Dr. Torcson

Patrick Torcson, MD, MMM, FACP, SFHM, has been named vice president and chief integration officer at St. Tammany Parish Hospital (STPH) in Covington, La.

Dr. Torcson's new duties will revolve around quality improvement through health information technology. Dr. Torcson will continue to work as director of STPH's hospital medicine program, which he helped establish in 2005.

Kathleen McGraw, MD, FHM, has been named 2013 Community Clinician of the Year by the Franklin District Medical Society. Dr. McGraw is chief medical officer at Brattleboro (Vt.) Memorial Hospital. She previously served as hospitalist medical director at Baystate Franklin Medical Center in Greenfield, Mass.

Hospitalist R. Wayne Cooper, MD, received the 2013 Physician of the Year Award from Lake Regional Health System in Osage Beach, Mo. Dr. Cooper was chosen by a panel of hospital staff doctors and administrators for his kindness, dedication, and positive attitude. Dr. Cooper has been a hospitalist at Lake Regional since 2010.

Steve Beerman, MD, is the new hospitalist medical director at Good Samaritan Hospital in Cincinnati. Dr. Beerman has been a hospitalist at the 650-bed acute-care hospital since 2003.

Bryan Strader, MD, is the new hospitalist medical director at 420-bed Bethesda North Hospital (BNH) in Cincinnati. Dr. Strader joined the BNH hospitalist team in 2006.

Bradley Lembcke, MD, recently received EmCare's Summit Award for 2013 Hospitalist of the Year. Dr. Lembcke is a hospitalist at Baylor University Medical Center (BUMC) in Dallas, the country's largest and oldest hospitalist group. BUMC is a 1,065-bed, nonprofit teaching hospital.

Chintu Sharma, MD, has been awarded the 2013 Physician of the Year award at Carroll Hospital Center in Westminster, Md. Dr. Sharma has been a practicing hospitalist at Carroll since 2010.

Business Moves

Brentwood, Tenn.-based Cogent HMG began providing hospitalist services to inpatients at 275-bed Western Maryland Regional Medical Center in Cumberland, Md., on April 1 as part of a new contract. Cogent supplies contracted hospitalist services to more than 100 U.S. hospitals.

Sound Physicians, based in Tacoma, Wash., has announced plans to begin managing hospitalist services at Sentara Obici Hospital in Suffolk, Va. The 168-bed facility is one of 10 Sentara Medical Group acute-care hospitals throughout Virginia. Sound Physicians manages more than 650 hospitalists at more than 70 facilities across the U.S.

IPC: The Hospitalist Company, based in North Hollywood, Calif., recently announced its acquisition of two Wichita, Kan.-area hospitalist practices. Kansas Inpatient Services LLC and Kansas Long Term Care Physicians LLC both provide hospitalists in and around the greater Wichita area. Together they encounter an estimated 90,000 inpatients per year. IPC serves hospitals and practices in 28 states.

Mauldin, S.C.-based OB Hospitalist Group (OBHG) is now providing OBGYN services to the new obstetrics emergency department at 350-bed Athens (Ga.) Regional Medical Center. OBHG provides OBGYN hospitalist services in 45 programs throughout the country.

Dr. Torcson

Patrick Torcson, MD, MMM, FACP, SFHM, has been named vice president and chief integration officer at St. Tammany Parish Hospital (STPH) in Covington, La.

Dr. Torcson's new duties will revolve around quality improvement through health information technology. Dr. Torcson will continue to work as director of STPH's hospital medicine program, which he helped establish in 2005.

Kathleen McGraw, MD, FHM, has been named 2013 Community Clinician of the Year by the Franklin District Medical Society. Dr. McGraw is chief medical officer at Brattleboro (Vt.) Memorial Hospital. She previously served as hospitalist medical director at Baystate Franklin Medical Center in Greenfield, Mass.

Hospitalist R. Wayne Cooper, MD, received the 2013 Physician of the Year Award from Lake Regional Health System in Osage Beach, Mo. Dr. Cooper was chosen by a panel of hospital staff doctors and administrators for his kindness, dedication, and positive attitude. Dr. Cooper has been a hospitalist at Lake Regional since 2010.

Steve Beerman, MD, is the new hospitalist medical director at Good Samaritan Hospital in Cincinnati. Dr. Beerman has been a hospitalist at the 650-bed acute-care hospital since 2003.

Bryan Strader, MD, is the new hospitalist medical director at 420-bed Bethesda North Hospital (BNH) in Cincinnati. Dr. Strader joined the BNH hospitalist team in 2006.

Bradley Lembcke, MD, recently received EmCare's Summit Award for 2013 Hospitalist of the Year. Dr. Lembcke is a hospitalist at Baylor University Medical Center (BUMC) in Dallas, the country's largest and oldest hospitalist group. BUMC is a 1,065-bed, nonprofit teaching hospital.

Chintu Sharma, MD, has been awarded the 2013 Physician of the Year award at Carroll Hospital Center in Westminster, Md. Dr. Sharma has been a practicing hospitalist at Carroll since 2010.

Business Moves

Brentwood, Tenn.-based Cogent HMG began providing hospitalist services to inpatients at 275-bed Western Maryland Regional Medical Center in Cumberland, Md., on April 1 as part of a new contract. Cogent supplies contracted hospitalist services to more than 100 U.S. hospitals.

Sound Physicians, based in Tacoma, Wash., has announced plans to begin managing hospitalist services at Sentara Obici Hospital in Suffolk, Va. The 168-bed facility is one of 10 Sentara Medical Group acute-care hospitals throughout Virginia. Sound Physicians manages more than 650 hospitalists at more than 70 facilities across the U.S.

IPC: The Hospitalist Company, based in North Hollywood, Calif., recently announced its acquisition of two Wichita, Kan.-area hospitalist practices. Kansas Inpatient Services LLC and Kansas Long Term Care Physicians LLC both provide hospitalists in and around the greater Wichita area. Together they encounter an estimated 90,000 inpatients per year. IPC serves hospitals and practices in 28 states.

Mauldin, S.C.-based OB Hospitalist Group (OBHG) is now providing OBGYN services to the new obstetrics emergency department at 350-bed Athens (Ga.) Regional Medical Center. OBHG provides OBGYN hospitalist services in 45 programs throughout the country.

Dr. Torcson

Patrick Torcson, MD, MMM, FACP, SFHM, has been named vice president and chief integration officer at St. Tammany Parish Hospital (STPH) in Covington, La.

Dr. Torcson's new duties will revolve around quality improvement through health information technology. Dr. Torcson will continue to work as director of STPH's hospital medicine program, which he helped establish in 2005.

Kathleen McGraw, MD, FHM, has been named 2013 Community Clinician of the Year by the Franklin District Medical Society. Dr. McGraw is chief medical officer at Brattleboro (Vt.) Memorial Hospital. She previously served as hospitalist medical director at Baystate Franklin Medical Center in Greenfield, Mass.

Hospitalist R. Wayne Cooper, MD, received the 2013 Physician of the Year Award from Lake Regional Health System in Osage Beach, Mo. Dr. Cooper was chosen by a panel of hospital staff doctors and administrators for his kindness, dedication, and positive attitude. Dr. Cooper has been a hospitalist at Lake Regional since 2010.

Steve Beerman, MD, is the new hospitalist medical director at Good Samaritan Hospital in Cincinnati. Dr. Beerman has been a hospitalist at the 650-bed acute-care hospital since 2003.

Bryan Strader, MD, is the new hospitalist medical director at 420-bed Bethesda North Hospital (BNH) in Cincinnati. Dr. Strader joined the BNH hospitalist team in 2006.

Bradley Lembcke, MD, recently received EmCare's Summit Award for 2013 Hospitalist of the Year. Dr. Lembcke is a hospitalist at Baylor University Medical Center (BUMC) in Dallas, the country's largest and oldest hospitalist group. BUMC is a 1,065-bed, nonprofit teaching hospital.

Chintu Sharma, MD, has been awarded the 2013 Physician of the Year award at Carroll Hospital Center in Westminster, Md. Dr. Sharma has been a practicing hospitalist at Carroll since 2010.

Business Moves

Brentwood, Tenn.-based Cogent HMG began providing hospitalist services to inpatients at 275-bed Western Maryland Regional Medical Center in Cumberland, Md., on April 1 as part of a new contract. Cogent supplies contracted hospitalist services to more than 100 U.S. hospitals.

Sound Physicians, based in Tacoma, Wash., has announced plans to begin managing hospitalist services at Sentara Obici Hospital in Suffolk, Va. The 168-bed facility is one of 10 Sentara Medical Group acute-care hospitals throughout Virginia. Sound Physicians manages more than 650 hospitalists at more than 70 facilities across the U.S.

IPC: The Hospitalist Company, based in North Hollywood, Calif., recently announced its acquisition of two Wichita, Kan.-area hospitalist practices. Kansas Inpatient Services LLC and Kansas Long Term Care Physicians LLC both provide hospitalists in and around the greater Wichita area. Together they encounter an estimated 90,000 inpatients per year. IPC serves hospitals and practices in 28 states.

Mauldin, S.C.-based OB Hospitalist Group (OBHG) is now providing OBGYN services to the new obstetrics emergency department at 350-bed Athens (Ga.) Regional Medical Center. OBHG provides OBGYN hospitalist services in 45 programs throughout the country.

click for large version

SHM has gotten behind the Choosing Wisely campaign in a big way. Earlier this year, SHM announced lists of suggested practices for adult and pediatric hospital medicine (see Table 1). To keep it on the front burner, hospitalists John Bulger and Ian Jenkins held a pre-course at HM13 devoted entirely to quality-improvement (QI) approaches to implementing and sustaining the practices outlined in the campaign. During the main meeting, they did an encore presentation, with Doug Carlson and Ricardo Quinonez presenting the elements of Choosing Wisely for pediatric hospital medicine.

The widely publicized campaign arose from an American Board of Internal Medicine (ABIM) Foundation grant program to “facilitate the development of innovative, emerging strategies to advance appropriate health-care decision-making and stewardship of health-care resources.” (For more information, visit www.abimfoundation.org.)

Adoption of many of the suggested Choosing Wisely practices will require a change in deeply ingrained, habitual behaviors. We assert that rational, reflective, cognitive processes might not be enough to overturn these behaviors, and that we must look to other mental systems to achieve the consistent adoption of the campaign’s suggested practices. An analogy exists in economics, where theories behind classical economics are challenged by behavioral economics.

What is behavioral economics? Classical economics asserts the individual as “homo economicus”: a person making rational, predictable decisions to advance their interests. However, due to social or professional influence, behavior often does not comport to expected ends. We succumb, sympathize, or follow the pack, diverging from the rulebook. Behavioral economics attempts to understand and compensate for these deviations.

In medicine, we often yield to cognitive biases. To simplify decision-making, we generalize our observations to arrive at decisions quickly. Daniel Kahneman, winner of the Nobel Memorial Prize in Economic Sciences, describes Type I thinking as fast and automatic, and Type II thinking as slow and effortful. Using Kahneman’s framework, we attempt to understand where reasoning may stray and, in turn, introduce environmental changes to achieve better outcomes.

How does this relate to Choosing Wisely? Embracing and embedding the practices of the Choosing Wisely campaign in day-to-day practice will require change in how we approach the clinical decisions we make each day. How can we create the conditions so as not to yield to the status quo?

The MINDSPACE framework

King et al in a recent Health Affairs article describe the MINDSPACE framework (see Table 2), which captures nine effects on behavior—messenger, incentives, norms, defaults, salience, priming, affect, commitments, and ego—that mostly involve automatic systems (Kahneman’s Type I), and how we can leverage them to minimize ineffective health care.¹ Below, we describe Choosing Wisely’s HM components and how MINDSPACE can help promote better practice.

click for large version

Messenger refers to the importance we place on the source of information conveyed to us. In the campaign, the ABIM Foundation engaged professional societies to come up with a list of specialty-specific practices. We know physicians pay more attention to messages from professional societies than, for example, insurance companies. Having the chair of medicine, the chief of hospital medicine, or the vice president of quality officially sanction the campaign’s practices at your organization leverages messengers.

Incentives, while widely used in health care, have had mixed results in terms of their utility in improving outcomes. People are loss-averse, and behavioral economics leverages that finding, which means incentives structured as penalties seem to have more powerful effects than bonuses. While the familiar pay-for-performance programs might not yield desired results, the evidence base continues to grow, and we have lots to learn. Does a 2% bonus change culture? What would really facilitate modifications in your test ordering patterns?

Norms, or what we perceive as the views of the majority, shape our behavior. How do we establish new ones? We all know the axiom “culture eats strategy for breakfast,” and, like patterned antibiotic administration, redirecting behavior requires examination of why we order items. Often, we order not because the drug combination conforms to standards, but because our training programs imbue us with less-than-ideal habits. These habits become standards, and their root causes require layered examination.

Defaults suggest that we are more likely to embrace a certain behavior if we otherwise need to “opt out” to avoid the behavior. We know that, for example, automatic enrollment in retirement savings plans has dramatically increased participation in such programs. For the Choosing Wisely campaign, the suggested practices should be set up as the default option. Examples include appropriate auto-stop orders for urinary catheters, telemetry, oximetry, or the requirement for added clicks to order daily CBCs. Think about ED orders and how they become substitute defaults once patients arrive on the wards. How do you disrupt the inertia?

Salience is when an individual makes a decision based on what is novel or what their attention is drawn to. Anticipating what subspecialists might expect, what your CMO demands, or what trainees envisage in their supervising attendings all may subconsciously override best judgment and deter best practice.

Priming describes how simple cues—often detected by our subconscious—influence decisions we make. When a physician, perhaps out of concern but often due to poorly reasoned or cavalier messaging, scribes “consider test X,” we involuntarily complete the act. We assume, because of the prime, that we need to act accordingly.

Affect is when we rely on gut feelings to make decisions. Emotions guide our ordering a urinary catheter for incontinence or transfusing to a HGB of 10, even when evidence contradicts what we might know as correct. Countering these actions requires credible stops to convert our emotions to reason (think clinical decision support with teeth).

Commitments are made in advance of an undertaking, behavioral economics suggests, as a way to combat the moment when willpower fails and desired behaviors go by the wayside. By publically signing a contract, in front of your group, chair, or medical director, and going on record as having pledged something, chances of success increase.

Ego, which underpins the need for a positive self-image, can drive the kind of automatic behavior that enables one to compare favorably to others. This effect has driven much of the motivation to perform well on public reporting of hospital quality measures. But ideal reporting of results must be valid; otherwise, attribution of subpar outcomes justifies the usual refrains of “not my responsibility” or the “system needs fixing, not me.”

Conclusions

Choosing Wisely is an ambitious undertaking made up of more than 90 suggested best practices put forth by 25 medical societies. In their book “Nudge,” authors Richard Thaler and Cass Sunstein describe how automatic behaviors arise from the environment or context in which choices to engage in such behaviors are presented.² For the Choosing Wisely campaign to have staying power, we submit that institutional leaders and front-line clinicians will need to create a context where the safest, most cost-effective choices are the automatic, or nearly automatic, ones.

Dr. Whitcomb is medical director of healthcare quality at Baystate Medical Center in Springfield, Mass. He is co-founder and past president of SHM. Email him at [email protected]. Dr. Flansbaum is director of hospitalist services at Lenox Hill Hospital in New York City and an SHM Public Policy Committee member.

References

1. King D, Greaves F, Vlaev I, Darzi A. Approaches based on behavioral economics could help nudge patients and providers toward lower health spending growth. Health Aff (Millwood). 2013;32(4):661-668.
2. Thaler RH, Sunstein CR. Nudge: improving decisions about health, wealth and happiness. New Haven, Conn: Yale University Press; 2008.

click for large version

SHM has gotten behind the Choosing Wisely campaign in a big way. Earlier this year, SHM announced lists of suggested practices for adult and pediatric hospital medicine (see Table 1). To keep it on the front burner, hospitalists John Bulger and Ian Jenkins held a pre-course at HM13 devoted entirely to quality-improvement (QI) approaches to implementing and sustaining the practices outlined in the campaign. During the main meeting, they did an encore presentation, with Doug Carlson and Ricardo Quinonez presenting the elements of Choosing Wisely for pediatric hospital medicine.

The widely publicized campaign arose from an American Board of Internal Medicine (ABIM) Foundation grant program to “facilitate the development of innovative, emerging strategies to advance appropriate health-care decision-making and stewardship of health-care resources.” (For more information, visit www.abimfoundation.org.)

Adoption of many of the suggested Choosing Wisely practices will require a change in deeply ingrained, habitual behaviors. We assert that rational, reflective, cognitive processes might not be enough to overturn these behaviors, and that we must look to other mental systems to achieve the consistent adoption of the campaign’s suggested practices. An analogy exists in economics, where theories behind classical economics are challenged by behavioral economics.

What is behavioral economics? Classical economics asserts the individual as “homo economicus”: a person making rational, predictable decisions to advance their interests. However, due to social or professional influence, behavior often does not comport to expected ends. We succumb, sympathize, or follow the pack, diverging from the rulebook. Behavioral economics attempts to understand and compensate for these deviations.

In medicine, we often yield to cognitive biases. To simplify decision-making, we generalize our observations to arrive at decisions quickly. Daniel Kahneman, winner of the Nobel Memorial Prize in Economic Sciences, describes Type I thinking as fast and automatic, and Type II thinking as slow and effortful. Using Kahneman’s framework, we attempt to understand where reasoning may stray and, in turn, introduce environmental changes to achieve better outcomes.

How does this relate to Choosing Wisely? Embracing and embedding the practices of the Choosing Wisely campaign in day-to-day practice will require change in how we approach the clinical decisions we make each day. How can we create the conditions so as not to yield to the status quo?

The MINDSPACE framework

King et al in a recent Health Affairs article describe the MINDSPACE framework (see Table 2), which captures nine effects on behavior—messenger, incentives, norms, defaults, salience, priming, affect, commitments, and ego—that mostly involve automatic systems (Kahneman’s Type I), and how we can leverage them to minimize ineffective health care.¹ Below, we describe Choosing Wisely’s HM components and how MINDSPACE can help promote better practice.

click for large version

Messenger refers to the importance we place on the source of information conveyed to us. In the campaign, the ABIM Foundation engaged professional societies to come up with a list of specialty-specific practices. We know physicians pay more attention to messages from professional societies than, for example, insurance companies. Having the chair of medicine, the chief of hospital medicine, or the vice president of quality officially sanction the campaign’s practices at your organization leverages messengers.

Incentives, while widely used in health care, have had mixed results in terms of their utility in improving outcomes. People are loss-averse, and behavioral economics leverages that finding, which means incentives structured as penalties seem to have more powerful effects than bonuses. While the familiar pay-for-performance programs might not yield desired results, the evidence base continues to grow, and we have lots to learn. Does a 2% bonus change culture? What would really facilitate modifications in your test ordering patterns?

Norms, or what we perceive as the views of the majority, shape our behavior. How do we establish new ones? We all know the axiom “culture eats strategy for breakfast,” and, like patterned antibiotic administration, redirecting behavior requires examination of why we order items. Often, we order not because the drug combination conforms to standards, but because our training programs imbue us with less-than-ideal habits. These habits become standards, and their root causes require layered examination.

Defaults suggest that we are more likely to embrace a certain behavior if we otherwise need to “opt out” to avoid the behavior. We know that, for example, automatic enrollment in retirement savings plans has dramatically increased participation in such programs. For the Choosing Wisely campaign, the suggested practices should be set up as the default option. Examples include appropriate auto-stop orders for urinary catheters, telemetry, oximetry, or the requirement for added clicks to order daily CBCs. Think about ED orders and how they become substitute defaults once patients arrive on the wards. How do you disrupt the inertia?

Salience is when an individual makes a decision based on what is novel or what their attention is drawn to. Anticipating what subspecialists might expect, what your CMO demands, or what trainees envisage in their supervising attendings all may subconsciously override best judgment and deter best practice.

Priming describes how simple cues—often detected by our subconscious—influence decisions we make. When a physician, perhaps out of concern but often due to poorly reasoned or cavalier messaging, scribes “consider test X,” we involuntarily complete the act. We assume, because of the prime, that we need to act accordingly.

Affect is when we rely on gut feelings to make decisions. Emotions guide our ordering a urinary catheter for incontinence or transfusing to a HGB of 10, even when evidence contradicts what we might know as correct. Countering these actions requires credible stops to convert our emotions to reason (think clinical decision support with teeth).

Commitments are made in advance of an undertaking, behavioral economics suggests, as a way to combat the moment when willpower fails and desired behaviors go by the wayside. By publically signing a contract, in front of your group, chair, or medical director, and going on record as having pledged something, chances of success increase.

Ego, which underpins the need for a positive self-image, can drive the kind of automatic behavior that enables one to compare favorably to others. This effect has driven much of the motivation to perform well on public reporting of hospital quality measures. But ideal reporting of results must be valid; otherwise, attribution of subpar outcomes justifies the usual refrains of “not my responsibility” or the “system needs fixing, not me.”

Conclusions

Choosing Wisely is an ambitious undertaking made up of more than 90 suggested best practices put forth by 25 medical societies. In their book “Nudge,” authors Richard Thaler and Cass Sunstein describe how automatic behaviors arise from the environment or context in which choices to engage in such behaviors are presented.² For the Choosing Wisely campaign to have staying power, we submit that institutional leaders and front-line clinicians will need to create a context where the safest, most cost-effective choices are the automatic, or nearly automatic, ones.

Dr. Whitcomb is medical director of healthcare quality at Baystate Medical Center in Springfield, Mass. He is co-founder and past president of SHM. Email him at [email protected]. Dr. Flansbaum is director of hospitalist services at Lenox Hill Hospital in New York City and an SHM Public Policy Committee member.

