skeptics. She agrees with Dr. Williams that the post-discharge concept is more of a temporary fix to the long-term issues in primary care. “I think the idea is getting more play than actual activity out there right now,” she says. “We need to find opportunities to manage transitions within our scope today and tomorrow while strategically looking at where we want to be in five years [as hospitals and health systems].”

Dr. Boutwell says she’s experienced the frustration of trying to make follow-up appointments with physicians who don’t have any open slots for hospitalized patients awaiting discharge. “We think of follow up as physician-led, but there are alternatives and physician extenders,” she says. “It is well-documented that our healthcare system underuses home health care and other services that might be helpful. We forget how many other opportunities there are in our communities to get another clinician to touch the patient.”

Hospitalists, as key players in the healthcare system, can speak out in support of strengthening primary-care networks and building more collaborative relationships with PCPs, according to Dr. Williams. “If you’re going to set up an outpatient clinic, ideally, have it staffed by PCPs who can funnel the patients into primary-care networks. If that’s not feasible, then hospitalists should proceed with caution, since this approach begins to take them out of their scope of practice,” he says.

With 13 years of experience in urban hospital settings, Dr. Williams is familiar with the dangers unassigned patients present at discharge. “But I don’t know that we’ve yet optimized the hospital discharge process at any hospital in the United States,” he says.

That said, Dr. Williams knows his hospital in downtown Chicago is now working to establish a post-discharge clinic. It will be staffed by PCPs and will target patients who don’t have a PCP, are on Medicaid, or lack insurance.

“Where it starts to make me uncomfortable,” Dr. Williams says, “is what happens when you follow patients out into the outpatient setting?

It’s hard to do just one visit and draw the line. Yes, you may prevent a readmission, but the patient is still left with chronic illness and the need for primary care.”

Larry Beresford is a freelance writer based in Oakland, Calif.

 

References

1. Goodman, DC, Fisher ES, Chang C. After Hospitalization: A Dartmouth Atlas Report on Post-Acute Care for Medicare Beneficiaries. Dartmouth Atlas website. Available at: www.dartmouthatlas.org/downloads/reports/Post_discharge_events_092811.pdf. Accessed Nov. 3, 2011.
2. Hansen LO, Young RS, Hinami K, Leung A, Williams MV. Interventions to reduce 3-day rehospitalization: A systematic review. Ann Int Med. 2011;155(8): 520-528.
3. Misky GJ, Wald HL, Coleman EA. Post-hospitalization transitions: Examining the effects of timing of primary care provider follow-up. J Hosp Med. 2010;5(7):392-397.
4. Shu CC, Hsu NC, Lin YF, et al. Integrated post-discharge transitional care in Taiwan. BMC Medicine website. Available at: www.biomedcentral.com/1741-7015/9/96. Accessed Nov. 1, 2011.

The hospitalist concept was established on the foundation of timely, informative handoffs to primary-care physicians (PCPs) once a patient’s hospital stay is complete. With sicker patients and shorter hospital stays, pending test results, and complex post-discharge medication regimens to sort out, this handoff is crucial to successful discharges. But what if a discharged patient can’t get in to see the PCP, or has no established PCP?

Recent research on hospital readmissions by the Dartmouth Atlas Project found that only 42% of hospitalized Medicare patients had any contact with a primary-care clinician within 14 days of discharge.¹ For patients with ongoing medical needs, such missed connections are a major contributor to hospital readmissions, and thus a target for hospitals and HM groups wanting to control their readmission rates before Medicare imposes reimbursement penalties starting in October 2012 (see “Value-Based Purchasing Raises the Stakes,” May 2011, p. 1).

One proposed solution is the post-discharge clinic, typically located on or near a hospital’s campus and staffed by hospitalists, PCPs, or advanced-practice nurses. The patient can be seen once or a few times in the post-discharge clinic to make sure that health education started in the hospital is understood and followed, and that prescriptions ordered in the hospital are being taken on schedule.

Mark V. Williams, MD, FACP, FHM, professor and chief of the division of hospital medicine at Northwestern University’s Feinberg School of Medicine in Chicago, describes hospitalist-led post-discharge clinics as “Band-Aids for an inadequate primary-care system.” What would be better, he says, is focusing on the underlying problem and working to improve post-discharge access to primary care. Dr. Williams acknowledges, however, that sometimes a patch is needed to stanch the blood flow—e.g., to better manage care transitions—while waiting on healthcare reform and medical homes to improve care coordination throughout the system.

Working in a post-discharge clinic might seem like “a stretch for many hospitalists, especially those who chose this field because they didn’t want to do outpatient medicine,” says Lauren Doctoroff, MD, a hospitalist who directs a post-discharge clinic at Beth Israel Deaconess Medical Center (BIDMC) in Boston. “But there are times when it may be appropriate for hospital-based doctors to extend their responsibility out of the hospital.”

Dr. Doctoroff also says that working in such a clinic can be practice-changing for hospitalists. “All of a sudden, you have a different view of your hospitalized patients, and you start to ask different questions while they’re in the hospital than you ever did before,” she explains.

What is a Post-Discharge Clinic?

click for large version

The post-discharge clinic, also known as a transitional-care clinic or after-care clinic, is intended to bridge medical coverage between the hospital and primary care. The clinic at BIDMC is for patients affiliated with its Health Care Associates faculty practice “discharged from either our hospital or another hospital, who need care that their PCP or specialist, because of scheduling conflicts, cannot provide within the needed time frame,” Dr. Doctoroff says.

Four hospitalists from BIDMC’s large HM group were selected to staff the clinic. The hospitalists work in one-month rotations (a total of three months on service per year), and are relieved of other responsibilities during their month in clinic. They provide five half-day clinic sessions per week, with a 40-minute-per-patient visit schedule. Thirty minutes are allotted for patients referred from the hospital’s ED who did not get admitted to the hospital but need clinical follow-up.

 

The clinic is based in a BIDMC-affiliated primary-care practice, “which allows us to use its administrative structure and logistical support,” Dr. Doctoroff explains. “A hospital-based administrative service helps set up outpatient visits prior to discharge using computerized physician order entry and a scheduling algorhythm.” (See Figure 1) Patients who can be seen by their PCP in a timely fashion are referred to the PCP office; if not, they are scheduled in the post-discharge clinic. “That helps preserve the PCP relationship, which I think is paramount,” she says.

The first two years were spent getting the clinic established, but in the near future, BIDMC will start measuring such outcomes as access to care and quality. “But not necessarily readmission rates,” Dr. Doctoroff adds. “I know many people think of post-discharge clinics in the context of preventing readmissions, although we don’t have the data yet to fully support that. In fact, some readmissions may result from seeing a doctor. If you get a closer look at some patients after discharge and they are doing badly, they are more likely to be readmitted than if they had just stayed home.” In such cases, readmission could actually be a better outcome for the patient, she notes.

Dr. Doctoroff describes a typical user of her post-discharge clinic as a non-English-speaking patient who was discharged from the hospital with severe back pain from a herniated disk. “He came back to see me 10 days later, still barely able to walk. He hadn’t been able to fill any of the prescriptions from his hospital stay. Within two hours after I saw him, we got his meds filled and outpatient services set up,” she says. “We take care of many patients like him in the hospital with acute pain issues, whom we discharge as soon as they can walk, and later we see them limping into outpatient clinics. It makes me think differently now about how I plan their discharges.”

Who else needs these clinics? Dr. Doctoroff suggests two ways of looking at the question.

“Even for a simple patient admitted to the hospital, that can represent a significant change in the medical picture—a sort of sentinel event. In the discharge clinic, we give them an opportunity to review the hospitalization and answer their questions,” she says. “A lot of information presented to patients in the hospital is not well heard, and the initial visit may be their first time to really talk about what happened.” For other patients with conditions such as congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), or poorly controlled diabetes, treatment guidelines might dictate a pattern for post-discharge follow-up—for example, medical visits in seven or 10 days.

In Seattle, Harborview Medical Center established its After Care Clinic, staffed by hospitalists and nurse practitioners, to provide transitional care for patients discharged from inpatient wards or the ED in need of follow-up, says medical director and hospitalist Shay Martinez, MD. A second priority is to see any CHF patient within 48 hours of discharge.

“We try to limit patients to a maximum of three visits in our clinic,” she says. “At that point, we help them get established in a medical home, either here in one of our primary-care clinics, or in one of the many excellent community clinics in the area.

 

“This model works well with our patient population. We actually try to do primary care on the inpatient side as well. Our hospitalists are specialized in that approach, given our patient population. We see a lot of immigrants, non-English speakers, people with low health literacy, and the homeless, many of whom lack primary care,” Dr. Martinez says. “We do medication reconciliation, reassessments, and follow-ups with lab tests. We also try to assess who is more likely to be a no-show, and who needs more help with scheduling follow-up appointments.”

Clinical coverage of post-discharge clinics varies by setting, staffing, and scope. If demand is low, hospitalists or ED physicians can be called off the floor to see patients who return to the clinic, or they could staff the clinic after their hospitalist shift ends. Post-discharge clinic staff whose schedules are light can flex into providing primary-care visits in the clinic. Post-discharge can also could be provided in conjunction with—or as an alternative to—physician house calls to patients’ homes. Some post-discharge clinics work with medical call centers or telephonic case managers; some even use telemedicine.

It also could be a growth opportunity for hospitalist practices. “It is an exciting potential role for hospitalists interested in doing a little outpatient care,” Dr. Martinez says. “This is also a good way to be a safety net for your safety-net hospital.”

continued below...

Partner with Community

Tallahassee (Fla.) Memorial Hospital (TMH) in February launched a transitional-care clinic in collaboration with faculty from Florida State University, community-based health providers, and the local Capital Health Plan. Hospitalists don’t staff the clinic, but the HM group is its major source of referrals, says Dean Watson, MD, chief medical officer at TMH. Patients can be followed for up to eight weeks, during which time they get comprehensive assessments, medication review and optimization, and referral by the clinic social worker to a PCP and to available community services.

 

“Three years ago, we came up with the idea for a patient population we know is at high risk for readmission. Why don’t we partner with organizations in the community, form a clinic, teach students and residents, and learn together?” Dr. Watson says. “In addition to the usual patients, TMH targets those who have been readmitted to the hospital three times or more in the past year.”

The clinic, open five days a week, is staffed by a physician, nurse practitioner, telephonic nurse, and social worker, and also has a geriatric assessment clinic.

“We set up a system to identify patients through our electronic health record, and when they come to the clinic, we focus on their social environment and other non-medical issues that might cause readmissions,” he says. The clinic has a pharmacy and funds to support medications for patients without insurance. “In our first six months, we reduced emergency room visits and readmissions for these patients by 68 percent.”

One key partner, Capital Health Plan, bought and refurbished a building, and made it available for the clinic at no cost. Capital’s motivation, says Tom Glennon, a senior vice president for the plan, is its commitment to the community and to community service.

“We’re a nonprofit HMO. We’re focused on what we can do to serve the community, and we’re looking at this as a way for the hospital to have fewer costly, unreimbursed bouncebacks,” Glennon says. “That’s a win-win for all of us.”

Most of the patients who use the clinic are not members of Capital Health Plan, Glennon adds. “If we see CHP members turning up at the transitions clinic, then we have a problem—a breakdown in our case management,” he explains. “Our goal is to have our members taken care of by primary-care providers.”

Hard Data? Not So Fast

How many post-discharge clinics are in operation today is not known. Fundamental financial data, too, are limited, but some say it is unlikely a post-discharge clinic will cover operating expenses from billing revenues alone.

Thus, such clinics will require funding from the hospital, HM group, health system, or health plans, based on the benefits the clinic provides to discharged patients and the impact on 30-day readmissions (for more about the logistical challenges post-discharge clinics present, see “What Do PCPs Think?”).

Some also suggest that many of the post-discharge clinics now in operation are too new to have demonstrated financial impact or return on investment. “We have not yet been asked to show our financial viability,” Dr. Doctoroff says. “I think the clinic leadership thinks we are fulfilling other goals for now, such as creating easier access for their patients after discharge.”

 

Amy Boutwell, MD, MPP, a hospitalist at Newton Wellesley Hospital in Massachusetts and founder of Collaborative Healthcare Strategies, is among the post-discharge skeptics. She agrees with Dr. Williams that the post-discharge concept is more of a temporary fix to the long-term issues in primary care. “I think the idea is getting more play than actual activity out there right now,” she says. “We need to find opportunities to manage transitions within our scope today and tomorrow while strategically looking at where we want to be in five years [as hospitals and health systems].”

Dr. Boutwell says she’s experienced the frustration of trying to make follow-up appointments with physicians who don’t have any open slots for hospitalized patients awaiting discharge. “We think of follow up as physician-led, but there are alternatives and physician extenders,” she says. “It is well-documented that our healthcare system underuses home health care and other services that might be helpful. We forget how many other opportunities there are in our communities to get another clinician to touch the patient.”

Hospitalists, as key players in the healthcare system, can speak out in support of strengthening primary-care networks and building more collaborative relationships with PCPs, according to Dr. Williams. “If you’re going to set up an outpatient clinic, ideally, have it staffed by PCPs who can funnel the patients into primary-care networks. If that’s not feasible, then hospitalists should proceed with caution, since this approach begins to take them out of their scope of practice,” he says.

With 13 years of experience in urban hospital settings, Dr. Williams is familiar with the dangers unassigned patients present at discharge. “But I don’t know that we’ve yet optimized the hospital discharge process at any hospital in the United States,” he says.

That said, Dr. Williams knows his hospital in downtown Chicago is now working to establish a post-discharge clinic. It will be staffed by PCPs and will target patients who don’t have a PCP, are on Medicaid, or lack insurance.

“Where it starts to make me uncomfortable,” Dr. Williams says, “is what happens when you follow patients out into the outpatient setting?

It’s hard to do just one visit and draw the line. Yes, you may prevent a readmission, but the patient is still left with chronic illness and the need for primary care.”

Larry Beresford is a freelance writer based in Oakland, Calif.

 

References

1. Goodman, DC, Fisher ES, Chang C. After Hospitalization: A Dartmouth Atlas Report on Post-Acute Care for Medicare Beneficiaries. Dartmouth Atlas website. Available at: www.dartmouthatlas.org/downloads/reports/Post_discharge_events_092811.pdf. Accessed Nov. 3, 2011.
2. Hansen LO, Young RS, Hinami K, Leung A, Williams MV. Interventions to reduce 3-day rehospitalization: A systematic review. Ann Int Med. 2011;155(8): 520-528.
3. Misky GJ, Wald HL, Coleman EA. Post-hospitalization transitions: Examining the effects of timing of primary care provider follow-up. J Hosp Med. 2010;5(7):392-397.
4. Shu CC, Hsu NC, Lin YF, et al. Integrated post-discharge transitional care in Taiwan. BMC Medicine website. Available at: www.biomedcentral.com/1741-7015/9/96. Accessed Nov. 1, 2011.

The hospitalist concept was established on the foundation of timely, informative handoffs to primary-care physicians (PCPs) once a patient’s hospital stay is complete. With sicker patients and shorter hospital stays, pending test results, and complex post-discharge medication regimens to sort out, this handoff is crucial to successful discharges. But what if a discharged patient can’t get in to see the PCP, or has no established PCP?

Recent research on hospital readmissions by the Dartmouth Atlas Project found that only 42% of hospitalized Medicare patients had any contact with a primary-care clinician within 14 days of discharge.¹ For patients with ongoing medical needs, such missed connections are a major contributor to hospital readmissions, and thus a target for hospitals and HM groups wanting to control their readmission rates before Medicare imposes reimbursement penalties starting in October 2012 (see “Value-Based Purchasing Raises the Stakes,” May 2011, p. 1).

One proposed solution is the post-discharge clinic, typically located on or near a hospital’s campus and staffed by hospitalists, PCPs, or advanced-practice nurses. The patient can be seen once or a few times in the post-discharge clinic to make sure that health education started in the hospital is understood and followed, and that prescriptions ordered in the hospital are being taken on schedule.

Mark V. Williams, MD, FACP, FHM, professor and chief of the division of hospital medicine at Northwestern University’s Feinberg School of Medicine in Chicago, describes hospitalist-led post-discharge clinics as “Band-Aids for an inadequate primary-care system.” What would be better, he says, is focusing on the underlying problem and working to improve post-discharge access to primary care. Dr. Williams acknowledges, however, that sometimes a patch is needed to stanch the blood flow—e.g., to better manage care transitions—while waiting on healthcare reform and medical homes to improve care coordination throughout the system.

Working in a post-discharge clinic might seem like “a stretch for many hospitalists, especially those who chose this field because they didn’t want to do outpatient medicine,” says Lauren Doctoroff, MD, a hospitalist who directs a post-discharge clinic at Beth Israel Deaconess Medical Center (BIDMC) in Boston. “But there are times when it may be appropriate for hospital-based doctors to extend their responsibility out of the hospital.”

