First, SHM’s new Learning Portal was the one-stop shop for free and discounted continuing medical education (CME) credits online. Now, the Learning Portal can help hospitalists report into the physician quality reporting system (PQRS) at a discounted individual rate.

And the time to start reporting measures in PQRS is now.

The PQRS was developed by the Centers for Medicare & Medicaid Services (CMS) in 2007 as a voluntary reporting program that provides a financial incentive to physicians and other eligible professionals who report data on quality measures for covered services furnished to Medicare beneficiaries. Starting in 2013, reporting in PQRS becomes mandatory for all eligible professionals.

SHM has encouraged its members to participate in the PQRS since the system’s inception in 2007. With the exciting launch of the SHM Learning Portal, it is easier than ever to get started. If you or your group are not currently reporting, there are still incentive payments available in 2013 and 2014. Beginning in 2015, there will be a penalty for not reporting quality measures based on 2013 performance.

Access the PQRIwizard through the SHM Learning Portal

SHM has secured a significant discount for members to report PQRS through the PQRIwizard. Located within the SHM Learning Portal, this online tool is a fast, convenient, and cost-effective solution to help collect and report quality measures data for the PQRS program. Similar to online tax-preparation software, the PQRIwizard guides you through a few easy steps to help rapidly collect, validate, report, and submit your results to CMS. The tool is powered by the CECity Registry, a CMS-qualified registry for PQRS reporting.

What Measures Are Available?

The SHM PQRIwizard features six individual quality measures in the areas of stroke and stroke rehabilitation, including measures on screening for dysphagia and thrombolytic therapy. To report on any of these measures, simply select three measures and report on 80 percent of your Medicare Part B fee-for-services patients who apply to the measures you selected.

PQRIwizard has a built-in progress monitor that validates your report by checking for missing data. The monitor also tracks your data to provide you with continuous feedback regarding valid patients. The system even calculates your measures and provides a printable report of your measure results in real time.

First, SHM’s new Learning Portal was the one-stop shop for free and discounted continuing medical education (CME) credits online. Now, the Learning Portal can help hospitalists report into the physician quality reporting system (PQRS) at a discounted individual rate.

And the time to start reporting measures in PQRS is now.

The PQRS was developed by the Centers for Medicare & Medicaid Services (CMS) in 2007 as a voluntary reporting program that provides a financial incentive to physicians and other eligible professionals who report data on quality measures for covered services furnished to Medicare beneficiaries. Starting in 2013, reporting in PQRS becomes mandatory for all eligible professionals.

SHM has encouraged its members to participate in the PQRS since the system’s inception in 2007. With the exciting launch of the SHM Learning Portal, it is easier than ever to get started. If you or your group are not currently reporting, there are still incentive payments available in 2013 and 2014. Beginning in 2015, there will be a penalty for not reporting quality measures based on 2013 performance.

Access the PQRIwizard through the SHM Learning Portal

SHM has secured a significant discount for members to report PQRS through the PQRIwizard. Located within the SHM Learning Portal, this online tool is a fast, convenient, and cost-effective solution to help collect and report quality measures data for the PQRS program. Similar to online tax-preparation software, the PQRIwizard guides you through a few easy steps to help rapidly collect, validate, report, and submit your results to CMS. The tool is powered by the CECity Registry, a CMS-qualified registry for PQRS reporting.

What Measures Are Available?

The SHM PQRIwizard features six individual quality measures in the areas of stroke and stroke rehabilitation, including measures on screening for dysphagia and thrombolytic therapy. To report on any of these measures, simply select three measures and report on 80 percent of your Medicare Part B fee-for-services patients who apply to the measures you selected.

PQRIwizard has a built-in progress monitor that validates your report by checking for missing data. The monitor also tracks your data to provide you with continuous feedback regarding valid patients. The system even calculates your measures and provides a printable report of your measure results in real time.

First, SHM’s new Learning Portal was the one-stop shop for free and discounted continuing medical education (CME) credits online. Now, the Learning Portal can help hospitalists report into the physician quality reporting system (PQRS) at a discounted individual rate.

And the time to start reporting measures in PQRS is now.

The PQRS was developed by the Centers for Medicare & Medicaid Services (CMS) in 2007 as a voluntary reporting program that provides a financial incentive to physicians and other eligible professionals who report data on quality measures for covered services furnished to Medicare beneficiaries. Starting in 2013, reporting in PQRS becomes mandatory for all eligible professionals.

SHM has encouraged its members to participate in the PQRS since the system’s inception in 2007. With the exciting launch of the SHM Learning Portal, it is easier than ever to get started. If you or your group are not currently reporting, there are still incentive payments available in 2013 and 2014. Beginning in 2015, there will be a penalty for not reporting quality measures based on 2013 performance.

Access the PQRIwizard through the SHM Learning Portal

SHM has secured a significant discount for members to report PQRS through the PQRIwizard. Located within the SHM Learning Portal, this online tool is a fast, convenient, and cost-effective solution to help collect and report quality measures data for the PQRS program. Similar to online tax-preparation software, the PQRIwizard guides you through a few easy steps to help rapidly collect, validate, report, and submit your results to CMS. The tool is powered by the CECity Registry, a CMS-qualified registry for PQRS reporting.

What Measures Are Available?

The SHM PQRIwizard features six individual quality measures in the areas of stroke and stroke rehabilitation, including measures on screening for dysphagia and thrombolytic therapy. To report on any of these measures, simply select three measures and report on 80 percent of your Medicare Part B fee-for-services patients who apply to the measures you selected.

PQRIwizard has a built-in progress monitor that validates your report by checking for missing data. The monitor also tracks your data to provide you with continuous feedback regarding valid patients. The system even calculates your measures and provides a printable report of your measure results in real time.

Are you ready to shape the future of hospital medicine, collaborate with leaders in the field, and advance your career? Now is the time—by nominating yourself (or a colleague) for any one of dozens of SHM committees or the board of directors. But don’t delay: The deadline for nominations is Oct. 21.

To learn more about SHM’s 20-plus committees and submit a nomination, visit www.hospitalmedicine.org/committees.

To learn about board eligibility, visit the “About SHM” section at www.hospitalmedicine.org and select “Election Information.”

Why get involved in committees or SHM’s board of directors? Here are some of the reasons current leaders in the field got involved:

Eric Howell, MD, SFHM

Eric Howell, MD, SFHM, SHM president; chief of the division of hospital medicine, John Hopkins Bayview Hospital, Baltimore

The most valuable thing to me is interacting with the nation’s HM leaders, not just other board members. Serving on the board provides connections with many of the best and brightest in our field, from “masters” to brilliant staff, and many, many insightful and thoughtful members.

Serving on the board has been a huge help in my career. The networking is fabulous and absolutely cannot be understated. Plus, you learn a ton from serving on the board, from cutting-edge topics to being involved in areas of HM that might not be present at your home institution. There are multiple opportunities to grow and advance your own leadership skills, from running for a board of directors officer position (treasurer, secretary, president) to opportunities to participate in the Leadership Academy to the AHA to QSEA and more.

Nasim Afsar, MD, SFHM

Nasim Afsar, MD, SFHM, SHM board member; associate chief medical officer, assistant clinical professor, medicine and neurosurgery, executive director of quality and safety, medicine and neurosurgery, UCLA Hospitals, Los Angeles.

If you want to work on challenges facing our specialty, with an incredibly insightful, dedicated, and thoughtful group, come on board. Participating as an SHM board member is invaluable. We have such a dedicated and accomplished group of colleagues focused on the challenges in health care, and we are working toward solutions for the future.

It has enabled me to have a broader perspective on the field of hospital medicine as well as the various roles hospitalists play locally and nationally.

Alexander Carbo, MD, SFHM

Alexander Carbo, MD, SFHM, SHM Membership Committee chair; assistant professor of medicine, Beth Israel Deaconess Medical Center, Boston

There are several benefits to serving on an SHM committee. It allows you to meet and collaborate with a fantastic group of individuals, and easily establishes connections that would otherwise take much longer to foster. It also allows you to participate in the field at a national level: If there is something that you are passionate about, committee service can provide a platform for that passion.

It is great fun to participate in SHM committees and to be a part of the process in which this society shapes policy and provides educational opportunities for hospitalists.

Serving on an SHM committee has certainly expanded my network of contacts within hospital medicine!

We are trying to listen to what front-line providers want and need to know about patient safety and quality improvement, and to provide that information for them.

Kim Dickinson, MA, RRT, SFHM

Kim Dickinson, MA, RRT, SFHM, SHM Administrators Committee chair; executive vice president, Acute Services Hospitalists Now Inc., Tucson, Ariz.

I have appreciated the opportunity for continued personal leadership development and the ability to interact closely with others in our industry. I have found hospitalists to be very transparent regarding improving patient care best practices.

It is fun. You meet a subset of people you may have never known. Deep friendships are formed. HM is a large specialty in a very small world. People I have worked with in past committees resurface in my life with regularity.

Our committee has been active in providing broad education about the best practices in HM administration, as well as providing a fellowship track for nonphysicians. This is a landmark achievement for us. Recognition for being part of the HM transformation of health care is immensely satisfying.

Tierza Stephan, MD, FACP, SFHM

Tierza Stephan, MD, FACP, SFHM, SHM Practice Analysis Committee member, hospitalist regional medical director, Allina Health, Minneapolis

Serving on the Practice Analysis Committee has helped me to be a more informed, credible source of hospitalist information for senior leaders in my organization. It has definitely provided me a set of knowledgeable hospitalist colleagues outside of my health system to whom I can turn to for advice and help with problem-solving.

Hospitalists across the country share an amazing number of similar issues despite every hospital having its own unique culture. It’s helpful to hear others talk about the solutions they’ve considered and tried, what went well, and what didn’t. I’ve learned more about the complexity of analyzing a hospitalist practice.

Kendall M. Rogers, MD, CPE, FACP, SFHM

Kendall M. Rogers, MD, CPE, FACP, SFHM, SHM IT Executive Committee chair, associate professor of medicine, chief of the division of hospital medicine, University of New Mexico Health Sciences Center, Albuquerque

My time on SHM committees has been one of the most professionally satisfying activities I have engaged in. In addition to meeting and working closely with national leaders and role models, it has expanded my local idea of what our HM group was capable of achieving by seeing the accomplishments of others and allowing me to incorporate many aspects of these practices without having to develop it from scratch. It also has given me a great sense of pride in our specialty, which has also added to my job satisfaction.

Much of this would not have been possible without the support structure I have built through SHM, which all began with serving on one committee. That has grown to chairing committees, serving as SHM faculty, being a mentee, then mentor, then lead mentor in SHM’s mentored implementation programs.

Committee membership gives you a source of professional satisfaction that is different from your local work. It ties you into a network of people with similar interests while also making you more effective in your local work.

As chair of the Information Technology (IT) Executive Committee, I received a message from my administrative assistant that stated: “The Society of Hospital Medicine called and they need you to go to the White House next week.” I was invited to represent SHM at a town hall meeting on IT with the ONC director at the White House with SHM’s senior advisor for advocacy and government affairs. I have traveled with the CEO, Larry Wellikson, to visit major [electronic medical records] vendors and advocate for the IT tools we need for our members to provide the highest quality of care.

Are you ready to shape the future of hospital medicine, collaborate with leaders in the field, and advance your career? Now is the time—by nominating yourself (or a colleague) for any one of dozens of SHM committees or the board of directors. But don’t delay: The deadline for nominations is Oct. 21.

To learn more about SHM’s 20-plus committees and submit a nomination, visit www.hospitalmedicine.org/committees.

To learn about board eligibility, visit the “About SHM” section at www.hospitalmedicine.org and select “Election Information.”

Why get involved in committees or SHM’s board of directors? Here are some of the reasons current leaders in the field got involved:

Eric Howell, MD, SFHM

Eric Howell, MD, SFHM, SHM president; chief of the division of hospital medicine, John Hopkins Bayview Hospital, Baltimore

The most valuable thing to me is interacting with the nation’s HM leaders, not just other board members. Serving on the board provides connections with many of the best and brightest in our field, from “masters” to brilliant staff, and many, many insightful and thoughtful members.

Serving on the board has been a huge help in my career. The networking is fabulous and absolutely cannot be understated. Plus, you learn a ton from serving on the board, from cutting-edge topics to being involved in areas of HM that might not be present at your home institution. There are multiple opportunities to grow and advance your own leadership skills, from running for a board of directors officer position (treasurer, secretary, president) to opportunities to participate in the Leadership Academy to the AHA to QSEA and more.

Nasim Afsar, MD, SFHM

Nasim Afsar, MD, SFHM, SHM board member; associate chief medical officer, assistant clinical professor, medicine and neurosurgery, executive director of quality and safety, medicine and neurosurgery, UCLA Hospitals, Los Angeles.

If you want to work on challenges facing our specialty, with an incredibly insightful, dedicated, and thoughtful group, come on board. Participating as an SHM board member is invaluable. We have such a dedicated and accomplished group of colleagues focused on the challenges in health care, and we are working toward solutions for the future.

It has enabled me to have a broader perspective on the field of hospital medicine as well as the various roles hospitalists play locally and nationally.

Alexander Carbo, MD, SFHM

Alexander Carbo, MD, SFHM, SHM Membership Committee chair; assistant professor of medicine, Beth Israel Deaconess Medical Center, Boston

There are several benefits to serving on an SHM committee. It allows you to meet and collaborate with a fantastic group of individuals, and easily establishes connections that would otherwise take much longer to foster. It also allows you to participate in the field at a national level: If there is something that you are passionate about, committee service can provide a platform for that passion.

It is great fun to participate in SHM committees and to be a part of the process in which this society shapes policy and provides educational opportunities for hospitalists.

Serving on an SHM committee has certainly expanded my network of contacts within hospital medicine!

We are trying to listen to what front-line providers want and need to know about patient safety and quality improvement, and to provide that information for them.

Kim Dickinson, MA, RRT, SFHM

Kim Dickinson, MA, RRT, SFHM, SHM Administrators Committee chair; executive vice president, Acute Services Hospitalists Now Inc., Tucson, Ariz.

I have appreciated the opportunity for continued personal leadership development and the ability to interact closely with others in our industry. I have found hospitalists to be very transparent regarding improving patient care best practices.

It is fun. You meet a subset of people you may have never known. Deep friendships are formed. HM is a large specialty in a very small world. People I have worked with in past committees resurface in my life with regularity.

Our committee has been active in providing broad education about the best practices in HM administration, as well as providing a fellowship track for nonphysicians. This is a landmark achievement for us. Recognition for being part of the HM transformation of health care is immensely satisfying.

Tierza Stephan, MD, FACP, SFHM

Tierza Stephan, MD, FACP, SFHM, SHM Practice Analysis Committee member, hospitalist regional medical director, Allina Health, Minneapolis

Serving on the Practice Analysis Committee has helped me to be a more informed, credible source of hospitalist information for senior leaders in my organization. It has definitely provided me a set of knowledgeable hospitalist colleagues outside of my health system to whom I can turn to for advice and help with problem-solving.

Hospitalists across the country share an amazing number of similar issues despite every hospital having its own unique culture. It’s helpful to hear others talk about the solutions they’ve considered and tried, what went well, and what didn’t. I’ve learned more about the complexity of analyzing a hospitalist practice.

Kendall M. Rogers, MD, CPE, FACP, SFHM

Kendall M. Rogers, MD, CPE, FACP, SFHM, SHM IT Executive Committee chair, associate professor of medicine, chief of the division of hospital medicine, University of New Mexico Health Sciences Center, Albuquerque

My time on SHM committees has been one of the most professionally satisfying activities I have engaged in. In addition to meeting and working closely with national leaders and role models, it has expanded my local idea of what our HM group was capable of achieving by seeing the accomplishments of others and allowing me to incorporate many aspects of these practices without having to develop it from scratch. It also has given me a great sense of pride in our specialty, which has also added to my job satisfaction.

Much of this would not have been possible without the support structure I have built through SHM, which all began with serving on one committee. That has grown to chairing committees, serving as SHM faculty, being a mentee, then mentor, then lead mentor in SHM’s mentored implementation programs.

Committee membership gives you a source of professional satisfaction that is different from your local work. It ties you into a network of people with similar interests while also making you more effective in your local work.

As chair of the Information Technology (IT) Executive Committee, I received a message from my administrative assistant that stated: “The Society of Hospital Medicine called and they need you to go to the White House next week.” I was invited to represent SHM at a town hall meeting on IT with the ONC director at the White House with SHM’s senior advisor for advocacy and government affairs. I have traveled with the CEO, Larry Wellikson, to visit major [electronic medical records] vendors and advocate for the IT tools we need for our members to provide the highest quality of care.

Are you ready to shape the future of hospital medicine, collaborate with leaders in the field, and advance your career? Now is the time—by nominating yourself (or a colleague) for any one of dozens of SHM committees or the board of directors. But don’t delay: The deadline for nominations is Oct. 21.

To learn more about SHM’s 20-plus committees and submit a nomination, visit www.hospitalmedicine.org/committees.

To learn about board eligibility, visit the “About SHM” section at www.hospitalmedicine.org and select “Election Information.”

Why get involved in committees or SHM’s board of directors? Here are some of the reasons current leaders in the field got involved:

Eric Howell, MD, SFHM

Eric Howell, MD, SFHM, SHM president; chief of the division of hospital medicine, John Hopkins Bayview Hospital, Baltimore

The most valuable thing to me is interacting with the nation’s HM leaders, not just other board members. Serving on the board provides connections with many of the best and brightest in our field, from “masters” to brilliant staff, and many, many insightful and thoughtful members.

Serving on the board has been a huge help in my career. The networking is fabulous and absolutely cannot be understated. Plus, you learn a ton from serving on the board, from cutting-edge topics to being involved in areas of HM that might not be present at your home institution. There are multiple opportunities to grow and advance your own leadership skills, from running for a board of directors officer position (treasurer, secretary, president) to opportunities to participate in the Leadership Academy to the AHA to QSEA and more.

Nasim Afsar, MD, SFHM

Nasim Afsar, MD, SFHM, SHM board member; associate chief medical officer, assistant clinical professor, medicine and neurosurgery, executive director of quality and safety, medicine and neurosurgery, UCLA Hospitals, Los Angeles.

If you want to work on challenges facing our specialty, with an incredibly insightful, dedicated, and thoughtful group, come on board. Participating as an SHM board member is invaluable. We have such a dedicated and accomplished group of colleagues focused on the challenges in health care, and we are working toward solutions for the future.

It has enabled me to have a broader perspective on the field of hospital medicine as well as the various roles hospitalists play locally and nationally.

Alexander Carbo, MD, SFHM

Alexander Carbo, MD, SFHM, SHM Membership Committee chair; assistant professor of medicine, Beth Israel Deaconess Medical Center, Boston

There are several benefits to serving on an SHM committee. It allows you to meet and collaborate with a fantastic group of individuals, and easily establishes connections that would otherwise take much longer to foster. It also allows you to participate in the field at a national level: If there is something that you are passionate about, committee service can provide a platform for that passion.

It is great fun to participate in SHM committees and to be a part of the process in which this society shapes policy and provides educational opportunities for hospitalists.

Serving on an SHM committee has certainly expanded my network of contacts within hospital medicine!

We are trying to listen to what front-line providers want and need to know about patient safety and quality improvement, and to provide that information for them.

Kim Dickinson, MA, RRT, SFHM

Kim Dickinson, MA, RRT, SFHM, SHM Administrators Committee chair; executive vice president, Acute Services Hospitalists Now Inc., Tucson, Ariz.

I have appreciated the opportunity for continued personal leadership development and the ability to interact closely with others in our industry. I have found hospitalists to be very transparent regarding improving patient care best practices.

It is fun. You meet a subset of people you may have never known. Deep friendships are formed. HM is a large specialty in a very small world. People I have worked with in past committees resurface in my life with regularity.

Our committee has been active in providing broad education about the best practices in HM administration, as well as providing a fellowship track for nonphysicians. This is a landmark achievement for us. Recognition for being part of the HM transformation of health care is immensely satisfying.

Tierza Stephan, MD, FACP, SFHM

Tierza Stephan, MD, FACP, SFHM, SHM Practice Analysis Committee member, hospitalist regional medical director, Allina Health, Minneapolis

Serving on the Practice Analysis Committee has helped me to be a more informed, credible source of hospitalist information for senior leaders in my organization. It has definitely provided me a set of knowledgeable hospitalist colleagues outside of my health system to whom I can turn to for advice and help with problem-solving.

Hospitalists across the country share an amazing number of similar issues despite every hospital having its own unique culture. It’s helpful to hear others talk about the solutions they’ve considered and tried, what went well, and what didn’t. I’ve learned more about the complexity of analyzing a hospitalist practice.

Kendall M. Rogers, MD, CPE, FACP, SFHM

Kendall M. Rogers, MD, CPE, FACP, SFHM, SHM IT Executive Committee chair, associate professor of medicine, chief of the division of hospital medicine, University of New Mexico Health Sciences Center, Albuquerque

My time on SHM committees has been one of the most professionally satisfying activities I have engaged in. In addition to meeting and working closely with national leaders and role models, it has expanded my local idea of what our HM group was capable of achieving by seeing the accomplishments of others and allowing me to incorporate many aspects of these practices without having to develop it from scratch. It also has given me a great sense of pride in our specialty, which has also added to my job satisfaction.

Much of this would not have been possible without the support structure I have built through SHM, which all began with serving on one committee. That has grown to chairing committees, serving as SHM faculty, being a mentee, then mentor, then lead mentor in SHM’s mentored implementation programs.

Committee membership gives you a source of professional satisfaction that is different from your local work. It ties you into a network of people with similar interests while also making you more effective in your local work.

As chair of the Information Technology (IT) Executive Committee, I received a message from my administrative assistant that stated: “The Society of Hospital Medicine called and they need you to go to the White House next week.” I was invited to represent SHM at a town hall meeting on IT with the ONC director at the White House with SHM’s senior advisor for advocacy and government affairs. I have traveled with the CEO, Larry Wellikson, to visit major [electronic medical records] vendors and advocate for the IT tools we need for our members to provide the highest quality of care.

Robert Wachter, MD, MHM

Robert Wachter, MD, MHM, has been named to the board of directors and chair of the quality committee for IPC: The Hospitalist Company, based in North Hollywood, Calif. Dr. Wachter currently serves as director of the division of hospital medicine and associate chair of the department of medicine at the University of California at San Francisco. A well-known and respected authority on quality and safety, he was recognized with the John M. Eisenberg Award for excellence in patient safety in 2004. He also pens the Wachter’s World blog at www.wachtersworld.com.

Raffi Hodikian, MD

Raffi Hodikian, MD, a hospitalist and longtime member of SHM, was named the 2013 Physician of the Year at Foothill Presbyterian Hospital in Glendora, Calif. “Not only was this the greatest honor of my career, but I thought it further reaffirmed the vital role hospitalists play in our community hospitals,” Dr. Hodikian said of the award.

Kimberly A. Bell, MD, is the new associate vice president of hospital medicine for Franciscan Health System (FHS) in Tacoma, Wash. In her new role, Dr. Bell will oversee hospitalist services at five of FHS’ seven area hospitals. FHS employs nearly 100 hospital medicine providers, including physicians and physician extenders.

Felix T. Cabrera, MD, has been named associate medical director at Guam Memorial Hospital (GMH) in Tamuning, Guam, after working as a hospitalist at GMH for more than two years. In his new role, Dr. Cabrera hopes to improve the technological infrastructure within the hospital. He will continue with his regular hospitalist rounds and private practice at International Health Providers Medical Group in Dededo, Guam. GMH is a 158-bed acute-care facility and the only hospital dedicated to civilian care on the island.

Troy Martin, MD, has been appointed chief medical officer for Questcare Hospitalists, based in Dallas. Dr. Martin comes to the Questcare executive team from the Medical Center of McKinney in McKinney, Texas, where he served as medical director of Questcare’s hospitalist program.

Robert Wachter, MD, MHM

Robert Wachter, MD, MHM, has been named to the board of directors and chair of the quality committee for IPC: The Hospitalist Company, based in North Hollywood, Calif. Dr. Wachter currently serves as director of the division of hospital medicine and associate chair of the department of medicine at the University of California at San Francisco. A well-known and respected authority on quality and safety, he was recognized with the John M. Eisenberg Award for excellence in patient safety in 2004. He also pens the Wachter’s World blog at www.wachtersworld.com.

Raffi Hodikian, MD

Raffi Hodikian, MD, a hospitalist and longtime member of SHM, was named the 2013 Physician of the Year at Foothill Presbyterian Hospital in Glendora, Calif. “Not only was this the greatest honor of my career, but I thought it further reaffirmed the vital role hospitalists play in our community hospitals,” Dr. Hodikian said of the award.

Kimberly A. Bell, MD, is the new associate vice president of hospital medicine for Franciscan Health System (FHS) in Tacoma, Wash. In her new role, Dr. Bell will oversee hospitalist services at five of FHS’ seven area hospitals. FHS employs nearly 100 hospital medicine providers, including physicians and physician extenders.

Felix T. Cabrera, MD, has been named associate medical director at Guam Memorial Hospital (GMH) in Tamuning, Guam, after working as a hospitalist at GMH for more than two years. In his new role, Dr. Cabrera hopes to improve the technological infrastructure within the hospital. He will continue with his regular hospitalist rounds and private practice at International Health Providers Medical Group in Dededo, Guam. GMH is a 158-bed acute-care facility and the only hospital dedicated to civilian care on the island.

Troy Martin, MD, has been appointed chief medical officer for Questcare Hospitalists, based in Dallas. Dr. Martin comes to the Questcare executive team from the Medical Center of McKinney in McKinney, Texas, where he served as medical director of Questcare’s hospitalist program.