References

1. King D, Greaves F, Vlaev I, Darzi A. Approaches based on behavioral economics could help nudge patients and providers toward lower health spending growth. Health Aff (Millwood). 2013;32(4):661-668.
2. Thaler RH, Sunstein CR. Nudge: improving decisions about health, wealth and happiness. New Haven, Conn: Yale University Press; 2008.

click for large version

SHM has gotten behind the Choosing Wisely campaign in a big way. Earlier this year, SHM announced lists of suggested practices for adult and pediatric hospital medicine (see Table 1). To keep it on the front burner, hospitalists John Bulger and Ian Jenkins held a pre-course at HM13 devoted entirely to quality-improvement (QI) approaches to implementing and sustaining the practices outlined in the campaign. During the main meeting, they did an encore presentation, with Doug Carlson and Ricardo Quinonez presenting the elements of Choosing Wisely for pediatric hospital medicine.

The widely publicized campaign arose from an American Board of Internal Medicine (ABIM) Foundation grant program to “facilitate the development of innovative, emerging strategies to advance appropriate health-care decision-making and stewardship of health-care resources.” (For more information, visit www.abimfoundation.org.)

Adoption of many of the suggested Choosing Wisely practices will require a change in deeply ingrained, habitual behaviors. We assert that rational, reflective, cognitive processes might not be enough to overturn these behaviors, and that we must look to other mental systems to achieve the consistent adoption of the campaign’s suggested practices. An analogy exists in economics, where theories behind classical economics are challenged by behavioral economics.

What is behavioral economics? Classical economics asserts the individual as “homo economicus”: a person making rational, predictable decisions to advance their interests. However, due to social or professional influence, behavior often does not comport to expected ends. We succumb, sympathize, or follow the pack, diverging from the rulebook. Behavioral economics attempts to understand and compensate for these deviations.

In medicine, we often yield to cognitive biases. To simplify decision-making, we generalize our observations to arrive at decisions quickly. Daniel Kahneman, winner of the Nobel Memorial Prize in Economic Sciences, describes Type I thinking as fast and automatic, and Type II thinking as slow and effortful. Using Kahneman’s framework, we attempt to understand where reasoning may stray and, in turn, introduce environmental changes to achieve better outcomes.

How does this relate to Choosing Wisely? Embracing and embedding the practices of the Choosing Wisely campaign in day-to-day practice will require change in how we approach the clinical decisions we make each day. How can we create the conditions so as not to yield to the status quo?

The MINDSPACE framework

King et al in a recent Health Affairs article describe the MINDSPACE framework (see Table 2), which captures nine effects on behavior—messenger, incentives, norms, defaults, salience, priming, affect, commitments, and ego—that mostly involve automatic systems (Kahneman’s Type I), and how we can leverage them to minimize ineffective health care.¹ Below, we describe Choosing Wisely’s HM components and how MINDSPACE can help promote better practice.

click for large version

Messenger refers to the importance we place on the source of information conveyed to us. In the campaign, the ABIM Foundation engaged professional societies to come up with a list of specialty-specific practices. We know physicians pay more attention to messages from professional societies than, for example, insurance companies. Having the chair of medicine, the chief of hospital medicine, or the vice president of quality officially sanction the campaign’s practices at your organization leverages messengers.

Incentives, while widely used in health care, have had mixed results in terms of their utility in improving outcomes. People are loss-averse, and behavioral economics leverages that finding, which means incentives structured as penalties seem to have more powerful effects than bonuses. While the familiar pay-for-performance programs might not yield desired results, the evidence base continues to grow, and we have lots to learn. Does a 2% bonus change culture? What would really facilitate modifications in your test ordering patterns?

Norms, or what we perceive as the views of the majority, shape our behavior. How do we establish new ones? We all know the axiom “culture eats strategy for breakfast,” and, like patterned antibiotic administration, redirecting behavior requires examination of why we order items. Often, we order not because the drug combination conforms to standards, but because our training programs imbue us with less-than-ideal habits. These habits become standards, and their root causes require layered examination.

Defaults suggest that we are more likely to embrace a certain behavior if we otherwise need to “opt out” to avoid the behavior. We know that, for example, automatic enrollment in retirement savings plans has dramatically increased participation in such programs. For the Choosing Wisely campaign, the suggested practices should be set up as the default option. Examples include appropriate auto-stop orders for urinary catheters, telemetry, oximetry, or the requirement for added clicks to order daily CBCs. Think about ED orders and how they become substitute defaults once patients arrive on the wards. How do you disrupt the inertia?

Salience is when an individual makes a decision based on what is novel or what their attention is drawn to. Anticipating what subspecialists might expect, what your CMO demands, or what trainees envisage in their supervising attendings all may subconsciously override best judgment and deter best practice.

Priming describes how simple cues—often detected by our subconscious—influence decisions we make. When a physician, perhaps out of concern but often due to poorly reasoned or cavalier messaging, scribes “consider test X,” we involuntarily complete the act. We assume, because of the prime, that we need to act accordingly.

Affect is when we rely on gut feelings to make decisions. Emotions guide our ordering a urinary catheter for incontinence or transfusing to a HGB of 10, even when evidence contradicts what we might know as correct. Countering these actions requires credible stops to convert our emotions to reason (think clinical decision support with teeth).

Commitments are made in advance of an undertaking, behavioral economics suggests, as a way to combat the moment when willpower fails and desired behaviors go by the wayside. By publically signing a contract, in front of your group, chair, or medical director, and going on record as having pledged something, chances of success increase.

Ego, which underpins the need for a positive self-image, can drive the kind of automatic behavior that enables one to compare favorably to others. This effect has driven much of the motivation to perform well on public reporting of hospital quality measures. But ideal reporting of results must be valid; otherwise, attribution of subpar outcomes justifies the usual refrains of “not my responsibility” or the “system needs fixing, not me.”

Conclusions

Choosing Wisely is an ambitious undertaking made up of more than 90 suggested best practices put forth by 25 medical societies. In their book “Nudge,” authors Richard Thaler and Cass Sunstein describe how automatic behaviors arise from the environment or context in which choices to engage in such behaviors are presented.² For the Choosing Wisely campaign to have staying power, we submit that institutional leaders and front-line clinicians will need to create a context where the safest, most cost-effective choices are the automatic, or nearly automatic, ones.

Dr. Whitcomb is medical director of healthcare quality at Baystate Medical Center in Springfield, Mass. He is co-founder and past president of SHM. Email him at [email protected]. Dr. Flansbaum is director of hospitalist services at Lenox Hill Hospital in New York City and an SHM Public Policy Committee member.

References

1. King D, Greaves F, Vlaev I, Darzi A. Approaches based on behavioral economics could help nudge patients and providers toward lower health spending growth. Health Aff (Millwood). 2013;32(4):661-668.
2. Thaler RH, Sunstein CR. Nudge: improving decisions about health, wealth and happiness. New Haven, Conn: Yale University Press; 2008.

Back in the 1980s, I would go by medical records every day or two and find, on the front of the charts of my recently discharged patients, a form listing the diagnoses the hospital was billing to Medicare. Before the hospital could submit a patient’s bill, the attending physician was required to review the form and, by signing it, indicate agreement.

The requirement for this signature by the physician went away a long time ago and in my memory is one of the very few examples of reducing a doctor’s paperwork.

For my first few months in practice, I regularly would seek out the people who completed the form and explain they had misunderstood the patient’s clinical situation. “The main issue was a urinary tract infection,” I would say, “but you listed diabetes as the principal diagnosis.”

I don’t ever remember them changing anything based on my feedback. Instead, they explained to me that, for billing purposes, it was legitimate to list diabetes as the principal diagnosis because it had the additional benefit of resulting in a higher payment to the hospital than having “urinary tract infection” listed first.

Such was my introduction to the world of documentation and coding for hospital billing purposes and how it can sometimes differ significantly from the way a doctor sees the clinical picture. Things have evolved a lot since then, but the way doctors document medical conditions still has a huge influence on hospital reimbursement.

Hospital CDI Programs

About 80% of hospitals have formal clinical documentation improvement (CDI) programs to help ensure all clinical conditions are captured and described in the medical record in ways that are valuable for billing and other recordkeeping purposes. These programs might lead to you receive queries about your documentation. For example, you might be asked to clarify whether your patient’s pneumonia might be on the basis of aspiration.

Within SHM’s Code-H program, Dr. Richard Pinson, a former ED physician who now works with Houston-based HCQ Consulting, has a good presentation explaining these documentation issues. In it, he makes the point that, in addition to influencing how hospitals are paid, the way various conditions are documented also influences quality ratings.

click for large version

Novel Approach

The most common approach to engaging hospitalists in CDI initiatives is to have them attend a presentation on the topic, then put in place documentation specialists who generate queries asking the doctor to clarify diagnoses when it might influence payment, severity of illness determination, etc. Dr. Kenji Asakura, a Seattle hospitalist, and Erik Ordal, MBA, have a company called ClinIntell that analyzes each hospitalist (or other specialty) group’s historical patient mix and trains them on the documentation issues that they see most often. The idea of this focused approach is to make “documentation queries” unnecessary, or at least much less necessary. The benefits of this approach are many, including reducing or eliminating the risk of “leading queries”—that is, queries that seem to encourage the doctor to document a diagnosis because it is an advantage to the hospital rather than a well-considered medical opinion. Leading queries can be regarded as fraudulent and can get a lot of people in trouble.

I asked Kenji and Erik if they could provide me with a list of common documentation issues that most hospitalists need to know more about. Table 1 is what they came up with. I hope it helps you and your practice.

Dr. Nelson has been a practicing hospitalist since 1988. He is co-founder and past president of SHM, and principal in Nelson Flores Hospital Medicine Consultants. He is co-director for SHM's "Best Practices in Managing a Hospital Medicine Program" course. Write to him at [email protected].

Back in the 1980s, I would go by medical records every day or two and find, on the front of the charts of my recently discharged patients, a form listing the diagnoses the hospital was billing to Medicare. Before the hospital could submit a patient’s bill, the attending physician was required to review the form and, by signing it, indicate agreement.

The requirement for this signature by the physician went away a long time ago and in my memory is one of the very few examples of reducing a doctor’s paperwork.

For my first few months in practice, I regularly would seek out the people who completed the form and explain they had misunderstood the patient’s clinical situation. “The main issue was a urinary tract infection,” I would say, “but you listed diabetes as the principal diagnosis.”

I don’t ever remember them changing anything based on my feedback. Instead, they explained to me that, for billing purposes, it was legitimate to list diabetes as the principal diagnosis because it had the additional benefit of resulting in a higher payment to the hospital than having “urinary tract infection” listed first.

Such was my introduction to the world of documentation and coding for hospital billing purposes and how it can sometimes differ significantly from the way a doctor sees the clinical picture. Things have evolved a lot since then, but the way doctors document medical conditions still has a huge influence on hospital reimbursement.

Hospital CDI Programs

About 80% of hospitals have formal clinical documentation improvement (CDI) programs to help ensure all clinical conditions are captured and described in the medical record in ways that are valuable for billing and other recordkeeping purposes. These programs might lead to you receive queries about your documentation. For example, you might be asked to clarify whether your patient’s pneumonia might be on the basis of aspiration.

Within SHM’s Code-H program, Dr. Richard Pinson, a former ED physician who now works with Houston-based HCQ Consulting, has a good presentation explaining these documentation issues. In it, he makes the point that, in addition to influencing how hospitals are paid, the way various conditions are documented also influences quality ratings.

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Novel Approach

The most common approach to engaging hospitalists in CDI initiatives is to have them attend a presentation on the topic, then put in place documentation specialists who generate queries asking the doctor to clarify diagnoses when it might influence payment, severity of illness determination, etc. Dr. Kenji Asakura, a Seattle hospitalist, and Erik Ordal, MBA, have a company called ClinIntell that analyzes each hospitalist (or other specialty) group’s historical patient mix and trains them on the documentation issues that they see most often. The idea of this focused approach is to make “documentation queries” unnecessary, or at least much less necessary. The benefits of this approach are many, including reducing or eliminating the risk of “leading queries”—that is, queries that seem to encourage the doctor to document a diagnosis because it is an advantage to the hospital rather than a well-considered medical opinion. Leading queries can be regarded as fraudulent and can get a lot of people in trouble.

I asked Kenji and Erik if they could provide me with a list of common documentation issues that most hospitalists need to know more about. Table 1 is what they came up with. I hope it helps you and your practice.

Dr. Nelson has been a practicing hospitalist since 1988. He is co-founder and past president of SHM, and principal in Nelson Flores Hospital Medicine Consultants. He is co-director for SHM's "Best Practices in Managing a Hospital Medicine Program" course. Write to him at [email protected].

Back in the 1980s, I would go by medical records every day or two and find, on the front of the charts of my recently discharged patients, a form listing the diagnoses the hospital was billing to Medicare. Before the hospital could submit a patient’s bill, the attending physician was required to review the form and, by signing it, indicate agreement.

The requirement for this signature by the physician went away a long time ago and in my memory is one of the very few examples of reducing a doctor’s paperwork.

For my first few months in practice, I regularly would seek out the people who completed the form and explain they had misunderstood the patient’s clinical situation. “The main issue was a urinary tract infection,” I would say, “but you listed diabetes as the principal diagnosis.”

I don’t ever remember them changing anything based on my feedback. Instead, they explained to me that, for billing purposes, it was legitimate to list diabetes as the principal diagnosis because it had the additional benefit of resulting in a higher payment to the hospital than having “urinary tract infection” listed first.

Such was my introduction to the world of documentation and coding for hospital billing purposes and how it can sometimes differ significantly from the way a doctor sees the clinical picture. Things have evolved a lot since then, but the way doctors document medical conditions still has a huge influence on hospital reimbursement.

Hospital CDI Programs

About 80% of hospitals have formal clinical documentation improvement (CDI) programs to help ensure all clinical conditions are captured and described in the medical record in ways that are valuable for billing and other recordkeeping purposes. These programs might lead to you receive queries about your documentation. For example, you might be asked to clarify whether your patient’s pneumonia might be on the basis of aspiration.

Within SHM’s Code-H program, Dr. Richard Pinson, a former ED physician who now works with Houston-based HCQ Consulting, has a good presentation explaining these documentation issues. In it, he makes the point that, in addition to influencing how hospitals are paid, the way various conditions are documented also influences quality ratings.

click for large version

Novel Approach

The most common approach to engaging hospitalists in CDI initiatives is to have them attend a presentation on the topic, then put in place documentation specialists who generate queries asking the doctor to clarify diagnoses when it might influence payment, severity of illness determination, etc. Dr. Kenji Asakura, a Seattle hospitalist, and Erik Ordal, MBA, have a company called ClinIntell that analyzes each hospitalist (or other specialty) group’s historical patient mix and trains them on the documentation issues that they see most often. The idea of this focused approach is to make “documentation queries” unnecessary, or at least much less necessary. The benefits of this approach are many, including reducing or eliminating the risk of “leading queries”—that is, queries that seem to encourage the doctor to document a diagnosis because it is an advantage to the hospital rather than a well-considered medical opinion. Leading queries can be regarded as fraudulent and can get a lot of people in trouble.

I asked Kenji and Erik if they could provide me with a list of common documentation issues that most hospitalists need to know more about. Table 1 is what they came up with. I hope it helps you and your practice.

Dr. Nelson has been a practicing hospitalist since 1988. He is co-founder and past president of SHM, and principal in Nelson Flores Hospital Medicine Consultants. He is co-director for SHM's "Best Practices in Managing a Hospital Medicine Program" course. Write to him at [email protected].

Dr. Hospitalist

Refrain from Texting about Your Patients

Can I text my partners patient information?

–Stephen Henry, San Luis Obispo, Calif.

Dr. Hospitalist responds:

Can you? Sure. Do you? Probably. Should you? No.

Texting any patient information falls under the category of ePHI (Electronic Protected Health Information) as part of HIPAA. Technically, such patient-specific information must be protected at all times. Once you send a text, at least three copies are known to exist: one on each of the devices, plus one copy on the network it went through, adding for each network it has to cross. Sure, your phone may be password-protected, but is your partner’s? What about the carrier? How protected is their data?

HIPAA goes into excruciating technical detail about all the safeguards that must be present. You are more than welcome to read it (www.hhs.gov/ocr/privacy/hipaa/administrative/securityrule) to see if you meet all the standards. Or you can take my word for it: You don’t.

So you can see why most health organizations expressly prohibit the texting of patient information. If you rang up your local health-care or hospital lawyer, I’m sure they would tell you to never text patient information. Is that reasonable advice? In 2013, I doubt it.

So what’s the practical advice to follow? For starters, password-protect your phone, if you haven’t already. Nothing worse than losing your phone and having patient information on it. A lot of the OCR (Office for Civil Rights, a branch of Health and Human Services) fines for HIPAA violations stem from folks misplacing unencrypted devices with patient information on them.

Just as important, don’t text anything that you wouldn’t want to see blown up on a lawyer’s display board in court. I’ve seen some really egregious examples of communication between doctors that have no business being preserved electronically. Texting “Mr. X in Room 2101 is a meth-using, narcotic-seeking, half-naked, lunatic troll” is an absolutely stupid thing to do. For that matter, so are remarks that seem less offensive: “And his son is completely unreasonable.” Save your commentary and stick to the facts, because you just generated three copies forever.

If you receive an insensitive text, don’t reply. Simply call the sending physician to discuss any issues. Even being on a “secure” texting network won’t protect you from errors of commission.

If I were to text about a patient (purely hypothetically, mind you), I would limit the information as much as possible. Keep it simple and generic (what HIPAA likes to call “de-identified information”)—for example, “Room 428 is ready for discharge.”

Please, hold the subjective commentary. There is no good reason to have an extended text exchange about a patient; you are creating an electronic trail that has no good reason to exist and never really goes away. It’s just the same as writing in the chart, except that it has the illusion of privacy. And that’s all it is: an illusion.

At the end of the day, I’d probably worry more about the discoverable aspect of your text messages in a lawsuit than the possibility of a HIPAA fine, but neither one sounds like much fun to me.

Dr. Hospitalist

Refrain from Texting about Your Patients

Can I text my partners patient information?

–Stephen Henry, San Luis Obispo, Calif.

Dr. Hospitalist responds:

Can you? Sure. Do you? Probably. Should you? No.

Texting any patient information falls under the category of ePHI (Electronic Protected Health Information) as part of HIPAA. Technically, such patient-specific information must be protected at all times. Once you send a text, at least three copies are known to exist: one on each of the devices, plus one copy on the network it went through, adding for each network it has to cross. Sure, your phone may be password-protected, but is your partner’s? What about the carrier? How protected is their data?

HIPAA goes into excruciating technical detail about all the safeguards that must be present. You are more than welcome to read it (www.hhs.gov/ocr/privacy/hipaa/administrative/securityrule) to see if you meet all the standards. Or you can take my word for it: You don’t.

So you can see why most health organizations expressly prohibit the texting of patient information. If you rang up your local health-care or hospital lawyer, I’m sure they would tell you to never text patient information. Is that reasonable advice? In 2013, I doubt it.

So what’s the practical advice to follow? For starters, password-protect your phone, if you haven’t already. Nothing worse than losing your phone and having patient information on it. A lot of the OCR (Office for Civil Rights, a branch of Health and Human Services) fines for HIPAA violations stem from folks misplacing unencrypted devices with patient information on them.

Just as important, don’t text anything that you wouldn’t want to see blown up on a lawyer’s display board in court. I’ve seen some really egregious examples of communication between doctors that have no business being preserved electronically. Texting “Mr. X in Room 2101 is a meth-using, narcotic-seeking, half-naked, lunatic troll” is an absolutely stupid thing to do. For that matter, so are remarks that seem less offensive: “And his son is completely unreasonable.” Save your commentary and stick to the facts, because you just generated three copies forever.

If you receive an insensitive text, don’t reply. Simply call the sending physician to discuss any issues. Even being on a “secure” texting network won’t protect you from errors of commission.

If I were to text about a patient (purely hypothetically, mind you), I would limit the information as much as possible. Keep it simple and generic (what HIPAA likes to call “de-identified information”)—for example, “Room 428 is ready for discharge.”

Please, hold the subjective commentary. There is no good reason to have an extended text exchange about a patient; you are creating an electronic trail that has no good reason to exist and never really goes away. It’s just the same as writing in the chart, except that it has the illusion of privacy. And that’s all it is: an illusion.

At the end of the day, I’d probably worry more about the discoverable aspect of your text messages in a lawsuit than the possibility of a HIPAA fine, but neither one sounds like much fun to me.

Dr. Hospitalist

Refrain from Texting about Your Patients

Can I text my partners patient information?

–Stephen Henry, San Luis Obispo, Calif.

Dr. Hospitalist responds:

Can you? Sure. Do you? Probably. Should you? No.

Texting any patient information falls under the category of ePHI (Electronic Protected Health Information) as part of HIPAA. Technically, such patient-specific information must be protected at all times. Once you send a text, at least three copies are known to exist: one on each of the devices, plus one copy on the network it went through, adding for each network it has to cross. Sure, your phone may be password-protected, but is your partner’s? What about the carrier? How protected is their data?

HIPAA goes into excruciating technical detail about all the safeguards that must be present. You are more than welcome to read it (www.hhs.gov/ocr/privacy/hipaa/administrative/securityrule) to see if you meet all the standards. Or you can take my word for it: You don’t.

So you can see why most health organizations expressly prohibit the texting of patient information. If you rang up your local health-care or hospital lawyer, I’m sure they would tell you to never text patient information. Is that reasonable advice? In 2013, I doubt it.