Dr. Doctoroff also says that working in such a clinic can be practice-changing for hospitalists. “All of a sudden, you have a different view of your hospitalized patients, and you start to ask different questions while they’re in the hospital than you ever did before,” she explains.

What is a Post-Discharge Clinic?

click for large version

The post-discharge clinic, also known as a transitional-care clinic or after-care clinic, is intended to bridge medical coverage between the hospital and primary care. The clinic at BIDMC is for patients affiliated with its Health Care Associates faculty practice “discharged from either our hospital or another hospital, who need care that their PCP or specialist, because of scheduling conflicts, cannot provide within the needed time frame,” Dr. Doctoroff says.

Four hospitalists from BIDMC’s large HM group were selected to staff the clinic. The hospitalists work in one-month rotations (a total of three months on service per year), and are relieved of other responsibilities during their month in clinic. They provide five half-day clinic sessions per week, with a 40-minute-per-patient visit schedule. Thirty minutes are allotted for patients referred from the hospital’s ED who did not get admitted to the hospital but need clinical follow-up.

 

The clinic is based in a BIDMC-affiliated primary-care practice, “which allows us to use its administrative structure and logistical support,” Dr. Doctoroff explains. “A hospital-based administrative service helps set up outpatient visits prior to discharge using computerized physician order entry and a scheduling algorhythm.” (See Figure 1) Patients who can be seen by their PCP in a timely fashion are referred to the PCP office; if not, they are scheduled in the post-discharge clinic. “That helps preserve the PCP relationship, which I think is paramount,” she says.

The first two years were spent getting the clinic established, but in the near future, BIDMC will start measuring such outcomes as access to care and quality. “But not necessarily readmission rates,” Dr. Doctoroff adds. “I know many people think of post-discharge clinics in the context of preventing readmissions, although we don’t have the data yet to fully support that. In fact, some readmissions may result from seeing a doctor. If you get a closer look at some patients after discharge and they are doing badly, they are more likely to be readmitted than if they had just stayed home.” In such cases, readmission could actually be a better outcome for the patient, she notes.

Dr. Doctoroff describes a typical user of her post-discharge clinic as a non-English-speaking patient who was discharged from the hospital with severe back pain from a herniated disk. “He came back to see me 10 days later, still barely able to walk. He hadn’t been able to fill any of the prescriptions from his hospital stay. Within two hours after I saw him, we got his meds filled and outpatient services set up,” she says. “We take care of many patients like him in the hospital with acute pain issues, whom we discharge as soon as they can walk, and later we see them limping into outpatient clinics. It makes me think differently now about how I plan their discharges.”

Who else needs these clinics? Dr. Doctoroff suggests two ways of looking at the question.

“Even for a simple patient admitted to the hospital, that can represent a significant change in the medical picture—a sort of sentinel event. In the discharge clinic, we give them an opportunity to review the hospitalization and answer their questions,” she says. “A lot of information presented to patients in the hospital is not well heard, and the initial visit may be their first time to really talk about what happened.” For other patients with conditions such as congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), or poorly controlled diabetes, treatment guidelines might dictate a pattern for post-discharge follow-up—for example, medical visits in seven or 10 days.

In Seattle, Harborview Medical Center established its After Care Clinic, staffed by hospitalists and nurse practitioners, to provide transitional care for patients discharged from inpatient wards or the ED in need of follow-up, says medical director and hospitalist Shay Martinez, MD. A second priority is to see any CHF patient within 48 hours of discharge.

“We try to limit patients to a maximum of three visits in our clinic,” she says. “At that point, we help them get established in a medical home, either here in one of our primary-care clinics, or in one of the many excellent community clinics in the area.

 

“This model works well with our patient population. We actually try to do primary care on the inpatient side as well. Our hospitalists are specialized in that approach, given our patient population. We see a lot of immigrants, non-English speakers, people with low health literacy, and the homeless, many of whom lack primary care,” Dr. Martinez says. “We do medication reconciliation, reassessments, and follow-ups with lab tests. We also try to assess who is more likely to be a no-show, and who needs more help with scheduling follow-up appointments.”

Clinical coverage of post-discharge clinics varies by setting, staffing, and scope. If demand is low, hospitalists or ED physicians can be called off the floor to see patients who return to the clinic, or they could staff the clinic after their hospitalist shift ends. Post-discharge clinic staff whose schedules are light can flex into providing primary-care visits in the clinic. Post-discharge can also could be provided in conjunction with—or as an alternative to—physician house calls to patients’ homes. Some post-discharge clinics work with medical call centers or telephonic case managers; some even use telemedicine.

It also could be a growth opportunity for hospitalist practices. “It is an exciting potential role for hospitalists interested in doing a little outpatient care,” Dr. Martinez says. “This is also a good way to be a safety net for your safety-net hospital.”

continued below...

Partner with Community

Tallahassee (Fla.) Memorial Hospital (TMH) in February launched a transitional-care clinic in collaboration with faculty from Florida State University, community-based health providers, and the local Capital Health Plan. Hospitalists don’t staff the clinic, but the HM group is its major source of referrals, says Dean Watson, MD, chief medical officer at TMH. Patients can be followed for up to eight weeks, during which time they get comprehensive assessments, medication review and optimization, and referral by the clinic social worker to a PCP and to available community services.

 

“Three years ago, we came up with the idea for a patient population we know is at high risk for readmission. Why don’t we partner with organizations in the community, form a clinic, teach students and residents, and learn together?” Dr. Watson says. “In addition to the usual patients, TMH targets those who have been readmitted to the hospital three times or more in the past year.”

The clinic, open five days a week, is staffed by a physician, nurse practitioner, telephonic nurse, and social worker, and also has a geriatric assessment clinic.

“We set up a system to identify patients through our electronic health record, and when they come to the clinic, we focus on their social environment and other non-medical issues that might cause readmissions,” he says. The clinic has a pharmacy and funds to support medications for patients without insurance. “In our first six months, we reduced emergency room visits and readmissions for these patients by 68 percent.”

One key partner, Capital Health Plan, bought and refurbished a building, and made it available for the clinic at no cost. Capital’s motivation, says Tom Glennon, a senior vice president for the plan, is its commitment to the community and to community service.

“We’re a nonprofit HMO. We’re focused on what we can do to serve the community, and we’re looking at this as a way for the hospital to have fewer costly, unreimbursed bouncebacks,” Glennon says. “That’s a win-win for all of us.”

Most of the patients who use the clinic are not members of Capital Health Plan, Glennon adds. “If we see CHP members turning up at the transitions clinic, then we have a problem—a breakdown in our case management,” he explains. “Our goal is to have our members taken care of by primary-care providers.”

Hard Data? Not So Fast

How many post-discharge clinics are in operation today is not known. Fundamental financial data, too, are limited, but some say it is unlikely a post-discharge clinic will cover operating expenses from billing revenues alone.

Thus, such clinics will require funding from the hospital, HM group, health system, or health plans, based on the benefits the clinic provides to discharged patients and the impact on 30-day readmissions (for more about the logistical challenges post-discharge clinics present, see “What Do PCPs Think?”).

Some also suggest that many of the post-discharge clinics now in operation are too new to have demonstrated financial impact or return on investment. “We have not yet been asked to show our financial viability,” Dr. Doctoroff says. “I think the clinic leadership thinks we are fulfilling other goals for now, such as creating easier access for their patients after discharge.”

 

Amy Boutwell, MD, MPP, a hospitalist at Newton Wellesley Hospital in Massachusetts and founder of Collaborative Healthcare Strategies, is among the post-discharge skeptics. She agrees with Dr. Williams that the post-discharge concept is more of a temporary fix to the long-term issues in primary care. “I think the idea is getting more play than actual activity out there right now,” she says. “We need to find opportunities to manage transitions within our scope today and tomorrow while strategically looking at where we want to be in five years [as hospitals and health systems].”

Dr. Boutwell says she’s experienced the frustration of trying to make follow-up appointments with physicians who don’t have any open slots for hospitalized patients awaiting discharge. “We think of follow up as physician-led, but there are alternatives and physician extenders,” she says. “It is well-documented that our healthcare system underuses home health care and other services that might be helpful. We forget how many other opportunities there are in our communities to get another clinician to touch the patient.”

Hospitalists, as key players in the healthcare system, can speak out in support of strengthening primary-care networks and building more collaborative relationships with PCPs, according to Dr. Williams. “If you’re going to set up an outpatient clinic, ideally, have it staffed by PCPs who can funnel the patients into primary-care networks. If that’s not feasible, then hospitalists should proceed with caution, since this approach begins to take them out of their scope of practice,” he says.

With 13 years of experience in urban hospital settings, Dr. Williams is familiar with the dangers unassigned patients present at discharge. “But I don’t know that we’ve yet optimized the hospital discharge process at any hospital in the United States,” he says.

That said, Dr. Williams knows his hospital in downtown Chicago is now working to establish a post-discharge clinic. It will be staffed by PCPs and will target patients who don’t have a PCP, are on Medicaid, or lack insurance.

“Where it starts to make me uncomfortable,” Dr. Williams says, “is what happens when you follow patients out into the outpatient setting?

It’s hard to do just one visit and draw the line. Yes, you may prevent a readmission, but the patient is still left with chronic illness and the need for primary care.”

Larry Beresford is a freelance writer based in Oakland, Calif.

 

References

1. Goodman, DC, Fisher ES, Chang C. After Hospitalization: A Dartmouth Atlas Report on Post-Acute Care for Medicare Beneficiaries. Dartmouth Atlas website. Available at: www.dartmouthatlas.org/downloads/reports/Post_discharge_events_092811.pdf. Accessed Nov. 3, 2011.
2. Hansen LO, Young RS, Hinami K, Leung A, Williams MV. Interventions to reduce 3-day rehospitalization: A systematic review. Ann Int Med. 2011;155(8): 520-528.
3. Misky GJ, Wald HL, Coleman EA. Post-hospitalization transitions: Examining the effects of timing of primary care provider follow-up. J Hosp Med. 2010;5(7):392-397.
4. Shu CC, Hsu NC, Lin YF, et al. Integrated post-discharge transitional care in Taiwan. BMC Medicine website. Available at: www.biomedcentral.com/1741-7015/9/96. Accessed Nov. 1, 2011.

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Case

A 63-year-old man with severe chronic obstructive pulmonary disease (COPD) presents with one week of increasing sputum, cough, and dyspnea. His respiratory rate is 26/minute and oxygen saturation is 86% on room air (RA). He is lethargic and appears mildly uncomfortable, but he responds appropriately to questions in three- to four-word sentences. He is tachypneic with accessory muscle use and has diffuse wheezes throughout his bilateral lung fields. His initial room air arterial blood gas (ABG) is 7.32/68/86/32. Chest radiograph is notable for flattened hemidiaphragms without focal opacity. The patient is placed on oxygen and receives prednisone with nebulized albuterol and ipratropium, but his dyspnea and tachypnea persist. Due to his respiratory distress, bilevel positive airway pressure (BiPAP) is considered.

What are the clinical indications for noninvasive positive pressure ventilation (NPPV)?

Overview

NPPV assists ventilation by delivering positive expiratory and/or inspiratory pressure without the use of an endotracheal tube. Theoretically, NPPV is a preferred method of ventilation as it may eliminate the need for endotracheal intubation and its associated morbidity and mortality, including airway trauma, loss of airway defense mechanisms (ventilator-associated pneumonia), mechanical ventilation (barotrauma), and disruption of speech and swallowing.¹

NPPV is generally delivered via full-face mask or nasal mask. Nasal mask is often preferred for patient comfort, though air leaks occur with mouth breathing. There is no difference between nasal and full-face masks in outcomes including intubation rates and mortality.^2,3,4 NPPV can be delivered via a portable or standard ventilator using the same modes available for endotracheal intubation, though pressure-cycled ventilators utilizing continuous positive airway pressure (CPAP) and BiPAP are most common. CPAP delivers air at a continuous fixed pressure throughout the respiratory cycle. BiPAP delivers positive pressure at alternating levels—higher for inspiration and lower for expiration. Guidelines suggest choosing a mode based on the etiology and pathophysiology of the respiratory failure and leveraging local comfort and expertise.^2,3

In general, good candidates for NPPV display signs of tachypnea and dyspnea due to hypoxic or hypercapnic respiratory failure but are hemodynamically stable, without excessive secretions, and can protect their airway and achieve a proper seal with the mask.³ Difficulty may arise due to patient intolerance, claustrophobia, gastric distention, and poor fit that leads to air leak or skin erosion. With initiation of NPPV, patients should be followed in a care setting with the capacity for frequent monitoring and, if needed, quick access to invasive airway management. Monitoring should include patient comfort and ability to tolerate the device, vital signs, breathing pattern, oxygen saturation, ABG, and mental status. This initial evaluation may help predict the success of NPPV (see Table 2). Appropriately chosen candidates who do well with NPPV often demonstrate respiratory turnaround in a relatively brief interval^.2,3

click for large version

Review of the Data

NPPV is increasingly utilized in a variety of clinical situations. In 2000, the American Thoracic Society published consensus guidelines on the use of NPPV in acute respiratory failure.² More recently, the Canadian Medical Association developed clinical guidelines for the use of NPPV in the acute-care setting.⁴ Clinical scenarios in which there is evidence for the efficacy of NPPV include severe exacerbations of COPD, cardiogenic pulmonary edema, immunosuppressed patients with pulmonary infiltrates, and hypoxia; it can also be used as a bridge to extubation in COPD patients.^1-4

 

Acute exacerbation of COPD. Several randomized controlled trials (RCT) and meta-analyses have assessed the potential benefits of NPPV in patients with acute exacerbations of COPD. In COPD, NPPV improves gas exchange and facilitates respiratory muscle rest to decrease the work of breathing, which allows for respiratory recovery and time to effectiveness of standard therapies.⁵ Multiple trials have demonstrated that the addition of NPPV to usual care decreases intubation and mortality rates, as well as hospital lengths of stay (LOS).^5-8

A Cochrane review of eight RCTs comparing NPPV with usual care noted a greater than 50% reduction in risk of intubation, and a number needed to treat (NNT) of eight patients to prevent one death.⁵ Quon and colleagues also compared NPPV to usual care in a meta-analysis of 14 trials.⁶ Eleven of these trials evaluated hospital mortality, which was decreased by 55% in patients receiving NPPV. Twelve trials assessed need for intubation, which decreased by 65%. In these trials, BiPAP was the most commonly used modality (see Table 3, for a comparison of NPPV modalities). Study patients had an average pH of 7.31 with an average PaCO2 of 68 mmHg. It was noted that the beneficial effects of NPPV increased as pH decreased. An earlier meta-analysis from Keenan and colleagues supported this notion, noting that the subgroup of patients with pH <7.3 benefited most in terms of decreased rates of intubation, hospital LOS, and hospital mortality.7 In this 2003 study, patients with relatively mild exacerbations of COPD did not benefit from the addition of NPPV to usual care. Based on the amount of positive evidence, NPPV is recommended in patients experiencing severe exacerbations of COPD as evidenced by a pH <7.35 and relative hypercarbia.^1,2,4,7

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Cardiogenic pulmonary edema. In patients with acute cardiogenic pulmonary edema, NPPV has been found to be beneficial, decreasing mortality, rates of intubation, and hospital LOS. Physiologically, NPPV augments cardiac output, improves respiratory mechanics, and decreases afterload.10 Cardiogenic edema is variably defined and has a number of causes elucidated in an analysis of 11 RCTs conducted by Masip and colleagues. These causes included acute coronary syndrome (31%), hypertension (27%), congestive heart failure (14%), and a combination of respiratory infection, arrhythmia, volume overload, and treatment noncompliance (28%).⁹ In this analysis, CPAP and BiPAP demonstrated a combined 43% reduction in mortality and a 57% reduction in intubation. More recently, Peter and colleagues described a statistically significant reduction in hospital mortality and the need for intubation with CPAP, while BiPAP only demonstrated a statistically significant decrease in need for intubation.¹⁰ Thus, there appears to be some evidence that CPAP is the preferred NPPV mode in patients with acute cardiogenic pulmonary edema. Despite inclusion of a recent, large RCT showing no benefit of NPPV versus usual care in cardiogenic pulmonary edema, the overall positive effect of NPPV persisted, particularly when the cause of pulmonary edema was acute coronary syndrome.¹¹

Weaning after intubation. NPPV has been evaluated as a method to facilitate early extubation, as a measure to prevent extubation failure, and as a treatment modality for respiratory failure following extubation, with mixed results.^12,13 In 1998, a small trial compared the use of NPPV in COPD patients to facilitate early extubation with a standard weaning protocol. In this population, early NPPV resulted in better weaning rates with shorter times of mechanical ventilation (10 vs. 16 days), fewer days in the ICU, and improved 60-day survival rates (92% vs. 72%).^3,14 In another RCT not limited to COPD patients, Grault and colleagues found that NPPV reduced the duration of intubation (4.5 vs. 7.6 days) but was not associated with benefits in ICU length of stay or survival previously described.^3,15 Thus, though NPPV may be beneficial in facilitating early extubation in COPD patients, it is not recommended in other patient populations.⁴

 

NPPV has also been evaluated as a measure to prevent respiratory failure in patients at high risk for extubation failure. When applied immediately after extubation in patients with COPD and obesity, NPPV reduced reintubation rates and ICU mortality.^3,4 In 2004, Esteban and colleagues examined NPPV in patients who had respiratory failure following extubation. In this setting, NPPV was ineffective at preventing reintubation and had no survival benefit.