Robert Wachter, MD, MHM

Robert Wachter, MD, MHM, has been named to the board of directors and chair of the quality committee for IPC: The Hospitalist Company, based in North Hollywood, Calif. Dr. Wachter currently serves as director of the division of hospital medicine and associate chair of the department of medicine at the University of California at San Francisco. A well-known and respected authority on quality and safety, he was recognized with the John M. Eisenberg Award for excellence in patient safety in 2004. He also pens the Wachter’s World blog at www.wachtersworld.com.

Raffi Hodikian, MD

Raffi Hodikian, MD, a hospitalist and longtime member of SHM, was named the 2013 Physician of the Year at Foothill Presbyterian Hospital in Glendora, Calif. “Not only was this the greatest honor of my career, but I thought it further reaffirmed the vital role hospitalists play in our community hospitals,” Dr. Hodikian said of the award.

Kimberly A. Bell, MD, is the new associate vice president of hospital medicine for Franciscan Health System (FHS) in Tacoma, Wash. In her new role, Dr. Bell will oversee hospitalist services at five of FHS’ seven area hospitals. FHS employs nearly 100 hospital medicine providers, including physicians and physician extenders.

Felix T. Cabrera, MD, has been named associate medical director at Guam Memorial Hospital (GMH) in Tamuning, Guam, after working as a hospitalist at GMH for more than two years. In his new role, Dr. Cabrera hopes to improve the technological infrastructure within the hospital. He will continue with his regular hospitalist rounds and private practice at International Health Providers Medical Group in Dededo, Guam. GMH is a 158-bed acute-care facility and the only hospital dedicated to civilian care on the island.

Troy Martin, MD, has been appointed chief medical officer for Questcare Hospitalists, based in Dallas. Dr. Martin comes to the Questcare executive team from the Medical Center of McKinney in McKinney, Texas, where he served as medical director of Questcare’s hospitalist program.

In This Edition

9 Things: At a Glance

An occasional series providing specialty-specific advice for hospitalists from experts in the field.

1. Recognize the differential diagnosis for pain exacerbation in a chronic opioid therapy (COT) patient/chronic pain patient.
2. Know where the opioids are going.
3. Sometimes stopping pills, rather than adding them, can cure pain.
4. Take time to educate patients about methadone and its risk of mortality if not used as prescribed.
5. A little local anesthetic (and some steroid) goes a long way.
6. Addiction to opioids is not rare.
7. Safely changing opioid regimens requires good math and good judgment.
8. For a low-risk chronic pain patient on low-dose opioids, don’t change the regimen, even if the indication for opioids isn’t clear.
9. If a patient has pain all the time, they need to be on a medication that works all the time.

The differential diagnosis for pain exacerbation in a chronic opioid therapy (COT) patient/chronic pain patient is:

1. Worsening medical problem;
2. New medical problem;
3. Nonopioid problem (side effect);
4. Opioid problem (resistance/tolerance/side effect); and
5. Opioid-induced hyperalgesia.

The search for an etiology and treatment for chronic pain should not end, even if a patient is labeled with “chronic pain syndrome.” The patient could simply be chronically undiagnosed or on an incorrect therapy.

Know where the opioids are going.

Whether it’s auditing a prescription-monitoring program (PMP), checking a urine drug screen, or calling a pharmacist, try to ensure that chronic pain patients are taking the opioids as prescribed. A phone call to the primary opioid prescriber or chronic pain provider could save a busy hospitalist a lot of time.

Using PMP data can consume a lot of time. Typically, only prescribing providers can access PMPs, so delegating this responsibility to someone else is not possible. If your state PMP does not help, simply call the patient’s pharmacy and ask for the last three fill dates on an opioid prescription. This also works well in case the patient’s pharmacy doesn’t participate in a PMP or is delayed in uploading recent prescriber data. Many COT patients have an opioid treatment agreement with their prescriber and must use only one pharmacy to fill opioids.

In January 2013, the University of North Carolina Injury Prevention Center published an analysis of three years of North Carolina PMP data.1 Patients followed by providers who consistently used the state PMP were five times more likely to receive treatment for opioid dependence compared with patients of providers who never used the state PMP.¹

Why go through all this trouble if a chronic pain specialist is also doing it? It’s good documentation and good care, like monitoring levels of transplant meds or making sure hemoglobin A1Cs are up to date and trending toward goal. It may only take one misused or diverted opioid pill to result in a serious adverse event.

Sometimes stopping pills, rather than adding them, can cure pain.

Many chronic pain patients accumulate a patchwork of pills (e.g. benzodiazepines, opioids, muscle relaxants, and antidepressants). Many interpret noxious symptoms associated with the drug burden as “uncontrolled pain.” Two conditions that might afflict the pain sufferer who takes multiple medications are opioid-induced hyperalgesia (OIH) and medication-overuse headaches (MOH). They are uncommon but should be on a hospitalist’s differential for difficult-to-control chronic pain. Opioids commonly are implicated in causing MOH, a chronic headache occurring at least 15 days a month, four hours a day if untreated, and for at least three consecutive months. OIH is a nociceptive sensitization caused by opioids that can occur suddenly or insidiously.

If a drug isn’t absolutely necessary, stop it. If you and the patient start by agreeing to the shared goal of improving health, the conversation should go better. An axiom we learned from mentors at the University of Washington is: “There is no pain that cannot be made worse with inappropriate therapy.”

Take time to educate patients about methadone and its risk of mortality if not used as prescribed.

Methadone is less frequently prescribed than other opioids, yet it is more frequently associated with death from overdose. Though there is a risk of overdose and death with any opioid, managing methadone is more difficult. A desperate chronic pain patient may self-escalate their methadone without proper insight into the consequences.

Remember the logarithmic relationship methadone doses have with their morphine equivalency. The following highlights how deceiving the numbers are: 50 mg of methadone is about 100 mg of morphine-equivalent, but 100 mg of methadone is about 1,000 mg of morphine-equivalent, or 10 times as strong.

From 1999 to 2005, methadone-related deaths increased by 468%.² If the patient doesn’t seem to understand these risks, they are not a good candidate for methadone treatment.

A little local anesthetic (and some steroid) goes a long way.

Hospitalists should offer an assortment of diagnostic and therapeutic injections to chronic pain patients. First, be sure you’ve done your due diligence:

• What procedures do you have privileges to do?
• Do you need to be proctored first?
• How do your local specialists feel about you doing injections?

In light of these considerations, hospitalists should be able to train and be credentialed to offer such procedures as trigger-point injections, joint injections (knees, shoulders), or even a peripheral nerve injection (e.g. lateral femoral cutaneous nerve or ilioinguinal nerve injection). Some hospitalists might even want to learn ultrasound-guided sacroiliac joint injections for chronic unexplained back pain.

Offering an indicated and effective injection is a good nonopioid option. And local anesthetic injections can help hospitalists establish an elusive diagnosis. For example, many patients spend years getting worked up for head and neck pain when dry-needling with a small volume (1 cc) of local anesthetic into a neck muscle trigger point can break their pain generator, eliminating their pain.

Addiction to opioids is not rare.

The use, misuse, and diversion of opioids and all the associated complications have appropriately received considerable media attention. A seminal paper by Porter and Jick titled “Addiction Is Rare in Patients Treated with Narcotics” is one of many tipping points associated with the boom in opioid prescribing.³ Whether it’s a three-day supply of hydrocodone, 24 hours on a PCA, or an opioid rotation, any exposure to opioids can put a patient on the runway to addiction.

There are only 3,071 board-certified addiction specialists certified by the American Board of Addiction Medicine, so access to an addiction specialist might be difficult.⁴

Nonetheless, do not become complacent and just continue the opioid therapy in a difficult opioid-addicted patient. Express your concerns to the primary opioid prescriber, or help patients who don’t have an opioid prescriber get access and treatment. Otherwise, you have no choice but to taper the opioids.

Ideally, chronic pain management should be delivered in the outpatient arena where long-term monitoring can take place.

Safely changing opioid regimens requires good math and good judgment.

During training and practice, hospitalists become accustomed to rapidly analyze objective data, such as ABGs, ECGs, anion gaps, and vent settings. A hospitalist should become similarly efficient at calculating morphine equivalencies (cautiously with methadone and fentanyl), making dose reductions, and rotating opioids. The more comfortable you are with morphine equivalencies, the faster and safer you will be at rotating opioids. Whatever morphine-equivalence table you feel comfortable with is the one you should use consistently.

We see many providers who unwittingly take, for example, a patient who has become resistant to hydrocodone/acetaminophen 10/325 mg PO TID (30 mg of morphine) and convert them to oxycodone/acetaminophen 10/325 mg PO QID (60 mg of morphine—a doubling), when doubling could cause respiratory depression or a faster path to addiction and dependency.

But there are cases in which judgment should trump math, such as when converting from an IV to an oral regimen. We frequently see patients in the clinic requesting refills for more than 100 mg of hydromorphone because “that’s what I was on when I was hospitalized and on the pump.” If the IV-to-oral conversion leaves you prescribing high doses of oral opioids, plan for a rapid taper and a smooth handoff to the outpatient setting.

One strategy to decrease an error in math and judgment is to use IV PCAs as infrequently as possible if a patient isn’t post-operative and they are able to take oral meds. And never hesitate to consult with your inpatient pharmacist or a chronic pain specialist.

For a low-risk chronic pain patient on low-dose opioids, don’t change the regimen, even if the indication for opioids isn’t clear.

Although it is tempting to become an opioid prohibitionist, if a patient has been taking an opioid for years and is functioning, working, compliant, and has no risk factors for complications from COT, it is likely fine to continue their current regimen. Touch base with the primary opioid prescriber, and if you’re concerned, use some of the monitoring instruments described earlier (PMP, urine drug screen, opioid treatment agreement, pill counts).

If a patient has pain all the time, they need to be on a medication that works all the time.

A good pain history followed by a good neurological and mental health assessment is of incalculable value, especially because physicians often underestimate a patient’s pain intensity and its impact on a patient’s quality of life.^5,6 A patient’s pain intensity, quality of life, and function can be dramatically improved by starting a long-acting medication for “constant pain.”

If a patient hurts “24 hours a day” and cannot function on hydrocodone/acetaminophen 10/325 QID, it’s probably because they are constantly reacting to spikes in pain and using a “some of the time” medicine to treat “all the time” pain. Switching to a long-acting medication—and it doesn’t have to be an opioid—could improve control and decrease how much narcotic the patient needs.

If you choose a long-acting opioid (in this case, you could try morphine sulphate extended-release 15 mg BID and satisfy 50% of the hydrocodone need), then you could titrate slowly upwards to where the patient would not need hydrocodone. If the patient still had uncontrolled pain, then either morphine is the wrong compound for them or they are benefiting from the “nonanalgesic properties” of the opioids.

Give the patient the benefit of the doubt; because of genetic polymorphisms, a patient may need several opioid rotations before the right opioid compound is found.

Dr. Schultz is a hospitalist and assistant professor in the department of internal medicine at the University of Miami Miller School of Medicine. She is board-certified in hospice and palliative care and specializes in chronic pain management. Dr. Ajam is a hospitalist and a clinical assistant professor in the department of anesthesiology at Wake Forest University Baptist Medical Center and the Carolinas Pain Institute. He is board-certified in chronic pain management.

References

1. Garrettson M, Ringwalt C. An evaluation of the North Carolina controlled substances reporting system: part II impact evaluation, January 2013. PDMP Center of Excellence website. Available at: http://pdmpexcellence.org/sites/all/pdfs/NC_control_sub_eval_pt_2.pdf. Accessed Sept. 3, 2013.
2. Kung HC, Hoyert DL, Xu JQ, Murphy SL. Deaths: Final data for 2005, national vital statistics reports; Vol. 56 No. 10. Hyattsville, Md.: National Center for Health Statistics; 2008.
3. Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med. 1980;302(2):123.
4. American Society of Addiction Medicine; personal communication, 2013.
5. Mäntyselkä P, Kumpusalo E, Ahonen R, Takala J. Patients’ versus general practitioners’ assessments of pain intensity in primary care patients with non-cancer pain. Br J Gen Pract. 2001;51(473):995-997.
6. Petersen MA, Larsen H, Pedersen L, Sonne N, Groenvold M. Assessing health-related quality of life in palliative care: comparing patient and physician assessments. Eur J Cancer. 2006;42(8):1159-1166.

In This Edition

9 Things: At a Glance

An occasional series providing specialty-specific advice for hospitalists from experts in the field.

1. Recognize the differential diagnosis for pain exacerbation in a chronic opioid therapy (COT) patient/chronic pain patient.
2. Know where the opioids are going.
3. Sometimes stopping pills, rather than adding them, can cure pain.
4. Take time to educate patients about methadone and its risk of mortality if not used as prescribed.
5. A little local anesthetic (and some steroid) goes a long way.
6. Addiction to opioids is not rare.
7. Safely changing opioid regimens requires good math and good judgment.
8. For a low-risk chronic pain patient on low-dose opioids, don’t change the regimen, even if the indication for opioids isn’t clear.
9. If a patient has pain all the time, they need to be on a medication that works all the time.

The differential diagnosis for pain exacerbation in a chronic opioid therapy (COT) patient/chronic pain patient is:

1. Worsening medical problem;
2. New medical problem;
3. Nonopioid problem (side effect);
4. Opioid problem (resistance/tolerance/side effect); and
5. Opioid-induced hyperalgesia.

The search for an etiology and treatment for chronic pain should not end, even if a patient is labeled with “chronic pain syndrome.” The patient could simply be chronically undiagnosed or on an incorrect therapy.

Know where the opioids are going.

Whether it’s auditing a prescription-monitoring program (PMP), checking a urine drug screen, or calling a pharmacist, try to ensure that chronic pain patients are taking the opioids as prescribed. A phone call to the primary opioid prescriber or chronic pain provider could save a busy hospitalist a lot of time.

Using PMP data can consume a lot of time. Typically, only prescribing providers can access PMPs, so delegating this responsibility to someone else is not possible. If your state PMP does not help, simply call the patient’s pharmacy and ask for the last three fill dates on an opioid prescription. This also works well in case the patient’s pharmacy doesn’t participate in a PMP or is delayed in uploading recent prescriber data. Many COT patients have an opioid treatment agreement with their prescriber and must use only one pharmacy to fill opioids.

In January 2013, the University of North Carolina Injury Prevention Center published an analysis of three years of North Carolina PMP data.1 Patients followed by providers who consistently used the state PMP were five times more likely to receive treatment for opioid dependence compared with patients of providers who never used the state PMP.¹

Why go through all this trouble if a chronic pain specialist is also doing it? It’s good documentation and good care, like monitoring levels of transplant meds or making sure hemoglobin A1Cs are up to date and trending toward goal. It may only take one misused or diverted opioid pill to result in a serious adverse event.

Sometimes stopping pills, rather than adding them, can cure pain.

Many chronic pain patients accumulate a patchwork of pills (e.g. benzodiazepines, opioids, muscle relaxants, and antidepressants). Many interpret noxious symptoms associated with the drug burden as “uncontrolled pain.” Two conditions that might afflict the pain sufferer who takes multiple medications are opioid-induced hyperalgesia (OIH) and medication-overuse headaches (MOH). They are uncommon but should be on a hospitalist’s differential for difficult-to-control chronic pain. Opioids commonly are implicated in causing MOH, a chronic headache occurring at least 15 days a month, four hours a day if untreated, and for at least three consecutive months. OIH is a nociceptive sensitization caused by opioids that can occur suddenly or insidiously.

If a drug isn’t absolutely necessary, stop it. If you and the patient start by agreeing to the shared goal of improving health, the conversation should go better. An axiom we learned from mentors at the University of Washington is: “There is no pain that cannot be made worse with inappropriate therapy.”

Take time to educate patients about methadone and its risk of mortality if not used as prescribed.

Methadone is less frequently prescribed than other opioids, yet it is more frequently associated with death from overdose. Though there is a risk of overdose and death with any opioid, managing methadone is more difficult. A desperate chronic pain patient may self-escalate their methadone without proper insight into the consequences.

Remember the logarithmic relationship methadone doses have with their morphine equivalency. The following highlights how deceiving the numbers are: 50 mg of methadone is about 100 mg of morphine-equivalent, but 100 mg of methadone is about 1,000 mg of morphine-equivalent, or 10 times as strong.

From 1999 to 2005, methadone-related deaths increased by 468%.² If the patient doesn’t seem to understand these risks, they are not a good candidate for methadone treatment.

A little local anesthetic (and some steroid) goes a long way.

Hospitalists should offer an assortment of diagnostic and therapeutic injections to chronic pain patients. First, be sure you’ve done your due diligence:

• What procedures do you have privileges to do?
• Do you need to be proctored first?
• How do your local specialists feel about you doing injections?

In light of these considerations, hospitalists should be able to train and be credentialed to offer such procedures as trigger-point injections, joint injections (knees, shoulders), or even a peripheral nerve injection (e.g. lateral femoral cutaneous nerve or ilioinguinal nerve injection). Some hospitalists might even want to learn ultrasound-guided sacroiliac joint injections for chronic unexplained back pain.

Offering an indicated and effective injection is a good nonopioid option. And local anesthetic injections can help hospitalists establish an elusive diagnosis. For example, many patients spend years getting worked up for head and neck pain when dry-needling with a small volume (1 cc) of local anesthetic into a neck muscle trigger point can break their pain generator, eliminating their pain.

Addiction to opioids is not rare.

The use, misuse, and diversion of opioids and all the associated complications have appropriately received considerable media attention. A seminal paper by Porter and Jick titled “Addiction Is Rare in Patients Treated with Narcotics” is one of many tipping points associated with the boom in opioid prescribing.³ Whether it’s a three-day supply of hydrocodone, 24 hours on a PCA, or an opioid rotation, any exposure to opioids can put a patient on the runway to addiction.

There are only 3,071 board-certified addiction specialists certified by the American Board of Addiction Medicine, so access to an addiction specialist might be difficult.⁴

Nonetheless, do not become complacent and just continue the opioid therapy in a difficult opioid-addicted patient. Express your concerns to the primary opioid prescriber, or help patients who don’t have an opioid prescriber get access and treatment. Otherwise, you have no choice but to taper the opioids.

Ideally, chronic pain management should be delivered in the outpatient arena where long-term monitoring can take place.

Safely changing opioid regimens requires good math and good judgment.

During training and practice, hospitalists become accustomed to rapidly analyze objective data, such as ABGs, ECGs, anion gaps, and vent settings. A hospitalist should become similarly efficient at calculating morphine equivalencies (cautiously with methadone and fentanyl), making dose reductions, and rotating opioids. The more comfortable you are with morphine equivalencies, the faster and safer you will be at rotating opioids. Whatever morphine-equivalence table you feel comfortable with is the one you should use consistently.

We see many providers who unwittingly take, for example, a patient who has become resistant to hydrocodone/acetaminophen 10/325 mg PO TID (30 mg of morphine) and convert them to oxycodone/acetaminophen 10/325 mg PO QID (60 mg of morphine—a doubling), when doubling could cause respiratory depression or a faster path to addiction and dependency.

But there are cases in which judgment should trump math, such as when converting from an IV to an oral regimen. We frequently see patients in the clinic requesting refills for more than 100 mg of hydromorphone because “that’s what I was on when I was hospitalized and on the pump.” If the IV-to-oral conversion leaves you prescribing high doses of oral opioids, plan for a rapid taper and a smooth handoff to the outpatient setting.

One strategy to decrease an error in math and judgment is to use IV PCAs as infrequently as possible if a patient isn’t post-operative and they are able to take oral meds. And never hesitate to consult with your inpatient pharmacist or a chronic pain specialist.

For a low-risk chronic pain patient on low-dose opioids, don’t change the regimen, even if the indication for opioids isn’t clear.

Although it is tempting to become an opioid prohibitionist, if a patient has been taking an opioid for years and is functioning, working, compliant, and has no risk factors for complications from COT, it is likely fine to continue their current regimen. Touch base with the primary opioid prescriber, and if you’re concerned, use some of the monitoring instruments described earlier (PMP, urine drug screen, opioid treatment agreement, pill counts).

If a patient has pain all the time, they need to be on a medication that works all the time.

A good pain history followed by a good neurological and mental health assessment is of incalculable value, especially because physicians often underestimate a patient’s pain intensity and its impact on a patient’s quality of life.^5,6 A patient’s pain intensity, quality of life, and function can be dramatically improved by starting a long-acting medication for “constant pain.”

If a patient hurts “24 hours a day” and cannot function on hydrocodone/acetaminophen 10/325 QID, it’s probably because they are constantly reacting to spikes in pain and using a “some of the time” medicine to treat “all the time” pain. Switching to a long-acting medication—and it doesn’t have to be an opioid—could improve control and decrease how much narcotic the patient needs.

If you choose a long-acting opioid (in this case, you could try morphine sulphate extended-release 15 mg BID and satisfy 50% of the hydrocodone need), then you could titrate slowly upwards to where the patient would not need hydrocodone. If the patient still had uncontrolled pain, then either morphine is the wrong compound for them or they are benefiting from the “nonanalgesic properties” of the opioids.

Give the patient the benefit of the doubt; because of genetic polymorphisms, a patient may need several opioid rotations before the right opioid compound is found.

Dr. Schultz is a hospitalist and assistant professor in the department of internal medicine at the University of Miami Miller School of Medicine. She is board-certified in hospice and palliative care and specializes in chronic pain management. Dr. Ajam is a hospitalist and a clinical assistant professor in the department of anesthesiology at Wake Forest University Baptist Medical Center and the Carolinas Pain Institute. He is board-certified in chronic pain management.

References

1. Garrettson M, Ringwalt C. An evaluation of the North Carolina controlled substances reporting system: part II impact evaluation, January 2013. PDMP Center of Excellence website. Available at: http://pdmpexcellence.org/sites/all/pdfs/NC_control_sub_eval_pt_2.pdf. Accessed Sept. 3, 2013.
2. Kung HC, Hoyert DL, Xu JQ, Murphy SL. Deaths: Final data for 2005, national vital statistics reports; Vol. 56 No. 10. Hyattsville, Md.: National Center for Health Statistics; 2008.
3. Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med. 1980;302(2):123.
4. American Society of Addiction Medicine; personal communication, 2013.
5. Mäntyselkä P, Kumpusalo E, Ahonen R, Takala J. Patients’ versus general practitioners’ assessments of pain intensity in primary care patients with non-cancer pain. Br J Gen Pract. 2001;51(473):995-997.
6. Petersen MA, Larsen H, Pedersen L, Sonne N, Groenvold M. Assessing health-related quality of life in palliative care: comparing patient and physician assessments. Eur J Cancer. 2006;42(8):1159-1166.

In This Edition

9 Things: At a Glance

An occasional series providing specialty-specific advice for hospitalists from experts in the field.

1. Recognize the differential diagnosis for pain exacerbation in a chronic opioid therapy (COT) patient/chronic pain patient.
2. Know where the opioids are going.
3. Sometimes stopping pills, rather than adding them, can cure pain.
4. Take time to educate patients about methadone and its risk of mortality if not used as prescribed.
5. A little local anesthetic (and some steroid) goes a long way.
6. Addiction to opioids is not rare.
7. Safely changing opioid regimens requires good math and good judgment.
8. For a low-risk chronic pain patient on low-dose opioids, don’t change the regimen, even if the indication for opioids isn’t clear.
9. If a patient has pain all the time, they need to be on a medication that works all the time.

The differential diagnosis for pain exacerbation in a chronic opioid therapy (COT) patient/chronic pain patient is:

1. Worsening medical problem;
2. New medical problem;
3. Nonopioid problem (side effect);
4. Opioid problem (resistance/tolerance/side effect); and
5. Opioid-induced hyperalgesia.

The search for an etiology and treatment for chronic pain should not end, even if a patient is labeled with “chronic pain syndrome.” The patient could simply be chronically undiagnosed or on an incorrect therapy.

Know where the opioids are going.

Whether it’s auditing a prescription-monitoring program (PMP), checking a urine drug screen, or calling a pharmacist, try to ensure that chronic pain patients are taking the opioids as prescribed. A phone call to the primary opioid prescriber or chronic pain provider could save a busy hospitalist a lot of time.

Using PMP data can consume a lot of time. Typically, only prescribing providers can access PMPs, so delegating this responsibility to someone else is not possible. If your state PMP does not help, simply call the patient’s pharmacy and ask for the last three fill dates on an opioid prescription. This also works well in case the patient’s pharmacy doesn’t participate in a PMP or is delayed in uploading recent prescriber data. Many COT patients have an opioid treatment agreement with their prescriber and must use only one pharmacy to fill opioids.

In January 2013, the University of North Carolina Injury Prevention Center published an analysis of three years of North Carolina PMP data.1 Patients followed by providers who consistently used the state PMP were five times more likely to receive treatment for opioid dependence compared with patients of providers who never used the state PMP.¹

Why go through all this trouble if a chronic pain specialist is also doing it? It’s good documentation and good care, like monitoring levels of transplant meds or making sure hemoglobin A1Cs are up to date and trending toward goal. It may only take one misused or diverted opioid pill to result in a serious adverse event.

Sometimes stopping pills, rather than adding them, can cure pain.

Many chronic pain patients accumulate a patchwork of pills (e.g. benzodiazepines, opioids, muscle relaxants, and antidepressants). Many interpret noxious symptoms associated with the drug burden as “uncontrolled pain.” Two conditions that might afflict the pain sufferer who takes multiple medications are opioid-induced hyperalgesia (OIH) and medication-overuse headaches (MOH). They are uncommon but should be on a hospitalist’s differential for difficult-to-control chronic pain. Opioids commonly are implicated in causing MOH, a chronic headache occurring at least 15 days a month, four hours a day if untreated, and for at least three consecutive months. OIH is a nociceptive sensitization caused by opioids that can occur suddenly or insidiously.

If a drug isn’t absolutely necessary, stop it. If you and the patient start by agreeing to the shared goal of improving health, the conversation should go better. An axiom we learned from mentors at the University of Washington is: “There is no pain that cannot be made worse with inappropriate therapy.”