So what’s the practical advice to follow? For starters, password-protect your phone, if you haven’t already. Nothing worse than losing your phone and having patient information on it. A lot of the OCR (Office for Civil Rights, a branch of Health and Human Services) fines for HIPAA violations stem from folks misplacing unencrypted devices with patient information on them.

Just as important, don’t text anything that you wouldn’t want to see blown up on a lawyer’s display board in court. I’ve seen some really egregious examples of communication between doctors that have no business being preserved electronically. Texting “Mr. X in Room 2101 is a meth-using, narcotic-seeking, half-naked, lunatic troll” is an absolutely stupid thing to do. For that matter, so are remarks that seem less offensive: “And his son is completely unreasonable.” Save your commentary and stick to the facts, because you just generated three copies forever.

If you receive an insensitive text, don’t reply. Simply call the sending physician to discuss any issues. Even being on a “secure” texting network won’t protect you from errors of commission.

If I were to text about a patient (purely hypothetically, mind you), I would limit the information as much as possible. Keep it simple and generic (what HIPAA likes to call “de-identified information”)—for example, “Room 428 is ready for discharge.”

Please, hold the subjective commentary. There is no good reason to have an extended text exchange about a patient; you are creating an electronic trail that has no good reason to exist and never really goes away. It’s just the same as writing in the chart, except that it has the illusion of privacy. And that’s all it is: an illusion.

At the end of the day, I’d probably worry more about the discoverable aspect of your text messages in a lawsuit than the possibility of a HIPAA fine, but neither one sounds like much fun to me.

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Case

A 36-year-old man with a known history of hereditary angioedema (HAE) presents with severe orofacial swelling and laryngeal angioedema, requiring expectant management, including endotracheal intubation. His previous angioedema (AE) episodes involved his hands, feet, and genitalia; episodes generally occurred after physical trauma. Ten years prior to admission, he had an episode of secondary small bowel obstruction. The patient had been prescribed prophylactic danazol (Danacrine) 100 mg BID but he had gradually been reducing the dosage due to mood changes; at the time of presentation, he had already tapered to 100 mg danazol three times per week (Monday, Wednesday, and Friday).

Overview

HAE is an autosomal dominant condition characterized by localized, episodic swelling of the deeper dermal layers and/or mucosal tissue. Its acute presentation can vary in severity; presentations can be lethal.

HAE is generally unresponsive to conventional treatments used for other causes of AE (e.g. food or drug reactions) including glucocorticoids, antihistamines, and epinephrine. The pharmacologic treatment of acute attacks, as well as for short- and long-term prophylaxis of HAE, has evolved significantly in recent years and now includes several forms of C1 inhibitor (C1INH) protein replacement, as well as a bradykinin antagonist, and a kallikrein inhibitor.

Review of the Data

Epidemiology. HAE is an autosomal dominant disease with prevalence in the U.S. of 1 in 10,000 to 1 in 50,000 patients. All ethnic groups are equally affected, with no gender predilection. In most cases, a positive family history is present; however, in 25% of cases, spontaneous mutations occur such that an unremarkable family history does not rule out the diagnosis.¹

Pathophysiology. In the past decade, there has been substantial advancement in our understanding of HAE pathophysiology. HAE occurs as a result of functional or quantitative C1 esterase inhibitor (C1INH) deficiency.

C1INH belongs to a group of proteins known as serpins (serine protease inhibitors). The C1INH gene is located on chromosome 11, and has several polymorphic sites, which predispose to spontaneous mutations.¹

Bradykinin is the core bioactive mediator, which causes vasodilation, smooth muscle contraction, and subsequent edema.¹ C1INH regulates bradykinin production by blocking kallikrein’s conversion of factor XII into XIIa, prekallikrein to kallikrein, and cleavage of high-molecular-weight kininogen by activated kallikrein to form bradykinin (see Figure 1).^1,2

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Clinical Manifestations

HAE is characterized by recurrent episodes of swelling, the frequency and severity of which are quite variable. Virtually all HAE patients have abdominal- and extremity-swelling episodes, and 50% will have episodes of laryngeal swelling; other involved areas might include the face, oropharynx, and genitalia.4 These episodes are usually unilateral; edema is nonpruritic, nonpitting, and often painless. Episodes involving the oropharynx, larynx, and abdomen can be associated with potentially serious morbidity and mortality.^{1, 3}

HAE episodes usually commence during late childhood and early puberty (on average at age 11). Approximately half of HAE patients will have oropharyngeal involvement that might occur many years, even decades, after the initial onset of the disease. The annual rate of severe, life-threatening laryngeal edema was 0.9% in a recent retrospective study.⁴

Severity of the disease is variable. Attacks are episodic, and occur on average every 10 to 20 days in untreated patients. These attacks typically peak over 24 hours, then usually resolve after 48 to 72 hours. However, the complete resolution of signs and symptoms can last for up to one week after the attacks.⁵

There is no concomitant pruritus or urticaria that accompanies the AE. However, erythema marginatum, an evanescent nonpruritic rash with serpiginous borders involving the trunk and inner surface of extremities but sparing the face, might herald the onset of an episode. This rash usually has central pallor that blanches with pressure and worsens with heat.

HAE can be triggered by stressful events, including trauma, surgery, menstruation, and viral infections. However, in many instances, HAE attacks occur without an identifiable cause.⁵

Differential Diagnosis from Other Causes of Angioedema

Type I HAE is characterized by a quantitative C1INH deficiency (which is functionally abnormal as well), and occurs in 85% of patients. Type II HAE occurs in 15% of patients, and results from a functionally abnormal C1INH.

In patients with Type I and II HAE, as well as acquired C1 inhibitor deficiency (ACID), C4 levels are low during and between attacks. C2 levels are also low during acute attacks. In ACID, levels of C1q are also reduced; these patients require further workup to rule out an undiagnosed malignancy or an autoimmune process. In contrast, patients with ACE-induced, idiopathic, and allergic AE have normal complement profiles.^3,6

Type III is a more recently described type of HAE that is rare, not well understood, and generally affects women.^3,6 Clinically, it resembles Type I and Type II HAE but complement levels, including C1 inhibitor, are normal (see Table 1).

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Treatment

HAE types I, II, III, and ACID are generally unresponsive to glucocorticoids, antihistamines, and epinephrine. These forms of AE may be exacerbated by exogenous estrogen.^1,8 For this reason, HAE patients should avoid oral hormonal contraception and estrogen replacement therapy. In addition, ACE inhibitors should also be avoided based on their effect on bradykinin degradation.

Until the introduction of newer therapeutic choices, as noted in our case, the treatment of acute attacks of AE was essentially supportive. Patients with impending laryngeal obstruction were managed with intubation prior to progression of the AE to limit airway patency. Prior to the modern era, a substantial proportion of HAE patients died of asphyxiation.

Fresh frozen plasma (FFP) has been used to treat acute HAE attacks, but given its content of contact system proteins (in addition to C1INH), FFP might also pose a risk for worsening of HAE; for this reason, it must be given cautiously to patients who are symptomatic.⁹

In the past decade, there has been significant progress in the available treatments for HAE. Currently in the U.S., there are several agents recently approved by, or have pending approvals from, the FDA, including several forms of C1INH replacement, a bradykinin antagonist, and a kallikrein inhibitor.

The C1 esterase inhibitor (human) drugs are administered intravenously; both have been shown to be efficacious and safe. Nanofiltered C1 inhibitor provided relief in a median time of two hours when used acutely; when used as prophylaxis, it decreased the number of attacks in a three-month period by 50% (six vs. 12 with placebo, P<0.001).¹¹

The other C1INH is rhucin, still not approved in U.S. This drug is characterized by a short half-life (approximately two to four hours) compared with the plasma-derived C1INH agents (24 to 48 hours). It is contraindicated in patients with rabbit hypersensitivity, as it is purified from rabbit breast milk.¹⁰

Ecallantide is a kallikrein inhibitor for acute therapy that is administered via three subcutaneous injections. This agent has been linked to allergic/anaphylactic reactions in a minority of patients (approximately 4%); therefore, it should be administered cautiously, by a health-care provider, and in a setting where anaphylaxis can be successfully managed.¹² Icatibant is a bradykinin antagonist recently approved in the U.S. and administered SC via a single injection.¹⁰

In light of the development of these new agents, there is a need for updated guidelines for the long- and short-term prophylaxis and acute management of HAE. A recent guideline focused on the management of HAE in gynecologic and obstetric patients recommended the use of plasma-derived C1INH C1 esterase inhibitor (human) (Cinryze) for short- and long-term prophylaxis and acute treatment of HAE.¹³ The effect of pregnancy on HAE is variable: Some women worsen and other women have less swelling during their pregnancy. Swelling at the time of parturition is rare; however, the risk rises during the post-partum period.

Type III HAE. An additional form of HAE has been recognized with a pattern of AE episodes that mimics Type I or Type II HAE but with unremarkable laboratory studies of the complement cascade, including C1 inhibitor level and function. At this time, there is no laboratory test with which a diagnosis of Type III HAE can be confirmed. The diagnosis should be suspected in patients with a strong family history of AE reflecting autosomal dominant inheritance. In some, but not all, cases, the condition is manifest in association with high estrogen levels (e.g. pregnancy or administration of oral contraceptives). Type III HAE patients have a salutary response to the same agents that are efficacious for Type I and II HAE.

Acquired C1 inhibitor deficiency (ACID). ACID generally occurs in adults and is clinically indistinguishable from HAE. ACID is not associated with a remarkable family history of AE. In contrast to HAE, this is a consumptive deficiency of C1 inhibitor and results from enhanced catabolism that exceeds the capacity for regenerating C1 inhibitor protein. It is often associated with neoplastic (usually lymphoproliferative) or autoimmune disorders; treatment of the underlying condition frequently leads to improvement in ACID. Although its management is similar to HAE, it tends to be more responsive to anti-fibrinolytics. A salutary response to C1INH replacement therapy might not occur in patients with autoantibodies to C1 inhibitor, but efficacy of ecallantide and icatibant for the treatment of acquired AE has been reported.^{14, 15}

ACEI angioedema. Treatment with angiotensin-converting enzyme inhibitors (ACE-I) has been associated with recurrent AE without urticaria in 0.1 to 0.7% of patients exposed to these drugs.¹⁶ Angioedema from ACE-I more frequently occurs within the first few months of therapy, but it might occur even after years of continuous therapy. ACEI-induced AE is secondary to impaired degradation of bradykinin. The main treatment is to discontinue the offending agent and avoid all other ACE-I, as this is a class-specific reaction.¹⁷

Angiotensin receptor blockers (ARBs) have been associated less commonly with AE. The mechanism for ARB-associated AE has not been elucidated. A meta-analysis showed that in 2% to 17% of patients who were switched to ARBs, recurrence of AE was observed.¹⁸ From the pooling of these data with two randomized controlled trials, it is estimated that approximately 10% or less of patients with ACEI-associated AE who switched to ARBs will develop AE.¹⁹ In the majority of cases, patients can be switched to ARBs with no recurrence of AE; however, the decision to prescribe an ARB to a patient who has had AE while receiving ACEI should be made carefully on an individualized risk/benefit basis.¹⁹

Preventive Treatment

The 17 α-alkylated androgens that can be used for treatment of HAE are danazol (Danacrine), stanozolol (Winstrol), oxandralone (Oxandrine) and methyltestosterone (Android). In patients with HAE, attenuated androgens can significantly reduce the frequency and severity of attacks; however, their use is limited by risk for untoward effects (virilization, abnormal liver function tests, change in libido, anxiety, etc.).²¹ There is also a risk for hepatotoxicity, including development of hepatic adenomas and hepatic carcinoma.

Antifibrinolytics also may have efficacy for HAE, but these agents have been associated with a variety of adverse effects, including nausea and diarrhea, postural hypotension, fatigue, enhanced thrombosis, retinal changes, and teratogenicity.^{8, 22, 23}

In 2009, long-term prophylaxis with C1-INH concentrate was recommended for patients with HAE with frequent or disabling attacks, a history of laryngeal attacks, and poor quality of life. The 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of HAE recommended long-term prophylaxis in patients with more than one monthly severe HAE attack, more than five days of disability per month, or any history of airway compromise.^{24, 25}

The decision to prescribe long-term prophylaxis, and the dose/frequency of medication required, should be individualized based on clinical parameters, such as frequency and severity of attacks, and not on C1 INH or C4 levels.

Perioperative Considerations

It is well established that any trauma, including dental procedures or surgery, can precipitate HAE attacks. For this reason, short-term prophylactic treatment in HAE patients undergoing procedures is recommended. Ideally, avoiding endotracheal intubation is the best approach; however, if intubation cannot be avoided, then adequate prophylaxis should be administered.²

Attenuated androgens can be given up to seven days before a procedure, or C1 INH can be administered 24 hours in advance. If C1 INH is unavailable, FFP can be given six to 12 hours in advance in patients who are not symptomatic; in case of endotracheal intubation, either FFP or C1 INH should be administered immediately before.²

Several case reports in multiple specialty surgical patients (abdominal surgery, cardiopulmonary bypass, orthopedic surgery, etc.) have confirmed the successful use of C1 INH in the prevention of acute attacks with favorable outcomes.²

There is no need to follow C1 INH levels, as it has no clinical relevance.

Back to the Case

The patient was admitted to the ICU and received a total of eight units of FFP. He was transferred to our institution and was able to be extubated three days after initial presentation. Laboratory studies revealed C4 10mg/dL and C1 esterase inhibitor 10mg/dL (both low).

Danazol was resumed. However, within several months after discharge, Cinryze became available in the U.S. market and was eventually prescribed. The patient has not had further significant attacks requiring inpatient management.

Dr. Auron is an assistant professor of medicine and pediatrics at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Dr. Lang is co-director of the Asthma Center and director of the Allergy/Immunology Fellowship Training Program at the Cleveland Clinic.

References

1. Bernstein, JA. Update on angioedema: evaluation, diagnosis, and treatment. Allergy Asthma Proc. 2011;32(6):408-412.
2. Levy JH, Freiberger DJ, Roback J. Hereditary angioedema: current and emerging treatment options. Anesth Analg. 2010;110(5):1271-1280.
3. Busse PJ. Angioedema: Differential diagnosis and treatment. Allergy Asthma Proc. 2011;32:Suppl 1:S3-S11.
4. Khan DA. Hereditary angioedema: historical aspects, classification, pathophysiology, clinical presentation, and laboratory diagnosis. Allergy Asthma Proc. 2011;32(1):1-10.
5. Bork K, Meng G, Staubach P, Hardt, J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006;119(3):267-274.
6. Zuraw BL, Christiansen SC. Pathogenesis and laboratory diagnosis of hereditary angioedema. Allergy Asthma Proc. 2009;30:487-492.
7. Frazer-Abel A, Giclas PC. Update on laboratory tests for the diagnosis and differentiation of hereditary angioedema and acquired angioedema. Allergy Asthma Proc. 2011;32:Suppl 1:S17-S21.
8. Banerjee A. Current treatment of hereditary angioedema: an update on clinical studies. Allergy Asthma Proc. 2010;31:398-406.
9. Donaldson VH. Therapy of "the neurotic edema." N Engl J Med. 1972;286(15):835-836.
10. Riedl MA. Update on the acute treatment of hereditary angioedema. Allergy Asthma Proc. 2011;32:11-16.
11. Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010;363:513-522.
12. Cicardi M, Levy RJ, McNeil DL. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. 2010;363:523-531.
13. Caballero T, Farkas H, Bouillet L, et al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol. 2012;129(2):308-320.
14. Cicardi M, Zanichelli A. Acquired angioedema. J Allergy Clin Immunol. 2010;6(1):14.
15. Zanichelli A, Badini M, Nataloni I, Montano N, Cicardi M. Treatment of acquired angioedema with icatibant: a case report. Intern Emerg Med. 2011;6(3):279-280.
16. Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor-associated angioedema. Immunol Allergy Clin North Am. 2006;26(4):725-737.
17. Haymore BR, Yoon J, Mikita CP, Klote MM, DeZee KJ. Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated with angiotensin-converting enzyme inhibitors: a meta-analysis. Ann Allergy Asthma Immunol. 2008;101(5):495-499.
18. Beavers CJ, Dunn SP, Macaulay TE. The role of angiotensin receptor blockers in patients with angiotensin-converting enzyme inhibitor-induced angioedema. Ann Pharmacother. 2011;45(4):520-524.
19. Nzeako UC. Diagnosis and management of angioedema with abdominal involvement: a gastroenterology perspective. World J Gastroenterol. 2010; 16(39):4913-4921.
20. Banerji A, Sloane DE, Sheffer AL. Hereditary angioedema: a current state-of-the-art review, V: attenuated androgens for the treatment of hereditary angioedema. Ann Allergy Asthma Immunol. 2008;100(1) (Suppl 2):S19-22.
21. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008; 359(10):1027-1036.
22. Zuraw BL. Hereditary angioedema: a current state-of-the-art review, IV: short- and long-term treatment of hereditary angioedema: out with the old and in with the new? Ann Allergy Asthma Immunol. 2008;100(1) (Suppl 2):S13-S18.
23. Bowen T, Cicardi M, Bork K, et al. Hereditary angioedema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann Allergy Asthma Immunol. 2008;100(1)(Suppl 2):S30-40.
24. Craig T, Riedl M, Dykewicz M, et al. When is prophylaxis for hereditary angioedema necessary? Ann Allergy Asthma Immunol. 2009.102(5):366-372.
25. Frank MM. Update on preventive therapy (prophylaxis) of hereditary angioedema. Allergy Asthma Proc. 2011;32(1):17-21.

click for large version

Case

A 36-year-old man with a known history of hereditary angioedema (HAE) presents with severe orofacial swelling and laryngeal angioedema, requiring expectant management, including endotracheal intubation. His previous angioedema (AE) episodes involved his hands, feet, and genitalia; episodes generally occurred after physical trauma. Ten years prior to admission, he had an episode of secondary small bowel obstruction. The patient had been prescribed prophylactic danazol (Danacrine) 100 mg BID but he had gradually been reducing the dosage due to mood changes; at the time of presentation, he had already tapered to 100 mg danazol three times per week (Monday, Wednesday, and Friday).

Overview

HAE is an autosomal dominant condition characterized by localized, episodic swelling of the deeper dermal layers and/or mucosal tissue. Its acute presentation can vary in severity; presentations can be lethal.

HAE is generally unresponsive to conventional treatments used for other causes of AE (e.g. food or drug reactions) including glucocorticoids, antihistamines, and epinephrine. The pharmacologic treatment of acute attacks, as well as for short- and long-term prophylaxis of HAE, has evolved significantly in recent years and now includes several forms of C1 inhibitor (C1INH) protein replacement, as well as a bradykinin antagonist, and a kallikrein inhibitor.

Review of the Data

Epidemiology. HAE is an autosomal dominant disease with prevalence in the U.S. of 1 in 10,000 to 1 in 50,000 patients. All ethnic groups are equally affected, with no gender predilection. In most cases, a positive family history is present; however, in 25% of cases, spontaneous mutations occur such that an unremarkable family history does not rule out the diagnosis.¹

Pathophysiology. In the past decade, there has been substantial advancement in our understanding of HAE pathophysiology. HAE occurs as a result of functional or quantitative C1 esterase inhibitor (C1INH) deficiency.

C1INH belongs to a group of proteins known as serpins (serine protease inhibitors). The C1INH gene is located on chromosome 11, and has several polymorphic sites, which predispose to spontaneous mutations.¹

Bradykinin is the core bioactive mediator, which causes vasodilation, smooth muscle contraction, and subsequent edema.¹ C1INH regulates bradykinin production by blocking kallikrein’s conversion of factor XII into XIIa, prekallikrein to kallikrein, and cleavage of high-molecular-weight kininogen by activated kallikrein to form bradykinin (see Figure 1).^1,2

click for large version

Clinical Manifestations

HAE is characterized by recurrent episodes of swelling, the frequency and severity of which are quite variable. Virtually all HAE patients have abdominal- and extremity-swelling episodes, and 50% will have episodes of laryngeal swelling; other involved areas might include the face, oropharynx, and genitalia.4 These episodes are usually unilateral; edema is nonpruritic, nonpitting, and often painless. Episodes involving the oropharynx, larynx, and abdomen can be associated with potentially serious morbidity and mortality.^{1, 3}

HAE episodes usually commence during late childhood and early puberty (on average at age 11). Approximately half of HAE patients will have oropharyngeal involvement that might occur many years, even decades, after the initial onset of the disease. The annual rate of severe, life-threatening laryngeal edema was 0.9% in a recent retrospective study.⁴

Severity of the disease is variable. Attacks are episodic, and occur on average every 10 to 20 days in untreated patients. These attacks typically peak over 24 hours, then usually resolve after 48 to 72 hours. However, the complete resolution of signs and symptoms can last for up to one week after the attacks.⁵

There is no concomitant pruritus or urticaria that accompanies the AE. However, erythema marginatum, an evanescent nonpruritic rash with serpiginous borders involving the trunk and inner surface of extremities but sparing the face, might herald the onset of an episode. This rash usually has central pallor that blanches with pressure and worsens with heat.

HAE can be triggered by stressful events, including trauma, surgery, menstruation, and viral infections. However, in many instances, HAE attacks occur without an identifiable cause.⁵

Differential Diagnosis from Other Causes of Angioedema

Type I HAE is characterized by a quantitative C1INH deficiency (which is functionally abnormal as well), and occurs in 85% of patients. Type II HAE occurs in 15% of patients, and results from a functionally abnormal C1INH.

