As the American Medical Association (AMA) develops a toolkit to help physicians implement contracts that govern the professional relationship between physicians and non-physician providers (NPPs), one SHM committee member says the trade group should keep an open mind on the pros and cons of such agreements.

The AMA House of Delegates last month tasked its staff to develop the toolkit after several delegates expressed concerns that without the so-called “practice agreements,” NPPs and physicians do not have clear boundaries on the scope of practice responsibilities, according to American Medical News, the society’s newspaper.

Lorraine Britting, MS, NP-C, a member of SHM’s Non-Physician Provider Committee, says the agreements can be a framework for certain practices but might be seen as burdensome to HM groups that have worked for years without the contracts in place.

“In the states that already have practice agreements mandated, you put these regulations in place and they work well. That being said, if new requirements are too restrictive, there is certainly potential for there to be some conflict between the physicians and the nurse practitioners,” says Britting, lead nurse practitioner in the department of cardiology medicine at the Cardiovascular Institute at Beth Israel Deaconess Medical Center in Boston.

Britting notes that many HM groups already have practice agreements in place and that she has never worked without one because Massachusetts requires them. She says professional relationships between doctors and NPPs could be helped by rules on who is responsible for what—but only if those agreements are developed with input from all stakeholders.

“It’s hard to make a blanket statement. Someone who has 10 years’ experience working in hospital medicine versus somebody who just graduated ... their needs are going to be very different,” Britting says. “It has to be individually tailored.”

As the American Medical Association (AMA) develops a toolkit to help physicians implement contracts that govern the professional relationship between physicians and non-physician providers (NPPs), one SHM committee member says the trade group should keep an open mind on the pros and cons of such agreements.

The AMA House of Delegates last month tasked its staff to develop the toolkit after several delegates expressed concerns that without the so-called “practice agreements,” NPPs and physicians do not have clear boundaries on the scope of practice responsibilities, according to American Medical News, the society’s newspaper.

Lorraine Britting, MS, NP-C, a member of SHM’s Non-Physician Provider Committee, says the agreements can be a framework for certain practices but might be seen as burdensome to HM groups that have worked for years without the contracts in place.

“In the states that already have practice agreements mandated, you put these regulations in place and they work well. That being said, if new requirements are too restrictive, there is certainly potential for there to be some conflict between the physicians and the nurse practitioners,” says Britting, lead nurse practitioner in the department of cardiology medicine at the Cardiovascular Institute at Beth Israel Deaconess Medical Center in Boston.

Britting notes that many HM groups already have practice agreements in place and that she has never worked without one because Massachusetts requires them. She says professional relationships between doctors and NPPs could be helped by rules on who is responsible for what—but only if those agreements are developed with input from all stakeholders.

“It’s hard to make a blanket statement. Someone who has 10 years’ experience working in hospital medicine versus somebody who just graduated ... their needs are going to be very different,” Britting says. “It has to be individually tailored.”

As the American Medical Association (AMA) develops a toolkit to help physicians implement contracts that govern the professional relationship between physicians and non-physician providers (NPPs), one SHM committee member says the trade group should keep an open mind on the pros and cons of such agreements.

The AMA House of Delegates last month tasked its staff to develop the toolkit after several delegates expressed concerns that without the so-called “practice agreements,” NPPs and physicians do not have clear boundaries on the scope of practice responsibilities, according to American Medical News, the society’s newspaper.

Lorraine Britting, MS, NP-C, a member of SHM’s Non-Physician Provider Committee, says the agreements can be a framework for certain practices but might be seen as burdensome to HM groups that have worked for years without the contracts in place.

“In the states that already have practice agreements mandated, you put these regulations in place and they work well. That being said, if new requirements are too restrictive, there is certainly potential for there to be some conflict between the physicians and the nurse practitioners,” says Britting, lead nurse practitioner in the department of cardiology medicine at the Cardiovascular Institute at Beth Israel Deaconess Medical Center in Boston.

Britting notes that many HM groups already have practice agreements in place and that she has never worked without one because Massachusetts requires them. She says professional relationships between doctors and NPPs could be helped by rules on who is responsible for what—but only if those agreements are developed with input from all stakeholders.

“It’s hard to make a blanket statement. Someone who has 10 years’ experience working in hospital medicine versus somebody who just graduated ... their needs are going to be very different,” Britting says. “It has to be individually tailored.”

More than 350 pediatric hospitalists convened in Tampa, Fla., last week for Pediatric Hospital Medicine (PHM) 2009, tri-sponsored by SHM, the Academic Pediatric Association (APA), and the American Academy of Pediatrics (AAP). More impressive than the continued growth of the field, however, was the palpable theme of development and maturation.

The theme was immediately evident as Patrick Conway, MD, MSc, took the stage to give the keynote address. Dr. Conway, a card-carrying pediatric hospitalist, has built upon his beginnings in health services research and a White House fellowship to become the chief medical officer in the Department of Health and Human Services (HHS) Office of the Secretary/Assistant Secretary for Planning and Evaluation. He also is the executive director of the Federal Coordinating Council for Comparative Effectiveness Research.

After providing an insider’s view of HHS, comparative effectiveness research, and healthcare reform and policy, he challenged pediatric hospitalists to demonstrate their value to the healthcare system.

Synergistically, this year’s meeting also provided an opportunity for the PHM Roundtable, a strategic planning session of pediatric hospitalist leaders, to fully share its vision for transforming the delivery of hospital care to children. As a manifestation of this vision, collaborative discussions and workgroup plans coalesced amid the enlightening mix of clinical, practice management, academic, and quality and patient safety workshops.

Growth and development are central concepts in pediatrics, and PHM 2009 highlighted the field’s energetic steps towards maturation.

Dr. Shen is pediatric editor of The Hospitalist and medical director of hospital medicine at Dell Children’s Medical Center in Austin, Texas

More than 350 pediatric hospitalists convened in Tampa, Fla., last week for Pediatric Hospital Medicine (PHM) 2009, tri-sponsored by SHM, the Academic Pediatric Association (APA), and the American Academy of Pediatrics (AAP). More impressive than the continued growth of the field, however, was the palpable theme of development and maturation.

The theme was immediately evident as Patrick Conway, MD, MSc, took the stage to give the keynote address. Dr. Conway, a card-carrying pediatric hospitalist, has built upon his beginnings in health services research and a White House fellowship to become the chief medical officer in the Department of Health and Human Services (HHS) Office of the Secretary/Assistant Secretary for Planning and Evaluation. He also is the executive director of the Federal Coordinating Council for Comparative Effectiveness Research.

After providing an insider’s view of HHS, comparative effectiveness research, and healthcare reform and policy, he challenged pediatric hospitalists to demonstrate their value to the healthcare system.

Synergistically, this year’s meeting also provided an opportunity for the PHM Roundtable, a strategic planning session of pediatric hospitalist leaders, to fully share its vision for transforming the delivery of hospital care to children. As a manifestation of this vision, collaborative discussions and workgroup plans coalesced amid the enlightening mix of clinical, practice management, academic, and quality and patient safety workshops.

Growth and development are central concepts in pediatrics, and PHM 2009 highlighted the field’s energetic steps towards maturation.

Dr. Shen is pediatric editor of The Hospitalist and medical director of hospital medicine at Dell Children’s Medical Center in Austin, Texas

More than 350 pediatric hospitalists convened in Tampa, Fla., last week for Pediatric Hospital Medicine (PHM) 2009, tri-sponsored by SHM, the Academic Pediatric Association (APA), and the American Academy of Pediatrics (AAP). More impressive than the continued growth of the field, however, was the palpable theme of development and maturation.

The theme was immediately evident as Patrick Conway, MD, MSc, took the stage to give the keynote address. Dr. Conway, a card-carrying pediatric hospitalist, has built upon his beginnings in health services research and a White House fellowship to become the chief medical officer in the Department of Health and Human Services (HHS) Office of the Secretary/Assistant Secretary for Planning and Evaluation. He also is the executive director of the Federal Coordinating Council for Comparative Effectiveness Research.

After providing an insider’s view of HHS, comparative effectiveness research, and healthcare reform and policy, he challenged pediatric hospitalists to demonstrate their value to the healthcare system.

Synergistically, this year’s meeting also provided an opportunity for the PHM Roundtable, a strategic planning session of pediatric hospitalist leaders, to fully share its vision for transforming the delivery of hospital care to children. As a manifestation of this vision, collaborative discussions and workgroup plans coalesced amid the enlightening mix of clinical, practice management, academic, and quality and patient safety workshops.

Growth and development are central concepts in pediatrics, and PHM 2009 highlighted the field’s energetic steps towards maturation.

Dr. Shen is pediatric editor of The Hospitalist and medical director of hospital medicine at Dell Children’s Medical Center in Austin, Texas

Boston—Postmenopausal women on hormone replacement therapy (HRT) are known to be at increased risk of venous thromboembolism (VTE). But whether the route of administration influences the risk was not known until now.

Investigators at Kings College Hospital NHS Foundation Trust in London discovered that VTE risk is increased in women using oral HRT but not in those using a transdermal patch. Catherine N. Bagot, MD, reported these results at the 22^nd Congress of the International Society on Thrombosis and Haemostasis (ISTH).

The investigators have thus far recruited 155 women to this ongoing study, 98 on HRT and 57 controls not on HRT. Fifty-four women were on oral HRT and 44 were using the transdermal patch.

Dr Bagot and colleagues used thrombin generation as a marker of thrombotic risk. They found that women taking HRT had significantly higher peak thrombin generation than controls (P=0.0019). They performed a subgroup analysis and the difference was only detectable in women using oral HRT (P<0.0001) and not in women using the transdermal route (P=0.7).

Investigators verified the data further and confirmed that peak thrombin generation was significantly higher in women on oral compared to transdermal HRT (P<0.0001).

The presence of progestogen or testosterone did not have any impact on the results.

These findings indicate that postmenopausal women taking oral HRT are at greater risk for VTE than those using transdermal administration. Dr Bagot suggested that transdermal administration may be safe in women who have had previous VTEs.

The research team also investigated the relationship between estradiol and peak thrombin generation.

They analyzed blood samples of 132 women. Eighty-six women were on HRT, 42 oral and 44 transdermal. The remaining women not on HRT served as controls.

Investigators excluded women whose HRT formulation contained equine estrogens or who had less than 100 pMol/L estradiol levels.

They found that estradiol levels were significantly higher in women using either formulation of HRT than controls. However, the levels were not significantly different between the two HRT groups.

Investigators also found peak thrombin generation to be significantly higher in women on HRT than controls, and this correlated with estradiol concentrations. Women taking oral HRT had a significantly higher peak thrombin generation compared to women using the patch. Investigators observed a correlation between estradiol levels and peak thrombin generation only in women using oral HRT.

Dr Bagot indicated that a limitation of this second study was that there was no way of knowing whether the estradiol levels were at the peak or trough. Nevertheless, this study confirmed further a causal link between oral estrogens, hypercoagulability, and an increased risk of VTE.