Take time to educate patients about methadone and its risk of mortality if not used as prescribed.

Methadone is less frequently prescribed than other opioids, yet it is more frequently associated with death from overdose. Though there is a risk of overdose and death with any opioid, managing methadone is more difficult. A desperate chronic pain patient may self-escalate their methadone without proper insight into the consequences.

Remember the logarithmic relationship methadone doses have with their morphine equivalency. The following highlights how deceiving the numbers are: 50 mg of methadone is about 100 mg of morphine-equivalent, but 100 mg of methadone is about 1,000 mg of morphine-equivalent, or 10 times as strong.

From 1999 to 2005, methadone-related deaths increased by 468%.² If the patient doesn’t seem to understand these risks, they are not a good candidate for methadone treatment.

A little local anesthetic (and some steroid) goes a long way.

Hospitalists should offer an assortment of diagnostic and therapeutic injections to chronic pain patients. First, be sure you’ve done your due diligence:

• What procedures do you have privileges to do?
• Do you need to be proctored first?
• How do your local specialists feel about you doing injections?

In light of these considerations, hospitalists should be able to train and be credentialed to offer such procedures as trigger-point injections, joint injections (knees, shoulders), or even a peripheral nerve injection (e.g. lateral femoral cutaneous nerve or ilioinguinal nerve injection). Some hospitalists might even want to learn ultrasound-guided sacroiliac joint injections for chronic unexplained back pain.

Offering an indicated and effective injection is a good nonopioid option. And local anesthetic injections can help hospitalists establish an elusive diagnosis. For example, many patients spend years getting worked up for head and neck pain when dry-needling with a small volume (1 cc) of local anesthetic into a neck muscle trigger point can break their pain generator, eliminating their pain.

Addiction to opioids is not rare.

The use, misuse, and diversion of opioids and all the associated complications have appropriately received considerable media attention. A seminal paper by Porter and Jick titled “Addiction Is Rare in Patients Treated with Narcotics” is one of many tipping points associated with the boom in opioid prescribing.³ Whether it’s a three-day supply of hydrocodone, 24 hours on a PCA, or an opioid rotation, any exposure to opioids can put a patient on the runway to addiction.

There are only 3,071 board-certified addiction specialists certified by the American Board of Addiction Medicine, so access to an addiction specialist might be difficult.⁴

Nonetheless, do not become complacent and just continue the opioid therapy in a difficult opioid-addicted patient. Express your concerns to the primary opioid prescriber, or help patients who don’t have an opioid prescriber get access and treatment. Otherwise, you have no choice but to taper the opioids.

Ideally, chronic pain management should be delivered in the outpatient arena where long-term monitoring can take place.

Safely changing opioid regimens requires good math and good judgment.

During training and practice, hospitalists become accustomed to rapidly analyze objective data, such as ABGs, ECGs, anion gaps, and vent settings. A hospitalist should become similarly efficient at calculating morphine equivalencies (cautiously with methadone and fentanyl), making dose reductions, and rotating opioids. The more comfortable you are with morphine equivalencies, the faster and safer you will be at rotating opioids. Whatever morphine-equivalence table you feel comfortable with is the one you should use consistently.

We see many providers who unwittingly take, for example, a patient who has become resistant to hydrocodone/acetaminophen 10/325 mg PO TID (30 mg of morphine) and convert them to oxycodone/acetaminophen 10/325 mg PO QID (60 mg of morphine—a doubling), when doubling could cause respiratory depression or a faster path to addiction and dependency.

But there are cases in which judgment should trump math, such as when converting from an IV to an oral regimen. We frequently see patients in the clinic requesting refills for more than 100 mg of hydromorphone because “that’s what I was on when I was hospitalized and on the pump.” If the IV-to-oral conversion leaves you prescribing high doses of oral opioids, plan for a rapid taper and a smooth handoff to the outpatient setting.

One strategy to decrease an error in math and judgment is to use IV PCAs as infrequently as possible if a patient isn’t post-operative and they are able to take oral meds. And never hesitate to consult with your inpatient pharmacist or a chronic pain specialist.

For a low-risk chronic pain patient on low-dose opioids, don’t change the regimen, even if the indication for opioids isn’t clear.

Although it is tempting to become an opioid prohibitionist, if a patient has been taking an opioid for years and is functioning, working, compliant, and has no risk factors for complications from COT, it is likely fine to continue their current regimen. Touch base with the primary opioid prescriber, and if you’re concerned, use some of the monitoring instruments described earlier (PMP, urine drug screen, opioid treatment agreement, pill counts).

If a patient has pain all the time, they need to be on a medication that works all the time.

A good pain history followed by a good neurological and mental health assessment is of incalculable value, especially because physicians often underestimate a patient’s pain intensity and its impact on a patient’s quality of life.^5,6 A patient’s pain intensity, quality of life, and function can be dramatically improved by starting a long-acting medication for “constant pain.”

If a patient hurts “24 hours a day” and cannot function on hydrocodone/acetaminophen 10/325 QID, it’s probably because they are constantly reacting to spikes in pain and using a “some of the time” medicine to treat “all the time” pain. Switching to a long-acting medication—and it doesn’t have to be an opioid—could improve control and decrease how much narcotic the patient needs.

If you choose a long-acting opioid (in this case, you could try morphine sulphate extended-release 15 mg BID and satisfy 50% of the hydrocodone need), then you could titrate slowly upwards to where the patient would not need hydrocodone. If the patient still had uncontrolled pain, then either morphine is the wrong compound for them or they are benefiting from the “nonanalgesic properties” of the opioids.

Give the patient the benefit of the doubt; because of genetic polymorphisms, a patient may need several opioid rotations before the right opioid compound is found.

Dr. Schultz is a hospitalist and assistant professor in the department of internal medicine at the University of Miami Miller School of Medicine. She is board-certified in hospice and palliative care and specializes in chronic pain management. Dr. Ajam is a hospitalist and a clinical assistant professor in the department of anesthesiology at Wake Forest University Baptist Medical Center and the Carolinas Pain Institute. He is board-certified in chronic pain management.

References

1. Garrettson M, Ringwalt C. An evaluation of the North Carolina controlled substances reporting system: part II impact evaluation, January 2013. PDMP Center of Excellence website. Available at: http://pdmpexcellence.org/sites/all/pdfs/NC_control_sub_eval_pt_2.pdf. Accessed Sept. 3, 2013.
2. Kung HC, Hoyert DL, Xu JQ, Murphy SL. Deaths: Final data for 2005, national vital statistics reports; Vol. 56 No. 10. Hyattsville, Md.: National Center for Health Statistics; 2008.
3. Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med. 1980;302(2):123.
4. American Society of Addiction Medicine; personal communication, 2013.
5. Mäntyselkä P, Kumpusalo E, Ahonen R, Takala J. Patients’ versus general practitioners’ assessments of pain intensity in primary care patients with non-cancer pain. Br J Gen Pract. 2001;51(473):995-997.
6. Petersen MA, Larsen H, Pedersen L, Sonne N, Groenvold M. Assessing health-related quality of life in palliative care: comparing patient and physician assessments. Eur J Cancer. 2006;42(8):1159-1166.

In one recently publicized demonstration of data mining’s potential, Austin, Texas-based Seton Healthcare Family used software developed by IBM to pore over doctors’ notes and predict the risk of readmission among patients with congestive heart failure. Among the shortlist of biggest predictors, the analysis pointed to a lack of emotional support and a bulging jugular vein—factors that could be easily identified through inpatient screening but might otherwise be overlooked by staff.

Similarly, New York-Presbyterian Hospital used a system by Microsoft to help reduce the rates of blood clotting in patients through an objective analysis of such risk factors as cancer, smoking, and bed confinement.

In June, Deloitte and Utah-based Intermountain Healthcare announced the launch of OutcomesMiner, an analytics tool that uses electronic health records to ferret out important variations and associations among patient populations. Brett Davis, general manager of Deloitte Health Informatics, says understanding asthma patients who are in different age brackets, have different comorbidities, and are on different drugs, for example, can allow providers to better manage the population. Merely using ICD-9 codes often results in inaccurate patient classifications, he warns. Instead, capturing and analyzing data from medications and clinical encounters can be vital for properly defining an asthma patient and separating the signal from the noise.

In one recently publicized demonstration of data mining’s potential, Austin, Texas-based Seton Healthcare Family used software developed by IBM to pore over doctors’ notes and predict the risk of readmission among patients with congestive heart failure. Among the shortlist of biggest predictors, the analysis pointed to a lack of emotional support and a bulging jugular vein—factors that could be easily identified through inpatient screening but might otherwise be overlooked by staff.

Similarly, New York-Presbyterian Hospital used a system by Microsoft to help reduce the rates of blood clotting in patients through an objective analysis of such risk factors as cancer, smoking, and bed confinement.

In June, Deloitte and Utah-based Intermountain Healthcare announced the launch of OutcomesMiner, an analytics tool that uses electronic health records to ferret out important variations and associations among patient populations. Brett Davis, general manager of Deloitte Health Informatics, says understanding asthma patients who are in different age brackets, have different comorbidities, and are on different drugs, for example, can allow providers to better manage the population. Merely using ICD-9 codes often results in inaccurate patient classifications, he warns. Instead, capturing and analyzing data from medications and clinical encounters can be vital for properly defining an asthma patient and separating the signal from the noise.

In one recently publicized demonstration of data mining’s potential, Austin, Texas-based Seton Healthcare Family used software developed by IBM to pore over doctors’ notes and predict the risk of readmission among patients with congestive heart failure. Among the shortlist of biggest predictors, the analysis pointed to a lack of emotional support and a bulging jugular vein—factors that could be easily identified through inpatient screening but might otherwise be overlooked by staff.

Similarly, New York-Presbyterian Hospital used a system by Microsoft to help reduce the rates of blood clotting in patients through an objective analysis of such risk factors as cancer, smoking, and bed confinement.

In June, Deloitte and Utah-based Intermountain Healthcare announced the launch of OutcomesMiner, an analytics tool that uses electronic health records to ferret out important variations and associations among patient populations. Brett Davis, general manager of Deloitte Health Informatics, says understanding asthma patients who are in different age brackets, have different comorbidities, and are on different drugs, for example, can allow providers to better manage the population. Merely using ICD-9 codes often results in inaccurate patient classifications, he warns. Instead, capturing and analyzing data from medications and clinical encounters can be vital for properly defining an asthma patient and separating the signal from the noise.

One hospital wanted to reduce readmissions among patients with congestive heart failure. Another hoped to improve upon its sepsis mortality rates. A third sought to determine whether its doctors were providing cost-effective care for pneumonia patients. All of them adopted the same type of technology to help identify a solution.

As the healthcare industry tilts toward accountable care, pay for performance and an increasingly

cost-conscious mindset, hospitalists and other providers are tapping into a fast-growing analytical tool collectively known as data mining to help make sense of the growing mounds of information. Although no single technology can be considered a cure-all, HM leaders are so optimistic about data mining’s potential to address cost, outcome, and performance issues that some have labeled it a “game changer” for hospitalists.

Karim Godamunne, MD, MBA, SFHM, chief medical officer at North Fulton Hospital in Roswell, Ga., and a member of SHM’s Practice Management Committee, says he can’t overstate the importance of hospitalists’ involvement in physician data mining. “From my perspective, we’re looking to hospitalists to help drive this quality-utilization bandwagon, to be the real leaders in it,” he says. With the tremendous value that can be generated through understanding and using the information, “it’s good for your group and can be good to your hospital as a whole.”

So what is data mining? The technology fully emerged in the mid-1990s as a way to help scientists analyze large and often disparate bodies of data, present relevant information in new ways, and illuminate previously unknown relationships.¹ In the healthcare industry, early adopters realized that the insights gleaned from data mining could help inform their clinical decision-making; organizations used the new tools to help predict health insurance fraud and identify at-risk patients, for example.

Cynthia Burghard, research director of Accountable Care IT Strategies at IDC Health Insights in Framingham, Mass., says researchers in academic medical centers initially conducted most of the clinical analytical work. Within the past few years, however, the increasing availability of data has allowed more hospitals to begin analyzing chronic disease, readmissions, and other areas of concern. In addition, Burghard says, new tools based on natural language processing are giving hospitals better access to unstructured clinical data, such as notes written by doctors and nurses.

“What I’m seeing both in my surveys as well as in conversations with hospitals is that analytics is the top of the investment priority for both hospitals and health plans,” Burghard says. According to IDC estimates, total spending for clinical analytics in the U.S. reached $3.7 billion in 2012 and is expected to grow to $5.14 billion by 2016. Much of the growth, she notes, is being driven by healthcare reform. “If your mandate is to manage populations of patients, it behooves you to know who those patients are and what their illnesses are, and to monitor what you’re doing for them,” she says.

Practice Improvement

Accordingly, a major goal of all this data-mining technology is to change practice behavior in a way that achieves the triple aim of improving quality of care, controlling costs, and bettering patient outcomes.

A growing number of companies are releasing tools that can compile and analyze the separate bits of information captured from claims and billing systems, Medicare reporting requirements, internal benchmarks, and other sources. Unlike passive data sources, such as Medicare’s Hospital Compare website, more active analytics can help their users zoom down to the level of an individual doctor or patient, pan out to the level of a hospitalist group, or expand out even more for a broader comparison among peer institutions.

Some newer data-mining tools with names like CRIMSON, Truven, Iodine, and Imagine are billing themselves as hospitalist-friendly performance-improvement aids and giving individual providers the ability to access and analyze the data themselves. A few of these applications can even provide real-time data via mobile devices (see “Physician Performance Aids,”).

Thomas Frederickson, MD, MBA, SFHM, medical director of the HM service at Alegent Creighton Health in Omaha, Neb., and a member of SHM’s Practice Management Committee, sees the biggest potential of this data-mining technology in its ability to help drive practice consistency. “You can use the database to analyze practice patterns of large groups, or even individuals, and see where variability exists,” he says. “And then, based on that, you can analyze why the variability exists and begin to address whether it’s variability that’s clinically indicated or not.”

When Alegent Creighton Health was scrutinizing the care of its pneumonia patients, for example, officials could compare the number of chest X-rays per pneumonia patient by hospital or across the entire CRIMSON database. At a deeper level, the officials could see how often individual providers ordered the tests compared to their peers. For outliers, they could follow up to determine whether the variability was warranted.

As champions of process improvement, Dr. Frederickson says, hospitalists can make particularly good use of database analytics. “It’s part of the process of making hospitalists invaluable to their hospitals and their systems,” he says. “Part of that is building up expertise on process improvement and safety, and familiarity with these kinds of tools is one thing that will help us do that.”

North Fulton Hospital used CRIMSON to analyze how its doctors care for patients with sepsis and to establish new benchmarks. Dr. Godamunne says the tools allowed the hospital to track its doctors’ progress over time and identify potential problems. “If a patient with sepsis is staying too long, you can see who admitted the patient and see if, a few months ago, the same physician was having similar problems,” he says. Similarly, the hospital was able to track the top DRGs resulting in excess length of stay among patients, to identify potential bottlenecks in the care and discharge processes.

Some tools require only two-day training sessions for basic proficiency, though more advanced manipulations often require a bigger commitment, like the 12-week training session that Dr. Godamunne completed. That training included one hour of online learning and one hour of homework every week, and most of the cases highlighted during his coursework, he says, focused on hospitalists—another sign of the major role he believes HM will play in harnessing data to improve performance quality.

You can use the database to analyze practice patterns of large groups, or even individuals, and see where variability exists. And then, based on that, you can analyze why the variability exists and begin to address whether it’s variability that’s clinically indicated or not.

—Thomas Frederickson, MD, MBA, SFHM, medical director, hospital medicine service, Alegent Creighton Health, Omaha, Neb., SHM Practice Management Committee member

Slow—Construction Ahead

The best information is meaningful, individualized, and timely, says Steven Deitelzweig, MD, SFHM, system chairman for hospital medicine and medical director of regional business development at Ochsner Health System in New Orleans. “If you get something back six months after you’ve delivered the care, you’ll have a limited opportunity to improve, versus if you get it back in a week or two, or ideally, in real time,” says Dr. Deitelzweig, chair of SHM’s Practice Management Committee.

In examining length of stay, Dr. Deitelzweig says doctors could use data mining to look at time-stamped elements of patient flow and the timeliness of provider response: how patients go through the ED, and when they receive written orders or lab results. “It could be really powerful, and right now it’s a little bit of a black hole,” he says.

Based on her conversations with hospital executives and leaders, however, Burghard cautions that some real-time mobile applications, although technologically impressive, may be less useful or necessary in practice. “If it’s performance measurement, why do you need that in real time? It’s not going to change your behavior in the moment,” she says. “What you may want to get is an alert that your patient, who is in the hospital, has had some sort of negative event.”

Data mining has other potential limitations. “There’s always going to be questions of attribution, and you need to have clinical knowledge of your location,” Dr. Godamunne says. And data mining is only as good as the data that have been documented, underscoring the importance of securing provider cooperation.

Dr. Frederickson says physician acceptance, in fact, might be one of the biggest obstacles—a major reason why he recommends introducing the technology slowly and explaining why and how it will be used. If introduced too quickly and without adequate explanation about what a hospital or health system hopes to accomplish, he says, “there certainly is the potential for suspicion.” The key, he says, is to emphasize that the tools provide a valuable mechanism for gleaning new insights into doctors’ practice patterns, “not something that’s going to be used against them.”

Paul Roscoe, CEO of the Washington, D.C.-based Advisory Board Company's Crimson division, agrees that personally engaging physicians is essential for a good return on investment in analytical tools like his company’s suite of CRIMSON products. “If you can’t work with the physicians to get them to understand the data and actively use the data in their practice patterns, it becomes a bit meaningless,” he says.

We’re looking to hospitalists to help drive this quality utilization bandwagon, to be the real leaders in it.…It’s good for your group and can be good to your hospital as a whole.

—Karim Godamunne, MD, MBA, SFHM, chief medical officer, North Fulton Hospital, Roswell, Ga., SHM Practice Management Committee member

Roscoe sees big opportunities in prospectively examining information while a patient is still in the hospital and when a change of course by providers could avert a bad outcome. “Suggesting a set of interventions that they could do differently is really the value-add,” he says. But he cautions that those suggestions must be worded carefully to avoid alienating physicians.

“If doctors don’t feel like they’re being judged, they’ll engage with you,” Roscoe says.

Similar nuances can affect how users perceive the tools themselves. After hearing feedback from members that the words “data mining” didn’t conjure trust and confidence, the Advisory Board Company dropped the phrase altogether in favor of “data analytics,” “physician engagement,” and similar descriptors. “It’s simple things like that that can very quickly either turn a physician on or off,” Roscoe says.

Once users take the time to understand data-mining tools and how they can be properly harnessed, advocates say, the technology can lead to a host of unanticipated benefits. When a hospital bills the federal government for a Medicare patient, for example, it must submit an HCC code that describes the patient’s condition. By doing a better job of mining the data, Burghard says, a hospital can more accurately reflect that patient’s contdition. For example, if a hospital is treating a diabetic who comes in with a broken leg, the hospital could receive a lower payment rate if it does not properly identify and record both conditions.

And by using the tools prospectively, Burghard says, “I think there’s the opportunity to make a quantum leap from what we’re doing today. We usually just report on facts, and usually retrospectively. With some of the new technology that’s available, the healthcare industry can begin to do discovery analytics—you’re identifying insights, patterns, and relationships.”

Better integration of computerized physician order entry with data-mining ports, Dr. Godamunne predicts, will allow for much better attribution and finer parsing of the data. As the transparency increases, though, hospitalists will have to adapt to a new reality in which stronger analytical tools may point out individual outliers. And that level of detail, in turn, will require some hospitalists to justify why they’re different than their peers.

Even so, Roscoe says, he’s found that hospitalists are very open to using data to improve performance and that they make up a high percentage of CRIMSON users. “There isn’t a physician group that is in a better position to help drive this quality- and data-driven culture,” he says.

Bryn Nelson is a freelance medical writer in Seattle.

Physician Performance Aids

Company: The Advisory Board Company

Sample product: CRIMSON Continuum of Care

Claim: “Places credible, severity-adjusted performance profiles directly in the hands of physicians, enabling the hospital-physician collaboration needed to advance quality goals and secure cost savings.”

Number of users: More than 850 hospitals

Real-time data? No, but available as add-on service

To learn more: www.advisory.com/Technology/Crimson-Continuum-of-Care

Company: Panacea Developments

Sample product: Iodine

Claim: “An easy-to-use mobile system that analyzes a hospital’s sea of data for knowledge that physicians, case managers, and documentation specialists can act upon to improve length-of-stay, readmissions, and documentation.”

Number of users: More than 50 hospitals

Real-time data? Yes

To learn more: www.panaceadevelopments.com/iodine

Company: Truven Health

Sample product: CareDiscovery

Claim: “Provides powerful insights into a hospital’s or health system’s quality measures and resource utilization to support improvement with objective, fact-based information.”

Real-time data? No

Number of users: More than 3,000 users in 400 hospitals

To learn more: http://truvenhealth.com/products/carediscovery

Company: Ingenious Med

Sample product: Imagine

Claim: “A comprehensive analytics dashboard platform that provides actionable decision making data to optimize physician performance and revenue.”

Real-time data? Yes

Number of users: 25,000 total users (not separated by individual products)

To learn more: http://ingeniousmed.com/what-we-do/imagine

Reference

1. Yoo I, Alafaireet P, Marinov M, et al. Data mining in healthcare and biomedicine: a survey of the literature. J Med Syst. 2012;36:2431-2448.

One hospital wanted to reduce readmissions among patients with congestive heart failure. Another hoped to improve upon its sepsis mortality rates. A third sought to determine whether its doctors were providing cost-effective care for pneumonia patients. All of them adopted the same type of technology to help identify a solution.

As the healthcare industry tilts toward accountable care, pay for performance and an increasingly

cost-conscious mindset, hospitalists and other providers are tapping into a fast-growing analytical tool collectively known as data mining to help make sense of the growing mounds of information. Although no single technology can be considered a cure-all, HM leaders are so optimistic about data mining’s potential to address cost, outcome, and performance issues that some have labeled it a “game changer” for hospitalists.

Karim Godamunne, MD, MBA, SFHM, chief medical officer at North Fulton Hospital in Roswell, Ga., and a member of SHM’s Practice Management Committee, says he can’t overstate the importance of hospitalists’ involvement in physician data mining. “From my perspective, we’re looking to hospitalists to help drive this quality-utilization bandwagon, to be the real leaders in it,” he says. With the tremendous value that can be generated through understanding and using the information, “it’s good for your group and can be good to your hospital as a whole.”

So what is data mining? The technology fully emerged in the mid-1990s as a way to help scientists analyze large and often disparate bodies of data, present relevant information in new ways, and illuminate previously unknown relationships.¹ In the healthcare industry, early adopters realized that the insights gleaned from data mining could help inform their clinical decision-making; organizations used the new tools to help predict health insurance fraud and identify at-risk patients, for example.

Cynthia Burghard, research director of Accountable Care IT Strategies at IDC Health Insights in Framingham, Mass., says researchers in academic medical centers initially conducted most of the clinical analytical work. Within the past few years, however, the increasing availability of data has allowed more hospitals to begin analyzing chronic disease, readmissions, and other areas of concern. In addition, Burghard says, new tools based on natural language processing are giving hospitals better access to unstructured clinical data, such as notes written by doctors and nurses.

“What I’m seeing both in my surveys as well as in conversations with hospitals is that analytics is the top of the investment priority for both hospitals and health plans,” Burghard says. According to IDC estimates, total spending for clinical analytics in the U.S. reached $3.7 billion in 2012 and is expected to grow to $5.14 billion by 2016. Much of the growth, she notes, is being driven by healthcare reform. “If your mandate is to manage populations of patients, it behooves you to know who those patients are and what their illnesses are, and to monitor what you’re doing for them,” she says.

Practice Improvement

Accordingly, a major goal of all this data-mining technology is to change practice behavior in a way that achieves the triple aim of improving quality of care, controlling costs, and bettering patient outcomes.

A growing number of companies are releasing tools that can compile and analyze the separate bits of information captured from claims and billing systems, Medicare reporting requirements, internal benchmarks, and other sources. Unlike passive data sources, such as Medicare’s Hospital Compare website, more active analytics can help their users zoom down to the level of an individual doctor or patient, pan out to the level of a hospitalist group, or expand out even more for a broader comparison among peer institutions.

Some newer data-mining tools with names like CRIMSON, Truven, Iodine, and Imagine are billing themselves as hospitalist-friendly performance-improvement aids and giving individual providers the ability to access and analyze the data themselves. A few of these applications can even provide real-time data via mobile devices (see “Physician Performance Aids,”).

Thomas Frederickson, MD, MBA, SFHM, medical director of the HM service at Alegent Creighton Health in Omaha, Neb., and a member of SHM’s Practice Management Committee, sees the biggest potential of this data-mining technology in its ability to help drive practice consistency. “You can use the database to analyze practice patterns of large groups, or even individuals, and see where variability exists,” he says. “And then, based on that, you can analyze why the variability exists and begin to address whether it’s variability that’s clinically indicated or not.”

When Alegent Creighton Health was scrutinizing the care of its pneumonia patients, for example, officials could compare the number of chest X-rays per pneumonia patient by hospital or across the entire CRIMSON database. At a deeper level, the officials could see how often individual providers ordered the tests compared to their peers. For outliers, they could follow up to determine whether the variability was warranted.

As champions of process improvement, Dr. Frederickson says, hospitalists can make particularly good use of database analytics. “It’s part of the process of making hospitalists invaluable to their hospitals and their systems,” he says. “Part of that is building up expertise on process improvement and safety, and familiarity with these kinds of tools is one thing that will help us do that.”