In summary, NPPV may facilitate early extubation and prevent extubation failure in appropriate patients, such as those with COPD, but is unlikely to be beneficial and is not recommended in patients with existing respiratory failure after extubation.^4,15

Immunosuppressed patients. A 2001 single-center, randomized-controlled trial by Holbert and colleagues demonstrated decreased intubation rates and mortality with the application of NPPV in immunosuppressed patients with hypoxemic respiratory failure, fever, and pulmonary infiltrates.¹⁶

In this study, immunosuppression occurred most commonly as a result of malignancy. In the group receiving NPPV alternating with oxygen (at least 45 minutes of NPPV alternated every three hours with periods of spontaneous breathing), the rate of subsequent intubation decreased to 46%, compared with 77% in those receiving oxygen alone. The mortality rate was 38% in the NPPV group, as compared with 69% in the standard treatment group.

Though the outcomes in immunocompromised patients with hypoxemia, fever, and pulmonary infiltrates were very poor (38% mortality even with NPPV), this small study and recent guidelines suggest a trial of NPPV in this population.^4,16

Other indications. NPPV has been applied in multiple other clinical scenarios, including exacerbation of asthma, community-acquired pneumonia, acute lung injury, and bronchoscopy in hypoxemic patients. It has also been evaluated in the postsurgical period and in chest trauma. There are mixed and less robust data in these various applications, and larger controlled trials are lacking.

In asthma exacerbation, NPPV may improve dyspnea, but data regarding outcomes (intubation, mortality) are lacking. A 2005 Cochrane review concluded that data remain controversial due to insufficient evidence, and guidelines make no recommendations concerning NPPV in asthma exacerbation.^4,17 Similarly, in community-acquired pneumonia without prior history of COPD, there is no major role for NPPV.^1,3,4 Limited data suggest that NPPV lacks efficacy in preventing post-surgical respiratory failure, though it may be useful in treating existing respiratory failure or preventing intubation in patients following lung resection or abdominal surgery.^1,4 In hypoxemic patients undergoing bronchoscopy, NPPV may improve oxygenation (lower respiratory rates and improved PaO2 to FiO2 ratios, compared with oxygen alone) as well as hemodynamics (minimizing the drop in mean arterial pressure). However, outcome data are lacking and the data set is small.^4,18 In acute lung injury/acute respiratory distress syndrome, data are also limited, but NPPV appears to have a high failure rate and confers little benefit.^1,4

Back to the Case

The patient was admitted to the hospital and placed on BiPAP for approximately 1.5 hours. The patient’s respiratory rate improved to 20/minute and he appeared increasingly comfortable and alert. A repeat ABG revealed improved hypercarbia and acidosis. He was continued on steroids and antibiotics and eventually was weaned from BiPAP and discharged home.

Bottom Line

NPPV is an effective method to decrease mortality, intubation rates, and duration of ICU stay in severe exacerbations of COPD, cardiogenic pulmonary edema, immunosuppressed patients with pulmonary infiltrates, and hypoxia, and as a bridge to extubation in COPD patients.

Dr. Kraynek is an internal medicine resident in the Department of Medicine at the University of Washington School of Medicine in Seattle. Dr. Best is assistant professor of medicine in the Division of General Internal Medicine at the University of Washington School of Medicine.

 

References

1. Ambrosino N, Vagheggini G. Noninvasive positive pressure ventilation in the acute care setting: where are we? Euro Resp J. 2008;31:874-856.
2. American Thoracic Society. International Consensus Conferences in Intensive Care Medicine: Noninvasive Positive Pressure Ventilation in Acute Respiratory Failure. Am J Respir Crit Care Med. 2001;163:283-291.
3. Liesching T, Kwok H, Hill N. Acute applications of noninvasive positive pressure ventilation. Chest. 2003;124:699-713.
4. Keenan S, Sinuff T, Burns K, et al. Clinical practice guidelines for the use of noninvasive positive pressure ventilation and noninvasive continuous positive airway pressure in the acute care setting. CMAJ. 2001;183:E195-E214.
5. Lightowler J, Wedzicha J, Elliot M, Ram F. Noninvasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis. BMJ. 2003;326:185.
6. Quon B, Gan W, Sin D. Contemporary management of acute exacerbations of COPD: a systematic review of the metaanalysis. Chest. 2008;133:756-766.
7. Keenan S, Sinuff T, Cook D, Hill, N. Which patients with acute exacerbation of chronic obstructive pulmonary disease benefit from noninvasive positive pressure ventilation? Ann Intern Med. 2003;138:861-870.
8. Scala R, Naldi M, Archinucci I, Conigilo G, Nava S. Noninvasive positive pressure ventilation in patients with acute exacerbations of COPD and varying levels of consciousness. Chest. 2005;128:1657-1666.
9. Masip J, Roque M, Sanchez B, Fernandez R, Subirana M, Exposito J. Noninvasive ventilation in acute cardiogenic pulmonary edema. JAMA. 2005;294:3124-3130.
10. Peter J, Moran J, Phillips-Hughes J, Graham P, Bersten A. Effect of non-invasive positive pressure ventilation (NIPPV) on mortality in patients with acute cardiogenic pulmonary oedema: a meta-anaylsis. Lancet. 2006;367:1155-1163.
11. Weng C, Zhao Y, Liu Q, et al. Meta-analysis: noninvasive ventilation in acute cardiogenic pulmonary edema. Ann Intern Med. 2010;152:560-600.
12. Keenan S, Sinuff T, Cook D, Hill N. Does noninvasive positive pressure ventilation improve outcome in acute hypoxemic respiratory failure? A systematic review. Crit Care Med. 2004;32:2516-2523.
13. Esteban A, Frutos-Vivar F, Fergusun N, et al. Noninvasive positive pressure ventilation for respiratory failure after extubation. N Engl J Med. 2004;350:2452-2460.
14. Nava S, Ambrosino N, Clinie E, et al. Noninvasive mechanical ventilation in the weaning of patients with respiratory failure due to chronic obstructive pulmonary disease: a randomized, controlled trial. Ann Intern Med. 1998;128:721-728.
15. Grault C, Daudenthun I, Chevron V, et al. Noninvasive ventilation as a systematic extubation and weaning technique in acute on chronic respiratory failure: a prospective, randomized controlled study. Am J Respir Crit Care Med. 1999;160:86-92.
16. Hilbert G, Gruson D, Vargas F, et al. Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med. 2001;344:481-487.
17. Ram FSF, Wellington SR, Rowe BH, Wedzicha JA. Non-invasive positive pressure ventilation for treatment of respiratory failure due to severe acute exacerbations of asthma. Cochrane Database of Systematic Reviews. 2005, Issue 3.
18. Antonelli M, Conti G, Rocco M, et al. Noninvasive positive pressure ventilation vs. conventional oxygen supplementation in hypoxemic patients undergoing diagnostic bronchoscopy. Chest. 2002;121:1149-1154.

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Case

A 63-year-old man with severe chronic obstructive pulmonary disease (COPD) presents with one week of increasing sputum, cough, and dyspnea. His respiratory rate is 26/minute and oxygen saturation is 86% on room air (RA). He is lethargic and appears mildly uncomfortable, but he responds appropriately to questions in three- to four-word sentences. He is tachypneic with accessory muscle use and has diffuse wheezes throughout his bilateral lung fields. His initial room air arterial blood gas (ABG) is 7.32/68/86/32. Chest radiograph is notable for flattened hemidiaphragms without focal opacity. The patient is placed on oxygen and receives prednisone with nebulized albuterol and ipratropium, but his dyspnea and tachypnea persist. Due to his respiratory distress, bilevel positive airway pressure (BiPAP) is considered.

What are the clinical indications for noninvasive positive pressure ventilation (NPPV)?

Overview

NPPV assists ventilation by delivering positive expiratory and/or inspiratory pressure without the use of an endotracheal tube. Theoretically, NPPV is a preferred method of ventilation as it may eliminate the need for endotracheal intubation and its associated morbidity and mortality, including airway trauma, loss of airway defense mechanisms (ventilator-associated pneumonia), mechanical ventilation (barotrauma), and disruption of speech and swallowing.¹

NPPV is generally delivered via full-face mask or nasal mask. Nasal mask is often preferred for patient comfort, though air leaks occur with mouth breathing. There is no difference between nasal and full-face masks in outcomes including intubation rates and mortality.^2,3,4 NPPV can be delivered via a portable or standard ventilator using the same modes available for endotracheal intubation, though pressure-cycled ventilators utilizing continuous positive airway pressure (CPAP) and BiPAP are most common. CPAP delivers air at a continuous fixed pressure throughout the respiratory cycle. BiPAP delivers positive pressure at alternating levels—higher for inspiration and lower for expiration. Guidelines suggest choosing a mode based on the etiology and pathophysiology of the respiratory failure and leveraging local comfort and expertise.^2,3

In general, good candidates for NPPV display signs of tachypnea and dyspnea due to hypoxic or hypercapnic respiratory failure but are hemodynamically stable, without excessive secretions, and can protect their airway and achieve a proper seal with the mask.³ Difficulty may arise due to patient intolerance, claustrophobia, gastric distention, and poor fit that leads to air leak or skin erosion. With initiation of NPPV, patients should be followed in a care setting with the capacity for frequent monitoring and, if needed, quick access to invasive airway management. Monitoring should include patient comfort and ability to tolerate the device, vital signs, breathing pattern, oxygen saturation, ABG, and mental status. This initial evaluation may help predict the success of NPPV (see Table 2). Appropriately chosen candidates who do well with NPPV often demonstrate respiratory turnaround in a relatively brief interval^.2,3

click for large version

Review of the Data

NPPV is increasingly utilized in a variety of clinical situations. In 2000, the American Thoracic Society published consensus guidelines on the use of NPPV in acute respiratory failure.² More recently, the Canadian Medical Association developed clinical guidelines for the use of NPPV in the acute-care setting.⁴ Clinical scenarios in which there is evidence for the efficacy of NPPV include severe exacerbations of COPD, cardiogenic pulmonary edema, immunosuppressed patients with pulmonary infiltrates, and hypoxia; it can also be used as a bridge to extubation in COPD patients.^1-4

 

Acute exacerbation of COPD. Several randomized controlled trials (RCT) and meta-analyses have assessed the potential benefits of NPPV in patients with acute exacerbations of COPD. In COPD, NPPV improves gas exchange and facilitates respiratory muscle rest to decrease the work of breathing, which allows for respiratory recovery and time to effectiveness of standard therapies.⁵ Multiple trials have demonstrated that the addition of NPPV to usual care decreases intubation and mortality rates, as well as hospital lengths of stay (LOS).^5-8

A Cochrane review of eight RCTs comparing NPPV with usual care noted a greater than 50% reduction in risk of intubation, and a number needed to treat (NNT) of eight patients to prevent one death.⁵ Quon and colleagues also compared NPPV to usual care in a meta-analysis of 14 trials.⁶ Eleven of these trials evaluated hospital mortality, which was decreased by 55% in patients receiving NPPV. Twelve trials assessed need for intubation, which decreased by 65%. In these trials, BiPAP was the most commonly used modality (see Table 3, for a comparison of NPPV modalities). Study patients had an average pH of 7.31 with an average PaCO2 of 68 mmHg. It was noted that the beneficial effects of NPPV increased as pH decreased. An earlier meta-analysis from Keenan and colleagues supported this notion, noting that the subgroup of patients with pH <7.3 benefited most in terms of decreased rates of intubation, hospital LOS, and hospital mortality.7 In this 2003 study, patients with relatively mild exacerbations of COPD did not benefit from the addition of NPPV to usual care. Based on the amount of positive evidence, NPPV is recommended in patients experiencing severe exacerbations of COPD as evidenced by a pH <7.35 and relative hypercarbia.^1,2,4,7

click for large version

Cardiogenic pulmonary edema. In patients with acute cardiogenic pulmonary edema, NPPV has been found to be beneficial, decreasing mortality, rates of intubation, and hospital LOS. Physiologically, NPPV augments cardiac output, improves respiratory mechanics, and decreases afterload.10 Cardiogenic edema is variably defined and has a number of causes elucidated in an analysis of 11 RCTs conducted by Masip and colleagues. These causes included acute coronary syndrome (31%), hypertension (27%), congestive heart failure (14%), and a combination of respiratory infection, arrhythmia, volume overload, and treatment noncompliance (28%).⁹ In this analysis, CPAP and BiPAP demonstrated a combined 43% reduction in mortality and a 57% reduction in intubation. More recently, Peter and colleagues described a statistically significant reduction in hospital mortality and the need for intubation with CPAP, while BiPAP only demonstrated a statistically significant decrease in need for intubation.¹⁰ Thus, there appears to be some evidence that CPAP is the preferred NPPV mode in patients with acute cardiogenic pulmonary edema. Despite inclusion of a recent, large RCT showing no benefit of NPPV versus usual care in cardiogenic pulmonary edema, the overall positive effect of NPPV persisted, particularly when the cause of pulmonary edema was acute coronary syndrome.¹¹

Weaning after intubation. NPPV has been evaluated as a method to facilitate early extubation, as a measure to prevent extubation failure, and as a treatment modality for respiratory failure following extubation, with mixed results.^12,13 In 1998, a small trial compared the use of NPPV in COPD patients to facilitate early extubation with a standard weaning protocol. In this population, early NPPV resulted in better weaning rates with shorter times of mechanical ventilation (10 vs. 16 days), fewer days in the ICU, and improved 60-day survival rates (92% vs. 72%).^3,14 In another RCT not limited to COPD patients, Grault and colleagues found that NPPV reduced the duration of intubation (4.5 vs. 7.6 days) but was not associated with benefits in ICU length of stay or survival previously described.^3,15 Thus, though NPPV may be beneficial in facilitating early extubation in COPD patients, it is not recommended in other patient populations.⁴

 

NPPV has also been evaluated as a measure to prevent respiratory failure in patients at high risk for extubation failure. When applied immediately after extubation in patients with COPD and obesity, NPPV reduced reintubation rates and ICU mortality.^3,4 In 2004, Esteban and colleagues examined NPPV in patients who had respiratory failure following extubation. In this setting, NPPV was ineffective at preventing reintubation and had no survival benefit.

In summary, NPPV may facilitate early extubation and prevent extubation failure in appropriate patients, such as those with COPD, but is unlikely to be beneficial and is not recommended in patients with existing respiratory failure after extubation.^4,15

Immunosuppressed patients. A 2001 single-center, randomized-controlled trial by Holbert and colleagues demonstrated decreased intubation rates and mortality with the application of NPPV in immunosuppressed patients with hypoxemic respiratory failure, fever, and pulmonary infiltrates.¹⁶

In this study, immunosuppression occurred most commonly as a result of malignancy. In the group receiving NPPV alternating with oxygen (at least 45 minutes of NPPV alternated every three hours with periods of spontaneous breathing), the rate of subsequent intubation decreased to 46%, compared with 77% in those receiving oxygen alone. The mortality rate was 38% in the NPPV group, as compared with 69% in the standard treatment group.

Though the outcomes in immunocompromised patients with hypoxemia, fever, and pulmonary infiltrates were very poor (38% mortality even with NPPV), this small study and recent guidelines suggest a trial of NPPV in this population.^4,16

Other indications. NPPV has been applied in multiple other clinical scenarios, including exacerbation of asthma, community-acquired pneumonia, acute lung injury, and bronchoscopy in hypoxemic patients. It has also been evaluated in the postsurgical period and in chest trauma. There are mixed and less robust data in these various applications, and larger controlled trials are lacking.