The investigators again recommended the transdermal route over oral HRT administration in postmenopausal women to achieve the lowest thrombotic risk.

Boston—Postmenopausal women on hormone replacement therapy (HRT) are known to be at increased risk of venous thromboembolism (VTE). But whether the route of administration influences the risk was not known until now.

Investigators at Kings College Hospital NHS Foundation Trust in London discovered that VTE risk is increased in women using oral HRT but not in those using a transdermal patch. Catherine N. Bagot, MD, reported these results at the 22^nd Congress of the International Society on Thrombosis and Haemostasis (ISTH).

The investigators have thus far recruited 155 women to this ongoing study, 98 on HRT and 57 controls not on HRT. Fifty-four women were on oral HRT and 44 were using the transdermal patch.

Dr Bagot and colleagues used thrombin generation as a marker of thrombotic risk. They found that women taking HRT had significantly higher peak thrombin generation than controls (P=0.0019). They performed a subgroup analysis and the difference was only detectable in women using oral HRT (P<0.0001) and not in women using the transdermal route (P=0.7).

Investigators verified the data further and confirmed that peak thrombin generation was significantly higher in women on oral compared to transdermal HRT (P<0.0001).

The presence of progestogen or testosterone did not have any impact on the results.

These findings indicate that postmenopausal women taking oral HRT are at greater risk for VTE than those using transdermal administration. Dr Bagot suggested that transdermal administration may be safe in women who have had previous VTEs.

The research team also investigated the relationship between estradiol and peak thrombin generation.

They analyzed blood samples of 132 women. Eighty-six women were on HRT, 42 oral and 44 transdermal. The remaining women not on HRT served as controls.

Investigators excluded women whose HRT formulation contained equine estrogens or who had less than 100 pMol/L estradiol levels.

They found that estradiol levels were significantly higher in women using either formulation of HRT than controls. However, the levels were not significantly different between the two HRT groups.

Investigators also found peak thrombin generation to be significantly higher in women on HRT than controls, and this correlated with estradiol concentrations. Women taking oral HRT had a significantly higher peak thrombin generation compared to women using the patch. Investigators observed a correlation between estradiol levels and peak thrombin generation only in women using oral HRT.

Dr Bagot indicated that a limitation of this second study was that there was no way of knowing whether the estradiol levels were at the peak or trough. Nevertheless, this study confirmed further a causal link between oral estrogens, hypercoagulability, and an increased risk of VTE.

The investigators again recommended the transdermal route over oral HRT administration in postmenopausal women to achieve the lowest thrombotic risk.

Boston—Postmenopausal women on hormone replacement therapy (HRT) are known to be at increased risk of venous thromboembolism (VTE). But whether the route of administration influences the risk was not known until now.

Investigators at Kings College Hospital NHS Foundation Trust in London discovered that VTE risk is increased in women using oral HRT but not in those using a transdermal patch. Catherine N. Bagot, MD, reported these results at the 22^nd Congress of the International Society on Thrombosis and Haemostasis (ISTH).

The investigators have thus far recruited 155 women to this ongoing study, 98 on HRT and 57 controls not on HRT. Fifty-four women were on oral HRT and 44 were using the transdermal patch.

Dr Bagot and colleagues used thrombin generation as a marker of thrombotic risk. They found that women taking HRT had significantly higher peak thrombin generation than controls (P=0.0019). They performed a subgroup analysis and the difference was only detectable in women using oral HRT (P<0.0001) and not in women using the transdermal route (P=0.7).

Investigators verified the data further and confirmed that peak thrombin generation was significantly higher in women on oral compared to transdermal HRT (P<0.0001).

The presence of progestogen or testosterone did not have any impact on the results.

These findings indicate that postmenopausal women taking oral HRT are at greater risk for VTE than those using transdermal administration. Dr Bagot suggested that transdermal administration may be safe in women who have had previous VTEs.

The research team also investigated the relationship between estradiol and peak thrombin generation.

They analyzed blood samples of 132 women. Eighty-six women were on HRT, 42 oral and 44 transdermal. The remaining women not on HRT served as controls.

Investigators excluded women whose HRT formulation contained equine estrogens or who had less than 100 pMol/L estradiol levels.

They found that estradiol levels were significantly higher in women using either formulation of HRT than controls. However, the levels were not significantly different between the two HRT groups.

Investigators also found peak thrombin generation to be significantly higher in women on HRT than controls, and this correlated with estradiol concentrations. Women taking oral HRT had a significantly higher peak thrombin generation compared to women using the patch. Investigators observed a correlation between estradiol levels and peak thrombin generation only in women using oral HRT.

Dr Bagot indicated that a limitation of this second study was that there was no way of knowing whether the estradiol levels were at the peak or trough. Nevertheless, this study confirmed further a causal link between oral estrogens, hypercoagulability, and an increased risk of VTE.

The investigators again recommended the transdermal route over oral HRT administration in postmenopausal women to achieve the lowest thrombotic risk.

A series of studies reported last month by a European health organization has questioned whether the use of insulin glargine, known commercially as Lantus, inflates a patient’s risk of cancer. But according to one source, hospitalists with a large census of diabetic or hypoglycemic patients shouldn’t pull their patients off the treatment just yet.

Four different population-based studies were reported on the Web site for Diabetologia, the journal of the European Association of the Study of Diabetes. A German study of 127,000 patients in an insurance database found that for every 100 patients taking Lantus, there was one more person diagnosed with cancer when compared with 100 patients taking similar doses of human insulin. The risk increased with the dosage, the study reported.

But the American Diabetes Association quickly released a statement calling the studies “conflicting and confusing.”

Hospitalist Jeffrey Schnipper, MD, MPH, FHM, who estimates one-third of his patients are either diabetic or hypoglycemic, agrees, saying that observational studies make it hard to draw any conclusions.

“I tell patients we don’t know enough,” says Dr. Schnipper, director of clinical research and associate physician in the Division of General Medicine at Brigham and Women’s Hospital Hospitalist Service in Boston. “Right now, there’s no good strong evidence that Lantus is worse than any other alternative.”

Dr. Schnipper cautioned fellow hospitalists to not overreact to the reports, noting that without a randomized trial to follow through on the hypotheses raised, there is no resolution to the confounding-by-indication bias that can plague observational studies.

“There’s an adage in medicine that you never want to be the first person or the last person to use a drug,” Dr. Schnipper says. “I would say you should never be the first person or the last person to stop using a drug.”

A series of studies reported last month by a European health organization has questioned whether the use of insulin glargine, known commercially as Lantus, inflates a patient’s risk of cancer. But according to one source, hospitalists with a large census of diabetic or hypoglycemic patients shouldn’t pull their patients off the treatment just yet.

Four different population-based studies were reported on the Web site for Diabetologia, the journal of the European Association of the Study of Diabetes. A German study of 127,000 patients in an insurance database found that for every 100 patients taking Lantus, there was one more person diagnosed with cancer when compared with 100 patients taking similar doses of human insulin. The risk increased with the dosage, the study reported.

But the American Diabetes Association quickly released a statement calling the studies “conflicting and confusing.”

Hospitalist Jeffrey Schnipper, MD, MPH, FHM, who estimates one-third of his patients are either diabetic or hypoglycemic, agrees, saying that observational studies make it hard to draw any conclusions.

“I tell patients we don’t know enough,” says Dr. Schnipper, director of clinical research and associate physician in the Division of General Medicine at Brigham and Women’s Hospital Hospitalist Service in Boston. “Right now, there’s no good strong evidence that Lantus is worse than any other alternative.”

Dr. Schnipper cautioned fellow hospitalists to not overreact to the reports, noting that without a randomized trial to follow through on the hypotheses raised, there is no resolution to the confounding-by-indication bias that can plague observational studies.

“There’s an adage in medicine that you never want to be the first person or the last person to use a drug,” Dr. Schnipper says. “I would say you should never be the first person or the last person to stop using a drug.”

A series of studies reported last month by a European health organization has questioned whether the use of insulin glargine, known commercially as Lantus, inflates a patient’s risk of cancer. But according to one source, hospitalists with a large census of diabetic or hypoglycemic patients shouldn’t pull their patients off the treatment just yet.

Four different population-based studies were reported on the Web site for Diabetologia, the journal of the European Association of the Study of Diabetes. A German study of 127,000 patients in an insurance database found that for every 100 patients taking Lantus, there was one more person diagnosed with cancer when compared with 100 patients taking similar doses of human insulin. The risk increased with the dosage, the study reported.

But the American Diabetes Association quickly released a statement calling the studies “conflicting and confusing.”

Hospitalist Jeffrey Schnipper, MD, MPH, FHM, who estimates one-third of his patients are either diabetic or hypoglycemic, agrees, saying that observational studies make it hard to draw any conclusions.

“I tell patients we don’t know enough,” says Dr. Schnipper, director of clinical research and associate physician in the Division of General Medicine at Brigham and Women’s Hospital Hospitalist Service in Boston. “Right now, there’s no good strong evidence that Lantus is worse than any other alternative.”

Dr. Schnipper cautioned fellow hospitalists to not overreact to the reports, noting that without a randomized trial to follow through on the hypotheses raised, there is no resolution to the confounding-by-indication bias that can plague observational studies.

“There’s an adage in medicine that you never want to be the first person or the last person to use a drug,” Dr. Schnipper says. “I would say you should never be the first person or the last person to stop using a drug.”

Some physicians have an interest in teaching; some are really good at it, and some make a career out of it. For Thomas Baudendistel, MD, teaching comes second nature and, as one of his former colleagues says, is a definition of who he is.

It’s those qualities, his experience in both academic and community hospital settings, and a passion for innovation that Dr. Baudendistel, the internal-medicine residency program director for Kaiser Permanente in Oakland, Calif., hopes to infuse as CME editor of the Journal of Hospital Medicine (JHM). He was appointed to the new position in June; the first issue containing article-level CME, the answers to which will be submitted online, is scheduled to appear in October.

“Tom is a superlative educator. He has defined himself that way. He has a passion for it and a talent for it,” says Brian J. Harte, MD, FHM, chair of the department of hospital medicine at The Cleveland Clinic and a deputy editor of JHM.

Dr. Harte, who first met Dr. Baudendistel in 1996 during his residency at the University of California at San Francisco, says his former mentor “can take a submission, drill down to the most important teaching point, and challenge the readership.”

Dr. Baudendistel, who admits teaching is why he “gets out of bed in the morning,” says he wants to take advantage of the young, tech-savvy nature of most HM physicians. “JHM has been an innovative journal. I see the CME piece as being equally innovative,” he says. “I’d like to move [CME] past the pencil-and-paper phase.”

Some physicians have an interest in teaching; some are really good at it, and some make a career out of it. For Thomas Baudendistel, MD, teaching comes second nature and, as one of his former colleagues says, is a definition of who he is.

It’s those qualities, his experience in both academic and community hospital settings, and a passion for innovation that Dr. Baudendistel, the internal-medicine residency program director for Kaiser Permanente in Oakland, Calif., hopes to infuse as CME editor of the Journal of Hospital Medicine (JHM). He was appointed to the new position in June; the first issue containing article-level CME, the answers to which will be submitted online, is scheduled to appear in October.

