Only about a third of ideal candidates with heart failure are currently treated with [aldosterone antagonists], even though it markedly improves outcome and is Class I-recommended in the guidelines.

—Gregg Fonarow, MD, co-chief, University of California at Los Angeles division of cardiology, chair, American Heart Association’s Get With The Guidelines program steering committee

You might not have done a fellowship in cardiology, but quite often you probably feel like a cardiologist. Hospitalists frequently attend to patients on observation for heart problems and help manage even the most complex patients.

Often, you are working alongside the cardiologist. But other times, you’re on your own. Hospitalists are expected to carry an increasingly heavy load when it comes to heart-failure patients and many other kinds of patients with specialized disorders. It can be hard to keep up with what you need to know.

Top Twelve

1. Recognize the new importance of beta-blockers for heart failure, and go with the best of them.
2. It’s not readmissions that are the problem—it’s avoidable readmissions.
3. New interventional technologies will mean more complex patients, so be ready.
4. Aldosterone antagonists, though probably underutilized, can be very effective but require caution.
5. Switching from IV diuretics to an oral regimen calls for careful monitoring.
6. Patients with heart failure with preserved ejection fraction have outcomes over the longer haul similar to those with heart failure with reduced ejection fraction. And in preserved ejection fraction cases, the contributing illnesses must be addressed.
7. Inotropic agents can do more harm than good.
8. Pay attention to the ins and outs of new antiplatelet therapies.
9. Bridging anticoagulant therapy in patients going for electrophysiology procedures should be done only some, not most, of the time.
10. Some non-STEMI patients might benefit from getting to the catheterization lab quickly.
11. Beware the idiosyncrasies of new anticoagulants.
12. Be cognizant of stent thrombosis and how to manage it.

The Hospitalist spoke to several cardiologists about the latest in treatments, technologies, and HM’s role in the system of care. The following are their suggestions for what you really need to know about treating patients with heart conditions.

1) Recognize the new importance of beta-blockers for heart failure, and go with the best of them.

Angiotensin converting enzyme inhibitors and angiotensive receptor blockers have been part of the Centers for Medicare & Medicaid Services’ (CMS) core measures for heart failure for a long time, but beta-blockers at hospital discharge only recently have been added as American College of Cardiology/American Heart Association/American Medical Association–Physician Consortium for Performance Improvement measures for heart failure.¹

“For those with heart failure and reduced left ventricular ejection fraction, very old and outdated concepts would have talked about potentially holding the beta-blocker during hospitalization for heart failure—or not initiating until the patient was an outpatient,” says Gregg Fonarow, MD, co-chief of the University of California at Los Angeles’ division of cardiology and chair of the steering committee for the American Heart Association’s Get With The Guidelines program. “[But] the guidelines and evidence, and often performance measures, linked to them are now explicit about initiating or maintaining beta-blockers during the heart-failure hospitalization.”

Beta-blockers should be initiated as patients are stabilized before discharge. Dr. Fonarow suggests hospitalists use only one of the three evidence-based therapies: carvedilol, metoprolol succinate, or bisoprolol.

“Many physicians have been using metoprolol tartrate or atenolol in heart-failure patients,” Dr. Fonarow says. “These are not known to improve clinical outcomes. So here’s an example where the specific medication is absolutely, critically important.”

2) It’s not readmissions that are the problem—it’s avoidable readmissions.

“The modifier is very important,” says Clyde Yancy, MD, chief of the division of cardiology at the Northwestern University Feinberg School of Medicine in Chicago. “Heart failure continues to be a problematic disease. Many patients now do really well, but some do not. Those patients are symptomatic and may require frequent hospitalizations for stabilization. We should not disallow or misdirect those patients who need inpatient care from receiving such because of an arbitrary incentive to reduce rehospitalizations out of fear of punitive financial damages. The unforeseen risks here are real.”

Dr. Yancy says studies based on CMS data have found that institutions with higher readmission rates have lower 30-day mortality rates.² He cautions hospitalists to be “very thoughtful about an overzealous embrace of reducing all readmissions for heart failure.” Instead, the goal should be to limit the “avoidable readmissions.”

“And for the patient that clearly has advanced disease,” he says, “rather than triaging them away from the hospital, we really should be very respectful of their disease. Keep those patients where disease-modifying interventions can be deployed, and we can work to achieve the best possible outcome for those that have the most advanced disease.”

3) New interventional technologies will mean more complex patients, so be ready.

Advances in interventional procedures, including transcatheter aortic valve replacement (TAVR) and endoscopic mitral valve repair, will translate into a new population of highly complex patients. Many of these patients will be in their 80s or 90s.

“It’s a whole new paradigm shift of technology,” says John Harold, MD, president-elect of the American College of Cardiology and past chief of staff and department of medicine clinical chief of staff at Cedars-Sinai Medical Center in Los Angeles. “Very often, the hospitalist is at the front dealing with all of these issues.”

Many of these patients have other problems, including renal insufficiency, diabetes, and the like.

“They have all sorts of other things going on simultaneously, so very often the hospitalist becomes … the point person in dealing with all of these issues,” Dr. Harold says.

4) Aldosterone antagonists, though probably underutilized, can be very effective but require caution.

Aldosterone antagonists can greatly improve outcomes and reduce hospitalization in heart-failure patients, but they have to be used with very careful dosing and patient selection, Dr. Fonarow says. And they require early follow-up once patients are discharged.

“Only about a third of ideal candidates with heart failure are currently treated with this agent, even though it markedly improves outcome and is Class I-recommended in the guidelines,” Dr. Fonarow says. “But this is one where it needs to be started at appropriate low doses, with meticulous monitoring in both the inpatient and the outpatient setting, early follow-up, and early laboratory checks.”

5) Switching from IV diuretics to an oral regimen calls for careful monitoring.

Transitioning patients from IV diuretics to oral regimens is an area rife with mistakes, Dr. Fonarow says. It requires a lot of “meticulous attention to proper potassium supplementation and monitoring of renal function and electrolyte levels,” he says.

Medication reconciliation—“med rec”—is especially important during the transition from inpatient to outpatient.

“There are common medication errors that are made during this transition,” Dr. Fonarow says. “Hospitalists, along with other [care team] members, can really play a critically important role in trying to reduce that risk.”

6) Patients with heart failure with preserved ejection

fraction have outcomes over the longer haul similar to those with heart failure with reduced ejection fraction. And in preserved ejection fraction cases, the contributing illnesses must be addressed.

“We really can’t exercise a thought economy that just says, ‘Extrapolate the evidence-based therapies for heart failure with reduced ejection fraction to heart failure with preserved ejection fraction’ and expect good outcomes,” Dr. Yancy says. “That’s not the case. We don’t have an evidence base to substantiate that.”

He says one or more common comorbidities (e.g. atrial fibrillation, hypertension, obesity, diabetes, renal insufficiency) are present in 90% of patients with preserved ejection fraction. Treatment of those comorbidities—for example, rate control in afib patients, lowering the blood pressure in hypertension patients—has to be done with care.

“We should recognize that the therapy for this condition, albeit absent any specifically indicated interventions that will change its natural history, can still be skillfully constructed,” Dr. Yancy says. “But that construct needs to reflect the recommended, guideline-driven interventions for the concomitant other comorbidities.”

7) Inotropic agents can do more harm than good.

For patients who aren’t in cardiogenic shock, using inotropic agents doesn’t help. In fact, it might actually hurt. Dr. Fonarow says studies have shown these agents can “prolong length of stay, cause complications, and increase mortality risk.”

He notes that the use of inotropes should be avoided, or if it’s being considered, a cardiologist with knowledge and experience in heart failure should be involved in the treatment and care.

Statements about avoiding inotropes in heart failure, except under very specific circumstances, have been “incredibly strengthened” recently in the American College of Cardiology and Heart Failure Society of America guidelines.³

8) Pay attention to the ins and outs of new antiplatelet therapies.

For the majority of these, there’s no specific way to reverse the anticoagulant effect in the event of a major bleeding event. There’s no simple antidote.

—John Harold, MD, president-elect, American College of Cardiology, former chief of staff, department of medicine, Cedars-Sinai Medical Center, Los Angeles

Hospitalists caring for acute coronary syndrome patients need to familiarize themselves with updated guidelines and additional therapies that are now available, Dr. Fonarow says. New antiplatelet therapies (e.g. prasugrel and ticagrelor) are available as part of the armamentarium, along with the mainstay clopidogrel.

“These therapies lower the risk of recurrent events, lowered the risk of stent thrombosis,” he says. “In the case of ticagrelor, it actually lowered all-cause mortality. These are important new therapies, with new guideline recommendations, that all hospitalists should be aware of.”

9) Bridging anticoagulant therapy in patients going for electrophysiology procedures should be done only some, not most, of the time.

“Patients getting such devices as pacemakers or implantable cardioverter defribrillators (ICD) installed tend not to need bridging,” says Joaquin Cigarroa, MD, clinical chief of cardiology at Oregon Health & Science University in Portland.

He says it’s actually “safer” to do the procedure when patients “are on oral antithrombotics than switching them from an oral agent, and bridging with low- molecular-weight- or unfractionated heparin.”

“It’s a big deal,” Dr. Cigarroa adds, because it is risky to have elderly and frail patients on multiple antithrombotics. “Hemorrhagic complications in cardiology patients still occurs very frequently, so really be attuned to estimating bleeding risk and making sure that we’re dosing antithrombotics appropriately. Bridging should be the minority of patients, not the majority of patients.”

10) Some non-STEMI patients might benefit from getting to the catheterization lab quickly.

Door-to-balloon time is recognized as critical for ST-segment elevation myocardial infarction (STEMI) patients, but more recent work—such as in the TIMACS trial—finds benefits of early revascularization for some non-STEMI patients as well.²

“This trial showed that among higher-risk patients, using a validated risk score, that those patients did benefit from an early approach, meaning going to the cath lab in the first 12 hours of hospitalization,” Dr. Fonarow says. “We now have more information about the optimal timing of coronary angiography and potential revascularization of higher-risk patients with non-ST-segment elevation MI.”

11) Beware the idiosyncrasies of new anticoagulants.

The introduction of dabigatran and rivaroxaban (and, perhaps soon, apixaban) to the array of anticoagulant therapies brings a new slate of considerations for hospitalists, Dr. Harold says.

“For the majority of these, there’s no specific way to reverse the anticoagulant effect in the event of a major bleeding event,” he says. “There’s no simple antidote. And the effect can last up to 12 to 24 hours, depending on the renal function. This is what the hospitalist will be called to deal with: bleeding complications in patients who have these newer anticoagulants on board.”

Dr. Fonarow says that the new CHA2DS2-VASc score has been found to do a better job than the traditional CHADS2 score in assessing afib stroke risk.⁴

12) Be cognizant of stent thrombosis and how to manage it.

Dr. Harold says that most hospitalists probably are up to date on drug-eluting stents and the risk of stopping dual antiplatelet therapy within several months of implant, but that doesn’t mean they won’t treat patients whose primary-care physicians (PCPs) aren’t up to date. He recommends working on these cases with hematologists.

“That knowledge is not widespread in terms of the internal-medicine community,” he says. “I’ve seen situations where patients have had their Plavix stopped for colonoscopies and they’ve had stent thrombosis. It’s this knowledge of cardiac patients who come in with recent deployment of drug-eluting stents who may end up having other issues.”

Tom Collins is a freelance writer in South Florida.

References

1. 2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults. Circulation. 2009;119:1977-2016 an HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Cardiac Failure. 2010;16(6):475-539.
2. Gorodeski EZ, Starling RC, Blackstone EH. Are all readmissions bad readmissions? N Engl J Med. 2010;363:297-298.
3. Mehta SR, Granger CB, Boden WE, et al. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med. 2009;360(21):2165-2175.
4. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of the CHA2DS2-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort study. Thromb Haemost. 2012;107(6):1172-1179.
5. Associations between outpatient heart failure process-of-care measures and mortality. Circulation. 2011;123(15):1601-1610.

Only about a third of ideal candidates with heart failure are currently treated with [aldosterone antagonists], even though it markedly improves outcome and is Class I-recommended in the guidelines.

—Gregg Fonarow, MD, co-chief, University of California at Los Angeles division of cardiology, chair, American Heart Association’s Get With The Guidelines program steering committee

You might not have done a fellowship in cardiology, but quite often you probably feel like a cardiologist. Hospitalists frequently attend to patients on observation for heart problems and help manage even the most complex patients.

Often, you are working alongside the cardiologist. But other times, you’re on your own. Hospitalists are expected to carry an increasingly heavy load when it comes to heart-failure patients and many other kinds of patients with specialized disorders. It can be hard to keep up with what you need to know.

Top Twelve

1. Recognize the new importance of beta-blockers for heart failure, and go with the best of them.
2. It’s not readmissions that are the problem—it’s avoidable readmissions.
3. New interventional technologies will mean more complex patients, so be ready.
4. Aldosterone antagonists, though probably underutilized, can be very effective but require caution.
5. Switching from IV diuretics to an oral regimen calls for careful monitoring.
6. Patients with heart failure with preserved ejection fraction have outcomes over the longer haul similar to those with heart failure with reduced ejection fraction. And in preserved ejection fraction cases, the contributing illnesses must be addressed.
7. Inotropic agents can do more harm than good.
8. Pay attention to the ins and outs of new antiplatelet therapies.
9. Bridging anticoagulant therapy in patients going for electrophysiology procedures should be done only some, not most, of the time.
10. Some non-STEMI patients might benefit from getting to the catheterization lab quickly.
11. Beware the idiosyncrasies of new anticoagulants.
12. Be cognizant of stent thrombosis and how to manage it.

The Hospitalist spoke to several cardiologists about the latest in treatments, technologies, and HM’s role in the system of care. The following are their suggestions for what you really need to know about treating patients with heart conditions.

1) Recognize the new importance of beta-blockers for heart failure, and go with the best of them.

Angiotensin converting enzyme inhibitors and angiotensive receptor blockers have been part of the Centers for Medicare & Medicaid Services’ (CMS) core measures for heart failure for a long time, but beta-blockers at hospital discharge only recently have been added as American College of Cardiology/American Heart Association/American Medical Association–Physician Consortium for Performance Improvement measures for heart failure.¹

“For those with heart failure and reduced left ventricular ejection fraction, very old and outdated concepts would have talked about potentially holding the beta-blocker during hospitalization for heart failure—or not initiating until the patient was an outpatient,” says Gregg Fonarow, MD, co-chief of the University of California at Los Angeles’ division of cardiology and chair of the steering committee for the American Heart Association’s Get With The Guidelines program. “[But] the guidelines and evidence, and often performance measures, linked to them are now explicit about initiating or maintaining beta-blockers during the heart-failure hospitalization.”

Beta-blockers should be initiated as patients are stabilized before discharge. Dr. Fonarow suggests hospitalists use only one of the three evidence-based therapies: carvedilol, metoprolol succinate, or bisoprolol.

“Many physicians have been using metoprolol tartrate or atenolol in heart-failure patients,” Dr. Fonarow says. “These are not known to improve clinical outcomes. So here’s an example where the specific medication is absolutely, critically important.”

2) It’s not readmissions that are the problem—it’s avoidable readmissions.

“The modifier is very important,” says Clyde Yancy, MD, chief of the division of cardiology at the Northwestern University Feinberg School of Medicine in Chicago. “Heart failure continues to be a problematic disease. Many patients now do really well, but some do not. Those patients are symptomatic and may require frequent hospitalizations for stabilization. We should not disallow or misdirect those patients who need inpatient care from receiving such because of an arbitrary incentive to reduce rehospitalizations out of fear of punitive financial damages. The unforeseen risks here are real.”

Dr. Yancy says studies based on CMS data have found that institutions with higher readmission rates have lower 30-day mortality rates.² He cautions hospitalists to be “very thoughtful about an overzealous embrace of reducing all readmissions for heart failure.” Instead, the goal should be to limit the “avoidable readmissions.”

“And for the patient that clearly has advanced disease,” he says, “rather than triaging them away from the hospital, we really should be very respectful of their disease. Keep those patients where disease-modifying interventions can be deployed, and we can work to achieve the best possible outcome for those that have the most advanced disease.”

3) New interventional technologies will mean more complex patients, so be ready.

Advances in interventional procedures, including transcatheter aortic valve replacement (TAVR) and endoscopic mitral valve repair, will translate into a new population of highly complex patients. Many of these patients will be in their 80s or 90s.

“It’s a whole new paradigm shift of technology,” says John Harold, MD, president-elect of the American College of Cardiology and past chief of staff and department of medicine clinical chief of staff at Cedars-Sinai Medical Center in Los Angeles. “Very often, the hospitalist is at the front dealing with all of these issues.”

Many of these patients have other problems, including renal insufficiency, diabetes, and the like.

“They have all sorts of other things going on simultaneously, so very often the hospitalist becomes … the point person in dealing with all of these issues,” Dr. Harold says.

4) Aldosterone antagonists, though probably underutilized, can be very effective but require caution.

Aldosterone antagonists can greatly improve outcomes and reduce hospitalization in heart-failure patients, but they have to be used with very careful dosing and patient selection, Dr. Fonarow says. And they require early follow-up once patients are discharged.

“Only about a third of ideal candidates with heart failure are currently treated with this agent, even though it markedly improves outcome and is Class I-recommended in the guidelines,” Dr. Fonarow says. “But this is one where it needs to be started at appropriate low doses, with meticulous monitoring in both the inpatient and the outpatient setting, early follow-up, and early laboratory checks.”

5) Switching from IV diuretics to an oral regimen calls for careful monitoring.

Transitioning patients from IV diuretics to oral regimens is an area rife with mistakes, Dr. Fonarow says. It requires a lot of “meticulous attention to proper potassium supplementation and monitoring of renal function and electrolyte levels,” he says.

Medication reconciliation—“med rec”—is especially important during the transition from inpatient to outpatient.

“There are common medication errors that are made during this transition,” Dr. Fonarow says. “Hospitalists, along with other [care team] members, can really play a critically important role in trying to reduce that risk.”

6) Patients with heart failure with preserved ejection

fraction have outcomes over the longer haul similar to those with heart failure with reduced ejection fraction. And in preserved ejection fraction cases, the contributing illnesses must be addressed.

“We really can’t exercise a thought economy that just says, ‘Extrapolate the evidence-based therapies for heart failure with reduced ejection fraction to heart failure with preserved ejection fraction’ and expect good outcomes,” Dr. Yancy says. “That’s not the case. We don’t have an evidence base to substantiate that.”

He says one or more common comorbidities (e.g. atrial fibrillation, hypertension, obesity, diabetes, renal insufficiency) are present in 90% of patients with preserved ejection fraction. Treatment of those comorbidities—for example, rate control in afib patients, lowering the blood pressure in hypertension patients—has to be done with care.

“We should recognize that the therapy for this condition, albeit absent any specifically indicated interventions that will change its natural history, can still be skillfully constructed,” Dr. Yancy says. “But that construct needs to reflect the recommended, guideline-driven interventions for the concomitant other comorbidities.”

7) Inotropic agents can do more harm than good.

For patients who aren’t in cardiogenic shock, using inotropic agents doesn’t help. In fact, it might actually hurt. Dr. Fonarow says studies have shown these agents can “prolong length of stay, cause complications, and increase mortality risk.”

He notes that the use of inotropes should be avoided, or if it’s being considered, a cardiologist with knowledge and experience in heart failure should be involved in the treatment and care.

Statements about avoiding inotropes in heart failure, except under very specific circumstances, have been “incredibly strengthened” recently in the American College of Cardiology and Heart Failure Society of America guidelines.³

8) Pay attention to the ins and outs of new antiplatelet therapies.

For the majority of these, there’s no specific way to reverse the anticoagulant effect in the event of a major bleeding event. There’s no simple antidote.

—John Harold, MD, president-elect, American College of Cardiology, former chief of staff, department of medicine, Cedars-Sinai Medical Center, Los Angeles

Hospitalists caring for acute coronary syndrome patients need to familiarize themselves with updated guidelines and additional therapies that are now available, Dr. Fonarow says. New antiplatelet therapies (e.g. prasugrel and ticagrelor) are available as part of the armamentarium, along with the mainstay clopidogrel.

“These therapies lower the risk of recurrent events, lowered the risk of stent thrombosis,” he says. “In the case of ticagrelor, it actually lowered all-cause mortality. These are important new therapies, with new guideline recommendations, that all hospitalists should be aware of.”

9) Bridging anticoagulant therapy in patients going for electrophysiology procedures should be done only some, not most, of the time.

“Patients getting such devices as pacemakers or implantable cardioverter defribrillators (ICD) installed tend not to need bridging,” says Joaquin Cigarroa, MD, clinical chief of cardiology at Oregon Health & Science University in Portland.

He says it’s actually “safer” to do the procedure when patients “are on oral antithrombotics than switching them from an oral agent, and bridging with low- molecular-weight- or unfractionated heparin.”

“It’s a big deal,” Dr. Cigarroa adds, because it is risky to have elderly and frail patients on multiple antithrombotics. “Hemorrhagic complications in cardiology patients still occurs very frequently, so really be attuned to estimating bleeding risk and making sure that we’re dosing antithrombotics appropriately. Bridging should be the minority of patients, not the majority of patients.”

10) Some non-STEMI patients might benefit from getting to the catheterization lab quickly.

Door-to-balloon time is recognized as critical for ST-segment elevation myocardial infarction (STEMI) patients, but more recent work—such as in the TIMACS trial—finds benefits of early revascularization for some non-STEMI patients as well.²

“This trial showed that among higher-risk patients, using a validated risk score, that those patients did benefit from an early approach, meaning going to the cath lab in the first 12 hours of hospitalization,” Dr. Fonarow says. “We now have more information about the optimal timing of coronary angiography and potential revascularization of higher-risk patients with non-ST-segment elevation MI.”

11) Beware the idiosyncrasies of new anticoagulants.

The introduction of dabigatran and rivaroxaban (and, perhaps soon, apixaban) to the array of anticoagulant therapies brings a new slate of considerations for hospitalists, Dr. Harold says.

“For the majority of these, there’s no specific way to reverse the anticoagulant effect in the event of a major bleeding event,” he says. “There’s no simple antidote. And the effect can last up to 12 to 24 hours, depending on the renal function. This is what the hospitalist will be called to deal with: bleeding complications in patients who have these newer anticoagulants on board.”

Dr. Fonarow says that the new CHA2DS2-VASc score has been found to do a better job than the traditional CHADS2 score in assessing afib stroke risk.⁴

12) Be cognizant of stent thrombosis and how to manage it.

Dr. Harold says that most hospitalists probably are up to date on drug-eluting stents and the risk of stopping dual antiplatelet therapy within several months of implant, but that doesn’t mean they won’t treat patients whose primary-care physicians (PCPs) aren’t up to date. He recommends working on these cases with hematologists.

