Guidelines

Background

Atrial fibrillation (AF) is a common condition, affecting more than 2 million Americans.¹ Hospital admissions due to AF have increased 66% in the past two decades. Hospitalization accounts for 52% of the cost of AF management, and the mortality rate of patients with this arrhythmia is twice that of patients in sinus rhythm.1

AF management decisions include choices for rate control, rhythm control, and prevention of thromboembolism. The benefits of a rhythm-control versus a rate-control strategy continue to be evaluated, along with consideration regarding an appropriate heart-rate goal. The modifiable risk factor of stroke in atrial fibrillation also continues to be a target for intervention as atrial fibrillation accounts for one-sixth of all strokes.

Guideline Update

The American College of Cardiology Foundation and American Heart Association (ACC/AHA), in conjunction with the European Society of Cardiology, released practice guidelines on the management of patients with atrial fibrillation in 2006. The ACCF/AHA, writing with the Heart Rhythm Society, released focused updates in early 2011 to be incorporated into the previous guidelines, given new data from major clinical trials and the FDA approval of new medications with indications for AF treatment.^2,3

The new recommendations address components of all three major management decisions for AF: rate control, rhythm control, and prevention of thromboembolism.

When managing AF with a rate-control strategy, new guidelines no longer recommend the goal of a resting heart rate of <80 bpm or <115 bpm with activity. This is based on data from the RACE II trial that show no difference in meaningful outcomes with a more aggressive heart-rate goal. Achieving a resting heart rate of 110 bpm was deemed a reasonable approach, as long as the patient has stable ventricular function and acceptable symptoms.

The new drug dronedarone has been introduced in the algorithm for maintenance of sinus rhythm strategy, based on the DIONYSOS, ATHENA, and ANDROMEDA studies. The new algorithm excluded the use of dronedarone in patients with left ventricular hypertrophy, decompensated heart failure, or Class IV heart failure because it was shown to increase mortality in these groups. The guidelines also recommend that it should also be used with caution in patients with bradycardia, prolonged QT interval, increased creatinine, and in patients on agents that moderate CYP3A4 function.

The risks of interventions to decrease thromboembolism against bleeding risk continue to be evaluated in specified patient populations. Although dabigatran did not have FDA approval prior to submission of the 2011 updated guidelines, the 2011 “focused update” incorporated the results of the RE-LY trial. Publication of RE-LY resulted in a Class 1 recommendation for dabigatran as a useful alternative to warfarin in patients with nonvalvular AF without severe renal failure or advanced liver disease.³ However, there is no specific antidote, and dabigatran use is associated with higher rates of dyspepsia and a nonsignificant increase in rates of myocardial infarction. In patients for whom oral anticoagulation with warfarin is considered unsuitable, aspirin with clopidogrel may be considered, although warfarin therapy continues to be a superior therapy to this dual antiplatelet regimen based on the ACTIVE-W and ACTIVE-A studies.²

Established Guideline Analysis

Apart from the listed updates, the management of AF has not changed considerably in the past decade. Rate control continues to be the recommended strategy for older patients along with appropriate symptom control, particularly if they have hypertension or heart disease. Rhythm control is a frequent strategy in AF management, but several studies have not found any difference in quality of life, development or progression of heart failure, or stroke rates in patients for whom a rhythm-control strategy was chosen.

Additionally, these patients still require anticoagulation, and the side effects of anti-arrhythmic drugs might offset the benefits of sinus rhythm. Therefore, rate control is an appropriate strategy. The stroke rate and side-effect risks with anti-arrhythmics are considerably lower in younger patients or those with paroxysmal lone AF, and so a rhythm-control strategy in these groups is reasonable.

Stroke rate in AF increases with known high-risk factors (prior thromboembolism or rheumatic mitral stenosis) and moderate-risk factors (heart failure, hypertension, age over 75, and diabetes). Less validated risk factors include female gender, age 65-74, thyrotoxicosis, and the presence of coronary artery disease.

There are well-defined recommendations for how to anticoagulate specific subgroups that pose clinical challenges not directly addressed in studies, but the guidelines do assist with:

• Patients who have a stroke with a therapeutic INR: Rather than adding antiplatelet agents, INR goal can be raised to 3-3.5;
• Patients >75 years old who are at a high risk for bleeding: A target INR of 2.0 (target range 1.6-2.5) seems reasonable;1 and
• Patients with stable coronary artery disease and AF: Warfarin anticoagulation alone should provide satisfactory antithrombotic prophylaxis against cerebrovascular and coronary atheroembolic events.¹

Decisions involving perioperative management of anticoagulation in patients with AF frequently arise. Per the guidelines, in patients with nonvalvular AF, anticoagulation can be stopped for up to one week without bridging for surgical or diagnostic procedures, but bridging should be considered in high-risk patients.

HM Takeaways

Hospitalists are likely to manage AF, whether alone or in conjunction with cardiology consultation. These new comprehensive guidelines deal with rate control, rhythm control, and prevention of thromboembolism. Hospitalists should take particular interest in the guidelines regarding lenient rate control, dronedarone for rhythm control, and dabigatran as a new alternative for anticoagulation in appropriate populations.

Drs. Farrell and Carbo are hospitalists at Beth Israel Deaconess Medical Center in Boston.

References

1. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011;57(11):e101-98.
2. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Heart Rhythm. 2011;8(1):157-76.
3. Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2011;57(11):1330-7.

Background

Atrial fibrillation (AF) is a common condition, affecting more than 2 million Americans.¹ Hospital admissions due to AF have increased 66% in the past two decades. Hospitalization accounts for 52% of the cost of AF management, and the mortality rate of patients with this arrhythmia is twice that of patients in sinus rhythm.1

AF management decisions include choices for rate control, rhythm control, and prevention of thromboembolism. The benefits of a rhythm-control versus a rate-control strategy continue to be evaluated, along with consideration regarding an appropriate heart-rate goal. The modifiable risk factor of stroke in atrial fibrillation also continues to be a target for intervention as atrial fibrillation accounts for one-sixth of all strokes.

Guideline Update

The American College of Cardiology Foundation and American Heart Association (ACC/AHA), in conjunction with the European Society of Cardiology, released practice guidelines on the management of patients with atrial fibrillation in 2006. The ACCF/AHA, writing with the Heart Rhythm Society, released focused updates in early 2011 to be incorporated into the previous guidelines, given new data from major clinical trials and the FDA approval of new medications with indications for AF treatment.^2,3

The new recommendations address components of all three major management decisions for AF: rate control, rhythm control, and prevention of thromboembolism.

When managing AF with a rate-control strategy, new guidelines no longer recommend the goal of a resting heart rate of <80 bpm or <115 bpm with activity. This is based on data from the RACE II trial that show no difference in meaningful outcomes with a more aggressive heart-rate goal. Achieving a resting heart rate of 110 bpm was deemed a reasonable approach, as long as the patient has stable ventricular function and acceptable symptoms.

The new drug dronedarone has been introduced in the algorithm for maintenance of sinus rhythm strategy, based on the DIONYSOS, ATHENA, and ANDROMEDA studies. The new algorithm excluded the use of dronedarone in patients with left ventricular hypertrophy, decompensated heart failure, or Class IV heart failure because it was shown to increase mortality in these groups. The guidelines also recommend that it should also be used with caution in patients with bradycardia, prolonged QT interval, increased creatinine, and in patients on agents that moderate CYP3A4 function.

The risks of interventions to decrease thromboembolism against bleeding risk continue to be evaluated in specified patient populations. Although dabigatran did not have FDA approval prior to submission of the 2011 updated guidelines, the 2011 “focused update” incorporated the results of the RE-LY trial. Publication of RE-LY resulted in a Class 1 recommendation for dabigatran as a useful alternative to warfarin in patients with nonvalvular AF without severe renal failure or advanced liver disease.³ However, there is no specific antidote, and dabigatran use is associated with higher rates of dyspepsia and a nonsignificant increase in rates of myocardial infarction. In patients for whom oral anticoagulation with warfarin is considered unsuitable, aspirin with clopidogrel may be considered, although warfarin therapy continues to be a superior therapy to this dual antiplatelet regimen based on the ACTIVE-W and ACTIVE-A studies.²

Established Guideline Analysis

Apart from the listed updates, the management of AF has not changed considerably in the past decade. Rate control continues to be the recommended strategy for older patients along with appropriate symptom control, particularly if they have hypertension or heart disease. Rhythm control is a frequent strategy in AF management, but several studies have not found any difference in quality of life, development or progression of heart failure, or stroke rates in patients for whom a rhythm-control strategy was chosen.

Additionally, these patients still require anticoagulation, and the side effects of anti-arrhythmic drugs might offset the benefits of sinus rhythm. Therefore, rate control is an appropriate strategy. The stroke rate and side-effect risks with anti-arrhythmics are considerably lower in younger patients or those with paroxysmal lone AF, and so a rhythm-control strategy in these groups is reasonable.

Stroke rate in AF increases with known high-risk factors (prior thromboembolism or rheumatic mitral stenosis) and moderate-risk factors (heart failure, hypertension, age over 75, and diabetes). Less validated risk factors include female gender, age 65-74, thyrotoxicosis, and the presence of coronary artery disease.

There are well-defined recommendations for how to anticoagulate specific subgroups that pose clinical challenges not directly addressed in studies, but the guidelines do assist with:

• Patients who have a stroke with a therapeutic INR: Rather than adding antiplatelet agents, INR goal can be raised to 3-3.5;
• Patients >75 years old who are at a high risk for bleeding: A target INR of 2.0 (target range 1.6-2.5) seems reasonable;1 and
• Patients with stable coronary artery disease and AF: Warfarin anticoagulation alone should provide satisfactory antithrombotic prophylaxis against cerebrovascular and coronary atheroembolic events.¹

Decisions involving perioperative management of anticoagulation in patients with AF frequently arise. Per the guidelines, in patients with nonvalvular AF, anticoagulation can be stopped for up to one week without bridging for surgical or diagnostic procedures, but bridging should be considered in high-risk patients.

HM Takeaways

Hospitalists are likely to manage AF, whether alone or in conjunction with cardiology consultation. These new comprehensive guidelines deal with rate control, rhythm control, and prevention of thromboembolism. Hospitalists should take particular interest in the guidelines regarding lenient rate control, dronedarone for rhythm control, and dabigatran as a new alternative for anticoagulation in appropriate populations.

Drs. Farrell and Carbo are hospitalists at Beth Israel Deaconess Medical Center in Boston.

References

1. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011;57(11):e101-98.
2. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Heart Rhythm. 2011;8(1):157-76.
3. Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2011;57(11):1330-7.

Background

Atrial fibrillation (AF) is a common condition, affecting more than 2 million Americans.¹ Hospital admissions due to AF have increased 66% in the past two decades. Hospitalization accounts for 52% of the cost of AF management, and the mortality rate of patients with this arrhythmia is twice that of patients in sinus rhythm.1

AF management decisions include choices for rate control, rhythm control, and prevention of thromboembolism. The benefits of a rhythm-control versus a rate-control strategy continue to be evaluated, along with consideration regarding an appropriate heart-rate goal. The modifiable risk factor of stroke in atrial fibrillation also continues to be a target for intervention as atrial fibrillation accounts for one-sixth of all strokes.

Guideline Update

The American College of Cardiology Foundation and American Heart Association (ACC/AHA), in conjunction with the European Society of Cardiology, released practice guidelines on the management of patients with atrial fibrillation in 2006. The ACCF/AHA, writing with the Heart Rhythm Society, released focused updates in early 2011 to be incorporated into the previous guidelines, given new data from major clinical trials and the FDA approval of new medications with indications for AF treatment.^2,3

The new recommendations address components of all three major management decisions for AF: rate control, rhythm control, and prevention of thromboembolism.

When managing AF with a rate-control strategy, new guidelines no longer recommend the goal of a resting heart rate of <80 bpm or <115 bpm with activity. This is based on data from the RACE II trial that show no difference in meaningful outcomes with a more aggressive heart-rate goal. Achieving a resting heart rate of 110 bpm was deemed a reasonable approach, as long as the patient has stable ventricular function and acceptable symptoms.

The new drug dronedarone has been introduced in the algorithm for maintenance of sinus rhythm strategy, based on the DIONYSOS, ATHENA, and ANDROMEDA studies. The new algorithm excluded the use of dronedarone in patients with left ventricular hypertrophy, decompensated heart failure, or Class IV heart failure because it was shown to increase mortality in these groups. The guidelines also recommend that it should also be used with caution in patients with bradycardia, prolonged QT interval, increased creatinine, and in patients on agents that moderate CYP3A4 function.

The risks of interventions to decrease thromboembolism against bleeding risk continue to be evaluated in specified patient populations. Although dabigatran did not have FDA approval prior to submission of the 2011 updated guidelines, the 2011 “focused update” incorporated the results of the RE-LY trial. Publication of RE-LY resulted in a Class 1 recommendation for dabigatran as a useful alternative to warfarin in patients with nonvalvular AF without severe renal failure or advanced liver disease.³ However, there is no specific antidote, and dabigatran use is associated with higher rates of dyspepsia and a nonsignificant increase in rates of myocardial infarction. In patients for whom oral anticoagulation with warfarin is considered unsuitable, aspirin with clopidogrel may be considered, although warfarin therapy continues to be a superior therapy to this dual antiplatelet regimen based on the ACTIVE-W and ACTIVE-A studies.²

Established Guideline Analysis

Apart from the listed updates, the management of AF has not changed considerably in the past decade. Rate control continues to be the recommended strategy for older patients along with appropriate symptom control, particularly if they have hypertension or heart disease. Rhythm control is a frequent strategy in AF management, but several studies have not found any difference in quality of life, development or progression of heart failure, or stroke rates in patients for whom a rhythm-control strategy was chosen.

Additionally, these patients still require anticoagulation, and the side effects of anti-arrhythmic drugs might offset the benefits of sinus rhythm. Therefore, rate control is an appropriate strategy. The stroke rate and side-effect risks with anti-arrhythmics are considerably lower in younger patients or those with paroxysmal lone AF, and so a rhythm-control strategy in these groups is reasonable.

Stroke rate in AF increases with known high-risk factors (prior thromboembolism or rheumatic mitral stenosis) and moderate-risk factors (heart failure, hypertension, age over 75, and diabetes). Less validated risk factors include female gender, age 65-74, thyrotoxicosis, and the presence of coronary artery disease.

There are well-defined recommendations for how to anticoagulate specific subgroups that pose clinical challenges not directly addressed in studies, but the guidelines do assist with:

• Patients who have a stroke with a therapeutic INR: Rather than adding antiplatelet agents, INR goal can be raised to 3-3.5;
• Patients >75 years old who are at a high risk for bleeding: A target INR of 2.0 (target range 1.6-2.5) seems reasonable;1 and
• Patients with stable coronary artery disease and AF: Warfarin anticoagulation alone should provide satisfactory antithrombotic prophylaxis against cerebrovascular and coronary atheroembolic events.¹

Decisions involving perioperative management of anticoagulation in patients with AF frequently arise. Per the guidelines, in patients with nonvalvular AF, anticoagulation can be stopped for up to one week without bridging for surgical or diagnostic procedures, but bridging should be considered in high-risk patients.

HM Takeaways

Hospitalists are likely to manage AF, whether alone or in conjunction with cardiology consultation. These new comprehensive guidelines deal with rate control, rhythm control, and prevention of thromboembolism. Hospitalists should take particular interest in the guidelines regarding lenient rate control, dronedarone for rhythm control, and dabigatran as a new alternative for anticoagulation in appropriate populations.

Drs. Farrell and Carbo are hospitalists at Beth Israel Deaconess Medical Center in Boston.

References

1. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011;57(11):e101-98.
2. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Heart Rhythm. 2011;8(1):157-76.
3. Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2011;57(11):1330-7.

The new “Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage,” published online May 3 in Stroke, call for hospitals treating fewer than 10 aneurysmal subarachnoid hemorrhage (aSAH) cases per year to consider their immediate transfer to facilities that handle at least 35 such cases annually.¹ The recommendation is based on research suggesting that 30-day death rates were significantly higher in low-volume facilities (39%) vs. facilities treating more than 35 cases per year (27%), reflecting the latter’s greater access to cerebrovascular surgeons, endovascular specialists, and neuro-intensive-care services.

This type of hemorrhage accounts for 5% of all strokes and affects more than 30,000 Americans annually.

Reference

1. Connolly ES Jr., Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43(6):1711-1737.

The new “Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage,” published online May 3 in Stroke, call for hospitals treating fewer than 10 aneurysmal subarachnoid hemorrhage (aSAH) cases per year to consider their immediate transfer to facilities that handle at least 35 such cases annually.¹ The recommendation is based on research suggesting that 30-day death rates were significantly higher in low-volume facilities (39%) vs. facilities treating more than 35 cases per year (27%), reflecting the latter’s greater access to cerebrovascular surgeons, endovascular specialists, and neuro-intensive-care services.

This type of hemorrhage accounts for 5% of all strokes and affects more than 30,000 Americans annually.

Reference

1. Connolly ES Jr., Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43(6):1711-1737.

The new “Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage,” published online May 3 in Stroke, call for hospitals treating fewer than 10 aneurysmal subarachnoid hemorrhage (aSAH) cases per year to consider their immediate transfer to facilities that handle at least 35 such cases annually.¹ The recommendation is based on research suggesting that 30-day death rates were significantly higher in low-volume facilities (39%) vs. facilities treating more than 35 cases per year (27%), reflecting the latter’s greater access to cerebrovascular surgeons, endovascular specialists, and neuro-intensive-care services.

This type of hemorrhage accounts for 5% of all strokes and affects more than 30,000 Americans annually.

Reference

1. Connolly ES Jr., Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43(6):1711-1737.

A recent report that states the choice between warfarin and aspirin in patients with heart failure and sinus rhythm should be individualized is the most definitive word to date on the topic, says a hospitalist focused on anticoagulation therapies.

The report, “Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm,” focused on patients in sinus rhythm who had reduced left ventricular ejection fraction (LVEF). The authors concluded that the reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage.

“The new thing about this study is it’s really the definitive, well-designed, large trial that provides guidance to us as to what is right,” says Margaret Fang, MD, MPH, an associate professor of medicine at the University of California at San Francisco (UCSF) and medical director of the UCSF Anticoagulation Clinic. “Is warfarin really the right decision?”