In patients with Type I and II HAE, as well as acquired C1 inhibitor deficiency (ACID), C4 levels are low during and between attacks. C2 levels are also low during acute attacks. In ACID, levels of C1q are also reduced; these patients require further workup to rule out an undiagnosed malignancy or an autoimmune process. In contrast, patients with ACE-induced, idiopathic, and allergic AE have normal complement profiles.^3,6

Type III is a more recently described type of HAE that is rare, not well understood, and generally affects women.^3,6 Clinically, it resembles Type I and Type II HAE but complement levels, including C1 inhibitor, are normal (see Table 1).

click for large version

click for large version

Treatment

HAE types I, II, III, and ACID are generally unresponsive to glucocorticoids, antihistamines, and epinephrine. These forms of AE may be exacerbated by exogenous estrogen.^1,8 For this reason, HAE patients should avoid oral hormonal contraception and estrogen replacement therapy. In addition, ACE inhibitors should also be avoided based on their effect on bradykinin degradation.

Until the introduction of newer therapeutic choices, as noted in our case, the treatment of acute attacks of AE was essentially supportive. Patients with impending laryngeal obstruction were managed with intubation prior to progression of the AE to limit airway patency. Prior to the modern era, a substantial proportion of HAE patients died of asphyxiation.

Fresh frozen plasma (FFP) has been used to treat acute HAE attacks, but given its content of contact system proteins (in addition to C1INH), FFP might also pose a risk for worsening of HAE; for this reason, it must be given cautiously to patients who are symptomatic.⁹

In the past decade, there has been significant progress in the available treatments for HAE. Currently in the U.S., there are several agents recently approved by, or have pending approvals from, the FDA, including several forms of C1INH replacement, a bradykinin antagonist, and a kallikrein inhibitor.

The C1 esterase inhibitor (human) drugs are administered intravenously; both have been shown to be efficacious and safe. Nanofiltered C1 inhibitor provided relief in a median time of two hours when used acutely; when used as prophylaxis, it decreased the number of attacks in a three-month period by 50% (six vs. 12 with placebo, P<0.001).¹¹

The other C1INH is rhucin, still not approved in U.S. This drug is characterized by a short half-life (approximately two to four hours) compared with the plasma-derived C1INH agents (24 to 48 hours). It is contraindicated in patients with rabbit hypersensitivity, as it is purified from rabbit breast milk.¹⁰

Ecallantide is a kallikrein inhibitor for acute therapy that is administered via three subcutaneous injections. This agent has been linked to allergic/anaphylactic reactions in a minority of patients (approximately 4%); therefore, it should be administered cautiously, by a health-care provider, and in a setting where anaphylaxis can be successfully managed.¹² Icatibant is a bradykinin antagonist recently approved in the U.S. and administered SC via a single injection.¹⁰

In light of the development of these new agents, there is a need for updated guidelines for the long- and short-term prophylaxis and acute management of HAE. A recent guideline focused on the management of HAE in gynecologic and obstetric patients recommended the use of plasma-derived C1INH C1 esterase inhibitor (human) (Cinryze) for short- and long-term prophylaxis and acute treatment of HAE.¹³ The effect of pregnancy on HAE is variable: Some women worsen and other women have less swelling during their pregnancy. Swelling at the time of parturition is rare; however, the risk rises during the post-partum period.

Type III HAE. An additional form of HAE has been recognized with a pattern of AE episodes that mimics Type I or Type II HAE but with unremarkable laboratory studies of the complement cascade, including C1 inhibitor level and function. At this time, there is no laboratory test with which a diagnosis of Type III HAE can be confirmed. The diagnosis should be suspected in patients with a strong family history of AE reflecting autosomal dominant inheritance. In some, but not all, cases, the condition is manifest in association with high estrogen levels (e.g. pregnancy or administration of oral contraceptives). Type III HAE patients have a salutary response to the same agents that are efficacious for Type I and II HAE.

Acquired C1 inhibitor deficiency (ACID). ACID generally occurs in adults and is clinically indistinguishable from HAE. ACID is not associated with a remarkable family history of AE. In contrast to HAE, this is a consumptive deficiency of C1 inhibitor and results from enhanced catabolism that exceeds the capacity for regenerating C1 inhibitor protein. It is often associated with neoplastic (usually lymphoproliferative) or autoimmune disorders; treatment of the underlying condition frequently leads to improvement in ACID. Although its management is similar to HAE, it tends to be more responsive to anti-fibrinolytics. A salutary response to C1INH replacement therapy might not occur in patients with autoantibodies to C1 inhibitor, but efficacy of ecallantide and icatibant for the treatment of acquired AE has been reported.^{14, 15}

ACEI angioedema. Treatment with angiotensin-converting enzyme inhibitors (ACE-I) has been associated with recurrent AE without urticaria in 0.1 to 0.7% of patients exposed to these drugs.¹⁶ Angioedema from ACE-I more frequently occurs within the first few months of therapy, but it might occur even after years of continuous therapy. ACEI-induced AE is secondary to impaired degradation of bradykinin. The main treatment is to discontinue the offending agent and avoid all other ACE-I, as this is a class-specific reaction.¹⁷

Angiotensin receptor blockers (ARBs) have been associated less commonly with AE. The mechanism for ARB-associated AE has not been elucidated. A meta-analysis showed that in 2% to 17% of patients who were switched to ARBs, recurrence of AE was observed.¹⁸ From the pooling of these data with two randomized controlled trials, it is estimated that approximately 10% or less of patients with ACEI-associated AE who switched to ARBs will develop AE.¹⁹ In the majority of cases, patients can be switched to ARBs with no recurrence of AE; however, the decision to prescribe an ARB to a patient who has had AE while receiving ACEI should be made carefully on an individualized risk/benefit basis.¹⁹

Preventive Treatment

The 17 α-alkylated androgens that can be used for treatment of HAE are danazol (Danacrine), stanozolol (Winstrol), oxandralone (Oxandrine) and methyltestosterone (Android). In patients with HAE, attenuated androgens can significantly reduce the frequency and severity of attacks; however, their use is limited by risk for untoward effects (virilization, abnormal liver function tests, change in libido, anxiety, etc.).²¹ There is also a risk for hepatotoxicity, including development of hepatic adenomas and hepatic carcinoma.

Antifibrinolytics also may have efficacy for HAE, but these agents have been associated with a variety of adverse effects, including nausea and diarrhea, postural hypotension, fatigue, enhanced thrombosis, retinal changes, and teratogenicity.^{8, 22, 23}

In 2009, long-term prophylaxis with C1-INH concentrate was recommended for patients with HAE with frequent or disabling attacks, a history of laryngeal attacks, and poor quality of life. The 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of HAE recommended long-term prophylaxis in patients with more than one monthly severe HAE attack, more than five days of disability per month, or any history of airway compromise.^{24, 25}

The decision to prescribe long-term prophylaxis, and the dose/frequency of medication required, should be individualized based on clinical parameters, such as frequency and severity of attacks, and not on C1 INH or C4 levels.

Perioperative Considerations

It is well established that any trauma, including dental procedures or surgery, can precipitate HAE attacks. For this reason, short-term prophylactic treatment in HAE patients undergoing procedures is recommended. Ideally, avoiding endotracheal intubation is the best approach; however, if intubation cannot be avoided, then adequate prophylaxis should be administered.²

Attenuated androgens can be given up to seven days before a procedure, or C1 INH can be administered 24 hours in advance. If C1 INH is unavailable, FFP can be given six to 12 hours in advance in patients who are not symptomatic; in case of endotracheal intubation, either FFP or C1 INH should be administered immediately before.²

Several case reports in multiple specialty surgical patients (abdominal surgery, cardiopulmonary bypass, orthopedic surgery, etc.) have confirmed the successful use of C1 INH in the prevention of acute attacks with favorable outcomes.²

There is no need to follow C1 INH levels, as it has no clinical relevance.

Back to the Case

The patient was admitted to the ICU and received a total of eight units of FFP. He was transferred to our institution and was able to be extubated three days after initial presentation. Laboratory studies revealed C4 10mg/dL and C1 esterase inhibitor 10mg/dL (both low).

Danazol was resumed. However, within several months after discharge, Cinryze became available in the U.S. market and was eventually prescribed. The patient has not had further significant attacks requiring inpatient management.

Dr. Auron is an assistant professor of medicine and pediatrics at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Dr. Lang is co-director of the Asthma Center and director of the Allergy/Immunology Fellowship Training Program at the Cleveland Clinic.

References

1. Bernstein, JA. Update on angioedema: evaluation, diagnosis, and treatment. Allergy Asthma Proc. 2011;32(6):408-412.
2. Levy JH, Freiberger DJ, Roback J. Hereditary angioedema: current and emerging treatment options. Anesth Analg. 2010;110(5):1271-1280.
3. Busse PJ. Angioedema: Differential diagnosis and treatment. Allergy Asthma Proc. 2011;32:Suppl 1:S3-S11.
4. Khan DA. Hereditary angioedema: historical aspects, classification, pathophysiology, clinical presentation, and laboratory diagnosis. Allergy Asthma Proc. 2011;32(1):1-10.
5. Bork K, Meng G, Staubach P, Hardt, J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006;119(3):267-274.
6. Zuraw BL, Christiansen SC. Pathogenesis and laboratory diagnosis of hereditary angioedema. Allergy Asthma Proc. 2009;30:487-492.
7. Frazer-Abel A, Giclas PC. Update on laboratory tests for the diagnosis and differentiation of hereditary angioedema and acquired angioedema. Allergy Asthma Proc. 2011;32:Suppl 1:S17-S21.
8. Banerjee A. Current treatment of hereditary angioedema: an update on clinical studies. Allergy Asthma Proc. 2010;31:398-406.
9. Donaldson VH. Therapy of "the neurotic edema." N Engl J Med. 1972;286(15):835-836.
10. Riedl MA. Update on the acute treatment of hereditary angioedema. Allergy Asthma Proc. 2011;32:11-16.
11. Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010;363:513-522.
12. Cicardi M, Levy RJ, McNeil DL. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. 2010;363:523-531.
13. Caballero T, Farkas H, Bouillet L, et al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol. 2012;129(2):308-320.
14. Cicardi M, Zanichelli A. Acquired angioedema. J Allergy Clin Immunol. 2010;6(1):14.
15. Zanichelli A, Badini M, Nataloni I, Montano N, Cicardi M. Treatment of acquired angioedema with icatibant: a case report. Intern Emerg Med. 2011;6(3):279-280.
16. Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor-associated angioedema. Immunol Allergy Clin North Am. 2006;26(4):725-737.
17. Haymore BR, Yoon J, Mikita CP, Klote MM, DeZee KJ. Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated with angiotensin-converting enzyme inhibitors: a meta-analysis. Ann Allergy Asthma Immunol. 2008;101(5):495-499.
18. Beavers CJ, Dunn SP, Macaulay TE. The role of angiotensin receptor blockers in patients with angiotensin-converting enzyme inhibitor-induced angioedema. Ann Pharmacother. 2011;45(4):520-524.
19. Nzeako UC. Diagnosis and management of angioedema with abdominal involvement: a gastroenterology perspective. World J Gastroenterol. 2010; 16(39):4913-4921.
20. Banerji A, Sloane DE, Sheffer AL. Hereditary angioedema: a current state-of-the-art review, V: attenuated androgens for the treatment of hereditary angioedema. Ann Allergy Asthma Immunol. 2008;100(1) (Suppl 2):S19-22.
21. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008; 359(10):1027-1036.
22. Zuraw BL. Hereditary angioedema: a current state-of-the-art review, IV: short- and long-term treatment of hereditary angioedema: out with the old and in with the new? Ann Allergy Asthma Immunol. 2008;100(1) (Suppl 2):S13-S18.
23. Bowen T, Cicardi M, Bork K, et al. Hereditary angioedema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann Allergy Asthma Immunol. 2008;100(1)(Suppl 2):S30-40.
24. Craig T, Riedl M, Dykewicz M, et al. When is prophylaxis for hereditary angioedema necessary? Ann Allergy Asthma Immunol. 2009.102(5):366-372.
25. Frank MM. Update on preventive therapy (prophylaxis) of hereditary angioedema. Allergy Asthma Proc. 2011;32(1):17-21.

click for large version

Case

A 36-year-old man with a known history of hereditary angioedema (HAE) presents with severe orofacial swelling and laryngeal angioedema, requiring expectant management, including endotracheal intubation. His previous angioedema (AE) episodes involved his hands, feet, and genitalia; episodes generally occurred after physical trauma. Ten years prior to admission, he had an episode of secondary small bowel obstruction. The patient had been prescribed prophylactic danazol (Danacrine) 100 mg BID but he had gradually been reducing the dosage due to mood changes; at the time of presentation, he had already tapered to 100 mg danazol three times per week (Monday, Wednesday, and Friday).

Overview

HAE is an autosomal dominant condition characterized by localized, episodic swelling of the deeper dermal layers and/or mucosal tissue. Its acute presentation can vary in severity; presentations can be lethal.

HAE is generally unresponsive to conventional treatments used for other causes of AE (e.g. food or drug reactions) including glucocorticoids, antihistamines, and epinephrine. The pharmacologic treatment of acute attacks, as well as for short- and long-term prophylaxis of HAE, has evolved significantly in recent years and now includes several forms of C1 inhibitor (C1INH) protein replacement, as well as a bradykinin antagonist, and a kallikrein inhibitor.

Review of the Data

Epidemiology. HAE is an autosomal dominant disease with prevalence in the U.S. of 1 in 10,000 to 1 in 50,000 patients. All ethnic groups are equally affected, with no gender predilection. In most cases, a positive family history is present; however, in 25% of cases, spontaneous mutations occur such that an unremarkable family history does not rule out the diagnosis.¹

Pathophysiology. In the past decade, there has been substantial advancement in our understanding of HAE pathophysiology. HAE occurs as a result of functional or quantitative C1 esterase inhibitor (C1INH) deficiency.

C1INH belongs to a group of proteins known as serpins (serine protease inhibitors). The C1INH gene is located on chromosome 11, and has several polymorphic sites, which predispose to spontaneous mutations.¹

Bradykinin is the core bioactive mediator, which causes vasodilation, smooth muscle contraction, and subsequent edema.¹ C1INH regulates bradykinin production by blocking kallikrein’s conversion of factor XII into XIIa, prekallikrein to kallikrein, and cleavage of high-molecular-weight kininogen by activated kallikrein to form bradykinin (see Figure 1).^1,2

click for large version

Clinical Manifestations

HAE is characterized by recurrent episodes of swelling, the frequency and severity of which are quite variable. Virtually all HAE patients have abdominal- and extremity-swelling episodes, and 50% will have episodes of laryngeal swelling; other involved areas might include the face, oropharynx, and genitalia.4 These episodes are usually unilateral; edema is nonpruritic, nonpitting, and often painless. Episodes involving the oropharynx, larynx, and abdomen can be associated with potentially serious morbidity and mortality.^{1, 3}

HAE episodes usually commence during late childhood and early puberty (on average at age 11). Approximately half of HAE patients will have oropharyngeal involvement that might occur many years, even decades, after the initial onset of the disease. The annual rate of severe, life-threatening laryngeal edema was 0.9% in a recent retrospective study.⁴

Severity of the disease is variable. Attacks are episodic, and occur on average every 10 to 20 days in untreated patients. These attacks typically peak over 24 hours, then usually resolve after 48 to 72 hours. However, the complete resolution of signs and symptoms can last for up to one week after the attacks.⁵

There is no concomitant pruritus or urticaria that accompanies the AE. However, erythema marginatum, an evanescent nonpruritic rash with serpiginous borders involving the trunk and inner surface of extremities but sparing the face, might herald the onset of an episode. This rash usually has central pallor that blanches with pressure and worsens with heat.

HAE can be triggered by stressful events, including trauma, surgery, menstruation, and viral infections. However, in many instances, HAE attacks occur without an identifiable cause.⁵

Differential Diagnosis from Other Causes of Angioedema

Type I HAE is characterized by a quantitative C1INH deficiency (which is functionally abnormal as well), and occurs in 85% of patients. Type II HAE occurs in 15% of patients, and results from a functionally abnormal C1INH.

In patients with Type I and II HAE, as well as acquired C1 inhibitor deficiency (ACID), C4 levels are low during and between attacks. C2 levels are also low during acute attacks. In ACID, levels of C1q are also reduced; these patients require further workup to rule out an undiagnosed malignancy or an autoimmune process. In contrast, patients with ACE-induced, idiopathic, and allergic AE have normal complement profiles.^3,6

Type III is a more recently described type of HAE that is rare, not well understood, and generally affects women.^3,6 Clinically, it resembles Type I and Type II HAE but complement levels, including C1 inhibitor, are normal (see Table 1).

click for large version

click for large version

Treatment

HAE types I, II, III, and ACID are generally unresponsive to glucocorticoids, antihistamines, and epinephrine. These forms of AE may be exacerbated by exogenous estrogen.^1,8 For this reason, HAE patients should avoid oral hormonal contraception and estrogen replacement therapy. In addition, ACE inhibitors should also be avoided based on their effect on bradykinin degradation.

Until the introduction of newer therapeutic choices, as noted in our case, the treatment of acute attacks of AE was essentially supportive. Patients with impending laryngeal obstruction were managed with intubation prior to progression of the AE to limit airway patency. Prior to the modern era, a substantial proportion of HAE patients died of asphyxiation.

Fresh frozen plasma (FFP) has been used to treat acute HAE attacks, but given its content of contact system proteins (in addition to C1INH), FFP might also pose a risk for worsening of HAE; for this reason, it must be given cautiously to patients who are symptomatic.⁹

In the past decade, there has been significant progress in the available treatments for HAE. Currently in the U.S., there are several agents recently approved by, or have pending approvals from, the FDA, including several forms of C1INH replacement, a bradykinin antagonist, and a kallikrein inhibitor.

The C1 esterase inhibitor (human) drugs are administered intravenously; both have been shown to be efficacious and safe. Nanofiltered C1 inhibitor provided relief in a median time of two hours when used acutely; when used as prophylaxis, it decreased the number of attacks in a three-month period by 50% (six vs. 12 with placebo, P<0.001).¹¹

The other C1INH is rhucin, still not approved in U.S. This drug is characterized by a short half-life (approximately two to four hours) compared with the plasma-derived C1INH agents (24 to 48 hours). It is contraindicated in patients with rabbit hypersensitivity, as it is purified from rabbit breast milk.¹⁰

Ecallantide is a kallikrein inhibitor for acute therapy that is administered via three subcutaneous injections. This agent has been linked to allergic/anaphylactic reactions in a minority of patients (approximately 4%); therefore, it should be administered cautiously, by a health-care provider, and in a setting where anaphylaxis can be successfully managed.¹² Icatibant is a bradykinin antagonist recently approved in the U.S. and administered SC via a single injection.¹⁰

In light of the development of these new agents, there is a need for updated guidelines for the long- and short-term prophylaxis and acute management of HAE. A recent guideline focused on the management of HAE in gynecologic and obstetric patients recommended the use of plasma-derived C1INH C1 esterase inhibitor (human) (Cinryze) for short- and long-term prophylaxis and acute treatment of HAE.¹³ The effect of pregnancy on HAE is variable: Some women worsen and other women have less swelling during their pregnancy. Swelling at the time of parturition is rare; however, the risk rises during the post-partum period.

Type III HAE. An additional form of HAE has been recognized with a pattern of AE episodes that mimics Type I or Type II HAE but with unremarkable laboratory studies of the complement cascade, including C1 inhibitor level and function. At this time, there is no laboratory test with which a diagnosis of Type III HAE can be confirmed. The diagnosis should be suspected in patients with a strong family history of AE reflecting autosomal dominant inheritance. In some, but not all, cases, the condition is manifest in association with high estrogen levels (e.g. pregnancy or administration of oral contraceptives). Type III HAE patients have a salutary response to the same agents that are efficacious for Type I and II HAE.

Acquired C1 inhibitor deficiency (ACID). ACID generally occurs in adults and is clinically indistinguishable from HAE. ACID is not associated with a remarkable family history of AE. In contrast to HAE, this is a consumptive deficiency of C1 inhibitor and results from enhanced catabolism that exceeds the capacity for regenerating C1 inhibitor protein. It is often associated with neoplastic (usually lymphoproliferative) or autoimmune disorders; treatment of the underlying condition frequently leads to improvement in ACID. Although its management is similar to HAE, it tends to be more responsive to anti-fibrinolytics. A salutary response to C1INH replacement therapy might not occur in patients with autoantibodies to C1 inhibitor, but efficacy of ecallantide and icatibant for the treatment of acquired AE has been reported.^{14, 15}

ACEI angioedema. Treatment with angiotensin-converting enzyme inhibitors (ACE-I) has been associated with recurrent AE without urticaria in 0.1 to 0.7% of patients exposed to these drugs.¹⁶ Angioedema from ACE-I more frequently occurs within the first few months of therapy, but it might occur even after years of continuous therapy. ACEI-induced AE is secondary to impaired degradation of bradykinin. The main treatment is to discontinue the offending agent and avoid all other ACE-I, as this is a class-specific reaction.¹⁷

Angiotensin receptor blockers (ARBs) have been associated less commonly with AE. The mechanism for ARB-associated AE has not been elucidated. A meta-analysis showed that in 2% to 17% of patients who were switched to ARBs, recurrence of AE was observed.¹⁸ From the pooling of these data with two randomized controlled trials, it is estimated that approximately 10% or less of patients with ACEI-associated AE who switched to ARBs will develop AE.¹⁹ In the majority of cases, patients can be switched to ARBs with no recurrence of AE; however, the decision to prescribe an ARB to a patient who has had AE while receiving ACEI should be made carefully on an individualized risk/benefit basis.¹⁹

Preventive Treatment

The 17 α-alkylated androgens that can be used for treatment of HAE are danazol (Danacrine), stanozolol (Winstrol), oxandralone (Oxandrine) and methyltestosterone (Android). In patients with HAE, attenuated androgens can significantly reduce the frequency and severity of attacks; however, their use is limited by risk for untoward effects (virilization, abnormal liver function tests, change in libido, anxiety, etc.).²¹ There is also a risk for hepatotoxicity, including development of hepatic adenomas and hepatic carcinoma.