North Fulton Hospital used CRIMSON to analyze how its doctors care for patients with sepsis and to establish new benchmarks. Dr. Godamunne says the tools allowed the hospital to track its doctors’ progress over time and identify potential problems. “If a patient with sepsis is staying too long, you can see who admitted the patient and see if, a few months ago, the same physician was having similar problems,” he says. Similarly, the hospital was able to track the top DRGs resulting in excess length of stay among patients, to identify potential bottlenecks in the care and discharge processes.

Some tools require only two-day training sessions for basic proficiency, though more advanced manipulations often require a bigger commitment, like the 12-week training session that Dr. Godamunne completed. That training included one hour of online learning and one hour of homework every week, and most of the cases highlighted during his coursework, he says, focused on hospitalists—another sign of the major role he believes HM will play in harnessing data to improve performance quality.

You can use the database to analyze practice patterns of large groups, or even individuals, and see where variability exists. And then, based on that, you can analyze why the variability exists and begin to address whether it’s variability that’s clinically indicated or not.

—Thomas Frederickson, MD, MBA, SFHM, medical director, hospital medicine service, Alegent Creighton Health, Omaha, Neb., SHM Practice Management Committee member

Slow—Construction Ahead

The best information is meaningful, individualized, and timely, says Steven Deitelzweig, MD, SFHM, system chairman for hospital medicine and medical director of regional business development at Ochsner Health System in New Orleans. “If you get something back six months after you’ve delivered the care, you’ll have a limited opportunity to improve, versus if you get it back in a week or two, or ideally, in real time,” says Dr. Deitelzweig, chair of SHM’s Practice Management Committee.

In examining length of stay, Dr. Deitelzweig says doctors could use data mining to look at time-stamped elements of patient flow and the timeliness of provider response: how patients go through the ED, and when they receive written orders or lab results. “It could be really powerful, and right now it’s a little bit of a black hole,” he says.

Based on her conversations with hospital executives and leaders, however, Burghard cautions that some real-time mobile applications, although technologically impressive, may be less useful or necessary in practice. “If it’s performance measurement, why do you need that in real time? It’s not going to change your behavior in the moment,” she says. “What you may want to get is an alert that your patient, who is in the hospital, has had some sort of negative event.”

Data mining has other potential limitations. “There’s always going to be questions of attribution, and you need to have clinical knowledge of your location,” Dr. Godamunne says. And data mining is only as good as the data that have been documented, underscoring the importance of securing provider cooperation.

Dr. Frederickson says physician acceptance, in fact, might be one of the biggest obstacles—a major reason why he recommends introducing the technology slowly and explaining why and how it will be used. If introduced too quickly and without adequate explanation about what a hospital or health system hopes to accomplish, he says, “there certainly is the potential for suspicion.” The key, he says, is to emphasize that the tools provide a valuable mechanism for gleaning new insights into doctors’ practice patterns, “not something that’s going to be used against them.”

Paul Roscoe, CEO of the Washington, D.C.-based Advisory Board Company's Crimson division, agrees that personally engaging physicians is essential for a good return on investment in analytical tools like his company’s suite of CRIMSON products. “If you can’t work with the physicians to get them to understand the data and actively use the data in their practice patterns, it becomes a bit meaningless,” he says.

We’re looking to hospitalists to help drive this quality utilization bandwagon, to be the real leaders in it.…It’s good for your group and can be good to your hospital as a whole.

—Karim Godamunne, MD, MBA, SFHM, chief medical officer, North Fulton Hospital, Roswell, Ga., SHM Practice Management Committee member

Roscoe sees big opportunities in prospectively examining information while a patient is still in the hospital and when a change of course by providers could avert a bad outcome. “Suggesting a set of interventions that they could do differently is really the value-add,” he says. But he cautions that those suggestions must be worded carefully to avoid alienating physicians.

“If doctors don’t feel like they’re being judged, they’ll engage with you,” Roscoe says.

Similar nuances can affect how users perceive the tools themselves. After hearing feedback from members that the words “data mining” didn’t conjure trust and confidence, the Advisory Board Company dropped the phrase altogether in favor of “data analytics,” “physician engagement,” and similar descriptors. “It’s simple things like that that can very quickly either turn a physician on or off,” Roscoe says.

Once users take the time to understand data-mining tools and how they can be properly harnessed, advocates say, the technology can lead to a host of unanticipated benefits. When a hospital bills the federal government for a Medicare patient, for example, it must submit an HCC code that describes the patient’s condition. By doing a better job of mining the data, Burghard says, a hospital can more accurately reflect that patient’s contdition. For example, if a hospital is treating a diabetic who comes in with a broken leg, the hospital could receive a lower payment rate if it does not properly identify and record both conditions.

And by using the tools prospectively, Burghard says, “I think there’s the opportunity to make a quantum leap from what we’re doing today. We usually just report on facts, and usually retrospectively. With some of the new technology that’s available, the healthcare industry can begin to do discovery analytics—you’re identifying insights, patterns, and relationships.”

Better integration of computerized physician order entry with data-mining ports, Dr. Godamunne predicts, will allow for much better attribution and finer parsing of the data. As the transparency increases, though, hospitalists will have to adapt to a new reality in which stronger analytical tools may point out individual outliers. And that level of detail, in turn, will require some hospitalists to justify why they’re different than their peers.

Even so, Roscoe says, he’s found that hospitalists are very open to using data to improve performance and that they make up a high percentage of CRIMSON users. “There isn’t a physician group that is in a better position to help drive this quality- and data-driven culture,” he says.

Bryn Nelson is a freelance medical writer in Seattle.

Physician Performance Aids

Company: The Advisory Board Company

Sample product: CRIMSON Continuum of Care

Claim: “Places credible, severity-adjusted performance profiles directly in the hands of physicians, enabling the hospital-physician collaboration needed to advance quality goals and secure cost savings.”

Number of users: More than 850 hospitals

Real-time data? No, but available as add-on service

To learn more: www.advisory.com/Technology/Crimson-Continuum-of-Care

Company: Panacea Developments

Sample product: Iodine

Claim: “An easy-to-use mobile system that analyzes a hospital’s sea of data for knowledge that physicians, case managers, and documentation specialists can act upon to improve length-of-stay, readmissions, and documentation.”

Number of users: More than 50 hospitals

Real-time data? Yes

To learn more: www.panaceadevelopments.com/iodine

Company: Truven Health

Sample product: CareDiscovery

Claim: “Provides powerful insights into a hospital’s or health system’s quality measures and resource utilization to support improvement with objective, fact-based information.”

Real-time data? No

Number of users: More than 3,000 users in 400 hospitals

To learn more: http://truvenhealth.com/products/carediscovery

Company: Ingenious Med

Sample product: Imagine

Claim: “A comprehensive analytics dashboard platform that provides actionable decision making data to optimize physician performance and revenue.”

Real-time data? Yes

Number of users: 25,000 total users (not separated by individual products)

To learn more: http://ingeniousmed.com/what-we-do/imagine

Reference

1. Yoo I, Alafaireet P, Marinov M, et al. Data mining in healthcare and biomedicine: a survey of the literature. J Med Syst. 2012;36:2431-2448.

One hospital wanted to reduce readmissions among patients with congestive heart failure. Another hoped to improve upon its sepsis mortality rates. A third sought to determine whether its doctors were providing cost-effective care for pneumonia patients. All of them adopted the same type of technology to help identify a solution.

As the healthcare industry tilts toward accountable care, pay for performance and an increasingly

cost-conscious mindset, hospitalists and other providers are tapping into a fast-growing analytical tool collectively known as data mining to help make sense of the growing mounds of information. Although no single technology can be considered a cure-all, HM leaders are so optimistic about data mining’s potential to address cost, outcome, and performance issues that some have labeled it a “game changer” for hospitalists.

Karim Godamunne, MD, MBA, SFHM, chief medical officer at North Fulton Hospital in Roswell, Ga., and a member of SHM’s Practice Management Committee, says he can’t overstate the importance of hospitalists’ involvement in physician data mining. “From my perspective, we’re looking to hospitalists to help drive this quality-utilization bandwagon, to be the real leaders in it,” he says. With the tremendous value that can be generated through understanding and using the information, “it’s good for your group and can be good to your hospital as a whole.”

So what is data mining? The technology fully emerged in the mid-1990s as a way to help scientists analyze large and often disparate bodies of data, present relevant information in new ways, and illuminate previously unknown relationships.¹ In the healthcare industry, early adopters realized that the insights gleaned from data mining could help inform their clinical decision-making; organizations used the new tools to help predict health insurance fraud and identify at-risk patients, for example.

Cynthia Burghard, research director of Accountable Care IT Strategies at IDC Health Insights in Framingham, Mass., says researchers in academic medical centers initially conducted most of the clinical analytical work. Within the past few years, however, the increasing availability of data has allowed more hospitals to begin analyzing chronic disease, readmissions, and other areas of concern. In addition, Burghard says, new tools based on natural language processing are giving hospitals better access to unstructured clinical data, such as notes written by doctors and nurses.

“What I’m seeing both in my surveys as well as in conversations with hospitals is that analytics is the top of the investment priority for both hospitals and health plans,” Burghard says. According to IDC estimates, total spending for clinical analytics in the U.S. reached $3.7 billion in 2012 and is expected to grow to $5.14 billion by 2016. Much of the growth, she notes, is being driven by healthcare reform. “If your mandate is to manage populations of patients, it behooves you to know who those patients are and what their illnesses are, and to monitor what you’re doing for them,” she says.

Practice Improvement

Accordingly, a major goal of all this data-mining technology is to change practice behavior in a way that achieves the triple aim of improving quality of care, controlling costs, and bettering patient outcomes.

A growing number of companies are releasing tools that can compile and analyze the separate bits of information captured from claims and billing systems, Medicare reporting requirements, internal benchmarks, and other sources. Unlike passive data sources, such as Medicare’s Hospital Compare website, more active analytics can help their users zoom down to the level of an individual doctor or patient, pan out to the level of a hospitalist group, or expand out even more for a broader comparison among peer institutions.

Some newer data-mining tools with names like CRIMSON, Truven, Iodine, and Imagine are billing themselves as hospitalist-friendly performance-improvement aids and giving individual providers the ability to access and analyze the data themselves. A few of these applications can even provide real-time data via mobile devices (see “Physician Performance Aids,”).

Thomas Frederickson, MD, MBA, SFHM, medical director of the HM service at Alegent Creighton Health in Omaha, Neb., and a member of SHM’s Practice Management Committee, sees the biggest potential of this data-mining technology in its ability to help drive practice consistency. “You can use the database to analyze practice patterns of large groups, or even individuals, and see where variability exists,” he says. “And then, based on that, you can analyze why the variability exists and begin to address whether it’s variability that’s clinically indicated or not.”

When Alegent Creighton Health was scrutinizing the care of its pneumonia patients, for example, officials could compare the number of chest X-rays per pneumonia patient by hospital or across the entire CRIMSON database. At a deeper level, the officials could see how often individual providers ordered the tests compared to their peers. For outliers, they could follow up to determine whether the variability was warranted.

As champions of process improvement, Dr. Frederickson says, hospitalists can make particularly good use of database analytics. “It’s part of the process of making hospitalists invaluable to their hospitals and their systems,” he says. “Part of that is building up expertise on process improvement and safety, and familiarity with these kinds of tools is one thing that will help us do that.”

North Fulton Hospital used CRIMSON to analyze how its doctors care for patients with sepsis and to establish new benchmarks. Dr. Godamunne says the tools allowed the hospital to track its doctors’ progress over time and identify potential problems. “If a patient with sepsis is staying too long, you can see who admitted the patient and see if, a few months ago, the same physician was having similar problems,” he says. Similarly, the hospital was able to track the top DRGs resulting in excess length of stay among patients, to identify potential bottlenecks in the care and discharge processes.

Some tools require only two-day training sessions for basic proficiency, though more advanced manipulations often require a bigger commitment, like the 12-week training session that Dr. Godamunne completed. That training included one hour of online learning and one hour of homework every week, and most of the cases highlighted during his coursework, he says, focused on hospitalists—another sign of the major role he believes HM will play in harnessing data to improve performance quality.

You can use the database to analyze practice patterns of large groups, or even individuals, and see where variability exists. And then, based on that, you can analyze why the variability exists and begin to address whether it’s variability that’s clinically indicated or not.

—Thomas Frederickson, MD, MBA, SFHM, medical director, hospital medicine service, Alegent Creighton Health, Omaha, Neb., SHM Practice Management Committee member

Slow—Construction Ahead

The best information is meaningful, individualized, and timely, says Steven Deitelzweig, MD, SFHM, system chairman for hospital medicine and medical director of regional business development at Ochsner Health System in New Orleans. “If you get something back six months after you’ve delivered the care, you’ll have a limited opportunity to improve, versus if you get it back in a week or two, or ideally, in real time,” says Dr. Deitelzweig, chair of SHM’s Practice Management Committee.

In examining length of stay, Dr. Deitelzweig says doctors could use data mining to look at time-stamped elements of patient flow and the timeliness of provider response: how patients go through the ED, and when they receive written orders or lab results. “It could be really powerful, and right now it’s a little bit of a black hole,” he says.

Based on her conversations with hospital executives and leaders, however, Burghard cautions that some real-time mobile applications, although technologically impressive, may be less useful or necessary in practice. “If it’s performance measurement, why do you need that in real time? It’s not going to change your behavior in the moment,” she says. “What you may want to get is an alert that your patient, who is in the hospital, has had some sort of negative event.”

Data mining has other potential limitations. “There’s always going to be questions of attribution, and you need to have clinical knowledge of your location,” Dr. Godamunne says. And data mining is only as good as the data that have been documented, underscoring the importance of securing provider cooperation.

Dr. Frederickson says physician acceptance, in fact, might be one of the biggest obstacles—a major reason why he recommends introducing the technology slowly and explaining why and how it will be used. If introduced too quickly and without adequate explanation about what a hospital or health system hopes to accomplish, he says, “there certainly is the potential for suspicion.” The key, he says, is to emphasize that the tools provide a valuable mechanism for gleaning new insights into doctors’ practice patterns, “not something that’s going to be used against them.”

Paul Roscoe, CEO of the Washington, D.C.-based Advisory Board Company's Crimson division, agrees that personally engaging physicians is essential for a good return on investment in analytical tools like his company’s suite of CRIMSON products. “If you can’t work with the physicians to get them to understand the data and actively use the data in their practice patterns, it becomes a bit meaningless,” he says.

We’re looking to hospitalists to help drive this quality utilization bandwagon, to be the real leaders in it.…It’s good for your group and can be good to your hospital as a whole.

—Karim Godamunne, MD, MBA, SFHM, chief medical officer, North Fulton Hospital, Roswell, Ga., SHM Practice Management Committee member

Roscoe sees big opportunities in prospectively examining information while a patient is still in the hospital and when a change of course by providers could avert a bad outcome. “Suggesting a set of interventions that they could do differently is really the value-add,” he says. But he cautions that those suggestions must be worded carefully to avoid alienating physicians.

“If doctors don’t feel like they’re being judged, they’ll engage with you,” Roscoe says.

Similar nuances can affect how users perceive the tools themselves. After hearing feedback from members that the words “data mining” didn’t conjure trust and confidence, the Advisory Board Company dropped the phrase altogether in favor of “data analytics,” “physician engagement,” and similar descriptors. “It’s simple things like that that can very quickly either turn a physician on or off,” Roscoe says.

Once users take the time to understand data-mining tools and how they can be properly harnessed, advocates say, the technology can lead to a host of unanticipated benefits. When a hospital bills the federal government for a Medicare patient, for example, it must submit an HCC code that describes the patient’s condition. By doing a better job of mining the data, Burghard says, a hospital can more accurately reflect that patient’s contdition. For example, if a hospital is treating a diabetic who comes in with a broken leg, the hospital could receive a lower payment rate if it does not properly identify and record both conditions.

And by using the tools prospectively, Burghard says, “I think there’s the opportunity to make a quantum leap from what we’re doing today. We usually just report on facts, and usually retrospectively. With some of the new technology that’s available, the healthcare industry can begin to do discovery analytics—you’re identifying insights, patterns, and relationships.”

Better integration of computerized physician order entry with data-mining ports, Dr. Godamunne predicts, will allow for much better attribution and finer parsing of the data. As the transparency increases, though, hospitalists will have to adapt to a new reality in which stronger analytical tools may point out individual outliers. And that level of detail, in turn, will require some hospitalists to justify why they’re different than their peers.

Even so, Roscoe says, he’s found that hospitalists are very open to using data to improve performance and that they make up a high percentage of CRIMSON users. “There isn’t a physician group that is in a better position to help drive this quality- and data-driven culture,” he says.

Bryn Nelson is a freelance medical writer in Seattle.

Physician Performance Aids

Company: The Advisory Board Company

Sample product: CRIMSON Continuum of Care

Claim: “Places credible, severity-adjusted performance profiles directly in the hands of physicians, enabling the hospital-physician collaboration needed to advance quality goals and secure cost savings.”

Number of users: More than 850 hospitals

Real-time data? No, but available as add-on service

To learn more: www.advisory.com/Technology/Crimson-Continuum-of-Care

Company: Panacea Developments

Sample product: Iodine

Claim: “An easy-to-use mobile system that analyzes a hospital’s sea of data for knowledge that physicians, case managers, and documentation specialists can act upon to improve length-of-stay, readmissions, and documentation.”

Number of users: More than 50 hospitals

Real-time data? Yes

To learn more: www.panaceadevelopments.com/iodine

Company: Truven Health

Sample product: CareDiscovery

Claim: “Provides powerful insights into a hospital’s or health system’s quality measures and resource utilization to support improvement with objective, fact-based information.”

Real-time data? No

Number of users: More than 3,000 users in 400 hospitals

To learn more: http://truvenhealth.com/products/carediscovery

Company: Ingenious Med

Sample product: Imagine

Claim: “A comprehensive analytics dashboard platform that provides actionable decision making data to optimize physician performance and revenue.”

Real-time data? Yes

Number of users: 25,000 total users (not separated by individual products)

To learn more: http://ingeniousmed.com/what-we-do/imagine

Reference

1. Yoo I, Alafaireet P, Marinov M, et al. Data mining in healthcare and biomedicine: a survey of the literature. J Med Syst. 2012;36:2431-2448.

For over a half a century, the vitamin K antagonists coumarin and warfarin have been the only anticoagulants available to prevent clot formation in a variety of cardiovascular clinical settings. They are now about to be replaced with direct thrombin and factor Xa inhibitors. Vitamin K antagonists have not only dominated anticoagulant therapy, they have created an entire industry within the cardiovascular domain for the monitoring and control of its dose administration.

The story began in 1933 when Karl Paul Link, Ph.D., working in a laboratory at the University of Wisconsin School of Agriculture, was asked to examine the blood of cows dying of hemorrhage thought to be due to the ingestion of spoiled sweet clover. After years of research, Link was able to isolate an anticoagulant from the clover feed, called dicumarol, and he initially patented it in 1941 as rat poison. The marketed drug was called warfarin, after the Wisconsin Agricultural Research Foundation (WARF). Based on that patent, billions of dollars were generated for future research at the WARF.

Warfarin began to be used in the 1950s by a number of clinical investigators to prevent pulmonary embolism in the setting of an acute myocardial infarction (Lancet 1954;266:92-5). At that time, 1 month of complete bed rest was standard therapy for an AMI, and thrombophlebitis together with pulmonary and systemic embolism were the main causes of mortality. When early ambulation became acceptable for AMI patients, warfarin use tapered off. As clinicians became more focused on the prevention of intravascular thrombus formation after prosthetic valve surgery, and to prevent thromboembolism in patients with atrial fibrillation, warfarin therapy became more widely used, and the definition of the therapeutic dose of warfarin became important.

It soon became evident that vitamin K antagonists had a very narrow therapeutic window, framed by excessive bleeding at high doses and inefficacy at lower dose. As a result, the need for closer dose monitoring became important, and this led to the establishment of anticoagulant clinics. However, even with the establishment of these clinics, it became obvious that the clinical status of patients and dietary variability played major roles in dosing. The need for frequent blood sampling and the logistics of dose management were frustrations for both the patient and physician for decades.

As the need for better anticoagulant therapy became evident, drugs were developed that had a wider therapeutic range and that could be administered orally without the need of blood monitoring. The development of direct-acting thrombin and factor Xa inhibitors have led to major advances in anticoagulant therapy, resulting in safer oral fixed-dose drugs with therapeutic efficacy comparable to or better than vitamin K antagonists. In addition, they appear to be free from the effects of dietary variation. The factor Xa inhibitors apixaban and rivaroxaban have been approved by the Food and Drug Administration for the prevention of systemic emboli in patients with atrial fibrillation. Rivaroxaban is also indicated for preventing and treating deep vein thrombosis and pulmonary embolism. The direct thrombin inhibitor dabigatran has also been approved for the prevention of thromboembolism in patients with atrial fibrillation. The only settings for which the new anticoagulants have not been approved are acute coronary syndrome and prevention of thromboembolism with prosthetic valves.

The development of new anticoagulants provides an opportunity to improve therapy and witness the retirement of a ponderous and complicated dosing program that has been inconvenient to both patients and doctors. The retirement of warfarin and the death of the anticoagulant clinic will be appreciated by all.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

For over a half a century, the vitamin K antagonists coumarin and warfarin have been the only anticoagulants available to prevent clot formation in a variety of cardiovascular clinical settings. They are now about to be replaced with direct thrombin and factor Xa inhibitors. Vitamin K antagonists have not only dominated anticoagulant therapy, they have created an entire industry within the cardiovascular domain for the monitoring and control of its dose administration.

The story began in 1933 when Karl Paul Link, Ph.D., working in a laboratory at the University of Wisconsin School of Agriculture, was asked to examine the blood of cows dying of hemorrhage thought to be due to the ingestion of spoiled sweet clover. After years of research, Link was able to isolate an anticoagulant from the clover feed, called dicumarol, and he initially patented it in 1941 as rat poison. The marketed drug was called warfarin, after the Wisconsin Agricultural Research Foundation (WARF). Based on that patent, billions of dollars were generated for future research at the WARF.

Warfarin began to be used in the 1950s by a number of clinical investigators to prevent pulmonary embolism in the setting of an acute myocardial infarction (Lancet 1954;266:92-5). At that time, 1 month of complete bed rest was standard therapy for an AMI, and thrombophlebitis together with pulmonary and systemic embolism were the main causes of mortality. When early ambulation became acceptable for AMI patients, warfarin use tapered off. As clinicians became more focused on the prevention of intravascular thrombus formation after prosthetic valve surgery, and to prevent thromboembolism in patients with atrial fibrillation, warfarin therapy became more widely used, and the definition of the therapeutic dose of warfarin became important.

It soon became evident that vitamin K antagonists had a very narrow therapeutic window, framed by excessive bleeding at high doses and inefficacy at lower dose. As a result, the need for closer dose monitoring became important, and this led to the establishment of anticoagulant clinics. However, even with the establishment of these clinics, it became obvious that the clinical status of patients and dietary variability played major roles in dosing. The need for frequent blood sampling and the logistics of dose management were frustrations for both the patient and physician for decades.

As the need for better anticoagulant therapy became evident, drugs were developed that had a wider therapeutic range and that could be administered orally without the need of blood monitoring. The development of direct-acting thrombin and factor Xa inhibitors have led to major advances in anticoagulant therapy, resulting in safer oral fixed-dose drugs with therapeutic efficacy comparable to or better than vitamin K antagonists. In addition, they appear to be free from the effects of dietary variation. The factor Xa inhibitors apixaban and rivaroxaban have been approved by the Food and Drug Administration for the prevention of systemic emboli in patients with atrial fibrillation. Rivaroxaban is also indicated for preventing and treating deep vein thrombosis and pulmonary embolism. The direct thrombin inhibitor dabigatran has also been approved for the prevention of thromboembolism in patients with atrial fibrillation. The only settings for which the new anticoagulants have not been approved are acute coronary syndrome and prevention of thromboembolism with prosthetic valves.

The development of new anticoagulants provides an opportunity to improve therapy and witness the retirement of a ponderous and complicated dosing program that has been inconvenient to both patients and doctors. The retirement of warfarin and the death of the anticoagulant clinic will be appreciated by all.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

For over a half a century, the vitamin K antagonists coumarin and warfarin have been the only anticoagulants available to prevent clot formation in a variety of cardiovascular clinical settings. They are now about to be replaced with direct thrombin and factor Xa inhibitors. Vitamin K antagonists have not only dominated anticoagulant therapy, they have created an entire industry within the cardiovascular domain for the monitoring and control of its dose administration.

The story began in 1933 when Karl Paul Link, Ph.D., working in a laboratory at the University of Wisconsin School of Agriculture, was asked to examine the blood of cows dying of hemorrhage thought to be due to the ingestion of spoiled sweet clover. After years of research, Link was able to isolate an anticoagulant from the clover feed, called dicumarol, and he initially patented it in 1941 as rat poison. The marketed drug was called warfarin, after the Wisconsin Agricultural Research Foundation (WARF). Based on that patent, billions of dollars were generated for future research at the WARF.

Warfarin began to be used in the 1950s by a number of clinical investigators to prevent pulmonary embolism in the setting of an acute myocardial infarction (Lancet 1954;266:92-5). At that time, 1 month of complete bed rest was standard therapy for an AMI, and thrombophlebitis together with pulmonary and systemic embolism were the main causes of mortality. When early ambulation became acceptable for AMI patients, warfarin use tapered off. As clinicians became more focused on the prevention of intravascular thrombus formation after prosthetic valve surgery, and to prevent thromboembolism in patients with atrial fibrillation, warfarin therapy became more widely used, and the definition of the therapeutic dose of warfarin became important.