Dr. Fang notes that the report, known more commonly as the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, did find that, over time, warfarin began to show improvement over aspirin. But the improvements, which favored warfarin by the fourth year of the six-year trial, were deemed only marginally significant (P=.046).

An editorial accompanying the study noted that while warfarin is often a go-to therapy, the WARCEF trial corroborates other, smaller trials that did not associate it with a reduction in mortality among heart failure patients.

“The WARCEF trial provides clear evidence that anticoagulant therapy prevents stroke, probably embolic stroke, in patients with heart failure who have severe systolic dysfunction, but the rates of stroke are too low to justify the routine clinical use of warfarin in most patients with heart failure, in light of the increase in the risk of bleeding,” the editorial reads.

A recent report that states the choice between warfarin and aspirin in patients with heart failure and sinus rhythm should be individualized is the most definitive word to date on the topic, says a hospitalist focused on anticoagulation therapies.

The report, “Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm,” focused on patients in sinus rhythm who had reduced left ventricular ejection fraction (LVEF). The authors concluded that the reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage.

“The new thing about this study is it’s really the definitive, well-designed, large trial that provides guidance to us as to what is right,” says Margaret Fang, MD, MPH, an associate professor of medicine at the University of California at San Francisco (UCSF) and medical director of the UCSF Anticoagulation Clinic. “Is warfarin really the right decision?”

Dr. Fang notes that the report, known more commonly as the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, did find that, over time, warfarin began to show improvement over aspirin. But the improvements, which favored warfarin by the fourth year of the six-year trial, were deemed only marginally significant (P=.046).

An editorial accompanying the study noted that while warfarin is often a go-to therapy, the WARCEF trial corroborates other, smaller trials that did not associate it with a reduction in mortality among heart failure patients.

“The WARCEF trial provides clear evidence that anticoagulant therapy prevents stroke, probably embolic stroke, in patients with heart failure who have severe systolic dysfunction, but the rates of stroke are too low to justify the routine clinical use of warfarin in most patients with heart failure, in light of the increase in the risk of bleeding,” the editorial reads.

A recent report that states the choice between warfarin and aspirin in patients with heart failure and sinus rhythm should be individualized is the most definitive word to date on the topic, says a hospitalist focused on anticoagulation therapies.

The report, “Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm,” focused on patients in sinus rhythm who had reduced left ventricular ejection fraction (LVEF). The authors concluded that the reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage.

“The new thing about this study is it’s really the definitive, well-designed, large trial that provides guidance to us as to what is right,” says Margaret Fang, MD, MPH, an associate professor of medicine at the University of California at San Francisco (UCSF) and medical director of the UCSF Anticoagulation Clinic. “Is warfarin really the right decision?”

Dr. Fang notes that the report, known more commonly as the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, did find that, over time, warfarin began to show improvement over aspirin. But the improvements, which favored warfarin by the fourth year of the six-year trial, were deemed only marginally significant (P=.046).

An editorial accompanying the study noted that while warfarin is often a go-to therapy, the WARCEF trial corroborates other, smaller trials that did not associate it with a reduction in mortality among heart failure patients.

“The WARCEF trial provides clear evidence that anticoagulant therapy prevents stroke, probably embolic stroke, in patients with heart failure who have severe systolic dysfunction, but the rates of stroke are too low to justify the routine clinical use of warfarin in most patients with heart failure, in light of the increase in the risk of bleeding,” the editorial reads.

A new report on acute myocardial infarction (AMI) suggests that implementing a handful of relatively easy strategies can improve mortality rates.

The research, "Hospital Strategies for Reducing Risk-Standardized Mortality Rates in Acute Myocardial Infarction," highlights several techniques for lowering risk-standardized mortality rates (RSMR) in this patient population:

• Holding monthly meetings to review AMI cases (lowered RSMR by 0.7%);

• Fostering an environment that encourages clinicians to solve problems creatively (lowered RSMR by 0.84%);

• Having 24-hour coverage by cardiologists (lowered RSMR by 0.54%);

• Having both a nurse and physician champion for quality in AMI (lowered RSMR by 0.88%); and

• Avoiding cross-training nurses from ICUs for cardiac catheterization laboratories (lowered RSMR by 0.44%).

Fewer than 10% of the 537 hospitals in the cross-sectional survey reported using at least four of the five strategies. Lead author Elizabeth H. Bradley, PhD, faculty director of the Global Health Leadership Institute and professor of public health at Yale University, says the challenge in implementing the strategies lies in changing the often-obstinate culture of healthcare institutions.

"The root of this is the culture," she says, adding if nothing else, "begin with the problems, begin with an analytical mind when errors occur." Dr. Bradley adds that culture of teamwork works only when it has buy-in from in-the-trenches physicians, such as hospitalists and C-suite executives.

"It has to come from the front line and from the top," she says. "In all of our studies over the last decade, [physicians and administrators] need to be supportive of an environment in which problem solving can happen."

A new report on acute myocardial infarction (AMI) suggests that implementing a handful of relatively easy strategies can improve mortality rates.

The research, "Hospital Strategies for Reducing Risk-Standardized Mortality Rates in Acute Myocardial Infarction," highlights several techniques for lowering risk-standardized mortality rates (RSMR) in this patient population:

• Holding monthly meetings to review AMI cases (lowered RSMR by 0.7%);

• Fostering an environment that encourages clinicians to solve problems creatively (lowered RSMR by 0.84%);

• Having 24-hour coverage by cardiologists (lowered RSMR by 0.54%);

• Having both a nurse and physician champion for quality in AMI (lowered RSMR by 0.88%); and

• Avoiding cross-training nurses from ICUs for cardiac catheterization laboratories (lowered RSMR by 0.44%).

Fewer than 10% of the 537 hospitals in the cross-sectional survey reported using at least four of the five strategies. Lead author Elizabeth H. Bradley, PhD, faculty director of the Global Health Leadership Institute and professor of public health at Yale University, says the challenge in implementing the strategies lies in changing the often-obstinate culture of healthcare institutions.

"The root of this is the culture," she says, adding if nothing else, "begin with the problems, begin with an analytical mind when errors occur." Dr. Bradley adds that culture of teamwork works only when it has buy-in from in-the-trenches physicians, such as hospitalists and C-suite executives.

"It has to come from the front line and from the top," she says. "In all of our studies over the last decade, [physicians and administrators] need to be supportive of an environment in which problem solving can happen."

A new report on acute myocardial infarction (AMI) suggests that implementing a handful of relatively easy strategies can improve mortality rates.

The research, "Hospital Strategies for Reducing Risk-Standardized Mortality Rates in Acute Myocardial Infarction," highlights several techniques for lowering risk-standardized mortality rates (RSMR) in this patient population:

• Holding monthly meetings to review AMI cases (lowered RSMR by 0.7%);

• Fostering an environment that encourages clinicians to solve problems creatively (lowered RSMR by 0.84%);

• Having 24-hour coverage by cardiologists (lowered RSMR by 0.54%);

• Having both a nurse and physician champion for quality in AMI (lowered RSMR by 0.88%); and

• Avoiding cross-training nurses from ICUs for cardiac catheterization laboratories (lowered RSMR by 0.44%).

Fewer than 10% of the 537 hospitals in the cross-sectional survey reported using at least four of the five strategies. Lead author Elizabeth H. Bradley, PhD, faculty director of the Global Health Leadership Institute and professor of public health at Yale University, says the challenge in implementing the strategies lies in changing the often-obstinate culture of healthcare institutions.

"The root of this is the culture," she says, adding if nothing else, "begin with the problems, begin with an analytical mind when errors occur." Dr. Bradley adds that culture of teamwork works only when it has buy-in from in-the-trenches physicians, such as hospitalists and C-suite executives.

"It has to come from the front line and from the top," she says. "In all of our studies over the last decade, [physicians and administrators] need to be supportive of an environment in which problem solving can happen."

Clinical question: What is the association between delayed acyclovir therapy and death in neonates with herpes simplex virus (HSV) infection?

Background: Neonatal HSV infection may result in significant morbidity and mortality if untreated. Because symptoms upon presentation may be nonspecific and testing may take several days, clinicians must often decide whether to initiate empiric therapy with acyclovir. However, this may also have consequences related to increased costs of care and the side effects of acyclovir.

Study design: Multicenter retrospective cohort study.

Setting: Forty-one freestanding tertiary-care children’s hospitals.

Synopsis: The Pediatric Health Information System (PHIS) database was used to identify 1,086 infants <28 days of age with a discharge diagnosis of HSV from 2003 to 2009 who received their first dose of intravenous acyclovir within the first seven days of admission. Delayed acyclovir was defined as administration after hospital Day One. Propensity scores and multivariate logistic regression analysis were used to attempt to account for patient (e.g. severity of illness) and hospital confounders. The mortality rate was 9.5% (95% confidence interval [CI]: 6.3%-13.82%) for delayed therapy compared with 6.6% (95% CI: 5.0%-8.5%) for early therapy.

Limitations of this study include the inability to identify all potential patient-level confounders that might have led clinicians to initiate early acyclovir therapy. Although the authors attempted to account for variables that might have defined sicker patients, such as intubation or vasoactive agent infusion, they could not identify patients with just skin, eye, or mouth disease from this database, nor could they identify specific clinical concerns, such as hypothermia. Thus, while the authors conclude that empiric acyclovir is prudent if HSV testing is performed, more specific clinical indications cannot be gleaned from this review.

Bottom line: Delayed initiation of acyclovir increases mortality in neonatal HSV infection.

Citation: Shah SS, Aronson PL, Mohamad Z, Lorch SA. Delayed acyclovir therapy and death among neonates with herpes simplex virus infection. Pediatrics. 2011;128(6):1153-1160.

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

Clinical question: What is the association between delayed acyclovir therapy and death in neonates with herpes simplex virus (HSV) infection?

Background: Neonatal HSV infection may result in significant morbidity and mortality if untreated. Because symptoms upon presentation may be nonspecific and testing may take several days, clinicians must often decide whether to initiate empiric therapy with acyclovir. However, this may also have consequences related to increased costs of care and the side effects of acyclovir.

Study design: Multicenter retrospective cohort study.

Setting: Forty-one freestanding tertiary-care children’s hospitals.

Synopsis: The Pediatric Health Information System (PHIS) database was used to identify 1,086 infants <28 days of age with a discharge diagnosis of HSV from 2003 to 2009 who received their first dose of intravenous acyclovir within the first seven days of admission. Delayed acyclovir was defined as administration after hospital Day One. Propensity scores and multivariate logistic regression analysis were used to attempt to account for patient (e.g. severity of illness) and hospital confounders. The mortality rate was 9.5% (95% confidence interval [CI]: 6.3%-13.82%) for delayed therapy compared with 6.6% (95% CI: 5.0%-8.5%) for early therapy.

Limitations of this study include the inability to identify all potential patient-level confounders that might have led clinicians to initiate early acyclovir therapy. Although the authors attempted to account for variables that might have defined sicker patients, such as intubation or vasoactive agent infusion, they could not identify patients with just skin, eye, or mouth disease from this database, nor could they identify specific clinical concerns, such as hypothermia. Thus, while the authors conclude that empiric acyclovir is prudent if HSV testing is performed, more specific clinical indications cannot be gleaned from this review.

Bottom line: Delayed initiation of acyclovir increases mortality in neonatal HSV infection.

Citation: Shah SS, Aronson PL, Mohamad Z, Lorch SA. Delayed acyclovir therapy and death among neonates with herpes simplex virus infection. Pediatrics. 2011;128(6):1153-1160.

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

Clinical question: What is the association between delayed acyclovir therapy and death in neonates with herpes simplex virus (HSV) infection?

Background: Neonatal HSV infection may result in significant morbidity and mortality if untreated. Because symptoms upon presentation may be nonspecific and testing may take several days, clinicians must often decide whether to initiate empiric therapy with acyclovir. However, this may also have consequences related to increased costs of care and the side effects of acyclovir.

Study design: Multicenter retrospective cohort study.

Setting: Forty-one freestanding tertiary-care children’s hospitals.

Synopsis: The Pediatric Health Information System (PHIS) database was used to identify 1,086 infants <28 days of age with a discharge diagnosis of HSV from 2003 to 2009 who received their first dose of intravenous acyclovir within the first seven days of admission. Delayed acyclovir was defined as administration after hospital Day One. Propensity scores and multivariate logistic regression analysis were used to attempt to account for patient (e.g. severity of illness) and hospital confounders. The mortality rate was 9.5% (95% confidence interval [CI]: 6.3%-13.82%) for delayed therapy compared with 6.6% (95% CI: 5.0%-8.5%) for early therapy.

Limitations of this study include the inability to identify all potential patient-level confounders that might have led clinicians to initiate early acyclovir therapy. Although the authors attempted to account for variables that might have defined sicker patients, such as intubation or vasoactive agent infusion, they could not identify patients with just skin, eye, or mouth disease from this database, nor could they identify specific clinical concerns, such as hypothermia. Thus, while the authors conclude that empiric acyclovir is prudent if HSV testing is performed, more specific clinical indications cannot be gleaned from this review.

Bottom line: Delayed initiation of acyclovir increases mortality in neonatal HSV infection.

Citation: Shah SS, Aronson PL, Mohamad Z, Lorch SA. Delayed acyclovir therapy and death among neonates with herpes simplex virus infection. Pediatrics. 2011;128(6):1153-1160.

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

Clinical question: What is the epidemiology of 15-day readmissions to a children’s hospital?

Background: Readmissions are a common event in the adult population. Given the national focus on accountable care across the continuum, the Centers for Medicare & Medicaid Services (CMS) has devoted increasing attention to readmissions as a reportable quality metric in certain conditions and a target for improvement. Recommendations for pediatric patients are currently not available, primarily due to limited evidence.

Study design: Retrospective chart review.

Setting: Tertiary-care children’s hospital.

Synopsis: Of the 30,188 admissions over a two-year period, 2,546 (8.4%) resulted in readmission within 15 days. There were a total of 1,435 individual patients who were readmitted, for an average readmission rate of 1.8 per patient. Oncology patients represented the most likely group of patients to be readmitted (13.9%) and had the most number of readmissions per patient (4.1). Children with acute infectious disease, newborns, and patients with neurologic diseases represented 11.4%, 11.1%, and 10% of the readmitted patients, respectively.

Children with short-bowel syndrome and biliary atresia had a high number of readmissions per patient: 3.9 and 3.8, respectively. The majority of readmissions were unplanned (79.4%) and occurred in patients with an underlying chronic condition (78%). Readmissions 7 days from discharge accounted for 59.5% of the total, with the remaining 40.5% occurring between eight and 15 days of discharge.

This study provides one of the more comprehensive pictures of readmissions to a children’s hospital. Although the data are limited by an inability to account for readmissions to and from other facilities, they nonetheless clearly differentiate pediatric readmissions from those in an adult population.

Bottom line: Pediatric readmissions are quantitatively and qualitatively different from adult readmissions.

Citation: Gay JC, Hain PD, Grantham JA, Saville BR. Epidemiology of 15-day readmissions to a children’s hospital. Pediatrics. 2011;127:e1-e8.

Clinical question: What is the epidemiology of 15-day readmissions to a children’s hospital?

Background: Readmissions are a common event in the adult population. Given the national focus on accountable care across the continuum, the Centers for Medicare & Medicaid Services (CMS) has devoted increasing attention to readmissions as a reportable quality metric in certain conditions and a target for improvement. Recommendations for pediatric patients are currently not available, primarily due to limited evidence.

Study design: Retrospective chart review.

Setting: Tertiary-care children’s hospital.

Synopsis: Of the 30,188 admissions over a two-year period, 2,546 (8.4%) resulted in readmission within 15 days. There were a total of 1,435 individual patients who were readmitted, for an average readmission rate of 1.8 per patient. Oncology patients represented the most likely group of patients to be readmitted (13.9%) and had the most number of readmissions per patient (4.1). Children with acute infectious disease, newborns, and patients with neurologic diseases represented 11.4%, 11.1%, and 10% of the readmitted patients, respectively.

Children with short-bowel syndrome and biliary atresia had a high number of readmissions per patient: 3.9 and 3.8, respectively. The majority of readmissions were unplanned (79.4%) and occurred in patients with an underlying chronic condition (78%). Readmissions 7 days from discharge accounted for 59.5% of the total, with the remaining 40.5% occurring between eight and 15 days of discharge.

This study provides one of the more comprehensive pictures of readmissions to a children’s hospital. Although the data are limited by an inability to account for readmissions to and from other facilities, they nonetheless clearly differentiate pediatric readmissions from those in an adult population.

Bottom line: Pediatric readmissions are quantitatively and qualitatively different from adult readmissions.

Citation: Gay JC, Hain PD, Grantham JA, Saville BR. Epidemiology of 15-day readmissions to a children’s hospital. Pediatrics. 2011;127:e1-e8.

Clinical question: What is the epidemiology of 15-day readmissions to a children’s hospital?

Background: Readmissions are a common event in the adult population. Given the national focus on accountable care across the continuum, the Centers for Medicare & Medicaid Services (CMS) has devoted increasing attention to readmissions as a reportable quality metric in certain conditions and a target for improvement. Recommendations for pediatric patients are currently not available, primarily due to limited evidence.

Study design: Retrospective chart review.

Setting: Tertiary-care children’s hospital.

Synopsis: Of the 30,188 admissions over a two-year period, 2,546 (8.4%) resulted in readmission within 15 days. There were a total of 1,435 individual patients who were readmitted, for an average readmission rate of 1.8 per patient. Oncology patients represented the most likely group of patients to be readmitted (13.9%) and had the most number of readmissions per patient (4.1). Children with acute infectious disease, newborns, and patients with neurologic diseases represented 11.4%, 11.1%, and 10% of the readmitted patients, respectively.

Children with short-bowel syndrome and biliary atresia had a high number of readmissions per patient: 3.9 and 3.8, respectively. The majority of readmissions were unplanned (79.4%) and occurred in patients with an underlying chronic condition (78%). Readmissions 7 days from discharge accounted for 59.5% of the total, with the remaining 40.5% occurring between eight and 15 days of discharge.

This study provides one of the more comprehensive pictures of readmissions to a children’s hospital. Although the data are limited by an inability to account for readmissions to and from other facilities, they nonetheless clearly differentiate pediatric readmissions from those in an adult population.