Antifibrinolytics also may have efficacy for HAE, but these agents have been associated with a variety of adverse effects, including nausea and diarrhea, postural hypotension, fatigue, enhanced thrombosis, retinal changes, and teratogenicity.^{8, 22, 23}

In 2009, long-term prophylaxis with C1-INH concentrate was recommended for patients with HAE with frequent or disabling attacks, a history of laryngeal attacks, and poor quality of life. The 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of HAE recommended long-term prophylaxis in patients with more than one monthly severe HAE attack, more than five days of disability per month, or any history of airway compromise.^{24, 25}

The decision to prescribe long-term prophylaxis, and the dose/frequency of medication required, should be individualized based on clinical parameters, such as frequency and severity of attacks, and not on C1 INH or C4 levels.

Perioperative Considerations

It is well established that any trauma, including dental procedures or surgery, can precipitate HAE attacks. For this reason, short-term prophylactic treatment in HAE patients undergoing procedures is recommended. Ideally, avoiding endotracheal intubation is the best approach; however, if intubation cannot be avoided, then adequate prophylaxis should be administered.²

Attenuated androgens can be given up to seven days before a procedure, or C1 INH can be administered 24 hours in advance. If C1 INH is unavailable, FFP can be given six to 12 hours in advance in patients who are not symptomatic; in case of endotracheal intubation, either FFP or C1 INH should be administered immediately before.²

Several case reports in multiple specialty surgical patients (abdominal surgery, cardiopulmonary bypass, orthopedic surgery, etc.) have confirmed the successful use of C1 INH in the prevention of acute attacks with favorable outcomes.²

There is no need to follow C1 INH levels, as it has no clinical relevance.

Back to the Case

The patient was admitted to the ICU and received a total of eight units of FFP. He was transferred to our institution and was able to be extubated three days after initial presentation. Laboratory studies revealed C4 10mg/dL and C1 esterase inhibitor 10mg/dL (both low).

Danazol was resumed. However, within several months after discharge, Cinryze became available in the U.S. market and was eventually prescribed. The patient has not had further significant attacks requiring inpatient management.

Dr. Auron is an assistant professor of medicine and pediatrics at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Dr. Lang is co-director of the Asthma Center and director of the Allergy/Immunology Fellowship Training Program at the Cleveland Clinic.

References

1. Bernstein, JA. Update on angioedema: evaluation, diagnosis, and treatment. Allergy Asthma Proc. 2011;32(6):408-412.
2. Levy JH, Freiberger DJ, Roback J. Hereditary angioedema: current and emerging treatment options. Anesth Analg. 2010;110(5):1271-1280.
3. Busse PJ. Angioedema: Differential diagnosis and treatment. Allergy Asthma Proc. 2011;32:Suppl 1:S3-S11.
4. Khan DA. Hereditary angioedema: historical aspects, classification, pathophysiology, clinical presentation, and laboratory diagnosis. Allergy Asthma Proc. 2011;32(1):1-10.
5. Bork K, Meng G, Staubach P, Hardt, J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006;119(3):267-274.
6. Zuraw BL, Christiansen SC. Pathogenesis and laboratory diagnosis of hereditary angioedema. Allergy Asthma Proc. 2009;30:487-492.
7. Frazer-Abel A, Giclas PC. Update on laboratory tests for the diagnosis and differentiation of hereditary angioedema and acquired angioedema. Allergy Asthma Proc. 2011;32:Suppl 1:S17-S21.
8. Banerjee A. Current treatment of hereditary angioedema: an update on clinical studies. Allergy Asthma Proc. 2010;31:398-406.
9. Donaldson VH. Therapy of "the neurotic edema." N Engl J Med. 1972;286(15):835-836.
10. Riedl MA. Update on the acute treatment of hereditary angioedema. Allergy Asthma Proc. 2011;32:11-16.
11. Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010;363:513-522.
12. Cicardi M, Levy RJ, McNeil DL. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. 2010;363:523-531.
13. Caballero T, Farkas H, Bouillet L, et al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol. 2012;129(2):308-320.
14. Cicardi M, Zanichelli A. Acquired angioedema. J Allergy Clin Immunol. 2010;6(1):14.
15. Zanichelli A, Badini M, Nataloni I, Montano N, Cicardi M. Treatment of acquired angioedema with icatibant: a case report. Intern Emerg Med. 2011;6(3):279-280.
16. Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor-associated angioedema. Immunol Allergy Clin North Am. 2006;26(4):725-737.
17. Haymore BR, Yoon J, Mikita CP, Klote MM, DeZee KJ. Risk of angioedema with angiotensin receptor blockers in patients with prior angioedema associated with angiotensin-converting enzyme inhibitors: a meta-analysis. Ann Allergy Asthma Immunol. 2008;101(5):495-499.
18. Beavers CJ, Dunn SP, Macaulay TE. The role of angiotensin receptor blockers in patients with angiotensin-converting enzyme inhibitor-induced angioedema. Ann Pharmacother. 2011;45(4):520-524.
19. Nzeako UC. Diagnosis and management of angioedema with abdominal involvement: a gastroenterology perspective. World J Gastroenterol. 2010; 16(39):4913-4921.
20. Banerji A, Sloane DE, Sheffer AL. Hereditary angioedema: a current state-of-the-art review, V: attenuated androgens for the treatment of hereditary angioedema. Ann Allergy Asthma Immunol. 2008;100(1) (Suppl 2):S19-22.
21. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008; 359(10):1027-1036.
22. Zuraw BL. Hereditary angioedema: a current state-of-the-art review, IV: short- and long-term treatment of hereditary angioedema: out with the old and in with the new? Ann Allergy Asthma Immunol. 2008;100(1) (Suppl 2):S13-S18.
23. Bowen T, Cicardi M, Bork K, et al. Hereditary angioedema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann Allergy Asthma Immunol. 2008;100(1)(Suppl 2):S30-40.
24. Craig T, Riedl M, Dykewicz M, et al. When is prophylaxis for hereditary angioedema necessary? Ann Allergy Asthma Immunol. 2009.102(5):366-372.
25. Frank MM. Update on preventive therapy (prophylaxis) of hereditary angioedema. Allergy Asthma Proc. 2011;32(1):17-21.

Clinical question: Do weekend admissions for failure to thrive (FTT) result in higher costs and length of stay (LOS)?

Background: FTT accounts for up to 5% of all admissions for children younger than 2 years of age. The optimal approach to inpatient or outpatient care is not well defined. Hospitalizations sometimes are used to facilitate costly and intense workups for organic disease. Given the nonurgent nature of this condition and expected barriers to efficient workup on weekends, it is likely that weekend admissions for FTT might not add much value.

Study design: Retrospective cohort study.

Setting: Forty-two tertiary-care pediatric hospitals.

Synopsis: A total of 23,332 children younger than 2 were studied over an eight-year period. Saturday and Sunday admissions resulted in an average increase in LOS by 1.93 days and an increase in cost by $2,785 when compared with weekday admissions. Patients admitted on weekends were more likely to have imaging studies and lab tests performed, but were less likely to have a discharge diagnosis of FTT. The authors estimate that if one-half of the weekend admissions from 2010 with a consistent FTT diagnosis at admission and discharge were converted to a Monday admission, $534,145 in savings to the health-care system would result.

One notable limitation of the authors’ conclusions is that patients admitted on weekends appeared to have more organic diagnoses documented and might in fact have been more acutely ill, requiring more workup and intervention. Researchers were not able to further explore this using the administrative data. Nonetheless, a subset of weekend admissions with a consistent FTT diagnosis appeared to represent no value added to the system, and potentially could have resulted in a $3.5 million cost savings had they simply been admitted instead on a weekday.

Bottom line: Nonurgent weekend admissions for FTT are inefficient.

Citation: Thompson RT, Bennett WE, Finnell SME, Downs SM. Increased length of stay and costs associated with weekend admissions for failure to thrive. Pediatrics. 2012;131:e805-e810.

Reviewed by Pediatric Editor Mark Shen, MD, SFHM, medical director of hospital medicine at Dell Children's Medical Center, Austin, Texas.

Clinical question: Do weekend admissions for failure to thrive (FTT) result in higher costs and length of stay (LOS)?

Background: FTT accounts for up to 5% of all admissions for children younger than 2 years of age. The optimal approach to inpatient or outpatient care is not well defined. Hospitalizations sometimes are used to facilitate costly and intense workups for organic disease. Given the nonurgent nature of this condition and expected barriers to efficient workup on weekends, it is likely that weekend admissions for FTT might not add much value.

Study design: Retrospective cohort study.

Setting: Forty-two tertiary-care pediatric hospitals.

Synopsis: A total of 23,332 children younger than 2 were studied over an eight-year period. Saturday and Sunday admissions resulted in an average increase in LOS by 1.93 days and an increase in cost by $2,785 when compared with weekday admissions. Patients admitted on weekends were more likely to have imaging studies and lab tests performed, but were less likely to have a discharge diagnosis of FTT. The authors estimate that if one-half of the weekend admissions from 2010 with a consistent FTT diagnosis at admission and discharge were converted to a Monday admission, $534,145 in savings to the health-care system would result.

One notable limitation of the authors’ conclusions is that patients admitted on weekends appeared to have more organic diagnoses documented and might in fact have been more acutely ill, requiring more workup and intervention. Researchers were not able to further explore this using the administrative data. Nonetheless, a subset of weekend admissions with a consistent FTT diagnosis appeared to represent no value added to the system, and potentially could have resulted in a $3.5 million cost savings had they simply been admitted instead on a weekday.

Bottom line: Nonurgent weekend admissions for FTT are inefficient.

Citation: Thompson RT, Bennett WE, Finnell SME, Downs SM. Increased length of stay and costs associated with weekend admissions for failure to thrive. Pediatrics. 2012;131:e805-e810.

Reviewed by Pediatric Editor Mark Shen, MD, SFHM, medical director of hospital medicine at Dell Children's Medical Center, Austin, Texas.

Clinical question: Do weekend admissions for failure to thrive (FTT) result in higher costs and length of stay (LOS)?

Background: FTT accounts for up to 5% of all admissions for children younger than 2 years of age. The optimal approach to inpatient or outpatient care is not well defined. Hospitalizations sometimes are used to facilitate costly and intense workups for organic disease. Given the nonurgent nature of this condition and expected barriers to efficient workup on weekends, it is likely that weekend admissions for FTT might not add much value.

Study design: Retrospective cohort study.

Setting: Forty-two tertiary-care pediatric hospitals.

Synopsis: A total of 23,332 children younger than 2 were studied over an eight-year period. Saturday and Sunday admissions resulted in an average increase in LOS by 1.93 days and an increase in cost by $2,785 when compared with weekday admissions. Patients admitted on weekends were more likely to have imaging studies and lab tests performed, but were less likely to have a discharge diagnosis of FTT. The authors estimate that if one-half of the weekend admissions from 2010 with a consistent FTT diagnosis at admission and discharge were converted to a Monday admission, $534,145 in savings to the health-care system would result.

One notable limitation of the authors’ conclusions is that patients admitted on weekends appeared to have more organic diagnoses documented and might in fact have been more acutely ill, requiring more workup and intervention. Researchers were not able to further explore this using the administrative data. Nonetheless, a subset of weekend admissions with a consistent FTT diagnosis appeared to represent no value added to the system, and potentially could have resulted in a $3.5 million cost savings had they simply been admitted instead on a weekday.

Bottom line: Nonurgent weekend admissions for FTT are inefficient.

Citation: Thompson RT, Bennett WE, Finnell SME, Downs SM. Increased length of stay and costs associated with weekend admissions for failure to thrive. Pediatrics. 2012;131:e805-e810.

Reviewed by Pediatric Editor Mark Shen, MD, SFHM, medical director of hospital medicine at Dell Children's Medical Center, Austin, Texas.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Prices for common hospital procedures not readily available
2. Antibiotics associated with decreased mortality in acute COPD exacerbation
3. Endovascular therapy has no benefit to systemic t-PA in acute stroke
4. Net harm observed with rivaroxaban for thromboprophylaxis
5. Noninvasive ventilation more effective, safer for AECOPD patients
6. Synthetic cannabinoid use and acute kidney injury
7. Dabigatran vs. warfarin in the extended treatment of VTE
8. Spironolactone improves diastolic function
9. Real-time EMR-based prediction tool for clinical deterioration
10. Hypothermia protocol and cardiac arrest

Prices for Common Hospital Procedures Not Readily Available

Clinical question: Are patients able to select health-care providers based on price of service?

Background: With health-care costs rising, patients are encouraged to take a more active role in cost containment. Many initiatives call for greater pricing transparency in the health-care system. This study evaluated price availability for a common surgical procedure.

Study design: Telephone inquiries with standardized interview script.

Setting: Twenty top-ranked orthopedic hospitals and 102 non-top-ranked U.S. hospitals.

Synopsis: Hospitals were contacted by phone with a standardized, scripted request for their price of an elective total hip arthroplasty. The script described the patient as a 62-year-old grandmother without insurance who is able to pay out of pocket and wishes to compare hospital prices. On the first or second attempt, 40% of top-ranked and 32% of non-top-ranked hospitals were able to provide their price; after five attempts, authors were unable to obtain full pricing information (both hospital and physician fee) from 40% of top-ranked and 37% of non-top-ranked hospitals. Neither fee was made available by 15% of top-ranked and 16% of non-top-ranked hospitals. Wide variation of pricing was found across hospitals. The authors commented on the difficulties they encountered, such as the transfer of calls between departments and the uncertainty of representatives on how to assist.

Bottom line: For individual patients, applying basic economic principles as a consumer might be tiresome and often impossible, with no major differences between top-ranked and non-top-ranked hospitals.

Citation: Rosenthal JA, Lu X, Cram P. Availability of consumer prices from US hospitals for a common surgical procedure. JAMA Intern Med. 2013;173(6):427-432.

Antibiotics Associated with Decreased Mortality in Acute COPD Exacerbation

Clinical question: Do antibiotics when added to systemic steroids provide clinical benefit for patients with acute COPD exacerbation?

Background: Despite widespread use of antibiotics in the treatment of acute COPD, their benefit is not clear.

Study design: Retrospective cohort study.Setting: Four hundred ten U.S. hospitals participating in Perspective, an inpatient administrative database.

Synopsis: More than 50,000 patients treated with systemic steroids for acute COPD exacerbation were included in this study; 85% of them received empiric antibiotics within the first two hospital days. They were compared with those treated with systemic steroids alone. In-hospital mortality was 1.02% for patients on steroids plus antibiotics versus 1.78% on steroids alone. Use of antibiotics was associated with a 40% reduction in the odds of in-hospital mortality (OR, 0.60; 95% CI, 0.50-0.74) and reduced readmissions. In an analysis of matched cohorts, hospital mortality was 1% for patients on antibiotics and 1.8% for patients without antibiotics (OR, 0.53; 95% CI, 0.40-0.71). The risk for readmission for Clostridium difficile colitis was not different between the groups, but other potential adverse effects of antibiotic use, such as development of resistant micro-organisms, were not studied. In a subset analysis, three groups of antibiotics were compared: macrolides, quinolones, and cephalosporins. None was better than another, but those treated with macrolides had a lower readmission rate for C. diff.

Bottom line: Treatment with antibiotics when added to systemic steroids is associated with improved outcomes in acute COPD exacerbations, but there is no clear advantage of one antibiotic class over another.

Citation: Stefan MS, Rothberg MB, Shieh M, Pekow PS, Lindenauer PK. Association between antibiotic treatment and outcomes in patients hospitalized with acute exacerbation of COPD treated with systemic steroids. Chest. 2013;143(1):82-90.

Endovascular Therapy Added to Systemic t-PA Has No Benefit in Acute Stroke

Clinical question: Does adding endovascular therapy to intravenous tissue plasminogen activator (t-PA) reduce disability in acute stroke?

Background: Early systemic t-PA is the only proven reperfusion therapy in acute stroke, but it is unknown if adding localized endovascular therapy is beneficial.

Study design: Randomized, open-label, blinded-outcome trial.

Setting: Fifty-eight centers in North America, Europe, and Australia.

Synopsis: Patients aged 18 to 82 with acute ischemic stroke were eligible if they received t-PA within three hours of enrollment and had moderate to severe neurologic deficit (National Institutes of Health Stroke Scale [NIHSS] >10, or NIHSS 8 or 9 with CT angiographic evidence of specific major artery occlusion). All patients received standard-dose t-PA; those randomized to endovascular treatment underwent angiography, and, if indicated, underwent one of the endovascular treatments chosen by the neurointerventionalist. The primary outcome measure was a modified Rankin score of 2 or lower (indicating functional independence) at 90 days (assessed by a neurologist).

After enrollment of 656 patients, the trial was terminated early for futility. There was no significant difference in the primary outcome, with 40.8% of patients in the endovascular intervention group and 38.7% in the t-PA-only group having a modified Rankin score of 2 or lower. There was also no difference in mortality or other secondary outcomes, even when the analysis was limited to patients presenting with more severe neurologic deficits.

Bottom line: The addition of endovascular therapy to systemic t-PA in acute ischemic stroke does not improve functional outcomes or mortality.

Citation: Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368:893-903.

Rivaroxaban Compared with Enoxaparin for Thromboprophylaxis

Clinical question: Is extended-duration rivaroxaban more effective than standard-duration enoxaparin in preventing deep venous thrombosis in acutely ill medical patients?

Background: Trials have shown benefits of thromboprophylaxis in acutely ill medical patients at increased risk of venous thrombosis, but the optimal duration and type of anticoagulation is unknown.

Study design: Prospective, randomized, double-blinded, active-comparator controlled trial.

Setting: Five hundred fifty-two centers in 52 countries.

Synopsis: The trial enrolled 8,428 patients hospitalized with an acute medical condition and reduced mobility. Patients were randomized to receive either enoxaparin for 10 (+/-4) days or rivaroxaban for 35 (+/-4) days. The co-primary composite outcomes were the incidence of asymptomatic proximal deep venous thrombosis, symptomatic deep venous thrombosis, pulmonary embolism, or death related to venous thromboembolism over 10 days and over 35 days.

Both groups had a 2.7% incidence of the primary endpoint over 10 days; over 35 days, the extended-duration rivaroxaban group had a reduced incidence of the primary endpoint of 4.4% compared with 5.7% for enoxaparin. However, there was an increase of clinically relevant bleeding in the rivaroxaban group, occurring in 2.8% and 4.1% of patients over 10 and 35 days, respectively, compared with 1.2% and 1.7% for enoxaparin.

Overall, there was net harm with rivaroxaban over both time periods: 6.6% and 9.4% of patients in the rivaroxaban group had a negative outcome at 10 and 35 days, compared with 4.4% and 7.8% with enoxaparin.

Bottom line: There was net harm with extended-duration rivaroxaban versus standard-duration enoxaparin for thromboprophylaxis in hospitalized medical patients.

Citation: Cohen AT, Spiro TE, Büller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368:513-523.

Noninvasive Ventilation More Effective, Safer for Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD)

Clinical question: What are the patterns in use of noninvasive ventilation (NIV) and invasive mechanical ventilation (IMV) in patients with AECOPD, and which method produces better outcomes?

Background: Multiple randomized controlled trials and meta-analyses have suggested a mortality benefit with NIV compared to standard medical care in AECOPD. However, little evidence exists on head-to-head comparisons of NIV and IMV.

Study design: Retrospective cohort study.

Setting: Non-federal, short-term, general, and other specialty hospitals nationwide.

Synopsis: A sample of 67,651 ED visits for AECOPD with acute respiratory failure was analyzed from the National Emergency Department Sample (NEDS) database between 2006 and 2008. The study found that NIV use increased to 16% in 2008 from 14% in 2006. Use varied widely between hospitals and was more utilized in higher-case-volume, nonmetropolitan, and Northeastern hospitals. Compared with IMV, NIV was associated with 46% lower inpatient mortality (risk ratio 0.54, 95% confidence interval [CI] 0.50-0.59), shortened hospital length of stay (-3.2 days, 95% CI -3.4 to -2.9), lower hospital charges (-$35,012, 95% CI -$36,848 to -$33,176), and lower risk of iatrogenic pneumothorax (0.05% vs. 0.5%, P<0.001). Causality could not be established given the observational study design.

Bottom line: NIV is associated with better outcomes than IMV in the management of AECOPD, and might be underutilized.

Citation: Tsai CL, Lee WY, Delclos GL, Hanania NA, Camargo CA Jr. Comparative effectiveness of noninvasive ventilation vs. invasive mechanical ventilation in chronic obstructive pulmonary disease patients with acute respiratory failure. J Hosp Med. 2013;8(4):165-172.

Synthetic Cannabinoid Use May Cause Acute Kidney Injury

Clinical question: Are synthetic cannabinoids associated with acute kidney injury (AKI)?

Background: Synthetic cannabinoids are designer drugs of abuse with a growing popularity in the U.S.

Study design: Retrospective case series.

Setting: Hospitals in Wyoming, Oklahoma, Rhode Island, New York, Kansas, and Oregon.