In asthma exacerbation, NPPV may improve dyspnea, but data regarding outcomes (intubation, mortality) are lacking. A 2005 Cochrane review concluded that data remain controversial due to insufficient evidence, and guidelines make no recommendations concerning NPPV in asthma exacerbation.^4,17 Similarly, in community-acquired pneumonia without prior history of COPD, there is no major role for NPPV.^1,3,4 Limited data suggest that NPPV lacks efficacy in preventing post-surgical respiratory failure, though it may be useful in treating existing respiratory failure or preventing intubation in patients following lung resection or abdominal surgery.^1,4 In hypoxemic patients undergoing bronchoscopy, NPPV may improve oxygenation (lower respiratory rates and improved PaO2 to FiO2 ratios, compared with oxygen alone) as well as hemodynamics (minimizing the drop in mean arterial pressure). However, outcome data are lacking and the data set is small.^4,18 In acute lung injury/acute respiratory distress syndrome, data are also limited, but NPPV appears to have a high failure rate and confers little benefit.^1,4

Back to the Case

The patient was admitted to the hospital and placed on BiPAP for approximately 1.5 hours. The patient’s respiratory rate improved to 20/minute and he appeared increasingly comfortable and alert. A repeat ABG revealed improved hypercarbia and acidosis. He was continued on steroids and antibiotics and eventually was weaned from BiPAP and discharged home.

Bottom Line

NPPV is an effective method to decrease mortality, intubation rates, and duration of ICU stay in severe exacerbations of COPD, cardiogenic pulmonary edema, immunosuppressed patients with pulmonary infiltrates, and hypoxia, and as a bridge to extubation in COPD patients.

Dr. Kraynek is an internal medicine resident in the Department of Medicine at the University of Washington School of Medicine in Seattle. Dr. Best is assistant professor of medicine in the Division of General Internal Medicine at the University of Washington School of Medicine.

 

References

1. Ambrosino N, Vagheggini G. Noninvasive positive pressure ventilation in the acute care setting: where are we? Euro Resp J. 2008;31:874-856.
2. American Thoracic Society. International Consensus Conferences in Intensive Care Medicine: Noninvasive Positive Pressure Ventilation in Acute Respiratory Failure. Am J Respir Crit Care Med. 2001;163:283-291.
3. Liesching T, Kwok H, Hill N. Acute applications of noninvasive positive pressure ventilation. Chest. 2003;124:699-713.
4. Keenan S, Sinuff T, Burns K, et al. Clinical practice guidelines for the use of noninvasive positive pressure ventilation and noninvasive continuous positive airway pressure in the acute care setting. CMAJ. 2001;183:E195-E214.
5. Lightowler J, Wedzicha J, Elliot M, Ram F. Noninvasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis. BMJ. 2003;326:185.
6. Quon B, Gan W, Sin D. Contemporary management of acute exacerbations of COPD: a systematic review of the metaanalysis. Chest. 2008;133:756-766.
7. Keenan S, Sinuff T, Cook D, Hill, N. Which patients with acute exacerbation of chronic obstructive pulmonary disease benefit from noninvasive positive pressure ventilation? Ann Intern Med. 2003;138:861-870.
8. Scala R, Naldi M, Archinucci I, Conigilo G, Nava S. Noninvasive positive pressure ventilation in patients with acute exacerbations of COPD and varying levels of consciousness. Chest. 2005;128:1657-1666.
9. Masip J, Roque M, Sanchez B, Fernandez R, Subirana M, Exposito J. Noninvasive ventilation in acute cardiogenic pulmonary edema. JAMA. 2005;294:3124-3130.
10. Peter J, Moran J, Phillips-Hughes J, Graham P, Bersten A. Effect of non-invasive positive pressure ventilation (NIPPV) on mortality in patients with acute cardiogenic pulmonary oedema: a meta-anaylsis. Lancet. 2006;367:1155-1163.
11. Weng C, Zhao Y, Liu Q, et al. Meta-analysis: noninvasive ventilation in acute cardiogenic pulmonary edema. Ann Intern Med. 2010;152:560-600.
12. Keenan S, Sinuff T, Cook D, Hill N. Does noninvasive positive pressure ventilation improve outcome in acute hypoxemic respiratory failure? A systematic review. Crit Care Med. 2004;32:2516-2523.
13. Esteban A, Frutos-Vivar F, Fergusun N, et al. Noninvasive positive pressure ventilation for respiratory failure after extubation. N Engl J Med. 2004;350:2452-2460.
14. Nava S, Ambrosino N, Clinie E, et al. Noninvasive mechanical ventilation in the weaning of patients with respiratory failure due to chronic obstructive pulmonary disease: a randomized, controlled trial. Ann Intern Med. 1998;128:721-728.
15. Grault C, Daudenthun I, Chevron V, et al. Noninvasive ventilation as a systematic extubation and weaning technique in acute on chronic respiratory failure: a prospective, randomized controlled study. Am J Respir Crit Care Med. 1999;160:86-92.
16. Hilbert G, Gruson D, Vargas F, et al. Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med. 2001;344:481-487.
17. Ram FSF, Wellington SR, Rowe BH, Wedzicha JA. Non-invasive positive pressure ventilation for treatment of respiratory failure due to severe acute exacerbations of asthma. Cochrane Database of Systematic Reviews. 2005, Issue 3.
18. Antonelli M, Conti G, Rocco M, et al. Noninvasive positive pressure ventilation vs. conventional oxygen supplementation in hypoxemic patients undergoing diagnostic bronchoscopy. Chest. 2002;121:1149-1154.

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Case

A 63-year-old man with severe chronic obstructive pulmonary disease (COPD) presents with one week of increasing sputum, cough, and dyspnea. His respiratory rate is 26/minute and oxygen saturation is 86% on room air (RA). He is lethargic and appears mildly uncomfortable, but he responds appropriately to questions in three- to four-word sentences. He is tachypneic with accessory muscle use and has diffuse wheezes throughout his bilateral lung fields. His initial room air arterial blood gas (ABG) is 7.32/68/86/32. Chest radiograph is notable for flattened hemidiaphragms without focal opacity. The patient is placed on oxygen and receives prednisone with nebulized albuterol and ipratropium, but his dyspnea and tachypnea persist. Due to his respiratory distress, bilevel positive airway pressure (BiPAP) is considered.

What are the clinical indications for noninvasive positive pressure ventilation (NPPV)?

Overview

NPPV assists ventilation by delivering positive expiratory and/or inspiratory pressure without the use of an endotracheal tube. Theoretically, NPPV is a preferred method of ventilation as it may eliminate the need for endotracheal intubation and its associated morbidity and mortality, including airway trauma, loss of airway defense mechanisms (ventilator-associated pneumonia), mechanical ventilation (barotrauma), and disruption of speech and swallowing.¹

NPPV is generally delivered via full-face mask or nasal mask. Nasal mask is often preferred for patient comfort, though air leaks occur with mouth breathing. There is no difference between nasal and full-face masks in outcomes including intubation rates and mortality.^2,3,4 NPPV can be delivered via a portable or standard ventilator using the same modes available for endotracheal intubation, though pressure-cycled ventilators utilizing continuous positive airway pressure (CPAP) and BiPAP are most common. CPAP delivers air at a continuous fixed pressure throughout the respiratory cycle. BiPAP delivers positive pressure at alternating levels—higher for inspiration and lower for expiration. Guidelines suggest choosing a mode based on the etiology and pathophysiology of the respiratory failure and leveraging local comfort and expertise.^2,3

In general, good candidates for NPPV display signs of tachypnea and dyspnea due to hypoxic or hypercapnic respiratory failure but are hemodynamically stable, without excessive secretions, and can protect their airway and achieve a proper seal with the mask.³ Difficulty may arise due to patient intolerance, claustrophobia, gastric distention, and poor fit that leads to air leak or skin erosion. With initiation of NPPV, patients should be followed in a care setting with the capacity for frequent monitoring and, if needed, quick access to invasive airway management. Monitoring should include patient comfort and ability to tolerate the device, vital signs, breathing pattern, oxygen saturation, ABG, and mental status. This initial evaluation may help predict the success of NPPV (see Table 2). Appropriately chosen candidates who do well with NPPV often demonstrate respiratory turnaround in a relatively brief interval^.2,3

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Review of the Data

NPPV is increasingly utilized in a variety of clinical situations. In 2000, the American Thoracic Society published consensus guidelines on the use of NPPV in acute respiratory failure.² More recently, the Canadian Medical Association developed clinical guidelines for the use of NPPV in the acute-care setting.⁴ Clinical scenarios in which there is evidence for the efficacy of NPPV include severe exacerbations of COPD, cardiogenic pulmonary edema, immunosuppressed patients with pulmonary infiltrates, and hypoxia; it can also be used as a bridge to extubation in COPD patients.^1-4

 

Acute exacerbation of COPD. Several randomized controlled trials (RCT) and meta-analyses have assessed the potential benefits of NPPV in patients with acute exacerbations of COPD. In COPD, NPPV improves gas exchange and facilitates respiratory muscle rest to decrease the work of breathing, which allows for respiratory recovery and time to effectiveness of standard therapies.⁵ Multiple trials have demonstrated that the addition of NPPV to usual care decreases intubation and mortality rates, as well as hospital lengths of stay (LOS).^5-8

A Cochrane review of eight RCTs comparing NPPV with usual care noted a greater than 50% reduction in risk of intubation, and a number needed to treat (NNT) of eight patients to prevent one death.⁵ Quon and colleagues also compared NPPV to usual care in a meta-analysis of 14 trials.⁶ Eleven of these trials evaluated hospital mortality, which was decreased by 55% in patients receiving NPPV. Twelve trials assessed need for intubation, which decreased by 65%. In these trials, BiPAP was the most commonly used modality (see Table 3, for a comparison of NPPV modalities). Study patients had an average pH of 7.31 with an average PaCO2 of 68 mmHg. It was noted that the beneficial effects of NPPV increased as pH decreased. An earlier meta-analysis from Keenan and colleagues supported this notion, noting that the subgroup of patients with pH <7.3 benefited most in terms of decreased rates of intubation, hospital LOS, and hospital mortality.7 In this 2003 study, patients with relatively mild exacerbations of COPD did not benefit from the addition of NPPV to usual care. Based on the amount of positive evidence, NPPV is recommended in patients experiencing severe exacerbations of COPD as evidenced by a pH <7.35 and relative hypercarbia.^1,2,4,7

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Cardiogenic pulmonary edema. In patients with acute cardiogenic pulmonary edema, NPPV has been found to be beneficial, decreasing mortality, rates of intubation, and hospital LOS. Physiologically, NPPV augments cardiac output, improves respiratory mechanics, and decreases afterload.10 Cardiogenic edema is variably defined and has a number of causes elucidated in an analysis of 11 RCTs conducted by Masip and colleagues. These causes included acute coronary syndrome (31%), hypertension (27%), congestive heart failure (14%), and a combination of respiratory infection, arrhythmia, volume overload, and treatment noncompliance (28%).⁹ In this analysis, CPAP and BiPAP demonstrated a combined 43% reduction in mortality and a 57% reduction in intubation. More recently, Peter and colleagues described a statistically significant reduction in hospital mortality and the need for intubation with CPAP, while BiPAP only demonstrated a statistically significant decrease in need for intubation.¹⁰ Thus, there appears to be some evidence that CPAP is the preferred NPPV mode in patients with acute cardiogenic pulmonary edema. Despite inclusion of a recent, large RCT showing no benefit of NPPV versus usual care in cardiogenic pulmonary edema, the overall positive effect of NPPV persisted, particularly when the cause of pulmonary edema was acute coronary syndrome.¹¹

Weaning after intubation. NPPV has been evaluated as a method to facilitate early extubation, as a measure to prevent extubation failure, and as a treatment modality for respiratory failure following extubation, with mixed results.^12,13 In 1998, a small trial compared the use of NPPV in COPD patients to facilitate early extubation with a standard weaning protocol. In this population, early NPPV resulted in better weaning rates with shorter times of mechanical ventilation (10 vs. 16 days), fewer days in the ICU, and improved 60-day survival rates (92% vs. 72%).^3,14 In another RCT not limited to COPD patients, Grault and colleagues found that NPPV reduced the duration of intubation (4.5 vs. 7.6 days) but was not associated with benefits in ICU length of stay or survival previously described.^3,15 Thus, though NPPV may be beneficial in facilitating early extubation in COPD patients, it is not recommended in other patient populations.⁴

 

NPPV has also been evaluated as a measure to prevent respiratory failure in patients at high risk for extubation failure. When applied immediately after extubation in patients with COPD and obesity, NPPV reduced reintubation rates and ICU mortality.^3,4 In 2004, Esteban and colleagues examined NPPV in patients who had respiratory failure following extubation. In this setting, NPPV was ineffective at preventing reintubation and had no survival benefit.

In summary, NPPV may facilitate early extubation and prevent extubation failure in appropriate patients, such as those with COPD, but is unlikely to be beneficial and is not recommended in patients with existing respiratory failure after extubation.^4,15

Immunosuppressed patients. A 2001 single-center, randomized-controlled trial by Holbert and colleagues demonstrated decreased intubation rates and mortality with the application of NPPV in immunosuppressed patients with hypoxemic respiratory failure, fever, and pulmonary infiltrates.¹⁶

In this study, immunosuppression occurred most commonly as a result of malignancy. In the group receiving NPPV alternating with oxygen (at least 45 minutes of NPPV alternated every three hours with periods of spontaneous breathing), the rate of subsequent intubation decreased to 46%, compared with 77% in those receiving oxygen alone. The mortality rate was 38% in the NPPV group, as compared with 69% in the standard treatment group.

Though the outcomes in immunocompromised patients with hypoxemia, fever, and pulmonary infiltrates were very poor (38% mortality even with NPPV), this small study and recent guidelines suggest a trial of NPPV in this population.^4,16

Other indications. NPPV has been applied in multiple other clinical scenarios, including exacerbation of asthma, community-acquired pneumonia, acute lung injury, and bronchoscopy in hypoxemic patients. It has also been evaluated in the postsurgical period and in chest trauma. There are mixed and less robust data in these various applications, and larger controlled trials are lacking.

In asthma exacerbation, NPPV may improve dyspnea, but data regarding outcomes (intubation, mortality) are lacking. A 2005 Cochrane review concluded that data remain controversial due to insufficient evidence, and guidelines make no recommendations concerning NPPV in asthma exacerbation.^4,17 Similarly, in community-acquired pneumonia without prior history of COPD, there is no major role for NPPV.^1,3,4 Limited data suggest that NPPV lacks efficacy in preventing post-surgical respiratory failure, though it may be useful in treating existing respiratory failure or preventing intubation in patients following lung resection or abdominal surgery.^1,4 In hypoxemic patients undergoing bronchoscopy, NPPV may improve oxygenation (lower respiratory rates and improved PaO2 to FiO2 ratios, compared with oxygen alone) as well as hemodynamics (minimizing the drop in mean arterial pressure). However, outcome data are lacking and the data set is small.^4,18 In acute lung injury/acute respiratory distress syndrome, data are also limited, but NPPV appears to have a high failure rate and confers little benefit.^1,4

Back to the Case

The patient was admitted to the hospital and placed on BiPAP for approximately 1.5 hours. The patient’s respiratory rate improved to 20/minute and he appeared increasingly comfortable and alert. A repeat ABG revealed improved hypercarbia and acidosis. He was continued on steroids and antibiotics and eventually was weaned from BiPAP and discharged home.

Bottom Line

NPPV is an effective method to decrease mortality, intubation rates, and duration of ICU stay in severe exacerbations of COPD, cardiogenic pulmonary edema, immunosuppressed patients with pulmonary infiltrates, and hypoxia, and as a bridge to extubation in COPD patients.

Dr. Kraynek is an internal medicine resident in the Department of Medicine at the University of Washington School of Medicine in Seattle. Dr. Best is assistant professor of medicine in the Division of General Internal Medicine at the University of Washington School of Medicine.