Bottom line: Pediatric readmissions are quantitatively and qualitatively different from adult readmissions.

Citation: Gay JC, Hain PD, Grantham JA, Saville BR. Epidemiology of 15-day readmissions to a children’s hospital. Pediatrics. 2011;127:e1-e8.

In This Edition

Literature at a Glance

A guide to this month’s studies

• Continuous insulin infusion in non-ICU patients
• How hospitalists spend their day
• Outcomes of patients leaving against medical advice
• Prediction rule for readmission
• Effects of high- vs. low-dose PPIs for peptic ulcer
• Hospital utilization by generalists before hospitalists
• Effect of hospitalist fragmentation on length of stay
• Medication errors at admissions in older patients

Continuous Insulin Infusion Provides Effective Glycemic Control in Non-ICU Patients

Clinical question: Is continuous insulin infusion (CII) a safe and effective option in the management of hyperglycemia in non-ICU patients?

Background: Hyperglycemia has been associated with worse outcomes in hospitalized patients. Prior research has demonstrated the benefit of CII in managing hyperglycemia in the ICU setting. However, outcomes have not been evaluated in the general medical (non-ICU) setting, where hyperglycemia is often inadequately addressed.

Study design: Retrospective chart review.

Setting: Urban tertiary-care medical center.

Synopsis: Charts of 200 adult patients treated with CII in non-ICU areas were reviewed with the primary outcomes including mean daily blood glucose (BG) levels and number of hyper- and hypoglycemic events occurring on CII. Mean BG dropped from 323 mg/dL to 182 mg/dL by day one, with a BG≤of 150 achieved in 67% of patients by day two of therapy. Twenty-two percent of patients suffered a hypoglycemic event (BG<60), reportedly similar to prior studies of insulin use in ICU and non-ICU settings. Eighty-two percent of patients received some form of nutritional support while on CII. In multivariate analyses, receiving oral nutrition (either a solid or liquid diet) was the only factor associated with increased risk of hyperglycemia and hypoglycemia.

This study was limited by its retrospective analysis in a single center. No comparison was made with basal-bolus or sliding-scale insulin therapy regarding efficacy or safety.

Bottom line: Non-ICU patients with hyperglycemia who received CII were able to achieve effective glycemic control within 48 hours of initiation, with rates of hypoglycemia comparable to those observed in ICU settings.

Citation: Smiley D, Rhee M, Peng L, et al. Safety and efficacy of continuous insulin infusion in noncritical care settings. J Hosp Med. 2010;5(4):212-217.

Hospitalists Spend More Time on Indirect, Rather Than Direct, Patient Care

Clinical question: What are the components of the daily workflow of hospitalists working on a non-housestaff service?

Background: The use of hospitalists is associated with increased efficiency in the hospital setting. However, it is not known how this efficiency is achieved. Prior literature has attempted to address this question, but with increasing demands and patient census, the representativeness of existing data is unclear.

Study design: Observational time-motion study.

Setting: Urban tertiary-care academic medical center.

Synopsis: Twenty-four hospitalists were directly observed for two weekday shifts. An electronic collection tool was developed using initial data on hospitalist activities and piloted prior to formal study data collection. Direct patient care was defined as involving face-to-face interaction between hospitalist and patient, while indirect patient care involved activities relevant to patient care but not performed in the patient’s presence.

Approximately 500 hours of observation were collected. Direct patient care comprised only a mean of 17.4% of the hospitalists’ daily workflow, while more was spent on indirect care, mainly electronic health record (EHR) documentation (mean 34.1%) and communication activities (mean 25.9%). Multitasking occurred 16% of the time, typically during communication or “critical documentation activities” (e.g. writing prescriptions). As patient volume increased, less time was spent in communication, and documentation was deferred to after hours.

These results were consistent with prior observational studies but were limited to a single center and might not represent the workflow of hospitalists in other settings, such as community hospitals, or nocturnists.

Bottom line: Hospitalists on non-housestaff services spend most of their time on indirect patient care and, with increasing patient census, communication is sacrificed. Multitasking is common during periods of communication and critical documentation.

Citation: Tipping MD, Forth VE, O’Leary KJ, et al. Where did the day go?—a time-motion study of hospitalists. J Hosp Med. 2010;5(6):323-328.

Patients Who Leave Against Medical Advice Have Higher Readmission, Mortality Rates

Clinical question: What are the 30-day hospital readmission and mortality rates for Veterans Administration (VA) patients discharged against medical advice (AMA) compared with those appropriately discharged from the hospital?

Background: Patients discharged AMA might be at increased risk of experiencing worse outcomes. Small studies have demonstrated that patients with asthma and acute myocardial infarction (MI) discharged AMA have increased risk of readmission and death. However, it is unclear whether these risks are generalizable to a wider medical population.

Study design: Five-year retrospective cohort study.

Setting: One hundred twenty-nine VA acute-care hospitals.

Synopsis: Of the nearly 2 million patients admitted to the VA from 2004 to 2008, 1.7% were discharged AMA. Patients discharged AMA generally were younger, had lower incomes, and were more likely to be black. Furthermore, patients discharged AMA had statistically significant higher rates of 30-day readmission (17.7% vs. 11%, P<0.001) and higher 30-day mortality rates (0.75% vs. 0.61%, P=0.001) compared with those who had been appropriately discharged. In hazard models, discharge AMA was a significant predictor of 30-day readmission and conferred a nonstatistically significant increase in 30-day mortality.

Because all patients were seen in VA facilities, the results might not be generalizable to other acute-care settings. Although VA patients differ from the general medical population, the characteristics of patients discharged AMA are similar to those in previously published studies. The study utilized administrative data, which are very reliable but limited by little information on clinical factors that could contribute to AMA discharges.

Bottom line: Patients discharged AMA are at increased risk of worse post-hospitalization outcomes, including hospital readmission and death.

Citation: Glasgow JM, Vaughn-Sarrazin M, Kaboli PJ. Leaving against medical advice (AMA): risk of 30-day mortality and hospital readmission. J Gen Intern Med. 2010;25(9): 926-929.

Simple Model Predicts Hospital Readmission

Clinical question: Which patient-level factors can be used in a simple model to predict hospital readmission of medicine patients?

Background: Hospital readmissions are common and costly. Previously published readmission prediction models have had limited utility because they focused on a specific condition, setting, or population, or were too cumbersome for practical use.

Study design: Prospective observational cohort study.

Setting: Six academic medical centers.

Synopsis: Data from nearly 11,000 general medicine patients were included in the analysis. Overall, almost 18% of patients were readmitted within 30 days of discharge.

In the prediction model derived and validated from the data, seven factors were significant predictors of readmission within 30 days of discharge: insurance status, marital status, having a regular healthcare provider, Charlson comorbidity index, SF 12 physical component score, one or more admissions within the last year, and current length of stay greater than two days. Points assigned from each significant predictor were used to create a risk score. The 5% of patients with risk scores of 25 and higher had 30-day readmission rates of approximately 30%, compared to readmission rates of approximately 16% in patients with scores of less than 25.

These results might not be generalizable to small, rural, nonacademic settings. Planned admissions could not be excluded from the data, and readmissions to nonstudy hospitals could not be ascertained. Despite these limitations, this model is easier to use than prior models and relevant to a broad population of patients.

Bottom line: A simple prediction model using patient-level factors can be used to identify patients at higher risk of readmission within 30 days of discharge to home.

Citation: Hasan O, Meltzer DO, Shaykevich SA, et al. Hospital readmission in general medicine patients: a prediction model. J Gen Intern Med. 2010;25(3):211-219.

No Difference in Outcomes Between High- and Non-High-Dose Proton Pump Inhibitors in Bleeding Peptic Ulcers

Clinical question: Do high-dose proton pump inhibitors (PPIs) decrease the rate of rebleeding, surgical intervention, or mortality in patients with bleeding peptic ulcers who have undergone endoscopic treatment?

Background: Previous studies have demonstrated superiority of both high- and low-dose PPIs to H2 receptor antagonists and placebo in reducing rebleeding rates in patients with peptic ulcers. However, no clear evidence is available to suggest that high-dose PPIs are more effective than non-high-dose PPIs for treatment of bleeding peptic ulcers.

Study design: Systematic review and meta-analysis.

Setting: Multicenter and single-site studies conducted in several countries.

Synopsis: Studies were included if they were randomized controlled trials, compared high- versus non-high-dose PPIs, evaluated endoscopically confirmed bleeding ulcers, gave PPIs after endoscopy, and documented outcomes regarding rates of rebleeding, surgical intervention, or mortality. High-dose PPIs were defined as equivalent to omeprazole 80 mg intravenous bolus followed by continuous intravenous infusion at 8 mg/hr for 72 hours.

Seven studies met inclusion criteria. The pooled odds ratios for rebleeding, surgical intervention, and mortality were 1.30 (95% CI, 0.88-1.91), 1.49 (95% CI, 0.66-3.37), and 0.89 (95% CI, 0.37-2.13), respectively, for high-dose versus non-high-dose PPIs. The authors concluded that high-dose PPIs were not superior to non-high-dose PPIs in reducing the rates of these adverse outcomes after endoscopic treatment of bleeding ulcers. Considering the cost of high-dose PPIs, further studies are indicated to help guide PPI dosing for patients with peptic ulcers.

Major limitations of this study were the small number of studies (1,157 patients in total) and their heterogeneity, and the lack of intention-to-treat analysis. The studies also included a high Asian predominance, and it has been shown that Asian populations have an enhanced PPI effect.

Bottom line: High-dose PPIs did not demonstrate reduced rates of ulcer rebleeding, surgical intervention, or mortality compared with non-high-dose PPIs in this meta-analysis, which included a small number of studies and patients.

Citation: Wang CH, Ma MH, Chou HC, et al. High-dose vs. non-high-dose proton pump inhibitors after endoscopic treatment in patients with bleeding peptic ulcer: a systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2010;170(9):751-758.

Hospital Utilization by Practicing Generalists Declined before the Emergence of Hospitalists

Clinical question: What has been the pattern of hospital utilization by generalists before and after the emergence of hospitalists?

Background: It has been proposed that the emergence of hospitalists has “crowded out” generalist physicians from the U.S. hospital setting. This study evaluated the trends of inpatient practice by generalists both before and after the emergence of hospitalists.

Study design: Retrospective analysis of national databases.

Setting: U.S. data from 1980 to 2005.

Synopsis: Utilizing the National Hospital Discharge Survey and the American Medical Association’s Physician Characteristics and Distribution in the U.S., information was extracted to evaluate the average number of annual inpatient encounters relative to generalist workforce from 1980 to 2005. Total inpatient encounters for each year were calculated by multiplying the total number of hospital admissions by the average hospital length of stay. The emergence of hospitalists was defined as beginning in 1994.

Total inpatient encounters by generalists declined by 35% in the pre-hospitalist era but remained essentially unchanged in the hospitalist era. During the pre-hospitalist period, the number of generalists doubled, to more than 200,000 from approximately 100,000, while the number of hospital discharges remained relatively stable and the length of stay declined by a third. The decrease in average inpatient encounters in the pre-hospitalist era is thought to have been secondary to decreased length of stay and increased workforce.

Bottom line: Hospital utilization relative to generalist physician workforce was decreasing prior to the emergence of hospitalists mainly due to decreased length of hospital stay and increased numbers of physicians.

Citation: Meltzer DO, Chung JW. U.S. trends in hospitalization and generalist physician workforce and the emergence of hospitalists. J Gen Intern Med. 2010;25(5):453-459.

Fragmentation of Hospitalist Care Is Associated with Increased Length of Stay

Clinical question: Does fragmentation of care (FOC) by hospitalists affect length of stay (LOS)?

Background: Previous investigations have explored the impact of FOC provided by residency programs on LOS and quality of care. Results of these studies have been mixed. However, there have been no prior studies on the impact of the fragmentation of hospitalist care on LOS.

Study design: Concurrent control study.

Setting: Hospitalist practices all over the country managed by IPC: The Hospitalist Company.

Synopsis: Investigators looked at 10,977 patients admitted with diagnoses of pneumonia or heart failure. The primary endpoint was LOS. The independent variable of interest was a measure of FOC. The FOC was calculated as a quantitative index, by determining the percentage of hospitalist care delivered by a physician other than the primary hospitalist.

Multivariable analyses revealed a statistically significant increase in LOS of 0.39 days for each 10% increase in fragmentation level for pneumonia admissions. Similarly, for patients with heart failure, there was a significant increase in LOS of 0.30 days for each 10% increase in fragmentation level.

The study is a concurrent control study, so conclusions cannot be drawn about causality. Additionally, there are likely unmeasured differences between every hospital and hospitalist practice, which could further confound the relationships between hospitalist care and LOS.

Bottom line: Fragmentation of care provided by hospitalists is associated with an increased LOS in patients hospitalized for pneumonia or heart failure.

Citation: Epstein K, Juarez E, Epstein A, Loya K, Singer A. The impact of fragmentation of hospitalist care on length of stay. J Hosp Med. 2010;5(6):335-338.

Admission Medication Errors Are Common and Most Harmful in Older Patients Taking Many Medications

Clinical question: What are the risk factors and potential harm associated with medication errors at hospital admission?

Background: Obtaining a medication history from a hospitalized patient is an error-prone process. Several variables can affect the completeness and quality of medication histories, but existing data are limited regarding patient or medication risk factors associated with medication errors at admission.

Study design: Prospective cohort study.

Setting: Academic hospital in Chicago.

Synopsis: Pharmacist and admitting physician medication histories were compared with admission medication orders to identify any unexplained discrepancies. Discrepancies resulting in order changes were defined as medication errors.

Of the 651 adult medical inpatients studied, 234 (35.9%) had medication order errors identified at admission. Errors originated in the medication histories for 85% of these patients. The most frequent type of error was an omission (48.9%). An age of 65 or older (odds ratio [OR]=2.17, 95% confidence interval [CI], 1.09-4.30) and increased number of medications (OR=1.21, 95% CI, 1.14-1.29) were the only risk factors identified by multivariate analysis to be independently associated with increased risk of medication order errors potentially causing harm or requiring monitoring or intervention. Presenting a medication list upon admission was a significant protective factor (OR=0.35, 95% CI, 0.19-0.63).

Though this is the largest study to date evaluating admission medication errors in hospitalized medical patients, it remains limited by its single hospital site. Because the authors were unable to interview patients who were too ill or unwilling to participate and had no caregiver present, they might have underestimated the number of admission errors. Further, the harm assessment was based on potential and not actual harm.

Bottom line: Admission medication order errors are frequent, most commonly originate in the medication histories, and have increased potential to cause adverse outcomes in older patients and those taking higher numbers of medications.

Citation: Gleason KM, McDaniel MR, Feinglass J, et al. Results of the Medications At Transitions and Clinical Handoffs (MATCH) study: an analysis of medication reconciliation errors and risk factors at hospital admission. J Gen Intern Med. 2010;25(5):441-447.

In This Edition

Literature at a Glance

A guide to this month’s studies

• Continuous insulin infusion in non-ICU patients
• How hospitalists spend their day
• Outcomes of patients leaving against medical advice
• Prediction rule for readmission
• Effects of high- vs. low-dose PPIs for peptic ulcer
• Hospital utilization by generalists before hospitalists
• Effect of hospitalist fragmentation on length of stay
• Medication errors at admissions in older patients

Continuous Insulin Infusion Provides Effective Glycemic Control in Non-ICU Patients

Clinical question: Is continuous insulin infusion (CII) a safe and effective option in the management of hyperglycemia in non-ICU patients?

Background: Hyperglycemia has been associated with worse outcomes in hospitalized patients. Prior research has demonstrated the benefit of CII in managing hyperglycemia in the ICU setting. However, outcomes have not been evaluated in the general medical (non-ICU) setting, where hyperglycemia is often inadequately addressed.

Study design: Retrospective chart review.

Setting: Urban tertiary-care medical center.

Synopsis: Charts of 200 adult patients treated with CII in non-ICU areas were reviewed with the primary outcomes including mean daily blood glucose (BG) levels and number of hyper- and hypoglycemic events occurring on CII. Mean BG dropped from 323 mg/dL to 182 mg/dL by day one, with a BG≤of 150 achieved in 67% of patients by day two of therapy. Twenty-two percent of patients suffered a hypoglycemic event (BG<60), reportedly similar to prior studies of insulin use in ICU and non-ICU settings. Eighty-two percent of patients received some form of nutritional support while on CII. In multivariate analyses, receiving oral nutrition (either a solid or liquid diet) was the only factor associated with increased risk of hyperglycemia and hypoglycemia.

This study was limited by its retrospective analysis in a single center. No comparison was made with basal-bolus or sliding-scale insulin therapy regarding efficacy or safety.

Bottom line: Non-ICU patients with hyperglycemia who received CII were able to achieve effective glycemic control within 48 hours of initiation, with rates of hypoglycemia comparable to those observed in ICU settings.

Citation: Smiley D, Rhee M, Peng L, et al. Safety and efficacy of continuous insulin infusion in noncritical care settings. J Hosp Med. 2010;5(4):212-217.

Hospitalists Spend More Time on Indirect, Rather Than Direct, Patient Care

Clinical question: What are the components of the daily workflow of hospitalists working on a non-housestaff service?

Background: The use of hospitalists is associated with increased efficiency in the hospital setting. However, it is not known how this efficiency is achieved. Prior literature has attempted to address this question, but with increasing demands and patient census, the representativeness of existing data is unclear.

Study design: Observational time-motion study.

Setting: Urban tertiary-care academic medical center.

Synopsis: Twenty-four hospitalists were directly observed for two weekday shifts. An electronic collection tool was developed using initial data on hospitalist activities and piloted prior to formal study data collection. Direct patient care was defined as involving face-to-face interaction between hospitalist and patient, while indirect patient care involved activities relevant to patient care but not performed in the patient’s presence.

Approximately 500 hours of observation were collected. Direct patient care comprised only a mean of 17.4% of the hospitalists’ daily workflow, while more was spent on indirect care, mainly electronic health record (EHR) documentation (mean 34.1%) and communication activities (mean 25.9%). Multitasking occurred 16% of the time, typically during communication or “critical documentation activities” (e.g. writing prescriptions). As patient volume increased, less time was spent in communication, and documentation was deferred to after hours.