“Tom is a superlative educator. He has defined himself that way. He has a passion for it and a talent for it,” says Brian J. Harte, MD, FHM, chair of the department of hospital medicine at The Cleveland Clinic and a deputy editor of JHM.

Dr. Harte, who first met Dr. Baudendistel in 1996 during his residency at the University of California at San Francisco, says his former mentor “can take a submission, drill down to the most important teaching point, and challenge the readership.”

Dr. Baudendistel, who admits teaching is why he “gets out of bed in the morning,” says he wants to take advantage of the young, tech-savvy nature of most HM physicians. “JHM has been an innovative journal. I see the CME piece as being equally innovative,” he says. “I’d like to move [CME] past the pencil-and-paper phase.”

Some physicians have an interest in teaching; some are really good at it, and some make a career out of it. For Thomas Baudendistel, MD, teaching comes second nature and, as one of his former colleagues says, is a definition of who he is.

It’s those qualities, his experience in both academic and community hospital settings, and a passion for innovation that Dr. Baudendistel, the internal-medicine residency program director for Kaiser Permanente in Oakland, Calif., hopes to infuse as CME editor of the Journal of Hospital Medicine (JHM). He was appointed to the new position in June; the first issue containing article-level CME, the answers to which will be submitted online, is scheduled to appear in October.

“Tom is a superlative educator. He has defined himself that way. He has a passion for it and a talent for it,” says Brian J. Harte, MD, FHM, chair of the department of hospital medicine at The Cleveland Clinic and a deputy editor of JHM.

Dr. Harte, who first met Dr. Baudendistel in 1996 during his residency at the University of California at San Francisco, says his former mentor “can take a submission, drill down to the most important teaching point, and challenge the readership.”

Dr. Baudendistel, who admits teaching is why he “gets out of bed in the morning,” says he wants to take advantage of the young, tech-savvy nature of most HM physicians. “JHM has been an innovative journal. I see the CME piece as being equally innovative,” he says. “I’d like to move [CME] past the pencil-and-paper phase.”

The H1N1 pandemic has contributed to more than 200 U.S. deaths and the Center for Disease Control reports more than 37,000 probable or confirmed cases nationwide, which highlights the need for increased education for adult immunizations.

The H1N1 vaccination is expected to be available this fall and has attracted the attention of inpatient and outpatient physicians alike, says hospitalist and infectious-disease specialist John J. Ross, MD, of Brigham and Women's Hospital in Boston. Dr. Ross expects a spike in adult vaccinations similar to the increase witnessed after the Sept. 11 attacks. "You saw an increase in vaccinations because of increased panic," he says. "I expect that to be the same this fall with the introduction of the swine flu shot.”

The American College of Physicians (ACP) and the Infectious Diseases Society of America (IDSA) also express the need for heightened awareness. The medical groups recently issued a joint statement calling for a "renewed and stronger" emphasis on adult vaccinations. The statement, also supported by SHM, emphasizes an increase in patient education and documentation. It suggests hospital workers review and update their own immunizations, with particular attention to annual influenza immunizations.

Though most vaccinations are administered in the outpatient setting, hospitalists are required to update their patients’ vaccination status. "While hospitalists are doing a good job of handling pneumonia and influenza vaccinations, they could do a better job of handling some of the less common disease vaccinations,” says Ross.

Dr. Ross says hospitalists should remain knowledgeable in all of the immunization categories, a complete list of which is available at the CDC Web site. "The more knowledgeable the hospitalist is on vaccinations, the more they can educate their patients," he says.

The H1N1 pandemic has contributed to more than 200 U.S. deaths and the Center for Disease Control reports more than 37,000 probable or confirmed cases nationwide, which highlights the need for increased education for adult immunizations.

The H1N1 vaccination is expected to be available this fall and has attracted the attention of inpatient and outpatient physicians alike, says hospitalist and infectious-disease specialist John J. Ross, MD, of Brigham and Women's Hospital in Boston. Dr. Ross expects a spike in adult vaccinations similar to the increase witnessed after the Sept. 11 attacks. "You saw an increase in vaccinations because of increased panic," he says. "I expect that to be the same this fall with the introduction of the swine flu shot.”

The American College of Physicians (ACP) and the Infectious Diseases Society of America (IDSA) also express the need for heightened awareness. The medical groups recently issued a joint statement calling for a "renewed and stronger" emphasis on adult vaccinations. The statement, also supported by SHM, emphasizes an increase in patient education and documentation. It suggests hospital workers review and update their own immunizations, with particular attention to annual influenza immunizations.

Though most vaccinations are administered in the outpatient setting, hospitalists are required to update their patients’ vaccination status. "While hospitalists are doing a good job of handling pneumonia and influenza vaccinations, they could do a better job of handling some of the less common disease vaccinations,” says Ross.

Dr. Ross says hospitalists should remain knowledgeable in all of the immunization categories, a complete list of which is available at the CDC Web site. "The more knowledgeable the hospitalist is on vaccinations, the more they can educate their patients," he says.

The H1N1 pandemic has contributed to more than 200 U.S. deaths and the Center for Disease Control reports more than 37,000 probable or confirmed cases nationwide, which highlights the need for increased education for adult immunizations.

The H1N1 vaccination is expected to be available this fall and has attracted the attention of inpatient and outpatient physicians alike, says hospitalist and infectious-disease specialist John J. Ross, MD, of Brigham and Women's Hospital in Boston. Dr. Ross expects a spike in adult vaccinations similar to the increase witnessed after the Sept. 11 attacks. "You saw an increase in vaccinations because of increased panic," he says. "I expect that to be the same this fall with the introduction of the swine flu shot.”

The American College of Physicians (ACP) and the Infectious Diseases Society of America (IDSA) also express the need for heightened awareness. The medical groups recently issued a joint statement calling for a "renewed and stronger" emphasis on adult vaccinations. The statement, also supported by SHM, emphasizes an increase in patient education and documentation. It suggests hospital workers review and update their own immunizations, with particular attention to annual influenza immunizations.

Though most vaccinations are administered in the outpatient setting, hospitalists are required to update their patients’ vaccination status. "While hospitalists are doing a good job of handling pneumonia and influenza vaccinations, they could do a better job of handling some of the less common disease vaccinations,” says Ross.

Dr. Ross says hospitalists should remain knowledgeable in all of the immunization categories, a complete list of which is available at the CDC Web site. "The more knowledgeable the hospitalist is on vaccinations, the more they can educate their patients," he says.

Clinical question: Can one or both antiplatelet agents be held in a patient requiring surgery who is on dual antiplatelet therapy to manage a drug-eluting stent?

Background: Data suggest that cessation of antiplatelet therapy within one year of placement of a drug-eluting stent, even for brief time periods, is associated with rapid development of stent thrombosis (ST). However, continuation of antiplatelet agents increases perioperative risk related to hemostasis. No published data is available regarding how long one or both antiplatelet agents can be stopped to allow for safer surgery.

Study design: Case review.

Setting: Cases identified through literature search.

Synopsis: In patients with drug-eluting stents, stopping aspirin presents more risk than stopping thienopyridines. Patients who stopped both antiplatelet agents had ST at seven days (median time to event). If a patient stopped thienopyridines but not aspirin, mean time to ST was 122 days. If a patient stopped thienopyridines then subsequently stopped aspirin, the median time to ST was seven days. This suggests a potential seven-day window when both agents might be stopped, and a longer window when thienopyridines might be stopped if aspirin is continued.

The study only looked at ST cases, not the incidence of ST in all patients undergoing surgery for drug-eluting stents while on dual-antiplatelet therapy, so these results only describe the small fraction of patients who actually have surgery when antiplatelet agents are stopped.

The study design, analyzing existing cases without controls, is limited by the infrequency of the event, resulting in huge sample sizes needed to detect a significant result. The study also describes a median time to ST, which does not provide a true window of protection for the entire duration of the window.

Bottom line: The risks of bleeding complications need to be weighed against the risk of stent thrombosis in individual patients. This study also suggests that the risk of thrombosis is lower if a patient is continued on aspirin while thienopyridines are held.

Citation Eisenberg MJ, Richard PR, Libersan D, Filion KB. Safety of short-term discontinuation of antiplatelet therapy in patients with drug-eluting stents. Circulation. 2009;119:1634-1642.

Reviewed for TH eWire by Erin A. Egan, MD, JD, Ethan Cumbler, MD, Jodie Grout, RN, MS, ANP-C, Jeannette Guerrasio, MD, Nichole Zehnder, MD, and Judy Zerzan, MD, MPH, Hospital Medicine Group, University of Colorado Denver.

Clinical question: Can one or both antiplatelet agents be held in a patient requiring surgery who is on dual antiplatelet therapy to manage a drug-eluting stent?

Background: Data suggest that cessation of antiplatelet therapy within one year of placement of a drug-eluting stent, even for brief time periods, is associated with rapid development of stent thrombosis (ST). However, continuation of antiplatelet agents increases perioperative risk related to hemostasis. No published data is available regarding how long one or both antiplatelet agents can be stopped to allow for safer surgery.

Study design: Case review.

Setting: Cases identified through literature search.

Synopsis: In patients with drug-eluting stents, stopping aspirin presents more risk than stopping thienopyridines. Patients who stopped both antiplatelet agents had ST at seven days (median time to event). If a patient stopped thienopyridines but not aspirin, mean time to ST was 122 days. If a patient stopped thienopyridines then subsequently stopped aspirin, the median time to ST was seven days. This suggests a potential seven-day window when both agents might be stopped, and a longer window when thienopyridines might be stopped if aspirin is continued.

The study only looked at ST cases, not the incidence of ST in all patients undergoing surgery for drug-eluting stents while on dual-antiplatelet therapy, so these results only describe the small fraction of patients who actually have surgery when antiplatelet agents are stopped.

The study design, analyzing existing cases without controls, is limited by the infrequency of the event, resulting in huge sample sizes needed to detect a significant result. The study also describes a median time to ST, which does not provide a true window of protection for the entire duration of the window.

Bottom line: The risks of bleeding complications need to be weighed against the risk of stent thrombosis in individual patients. This study also suggests that the risk of thrombosis is lower if a patient is continued on aspirin while thienopyridines are held.

Citation Eisenberg MJ, Richard PR, Libersan D, Filion KB. Safety of short-term discontinuation of antiplatelet therapy in patients with drug-eluting stents. Circulation. 2009;119:1634-1642.

Reviewed for TH eWire by Erin A. Egan, MD, JD, Ethan Cumbler, MD, Jodie Grout, RN, MS, ANP-C, Jeannette Guerrasio, MD, Nichole Zehnder, MD, and Judy Zerzan, MD, MPH, Hospital Medicine Group, University of Colorado Denver.

Clinical question: Can one or both antiplatelet agents be held in a patient requiring surgery who is on dual antiplatelet therapy to manage a drug-eluting stent?