“That knowledge is not widespread in terms of the internal-medicine community,” he says. “I’ve seen situations where patients have had their Plavix stopped for colonoscopies and they’ve had stent thrombosis. It’s this knowledge of cardiac patients who come in with recent deployment of drug-eluting stents who may end up having other issues.”

Tom Collins is a freelance writer in South Florida.

References

1. 2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults. Circulation. 2009;119:1977-2016 an HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Cardiac Failure. 2010;16(6):475-539.
2. Gorodeski EZ, Starling RC, Blackstone EH. Are all readmissions bad readmissions? N Engl J Med. 2010;363:297-298.
3. Mehta SR, Granger CB, Boden WE, et al. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med. 2009;360(21):2165-2175.
4. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of the CHA2DS2-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort study. Thromb Haemost. 2012;107(6):1172-1179.
5. Associations between outpatient heart failure process-of-care measures and mortality. Circulation. 2011;123(15):1601-1610.

Only about a third of ideal candidates with heart failure are currently treated with [aldosterone antagonists], even though it markedly improves outcome and is Class I-recommended in the guidelines.

—Gregg Fonarow, MD, co-chief, University of California at Los Angeles division of cardiology, chair, American Heart Association’s Get With The Guidelines program steering committee

You might not have done a fellowship in cardiology, but quite often you probably feel like a cardiologist. Hospitalists frequently attend to patients on observation for heart problems and help manage even the most complex patients.

Often, you are working alongside the cardiologist. But other times, you’re on your own. Hospitalists are expected to carry an increasingly heavy load when it comes to heart-failure patients and many other kinds of patients with specialized disorders. It can be hard to keep up with what you need to know.

Top Twelve

1. Recognize the new importance of beta-blockers for heart failure, and go with the best of them.
2. It’s not readmissions that are the problem—it’s avoidable readmissions.
3. New interventional technologies will mean more complex patients, so be ready.
4. Aldosterone antagonists, though probably underutilized, can be very effective but require caution.
5. Switching from IV diuretics to an oral regimen calls for careful monitoring.
6. Patients with heart failure with preserved ejection fraction have outcomes over the longer haul similar to those with heart failure with reduced ejection fraction. And in preserved ejection fraction cases, the contributing illnesses must be addressed.
7. Inotropic agents can do more harm than good.
8. Pay attention to the ins and outs of new antiplatelet therapies.
9. Bridging anticoagulant therapy in patients going for electrophysiology procedures should be done only some, not most, of the time.
10. Some non-STEMI patients might benefit from getting to the catheterization lab quickly.
11. Beware the idiosyncrasies of new anticoagulants.
12. Be cognizant of stent thrombosis and how to manage it.

The Hospitalist spoke to several cardiologists about the latest in treatments, technologies, and HM’s role in the system of care. The following are their suggestions for what you really need to know about treating patients with heart conditions.

1) Recognize the new importance of beta-blockers for heart failure, and go with the best of them.

Angiotensin converting enzyme inhibitors and angiotensive receptor blockers have been part of the Centers for Medicare & Medicaid Services’ (CMS) core measures for heart failure for a long time, but beta-blockers at hospital discharge only recently have been added as American College of Cardiology/American Heart Association/American Medical Association–Physician Consortium for Performance Improvement measures for heart failure.¹

“For those with heart failure and reduced left ventricular ejection fraction, very old and outdated concepts would have talked about potentially holding the beta-blocker during hospitalization for heart failure—or not initiating until the patient was an outpatient,” says Gregg Fonarow, MD, co-chief of the University of California at Los Angeles’ division of cardiology and chair of the steering committee for the American Heart Association’s Get With The Guidelines program. “[But] the guidelines and evidence, and often performance measures, linked to them are now explicit about initiating or maintaining beta-blockers during the heart-failure hospitalization.”

Beta-blockers should be initiated as patients are stabilized before discharge. Dr. Fonarow suggests hospitalists use only one of the three evidence-based therapies: carvedilol, metoprolol succinate, or bisoprolol.

“Many physicians have been using metoprolol tartrate or atenolol in heart-failure patients,” Dr. Fonarow says. “These are not known to improve clinical outcomes. So here’s an example where the specific medication is absolutely, critically important.”

2) It’s not readmissions that are the problem—it’s avoidable readmissions.

“The modifier is very important,” says Clyde Yancy, MD, chief of the division of cardiology at the Northwestern University Feinberg School of Medicine in Chicago. “Heart failure continues to be a problematic disease. Many patients now do really well, but some do not. Those patients are symptomatic and may require frequent hospitalizations for stabilization. We should not disallow or misdirect those patients who need inpatient care from receiving such because of an arbitrary incentive to reduce rehospitalizations out of fear of punitive financial damages. The unforeseen risks here are real.”

Dr. Yancy says studies based on CMS data have found that institutions with higher readmission rates have lower 30-day mortality rates.² He cautions hospitalists to be “very thoughtful about an overzealous embrace of reducing all readmissions for heart failure.” Instead, the goal should be to limit the “avoidable readmissions.”

“And for the patient that clearly has advanced disease,” he says, “rather than triaging them away from the hospital, we really should be very respectful of their disease. Keep those patients where disease-modifying interventions can be deployed, and we can work to achieve the best possible outcome for those that have the most advanced disease.”

3) New interventional technologies will mean more complex patients, so be ready.

Advances in interventional procedures, including transcatheter aortic valve replacement (TAVR) and endoscopic mitral valve repair, will translate into a new population of highly complex patients. Many of these patients will be in their 80s or 90s.

“It’s a whole new paradigm shift of technology,” says John Harold, MD, president-elect of the American College of Cardiology and past chief of staff and department of medicine clinical chief of staff at Cedars-Sinai Medical Center in Los Angeles. “Very often, the hospitalist is at the front dealing with all of these issues.”

Many of these patients have other problems, including renal insufficiency, diabetes, and the like.

“They have all sorts of other things going on simultaneously, so very often the hospitalist becomes … the point person in dealing with all of these issues,” Dr. Harold says.

4) Aldosterone antagonists, though probably underutilized, can be very effective but require caution.

Aldosterone antagonists can greatly improve outcomes and reduce hospitalization in heart-failure patients, but they have to be used with very careful dosing and patient selection, Dr. Fonarow says. And they require early follow-up once patients are discharged.

“Only about a third of ideal candidates with heart failure are currently treated with this agent, even though it markedly improves outcome and is Class I-recommended in the guidelines,” Dr. Fonarow says. “But this is one where it needs to be started at appropriate low doses, with meticulous monitoring in both the inpatient and the outpatient setting, early follow-up, and early laboratory checks.”

5) Switching from IV diuretics to an oral regimen calls for careful monitoring.

Transitioning patients from IV diuretics to oral regimens is an area rife with mistakes, Dr. Fonarow says. It requires a lot of “meticulous attention to proper potassium supplementation and monitoring of renal function and electrolyte levels,” he says.

Medication reconciliation—“med rec”—is especially important during the transition from inpatient to outpatient.

“There are common medication errors that are made during this transition,” Dr. Fonarow says. “Hospitalists, along with other [care team] members, can really play a critically important role in trying to reduce that risk.”

6) Patients with heart failure with preserved ejection

fraction have outcomes over the longer haul similar to those with heart failure with reduced ejection fraction. And in preserved ejection fraction cases, the contributing illnesses must be addressed.

“We really can’t exercise a thought economy that just says, ‘Extrapolate the evidence-based therapies for heart failure with reduced ejection fraction to heart failure with preserved ejection fraction’ and expect good outcomes,” Dr. Yancy says. “That’s not the case. We don’t have an evidence base to substantiate that.”

He says one or more common comorbidities (e.g. atrial fibrillation, hypertension, obesity, diabetes, renal insufficiency) are present in 90% of patients with preserved ejection fraction. Treatment of those comorbidities—for example, rate control in afib patients, lowering the blood pressure in hypertension patients—has to be done with care.

“We should recognize that the therapy for this condition, albeit absent any specifically indicated interventions that will change its natural history, can still be skillfully constructed,” Dr. Yancy says. “But that construct needs to reflect the recommended, guideline-driven interventions for the concomitant other comorbidities.”

7) Inotropic agents can do more harm than good.

For patients who aren’t in cardiogenic shock, using inotropic agents doesn’t help. In fact, it might actually hurt. Dr. Fonarow says studies have shown these agents can “prolong length of stay, cause complications, and increase mortality risk.”

He notes that the use of inotropes should be avoided, or if it’s being considered, a cardiologist with knowledge and experience in heart failure should be involved in the treatment and care.

Statements about avoiding inotropes in heart failure, except under very specific circumstances, have been “incredibly strengthened” recently in the American College of Cardiology and Heart Failure Society of America guidelines.³

8) Pay attention to the ins and outs of new antiplatelet therapies.

For the majority of these, there’s no specific way to reverse the anticoagulant effect in the event of a major bleeding event. There’s no simple antidote.

—John Harold, MD, president-elect, American College of Cardiology, former chief of staff, department of medicine, Cedars-Sinai Medical Center, Los Angeles

Hospitalists caring for acute coronary syndrome patients need to familiarize themselves with updated guidelines and additional therapies that are now available, Dr. Fonarow says. New antiplatelet therapies (e.g. prasugrel and ticagrelor) are available as part of the armamentarium, along with the mainstay clopidogrel.

“These therapies lower the risk of recurrent events, lowered the risk of stent thrombosis,” he says. “In the case of ticagrelor, it actually lowered all-cause mortality. These are important new therapies, with new guideline recommendations, that all hospitalists should be aware of.”

9) Bridging anticoagulant therapy in patients going for electrophysiology procedures should be done only some, not most, of the time.

“Patients getting such devices as pacemakers or implantable cardioverter defribrillators (ICD) installed tend not to need bridging,” says Joaquin Cigarroa, MD, clinical chief of cardiology at Oregon Health & Science University in Portland.

He says it’s actually “safer” to do the procedure when patients “are on oral antithrombotics than switching them from an oral agent, and bridging with low- molecular-weight- or unfractionated heparin.”

“It’s a big deal,” Dr. Cigarroa adds, because it is risky to have elderly and frail patients on multiple antithrombotics. “Hemorrhagic complications in cardiology patients still occurs very frequently, so really be attuned to estimating bleeding risk and making sure that we’re dosing antithrombotics appropriately. Bridging should be the minority of patients, not the majority of patients.”

10) Some non-STEMI patients might benefit from getting to the catheterization lab quickly.

Door-to-balloon time is recognized as critical for ST-segment elevation myocardial infarction (STEMI) patients, but more recent work—such as in the TIMACS trial—finds benefits of early revascularization for some non-STEMI patients as well.²

“This trial showed that among higher-risk patients, using a validated risk score, that those patients did benefit from an early approach, meaning going to the cath lab in the first 12 hours of hospitalization,” Dr. Fonarow says. “We now have more information about the optimal timing of coronary angiography and potential revascularization of higher-risk patients with non-ST-segment elevation MI.”

11) Beware the idiosyncrasies of new anticoagulants.

The introduction of dabigatran and rivaroxaban (and, perhaps soon, apixaban) to the array of anticoagulant therapies brings a new slate of considerations for hospitalists, Dr. Harold says.

“For the majority of these, there’s no specific way to reverse the anticoagulant effect in the event of a major bleeding event,” he says. “There’s no simple antidote. And the effect can last up to 12 to 24 hours, depending on the renal function. This is what the hospitalist will be called to deal with: bleeding complications in patients who have these newer anticoagulants on board.”

Dr. Fonarow says that the new CHA2DS2-VASc score has been found to do a better job than the traditional CHADS2 score in assessing afib stroke risk.⁴

12) Be cognizant of stent thrombosis and how to manage it.

Dr. Harold says that most hospitalists probably are up to date on drug-eluting stents and the risk of stopping dual antiplatelet therapy within several months of implant, but that doesn’t mean they won’t treat patients whose primary-care physicians (PCPs) aren’t up to date. He recommends working on these cases with hematologists.

“That knowledge is not widespread in terms of the internal-medicine community,” he says. “I’ve seen situations where patients have had their Plavix stopped for colonoscopies and they’ve had stent thrombosis. It’s this knowledge of cardiac patients who come in with recent deployment of drug-eluting stents who may end up having other issues.”

Tom Collins is a freelance writer in South Florida.

References

1. 2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults. Circulation. 2009;119:1977-2016 an HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Cardiac Failure. 2010;16(6):475-539.
2. Gorodeski EZ, Starling RC, Blackstone EH. Are all readmissions bad readmissions? N Engl J Med. 2010;363:297-298.
3. Mehta SR, Granger CB, Boden WE, et al. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med. 2009;360(21):2165-2175.
4. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of the CHA2DS2-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort study. Thromb Haemost. 2012;107(6):1172-1179.
5. Associations between outpatient heart failure process-of-care measures and mortality. Circulation. 2011;123(15):1601-1610.

When heart-failure patients have follow-up appointments with their outpatient doctors, outcomes are good, Dr. Fonarow says. However, they are not done nearly enough.

“Early follow-up is essential,” he says. “Follow-up within seven days—in higher-risk patients, even earlier, within three days—is something that has been associated with a lower risk of rehospitalization.”

Despite the research, only about 30% to 40% of patients hospitalized with heart failure are seen by any outpatient provider in the first week post-discharge.

“We have a real opportunity there,” Dr. Fonarow says. “The inpatient physicians can play a really critical role in ensuring that there’s early and appropriate follow-up, and good communication and handoff to the outpatient physician.”

When heart-failure patients have follow-up appointments with their outpatient doctors, outcomes are good, Dr. Fonarow says. However, they are not done nearly enough.

“Early follow-up is essential,” he says. “Follow-up within seven days—in higher-risk patients, even earlier, within three days—is something that has been associated with a lower risk of rehospitalization.”

Despite the research, only about 30% to 40% of patients hospitalized with heart failure are seen by any outpatient provider in the first week post-discharge.

“We have a real opportunity there,” Dr. Fonarow says. “The inpatient physicians can play a really critical role in ensuring that there’s early and appropriate follow-up, and good communication and handoff to the outpatient physician.”

When heart-failure patients have follow-up appointments with their outpatient doctors, outcomes are good, Dr. Fonarow says. However, they are not done nearly enough.

“Early follow-up is essential,” he says. “Follow-up within seven days—in higher-risk patients, even earlier, within three days—is something that has been associated with a lower risk of rehospitalization.”

Despite the research, only about 30% to 40% of patients hospitalized with heart failure are seen by any outpatient provider in the first week post-discharge.

“We have a real opportunity there,” Dr. Fonarow says. “The inpatient physicians can play a really critical role in ensuring that there’s early and appropriate follow-up, and good communication and handoff to the outpatient physician.”

Larry Wellikson, MD, SFHM

I needed an oil change, so I took my car to Jiffy Lube. I had just pulled into the entrance to one of the service bays when a smiling man whose nametag read “Tony” approached me. “Welcome back, Mr. Wellikson. What can we help you with today?” Well, that was nice and so unexpected, as I had not remembered ever going to that Jiffy Lube. As it turns out, they have a video camera that shows incoming cars in their control room. They can read my license plate and call up my car on their computer system, access my record, and create a personal greeting. They also used my car’s past history as a starting point for this encounter. We were off to a good start.

Once I indicated I just wanted a routine oil change, Tony indicated he would be back in five to 10 minutes. He told me I should wait in the waiting room where they had wireless Internet, TV, magazines, and comfortable chairs.

In less than 10 minutes, Tony was back, clipboard in hand, with an assessment of my car’s status, including previous work and manufacturer’s recommendations, based on my car’s age and mileage. Once we negotiated not replacing all of the fluids and filters, Tony smiled and said the work should be completed in 10 minutes.

Soon, Tony came back to lead me out to my car, which had been wheeled out to the front of the garage bay with an open driver’s door waiting for me. After helping me into my seat, Tony came around and sat in the passenger seat and, once again with his ready clipboard, walked me through the 29 steps of inspections and fluid changes that had been made on my visit, reviewed the frequency of future needs for my vehicle, put a sticker on my inside windshield as a reminder, included $5 off for my next service, then patiently asked me if I had any questions.

Total time at Jiffy Lube: less than 30 minutes. Total cost: $29.99. Total customer experience: exceptional. Considering it was the third Jiffy Lube location I had used in the past three years, I can tell you the experience and system is the same throughout the company, whether the uniform name is Tony or Jose or Gladys.

Can such experiences offer hospitalists lessons about how we manage the customer experience in hospital care?

Scalable Innovation

In August 2012, Atul Gawande, MD, wrote a thought-provoking article in The New Yorker in which he coupled his detailed observation of how the restaurant chain The Cheesecake Factory manages to deliver 8 million meals annually nationwide with high quality at a reasonable cost and strong corporate profits with the emerging trend of healthcare delivery innovations being sought by large hospital chains and such innovations as ICU telemedicine.¹

He noted that, according to the Bureau of Labor Statistics, less than 25% of physicians are currently self-employed, and the growing trend is hospitals being acquired or merged into larger and larger hospital chains. He observed that recent and future financial changes are moving toward payment for results and efficiencies and further away from just rewarding transactions and supplying services, whether of measureable value or with proven results. Cheesecake Factory has built its success on large-scale production-line processes that produce consistent results across hundreds of locations and millions of meals. It may now be time for healthcare, especially hospital care, to come into the 21st century, too.

How did Cheesecake Factory get to where they are? They studied what the best people were doing, figured out a way to standardize it, then looked for ways to bring it to everyone. Although we could look at research as medicine’s way of bringing new concepts forward, where we have fallen down as an industry and culture is our ability to deliver on this at the bedside. Why aren’t most myocardial infarction patients on beta-blockers? Why isn’t DVT prophylaxis universal? Why can’t we all wash our hands on a regular basis?

Medical care, especially the physician portion, has always placed an overwhelming bias on autonomy. We all know that even at the same hospital or within the same physician group of cardiologists or orthopedists (or even hospitalists) that there can be multiple ways to treat chest pain, replace a joint, or manage pneumonia. Dr. Gawande postulates that “customization should be 5%, not 95%, of what we do.” He is not suggesting cookbook medicine—rather, that we bring all of the current proven and consensus medical knowledge together and allow local professionals to agree to narrow their choices down to a consistent and reproducible process for managing care.

Hoag, a health network near my home in Orange County, Calif., has brought this approach to orthopedic care. Hoag purchased a smaller hospital near its main campus and is emphasizing state-of-the-art orthopedic care at the new facility. They aligned the incentives—clinically and financially—with a large but select group of orthopedists, and they have chosen just a few prosthetic choices for hip and knee replacements. They have narrowed their protocols for pre- and post-op care, and now do same-day joint replacements with lower complication rates and better return-to-activity results at lower costs. And trust me, the orthopedists at Hoag were as independent as any physicians you might run into. The demands of the new payor models and competition to provide consumers (i.e. patients) with a 21st-century experience pushed, pulled, and prodded these orthopedists, and an enlightened hospital leadership, to rise to the challenges.

HM Takeaway

So where do hospitalists fit into this emerging world of customer service, standardization, accountability for results, and payment change? As you might imagine, we are right in the middle of all of this. High-functioning HM groups have understood that we must help shape a better system for us to work in. We cannot perpetuate the old paradigm in which the hospital was simply a swap meet where each physician had a booth and performed a procedure with little regard to how efficient or effective the entire enterprise might be.

Hospitalists have always performed in a group setting and worked across the professional disciplines of medicine, surgery, and subspecialties, and with nurses, pharmacists, and therapists. In the best of breed, hospitalists are enculturated to think systemwide yet deliver to an individual patient.

As hospital chains look to standardize and deliver the best results and the most efficient use of resources, hospitalists can be positioned in a variety of ways. You can be an innovative partner, working with other professionals and the administration to seek new ways of doing things. You can be the manager or coordinator of other professionals and the rest of the team. But you also could evolve to be line workers and cogs in a larger machine, replaceable and commoditized. In the end, hospitalists will not only need to create value, but also position themselves to be professionally rewarded and respected for the value they create.

Dr. Gawande considers the perspectives of healthcare providers and patients as he looks to the future. “Patients won’t just look for the best specialist anymore; they’ll look for the best system,” he says. “Nurses and doctors will have to get used to delivering care in which our own convenience counts for less and the patients’ experience counts for more.”

The changes ahead will be rapid and disruptive; some hospitals will be driven out of business, while some will be consolidated. Physicians will aggregate and become employees (although many will still think they are free agents). Standardization will be pushed, and customization and one-offs will be tolerated less and less.

In this new world, hospitalists have the opportunity to be at the leading edge, not just for other physicians but the entire healthcare team. We need to prepare for this challenge, not just with clinical skills, but with a culture and a mindset to adapt and evolve. We need to decide if we will be cogs in a machine or the innovators and managers of change. The time is now; the choice is ours.

Dr. Wellikson is CEO of SHM.

Reference

1. Gawande A. The New Yorker. “Big Med.” The New Yorker website. Available at: http://www.newyorker.com/reporting/2012/08/13/120813fa_fact_gawande. Accessed Aug. 20, 2012.

Larry Wellikson, MD, SFHM

I needed an oil change, so I took my car to Jiffy Lube. I had just pulled into the entrance to one of the service bays when a smiling man whose nametag read “Tony” approached me. “Welcome back, Mr. Wellikson. What can we help you with today?” Well, that was nice and so unexpected, as I had not remembered ever going to that Jiffy Lube. As it turns out, they have a video camera that shows incoming cars in their control room. They can read my license plate and call up my car on their computer system, access my record, and create a personal greeting. They also used my car’s past history as a starting point for this encounter. We were off to a good start.

Once I indicated I just wanted a routine oil change, Tony indicated he would be back in five to 10 minutes. He told me I should wait in the waiting room where they had wireless Internet, TV, magazines, and comfortable chairs.

In less than 10 minutes, Tony was back, clipboard in hand, with an assessment of my car’s status, including previous work and manufacturer’s recommendations, based on my car’s age and mileage. Once we negotiated not replacing all of the fluids and filters, Tony smiled and said the work should be completed in 10 minutes.

Soon, Tony came back to lead me out to my car, which had been wheeled out to the front of the garage bay with an open driver’s door waiting for me. After helping me into my seat, Tony came around and sat in the passenger seat and, once again with his ready clipboard, walked me through the 29 steps of inspections and fluid changes that had been made on my visit, reviewed the frequency of future needs for my vehicle, put a sticker on my inside windshield as a reminder, included $5 off for my next service, then patiently asked me if I had any questions.

Total time at Jiffy Lube: less than 30 minutes. Total cost: $29.99. Total customer experience: exceptional. Considering it was the third Jiffy Lube location I had used in the past three years, I can tell you the experience and system is the same throughout the company, whether the uniform name is Tony or Jose or Gladys.

Can such experiences offer hospitalists lessons about how we manage the customer experience in hospital care?