These results were consistent with prior observational studies but were limited to a single center and might not represent the workflow of hospitalists in other settings, such as community hospitals, or nocturnists.

Bottom line: Hospitalists on non-housestaff services spend most of their time on indirect patient care and, with increasing patient census, communication is sacrificed. Multitasking is common during periods of communication and critical documentation.

Citation: Tipping MD, Forth VE, O’Leary KJ, et al. Where did the day go?—a time-motion study of hospitalists. J Hosp Med. 2010;5(6):323-328.

Patients Who Leave Against Medical Advice Have Higher Readmission, Mortality Rates

Clinical question: What are the 30-day hospital readmission and mortality rates for Veterans Administration (VA) patients discharged against medical advice (AMA) compared with those appropriately discharged from the hospital?

Background: Patients discharged AMA might be at increased risk of experiencing worse outcomes. Small studies have demonstrated that patients with asthma and acute myocardial infarction (MI) discharged AMA have increased risk of readmission and death. However, it is unclear whether these risks are generalizable to a wider medical population.

Study design: Five-year retrospective cohort study.

Setting: One hundred twenty-nine VA acute-care hospitals.

Synopsis: Of the nearly 2 million patients admitted to the VA from 2004 to 2008, 1.7% were discharged AMA. Patients discharged AMA generally were younger, had lower incomes, and were more likely to be black. Furthermore, patients discharged AMA had statistically significant higher rates of 30-day readmission (17.7% vs. 11%, P<0.001) and higher 30-day mortality rates (0.75% vs. 0.61%, P=0.001) compared with those who had been appropriately discharged. In hazard models, discharge AMA was a significant predictor of 30-day readmission and conferred a nonstatistically significant increase in 30-day mortality.

Because all patients were seen in VA facilities, the results might not be generalizable to other acute-care settings. Although VA patients differ from the general medical population, the characteristics of patients discharged AMA are similar to those in previously published studies. The study utilized administrative data, which are very reliable but limited by little information on clinical factors that could contribute to AMA discharges.

Bottom line: Patients discharged AMA are at increased risk of worse post-hospitalization outcomes, including hospital readmission and death.

Citation: Glasgow JM, Vaughn-Sarrazin M, Kaboli PJ. Leaving against medical advice (AMA): risk of 30-day mortality and hospital readmission. J Gen Intern Med. 2010;25(9): 926-929.

Simple Model Predicts Hospital Readmission

Clinical question: Which patient-level factors can be used in a simple model to predict hospital readmission of medicine patients?

Background: Hospital readmissions are common and costly. Previously published readmission prediction models have had limited utility because they focused on a specific condition, setting, or population, or were too cumbersome for practical use.

Study design: Prospective observational cohort study.

Setting: Six academic medical centers.

Synopsis: Data from nearly 11,000 general medicine patients were included in the analysis. Overall, almost 18% of patients were readmitted within 30 days of discharge.

In the prediction model derived and validated from the data, seven factors were significant predictors of readmission within 30 days of discharge: insurance status, marital status, having a regular healthcare provider, Charlson comorbidity index, SF 12 physical component score, one or more admissions within the last year, and current length of stay greater than two days. Points assigned from each significant predictor were used to create a risk score. The 5% of patients with risk scores of 25 and higher had 30-day readmission rates of approximately 30%, compared to readmission rates of approximately 16% in patients with scores of less than 25.

These results might not be generalizable to small, rural, nonacademic settings. Planned admissions could not be excluded from the data, and readmissions to nonstudy hospitals could not be ascertained. Despite these limitations, this model is easier to use than prior models and relevant to a broad population of patients.

Bottom line: A simple prediction model using patient-level factors can be used to identify patients at higher risk of readmission within 30 days of discharge to home.

Citation: Hasan O, Meltzer DO, Shaykevich SA, et al. Hospital readmission in general medicine patients: a prediction model. J Gen Intern Med. 2010;25(3):211-219.

No Difference in Outcomes Between High- and Non-High-Dose Proton Pump Inhibitors in Bleeding Peptic Ulcers

Clinical question: Do high-dose proton pump inhibitors (PPIs) decrease the rate of rebleeding, surgical intervention, or mortality in patients with bleeding peptic ulcers who have undergone endoscopic treatment?

Background: Previous studies have demonstrated superiority of both high- and low-dose PPIs to H2 receptor antagonists and placebo in reducing rebleeding rates in patients with peptic ulcers. However, no clear evidence is available to suggest that high-dose PPIs are more effective than non-high-dose PPIs for treatment of bleeding peptic ulcers.

Study design: Systematic review and meta-analysis.

Setting: Multicenter and single-site studies conducted in several countries.

Synopsis: Studies were included if they were randomized controlled trials, compared high- versus non-high-dose PPIs, evaluated endoscopically confirmed bleeding ulcers, gave PPIs after endoscopy, and documented outcomes regarding rates of rebleeding, surgical intervention, or mortality. High-dose PPIs were defined as equivalent to omeprazole 80 mg intravenous bolus followed by continuous intravenous infusion at 8 mg/hr for 72 hours.

Seven studies met inclusion criteria. The pooled odds ratios for rebleeding, surgical intervention, and mortality were 1.30 (95% CI, 0.88-1.91), 1.49 (95% CI, 0.66-3.37), and 0.89 (95% CI, 0.37-2.13), respectively, for high-dose versus non-high-dose PPIs. The authors concluded that high-dose PPIs were not superior to non-high-dose PPIs in reducing the rates of these adverse outcomes after endoscopic treatment of bleeding ulcers. Considering the cost of high-dose PPIs, further studies are indicated to help guide PPI dosing for patients with peptic ulcers.

Major limitations of this study were the small number of studies (1,157 patients in total) and their heterogeneity, and the lack of intention-to-treat analysis. The studies also included a high Asian predominance, and it has been shown that Asian populations have an enhanced PPI effect.

Bottom line: High-dose PPIs did not demonstrate reduced rates of ulcer rebleeding, surgical intervention, or mortality compared with non-high-dose PPIs in this meta-analysis, which included a small number of studies and patients.

Citation: Wang CH, Ma MH, Chou HC, et al. High-dose vs. non-high-dose proton pump inhibitors after endoscopic treatment in patients with bleeding peptic ulcer: a systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2010;170(9):751-758.

Hospital Utilization by Practicing Generalists Declined before the Emergence of Hospitalists

Clinical question: What has been the pattern of hospital utilization by generalists before and after the emergence of hospitalists?

Background: It has been proposed that the emergence of hospitalists has “crowded out” generalist physicians from the U.S. hospital setting. This study evaluated the trends of inpatient practice by generalists both before and after the emergence of hospitalists.

Study design: Retrospective analysis of national databases.

Setting: U.S. data from 1980 to 2005.

Synopsis: Utilizing the National Hospital Discharge Survey and the American Medical Association’s Physician Characteristics and Distribution in the U.S., information was extracted to evaluate the average number of annual inpatient encounters relative to generalist workforce from 1980 to 2005. Total inpatient encounters for each year were calculated by multiplying the total number of hospital admissions by the average hospital length of stay. The emergence of hospitalists was defined as beginning in 1994.

Total inpatient encounters by generalists declined by 35% in the pre-hospitalist era but remained essentially unchanged in the hospitalist era. During the pre-hospitalist period, the number of generalists doubled, to more than 200,000 from approximately 100,000, while the number of hospital discharges remained relatively stable and the length of stay declined by a third. The decrease in average inpatient encounters in the pre-hospitalist era is thought to have been secondary to decreased length of stay and increased workforce.

Bottom line: Hospital utilization relative to generalist physician workforce was decreasing prior to the emergence of hospitalists mainly due to decreased length of hospital stay and increased numbers of physicians.

Citation: Meltzer DO, Chung JW. U.S. trends in hospitalization and generalist physician workforce and the emergence of hospitalists. J Gen Intern Med. 2010;25(5):453-459.

Fragmentation of Hospitalist Care Is Associated with Increased Length of Stay

Clinical question: Does fragmentation of care (FOC) by hospitalists affect length of stay (LOS)?

Background: Previous investigations have explored the impact of FOC provided by residency programs on LOS and quality of care. Results of these studies have been mixed. However, there have been no prior studies on the impact of the fragmentation of hospitalist care on LOS.

Study design: Concurrent control study.

Setting: Hospitalist practices all over the country managed by IPC: The Hospitalist Company.

Synopsis: Investigators looked at 10,977 patients admitted with diagnoses of pneumonia or heart failure. The primary endpoint was LOS. The independent variable of interest was a measure of FOC. The FOC was calculated as a quantitative index, by determining the percentage of hospitalist care delivered by a physician other than the primary hospitalist.

Multivariable analyses revealed a statistically significant increase in LOS of 0.39 days for each 10% increase in fragmentation level for pneumonia admissions. Similarly, for patients with heart failure, there was a significant increase in LOS of 0.30 days for each 10% increase in fragmentation level.

The study is a concurrent control study, so conclusions cannot be drawn about causality. Additionally, there are likely unmeasured differences between every hospital and hospitalist practice, which could further confound the relationships between hospitalist care and LOS.

Bottom line: Fragmentation of care provided by hospitalists is associated with an increased LOS in patients hospitalized for pneumonia or heart failure.

Citation: Epstein K, Juarez E, Epstein A, Loya K, Singer A. The impact of fragmentation of hospitalist care on length of stay. J Hosp Med. 2010;5(6):335-338.

Admission Medication Errors Are Common and Most Harmful in Older Patients Taking Many Medications

Clinical question: What are the risk factors and potential harm associated with medication errors at hospital admission?

Background: Obtaining a medication history from a hospitalized patient is an error-prone process. Several variables can affect the completeness and quality of medication histories, but existing data are limited regarding patient or medication risk factors associated with medication errors at admission.

Study design: Prospective cohort study.

Setting: Academic hospital in Chicago.

Synopsis: Pharmacist and admitting physician medication histories were compared with admission medication orders to identify any unexplained discrepancies. Discrepancies resulting in order changes were defined as medication errors.

Of the 651 adult medical inpatients studied, 234 (35.9%) had medication order errors identified at admission. Errors originated in the medication histories for 85% of these patients. The most frequent type of error was an omission (48.9%). An age of 65 or older (odds ratio [OR]=2.17, 95% confidence interval [CI], 1.09-4.30) and increased number of medications (OR=1.21, 95% CI, 1.14-1.29) were the only risk factors identified by multivariate analysis to be independently associated with increased risk of medication order errors potentially causing harm or requiring monitoring or intervention. Presenting a medication list upon admission was a significant protective factor (OR=0.35, 95% CI, 0.19-0.63).

Though this is the largest study to date evaluating admission medication errors in hospitalized medical patients, it remains limited by its single hospital site. Because the authors were unable to interview patients who were too ill or unwilling to participate and had no caregiver present, they might have underestimated the number of admission errors. Further, the harm assessment was based on potential and not actual harm.

Bottom line: Admission medication order errors are frequent, most commonly originate in the medication histories, and have increased potential to cause adverse outcomes in older patients and those taking higher numbers of medications.

Citation: Gleason KM, McDaniel MR, Feinglass J, et al. Results of the Medications At Transitions and Clinical Handoffs (MATCH) study: an analysis of medication reconciliation errors and risk factors at hospital admission. J Gen Intern Med. 2010;25(5):441-447.

In This Edition

Literature at a Glance

A guide to this month’s studies

• Continuous insulin infusion in non-ICU patients
• How hospitalists spend their day
• Outcomes of patients leaving against medical advice
• Prediction rule for readmission
• Effects of high- vs. low-dose PPIs for peptic ulcer
• Hospital utilization by generalists before hospitalists
• Effect of hospitalist fragmentation on length of stay
• Medication errors at admissions in older patients

Continuous Insulin Infusion Provides Effective Glycemic Control in Non-ICU Patients

Clinical question: Is continuous insulin infusion (CII) a safe and effective option in the management of hyperglycemia in non-ICU patients?

Background: Hyperglycemia has been associated with worse outcomes in hospitalized patients. Prior research has demonstrated the benefit of CII in managing hyperglycemia in the ICU setting. However, outcomes have not been evaluated in the general medical (non-ICU) setting, where hyperglycemia is often inadequately addressed.

Study design: Retrospective chart review.

Setting: Urban tertiary-care medical center.

Synopsis: Charts of 200 adult patients treated with CII in non-ICU areas were reviewed with the primary outcomes including mean daily blood glucose (BG) levels and number of hyper- and hypoglycemic events occurring on CII. Mean BG dropped from 323 mg/dL to 182 mg/dL by day one, with a BG≤of 150 achieved in 67% of patients by day two of therapy. Twenty-two percent of patients suffered a hypoglycemic event (BG<60), reportedly similar to prior studies of insulin use in ICU and non-ICU settings. Eighty-two percent of patients received some form of nutritional support while on CII. In multivariate analyses, receiving oral nutrition (either a solid or liquid diet) was the only factor associated with increased risk of hyperglycemia and hypoglycemia.

This study was limited by its retrospective analysis in a single center. No comparison was made with basal-bolus or sliding-scale insulin therapy regarding efficacy or safety.

Bottom line: Non-ICU patients with hyperglycemia who received CII were able to achieve effective glycemic control within 48 hours of initiation, with rates of hypoglycemia comparable to those observed in ICU settings.

Citation: Smiley D, Rhee M, Peng L, et al. Safety and efficacy of continuous insulin infusion in noncritical care settings. J Hosp Med. 2010;5(4):212-217.

Hospitalists Spend More Time on Indirect, Rather Than Direct, Patient Care

Clinical question: What are the components of the daily workflow of hospitalists working on a non-housestaff service?

Background: The use of hospitalists is associated with increased efficiency in the hospital setting. However, it is not known how this efficiency is achieved. Prior literature has attempted to address this question, but with increasing demands and patient census, the representativeness of existing data is unclear.

Study design: Observational time-motion study.

Setting: Urban tertiary-care academic medical center.

Synopsis: Twenty-four hospitalists were directly observed for two weekday shifts. An electronic collection tool was developed using initial data on hospitalist activities and piloted prior to formal study data collection. Direct patient care was defined as involving face-to-face interaction between hospitalist and patient, while indirect patient care involved activities relevant to patient care but not performed in the patient’s presence.

Approximately 500 hours of observation were collected. Direct patient care comprised only a mean of 17.4% of the hospitalists’ daily workflow, while more was spent on indirect care, mainly electronic health record (EHR) documentation (mean 34.1%) and communication activities (mean 25.9%). Multitasking occurred 16% of the time, typically during communication or “critical documentation activities” (e.g. writing prescriptions). As patient volume increased, less time was spent in communication, and documentation was deferred to after hours.

These results were consistent with prior observational studies but were limited to a single center and might not represent the workflow of hospitalists in other settings, such as community hospitals, or nocturnists.

Bottom line: Hospitalists on non-housestaff services spend most of their time on indirect patient care and, with increasing patient census, communication is sacrificed. Multitasking is common during periods of communication and critical documentation.

Citation: Tipping MD, Forth VE, O’Leary KJ, et al. Where did the day go?—a time-motion study of hospitalists. J Hosp Med. 2010;5(6):323-328.

Patients Who Leave Against Medical Advice Have Higher Readmission, Mortality Rates

Clinical question: What are the 30-day hospital readmission and mortality rates for Veterans Administration (VA) patients discharged against medical advice (AMA) compared with those appropriately discharged from the hospital?

Background: Patients discharged AMA might be at increased risk of experiencing worse outcomes. Small studies have demonstrated that patients with asthma and acute myocardial infarction (MI) discharged AMA have increased risk of readmission and death. However, it is unclear whether these risks are generalizable to a wider medical population.

Study design: Five-year retrospective cohort study.

Setting: One hundred twenty-nine VA acute-care hospitals.

Synopsis: Of the nearly 2 million patients admitted to the VA from 2004 to 2008, 1.7% were discharged AMA. Patients discharged AMA generally were younger, had lower incomes, and were more likely to be black. Furthermore, patients discharged AMA had statistically significant higher rates of 30-day readmission (17.7% vs. 11%, P<0.001) and higher 30-day mortality rates (0.75% vs. 0.61%, P=0.001) compared with those who had been appropriately discharged. In hazard models, discharge AMA was a significant predictor of 30-day readmission and conferred a nonstatistically significant increase in 30-day mortality.

Because all patients were seen in VA facilities, the results might not be generalizable to other acute-care settings. Although VA patients differ from the general medical population, the characteristics of patients discharged AMA are similar to those in previously published studies. The study utilized administrative data, which are very reliable but limited by little information on clinical factors that could contribute to AMA discharges.

Bottom line: Patients discharged AMA are at increased risk of worse post-hospitalization outcomes, including hospital readmission and death.

Citation: Glasgow JM, Vaughn-Sarrazin M, Kaboli PJ. Leaving against medical advice (AMA): risk of 30-day mortality and hospital readmission. J Gen Intern Med. 2010;25(9): 926-929.

Simple Model Predicts Hospital Readmission

Clinical question: Which patient-level factors can be used in a simple model to predict hospital readmission of medicine patients?

Background: Hospital readmissions are common and costly. Previously published readmission prediction models have had limited utility because they focused on a specific condition, setting, or population, or were too cumbersome for practical use.

Study design: Prospective observational cohort study.

Setting: Six academic medical centers.

Synopsis: Data from nearly 11,000 general medicine patients were included in the analysis. Overall, almost 18% of patients were readmitted within 30 days of discharge.

In the prediction model derived and validated from the data, seven factors were significant predictors of readmission within 30 days of discharge: insurance status, marital status, having a regular healthcare provider, Charlson comorbidity index, SF 12 physical component score, one or more admissions within the last year, and current length of stay greater than two days. Points assigned from each significant predictor were used to create a risk score. The 5% of patients with risk scores of 25 and higher had 30-day readmission rates of approximately 30%, compared to readmission rates of approximately 16% in patients with scores of less than 25.

These results might not be generalizable to small, rural, nonacademic settings. Planned admissions could not be excluded from the data, and readmissions to nonstudy hospitals could not be ascertained. Despite these limitations, this model is easier to use than prior models and relevant to a broad population of patients.

Bottom line: A simple prediction model using patient-level factors can be used to identify patients at higher risk of readmission within 30 days of discharge to home.