It soon became evident that vitamin K antagonists had a very narrow therapeutic window, framed by excessive bleeding at high doses and inefficacy at lower dose. As a result, the need for closer dose monitoring became important, and this led to the establishment of anticoagulant clinics. However, even with the establishment of these clinics, it became obvious that the clinical status of patients and dietary variability played major roles in dosing. The need for frequent blood sampling and the logistics of dose management were frustrations for both the patient and physician for decades.

As the need for better anticoagulant therapy became evident, drugs were developed that had a wider therapeutic range and that could be administered orally without the need of blood monitoring. The development of direct-acting thrombin and factor Xa inhibitors have led to major advances in anticoagulant therapy, resulting in safer oral fixed-dose drugs with therapeutic efficacy comparable to or better than vitamin K antagonists. In addition, they appear to be free from the effects of dietary variation. The factor Xa inhibitors apixaban and rivaroxaban have been approved by the Food and Drug Administration for the prevention of systemic emboli in patients with atrial fibrillation. Rivaroxaban is also indicated for preventing and treating deep vein thrombosis and pulmonary embolism. The direct thrombin inhibitor dabigatran has also been approved for the prevention of thromboembolism in patients with atrial fibrillation. The only settings for which the new anticoagulants have not been approved are acute coronary syndrome and prevention of thromboembolism with prosthetic valves.

The development of new anticoagulants provides an opportunity to improve therapy and witness the retirement of a ponderous and complicated dosing program that has been inconvenient to both patients and doctors. The retirement of warfarin and the death of the anticoagulant clinic will be appreciated by all.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

Hepatocellular carcinoma (HCC) is a common cause of death worldwide. However, it can be detected early in high-risk individuals by using effective screening strategies, resulting in the ability to provide curative treatment.

Here, we review the risk factors for HCC, strategies for surveillance and diagnosis, and therapies that can be used.

EPIDEMIOLOGY

HCC is the most common primary malignancy of the liver. Overall, it is the fifth most common type of cancer in men and the seventh most common in women.¹

Cirrhosis is present in 80% to 90% of patients with HCC.

Male sex. The male-to-female ratio is from 2:1 to 4:1, depending on the region.² In the United States, the overall male-to-female ratio has been reported² as 2.4:1. In another report,³ the incidence rate of HCC per 100,000 person-years was 3.7 for men and 2.0 for women.

Reproduced from Altekruse SF, et al. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009; 27:1485–1491, with permission from the American Society of Clinical Oncology.

Geographic areas with a high incidence of HCC include sub-Saharan Africa and eastern Asia, whereas Canada and the United States are low-incidence areas. The difference has been because of a lower prevalence of hepatitis B virus infection in North America. However, recent data show a downward trend in incidence of HCC in eastern Asia and an upward trend in North America (Figure 1).^3,4

Viral hepatitis (ie, hepatitis B or hepatitis C) is the main risk factor for cirrhosis and HCC.

Diabetes mellitus can predispose to nonalcoholic steatohepatitis, which can subsequently progress to cirrhosis. Thus, it increases the risk of HCC.

Obesity increases the risk of death from liver cancer, with obese people (body mass index ≥ 30 kg/m²) having a higher HCC-related death rate than leaner individuals.⁵ And as obesity becomes more prevalent, the number of deaths from HCC could increase.

Other diseases that predispose to HCC include alcohol abuse, hereditary hemochromatosis, alpha-1-antitrypsin deficiency, and glycogen storage disease.

SURVEILLANCE OF PATIENTS AT RISK

Patients at high risk of developing liver cancer require frequent screening (Table 1).

Patients with cirrhosis. Sarasin et al⁶ calculated that surveillance is cost-effective and increases the odds of survival in patients with cirrhosis if the incidence of HCC exceeds 1.5% per year (which it does). In view of this finding, all patients with cirrhosis should be screened every 6 months, irrespective of the cause of the cirrhosis.

Hepatitis B carriers. Surveillance is also indicated in some hepatitis B carriers (Table 1), eg, those with a family history of HCC in a first-degree relative (an independent risk factor for developing the disease in this group).⁷ Also, Africans with hepatitis B tend to develop HCC early in life.⁸ Though it has been recommended that surveillance be started at a younger age in these patients,⁹ the age at which it should begin has not been clearly established. In addition, it is not clear if black people born outside Africa are at higher risk.

Benefit of surveillance

HCC surveillance has shown to lower the death rate. A randomized controlled trial in China compared screening (with abdominal ultrasonography and alpha-fetoprotein levels) vs no screening in patients with hepatitis B. It showed that screening led to a 37% decrease in the death rate.¹² Studies have also established that patients with early-stage HCC have a better survival rate than patients with more-advanced disease.^10,11 This survival benefit is largely explained by the availability of effective treatments for early-stage cancer, including liver transplantation. Therefore, early-stage asymptomatic patients diagnosed by a surveillance program should have a better survival rate than symptomatic patients.

The tests most often used in surveillance for HCC are serum alpha-fetoprotein levels and liver ultrasonography.

Serum alpha-fetoprotein levels by themselves have not been shown to be useful, whereas the combination of alpha-fetoprotein levels and ultrasonography has been shown to reduce the death rate when used for surveillance in a randomized trial.¹² A 2012 study reported that the combination of alpha-fetoprotein testing and ultrasonography had a higher sensitivity (90%) than ultrasonography alone (58%), but at the expense of a lower specificity.¹³

Alpha-fetoprotein has a low sensitivity (ie, 54%) for HCC.¹⁴ Tumor size is one of the factors limiting the sensitivity of alpha-fetoprotein, ¹⁴ and this would imply that this test may not be helpful in detecting HCC at an early stage. Alpha-fetoprotein L3, an isoform of alpha-fetoprotein, may be helpful in patients with alpha-fetoprotein levels in the intermediate range, and it is currently being studied.

Liver ultrasonography is operator-dependent, and it may not be as accurate in overweight or obese people.

Computed tomography (CT) and magnetic resonance imaging (MRI) are not recommended for surveillance. Serial CT poses risks of radiation-induced damage, contrast-related anaphylaxis, and renal failure, and MRI is not cost-effective and can also lead to gadolinium-induced nephrogenic systemic fibrosis in patients with renal failure.

Currently, the American Association for the Study of Liver Diseases⁹ recommends ultrasonography only, every 6 months, for surveillance for HCC. However, it may be premature to conclude that alpha-fetoprotein measurement is no longer required for surveillance, and if new data emerge that support its role, it may be reincorporated into the guidelines.

DIAGNOSING HEPATOCELLULAR CARCINOMA

Lesions larger than 1 cm on ultrasonography

The finding of a liver lesion larger than 1 cm on ultrasonography during surveillance warrants further testing.

Noninvasive testing with four-phase multidetector CT or dynamic contrast-enhanced MRI is the next step. Typical findings on either of these imaging studies are sufficient to make a diagnosis of HCC, as they have a high specificity and positive predictive value.¹⁵ Arterial hyperenhancement with a venous-phase or delayed-phase washout of contrast medium confirms the diagnosis  (Figure 2).⁹ If one of the two imaging studies is typical for HCC, liver biopsy is not needed.

Other imaging studies, including contrast-enhanced ultrasonography, have not been shown to be specific for this diagnosis.¹⁶

Liver biopsy is indicated in patients in whom the imaging findings are atypical for HCC.^9,17 Biopsy has very good sensitivity and specificity for cancer, but false-negative findings do occur.¹⁸ Therefore, a negative biopsy does not entirely exclude HCC. In this situation, patients should be followed by serial ultrasonography, and any further growth or change in character should be reevaluated.

Lesions smaller than 1 cm

For lesions smaller than 1 cm, the incidence of HCC is low, and currently available diagnostic tests are not reliable.^15,19 Lesions of this size should be followed by serial ultrasonography every 3 to 4 months until they either enlarge to greater than 1 cm or remain stable at 2 years.⁹ If they remain stable at the end of 2 years, regular surveillance ultrasonography once every 6 months can be continued.

CURATIVE AND PALLIATIVE THERAPIES

Therapies for HCC (Table 2) can be divided into two categories: curative and palliative.

Curative treatments include surgical resection, liver transplantation, and radiofrequency ablation. All other treatments are palliative, including transarterial chemoembolization and medical therapy with sorafenib.

The choice of treatment depends on the characteristics of the tumor, the degree of liver dysfunction, and the patient’s current level of function. The Barcelona Clinic Liver Cancer classification is widely used in making these decisions, as it incorporates both clinical features and tumor stage.⁹ Figure 3 shows a simplified management algorithm.

SURGICAL RESECTION

Surgical resection is the preferred treatment for patients who have a solitary HCC lesion without cirrhosis.⁹ It is also indicated in patients with well-compensated cirrhosis who have normal portal pressure, a normal serum bilirubin level, and a platelet count greater than 100 × 10⁹/L.^20,21 In such patients, the 5-year survival rate is about 74%, compared with 25% in patients with portal hypertension and serum bilirubin levels higher than 1 mg/dL.²¹

Surgical resection is not recommended for patients with decompensated cirrhosis, as it can worsen liver function postoperatively and increase the risk of death.^19,20 In Western countries, where cirrhosis from hepatitis C is the commonest cause of HCC, most patients have poorly preserved hepatic function at the time of diagnosis, leaving only a minority of patients as candidates for surgical resection.

After surgical resection of HCC, the recurrence rate can be as high as 70% to 80% at 5 years.22,23 Studies have consistently found larger tumor size and vascular invasion to be factors that predict recurrence.24,25 Vascular invasion was also found to predict poor survival after recurrence.24 Studies have so far not shown any conclusive benefit from post-surgical adjuvant chemotherapy in reducing the rate of recurrence of HCC.26,27

How to treat recurrent HCC after surgical resection has not been clearly established. Radiofrequency ablation, transarterial chemoembolization, repeat resection, and liver transplantation have all improved survival when used alone or in combination.²⁸ However, randomized controlled trials are needed to establish the effective treatment strategy and the benefit of multimodal treatment of recurrent HCC.

LIVER TRANSPLANTATION

Orthotopic liver transplantation is the preferred treatment for patients with HCC complicated by cirrhosis and portal hypertension. It has the advantage not only of being potentially curative, but also of overcoming liver cirrhosis by replacing the liver.

To qualify for liver transplantation, patients must meet the Milan criteria (ie, have a single nodule less than 5 cm in diameter or up to three nodules, with the largest being less than 3 cm in diameter, with no evidence of vascular invasion or distant metastasis). These patients have an expected 4-year survival rate of 85% and a recurrence-free survival rate of 92% after transplantation, compared with 50% and 59%, respectively, in patients whose tumors exceeded these criteria.²⁹

Some believe that the Milan criteria are too restrictive and could be expanded. Yao et al at the University of California-San Francisco³⁰ reported that patients with HCC meeting the criteria of having a solitary tumor smaller than 6.5 cm or having up to three nodules, with the largest smaller than 4.5 cm, and total tumor diameter less than 8 cm, had survival rates of 90% at 1 year and 75.2% at 5 years after liver transplantation, compared with 50% at 1 year for patients with tumors exceeding these limits. (These have come to be known as the UCSF criteria.) However, the United Network for Organ Sharing (UNOS) has not adopted these expanded criteria. UNOS has a point system for allocating livers for transplant called the Model for End-Stage Liver Disease (MELD). Patients who meet the Milan criteria receive extra points, putting them higher on the transplant list. This allows for early transplantation, thus reducing tumor progression and dropout from the transplant list. UNOS allocates a MELD score of 22 to all patients who meet the Milan criteria, and the score is further adjusted once every 3 months to reflect a 10% increase in the mortality rate. However, patients who have a single lesion smaller than 2 cm and are candidates for liver transplantation are not assigned additional MELD points per UNOS policy, as the risk of tumor progression beyond the Milan criteria in these patients is deemed to be low.

Therapies while awaiting transplantation

Even if they receive additional MELD points to give them priority on the waiting list, patients face a considerable wait before transplantation because of the limited availability of donor organs. In the interim, they have a risk of tumor progression beyond the Milan criteria and subsequent dropout from the transplant list.³¹ Patients on the waiting list may therefore undergo a locoregional therapy such as transarterial chemoembolization or radiofrequency ablation as bridging therapy.

These therapies have been shown to decrease dropout from the waiting list.³¹ A prospective study showed that in 48 patients who underwent transarterial chemoembolization while awaiting liver transplantation, none had tumor progression, and 41 did receive a transplant, with excellent posttransplantation survival rates.³² Similarly, radioembolization using yttrium-90-labeled microspheres or radiofrequency ablation while on the waiting list has been shown to significantly decrease the rate of dropout, with good posttransplantation outcomes.^33,34

However, in spite of these benefits, these bridging therapies do not increase survival rates after transplantation. It is also unclear whether they are useful in regions with short waiting times for liver transplantation.

Adjuvant systemic chemotherapy has not been shown to improve survival in patients undergoing liver transplantation. For example, in a randomized controlled trial of doxorubicin given before, during, and after surgery, the survival rate at 5 years was 38% with doxorubicin and 40% without.³⁵

ABLATIVE LOCOREGIONAL THERAPIES

Locoregional therapies play an important role in managing HCC. They are classified as ablative and perfusion-based.

Ablative locoregional therapies include chemical modalities such as percutaneous ethanol injection; thermal therapies such as radiofrequency ablation, microwave ablation, laser ablation, and cryotherapy; and newer methods such as irreversible electroporation and light-activated drug therapy. Of these, radiofrequency ablation is the most widely used.

Radiofrequency ablation

Radiofrequency ablation induces thermal injury, resulting in tumor necrosis. It can be used as an alternative to surgery in patients who have a single HCC lesion less than 3 to 5 cm in diameter, confined to the liver, and in a site amenable to this procedure and who have a reasonable coagulation profile. The procedure can be performed percutaneously or via laparoscopy.

Radiofrequency ablation is contraindicated in patients with decompensated cirrhosis, Child-Pugh class C cirrhosis (the most severe category), vascular or bile duct invasion, extrahepatic disease, or lesions that are not accessible or are adjacent to structures such as the gall bladder, bowel, stomach, or diaphragm.

Radiofrequency ablation has been compared with surgical resection in patients who had small tumors. Though a randomized controlled trial did not show any difference between the two treatment groups in terms of survival at 5 years and recurrence rates,³⁶ a meta-analysis showed that overall survival rates at 3 years and 5 years were significantly higher with surgical resection than with radiofrequency ablation.³⁷ Patients also had a higher rate of local recurrence with radiofrequency ablation than with surgical resection.³⁷ In addition, radiofrequency ablation has been shown to be effective only in small tumors and does not perform as well in lesions larger than 2 or 3 cm.

Thus, based on current evidence, surgical resection is preferable to radiofrequency ablation as first-line treatment. The latter, however, is also used as a bridging therapy in patients awaiting liver transplantation.

Percutaneous ethanol injection

Percutaneous ethanol injection is used less frequently than radiofrequency ablation, as studies have shown the latter to be superior in regard to local recurrence-free survival rates.³⁸ However, percutaneous ethanol injection is used instead of radiofrequency ablation in a small number of patients, when the lesion is very close to organs such as the bile duct (which could be damaged by radiofrequency ablation) or the large vessels (which may make radiofrequency ablation less effective, since heat may dissipate as a result of excessive blood flow in this region).

Microwave ablation

Microwave ablation is an emerging therapy for HCC. Its advantage over radiofrequency ablation is that its use is not limited by blood vessels in close proximity to the ablation site.

Earlier studies did not show microwave ablation to be superior to radiofrequency ablation.^39,40 However, current studies involving newer techniques of microwave ablation are more promising.⁴¹

PERFUSION-BASED LOCOREGIONAL THERAPIES

Perfusion-based locoregional therapies deliver embolic particles, chemotherapeutic agents, or radioactive materials into the artery feeding the tumor. The portal blood flow allows for preservation of vital liver tissue during arterial embolization of liver tumors. Perfusionbased therapies include transarterial chemoembolization, transarterial chemoembolization with doxorubicin-eluting beads (DEB-TACE), “bland” embolization, and radioembolization.

Transarterial chemoembolization

Transarterial chemoembolization is a minimally invasive procedure in which the hepatic artery is cannulated through a percutaneous puncture, the branches of the hepatic artery supplying the tumor are identified, and then embolic particles and chemotherapeutic agents are injected. This serves a dual purpose: it embolizes the feeding vessel that supplies the tumor, causing tumor necrosis, and it focuses the chemotherapy on the tumor and thus minimizes the systemic effects of the chemotherapeutic agent.

This therapy is contraindicated in patients with portal vein thrombosis, advanced liver dysfunction, or a transjugular intrahepatic portosystemic shunt. Side effects of the procedure include a postembolization syndrome of abdominal pain and fever (occurring in about 50% of patients from ischemic injury to the liver), hepatic abscesses, injury to the hepatic artery, development of ascites, liver dysfunction, and contrast-induced renal failure.

In addition to bridging patients to liver transplantation, transarterial chemoembolization is recommended as palliative treatment to prolong survival in patients with HCC who are not candidates for liver transplantation, surgical resection, or radiofrequency ablation.^9,42 Patients who have Child-Pugh grade A or B cirrhosis but do not have main portal vein thrombosis or extrahepatic spread are candidates for this therapy. Patients such as these who undergo this therapy have a better survival rate at 2 years compared with untreated patients.^43,44

Transarterial chemoembolization has also been used to reduce the size of (ie, to “downstage”) tumors that are outside the Milan criteria in patients who are otherwise candidates for liver transplantation. It induces tumor necrosis and has been shown to decrease the tumor size in a selected group of patients and to bring them within the Milan criteria, thus potentially enabling them to be put on the transplant list.⁴⁵ Studies have shown that patients who receive a transplant after successful down-staging may achieve a 5-year survival rate comparable with that of patients who were initially within the Milan criteria and received a transplant without the need for down-staging.⁴⁵ However, factors that predict successful down-staging have not been clearly established.

Newer techniques have been developed. A randomized controlled trial found transarterial chemoembolization with doxorubicin-eluting beads to be safer and better tolerated than conventional transarterial chemembolization.⁴⁶

Bland embolization is transarterial embolization without chemotherapeutic agents and is performed in patients with significant liver dysfunction who might not tolerate chemotherapy. The benefits of this approach are yet to be determined.

Radioembolization

Radioembolization with yttrium-90 microspheres has recently been introduced as an alternative to transarterial chemoembolization, especially in patients with portal vein thrombosis, a portocaval shunt, or a transjugular intrahepatic portosystemic shunt.

In observational studies, radioembolization was as effective as transarterial chemoembolization, with a similar survival benefit.⁴⁷ However, significant pulmonary shunting must be ruled out before radioembolization, as it would lead to radiation-induced pulmonary disease. Randomized controlled trials are under way to compare the efficacy of the two methods.

CHEMOTHERAPY

Sorafenib

Sorafenib is an oral antiangiogenic agent. A kinase inhibitor, it interacts with multiple intracellular and cell-surface kinases, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and Raf proto-oncogene, inhibiting tumor cell proliferation and angiogenesis.

Sorafenib has been shown to prolong survival in patients with advanced-stage HCC.⁴⁸ A randomized placebo-controlled trial in patients with Child-Pugh grade A cirrhosis and advanced HCC who had not received chemotherapy showed that sorafenib increased the life expectancy by nearly 3 months compared with placebo.⁴⁷ Sorafenib therapy is very expensive, but it is usually covered by insurance.

Sorafenib is recommended in patients who have advanced HCC with vascular invasion, extrahepatic dissemination, or minimal constitutional symptoms. It is not recommended for patients with severe advanced liver disease who have moderate to severe tumor-related constitutional symptoms or Child-Pugh grade C cirrhosis, or for patients with a life expectancy of less than 3 months.

The most common side effects of sorafenib are diarrhea, weight loss, and skin reactions on the hands and feet. These commonly lead to decreased tolerability and dose reductions.⁴⁷ Doses should be adjusted on the basis of the bilirubin and albumin levels.⁴⁹

Other chemotherapeutic agents

Several molecular targeted agents are undergoing clinical trials for the treatment of HCC. These include bevacizumab, erlotinib, brivanib, and ramucirumab. Chemotherapeutic agents such as doxorubicin and everolimus are also being studied.

PALLIATIVE TREATMENT

Patients with end-stage HCC with moderate to severe constitutional symptoms, extrahepatic disease progression, and decompensated liver disease have a survival of less than 3 months and are treated for pain and symptom control.⁹

Hepatocellular carcinoma (HCC) is a common cause of death worldwide. However, it can be detected early in high-risk individuals by using effective screening strategies, resulting in the ability to provide curative treatment.

Here, we review the risk factors for HCC, strategies for surveillance and diagnosis, and therapies that can be used.

EPIDEMIOLOGY

HCC is the most common primary malignancy of the liver. Overall, it is the fifth most common type of cancer in men and the seventh most common in women.¹

Cirrhosis is present in 80% to 90% of patients with HCC.

Male sex. The male-to-female ratio is from 2:1 to 4:1, depending on the region.² In the United States, the overall male-to-female ratio has been reported² as 2.4:1. In another report,³ the incidence rate of HCC per 100,000 person-years was 3.7 for men and 2.0 for women.

Reproduced from Altekruse SF, et al. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009; 27:1485–1491, with permission from the American Society of Clinical Oncology.

Geographic areas with a high incidence of HCC include sub-Saharan Africa and eastern Asia, whereas Canada and the United States are low-incidence areas. The difference has been because of a lower prevalence of hepatitis B virus infection in North America. However, recent data show a downward trend in incidence of HCC in eastern Asia and an upward trend in North America (Figure 1).^3,4

Viral hepatitis (ie, hepatitis B or hepatitis C) is the main risk factor for cirrhosis and HCC.

Diabetes mellitus can predispose to nonalcoholic steatohepatitis, which can subsequently progress to cirrhosis. Thus, it increases the risk of HCC.

Obesity increases the risk of death from liver cancer, with obese people (body mass index ≥ 30 kg/m²) having a higher HCC-related death rate than leaner individuals.⁵ And as obesity becomes more prevalent, the number of deaths from HCC could increase.

Other diseases that predispose to HCC include alcohol abuse, hereditary hemochromatosis, alpha-1-antitrypsin deficiency, and glycogen storage disease.

SURVEILLANCE OF PATIENTS AT RISK

Patients at high risk of developing liver cancer require frequent screening (Table 1).

Patients with cirrhosis. Sarasin et al⁶ calculated that surveillance is cost-effective and increases the odds of survival in patients with cirrhosis if the incidence of HCC exceeds 1.5% per year (which it does). In view of this finding, all patients with cirrhosis should be screened every 6 months, irrespective of the cause of the cirrhosis.

Hepatitis B carriers. Surveillance is also indicated in some hepatitis B carriers (Table 1), eg, those with a family history of HCC in a first-degree relative (an independent risk factor for developing the disease in this group).⁷ Also, Africans with hepatitis B tend to develop HCC early in life.⁸ Though it has been recommended that surveillance be started at a younger age in these patients,⁹ the age at which it should begin has not been clearly established. In addition, it is not clear if black people born outside Africa are at higher risk.

Benefit of surveillance

HCC surveillance has shown to lower the death rate. A randomized controlled trial in China compared screening (with abdominal ultrasonography and alpha-fetoprotein levels) vs no screening in patients with hepatitis B. It showed that screening led to a 37% decrease in the death rate.¹² Studies have also established that patients with early-stage HCC have a better survival rate than patients with more-advanced disease.^10,11 This survival benefit is largely explained by the availability of effective treatments for early-stage cancer, including liver transplantation. Therefore, early-stage asymptomatic patients diagnosed by a surveillance program should have a better survival rate than symptomatic patients.

The tests most often used in surveillance for HCC are serum alpha-fetoprotein levels and liver ultrasonography.

Serum alpha-fetoprotein levels by themselves have not been shown to be useful, whereas the combination of alpha-fetoprotein levels and ultrasonography has been shown to reduce the death rate when used for surveillance in a randomized trial.¹² A 2012 study reported that the combination of alpha-fetoprotein testing and ultrasonography had a higher sensitivity (90%) than ultrasonography alone (58%), but at the expense of a lower specificity.¹³

Alpha-fetoprotein has a low sensitivity (ie, 54%) for HCC.¹⁴ Tumor size is one of the factors limiting the sensitivity of alpha-fetoprotein, ¹⁴ and this would imply that this test may not be helpful in detecting HCC at an early stage. Alpha-fetoprotein L3, an isoform of alpha-fetoprotein, may be helpful in patients with alpha-fetoprotein levels in the intermediate range, and it is currently being studied.

Liver ultrasonography is operator-dependent, and it may not be as accurate in overweight or obese people.

Computed tomography (CT) and magnetic resonance imaging (MRI) are not recommended for surveillance. Serial CT poses risks of radiation-induced damage, contrast-related anaphylaxis, and renal failure, and MRI is not cost-effective and can also lead to gadolinium-induced nephrogenic systemic fibrosis in patients with renal failure.

Currently, the American Association for the Study of Liver Diseases⁹ recommends ultrasonography only, every 6 months, for surveillance for HCC. However, it may be premature to conclude that alpha-fetoprotein measurement is no longer required for surveillance, and if new data emerge that support its role, it may be reincorporated into the guidelines.

DIAGNOSING HEPATOCELLULAR CARCINOMA

Lesions larger than 1 cm on ultrasonography

The finding of a liver lesion larger than 1 cm on ultrasonography during surveillance warrants further testing.

Noninvasive testing with four-phase multidetector CT or dynamic contrast-enhanced MRI is the next step. Typical findings on either of these imaging studies are sufficient to make a diagnosis of HCC, as they have a high specificity and positive predictive value.¹⁵ Arterial hyperenhancement with a venous-phase or delayed-phase washout of contrast medium confirms the diagnosis  (Figure 2).⁹ If one of the two imaging studies is typical for HCC, liver biopsy is not needed.