Scalable Innovation

In August 2012, Atul Gawande, MD, wrote a thought-provoking article in The New Yorker in which he coupled his detailed observation of how the restaurant chain The Cheesecake Factory manages to deliver 8 million meals annually nationwide with high quality at a reasonable cost and strong corporate profits with the emerging trend of healthcare delivery innovations being sought by large hospital chains and such innovations as ICU telemedicine.¹

He noted that, according to the Bureau of Labor Statistics, less than 25% of physicians are currently self-employed, and the growing trend is hospitals being acquired or merged into larger and larger hospital chains. He observed that recent and future financial changes are moving toward payment for results and efficiencies and further away from just rewarding transactions and supplying services, whether of measureable value or with proven results. Cheesecake Factory has built its success on large-scale production-line processes that produce consistent results across hundreds of locations and millions of meals. It may now be time for healthcare, especially hospital care, to come into the 21st century, too.

How did Cheesecake Factory get to where they are? They studied what the best people were doing, figured out a way to standardize it, then looked for ways to bring it to everyone. Although we could look at research as medicine’s way of bringing new concepts forward, where we have fallen down as an industry and culture is our ability to deliver on this at the bedside. Why aren’t most myocardial infarction patients on beta-blockers? Why isn’t DVT prophylaxis universal? Why can’t we all wash our hands on a regular basis?

Medical care, especially the physician portion, has always placed an overwhelming bias on autonomy. We all know that even at the same hospital or within the same physician group of cardiologists or orthopedists (or even hospitalists) that there can be multiple ways to treat chest pain, replace a joint, or manage pneumonia. Dr. Gawande postulates that “customization should be 5%, not 95%, of what we do.” He is not suggesting cookbook medicine—rather, that we bring all of the current proven and consensus medical knowledge together and allow local professionals to agree to narrow their choices down to a consistent and reproducible process for managing care.

Hoag, a health network near my home in Orange County, Calif., has brought this approach to orthopedic care. Hoag purchased a smaller hospital near its main campus and is emphasizing state-of-the-art orthopedic care at the new facility. They aligned the incentives—clinically and financially—with a large but select group of orthopedists, and they have chosen just a few prosthetic choices for hip and knee replacements. They have narrowed their protocols for pre- and post-op care, and now do same-day joint replacements with lower complication rates and better return-to-activity results at lower costs. And trust me, the orthopedists at Hoag were as independent as any physicians you might run into. The demands of the new payor models and competition to provide consumers (i.e. patients) with a 21st-century experience pushed, pulled, and prodded these orthopedists, and an enlightened hospital leadership, to rise to the challenges.

HM Takeaway

So where do hospitalists fit into this emerging world of customer service, standardization, accountability for results, and payment change? As you might imagine, we are right in the middle of all of this. High-functioning HM groups have understood that we must help shape a better system for us to work in. We cannot perpetuate the old paradigm in which the hospital was simply a swap meet where each physician had a booth and performed a procedure with little regard to how efficient or effective the entire enterprise might be.

Hospitalists have always performed in a group setting and worked across the professional disciplines of medicine, surgery, and subspecialties, and with nurses, pharmacists, and therapists. In the best of breed, hospitalists are enculturated to think systemwide yet deliver to an individual patient.

As hospital chains look to standardize and deliver the best results and the most efficient use of resources, hospitalists can be positioned in a variety of ways. You can be an innovative partner, working with other professionals and the administration to seek new ways of doing things. You can be the manager or coordinator of other professionals and the rest of the team. But you also could evolve to be line workers and cogs in a larger machine, replaceable and commoditized. In the end, hospitalists will not only need to create value, but also position themselves to be professionally rewarded and respected for the value they create.

Dr. Gawande considers the perspectives of healthcare providers and patients as he looks to the future. “Patients won’t just look for the best specialist anymore; they’ll look for the best system,” he says. “Nurses and doctors will have to get used to delivering care in which our own convenience counts for less and the patients’ experience counts for more.”

The changes ahead will be rapid and disruptive; some hospitals will be driven out of business, while some will be consolidated. Physicians will aggregate and become employees (although many will still think they are free agents). Standardization will be pushed, and customization and one-offs will be tolerated less and less.

In this new world, hospitalists have the opportunity to be at the leading edge, not just for other physicians but the entire healthcare team. We need to prepare for this challenge, not just with clinical skills, but with a culture and a mindset to adapt and evolve. We need to decide if we will be cogs in a machine or the innovators and managers of change. The time is now; the choice is ours.

Dr. Wellikson is CEO of SHM.

Reference

1. Gawande A. The New Yorker. “Big Med.” The New Yorker website. Available at: http://www.newyorker.com/reporting/2012/08/13/120813fa_fact_gawande. Accessed Aug. 20, 2012.

Larry Wellikson, MD, SFHM

I needed an oil change, so I took my car to Jiffy Lube. I had just pulled into the entrance to one of the service bays when a smiling man whose nametag read “Tony” approached me. “Welcome back, Mr. Wellikson. What can we help you with today?” Well, that was nice and so unexpected, as I had not remembered ever going to that Jiffy Lube. As it turns out, they have a video camera that shows incoming cars in their control room. They can read my license plate and call up my car on their computer system, access my record, and create a personal greeting. They also used my car’s past history as a starting point for this encounter. We were off to a good start.

Once I indicated I just wanted a routine oil change, Tony indicated he would be back in five to 10 minutes. He told me I should wait in the waiting room where they had wireless Internet, TV, magazines, and comfortable chairs.

In less than 10 minutes, Tony was back, clipboard in hand, with an assessment of my car’s status, including previous work and manufacturer’s recommendations, based on my car’s age and mileage. Once we negotiated not replacing all of the fluids and filters, Tony smiled and said the work should be completed in 10 minutes.

Soon, Tony came back to lead me out to my car, which had been wheeled out to the front of the garage bay with an open driver’s door waiting for me. After helping me into my seat, Tony came around and sat in the passenger seat and, once again with his ready clipboard, walked me through the 29 steps of inspections and fluid changes that had been made on my visit, reviewed the frequency of future needs for my vehicle, put a sticker on my inside windshield as a reminder, included $5 off for my next service, then patiently asked me if I had any questions.

Total time at Jiffy Lube: less than 30 minutes. Total cost: $29.99. Total customer experience: exceptional. Considering it was the third Jiffy Lube location I had used in the past three years, I can tell you the experience and system is the same throughout the company, whether the uniform name is Tony or Jose or Gladys.

Can such experiences offer hospitalists lessons about how we manage the customer experience in hospital care?

Scalable Innovation

In August 2012, Atul Gawande, MD, wrote a thought-provoking article in The New Yorker in which he coupled his detailed observation of how the restaurant chain The Cheesecake Factory manages to deliver 8 million meals annually nationwide with high quality at a reasonable cost and strong corporate profits with the emerging trend of healthcare delivery innovations being sought by large hospital chains and such innovations as ICU telemedicine.¹

He noted that, according to the Bureau of Labor Statistics, less than 25% of physicians are currently self-employed, and the growing trend is hospitals being acquired or merged into larger and larger hospital chains. He observed that recent and future financial changes are moving toward payment for results and efficiencies and further away from just rewarding transactions and supplying services, whether of measureable value or with proven results. Cheesecake Factory has built its success on large-scale production-line processes that produce consistent results across hundreds of locations and millions of meals. It may now be time for healthcare, especially hospital care, to come into the 21st century, too.

How did Cheesecake Factory get to where they are? They studied what the best people were doing, figured out a way to standardize it, then looked for ways to bring it to everyone. Although we could look at research as medicine’s way of bringing new concepts forward, where we have fallen down as an industry and culture is our ability to deliver on this at the bedside. Why aren’t most myocardial infarction patients on beta-blockers? Why isn’t DVT prophylaxis universal? Why can’t we all wash our hands on a regular basis?

Medical care, especially the physician portion, has always placed an overwhelming bias on autonomy. We all know that even at the same hospital or within the same physician group of cardiologists or orthopedists (or even hospitalists) that there can be multiple ways to treat chest pain, replace a joint, or manage pneumonia. Dr. Gawande postulates that “customization should be 5%, not 95%, of what we do.” He is not suggesting cookbook medicine—rather, that we bring all of the current proven and consensus medical knowledge together and allow local professionals to agree to narrow their choices down to a consistent and reproducible process for managing care.

Hoag, a health network near my home in Orange County, Calif., has brought this approach to orthopedic care. Hoag purchased a smaller hospital near its main campus and is emphasizing state-of-the-art orthopedic care at the new facility. They aligned the incentives—clinically and financially—with a large but select group of orthopedists, and they have chosen just a few prosthetic choices for hip and knee replacements. They have narrowed their protocols for pre- and post-op care, and now do same-day joint replacements with lower complication rates and better return-to-activity results at lower costs. And trust me, the orthopedists at Hoag were as independent as any physicians you might run into. The demands of the new payor models and competition to provide consumers (i.e. patients) with a 21st-century experience pushed, pulled, and prodded these orthopedists, and an enlightened hospital leadership, to rise to the challenges.

HM Takeaway

So where do hospitalists fit into this emerging world of customer service, standardization, accountability for results, and payment change? As you might imagine, we are right in the middle of all of this. High-functioning HM groups have understood that we must help shape a better system for us to work in. We cannot perpetuate the old paradigm in which the hospital was simply a swap meet where each physician had a booth and performed a procedure with little regard to how efficient or effective the entire enterprise might be.

Hospitalists have always performed in a group setting and worked across the professional disciplines of medicine, surgery, and subspecialties, and with nurses, pharmacists, and therapists. In the best of breed, hospitalists are enculturated to think systemwide yet deliver to an individual patient.

As hospital chains look to standardize and deliver the best results and the most efficient use of resources, hospitalists can be positioned in a variety of ways. You can be an innovative partner, working with other professionals and the administration to seek new ways of doing things. You can be the manager or coordinator of other professionals and the rest of the team. But you also could evolve to be line workers and cogs in a larger machine, replaceable and commoditized. In the end, hospitalists will not only need to create value, but also position themselves to be professionally rewarded and respected for the value they create.

Dr. Gawande considers the perspectives of healthcare providers and patients as he looks to the future. “Patients won’t just look for the best specialist anymore; they’ll look for the best system,” he says. “Nurses and doctors will have to get used to delivering care in which our own convenience counts for less and the patients’ experience counts for more.”

The changes ahead will be rapid and disruptive; some hospitals will be driven out of business, while some will be consolidated. Physicians will aggregate and become employees (although many will still think they are free agents). Standardization will be pushed, and customization and one-offs will be tolerated less and less.

In this new world, hospitalists have the opportunity to be at the leading edge, not just for other physicians but the entire healthcare team. We need to prepare for this challenge, not just with clinical skills, but with a culture and a mindset to adapt and evolve. We need to decide if we will be cogs in a machine or the innovators and managers of change. The time is now; the choice is ours.

Dr. Wellikson is CEO of SHM.

Reference

1. Gawande A. The New Yorker. “Big Med.” The New Yorker website. Available at: http://www.newyorker.com/reporting/2012/08/13/120813fa_fact_gawande. Accessed Aug. 20, 2012.

Danielle Scheurer, MD, MSCR, SFHM

This is a tumultuous time in healthcare: regulatory burdens, payment reductions, public scrutiny. And the rapidity of change is mind-boggling. All of this would probably be fine, except that people generally resist change, especially rapid change. Here today, gone tomorrow. That usually does not go over very well.

But given that this is the state of affairs for the foreseeable future, the question is, why is change so hard, and what can we do make it easier?

I thought about this at church the other day. My family and I attend church weekly (except when we don’t) at a small, old, quaint Catholic church built in 1789. My husband and I were raised Catholic, but as you may know, not every Catholic is really a Catholic. Based on my childhood churchgoing routine, my family would best be described as “Creasters,” which are “Catholics” (in quotations on purpose) who dedicate most of their religious energy to showing up only on Christmas and Easter. We are also known as “diet Catholics” or “lite Catholics.” Although I can plow through the “Our Father” with ease and grace, the Lord’s Prayer usually results in some mumbling, hushed tones and ceiling-staring.

My husband, on the other hand, was raised a real Catholic. He went to Catholic grade school, received communion six days a week, routinely served as an altar boy, and only missed Sunday Mass for a fever of more than 101 degrees (and even that was a stretch). For years, I have looked to him for cues on when to sit, stand, kneel, talk, sing, and be silent. When Sunday school questions come to the dinner table by way of our 8-year-old, I generally feign a choking episode and defer to my husband.

So this has been our routine for more than a decade: he the leader and I the limper. But then something shocking happened several months ago. In the middle of Mass, I realized my husband had no idea what was going on. He fumbled awkwardly through the service, lowered his speech volume with each passing misstep, and was almost completely silent by the end of the service.

As it ends up, every couple of hundred years, the Catholic Church decides to shake things up and change the Mass around. During key repeatings, the words are now different. What used to be “and also with you” is now “and with your spirit.” These changes were not monumental and went relatively unnoticed by current or former Creasters, but they were mind-boggling for the real Catholics.

The Church must have anticipated that these changes would be difficult to assimilate, as they placed countless numbers of laminated cue cards all over the church, in every pew, the confessional stand, and at all entry and exit points. Undoubtedly, they were hoping (assuming) we would take them home and learn the changes on our own, outside of Mass. So some months passed by, and after a few weeks with a cue card, I was in pretty good shape. My brain rewired the sayings, and I was able to shed my cue-card crutch.

My husband, on the other hand, is still reaching for the cue cards, with a long-standing dependence that now resembles that of an addict. Occasionally feeling confident, he will lay the card down, and will start spewing out the old sayings from a short circuit in the amygdala, programmed in fifth grade and hard-wired for accuracy. Then he will regain consciousness and realize everyone is staring at him.

As hospitalists, we know how hard it is to change, but we also know we have to routinely change to keep pace with the industry. So how do we reconcile the differences?

I recently read the book “Switch,” which describes some techniques on how to change when change is hard.¹ The authors write about a rider, an elephant, and a path. If all three are aligned toward a change, it will most likely succeed; without all three, change will be very difficult or unsuccessful altogether.

The rider is the intellectual portion, which will find the rational, statistical, logical solution to get from point A to point B. But the rider is steering an elephant, which is bulky, unruly, and emotional. The rider has to figure out how to motivate and direct the elephant; the two of them then have to get down a common path, which could be winding, confusing, and full of roadblocks. So to overcome all of these, the book gives innumerable, tangible examples of how to maneuver all three of these to facilitate change. In the case of my husband’s Mass issue, a few things could have facilitated the change for many:

Direct the rider:

• Find the bright spots. Find a success story of how others quickly relearned Mass within weeks and see how they accomplished it.
• Script the critical moves. Be very precise about what needs to be done differently; don’t just tell people to “learn the Mass,” but instead tell them to “repeat three new lines every day in the shower” until they have an error-free Mass.
• Point to the destination. Be very specific about the future goal, such as “You will be cue-card-free by October.”

Motivate the elephant:

• Find the feeling. Find a “heavy” emotion that will motivate the change. Shame, embarrassment, or anger from being stared at by a 10-year-old after missing so many lines should be pretty effective.
• Shrink the change. Make it seem like all the lines are easy to learn, if learned only one at a time.
• Grow the person. Motivate the Catholic to learn it as quickly and seamlessly as they did in fifth grade; if you already did it once, you just have do it again!

Shape the path:

• Tweak the environment. Have cue cards all over the place, laminate them, make them easy to fit in a pocket or purse.
• Build habits. Have the Catholic go to church every week until they have an “error-free” Mass.
• Rally the herd. Have them watch others for cues on behavior; this has worked for me for decades!

You can see that many of these techniques should be easier in healthcare than in other industries, especially motivating the elephant and shaping the path. To facilitate change, hospitalists should find ways to direct the rider, motivate the elephant, and shape the path, and we may find that change is not as daunting and overwhelming as it might at first seem.

And when you finally do make a positive change happen, give yourself a high-five—and send a “Hail Mary” to the Creasters.

Dr. Scheurer is physician editor of The Hospitalist.

Reference

1. Heath C, Heath D. Switch: How to Change Things when Change is Hard. New York: Random House; 2010.

Danielle Scheurer, MD, MSCR, SFHM

This is a tumultuous time in healthcare: regulatory burdens, payment reductions, public scrutiny. And the rapidity of change is mind-boggling. All of this would probably be fine, except that people generally resist change, especially rapid change. Here today, gone tomorrow. That usually does not go over very well.

But given that this is the state of affairs for the foreseeable future, the question is, why is change so hard, and what can we do make it easier?

I thought about this at church the other day. My family and I attend church weekly (except when we don’t) at a small, old, quaint Catholic church built in 1789. My husband and I were raised Catholic, but as you may know, not every Catholic is really a Catholic. Based on my childhood churchgoing routine, my family would best be described as “Creasters,” which are “Catholics” (in quotations on purpose) who dedicate most of their religious energy to showing up only on Christmas and Easter. We are also known as “diet Catholics” or “lite Catholics.” Although I can plow through the “Our Father” with ease and grace, the Lord’s Prayer usually results in some mumbling, hushed tones and ceiling-staring.

My husband, on the other hand, was raised a real Catholic. He went to Catholic grade school, received communion six days a week, routinely served as an altar boy, and only missed Sunday Mass for a fever of more than 101 degrees (and even that was a stretch). For years, I have looked to him for cues on when to sit, stand, kneel, talk, sing, and be silent. When Sunday school questions come to the dinner table by way of our 8-year-old, I generally feign a choking episode and defer to my husband.

So this has been our routine for more than a decade: he the leader and I the limper. But then something shocking happened several months ago. In the middle of Mass, I realized my husband had no idea what was going on. He fumbled awkwardly through the service, lowered his speech volume with each passing misstep, and was almost completely silent by the end of the service.

As it ends up, every couple of hundred years, the Catholic Church decides to shake things up and change the Mass around. During key repeatings, the words are now different. What used to be “and also with you” is now “and with your spirit.” These changes were not monumental and went relatively unnoticed by current or former Creasters, but they were mind-boggling for the real Catholics.

The Church must have anticipated that these changes would be difficult to assimilate, as they placed countless numbers of laminated cue cards all over the church, in every pew, the confessional stand, and at all entry and exit points. Undoubtedly, they were hoping (assuming) we would take them home and learn the changes on our own, outside of Mass. So some months passed by, and after a few weeks with a cue card, I was in pretty good shape. My brain rewired the sayings, and I was able to shed my cue-card crutch.

My husband, on the other hand, is still reaching for the cue cards, with a long-standing dependence that now resembles that of an addict. Occasionally feeling confident, he will lay the card down, and will start spewing out the old sayings from a short circuit in the amygdala, programmed in fifth grade and hard-wired for accuracy. Then he will regain consciousness and realize everyone is staring at him.

As hospitalists, we know how hard it is to change, but we also know we have to routinely change to keep pace with the industry. So how do we reconcile the differences?

I recently read the book “Switch,” which describes some techniques on how to change when change is hard.¹ The authors write about a rider, an elephant, and a path. If all three are aligned toward a change, it will most likely succeed; without all three, change will be very difficult or unsuccessful altogether.

The rider is the intellectual portion, which will find the rational, statistical, logical solution to get from point A to point B. But the rider is steering an elephant, which is bulky, unruly, and emotional. The rider has to figure out how to motivate and direct the elephant; the two of them then have to get down a common path, which could be winding, confusing, and full of roadblocks. So to overcome all of these, the book gives innumerable, tangible examples of how to maneuver all three of these to facilitate change. In the case of my husband’s Mass issue, a few things could have facilitated the change for many:

Direct the rider:

• Find the bright spots. Find a success story of how others quickly relearned Mass within weeks and see how they accomplished it.
• Script the critical moves. Be very precise about what needs to be done differently; don’t just tell people to “learn the Mass,” but instead tell them to “repeat three new lines every day in the shower” until they have an error-free Mass.
• Point to the destination. Be very specific about the future goal, such as “You will be cue-card-free by October.”

Motivate the elephant:

• Find the feeling. Find a “heavy” emotion that will motivate the change. Shame, embarrassment, or anger from being stared at by a 10-year-old after missing so many lines should be pretty effective.
• Shrink the change. Make it seem like all the lines are easy to learn, if learned only one at a time.
• Grow the person. Motivate the Catholic to learn it as quickly and seamlessly as they did in fifth grade; if you already did it once, you just have do it again!

Shape the path:

• Tweak the environment. Have cue cards all over the place, laminate them, make them easy to fit in a pocket or purse.
• Build habits. Have the Catholic go to church every week until they have an “error-free” Mass.
• Rally the herd. Have them watch others for cues on behavior; this has worked for me for decades!

You can see that many of these techniques should be easier in healthcare than in other industries, especially motivating the elephant and shaping the path. To facilitate change, hospitalists should find ways to direct the rider, motivate the elephant, and shape the path, and we may find that change is not as daunting and overwhelming as it might at first seem.

And when you finally do make a positive change happen, give yourself a high-five—and send a “Hail Mary” to the Creasters.

Dr. Scheurer is physician editor of The Hospitalist.

Reference

1. Heath C, Heath D. Switch: How to Change Things when Change is Hard. New York: Random House; 2010.

Danielle Scheurer, MD, MSCR, SFHM

This is a tumultuous time in healthcare: regulatory burdens, payment reductions, public scrutiny. And the rapidity of change is mind-boggling. All of this would probably be fine, except that people generally resist change, especially rapid change. Here today, gone tomorrow. That usually does not go over very well.

But given that this is the state of affairs for the foreseeable future, the question is, why is change so hard, and what can we do make it easier?

I thought about this at church the other day. My family and I attend church weekly (except when we don’t) at a small, old, quaint Catholic church built in 1789. My husband and I were raised Catholic, but as you may know, not every Catholic is really a Catholic. Based on my childhood churchgoing routine, my family would best be described as “Creasters,” which are “Catholics” (in quotations on purpose) who dedicate most of their religious energy to showing up only on Christmas and Easter. We are also known as “diet Catholics” or “lite Catholics.” Although I can plow through the “Our Father” with ease and grace, the Lord’s Prayer usually results in some mumbling, hushed tones and ceiling-staring.

My husband, on the other hand, was raised a real Catholic. He went to Catholic grade school, received communion six days a week, routinely served as an altar boy, and only missed Sunday Mass for a fever of more than 101 degrees (and even that was a stretch). For years, I have looked to him for cues on when to sit, stand, kneel, talk, sing, and be silent. When Sunday school questions come to the dinner table by way of our 8-year-old, I generally feign a choking episode and defer to my husband.

So this has been our routine for more than a decade: he the leader and I the limper. But then something shocking happened several months ago. In the middle of Mass, I realized my husband had no idea what was going on. He fumbled awkwardly through the service, lowered his speech volume with each passing misstep, and was almost completely silent by the end of the service.

As it ends up, every couple of hundred years, the Catholic Church decides to shake things up and change the Mass around. During key repeatings, the words are now different. What used to be “and also with you” is now “and with your spirit.” These changes were not monumental and went relatively unnoticed by current or former Creasters, but they were mind-boggling for the real Catholics.