Citation: Hasan O, Meltzer DO, Shaykevich SA, et al. Hospital readmission in general medicine patients: a prediction model. J Gen Intern Med. 2010;25(3):211-219.

No Difference in Outcomes Between High- and Non-High-Dose Proton Pump Inhibitors in Bleeding Peptic Ulcers

Clinical question: Do high-dose proton pump inhibitors (PPIs) decrease the rate of rebleeding, surgical intervention, or mortality in patients with bleeding peptic ulcers who have undergone endoscopic treatment?

Background: Previous studies have demonstrated superiority of both high- and low-dose PPIs to H2 receptor antagonists and placebo in reducing rebleeding rates in patients with peptic ulcers. However, no clear evidence is available to suggest that high-dose PPIs are more effective than non-high-dose PPIs for treatment of bleeding peptic ulcers.

Study design: Systematic review and meta-analysis.

Setting: Multicenter and single-site studies conducted in several countries.

Synopsis: Studies were included if they were randomized controlled trials, compared high- versus non-high-dose PPIs, evaluated endoscopically confirmed bleeding ulcers, gave PPIs after endoscopy, and documented outcomes regarding rates of rebleeding, surgical intervention, or mortality. High-dose PPIs were defined as equivalent to omeprazole 80 mg intravenous bolus followed by continuous intravenous infusion at 8 mg/hr for 72 hours.

Seven studies met inclusion criteria. The pooled odds ratios for rebleeding, surgical intervention, and mortality were 1.30 (95% CI, 0.88-1.91), 1.49 (95% CI, 0.66-3.37), and 0.89 (95% CI, 0.37-2.13), respectively, for high-dose versus non-high-dose PPIs. The authors concluded that high-dose PPIs were not superior to non-high-dose PPIs in reducing the rates of these adverse outcomes after endoscopic treatment of bleeding ulcers. Considering the cost of high-dose PPIs, further studies are indicated to help guide PPI dosing for patients with peptic ulcers.

Major limitations of this study were the small number of studies (1,157 patients in total) and their heterogeneity, and the lack of intention-to-treat analysis. The studies also included a high Asian predominance, and it has been shown that Asian populations have an enhanced PPI effect.

Bottom line: High-dose PPIs did not demonstrate reduced rates of ulcer rebleeding, surgical intervention, or mortality compared with non-high-dose PPIs in this meta-analysis, which included a small number of studies and patients.

Citation: Wang CH, Ma MH, Chou HC, et al. High-dose vs. non-high-dose proton pump inhibitors after endoscopic treatment in patients with bleeding peptic ulcer: a systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2010;170(9):751-758.

Hospital Utilization by Practicing Generalists Declined before the Emergence of Hospitalists

Clinical question: What has been the pattern of hospital utilization by generalists before and after the emergence of hospitalists?

Background: It has been proposed that the emergence of hospitalists has “crowded out” generalist physicians from the U.S. hospital setting. This study evaluated the trends of inpatient practice by generalists both before and after the emergence of hospitalists.

Study design: Retrospective analysis of national databases.

Setting: U.S. data from 1980 to 2005.

Synopsis: Utilizing the National Hospital Discharge Survey and the American Medical Association’s Physician Characteristics and Distribution in the U.S., information was extracted to evaluate the average number of annual inpatient encounters relative to generalist workforce from 1980 to 2005. Total inpatient encounters for each year were calculated by multiplying the total number of hospital admissions by the average hospital length of stay. The emergence of hospitalists was defined as beginning in 1994.

Total inpatient encounters by generalists declined by 35% in the pre-hospitalist era but remained essentially unchanged in the hospitalist era. During the pre-hospitalist period, the number of generalists doubled, to more than 200,000 from approximately 100,000, while the number of hospital discharges remained relatively stable and the length of stay declined by a third. The decrease in average inpatient encounters in the pre-hospitalist era is thought to have been secondary to decreased length of stay and increased workforce.

Bottom line: Hospital utilization relative to generalist physician workforce was decreasing prior to the emergence of hospitalists mainly due to decreased length of hospital stay and increased numbers of physicians.

Citation: Meltzer DO, Chung JW. U.S. trends in hospitalization and generalist physician workforce and the emergence of hospitalists. J Gen Intern Med. 2010;25(5):453-459.

Fragmentation of Hospitalist Care Is Associated with Increased Length of Stay

Clinical question: Does fragmentation of care (FOC) by hospitalists affect length of stay (LOS)?

Background: Previous investigations have explored the impact of FOC provided by residency programs on LOS and quality of care. Results of these studies have been mixed. However, there have been no prior studies on the impact of the fragmentation of hospitalist care on LOS.

Study design: Concurrent control study.

Setting: Hospitalist practices all over the country managed by IPC: The Hospitalist Company.

Synopsis: Investigators looked at 10,977 patients admitted with diagnoses of pneumonia or heart failure. The primary endpoint was LOS. The independent variable of interest was a measure of FOC. The FOC was calculated as a quantitative index, by determining the percentage of hospitalist care delivered by a physician other than the primary hospitalist.

Multivariable analyses revealed a statistically significant increase in LOS of 0.39 days for each 10% increase in fragmentation level for pneumonia admissions. Similarly, for patients with heart failure, there was a significant increase in LOS of 0.30 days for each 10% increase in fragmentation level.

The study is a concurrent control study, so conclusions cannot be drawn about causality. Additionally, there are likely unmeasured differences between every hospital and hospitalist practice, which could further confound the relationships between hospitalist care and LOS.

Bottom line: Fragmentation of care provided by hospitalists is associated with an increased LOS in patients hospitalized for pneumonia or heart failure.

Citation: Epstein K, Juarez E, Epstein A, Loya K, Singer A. The impact of fragmentation of hospitalist care on length of stay. J Hosp Med. 2010;5(6):335-338.

Admission Medication Errors Are Common and Most Harmful in Older Patients Taking Many Medications

Clinical question: What are the risk factors and potential harm associated with medication errors at hospital admission?

Background: Obtaining a medication history from a hospitalized patient is an error-prone process. Several variables can affect the completeness and quality of medication histories, but existing data are limited regarding patient or medication risk factors associated with medication errors at admission.

Study design: Prospective cohort study.

Setting: Academic hospital in Chicago.

Synopsis: Pharmacist and admitting physician medication histories were compared with admission medication orders to identify any unexplained discrepancies. Discrepancies resulting in order changes were defined as medication errors.

Of the 651 adult medical inpatients studied, 234 (35.9%) had medication order errors identified at admission. Errors originated in the medication histories for 85% of these patients. The most frequent type of error was an omission (48.9%). An age of 65 or older (odds ratio [OR]=2.17, 95% confidence interval [CI], 1.09-4.30) and increased number of medications (OR=1.21, 95% CI, 1.14-1.29) were the only risk factors identified by multivariate analysis to be independently associated with increased risk of medication order errors potentially causing harm or requiring monitoring or intervention. Presenting a medication list upon admission was a significant protective factor (OR=0.35, 95% CI, 0.19-0.63).

Though this is the largest study to date evaluating admission medication errors in hospitalized medical patients, it remains limited by its single hospital site. Because the authors were unable to interview patients who were too ill or unwilling to participate and had no caregiver present, they might have underestimated the number of admission errors. Further, the harm assessment was based on potential and not actual harm.

Bottom line: Admission medication order errors are frequent, most commonly originate in the medication histories, and have increased potential to cause adverse outcomes in older patients and those taking higher numbers of medications.

Citation: Gleason KM, McDaniel MR, Feinglass J, et al. Results of the Medications At Transitions and Clinical Handoffs (MATCH) study: an analysis of medication reconciliation errors and risk factors at hospital admission. J Gen Intern Med. 2010;25(5):441-447.

Clinical question: What is the relationship between duration of intravenous (IV) antibiotic therapy and treatment failure in infants <6 months of age hospitalized with urinary tract infections (UTIs)?

Background: There is an inadequate evidence base to drive decisions regarding duration of IV antibiotic therapy in young infants hospitalized with UTIs. Documented variability exists in length of stay (LOS) and resource utilization for these infants, which might be a direct result of practice variation with respect to IV therapy.

Study design: Retrospective cohort study.

Setting: Twenty-four freestanding children’s hospitals.

Synopsis: The Pediatric Health Information System (PHIS) administrative database was used to identify healthy infants <6 months of age admitted with a primary or secondary diagnosis of UTI or pyelonephritis from 1999 to 2004 to participating hospitals. Duration of IV therapy was defined as a dichotomous variable with three days (short course: three days) selected because it was the median length of therapy. Treatment failure was defined as readmission within 30 days.

More than 12,300 records were analyzed. Male gender, neonatal status, black race, Hispanic ethnicity, nonprivate insurance, severity of illness, known bacteremia, known genitourinary tract disorders, and specific hospital were independently associated with increased likelihood of long-course (four days) therapy.

Unadjusted analysis initially revealed that long-course therapy was significantly associated with a higher rate of treatment failure. After multivariate (to include propensity scores) adjustment, a significant association between treatment duration and failure was no longer identified. Treatment failure association with known genitourinary abnormalities and higher severity of illness remained.

A significant limitation of this study is the potential for multivariate analysis to fail to mitigate a bias toward sicker patients receiving longer duration of antibiotic therapy and, thus, having a higher likelihood of treatment failure. In addition, the greater question of when IV antibiotics (and hospital admission) are indicated in this population was not addressed by the study design.

Nonetheless, the data likely support a limited utility to long-course IV antibiotic therapy in this population. The study also adds to the evolving picture of considerable and widespread variation in physician practice.

Bottom line: Short-course IV therapy for infants with UTIs does not increase risk of treatment failure.

Citation: Brady PW, Conway PH, Goudie A. Length of intravenous antibiotic therapy and treatment failure in infants with urinary tract infections. Pediatrics. 2010;126(2):196-203.

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

Clinical question: What is the relationship between duration of intravenous (IV) antibiotic therapy and treatment failure in infants <6 months of age hospitalized with urinary tract infections (UTIs)?

Background: There is an inadequate evidence base to drive decisions regarding duration of IV antibiotic therapy in young infants hospitalized with UTIs. Documented variability exists in length of stay (LOS) and resource utilization for these infants, which might be a direct result of practice variation with respect to IV therapy.

Study design: Retrospective cohort study.

Setting: Twenty-four freestanding children’s hospitals.

Synopsis: The Pediatric Health Information System (PHIS) administrative database was used to identify healthy infants <6 months of age admitted with a primary or secondary diagnosis of UTI or pyelonephritis from 1999 to 2004 to participating hospitals. Duration of IV therapy was defined as a dichotomous variable with three days (short course: three days) selected because it was the median length of therapy. Treatment failure was defined as readmission within 30 days.

More than 12,300 records were analyzed. Male gender, neonatal status, black race, Hispanic ethnicity, nonprivate insurance, severity of illness, known bacteremia, known genitourinary tract disorders, and specific hospital were independently associated with increased likelihood of long-course (four days) therapy.

Unadjusted analysis initially revealed that long-course therapy was significantly associated with a higher rate of treatment failure. After multivariate (to include propensity scores) adjustment, a significant association between treatment duration and failure was no longer identified. Treatment failure association with known genitourinary abnormalities and higher severity of illness remained.

A significant limitation of this study is the potential for multivariate analysis to fail to mitigate a bias toward sicker patients receiving longer duration of antibiotic therapy and, thus, having a higher likelihood of treatment failure. In addition, the greater question of when IV antibiotics (and hospital admission) are indicated in this population was not addressed by the study design.

Nonetheless, the data likely support a limited utility to long-course IV antibiotic therapy in this population. The study also adds to the evolving picture of considerable and widespread variation in physician practice.

Bottom line: Short-course IV therapy for infants with UTIs does not increase risk of treatment failure.

Citation: Brady PW, Conway PH, Goudie A. Length of intravenous antibiotic therapy and treatment failure in infants with urinary tract infections. Pediatrics. 2010;126(2):196-203.

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

Clinical question: What is the relationship between duration of intravenous (IV) antibiotic therapy and treatment failure in infants <6 months of age hospitalized with urinary tract infections (UTIs)?

Background: There is an inadequate evidence base to drive decisions regarding duration of IV antibiotic therapy in young infants hospitalized with UTIs. Documented variability exists in length of stay (LOS) and resource utilization for these infants, which might be a direct result of practice variation with respect to IV therapy.

Study design: Retrospective cohort study.

Setting: Twenty-four freestanding children’s hospitals.

Synopsis: The Pediatric Health Information System (PHIS) administrative database was used to identify healthy infants <6 months of age admitted with a primary or secondary diagnosis of UTI or pyelonephritis from 1999 to 2004 to participating hospitals. Duration of IV therapy was defined as a dichotomous variable with three days (short course: three days) selected because it was the median length of therapy. Treatment failure was defined as readmission within 30 days.

More than 12,300 records were analyzed. Male gender, neonatal status, black race, Hispanic ethnicity, nonprivate insurance, severity of illness, known bacteremia, known genitourinary tract disorders, and specific hospital were independently associated with increased likelihood of long-course (four days) therapy.

Unadjusted analysis initially revealed that long-course therapy was significantly associated with a higher rate of treatment failure. After multivariate (to include propensity scores) adjustment, a significant association between treatment duration and failure was no longer identified. Treatment failure association with known genitourinary abnormalities and higher severity of illness remained.

A significant limitation of this study is the potential for multivariate analysis to fail to mitigate a bias toward sicker patients receiving longer duration of antibiotic therapy and, thus, having a higher likelihood of treatment failure. In addition, the greater question of when IV antibiotics (and hospital admission) are indicated in this population was not addressed by the study design.

Nonetheless, the data likely support a limited utility to long-course IV antibiotic therapy in this population. The study also adds to the evolving picture of considerable and widespread variation in physician practice.

Bottom line: Short-course IV therapy for infants with UTIs does not increase risk of treatment failure.

Citation: Brady PW, Conway PH, Goudie A. Length of intravenous antibiotic therapy and treatment failure in infants with urinary tract infections. Pediatrics. 2010;126(2):196-203.

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

New Generics

• Atomoxetine capsules (Strattera)¹
• Clonidine transdermal system USP (catapres-TTS)²
• Enoxaparin sodium injection (Lovenox)³
• Naratriptan hydrochloride 2.5-mg tablets (Amerge)⁴

New Drugs, Devices, Indications, and Dosage Forms

• A combination tablet containing both aliskiren and amlodipine (Tekamlo) has been approved by the FDA for the treatment of hypertension (HTN).⁵ Four strengths for once-daily dosing are available.
• Antihemophilic factor VIII (recombinant) injection (Xyntha) for treatment of hemophilia A has been approved by the FDA in a pre-filled, dual-chamber syringe for intravenous (IV) infusion following reconstitution of the freeze-dried powder with 0.9% sodium chloride diluent (both supplied in the dosage form).⁶ The first dose will be available in the 3,000 international units strength (4 mL). Other dosages will be available in 2011.
• Bimatoprost ophthalmic solution 0.01% (Lumigan) has been approved by the FDA as a first-line treatment for reducing intraocular pressure in patients with open-angle glaucoma or ocular hypertension.⁷
• Buprenorphine/naloxone sublingual film (Suboxone sublingual) has been approved by the FDA for the treatment of opioid dependence.⁸
• Coagulation factor VIIa room temperature stable (recombinant) (NovoSeven RT) has been approved by the FDA in an 8-mg vial.⁹ This larger size allows rapid initiation and administration of this product for patients who need a larger dose. Additionally, this product is approved for an extended shelf life, for all vial sizes, to 36 months at room temperature.
• Donepezil 21-mg tablets (Aricept) have been approved by the FDA for the treatment of moderate to severe Alzheimer’s disease.¹⁰
• Glycopyrrolate cherry-flavored oral solution (Cuvposa) has been approved by the FDA as an orphan drug for treating chronic severe drooling in patients ages 3 to 16 with neurological conditions such as cerebral palsy.¹¹
• Immune globulin subcutaneous (human) 20% liquid (Hizentra) has been approved by the FDA for a 24-month shelf life at room temperature when protected from light.¹²
• Miconazole 50-mg buccal tablets (Oravig) have been approved by the FDA to topically treat oropharyngeal candidiasis in patients 16 and older.¹³
• Niacin extended release/simvastatin tablets (Simcor) have been approved by the FDA in two new dosage strengths: 500 mg/40 mg and 1000 mg/40 mg.¹⁴
• Olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide tablets (HCTZ) (Tribenzor) have been approved by the FDA in a single tablet to treat hypertension (not initial therapy).¹⁵ This combination should not be used in patients with a creatinine clearance <30 mL/minute, or in patients with renal artery stenosis.
• STX-100 has received orphan drug status for treating idiopathic pulmonary fibrosis (IPF) for which there currently are no FDA-approved treatments.¹⁶ STX-100 is a humanized, monoclonal antibody that targets integrin vb6, which exhibited major antifibrotic activity in preclinical animal models of the lung and other organs. The FDA previously granted orphan drug designation for STX-100 for chronic allograft nephropathy. A Phase 2 trial in IPF is planned for 2011.
• Docetaxel injection concentrate (Taxotere) has been approved by the FDA in a one-vial system, which eliminates the dilution step.¹⁷
• Valganciclovir injection (Valcyte) is FDA-approved for an increased therapy length (200 days) in adult renal transplant patients at high risk of developing cytomegalovirus disease (CMV).¹⁸ This extends the length of therapy from 100 days.

Safety, Warnings, and Label Changes

• Carbidopa/levodopa and entacapone tablets (Stalevo) are undergoing a safety review in relation to a possible increased cardiovascular event risk, including myocardial infarction, stroke, and cardiovascular death, compared with patients only taking carbidopa/levodopa.¹⁹ An FDA meta-analysis of 15 clinical trials found a small increased risk of cardiovascular events. However, this meta-analysis was not specifically designed to assess cardiovascular safety, and most patients had pre-existing cardiovascular disease risk factors, so even small differences in the level of these risks could significantly affect the study outcomes. Additionally, most negative cardiovascular events occurred in a single trial. The FDA recommends regular evaluation of patients’ cardiovascular status.
• Tigecycline IV injection (Tygacil) has undergone a label change in its “Warnings” and “Precautions” in relation to an increased mortality risk.²⁰ A pooled analysis compared tigecycline use to other similar antibacterials for managing different serious infections. Patients who had a greater increased risk of death were those with hospital-acquired pneumonia, ventilator-associated pneumonia, complicated skin and skin structure infections, diabetic foot infections, and complicated intra-abdominal infections.