Background: Data suggest that cessation of antiplatelet therapy within one year of placement of a drug-eluting stent, even for brief time periods, is associated with rapid development of stent thrombosis (ST). However, continuation of antiplatelet agents increases perioperative risk related to hemostasis. No published data is available regarding how long one or both antiplatelet agents can be stopped to allow for safer surgery.

Study design: Case review.

Setting: Cases identified through literature search.

Synopsis: In patients with drug-eluting stents, stopping aspirin presents more risk than stopping thienopyridines. Patients who stopped both antiplatelet agents had ST at seven days (median time to event). If a patient stopped thienopyridines but not aspirin, mean time to ST was 122 days. If a patient stopped thienopyridines then subsequently stopped aspirin, the median time to ST was seven days. This suggests a potential seven-day window when both agents might be stopped, and a longer window when thienopyridines might be stopped if aspirin is continued.

The study only looked at ST cases, not the incidence of ST in all patients undergoing surgery for drug-eluting stents while on dual-antiplatelet therapy, so these results only describe the small fraction of patients who actually have surgery when antiplatelet agents are stopped.

The study design, analyzing existing cases without controls, is limited by the infrequency of the event, resulting in huge sample sizes needed to detect a significant result. The study also describes a median time to ST, which does not provide a true window of protection for the entire duration of the window.

Bottom line: The risks of bleeding complications need to be weighed against the risk of stent thrombosis in individual patients. This study also suggests that the risk of thrombosis is lower if a patient is continued on aspirin while thienopyridines are held.

Citation Eisenberg MJ, Richard PR, Libersan D, Filion KB. Safety of short-term discontinuation of antiplatelet therapy in patients with drug-eluting stents. Circulation. 2009;119:1634-1642.

Reviewed for TH eWire by Erin A. Egan, MD, JD, Ethan Cumbler, MD, Jodie Grout, RN, MS, ANP-C, Jeannette Guerrasio, MD, Nichole Zehnder, MD, and Judy Zerzan, MD, MPH, Hospital Medicine Group, University of Colorado Denver.

Sickle cell anemia is a prototypical single gene deletion disorder familiar to medical students everywhere. Most physicians recall that it is a devastating disorder that starts with a single substitution of valine for glutamic acid in the beta-globin gene of the hemoglobin molecule, rendering the hemoglobin molecule unstable in its de-oxygenated state. This leads to polymerization of hemoglobin molecules within the red cell, deformation of the cell membrane, and sickling. Sickling, in turn, causes blood vessel damage, vaso-occlusion, and various other physiologic effects, which lead to both micro- and macro-vascular protean complications.1

Despite extensive basic research in sickle cell disease (SCD), clinical research into the optimal management of this complex disease has lagged behind. Many adult hospitalists may be unfamiliar with the care of adult SCD patients because most of these patients are cared for in academic centers by hematologists.

In this article we review the common complications of sickle cell anemia in adult patients, the management of associated conditions, and the evidence base for treatment guidelines.

click for large version

Overview

Sickle cell anemia is not just one disorder, but is, rather, a collection of related disorders involving mutations of the hemoglobin molecule. (These disorders are categorized in Table 1, p. 40) In the United States, SCD primarily affects black Americans, with about 9% of this population having sickle trait.2 One in 600 black Americans has sickle cell anemia, also known as hemoglobin SS disease, and there are an estimated 72,000 patients with SCD in the United States.2

In the early 1970s, the average life expectancy for patients with SCD was estimated to be 14.3 years.3 At that time, more than half of SCD patients died before age five, primarily from infectious complications such as pneumococcal sepsis. Twenty years later, the Cooperative Study of SCD documented a much better life expectancy: an average of 42 for males and 48 for females with homozygous S disease (the set of patients with two copies of the defective hemoglobin S mutation).

On average, patients with hemoglobin SCD routinely survive into their 60s. Many factors, including earlier diagnosis of SCD through universal screening programs, better vaccines and vaccination rates, prophylactic antibiotics in infancy and young childhood, and aggressive treatment of fever in infants, as well as other advances in care, have contributed to this progress. A longer life expectancy in this population has heralded the extension of common complications into adulthood, however, along with the emergence of other adult-specific complications of SCD. (See Table 2, p. 40.) In order to best treat adults with SCD, hospitalists should be aware of these complications, as well as of the advances that have been achieved.

click for large version

Extension of Pediatric Complications

Perhaps the most common manifestation of SCD in children and adults is the painful crisis. This manifests in infants as a painful swelling in the digits of the hands and feet known as dactylitis. In older children and adults, pain occurs more often in the long bones of the arms and legs and in the sternum, vertebrae, and pelvic bones. Risk factors for painful crises include higher hematocrit values and higher sickle fractions, typically greater than 30%.4 Frequent painful crises are a marker of disease severity and an independent risk factor for death in SCD.

Hospitalists who regularly admit SCD patients are familiar with a subset of “frequent flyers” who experience recurrent painful crises. Remember that this is a small fraction of the total SCD population. In fact, 40% of SCD patients don’t suffer any painful crises requiring medical attention in a given year, and only 1% face more than six such events.5 Pain management in SCD is perhaps beyond the scope of this article, and there are no widely accepted guidelines. A few expert reviews are available for guidance, however.6,7

Treatment Options for Painful Crises

The most beneficial new treatment for painful crisis in the past two decades has been the use of hydroxyurea. After early studies showed promise, a phase III clinical trial in adults with SCD who suffered frequent painful crises (i.e., more than four per year) and who were given doses of up to 35 mg/kg/day of hydroxyurea showed a dramatic decrease in painful episodes. These patients also endured fewer episodes of acute chest syndrome, with a relative risk of 0.44, and experienced a reduced need for transfusions, with a relative risk of 0.64. This trial was stopped early (at 21 months average follow-up) due to the striking findings.8 Subsequent longer-term trials have not shown any of the feared theoretical complications of hydroxyurea, including cytopenias (when the production of one or more blood cell types ceases or is greatly reduced) or secondary malignancies.9 (See Table 3, p. 40.)

click for large version

Childhood Complications

Some SCD complications are more prominent or more severe in early childhood than in adulthood. Two examples of this phenomenon are infectious complications and splenic sequestration. Pediatricians and parents of children with SCD live in fear of febrile illness because overwhelming infections such as pneumococcal sepsis remain the primary reason for death in children with SCD. This was especially true before Hemophilus influenza type b (Hib) and pneumococcal conjugate vaccines were introduced and before penicillin prophylaxis from birth through age five became universal.

Though functionally asplenic, adult patients are at a relatively low risk for overwhelming infections because their immune systems have matured enough to allow type-specific antibody production to polysaccharide antigens.7 Still, adults with SCD should be aggressively evaluated for infectious etiology of any febrile illness and routinely administered empiric antibiotics to cover strep species.

Splenic sequestration occurs when sickled cells are caught up in the spleen; this causes massive hemolysis, splenic enlargement, and cardiovascular compromise, and it is most common in SCD patients younger than five. Thankfully, this is rare in adults with SS and SB0Thal; however, the notable exception to this rule is in patients with hemoglobin SC disease or SB+Thal, where complete splenic infarction does not routinely occur.

Acute chest syndrome (ACS) is perhaps the most feared complication in both children and adults with SCD—and with good reason. It is the second most common cause for hospital admission in SCD patients, and it is an independent risk factor for death in SCD.7,10 Occurring more often in children, ACS is typically more severe in adults, in whom ACS can progress rapidly to an acute respiratory distress syndrome (ARDS)-like picture, with mortality reaching 5%-9%.11

ACS involves a classic triad of fever, chest pain, and new pulmonary infiltrates on chest X-ray, but patients are invariably hypoxic and dyspneic as well. The etiology of ACS varies. In one series, 54% of patients had an identified infectious pathogen, most commonly chlamydia or mycoplasma. Bronchoalveolar lavage (BAL) showed lipid-laden macrophages in about 16%, suggesting fat embolism after bony infarcts. The remainder of patients were presumed to have primary pulmonary infarctions.11 The treatment of ACS involves broad-spectrum antibiotics, especially atypical coverage, along with transfusion (simple versus exchange), supplemental oxygen, pain control, and judicious use of IV fluids.

The second most feared complication in SCD is stroke, which can be devastating in both children and young adults. Eleven percent of patients younger than 20 have ischemic strokes, with a risk of stroke that is 200 times higher than that of age-matched peers.9,12 The peak incidence of ischemic stroke occurs before 10 and after 30. These patients are also susceptible to hemorrhagic strokes, the incidence of which peaks in the third decade, for reasons that are unclear.13

Management of acute ischemic stroke in patients with SCD is similar to that used with general patients: antiplatelet therapy, careful attention to normo-glycemia and normovolemia, and maintenance of cerebral perfusion pressure. In addition, SCD patients should receive emergent transfusion to reduce the sickle fraction to less than 30%. Patients with prior transient ischemic attack (TIA) or stroke should be on a chronic monthly transfusion regimen. Also, based on the results of the 1997 STOP I trial (Stroke Prevention Trial in Sickle Cell Anemia), children with SCD should be screened with transcranial Doppler for high velocity flow (>200 cm/second) in the internal jugular and vertebral arteries.14 Children with high velocity flow who were treated with preventative transfusion regimens had a 90% absolute risk reduction in the incidence of first stroke.

In 2001-2006, a follow-up trial (STOP 2) revealed that among patients receiving at least 30 months of chronic transfusion to prevent a first stroke 39% of those randomized to discontinue transfusion had a reversion to high risk Doppler or suffered a stroke within an average of 4.5 months. This has led many to believe that prophylactic transfusion should be a lifelong treatment.15

click for large version

Complications Seen Primarily in Adults

As the SCD population in this country has grown older, some previously uncommon complications have become more prominent. One predominantly adult complication of SCD is avascular necrosis of the femoral and humeral heads. Though clearly recognized in younger children in whom the incidence is estimated at about 3%, the major burden of femoral osteonecrosis is seen in adults older than 35, in whom prevalence reaches 50%.16 Necrosis of the humeral head can affect nearly 20% of SCD adults as well.17

It is important to recognize this complication as a new or different type of pain, separate from the vaso-occlusive pain usually experienced by SCD patients because it benefits from different therapies. Diagnosis by plain radiography is possible in the late stages, when evidence of remodeling, cystic changes, and sclerosis can be seen, but MRI has become the gold standard, with an estimated diagnostic accuracy of 90%.16 Conservative treatments include NSAIDs and steroid joint injections, but many afflicted patients may need orthopedic referral for joint replacement.

While acute chest syndrome remains a primary cause of mortality in SCD, adults with SCD are also at high risk for the chronic effects of pulmonary arterial hypertension (PAH). Thought to be uncommon in children, PAH affects up to one-third of adult SCD patients.18 Suspicion of this condition can be based on worsened fatigue, new resting hypoxemia, or increased painful crises, but experts advocate universal screening using transthoracic echocardiography. Patients with a tricuspid regurgitant jet velocity of 2.5 m/sec meet diagnostic criteria, and it is notable that the relative risk of death is 7.4 compared with SCD patients without PAH. This correlates with only moderate elevation of pulmonary pressures, suggesting that SCD patients tolerate PAH less well than other populations. Treatment options advocated include hydroxyurea, chronic transfusions, oxygen, pulmonary vasodilators such as prostacyclin and bosentan, and phosphodiesterase inhibitors such as sildenafil.