The Church must have anticipated that these changes would be difficult to assimilate, as they placed countless numbers of laminated cue cards all over the church, in every pew, the confessional stand, and at all entry and exit points. Undoubtedly, they were hoping (assuming) we would take them home and learn the changes on our own, outside of Mass. So some months passed by, and after a few weeks with a cue card, I was in pretty good shape. My brain rewired the sayings, and I was able to shed my cue-card crutch.

My husband, on the other hand, is still reaching for the cue cards, with a long-standing dependence that now resembles that of an addict. Occasionally feeling confident, he will lay the card down, and will start spewing out the old sayings from a short circuit in the amygdala, programmed in fifth grade and hard-wired for accuracy. Then he will regain consciousness and realize everyone is staring at him.

As hospitalists, we know how hard it is to change, but we also know we have to routinely change to keep pace with the industry. So how do we reconcile the differences?

I recently read the book “Switch,” which describes some techniques on how to change when change is hard.¹ The authors write about a rider, an elephant, and a path. If all three are aligned toward a change, it will most likely succeed; without all three, change will be very difficult or unsuccessful altogether.

The rider is the intellectual portion, which will find the rational, statistical, logical solution to get from point A to point B. But the rider is steering an elephant, which is bulky, unruly, and emotional. The rider has to figure out how to motivate and direct the elephant; the two of them then have to get down a common path, which could be winding, confusing, and full of roadblocks. So to overcome all of these, the book gives innumerable, tangible examples of how to maneuver all three of these to facilitate change. In the case of my husband’s Mass issue, a few things could have facilitated the change for many:

Direct the rider:

• Find the bright spots. Find a success story of how others quickly relearned Mass within weeks and see how they accomplished it.
• Script the critical moves. Be very precise about what needs to be done differently; don’t just tell people to “learn the Mass,” but instead tell them to “repeat three new lines every day in the shower” until they have an error-free Mass.
• Point to the destination. Be very specific about the future goal, such as “You will be cue-card-free by October.”

Motivate the elephant:

• Find the feeling. Find a “heavy” emotion that will motivate the change. Shame, embarrassment, or anger from being stared at by a 10-year-old after missing so many lines should be pretty effective.
• Shrink the change. Make it seem like all the lines are easy to learn, if learned only one at a time.
• Grow the person. Motivate the Catholic to learn it as quickly and seamlessly as they did in fifth grade; if you already did it once, you just have do it again!

Shape the path:

• Tweak the environment. Have cue cards all over the place, laminate them, make them easy to fit in a pocket or purse.
• Build habits. Have the Catholic go to church every week until they have an “error-free” Mass.
• Rally the herd. Have them watch others for cues on behavior; this has worked for me for decades!

You can see that many of these techniques should be easier in healthcare than in other industries, especially motivating the elephant and shaping the path. To facilitate change, hospitalists should find ways to direct the rider, motivate the elephant, and shape the path, and we may find that change is not as daunting and overwhelming as it might at first seem.

And when you finally do make a positive change happen, give yourself a high-five—and send a “Hail Mary” to the Creasters.

Dr. Scheurer is physician editor of The Hospitalist.

Reference

1. Heath C, Heath D. Switch: How to Change Things when Change is Hard. New York: Random House; 2010.

The doctor’s office, at least my office, has changed over the last few decades with an increase in personnel added to make my life easier. Much of it has occurred as a response to the increased billing and authentication process that is required for reimbursement.

After all, when doctors were paid in cash or with a dozen eggs, there was little need for all the paperwork. Health insurance, both private and federal, has been the cause of much of this. At the same time, medical assistants, registered nurses, and a variety of ancillary staff have been added to make the patient’s visit smoother and to acquire the requisite information to satiate the vast network of communications that are generated with each office visit. All of these personnel are now an undisputable requirement for the function of today’s medical office.

In the process, the distance between the physician and the patient has increased. In many offices today, the patient may never see the doctor during the visit. To an increasing extent, the office contact with the patient is solely by an RN or physician assistant. In most cases, patients are satisfied with the service and are delighted not to spend a long time waiting to see the "doctor." Many of the visits are check-ups or annual or semiannual visits without any associated symptoms that can often be dealt with by a sympathetic and knowledgeable nurse. The patient is the winner to a great extent in this process by acquiring a sensitive ear and an expeditious visit. What is lost is the continued relationship of the patients and their physician. The biggest loss, I would suggest, is the doctor’s satisfaction of providing medical care that comes with every patient encounter, which keeps many of us energized to keep practicing medicine.

Now we have a new vision of how the primary care office of the future will function as a medical home (N. Engl. J. Med. 2012;367:891-3). In this vision, the physicians will be energized by a global payment system that will create an environment in which the doctor’s role is to pass real responsibility to their ancillary staff for which they would be held accountable. According to the authors, the physician’s office will be committed to promoting a healthy environment rather than merely treating disease. Why bother with the simple issue of treating sick patients when you can take on the entire environment of your community to prevent disease?

The authors go on to state that the physician would not waste time focusing on the "10% premature mortality that is influenced by medical treatment." In this work environment, the physician would be the team manager of a host of ancillary personnel, including medical assistants, RNs, social workers, nutritionists, and pharmacists, to name but a few. The physician would be energized by his or her role as a team leader. The physician, the authors explain, would see fewer patients and would not be caught running from room to room to see patients. Instead, he or she will become involved with care of the "community and understanding the upstream determinants of downstream sickness" and would spend there time in the community "advocating for the local farmer’s market to accept food stamps, organizing walking clubs for physical exercise, and lobbying ... to reduce emissions to improve air quality."

This, of course, is a far cry from the doctors who negotiated the care for their patient for a dozen eggs. It is clearly a role that is foreign to my generation. To some extent, though, patients may well gain in this futuristic environment. They will acquire an empathetic nurse who will be sensitive to their needs and who may be as good as a crotchety overworked doctor. All of the ancillary medical staff will gain a larger and more responsible role in the medical home. The physicians will morph into a new role that is more characteristic of an administrator and less as a practitioner. The doctors, however, will be the biggest losers as they disengage from the patient contact and care that is so crucial to the satisfaction of being a doctor.

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

The doctor’s office, at least my office, has changed over the last few decades with an increase in personnel added to make my life easier. Much of it has occurred as a response to the increased billing and authentication process that is required for reimbursement.

After all, when doctors were paid in cash or with a dozen eggs, there was little need for all the paperwork. Health insurance, both private and federal, has been the cause of much of this. At the same time, medical assistants, registered nurses, and a variety of ancillary staff have been added to make the patient’s visit smoother and to acquire the requisite information to satiate the vast network of communications that are generated with each office visit. All of these personnel are now an undisputable requirement for the function of today’s medical office.

In the process, the distance between the physician and the patient has increased. In many offices today, the patient may never see the doctor during the visit. To an increasing extent, the office contact with the patient is solely by an RN or physician assistant. In most cases, patients are satisfied with the service and are delighted not to spend a long time waiting to see the "doctor." Many of the visits are check-ups or annual or semiannual visits without any associated symptoms that can often be dealt with by a sympathetic and knowledgeable nurse. The patient is the winner to a great extent in this process by acquiring a sensitive ear and an expeditious visit. What is lost is the continued relationship of the patients and their physician. The biggest loss, I would suggest, is the doctor’s satisfaction of providing medical care that comes with every patient encounter, which keeps many of us energized to keep practicing medicine.

Now we have a new vision of how the primary care office of the future will function as a medical home (N. Engl. J. Med. 2012;367:891-3). In this vision, the physicians will be energized by a global payment system that will create an environment in which the doctor’s role is to pass real responsibility to their ancillary staff for which they would be held accountable. According to the authors, the physician’s office will be committed to promoting a healthy environment rather than merely treating disease. Why bother with the simple issue of treating sick patients when you can take on the entire environment of your community to prevent disease?

The authors go on to state that the physician would not waste time focusing on the "10% premature mortality that is influenced by medical treatment." In this work environment, the physician would be the team manager of a host of ancillary personnel, including medical assistants, RNs, social workers, nutritionists, and pharmacists, to name but a few. The physician would be energized by his or her role as a team leader. The physician, the authors explain, would see fewer patients and would not be caught running from room to room to see patients. Instead, he or she will become involved with care of the "community and understanding the upstream determinants of downstream sickness" and would spend there time in the community "advocating for the local farmer’s market to accept food stamps, organizing walking clubs for physical exercise, and lobbying ... to reduce emissions to improve air quality."

This, of course, is a far cry from the doctors who negotiated the care for their patient for a dozen eggs. It is clearly a role that is foreign to my generation. To some extent, though, patients may well gain in this futuristic environment. They will acquire an empathetic nurse who will be sensitive to their needs and who may be as good as a crotchety overworked doctor. All of the ancillary medical staff will gain a larger and more responsible role in the medical home. The physicians will morph into a new role that is more characteristic of an administrator and less as a practitioner. The doctors, however, will be the biggest losers as they disengage from the patient contact and care that is so crucial to the satisfaction of being a doctor.

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

The doctor’s office, at least my office, has changed over the last few decades with an increase in personnel added to make my life easier. Much of it has occurred as a response to the increased billing and authentication process that is required for reimbursement.

After all, when doctors were paid in cash or with a dozen eggs, there was little need for all the paperwork. Health insurance, both private and federal, has been the cause of much of this. At the same time, medical assistants, registered nurses, and a variety of ancillary staff have been added to make the patient’s visit smoother and to acquire the requisite information to satiate the vast network of communications that are generated with each office visit. All of these personnel are now an undisputable requirement for the function of today’s medical office.

In the process, the distance between the physician and the patient has increased. In many offices today, the patient may never see the doctor during the visit. To an increasing extent, the office contact with the patient is solely by an RN or physician assistant. In most cases, patients are satisfied with the service and are delighted not to spend a long time waiting to see the "doctor." Many of the visits are check-ups or annual or semiannual visits without any associated symptoms that can often be dealt with by a sympathetic and knowledgeable nurse. The patient is the winner to a great extent in this process by acquiring a sensitive ear and an expeditious visit. What is lost is the continued relationship of the patients and their physician. The biggest loss, I would suggest, is the doctor’s satisfaction of providing medical care that comes with every patient encounter, which keeps many of us energized to keep practicing medicine.

Now we have a new vision of how the primary care office of the future will function as a medical home (N. Engl. J. Med. 2012;367:891-3). In this vision, the physicians will be energized by a global payment system that will create an environment in which the doctor’s role is to pass real responsibility to their ancillary staff for which they would be held accountable. According to the authors, the physician’s office will be committed to promoting a healthy environment rather than merely treating disease. Why bother with the simple issue of treating sick patients when you can take on the entire environment of your community to prevent disease?

The authors go on to state that the physician would not waste time focusing on the "10% premature mortality that is influenced by medical treatment." In this work environment, the physician would be the team manager of a host of ancillary personnel, including medical assistants, RNs, social workers, nutritionists, and pharmacists, to name but a few. The physician would be energized by his or her role as a team leader. The physician, the authors explain, would see fewer patients and would not be caught running from room to room to see patients. Instead, he or she will become involved with care of the "community and understanding the upstream determinants of downstream sickness" and would spend there time in the community "advocating for the local farmer’s market to accept food stamps, organizing walking clubs for physical exercise, and lobbying ... to reduce emissions to improve air quality."

This, of course, is a far cry from the doctors who negotiated the care for their patient for a dozen eggs. It is clearly a role that is foreign to my generation. To some extent, though, patients may well gain in this futuristic environment. They will acquire an empathetic nurse who will be sensitive to their needs and who may be as good as a crotchety overworked doctor. All of the ancillary medical staff will gain a larger and more responsible role in the medical home. The physicians will morph into a new role that is more characteristic of an administrator and less as a practitioner. The doctors, however, will be the biggest losers as they disengage from the patient contact and care that is so crucial to the satisfaction of being a doctor.

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

Dr. Rossi discusses dermal fillers for a natural approach to lip augmentation. For more information, read Dr. Rossi's article in the June 2012 issue, "Soft Tissue Augmentation With Dermal Fillers, Part 1: Lips and Lower Face."

Dr. Rossi discusses dermal fillers for a natural approach to lip augmentation. For more information, read Dr. Rossi's article in the June 2012 issue, "Soft Tissue Augmentation With Dermal Fillers, Part 1: Lips and Lower Face."

Dr. Rossi discusses dermal fillers for a natural approach to lip augmentation. For more information, read Dr. Rossi's article in the June 2012 issue, "Soft Tissue Augmentation With Dermal Fillers, Part 1: Lips and Lower Face."

“Healthy citizens are the greatest asset any country can have.”

—Winston Churchill

Diabetes and high blood pressure take a toll on the kidneys, especially in African Americans. To prevent chronic kidney disease (CKD) and to slow or stop its progression, the same principles apply in African Americans as in other patients—ie, vigilance for the onset of proteinuria, aggressive control of blood pressure, drug treatment to block the renin-angiotensin system, and attention to lifestyle factors (Table 1). However, we need to try to do better in the care of African Americans.

The purpose of this article is to review recent evidence- and consensus-based recommendations and to present a practical approach for the evaluation and treatment of CKD in African Americans.

CKD DEFINED

In 2002, the National Kidney Foundation¹ defined CKD as either:

• Kidney damage for 3 or more months, as defined by structural or functional abnormalities of the kidney, with or without a decreased glomerular filtration rate (GFR), manifested either by pathologic abnormalities or by markers of kidney damage, including abnormalities in the composition of the blood or urine (eg, proteinuria), or abnormalities in imaging tests; or
• A GFR less than 60 mL/min/1.73 m² for 3 or more months, with or without kidney damage.

The definition divides CKD into five progressive stages according to the GFR:

• Stage 1 (kidney damage with normal or increased GFR): GFR ≥ 90 mL/min/1.73m²
• Stage 2 (kidney damage with mildly decreased GFR): GFR 60–89
• Stage 3 (moderately decreased GFR): GFR 30–59
• Stage 4 (severely decreased GFR): GFR 15–29
• Stage 5 (kidney failure): GFR < 15 or dialysis.

Because the definition includes markers of kidney damage such as albuminuria, it allows CKD to be detected in its earliest stages, when the estimated GFR might still be well within normal limits.

CKD APPEARS EARLIER, PROGRESSES FASTER IN AFRICAN AMERICANS

“Not everything that counts can be counted, and not everything that can be counted counts.”

—Albert Einstein

CKD with or without a sustained reduction in the estimated GFR affects about one in every nine American adults.2 Its course varies depending on the cause and also from patient to patient, even in those with the same cause of CKD.

In general, the prevalence of early CKD is comparable across racial and ethnic groups in the United States, but CKD progresses to end-stage renal disease far more rapidly in minority populations, with rates nearly four times higher in black Americans than in white Americans.³ Also, the onset of CKD is earlier in African Americans.

HYPERTENSION AND DIABETES AS REASONS FOR THE DISPARITIES

Part of the reason for these differences is that minority populations have higher rates of diabetes and hypertension, and these diseases tend to be more severe in these groups. Poverty, less access to health care, exposure to environmental toxins, and genetic variation may also contribute.^4–7

Compared with whites, blacks have higher rates of diabetes and hypertension and earlier onset of these diseases, poorer control, and higher rates of complications such as CKD, stroke, and heart disease.^8,9 The higher rate of hypertension and the lower rate of blood pressure control in African Americans with CKD may contribute to the more rapid progression of CKD to end-stage renal disease.

In the Chronic Renal Insufficiency Cohort, ¹⁰ a racially and ethnically diverse group of 3,612 adults with a broad spectrum of renal disease severity, 93% of African Americans had hypertension at baseline compared with 80% of whites. In addition, African Americans were 18% less likely to have their blood pressure controlled to 140/90 mm Hg (the rates of control were 76% vs 60%), and 28% were less likely to have it controlled to 130/80 mm Hg (56% vs 38%).¹⁰ These factors may partially explain the faster progression to end-stage renal disease in African Americans with CKD.

Despite the potential efficacy of strict control of serum glucose levels and blood pressure,¹¹ the high rate of poor blood pressure control has contributed to the epidemic of diabetic nephropathy, especially among African Americans. Fortunately, hypertension control in the general population, while still not ideal, has improved from 27% in 1988–1994 to 50% in 2007–2008 and is now similar across racial and ethnic groups.¹² This, hopefully, is a preface for improved hypertension-related outcomes for all Americans over the next decade.

OTHER REASONS FOR THE DISPARITIES

“There are no unnatural or supernatural phenomena, only a very large gap in our knowledge of what is natural.”

—Edgar Mitchell, Apollo 14 astronaut

Proteinuria

Proteinuria is another key cardiorenal risk factor prevalent in African Americans.

Knight et al,¹³ analyzing data from the Third National Health and Nutrition Examination Survey, found that people with high-normal blood pressure (systolic pressure 130–139 mm Hg or diastolic pressure 85–89 mm Hg) were twice as likely to have microalbuminuria (odds ratio 2.13, 95% confidence interval [CI] 1.51–3.01) compared with people with optimal blood pressure (systolic pressure < 120 mm Hg and diastolic pressure < 80 mm Hg). Compared with whites as the reference group, Mexican Americans had slightly but not statistically significantly higher odds of microalbuminuria (odds ratio 1.16; 95% CI 0.90–1.51), and African Americans had significantly higher odds (odds ratio 1.30; 95% CI 1.04–1.64).

The incidence of hypertension-related end-stage renal disease is nearly five times higher in African Americans than in whites, and the rate of hypertension-related end-stage renal disease is 15 times higher in African American men ages 24 to 44 than in whites of the same ages.³ The greater risk of proteinuria in African Americans at any given level of higher blood pressure is thought to contribute in part to these disparate rates.

The renin-angiotensin system

The renin-angiotensin system plays a role in modulating hypertension and mediating hypertension-related complications. Hypertensive African Americans are more likely than hypertensive whites to have low-renin, salt-sensitive hypertension. Therein lies a paradox.

Since the renin-angiotensin system promotes the progression of CKD, we would expect patients with low-renin hypertension to have a lower risk of hypertension-related endorgan damage than patients with high-renin hypertension. However, many African Americans (who as a group have high rates of sodium sensitivity and low plasma renin levels) experience more severe hypertension-related end-organ complications such as proteinuria and cardiorenal disease.¹⁴

A reason for this paradox may be that the circulating renin-angiotensin system is separate from the intrarenal one. Supporting this theory is the observation that up-regulation of the intrarenal renin-angiotensin system accompanies renal interstitial inflammation and oxidative stress in the kidneys and cardiovascular tissues of salt-sensitive rats fed a high-salt diet.¹⁵ In other experiments in salt-sensitive rats, renin-angiotensin system blockade reversed endothelial dysfunction, attenuated proteinuria, and reduced renal injury independent of blood pressure changes even though the animals had low circulating renin levels.¹⁶

These findings imply that drugs that block the renin-angiotensin system, ie, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, could still be a rational therapy for CKD patients with low-renin hypertension, particularly African Americans, in whom local up-regulation of the renin-angiotensin system in the kidney could exacerbate both diabetic and hypertensive CKD.¹⁷ Although these drugs may not lower blood pressure as much in low-renin hypertension as in high-renin hypertension, they may still afford the same cardiorenal protection.

Genetic factors

Variations in the MYH9 and APOL1 genes on chromosome 22 have recently been found in genome-wide admixture mapping studies and may explain as much as 70% of the differences in the rates of nondiabetic end-stage renal disease between white and black Americans.^7,18,19 In addition, genetic variations may modulate differences in blood-pressure response to antihypertensive medications across racial and ethnic groups,²⁰ complicating treatment recommendations and clinical outcomes in our increasingly diverse nation.

Comment. The pathophysiologic basis for the variability in the course of CKD is probably multifactorial and is still poorly understood. Nevertheless, we may be able to delay the progression of CKD and prevent its complications with specific therapeutic and life-style interventions.

Race and ethnicity are associated with sociocultural and biologic variations that influence the risk and progression of CKD. Understanding these factors for minority populations can help in targeting interventions to attenuate the disproportionately high rates of CKD progression and complications.

The pathophysiologic reason African Americans have a greater prevalence of end-stage renal disease and a more rapid progression of CKD is complex and probably involves the interplay of biological, behavioral, and environmental factors such as salt intake, stress levels, and exposure to heavy metals.²¹

TRIALS OF ANTIHYPERTENSIVE THERAPY IN AFRICAN AMERICANS WITH CKD

“If we knew what we were doing, it wouldn’t be called research.”

—Albert Einstein

Until recently, trials of antihypertensive therapy in patients with CKD did not include adequate numbers of African American participants, but the following clinical trials have added to our knowledge (Table 2).^22–26

African American Study of Kidney Disease and Hypertension (AASK)

The African American Study of Kidney Disease and Hypertension (AASK),^22,23 with 1,094 patients, was the largest prospective study of CKD to date designed to focus on African Americans.

AASK examined the effects of two levels of blood-pressure control:

• Standard, with a goal blood pressure of 135–140/85–90 mm Hg (mean arterial pressure 102–107 mm Hg)
• Intensive, with a goal of 120/80 mm Hg or less (mean arterial pressure ≤ 92 mm Hg).

In a two-by two factorial design, patients were also randomized to receive one of three antihypertensive drugs as initial therapy:

• The ACE inhibitor ramipril (Altace)
• The sustained-release beta-blocker metoprolol succinate (Toprol XL)
• The calcium channel blocker amlodipine (Norvasc).

To enter the study, patients had to be African American, have at least one diastolic pressure reading of 95 mm Hg or greater during the screening period, and have a measured GFR between 20 and 65 mL/min/1.83 m². They could not have diabetes, substantial proteinuria (> 2.5 g/day), or other causes of CKD.²²

AASK was distinct from many of the larger hypertension trials in which secondary analyses of outcomes in patients with CKD were performed in that it was implicit in the design that most, if not all, study participants had substantial GFR reduction and would need diuretic therapy.

At baseline, after blood pressure medications had been tapered to define eligibility and then reintroduced before randomization, 20.0% of the patients in the intensive blood pressure goal group had pressure lower than 140/90 mm Hg, and this increased to 78.9% by 14 months after randomization. In the standard goal group, the numbers were 21.5% at baseline but only 41.8% at 14 months.²³ In spite of this difference, the rate of decline in GFR (the main clinical outcome measure) was the same in both groups.

However, the class of drug did make a difference. Secondary clinical outcomes, including the composite end point of development of end-stage renal disease, doubling of serum creatinine, or death, were less frequent in the ACE inhibitor group than in the beta-blocker and calcium channel blocker groups. As anticipated and consistent with real world practice, nearly 90% of all participants received concomitant diuretic therapy to achieve target blood pressure levels.