Synopsis: The Centers for Disease Control and Prevention (CDC) issued an alert when 16 cases of unexplained AKI after exposure to synthetic cannabinoids were reported between March and December 2012. Synthetic cannabinoid use is associated with neurologic, sympathomimetic, and cardiovascular toxicity; however, this is the first case series reporting renal toxicity. The 16 patients included 15 males and one female, aged 15-33 years, with no pre-existing renal disease or nephrotoxic medication consumption. All used synthetic cannabinoids within hours to days before developing nausea, vomiting, abdominal, and flank and/or back pain.

Creatinine peaked one to six days after symptom onset. Five patients required hemodialysis, and all 16 recovered. There was no finding specific for all cases on ultrasound and/or biopsy. Toxicologic analysis of specimens was possible in seven cases and revealed a previously unreported fluorinated synthetic cannabinoid compound XLR-11 in all clinical specimens of patients who used the drug within two days of being tested.

Overall, the analysis did not reveal any single compound or brand that could explain all cases.

Bottom line: Clinicians should be aware of the potential for renal or other toxicities in users of synthetic cannabinoid products and should ask about their use in cases of unexplained AKI.

Citation: Murphy TD, Weidenbach KN, Van Houten C, et al. Centers for Disease Control and Prevention. Acute kidney injury associated with synthetic cannabinoid use—multiple states, 2012. MMWR Morb Mortal Wkly Rep. 2013;62(6):93-98.

Dabigatran versus Warfarin in Extended VTE Treatment

Clinical question: Is dabigatran suitable for extended treatment VTE?

Background: In contrast to warfarin (Coumadin), dabigatran (Pradaxa) is given in a fixed dose and does not require frequent laboratory monitoring. Dabigatran has been shown to be noninferior to warfarin in the initial six-month treatment of VTE.

Study design: Two double-blinded, randomized trials: an active-control study and a placebo-control study.

Setting: Two hundred sixty-five sites in 33 countries for the active-control study, and 147 sites in 21 countries for the placebo-control study.

Synopsis: This study enrolled 4,299 adult patients with objectively confirmed, symptomatic, proximal deep vein thrombosis or pulmonary embolism. In the active-control study comparing warfarin and dabigatran, recurrent objectively confirmed symptomatic or fatal VTE was observed in 1.8% of patients in the dabigatran group compared with 1.3% of patients in the warfarin group (P=0.01 for noninferiority). While major or clinically relevant bleeding was less frequent with dabigatran compared to warfarin (hazard ratio, 0.54), more acute coronary syndromes were observed with dabigatran (0.9% vs. 0.2%, P=0.02). In the placebo-control study, symptomatic or fatal VTE was observed in 0.4% of patients in the dabigatran group compared with 5.6% in the placebo group. Clinically relevant bleeding was more common with dabigatran (5.3% vs. 1.8%; hazard ratio 2.92).

Bottom line: Treatment with dabigatran met the pre-specified noninferiority margin in this study. However, it is worth noting that patients with VTE given extended treatment with dabigatran had significantly higher rates of recurrent symptomatic or fatal VTE than patients treated with warfarin.

Citation: Schulman S, Kearson C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709-718.

Spironolactone Improves Diastolic Function

Clinical question: What is the efficacy of aldosterone receptor blockers on diastolic function and exercise capacity?

Background: Mineralocorticoid receptor activation by aldosterone contributes to the pathophysiology of heart failure (HF) in patients with and without reduced ejection fraction (EF). Aldosterone receptor blockers (spironolactone) reduce overall and cardiovascular mortality in HF patients with reduced EF; however, its effect on HF patients with preserved EF is unknown.

Study design: Prospective, randomized, double-blinded, placebo-controlled trial.

Setting: Ten ambulatory sites in Germany and Austria.

Synopsis: This study enrolled 422 men and women, aged 50 or older, with New York Heart Association (NYHA) Class II or III HF and preserved EF, and randomized them to receive spironolactone 25 mg daily or placebo for one year.

The endpoints included echocardiographic measures of diastolic function and remodeling; N-terminal pro b-type natriuretic peptide (NT pro-BNP) levels; exercise capacity; quality of life; and HF symptoms.

In the spironolactone group, there was significant improvement in echocardiographic measures of diastolic function and remodeling as well as NT pro-BNP levels. However, there was no difference in exercise capacity, quality of life, or HF symptoms when compared to placebo.

The spironolactone group had significantly lower blood pressure than the control group, which may account for some of the remodeling effects. The study may have been underpowered, and the study population might not have had severe enough disease to detect a difference in clinical measures. It remains unknown if structural changes on echocardiography will translate into clinical benefits.

Bottom line: Compared to placebo, spironolactone did improve diastolic function by echo but did not improve exercise capacity.

Citation: Edelmann F, Wachter R, Schmidt A, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA. 2013;309(8):781-791.

Real-Time, EMR-Based Prediction Tool Accurately Predicts ICU Transfer Risks

Clinical question: Can clinical deterioration be accurately predicted using real-time data from an electronic medical record (EMR), and can it lead to better outcomes using a floor-based intervention?

Background: Research has shown that EMR-based prediction tools can help identify real-time clinical deterioration in ward patients, but an intervention based on these computer-based alerts has not been shown to be effective.

Study design: Randomized controlled crossover study.

Setting: Eight adult medicine wards in an academic medical center in the Midwest.

Synopsis: There were 20,031 patients assigned to intervention versus control based on their floor location. Computerized alerts were generated using a prediction algorithm. For patients admitted to intervention wards, the alerts were sent to the charge nurse via pager. Patients meeting the alert threshold based on the computerized prediction tool had five times higher risk of ICU transfer, and nine times higher risk of death than patients not meeting the alert threshold. Intervention of charge nurse notification via pager did not result in any significant change in length of stay (LOS), ICU transfer, or mortality. Charge nurses in the intervention group were supposed to alert a physician after receiving the computer alert, but the authors did not measure how often this occurred.

Bottom line: A real-time EMR-based prediction tool accurately predicts higher risk of ICU transfer and death, as well as LOS, but a floor-based intervention to alert the charge nurse in real time did not lead to better outcomes.

Citation: Bailey TC, Chen Y, Mao Y, et al. A trial of a real-time alert for clinical deterioration in patients hospitalized on general medicine wards. J Hosp Med. 2013 Feb 25. doi: 10.1002/jhm.2009 [Epub ahead of print].

Hypothermia Protocol and Cardiac Arrest

Clinical question: Is mild therapeutic hypothermia (MTH) following cardiac arrest beneficial and safe?

Background: Those with sudden cardiac arrest often have poor neurologic outcome. There are some studies that show benefit with hypothermia, but information on safety is limited.

Study design: Meta-analysis.

Setting: Europe, the United Kingdom, the U.S., Canada, Japan, and South Korea.

Synopsis: This study pooled data from 63 studies that looked at MTH protocols in the setting of comatose patients as a result of cardiac arrest. The end points included mortality and any complication potentially attributed to the MTH.

When restricting the analysis to include only randomized controlled trials, MTH was associated with decreased risk of in-hospital mortality (RR=0.75, 95% CI: 0.62-0.92), 30-day mortality (RR=0.61, 95% CI 0.45-0.81), and six-month mortality (RR=0.73, 95% CI 0.61-0.88). MTH was associated with increased risk of arrhythmia (RR=1.25, 95% CI: 1.00-1.55) and hypokalemia (RR=2.35, 95% CI: 1.35-4.11); all other complications were similar between groups.

There were inconsistent results regarding benefit in pediatric patients, as well as comatose patients with non-ventricular fibrillation (non-v-fib) arrest (i.e. asystole or pulseless electrical activity).

Bottom line: Mild therapeutic hypothermia can improve survival of comatose patients after v-fib cardiac arrest and is generally safe.

Citation: Xiao G, Guo Q, Xie X, et al. Safety profile and outcome of mild therapeutic hypothermia in patients following cardiac arrest: systematic review and meta-analysis. Emerg Med J. 2013;30:90-100.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Prices for common hospital procedures not readily available
2. Antibiotics associated with decreased mortality in acute COPD exacerbation
3. Endovascular therapy has no benefit to systemic t-PA in acute stroke
4. Net harm observed with rivaroxaban for thromboprophylaxis
5. Noninvasive ventilation more effective, safer for AECOPD patients
6. Synthetic cannabinoid use and acute kidney injury
7. Dabigatran vs. warfarin in the extended treatment of VTE
8. Spironolactone improves diastolic function
9. Real-time EMR-based prediction tool for clinical deterioration
10. Hypothermia protocol and cardiac arrest

Prices for Common Hospital Procedures Not Readily Available

Clinical question: Are patients able to select health-care providers based on price of service?

Background: With health-care costs rising, patients are encouraged to take a more active role in cost containment. Many initiatives call for greater pricing transparency in the health-care system. This study evaluated price availability for a common surgical procedure.

Study design: Telephone inquiries with standardized interview script.

Setting: Twenty top-ranked orthopedic hospitals and 102 non-top-ranked U.S. hospitals.

Synopsis: Hospitals were contacted by phone with a standardized, scripted request for their price of an elective total hip arthroplasty. The script described the patient as a 62-year-old grandmother without insurance who is able to pay out of pocket and wishes to compare hospital prices. On the first or second attempt, 40% of top-ranked and 32% of non-top-ranked hospitals were able to provide their price; after five attempts, authors were unable to obtain full pricing information (both hospital and physician fee) from 40% of top-ranked and 37% of non-top-ranked hospitals. Neither fee was made available by 15% of top-ranked and 16% of non-top-ranked hospitals. Wide variation of pricing was found across hospitals. The authors commented on the difficulties they encountered, such as the transfer of calls between departments and the uncertainty of representatives on how to assist.

Bottom line: For individual patients, applying basic economic principles as a consumer might be tiresome and often impossible, with no major differences between top-ranked and non-top-ranked hospitals.

Citation: Rosenthal JA, Lu X, Cram P. Availability of consumer prices from US hospitals for a common surgical procedure. JAMA Intern Med. 2013;173(6):427-432.

Antibiotics Associated with Decreased Mortality in Acute COPD Exacerbation

Clinical question: Do antibiotics when added to systemic steroids provide clinical benefit for patients with acute COPD exacerbation?

Background: Despite widespread use of antibiotics in the treatment of acute COPD, their benefit is not clear.

Study design: Retrospective cohort study.Setting: Four hundred ten U.S. hospitals participating in Perspective, an inpatient administrative database.

Synopsis: More than 50,000 patients treated with systemic steroids for acute COPD exacerbation were included in this study; 85% of them received empiric antibiotics within the first two hospital days. They were compared with those treated with systemic steroids alone. In-hospital mortality was 1.02% for patients on steroids plus antibiotics versus 1.78% on steroids alone. Use of antibiotics was associated with a 40% reduction in the odds of in-hospital mortality (OR, 0.60; 95% CI, 0.50-0.74) and reduced readmissions. In an analysis of matched cohorts, hospital mortality was 1% for patients on antibiotics and 1.8% for patients without antibiotics (OR, 0.53; 95% CI, 0.40-0.71). The risk for readmission for Clostridium difficile colitis was not different between the groups, but other potential adverse effects of antibiotic use, such as development of resistant micro-organisms, were not studied. In a subset analysis, three groups of antibiotics were compared: macrolides, quinolones, and cephalosporins. None was better than another, but those treated with macrolides had a lower readmission rate for C. diff.

Bottom line: Treatment with antibiotics when added to systemic steroids is associated with improved outcomes in acute COPD exacerbations, but there is no clear advantage of one antibiotic class over another.

Citation: Stefan MS, Rothberg MB, Shieh M, Pekow PS, Lindenauer PK. Association between antibiotic treatment and outcomes in patients hospitalized with acute exacerbation of COPD treated with systemic steroids. Chest. 2013;143(1):82-90.

Endovascular Therapy Added to Systemic t-PA Has No Benefit in Acute Stroke

Clinical question: Does adding endovascular therapy to intravenous tissue plasminogen activator (t-PA) reduce disability in acute stroke?

Background: Early systemic t-PA is the only proven reperfusion therapy in acute stroke, but it is unknown if adding localized endovascular therapy is beneficial.

Study design: Randomized, open-label, blinded-outcome trial.

Setting: Fifty-eight centers in North America, Europe, and Australia.

Synopsis: Patients aged 18 to 82 with acute ischemic stroke were eligible if they received t-PA within three hours of enrollment and had moderate to severe neurologic deficit (National Institutes of Health Stroke Scale [NIHSS] >10, or NIHSS 8 or 9 with CT angiographic evidence of specific major artery occlusion). All patients received standard-dose t-PA; those randomized to endovascular treatment underwent angiography, and, if indicated, underwent one of the endovascular treatments chosen by the neurointerventionalist. The primary outcome measure was a modified Rankin score of 2 or lower (indicating functional independence) at 90 days (assessed by a neurologist).

After enrollment of 656 patients, the trial was terminated early for futility. There was no significant difference in the primary outcome, with 40.8% of patients in the endovascular intervention group and 38.7% in the t-PA-only group having a modified Rankin score of 2 or lower. There was also no difference in mortality or other secondary outcomes, even when the analysis was limited to patients presenting with more severe neurologic deficits.

Bottom line: The addition of endovascular therapy to systemic t-PA in acute ischemic stroke does not improve functional outcomes or mortality.

Citation: Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368:893-903.

Rivaroxaban Compared with Enoxaparin for Thromboprophylaxis

Clinical question: Is extended-duration rivaroxaban more effective than standard-duration enoxaparin in preventing deep venous thrombosis in acutely ill medical patients?

Background: Trials have shown benefits of thromboprophylaxis in acutely ill medical patients at increased risk of venous thrombosis, but the optimal duration and type of anticoagulation is unknown.

Study design: Prospective, randomized, double-blinded, active-comparator controlled trial.

Setting: Five hundred fifty-two centers in 52 countries.

Synopsis: The trial enrolled 8,428 patients hospitalized with an acute medical condition and reduced mobility. Patients were randomized to receive either enoxaparin for 10 (+/-4) days or rivaroxaban for 35 (+/-4) days. The co-primary composite outcomes were the incidence of asymptomatic proximal deep venous thrombosis, symptomatic deep venous thrombosis, pulmonary embolism, or death related to venous thromboembolism over 10 days and over 35 days.

Both groups had a 2.7% incidence of the primary endpoint over 10 days; over 35 days, the extended-duration rivaroxaban group had a reduced incidence of the primary endpoint of 4.4% compared with 5.7% for enoxaparin. However, there was an increase of clinically relevant bleeding in the rivaroxaban group, occurring in 2.8% and 4.1% of patients over 10 and 35 days, respectively, compared with 1.2% and 1.7% for enoxaparin.

Overall, there was net harm with rivaroxaban over both time periods: 6.6% and 9.4% of patients in the rivaroxaban group had a negative outcome at 10 and 35 days, compared with 4.4% and 7.8% with enoxaparin.

Bottom line: There was net harm with extended-duration rivaroxaban versus standard-duration enoxaparin for thromboprophylaxis in hospitalized medical patients.

Citation: Cohen AT, Spiro TE, Büller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368:513-523.

Noninvasive Ventilation More Effective, Safer for Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD)

Clinical question: What are the patterns in use of noninvasive ventilation (NIV) and invasive mechanical ventilation (IMV) in patients with AECOPD, and which method produces better outcomes?

Background: Multiple randomized controlled trials and meta-analyses have suggested a mortality benefit with NIV compared to standard medical care in AECOPD. However, little evidence exists on head-to-head comparisons of NIV and IMV.

Study design: Retrospective cohort study.

Setting: Non-federal, short-term, general, and other specialty hospitals nationwide.

Synopsis: A sample of 67,651 ED visits for AECOPD with acute respiratory failure was analyzed from the National Emergency Department Sample (NEDS) database between 2006 and 2008. The study found that NIV use increased to 16% in 2008 from 14% in 2006. Use varied widely between hospitals and was more utilized in higher-case-volume, nonmetropolitan, and Northeastern hospitals. Compared with IMV, NIV was associated with 46% lower inpatient mortality (risk ratio 0.54, 95% confidence interval [CI] 0.50-0.59), shortened hospital length of stay (-3.2 days, 95% CI -3.4 to -2.9), lower hospital charges (-$35,012, 95% CI -$36,848 to -$33,176), and lower risk of iatrogenic pneumothorax (0.05% vs. 0.5%, P<0.001). Causality could not be established given the observational study design.

Bottom line: NIV is associated with better outcomes than IMV in the management of AECOPD, and might be underutilized.

Citation: Tsai CL, Lee WY, Delclos GL, Hanania NA, Camargo CA Jr. Comparative effectiveness of noninvasive ventilation vs. invasive mechanical ventilation in chronic obstructive pulmonary disease patients with acute respiratory failure. J Hosp Med. 2013;8(4):165-172.

Synthetic Cannabinoid Use May Cause Acute Kidney Injury

Clinical question: Are synthetic cannabinoids associated with acute kidney injury (AKI)?

Background: Synthetic cannabinoids are designer drugs of abuse with a growing popularity in the U.S.

Study design: Retrospective case series.

Setting: Hospitals in Wyoming, Oklahoma, Rhode Island, New York, Kansas, and Oregon.

Synopsis: The Centers for Disease Control and Prevention (CDC) issued an alert when 16 cases of unexplained AKI after exposure to synthetic cannabinoids were reported between March and December 2012. Synthetic cannabinoid use is associated with neurologic, sympathomimetic, and cardiovascular toxicity; however, this is the first case series reporting renal toxicity. The 16 patients included 15 males and one female, aged 15-33 years, with no pre-existing renal disease or nephrotoxic medication consumption. All used synthetic cannabinoids within hours to days before developing nausea, vomiting, abdominal, and flank and/or back pain.

Creatinine peaked one to six days after symptom onset. Five patients required hemodialysis, and all 16 recovered. There was no finding specific for all cases on ultrasound and/or biopsy. Toxicologic analysis of specimens was possible in seven cases and revealed a previously unreported fluorinated synthetic cannabinoid compound XLR-11 in all clinical specimens of patients who used the drug within two days of being tested.

Overall, the analysis did not reveal any single compound or brand that could explain all cases.

Bottom line: Clinicians should be aware of the potential for renal or other toxicities in users of synthetic cannabinoid products and should ask about their use in cases of unexplained AKI.

Citation: Murphy TD, Weidenbach KN, Van Houten C, et al. Centers for Disease Control and Prevention. Acute kidney injury associated with synthetic cannabinoid use—multiple states, 2012. MMWR Morb Mortal Wkly Rep. 2013;62(6):93-98.

Dabigatran versus Warfarin in Extended VTE Treatment

Clinical question: Is dabigatran suitable for extended treatment VTE?

Background: In contrast to warfarin (Coumadin), dabigatran (Pradaxa) is given in a fixed dose and does not require frequent laboratory monitoring. Dabigatran has been shown to be noninferior to warfarin in the initial six-month treatment of VTE.

Study design: Two double-blinded, randomized trials: an active-control study and a placebo-control study.

Setting: Two hundred sixty-five sites in 33 countries for the active-control study, and 147 sites in 21 countries for the placebo-control study.

Synopsis: This study enrolled 4,299 adult patients with objectively confirmed, symptomatic, proximal deep vein thrombosis or pulmonary embolism. In the active-control study comparing warfarin and dabigatran, recurrent objectively confirmed symptomatic or fatal VTE was observed in 1.8% of patients in the dabigatran group compared with 1.3% of patients in the warfarin group (P=0.01 for noninferiority). While major or clinically relevant bleeding was less frequent with dabigatran compared to warfarin (hazard ratio, 0.54), more acute coronary syndromes were observed with dabigatran (0.9% vs. 0.2%, P=0.02). In the placebo-control study, symptomatic or fatal VTE was observed in 0.4% of patients in the dabigatran group compared with 5.6% in the placebo group. Clinically relevant bleeding was more common with dabigatran (5.3% vs. 1.8%; hazard ratio 2.92).

Bottom line: Treatment with dabigatran met the pre-specified noninferiority margin in this study. However, it is worth noting that patients with VTE given extended treatment with dabigatran had significantly higher rates of recurrent symptomatic or fatal VTE than patients treated with warfarin.

Citation: Schulman S, Kearson C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709-718.

Spironolactone Improves Diastolic Function

Clinical question: What is the efficacy of aldosterone receptor blockers on diastolic function and exercise capacity?

Background: Mineralocorticoid receptor activation by aldosterone contributes to the pathophysiology of heart failure (HF) in patients with and without reduced ejection fraction (EF). Aldosterone receptor blockers (spironolactone) reduce overall and cardiovascular mortality in HF patients with reduced EF; however, its effect on HF patients with preserved EF is unknown.

Study design: Prospective, randomized, double-blinded, placebo-controlled trial.

Setting: Ten ambulatory sites in Germany and Austria.

Synopsis: This study enrolled 422 men and women, aged 50 or older, with New York Heart Association (NYHA) Class II or III HF and preserved EF, and randomized them to receive spironolactone 25 mg daily or placebo for one year.

The endpoints included echocardiographic measures of diastolic function and remodeling; N-terminal pro b-type natriuretic peptide (NT pro-BNP) levels; exercise capacity; quality of life; and HF symptoms.

In the spironolactone group, there was significant improvement in echocardiographic measures of diastolic function and remodeling as well as NT pro-BNP levels. However, there was no difference in exercise capacity, quality of life, or HF symptoms when compared to placebo.

The spironolactone group had significantly lower blood pressure than the control group, which may account for some of the remodeling effects. The study may have been underpowered, and the study population might not have had severe enough disease to detect a difference in clinical measures. It remains unknown if structural changes on echocardiography will translate into clinical benefits.