As SCD patients age, kidney disease is seen with increasing frequency, and three primary mechanisms are recognized. First, ischemic damage in the tubules causes tubular necrosis, which leads to hematuria.19 This condition can range from microscopic to severe gross hematuria, threatening urinary obstruction. Second, damage in the collecting duct impairs the body’s ability to concentrate urine, a condition that is called hyposthenuria. This condition makes SCD patients susceptible to dehydration, especially during physical exertion or in hot weather.

Interestingly, these first two mechanisms of kidney damage are also seen in patients with sickle cell trait. Finally, and most importantly, medullary interstitial fibrosis damages the glomerulus. Clinically, this is the most important mechanism because it leads to nephritic syndrome and chronic kidney disease as well as end-stage renal disease (ESRD).19

Priapism is the persistent, painful erection of the penis in post-pubertal SCD males not associated with sexual desire or relieved by orgasm; this condition is typically defined as lasting more than four to six hours.20 It is particularly common in younger males, with a yearly incidence of 6%-27%; the incidence of priapism in adults approaches 42%. In addition to being extremely painful, prolonged or repeated episodes can lead to impotence. Unfortunately, there are few well-studied treatment options; expert opinion suggests supportive care, including IV fluids, oxygen, ice, elevation, narcotic pain control, and even red cell transfusion in selected cases. Medications used include oral terbutaline, pseudoephedrine, and even stilboestrol, as well as injected phenylephrine, epinephrine, methylene blue, and tenecteplase (TNK-tPA). Surgical procedures attempted have included dorsal penile nerve block, cavernous aspiration, and the Winter procedure, which involves creating a vascular shunt from the corpora cavernosa to the glans penis. Urology consultation is often required for severe cases.

Several forms of eye disease occur in SCD patients. They can be broadly grouped into non-proliferative and proliferative diseases. In the former group, ocular trauma should be recognized as a visual emergency because patients are at risk for developing hyphema, occlusion of the trabeculae in the anterior chamber, and acute glaucoma. SCD patients of all ages are also at risk for acute retinal artery occlusion. Older SCD patients are at greatest risk, however, for a proliferative retinopathy similar to that seen in diabetes.21

Though red blood cell transfusions are helpful in many SCD patients, repeated transfusions can result in infections, immunologic consequences, and iron overload. (See Table 4, p. 41.) Infections that may result include parvovirus B19, HIV, human T-lymphotropic viruses (HTLV) I and II, and viral hepatitides. Immunologic consequences include alloimmunization, which occurs in up to 50% of SCD patients, and potentially fatal acute hemolytic reactions.22 Finally, patients who require frequent transfusions develop iron overload, which in turn causes fatigue, cardiomyopathy, diabetes mellitus, and cirrhosis. This necessitates iron chelators such as deferoxamine, which are disappointingly difficult to administer, requiring either IV or subcutaneous infusion over 12-24 hours daily. One bright note is the recent approval of deferasirox, an iron chelator that is taken orally once daily.

Conclusion

SCD is a complex genetic disease that affects multiple organs. Advances in medical care have increased longevity for SCD patients, and there are currently more adults living with the disease than ever before. Though patients often receive their care in academic centers, hospitalists may encounter them in routine practice. It is useful to have an understanding of the complications of SCD commonly seen in adults and to review the evidence base for care. TH

References

1. Platt OS. Preventing stroke in sickle cell anemia. N Engl J Med. 2005 Dec 29;353(26): 2743-2745.
2. Quinn CT, Rogers ZR, Buchanan GR. Survival of children with sickle cell disease. Blood. 2004 Jun 1;103(11):4023-4027.
3. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. [See comment.] N Engl J Med. 1994 Oct 13;331(15):1022-1023.
4. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease: rates and risk factors. N Engl J Med. 1991 Jul 4;325(1):11-16.
5. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. rates and risk factors. [See comment.] N Engl J Med. 1991;325(24):1747-1748.
6. Ballas SK. Pain management of sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct;19(5):785-802.
7. National Institutes of Health. The Management of Sickle Cell Disease. 4th ed. Washington, DC: National Heart, Lung, and Blood Institute; 2002. NIH publication No. 02-2117.
8. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. [See comment.] N Engl J Med. 1995 May 18;332(20):1317-1322.
9. Okpala IE. New therapies for sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct;19(5):975-987, ix. Review.
10. Johnson CS. The acute chest syndrome. Hematol Oncol Clin North Am. 2005;19(5):857-879, vi-vii.
11. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. 2000 Sep 14;342(25):1855-65.
12. Platt OS. Preventing stroke in sickle cell anemia. N Engl J Med. 2005 Dec 29;353(26): 2743-2745.
13. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998 Jan;91(1):288-294.
14. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. [See comment.] N Engl J Med. 1998 Jul;339(20):1477-1478.
15. Adams RJ, Brambilla D. Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. [See comment.] N Engl J Med. 2005;353(26):2743-2745.
16. Aguilar C, Vichinsky E, Neumayr L. Bone and joint disease in sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct;19(5):929-941, viii. Review.
17. Milner PF, Kraus AP, Sebes JI, et al. Osteonecrosis of the humeral head in sickle cell disease. Clin Orthop Relat Res. 1993;289:136-143.
18. Castro O, Gladwin MT. Pulmonary hypertension in sickle cell disease: mechanisms, diagnosis, and management. Hematol Oncol Clin North Am. 2005;19(5):881-896, vii.
19. Saborio P, Scheinman JI. Sickle cell nephropathy. J Am Soc Nephrol. 1999 Jan;10(1):187-192. Review.
20. Vilke GM, Harrigan RA, Ufberg JW, et al. Emergency evaluation and treatment of priapism. J Emerg Med. 2004 Apr;26(3):325-329. Review.
21. Charache S. Eye disease in sickling disorders. Hematol Oncol Clin North Am. 1996;10(6): 1357-1362.
22. Wanko SO, Telen MJ. Transfusion management in sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct;19(5):803-826, v-vi.
23. Ohene-Frempong K. Indications for red cell transfusion in sickle cell disease. Semin Hematol. 2001 Jan;38(1 Suppl 1):5-13.
24. Vichinsky EP, Haberkern CM, Neumayr L, et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. The Preoperative Transfusion in Sickle Cell Disease Study Group. [See comment.] N Engl J Med. 1995 Jul 27;333(4):206-213.
25. Piga A, Galanello R, Cappellini, MD, et al. Phase II study of oral chelator ICL670 in thalassaemia patients with transfusional iron overload: efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) after 6 months of therapy. Blood. 2002;100:5a (abstract).

Sickle cell anemia is a prototypical single gene deletion disorder familiar to medical students everywhere. Most physicians recall that it is a devastating disorder that starts with a single substitution of valine for glutamic acid in the beta-globin gene of the hemoglobin molecule, rendering the hemoglobin molecule unstable in its de-oxygenated state. This leads to polymerization of hemoglobin molecules within the red cell, deformation of the cell membrane, and sickling. Sickling, in turn, causes blood vessel damage, vaso-occlusion, and various other physiologic effects, which lead to both micro- and macro-vascular protean complications.1

Despite extensive basic research in sickle cell disease (SCD), clinical research into the optimal management of this complex disease has lagged behind. Many adult hospitalists may be unfamiliar with the care of adult SCD patients because most of these patients are cared for in academic centers by hematologists.

In this article we review the common complications of sickle cell anemia in adult patients, the management of associated conditions, and the evidence base for treatment guidelines.

click for large version

Overview

Sickle cell anemia is not just one disorder, but is, rather, a collection of related disorders involving mutations of the hemoglobin molecule. (These disorders are categorized in Table 1, p. 40) In the United States, SCD primarily affects black Americans, with about 9% of this population having sickle trait.2 One in 600 black Americans has sickle cell anemia, also known as hemoglobin SS disease, and there are an estimated 72,000 patients with SCD in the United States.2

In the early 1970s, the average life expectancy for patients with SCD was estimated to be 14.3 years.3 At that time, more than half of SCD patients died before age five, primarily from infectious complications such as pneumococcal sepsis. Twenty years later, the Cooperative Study of SCD documented a much better life expectancy: an average of 42 for males and 48 for females with homozygous S disease (the set of patients with two copies of the defective hemoglobin S mutation).

On average, patients with hemoglobin SCD routinely survive into their 60s. Many factors, including earlier diagnosis of SCD through universal screening programs, better vaccines and vaccination rates, prophylactic antibiotics in infancy and young childhood, and aggressive treatment of fever in infants, as well as other advances in care, have contributed to this progress. A longer life expectancy in this population has heralded the extension of common complications into adulthood, however, along with the emergence of other adult-specific complications of SCD. (See Table 2, p. 40.) In order to best treat adults with SCD, hospitalists should be aware of these complications, as well as of the advances that have been achieved.

click for large version

Extension of Pediatric Complications

Perhaps the most common manifestation of SCD in children and adults is the painful crisis. This manifests in infants as a painful swelling in the digits of the hands and feet known as dactylitis. In older children and adults, pain occurs more often in the long bones of the arms and legs and in the sternum, vertebrae, and pelvic bones. Risk factors for painful crises include higher hematocrit values and higher sickle fractions, typically greater than 30%.4 Frequent painful crises are a marker of disease severity and an independent risk factor for death in SCD.

Hospitalists who regularly admit SCD patients are familiar with a subset of “frequent flyers” who experience recurrent painful crises. Remember that this is a small fraction of the total SCD population. In fact, 40% of SCD patients don’t suffer any painful crises requiring medical attention in a given year, and only 1% face more than six such events.5 Pain management in SCD is perhaps beyond the scope of this article, and there are no widely accepted guidelines. A few expert reviews are available for guidance, however.6,7

Treatment Options for Painful Crises

The most beneficial new treatment for painful crisis in the past two decades has been the use of hydroxyurea. After early studies showed promise, a phase III clinical trial in adults with SCD who suffered frequent painful crises (i.e., more than four per year) and who were given doses of up to 35 mg/kg/day of hydroxyurea showed a dramatic decrease in painful episodes. These patients also endured fewer episodes of acute chest syndrome, with a relative risk of 0.44, and experienced a reduced need for transfusions, with a relative risk of 0.64. This trial was stopped early (at 21 months average follow-up) due to the striking findings.8 Subsequent longer-term trials have not shown any of the feared theoretical complications of hydroxyurea, including cytopenias (when the production of one or more blood cell types ceases or is greatly reduced) or secondary malignancies.9 (See Table 3, p. 40.)

click for large version

Childhood Complications

Some SCD complications are more prominent or more severe in early childhood than in adulthood. Two examples of this phenomenon are infectious complications and splenic sequestration. Pediatricians and parents of children with SCD live in fear of febrile illness because overwhelming infections such as pneumococcal sepsis remain the primary reason for death in children with SCD. This was especially true before Hemophilus influenza type b (Hib) and pneumococcal conjugate vaccines were introduced and before penicillin prophylaxis from birth through age five became universal.