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City and a clinical pharmacist at New York Downtown Hospital.

References

1. Actavis receives FDA approval of atomoxetine HCI capsules. Medical News Today website. Available at: http://www.medicalnewstoday.com/articles/199692.php. Accessed Sept. 2, 2010.
2. Mylan receives approval for generic version of Catapres-TTS. Mylan Inc. website. Available at: http://investor.mylan.com/releasedetail.cfm?ReleaseID=489338. Accessed July 20, 2010.
3. Riley K. FDA approves first generic enoxaparin sodium injection. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm220092.htm. Accessed Sept. 13, 2010.
4. First-time generic approvals August 2010. Formulary website. Available at: http://formularyjournal.modernmedicine.com/formulary/Modern+Medicine+Now/First-time-generic-approvals-Aug.-2010/ArticleStandard/Article/detail/683182?contextCategoryId=44276. Accessed Sept. 7, 2010.
5. Novartis receives FDA approval of Tekamlo, a single-pill combination of aliskiren and amlodipine to treat high blood pressure. Novartis Pharmaceuticals Corporation website. Available at: http://www.pharma.us.novartis.com/info/newsroom/press-release.jsp?PRID=2286. Accessed Sept. 13, 2010.
6. Xyntha prefilled dual-chamber syringe approved for hemophilia A treatment. Monthly Prescribing Reference website. Available at: http://www.empr.com/xyntha-pre-filled-dual-chamber-syringe-approved-for-hemophilia-a-treatment/article/176666/. Accessed Aug.18, 2010.
7. Allergan, Inc. receives FDA approval for Lumigan 0.01% as first-line therapy indicated for the reduction of elevated intraocular pressure in glaucoma patients. MarketWatch website. Available at: http://www.marketwatch.com/story/allergan-inc-receives-fda-approval-for-lumiganr-001-as-first-line-therapy-indicated-for-the-reduction-of-elevated-intraocular-pressure-in-glaucoma-patients-2010-08-31?reflink=MW_news_stmp. Accessed Sept. 2, 2010.
8. MonoSol Rx announces Reckitt Benckiser FDA approval of Suboxone sublingual film for treatment of opioid dependence. PR Newswire website. Available at: http://www.prnewswire.com/news-releases/monosol-rx-announces-reckitt-benckiser-fda-approval-of-suboxone-sublingual-film-for-treatment-of-opioid-dependence-101874388.html. Accessed Sept. 14, 2010.
9. NovoSeven RT 8mg vial approved for hemophilia A or B. Monthly Prescribing Reference website. Available at: http://www.empr.com/novoseven-rt-8mg-vial-approved-for-hemophilia-a-or-b/printarticle/176743/. Accessed Sept. 13, 2010.
10. Eisai announces U.S. FDA approval for new higher dose Aricept 23 mg tablet for the treatment of moderate-to-severe Alzheimer’s disease. Medical News Today website. Available at: http://www.medicalnewstoday.com/articles/196410.php. Accessed Sept. 13, 2010.
11. Cuvposa approved for chronic severe drooling associated with neurologic conditions. Monthly Prescribing Reference website. Available at: http://www.empr.com/cuvposa-approved-for-chronic-severe-drooling-associated-with-neurologic-conditions/article/175824/?DCMP=EMC-MPR_WeeklyNewsbrief. Accessed Aug. 2, 2010.
12. Shelf life of Hizentra extended from 18 to 24 months. Monthly Prescribing Reference website. Available at: http://www.empr.com/shelf-life-of-hizentra-extended-from-18-to-24-months/article/177068/?DCMP=EMC-MPR_WeeklyNewsbrief. Accessed Aug. 23, 2010.
13. Oravig available for oropharyngeal candidiasis. Monthly Prescribing Reference website. Available at: http://www.empr.com/oravig-available-for-oropharyngeal-candidiasis/article/177492/. Accessed Sept. 13, 2010.
14. Additional dosage strengths of Simcor approved. Monthly Prescribing Reference website. Available at: http://www.empr.com/additional-dosage-strengths-of-simcor-approved/article/175825/?DCMP=EMC-MPR_WeeklyNewsbrief. Accessed Sept. 13, 2010.
15. Tribenzor 20/5/12.5mg. Monthly Prescribing Reference website. Available at: http://www.empr.com/tribenzor-205125mg/drugproduct/129/. Accessed Sept. 13, 2010.
16. Stromedix receives FDA orphan drug designation for STX-100 for the treatment of idiopathic pulmonary fibrosis. Stromedix website. Available at: http://www.stromedix.com/Stromedix_STX-100_Orphan_Drug_IPF.pdf. Accessed Sept. 13, 2010.
17. Dane L. Sanofi-Aventis garners FDA approval for one-vial formulation of Taxotere. FirstWord website. Available at: http://www.firstwordplus.com/Fws.do?articleid=E0B4E517F06C4A9E94DC88EADBA079A8. Accessed Sept. 13, 2010.
18. FDA approves longer use of Valcyte for adult kidney transplant patients at high risk of developing cytomegalovirus (CMV) disease. Genentech website. Available at: http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=12907. Accessed Sept. 13, 2010.
19. FDA drug safety communication: ongoing safety review of Stalevo and possible increased cardiovascular risk. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm223060.htm. Accessed Sept. 13, 2010.
20. FDA drug safety communication: increased risk of death with Tygacil (tigecycline) compared to other antibiotics used to treat similar infections. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm224370.htm. Accessed Sept. 13, 2010.

New Generics

• Atomoxetine capsules (Strattera)¹
• Clonidine transdermal system USP (catapres-TTS)²
• Enoxaparin sodium injection (Lovenox)³
• Naratriptan hydrochloride 2.5-mg tablets (Amerge)⁴

New Drugs, Devices, Indications, and Dosage Forms

• A combination tablet containing both aliskiren and amlodipine (Tekamlo) has been approved by the FDA for the treatment of hypertension (HTN).⁵ Four strengths for once-daily dosing are available.
• Antihemophilic factor VIII (recombinant) injection (Xyntha) for treatment of hemophilia A has been approved by the FDA in a pre-filled, dual-chamber syringe for intravenous (IV) infusion following reconstitution of the freeze-dried powder with 0.9% sodium chloride diluent (both supplied in the dosage form).⁶ The first dose will be available in the 3,000 international units strength (4 mL). Other dosages will be available in 2011.
• Bimatoprost ophthalmic solution 0.01% (Lumigan) has been approved by the FDA as a first-line treatment for reducing intraocular pressure in patients with open-angle glaucoma or ocular hypertension.⁷
• Buprenorphine/naloxone sublingual film (Suboxone sublingual) has been approved by the FDA for the treatment of opioid dependence.⁸
• Coagulation factor VIIa room temperature stable (recombinant) (NovoSeven RT) has been approved by the FDA in an 8-mg vial.⁹ This larger size allows rapid initiation and administration of this product for patients who need a larger dose. Additionally, this product is approved for an extended shelf life, for all vial sizes, to 36 months at room temperature.
• Donepezil 21-mg tablets (Aricept) have been approved by the FDA for the treatment of moderate to severe Alzheimer’s disease.¹⁰
• Glycopyrrolate cherry-flavored oral solution (Cuvposa) has been approved by the FDA as an orphan drug for treating chronic severe drooling in patients ages 3 to 16 with neurological conditions such as cerebral palsy.¹¹
• Immune globulin subcutaneous (human) 20% liquid (Hizentra) has been approved by the FDA for a 24-month shelf life at room temperature when protected from light.¹²
• Miconazole 50-mg buccal tablets (Oravig) have been approved by the FDA to topically treat oropharyngeal candidiasis in patients 16 and older.¹³
• Niacin extended release/simvastatin tablets (Simcor) have been approved by the FDA in two new dosage strengths: 500 mg/40 mg and 1000 mg/40 mg.¹⁴
• Olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide tablets (HCTZ) (Tribenzor) have been approved by the FDA in a single tablet to treat hypertension (not initial therapy).¹⁵ This combination should not be used in patients with a creatinine clearance <30 mL/minute, or in patients with renal artery stenosis.
• STX-100 has received orphan drug status for treating idiopathic pulmonary fibrosis (IPF) for which there currently are no FDA-approved treatments.¹⁶ STX-100 is a humanized, monoclonal antibody that targets integrin vb6, which exhibited major antifibrotic activity in preclinical animal models of the lung and other organs. The FDA previously granted orphan drug designation for STX-100 for chronic allograft nephropathy. A Phase 2 trial in IPF is planned for 2011.
• Docetaxel injection concentrate (Taxotere) has been approved by the FDA in a one-vial system, which eliminates the dilution step.¹⁷
• Valganciclovir injection (Valcyte) is FDA-approved for an increased therapy length (200 days) in adult renal transplant patients at high risk of developing cytomegalovirus disease (CMV).¹⁸ This extends the length of therapy from 100 days.

Safety, Warnings, and Label Changes

• Carbidopa/levodopa and entacapone tablets (Stalevo) are undergoing a safety review in relation to a possible increased cardiovascular event risk, including myocardial infarction, stroke, and cardiovascular death, compared with patients only taking carbidopa/levodopa.¹⁹ An FDA meta-analysis of 15 clinical trials found a small increased risk of cardiovascular events. However, this meta-analysis was not specifically designed to assess cardiovascular safety, and most patients had pre-existing cardiovascular disease risk factors, so even small differences in the level of these risks could significantly affect the study outcomes. Additionally, most negative cardiovascular events occurred in a single trial. The FDA recommends regular evaluation of patients’ cardiovascular status.
• Tigecycline IV injection (Tygacil) has undergone a label change in its “Warnings” and “Precautions” in relation to an increased mortality risk.²⁰ A pooled analysis compared tigecycline use to other similar antibacterials for managing different serious infections. Patients who had a greater increased risk of death were those with hospital-acquired pneumonia, ventilator-associated pneumonia, complicated skin and skin structure infections, diabetic foot infections, and complicated intra-abdominal infections.

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City and a clinical pharmacist at New York Downtown Hospital.

References

1. Actavis receives FDA approval of atomoxetine HCI capsules. Medical News Today website. Available at: http://www.medicalnewstoday.com/articles/199692.php. Accessed Sept. 2, 2010.
2. Mylan receives approval for generic version of Catapres-TTS. Mylan Inc. website. Available at: http://investor.mylan.com/releasedetail.cfm?ReleaseID=489338. Accessed July 20, 2010.
3. Riley K. FDA approves first generic enoxaparin sodium injection. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm220092.htm. Accessed Sept. 13, 2010.
4. First-time generic approvals August 2010. Formulary website. Available at: http://formularyjournal.modernmedicine.com/formulary/Modern+Medicine+Now/First-time-generic-approvals-Aug.-2010/ArticleStandard/Article/detail/683182?contextCategoryId=44276. Accessed Sept. 7, 2010.
5. Novartis receives FDA approval of Tekamlo, a single-pill combination of aliskiren and amlodipine to treat high blood pressure. Novartis Pharmaceuticals Corporation website. Available at: http://www.pharma.us.novartis.com/info/newsroom/press-release.jsp?PRID=2286. Accessed Sept. 13, 2010.
6. Xyntha prefilled dual-chamber syringe approved for hemophilia A treatment. Monthly Prescribing Reference website. Available at: http://www.empr.com/xyntha-pre-filled-dual-chamber-syringe-approved-for-hemophilia-a-treatment/article/176666/. Accessed Aug.18, 2010.
7. Allergan, Inc. receives FDA approval for Lumigan 0.01% as first-line therapy indicated for the reduction of elevated intraocular pressure in glaucoma patients. MarketWatch website. Available at: http://www.marketwatch.com/story/allergan-inc-receives-fda-approval-for-lumiganr-001-as-first-line-therapy-indicated-for-the-reduction-of-elevated-intraocular-pressure-in-glaucoma-patients-2010-08-31?reflink=MW_news_stmp. Accessed Sept. 2, 2010.
8. MonoSol Rx announces Reckitt Benckiser FDA approval of Suboxone sublingual film for treatment of opioid dependence. PR Newswire website. Available at: http://www.prnewswire.com/news-releases/monosol-rx-announces-reckitt-benckiser-fda-approval-of-suboxone-sublingual-film-for-treatment-of-opioid-dependence-101874388.html. Accessed Sept. 14, 2010.
9. NovoSeven RT 8mg vial approved for hemophilia A or B. Monthly Prescribing Reference website. Available at: http://www.empr.com/novoseven-rt-8mg-vial-approved-for-hemophilia-a-or-b/printarticle/176743/. Accessed Sept. 13, 2010.
10. Eisai announces U.S. FDA approval for new higher dose Aricept 23 mg tablet for the treatment of moderate-to-severe Alzheimer’s disease. Medical News Today website. Available at: http://www.medicalnewstoday.com/articles/196410.php. Accessed Sept. 13, 2010.
11. Cuvposa approved for chronic severe drooling associated with neurologic conditions. Monthly Prescribing Reference website. Available at: http://www.empr.com/cuvposa-approved-for-chronic-severe-drooling-associated-with-neurologic-conditions/article/175824/?DCMP=EMC-MPR_WeeklyNewsbrief. Accessed Aug. 2, 2010.
12. Shelf life of Hizentra extended from 18 to 24 months. Monthly Prescribing Reference website. Available at: http://www.empr.com/shelf-life-of-hizentra-extended-from-18-to-24-months/article/177068/?DCMP=EMC-MPR_WeeklyNewsbrief. Accessed Aug. 23, 2010.
13. Oravig available for oropharyngeal candidiasis. Monthly Prescribing Reference website. Available at: http://www.empr.com/oravig-available-for-oropharyngeal-candidiasis/article/177492/. Accessed Sept. 13, 2010.
14. Additional dosage strengths of Simcor approved. Monthly Prescribing Reference website. Available at: http://www.empr.com/additional-dosage-strengths-of-simcor-approved/article/175825/?DCMP=EMC-MPR_WeeklyNewsbrief. Accessed Sept. 13, 2010.
15. Tribenzor 20/5/12.5mg. Monthly Prescribing Reference website. Available at: http://www.empr.com/tribenzor-205125mg/drugproduct/129/. Accessed Sept. 13, 2010.
16. Stromedix receives FDA orphan drug designation for STX-100 for the treatment of idiopathic pulmonary fibrosis. Stromedix website. Available at: http://www.stromedix.com/Stromedix_STX-100_Orphan_Drug_IPF.pdf. Accessed Sept. 13, 2010.
17. Dane L. Sanofi-Aventis garners FDA approval for one-vial formulation of Taxotere. FirstWord website. Available at: http://www.firstwordplus.com/Fws.do?articleid=E0B4E517F06C4A9E94DC88EADBA079A8. Accessed Sept. 13, 2010.
18. FDA approves longer use of Valcyte for adult kidney transplant patients at high risk of developing cytomegalovirus (CMV) disease. Genentech website. Available at: http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=12907. Accessed Sept. 13, 2010.
19. FDA drug safety communication: ongoing safety review of Stalevo and possible increased cardiovascular risk. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm223060.htm. Accessed Sept. 13, 2010.
20. FDA drug safety communication: increased risk of death with Tygacil (tigecycline) compared to other antibiotics used to treat similar infections. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm224370.htm. Accessed Sept. 13, 2010.

New Generics

• Atomoxetine capsules (Strattera)¹
• Clonidine transdermal system USP (catapres-TTS)²
• Enoxaparin sodium injection (Lovenox)³
• Naratriptan hydrochloride 2.5-mg tablets (Amerge)⁴

New Drugs, Devices, Indications, and Dosage Forms

• A combination tablet containing both aliskiren and amlodipine (Tekamlo) has been approved by the FDA for the treatment of hypertension (HTN).⁵ Four strengths for once-daily dosing are available.
• Antihemophilic factor VIII (recombinant) injection (Xyntha) for treatment of hemophilia A has been approved by the FDA in a pre-filled, dual-chamber syringe for intravenous (IV) infusion following reconstitution of the freeze-dried powder with 0.9% sodium chloride diluent (both supplied in the dosage form).⁶ The first dose will be available in the 3,000 international units strength (4 mL). Other dosages will be available in 2011.
• Bimatoprost ophthalmic solution 0.01% (Lumigan) has been approved by the FDA as a first-line treatment for reducing intraocular pressure in patients with open-angle glaucoma or ocular hypertension.⁷
• Buprenorphine/naloxone sublingual film (Suboxone sublingual) has been approved by the FDA for the treatment of opioid dependence.⁸
• Coagulation factor VIIa room temperature stable (recombinant) (NovoSeven RT) has been approved by the FDA in an 8-mg vial.⁹ This larger size allows rapid initiation and administration of this product for patients who need a larger dose. Additionally, this product is approved for an extended shelf life, for all vial sizes, to 36 months at room temperature.
• Donepezil 21-mg tablets (Aricept) have been approved by the FDA for the treatment of moderate to severe Alzheimer’s disease.¹⁰
• Glycopyrrolate cherry-flavored oral solution (Cuvposa) has been approved by the FDA as an orphan drug for treating chronic severe drooling in patients ages 3 to 16 with neurological conditions such as cerebral palsy.¹¹
• Immune globulin subcutaneous (human) 20% liquid (Hizentra) has been approved by the FDA for a 24-month shelf life at room temperature when protected from light.¹²
• Miconazole 50-mg buccal tablets (Oravig) have been approved by the FDA to topically treat oropharyngeal candidiasis in patients 16 and older.¹³
• Niacin extended release/simvastatin tablets (Simcor) have been approved by the FDA in two new dosage strengths: 500 mg/40 mg and 1000 mg/40 mg.¹⁴
• Olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide tablets (HCTZ) (Tribenzor) have been approved by the FDA in a single tablet to treat hypertension (not initial therapy).¹⁵ This combination should not be used in patients with a creatinine clearance <30 mL/minute, or in patients with renal artery stenosis.
• STX-100 has received orphan drug status for treating idiopathic pulmonary fibrosis (IPF) for which there currently are no FDA-approved treatments.¹⁶ STX-100 is a humanized, monoclonal antibody that targets integrin vb6, which exhibited major antifibrotic activity in preclinical animal models of the lung and other organs. The FDA previously granted orphan drug designation for STX-100 for chronic allograft nephropathy. A Phase 2 trial in IPF is planned for 2011.
• Docetaxel injection concentrate (Taxotere) has been approved by the FDA in a one-vial system, which eliminates the dilution step.¹⁷
• Valganciclovir injection (Valcyte) is FDA-approved for an increased therapy length (200 days) in adult renal transplant patients at high risk of developing cytomegalovirus disease (CMV).¹⁸ This extends the length of therapy from 100 days.