Comments. AASK showed that blood pressure can be controlled in African Americans who have CKD and that clinical cardiorenal outcomes can be improved by using an ACE inhibitor as initial therapy rather than a beta-blocker or calcium channel blocker, with diuretics and other agents added as needed.

AASK cohort phase

After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood pressure target was less than 130/80 mm Hg. The combined follow-up period was 8.8 to 12.2 years.²⁴

During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive group and 141/86 mm Hg in the standard group. During the cohort phase, the mean blood pressures were 131/78 mm Hg and 134/78 mm Hg, respectively, in these groups.

In both phases, there was no significant difference between groups in clinical outcomes (hazard ratio in the intensive-control group 0.91, P = .27). However, the groups differed when stratified by baseline level of proteinuria (P = .02 for the interaction), with a potential benefit of a blood pressure target lower than 130/80 mm Hg in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio 0.73, P = .01).²⁴

Comment. Given that many African Americans with hypertension and CKD have a protein-to-creatinine ratio of more than 0.22, these findings support a practical approach in clinical practice for a target blood pressure less than 130/80 mm Hg, using a first-line combination of a renin-angiotensin system inhibitor and a diuretic.

RENAAL study

The Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) study²⁵ included 1,513 patients, of whom 15% were African American and 18% were Hispanic; all had type 2 diabetes mellitus and nephropathy. They were randomized to receive the angiotensin II receptor antagonist losartan (Cozaar) or placebo in addition to other antihypertensive drugs.

At 3.4 years, the blood pressure was about 141/74 mm Hg in both groups. A post hoc analysis found lower rates of albuminuria and end-stage renal disease in the group treated with losartan,²⁵ with no racial or ethnic differences in its renoprotective effect.

Comments. While these findings support the recommendation of inhibiting the renin-angiotensin system for improving clinical outcomes in diabetic nephropathy in racial and ethnic minorities, the AASK study also proved a second important point. These patients required intense blood pressure management for several years in a clinical trial environment, which may be difficult to do in many clinical practice models.

To be cost-effective in today’s health care environment, such care will likely be limited to larger group practices or health care plans with large comprehensive covered populations. Payers and providers need to be willing to invest in intense early care in such high-risk subgroups with the understanding that they could recognize downstream gains from long-term improved outcomes. However, even in these settings, the ability to provide effective care to high-risk subgroups without generating significant financial losses remains a concern.

ALLHAT

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)²⁶ enrolled more than 33,000 hypertensive patients at high risk, of whom 32% were black, 16% were Hispanic, and 36% had diabetes. Their mean serum creatinine level was 1 mg/dL. Follow-up was for up to 8 years. At year 5, the mean blood pressure was 135/75 mm Hg.

In a secondary analysis, patients were stratified by GFR:

• Normal (> 90 mL/min/1.73 m²; n = 8,126)
• Mild reduction (60–89 mL/min/1.73 m²; n = 18,109)
• Moderate-severe reduction (< 60 mL/min/1.73 m²; n = 5,662).

In all three groups, amlodipine, lisinopril (Zestril), and chlorthalidone were equivalent as initial monotherapy in reducing the rate of the composite end point of end-stage renal disease or 50% or greater decrement in GFR.

Comments. The combined AASK, RENAAL, and ALLHAT findings are consistent with the practical recommendation of a diuretic, renin-angiotensin system inhibitor, or both, as initial therapy for blood pressure control in African American patients who have CKD, with a target blood pressure of less than 130/80 mm Hg.

A COMPREHENSIVE APPROACH TO CHRONIC KIDNEY DISEASE CARE

“It is much more important to know what sort of a patient has a disease, than what sort of disease a patient has.”

—William Osler

Many of the risk factors for cardiovascular disease in African Americans are behavioral and modifiable. These include too much salt and fat in the diet, too little physical activity, excessive alcohol intake, and smoking.

Education is key, to identify and communicate the risk attributable to health beliefs and behaviors, particularly in patients with known cardiovascular disease, and to encourage the patient to be proactive in risk-reduction strategies (Table 1). However, effective communication depends on compassion and concern by the health care provider to engender a sense of trust.²⁷ Other health care professionals such as dietitians, pharmacists, and social workers as well as family members can reinforce messages and improve communication with the patient to optimize outcomes.

The International Society on Hypertension in Blacks recommends a blood pressure target of less than 130/80 mm Hg in blacks with elevated blood pressure and target-organ damage. The authors suggest monotherapy with a diuretic or calcium channel blocker if the blood pressure is 10 mm Hg or less above target levels. When blood pressure is more than 15/10 mm Hg above target, two-drug therapy is recommended, either with a calcium channel blocker plus a renin-angiotensin system blocker or, alternatively, in edematous or volume-overload states, with a thiazide diuretic plus a renin-angiotensin system blocker.^28,29

The Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease of the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative recommend starting anti-hypertensive therapy with an ACE inhibitor or an angiotensin receptor blocker for most patients with CKD, regardless of ethnicity, recognizing that many will require combination therapy.³⁰ Evaluation of the response to therapy should include not only checking that the blood pressure is at or below the recommended target of 130/80 mm Hg, but also assessing for complications and monitoring the change in the level of proteinuria, which is a powerful predictor of progression of hypertensive kidney disease in all patients at any given GFR.³¹

OUR RECOMMENDATIONS

African Americans with hypertension and kidney disease require an aggressive and comprehensive approach to slow the progression of kidney disease and its complications, often necessitating aggressive care of the primary cause and the use of two or more antihypertensive agents to control blood pressure, proteinuria, or both (Figure 1).³²

We recommend that the initial evaluation of patients with hypertension include a screening for albuminuria and that the initial therapy for hypertension or proteinuria in all patients with CKD include renin-angiotensin system inhibition with a diuretic, because this combination appears most effective to achieve blood pressure control and to confer additional cardiorenal protection beyond that offered by blood-pressure control alone. Although some studies have reported that African Americans have lower blood-pressure response rates than whites to renin-angiotensin system inhibition, 18 it is nevertheless beneficial for clinical outcomes in this group, especially in the presence of proteinuria, a hallmark of hypertension-related CKD in African Americans. Thus, until more data are available, ethnicity should not be the primary criterion for selecting a given class of antihypertensive therapy, especially in patients with hypertensive nephropathy.

The overall treatment decision should be guided by individual response, coexisting risk factors, and potential cultural and socioeconomic considerations such as cost of medications and insurance coverage, which affect adherence to both pharmacologic and nonpharmacologic interventions.³³

Future studies should strive for adequate representation of racial and ethnic minority populations in order to enhance the evidence base for CKD treatment as we move toward using personalized medicine approaches in an increasingly diverse society.³⁴
 

Acknowledgment: Support for this paper was provided in part by NIH grants RR026138 and MD000182.

“Healthy citizens are the greatest asset any country can have.”

—Winston Churchill

Diabetes and high blood pressure take a toll on the kidneys, especially in African Americans. To prevent chronic kidney disease (CKD) and to slow or stop its progression, the same principles apply in African Americans as in other patients—ie, vigilance for the onset of proteinuria, aggressive control of blood pressure, drug treatment to block the renin-angiotensin system, and attention to lifestyle factors (Table 1). However, we need to try to do better in the care of African Americans.

The purpose of this article is to review recent evidence- and consensus-based recommendations and to present a practical approach for the evaluation and treatment of CKD in African Americans.

CKD DEFINED

In 2002, the National Kidney Foundation¹ defined CKD as either:

• Kidney damage for 3 or more months, as defined by structural or functional abnormalities of the kidney, with or without a decreased glomerular filtration rate (GFR), manifested either by pathologic abnormalities or by markers of kidney damage, including abnormalities in the composition of the blood or urine (eg, proteinuria), or abnormalities in imaging tests; or
• A GFR less than 60 mL/min/1.73 m² for 3 or more months, with or without kidney damage.

The definition divides CKD into five progressive stages according to the GFR:

• Stage 1 (kidney damage with normal or increased GFR): GFR ≥ 90 mL/min/1.73m²
• Stage 2 (kidney damage with mildly decreased GFR): GFR 60–89
• Stage 3 (moderately decreased GFR): GFR 30–59
• Stage 4 (severely decreased GFR): GFR 15–29
• Stage 5 (kidney failure): GFR < 15 or dialysis.

Because the definition includes markers of kidney damage such as albuminuria, it allows CKD to be detected in its earliest stages, when the estimated GFR might still be well within normal limits.

CKD APPEARS EARLIER, PROGRESSES FASTER IN AFRICAN AMERICANS

“Not everything that counts can be counted, and not everything that can be counted counts.”

—Albert Einstein

CKD with or without a sustained reduction in the estimated GFR affects about one in every nine American adults.2 Its course varies depending on the cause and also from patient to patient, even in those with the same cause of CKD.

In general, the prevalence of early CKD is comparable across racial and ethnic groups in the United States, but CKD progresses to end-stage renal disease far more rapidly in minority populations, with rates nearly four times higher in black Americans than in white Americans.³ Also, the onset of CKD is earlier in African Americans.

HYPERTENSION AND DIABETES AS REASONS FOR THE DISPARITIES

Part of the reason for these differences is that minority populations have higher rates of diabetes and hypertension, and these diseases tend to be more severe in these groups. Poverty, less access to health care, exposure to environmental toxins, and genetic variation may also contribute.^4–7

Compared with whites, blacks have higher rates of diabetes and hypertension and earlier onset of these diseases, poorer control, and higher rates of complications such as CKD, stroke, and heart disease.^8,9 The higher rate of hypertension and the lower rate of blood pressure control in African Americans with CKD may contribute to the more rapid progression of CKD to end-stage renal disease.

In the Chronic Renal Insufficiency Cohort, ¹⁰ a racially and ethnically diverse group of 3,612 adults with a broad spectrum of renal disease severity, 93% of African Americans had hypertension at baseline compared with 80% of whites. In addition, African Americans were 18% less likely to have their blood pressure controlled to 140/90 mm Hg (the rates of control were 76% vs 60%), and 28% were less likely to have it controlled to 130/80 mm Hg (56% vs 38%).¹⁰ These factors may partially explain the faster progression to end-stage renal disease in African Americans with CKD.

Despite the potential efficacy of strict control of serum glucose levels and blood pressure,¹¹ the high rate of poor blood pressure control has contributed to the epidemic of diabetic nephropathy, especially among African Americans. Fortunately, hypertension control in the general population, while still not ideal, has improved from 27% in 1988–1994 to 50% in 2007–2008 and is now similar across racial and ethnic groups.¹² This, hopefully, is a preface for improved hypertension-related outcomes for all Americans over the next decade.

OTHER REASONS FOR THE DISPARITIES

“There are no unnatural or supernatural phenomena, only a very large gap in our knowledge of what is natural.”

—Edgar Mitchell, Apollo 14 astronaut

Proteinuria

Proteinuria is another key cardiorenal risk factor prevalent in African Americans.

Knight et al,¹³ analyzing data from the Third National Health and Nutrition Examination Survey, found that people with high-normal blood pressure (systolic pressure 130–139 mm Hg or diastolic pressure 85–89 mm Hg) were twice as likely to have microalbuminuria (odds ratio 2.13, 95% confidence interval [CI] 1.51–3.01) compared with people with optimal blood pressure (systolic pressure < 120 mm Hg and diastolic pressure < 80 mm Hg). Compared with whites as the reference group, Mexican Americans had slightly but not statistically significantly higher odds of microalbuminuria (odds ratio 1.16; 95% CI 0.90–1.51), and African Americans had significantly higher odds (odds ratio 1.30; 95% CI 1.04–1.64).

The incidence of hypertension-related end-stage renal disease is nearly five times higher in African Americans than in whites, and the rate of hypertension-related end-stage renal disease is 15 times higher in African American men ages 24 to 44 than in whites of the same ages.³ The greater risk of proteinuria in African Americans at any given level of higher blood pressure is thought to contribute in part to these disparate rates.

The renin-angiotensin system

The renin-angiotensin system plays a role in modulating hypertension and mediating hypertension-related complications. Hypertensive African Americans are more likely than hypertensive whites to have low-renin, salt-sensitive hypertension. Therein lies a paradox.

Since the renin-angiotensin system promotes the progression of CKD, we would expect patients with low-renin hypertension to have a lower risk of hypertension-related endorgan damage than patients with high-renin hypertension. However, many African Americans (who as a group have high rates of sodium sensitivity and low plasma renin levels) experience more severe hypertension-related end-organ complications such as proteinuria and cardiorenal disease.¹⁴

A reason for this paradox may be that the circulating renin-angiotensin system is separate from the intrarenal one. Supporting this theory is the observation that up-regulation of the intrarenal renin-angiotensin system accompanies renal interstitial inflammation and oxidative stress in the kidneys and cardiovascular tissues of salt-sensitive rats fed a high-salt diet.¹⁵ In other experiments in salt-sensitive rats, renin-angiotensin system blockade reversed endothelial dysfunction, attenuated proteinuria, and reduced renal injury independent of blood pressure changes even though the animals had low circulating renin levels.¹⁶

These findings imply that drugs that block the renin-angiotensin system, ie, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, could still be a rational therapy for CKD patients with low-renin hypertension, particularly African Americans, in whom local up-regulation of the renin-angiotensin system in the kidney could exacerbate both diabetic and hypertensive CKD.¹⁷ Although these drugs may not lower blood pressure as much in low-renin hypertension as in high-renin hypertension, they may still afford the same cardiorenal protection.

Genetic factors

Variations in the MYH9 and APOL1 genes on chromosome 22 have recently been found in genome-wide admixture mapping studies and may explain as much as 70% of the differences in the rates of nondiabetic end-stage renal disease between white and black Americans.^7,18,19 In addition, genetic variations may modulate differences in blood-pressure response to antihypertensive medications across racial and ethnic groups,²⁰ complicating treatment recommendations and clinical outcomes in our increasingly diverse nation.

Comment. The pathophysiologic basis for the variability in the course of CKD is probably multifactorial and is still poorly understood. Nevertheless, we may be able to delay the progression of CKD and prevent its complications with specific therapeutic and life-style interventions.

Race and ethnicity are associated with sociocultural and biologic variations that influence the risk and progression of CKD. Understanding these factors for minority populations can help in targeting interventions to attenuate the disproportionately high rates of CKD progression and complications.

The pathophysiologic reason African Americans have a greater prevalence of end-stage renal disease and a more rapid progression of CKD is complex and probably involves the interplay of biological, behavioral, and environmental factors such as salt intake, stress levels, and exposure to heavy metals.²¹

TRIALS OF ANTIHYPERTENSIVE THERAPY IN AFRICAN AMERICANS WITH CKD

“If we knew what we were doing, it wouldn’t be called research.”

—Albert Einstein

Until recently, trials of antihypertensive therapy in patients with CKD did not include adequate numbers of African American participants, but the following clinical trials have added to our knowledge (Table 2).^22–26

African American Study of Kidney Disease and Hypertension (AASK)

The African American Study of Kidney Disease and Hypertension (AASK),^22,23 with 1,094 patients, was the largest prospective study of CKD to date designed to focus on African Americans.

AASK examined the effects of two levels of blood-pressure control:

• Standard, with a goal blood pressure of 135–140/85–90 mm Hg (mean arterial pressure 102–107 mm Hg)
• Intensive, with a goal of 120/80 mm Hg or less (mean arterial pressure ≤ 92 mm Hg).

In a two-by two factorial design, patients were also randomized to receive one of three antihypertensive drugs as initial therapy:

• The ACE inhibitor ramipril (Altace)
• The sustained-release beta-blocker metoprolol succinate (Toprol XL)
• The calcium channel blocker amlodipine (Norvasc).

To enter the study, patients had to be African American, have at least one diastolic pressure reading of 95 mm Hg or greater during the screening period, and have a measured GFR between 20 and 65 mL/min/1.83 m². They could not have diabetes, substantial proteinuria (> 2.5 g/day), or other causes of CKD.²²

AASK was distinct from many of the larger hypertension trials in which secondary analyses of outcomes in patients with CKD were performed in that it was implicit in the design that most, if not all, study participants had substantial GFR reduction and would need diuretic therapy.

At baseline, after blood pressure medications had been tapered to define eligibility and then reintroduced before randomization, 20.0% of the patients in the intensive blood pressure goal group had pressure lower than 140/90 mm Hg, and this increased to 78.9% by 14 months after randomization. In the standard goal group, the numbers were 21.5% at baseline but only 41.8% at 14 months.²³ In spite of this difference, the rate of decline in GFR (the main clinical outcome measure) was the same in both groups.

However, the class of drug did make a difference. Secondary clinical outcomes, including the composite end point of development of end-stage renal disease, doubling of serum creatinine, or death, were less frequent in the ACE inhibitor group than in the beta-blocker and calcium channel blocker groups. As anticipated and consistent with real world practice, nearly 90% of all participants received concomitant diuretic therapy to achieve target blood pressure levels.

Comments. AASK showed that blood pressure can be controlled in African Americans who have CKD and that clinical cardiorenal outcomes can be improved by using an ACE inhibitor as initial therapy rather than a beta-blocker or calcium channel blocker, with diuretics and other agents added as needed.

AASK cohort phase

After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood pressure target was less than 130/80 mm Hg. The combined follow-up period was 8.8 to 12.2 years.²⁴

During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive group and 141/86 mm Hg in the standard group. During the cohort phase, the mean blood pressures were 131/78 mm Hg and 134/78 mm Hg, respectively, in these groups.

In both phases, there was no significant difference between groups in clinical outcomes (hazard ratio in the intensive-control group 0.91, P = .27). However, the groups differed when stratified by baseline level of proteinuria (P = .02 for the interaction), with a potential benefit of a blood pressure target lower than 130/80 mm Hg in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio 0.73, P = .01).²⁴

Comment. Given that many African Americans with hypertension and CKD have a protein-to-creatinine ratio of more than 0.22, these findings support a practical approach in clinical practice for a target blood pressure less than 130/80 mm Hg, using a first-line combination of a renin-angiotensin system inhibitor and a diuretic.

RENAAL study

The Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) study²⁵ included 1,513 patients, of whom 15% were African American and 18% were Hispanic; all had type 2 diabetes mellitus and nephropathy. They were randomized to receive the angiotensin II receptor antagonist losartan (Cozaar) or placebo in addition to other antihypertensive drugs.

At 3.4 years, the blood pressure was about 141/74 mm Hg in both groups. A post hoc analysis found lower rates of albuminuria and end-stage renal disease in the group treated with losartan,²⁵ with no racial or ethnic differences in its renoprotective effect.

Comments. While these findings support the recommendation of inhibiting the renin-angiotensin system for improving clinical outcomes in diabetic nephropathy in racial and ethnic minorities, the AASK study also proved a second important point. These patients required intense blood pressure management for several years in a clinical trial environment, which may be difficult to do in many clinical practice models.

To be cost-effective in today’s health care environment, such care will likely be limited to larger group practices or health care plans with large comprehensive covered populations. Payers and providers need to be willing to invest in intense early care in such high-risk subgroups with the understanding that they could recognize downstream gains from long-term improved outcomes. However, even in these settings, the ability to provide effective care to high-risk subgroups without generating significant financial losses remains a concern.

ALLHAT

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)²⁶ enrolled more than 33,000 hypertensive patients at high risk, of whom 32% were black, 16% were Hispanic, and 36% had diabetes. Their mean serum creatinine level was 1 mg/dL. Follow-up was for up to 8 years. At year 5, the mean blood pressure was 135/75 mm Hg.

In a secondary analysis, patients were stratified by GFR:

• Normal (> 90 mL/min/1.73 m²; n = 8,126)
• Mild reduction (60–89 mL/min/1.73 m²; n = 18,109)
• Moderate-severe reduction (< 60 mL/min/1.73 m²; n = 5,662).

In all three groups, amlodipine, lisinopril (Zestril), and chlorthalidone were equivalent as initial monotherapy in reducing the rate of the composite end point of end-stage renal disease or 50% or greater decrement in GFR.

Comments. The combined AASK, RENAAL, and ALLHAT findings are consistent with the practical recommendation of a diuretic, renin-angiotensin system inhibitor, or both, as initial therapy for blood pressure control in African American patients who have CKD, with a target blood pressure of less than 130/80 mm Hg.

A COMPREHENSIVE APPROACH TO CHRONIC KIDNEY DISEASE CARE

“It is much more important to know what sort of a patient has a disease, than what sort of disease a patient has.”

—William Osler

Many of the risk factors for cardiovascular disease in African Americans are behavioral and modifiable. These include too much salt and fat in the diet, too little physical activity, excessive alcohol intake, and smoking.

Education is key, to identify and communicate the risk attributable to health beliefs and behaviors, particularly in patients with known cardiovascular disease, and to encourage the patient to be proactive in risk-reduction strategies (Table 1). However, effective communication depends on compassion and concern by the health care provider to engender a sense of trust.²⁷ Other health care professionals such as dietitians, pharmacists, and social workers as well as family members can reinforce messages and improve communication with the patient to optimize outcomes.

The International Society on Hypertension in Blacks recommends a blood pressure target of less than 130/80 mm Hg in blacks with elevated blood pressure and target-organ damage. The authors suggest monotherapy with a diuretic or calcium channel blocker if the blood pressure is 10 mm Hg or less above target levels. When blood pressure is more than 15/10 mm Hg above target, two-drug therapy is recommended, either with a calcium channel blocker plus a renin-angiotensin system blocker or, alternatively, in edematous or volume-overload states, with a thiazide diuretic plus a renin-angiotensin system blocker.^28,29

The Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease of the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative recommend starting anti-hypertensive therapy with an ACE inhibitor or an angiotensin receptor blocker for most patients with CKD, regardless of ethnicity, recognizing that many will require combination therapy.³⁰ Evaluation of the response to therapy should include not only checking that the blood pressure is at or below the recommended target of 130/80 mm Hg, but also assessing for complications and monitoring the change in the level of proteinuria, which is a powerful predictor of progression of hypertensive kidney disease in all patients at any given GFR.³¹

OUR RECOMMENDATIONS

African Americans with hypertension and kidney disease require an aggressive and comprehensive approach to slow the progression of kidney disease and its complications, often necessitating aggressive care of the primary cause and the use of two or more antihypertensive agents to control blood pressure, proteinuria, or both (Figure 1).³²

We recommend that the initial evaluation of patients with hypertension include a screening for albuminuria and that the initial therapy for hypertension or proteinuria in all patients with CKD include renin-angiotensin system inhibition with a diuretic, because this combination appears most effective to achieve blood pressure control and to confer additional cardiorenal protection beyond that offered by blood-pressure control alone. Although some studies have reported that African Americans have lower blood-pressure response rates than whites to renin-angiotensin system inhibition, 18 it is nevertheless beneficial for clinical outcomes in this group, especially in the presence of proteinuria, a hallmark of hypertension-related CKD in African Americans. Thus, until more data are available, ethnicity should not be the primary criterion for selecting a given class of antihypertensive therapy, especially in patients with hypertensive nephropathy.