Other imaging studies, including contrast-enhanced ultrasonography, have not been shown to be specific for this diagnosis.¹⁶

Liver biopsy is indicated in patients in whom the imaging findings are atypical for HCC.^9,17 Biopsy has very good sensitivity and specificity for cancer, but false-negative findings do occur.¹⁸ Therefore, a negative biopsy does not entirely exclude HCC. In this situation, patients should be followed by serial ultrasonography, and any further growth or change in character should be reevaluated.

Lesions smaller than 1 cm

For lesions smaller than 1 cm, the incidence of HCC is low, and currently available diagnostic tests are not reliable.^15,19 Lesions of this size should be followed by serial ultrasonography every 3 to 4 months until they either enlarge to greater than 1 cm or remain stable at 2 years.⁹ If they remain stable at the end of 2 years, regular surveillance ultrasonography once every 6 months can be continued.

CURATIVE AND PALLIATIVE THERAPIES

Therapies for HCC (Table 2) can be divided into two categories: curative and palliative.

Curative treatments include surgical resection, liver transplantation, and radiofrequency ablation. All other treatments are palliative, including transarterial chemoembolization and medical therapy with sorafenib.

The choice of treatment depends on the characteristics of the tumor, the degree of liver dysfunction, and the patient’s current level of function. The Barcelona Clinic Liver Cancer classification is widely used in making these decisions, as it incorporates both clinical features and tumor stage.⁹ Figure 3 shows a simplified management algorithm.

SURGICAL RESECTION

Surgical resection is the preferred treatment for patients who have a solitary HCC lesion without cirrhosis.⁹ It is also indicated in patients with well-compensated cirrhosis who have normal portal pressure, a normal serum bilirubin level, and a platelet count greater than 100 × 10⁹/L.^20,21 In such patients, the 5-year survival rate is about 74%, compared with 25% in patients with portal hypertension and serum bilirubin levels higher than 1 mg/dL.²¹

Surgical resection is not recommended for patients with decompensated cirrhosis, as it can worsen liver function postoperatively and increase the risk of death.^19,20 In Western countries, where cirrhosis from hepatitis C is the commonest cause of HCC, most patients have poorly preserved hepatic function at the time of diagnosis, leaving only a minority of patients as candidates for surgical resection.

After surgical resection of HCC, the recurrence rate can be as high as 70% to 80% at 5 years.22,23 Studies have consistently found larger tumor size and vascular invasion to be factors that predict recurrence.24,25 Vascular invasion was also found to predict poor survival after recurrence.24 Studies have so far not shown any conclusive benefit from post-surgical adjuvant chemotherapy in reducing the rate of recurrence of HCC.26,27

How to treat recurrent HCC after surgical resection has not been clearly established. Radiofrequency ablation, transarterial chemoembolization, repeat resection, and liver transplantation have all improved survival when used alone or in combination.²⁸ However, randomized controlled trials are needed to establish the effective treatment strategy and the benefit of multimodal treatment of recurrent HCC.

LIVER TRANSPLANTATION

Orthotopic liver transplantation is the preferred treatment for patients with HCC complicated by cirrhosis and portal hypertension. It has the advantage not only of being potentially curative, but also of overcoming liver cirrhosis by replacing the liver.

To qualify for liver transplantation, patients must meet the Milan criteria (ie, have a single nodule less than 5 cm in diameter or up to three nodules, with the largest being less than 3 cm in diameter, with no evidence of vascular invasion or distant metastasis). These patients have an expected 4-year survival rate of 85% and a recurrence-free survival rate of 92% after transplantation, compared with 50% and 59%, respectively, in patients whose tumors exceeded these criteria.²⁹

Some believe that the Milan criteria are too restrictive and could be expanded. Yao et al at the University of California-San Francisco³⁰ reported that patients with HCC meeting the criteria of having a solitary tumor smaller than 6.5 cm or having up to three nodules, with the largest smaller than 4.5 cm, and total tumor diameter less than 8 cm, had survival rates of 90% at 1 year and 75.2% at 5 years after liver transplantation, compared with 50% at 1 year for patients with tumors exceeding these limits. (These have come to be known as the UCSF criteria.) However, the United Network for Organ Sharing (UNOS) has not adopted these expanded criteria. UNOS has a point system for allocating livers for transplant called the Model for End-Stage Liver Disease (MELD). Patients who meet the Milan criteria receive extra points, putting them higher on the transplant list. This allows for early transplantation, thus reducing tumor progression and dropout from the transplant list. UNOS allocates a MELD score of 22 to all patients who meet the Milan criteria, and the score is further adjusted once every 3 months to reflect a 10% increase in the mortality rate. However, patients who have a single lesion smaller than 2 cm and are candidates for liver transplantation are not assigned additional MELD points per UNOS policy, as the risk of tumor progression beyond the Milan criteria in these patients is deemed to be low.

Therapies while awaiting transplantation

Even if they receive additional MELD points to give them priority on the waiting list, patients face a considerable wait before transplantation because of the limited availability of donor organs. In the interim, they have a risk of tumor progression beyond the Milan criteria and subsequent dropout from the transplant list.³¹ Patients on the waiting list may therefore undergo a locoregional therapy such as transarterial chemoembolization or radiofrequency ablation as bridging therapy.

These therapies have been shown to decrease dropout from the waiting list.³¹ A prospective study showed that in 48 patients who underwent transarterial chemoembolization while awaiting liver transplantation, none had tumor progression, and 41 did receive a transplant, with excellent posttransplantation survival rates.³² Similarly, radioembolization using yttrium-90-labeled microspheres or radiofrequency ablation while on the waiting list has been shown to significantly decrease the rate of dropout, with good posttransplantation outcomes.^33,34

However, in spite of these benefits, these bridging therapies do not increase survival rates after transplantation. It is also unclear whether they are useful in regions with short waiting times for liver transplantation.

Adjuvant systemic chemotherapy has not been shown to improve survival in patients undergoing liver transplantation. For example, in a randomized controlled trial of doxorubicin given before, during, and after surgery, the survival rate at 5 years was 38% with doxorubicin and 40% without.³⁵

ABLATIVE LOCOREGIONAL THERAPIES

Locoregional therapies play an important role in managing HCC. They are classified as ablative and perfusion-based.

Ablative locoregional therapies include chemical modalities such as percutaneous ethanol injection; thermal therapies such as radiofrequency ablation, microwave ablation, laser ablation, and cryotherapy; and newer methods such as irreversible electroporation and light-activated drug therapy. Of these, radiofrequency ablation is the most widely used.

Radiofrequency ablation

Radiofrequency ablation induces thermal injury, resulting in tumor necrosis. It can be used as an alternative to surgery in patients who have a single HCC lesion less than 3 to 5 cm in diameter, confined to the liver, and in a site amenable to this procedure and who have a reasonable coagulation profile. The procedure can be performed percutaneously or via laparoscopy.

Radiofrequency ablation is contraindicated in patients with decompensated cirrhosis, Child-Pugh class C cirrhosis (the most severe category), vascular or bile duct invasion, extrahepatic disease, or lesions that are not accessible or are adjacent to structures such as the gall bladder, bowel, stomach, or diaphragm.

Radiofrequency ablation has been compared with surgical resection in patients who had small tumors. Though a randomized controlled trial did not show any difference between the two treatment groups in terms of survival at 5 years and recurrence rates,³⁶ a meta-analysis showed that overall survival rates at 3 years and 5 years were significantly higher with surgical resection than with radiofrequency ablation.³⁷ Patients also had a higher rate of local recurrence with radiofrequency ablation than with surgical resection.³⁷ In addition, radiofrequency ablation has been shown to be effective only in small tumors and does not perform as well in lesions larger than 2 or 3 cm.

Thus, based on current evidence, surgical resection is preferable to radiofrequency ablation as first-line treatment. The latter, however, is also used as a bridging therapy in patients awaiting liver transplantation.

Percutaneous ethanol injection

Percutaneous ethanol injection is used less frequently than radiofrequency ablation, as studies have shown the latter to be superior in regard to local recurrence-free survival rates.³⁸ However, percutaneous ethanol injection is used instead of radiofrequency ablation in a small number of patients, when the lesion is very close to organs such as the bile duct (which could be damaged by radiofrequency ablation) or the large vessels (which may make radiofrequency ablation less effective, since heat may dissipate as a result of excessive blood flow in this region).

Microwave ablation

Microwave ablation is an emerging therapy for HCC. Its advantage over radiofrequency ablation is that its use is not limited by blood vessels in close proximity to the ablation site.

Earlier studies did not show microwave ablation to be superior to radiofrequency ablation.^39,40 However, current studies involving newer techniques of microwave ablation are more promising.⁴¹

PERFUSION-BASED LOCOREGIONAL THERAPIES

Perfusion-based locoregional therapies deliver embolic particles, chemotherapeutic agents, or radioactive materials into the artery feeding the tumor. The portal blood flow allows for preservation of vital liver tissue during arterial embolization of liver tumors. Perfusionbased therapies include transarterial chemoembolization, transarterial chemoembolization with doxorubicin-eluting beads (DEB-TACE), “bland” embolization, and radioembolization.

Transarterial chemoembolization

Transarterial chemoembolization is a minimally invasive procedure in which the hepatic artery is cannulated through a percutaneous puncture, the branches of the hepatic artery supplying the tumor are identified, and then embolic particles and chemotherapeutic agents are injected. This serves a dual purpose: it embolizes the feeding vessel that supplies the tumor, causing tumor necrosis, and it focuses the chemotherapy on the tumor and thus minimizes the systemic effects of the chemotherapeutic agent.

This therapy is contraindicated in patients with portal vein thrombosis, advanced liver dysfunction, or a transjugular intrahepatic portosystemic shunt. Side effects of the procedure include a postembolization syndrome of abdominal pain and fever (occurring in about 50% of patients from ischemic injury to the liver), hepatic abscesses, injury to the hepatic artery, development of ascites, liver dysfunction, and contrast-induced renal failure.

In addition to bridging patients to liver transplantation, transarterial chemoembolization is recommended as palliative treatment to prolong survival in patients with HCC who are not candidates for liver transplantation, surgical resection, or radiofrequency ablation.^9,42 Patients who have Child-Pugh grade A or B cirrhosis but do not have main portal vein thrombosis or extrahepatic spread are candidates for this therapy. Patients such as these who undergo this therapy have a better survival rate at 2 years compared with untreated patients.^43,44

Transarterial chemoembolization has also been used to reduce the size of (ie, to “downstage”) tumors that are outside the Milan criteria in patients who are otherwise candidates for liver transplantation. It induces tumor necrosis and has been shown to decrease the tumor size in a selected group of patients and to bring them within the Milan criteria, thus potentially enabling them to be put on the transplant list.⁴⁵ Studies have shown that patients who receive a transplant after successful down-staging may achieve a 5-year survival rate comparable with that of patients who were initially within the Milan criteria and received a transplant without the need for down-staging.⁴⁵ However, factors that predict successful down-staging have not been clearly established.

Newer techniques have been developed. A randomized controlled trial found transarterial chemoembolization with doxorubicin-eluting beads to be safer and better tolerated than conventional transarterial chemembolization.⁴⁶

Bland embolization is transarterial embolization without chemotherapeutic agents and is performed in patients with significant liver dysfunction who might not tolerate chemotherapy. The benefits of this approach are yet to be determined.

Radioembolization

Radioembolization with yttrium-90 microspheres has recently been introduced as an alternative to transarterial chemoembolization, especially in patients with portal vein thrombosis, a portocaval shunt, or a transjugular intrahepatic portosystemic shunt.

In observational studies, radioembolization was as effective as transarterial chemoembolization, with a similar survival benefit.⁴⁷ However, significant pulmonary shunting must be ruled out before radioembolization, as it would lead to radiation-induced pulmonary disease. Randomized controlled trials are under way to compare the efficacy of the two methods.

CHEMOTHERAPY

Sorafenib

Sorafenib is an oral antiangiogenic agent. A kinase inhibitor, it interacts with multiple intracellular and cell-surface kinases, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and Raf proto-oncogene, inhibiting tumor cell proliferation and angiogenesis.

Sorafenib has been shown to prolong survival in patients with advanced-stage HCC.⁴⁸ A randomized placebo-controlled trial in patients with Child-Pugh grade A cirrhosis and advanced HCC who had not received chemotherapy showed that sorafenib increased the life expectancy by nearly 3 months compared with placebo.⁴⁷ Sorafenib therapy is very expensive, but it is usually covered by insurance.

Sorafenib is recommended in patients who have advanced HCC with vascular invasion, extrahepatic dissemination, or minimal constitutional symptoms. It is not recommended for patients with severe advanced liver disease who have moderate to severe tumor-related constitutional symptoms or Child-Pugh grade C cirrhosis, or for patients with a life expectancy of less than 3 months.

The most common side effects of sorafenib are diarrhea, weight loss, and skin reactions on the hands and feet. These commonly lead to decreased tolerability and dose reductions.⁴⁷ Doses should be adjusted on the basis of the bilirubin and albumin levels.⁴⁹

Other chemotherapeutic agents

Several molecular targeted agents are undergoing clinical trials for the treatment of HCC. These include bevacizumab, erlotinib, brivanib, and ramucirumab. Chemotherapeutic agents such as doxorubicin and everolimus are also being studied.

PALLIATIVE TREATMENT

Patients with end-stage HCC with moderate to severe constitutional symptoms, extrahepatic disease progression, and decompensated liver disease have a survival of less than 3 months and are treated for pain and symptom control.⁹

Hepatocellular carcinoma (HCC) is a common cause of death worldwide. However, it can be detected early in high-risk individuals by using effective screening strategies, resulting in the ability to provide curative treatment.

Here, we review the risk factors for HCC, strategies for surveillance and diagnosis, and therapies that can be used.

EPIDEMIOLOGY

HCC is the most common primary malignancy of the liver. Overall, it is the fifth most common type of cancer in men and the seventh most common in women.¹

Cirrhosis is present in 80% to 90% of patients with HCC.

Male sex. The male-to-female ratio is from 2:1 to 4:1, depending on the region.² In the United States, the overall male-to-female ratio has been reported² as 2.4:1. In another report,³ the incidence rate of HCC per 100,000 person-years was 3.7 for men and 2.0 for women.

Reproduced from Altekruse SF, et al. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009; 27:1485–1491, with permission from the American Society of Clinical Oncology.

Geographic areas with a high incidence of HCC include sub-Saharan Africa and eastern Asia, whereas Canada and the United States are low-incidence areas. The difference has been because of a lower prevalence of hepatitis B virus infection in North America. However, recent data show a downward trend in incidence of HCC in eastern Asia and an upward trend in North America (Figure 1).^3,4

Viral hepatitis (ie, hepatitis B or hepatitis C) is the main risk factor for cirrhosis and HCC.

Diabetes mellitus can predispose to nonalcoholic steatohepatitis, which can subsequently progress to cirrhosis. Thus, it increases the risk of HCC.

Obesity increases the risk of death from liver cancer, with obese people (body mass index ≥ 30 kg/m²) having a higher HCC-related death rate than leaner individuals.⁵ And as obesity becomes more prevalent, the number of deaths from HCC could increase.

Other diseases that predispose to HCC include alcohol abuse, hereditary hemochromatosis, alpha-1-antitrypsin deficiency, and glycogen storage disease.

SURVEILLANCE OF PATIENTS AT RISK

Patients at high risk of developing liver cancer require frequent screening (Table 1).

Patients with cirrhosis. Sarasin et al⁶ calculated that surveillance is cost-effective and increases the odds of survival in patients with cirrhosis if the incidence of HCC exceeds 1.5% per year (which it does). In view of this finding, all patients with cirrhosis should be screened every 6 months, irrespective of the cause of the cirrhosis.

Hepatitis B carriers. Surveillance is also indicated in some hepatitis B carriers (Table 1), eg, those with a family history of HCC in a first-degree relative (an independent risk factor for developing the disease in this group).⁷ Also, Africans with hepatitis B tend to develop HCC early in life.⁸ Though it has been recommended that surveillance be started at a younger age in these patients,⁹ the age at which it should begin has not been clearly established. In addition, it is not clear if black people born outside Africa are at higher risk.

Benefit of surveillance

HCC surveillance has shown to lower the death rate. A randomized controlled trial in China compared screening (with abdominal ultrasonography and alpha-fetoprotein levels) vs no screening in patients with hepatitis B. It showed that screening led to a 37% decrease in the death rate.¹² Studies have also established that patients with early-stage HCC have a better survival rate than patients with more-advanced disease.^10,11 This survival benefit is largely explained by the availability of effective treatments for early-stage cancer, including liver transplantation. Therefore, early-stage asymptomatic patients diagnosed by a surveillance program should have a better survival rate than symptomatic patients.

The tests most often used in surveillance for HCC are serum alpha-fetoprotein levels and liver ultrasonography.

Serum alpha-fetoprotein levels by themselves have not been shown to be useful, whereas the combination of alpha-fetoprotein levels and ultrasonography has been shown to reduce the death rate when used for surveillance in a randomized trial.¹² A 2012 study reported that the combination of alpha-fetoprotein testing and ultrasonography had a higher sensitivity (90%) than ultrasonography alone (58%), but at the expense of a lower specificity.¹³

Alpha-fetoprotein has a low sensitivity (ie, 54%) for HCC.¹⁴ Tumor size is one of the factors limiting the sensitivity of alpha-fetoprotein, ¹⁴ and this would imply that this test may not be helpful in detecting HCC at an early stage. Alpha-fetoprotein L3, an isoform of alpha-fetoprotein, may be helpful in patients with alpha-fetoprotein levels in the intermediate range, and it is currently being studied.

Liver ultrasonography is operator-dependent, and it may not be as accurate in overweight or obese people.

Computed tomography (CT) and magnetic resonance imaging (MRI) are not recommended for surveillance. Serial CT poses risks of radiation-induced damage, contrast-related anaphylaxis, and renal failure, and MRI is not cost-effective and can also lead to gadolinium-induced nephrogenic systemic fibrosis in patients with renal failure.

Currently, the American Association for the Study of Liver Diseases⁹ recommends ultrasonography only, every 6 months, for surveillance for HCC. However, it may be premature to conclude that alpha-fetoprotein measurement is no longer required for surveillance, and if new data emerge that support its role, it may be reincorporated into the guidelines.

DIAGNOSING HEPATOCELLULAR CARCINOMA

Lesions larger than 1 cm on ultrasonography

The finding of a liver lesion larger than 1 cm on ultrasonography during surveillance warrants further testing.

Noninvasive testing with four-phase multidetector CT or dynamic contrast-enhanced MRI is the next step. Typical findings on either of these imaging studies are sufficient to make a diagnosis of HCC, as they have a high specificity and positive predictive value.¹⁵ Arterial hyperenhancement with a venous-phase or delayed-phase washout of contrast medium confirms the diagnosis  (Figure 2).⁹ If one of the two imaging studies is typical for HCC, liver biopsy is not needed.

Other imaging studies, including contrast-enhanced ultrasonography, have not been shown to be specific for this diagnosis.¹⁶

Liver biopsy is indicated in patients in whom the imaging findings are atypical for HCC.^9,17 Biopsy has very good sensitivity and specificity for cancer, but false-negative findings do occur.¹⁸ Therefore, a negative biopsy does not entirely exclude HCC. In this situation, patients should be followed by serial ultrasonography, and any further growth or change in character should be reevaluated.

Lesions smaller than 1 cm

For lesions smaller than 1 cm, the incidence of HCC is low, and currently available diagnostic tests are not reliable.^15,19 Lesions of this size should be followed by serial ultrasonography every 3 to 4 months until they either enlarge to greater than 1 cm or remain stable at 2 years.⁹ If they remain stable at the end of 2 years, regular surveillance ultrasonography once every 6 months can be continued.

CURATIVE AND PALLIATIVE THERAPIES

Therapies for HCC (Table 2) can be divided into two categories: curative and palliative.

Curative treatments include surgical resection, liver transplantation, and radiofrequency ablation. All other treatments are palliative, including transarterial chemoembolization and medical therapy with sorafenib.

The choice of treatment depends on the characteristics of the tumor, the degree of liver dysfunction, and the patient’s current level of function. The Barcelona Clinic Liver Cancer classification is widely used in making these decisions, as it incorporates both clinical features and tumor stage.⁹ Figure 3 shows a simplified management algorithm.

SURGICAL RESECTION

Surgical resection is the preferred treatment for patients who have a solitary HCC lesion without cirrhosis.⁹ It is also indicated in patients with well-compensated cirrhosis who have normal portal pressure, a normal serum bilirubin level, and a platelet count greater than 100 × 10⁹/L.^20,21 In such patients, the 5-year survival rate is about 74%, compared with 25% in patients with portal hypertension and serum bilirubin levels higher than 1 mg/dL.²¹

Surgical resection is not recommended for patients with decompensated cirrhosis, as it can worsen liver function postoperatively and increase the risk of death.^19,20 In Western countries, where cirrhosis from hepatitis C is the commonest cause of HCC, most patients have poorly preserved hepatic function at the time of diagnosis, leaving only a minority of patients as candidates for surgical resection.

After surgical resection of HCC, the recurrence rate can be as high as 70% to 80% at 5 years.22,23 Studies have consistently found larger tumor size and vascular invasion to be factors that predict recurrence.24,25 Vascular invasion was also found to predict poor survival after recurrence.24 Studies have so far not shown any conclusive benefit from post-surgical adjuvant chemotherapy in reducing the rate of recurrence of HCC.26,27

How to treat recurrent HCC after surgical resection has not been clearly established. Radiofrequency ablation, transarterial chemoembolization, repeat resection, and liver transplantation have all improved survival when used alone or in combination.²⁸ However, randomized controlled trials are needed to establish the effective treatment strategy and the benefit of multimodal treatment of recurrent HCC.

LIVER TRANSPLANTATION

Orthotopic liver transplantation is the preferred treatment for patients with HCC complicated by cirrhosis and portal hypertension. It has the advantage not only of being potentially curative, but also of overcoming liver cirrhosis by replacing the liver.

To qualify for liver transplantation, patients must meet the Milan criteria (ie, have a single nodule less than 5 cm in diameter or up to three nodules, with the largest being less than 3 cm in diameter, with no evidence of vascular invasion or distant metastasis). These patients have an expected 4-year survival rate of 85% and a recurrence-free survival rate of 92% after transplantation, compared with 50% and 59%, respectively, in patients whose tumors exceeded these criteria.²⁹

Some believe that the Milan criteria are too restrictive and could be expanded. Yao et al at the University of California-San Francisco³⁰ reported that patients with HCC meeting the criteria of having a solitary tumor smaller than 6.5 cm or having up to three nodules, with the largest smaller than 4.5 cm, and total tumor diameter less than 8 cm, had survival rates of 90% at 1 year and 75.2% at 5 years after liver transplantation, compared with 50% at 1 year for patients with tumors exceeding these limits. (These have come to be known as the UCSF criteria.) However, the United Network for Organ Sharing (UNOS) has not adopted these expanded criteria. UNOS has a point system for allocating livers for transplant called the Model for End-Stage Liver Disease (MELD). Patients who meet the Milan criteria receive extra points, putting them higher on the transplant list. This allows for early transplantation, thus reducing tumor progression and dropout from the transplant list. UNOS allocates a MELD score of 22 to all patients who meet the Milan criteria, and the score is further adjusted once every 3 months to reflect a 10% increase in the mortality rate. However, patients who have a single lesion smaller than 2 cm and are candidates for liver transplantation are not assigned additional MELD points per UNOS policy, as the risk of tumor progression beyond the Milan criteria in these patients is deemed to be low.

Therapies while awaiting transplantation

Even if they receive additional MELD points to give them priority on the waiting list, patients face a considerable wait before transplantation because of the limited availability of donor organs. In the interim, they have a risk of tumor progression beyond the Milan criteria and subsequent dropout from the transplant list.³¹ Patients on the waiting list may therefore undergo a locoregional therapy such as transarterial chemoembolization or radiofrequency ablation as bridging therapy.

These therapies have been shown to decrease dropout from the waiting list.³¹ A prospective study showed that in 48 patients who underwent transarterial chemoembolization while awaiting liver transplantation, none had tumor progression, and 41 did receive a transplant, with excellent posttransplantation survival rates.³² Similarly, radioembolization using yttrium-90-labeled microspheres or radiofrequency ablation while on the waiting list has been shown to significantly decrease the rate of dropout, with good posttransplantation outcomes.^33,34

However, in spite of these benefits, these bridging therapies do not increase survival rates after transplantation. It is also unclear whether they are useful in regions with short waiting times for liver transplantation.

Adjuvant systemic chemotherapy has not been shown to improve survival in patients undergoing liver transplantation. For example, in a randomized controlled trial of doxorubicin given before, during, and after surgery, the survival rate at 5 years was 38% with doxorubicin and 40% without.³⁵

ABLATIVE LOCOREGIONAL THERAPIES

Locoregional therapies play an important role in managing HCC. They are classified as ablative and perfusion-based.

Ablative locoregional therapies include chemical modalities such as percutaneous ethanol injection; thermal therapies such as radiofrequency ablation, microwave ablation, laser ablation, and cryotherapy; and newer methods such as irreversible electroporation and light-activated drug therapy. Of these, radiofrequency ablation is the most widely used.

Radiofrequency ablation

Radiofrequency ablation induces thermal injury, resulting in tumor necrosis. It can be used as an alternative to surgery in patients who have a single HCC lesion less than 3 to 5 cm in diameter, confined to the liver, and in a site amenable to this procedure and who have a reasonable coagulation profile. The procedure can be performed percutaneously or via laparoscopy.

Radiofrequency ablation is contraindicated in patients with decompensated cirrhosis, Child-Pugh class C cirrhosis (the most severe category), vascular or bile duct invasion, extrahepatic disease, or lesions that are not accessible or are adjacent to structures such as the gall bladder, bowel, stomach, or diaphragm.