 

References

1. Ambrosino N, Vagheggini G. Noninvasive positive pressure ventilation in the acute care setting: where are we? Euro Resp J. 2008;31:874-856.
2. American Thoracic Society. International Consensus Conferences in Intensive Care Medicine: Noninvasive Positive Pressure Ventilation in Acute Respiratory Failure. Am J Respir Crit Care Med. 2001;163:283-291.
3. Liesching T, Kwok H, Hill N. Acute applications of noninvasive positive pressure ventilation. Chest. 2003;124:699-713.
4. Keenan S, Sinuff T, Burns K, et al. Clinical practice guidelines for the use of noninvasive positive pressure ventilation and noninvasive continuous positive airway pressure in the acute care setting. CMAJ. 2001;183:E195-E214.
5. Lightowler J, Wedzicha J, Elliot M, Ram F. Noninvasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis. BMJ. 2003;326:185.
6. Quon B, Gan W, Sin D. Contemporary management of acute exacerbations of COPD: a systematic review of the metaanalysis. Chest. 2008;133:756-766.
7. Keenan S, Sinuff T, Cook D, Hill, N. Which patients with acute exacerbation of chronic obstructive pulmonary disease benefit from noninvasive positive pressure ventilation? Ann Intern Med. 2003;138:861-870.
8. Scala R, Naldi M, Archinucci I, Conigilo G, Nava S. Noninvasive positive pressure ventilation in patients with acute exacerbations of COPD and varying levels of consciousness. Chest. 2005;128:1657-1666.
9. Masip J, Roque M, Sanchez B, Fernandez R, Subirana M, Exposito J. Noninvasive ventilation in acute cardiogenic pulmonary edema. JAMA. 2005;294:3124-3130.
10. Peter J, Moran J, Phillips-Hughes J, Graham P, Bersten A. Effect of non-invasive positive pressure ventilation (NIPPV) on mortality in patients with acute cardiogenic pulmonary oedema: a meta-anaylsis. Lancet. 2006;367:1155-1163.
11. Weng C, Zhao Y, Liu Q, et al. Meta-analysis: noninvasive ventilation in acute cardiogenic pulmonary edema. Ann Intern Med. 2010;152:560-600.
12. Keenan S, Sinuff T, Cook D, Hill N. Does noninvasive positive pressure ventilation improve outcome in acute hypoxemic respiratory failure? A systematic review. Crit Care Med. 2004;32:2516-2523.
13. Esteban A, Frutos-Vivar F, Fergusun N, et al. Noninvasive positive pressure ventilation for respiratory failure after extubation. N Engl J Med. 2004;350:2452-2460.
14. Nava S, Ambrosino N, Clinie E, et al. Noninvasive mechanical ventilation in the weaning of patients with respiratory failure due to chronic obstructive pulmonary disease: a randomized, controlled trial. Ann Intern Med. 1998;128:721-728.
15. Grault C, Daudenthun I, Chevron V, et al. Noninvasive ventilation as a systematic extubation and weaning technique in acute on chronic respiratory failure: a prospective, randomized controlled study. Am J Respir Crit Care Med. 1999;160:86-92.
16. Hilbert G, Gruson D, Vargas F, et al. Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med. 2001;344:481-487.
17. Ram FSF, Wellington SR, Rowe BH, Wedzicha JA. Non-invasive positive pressure ventilation for treatment of respiratory failure due to severe acute exacerbations of asthma. Cochrane Database of Systematic Reviews. 2005, Issue 3.
18. Antonelli M, Conti G, Rocco M, et al. Noninvasive positive pressure ventilation vs. conventional oxygen supplementation in hypoxemic patients undergoing diagnostic bronchoscopy. Chest. 2002;121:1149-1154.

I read with interest this article and I must say it is inaccurate. My son was born in 2001. He had a bilirubin of 51. Having the diagnosis of kernicterus was difficult in coming. Why? Because the medical profession is terrified to admit that this is happening.

I am a proud member of PICK. My son is wheelchair-confined, he is completely deaf, visually impaired, and has cerebral palsy, epilepsy, and lung disease from the pneumonias that he suffers from almost monthly. Due to his many seizure medications, he now has a blood disease.

Please visit our website (www.pickonline.org) to do a little more research on this matter. Maybe call one of us, as parents, to find out more. My son is not from California. In fact, most of our parents are not from California. Maybe research in other states is warranted.

Christine Thau

I read with interest this article and I must say it is inaccurate. My son was born in 2001. He had a bilirubin of 51. Having the diagnosis of kernicterus was difficult in coming. Why? Because the medical profession is terrified to admit that this is happening.

I am a proud member of PICK. My son is wheelchair-confined, he is completely deaf, visually impaired, and has cerebral palsy, epilepsy, and lung disease from the pneumonias that he suffers from almost monthly. Due to his many seizure medications, he now has a blood disease.

Please visit our website (www.pickonline.org) to do a little more research on this matter. Maybe call one of us, as parents, to find out more. My son is not from California. In fact, most of our parents are not from California. Maybe research in other states is warranted.

Christine Thau

I read with interest this article and I must say it is inaccurate. My son was born in 2001. He had a bilirubin of 51. Having the diagnosis of kernicterus was difficult in coming. Why? Because the medical profession is terrified to admit that this is happening.

I am a proud member of PICK. My son is wheelchair-confined, he is completely deaf, visually impaired, and has cerebral palsy, epilepsy, and lung disease from the pneumonias that he suffers from almost monthly. Due to his many seizure medications, he now has a blood disease.

Please visit our website (www.pickonline.org) to do a little more research on this matter. Maybe call one of us, as parents, to find out more. My son is not from California. In fact, most of our parents are not from California. Maybe research in other states is warranted.

Christine Thau

Recent product endorsements from celebrities on television have brought a new term into the vocabulary of many American women: bioidentical hormone therapy—treatment with hormone products that are identical in molecular structure to those in the human body.

Since 2002, when results of the Women’s Health Initiative¹ raised questions about the safety of hormone replacement therapy, women have been inundated by commercials, talk shows, and self-help books that promote bioidentical hormone therapy as a safe and natural way to treat menopausal symptoms—and more.

Although this publicity has helped promote discussion about menopause, it has also perpetuated confusion and misinformation among the lay public and the general medical community concerning menopausal hormone therapy.

Many postmenopausal women suffering from vasomotor symptoms, vaginal dryness, and vaginal atrophy are apprehensive about seeking therapy, owing to concerns resulting from misinterpreted information derived from the Women’s Health Initiative trial.¹ (See “What are the known risks of FDA-approved hormone therapy.”^2–8) Many others are told to suffer through their symptoms, which may eventually pass. It is not surprising, then, that women turn to unconventional treatments that are claimed to be safer. This unfortunate situation has driven the business of many compounding pharmacies into the multibillion dollar level.

In this paper, we hope to clarify some of the misconceptions surrounding this issue. But first we need to define some terms in what has become a confusing area.

WHAT ARE BIOIDENTICAL HORMONES?

“Bioidentical” means identical in molecular structure to endogenous hormones. However, as we will see, a better distinction should be made between products that are approved and regulated by the US Food and Drug Administration (FDA) and those that are not.

Endogenous reproductive hormones

Women produce various reproductive hormones, including three estrogens—estradiol, estrone, and estriol—as well as progesterone and testosterone.⁹

17-beta estradiol (E2) is the most bioactive endogenous estrogen. It is primarily produced by the dominant ovarian follicle and the corpus luteum and is synthesized intracellularly through aromatase activity.^10,11 The rest of the circulating estradiol is derived from peripheral conversion of estrone to estradiol, and this is the primary source in postmenopausal women not on hormone therapy.¹¹

In postmenopausal women, serum estradiol levels are often below 15 pg/mL. Many physiologic effects of the cellular compartmentalized estradiol contribute to an over-riding force in certain tissues even after menopause.¹⁰ With the loss of estradiol, many tissues in postmenopausal women can be affected, particularly resulting in genitourinary atrophy and bone loss.

Estrone (E1), the second dominant human estrogen, is primarily derived from the metabolism of estradiol and from the aromatization of androstenedione in adipose tissue, with a small quantity being secreted directly by the ovary and the adrenal glands.⁹ In postmenopausal women, mean estrone levels are about 30 pg/mL.¹¹

Estriol (E3), the least active of the endogenous estrogens, is very short-acting.

Progesterone is a 21-carbon steroid secreted by the human ovary.⁹ It is formed during the transformation of cholesterol to estrogens and androgens and is no longer produced after menopause.⁹

Testosterone. In premenopausal women, the androgen testosterone is synthesized by the ovary, the adrenal cortex, and the peripheral conversion of circulating androstenedione and dehydroepiandrosterone (DHEA).⁹ Over a woman’s life span, her androgen levels decline progressively.¹⁰ The rate of decline has not been shown to be appreciably affected by the onset of menopause.¹⁰

All these hormone therapy products are synthesized

Many nonmedical women’s health books erroneously classify the forms of estrogen used in hormone therapy as either bioidentical or synthetic. In fact, they are all man-made.

Bioidentical hormones are synthesized by chemically extracting diosgenin from plants such as yams and soy.¹² Diosgenin is chemically modified to yield the precursor progesterone, which is then used to synthesize bioidentical estrogens and androgens.¹⁰

Nonbioidentical estrogen products include conjugated equine estrogens (CEE), which is extracted from the urine of pregnant mares. The two predominant estrogens found in CEE are equilin sulfate (native to horses) and estrone sulfate.¹⁰

Other nonbioidentical products include ethinyl estradiol, which is used in most combined oral contraceptives. It is formed after a minor chemical modification of estradiol that makes it one of the most potent estrogens. The ethinyl group at carbon 17 of ring D of the steroid nucleus greatly slows the hepatic and enzymatic degradation of the molecule and, thereby, makes oral ethinyl estradiol 15 to 20 times more active than oral estradiol.

Mestranol is an inactive prodrug that is converted in the body to ethinyl estradiol.

While many women may find the idea of natural bioidentical hormones derived from sweet potatoes or soybeans more acceptable than taking one made from horse’s urine, all the products undergo extensive chemical processing and modification.

Misconception: FDA-regulated products are not bioidentical

Although many FDA-regulated hormone products contain nonbioidentical hormones, many other regulated, brand-name hormone therapy products contain the bioidentical hormone 17-beta-estradiol. Examples are oral Estrace, the weekly Climara patch, and the twice-weekly Vivelle Dot.² The makers of Vivelle Dot have obtained approval from the FDA to use the term “bioidentical.” Oral Prometrium is a government-approved bioidentical progesterone product (Table 1).

 

WHAT IS CUSTOMIZED COMPOUNDED HORMONAL THERAPY?

There is often confusion between the terms “bioidentical hormones” and “customized compounded therapy,” which are often used interchangeably. Compounded therapy combines ratios of bioidentical hormones into a particular recipe or mixture. Customized compounding can be done by local compounding pharmacies.²

These customized compounds are often promoted as more “natural” and “individualized” therapy for postmenopausal women. These formulations, in fact, may have ingredients similar to those in FDA-approved products, but they are not regulated for safety, efficacy, and dosing consistency. There is no proof that compounded hormones have fewer side effects or are more effective than FDA-approved hormone preparations (Table 2).¹²

Compounded bioidentical estrogen products

There are several commonly marketed compounded products.

Tri-estrogen (tri-est) is a compounded hormone preparation made up of a mixture of 80% estriol, 10% estrone, and 10% estradiol.¹²

Bi-estrogen (bi-est) contains estriol and estradiol in a ratio of 8:1 or 9:1.

Although both tri-est and bi-est are largely composed of estriol, given the low potency of estriol, the effects of these products may be solely mediated by their major bioactive component, estradiol.^10,12 No large prospective, well-controlled clinical trial has investigated the compounded ratios of these mixtures of estrogens.¹⁰

Tri-est and bi-est are frequently promoted as posing less risk of breast or endometrial cancer than FDA-approved agents, although there is no research to back up this claim.¹² In fact, estriol may have a stimulatory effect on the breast and endometrium.⁹

In addition to these “standard” compounded preparations, women can receive more customized compounds.

Valid uses for customized compounded formulations

Some clinical providers use customized compounded formulations when prescribing hormone therapy to women who have allergies to certain ingredients, such as peanut oil (found in the FDA-regulated oral product Prometrium). Customized compounded formulations have also been used when prescribing hormones currently not FDA-approved for women, such as testosterone and DHEA.¹² Before oral micronized progesterone was marketed in the United States as Prometrium, it was frequently prescribed as a compounded hormone.

HORMONE THERAPY COMES IN VARIOUS FORMS

Both FDA-regulated hormone therapy and unregulated compounded hormone therapy come in various doses and dosage forms administered by different routes, allowing for individualization for each woman’s specific characteristics.

Estrogens: Oral, transdermal, others

Estrogen therapy can be given orally, transvaginally (as creams, tablets, and rings), transdermally (as patches, gels, and creams), subcutaneously in pellets, intranasally (in Europe), and by injection.¹¹

Most oral contraceptives contain the synthetic estrogen ethinyl estradiol. Ethinyl estradiol is more potent than human estrogens,¹¹ specifically in increasing the production of hepatic proteins (sex-hormone-binding globulin, renin substrate, corticosteroid-binding globulin, and thyroid-binding globulin).¹¹

Bioidentical estradiol, taken orally in tablet form, is first processed through the liver and converted into estrone.¹² This stimulates proteins such as C-reactive protein, activated protein C, and clotting factors, which may increase the risk of clotting.¹² Estradiol given transdermally by patch or gel or vaginally bypasses the liver and enters the bloodstream as 17-beta estradiol, therefore avoiding stimulation of these proteins.¹² Case-control data have shown an associated lower risk of deep venous thromboembolism with transdermal therapy.³

Subcutaneous pellet therapy is a less common, non-FDA-approved method of hormone therapy to relieve postmenopausal symptoms.¹⁰ In an outpatient procedure, the pellet is inserted into the subcutaneous fat of the abdomen.¹⁰ The crystalline pellet is biodegradable and contains a mixture of testosterone and 17-beta estradiol.¹⁰ It is important to remember that endometrial stimulation may be prolonged with this form of therapy and levels may be supraphysiologic.

 

 

Progestogens can also be given by different routes

Oral progesterone has poor gastrointestinal absorption and a short half-life.¹⁰ Therefore, it is micronized with oil for better absorption. Reported side effects include sedative and anesthetic effects; therefore, it is recommended that oral progesterone be taken at bedtime.⁹ Medroxyprogesterone acetate may interfere more with estrogen’s positive effects on cholesterol than micronized progesterone does.¹³

Topical progesterone preparations vary widely in dosage and formulation. Over-the-counter progesterone creams vary in concentration from no active ingredient to 450 mg or more of progesterone per ounce. Application sites for progesterone cream include the inner arm, chest, and inner thigh. No transdermal hormone should be applied to areas of the body that may allow possible contact and transference to others.

Progestogen products

Progestogen products include “natural” progesterone and synthetic progestins. They should be given concurrently with estrogen therapy in women who have an intact uterus to prevent endometrial hyperplasia.⁹

Bioidentical progesterone is micronized in the laboratory for better absorption in the gut.²

Nonbioidentical progestins significantly differ from endogenous progesterone in both their molecular structure and function.¹⁰ Progestins include oral medroxyprogesterone acetate, norethindrone acetate, drospirenone, and levonorgestrel (Table 3).

Misconception: Transdermal progesterone protects the endometrium

In general, transdermal progesterone should be avoided, as it does not protect against endometrial cancer.

Many forms of progesterone are available by prescription at compounding pharmacies as lotions, gels, creams, capsules, trochees, and suppositories.⁹ Transdermal progesterone creams are also available over the counter at health stores. Some of these creams contain only diosgenin, a progesterone precursor derived from wild yams.¹⁰ Diosgenin cannot be converted into progesterone within the body and thus does not provide an adequate amount of absorbable progesterone.⁹ Therefore, progesterone cream that contains only diosgenin is not effective in preventing endometrial hyperplasia and cancer.

To achieve a physiologic response, progesterone levels must be at least in the nanogram range.¹⁰ Transdermal progesterone cream has not been shown to reach this level and may not significantly improve vasomotor symptoms.¹² Some practitioners prescribe cream that contains more than 400 mg progesterone per ounce. This may achieve physiologic levels of progesterone, but no improvement has been proven for bone mineral density or endometrial protection. In general, no transdermal progesterone cream can be assumed to protect the endometrium against the stimulatory effects of estrogen.

CUSTOM COMPOUNDING AND SALIVA TESTING TO INDIVIDUALIZE THERAPY

Some clinicians who prescribe compounded hormones order saliva tests. They argue the tests help them to establish which hormones are deficient and therefore to customize therapy.¹² The basis for this is that saliva is similar to an ultrafiltrate of blood and, theoretically, hormone levels in saliva should represent the bioavailable hormone in serum.¹⁰

Unfortunately, this testing is often unreliable due to poor stability of samples in storage and large interassay variability.¹⁰ Many factors may alter hormone levels in saliva and make test results unreproducible, including the time of day the sample is collected and dietary habits.¹⁰ The FDA states that there is no scientific basis for using salivary testing to adjust hormone levels.²

Levels of drugs with clearance that varies depending on hepatic enzyme activity and plasma binding (capacity-limited metabolism) such as estradiol and testosterone can be monitored with total blood serum concentrations.¹⁰ However, many physiologic effects of estrogens are determined intracellularly at the level of tissues.¹⁰ Therefore, although levels during therapy with bioidentical estrogens can be monitored more precisely, the FDA states that hormone therapy should be guided by symptom response and findings on physical examination and not by hormone levels alone.^2,12 It may be reasonable to order serum levels of estradiol in women being treated with therapeutic doses of bioidentical estrogen but still not achieving symptom relief. If women are being treated with conjugated equine estrogens, serum levels cannot be monitored. Total estrogen can be monitored as a send-out laboratory test.