Safety, Warnings, and Label Changes

• Carbidopa/levodopa and entacapone tablets (Stalevo) are undergoing a safety review in relation to a possible increased cardiovascular event risk, including myocardial infarction, stroke, and cardiovascular death, compared with patients only taking carbidopa/levodopa.¹⁹ An FDA meta-analysis of 15 clinical trials found a small increased risk of cardiovascular events. However, this meta-analysis was not specifically designed to assess cardiovascular safety, and most patients had pre-existing cardiovascular disease risk factors, so even small differences in the level of these risks could significantly affect the study outcomes. Additionally, most negative cardiovascular events occurred in a single trial. The FDA recommends regular evaluation of patients’ cardiovascular status.
• Tigecycline IV injection (Tygacil) has undergone a label change in its “Warnings” and “Precautions” in relation to an increased mortality risk.²⁰ A pooled analysis compared tigecycline use to other similar antibacterials for managing different serious infections. Patients who had a greater increased risk of death were those with hospital-acquired pneumonia, ventilator-associated pneumonia, complicated skin and skin structure infections, diabetic foot infections, and complicated intra-abdominal infections.

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City and a clinical pharmacist at New York Downtown Hospital.

References

1. Actavis receives FDA approval of atomoxetine HCI capsules. Medical News Today website. Available at: http://www.medicalnewstoday.com/articles/199692.php. Accessed Sept. 2, 2010.
2. Mylan receives approval for generic version of Catapres-TTS. Mylan Inc. website. Available at: http://investor.mylan.com/releasedetail.cfm?ReleaseID=489338. Accessed July 20, 2010.
3. Riley K. FDA approves first generic enoxaparin sodium injection. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm220092.htm. Accessed Sept. 13, 2010.
4. First-time generic approvals August 2010. Formulary website. Available at: http://formularyjournal.modernmedicine.com/formulary/Modern+Medicine+Now/First-time-generic-approvals-Aug.-2010/ArticleStandard/Article/detail/683182?contextCategoryId=44276. Accessed Sept. 7, 2010.
5. Novartis receives FDA approval of Tekamlo, a single-pill combination of aliskiren and amlodipine to treat high blood pressure. Novartis Pharmaceuticals Corporation website. Available at: http://www.pharma.us.novartis.com/info/newsroom/press-release.jsp?PRID=2286. Accessed Sept. 13, 2010.
6. Xyntha prefilled dual-chamber syringe approved for hemophilia A treatment. Monthly Prescribing Reference website. Available at: http://www.empr.com/xyntha-pre-filled-dual-chamber-syringe-approved-for-hemophilia-a-treatment/article/176666/. Accessed Aug.18, 2010.
7. Allergan, Inc. receives FDA approval for Lumigan 0.01% as first-line therapy indicated for the reduction of elevated intraocular pressure in glaucoma patients. MarketWatch website. Available at: http://www.marketwatch.com/story/allergan-inc-receives-fda-approval-for-lumiganr-001-as-first-line-therapy-indicated-for-the-reduction-of-elevated-intraocular-pressure-in-glaucoma-patients-2010-08-31?reflink=MW_news_stmp. Accessed Sept. 2, 2010.
8. MonoSol Rx announces Reckitt Benckiser FDA approval of Suboxone sublingual film for treatment of opioid dependence. PR Newswire website. Available at: http://www.prnewswire.com/news-releases/monosol-rx-announces-reckitt-benckiser-fda-approval-of-suboxone-sublingual-film-for-treatment-of-opioid-dependence-101874388.html. Accessed Sept. 14, 2010.
9. NovoSeven RT 8mg vial approved for hemophilia A or B. Monthly Prescribing Reference website. Available at: http://www.empr.com/novoseven-rt-8mg-vial-approved-for-hemophilia-a-or-b/printarticle/176743/. Accessed Sept. 13, 2010.
10. Eisai announces U.S. FDA approval for new higher dose Aricept 23 mg tablet for the treatment of moderate-to-severe Alzheimer’s disease. Medical News Today website. Available at: http://www.medicalnewstoday.com/articles/196410.php. Accessed Sept. 13, 2010.
11. Cuvposa approved for chronic severe drooling associated with neurologic conditions. Monthly Prescribing Reference website. Available at: http://www.empr.com/cuvposa-approved-for-chronic-severe-drooling-associated-with-neurologic-conditions/article/175824/?DCMP=EMC-MPR_WeeklyNewsbrief. Accessed Aug. 2, 2010.
12. Shelf life of Hizentra extended from 18 to 24 months. Monthly Prescribing Reference website. Available at: http://www.empr.com/shelf-life-of-hizentra-extended-from-18-to-24-months/article/177068/?DCMP=EMC-MPR_WeeklyNewsbrief. Accessed Aug. 23, 2010.
13. Oravig available for oropharyngeal candidiasis. Monthly Prescribing Reference website. Available at: http://www.empr.com/oravig-available-for-oropharyngeal-candidiasis/article/177492/. Accessed Sept. 13, 2010.
14. Additional dosage strengths of Simcor approved. Monthly Prescribing Reference website. Available at: http://www.empr.com/additional-dosage-strengths-of-simcor-approved/article/175825/?DCMP=EMC-MPR_WeeklyNewsbrief. Accessed Sept. 13, 2010.
15. Tribenzor 20/5/12.5mg. Monthly Prescribing Reference website. Available at: http://www.empr.com/tribenzor-205125mg/drugproduct/129/. Accessed Sept. 13, 2010.
16. Stromedix receives FDA orphan drug designation for STX-100 for the treatment of idiopathic pulmonary fibrosis. Stromedix website. Available at: http://www.stromedix.com/Stromedix_STX-100_Orphan_Drug_IPF.pdf. Accessed Sept. 13, 2010.
17. Dane L. Sanofi-Aventis garners FDA approval for one-vial formulation of Taxotere. FirstWord website. Available at: http://www.firstwordplus.com/Fws.do?articleid=E0B4E517F06C4A9E94DC88EADBA079A8. Accessed Sept. 13, 2010.
18. FDA approves longer use of Valcyte for adult kidney transplant patients at high risk of developing cytomegalovirus (CMV) disease. Genentech website. Available at: http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=12907. Accessed Sept. 13, 2010.
19. FDA drug safety communication: ongoing safety review of Stalevo and possible increased cardiovascular risk. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm223060.htm. Accessed Sept. 13, 2010.
20. FDA drug safety communication: increased risk of death with Tygacil (tigecycline) compared to other antibiotics used to treat similar infections. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm224370.htm. Accessed Sept. 13, 2010.

Case

A 46-year-old woman with Addison’s disease and type II diabetes presents with one day of right leg pain, swelling, and redness. She has had mild nausea and vomiting over the past week, with an episode of diarrhea three days prior. She takes hydrocortisone 30mg in the morning and 10mg at bedtime, as well as fludrocortisone 0.2mg in the morning. She is afebrile with a pulse of 108 beats per minute. Her initial blood pressure was 74/49 mmHg, which improved to 84/45 mmHg following one liter of normal saline. She is mentating appropriately. The physical exam is significant for a large, tender area of erythema and warmth from the right ankle to mid-calf. She is admitted for cellulitis and intravenous antibiotics are initiated.

Does she require an increase in her glucocorticoid dose during her acute illness?

Overview

Adrenal insufficiency occurs in approximately 5 out of every 10,000 people and results from primary failure of the adrenal gland, or secondary impairment of the hypothalamic-pituitary-adrenal (HPA) axis, which regulates cortisol secretion.1 In developed countries, 90% of primary adrenal insufficiency (Addison’s disease) cases are due to autoimmune adrenalitis, which might occur in isolation or as part of an autoimmune polyglandular syndrome.^1,2 Secondary adrenal insufficiency is most commonly the result of chronic glucocorticoid therapy, though lesions involving the hypothalamus or pituitary gland might be implicated.^2,3

In a healthy individual, cortisol is secreted in a diurnal pattern from the adrenal glands under the control of corticotropin (ACTH) produced by the pituitary gland and corticotropin-releasing hormone (CRH) produced by the hypothalamus (see Figure 1, p. 19). In the normal state, during periods of such systemic stress as illness, trauma, burns, or surgery, cortisol production increases to a degree roughly proportional to the degree of illness (as much as sixfold).^4,5 Patients with adrenal insufficiency are unable to mount an appropriate cortisol response and, therefore, are at risk for adrenal crisis—a life-threatening condition characterized by hypotension and hypovolemic shock.

Although recommendations for high-dose intravenous steroids in adrenally insufficient patients who are critically ill or undergoing surgery have been extensively discussed in the literature, there are relatively few data regarding the appropriate management of adrenal insufficiency in patients hospitalized for noncritical illness.

Several recent studies have investigated the patient characteristics, situations, and conditions most likely to provoke adrenal crisis in order to establish guidelines dictating the use of supra-physiologic steroid dosing.

Review of the Data

Studies have estimated the prevalence of adrenal crisis in patients with underlying insufficiency at 3.3 to 6.3 events per 100 patient years, with 42% of patients reporting at least one crisis.^2,5,6 A recent survey of 982 patients with Addison’s disease in the United Kingdom reported an 8% annual frequency.⁷

A retrospective Japanese study reviewed the medical charts of 137 adult patients receiving steroid replacement for established primary or secondary adrenal insufficiency. The authors noted a significant positive association between adrenal crisis and long-term steroid replacement (>4 years), concomitant mental disorder, and sex hormone deficiency. A combination of any of these factors further increased the risk.⁸

A more recent survey of 444 patients ages 17-81 assessed independent risk factors for adrenal crisis in the setting of primary (N=254) or secondary (N=190) adrenal insufficiency. The incidence of crisis was higher in primary versus secondary insufficiency. In patients with primary insufficiency, concomitant, non-endocrine disorders increased the risk of adrenal crisis, whereas diabetes insipidus and female gender increased risk in patients with secondary insufficiency. This same study also investigated events leading to a crisis and found gastrointestinal infection to be the most frequent factor, followed by other infectious or febrile illnesses. Overall, infection comprised 45% of all identified triggers.⁶

A similar study conducted by White and Arlt evaluated 841 Addison’s patients in the United Kingdom, Canada, Australia, and New Zealand.⁷ Again, gastrointestinal illness was the most common provoking factor, responsible for 56% of all reported crises. Flulike illness followed at 11%, followed by infections and surgical procedures at 6% each. This study found a higher risk of crisis in patients with diabetes (type I or II), premature ovarian failure, and asthma; the presence of multiple comorbidities further increased risk.

click for large version

Medications. Glucocorticoid therapy is known to suppress the HPA axis. Although it was once believed that the duration and dose of therapy correlated directly with the degree of HPA suppression, more recent studies have failed to find any definite relationship.⁹ Patients taking the equivalent of 5mg of prednisone per day should continue to have an intact HPA axis, as this dose mimics physiologic secretion of cortisol in a healthy individual.³

However, the dose and duration of therapy at which suppression occurs is highly variable between patients. In general, patients on 7.5mg of prednisone or more per day for at least three weeks should be considered to be suppressed.^3,9 Additionally, progesterone derivatives (i.e., megestrol) have glucocorticoid activity and might suppress HPA function. Other medications that might have related effects are those that inhibit enzymes involved in cortisol synthesis; ketoconazole and etomidate are common examples. Rifampin and several classes of anti-epileptic drugs induce enzymes, which increase hepatic metabolism of cortisol (see Table 1, p. 18).

Hyperthyroidism. Thyroid hormone is involved in the metabolism of cortisol, thus an increase in T4 correlates with lower levels. Adrenal insufficiency and thyroid disease might coexist within the autoimmune polyglandular syndrome. Initiation or uptitration of thyroid replacement should be avoided if acute adrenal insufficiency is suspected, as this might provoke an adrenal crisis. Conversely, any patient with adrenal insufficiency who has uncontrolled hyperthyroidism should receive two to three times their usual glucocorticoid replacement.^1,2

Pregnancy. Levels of cortisol-binding globulin increase throughout pregnancy. In women with intact adrenal function, free cortisol levels also rise during the third trimester. Therefore, glucocorticoid replacement should be increased by 50% during the last three months of pregnancy.²

click for large version

Acute illness. The cortisol response to stress is highly variable and dependent on a number of factors, including age, underlying health, and genetics. In general, most experts recommend doubling or tripling the daily replacement dose during mild to moderate illness until recovery (often referred to as the “sick-day rules”). What constitutes “recovery” is not clearly defined. When oral intake is compromised, as with vomiting or diarrhea, parenteral administration of steroids is recommended.^1-5,9,10 Patients with adrenal insufficiency should be provided an emergency injection kit to use and further counseled to seek medical attention. Injection kits typically consist of 100mg of hydrocortisone or 4mg of dexamethasone, although other glucocorticoids may be used (see Table 2, above left, for conversions).

Limited data are available to support guidelines for glucocorticoid adjustment during acute, non-critical illness. Published guidelines vary both in illness categorization and category-specific recommendations (see Table 3, below).

click for large version

Coursin and Wood devised a set of guidelines based on a literature review and consultation with experts, categorizing medical illness as minor, moderate, severe, and critical (see Table 3).³ For noncritical illness, they recommended continuation of standard replacement therapy with an additional, once-daily dose, which varied according to illness severity.

Cooper and Stewart conducted a similar review, basing their guidelines on a categorization of mild, moderate, severe/critical, or septic shock. These guidelines recommended a total daily dose of glucocorticoid supplementation, rather than an addition of a single dose to current therapy. They also stated that the least severe category of illness (defined as mild) did not require any change to a patient’s regular therapy.⁴

Jung et al classified illness as minimal, minor, moderate, severe, and critical.⁹ Under these guidelines, supplemental therapy was not advised for minimal (nonfebrile) illness. Moderate illness, including cellulitis, warranted a doubling or tripling of the outpatient dose until recovery, which was consistent with prior expert recommendation. More severe illness warranted intravenous administration of steroids.

Back to the Case

The patient had a mild case of cellulitis, classified by most experts as moderate illness, which responded well to vancomycin. Her outpatient glucocorticoid dose was doubled on admission and administered orally for the duration of her hospitalization, as she had no further episodes of vomiting or diarrhea.

Review of the patient’s records from prior hospitalizations and ambulatory visits revealed that her systolic blood pressure typically ran in the 80 mmHg to 100 mmHg range. Following initial volume resuscitation, her systolic blood pressure remained in the 90-100 mmHg range.

She was discharged home in stable condition, with instructions to complete a course of oral trimethoprim/sulfamethoxazole, resume her baseline dose of hydrocortisone the day after discharge, and follow up with her PCP for further monitoring and adjustment of her adrenal replacement therapy.

Bottom Line

For adults with adrenal insufficiency hospitalized with noncritical, nonsurgical illness, the expert recommendation is to double or triple the usual outpatient dose of glucocorticoid; however, data to support this is limited, and each patient should be assessed carefully and monitored to determine the optimal dose adjustment. TH

Dr. Shaw is a resident in the Department of Medicine at the University of Washington School of Medicine in Seattle. Dr. Best is an assistant professor of medicine in the division of general internal medicine, University of Washington School of Medicine.

References

1. Arlt W. The approach to the adult with newly diagnosed adrenal insufficiency. J Clin Endocrinol Metab. 2009;94(4):1059-1067.
2. Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003; 361:1881-1893.
3. Coursin DB, Wood KE. Corticosteroid supplementation for adrenal insufficiency. JAMA. 2002;287:236-240.
4. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003;348:727-734.
5. Hahner S, Allolio B. Therapeutic management of adrenal insufficiency. Best Pract Res Clin Endocrinol Metab. 2009;23:167-179.
6. Hahner S, Loeffler M, Bleicken B, et al. Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. Eur J Endocrinol. 2010;162:597:602.
7. White K, Arlt W. Adrenal crisis in treated Addison’s disease: a predictable but under-managed event. Eur J Endocrinol. 2010;162:115-120.
8. Omori K, Nomura K, Shimizu S, Omori N, Takano K. Risk factors for adrenal crises in patients with adrenal insufficiency. Endocr J. 2003;50:745-752.
9. Jung C, Inder WJ. Management of adrenal insufficiency during the stress of medical illness and surgery. Med J Aust. 2008;188:409-413.
10. Crown A, Lightman S. Why is the management of glucocorticoid deficiency still controversial: a review of the literature. Clin Endocrinol. 2005;63:483-492.

Case

A 46-year-old woman with Addison’s disease and type II diabetes presents with one day of right leg pain, swelling, and redness. She has had mild nausea and vomiting over the past week, with an episode of diarrhea three days prior. She takes hydrocortisone 30mg in the morning and 10mg at bedtime, as well as fludrocortisone 0.2mg in the morning. She is afebrile with a pulse of 108 beats per minute. Her initial blood pressure was 74/49 mmHg, which improved to 84/45 mmHg following one liter of normal saline. She is mentating appropriately. The physical exam is significant for a large, tender area of erythema and warmth from the right ankle to mid-calf. She is admitted for cellulitis and intravenous antibiotics are initiated.

Does she require an increase in her glucocorticoid dose during her acute illness?

Overview

Adrenal insufficiency occurs in approximately 5 out of every 10,000 people and results from primary failure of the adrenal gland, or secondary impairment of the hypothalamic-pituitary-adrenal (HPA) axis, which regulates cortisol secretion.1 In developed countries, 90% of primary adrenal insufficiency (Addison’s disease) cases are due to autoimmune adrenalitis, which might occur in isolation or as part of an autoimmune polyglandular syndrome.^1,2 Secondary adrenal insufficiency is most commonly the result of chronic glucocorticoid therapy, though lesions involving the hypothalamus or pituitary gland might be implicated.^2,3

In a healthy individual, cortisol is secreted in a diurnal pattern from the adrenal glands under the control of corticotropin (ACTH) produced by the pituitary gland and corticotropin-releasing hormone (CRH) produced by the hypothalamus (see Figure 1, p. 19). In the normal state, during periods of such systemic stress as illness, trauma, burns, or surgery, cortisol production increases to a degree roughly proportional to the degree of illness (as much as sixfold).^4,5 Patients with adrenal insufficiency are unable to mount an appropriate cortisol response and, therefore, are at risk for adrenal crisis—a life-threatening condition characterized by hypotension and hypovolemic shock.