Radiofrequency ablation has been compared with surgical resection in patients who had small tumors. Though a randomized controlled trial did not show any difference between the two treatment groups in terms of survival at 5 years and recurrence rates,³⁶ a meta-analysis showed that overall survival rates at 3 years and 5 years were significantly higher with surgical resection than with radiofrequency ablation.³⁷ Patients also had a higher rate of local recurrence with radiofrequency ablation than with surgical resection.³⁷ In addition, radiofrequency ablation has been shown to be effective only in small tumors and does not perform as well in lesions larger than 2 or 3 cm.

Thus, based on current evidence, surgical resection is preferable to radiofrequency ablation as first-line treatment. The latter, however, is also used as a bridging therapy in patients awaiting liver transplantation.

Percutaneous ethanol injection

Percutaneous ethanol injection is used less frequently than radiofrequency ablation, as studies have shown the latter to be superior in regard to local recurrence-free survival rates.³⁸ However, percutaneous ethanol injection is used instead of radiofrequency ablation in a small number of patients, when the lesion is very close to organs such as the bile duct (which could be damaged by radiofrequency ablation) or the large vessels (which may make radiofrequency ablation less effective, since heat may dissipate as a result of excessive blood flow in this region).

Microwave ablation

Microwave ablation is an emerging therapy for HCC. Its advantage over radiofrequency ablation is that its use is not limited by blood vessels in close proximity to the ablation site.

Earlier studies did not show microwave ablation to be superior to radiofrequency ablation.^39,40 However, current studies involving newer techniques of microwave ablation are more promising.⁴¹

PERFUSION-BASED LOCOREGIONAL THERAPIES

Perfusion-based locoregional therapies deliver embolic particles, chemotherapeutic agents, or radioactive materials into the artery feeding the tumor. The portal blood flow allows for preservation of vital liver tissue during arterial embolization of liver tumors. Perfusionbased therapies include transarterial chemoembolization, transarterial chemoembolization with doxorubicin-eluting beads (DEB-TACE), “bland” embolization, and radioembolization.

Transarterial chemoembolization

Transarterial chemoembolization is a minimally invasive procedure in which the hepatic artery is cannulated through a percutaneous puncture, the branches of the hepatic artery supplying the tumor are identified, and then embolic particles and chemotherapeutic agents are injected. This serves a dual purpose: it embolizes the feeding vessel that supplies the tumor, causing tumor necrosis, and it focuses the chemotherapy on the tumor and thus minimizes the systemic effects of the chemotherapeutic agent.

This therapy is contraindicated in patients with portal vein thrombosis, advanced liver dysfunction, or a transjugular intrahepatic portosystemic shunt. Side effects of the procedure include a postembolization syndrome of abdominal pain and fever (occurring in about 50% of patients from ischemic injury to the liver), hepatic abscesses, injury to the hepatic artery, development of ascites, liver dysfunction, and contrast-induced renal failure.

In addition to bridging patients to liver transplantation, transarterial chemoembolization is recommended as palliative treatment to prolong survival in patients with HCC who are not candidates for liver transplantation, surgical resection, or radiofrequency ablation.^9,42 Patients who have Child-Pugh grade A or B cirrhosis but do not have main portal vein thrombosis or extrahepatic spread are candidates for this therapy. Patients such as these who undergo this therapy have a better survival rate at 2 years compared with untreated patients.^43,44

Transarterial chemoembolization has also been used to reduce the size of (ie, to “downstage”) tumors that are outside the Milan criteria in patients who are otherwise candidates for liver transplantation. It induces tumor necrosis and has been shown to decrease the tumor size in a selected group of patients and to bring them within the Milan criteria, thus potentially enabling them to be put on the transplant list.⁴⁵ Studies have shown that patients who receive a transplant after successful down-staging may achieve a 5-year survival rate comparable with that of patients who were initially within the Milan criteria and received a transplant without the need for down-staging.⁴⁵ However, factors that predict successful down-staging have not been clearly established.

Newer techniques have been developed. A randomized controlled trial found transarterial chemoembolization with doxorubicin-eluting beads to be safer and better tolerated than conventional transarterial chemembolization.⁴⁶

Bland embolization is transarterial embolization without chemotherapeutic agents and is performed in patients with significant liver dysfunction who might not tolerate chemotherapy. The benefits of this approach are yet to be determined.

Radioembolization

Radioembolization with yttrium-90 microspheres has recently been introduced as an alternative to transarterial chemoembolization, especially in patients with portal vein thrombosis, a portocaval shunt, or a transjugular intrahepatic portosystemic shunt.

In observational studies, radioembolization was as effective as transarterial chemoembolization, with a similar survival benefit.⁴⁷ However, significant pulmonary shunting must be ruled out before radioembolization, as it would lead to radiation-induced pulmonary disease. Randomized controlled trials are under way to compare the efficacy of the two methods.

CHEMOTHERAPY

Sorafenib

Sorafenib is an oral antiangiogenic agent. A kinase inhibitor, it interacts with multiple intracellular and cell-surface kinases, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and Raf proto-oncogene, inhibiting tumor cell proliferation and angiogenesis.

Sorafenib has been shown to prolong survival in patients with advanced-stage HCC.⁴⁸ A randomized placebo-controlled trial in patients with Child-Pugh grade A cirrhosis and advanced HCC who had not received chemotherapy showed that sorafenib increased the life expectancy by nearly 3 months compared with placebo.⁴⁷ Sorafenib therapy is very expensive, but it is usually covered by insurance.

Sorafenib is recommended in patients who have advanced HCC with vascular invasion, extrahepatic dissemination, or minimal constitutional symptoms. It is not recommended for patients with severe advanced liver disease who have moderate to severe tumor-related constitutional symptoms or Child-Pugh grade C cirrhosis, or for patients with a life expectancy of less than 3 months.

The most common side effects of sorafenib are diarrhea, weight loss, and skin reactions on the hands and feet. These commonly lead to decreased tolerability and dose reductions.⁴⁷ Doses should be adjusted on the basis of the bilirubin and albumin levels.⁴⁹

Other chemotherapeutic agents

Several molecular targeted agents are undergoing clinical trials for the treatment of HCC. These include bevacizumab, erlotinib, brivanib, and ramucirumab. Chemotherapeutic agents such as doxorubicin and everolimus are also being studied.

PALLIATIVE TREATMENT

Patients with end-stage HCC with moderate to severe constitutional symptoms, extrahepatic disease progression, and decompensated liver disease have a survival of less than 3 months and are treated for pain and symptom control.⁹

In this age of technological marvels, it is easy to become so reliant on them as to neglect the value of bedside physical signs. Yet these signs provide information that adds no cost, is immediately available, and can be repeated at will.

Few physical findings are as useful but as undervalued as is the estimation of the jugular venous pressure. Unfortunately, many practitioners at many levels of seniority and experience do not measure it correctly, leading to a vicious circle of unreliable information, lack of confidence, and underuse. Another reason for its underuse is that the jugular venous pressure does not correlate precisely with the right atrial pressure, as we will see below.

In this review, we will attempt to clarify physiologic principles and describe technical details. Much of this is simple but, as always, the devil is in the details.

ANATOMIC CONSIDERATIONS

Think of the systemic veins as a soft-walled and mildly distensible reservoir with fingerlike projections, analogous to a partially fluidfilled surgical glove.¹ In a semi-upright position, the venous system is partially filled with blood and is collapsed above the level that this blood reaches up to.

Blood is constantly flowing in and out of this reservoir, flowing in by venous return and flowing out by the pumping action of the right side of the heart. The volume in the venous reservoir and hence the pressure are normally maintained by the variability of right ventricular stroke volume in accordance with the Frank-Starling law. Excess volume and pressure indicate failure of this homeostatic mechanism.

The internal jugular veins, being continuous with the superior vena cava, provide a visible measure of the degree to which the systemic venous reservoir is filled, a manometer that reflects the pressure in the right atrium—at least in theory.² Thus, the vertical height above the right atrium to which they are distended and above which they are in a collapsed state should reflect the right atrial pressure.

(In fact, the jugular venous pressure may underestimate the right atrial pressure, for reasons still not understood. This will be discussed below.)

In a healthy person, the visible jugular veins are fully collapsed when the person is standing and are often distended to a variable degree when the person is supine. Selecting an appropriate intermediate position permits the top of the column (the meniscus) to become visible in the neck between the clavicle and the mandible.

DISCREPANCY BETWEEN JUGULAR VENOUS AND RIGHT ATRIAL PRESSURE

Several reports have indicated that the jugular venous pressure may underestimate the right atrial pressure. Deol et al³ confirmed this, while establishing an excellent correlation between the level of venous collapse (observed on ultrasonography) and the jugular venous pressure. The difference between the right atrial pressure and the jugular venous pressure tended to be greater at higher venous pressures.³

Most people have a valve near the termination of the internal jugular vein, with variable competence. Inhibition of reflux of blood from the superior vena cava into the internal jugular vein by this valve is the most plausible cause of this disparity.⁴

The failure of the jugular venous pressure to correlate with the right atrial pressure has been cited by some as a reason to doubt the value of a sign that cardiologists have long relied on. How do we reconcile this apparent paradox? Careful review of the literature that has demonstrated this lack of correlation reveals the following:

• When unequal, the jugular venous pressure always underestimates the right atrial pressure.
• The lack of correlation is less evident at lower venous pressures.

This indicates the following:

• In the presence of congestive heart failure, the right atrial pressure is at least as high and perhaps higher than the jugular venous pressure. Hence, if the jugular venous pressure is high, further treatment, especially diuresis, is needed.
• A jugular venous pressure of zero implies a euvolemic state.

Thus, the jugular venous pressure provides excellent guidance when administering diuresis in congestive heart failure. These deductions obviously require the clinical judgment that the elevated right atrial pressure and jugular venous pressure do indeed reflect elevation of pulmonary capillary wedge pressure rather than other conditions discussed later in this article.

WHICH REFERENCE POINT TO USE?

The two points that can be used as references above which the jugular venous pressure is expressed are the center of the right atrium and the sternal angle. While the former may reflect physiology, the latter is preferred, as it is always visible and has the added advantage of being close to the upper limit of normal, which is about 3 cm above this level.

The difference in height between these two reference points has often been quoted as 5 cm, but this is an underestimate in the body positions used in examination.⁵ Seth et al⁶ found a mean of 8 cm at 30° elevation, 9.7 cm at 45°, and 9.8 cm at 60°. The difference also varied between patients, being larger in association with smoking, older age, large body mass index, and large anterior-posterior diameter. These factors should be considered when trying to evaluate the significance of a particular jugular venous pressure.

The junction of the midaxillary line and the fourth left intercostal space (“the phlebostatic point”) has been recommended as a reference point by some, as it is level with the mid-right atrium. However, using the phlebostatic point as a reference position is cumbersome and results in a valid measurement only with the patient in the supine position.⁷

TECHNIQUE IS VITAL

Close adherence to technical details is vital in reliably and reproducibly measuring the pressure in the internal jugular veins (Figure 1).

The right side is usually observed first, as it is the side on which the examiner usually stands. Using the right side also avoids the rare occurrence of external compression of the left brachiocephalic vein.

Head and shoulders

The sternocleidomastoid muscle lies anterior to each internal jugular vein.⁸ When tense, it impedes good observation. Shortening, and hence relaxing, this muscle permits the meniscus to be observed. Correct positioning is achieved by:

• Placing a folded pillow behind the patient’s head
• Keeping the shoulders on the mattress
• Turning the head away and elevating the jaw, both slightly; this is often best achieved by gentle pressure of the palm of the observer's hand on the patient's forehead.

Degree of head elevation

Although the proper degree of head elevation is sometimes said to be between 30° and 60°, these numbers are approximate. The correct angle is that which brings the venous meniscus into the window of visibility in the neck between the clavicle and mandible.

Lighting

Shining a flashlight tangentially to the skin is often helpful, casting shadows that improve the visibility of vein motion. Dimming the room lighting may further enhance this effect. Directing a light perpendicular to the skin is not helpful.

Also check the external jugular vein

Checking the external jugular vein can help establish that the jugular venous pressure is normal. If the vein is initially collapsed, light finger pressure at the base of the neck will distend it. If the distention rapidly clears after release of this pressure, the jugular venous pressure is not elevated. However, if external jugular venous distention persists, this does not prove true jugular venous pressure elevation, since it may reflect external compression of the vein by the cervical fascia or delayed blood flow caused by sclerotic venous valves.⁹ In these instances, the internal jugular pulsation level must be sought.

Jugular venous collapse with inspiration

Collapse of the inferior vena cava with forced inspiration is routinely evaluated during echocardiography as a way to estimate right atrial pressure. This finding has been extrapolated to the jugular veins, wherein the absence of venous collapse during vigorous inspiration or sniffing indicates elevated central venous pressures.¹⁰

Distinguishing venous from arterial pulsation

Features indicating venous rather than arterial pulsation were listed by Wood more than 50 years ago¹¹ and are still relevant today. These include internal jugular pulsation that:

• Is soft, diffuse, undulant
• Is not palpable
• Has two crests and two troughs per cardiac cycle
• Has crests that do not coincide with the palpated carotid pulse (exceptions may be seen with the systolic timing of the v wave of tricuspid regurgitation)
• Has higher pressure in expiration, lower in inspiration (exceptions may be seen when Kussmaul physiology is present)
• Has pressure that rises with abdominal pressure
• Is obliterated by light pressure at the base of the neck.

In addition to the above criteria, a wave whose movement is predominantly a descent is nearly always venous.

Abdominojugular reflex

Firm, steady pressure over the abdomen will often result in a small rise in jugular venous pressure. In healthy people, this normalizes in a few seconds, even while manual pressure is maintained. Persistence of jugular venous pressure elevation beyond 10 seconds, followed by an abrupt fall upon withdrawal of manual pressure, is abnormal. This finding has implications similar to those of an elevated baseline jugular venous pressure.

SIGNIFICANCE OF JUGULAR VENOUS PRESSURE ELEVATION

Elevated jugular venous pressure is a manifestation of abnormal right heart dynamics, mostly commonly reflecting elevated pulmonary capillary wedge pressure from left heart failure.¹² This usually implies fluid overload, indicating the need for diuresis.

Exceptions to this therapeutic implication include the presence of a primary right heart condition, pericardial disease, certain arrhythmias, and conditions that elevate intrathoracic pressure. These will be discussed below. One important example is the acute jugular venous pressure elevation seen in right ventricular infarction, in which the high venous pressure is compensatory and its reduction can produce hypotension and shock.¹³

Primary right heart conditions also include right-sided valvular disease, cor pulmonale (including pulmonary embolism and pulmonary hypertension), and the compressive effect of pericardial tamponade or constriction. A normal or near-normal jugular venous pressure significantly decreases the likelihood of significant constriction or of tamponade of a degree necessitating urgent pericardiocentesis.¹⁴

SPECIAL CIRCUMSTANCES

Presence of an intravenous line in the neck

An intravenous line in the neck will often prevent observation of the jugular venous pressure. A simple measure can often compensate for this. If the venous line can be temporarily disconnected, the central venous pressure can be measured directly. Using sterile technique, the line can be flushed with saline and aspirated to bring blood into the transparent tubing. Leaving the proximal end open to the air, and alternately raising and lowering it to confirm free flow, the level to which the blood rises can be easily observed. Observing small cardiac and respiratory variations of the meniscus confirms free communication with the central veins. Attaching the line to a transducer is another option, but this may be time-consuming, and establishing an accurate zero point is often difficult.

The previously described discrepancy between jugular venous pressure and central venous pressure has to be considered when drawing conclusions from this measurement.

Intrathoracic pressure elevators

Positive pressure ventilation will elevate intrathoracic pressure (including right atrial pressure) and hence the jugular venous pressure, making interpretation difficult.¹⁵ Large pleural effusions or pneumothorax may have a similar effect.¹⁶

Superior vena cava syndrome

Markedly elevated jugular venous pressure is here associated with absent or very diminished pulsation, as the caval obstruction has eliminated free communication with the right atrium.¹⁷ Associated facial plethora and edema, papilledema, and superficial venous distention over the chest wall will often confirm this diagnosis.

THE WAVEFORM

While the main purpose of viewing the neck veins is to establish the mean pressure, useful information can often be obtained by assessing the waveform. Abnormalities reflect arrhythmias, right heart hemodynamics, or pericardial disease.¹⁸ Changes may be subtle and difficult to detect, but some patterns can be quite readily appreciated (Figure 2). A limited selection follows.

Arrhythmias

Cannon a waves. These intermittent sharp positive deflections in the venous pulse represent right atrial contraction against a closed tricuspid valve. They are most commonly associated with premature ventricular complexes, but they occur in other conditions in which atrial and ventricular beating are dissociated, including complete heart block, atrioventricular dissociation, and electronic ventricular pacing.^19–21

Repetitive cannon waves. These may be seen with atrioventricular junctional tachycardia or ventricular tachycardia with 1:1 retrograde ventriculoatrial conduction in which the tricuspid valve is closed to every atrial beat.

Fine rapid regular pulsation may be seen in atrial flutter and may be a useful clue in distinguishing this from sinus rhythm when there is 4:1 atrioventricular conduction and a normal ventricular rate.

Abnormal right heart hemodynamics

Large v waves (Lancisi sign). These surges, replacing the usual x descent in systole, are seen in tricuspid insufficiency when the right atrium and its venous attachments are not protected from the right ventricular systolic pressure.²² High right ventricular pressure will obviously enhance this systolic surge.

Large a waves. These reflect resistance to right atrial outflow and may be seen when right ventricular compliance is reduced by hypertrophy from chronic pressure overload or in tricuspid stenosis.²³

Pericardial disease

Kussmaul sign is the paradoxical increase in jugular venous pressure with inspiration, observed in conditions associated with limited filling of the right ventricle. It is typically associated with constrictive pericarditis, although it occurs in only a minority of people with this condition.²⁴ It may also be seen in restrictive cardiomyopathy, massive pulmonary embolism, right ventricular infarction, and tricuspid stenosis.²⁵

Diaphragmatic descent during inspiration increases intra-abdominal pressure and decreases intrathoracic pressure. The resulting increased gradient between the abdomen and thorax enhances venous return from splanchnic vessels, which in the setting of a noncompliant right ventricle may result in increased right atrial (and, hence, jugular venous) pressure.²⁶

It is important to point out that the Kussmaul sign does not occur with cardiac tamponade in the absence of associated pericardial constriction.

Exaggerated y descent is typically seen in pericardial constriction, in which the high pressure of the v wave falls rapidly at the onset of diastole, given initial minimal right ventricular resistance. Flow is abruptly stopped when the intrapericardial space is filled.

In this age of technological marvels, it is easy to become so reliant on them as to neglect the value of bedside physical signs. Yet these signs provide information that adds no cost, is immediately available, and can be repeated at will.

Few physical findings are as useful but as undervalued as is the estimation of the jugular venous pressure. Unfortunately, many practitioners at many levels of seniority and experience do not measure it correctly, leading to a vicious circle of unreliable information, lack of confidence, and underuse. Another reason for its underuse is that the jugular venous pressure does not correlate precisely with the right atrial pressure, as we will see below.

In this review, we will attempt to clarify physiologic principles and describe technical details. Much of this is simple but, as always, the devil is in the details.

ANATOMIC CONSIDERATIONS

Think of the systemic veins as a soft-walled and mildly distensible reservoir with fingerlike projections, analogous to a partially fluidfilled surgical glove.¹ In a semi-upright position, the venous system is partially filled with blood and is collapsed above the level that this blood reaches up to.

Blood is constantly flowing in and out of this reservoir, flowing in by venous return and flowing out by the pumping action of the right side of the heart. The volume in the venous reservoir and hence the pressure are normally maintained by the variability of right ventricular stroke volume in accordance with the Frank-Starling law. Excess volume and pressure indicate failure of this homeostatic mechanism.

The internal jugular veins, being continuous with the superior vena cava, provide a visible measure of the degree to which the systemic venous reservoir is filled, a manometer that reflects the pressure in the right atrium—at least in theory.² Thus, the vertical height above the right atrium to which they are distended and above which they are in a collapsed state should reflect the right atrial pressure.

(In fact, the jugular venous pressure may underestimate the right atrial pressure, for reasons still not understood. This will be discussed below.)

In a healthy person, the visible jugular veins are fully collapsed when the person is standing and are often distended to a variable degree when the person is supine. Selecting an appropriate intermediate position permits the top of the column (the meniscus) to become visible in the neck between the clavicle and the mandible.

DISCREPANCY BETWEEN JUGULAR VENOUS AND RIGHT ATRIAL PRESSURE

Several reports have indicated that the jugular venous pressure may underestimate the right atrial pressure. Deol et al³ confirmed this, while establishing an excellent correlation between the level of venous collapse (observed on ultrasonography) and the jugular venous pressure. The difference between the right atrial pressure and the jugular venous pressure tended to be greater at higher venous pressures.³

Most people have a valve near the termination of the internal jugular vein, with variable competence. Inhibition of reflux of blood from the superior vena cava into the internal jugular vein by this valve is the most plausible cause of this disparity.⁴

The failure of the jugular venous pressure to correlate with the right atrial pressure has been cited by some as a reason to doubt the value of a sign that cardiologists have long relied on. How do we reconcile this apparent paradox? Careful review of the literature that has demonstrated this lack of correlation reveals the following:

• When unequal, the jugular venous pressure always underestimates the right atrial pressure.
• The lack of correlation is less evident at lower venous pressures.

This indicates the following:

• In the presence of congestive heart failure, the right atrial pressure is at least as high and perhaps higher than the jugular venous pressure. Hence, if the jugular venous pressure is high, further treatment, especially diuresis, is needed.
• A jugular venous pressure of zero implies a euvolemic state.

Thus, the jugular venous pressure provides excellent guidance when administering diuresis in congestive heart failure. These deductions obviously require the clinical judgment that the elevated right atrial pressure and jugular venous pressure do indeed reflect elevation of pulmonary capillary wedge pressure rather than other conditions discussed later in this article.

WHICH REFERENCE POINT TO USE?

The two points that can be used as references above which the jugular venous pressure is expressed are the center of the right atrium and the sternal angle. While the former may reflect physiology, the latter is preferred, as it is always visible and has the added advantage of being close to the upper limit of normal, which is about 3 cm above this level.

The difference in height between these two reference points has often been quoted as 5 cm, but this is an underestimate in the body positions used in examination.⁵ Seth et al⁶ found a mean of 8 cm at 30° elevation, 9.7 cm at 45°, and 9.8 cm at 60°. The difference also varied between patients, being larger in association with smoking, older age, large body mass index, and large anterior-posterior diameter. These factors should be considered when trying to evaluate the significance of a particular jugular venous pressure.

The junction of the midaxillary line and the fourth left intercostal space (“the phlebostatic point”) has been recommended as a reference point by some, as it is level with the mid-right atrium. However, using the phlebostatic point as a reference position is cumbersome and results in a valid measurement only with the patient in the supine position.⁷

TECHNIQUE IS VITAL

Close adherence to technical details is vital in reliably and reproducibly measuring the pressure in the internal jugular veins (Figure 1).

The right side is usually observed first, as it is the side on which the examiner usually stands. Using the right side also avoids the rare occurrence of external compression of the left brachiocephalic vein.

Head and shoulders

The sternocleidomastoid muscle lies anterior to each internal jugular vein.⁸ When tense, it impedes good observation. Shortening, and hence relaxing, this muscle permits the meniscus to be observed. Correct positioning is achieved by:

• Placing a folded pillow behind the patient’s head
• Keeping the shoulders on the mattress
• Turning the head away and elevating the jaw, both slightly; this is often best achieved by gentle pressure of the palm of the observer's hand on the patient's forehead.

Degree of head elevation

Although the proper degree of head elevation is sometimes said to be between 30° and 60°, these numbers are approximate. The correct angle is that which brings the venous meniscus into the window of visibility in the neck between the clavicle and mandible.

Lighting

Shining a flashlight tangentially to the skin is often helpful, casting shadows that improve the visibility of vein motion. Dimming the room lighting may further enhance this effect. Directing a light perpendicular to the skin is not helpful.

Also check the external jugular vein

Checking the external jugular vein can help establish that the jugular venous pressure is normal. If the vein is initially collapsed, light finger pressure at the base of the neck will distend it. If the distention rapidly clears after release of this pressure, the jugular venous pressure is not elevated. However, if external jugular venous distention persists, this does not prove true jugular venous pressure elevation, since it may reflect external compression of the vein by the cervical fascia or delayed blood flow caused by sclerotic venous valves.⁹ In these instances, the internal jugular pulsation level must be sought.

Jugular venous collapse with inspiration

Collapse of the inferior vena cava with forced inspiration is routinely evaluated during echocardiography as a way to estimate right atrial pressure. This finding has been extrapolated to the jugular veins, wherein the absence of venous collapse during vigorous inspiration or sniffing indicates elevated central venous pressures.¹⁰

Distinguishing venous from arterial pulsation

Features indicating venous rather than arterial pulsation were listed by Wood more than 50 years ago¹¹ and are still relevant today. These include internal jugular pulsation that:

• Is soft, diffuse, undulant
• Is not palpable
• Has two crests and two troughs per cardiac cycle
• Has crests that do not coincide with the palpated carotid pulse (exceptions may be seen with the systolic timing of the v wave of tricuspid regurgitation)
• Has higher pressure in expiration, lower in inspiration (exceptions may be seen when Kussmaul physiology is present)
• Has pressure that rises with abdominal pressure
• Is obliterated by light pressure at the base of the neck.

In addition to the above criteria, a wave whose movement is predominantly a descent is nearly always venous.

Abdominojugular reflex

Firm, steady pressure over the abdomen will often result in a small rise in jugular venous pressure. In healthy people, this normalizes in a few seconds, even while manual pressure is maintained. Persistence of jugular venous pressure elevation beyond 10 seconds, followed by an abrupt fall upon withdrawal of manual pressure, is abnormal. This finding has implications similar to those of an elevated baseline jugular venous pressure.