MISCONCEPTION: HORMONE THERAPY IS A FOUNTAIN OF YOUTH

Customized compounded hormonal therapy is marketed as being able to help with rejuvenation, improve memory, sexual function, and reverse the aging process, essentially promising to be an elixir or fountain of youth.

These claims are not substantiated. However, the actual benefits of hormone therapy in women who have menopausal symptoms include alleviation of moderate to severe vasomotor symptoms and vaginal atrophy that can result in dyspareunia. By alleviating their symptoms, hormone therapy improves women’s quality of life. It also reduces the incidence of postmenopausal osteoporotic fractures.

A research finding that is often overlooked is that postmenopausal women younger than 60 years who started estrogen or estrogenprogestin therapy soon after menopause had a 30% lower rate of death from all causes.^2,14 This difference was statistically significant when the estrogen and estrogen-progestin therapy groups were combined. No reduction in the mortality rate was seen if therapy was started after age 60.

MISCONCEPTION: COMPOUNDED THERAPY IS SAFER

Compounded hormone therapy is often marketed as a safer or more effective alternative to government-regulated and approved therapy. Unfortunately, these claims are often false and misleading, and safety information is not consistently provided to patients as is required with FDA-regulated hormone therapy.²

Since these compounds have not been approved by the FDA, there is no guarantee that the ingredients have been tested for purity, potency, and efficacy. There is no batch standardization. These unregulated therapies may use unapproved ingredients, routes of administration, and mixtures with contaminants such as dyes and preservatives.²

Also, custom-compounded prescriptions are considered experimental. Therefore, they are often not covered by insurance, and many women must pay for them out of pocket.¹¹

The North American Menopause Society does not recommend custom-mixed products over well-tested, government-approved commercial products for most women.² All bioidentical hormone prescriptions should include a patient package insert,¹¹ identical to that required of FDA-approved products.²

Recent product endorsements from celebrities on television have brought a new term into the vocabulary of many American women: bioidentical hormone therapy—treatment with hormone products that are identical in molecular structure to those in the human body.

Since 2002, when results of the Women’s Health Initiative¹ raised questions about the safety of hormone replacement therapy, women have been inundated by commercials, talk shows, and self-help books that promote bioidentical hormone therapy as a safe and natural way to treat menopausal symptoms—and more.

Although this publicity has helped promote discussion about menopause, it has also perpetuated confusion and misinformation among the lay public and the general medical community concerning menopausal hormone therapy.

Many postmenopausal women suffering from vasomotor symptoms, vaginal dryness, and vaginal atrophy are apprehensive about seeking therapy, owing to concerns resulting from misinterpreted information derived from the Women’s Health Initiative trial.¹ (See “What are the known risks of FDA-approved hormone therapy.”^2–8) Many others are told to suffer through their symptoms, which may eventually pass. It is not surprising, then, that women turn to unconventional treatments that are claimed to be safer. This unfortunate situation has driven the business of many compounding pharmacies into the multibillion dollar level.

In this paper, we hope to clarify some of the misconceptions surrounding this issue. But first we need to define some terms in what has become a confusing area.

WHAT ARE BIOIDENTICAL HORMONES?

“Bioidentical” means identical in molecular structure to endogenous hormones. However, as we will see, a better distinction should be made between products that are approved and regulated by the US Food and Drug Administration (FDA) and those that are not.

Endogenous reproductive hormones

Women produce various reproductive hormones, including three estrogens—estradiol, estrone, and estriol—as well as progesterone and testosterone.⁹

17-beta estradiol (E2) is the most bioactive endogenous estrogen. It is primarily produced by the dominant ovarian follicle and the corpus luteum and is synthesized intracellularly through aromatase activity.^10,11 The rest of the circulating estradiol is derived from peripheral conversion of estrone to estradiol, and this is the primary source in postmenopausal women not on hormone therapy.¹¹

In postmenopausal women, serum estradiol levels are often below 15 pg/mL. Many physiologic effects of the cellular compartmentalized estradiol contribute to an over-riding force in certain tissues even after menopause.¹⁰ With the loss of estradiol, many tissues in postmenopausal women can be affected, particularly resulting in genitourinary atrophy and bone loss.

Estrone (E1), the second dominant human estrogen, is primarily derived from the metabolism of estradiol and from the aromatization of androstenedione in adipose tissue, with a small quantity being secreted directly by the ovary and the adrenal glands.⁹ In postmenopausal women, mean estrone levels are about 30 pg/mL.¹¹

Estriol (E3), the least active of the endogenous estrogens, is very short-acting.

Progesterone is a 21-carbon steroid secreted by the human ovary.⁹ It is formed during the transformation of cholesterol to estrogens and androgens and is no longer produced after menopause.⁹

Testosterone. In premenopausal women, the androgen testosterone is synthesized by the ovary, the adrenal cortex, and the peripheral conversion of circulating androstenedione and dehydroepiandrosterone (DHEA).⁹ Over a woman’s life span, her androgen levels decline progressively.¹⁰ The rate of decline has not been shown to be appreciably affected by the onset of menopause.¹⁰

All these hormone therapy products are synthesized

Many nonmedical women’s health books erroneously classify the forms of estrogen used in hormone therapy as either bioidentical or synthetic. In fact, they are all man-made.

Bioidentical hormones are synthesized by chemically extracting diosgenin from plants such as yams and soy.¹² Diosgenin is chemically modified to yield the precursor progesterone, which is then used to synthesize bioidentical estrogens and androgens.¹⁰

Nonbioidentical estrogen products include conjugated equine estrogens (CEE), which is extracted from the urine of pregnant mares. The two predominant estrogens found in CEE are equilin sulfate (native to horses) and estrone sulfate.¹⁰

Other nonbioidentical products include ethinyl estradiol, which is used in most combined oral contraceptives. It is formed after a minor chemical modification of estradiol that makes it one of the most potent estrogens. The ethinyl group at carbon 17 of ring D of the steroid nucleus greatly slows the hepatic and enzymatic degradation of the molecule and, thereby, makes oral ethinyl estradiol 15 to 20 times more active than oral estradiol.

Mestranol is an inactive prodrug that is converted in the body to ethinyl estradiol.

While many women may find the idea of natural bioidentical hormones derived from sweet potatoes or soybeans more acceptable than taking one made from horse’s urine, all the products undergo extensive chemical processing and modification.

Misconception: FDA-regulated products are not bioidentical

Although many FDA-regulated hormone products contain nonbioidentical hormones, many other regulated, brand-name hormone therapy products contain the bioidentical hormone 17-beta-estradiol. Examples are oral Estrace, the weekly Climara patch, and the twice-weekly Vivelle Dot.² The makers of Vivelle Dot have obtained approval from the FDA to use the term “bioidentical.” Oral Prometrium is a government-approved bioidentical progesterone product (Table 1).

 

WHAT IS CUSTOMIZED COMPOUNDED HORMONAL THERAPY?

There is often confusion between the terms “bioidentical hormones” and “customized compounded therapy,” which are often used interchangeably. Compounded therapy combines ratios of bioidentical hormones into a particular recipe or mixture. Customized compounding can be done by local compounding pharmacies.²

These customized compounds are often promoted as more “natural” and “individualized” therapy for postmenopausal women. These formulations, in fact, may have ingredients similar to those in FDA-approved products, but they are not regulated for safety, efficacy, and dosing consistency. There is no proof that compounded hormones have fewer side effects or are more effective than FDA-approved hormone preparations (Table 2).¹²

Compounded bioidentical estrogen products

There are several commonly marketed compounded products.

Tri-estrogen (tri-est) is a compounded hormone preparation made up of a mixture of 80% estriol, 10% estrone, and 10% estradiol.¹²

Bi-estrogen (bi-est) contains estriol and estradiol in a ratio of 8:1 or 9:1.

Although both tri-est and bi-est are largely composed of estriol, given the low potency of estriol, the effects of these products may be solely mediated by their major bioactive component, estradiol.^10,12 No large prospective, well-controlled clinical trial has investigated the compounded ratios of these mixtures of estrogens.¹⁰

Tri-est and bi-est are frequently promoted as posing less risk of breast or endometrial cancer than FDA-approved agents, although there is no research to back up this claim.¹² In fact, estriol may have a stimulatory effect on the breast and endometrium.⁹

In addition to these “standard” compounded preparations, women can receive more customized compounds.

Valid uses for customized compounded formulations

Some clinical providers use customized compounded formulations when prescribing hormone therapy to women who have allergies to certain ingredients, such as peanut oil (found in the FDA-regulated oral product Prometrium). Customized compounded formulations have also been used when prescribing hormones currently not FDA-approved for women, such as testosterone and DHEA.¹² Before oral micronized progesterone was marketed in the United States as Prometrium, it was frequently prescribed as a compounded hormone.

HORMONE THERAPY COMES IN VARIOUS FORMS

Both FDA-regulated hormone therapy and unregulated compounded hormone therapy come in various doses and dosage forms administered by different routes, allowing for individualization for each woman’s specific characteristics.

Estrogens: Oral, transdermal, others

Estrogen therapy can be given orally, transvaginally (as creams, tablets, and rings), transdermally (as patches, gels, and creams), subcutaneously in pellets, intranasally (in Europe), and by injection.¹¹

Most oral contraceptives contain the synthetic estrogen ethinyl estradiol. Ethinyl estradiol is more potent than human estrogens,¹¹ specifically in increasing the production of hepatic proteins (sex-hormone-binding globulin, renin substrate, corticosteroid-binding globulin, and thyroid-binding globulin).¹¹

Bioidentical estradiol, taken orally in tablet form, is first processed through the liver and converted into estrone.¹² This stimulates proteins such as C-reactive protein, activated protein C, and clotting factors, which may increase the risk of clotting.¹² Estradiol given transdermally by patch or gel or vaginally bypasses the liver and enters the bloodstream as 17-beta estradiol, therefore avoiding stimulation of these proteins.¹² Case-control data have shown an associated lower risk of deep venous thromboembolism with transdermal therapy.³

Subcutaneous pellet therapy is a less common, non-FDA-approved method of hormone therapy to relieve postmenopausal symptoms.¹⁰ In an outpatient procedure, the pellet is inserted into the subcutaneous fat of the abdomen.¹⁰ The crystalline pellet is biodegradable and contains a mixture of testosterone and 17-beta estradiol.¹⁰ It is important to remember that endometrial stimulation may be prolonged with this form of therapy and levels may be supraphysiologic.

 

 

Progestogens can also be given by different routes

Oral progesterone has poor gastrointestinal absorption and a short half-life.¹⁰ Therefore, it is micronized with oil for better absorption. Reported side effects include sedative and anesthetic effects; therefore, it is recommended that oral progesterone be taken at bedtime.⁹ Medroxyprogesterone acetate may interfere more with estrogen’s positive effects on cholesterol than micronized progesterone does.¹³

Topical progesterone preparations vary widely in dosage and formulation. Over-the-counter progesterone creams vary in concentration from no active ingredient to 450 mg or more of progesterone per ounce. Application sites for progesterone cream include the inner arm, chest, and inner thigh. No transdermal hormone should be applied to areas of the body that may allow possible contact and transference to others.

Progestogen products

Progestogen products include “natural” progesterone and synthetic progestins. They should be given concurrently with estrogen therapy in women who have an intact uterus to prevent endometrial hyperplasia.⁹

Bioidentical progesterone is micronized in the laboratory for better absorption in the gut.²

Nonbioidentical progestins significantly differ from endogenous progesterone in both their molecular structure and function.¹⁰ Progestins include oral medroxyprogesterone acetate, norethindrone acetate, drospirenone, and levonorgestrel (Table 3).

Misconception: Transdermal progesterone protects the endometrium

In general, transdermal progesterone should be avoided, as it does not protect against endometrial cancer.

Many forms of progesterone are available by prescription at compounding pharmacies as lotions, gels, creams, capsules, trochees, and suppositories.⁹ Transdermal progesterone creams are also available over the counter at health stores. Some of these creams contain only diosgenin, a progesterone precursor derived from wild yams.¹⁰ Diosgenin cannot be converted into progesterone within the body and thus does not provide an adequate amount of absorbable progesterone.⁹ Therefore, progesterone cream that contains only diosgenin is not effective in preventing endometrial hyperplasia and cancer.

To achieve a physiologic response, progesterone levels must be at least in the nanogram range.¹⁰ Transdermal progesterone cream has not been shown to reach this level and may not significantly improve vasomotor symptoms.¹² Some practitioners prescribe cream that contains more than 400 mg progesterone per ounce. This may achieve physiologic levels of progesterone, but no improvement has been proven for bone mineral density or endometrial protection. In general, no transdermal progesterone cream can be assumed to protect the endometrium against the stimulatory effects of estrogen.

CUSTOM COMPOUNDING AND SALIVA TESTING TO INDIVIDUALIZE THERAPY

Some clinicians who prescribe compounded hormones order saliva tests. They argue the tests help them to establish which hormones are deficient and therefore to customize therapy.¹² The basis for this is that saliva is similar to an ultrafiltrate of blood and, theoretically, hormone levels in saliva should represent the bioavailable hormone in serum.¹⁰

Unfortunately, this testing is often unreliable due to poor stability of samples in storage and large interassay variability.¹⁰ Many factors may alter hormone levels in saliva and make test results unreproducible, including the time of day the sample is collected and dietary habits.¹⁰ The FDA states that there is no scientific basis for using salivary testing to adjust hormone levels.²

Levels of drugs with clearance that varies depending on hepatic enzyme activity and plasma binding (capacity-limited metabolism) such as estradiol and testosterone can be monitored with total blood serum concentrations.¹⁰ However, many physiologic effects of estrogens are determined intracellularly at the level of tissues.¹⁰ Therefore, although levels during therapy with bioidentical estrogens can be monitored more precisely, the FDA states that hormone therapy should be guided by symptom response and findings on physical examination and not by hormone levels alone.^2,12 It may be reasonable to order serum levels of estradiol in women being treated with therapeutic doses of bioidentical estrogen but still not achieving symptom relief. If women are being treated with conjugated equine estrogens, serum levels cannot be monitored. Total estrogen can be monitored as a send-out laboratory test.

MISCONCEPTION: HORMONE THERAPY IS A FOUNTAIN OF YOUTH

Customized compounded hormonal therapy is marketed as being able to help with rejuvenation, improve memory, sexual function, and reverse the aging process, essentially promising to be an elixir or fountain of youth.

These claims are not substantiated. However, the actual benefits of hormone therapy in women who have menopausal symptoms include alleviation of moderate to severe vasomotor symptoms and vaginal atrophy that can result in dyspareunia. By alleviating their symptoms, hormone therapy improves women’s quality of life. It also reduces the incidence of postmenopausal osteoporotic fractures.

A research finding that is often overlooked is that postmenopausal women younger than 60 years who started estrogen or estrogenprogestin therapy soon after menopause had a 30% lower rate of death from all causes.^2,14 This difference was statistically significant when the estrogen and estrogen-progestin therapy groups were combined. No reduction in the mortality rate was seen if therapy was started after age 60.

MISCONCEPTION: COMPOUNDED THERAPY IS SAFER

Compounded hormone therapy is often marketed as a safer or more effective alternative to government-regulated and approved therapy. Unfortunately, these claims are often false and misleading, and safety information is not consistently provided to patients as is required with FDA-regulated hormone therapy.²

Since these compounds have not been approved by the FDA, there is no guarantee that the ingredients have been tested for purity, potency, and efficacy. There is no batch standardization. These unregulated therapies may use unapproved ingredients, routes of administration, and mixtures with contaminants such as dyes and preservatives.²

Also, custom-compounded prescriptions are considered experimental. Therefore, they are often not covered by insurance, and many women must pay for them out of pocket.¹¹

The North American Menopause Society does not recommend custom-mixed products over well-tested, government-approved commercial products for most women.² All bioidentical hormone prescriptions should include a patient package insert,¹¹ identical to that required of FDA-approved products.²

Recent product endorsements from celebrities on television have brought a new term into the vocabulary of many American women: bioidentical hormone therapy—treatment with hormone products that are identical in molecular structure to those in the human body.

Since 2002, when results of the Women’s Health Initiative¹ raised questions about the safety of hormone replacement therapy, women have been inundated by commercials, talk shows, and self-help books that promote bioidentical hormone therapy as a safe and natural way to treat menopausal symptoms—and more.

Although this publicity has helped promote discussion about menopause, it has also perpetuated confusion and misinformation among the lay public and the general medical community concerning menopausal hormone therapy.

Many postmenopausal women suffering from vasomotor symptoms, vaginal dryness, and vaginal atrophy are apprehensive about seeking therapy, owing to concerns resulting from misinterpreted information derived from the Women’s Health Initiative trial.¹ (See “What are the known risks of FDA-approved hormone therapy.”^2–8) Many others are told to suffer through their symptoms, which may eventually pass. It is not surprising, then, that women turn to unconventional treatments that are claimed to be safer. This unfortunate situation has driven the business of many compounding pharmacies into the multibillion dollar level.