Although recommendations for high-dose intravenous steroids in adrenally insufficient patients who are critically ill or undergoing surgery have been extensively discussed in the literature, there are relatively few data regarding the appropriate management of adrenal insufficiency in patients hospitalized for noncritical illness.

Several recent studies have investigated the patient characteristics, situations, and conditions most likely to provoke adrenal crisis in order to establish guidelines dictating the use of supra-physiologic steroid dosing.

Review of the Data

Studies have estimated the prevalence of adrenal crisis in patients with underlying insufficiency at 3.3 to 6.3 events per 100 patient years, with 42% of patients reporting at least one crisis.^2,5,6 A recent survey of 982 patients with Addison’s disease in the United Kingdom reported an 8% annual frequency.⁷

A retrospective Japanese study reviewed the medical charts of 137 adult patients receiving steroid replacement for established primary or secondary adrenal insufficiency. The authors noted a significant positive association between adrenal crisis and long-term steroid replacement (>4 years), concomitant mental disorder, and sex hormone deficiency. A combination of any of these factors further increased the risk.⁸

A more recent survey of 444 patients ages 17-81 assessed independent risk factors for adrenal crisis in the setting of primary (N=254) or secondary (N=190) adrenal insufficiency. The incidence of crisis was higher in primary versus secondary insufficiency. In patients with primary insufficiency, concomitant, non-endocrine disorders increased the risk of adrenal crisis, whereas diabetes insipidus and female gender increased risk in patients with secondary insufficiency. This same study also investigated events leading to a crisis and found gastrointestinal infection to be the most frequent factor, followed by other infectious or febrile illnesses. Overall, infection comprised 45% of all identified triggers.⁶

A similar study conducted by White and Arlt evaluated 841 Addison’s patients in the United Kingdom, Canada, Australia, and New Zealand.⁷ Again, gastrointestinal illness was the most common provoking factor, responsible for 56% of all reported crises. Flulike illness followed at 11%, followed by infections and surgical procedures at 6% each. This study found a higher risk of crisis in patients with diabetes (type I or II), premature ovarian failure, and asthma; the presence of multiple comorbidities further increased risk.

click for large version

Medications. Glucocorticoid therapy is known to suppress the HPA axis. Although it was once believed that the duration and dose of therapy correlated directly with the degree of HPA suppression, more recent studies have failed to find any definite relationship.⁹ Patients taking the equivalent of 5mg of prednisone per day should continue to have an intact HPA axis, as this dose mimics physiologic secretion of cortisol in a healthy individual.³

However, the dose and duration of therapy at which suppression occurs is highly variable between patients. In general, patients on 7.5mg of prednisone or more per day for at least three weeks should be considered to be suppressed.^3,9 Additionally, progesterone derivatives (i.e., megestrol) have glucocorticoid activity and might suppress HPA function. Other medications that might have related effects are those that inhibit enzymes involved in cortisol synthesis; ketoconazole and etomidate are common examples. Rifampin and several classes of anti-epileptic drugs induce enzymes, which increase hepatic metabolism of cortisol (see Table 1, p. 18).

Hyperthyroidism. Thyroid hormone is involved in the metabolism of cortisol, thus an increase in T4 correlates with lower levels. Adrenal insufficiency and thyroid disease might coexist within the autoimmune polyglandular syndrome. Initiation or uptitration of thyroid replacement should be avoided if acute adrenal insufficiency is suspected, as this might provoke an adrenal crisis. Conversely, any patient with adrenal insufficiency who has uncontrolled hyperthyroidism should receive two to three times their usual glucocorticoid replacement.^1,2

Pregnancy. Levels of cortisol-binding globulin increase throughout pregnancy. In women with intact adrenal function, free cortisol levels also rise during the third trimester. Therefore, glucocorticoid replacement should be increased by 50% during the last three months of pregnancy.²

click for large version

Acute illness. The cortisol response to stress is highly variable and dependent on a number of factors, including age, underlying health, and genetics. In general, most experts recommend doubling or tripling the daily replacement dose during mild to moderate illness until recovery (often referred to as the “sick-day rules”). What constitutes “recovery” is not clearly defined. When oral intake is compromised, as with vomiting or diarrhea, parenteral administration of steroids is recommended.^1-5,9,10 Patients with adrenal insufficiency should be provided an emergency injection kit to use and further counseled to seek medical attention. Injection kits typically consist of 100mg of hydrocortisone or 4mg of dexamethasone, although other glucocorticoids may be used (see Table 2, above left, for conversions).

Limited data are available to support guidelines for glucocorticoid adjustment during acute, non-critical illness. Published guidelines vary both in illness categorization and category-specific recommendations (see Table 3, below).

click for large version

Coursin and Wood devised a set of guidelines based on a literature review and consultation with experts, categorizing medical illness as minor, moderate, severe, and critical (see Table 3).³ For noncritical illness, they recommended continuation of standard replacement therapy with an additional, once-daily dose, which varied according to illness severity.

Cooper and Stewart conducted a similar review, basing their guidelines on a categorization of mild, moderate, severe/critical, or septic shock. These guidelines recommended a total daily dose of glucocorticoid supplementation, rather than an addition of a single dose to current therapy. They also stated that the least severe category of illness (defined as mild) did not require any change to a patient’s regular therapy.⁴

Jung et al classified illness as minimal, minor, moderate, severe, and critical.⁹ Under these guidelines, supplemental therapy was not advised for minimal (nonfebrile) illness. Moderate illness, including cellulitis, warranted a doubling or tripling of the outpatient dose until recovery, which was consistent with prior expert recommendation. More severe illness warranted intravenous administration of steroids.

Back to the Case

The patient had a mild case of cellulitis, classified by most experts as moderate illness, which responded well to vancomycin. Her outpatient glucocorticoid dose was doubled on admission and administered orally for the duration of her hospitalization, as she had no further episodes of vomiting or diarrhea.

Review of the patient’s records from prior hospitalizations and ambulatory visits revealed that her systolic blood pressure typically ran in the 80 mmHg to 100 mmHg range. Following initial volume resuscitation, her systolic blood pressure remained in the 90-100 mmHg range.

She was discharged home in stable condition, with instructions to complete a course of oral trimethoprim/sulfamethoxazole, resume her baseline dose of hydrocortisone the day after discharge, and follow up with her PCP for further monitoring and adjustment of her adrenal replacement therapy.

Bottom Line

For adults with adrenal insufficiency hospitalized with noncritical, nonsurgical illness, the expert recommendation is to double or triple the usual outpatient dose of glucocorticoid; however, data to support this is limited, and each patient should be assessed carefully and monitored to determine the optimal dose adjustment. TH

Dr. Shaw is a resident in the Department of Medicine at the University of Washington School of Medicine in Seattle. Dr. Best is an assistant professor of medicine in the division of general internal medicine, University of Washington School of Medicine.

References

1. Arlt W. The approach to the adult with newly diagnosed adrenal insufficiency. J Clin Endocrinol Metab. 2009;94(4):1059-1067.
2. Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003; 361:1881-1893.
3. Coursin DB, Wood KE. Corticosteroid supplementation for adrenal insufficiency. JAMA. 2002;287:236-240.
4. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003;348:727-734.
5. Hahner S, Allolio B. Therapeutic management of adrenal insufficiency. Best Pract Res Clin Endocrinol Metab. 2009;23:167-179.
6. Hahner S, Loeffler M, Bleicken B, et al. Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. Eur J Endocrinol. 2010;162:597:602.
7. White K, Arlt W. Adrenal crisis in treated Addison’s disease: a predictable but under-managed event. Eur J Endocrinol. 2010;162:115-120.
8. Omori K, Nomura K, Shimizu S, Omori N, Takano K. Risk factors for adrenal crises in patients with adrenal insufficiency. Endocr J. 2003;50:745-752.
9. Jung C, Inder WJ. Management of adrenal insufficiency during the stress of medical illness and surgery. Med J Aust. 2008;188:409-413.
10. Crown A, Lightman S. Why is the management of glucocorticoid deficiency still controversial: a review of the literature. Clin Endocrinol. 2005;63:483-492.

Case

A 46-year-old woman with Addison’s disease and type II diabetes presents with one day of right leg pain, swelling, and redness. She has had mild nausea and vomiting over the past week, with an episode of diarrhea three days prior. She takes hydrocortisone 30mg in the morning and 10mg at bedtime, as well as fludrocortisone 0.2mg in the morning. She is afebrile with a pulse of 108 beats per minute. Her initial blood pressure was 74/49 mmHg, which improved to 84/45 mmHg following one liter of normal saline. She is mentating appropriately. The physical exam is significant for a large, tender area of erythema and warmth from the right ankle to mid-calf. She is admitted for cellulitis and intravenous antibiotics are initiated.

Does she require an increase in her glucocorticoid dose during her acute illness?

Overview

Adrenal insufficiency occurs in approximately 5 out of every 10,000 people and results from primary failure of the adrenal gland, or secondary impairment of the hypothalamic-pituitary-adrenal (HPA) axis, which regulates cortisol secretion.1 In developed countries, 90% of primary adrenal insufficiency (Addison’s disease) cases are due to autoimmune adrenalitis, which might occur in isolation or as part of an autoimmune polyglandular syndrome.^1,2 Secondary adrenal insufficiency is most commonly the result of chronic glucocorticoid therapy, though lesions involving the hypothalamus or pituitary gland might be implicated.^2,3

In a healthy individual, cortisol is secreted in a diurnal pattern from the adrenal glands under the control of corticotropin (ACTH) produced by the pituitary gland and corticotropin-releasing hormone (CRH) produced by the hypothalamus (see Figure 1, p. 19). In the normal state, during periods of such systemic stress as illness, trauma, burns, or surgery, cortisol production increases to a degree roughly proportional to the degree of illness (as much as sixfold).^4,5 Patients with adrenal insufficiency are unable to mount an appropriate cortisol response and, therefore, are at risk for adrenal crisis—a life-threatening condition characterized by hypotension and hypovolemic shock.

Although recommendations for high-dose intravenous steroids in adrenally insufficient patients who are critically ill or undergoing surgery have been extensively discussed in the literature, there are relatively few data regarding the appropriate management of adrenal insufficiency in patients hospitalized for noncritical illness.

Several recent studies have investigated the patient characteristics, situations, and conditions most likely to provoke adrenal crisis in order to establish guidelines dictating the use of supra-physiologic steroid dosing.

Review of the Data

Studies have estimated the prevalence of adrenal crisis in patients with underlying insufficiency at 3.3 to 6.3 events per 100 patient years, with 42% of patients reporting at least one crisis.^2,5,6 A recent survey of 982 patients with Addison’s disease in the United Kingdom reported an 8% annual frequency.⁷

A retrospective Japanese study reviewed the medical charts of 137 adult patients receiving steroid replacement for established primary or secondary adrenal insufficiency. The authors noted a significant positive association between adrenal crisis and long-term steroid replacement (>4 years), concomitant mental disorder, and sex hormone deficiency. A combination of any of these factors further increased the risk.⁸

A more recent survey of 444 patients ages 17-81 assessed independent risk factors for adrenal crisis in the setting of primary (N=254) or secondary (N=190) adrenal insufficiency. The incidence of crisis was higher in primary versus secondary insufficiency. In patients with primary insufficiency, concomitant, non-endocrine disorders increased the risk of adrenal crisis, whereas diabetes insipidus and female gender increased risk in patients with secondary insufficiency. This same study also investigated events leading to a crisis and found gastrointestinal infection to be the most frequent factor, followed by other infectious or febrile illnesses. Overall, infection comprised 45% of all identified triggers.⁶

A similar study conducted by White and Arlt evaluated 841 Addison’s patients in the United Kingdom, Canada, Australia, and New Zealand.⁷ Again, gastrointestinal illness was the most common provoking factor, responsible for 56% of all reported crises. Flulike illness followed at 11%, followed by infections and surgical procedures at 6% each. This study found a higher risk of crisis in patients with diabetes (type I or II), premature ovarian failure, and asthma; the presence of multiple comorbidities further increased risk.

click for large version

Medications. Glucocorticoid therapy is known to suppress the HPA axis. Although it was once believed that the duration and dose of therapy correlated directly with the degree of HPA suppression, more recent studies have failed to find any definite relationship.⁹ Patients taking the equivalent of 5mg of prednisone per day should continue to have an intact HPA axis, as this dose mimics physiologic secretion of cortisol in a healthy individual.³

However, the dose and duration of therapy at which suppression occurs is highly variable between patients. In general, patients on 7.5mg of prednisone or more per day for at least three weeks should be considered to be suppressed.^3,9 Additionally, progesterone derivatives (i.e., megestrol) have glucocorticoid activity and might suppress HPA function. Other medications that might have related effects are those that inhibit enzymes involved in cortisol synthesis; ketoconazole and etomidate are common examples. Rifampin and several classes of anti-epileptic drugs induce enzymes, which increase hepatic metabolism of cortisol (see Table 1, p. 18).

Hyperthyroidism. Thyroid hormone is involved in the metabolism of cortisol, thus an increase in T4 correlates with lower levels. Adrenal insufficiency and thyroid disease might coexist within the autoimmune polyglandular syndrome. Initiation or uptitration of thyroid replacement should be avoided if acute adrenal insufficiency is suspected, as this might provoke an adrenal crisis. Conversely, any patient with adrenal insufficiency who has uncontrolled hyperthyroidism should receive two to three times their usual glucocorticoid replacement.^1,2

Pregnancy. Levels of cortisol-binding globulin increase throughout pregnancy. In women with intact adrenal function, free cortisol levels also rise during the third trimester. Therefore, glucocorticoid replacement should be increased by 50% during the last three months of pregnancy.²

click for large version

Acute illness. The cortisol response to stress is highly variable and dependent on a number of factors, including age, underlying health, and genetics. In general, most experts recommend doubling or tripling the daily replacement dose during mild to moderate illness until recovery (often referred to as the “sick-day rules”). What constitutes “recovery” is not clearly defined. When oral intake is compromised, as with vomiting or diarrhea, parenteral administration of steroids is recommended.^1-5,9,10 Patients with adrenal insufficiency should be provided an emergency injection kit to use and further counseled to seek medical attention. Injection kits typically consist of 100mg of hydrocortisone or 4mg of dexamethasone, although other glucocorticoids may be used (see Table 2, above left, for conversions).

Limited data are available to support guidelines for glucocorticoid adjustment during acute, non-critical illness. Published guidelines vary both in illness categorization and category-specific recommendations (see Table 3, below).

click for large version

Coursin and Wood devised a set of guidelines based on a literature review and consultation with experts, categorizing medical illness as minor, moderate, severe, and critical (see Table 3).³ For noncritical illness, they recommended continuation of standard replacement therapy with an additional, once-daily dose, which varied according to illness severity.

Cooper and Stewart conducted a similar review, basing their guidelines on a categorization of mild, moderate, severe/critical, or septic shock. These guidelines recommended a total daily dose of glucocorticoid supplementation, rather than an addition of a single dose to current therapy. They also stated that the least severe category of illness (defined as mild) did not require any change to a patient’s regular therapy.⁴

Jung et al classified illness as minimal, minor, moderate, severe, and critical.⁹ Under these guidelines, supplemental therapy was not advised for minimal (nonfebrile) illness. Moderate illness, including cellulitis, warranted a doubling or tripling of the outpatient dose until recovery, which was consistent with prior expert recommendation. More severe illness warranted intravenous administration of steroids.

Back to the Case

The patient had a mild case of cellulitis, classified by most experts as moderate illness, which responded well to vancomycin. Her outpatient glucocorticoid dose was doubled on admission and administered orally for the duration of her hospitalization, as she had no further episodes of vomiting or diarrhea.

Review of the patient’s records from prior hospitalizations and ambulatory visits revealed that her systolic blood pressure typically ran in the 80 mmHg to 100 mmHg range. Following initial volume resuscitation, her systolic blood pressure remained in the 90-100 mmHg range.

She was discharged home in stable condition, with instructions to complete a course of oral trimethoprim/sulfamethoxazole, resume her baseline dose of hydrocortisone the day after discharge, and follow up with her PCP for further monitoring and adjustment of her adrenal replacement therapy.

Bottom Line

For adults with adrenal insufficiency hospitalized with noncritical, nonsurgical illness, the expert recommendation is to double or triple the usual outpatient dose of glucocorticoid; however, data to support this is limited, and each patient should be assessed carefully and monitored to determine the optimal dose adjustment. TH

Dr. Shaw is a resident in the Department of Medicine at the University of Washington School of Medicine in Seattle. Dr. Best is an assistant professor of medicine in the division of general internal medicine, University of Washington School of Medicine.

References

1. Arlt W. The approach to the adult with newly diagnosed adrenal insufficiency. J Clin Endocrinol Metab. 2009;94(4):1059-1067.
2. Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003; 361:1881-1893.
3. Coursin DB, Wood KE. Corticosteroid supplementation for adrenal insufficiency. JAMA. 2002;287:236-240.
4. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003;348:727-734.
5. Hahner S, Allolio B. Therapeutic management of adrenal insufficiency. Best Pract Res Clin Endocrinol Metab. 2009;23:167-179.
6. Hahner S, Loeffler M, Bleicken B, et al. Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. Eur J Endocrinol. 2010;162:597:602.
7. White K, Arlt W. Adrenal crisis in treated Addison’s disease: a predictable but under-managed event. Eur J Endocrinol. 2010;162:115-120.
8. Omori K, Nomura K, Shimizu S, Omori N, Takano K. Risk factors for adrenal crises in patients with adrenal insufficiency. Endocr J. 2003;50:745-752.
9. Jung C, Inder WJ. Management of adrenal insufficiency during the stress of medical illness and surgery. Med J Aust. 2008;188:409-413.
10. Crown A, Lightman S. Why is the management of glucocorticoid deficiency still controversial: a review of the literature. Clin Endocrinol. 2005;63:483-492.