Though functionally asplenic, adult patients are at a relatively low risk for overwhelming infections because their immune systems have matured enough to allow type-specific antibody production to polysaccharide antigens.7 Still, adults with SCD should be aggressively evaluated for infectious etiology of any febrile illness and routinely administered empiric antibiotics to cover strep species.

Splenic sequestration occurs when sickled cells are caught up in the spleen; this causes massive hemolysis, splenic enlargement, and cardiovascular compromise, and it is most common in SCD patients younger than five. Thankfully, this is rare in adults with SS and SB0Thal; however, the notable exception to this rule is in patients with hemoglobin SC disease or SB+Thal, where complete splenic infarction does not routinely occur.

Acute chest syndrome (ACS) is perhaps the most feared complication in both children and adults with SCD—and with good reason. It is the second most common cause for hospital admission in SCD patients, and it is an independent risk factor for death in SCD.7,10 Occurring more often in children, ACS is typically more severe in adults, in whom ACS can progress rapidly to an acute respiratory distress syndrome (ARDS)-like picture, with mortality reaching 5%-9%.11

ACS involves a classic triad of fever, chest pain, and new pulmonary infiltrates on chest X-ray, but patients are invariably hypoxic and dyspneic as well. The etiology of ACS varies. In one series, 54% of patients had an identified infectious pathogen, most commonly chlamydia or mycoplasma. Bronchoalveolar lavage (BAL) showed lipid-laden macrophages in about 16%, suggesting fat embolism after bony infarcts. The remainder of patients were presumed to have primary pulmonary infarctions.11 The treatment of ACS involves broad-spectrum antibiotics, especially atypical coverage, along with transfusion (simple versus exchange), supplemental oxygen, pain control, and judicious use of IV fluids.

The second most feared complication in SCD is stroke, which can be devastating in both children and young adults. Eleven percent of patients younger than 20 have ischemic strokes, with a risk of stroke that is 200 times higher than that of age-matched peers.9,12 The peak incidence of ischemic stroke occurs before 10 and after 30. These patients are also susceptible to hemorrhagic strokes, the incidence of which peaks in the third decade, for reasons that are unclear.13

Management of acute ischemic stroke in patients with SCD is similar to that used with general patients: antiplatelet therapy, careful attention to normo-glycemia and normovolemia, and maintenance of cerebral perfusion pressure. In addition, SCD patients should receive emergent transfusion to reduce the sickle fraction to less than 30%. Patients with prior transient ischemic attack (TIA) or stroke should be on a chronic monthly transfusion regimen. Also, based on the results of the 1997 STOP I trial (Stroke Prevention Trial in Sickle Cell Anemia), children with SCD should be screened with transcranial Doppler for high velocity flow (>200 cm/second) in the internal jugular and vertebral arteries.14 Children with high velocity flow who were treated with preventative transfusion regimens had a 90% absolute risk reduction in the incidence of first stroke.

In 2001-2006, a follow-up trial (STOP 2) revealed that among patients receiving at least 30 months of chronic transfusion to prevent a first stroke 39% of those randomized to discontinue transfusion had a reversion to high risk Doppler or suffered a stroke within an average of 4.5 months. This has led many to believe that prophylactic transfusion should be a lifelong treatment.15

click for large version

Complications Seen Primarily in Adults

As the SCD population in this country has grown older, some previously uncommon complications have become more prominent. One predominantly adult complication of SCD is avascular necrosis of the femoral and humeral heads. Though clearly recognized in younger children in whom the incidence is estimated at about 3%, the major burden of femoral osteonecrosis is seen in adults older than 35, in whom prevalence reaches 50%.16 Necrosis of the humeral head can affect nearly 20% of SCD adults as well.17

It is important to recognize this complication as a new or different type of pain, separate from the vaso-occlusive pain usually experienced by SCD patients because it benefits from different therapies. Diagnosis by plain radiography is possible in the late stages, when evidence of remodeling, cystic changes, and sclerosis can be seen, but MRI has become the gold standard, with an estimated diagnostic accuracy of 90%.16 Conservative treatments include NSAIDs and steroid joint injections, but many afflicted patients may need orthopedic referral for joint replacement.

While acute chest syndrome remains a primary cause of mortality in SCD, adults with SCD are also at high risk for the chronic effects of pulmonary arterial hypertension (PAH). Thought to be uncommon in children, PAH affects up to one-third of adult SCD patients.18 Suspicion of this condition can be based on worsened fatigue, new resting hypoxemia, or increased painful crises, but experts advocate universal screening using transthoracic echocardiography. Patients with a tricuspid regurgitant jet velocity of 2.5 m/sec meet diagnostic criteria, and it is notable that the relative risk of death is 7.4 compared with SCD patients without PAH. This correlates with only moderate elevation of pulmonary pressures, suggesting that SCD patients tolerate PAH less well than other populations. Treatment options advocated include hydroxyurea, chronic transfusions, oxygen, pulmonary vasodilators such as prostacyclin and bosentan, and phosphodiesterase inhibitors such as sildenafil.

As SCD patients age, kidney disease is seen with increasing frequency, and three primary mechanisms are recognized. First, ischemic damage in the tubules causes tubular necrosis, which leads to hematuria.19 This condition can range from microscopic to severe gross hematuria, threatening urinary obstruction. Second, damage in the collecting duct impairs the body’s ability to concentrate urine, a condition that is called hyposthenuria. This condition makes SCD patients susceptible to dehydration, especially during physical exertion or in hot weather.

Interestingly, these first two mechanisms of kidney damage are also seen in patients with sickle cell trait. Finally, and most importantly, medullary interstitial fibrosis damages the glomerulus. Clinically, this is the most important mechanism because it leads to nephritic syndrome and chronic kidney disease as well as end-stage renal disease (ESRD).19

Priapism is the persistent, painful erection of the penis in post-pubertal SCD males not associated with sexual desire or relieved by orgasm; this condition is typically defined as lasting more than four to six hours.20 It is particularly common in younger males, with a yearly incidence of 6%-27%; the incidence of priapism in adults approaches 42%. In addition to being extremely painful, prolonged or repeated episodes can lead to impotence. Unfortunately, there are few well-studied treatment options; expert opinion suggests supportive care, including IV fluids, oxygen, ice, elevation, narcotic pain control, and even red cell transfusion in selected cases. Medications used include oral terbutaline, pseudoephedrine, and even stilboestrol, as well as injected phenylephrine, epinephrine, methylene blue, and tenecteplase (TNK-tPA). Surgical procedures attempted have included dorsal penile nerve block, cavernous aspiration, and the Winter procedure, which involves creating a vascular shunt from the corpora cavernosa to the glans penis. Urology consultation is often required for severe cases.

Several forms of eye disease occur in SCD patients. They can be broadly grouped into non-proliferative and proliferative diseases. In the former group, ocular trauma should be recognized as a visual emergency because patients are at risk for developing hyphema, occlusion of the trabeculae in the anterior chamber, and acute glaucoma. SCD patients of all ages are also at risk for acute retinal artery occlusion. Older SCD patients are at greatest risk, however, for a proliferative retinopathy similar to that seen in diabetes.21

Though red blood cell transfusions are helpful in many SCD patients, repeated transfusions can result in infections, immunologic consequences, and iron overload. (See Table 4, p. 41.) Infections that may result include parvovirus B19, HIV, human T-lymphotropic viruses (HTLV) I and II, and viral hepatitides. Immunologic consequences include alloimmunization, which occurs in up to 50% of SCD patients, and potentially fatal acute hemolytic reactions.22 Finally, patients who require frequent transfusions develop iron overload, which in turn causes fatigue, cardiomyopathy, diabetes mellitus, and cirrhosis. This necessitates iron chelators such as deferoxamine, which are disappointingly difficult to administer, requiring either IV or subcutaneous infusion over 12-24 hours daily. One bright note is the recent approval of deferasirox, an iron chelator that is taken orally once daily.

Conclusion

SCD is a complex genetic disease that affects multiple organs. Advances in medical care have increased longevity for SCD patients, and there are currently more adults living with the disease than ever before. Though patients often receive their care in academic centers, hospitalists may encounter them in routine practice. It is useful to have an understanding of the complications of SCD commonly seen in adults and to review the evidence base for care. TH

References

1. Platt OS. Preventing stroke in sickle cell anemia. N Engl J Med. 2005 Dec 29;353(26): 2743-2745.
2. Quinn CT, Rogers ZR, Buchanan GR. Survival of children with sickle cell disease. Blood. 2004 Jun 1;103(11):4023-4027.
3. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. [See comment.] N Engl J Med. 1994 Oct 13;331(15):1022-1023.
4. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease: rates and risk factors. N Engl J Med. 1991 Jul 4;325(1):11-16.
5. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. rates and risk factors. [See comment.] N Engl J Med. 1991;325(24):1747-1748.
6. Ballas SK. Pain management of sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct;19(5):785-802.
7. National Institutes of Health. The Management of Sickle Cell Disease. 4th ed. Washington, DC: National Heart, Lung, and Blood Institute; 2002. NIH publication No. 02-2117.
8. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. [See comment.] N Engl J Med. 1995 May 18;332(20):1317-1322.
9. Okpala IE. New therapies for sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct;19(5):975-987, ix. Review.
10. Johnson CS. The acute chest syndrome. Hematol Oncol Clin North Am. 2005;19(5):857-879, vi-vii.
11. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. 2000 Sep 14;342(25):1855-65.
12. Platt OS. Preventing stroke in sickle cell anemia. N Engl J Med. 2005 Dec 29;353(26): 2743-2745.
13. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998 Jan;91(1):288-294.
14. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. [See comment.] N Engl J Med. 1998 Jul;339(20):1477-1478.
15. Adams RJ, Brambilla D. Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. [See comment.] N Engl J Med. 2005;353(26):2743-2745.
16. Aguilar C, Vichinsky E, Neumayr L. Bone and joint disease in sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct;19(5):929-941, viii. Review.
17. Milner PF, Kraus AP, Sebes JI, et al. Osteonecrosis of the humeral head in sickle cell disease. Clin Orthop Relat Res. 1993;289:136-143.
18. Castro O, Gladwin MT. Pulmonary hypertension in sickle cell disease: mechanisms, diagnosis, and management. Hematol Oncol Clin North Am. 2005;19(5):881-896, vii.
19. Saborio P, Scheinman JI. Sickle cell nephropathy. J Am Soc Nephrol. 1999 Jan;10(1):187-192. Review.
20. Vilke GM, Harrigan RA, Ufberg JW, et al. Emergency evaluation and treatment of priapism. J Emerg Med. 2004 Apr;26(3):325-329. Review.
21. Charache S. Eye disease in sickling disorders. Hematol Oncol Clin North Am. 1996;10(6): 1357-1362.
22. Wanko SO, Telen MJ. Transfusion management in sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct;19(5):803-826, v-vi.
23. Ohene-Frempong K. Indications for red cell transfusion in sickle cell disease. Semin Hematol. 2001 Jan;38(1 Suppl 1):5-13.
24. Vichinsky EP, Haberkern CM, Neumayr L, et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. The Preoperative Transfusion in Sickle Cell Disease Study Group. [See comment.] N Engl J Med. 1995 Jul 27;333(4):206-213.
25. Piga A, Galanello R, Cappellini, MD, et al. Phase II study of oral chelator ICL670 in thalassaemia patients with transfusional iron overload: efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) after 6 months of therapy. Blood. 2002;100:5a (abstract).