The overall treatment decision should be guided by individual response, coexisting risk factors, and potential cultural and socioeconomic considerations such as cost of medications and insurance coverage, which affect adherence to both pharmacologic and nonpharmacologic interventions.³³

Future studies should strive for adequate representation of racial and ethnic minority populations in order to enhance the evidence base for CKD treatment as we move toward using personalized medicine approaches in an increasingly diverse society.³⁴
 

Acknowledgment: Support for this paper was provided in part by NIH grants RR026138 and MD000182.

“Healthy citizens are the greatest asset any country can have.”

—Winston Churchill

Diabetes and high blood pressure take a toll on the kidneys, especially in African Americans. To prevent chronic kidney disease (CKD) and to slow or stop its progression, the same principles apply in African Americans as in other patients—ie, vigilance for the onset of proteinuria, aggressive control of blood pressure, drug treatment to block the renin-angiotensin system, and attention to lifestyle factors (Table 1). However, we need to try to do better in the care of African Americans.

The purpose of this article is to review recent evidence- and consensus-based recommendations and to present a practical approach for the evaluation and treatment of CKD in African Americans.

CKD DEFINED

In 2002, the National Kidney Foundation¹ defined CKD as either:

• Kidney damage for 3 or more months, as defined by structural or functional abnormalities of the kidney, with or without a decreased glomerular filtration rate (GFR), manifested either by pathologic abnormalities or by markers of kidney damage, including abnormalities in the composition of the blood or urine (eg, proteinuria), or abnormalities in imaging tests; or
• A GFR less than 60 mL/min/1.73 m² for 3 or more months, with or without kidney damage.

The definition divides CKD into five progressive stages according to the GFR:

• Stage 1 (kidney damage with normal or increased GFR): GFR ≥ 90 mL/min/1.73m²
• Stage 2 (kidney damage with mildly decreased GFR): GFR 60–89
• Stage 3 (moderately decreased GFR): GFR 30–59
• Stage 4 (severely decreased GFR): GFR 15–29
• Stage 5 (kidney failure): GFR < 15 or dialysis.

Because the definition includes markers of kidney damage such as albuminuria, it allows CKD to be detected in its earliest stages, when the estimated GFR might still be well within normal limits.

CKD APPEARS EARLIER, PROGRESSES FASTER IN AFRICAN AMERICANS

“Not everything that counts can be counted, and not everything that can be counted counts.”

—Albert Einstein

CKD with or without a sustained reduction in the estimated GFR affects about one in every nine American adults.2 Its course varies depending on the cause and also from patient to patient, even in those with the same cause of CKD.

In general, the prevalence of early CKD is comparable across racial and ethnic groups in the United States, but CKD progresses to end-stage renal disease far more rapidly in minority populations, with rates nearly four times higher in black Americans than in white Americans.³ Also, the onset of CKD is earlier in African Americans.

HYPERTENSION AND DIABETES AS REASONS FOR THE DISPARITIES

Part of the reason for these differences is that minority populations have higher rates of diabetes and hypertension, and these diseases tend to be more severe in these groups. Poverty, less access to health care, exposure to environmental toxins, and genetic variation may also contribute.^4–7

Compared with whites, blacks have higher rates of diabetes and hypertension and earlier onset of these diseases, poorer control, and higher rates of complications such as CKD, stroke, and heart disease.^8,9 The higher rate of hypertension and the lower rate of blood pressure control in African Americans with CKD may contribute to the more rapid progression of CKD to end-stage renal disease.

In the Chronic Renal Insufficiency Cohort, ¹⁰ a racially and ethnically diverse group of 3,612 adults with a broad spectrum of renal disease severity, 93% of African Americans had hypertension at baseline compared with 80% of whites. In addition, African Americans were 18% less likely to have their blood pressure controlled to 140/90 mm Hg (the rates of control were 76% vs 60%), and 28% were less likely to have it controlled to 130/80 mm Hg (56% vs 38%).¹⁰ These factors may partially explain the faster progression to end-stage renal disease in African Americans with CKD.

Despite the potential efficacy of strict control of serum glucose levels and blood pressure,¹¹ the high rate of poor blood pressure control has contributed to the epidemic of diabetic nephropathy, especially among African Americans. Fortunately, hypertension control in the general population, while still not ideal, has improved from 27% in 1988–1994 to 50% in 2007–2008 and is now similar across racial and ethnic groups.¹² This, hopefully, is a preface for improved hypertension-related outcomes for all Americans over the next decade.

OTHER REASONS FOR THE DISPARITIES

“There are no unnatural or supernatural phenomena, only a very large gap in our knowledge of what is natural.”

—Edgar Mitchell, Apollo 14 astronaut

Proteinuria

Proteinuria is another key cardiorenal risk factor prevalent in African Americans.

Knight et al,¹³ analyzing data from the Third National Health and Nutrition Examination Survey, found that people with high-normal blood pressure (systolic pressure 130–139 mm Hg or diastolic pressure 85–89 mm Hg) were twice as likely to have microalbuminuria (odds ratio 2.13, 95% confidence interval [CI] 1.51–3.01) compared with people with optimal blood pressure (systolic pressure < 120 mm Hg and diastolic pressure < 80 mm Hg). Compared with whites as the reference group, Mexican Americans had slightly but not statistically significantly higher odds of microalbuminuria (odds ratio 1.16; 95% CI 0.90–1.51), and African Americans had significantly higher odds (odds ratio 1.30; 95% CI 1.04–1.64).

The incidence of hypertension-related end-stage renal disease is nearly five times higher in African Americans than in whites, and the rate of hypertension-related end-stage renal disease is 15 times higher in African American men ages 24 to 44 than in whites of the same ages.³ The greater risk of proteinuria in African Americans at any given level of higher blood pressure is thought to contribute in part to these disparate rates.

The renin-angiotensin system

The renin-angiotensin system plays a role in modulating hypertension and mediating hypertension-related complications. Hypertensive African Americans are more likely than hypertensive whites to have low-renin, salt-sensitive hypertension. Therein lies a paradox.

Since the renin-angiotensin system promotes the progression of CKD, we would expect patients with low-renin hypertension to have a lower risk of hypertension-related endorgan damage than patients with high-renin hypertension. However, many African Americans (who as a group have high rates of sodium sensitivity and low plasma renin levels) experience more severe hypertension-related end-organ complications such as proteinuria and cardiorenal disease.¹⁴

A reason for this paradox may be that the circulating renin-angiotensin system is separate from the intrarenal one. Supporting this theory is the observation that up-regulation of the intrarenal renin-angiotensin system accompanies renal interstitial inflammation and oxidative stress in the kidneys and cardiovascular tissues of salt-sensitive rats fed a high-salt diet.¹⁵ In other experiments in salt-sensitive rats, renin-angiotensin system blockade reversed endothelial dysfunction, attenuated proteinuria, and reduced renal injury independent of blood pressure changes even though the animals had low circulating renin levels.¹⁶

These findings imply that drugs that block the renin-angiotensin system, ie, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, could still be a rational therapy for CKD patients with low-renin hypertension, particularly African Americans, in whom local up-regulation of the renin-angiotensin system in the kidney could exacerbate both diabetic and hypertensive CKD.¹⁷ Although these drugs may not lower blood pressure as much in low-renin hypertension as in high-renin hypertension, they may still afford the same cardiorenal protection.

Genetic factors

Variations in the MYH9 and APOL1 genes on chromosome 22 have recently been found in genome-wide admixture mapping studies and may explain as much as 70% of the differences in the rates of nondiabetic end-stage renal disease between white and black Americans.^7,18,19 In addition, genetic variations may modulate differences in blood-pressure response to antihypertensive medications across racial and ethnic groups,²⁰ complicating treatment recommendations and clinical outcomes in our increasingly diverse nation.

Comment. The pathophysiologic basis for the variability in the course of CKD is probably multifactorial and is still poorly understood. Nevertheless, we may be able to delay the progression of CKD and prevent its complications with specific therapeutic and life-style interventions.

Race and ethnicity are associated with sociocultural and biologic variations that influence the risk and progression of CKD. Understanding these factors for minority populations can help in targeting interventions to attenuate the disproportionately high rates of CKD progression and complications.

The pathophysiologic reason African Americans have a greater prevalence of end-stage renal disease and a more rapid progression of CKD is complex and probably involves the interplay of biological, behavioral, and environmental factors such as salt intake, stress levels, and exposure to heavy metals.²¹

TRIALS OF ANTIHYPERTENSIVE THERAPY IN AFRICAN AMERICANS WITH CKD

“If we knew what we were doing, it wouldn’t be called research.”

—Albert Einstein

Until recently, trials of antihypertensive therapy in patients with CKD did not include adequate numbers of African American participants, but the following clinical trials have added to our knowledge (Table 2).^22–26

African American Study of Kidney Disease and Hypertension (AASK)

The African American Study of Kidney Disease and Hypertension (AASK),^22,23 with 1,094 patients, was the largest prospective study of CKD to date designed to focus on African Americans.

AASK examined the effects of two levels of blood-pressure control:

• Standard, with a goal blood pressure of 135–140/85–90 mm Hg (mean arterial pressure 102–107 mm Hg)
• Intensive, with a goal of 120/80 mm Hg or less (mean arterial pressure ≤ 92 mm Hg).

In a two-by two factorial design, patients were also randomized to receive one of three antihypertensive drugs as initial therapy:

• The ACE inhibitor ramipril (Altace)
• The sustained-release beta-blocker metoprolol succinate (Toprol XL)
• The calcium channel blocker amlodipine (Norvasc).

To enter the study, patients had to be African American, have at least one diastolic pressure reading of 95 mm Hg or greater during the screening period, and have a measured GFR between 20 and 65 mL/min/1.83 m². They could not have diabetes, substantial proteinuria (> 2.5 g/day), or other causes of CKD.²²

AASK was distinct from many of the larger hypertension trials in which secondary analyses of outcomes in patients with CKD were performed in that it was implicit in the design that most, if not all, study participants had substantial GFR reduction and would need diuretic therapy.

At baseline, after blood pressure medications had been tapered to define eligibility and then reintroduced before randomization, 20.0% of the patients in the intensive blood pressure goal group had pressure lower than 140/90 mm Hg, and this increased to 78.9% by 14 months after randomization. In the standard goal group, the numbers were 21.5% at baseline but only 41.8% at 14 months.²³ In spite of this difference, the rate of decline in GFR (the main clinical outcome measure) was the same in both groups.

However, the class of drug did make a difference. Secondary clinical outcomes, including the composite end point of development of end-stage renal disease, doubling of serum creatinine, or death, were less frequent in the ACE inhibitor group than in the beta-blocker and calcium channel blocker groups. As anticipated and consistent with real world practice, nearly 90% of all participants received concomitant diuretic therapy to achieve target blood pressure levels.

Comments. AASK showed that blood pressure can be controlled in African Americans who have CKD and that clinical cardiorenal outcomes can be improved by using an ACE inhibitor as initial therapy rather than a beta-blocker or calcium channel blocker, with diuretics and other agents added as needed.

AASK cohort phase

After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood pressure target was less than 130/80 mm Hg. The combined follow-up period was 8.8 to 12.2 years.²⁴

During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive group and 141/86 mm Hg in the standard group. During the cohort phase, the mean blood pressures were 131/78 mm Hg and 134/78 mm Hg, respectively, in these groups.

In both phases, there was no significant difference between groups in clinical outcomes (hazard ratio in the intensive-control group 0.91, P = .27). However, the groups differed when stratified by baseline level of proteinuria (P = .02 for the interaction), with a potential benefit of a blood pressure target lower than 130/80 mm Hg in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio 0.73, P = .01).²⁴

Comment. Given that many African Americans with hypertension and CKD have a protein-to-creatinine ratio of more than 0.22, these findings support a practical approach in clinical practice for a target blood pressure less than 130/80 mm Hg, using a first-line combination of a renin-angiotensin system inhibitor and a diuretic.

RENAAL study

The Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) study²⁵ included 1,513 patients, of whom 15% were African American and 18% were Hispanic; all had type 2 diabetes mellitus and nephropathy. They were randomized to receive the angiotensin II receptor antagonist losartan (Cozaar) or placebo in addition to other antihypertensive drugs.

At 3.4 years, the blood pressure was about 141/74 mm Hg in both groups. A post hoc analysis found lower rates of albuminuria and end-stage renal disease in the group treated with losartan,²⁵ with no racial or ethnic differences in its renoprotective effect.

Comments. While these findings support the recommendation of inhibiting the renin-angiotensin system for improving clinical outcomes in diabetic nephropathy in racial and ethnic minorities, the AASK study also proved a second important point. These patients required intense blood pressure management for several years in a clinical trial environment, which may be difficult to do in many clinical practice models.

To be cost-effective in today’s health care environment, such care will likely be limited to larger group practices or health care plans with large comprehensive covered populations. Payers and providers need to be willing to invest in intense early care in such high-risk subgroups with the understanding that they could recognize downstream gains from long-term improved outcomes. However, even in these settings, the ability to provide effective care to high-risk subgroups without generating significant financial losses remains a concern.

ALLHAT

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)²⁶ enrolled more than 33,000 hypertensive patients at high risk, of whom 32% were black, 16% were Hispanic, and 36% had diabetes. Their mean serum creatinine level was 1 mg/dL. Follow-up was for up to 8 years. At year 5, the mean blood pressure was 135/75 mm Hg.

In a secondary analysis, patients were stratified by GFR:

• Normal (> 90 mL/min/1.73 m²; n = 8,126)
• Mild reduction (60–89 mL/min/1.73 m²; n = 18,109)
• Moderate-severe reduction (< 60 mL/min/1.73 m²; n = 5,662).

In all three groups, amlodipine, lisinopril (Zestril), and chlorthalidone were equivalent as initial monotherapy in reducing the rate of the composite end point of end-stage renal disease or 50% or greater decrement in GFR.

Comments. The combined AASK, RENAAL, and ALLHAT findings are consistent with the practical recommendation of a diuretic, renin-angiotensin system inhibitor, or both, as initial therapy for blood pressure control in African American patients who have CKD, with a target blood pressure of less than 130/80 mm Hg.

A COMPREHENSIVE APPROACH TO CHRONIC KIDNEY DISEASE CARE

“It is much more important to know what sort of a patient has a disease, than what sort of disease a patient has.”

—William Osler

Many of the risk factors for cardiovascular disease in African Americans are behavioral and modifiable. These include too much salt and fat in the diet, too little physical activity, excessive alcohol intake, and smoking.

Education is key, to identify and communicate the risk attributable to health beliefs and behaviors, particularly in patients with known cardiovascular disease, and to encourage the patient to be proactive in risk-reduction strategies (Table 1). However, effective communication depends on compassion and concern by the health care provider to engender a sense of trust.²⁷ Other health care professionals such as dietitians, pharmacists, and social workers as well as family members can reinforce messages and improve communication with the patient to optimize outcomes.

The International Society on Hypertension in Blacks recommends a blood pressure target of less than 130/80 mm Hg in blacks with elevated blood pressure and target-organ damage. The authors suggest monotherapy with a diuretic or calcium channel blocker if the blood pressure is 10 mm Hg or less above target levels. When blood pressure is more than 15/10 mm Hg above target, two-drug therapy is recommended, either with a calcium channel blocker plus a renin-angiotensin system blocker or, alternatively, in edematous or volume-overload states, with a thiazide diuretic plus a renin-angiotensin system blocker.^28,29

The Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease of the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative recommend starting anti-hypertensive therapy with an ACE inhibitor or an angiotensin receptor blocker for most patients with CKD, regardless of ethnicity, recognizing that many will require combination therapy.³⁰ Evaluation of the response to therapy should include not only checking that the blood pressure is at or below the recommended target of 130/80 mm Hg, but also assessing for complications and monitoring the change in the level of proteinuria, which is a powerful predictor of progression of hypertensive kidney disease in all patients at any given GFR.³¹

OUR RECOMMENDATIONS

African Americans with hypertension and kidney disease require an aggressive and comprehensive approach to slow the progression of kidney disease and its complications, often necessitating aggressive care of the primary cause and the use of two or more antihypertensive agents to control blood pressure, proteinuria, or both (Figure 1).³²

We recommend that the initial evaluation of patients with hypertension include a screening for albuminuria and that the initial therapy for hypertension or proteinuria in all patients with CKD include renin-angiotensin system inhibition with a diuretic, because this combination appears most effective to achieve blood pressure control and to confer additional cardiorenal protection beyond that offered by blood-pressure control alone. Although some studies have reported that African Americans have lower blood-pressure response rates than whites to renin-angiotensin system inhibition, 18 it is nevertheless beneficial for clinical outcomes in this group, especially in the presence of proteinuria, a hallmark of hypertension-related CKD in African Americans. Thus, until more data are available, ethnicity should not be the primary criterion for selecting a given class of antihypertensive therapy, especially in patients with hypertensive nephropathy.

The overall treatment decision should be guided by individual response, coexisting risk factors, and potential cultural and socioeconomic considerations such as cost of medications and insurance coverage, which affect adherence to both pharmacologic and nonpharmacologic interventions.³³

Future studies should strive for adequate representation of racial and ethnic minority populations in order to enhance the evidence base for CKD treatment as we move toward using personalized medicine approaches in an increasingly diverse society.³⁴
 

Acknowledgment: Support for this paper was provided in part by NIH grants RR026138 and MD000182.

Editor’s note: This article on the differential diagnosis of hypogonadism in men is the first of two articles. The second, to be published next month, focuses on the appropriate use of testosterone therapy.

A 54-year-old man is referred for evaluation of low testosterone. He had seen his primary care physician for complaints of diminished libido and erectile dysfunction for the past year and worsening fatigue over the past few years. He has not been formally diagnosed with any medical condition. His serum testosterone level is 180 ng/dL (reference range 249–836 ng/dL).

On physical examination, he is obese (body mass index 31 kg/m²) with a normal-appearing male body habitus, no gynecomastia, and normal testicles and prostate gland.

How should this patient be evaluated?

LOW TESTOSTERONE HAS MANY CAUSES

Male hypogonadism, ie, failure of the testes to produce adequate amounts of androgen or sperm, has become a common clinical finding, particularly in the older population. This is more likely the result of an increase in awareness and detection of the disorder by physicians rather than a true increase in prevalence.

The finding of a low serum testosterone value needs to be confirmed and thoroughly evaluated before starting treatment. It is important to determine whether the cause is a primary (hypergonadotropic) testicular disorder or secondary to a hypothalamic-pituitary process (hypogonadotropic or normogonadotropic).

THE HYPOTHALAMIC-PITUITARY-GONADAL AXIS

Testosterone production is under the control of luteinizing hormone (LH), whereas sperm production is under the control of follicle-stimulating hormone (FSH) (Figure 1). Both of these pituitary hormones are regulated by the pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH).

Testosterone (produced by Leydig cells) and inhibin B (produced by Sertoli cells within the seminiferous tubules) result in negative feedback inhibition of gonadotropin (LH and FSH) secretion. Testosterone and estradiol (produced by aromatization of testosterone) act at both pituitary and hypothalamic sites and are the principal regulators of LH secretion.^1,2 Inhibin B is the major regulator of FSH secretion in men,³ but steroid feedback also occurs.^2,4

TO FOLLOW UP A LOW TESTOSTERONE, CONFIRM THE VALUE NEAR 8 am

If a testosterone value is found to be low, it is important to determine the time that the sample was obtained. Serum testosterone levels follow a diurnal rhythm, at least in younger men, with values near 8 am being, on average, 30% higher than the trough levels later in the day.^5–7 The timing of the diurnal variation may be different in night-shift workers, who may require assessment at a more appropriate time of the day (ie, upon awakening).

Another factor affecting testosterone levels is the patient’s health status at the time of testing. Values obtained in the hospital during an acute illness should be repeated once the event has resolved, as testosterone values decrease considerably in this setting.⁸ Even in outpatients, particularly in men over age 60, one must be sure that the low testosterone level was not obtained during a period of decompensation of one of the many comorbidities seen in these patients, such as coronary artery disease, congestive heart failure, or uncontrolled diabetes.

If an 8 am testosterone value is low, it is reasonable to obtain at least one confirmatory testosterone level on another day, near 8 am, in the next few weeks, when the patient is in good health. Confirming the testosterone level is important, particularly since commercially available testosterone assays are not well standardized and some are frankly unreliable.^9,10 A repeat confirmatory level should always be performed by a reliable reference laboratory. If the testosterone level is still low, further evaluation is warranted.

TOTAL TESTOSTERONE VS BIOAVAILABLE TESTOSTERONE VS FREE TESTOSTERONE

Of the total circulating testosterone, 60% is bound to sex hormone-binding globulin (SHBG), 38% is bound to albumin, and only 2% is free. All of these fractions can be measured to assess for testosterone deficiency.

Free testosterone is the biologically active form of this hormone and, thus, the free testosterone level is considered to be a better representation of the true testosterone status. However, some clinicians believe that bioavailable testosterone (testosterone loosely bound to albumin + free testosterone) is a better reflection of the true level of the active hormone than the level of free testosterone alone.

There are situations in which the total testosterone level is low but bioavailable or free testosterone levels are normal. The level of total testosterone is affected by alterations in the levels of SHBG and albumin. A reduction in the level of SHBG can result in low total serum testosterone levels in patients with obesity or type 2 diabetes (states of insulin resistance), and also in cachexia, malnutrition, advanced cirrhosis, acromegaly, hypothyroidism, and nephrotic syndrome. SHBG can also be low in patients taking glucocorticoids, progestins, or androgenic steroids.¹¹ In these settings, checking the level of free testosterone (the active hormone), bioavailable testosterone, or both, by a reliable reference laboratory, may be more appropriate.^9,10

But regardless of which measurement is chosen, all testosterone levels—especially bioavailable and free testosterone values—should be interpreted with caution if they are not measured at a reliable reference laboratory.^9,10 Interested readers may wish to see the US Centers for Disease Control and Prevention (CDC) Hormone Standardization Program Web site (www.cdc.gov/labstandards/hs.html) for more details, including a list of CDC-certified laboratories.

CLINICAL FEATURES OF LOW TESTOSTERONE

A history of erectile dysfunction, decreased libido, and fatigue may be seen in patients with low testosterone. However, one must realize that these symptoms—as well as others reported by men with low testosterone, such as depression, difficulty concentrating, irritability, and insomnia—are nonspecific and may be related to other medical conditions.¹²

Likewise, physical findings such as muscle weakness, reduced body hair, and altered fat distribution (abdominal obesity) are seen in men with low testosterone, but also in those with a number of other medical conditions.

Additional features suggest specific disorders, eg, anosmia in Kallmann syndrome; eunuchoid body habitus, gynecomastia, and small testes in Klinefelter syndrome.

Men with low testosterone may have low bone mineral density or anemia, or both.