In this paper, we hope to clarify some of the misconceptions surrounding this issue. But first we need to define some terms in what has become a confusing area.

WHAT ARE BIOIDENTICAL HORMONES?

“Bioidentical” means identical in molecular structure to endogenous hormones. However, as we will see, a better distinction should be made between products that are approved and regulated by the US Food and Drug Administration (FDA) and those that are not.

Endogenous reproductive hormones

Women produce various reproductive hormones, including three estrogens—estradiol, estrone, and estriol—as well as progesterone and testosterone.⁹

17-beta estradiol (E2) is the most bioactive endogenous estrogen. It is primarily produced by the dominant ovarian follicle and the corpus luteum and is synthesized intracellularly through aromatase activity.^10,11 The rest of the circulating estradiol is derived from peripheral conversion of estrone to estradiol, and this is the primary source in postmenopausal women not on hormone therapy.¹¹

In postmenopausal women, serum estradiol levels are often below 15 pg/mL. Many physiologic effects of the cellular compartmentalized estradiol contribute to an over-riding force in certain tissues even after menopause.¹⁰ With the loss of estradiol, many tissues in postmenopausal women can be affected, particularly resulting in genitourinary atrophy and bone loss.

Estrone (E1), the second dominant human estrogen, is primarily derived from the metabolism of estradiol and from the aromatization of androstenedione in adipose tissue, with a small quantity being secreted directly by the ovary and the adrenal glands.⁹ In postmenopausal women, mean estrone levels are about 30 pg/mL.¹¹

Estriol (E3), the least active of the endogenous estrogens, is very short-acting.

Progesterone is a 21-carbon steroid secreted by the human ovary.⁹ It is formed during the transformation of cholesterol to estrogens and androgens and is no longer produced after menopause.⁹

Testosterone. In premenopausal women, the androgen testosterone is synthesized by the ovary, the adrenal cortex, and the peripheral conversion of circulating androstenedione and dehydroepiandrosterone (DHEA).⁹ Over a woman’s life span, her androgen levels decline progressively.¹⁰ The rate of decline has not been shown to be appreciably affected by the onset of menopause.¹⁰

All these hormone therapy products are synthesized

Many nonmedical women’s health books erroneously classify the forms of estrogen used in hormone therapy as either bioidentical or synthetic. In fact, they are all man-made.

Bioidentical hormones are synthesized by chemically extracting diosgenin from plants such as yams and soy.¹² Diosgenin is chemically modified to yield the precursor progesterone, which is then used to synthesize bioidentical estrogens and androgens.¹⁰

Nonbioidentical estrogen products include conjugated equine estrogens (CEE), which is extracted from the urine of pregnant mares. The two predominant estrogens found in CEE are equilin sulfate (native to horses) and estrone sulfate.¹⁰

Other nonbioidentical products include ethinyl estradiol, which is used in most combined oral contraceptives. It is formed after a minor chemical modification of estradiol that makes it one of the most potent estrogens. The ethinyl group at carbon 17 of ring D of the steroid nucleus greatly slows the hepatic and enzymatic degradation of the molecule and, thereby, makes oral ethinyl estradiol 15 to 20 times more active than oral estradiol.

Mestranol is an inactive prodrug that is converted in the body to ethinyl estradiol.

While many women may find the idea of natural bioidentical hormones derived from sweet potatoes or soybeans more acceptable than taking one made from horse’s urine, all the products undergo extensive chemical processing and modification.

Misconception: FDA-regulated products are not bioidentical

Although many FDA-regulated hormone products contain nonbioidentical hormones, many other regulated, brand-name hormone therapy products contain the bioidentical hormone 17-beta-estradiol. Examples are oral Estrace, the weekly Climara patch, and the twice-weekly Vivelle Dot.² The makers of Vivelle Dot have obtained approval from the FDA to use the term “bioidentical.” Oral Prometrium is a government-approved bioidentical progesterone product (Table 1).

 

WHAT IS CUSTOMIZED COMPOUNDED HORMONAL THERAPY?

There is often confusion between the terms “bioidentical hormones” and “customized compounded therapy,” which are often used interchangeably. Compounded therapy combines ratios of bioidentical hormones into a particular recipe or mixture. Customized compounding can be done by local compounding pharmacies.²

These customized compounds are often promoted as more “natural” and “individualized” therapy for postmenopausal women. These formulations, in fact, may have ingredients similar to those in FDA-approved products, but they are not regulated for safety, efficacy, and dosing consistency. There is no proof that compounded hormones have fewer side effects or are more effective than FDA-approved hormone preparations (Table 2).¹²

Compounded bioidentical estrogen products

There are several commonly marketed compounded products.

Tri-estrogen (tri-est) is a compounded hormone preparation made up of a mixture of 80% estriol, 10% estrone, and 10% estradiol.¹²

Bi-estrogen (bi-est) contains estriol and estradiol in a ratio of 8:1 or 9:1.

Although both tri-est and bi-est are largely composed of estriol, given the low potency of estriol, the effects of these products may be solely mediated by their major bioactive component, estradiol.^10,12 No large prospective, well-controlled clinical trial has investigated the compounded ratios of these mixtures of estrogens.¹⁰

Tri-est and bi-est are frequently promoted as posing less risk of breast or endometrial cancer than FDA-approved agents, although there is no research to back up this claim.¹² In fact, estriol may have a stimulatory effect on the breast and endometrium.⁹

In addition to these “standard” compounded preparations, women can receive more customized compounds.

Valid uses for customized compounded formulations

Some clinical providers use customized compounded formulations when prescribing hormone therapy to women who have allergies to certain ingredients, such as peanut oil (found in the FDA-regulated oral product Prometrium). Customized compounded formulations have also been used when prescribing hormones currently not FDA-approved for women, such as testosterone and DHEA.¹² Before oral micronized progesterone was marketed in the United States as Prometrium, it was frequently prescribed as a compounded hormone.

HORMONE THERAPY COMES IN VARIOUS FORMS

Both FDA-regulated hormone therapy and unregulated compounded hormone therapy come in various doses and dosage forms administered by different routes, allowing for individualization for each woman’s specific characteristics.

Estrogens: Oral, transdermal, others

Estrogen therapy can be given orally, transvaginally (as creams, tablets, and rings), transdermally (as patches, gels, and creams), subcutaneously in pellets, intranasally (in Europe), and by injection.¹¹

Most oral contraceptives contain the synthetic estrogen ethinyl estradiol. Ethinyl estradiol is more potent than human estrogens,¹¹ specifically in increasing the production of hepatic proteins (sex-hormone-binding globulin, renin substrate, corticosteroid-binding globulin, and thyroid-binding globulin).¹¹

Bioidentical estradiol, taken orally in tablet form, is first processed through the liver and converted into estrone.¹² This stimulates proteins such as C-reactive protein, activated protein C, and clotting factors, which may increase the risk of clotting.¹² Estradiol given transdermally by patch or gel or vaginally bypasses the liver and enters the bloodstream as 17-beta estradiol, therefore avoiding stimulation of these proteins.¹² Case-control data have shown an associated lower risk of deep venous thromboembolism with transdermal therapy.³

Subcutaneous pellet therapy is a less common, non-FDA-approved method of hormone therapy to relieve postmenopausal symptoms.¹⁰ In an outpatient procedure, the pellet is inserted into the subcutaneous fat of the abdomen.¹⁰ The crystalline pellet is biodegradable and contains a mixture of testosterone and 17-beta estradiol.¹⁰ It is important to remember that endometrial stimulation may be prolonged with this form of therapy and levels may be supraphysiologic.

 

 

Progestogens can also be given by different routes

Oral progesterone has poor gastrointestinal absorption and a short half-life.¹⁰ Therefore, it is micronized with oil for better absorption. Reported side effects include sedative and anesthetic effects; therefore, it is recommended that oral progesterone be taken at bedtime.⁹ Medroxyprogesterone acetate may interfere more with estrogen’s positive effects on cholesterol than micronized progesterone does.¹³

Topical progesterone preparations vary widely in dosage and formulation. Over-the-counter progesterone creams vary in concentration from no active ingredient to 450 mg or more of progesterone per ounce. Application sites for progesterone cream include the inner arm, chest, and inner thigh. No transdermal hormone should be applied to areas of the body that may allow possible contact and transference to others.

Progestogen products

Progestogen products include “natural” progesterone and synthetic progestins. They should be given concurrently with estrogen therapy in women who have an intact uterus to prevent endometrial hyperplasia.⁹

Bioidentical progesterone is micronized in the laboratory for better absorption in the gut.²

Nonbioidentical progestins significantly differ from endogenous progesterone in both their molecular structure and function.¹⁰ Progestins include oral medroxyprogesterone acetate, norethindrone acetate, drospirenone, and levonorgestrel (Table 3).

Misconception: Transdermal progesterone protects the endometrium

In general, transdermal progesterone should be avoided, as it does not protect against endometrial cancer.

Many forms of progesterone are available by prescription at compounding pharmacies as lotions, gels, creams, capsules, trochees, and suppositories.⁹ Transdermal progesterone creams are also available over the counter at health stores. Some of these creams contain only diosgenin, a progesterone precursor derived from wild yams.¹⁰ Diosgenin cannot be converted into progesterone within the body and thus does not provide an adequate amount of absorbable progesterone.⁹ Therefore, progesterone cream that contains only diosgenin is not effective in preventing endometrial hyperplasia and cancer.

To achieve a physiologic response, progesterone levels must be at least in the nanogram range.¹⁰ Transdermal progesterone cream has not been shown to reach this level and may not significantly improve vasomotor symptoms.¹² Some practitioners prescribe cream that contains more than 400 mg progesterone per ounce. This may achieve physiologic levels of progesterone, but no improvement has been proven for bone mineral density or endometrial protection. In general, no transdermal progesterone cream can be assumed to protect the endometrium against the stimulatory effects of estrogen.

CUSTOM COMPOUNDING AND SALIVA TESTING TO INDIVIDUALIZE THERAPY

Some clinicians who prescribe compounded hormones order saliva tests. They argue the tests help them to establish which hormones are deficient and therefore to customize therapy.¹² The basis for this is that saliva is similar to an ultrafiltrate of blood and, theoretically, hormone levels in saliva should represent the bioavailable hormone in serum.¹⁰

Unfortunately, this testing is often unreliable due to poor stability of samples in storage and large interassay variability.¹⁰ Many factors may alter hormone levels in saliva and make test results unreproducible, including the time of day the sample is collected and dietary habits.¹⁰ The FDA states that there is no scientific basis for using salivary testing to adjust hormone levels.²

Levels of drugs with clearance that varies depending on hepatic enzyme activity and plasma binding (capacity-limited metabolism) such as estradiol and testosterone can be monitored with total blood serum concentrations.¹⁰ However, many physiologic effects of estrogens are determined intracellularly at the level of tissues.¹⁰ Therefore, although levels during therapy with bioidentical estrogens can be monitored more precisely, the FDA states that hormone therapy should be guided by symptom response and findings on physical examination and not by hormone levels alone.^2,12 It may be reasonable to order serum levels of estradiol in women being treated with therapeutic doses of bioidentical estrogen but still not achieving symptom relief. If women are being treated with conjugated equine estrogens, serum levels cannot be monitored. Total estrogen can be monitored as a send-out laboratory test.

MISCONCEPTION: HORMONE THERAPY IS A FOUNTAIN OF YOUTH

Customized compounded hormonal therapy is marketed as being able to help with rejuvenation, improve memory, sexual function, and reverse the aging process, essentially promising to be an elixir or fountain of youth.

These claims are not substantiated. However, the actual benefits of hormone therapy in women who have menopausal symptoms include alleviation of moderate to severe vasomotor symptoms and vaginal atrophy that can result in dyspareunia. By alleviating their symptoms, hormone therapy improves women’s quality of life. It also reduces the incidence of postmenopausal osteoporotic fractures.

A research finding that is often overlooked is that postmenopausal women younger than 60 years who started estrogen or estrogenprogestin therapy soon after menopause had a 30% lower rate of death from all causes.^2,14 This difference was statistically significant when the estrogen and estrogen-progestin therapy groups were combined. No reduction in the mortality rate was seen if therapy was started after age 60.

MISCONCEPTION: COMPOUNDED THERAPY IS SAFER

Compounded hormone therapy is often marketed as a safer or more effective alternative to government-regulated and approved therapy. Unfortunately, these claims are often false and misleading, and safety information is not consistently provided to patients as is required with FDA-regulated hormone therapy.²

Since these compounds have not been approved by the FDA, there is no guarantee that the ingredients have been tested for purity, potency, and efficacy. There is no batch standardization. These unregulated therapies may use unapproved ingredients, routes of administration, and mixtures with contaminants such as dyes and preservatives.²

Also, custom-compounded prescriptions are considered experimental. Therefore, they are often not covered by insurance, and many women must pay for them out of pocket.¹¹

The North American Menopause Society does not recommend custom-mixed products over well-tested, government-approved commercial products for most women.² All bioidentical hormone prescriptions should include a patient package insert,¹¹ identical to that required of FDA-approved products.²

Essential tremor, one of the most common movement disorders, affects about 4% of adults 40 years of age and older.¹ It is often referred to as familial tremor in patients with a family history of tremor. It has also been called benign tremor to differentiate it from tremor associated with neurodegenerative diseases, particularly Parkinson disease, but this condition is certainly not benign, as it can cause substantial functional impairment and difficulties with routine activities of daily living. The terms “essential” and “idiopathic” refer to the primary nature of the disorder and differentiate it from tremor that is a feature of a distinct neurologic entity or is secondary to a metabolic disease or drug therapy.

Successful management entails exclusion of secondary causes and careful selection of drug therapy. To date, there is no cure for essential tremor; all currently available treatments are purely symptomatic.

In this review, we outline the major diagnostic and therapeutic principles of managing essential tremor, indications for referral to specialists, and alternative and advanced therapeutic options.

CLINICAL PICTURE

Tremor is defined as rhythmic to-and-fro movement in any body part. It can be slow or fast, and its amplitude can be large and coarse, or small or even “fine.” It can appear at rest, with action, or during a sustained posture. In contrast to parkinsonian tremor (which presents mainly at rest), essential tremor is typically but not exclusively postural, kinetic, or both.

Postural tremor refers to tremor seen when the patient holds the affected limb (commonly the arm) unsupported against gravity. Kinetic tremor refers to tremor that appears with active movements. This is often demonstrated clinically by the finger-nose-finger test. Patients with essential tremor commonly have both postural and kinetic tremor.

The tremor commonly involves the arms, hands, and fingers.² Less commonly, it involves the head, the lips, the tongue, the legs, and the voice. In contrast to parkinsonian tremor, which typically affects one side of the body first, bilateral involvement is the general rule in essential tremor. However, one side of the body may be affected first, or may be more affected than the other. The frequency of the tremor ranges from 4 to 12 Hz (ie, beats per second).

The tremor usually starts in middle age and progresses slowly over time,³ but onset in old age or childhood is also possible.⁴ Both sexes are equally affected.

The tremor usually gets worse with anxiety, stress, and caffeine intake. It usually gets temporarily better with the consumption of small amounts of alcohol.

The functional impact of essential tremor is judged by its effect on different daily activities, especially writing, eating, drinking, dressing, manual work, and household chores.

In addition to motor dysfunction, the tremor can also have a significant psychological impact on the patient, because it usually gets worse in social situations.

Although it has long been thought that tremor is the sole neurologic sign of essential tremor, recent studies have shown that many patients have additional subtle findings, such as mild gait difficulty,⁵ slight incoordination,⁶ mild cognitive impairment,⁷ and decreased hearing,⁸ and are more likely to have anxiety and social phobia.⁹

Although different studies have varied in their findings, it is generally thought that about 50% of patients with essential tremor have a positive family history, often in a first-degree relative, suggesting autosomal dominant inheritance with variable penetrance.^10,11 Polygenetic and sporadic variants are also common.

DIFFERENTIAL DIAGNOSIS

The postural and kinetic elements of essential tremor must be differentiated from other forms of tremor, namely resting tremor (Figure 1) and intentional tremor. Secondary causes of postural and kinetic tremor should also be ruled out before deciding on the diagnosis of essential tremor.

Resting tremor

Resting tremor is typically an extrapyramidal sign and, when accompanied by rigidity and bradykinesia, is often part of a parkinsonian syndrome. It is most pronounced at rest when the affected body part is fully supported and stationary. The tremor tends to improve with action or posture. It usually has a “pill-rolling” character and, as mentioned, is associated with other extrapyramidal signs, such as rigidity, slowness, and, later on, postural instability.