Sickle cell anemia is a prototypical single gene deletion disorder familiar to medical students everywhere. Most physicians recall that it is a devastating disorder that starts with a single substitution of valine for glutamic acid in the beta-globin gene of the hemoglobin molecule, rendering the hemoglobin molecule unstable in its de-oxygenated state. This leads to polymerization of hemoglobin molecules within the red cell, deformation of the cell membrane, and sickling. Sickling, in turn, causes blood vessel damage, vaso-occlusion, and various other physiologic effects, which lead to both micro- and macro-vascular protean complications.1

Despite extensive basic research in sickle cell disease (SCD), clinical research into the optimal management of this complex disease has lagged behind. Many adult hospitalists may be unfamiliar with the care of adult SCD patients because most of these patients are cared for in academic centers by hematologists.

In this article we review the common complications of sickle cell anemia in adult patients, the management of associated conditions, and the evidence base for treatment guidelines.

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Overview

Sickle cell anemia is not just one disorder, but is, rather, a collection of related disorders involving mutations of the hemoglobin molecule. (These disorders are categorized in Table 1, p. 40) In the United States, SCD primarily affects black Americans, with about 9% of this population having sickle trait.2 One in 600 black Americans has sickle cell anemia, also known as hemoglobin SS disease, and there are an estimated 72,000 patients with SCD in the United States.2

In the early 1970s, the average life expectancy for patients with SCD was estimated to be 14.3 years.3 At that time, more than half of SCD patients died before age five, primarily from infectious complications such as pneumococcal sepsis. Twenty years later, the Cooperative Study of SCD documented a much better life expectancy: an average of 42 for males and 48 for females with homozygous S disease (the set of patients with two copies of the defective hemoglobin S mutation).

On average, patients with hemoglobin SCD routinely survive into their 60s. Many factors, including earlier diagnosis of SCD through universal screening programs, better vaccines and vaccination rates, prophylactic antibiotics in infancy and young childhood, and aggressive treatment of fever in infants, as well as other advances in care, have contributed to this progress. A longer life expectancy in this population has heralded the extension of common complications into adulthood, however, along with the emergence of other adult-specific complications of SCD. (See Table 2, p. 40.) In order to best treat adults with SCD, hospitalists should be aware of these complications, as well as of the advances that have been achieved.

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Extension of Pediatric Complications

Perhaps the most common manifestation of SCD in children and adults is the painful crisis. This manifests in infants as a painful swelling in the digits of the hands and feet known as dactylitis. In older children and adults, pain occurs more often in the long bones of the arms and legs and in the sternum, vertebrae, and pelvic bones. Risk factors for painful crises include higher hematocrit values and higher sickle fractions, typically greater than 30%.4 Frequent painful crises are a marker of disease severity and an independent risk factor for death in SCD.

Hospitalists who regularly admit SCD patients are familiar with a subset of “frequent flyers” who experience recurrent painful crises. Remember that this is a small fraction of the total SCD population. In fact, 40% of SCD patients don’t suffer any painful crises requiring medical attention in a given year, and only 1% face more than six such events.5 Pain management in SCD is perhaps beyond the scope of this article, and there are no widely accepted guidelines. A few expert reviews are available for guidance, however.6,7

Treatment Options for Painful Crises

The most beneficial new treatment for painful crisis in the past two decades has been the use of hydroxyurea. After early studies showed promise, a phase III clinical trial in adults with SCD who suffered frequent painful crises (i.e., more than four per year) and who were given doses of up to 35 mg/kg/day of hydroxyurea showed a dramatic decrease in painful episodes. These patients also endured fewer episodes of acute chest syndrome, with a relative risk of 0.44, and experienced a reduced need for transfusions, with a relative risk of 0.64. This trial was stopped early (at 21 months average follow-up) due to the striking findings.8 Subsequent longer-term trials have not shown any of the feared theoretical complications of hydroxyurea, including cytopenias (when the production of one or more blood cell types ceases or is greatly reduced) or secondary malignancies.9 (See Table 3, p. 40.)

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Childhood Complications

Some SCD complications are more prominent or more severe in early childhood than in adulthood. Two examples of this phenomenon are infectious complications and splenic sequestration. Pediatricians and parents of children with SCD live in fear of febrile illness because overwhelming infections such as pneumococcal sepsis remain the primary reason for death in children with SCD. This was especially true before Hemophilus influenza type b (Hib) and pneumococcal conjugate vaccines were introduced and before penicillin prophylaxis from birth through age five became universal.

Though functionally asplenic, adult patients are at a relatively low risk for overwhelming infections because their immune systems have matured enough to allow type-specific antibody production to polysaccharide antigens.7 Still, adults with SCD should be aggressively evaluated for infectious etiology of any febrile illness and routinely administered empiric antibiotics to cover strep species.

Splenic sequestration occurs when sickled cells are caught up in the spleen; this causes massive hemolysis, splenic enlargement, and cardiovascular compromise, and it is most common in SCD patients younger than five. Thankfully, this is rare in adults with SS and SB0Thal; however, the notable exception to this rule is in patients with hemoglobin SC disease or SB+Thal, where complete splenic infarction does not routinely occur.

Acute chest syndrome (ACS) is perhaps the most feared complication in both children and adults with SCD—and with good reason. It is the second most common cause for hospital admission in SCD patients, and it is an independent risk factor for death in SCD.7,10 Occurring more often in children, ACS is typically more severe in adults, in whom ACS can progress rapidly to an acute respiratory distress syndrome (ARDS)-like picture, with mortality reaching 5%-9%.11

ACS involves a classic triad of fever, chest pain, and new pulmonary infiltrates on chest X-ray, but patients are invariably hypoxic and dyspneic as well. The etiology of ACS varies. In one series, 54% of patients had an identified infectious pathogen, most commonly chlamydia or mycoplasma. Bronchoalveolar lavage (BAL) showed lipid-laden macrophages in about 16%, suggesting fat embolism after bony infarcts. The remainder of patients were presumed to have primary pulmonary infarctions.11 The treatment of ACS involves broad-spectrum antibiotics, especially atypical coverage, along with transfusion (simple versus exchange), supplemental oxygen, pain control, and judicious use of IV fluids.

The second most feared complication in SCD is stroke, which can be devastating in both children and young adults. Eleven percent of patients younger than 20 have ischemic strokes, with a risk of stroke that is 200 times higher than that of age-matched peers.9,12 The peak incidence of ischemic stroke occurs before 10 and after 30. These patients are also susceptible to hemorrhagic strokes, the incidence of which peaks in the third decade, for reasons that are unclear.13

Management of acute ischemic stroke in patients with SCD is similar to that used with general patients: antiplatelet therapy, careful attention to normo-glycemia and normovolemia, and maintenance of cerebral perfusion pressure. In addition, SCD patients should receive emergent transfusion to reduce the sickle fraction to less than 30%. Patients with prior transient ischemic attack (TIA) or stroke should be on a chronic monthly transfusion regimen. Also, based on the results of the 1997 STOP I trial (Stroke Prevention Trial in Sickle Cell Anemia), children with SCD should be screened with transcranial Doppler for high velocity flow (>200 cm/second) in the internal jugular and vertebral arteries.14 Children with high velocity flow who were treated with preventative transfusion regimens had a 90% absolute risk reduction in the incidence of first stroke.

In 2001-2006, a follow-up trial (STOP 2) revealed that among patients receiving at least 30 months of chronic transfusion to prevent a first stroke 39% of those randomized to discontinue transfusion had a reversion to high risk Doppler or suffered a stroke within an average of 4.5 months. This has led many to believe that prophylactic transfusion should be a lifelong treatment.15

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Complications Seen Primarily in Adults

As the SCD population in this country has grown older, some previously uncommon complications have become more prominent. One predominantly adult complication of SCD is avascular necrosis of the femoral and humeral heads. Though clearly recognized in younger children in whom the incidence is estimated at about 3%, the major burden of femoral osteonecrosis is seen in adults older than 35, in whom prevalence reaches 50%.16 Necrosis of the humeral head can affect nearly 20% of SCD adults as well.17

It is important to recognize this complication as a new or different type of pain, separate from the vaso-occlusive pain usually experienced by SCD patients because it benefits from different therapies. Diagnosis by plain radiography is possible in the late stages, when evidence of remodeling, cystic changes, and sclerosis can be seen, but MRI has become the gold standard, with an estimated diagnostic accuracy of 90%.16 Conservative treatments include NSAIDs and steroid joint injections, but many afflicted patients may need orthopedic referral for joint replacement.

While acute chest syndrome remains a primary cause of mortality in SCD, adults with SCD are also at high risk for the chronic effects of pulmonary arterial hypertension (PAH). Thought to be uncommon in children, PAH affects up to one-third of adult SCD patients.18 Suspicion of this condition can be based on worsened fatigue, new resting hypoxemia, or increased painful crises, but experts advocate universal screening using transthoracic echocardiography. Patients with a tricuspid regurgitant jet velocity of 2.5 m/sec meet diagnostic criteria, and it is notable that the relative risk of death is 7.4 compared with SCD patients without PAH. This correlates with only moderate elevation of pulmonary pressures, suggesting that SCD patients tolerate PAH less well than other populations. Treatment options advocated include hydroxyurea, chronic transfusions, oxygen, pulmonary vasodilators such as prostacyclin and bosentan, and phosphodiesterase inhibitors such as sildenafil.

As SCD patients age, kidney disease is seen with increasing frequency, and three primary mechanisms are recognized. First, ischemic damage in the tubules causes tubular necrosis, which leads to hematuria.19 This condition can range from microscopic to severe gross hematuria, threatening urinary obstruction. Second, damage in the collecting duct impairs the body’s ability to concentrate urine, a condition that is called hyposthenuria. This condition makes SCD patients susceptible to dehydration, especially during physical exertion or in hot weather.