Careful examination of the breasts for gynecomastia and the testes for size, consistency, and masses (testicular tumors) helps in formulating a differential diagnosis and in appropriately directing subsequent laboratory evaluation and diagnostic imaging.

LOW TESTOSTERONE: PRIMARY VS SECONDARY

A history of testicular trauma, systemic chemotherapy, or mumps orchitis should direct the physician’s attention to a testicular etiology. On the other hand, darkened or tanned skin (suggesting hemochromatosis), galactorrhea (suggesting hyperprolactinemia), or visual field deficits (suggesting a sellar mass) should direct the physician’s attention toward a pituitary-hypothalamic process.

Once the low testosterone value has been confirmed at least one time near 8 am, one should obtain LH and FSH values to help direct further evaluation in deciphering the etiology (Figure 2). Elevated (hypergonadotropic) values indicate a testicular disorder (primary hypogonadism), whereas low (hypogonadotropic) or normal (normogonadotropic) values point to a pituitary-hypothalamic process (secondary hypogonadism). It should be emphasized that, in the setting of a low testosterone level, LH and FSH values within the normal range are “inappropriately normal” so that further investigation is required.

This evaluation should also include serum prolactin, thyroid-stimulating hormone (TSH, also known as thyrotropin), free thyroxine (T₄), and ferritin levels, the latter because hemochromatosis (iron overload) can cause both primary and secondary hypogonadism. If at any time in the evaluation the laboratory results suggest secondary hypogonadism, a full assessment of pituitary function should be undertaken.

Semen analysis is usually reserved for patients presenting with the primary complaint of infertility.

PRIMARY HYPOGONADISM

The patient should be carefully questioned about the age at which his problems began, about pubertal development, and about fertility. Causes of primary hypogonadism include:

• Karyotype abnormalities—Klinefelter syndrome (47, XXY syndrome) is the most common
• Toxin exposure, chemotherapy
• Congenital defects—anorchia, cryptorchidism¹³
• Orchitis (mumps, autoimmune)
• Testicular trauma or infarction
• Hemochromatosis
• Medications that inhibit androgen biosynthesis, eg, ketoconazole (Nizoral)¹⁴
• Increase in temperature of the testicular environment (due to varicocele or a large panniculus).

SECONDARY HYPOGONADISM

Causes of secondary hypogonadism include the following:

Congenital disorders

These disorders are usually diagnosed in childhood or adolescence, often after the patient is brought to the physician because of short stature or pubertal delay.

• Kallmann syndrome (anosmia and GnRH deficiency)¹⁵
• GnRH receptor mutation and deficiency¹⁶
• Genetic mutations associated with pituitary hormone deficiencies, eg, PROP-1 mutation.¹⁷

Drugs. Long-term therapy with common medications such as opioids or corticosteroids can result in secondary hypogonadism.^18–20 Others are GnRH analogues such as leuprolide (Lupron), which are used in treating advanced prostate cancer. The hypogonadism is usually transient and resolves after stopping the offending agent.

Obesity and related conditions such as obstructive sleep apnea, insulin resistance, and type 2 diabetes mellitus are associated with low testosterone levels.²¹ Treatment should be directed at these underlying conditions and should include lifestyle measures such as weight loss and exercise, rather than simple prescribing of testosterone supplementation, as these efforts may provide multiple health benefits in addition to raising testosterone levels.²²

Insulin resistance. In the setting of obesity, the total testosterone level may be low but the bioavailable and free testosterone (active hormone) levels may be normal. This is due to the effect of hyperinsulinemia on the liver, which results in a reduction in SHBG production.²³ Low levels of both total and free testosterone can be seen in morbid obesity,²⁴ but the cause remains unclear.

Type 2 diabetes mellitus. Testosterone levels have been reported to be lower in obese men who have diabetes than in those with obesity alone.²⁴ This decrement, comparable in magnitude to that seen with other chronic diseases, suggests that low testosterone may simply be a marker of poor health.^22,25,26

Sleep apnea. Disturbances in the sleep cycle, regardless of the underlying cause, can result in decreases in serum testosterone levels. Often, correcting the underlying sleep disturbance can result in a normalization of serum testosterone levels.^27,28 A caveat about testosterone therapy: a thorough evaluation for sleep apnea should be undertaken in patients at high risk, since testosterone replacement therapy can adversely affect ventilatory drive and induce or worsen obstructive sleep apnea.²⁹

Aging. Most reports have shown an agerelated decline in both total and free serum testosterone levels (commonly referred to as “andropause”), particularly in men over 60 years of age. There also appears to be a loss of circadian rhythm,³⁰ although not all reports agree.⁶ It appears that factors such as functional status and overall health may play a more important role in the pathophysiology of hypogonadism in men of advanced age than age alone.

Hemochromatosis. Iron overload, regardless of the cause, can result in hypogonadism via deposition of iron in the hypothalamus, pituitary, or testes. Hereditary hemochromatosis is a common autosomal recessive disease characterized by increased iron absorption. Although both primary and secondary hypogonadism can occur with long-standing iron overload, the latter is much more common.³¹ Some cases of hypogonadism have been reported to reverse with iron depletion therapy.³²

Hyperprolactinemia. Recognized causes of hyperprolactinemia in men include medications (dopamine antagonists, antipsychotics, metoclopramide [Reglan]), pituitary adenomas (microadenomas < 10 mm, macroadenomas ≥ 10 mm), lactotroph hyperfunction (stalk compression interrupting or reducing the tonic suppression of prolactin secretion by dopamine), hypothyroidism, stress, chronic renal failure, cirrhosis, chest wall injury (trauma), and active herpes zoster. The ensuing hypogonadism may be due to the compressive effect of a sellar mass or the direct effect of the prolactin elevation alone, since prolactin disrupts the pulsatile release of GnRH from the hypothalamus,³³ required for normal LH and FSH secretion.

Estrogen excess can be either exogenous (from exposure to estrogen-containing contraceptives and creams) or endogenous (from testicular^34,35 or very rare adrenal³⁶ estrogen-secreting tumors). Of note, some cases of testicular neoplasms may be detectable only with ultrasonography. Computed tomography may be performed if an adrenal lesion is suspected.

Anabolic steroid abuse. Exposure to anabolic steroids, deliberately or inadvertently, can result in secondary hypogonadism and testicular atrophy, both of which may persist for years after stopping the anabolic agents. If you suspect anabolic steroid abuse, a urine anabolic steroid screen can be obtained.

Anorexia nervosa is far less common in men than in women.^37,38 Elements in the history that suggest this disorder include excessive exercise and a low body mass index. Chronic malnutrition (cachexia), regardless of the cause, can result in secondary hypogonadism.

Acute illness (gonadotroph sick syndrome). Hypogonadism is a relatively common finding in any critical illness (analogous to euthyroid sick syndrome with respect to the hypothalamic-pituitary-thyroid axis).⁸ Testosterone levels are invariably low, so that assessment of testosterone status is not recommended in this setting. The low testosterone phase is usually transient and resolves with resolution or improvement of the underlying medical condition, such as sepsis or myocardial infarction.

HIV. Human immunodeficiency virus (HIV) infection can result in primary or secondary hypogonadism. It can occur with active HIV infection, in patients in whom control of viral replication has been achieved with highly active antiretroviral therapy, and even in patients who have normalized CD4+ cell counts.³⁹ Hypogonadism in HIV patients is multifactorial and may be related to weight loss, opportunistic infections of the pituitary-hypothalamus or testes, or medications such as opioids (licit or illicit), ganciclovir (Cytovene), ketoconazole, the appetite stimulant megestrol (Megace), or cyclophosphamide (Cytoxan). Testosterone replacement therapy does not adversely affect the HIV disease process and in fact may help to avoid complications.

Chronic medical conditions such as cirrhosis, renal failure, and rheumatoid arthritis commonly result in hypogonadism, the pathogenesis of which may involve dysfunction at all levels of the hypothalamic-pituitary-go-nadal axis.^40–45 Hypogonadism in the setting of chronic disease is multifactorial, being due not only to the metabolic disturbances seen with these illnesses (uremia in renal failure, elevated circulating estrogens in liver cirrhosis), but also to recurrent acute illness and hospitalization for infection in these immuno-compromised hosts, either from the underlying medical condition or as a result of medications (corticosteroids).

Alcohol abuse. Alcohol can have adverse effects at all levels of the hypothalamic-pituitary-gonadal axis, resulting in low serum testosterone and reduced spermatogenesis.⁴⁶

Severe chronic primary hypothyroidism, manifested by an extreme elevation of serum thyroid-stimulating hormone (TSH), can result in hypopituitarism. Pituitary function usually recovers with restoration of euthyroidism.^47,48

Pubertal delay. Depending on the age of presentation, differentiating pubertal delay from permanent hypogonadotropic hypogonadism can be challenging.

• Sellar mass or cyst—pituitary adenoma, craniopharyngioma, Rathke cleft cyst, meningioma
• Infiltrative lesion—lymphocytic hypophysitis, Langerhans cell histiocytosis, hemochromatosis, sarcoidosis, infection
• Metastatic lesion
• Trauma (head injury)
• Radiation exposure
• Surgery
• Stalk severance
• Pituitary apoplexy.

See Table 1 for a summary of the causes of male hypogonadism.

WHEN IS MRI INDICATED IN EVALUATING SECONDARY HYPOGONADISM?

The yield of pituitary-hypothalamic imaging in older men with secondary hypogonadism is fairly low in the absence of other pituitary hormone abnormalities and deficiencies. There are limited data regarding appropriate criteria for performing hypothalamic-pituitary imaging studies. However, a patient who has multiple anterior pituitary abnormalities on laboratory evaluation should undergo dedicated hypothalamic-pituitary magnetic resonance imaging (MRI).

The Endocrine Society Clinical Practice Guidelines¹¹ recommend that MRI be performed to exclude a pituitary or hypothalamic tumor or infiltrative disease if the patient has severe secondary hypogonadism (serum testosterone < 150 ng/dL), panhypopituitarism, persistent hyperprolactinemia, or symptoms or signs of tumor mass effect such as headache, visual impairment, or a visual field defect.

WHO SHOULD UNDERGO ASSESSMENT OF TESTOSTERONE STATUS?

Screening for androgen deficiency in the asymptomatic general population is not recommended.¹¹ The nonspecific nature of many of the signs and symptoms of androgen deficiency makes it difficult to give concrete recommendations as to who should have testosterone levels measured. Clinicians should consider testing if there is evidence of certain clinical disorders that are associated with low testosterone levels (see earlier discussion on the specific causes of primary and secondary hypogonadism).

When a male patient complains of erectile dysfunction, the investigation should include an assessment of serum testosterone. However, if a man who has a constellation of nonspecific symptoms asks for his testosterone level to be assessed (which is common, given the aggressive marketing of testosterone replacement by the pharmaceutical industry), we would recommend a basic evaluation that includes a comprehensive metabolic panel, complete blood count, and TSH level. Further testing should be determined by the history and physical examination. If no obvious explanation has been found for the patient’s symptoms at that point, assessment of serum testosterone may be warranted. More often than not the patient’s weight and limited physical activity are the driving forces behind the nonspecific symptoms, and counseling a patient on a life-style change can provide much benefit if the patient follows through with the physician’s recommendations.

Men whom we believe should not undergo assessment for testosterone deficiency are those who are acutely ill and hospitalized and those who are severely obese and are complaining of fatigue. Testosterone levels should be assessed only after the acute illness has resolved and, in a severely obese patient with fatigue, only after a thorough evaluation for sleep apnea has been undertaken.

TREAT THE UNDERLYING CAUSE, IF ONE CAN BE FOUND

If the evaluation of low testosterone leads to the diagnosis of a clear underlying condition that is amenable to treatment, such as prolactin elevation or sleep apnea, then treatment should be directed at the underlying cause, with subsequent monitoring of the patient’s symptoms and response in serum testosterone levels. In general, the use of dopamine agonist therapy in the management of hyperprolactinemia and, in cases of panhypopituitarism, of replacement therapy with levothyroxine (Synthroid), hydrocortisone, and possibly growth hormone and desmopressin (DDAVP), fall best under the purview of an endocrinologist. A caveat: serum TSH cannot be used to monitor levothyroxine replacement therapy in cases of secondary hypothyroidism. The clinical picture and serum free T₄ and free T₃ levels are used instead.

In the absence of a correctable (or immediately correctable) cause, testosterone supplementation can be initiated on an individualized basis in select patients who have clinical signs and symptoms of androgen deficiency if the benefits of treatment appear to outweigh the potential risks, and only after a thorough discussion with the patient.¹¹ The Endocrine Society recommends against offering testosterone therapy to all older men with low testosterone.¹¹

INFERTILITY

In men presenting with low serum testosterone, semen analysis is not routine. It is usually reserved for patients presenting with the primary complaint of infertility.

If an endocrine disorder such as prolactin elevation or hypothyroidism is the suspected cause of infertility, the patient should be referred to an endocrinologist for further evaluation and management. Treatment of male infertility should be directed at the underlying cause, but often requires exogenous human chorionic gonadotropin, FSH, GnRH (via a pulsatile pump), and possibly sperm harvesting from the testis with subsequent in vitro fertilization with intracytoplasmic sperm injection. It is critical that the partner be included in the evaluation of infertility.

These patients should be referred to a urologic or fertility center specializing in the diagnosis and treatment of infertility. For further information regarding male infertility, patients can be directed to www.fertilitylifelines.com.

CASE CONCLUDED

The patient’s low serum testosterone was confirmed on subsequent measurements at 8 am, with levels of 128 and 182 ng/dL (reference range 249–836). Other laboratory values:

• LH 1.4 mIU/mL (reference range 1.2–8.6)
• FSH 2.7 mIU/mL (1.3–9.9 mIU/mL)

(Both of these values are inappropriately normal in the setting of the low testosterone.)

• TSH 248 μIU/mL (0.4–5.5)
• Prolactin 24.6 ng/mL (1.6–18.8).

The patient was started on levothyroxine replacement therapy and after 3 months was noted to be euthyroid (TSH 1.8 μIU/mL) and to have a normal serum prolactin level. Testosterone levels (8 am) at this time were 350 ng/dL and 420 ng/dL.

Therefore, the cause of this patient’s hypogonadism was severe hypothyroidism and associated mild hyperprolactinemia. This case shows that a thorough evaluation is warranted before initiating testosterone therapy.

Editor’s note: This article on the differential diagnosis of hypogonadism in men is the first of two articles. The second, to be published next month, focuses on the appropriate use of testosterone therapy.

A 54-year-old man is referred for evaluation of low testosterone. He had seen his primary care physician for complaints of diminished libido and erectile dysfunction for the past year and worsening fatigue over the past few years. He has not been formally diagnosed with any medical condition. His serum testosterone level is 180 ng/dL (reference range 249–836 ng/dL).

On physical examination, he is obese (body mass index 31 kg/m²) with a normal-appearing male body habitus, no gynecomastia, and normal testicles and prostate gland.

How should this patient be evaluated?

LOW TESTOSTERONE HAS MANY CAUSES

Male hypogonadism, ie, failure of the testes to produce adequate amounts of androgen or sperm, has become a common clinical finding, particularly in the older population. This is more likely the result of an increase in awareness and detection of the disorder by physicians rather than a true increase in prevalence.

The finding of a low serum testosterone value needs to be confirmed and thoroughly evaluated before starting treatment. It is important to determine whether the cause is a primary (hypergonadotropic) testicular disorder or secondary to a hypothalamic-pituitary process (hypogonadotropic or normogonadotropic).

THE HYPOTHALAMIC-PITUITARY-GONADAL AXIS

Testosterone production is under the control of luteinizing hormone (LH), whereas sperm production is under the control of follicle-stimulating hormone (FSH) (Figure 1). Both of these pituitary hormones are regulated by the pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH).

Testosterone (produced by Leydig cells) and inhibin B (produced by Sertoli cells within the seminiferous tubules) result in negative feedback inhibition of gonadotropin (LH and FSH) secretion. Testosterone and estradiol (produced by aromatization of testosterone) act at both pituitary and hypothalamic sites and are the principal regulators of LH secretion.^1,2 Inhibin B is the major regulator of FSH secretion in men,³ but steroid feedback also occurs.^2,4

TO FOLLOW UP A LOW TESTOSTERONE, CONFIRM THE VALUE NEAR 8 am

If a testosterone value is found to be low, it is important to determine the time that the sample was obtained. Serum testosterone levels follow a diurnal rhythm, at least in younger men, with values near 8 am being, on average, 30% higher than the trough levels later in the day.^5–7 The timing of the diurnal variation may be different in night-shift workers, who may require assessment at a more appropriate time of the day (ie, upon awakening).

Another factor affecting testosterone levels is the patient’s health status at the time of testing. Values obtained in the hospital during an acute illness should be repeated once the event has resolved, as testosterone values decrease considerably in this setting.⁸ Even in outpatients, particularly in men over age 60, one must be sure that the low testosterone level was not obtained during a period of decompensation of one of the many comorbidities seen in these patients, such as coronary artery disease, congestive heart failure, or uncontrolled diabetes.

If an 8 am testosterone value is low, it is reasonable to obtain at least one confirmatory testosterone level on another day, near 8 am, in the next few weeks, when the patient is in good health. Confirming the testosterone level is important, particularly since commercially available testosterone assays are not well standardized and some are frankly unreliable.^9,10 A repeat confirmatory level should always be performed by a reliable reference laboratory. If the testosterone level is still low, further evaluation is warranted.

TOTAL TESTOSTERONE VS BIOAVAILABLE TESTOSTERONE VS FREE TESTOSTERONE

Of the total circulating testosterone, 60% is bound to sex hormone-binding globulin (SHBG), 38% is bound to albumin, and only 2% is free. All of these fractions can be measured to assess for testosterone deficiency.

Free testosterone is the biologically active form of this hormone and, thus, the free testosterone level is considered to be a better representation of the true testosterone status. However, some clinicians believe that bioavailable testosterone (testosterone loosely bound to albumin + free testosterone) is a better reflection of the true level of the active hormone than the level of free testosterone alone.

There are situations in which the total testosterone level is low but bioavailable or free testosterone levels are normal. The level of total testosterone is affected by alterations in the levels of SHBG and albumin. A reduction in the level of SHBG can result in low total serum testosterone levels in patients with obesity or type 2 diabetes (states of insulin resistance), and also in cachexia, malnutrition, advanced cirrhosis, acromegaly, hypothyroidism, and nephrotic syndrome. SHBG can also be low in patients taking glucocorticoids, progestins, or androgenic steroids.¹¹ In these settings, checking the level of free testosterone (the active hormone), bioavailable testosterone, or both, by a reliable reference laboratory, may be more appropriate.^9,10

But regardless of which measurement is chosen, all testosterone levels—especially bioavailable and free testosterone values—should be interpreted with caution if they are not measured at a reliable reference laboratory.^9,10 Interested readers may wish to see the US Centers for Disease Control and Prevention (CDC) Hormone Standardization Program Web site (www.cdc.gov/labstandards/hs.html) for more details, including a list of CDC-certified laboratories.

CLINICAL FEATURES OF LOW TESTOSTERONE

A history of erectile dysfunction, decreased libido, and fatigue may be seen in patients with low testosterone. However, one must realize that these symptoms—as well as others reported by men with low testosterone, such as depression, difficulty concentrating, irritability, and insomnia—are nonspecific and may be related to other medical conditions.¹²

Likewise, physical findings such as muscle weakness, reduced body hair, and altered fat distribution (abdominal obesity) are seen in men with low testosterone, but also in those with a number of other medical conditions.

Additional features suggest specific disorders, eg, anosmia in Kallmann syndrome; eunuchoid body habitus, gynecomastia, and small testes in Klinefelter syndrome.

Men with low testosterone may have low bone mineral density or anemia, or both.

Careful examination of the breasts for gynecomastia and the testes for size, consistency, and masses (testicular tumors) helps in formulating a differential diagnosis and in appropriately directing subsequent laboratory evaluation and diagnostic imaging.

LOW TESTOSTERONE: PRIMARY VS SECONDARY

A history of testicular trauma, systemic chemotherapy, or mumps orchitis should direct the physician’s attention to a testicular etiology. On the other hand, darkened or tanned skin (suggesting hemochromatosis), galactorrhea (suggesting hyperprolactinemia), or visual field deficits (suggesting a sellar mass) should direct the physician’s attention toward a pituitary-hypothalamic process.

Once the low testosterone value has been confirmed at least one time near 8 am, one should obtain LH and FSH values to help direct further evaluation in deciphering the etiology (Figure 2). Elevated (hypergonadotropic) values indicate a testicular disorder (primary hypogonadism), whereas low (hypogonadotropic) or normal (normogonadotropic) values point to a pituitary-hypothalamic process (secondary hypogonadism). It should be emphasized that, in the setting of a low testosterone level, LH and FSH values within the normal range are “inappropriately normal” so that further investigation is required.

This evaluation should also include serum prolactin, thyroid-stimulating hormone (TSH, also known as thyrotropin), free thyroxine (T₄), and ferritin levels, the latter because hemochromatosis (iron overload) can cause both primary and secondary hypogonadism. If at any time in the evaluation the laboratory results suggest secondary hypogonadism, a full assessment of pituitary function should be undertaken.

Semen analysis is usually reserved for patients presenting with the primary complaint of infertility.

PRIMARY HYPOGONADISM

The patient should be carefully questioned about the age at which his problems began, about pubertal development, and about fertility. Causes of primary hypogonadism include:

• Karyotype abnormalities—Klinefelter syndrome (47, XXY syndrome) is the most common
• Toxin exposure, chemotherapy
• Congenital defects—anorchia, cryptorchidism¹³
• Orchitis (mumps, autoimmune)
• Testicular trauma or infarction
• Hemochromatosis
• Medications that inhibit androgen biosynthesis, eg, ketoconazole (Nizoral)¹⁴
• Increase in temperature of the testicular environment (due to varicocele or a large panniculus).

SECONDARY HYPOGONADISM

Causes of secondary hypogonadism include the following:

Congenital disorders

These disorders are usually diagnosed in childhood or adolescence, often after the patient is brought to the physician because of short stature or pubertal delay.

• Kallmann syndrome (anosmia and GnRH deficiency)¹⁵
• GnRH receptor mutation and deficiency¹⁶
• Genetic mutations associated with pituitary hormone deficiencies, eg, PROP-1 mutation.¹⁷

Drugs. Long-term therapy with common medications such as opioids or corticosteroids can result in secondary hypogonadism.^18–20 Others are GnRH analogues such as leuprolide (Lupron), which are used in treating advanced prostate cancer. The hypogonadism is usually transient and resolves after stopping the offending agent.