Bottom line: Compared to placebo, spironolactone did improve diastolic function by echo but did not improve exercise capacity.

Citation: Edelmann F, Wachter R, Schmidt A, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA. 2013;309(8):781-791.

Real-Time, EMR-Based Prediction Tool Accurately Predicts ICU Transfer Risks

Clinical question: Can clinical deterioration be accurately predicted using real-time data from an electronic medical record (EMR), and can it lead to better outcomes using a floor-based intervention?

Background: Research has shown that EMR-based prediction tools can help identify real-time clinical deterioration in ward patients, but an intervention based on these computer-based alerts has not been shown to be effective.

Study design: Randomized controlled crossover study.

Setting: Eight adult medicine wards in an academic medical center in the Midwest.

Synopsis: There were 20,031 patients assigned to intervention versus control based on their floor location. Computerized alerts were generated using a prediction algorithm. For patients admitted to intervention wards, the alerts were sent to the charge nurse via pager. Patients meeting the alert threshold based on the computerized prediction tool had five times higher risk of ICU transfer, and nine times higher risk of death than patients not meeting the alert threshold. Intervention of charge nurse notification via pager did not result in any significant change in length of stay (LOS), ICU transfer, or mortality. Charge nurses in the intervention group were supposed to alert a physician after receiving the computer alert, but the authors did not measure how often this occurred.

Bottom line: A real-time EMR-based prediction tool accurately predicts higher risk of ICU transfer and death, as well as LOS, but a floor-based intervention to alert the charge nurse in real time did not lead to better outcomes.

Citation: Bailey TC, Chen Y, Mao Y, et al. A trial of a real-time alert for clinical deterioration in patients hospitalized on general medicine wards. J Hosp Med. 2013 Feb 25. doi: 10.1002/jhm.2009 [Epub ahead of print].

Hypothermia Protocol and Cardiac Arrest

Clinical question: Is mild therapeutic hypothermia (MTH) following cardiac arrest beneficial and safe?

Background: Those with sudden cardiac arrest often have poor neurologic outcome. There are some studies that show benefit with hypothermia, but information on safety is limited.

Study design: Meta-analysis.

Setting: Europe, the United Kingdom, the U.S., Canada, Japan, and South Korea.

Synopsis: This study pooled data from 63 studies that looked at MTH protocols in the setting of comatose patients as a result of cardiac arrest. The end points included mortality and any complication potentially attributed to the MTH.

When restricting the analysis to include only randomized controlled trials, MTH was associated with decreased risk of in-hospital mortality (RR=0.75, 95% CI: 0.62-0.92), 30-day mortality (RR=0.61, 95% CI 0.45-0.81), and six-month mortality (RR=0.73, 95% CI 0.61-0.88). MTH was associated with increased risk of arrhythmia (RR=1.25, 95% CI: 1.00-1.55) and hypokalemia (RR=2.35, 95% CI: 1.35-4.11); all other complications were similar between groups.

There were inconsistent results regarding benefit in pediatric patients, as well as comatose patients with non-ventricular fibrillation (non-v-fib) arrest (i.e. asystole or pulseless electrical activity).

Bottom line: Mild therapeutic hypothermia can improve survival of comatose patients after v-fib cardiac arrest and is generally safe.

Citation: Xiao G, Guo Q, Xie X, et al. Safety profile and outcome of mild therapeutic hypothermia in patients following cardiac arrest: systematic review and meta-analysis. Emerg Med J. 2013;30:90-100.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Prices for common hospital procedures not readily available
2. Antibiotics associated with decreased mortality in acute COPD exacerbation
3. Endovascular therapy has no benefit to systemic t-PA in acute stroke
4. Net harm observed with rivaroxaban for thromboprophylaxis
5. Noninvasive ventilation more effective, safer for AECOPD patients
6. Synthetic cannabinoid use and acute kidney injury
7. Dabigatran vs. warfarin in the extended treatment of VTE
8. Spironolactone improves diastolic function
9. Real-time EMR-based prediction tool for clinical deterioration
10. Hypothermia protocol and cardiac arrest

Prices for Common Hospital Procedures Not Readily Available

Clinical question: Are patients able to select health-care providers based on price of service?

Background: With health-care costs rising, patients are encouraged to take a more active role in cost containment. Many initiatives call for greater pricing transparency in the health-care system. This study evaluated price availability for a common surgical procedure.

Study design: Telephone inquiries with standardized interview script.

Setting: Twenty top-ranked orthopedic hospitals and 102 non-top-ranked U.S. hospitals.

Synopsis: Hospitals were contacted by phone with a standardized, scripted request for their price of an elective total hip arthroplasty. The script described the patient as a 62-year-old grandmother without insurance who is able to pay out of pocket and wishes to compare hospital prices. On the first or second attempt, 40% of top-ranked and 32% of non-top-ranked hospitals were able to provide their price; after five attempts, authors were unable to obtain full pricing information (both hospital and physician fee) from 40% of top-ranked and 37% of non-top-ranked hospitals. Neither fee was made available by 15% of top-ranked and 16% of non-top-ranked hospitals. Wide variation of pricing was found across hospitals. The authors commented on the difficulties they encountered, such as the transfer of calls between departments and the uncertainty of representatives on how to assist.

Bottom line: For individual patients, applying basic economic principles as a consumer might be tiresome and often impossible, with no major differences between top-ranked and non-top-ranked hospitals.

Citation: Rosenthal JA, Lu X, Cram P. Availability of consumer prices from US hospitals for a common surgical procedure. JAMA Intern Med. 2013;173(6):427-432.

Antibiotics Associated with Decreased Mortality in Acute COPD Exacerbation

Clinical question: Do antibiotics when added to systemic steroids provide clinical benefit for patients with acute COPD exacerbation?

Background: Despite widespread use of antibiotics in the treatment of acute COPD, their benefit is not clear.

Study design: Retrospective cohort study.Setting: Four hundred ten U.S. hospitals participating in Perspective, an inpatient administrative database.

Synopsis: More than 50,000 patients treated with systemic steroids for acute COPD exacerbation were included in this study; 85% of them received empiric antibiotics within the first two hospital days. They were compared with those treated with systemic steroids alone. In-hospital mortality was 1.02% for patients on steroids plus antibiotics versus 1.78% on steroids alone. Use of antibiotics was associated with a 40% reduction in the odds of in-hospital mortality (OR, 0.60; 95% CI, 0.50-0.74) and reduced readmissions. In an analysis of matched cohorts, hospital mortality was 1% for patients on antibiotics and 1.8% for patients without antibiotics (OR, 0.53; 95% CI, 0.40-0.71). The risk for readmission for Clostridium difficile colitis was not different between the groups, but other potential adverse effects of antibiotic use, such as development of resistant micro-organisms, were not studied. In a subset analysis, three groups of antibiotics were compared: macrolides, quinolones, and cephalosporins. None was better than another, but those treated with macrolides had a lower readmission rate for C. diff.

Bottom line: Treatment with antibiotics when added to systemic steroids is associated with improved outcomes in acute COPD exacerbations, but there is no clear advantage of one antibiotic class over another.

Citation: Stefan MS, Rothberg MB, Shieh M, Pekow PS, Lindenauer PK. Association between antibiotic treatment and outcomes in patients hospitalized with acute exacerbation of COPD treated with systemic steroids. Chest. 2013;143(1):82-90.

Endovascular Therapy Added to Systemic t-PA Has No Benefit in Acute Stroke

Clinical question: Does adding endovascular therapy to intravenous tissue plasminogen activator (t-PA) reduce disability in acute stroke?

Background: Early systemic t-PA is the only proven reperfusion therapy in acute stroke, but it is unknown if adding localized endovascular therapy is beneficial.

Study design: Randomized, open-label, blinded-outcome trial.

Setting: Fifty-eight centers in North America, Europe, and Australia.

Synopsis: Patients aged 18 to 82 with acute ischemic stroke were eligible if they received t-PA within three hours of enrollment and had moderate to severe neurologic deficit (National Institutes of Health Stroke Scale [NIHSS] >10, or NIHSS 8 or 9 with CT angiographic evidence of specific major artery occlusion). All patients received standard-dose t-PA; those randomized to endovascular treatment underwent angiography, and, if indicated, underwent one of the endovascular treatments chosen by the neurointerventionalist. The primary outcome measure was a modified Rankin score of 2 or lower (indicating functional independence) at 90 days (assessed by a neurologist).

After enrollment of 656 patients, the trial was terminated early for futility. There was no significant difference in the primary outcome, with 40.8% of patients in the endovascular intervention group and 38.7% in the t-PA-only group having a modified Rankin score of 2 or lower. There was also no difference in mortality or other secondary outcomes, even when the analysis was limited to patients presenting with more severe neurologic deficits.

Bottom line: The addition of endovascular therapy to systemic t-PA in acute ischemic stroke does not improve functional outcomes or mortality.

Citation: Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368:893-903.

Rivaroxaban Compared with Enoxaparin for Thromboprophylaxis

Clinical question: Is extended-duration rivaroxaban more effective than standard-duration enoxaparin in preventing deep venous thrombosis in acutely ill medical patients?

Background: Trials have shown benefits of thromboprophylaxis in acutely ill medical patients at increased risk of venous thrombosis, but the optimal duration and type of anticoagulation is unknown.

Study design: Prospective, randomized, double-blinded, active-comparator controlled trial.

Setting: Five hundred fifty-two centers in 52 countries.

Synopsis: The trial enrolled 8,428 patients hospitalized with an acute medical condition and reduced mobility. Patients were randomized to receive either enoxaparin for 10 (+/-4) days or rivaroxaban for 35 (+/-4) days. The co-primary composite outcomes were the incidence of asymptomatic proximal deep venous thrombosis, symptomatic deep venous thrombosis, pulmonary embolism, or death related to venous thromboembolism over 10 days and over 35 days.

Both groups had a 2.7% incidence of the primary endpoint over 10 days; over 35 days, the extended-duration rivaroxaban group had a reduced incidence of the primary endpoint of 4.4% compared with 5.7% for enoxaparin. However, there was an increase of clinically relevant bleeding in the rivaroxaban group, occurring in 2.8% and 4.1% of patients over 10 and 35 days, respectively, compared with 1.2% and 1.7% for enoxaparin.

Overall, there was net harm with rivaroxaban over both time periods: 6.6% and 9.4% of patients in the rivaroxaban group had a negative outcome at 10 and 35 days, compared with 4.4% and 7.8% with enoxaparin.

Bottom line: There was net harm with extended-duration rivaroxaban versus standard-duration enoxaparin for thromboprophylaxis in hospitalized medical patients.

Citation: Cohen AT, Spiro TE, Büller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368:513-523.

Noninvasive Ventilation More Effective, Safer for Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD)

Clinical question: What are the patterns in use of noninvasive ventilation (NIV) and invasive mechanical ventilation (IMV) in patients with AECOPD, and which method produces better outcomes?

Background: Multiple randomized controlled trials and meta-analyses have suggested a mortality benefit with NIV compared to standard medical care in AECOPD. However, little evidence exists on head-to-head comparisons of NIV and IMV.

Study design: Retrospective cohort study.

Setting: Non-federal, short-term, general, and other specialty hospitals nationwide.

Synopsis: A sample of 67,651 ED visits for AECOPD with acute respiratory failure was analyzed from the National Emergency Department Sample (NEDS) database between 2006 and 2008. The study found that NIV use increased to 16% in 2008 from 14% in 2006. Use varied widely between hospitals and was more utilized in higher-case-volume, nonmetropolitan, and Northeastern hospitals. Compared with IMV, NIV was associated with 46% lower inpatient mortality (risk ratio 0.54, 95% confidence interval [CI] 0.50-0.59), shortened hospital length of stay (-3.2 days, 95% CI -3.4 to -2.9), lower hospital charges (-$35,012, 95% CI -$36,848 to -$33,176), and lower risk of iatrogenic pneumothorax (0.05% vs. 0.5%, P<0.001). Causality could not be established given the observational study design.

Bottom line: NIV is associated with better outcomes than IMV in the management of AECOPD, and might be underutilized.

Citation: Tsai CL, Lee WY, Delclos GL, Hanania NA, Camargo CA Jr. Comparative effectiveness of noninvasive ventilation vs. invasive mechanical ventilation in chronic obstructive pulmonary disease patients with acute respiratory failure. J Hosp Med. 2013;8(4):165-172.

Synthetic Cannabinoid Use May Cause Acute Kidney Injury

Clinical question: Are synthetic cannabinoids associated with acute kidney injury (AKI)?

Background: Synthetic cannabinoids are designer drugs of abuse with a growing popularity in the U.S.

Study design: Retrospective case series.

Setting: Hospitals in Wyoming, Oklahoma, Rhode Island, New York, Kansas, and Oregon.

Synopsis: The Centers for Disease Control and Prevention (CDC) issued an alert when 16 cases of unexplained AKI after exposure to synthetic cannabinoids were reported between March and December 2012. Synthetic cannabinoid use is associated with neurologic, sympathomimetic, and cardiovascular toxicity; however, this is the first case series reporting renal toxicity. The 16 patients included 15 males and one female, aged 15-33 years, with no pre-existing renal disease or nephrotoxic medication consumption. All used synthetic cannabinoids within hours to days before developing nausea, vomiting, abdominal, and flank and/or back pain.

Creatinine peaked one to six days after symptom onset. Five patients required hemodialysis, and all 16 recovered. There was no finding specific for all cases on ultrasound and/or biopsy. Toxicologic analysis of specimens was possible in seven cases and revealed a previously unreported fluorinated synthetic cannabinoid compound XLR-11 in all clinical specimens of patients who used the drug within two days of being tested.

Overall, the analysis did not reveal any single compound or brand that could explain all cases.

Bottom line: Clinicians should be aware of the potential for renal or other toxicities in users of synthetic cannabinoid products and should ask about their use in cases of unexplained AKI.

Citation: Murphy TD, Weidenbach KN, Van Houten C, et al. Centers for Disease Control and Prevention. Acute kidney injury associated with synthetic cannabinoid use—multiple states, 2012. MMWR Morb Mortal Wkly Rep. 2013;62(6):93-98.

Dabigatran versus Warfarin in Extended VTE Treatment

Clinical question: Is dabigatran suitable for extended treatment VTE?

Background: In contrast to warfarin (Coumadin), dabigatran (Pradaxa) is given in a fixed dose and does not require frequent laboratory monitoring. Dabigatran has been shown to be noninferior to warfarin in the initial six-month treatment of VTE.

Study design: Two double-blinded, randomized trials: an active-control study and a placebo-control study.

Setting: Two hundred sixty-five sites in 33 countries for the active-control study, and 147 sites in 21 countries for the placebo-control study.

Synopsis: This study enrolled 4,299 adult patients with objectively confirmed, symptomatic, proximal deep vein thrombosis or pulmonary embolism. In the active-control study comparing warfarin and dabigatran, recurrent objectively confirmed symptomatic or fatal VTE was observed in 1.8% of patients in the dabigatran group compared with 1.3% of patients in the warfarin group (P=0.01 for noninferiority). While major or clinically relevant bleeding was less frequent with dabigatran compared to warfarin (hazard ratio, 0.54), more acute coronary syndromes were observed with dabigatran (0.9% vs. 0.2%, P=0.02). In the placebo-control study, symptomatic or fatal VTE was observed in 0.4% of patients in the dabigatran group compared with 5.6% in the placebo group. Clinically relevant bleeding was more common with dabigatran (5.3% vs. 1.8%; hazard ratio 2.92).

Bottom line: Treatment with dabigatran met the pre-specified noninferiority margin in this study. However, it is worth noting that patients with VTE given extended treatment with dabigatran had significantly higher rates of recurrent symptomatic or fatal VTE than patients treated with warfarin.

Citation: Schulman S, Kearson C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709-718.

Spironolactone Improves Diastolic Function

Clinical question: What is the efficacy of aldosterone receptor blockers on diastolic function and exercise capacity?

Background: Mineralocorticoid receptor activation by aldosterone contributes to the pathophysiology of heart failure (HF) in patients with and without reduced ejection fraction (EF). Aldosterone receptor blockers (spironolactone) reduce overall and cardiovascular mortality in HF patients with reduced EF; however, its effect on HF patients with preserved EF is unknown.

Study design: Prospective, randomized, double-blinded, placebo-controlled trial.

Setting: Ten ambulatory sites in Germany and Austria.

Synopsis: This study enrolled 422 men and women, aged 50 or older, with New York Heart Association (NYHA) Class II or III HF and preserved EF, and randomized them to receive spironolactone 25 mg daily or placebo for one year.

The endpoints included echocardiographic measures of diastolic function and remodeling; N-terminal pro b-type natriuretic peptide (NT pro-BNP) levels; exercise capacity; quality of life; and HF symptoms.

In the spironolactone group, there was significant improvement in echocardiographic measures of diastolic function and remodeling as well as NT pro-BNP levels. However, there was no difference in exercise capacity, quality of life, or HF symptoms when compared to placebo.

The spironolactone group had significantly lower blood pressure than the control group, which may account for some of the remodeling effects. The study may have been underpowered, and the study population might not have had severe enough disease to detect a difference in clinical measures. It remains unknown if structural changes on echocardiography will translate into clinical benefits.

Bottom line: Compared to placebo, spironolactone did improve diastolic function by echo but did not improve exercise capacity.

Citation: Edelmann F, Wachter R, Schmidt A, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA. 2013;309(8):781-791.

Real-Time, EMR-Based Prediction Tool Accurately Predicts ICU Transfer Risks

Clinical question: Can clinical deterioration be accurately predicted using real-time data from an electronic medical record (EMR), and can it lead to better outcomes using a floor-based intervention?

Background: Research has shown that EMR-based prediction tools can help identify real-time clinical deterioration in ward patients, but an intervention based on these computer-based alerts has not been shown to be effective.

Study design: Randomized controlled crossover study.

Setting: Eight adult medicine wards in an academic medical center in the Midwest.

Synopsis: There were 20,031 patients assigned to intervention versus control based on their floor location. Computerized alerts were generated using a prediction algorithm. For patients admitted to intervention wards, the alerts were sent to the charge nurse via pager. Patients meeting the alert threshold based on the computerized prediction tool had five times higher risk of ICU transfer, and nine times higher risk of death than patients not meeting the alert threshold. Intervention of charge nurse notification via pager did not result in any significant change in length of stay (LOS), ICU transfer, or mortality. Charge nurses in the intervention group were supposed to alert a physician after receiving the computer alert, but the authors did not measure how often this occurred.

Bottom line: A real-time EMR-based prediction tool accurately predicts higher risk of ICU transfer and death, as well as LOS, but a floor-based intervention to alert the charge nurse in real time did not lead to better outcomes.

Citation: Bailey TC, Chen Y, Mao Y, et al. A trial of a real-time alert for clinical deterioration in patients hospitalized on general medicine wards. J Hosp Med. 2013 Feb 25. doi: 10.1002/jhm.2009 [Epub ahead of print].

Hypothermia Protocol and Cardiac Arrest

Clinical question: Is mild therapeutic hypothermia (MTH) following cardiac arrest beneficial and safe?

Background: Those with sudden cardiac arrest often have poor neurologic outcome. There are some studies that show benefit with hypothermia, but information on safety is limited.

Study design: Meta-analysis.

Setting: Europe, the United Kingdom, the U.S., Canada, Japan, and South Korea.

Synopsis: This study pooled data from 63 studies that looked at MTH protocols in the setting of comatose patients as a result of cardiac arrest. The end points included mortality and any complication potentially attributed to the MTH.

When restricting the analysis to include only randomized controlled trials, MTH was associated with decreased risk of in-hospital mortality (RR=0.75, 95% CI: 0.62-0.92), 30-day mortality (RR=0.61, 95% CI 0.45-0.81), and six-month mortality (RR=0.73, 95% CI 0.61-0.88). MTH was associated with increased risk of arrhythmia (RR=1.25, 95% CI: 1.00-1.55) and hypokalemia (RR=2.35, 95% CI: 1.35-4.11); all other complications were similar between groups.

There were inconsistent results regarding benefit in pediatric patients, as well as comatose patients with non-ventricular fibrillation (non-v-fib) arrest (i.e. asystole or pulseless electrical activity).

Bottom line: Mild therapeutic hypothermia can improve survival of comatose patients after v-fib cardiac arrest and is generally safe.

Citation: Xiao G, Guo Q, Xie X, et al. Safety profile and outcome of mild therapeutic hypothermia in patients following cardiac arrest: systematic review and meta-analysis. Emerg Med J. 2013;30:90-100.

An attempt to define and classify acute-on-chronic liver failure showed that the syndrome carries a 28-day mortality rate that is 15 times greater than in cirrhosis patients who do not have the syndrome.

Moreover, the syndrome is extremely common, and may be found in nearly one-third of acutely decompensated cirrhosis patients, wrote Dr. Richard Moreau and colleagues. The study was published in the June issue of Gastroenterology.

Source: American Gastroenterological Association

"A universally accepted and used definition of acute-on-chronic liver failure (ACLF) is still lacking," said Dr. Moreau of Université Paris Diderot, Paris.

"Defining ACLF is not only a matter of nosology, but also is of great importance because it would allow early identification of patients at high risk for end-organ failure–related death, requiring specific treatments and/or intensive management," he added.

To that end, Dr. Moreau looked at 1,343 adult patients hospitalized for at least 1 day who had an acute decompensation of cirrhosis as defined by the acute development of large ascites, hepatic encephalopathy, gastrointestinal hemorrhage, bacterial infection, or any combination of the above.