Interestingly, these first two mechanisms of kidney damage are also seen in patients with sickle cell trait. Finally, and most importantly, medullary interstitial fibrosis damages the glomerulus. Clinically, this is the most important mechanism because it leads to nephritic syndrome and chronic kidney disease as well as end-stage renal disease (ESRD).19

Priapism is the persistent, painful erection of the penis in post-pubertal SCD males not associated with sexual desire or relieved by orgasm; this condition is typically defined as lasting more than four to six hours.20 It is particularly common in younger males, with a yearly incidence of 6%-27%; the incidence of priapism in adults approaches 42%. In addition to being extremely painful, prolonged or repeated episodes can lead to impotence. Unfortunately, there are few well-studied treatment options; expert opinion suggests supportive care, including IV fluids, oxygen, ice, elevation, narcotic pain control, and even red cell transfusion in selected cases. Medications used include oral terbutaline, pseudoephedrine, and even stilboestrol, as well as injected phenylephrine, epinephrine, methylene blue, and tenecteplase (TNK-tPA). Surgical procedures attempted have included dorsal penile nerve block, cavernous aspiration, and the Winter procedure, which involves creating a vascular shunt from the corpora cavernosa to the glans penis. Urology consultation is often required for severe cases.

Several forms of eye disease occur in SCD patients. They can be broadly grouped into non-proliferative and proliferative diseases. In the former group, ocular trauma should be recognized as a visual emergency because patients are at risk for developing hyphema, occlusion of the trabeculae in the anterior chamber, and acute glaucoma. SCD patients of all ages are also at risk for acute retinal artery occlusion. Older SCD patients are at greatest risk, however, for a proliferative retinopathy similar to that seen in diabetes.21

Though red blood cell transfusions are helpful in many SCD patients, repeated transfusions can result in infections, immunologic consequences, and iron overload. (See Table 4, p. 41.) Infections that may result include parvovirus B19, HIV, human T-lymphotropic viruses (HTLV) I and II, and viral hepatitides. Immunologic consequences include alloimmunization, which occurs in up to 50% of SCD patients, and potentially fatal acute hemolytic reactions.22 Finally, patients who require frequent transfusions develop iron overload, which in turn causes fatigue, cardiomyopathy, diabetes mellitus, and cirrhosis. This necessitates iron chelators such as deferoxamine, which are disappointingly difficult to administer, requiring either IV or subcutaneous infusion over 12-24 hours daily. One bright note is the recent approval of deferasirox, an iron chelator that is taken orally once daily.

Conclusion

SCD is a complex genetic disease that affects multiple organs. Advances in medical care have increased longevity for SCD patients, and there are currently more adults living with the disease than ever before. Though patients often receive their care in academic centers, hospitalists may encounter them in routine practice. It is useful to have an understanding of the complications of SCD commonly seen in adults and to review the evidence base for care. TH

References

1. Platt OS. Preventing stroke in sickle cell anemia. N Engl J Med. 2005 Dec 29;353(26): 2743-2745.
2. Quinn CT, Rogers ZR, Buchanan GR. Survival of children with sickle cell disease. Blood. 2004 Jun 1;103(11):4023-4027.
3. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. [See comment.] N Engl J Med. 1994 Oct 13;331(15):1022-1023.
4. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease: rates and risk factors. N Engl J Med. 1991 Jul 4;325(1):11-16.
5. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. rates and risk factors. [See comment.] N Engl J Med. 1991;325(24):1747-1748.
6. Ballas SK. Pain management of sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct;19(5):785-802.
7. National Institutes of Health. The Management of Sickle Cell Disease. 4th ed. Washington, DC: National Heart, Lung, and Blood Institute; 2002. NIH publication No. 02-2117.
8. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. [See comment.] N Engl J Med. 1995 May 18;332(20):1317-1322.
9. Okpala IE. New therapies for sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct;19(5):975-987, ix. Review.
10. Johnson CS. The acute chest syndrome. Hematol Oncol Clin North Am. 2005;19(5):857-879, vi-vii.
11. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. 2000 Sep 14;342(25):1855-65.
12. Platt OS. Preventing stroke in sickle cell anemia. N Engl J Med. 2005 Dec 29;353(26): 2743-2745.
13. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998 Jan;91(1):288-294.
14. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. [See comment.] N Engl J Med. 1998 Jul;339(20):1477-1478.
15. Adams RJ, Brambilla D. Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. [See comment.] N Engl J Med. 2005;353(26):2743-2745.
16. Aguilar C, Vichinsky E, Neumayr L. Bone and joint disease in sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct;19(5):929-941, viii. Review.
17. Milner PF, Kraus AP, Sebes JI, et al. Osteonecrosis of the humeral head in sickle cell disease. Clin Orthop Relat Res. 1993;289:136-143.
18. Castro O, Gladwin MT. Pulmonary hypertension in sickle cell disease: mechanisms, diagnosis, and management. Hematol Oncol Clin North Am. 2005;19(5):881-896, vii.
19. Saborio P, Scheinman JI. Sickle cell nephropathy. J Am Soc Nephrol. 1999 Jan;10(1):187-192. Review.
20. Vilke GM, Harrigan RA, Ufberg JW, et al. Emergency evaluation and treatment of priapism. J Emerg Med. 2004 Apr;26(3):325-329. Review.
21. Charache S. Eye disease in sickling disorders. Hematol Oncol Clin North Am. 1996;10(6): 1357-1362.
22. Wanko SO, Telen MJ. Transfusion management in sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct;19(5):803-826, v-vi.
23. Ohene-Frempong K. Indications for red cell transfusion in sickle cell disease. Semin Hematol. 2001 Jan;38(1 Suppl 1):5-13.
24. Vichinsky EP, Haberkern CM, Neumayr L, et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. The Preoperative Transfusion in Sickle Cell Disease Study Group. [See comment.] N Engl J Med. 1995 Jul 27;333(4):206-213.
25. Piga A, Galanello R, Cappellini, MD, et al. Phase II study of oral chelator ICL670 in thalassaemia patients with transfusional iron overload: efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) after 6 months of therapy. Blood. 2002;100:5a (abstract).

The Journal of Hospital Medicine’s debut impact factor (IF) ranks it in the top 20% of its cohort—no small achievement for a peer-reviewed medical journal in its fourth year of publication.

JHM’s 2008 IF is 3.163, a stronger-than-expected showing that Editor-in-Chief Mark V. Williams, MD, FACP, FHM, hopes will translate into increased submissions.

JHM ranks No. 21 out of 107 journals in the Medicine, General, and Internal subject category. Impact factors are an industry metric used as a rough average of citations received by peer-reviewed journals. For comparison's sake, the IF for the Journal of General Internal Medicine is 2.72; the IF for the Annals of Internal Medicine is 17.457; and the IF for the New England Journal of Medicine is 50.017.

“In context of other journals of similar editorial scope … an [IF score] does indicate something about its influence,” says James Testa, senior director of editorial development and publisher relations for Thomson Reuters, which calculates the score.

Dr. Williams is a little more effusive. The IF, he says, “tells us we need to keep doing what we’re doing. ... There are journals that are 20 years old that don’t have impact factors as high as we do.” Dr. Williams is professor and chief of the Division of Hospital Medicine at Northwestern University Feinberg School of Medicine in Chicago. “Hopefully, this will lead to academicians across the world being interested in submitting their scholarly work.”

JHM's top-cited source is Core Competencies in Hospital Medicine: A Framework for Curriculum Development, a supplement published with Volume 1, Issue 1. The supplement's clinical content is an essential tool for practicing hospitalists, providing guidance in the areas of clinical conditions, procedures, healthcare systems, development and methodologies.

"SHM is very proud of our journal, JHM, and getting such a sterling impact factor is a further acknowledgement of JHM’s credibility, reach, and world-class content,” says Larry Wellikson, MD, FHM, CEO of SHM.

The Journal of Hospital Medicine’s debut impact factor (IF) ranks it in the top 20% of its cohort—no small achievement for a peer-reviewed medical journal in its fourth year of publication.

JHM’s 2008 IF is 3.163, a stronger-than-expected showing that Editor-in-Chief Mark V. Williams, MD, FACP, FHM, hopes will translate into increased submissions.

JHM ranks No. 21 out of 107 journals in the Medicine, General, and Internal subject category. Impact factors are an industry metric used as a rough average of citations received by peer-reviewed journals. For comparison's sake, the IF for the Journal of General Internal Medicine is 2.72; the IF for the Annals of Internal Medicine is 17.457; and the IF for the New England Journal of Medicine is 50.017.

“In context of other journals of similar editorial scope … an [IF score] does indicate something about its influence,” says James Testa, senior director of editorial development and publisher relations for Thomson Reuters, which calculates the score.

Dr. Williams is a little more effusive. The IF, he says, “tells us we need to keep doing what we’re doing. ... There are journals that are 20 years old that don’t have impact factors as high as we do.” Dr. Williams is professor and chief of the Division of Hospital Medicine at Northwestern University Feinberg School of Medicine in Chicago. “Hopefully, this will lead to academicians across the world being interested in submitting their scholarly work.”

JHM's top-cited source is Core Competencies in Hospital Medicine: A Framework for Curriculum Development, a supplement published with Volume 1, Issue 1. The supplement's clinical content is an essential tool for practicing hospitalists, providing guidance in the areas of clinical conditions, procedures, healthcare systems, development and methodologies.

"SHM is very proud of our journal, JHM, and getting such a sterling impact factor is a further acknowledgement of JHM’s credibility, reach, and world-class content,” says Larry Wellikson, MD, FHM, CEO of SHM.

The Journal of Hospital Medicine’s debut impact factor (IF) ranks it in the top 20% of its cohort—no small achievement for a peer-reviewed medical journal in its fourth year of publication.

JHM’s 2008 IF is 3.163, a stronger-than-expected showing that Editor-in-Chief Mark V. Williams, MD, FACP, FHM, hopes will translate into increased submissions.

JHM ranks No. 21 out of 107 journals in the Medicine, General, and Internal subject category. Impact factors are an industry metric used as a rough average of citations received by peer-reviewed journals. For comparison's sake, the IF for the Journal of General Internal Medicine is 2.72; the IF for the Annals of Internal Medicine is 17.457; and the IF for the New England Journal of Medicine is 50.017.

“In context of other journals of similar editorial scope … an [IF score] does indicate something about its influence,” says James Testa, senior director of editorial development and publisher relations for Thomson Reuters, which calculates the score.

Dr. Williams is a little more effusive. The IF, he says, “tells us we need to keep doing what we’re doing. ... There are journals that are 20 years old that don’t have impact factors as high as we do.” Dr. Williams is professor and chief of the Division of Hospital Medicine at Northwestern University Feinberg School of Medicine in Chicago. “Hopefully, this will lead to academicians across the world being interested in submitting their scholarly work.”

JHM's top-cited source is Core Competencies in Hospital Medicine: A Framework for Curriculum Development, a supplement published with Volume 1, Issue 1. The supplement's clinical content is an essential tool for practicing hospitalists, providing guidance in the areas of clinical conditions, procedures, healthcare systems, development and methodologies.

"SHM is very proud of our journal, JHM, and getting such a sterling impact factor is a further acknowledgement of JHM’s credibility, reach, and world-class content,” says Larry Wellikson, MD, FHM, CEO of SHM.