About 20% of patients with essential tremor have resting tremor. These patients usually suffer from severe or long-standing disease.¹² However, the resting element in these cases is often milder than the postural and kinetic components, and it is typically not associated with other extrapyramidal signs. Also, some patients may have both essential tremor and Parkinson disease.¹³

Intentional tremor

Pure intentional tremor is usually seen with cerebellar pathology, which includes tumors, stroke, multiple sclerosis, trauma, and spinocerebellar degeneration. The amplitude of this type of tremor increases as the affected limb approaches the final target. It can best be demonstrated clinically by the finger-nose-finger test. The frequency of intentional tremor is slow (2 to 4 Hz) and is usually associated with other cerebellar signs, such as dysmetria, decomposition, rebound, and dysdiadochokinesia (ie, the inability to perform rapid alternating movements in a smooth and coordinated manner).

About 50% of patients with essential tremor have an intentional component to their tremor,⁶ or it can be mildly present in the form of a slight gait difficulty. However, in essential tremor, other features of cerebellar dysfunction are either absent or only very slight.

 

 

Secondary causes of postural-kinetic tremor

Enhanced physiologic tremor. A very mild postural tremor is present in almost all people and is considered “physiologic” since it has almost no clinical significance. This type of tremor is often invisible, but when “enhanced,” it can be visually demonstrated by placing a piece of paper over the stretched hands and watching the ripple from the paper.

Certain conditions can aggravate this physiologic tremor and can make it symptomatic. Common causes include anxiety, sleep deprivation, hypoglycemia, hyperthyroidism, pheochromocytoma, serotonin syndrome, and carcinoid syndrome.

Metabolic tremor. Hyperammonemia can cause tremor in patients with hepatic encephalopathy, and uremia can cause tremor in patients with renal failure. These metabolic conditions classically result in “flappy” tremor (asterixis), a special form of postural tremor characterized by jerking movements with high amplitude. It is best seen when the patient stretches out the arms and extends the wrists as if trying to stop traffic. But even though it may look like tremor, asterixis is thought to be a form of “negative” myoclonus.

Drug-related tremor. Postural-kinetic tremor can be induced by drugs, including lithium (Lithobid), valproate (Depakote), amiodarone (Cordarone), central nervous system stimulants, beta agonists (including inhalers), and some antidepressants. Tremor can also occur with alcohol or sedative withdrawal.

Psychogenic tremor. Tremor can be seen as part of a somatoform disorder commonly referred to as conversion disorder or conversion reaction. Psychogenic tremor is characterized by acute onset, commonly following a psychosocial stressor; it is often atypical, variable in frequency, amplitude, and body-part involvement, and it can readily be interrupted on examination by distracting the patient.

Neurologic disorders. The postural and kinetic elements of essential tremor may also be seen in the following neurologic conditions:

• Holmes (rubral) tremor, a combination of resting, postural, kinetic, and intentional tremor of low frequency and high amplitude. It usually has a proximal component and is often unilateral. It commonly is due to a lesion that involves the brainstem, eg, red nucleus, inferior olive, cerebellum, or thalamus. Common causes include stroke, prolonged hypoxia, and head trauma (including closed-head trauma with negative imaging). This type of tremor is usually associated with ataxia.¹⁴
• Dystonic tremor is predominantly postural and is associated with abnormal dystonic posturing of the affected body part, commonly the head, hands, or feet. Unlike the rhythmic oscillations of essential tremor, dystonic tremor is often irregular in rhythm.
• Multiple sclerosis can present with a combination of postural, kinetic, and intentional tremor. Patients usually have a clear history of recurrent neurologic deficits and show a combination of pyramidal, cerebellar, and sensory signs on examination consistent with multiple sclerosis.¹⁵
• Neuropathic tremor is seen in a small proportion of patients with peripheral neuropathy, especially demyelinating neuropathy.¹⁶ The tremor is usually posturalkinetic and is associated with signs of neuropathy, such as a glove-and-stocking pattern of hypoesthesia, reduced reflexes, and sensory ataxia (including intentional tremor when the eyes are closed).
• Posttraumatic tremor can occur after severe or even mild head trauma, especially in children. It is commonly rubral, but other types have been reported, including a presentation resembling essential tremor.¹⁷
• Monosymptomatic or isolated tremor. A number of conditions related to essential tremor with location-specific or task-specific tremor have been described. These rare conditions historically have been classified as “possible essential tremor” or “essential tremor variants” but are now considered separate entities. These include task-specific tremor (eg, writing tremor), isolated head tremor, isolated voice tremor, and orthostatic tremor (tremor in the legs and trunk upon standing in place, but not when sitting or walking).^18,19

DIAGNOSIS IS CLINICAL

Essential tremor is a clinical diagnosis. After a thorough review of the medical history and medication exposures, laboratory and imaging tests may be ordered to rule out a secondary cause. A complete metabolic panel, including blood glucose and thyroid-stimulating hormone levels, is usually sufficient. Brain imaging or other imaging is ordered for patients with an atypical presentation.

TREATMENT IS SYMPTOMATIC

Treatment of essential tremor is symptomatic. Several drugs of different pharmacologic classes can reduce the severity of the tremor and improve function.

Choosing the appropriate treatment depends on the type of tremor and the presence of associated conditions. The response to treatment and the development of side effects guide further adjustments. The following is a brief description of the available antitremor agents.

FIRST-LINE AGENTS

Propranolol

Propranolol (Inderal), a nonselective beta blocker, is the most widely used antitremor drug and the only agent approved by the US Food and Drug Administration for essential tremor. It should be started at a low dose and titrated upward gradually. The usual starting dose is 10 mg three times daily. The average effective dose is 120 mg daily. The dose can be increased up to 320 mg if needed and tolerated.

Sustained-release preparations are equally effective and are given as a single daily dose to improve compliance.²⁰

Propranolol improves tremor in 50% to 70% of patients with essential tremor and achieves an average tremor reduction of 50% to 60%.^1,21–25 Side effects include bronchoconstriction, bradycardia, hypotension, depression, impotence, fatigue, and gastrointestinal disturbances.

Other beta-blockers, such as nadolol (Corgard) and timolol, are also effective against tremor but are less potent than propranolol.^26,27 The selective beta-1-blocker metoprolol (Lopressor) may be effective and has fewer noncardiac side effects than propranolol.²⁸ It can be used in patients who discontinue propranolol because of adverse effects. Atenolol (Tenormin) and pindolol (Visken) have little or no effect on tremor.²⁹

A good candidate for propranolol therapy in essential tremor is:

• A patient with no known contraindication to propranolol
• A patient with hypertension, coronary heart disease, or tachyarrhythmia
• A patient with anxiety or social phobia.

Absolute contraindications to propranolol are:

• Moderate to severe bronchial asthma
• Significant bradycardia or heart block
• Symptomatic hypotension
• End-stage heart failure
• Concurrent use of a calcium channel blocker.

Relative contraindications are:

• Wheezing (eg, chronic obstructive pulmonary disease)
• Depression
• Diabetes mellitus in a patient more prone to hypoglycemia (propranolol masks the warning signs of hypoglycemia)
• Reduced sexual potency in a male patient.

 

 

Primidone

Primidone (Mysoline) is an antiepileptic drug structurally similar to barbiturates. Its antitremor effect is equal to that of propranolol, though some studies suggest it is slightly more efficacious.^30,31

It should be started at a low dose, ie, 25 mg once daily at bedtime. The dose should then be increased gradually until satisfactory and tolerable tremor control is achieved. Most patients respond to doses of around 250 mg per day.^1,22,24–25 The dose can be increased if needed and tolerated.

Primidone reduces tremor by about 50% to 60%.^1,22,24–25 Side effects include sedation, dizziness, fatigue, nausea, and depression, as well as ataxia and confusion in severe cases.

A good candidate for primidone in essential tremor is:

• A patient with no known contraindication to primidone
• A patient with contraindications to propranolol
• A younger patient
• A patient with epilepsy.

Absolute contraindications to primidone include:

• Confusion or dementia
• Oral anticoagulant therapy with difficulty controlling the International Normalized Ratio (primidone is a potent enzyme inducer).

Relative contraindications to primidone in essential tremor are:

• Depression
• Alcohol abuse
• Ongoing therapy with sedating drugs
• Ataxia or vertigo.

SECOND-LINE AGENTS

Other antiepileptics

Topiramate (Topamax) is a broad-spectrum antiepileptic shown to be significantly effective against essential tremor.³² It is usually started at a single daily dose of 25 mg and increased gradually to the most effective dose, usually around 300 mg.

Side effects include reduced appetite, weight loss, cognitive dysfunction, and paresthesia.

Favorable candidates include patients who are epileptic or overweight. Contraindications include cognitive impairment and low body weight. It is also not recommended in children so as to avoid any possible negative effect on cognitive development. In rare cases, topiramate has been reported to cause significant visual disturbances.

Gabapentin (Neurontin) is an antiepileptic that is now more often used as a symptomatic treatment for neuropathic pain. Studies have suggested a beneficial effect on essential tremor,^33,34 but some investigators have questioned its efficacy.³⁵

Like other antitremor agents, it should be started at a low dose, ie, around 300 mg, and escalated gradually until the tremor is controlled. The usual effective dose is 1,200 mg.

Gabapentin is generally well tolerated, and side effects such as dizziness, drowsiness, sedation, and unsteadiness are rare and usually mild.

The favorable candidate is a patient with associated neuropathy or multiple comorbidities. Gabapentin has also been reported to alleviate neuropathic tremor.

Contraindications are minimal and include intolerability or hypersensitivity to the drug. It also should be avoided in patients at a high risk of falling.

Levetiracetam (Keppra) is a novel antiepileptic effective against partial seizures. Studies have shown contradictory results regarding its antitremor effect. One double-blind, placebo-controlled study demonstrated significant reduction in essential tremor with 1,000 mg of levetiracetam.³⁶ However, its effect on tremor is believed to be short-lived, and some studies argue against its efficacy.³⁷ It has a favorable side-effect profile and is generally very well tolerated. It can be used as an adjunct to other antitremor agents and is preferred for patients with coexisting partial seizures or myoclonus.

Benzodiazepines. Minor tranquilizers are often used to control tremor, especially in coexisting anxiety or insomnia. Alprazolam (Xanax) is the one most widely used for this indication.³⁸ It can be started in a dose of 0.25 mg once at bedtime and increased gradually up to 0.75 to 2 mg. Clonazepam (Klonopin) is particularly useful for orthostatic tremor, a variant of essential tremor characterized by tremor of the legs and trunk upon standing.³⁹

Common side effects of benzodiazepines include sedation, cognitive dysfunction, hypotension, respiratory inhibition, and addiction after prolonged use. In the elderly, they can lead to confusion and disinhibition and can increase the risk of falling. They should be avoided in the elderly and in alcoholic patients and those with a high risk of substance abuse.

Stopping benzodiazepines should be done gradually to avoid withdrawal symptoms, including aggravation of tremor.

THIRD-LINE AGENTS

Clozapine

Clozapine (Clozaril) is a novel antipsychotic drug with no extrapyramidal side effects. It has been reported effective in essential tremor and drug-induced tremor,^40,41 but the results of these early studies have not been confirmed.

Clozapine is started as a single daily dose of 12.5 mg and is increased up to 75 mg or 100 mg. It is an attractive option for patients with coexisting psychosis, bipolar disorder, or chorea. Its main side effects are sedation, salivation, weight gain, hypertension, diabetes, and seizures.

One especially serious side effect is agranulocytosis. This potentially fatal effect is rare, occurring in about 1.3% of patients receiving this drug. Weekly monitoring of the white blood cell count is mandated during treatment with clozapine, and this has made clozapine a less attractive option for the routine treatment of essential tremor.

Mirtazapine

Mirtazapine (Remeron) is a novel antidepressant widely used in Parkinson disease as both an antidepressant and a sleeping aid. Case studies have reported efficacy in both essential tremor and parkinsonian tremor,⁴² but controlled studies have not confirmed this.⁴³ Mirtazapine is a reasonable option in patients with coexisting depression or insomnia. It is usually given as a single bedtime dose of 15 to 30 mg.

Other drugs

Studies of other agents for the treatment of essential tremor—eg, carbonic anhydrase enzyme inhibitors, calcium channel blockers, isoniazid (Tubizid), clonidine (Catapres), phenobarbital, and theophylline—have yielded highly contradictory results. Thus, they are not recommended as first- or second-line agents for essential tremor.

 

SPECIALTY-LEVEL CARE

When essential tremor does not respond to drug therapy or the patient cannot tolerate drug therapy, the patient should be referred to a center specializing in movement disorders for more advanced treatment options, ie, botulinum toxin injection and deep brain stimulation surgery.

Botulinum toxin

Botulinum toxin type A has been studied for the treatment of essential tremor with variable degrees of success. It has been effective in reducing hand tremor in essential tremor, but without a concomitant improvement in functional disability.⁴⁴ This limited functional improvement has been attributed to the development of muscle weakness after injection of the neurotoxin. This has also raised questions about unintentional unblinding when interpreting study results. Therefore, most clinicians restrict its use to focal forms of tremor such as voice tremor,⁴⁵ head tremor, and task-specific tremor.

Side effects are limited and temporary and include muscle weakness, pain at the injection site, dysphagia (when injected for head or voice tremor), and a breathy vocal quality (when injected for voice tremor). Botulinum toxin injection is the treatment of choice for focal dystonia, and therefore would be a good option for dystonic tremor.

Thalamic deep brain stimulation

This technique involves stereotactic implantation of a stimulation lead in the ventral intermediate nucleus of the thalamus. The lead connects via a subcutaneous wire to an intermittent pulse generator, implanted subcutaneously in the infraclavicular region. The stimulation lead produces continuous stimulation of the ventralis intermedius nucleus that is functionally equal to lesional surgery, thus antagonizing the relay of tremor signals at the thalamus.

The battery of the pulse generator must be replaced every 4 to 7 years depending on usage and stimulation parameters. Battery replacement can be performed with minor surgery at the infraclavicular region.

Thalamic deep brain stimulation is indicated for patients with severe, disabling essential tremor who have tremor resistant to drug therapy or who cannot tolerate drug therapy.

The procedure has been shown to provide benefit in 90% of patients, with more than an 80% improvement in tremor severity and functional impact.^46–49 Deep brain stimulation is effective against tremor affecting parts of the body other than the limbs, including the head; an exception to this is voice tremor, which usually does not improve dramatically. The procedure can be done unilaterally or bilaterally, depending on symptoms. Patients with asymmetrical tremor and those at risk of side effects can undergo unilateral surgery. Bilateral treatment is recommended for patients with symmetric tremor or significant head tremor, or who are young and healthy.

Surgical risks include brain hemorrhage and infection. Side effects of the stimulation include paresthesias, paresis, imbalance, dysarthria, and, in rare cases, dysphagia.

CHOOSING THE BEST MANAGEMENT PLAN FOR YOUR PATIENT

The choice of treatment may be challenging, given the multiple treatment options and the variability of tremor severity from one patient to another. The following guidelines can be used to help make this decision.

All patients should be advised to reduce caffeine intake, to have sufficient hours of sleep, and to avoid stressful situations.

Patients with minor, nondisabling tremor can be left untreated if the tremors are not bothersome or if the patient prefers not to pursue active treatment.

In patients who have bothersome tremor only when anxious or in certain social situations, give propranolol or alprazolam (or both) to be taken as needed. Relaxation techniques and meditation are also useful for these patients.

Patients with constant bothersome tremor should be started on either propranolol or primidone based on the patient’s profile and propensity to develop side effects from each of these drugs. The dosing should be optimized gradually according to the patient’s response and the drug’s tolerability.

If essential tremor is not sufficiently controlled with one first-line agent (propranolol or primidone), try combining the two first-line agents if the patient finds it tolerable.

A second-line agent can be added to either of the first-line agents or to the combination of both if tremor control is not yet sufficient. A second-line or third-line agent can also be used as the primary treatment if both first-line agents are contraindicated or intolerable. Combining two or more second- and third-line agents is another option. The choice of second- or third-line agent should be guided by the patient’s characteristics and comorbidities in relation to the agent’s side effects and contraindications as detailed in the above section.

Patients should be referred to a movement disorders specialist in cases of resistant tremor, intolerance to oral medications, severe disability, and atypical presentation. Types of tremor known to be poorly responsive to oral medications (eg, head tremor, voice tremor) deserve a specialist evaluation if they contribute significantly to the patient’s morbidity.

The usual specialist treatment of severe voice tremor and head tremor is botulinum toxin injection. Patients with resistant and disabling hand tremor are evaluated for thalamic deep brain stimulation.

Patients with residual disability despite medical and surgical treatment should be referred for occupational therapy. Occupational therapy can improve quality of life through the use of special utensils, pens, computer gadgets, and arm weights, among other devices.