Patients who were admitted for a scheduled procedure or treatment were excluded from the analysis, as were patients with severe chronic extrahepatic disease and patients with HIV infection.

The study subjects were then divided into four groups. The first group, which was judged not to have ACLF, had no organ failure, a serum creatinine less than 1.5 mg/dL, and no hepatic encephalopathy. This group made up 1,040 of the 1,343 enrolled patients (77.4%), and had 28-day and 90-day mortality rates of 4.7% and 14%, respectively.

The next cohort, called ACLF grade 1, comprised patients with a single coagulation, circulatory or respiratory failure; a serum creatinine between 1.5 and 1.9 mg/dL; and/or mild to moderate hepatic encephalopathy. The 148 patients in this class (11.0%) had 28- and 90-day mortality rates of 22.1% and 40.7%, respectively.

ACLF grade 2 was more severe, with two organ failures; 108 patients (8%) had this at enrollment, and exhibited 28- and 90-day mortality rates of 32.0% and 40.7%, respectively.

The most severely ill patients were classed as having ACLF grade 3, with three organ failures or more. A total of 47 patients (3.5%) fell into this category, and they had 28- and 90-day mortality rates of 76.7% and 79.1%, respectively.

Overall, according to the investigators, patients with ACLF were younger (mean age 56 years versus 58 years in patients without ACLF; P = .02), had a lower mean arterial blood pressure on admittance to the hospital (79 mm Hg versus 85 mm Hg in non-ACLF patients; P less than .001) and more frequently were actively alcoholic.

They also found that patients with ACLF had a significantly higher white cell count (9.7 x 109 compared with 6.6 x 109/L; P less than .001) and plasma C-reactive protein level (40.3 versus 24.9 mg/L; P less than .001) than the group without ACLF.

And finally, in what they called an "outstanding observation," the authors determined that up to 43.6% of patients with ACLF had no precipitating event leading to their acute decompensation, including gastrointestinal hemorrhage, bacterial infection, or active alcoholism.

The authors concluded that their novel diagnostic criteria show that ACLF is "distinct from ‘mere’ AD."

They conceded that their study was not designed to assess ideal management for these patients. "Whether patients with ACLF should be admitted or not to the intensive care unit is controversial," they wrote. "Nevertheless, our results can serve as a resource for designing studies aimed to investigate the appropriate site of hospitalization for patients with ACLF."

The authors disclosed that pharmaceutical companies provided funding for a chronic liver failure consortium, which provided the initiative for this study; several other investigators also disclosed ties with pharmaceutical companies.

An attempt to define and classify acute-on-chronic liver failure showed that the syndrome carries a 28-day mortality rate that is 15 times greater than in cirrhosis patients who do not have the syndrome.

Moreover, the syndrome is extremely common, and may be found in nearly one-third of acutely decompensated cirrhosis patients, wrote Dr. Richard Moreau and colleagues. The study was published in the June issue of Gastroenterology.

Source: American Gastroenterological Association

"A universally accepted and used definition of acute-on-chronic liver failure (ACLF) is still lacking," said Dr. Moreau of Université Paris Diderot, Paris.

"Defining ACLF is not only a matter of nosology, but also is of great importance because it would allow early identification of patients at high risk for end-organ failure–related death, requiring specific treatments and/or intensive management," he added.

To that end, Dr. Moreau looked at 1,343 adult patients hospitalized for at least 1 day who had an acute decompensation of cirrhosis as defined by the acute development of large ascites, hepatic encephalopathy, gastrointestinal hemorrhage, bacterial infection, or any combination of the above.

Patients who were admitted for a scheduled procedure or treatment were excluded from the analysis, as were patients with severe chronic extrahepatic disease and patients with HIV infection.

The study subjects were then divided into four groups. The first group, which was judged not to have ACLF, had no organ failure, a serum creatinine less than 1.5 mg/dL, and no hepatic encephalopathy. This group made up 1,040 of the 1,343 enrolled patients (77.4%), and had 28-day and 90-day mortality rates of 4.7% and 14%, respectively.

The next cohort, called ACLF grade 1, comprised patients with a single coagulation, circulatory or respiratory failure; a serum creatinine between 1.5 and 1.9 mg/dL; and/or mild to moderate hepatic encephalopathy. The 148 patients in this class (11.0%) had 28- and 90-day mortality rates of 22.1% and 40.7%, respectively.

ACLF grade 2 was more severe, with two organ failures; 108 patients (8%) had this at enrollment, and exhibited 28- and 90-day mortality rates of 32.0% and 40.7%, respectively.

The most severely ill patients were classed as having ACLF grade 3, with three organ failures or more. A total of 47 patients (3.5%) fell into this category, and they had 28- and 90-day mortality rates of 76.7% and 79.1%, respectively.

Overall, according to the investigators, patients with ACLF were younger (mean age 56 years versus 58 years in patients without ACLF; P = .02), had a lower mean arterial blood pressure on admittance to the hospital (79 mm Hg versus 85 mm Hg in non-ACLF patients; P less than .001) and more frequently were actively alcoholic.

They also found that patients with ACLF had a significantly higher white cell count (9.7 x 109 compared with 6.6 x 109/L; P less than .001) and plasma C-reactive protein level (40.3 versus 24.9 mg/L; P less than .001) than the group without ACLF.

And finally, in what they called an "outstanding observation," the authors determined that up to 43.6% of patients with ACLF had no precipitating event leading to their acute decompensation, including gastrointestinal hemorrhage, bacterial infection, or active alcoholism.

The authors concluded that their novel diagnostic criteria show that ACLF is "distinct from ‘mere’ AD."

They conceded that their study was not designed to assess ideal management for these patients. "Whether patients with ACLF should be admitted or not to the intensive care unit is controversial," they wrote. "Nevertheless, our results can serve as a resource for designing studies aimed to investigate the appropriate site of hospitalization for patients with ACLF."

The authors disclosed that pharmaceutical companies provided funding for a chronic liver failure consortium, which provided the initiative for this study; several other investigators also disclosed ties with pharmaceutical companies.

An attempt to define and classify acute-on-chronic liver failure showed that the syndrome carries a 28-day mortality rate that is 15 times greater than in cirrhosis patients who do not have the syndrome.

Moreover, the syndrome is extremely common, and may be found in nearly one-third of acutely decompensated cirrhosis patients, wrote Dr. Richard Moreau and colleagues. The study was published in the June issue of Gastroenterology.

Source: American Gastroenterological Association

"A universally accepted and used definition of acute-on-chronic liver failure (ACLF) is still lacking," said Dr. Moreau of Université Paris Diderot, Paris.

"Defining ACLF is not only a matter of nosology, but also is of great importance because it would allow early identification of patients at high risk for end-organ failure–related death, requiring specific treatments and/or intensive management," he added.

To that end, Dr. Moreau looked at 1,343 adult patients hospitalized for at least 1 day who had an acute decompensation of cirrhosis as defined by the acute development of large ascites, hepatic encephalopathy, gastrointestinal hemorrhage, bacterial infection, or any combination of the above.

Patients who were admitted for a scheduled procedure or treatment were excluded from the analysis, as were patients with severe chronic extrahepatic disease and patients with HIV infection.

The study subjects were then divided into four groups. The first group, which was judged not to have ACLF, had no organ failure, a serum creatinine less than 1.5 mg/dL, and no hepatic encephalopathy. This group made up 1,040 of the 1,343 enrolled patients (77.4%), and had 28-day and 90-day mortality rates of 4.7% and 14%, respectively.

The next cohort, called ACLF grade 1, comprised patients with a single coagulation, circulatory or respiratory failure; a serum creatinine between 1.5 and 1.9 mg/dL; and/or mild to moderate hepatic encephalopathy. The 148 patients in this class (11.0%) had 28- and 90-day mortality rates of 22.1% and 40.7%, respectively.

ACLF grade 2 was more severe, with two organ failures; 108 patients (8%) had this at enrollment, and exhibited 28- and 90-day mortality rates of 32.0% and 40.7%, respectively.

The most severely ill patients were classed as having ACLF grade 3, with three organ failures or more. A total of 47 patients (3.5%) fell into this category, and they had 28- and 90-day mortality rates of 76.7% and 79.1%, respectively.

Overall, according to the investigators, patients with ACLF were younger (mean age 56 years versus 58 years in patients without ACLF; P = .02), had a lower mean arterial blood pressure on admittance to the hospital (79 mm Hg versus 85 mm Hg in non-ACLF patients; P less than .001) and more frequently were actively alcoholic.

They also found that patients with ACLF had a significantly higher white cell count (9.7 x 109 compared with 6.6 x 109/L; P less than .001) and plasma C-reactive protein level (40.3 versus 24.9 mg/L; P less than .001) than the group without ACLF.

And finally, in what they called an "outstanding observation," the authors determined that up to 43.6% of patients with ACLF had no precipitating event leading to their acute decompensation, including gastrointestinal hemorrhage, bacterial infection, or active alcoholism.

The authors concluded that their novel diagnostic criteria show that ACLF is "distinct from ‘mere’ AD."

They conceded that their study was not designed to assess ideal management for these patients. "Whether patients with ACLF should be admitted or not to the intensive care unit is controversial," they wrote. "Nevertheless, our results can serve as a resource for designing studies aimed to investigate the appropriate site of hospitalization for patients with ACLF."

The authors disclosed that pharmaceutical companies provided funding for a chronic liver failure consortium, which provided the initiative for this study; several other investigators also disclosed ties with pharmaceutical companies.

The crude incidence of drug-induced liver injury is roughly 19.1 cases per 100,000 inhabitants, with amoxicillin-clavulanate the most commonly implicated agent.

That’s according to the second published population-based cohort study of drug-induced liver injury (DILI), wrote Dr. Einar S. Björnsson. The study was published in the June issue of Gastroenterology.

Dr. Björnsson, of the University of Iceland, and colleagues looked at all patients aged older than 15 years hospitalized for liver disease with suspected DILI, plus outpatients at the National University Hospital of Iceland, and all those seen in private practice between March 1, 2010, and Feb. 29, 2012.

^{Source: American Gastroenterological Association}

According to the authors, "In Iceland, every citizen is issued a specific personal identification number that is, among other things, connected to a nationwide pharmaceutical database on outpatient prescriptions."

Therefore, "The study examined the Icelandic Medicines Registry records of prescriptions for all drugs associated with DILI that had at least a possible causal relationship" according to the Roussel Uclaf Causality Assessment Method.

DILI was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than three times the upper limit of normal, and/or alkaline phosphatase (ALP) levels greater than two times the upper limit of normal.

Acetaminophen toxicity cases were excluded, though patients with preexisting chronic liver injury were not, if they were considered to have developed superimposed DILI on top of their baseline liver enzyme values.

The authors found that over the study period there were 96 cases eligible for inclusion, including 49 cases in the first year and 47 in the second. That translated into a crude annual incidence during the study period of 19.1 cases per 100,000 inhabitants.

Roughly half were female (56%), and the median age was 55 years (range, 16-91 years).

Looking at the clinical characteristics of the cohort, the authors calculated that only 27% of patients developed jaundice, while 10% of patients complained of rash and 6% of fever. Four of the patients had preexisting liver disease.

Overall, liver injury was judged to be due to a single prescription medication in 75% of cases, most commonly amoxicillin-clavulanate (22%), followed by diclofenac (6%), azathioprine (4%) infliximab (4%), and nitrofurantoin (4%).

By tying the injury to Iceland’s prescription drug database, that meant an incidence of DILI among outpatients of 1 per 133 filled azathioprine prescriptions and 1 in 2,350 amoxicillin-clavulanate users; among inpatients, the incidence of injury attributed to amoxicillin-clavulanate was 1 per 729 patients.

By drug classes, after antibiotics, immunosuppressants were found to be commonly associated with DILI (10%), followed by psychotropic drugs, which accounted for 7% of cases, and then nonsteroidal anti-inflammatory drugs, at 6%, "with diclofenac as the only agent."

Single-drug antineoplastic agents were the causes of DILI in 5% of the cohort, and lipid-lowering agents were the cause in just 3.1% of patients (atorvastatin, n = 2; simvastatin, n = 1).

After injuries due to a single agent, dietary supplements were assumed to be the culprit in 16% of cases, and the use of multiple agents was implicated in 9% of cases.

Looking at outcomes, the researchers reported that DILI was mild in 35 patients (36%), moderate in 55 patients (58%), and severe in 5 patients (5%); there was 1 death, in an 82-year-old patient.

Finally, the median duration from diagnosis of DILI to the normalization of liver enzymes was 64 days, and 7% still had abnormal liver tests 6 months after DILI diagnosis.

According to the authors, the only previously published population-based study, done in France, found an annual crude incidence rate of 13.9 cases per 100,000 inhabitants per year (Hepatology 2002;36:451-5).

They conceded that their rate is somewhat higher; however, "the French study provided no information about the patients at risk for DILI because information about drug consumption was not available," they wrote.

The authors stated that the study was funded by a grant from the National University Hospital of Iceland Research Fund; they disclosed no individual financial conflicts of interest.

The crude incidence of drug-induced liver injury is roughly 19.1 cases per 100,000 inhabitants, with amoxicillin-clavulanate the most commonly implicated agent.

That’s according to the second published population-based cohort study of drug-induced liver injury (DILI), wrote Dr. Einar S. Björnsson. The study was published in the June issue of Gastroenterology.

Dr. Björnsson, of the University of Iceland, and colleagues looked at all patients aged older than 15 years hospitalized for liver disease with suspected DILI, plus outpatients at the National University Hospital of Iceland, and all those seen in private practice between March 1, 2010, and Feb. 29, 2012.

^{Source: American Gastroenterological Association}

According to the authors, "In Iceland, every citizen is issued a specific personal identification number that is, among other things, connected to a nationwide pharmaceutical database on outpatient prescriptions."

Therefore, "The study examined the Icelandic Medicines Registry records of prescriptions for all drugs associated with DILI that had at least a possible causal relationship" according to the Roussel Uclaf Causality Assessment Method.

DILI was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than three times the upper limit of normal, and/or alkaline phosphatase (ALP) levels greater than two times the upper limit of normal.

Acetaminophen toxicity cases were excluded, though patients with preexisting chronic liver injury were not, if they were considered to have developed superimposed DILI on top of their baseline liver enzyme values.

The authors found that over the study period there were 96 cases eligible for inclusion, including 49 cases in the first year and 47 in the second. That translated into a crude annual incidence during the study period of 19.1 cases per 100,000 inhabitants.

Roughly half were female (56%), and the median age was 55 years (range, 16-91 years).

Looking at the clinical characteristics of the cohort, the authors calculated that only 27% of patients developed jaundice, while 10% of patients complained of rash and 6% of fever. Four of the patients had preexisting liver disease.

Overall, liver injury was judged to be due to a single prescription medication in 75% of cases, most commonly amoxicillin-clavulanate (22%), followed by diclofenac (6%), azathioprine (4%) infliximab (4%), and nitrofurantoin (4%).

By tying the injury to Iceland’s prescription drug database, that meant an incidence of DILI among outpatients of 1 per 133 filled azathioprine prescriptions and 1 in 2,350 amoxicillin-clavulanate users; among inpatients, the incidence of injury attributed to amoxicillin-clavulanate was 1 per 729 patients.

By drug classes, after antibiotics, immunosuppressants were found to be commonly associated with DILI (10%), followed by psychotropic drugs, which accounted for 7% of cases, and then nonsteroidal anti-inflammatory drugs, at 6%, "with diclofenac as the only agent."

Single-drug antineoplastic agents were the causes of DILI in 5% of the cohort, and lipid-lowering agents were the cause in just 3.1% of patients (atorvastatin, n = 2; simvastatin, n = 1).

After injuries due to a single agent, dietary supplements were assumed to be the culprit in 16% of cases, and the use of multiple agents was implicated in 9% of cases.

Looking at outcomes, the researchers reported that DILI was mild in 35 patients (36%), moderate in 55 patients (58%), and severe in 5 patients (5%); there was 1 death, in an 82-year-old patient.

Finally, the median duration from diagnosis of DILI to the normalization of liver enzymes was 64 days, and 7% still had abnormal liver tests 6 months after DILI diagnosis.

According to the authors, the only previously published population-based study, done in France, found an annual crude incidence rate of 13.9 cases per 100,000 inhabitants per year (Hepatology 2002;36:451-5).

They conceded that their rate is somewhat higher; however, "the French study provided no information about the patients at risk for DILI because information about drug consumption was not available," they wrote.

The authors stated that the study was funded by a grant from the National University Hospital of Iceland Research Fund; they disclosed no individual financial conflicts of interest.

The crude incidence of drug-induced liver injury is roughly 19.1 cases per 100,000 inhabitants, with amoxicillin-clavulanate the most commonly implicated agent.

That’s according to the second published population-based cohort study of drug-induced liver injury (DILI), wrote Dr. Einar S. Björnsson. The study was published in the June issue of Gastroenterology.

Dr. Björnsson, of the University of Iceland, and colleagues looked at all patients aged older than 15 years hospitalized for liver disease with suspected DILI, plus outpatients at the National University Hospital of Iceland, and all those seen in private practice between March 1, 2010, and Feb. 29, 2012.

^{Source: American Gastroenterological Association}

According to the authors, "In Iceland, every citizen is issued a specific personal identification number that is, among other things, connected to a nationwide pharmaceutical database on outpatient prescriptions."

Therefore, "The study examined the Icelandic Medicines Registry records of prescriptions for all drugs associated with DILI that had at least a possible causal relationship" according to the Roussel Uclaf Causality Assessment Method.

DILI was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than three times the upper limit of normal, and/or alkaline phosphatase (ALP) levels greater than two times the upper limit of normal.

Acetaminophen toxicity cases were excluded, though patients with preexisting chronic liver injury were not, if they were considered to have developed superimposed DILI on top of their baseline liver enzyme values.

The authors found that over the study period there were 96 cases eligible for inclusion, including 49 cases in the first year and 47 in the second. That translated into a crude annual incidence during the study period of 19.1 cases per 100,000 inhabitants.

Roughly half were female (56%), and the median age was 55 years (range, 16-91 years).

Looking at the clinical characteristics of the cohort, the authors calculated that only 27% of patients developed jaundice, while 10% of patients complained of rash and 6% of fever. Four of the patients had preexisting liver disease.

Overall, liver injury was judged to be due to a single prescription medication in 75% of cases, most commonly amoxicillin-clavulanate (22%), followed by diclofenac (6%), azathioprine (4%) infliximab (4%), and nitrofurantoin (4%).

By tying the injury to Iceland’s prescription drug database, that meant an incidence of DILI among outpatients of 1 per 133 filled azathioprine prescriptions and 1 in 2,350 amoxicillin-clavulanate users; among inpatients, the incidence of injury attributed to amoxicillin-clavulanate was 1 per 729 patients.

By drug classes, after antibiotics, immunosuppressants were found to be commonly associated with DILI (10%), followed by psychotropic drugs, which accounted for 7% of cases, and then nonsteroidal anti-inflammatory drugs, at 6%, "with diclofenac as the only agent."

Single-drug antineoplastic agents were the causes of DILI in 5% of the cohort, and lipid-lowering agents were the cause in just 3.1% of patients (atorvastatin, n = 2; simvastatin, n = 1).

After injuries due to a single agent, dietary supplements were assumed to be the culprit in 16% of cases, and the use of multiple agents was implicated in 9% of cases.

Looking at outcomes, the researchers reported that DILI was mild in 35 patients (36%), moderate in 55 patients (58%), and severe in 5 patients (5%); there was 1 death, in an 82-year-old patient.

Finally, the median duration from diagnosis of DILI to the normalization of liver enzymes was 64 days, and 7% still had abnormal liver tests 6 months after DILI diagnosis.

According to the authors, the only previously published population-based study, done in France, found an annual crude incidence rate of 13.9 cases per 100,000 inhabitants per year (Hepatology 2002;36:451-5).

They conceded that their rate is somewhat higher; however, "the French study provided no information about the patients at risk for DILI because information about drug consumption was not available," they wrote.

The authors stated that the study was funded by a grant from the National University Hospital of Iceland Research Fund; they disclosed no individual financial conflicts of interest.

There is an increased risk of malignancy after both solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT). In patients who undergo SOT, the second most common malignancy after nonmelanoma skin cancers is post-transplant lymphoproliferative disorders (PTLD). The term PTLD includes disorders ranging from benign hyperplasia to malignant lymphomas occurring in the setting of immunosuppression during SOT and HCT. The first cases of PTLD were described in renal transplant recipients in the late 1960s. Since then, PTLD has remained a serious and sometimes fatal complication in the posttransplant setting.

To read the full article in PDF:

Click here

There is an increased risk of malignancy after both solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT). In patients who undergo SOT, the second most common malignancy after nonmelanoma skin cancers is post-transplant lymphoproliferative disorders (PTLD). The term PTLD includes disorders ranging from benign hyperplasia to malignant lymphomas occurring in the setting of immunosuppression during SOT and HCT. The first cases of PTLD were described in renal transplant recipients in the late 1960s. Since then, PTLD has remained a serious and sometimes fatal complication in the posttransplant setting.

To read the full article in PDF:

Click here

There is an increased risk of malignancy after both solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT). In patients who undergo SOT, the second most common malignancy after nonmelanoma skin cancers is post-transplant lymphoproliferative disorders (PTLD). The term PTLD includes disorders ranging from benign hyperplasia to malignant lymphomas occurring in the setting of immunosuppression during SOT and HCT. The first cases of PTLD were described in renal transplant recipients in the late 1960s. Since then, PTLD has remained a serious and sometimes fatal complication in the posttransplant setting.

To read the full article in PDF:

Click here