SIGNIFICANCE OF JUGULAR VENOUS PRESSURE ELEVATION

Elevated jugular venous pressure is a manifestation of abnormal right heart dynamics, mostly commonly reflecting elevated pulmonary capillary wedge pressure from left heart failure.¹² This usually implies fluid overload, indicating the need for diuresis.

Exceptions to this therapeutic implication include the presence of a primary right heart condition, pericardial disease, certain arrhythmias, and conditions that elevate intrathoracic pressure. These will be discussed below. One important example is the acute jugular venous pressure elevation seen in right ventricular infarction, in which the high venous pressure is compensatory and its reduction can produce hypotension and shock.¹³

Primary right heart conditions also include right-sided valvular disease, cor pulmonale (including pulmonary embolism and pulmonary hypertension), and the compressive effect of pericardial tamponade or constriction. A normal or near-normal jugular venous pressure significantly decreases the likelihood of significant constriction or of tamponade of a degree necessitating urgent pericardiocentesis.¹⁴

SPECIAL CIRCUMSTANCES

Presence of an intravenous line in the neck

An intravenous line in the neck will often prevent observation of the jugular venous pressure. A simple measure can often compensate for this. If the venous line can be temporarily disconnected, the central venous pressure can be measured directly. Using sterile technique, the line can be flushed with saline and aspirated to bring blood into the transparent tubing. Leaving the proximal end open to the air, and alternately raising and lowering it to confirm free flow, the level to which the blood rises can be easily observed. Observing small cardiac and respiratory variations of the meniscus confirms free communication with the central veins. Attaching the line to a transducer is another option, but this may be time-consuming, and establishing an accurate zero point is often difficult.

The previously described discrepancy between jugular venous pressure and central venous pressure has to be considered when drawing conclusions from this measurement.

Intrathoracic pressure elevators

Positive pressure ventilation will elevate intrathoracic pressure (including right atrial pressure) and hence the jugular venous pressure, making interpretation difficult.¹⁵ Large pleural effusions or pneumothorax may have a similar effect.¹⁶

Superior vena cava syndrome

Markedly elevated jugular venous pressure is here associated with absent or very diminished pulsation, as the caval obstruction has eliminated free communication with the right atrium.¹⁷ Associated facial plethora and edema, papilledema, and superficial venous distention over the chest wall will often confirm this diagnosis.

THE WAVEFORM

While the main purpose of viewing the neck veins is to establish the mean pressure, useful information can often be obtained by assessing the waveform. Abnormalities reflect arrhythmias, right heart hemodynamics, or pericardial disease.¹⁸ Changes may be subtle and difficult to detect, but some patterns can be quite readily appreciated (Figure 2). A limited selection follows.

Arrhythmias

Cannon a waves. These intermittent sharp positive deflections in the venous pulse represent right atrial contraction against a closed tricuspid valve. They are most commonly associated with premature ventricular complexes, but they occur in other conditions in which atrial and ventricular beating are dissociated, including complete heart block, atrioventricular dissociation, and electronic ventricular pacing.^19–21

Repetitive cannon waves. These may be seen with atrioventricular junctional tachycardia or ventricular tachycardia with 1:1 retrograde ventriculoatrial conduction in which the tricuspid valve is closed to every atrial beat.

Fine rapid regular pulsation may be seen in atrial flutter and may be a useful clue in distinguishing this from sinus rhythm when there is 4:1 atrioventricular conduction and a normal ventricular rate.

Abnormal right heart hemodynamics

Large v waves (Lancisi sign). These surges, replacing the usual x descent in systole, are seen in tricuspid insufficiency when the right atrium and its venous attachments are not protected from the right ventricular systolic pressure.²² High right ventricular pressure will obviously enhance this systolic surge.

Large a waves. These reflect resistance to right atrial outflow and may be seen when right ventricular compliance is reduced by hypertrophy from chronic pressure overload or in tricuspid stenosis.²³

Pericardial disease

Kussmaul sign is the paradoxical increase in jugular venous pressure with inspiration, observed in conditions associated with limited filling of the right ventricle. It is typically associated with constrictive pericarditis, although it occurs in only a minority of people with this condition.²⁴ It may also be seen in restrictive cardiomyopathy, massive pulmonary embolism, right ventricular infarction, and tricuspid stenosis.²⁵

Diaphragmatic descent during inspiration increases intra-abdominal pressure and decreases intrathoracic pressure. The resulting increased gradient between the abdomen and thorax enhances venous return from splanchnic vessels, which in the setting of a noncompliant right ventricle may result in increased right atrial (and, hence, jugular venous) pressure.²⁶

It is important to point out that the Kussmaul sign does not occur with cardiac tamponade in the absence of associated pericardial constriction.

Exaggerated y descent is typically seen in pericardial constriction, in which the high pressure of the v wave falls rapidly at the onset of diastole, given initial minimal right ventricular resistance. Flow is abruptly stopped when the intrapericardial space is filled.

In this age of technological marvels, it is easy to become so reliant on them as to neglect the value of bedside physical signs. Yet these signs provide information that adds no cost, is immediately available, and can be repeated at will.

Few physical findings are as useful but as undervalued as is the estimation of the jugular venous pressure. Unfortunately, many practitioners at many levels of seniority and experience do not measure it correctly, leading to a vicious circle of unreliable information, lack of confidence, and underuse. Another reason for its underuse is that the jugular venous pressure does not correlate precisely with the right atrial pressure, as we will see below.

In this review, we will attempt to clarify physiologic principles and describe technical details. Much of this is simple but, as always, the devil is in the details.

ANATOMIC CONSIDERATIONS

Think of the systemic veins as a soft-walled and mildly distensible reservoir with fingerlike projections, analogous to a partially fluidfilled surgical glove.¹ In a semi-upright position, the venous system is partially filled with blood and is collapsed above the level that this blood reaches up to.

Blood is constantly flowing in and out of this reservoir, flowing in by venous return and flowing out by the pumping action of the right side of the heart. The volume in the venous reservoir and hence the pressure are normally maintained by the variability of right ventricular stroke volume in accordance with the Frank-Starling law. Excess volume and pressure indicate failure of this homeostatic mechanism.

The internal jugular veins, being continuous with the superior vena cava, provide a visible measure of the degree to which the systemic venous reservoir is filled, a manometer that reflects the pressure in the right atrium—at least in theory.² Thus, the vertical height above the right atrium to which they are distended and above which they are in a collapsed state should reflect the right atrial pressure.

(In fact, the jugular venous pressure may underestimate the right atrial pressure, for reasons still not understood. This will be discussed below.)

In a healthy person, the visible jugular veins are fully collapsed when the person is standing and are often distended to a variable degree when the person is supine. Selecting an appropriate intermediate position permits the top of the column (the meniscus) to become visible in the neck between the clavicle and the mandible.

DISCREPANCY BETWEEN JUGULAR VENOUS AND RIGHT ATRIAL PRESSURE

Several reports have indicated that the jugular venous pressure may underestimate the right atrial pressure. Deol et al³ confirmed this, while establishing an excellent correlation between the level of venous collapse (observed on ultrasonography) and the jugular venous pressure. The difference between the right atrial pressure and the jugular venous pressure tended to be greater at higher venous pressures.³

Most people have a valve near the termination of the internal jugular vein, with variable competence. Inhibition of reflux of blood from the superior vena cava into the internal jugular vein by this valve is the most plausible cause of this disparity.⁴

The failure of the jugular venous pressure to correlate with the right atrial pressure has been cited by some as a reason to doubt the value of a sign that cardiologists have long relied on. How do we reconcile this apparent paradox? Careful review of the literature that has demonstrated this lack of correlation reveals the following:

• When unequal, the jugular venous pressure always underestimates the right atrial pressure.
• The lack of correlation is less evident at lower venous pressures.

This indicates the following:

• In the presence of congestive heart failure, the right atrial pressure is at least as high and perhaps higher than the jugular venous pressure. Hence, if the jugular venous pressure is high, further treatment, especially diuresis, is needed.
• A jugular venous pressure of zero implies a euvolemic state.

Thus, the jugular venous pressure provides excellent guidance when administering diuresis in congestive heart failure. These deductions obviously require the clinical judgment that the elevated right atrial pressure and jugular venous pressure do indeed reflect elevation of pulmonary capillary wedge pressure rather than other conditions discussed later in this article.

WHICH REFERENCE POINT TO USE?

The two points that can be used as references above which the jugular venous pressure is expressed are the center of the right atrium and the sternal angle. While the former may reflect physiology, the latter is preferred, as it is always visible and has the added advantage of being close to the upper limit of normal, which is about 3 cm above this level.

The difference in height between these two reference points has often been quoted as 5 cm, but this is an underestimate in the body positions used in examination.⁵ Seth et al⁶ found a mean of 8 cm at 30° elevation, 9.7 cm at 45°, and 9.8 cm at 60°. The difference also varied between patients, being larger in association with smoking, older age, large body mass index, and large anterior-posterior diameter. These factors should be considered when trying to evaluate the significance of a particular jugular venous pressure.

The junction of the midaxillary line and the fourth left intercostal space (“the phlebostatic point”) has been recommended as a reference point by some, as it is level with the mid-right atrium. However, using the phlebostatic point as a reference position is cumbersome and results in a valid measurement only with the patient in the supine position.⁷

TECHNIQUE IS VITAL

Close adherence to technical details is vital in reliably and reproducibly measuring the pressure in the internal jugular veins (Figure 1).

The right side is usually observed first, as it is the side on which the examiner usually stands. Using the right side also avoids the rare occurrence of external compression of the left brachiocephalic vein.

Head and shoulders

The sternocleidomastoid muscle lies anterior to each internal jugular vein.⁸ When tense, it impedes good observation. Shortening, and hence relaxing, this muscle permits the meniscus to be observed. Correct positioning is achieved by:

• Placing a folded pillow behind the patient’s head
• Keeping the shoulders on the mattress
• Turning the head away and elevating the jaw, both slightly; this is often best achieved by gentle pressure of the palm of the observer's hand on the patient's forehead.

Degree of head elevation

Although the proper degree of head elevation is sometimes said to be between 30° and 60°, these numbers are approximate. The correct angle is that which brings the venous meniscus into the window of visibility in the neck between the clavicle and mandible.

Lighting

Shining a flashlight tangentially to the skin is often helpful, casting shadows that improve the visibility of vein motion. Dimming the room lighting may further enhance this effect. Directing a light perpendicular to the skin is not helpful.

Also check the external jugular vein

Checking the external jugular vein can help establish that the jugular venous pressure is normal. If the vein is initially collapsed, light finger pressure at the base of the neck will distend it. If the distention rapidly clears after release of this pressure, the jugular venous pressure is not elevated. However, if external jugular venous distention persists, this does not prove true jugular venous pressure elevation, since it may reflect external compression of the vein by the cervical fascia or delayed blood flow caused by sclerotic venous valves.⁹ In these instances, the internal jugular pulsation level must be sought.

Jugular venous collapse with inspiration

Collapse of the inferior vena cava with forced inspiration is routinely evaluated during echocardiography as a way to estimate right atrial pressure. This finding has been extrapolated to the jugular veins, wherein the absence of venous collapse during vigorous inspiration or sniffing indicates elevated central venous pressures.¹⁰

Distinguishing venous from arterial pulsation

Features indicating venous rather than arterial pulsation were listed by Wood more than 50 years ago¹¹ and are still relevant today. These include internal jugular pulsation that:

• Is soft, diffuse, undulant
• Is not palpable
• Has two crests and two troughs per cardiac cycle
• Has crests that do not coincide with the palpated carotid pulse (exceptions may be seen with the systolic timing of the v wave of tricuspid regurgitation)
• Has higher pressure in expiration, lower in inspiration (exceptions may be seen when Kussmaul physiology is present)
• Has pressure that rises with abdominal pressure
• Is obliterated by light pressure at the base of the neck.

In addition to the above criteria, a wave whose movement is predominantly a descent is nearly always venous.

Abdominojugular reflex

Firm, steady pressure over the abdomen will often result in a small rise in jugular venous pressure. In healthy people, this normalizes in a few seconds, even while manual pressure is maintained. Persistence of jugular venous pressure elevation beyond 10 seconds, followed by an abrupt fall upon withdrawal of manual pressure, is abnormal. This finding has implications similar to those of an elevated baseline jugular venous pressure.

SIGNIFICANCE OF JUGULAR VENOUS PRESSURE ELEVATION

Elevated jugular venous pressure is a manifestation of abnormal right heart dynamics, mostly commonly reflecting elevated pulmonary capillary wedge pressure from left heart failure.¹² This usually implies fluid overload, indicating the need for diuresis.

Exceptions to this therapeutic implication include the presence of a primary right heart condition, pericardial disease, certain arrhythmias, and conditions that elevate intrathoracic pressure. These will be discussed below. One important example is the acute jugular venous pressure elevation seen in right ventricular infarction, in which the high venous pressure is compensatory and its reduction can produce hypotension and shock.¹³

Primary right heart conditions also include right-sided valvular disease, cor pulmonale (including pulmonary embolism and pulmonary hypertension), and the compressive effect of pericardial tamponade or constriction. A normal or near-normal jugular venous pressure significantly decreases the likelihood of significant constriction or of tamponade of a degree necessitating urgent pericardiocentesis.¹⁴

SPECIAL CIRCUMSTANCES

Presence of an intravenous line in the neck

An intravenous line in the neck will often prevent observation of the jugular venous pressure. A simple measure can often compensate for this. If the venous line can be temporarily disconnected, the central venous pressure can be measured directly. Using sterile technique, the line can be flushed with saline and aspirated to bring blood into the transparent tubing. Leaving the proximal end open to the air, and alternately raising and lowering it to confirm free flow, the level to which the blood rises can be easily observed. Observing small cardiac and respiratory variations of the meniscus confirms free communication with the central veins. Attaching the line to a transducer is another option, but this may be time-consuming, and establishing an accurate zero point is often difficult.

The previously described discrepancy between jugular venous pressure and central venous pressure has to be considered when drawing conclusions from this measurement.

Intrathoracic pressure elevators

Positive pressure ventilation will elevate intrathoracic pressure (including right atrial pressure) and hence the jugular venous pressure, making interpretation difficult.¹⁵ Large pleural effusions or pneumothorax may have a similar effect.¹⁶

Superior vena cava syndrome

Markedly elevated jugular venous pressure is here associated with absent or very diminished pulsation, as the caval obstruction has eliminated free communication with the right atrium.¹⁷ Associated facial plethora and edema, papilledema, and superficial venous distention over the chest wall will often confirm this diagnosis.

THE WAVEFORM

While the main purpose of viewing the neck veins is to establish the mean pressure, useful information can often be obtained by assessing the waveform. Abnormalities reflect arrhythmias, right heart hemodynamics, or pericardial disease.¹⁸ Changes may be subtle and difficult to detect, but some patterns can be quite readily appreciated (Figure 2). A limited selection follows.

Arrhythmias

Cannon a waves. These intermittent sharp positive deflections in the venous pulse represent right atrial contraction against a closed tricuspid valve. They are most commonly associated with premature ventricular complexes, but they occur in other conditions in which atrial and ventricular beating are dissociated, including complete heart block, atrioventricular dissociation, and electronic ventricular pacing.^19–21

Repetitive cannon waves. These may be seen with atrioventricular junctional tachycardia or ventricular tachycardia with 1:1 retrograde ventriculoatrial conduction in which the tricuspid valve is closed to every atrial beat.

Fine rapid regular pulsation may be seen in atrial flutter and may be a useful clue in distinguishing this from sinus rhythm when there is 4:1 atrioventricular conduction and a normal ventricular rate.

Abnormal right heart hemodynamics

Large v waves (Lancisi sign). These surges, replacing the usual x descent in systole, are seen in tricuspid insufficiency when the right atrium and its venous attachments are not protected from the right ventricular systolic pressure.²² High right ventricular pressure will obviously enhance this systolic surge.

Large a waves. These reflect resistance to right atrial outflow and may be seen when right ventricular compliance is reduced by hypertrophy from chronic pressure overload or in tricuspid stenosis.²³

Pericardial disease

Kussmaul sign is the paradoxical increase in jugular venous pressure with inspiration, observed in conditions associated with limited filling of the right ventricle. It is typically associated with constrictive pericarditis, although it occurs in only a minority of people with this condition.²⁴ It may also be seen in restrictive cardiomyopathy, massive pulmonary embolism, right ventricular infarction, and tricuspid stenosis.²⁵

Diaphragmatic descent during inspiration increases intra-abdominal pressure and decreases intrathoracic pressure. The resulting increased gradient between the abdomen and thorax enhances venous return from splanchnic vessels, which in the setting of a noncompliant right ventricle may result in increased right atrial (and, hence, jugular venous) pressure.²⁶

It is important to point out that the Kussmaul sign does not occur with cardiac tamponade in the absence of associated pericardial constriction.

Exaggerated y descent is typically seen in pericardial constriction, in which the high pressure of the v wave falls rapidly at the onset of diastole, given initial minimal right ventricular resistance. Flow is abruptly stopped when the intrapericardial space is filled.

A 68-year-old man presented for evaluation of a diffuse rash with mucosal involvement. During the past 9 months, he had had oral ulcers, a truncal rash, and blistering lesions on his hands with fingernail erosion, and all of these had been getting worse (Figure 1). He also reported cycles of fever and a weight loss of 50 lb.

Computed tomography revealed diffuse lymphadenopathy, including a bulky 18-cm mediastinal mass. Lymph node biopsy confirmed follicular non-Hodgkin lymphoma.

On serum enzyme-linked immunosorbent assay (ELISA), the desmoglein 1 antibody titer was 62.4 U (< 14 is negative, > 20 is positive) and the desmoglein 3 antibody titer was 36.0 U (< 9 is negative, > 20 is positive). Indirect immunofluorescence testing on monkey esophagus substrate was reactive.

ELISA detected no immunoglobulin G (IgG) reactivity against the bullous pemphigoid autoantigens BP180 and BP230. Direct immunofluorescence testing revealed strong IgG and C3 deposition on epithelial cell surfaces, and indirect immunofluorescence on rat bladder substrate was positive, suggesting the diagnosis of paraneoplastic pemphigus.

The patient was treated with dexamethasone and bendamustine-rituximab. Five months later, desmoglein 1 and 3 antibody titers were measured again and were within normal limits. His lesions had improved significantly (Figure 2), but he had endured multiple medical setbacks, including Pseudomonas peritonitis, fistulizing cytomegalovirus perianal ulceration, septic shock secondary to fulminant Clostridium difficile colitis, and toxic megacolon necessitating total colectomy with end-ileostomy.

PARANEOPLASTIC PEMPHIGUS

Paraneoplastic pemphigus usually occurs in the presence of underlying lymphoproliferative neoplasm, most often non-Hodgkin lymphoma, chronic lymphocytic leukemia, or Castleman disease. It may also occur with epithelial carcinoma, mesenchymal sarcoma, and, rarely, malignant melanoma.¹ The association between malignancy and autoimmune mucocutaneous disease was first described in 1990.² Autoantibodies against periplakin, envoplakin, and desmoglein 3 are often present and may play a role in pathogenesis.

Paraneoplastic pemphigus associated with malignancy portends a poor prognosis. Although historically reported to have an overall death rate ranging from 75% to 90%, with a mean survival of less than 1 year, a recent retrospective cohort has shown slightly improved outcomes, with 49% of patients remaining alive at 1 year and 38% alive at 5 years.³ The most common causes of death are sepsis, respiratory failure, and the underlying malignancy. Bronchiolitis obliterans may occur late in the disease course and is an ominous prognostic factor, with a death rate of 41% after a median interval of 13 months.⁴

Immunosuppressive drugs are often used to control the disease. First-line treatment is with high-dose steroids. Immunosuppressives such as azathioprine and cyclosporin may be used in conjunction to reduce the steroid dose that is required and to limit the adverse effects of steroid therapy. Treating the underlying malignancy may decrease autoantibody production and lead to clinical improvement.

A 68-year-old man presented for evaluation of a diffuse rash with mucosal involvement. During the past 9 months, he had had oral ulcers, a truncal rash, and blistering lesions on his hands with fingernail erosion, and all of these had been getting worse (Figure 1). He also reported cycles of fever and a weight loss of 50 lb.

Computed tomography revealed diffuse lymphadenopathy, including a bulky 18-cm mediastinal mass. Lymph node biopsy confirmed follicular non-Hodgkin lymphoma.

On serum enzyme-linked immunosorbent assay (ELISA), the desmoglein 1 antibody titer was 62.4 U (< 14 is negative, > 20 is positive) and the desmoglein 3 antibody titer was 36.0 U (< 9 is negative, > 20 is positive). Indirect immunofluorescence testing on monkey esophagus substrate was reactive.

ELISA detected no immunoglobulin G (IgG) reactivity against the bullous pemphigoid autoantigens BP180 and BP230. Direct immunofluorescence testing revealed strong IgG and C3 deposition on epithelial cell surfaces, and indirect immunofluorescence on rat bladder substrate was positive, suggesting the diagnosis of paraneoplastic pemphigus.

The patient was treated with dexamethasone and bendamustine-rituximab. Five months later, desmoglein 1 and 3 antibody titers were measured again and were within normal limits. His lesions had improved significantly (Figure 2), but he had endured multiple medical setbacks, including Pseudomonas peritonitis, fistulizing cytomegalovirus perianal ulceration, septic shock secondary to fulminant Clostridium difficile colitis, and toxic megacolon necessitating total colectomy with end-ileostomy.

PARANEOPLASTIC PEMPHIGUS

Paraneoplastic pemphigus usually occurs in the presence of underlying lymphoproliferative neoplasm, most often non-Hodgkin lymphoma, chronic lymphocytic leukemia, or Castleman disease. It may also occur with epithelial carcinoma, mesenchymal sarcoma, and, rarely, malignant melanoma.¹ The association between malignancy and autoimmune mucocutaneous disease was first described in 1990.² Autoantibodies against periplakin, envoplakin, and desmoglein 3 are often present and may play a role in pathogenesis.

Paraneoplastic pemphigus associated with malignancy portends a poor prognosis. Although historically reported to have an overall death rate ranging from 75% to 90%, with a mean survival of less than 1 year, a recent retrospective cohort has shown slightly improved outcomes, with 49% of patients remaining alive at 1 year and 38% alive at 5 years.³ The most common causes of death are sepsis, respiratory failure, and the underlying malignancy. Bronchiolitis obliterans may occur late in the disease course and is an ominous prognostic factor, with a death rate of 41% after a median interval of 13 months.⁴

Immunosuppressive drugs are often used to control the disease. First-line treatment is with high-dose steroids. Immunosuppressives such as azathioprine and cyclosporin may be used in conjunction to reduce the steroid dose that is required and to limit the adverse effects of steroid therapy. Treating the underlying malignancy may decrease autoantibody production and lead to clinical improvement.

A 68-year-old man presented for evaluation of a diffuse rash with mucosal involvement. During the past 9 months, he had had oral ulcers, a truncal rash, and blistering lesions on his hands with fingernail erosion, and all of these had been getting worse (Figure 1). He also reported cycles of fever and a weight loss of 50 lb.

Computed tomography revealed diffuse lymphadenopathy, including a bulky 18-cm mediastinal mass. Lymph node biopsy confirmed follicular non-Hodgkin lymphoma.

On serum enzyme-linked immunosorbent assay (ELISA), the desmoglein 1 antibody titer was 62.4 U (< 14 is negative, > 20 is positive) and the desmoglein 3 antibody titer was 36.0 U (< 9 is negative, > 20 is positive). Indirect immunofluorescence testing on monkey esophagus substrate was reactive.

ELISA detected no immunoglobulin G (IgG) reactivity against the bullous pemphigoid autoantigens BP180 and BP230. Direct immunofluorescence testing revealed strong IgG and C3 deposition on epithelial cell surfaces, and indirect immunofluorescence on rat bladder substrate was positive, suggesting the diagnosis of paraneoplastic pemphigus.

The patient was treated with dexamethasone and bendamustine-rituximab. Five months later, desmoglein 1 and 3 antibody titers were measured again and were within normal limits. His lesions had improved significantly (Figure 2), but he had endured multiple medical setbacks, including Pseudomonas peritonitis, fistulizing cytomegalovirus perianal ulceration, septic shock secondary to fulminant Clostridium difficile colitis, and toxic megacolon necessitating total colectomy with end-ileostomy.

PARANEOPLASTIC PEMPHIGUS

Paraneoplastic pemphigus usually occurs in the presence of underlying lymphoproliferative neoplasm, most often non-Hodgkin lymphoma, chronic lymphocytic leukemia, or Castleman disease. It may also occur with epithelial carcinoma, mesenchymal sarcoma, and, rarely, malignant melanoma.¹ The association between malignancy and autoimmune mucocutaneous disease was first described in 1990.² Autoantibodies against periplakin, envoplakin, and desmoglein 3 are often present and may play a role in pathogenesis.

Paraneoplastic pemphigus associated with malignancy portends a poor prognosis. Although historically reported to have an overall death rate ranging from 75% to 90%, with a mean survival of less than 1 year, a recent retrospective cohort has shown slightly improved outcomes, with 49% of patients remaining alive at 1 year and 38% alive at 5 years.³ The most common causes of death are sepsis, respiratory failure, and the underlying malignancy. Bronchiolitis obliterans may occur late in the disease course and is an ominous prognostic factor, with a death rate of 41% after a median interval of 13 months.⁴

Immunosuppressive drugs are often used to control the disease. First-line treatment is with high-dose steroids. Immunosuppressives such as azathioprine and cyclosporin may be used in conjunction to reduce the steroid dose that is required and to limit the adverse effects of steroid therapy. Treating the underlying malignancy may decrease autoantibody production and lead to clinical improvement.