Obesity and related conditions such as obstructive sleep apnea, insulin resistance, and type 2 diabetes mellitus are associated with low testosterone levels.²¹ Treatment should be directed at these underlying conditions and should include lifestyle measures such as weight loss and exercise, rather than simple prescribing of testosterone supplementation, as these efforts may provide multiple health benefits in addition to raising testosterone levels.²²

Insulin resistance. In the setting of obesity, the total testosterone level may be low but the bioavailable and free testosterone (active hormone) levels may be normal. This is due to the effect of hyperinsulinemia on the liver, which results in a reduction in SHBG production.²³ Low levels of both total and free testosterone can be seen in morbid obesity,²⁴ but the cause remains unclear.

Type 2 diabetes mellitus. Testosterone levels have been reported to be lower in obese men who have diabetes than in those with obesity alone.²⁴ This decrement, comparable in magnitude to that seen with other chronic diseases, suggests that low testosterone may simply be a marker of poor health.^22,25,26

Sleep apnea. Disturbances in the sleep cycle, regardless of the underlying cause, can result in decreases in serum testosterone levels. Often, correcting the underlying sleep disturbance can result in a normalization of serum testosterone levels.^27,28 A caveat about testosterone therapy: a thorough evaluation for sleep apnea should be undertaken in patients at high risk, since testosterone replacement therapy can adversely affect ventilatory drive and induce or worsen obstructive sleep apnea.²⁹

Aging. Most reports have shown an agerelated decline in both total and free serum testosterone levels (commonly referred to as “andropause”), particularly in men over 60 years of age. There also appears to be a loss of circadian rhythm,³⁰ although not all reports agree.⁶ It appears that factors such as functional status and overall health may play a more important role in the pathophysiology of hypogonadism in men of advanced age than age alone.

Hemochromatosis. Iron overload, regardless of the cause, can result in hypogonadism via deposition of iron in the hypothalamus, pituitary, or testes. Hereditary hemochromatosis is a common autosomal recessive disease characterized by increased iron absorption. Although both primary and secondary hypogonadism can occur with long-standing iron overload, the latter is much more common.³¹ Some cases of hypogonadism have been reported to reverse with iron depletion therapy.³²

Hyperprolactinemia. Recognized causes of hyperprolactinemia in men include medications (dopamine antagonists, antipsychotics, metoclopramide [Reglan]), pituitary adenomas (microadenomas < 10 mm, macroadenomas ≥ 10 mm), lactotroph hyperfunction (stalk compression interrupting or reducing the tonic suppression of prolactin secretion by dopamine), hypothyroidism, stress, chronic renal failure, cirrhosis, chest wall injury (trauma), and active herpes zoster. The ensuing hypogonadism may be due to the compressive effect of a sellar mass or the direct effect of the prolactin elevation alone, since prolactin disrupts the pulsatile release of GnRH from the hypothalamus,³³ required for normal LH and FSH secretion.

Estrogen excess can be either exogenous (from exposure to estrogen-containing contraceptives and creams) or endogenous (from testicular^34,35 or very rare adrenal³⁶ estrogen-secreting tumors). Of note, some cases of testicular neoplasms may be detectable only with ultrasonography. Computed tomography may be performed if an adrenal lesion is suspected.

Anabolic steroid abuse. Exposure to anabolic steroids, deliberately or inadvertently, can result in secondary hypogonadism and testicular atrophy, both of which may persist for years after stopping the anabolic agents. If you suspect anabolic steroid abuse, a urine anabolic steroid screen can be obtained.

Anorexia nervosa is far less common in men than in women.^37,38 Elements in the history that suggest this disorder include excessive exercise and a low body mass index. Chronic malnutrition (cachexia), regardless of the cause, can result in secondary hypogonadism.

Acute illness (gonadotroph sick syndrome). Hypogonadism is a relatively common finding in any critical illness (analogous to euthyroid sick syndrome with respect to the hypothalamic-pituitary-thyroid axis).⁸ Testosterone levels are invariably low, so that assessment of testosterone status is not recommended in this setting. The low testosterone phase is usually transient and resolves with resolution or improvement of the underlying medical condition, such as sepsis or myocardial infarction.

HIV. Human immunodeficiency virus (HIV) infection can result in primary or secondary hypogonadism. It can occur with active HIV infection, in patients in whom control of viral replication has been achieved with highly active antiretroviral therapy, and even in patients who have normalized CD4+ cell counts.³⁹ Hypogonadism in HIV patients is multifactorial and may be related to weight loss, opportunistic infections of the pituitary-hypothalamus or testes, or medications such as opioids (licit or illicit), ganciclovir (Cytovene), ketoconazole, the appetite stimulant megestrol (Megace), or cyclophosphamide (Cytoxan). Testosterone replacement therapy does not adversely affect the HIV disease process and in fact may help to avoid complications.

Chronic medical conditions such as cirrhosis, renal failure, and rheumatoid arthritis commonly result in hypogonadism, the pathogenesis of which may involve dysfunction at all levels of the hypothalamic-pituitary-go-nadal axis.^40–45 Hypogonadism in the setting of chronic disease is multifactorial, being due not only to the metabolic disturbances seen with these illnesses (uremia in renal failure, elevated circulating estrogens in liver cirrhosis), but also to recurrent acute illness and hospitalization for infection in these immuno-compromised hosts, either from the underlying medical condition or as a result of medications (corticosteroids).

Alcohol abuse. Alcohol can have adverse effects at all levels of the hypothalamic-pituitary-gonadal axis, resulting in low serum testosterone and reduced spermatogenesis.⁴⁶

Severe chronic primary hypothyroidism, manifested by an extreme elevation of serum thyroid-stimulating hormone (TSH), can result in hypopituitarism. Pituitary function usually recovers with restoration of euthyroidism.^47,48

Pubertal delay. Depending on the age of presentation, differentiating pubertal delay from permanent hypogonadotropic hypogonadism can be challenging.

• Sellar mass or cyst—pituitary adenoma, craniopharyngioma, Rathke cleft cyst, meningioma
• Infiltrative lesion—lymphocytic hypophysitis, Langerhans cell histiocytosis, hemochromatosis, sarcoidosis, infection
• Metastatic lesion
• Trauma (head injury)
• Radiation exposure
• Surgery
• Stalk severance
• Pituitary apoplexy.

See Table 1 for a summary of the causes of male hypogonadism.

WHEN IS MRI INDICATED IN EVALUATING SECONDARY HYPOGONADISM?

The yield of pituitary-hypothalamic imaging in older men with secondary hypogonadism is fairly low in the absence of other pituitary hormone abnormalities and deficiencies. There are limited data regarding appropriate criteria for performing hypothalamic-pituitary imaging studies. However, a patient who has multiple anterior pituitary abnormalities on laboratory evaluation should undergo dedicated hypothalamic-pituitary magnetic resonance imaging (MRI).

The Endocrine Society Clinical Practice Guidelines¹¹ recommend that MRI be performed to exclude a pituitary or hypothalamic tumor or infiltrative disease if the patient has severe secondary hypogonadism (serum testosterone < 150 ng/dL), panhypopituitarism, persistent hyperprolactinemia, or symptoms or signs of tumor mass effect such as headache, visual impairment, or a visual field defect.

WHO SHOULD UNDERGO ASSESSMENT OF TESTOSTERONE STATUS?

Screening for androgen deficiency in the asymptomatic general population is not recommended.¹¹ The nonspecific nature of many of the signs and symptoms of androgen deficiency makes it difficult to give concrete recommendations as to who should have testosterone levels measured. Clinicians should consider testing if there is evidence of certain clinical disorders that are associated with low testosterone levels (see earlier discussion on the specific causes of primary and secondary hypogonadism).

When a male patient complains of erectile dysfunction, the investigation should include an assessment of serum testosterone. However, if a man who has a constellation of nonspecific symptoms asks for his testosterone level to be assessed (which is common, given the aggressive marketing of testosterone replacement by the pharmaceutical industry), we would recommend a basic evaluation that includes a comprehensive metabolic panel, complete blood count, and TSH level. Further testing should be determined by the history and physical examination. If no obvious explanation has been found for the patient’s symptoms at that point, assessment of serum testosterone may be warranted. More often than not the patient’s weight and limited physical activity are the driving forces behind the nonspecific symptoms, and counseling a patient on a life-style change can provide much benefit if the patient follows through with the physician’s recommendations.

Men whom we believe should not undergo assessment for testosterone deficiency are those who are acutely ill and hospitalized and those who are severely obese and are complaining of fatigue. Testosterone levels should be assessed only after the acute illness has resolved and, in a severely obese patient with fatigue, only after a thorough evaluation for sleep apnea has been undertaken.

TREAT THE UNDERLYING CAUSE, IF ONE CAN BE FOUND

If the evaluation of low testosterone leads to the diagnosis of a clear underlying condition that is amenable to treatment, such as prolactin elevation or sleep apnea, then treatment should be directed at the underlying cause, with subsequent monitoring of the patient’s symptoms and response in serum testosterone levels. In general, the use of dopamine agonist therapy in the management of hyperprolactinemia and, in cases of panhypopituitarism, of replacement therapy with levothyroxine (Synthroid), hydrocortisone, and possibly growth hormone and desmopressin (DDAVP), fall best under the purview of an endocrinologist. A caveat: serum TSH cannot be used to monitor levothyroxine replacement therapy in cases of secondary hypothyroidism. The clinical picture and serum free T₄ and free T₃ levels are used instead.

In the absence of a correctable (or immediately correctable) cause, testosterone supplementation can be initiated on an individualized basis in select patients who have clinical signs and symptoms of androgen deficiency if the benefits of treatment appear to outweigh the potential risks, and only after a thorough discussion with the patient.¹¹ The Endocrine Society recommends against offering testosterone therapy to all older men with low testosterone.¹¹

INFERTILITY

In men presenting with low serum testosterone, semen analysis is not routine. It is usually reserved for patients presenting with the primary complaint of infertility.

If an endocrine disorder such as prolactin elevation or hypothyroidism is the suspected cause of infertility, the patient should be referred to an endocrinologist for further evaluation and management. Treatment of male infertility should be directed at the underlying cause, but often requires exogenous human chorionic gonadotropin, FSH, GnRH (via a pulsatile pump), and possibly sperm harvesting from the testis with subsequent in vitro fertilization with intracytoplasmic sperm injection. It is critical that the partner be included in the evaluation of infertility.

These patients should be referred to a urologic or fertility center specializing in the diagnosis and treatment of infertility. For further information regarding male infertility, patients can be directed to www.fertilitylifelines.com.

CASE CONCLUDED

The patient’s low serum testosterone was confirmed on subsequent measurements at 8 am, with levels of 128 and 182 ng/dL (reference range 249–836). Other laboratory values:

• LH 1.4 mIU/mL (reference range 1.2–8.6)
• FSH 2.7 mIU/mL (1.3–9.9 mIU/mL)

(Both of these values are inappropriately normal in the setting of the low testosterone.)

• TSH 248 μIU/mL (0.4–5.5)
• Prolactin 24.6 ng/mL (1.6–18.8).

The patient was started on levothyroxine replacement therapy and after 3 months was noted to be euthyroid (TSH 1.8 μIU/mL) and to have a normal serum prolactin level. Testosterone levels (8 am) at this time were 350 ng/dL and 420 ng/dL.

Therefore, the cause of this patient’s hypogonadism was severe hypothyroidism and associated mild hyperprolactinemia. This case shows that a thorough evaluation is warranted before initiating testosterone therapy.

Editor’s note: This article on the differential diagnosis of hypogonadism in men is the first of two articles. The second, to be published next month, focuses on the appropriate use of testosterone therapy.

A 54-year-old man is referred for evaluation of low testosterone. He had seen his primary care physician for complaints of diminished libido and erectile dysfunction for the past year and worsening fatigue over the past few years. He has not been formally diagnosed with any medical condition. His serum testosterone level is 180 ng/dL (reference range 249–836 ng/dL).

On physical examination, he is obese (body mass index 31 kg/m²) with a normal-appearing male body habitus, no gynecomastia, and normal testicles and prostate gland.

How should this patient be evaluated?

LOW TESTOSTERONE HAS MANY CAUSES

Male hypogonadism, ie, failure of the testes to produce adequate amounts of androgen or sperm, has become a common clinical finding, particularly in the older population. This is more likely the result of an increase in awareness and detection of the disorder by physicians rather than a true increase in prevalence.

The finding of a low serum testosterone value needs to be confirmed and thoroughly evaluated before starting treatment. It is important to determine whether the cause is a primary (hypergonadotropic) testicular disorder or secondary to a hypothalamic-pituitary process (hypogonadotropic or normogonadotropic).

THE HYPOTHALAMIC-PITUITARY-GONADAL AXIS

Testosterone production is under the control of luteinizing hormone (LH), whereas sperm production is under the control of follicle-stimulating hormone (FSH) (Figure 1). Both of these pituitary hormones are regulated by the pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH).

Testosterone (produced by Leydig cells) and inhibin B (produced by Sertoli cells within the seminiferous tubules) result in negative feedback inhibition of gonadotropin (LH and FSH) secretion. Testosterone and estradiol (produced by aromatization of testosterone) act at both pituitary and hypothalamic sites and are the principal regulators of LH secretion.^1,2 Inhibin B is the major regulator of FSH secretion in men,³ but steroid feedback also occurs.^2,4

TO FOLLOW UP A LOW TESTOSTERONE, CONFIRM THE VALUE NEAR 8 am

If a testosterone value is found to be low, it is important to determine the time that the sample was obtained. Serum testosterone levels follow a diurnal rhythm, at least in younger men, with values near 8 am being, on average, 30% higher than the trough levels later in the day.^5–7 The timing of the diurnal variation may be different in night-shift workers, who may require assessment at a more appropriate time of the day (ie, upon awakening).

Another factor affecting testosterone levels is the patient’s health status at the time of testing. Values obtained in the hospital during an acute illness should be repeated once the event has resolved, as testosterone values decrease considerably in this setting.⁸ Even in outpatients, particularly in men over age 60, one must be sure that the low testosterone level was not obtained during a period of decompensation of one of the many comorbidities seen in these patients, such as coronary artery disease, congestive heart failure, or uncontrolled diabetes.

If an 8 am testosterone value is low, it is reasonable to obtain at least one confirmatory testosterone level on another day, near 8 am, in the next few weeks, when the patient is in good health. Confirming the testosterone level is important, particularly since commercially available testosterone assays are not well standardized and some are frankly unreliable.^9,10 A repeat confirmatory level should always be performed by a reliable reference laboratory. If the testosterone level is still low, further evaluation is warranted.

TOTAL TESTOSTERONE VS BIOAVAILABLE TESTOSTERONE VS FREE TESTOSTERONE

Of the total circulating testosterone, 60% is bound to sex hormone-binding globulin (SHBG), 38% is bound to albumin, and only 2% is free. All of these fractions can be measured to assess for testosterone deficiency.

Free testosterone is the biologically active form of this hormone and, thus, the free testosterone level is considered to be a better representation of the true testosterone status. However, some clinicians believe that bioavailable testosterone (testosterone loosely bound to albumin + free testosterone) is a better reflection of the true level of the active hormone than the level of free testosterone alone.

There are situations in which the total testosterone level is low but bioavailable or free testosterone levels are normal. The level of total testosterone is affected by alterations in the levels of SHBG and albumin. A reduction in the level of SHBG can result in low total serum testosterone levels in patients with obesity or type 2 diabetes (states of insulin resistance), and also in cachexia, malnutrition, advanced cirrhosis, acromegaly, hypothyroidism, and nephrotic syndrome. SHBG can also be low in patients taking glucocorticoids, progestins, or androgenic steroids.¹¹ In these settings, checking the level of free testosterone (the active hormone), bioavailable testosterone, or both, by a reliable reference laboratory, may be more appropriate.^9,10

But regardless of which measurement is chosen, all testosterone levels—especially bioavailable and free testosterone values—should be interpreted with caution if they are not measured at a reliable reference laboratory.^9,10 Interested readers may wish to see the US Centers for Disease Control and Prevention (CDC) Hormone Standardization Program Web site (www.cdc.gov/labstandards/hs.html) for more details, including a list of CDC-certified laboratories.

CLINICAL FEATURES OF LOW TESTOSTERONE

A history of erectile dysfunction, decreased libido, and fatigue may be seen in patients with low testosterone. However, one must realize that these symptoms—as well as others reported by men with low testosterone, such as depression, difficulty concentrating, irritability, and insomnia—are nonspecific and may be related to other medical conditions.¹²

Likewise, physical findings such as muscle weakness, reduced body hair, and altered fat distribution (abdominal obesity) are seen in men with low testosterone, but also in those with a number of other medical conditions.

Additional features suggest specific disorders, eg, anosmia in Kallmann syndrome; eunuchoid body habitus, gynecomastia, and small testes in Klinefelter syndrome.

Men with low testosterone may have low bone mineral density or anemia, or both.

Careful examination of the breasts for gynecomastia and the testes for size, consistency, and masses (testicular tumors) helps in formulating a differential diagnosis and in appropriately directing subsequent laboratory evaluation and diagnostic imaging.

LOW TESTOSTERONE: PRIMARY VS SECONDARY

A history of testicular trauma, systemic chemotherapy, or mumps orchitis should direct the physician’s attention to a testicular etiology. On the other hand, darkened or tanned skin (suggesting hemochromatosis), galactorrhea (suggesting hyperprolactinemia), or visual field deficits (suggesting a sellar mass) should direct the physician’s attention toward a pituitary-hypothalamic process.

Once the low testosterone value has been confirmed at least one time near 8 am, one should obtain LH and FSH values to help direct further evaluation in deciphering the etiology (Figure 2). Elevated (hypergonadotropic) values indicate a testicular disorder (primary hypogonadism), whereas low (hypogonadotropic) or normal (normogonadotropic) values point to a pituitary-hypothalamic process (secondary hypogonadism). It should be emphasized that, in the setting of a low testosterone level, LH and FSH values within the normal range are “inappropriately normal” so that further investigation is required.

This evaluation should also include serum prolactin, thyroid-stimulating hormone (TSH, also known as thyrotropin), free thyroxine (T₄), and ferritin levels, the latter because hemochromatosis (iron overload) can cause both primary and secondary hypogonadism. If at any time in the evaluation the laboratory results suggest secondary hypogonadism, a full assessment of pituitary function should be undertaken.

Semen analysis is usually reserved for patients presenting with the primary complaint of infertility.

PRIMARY HYPOGONADISM

The patient should be carefully questioned about the age at which his problems began, about pubertal development, and about fertility. Causes of primary hypogonadism include:

• Karyotype abnormalities—Klinefelter syndrome (47, XXY syndrome) is the most common
• Toxin exposure, chemotherapy
• Congenital defects—anorchia, cryptorchidism¹³
• Orchitis (mumps, autoimmune)
• Testicular trauma or infarction
• Hemochromatosis
• Medications that inhibit androgen biosynthesis, eg, ketoconazole (Nizoral)¹⁴
• Increase in temperature of the testicular environment (due to varicocele or a large panniculus).

SECONDARY HYPOGONADISM

Causes of secondary hypogonadism include the following:

Congenital disorders

These disorders are usually diagnosed in childhood or adolescence, often after the patient is brought to the physician because of short stature or pubertal delay.

• Kallmann syndrome (anosmia and GnRH deficiency)¹⁵
• GnRH receptor mutation and deficiency¹⁶
• Genetic mutations associated with pituitary hormone deficiencies, eg, PROP-1 mutation.¹⁷

Drugs. Long-term therapy with common medications such as opioids or corticosteroids can result in secondary hypogonadism.^18–20 Others are GnRH analogues such as leuprolide (Lupron), which are used in treating advanced prostate cancer. The hypogonadism is usually transient and resolves after stopping the offending agent.

Obesity and related conditions such as obstructive sleep apnea, insulin resistance, and type 2 diabetes mellitus are associated with low testosterone levels.²¹ Treatment should be directed at these underlying conditions and should include lifestyle measures such as weight loss and exercise, rather than simple prescribing of testosterone supplementation, as these efforts may provide multiple health benefits in addition to raising testosterone levels.²²

Insulin resistance. In the setting of obesity, the total testosterone level may be low but the bioavailable and free testosterone (active hormone) levels may be normal. This is due to the effect of hyperinsulinemia on the liver, which results in a reduction in SHBG production.²³ Low levels of both total and free testosterone can be seen in morbid obesity,²⁴ but the cause remains unclear.

Type 2 diabetes mellitus. Testosterone levels have been reported to be lower in obese men who have diabetes than in those with obesity alone.²⁴ This decrement, comparable in magnitude to that seen with other chronic diseases, suggests that low testosterone may simply be a marker of poor health.^22,25,26

Sleep apnea. Disturbances in the sleep cycle, regardless of the underlying cause, can result in decreases in serum testosterone levels. Often, correcting the underlying sleep disturbance can result in a normalization of serum testosterone levels.^27,28 A caveat about testosterone therapy: a thorough evaluation for sleep apnea should be undertaken in patients at high risk, since testosterone replacement therapy can adversely affect ventilatory drive and induce or worsen obstructive sleep apnea.²⁹

Aging. Most reports have shown an agerelated decline in both total and free serum testosterone levels (commonly referred to as “andropause”), particularly in men over 60 years of age. There also appears to be a loss of circadian rhythm,³⁰ although not all reports agree.⁶ It appears that factors such as functional status and overall health may play a more important role in the pathophysiology of hypogonadism in men of advanced age than age alone.

Hemochromatosis. Iron overload, regardless of the cause, can result in hypogonadism via deposition of iron in the hypothalamus, pituitary, or testes. Hereditary hemochromatosis is a common autosomal recessive disease characterized by increased iron absorption. Although both primary and secondary hypogonadism can occur with long-standing iron overload, the latter is much more common.³¹ Some cases of hypogonadism have been reported to reverse with iron depletion therapy.³²

Hyperprolactinemia. Recognized causes of hyperprolactinemia in men include medications (dopamine antagonists, antipsychotics, metoclopramide [Reglan]), pituitary adenomas (microadenomas < 10 mm, macroadenomas ≥ 10 mm), lactotroph hyperfunction (stalk compression interrupting or reducing the tonic suppression of prolactin secretion by dopamine), hypothyroidism, stress, chronic renal failure, cirrhosis, chest wall injury (trauma), and active herpes zoster. The ensuing hypogonadism may be due to the compressive effect of a sellar mass or the direct effect of the prolactin elevation alone, since prolactin disrupts the pulsatile release of GnRH from the hypothalamus,³³ required for normal LH and FSH secretion.

Estrogen excess can be either exogenous (from exposure to estrogen-containing contraceptives and creams) or endogenous (from testicular^34,35 or very rare adrenal³⁶ estrogen-secreting tumors). Of note, some cases of testicular neoplasms may be detectable only with ultrasonography. Computed tomography may be performed if an adrenal lesion is suspected.

Anabolic steroid abuse. Exposure to anabolic steroids, deliberately or inadvertently, can result in secondary hypogonadism and testicular atrophy, both of which may persist for years after stopping the anabolic agents. If you suspect anabolic steroid abuse, a urine anabolic steroid screen can be obtained.

Anorexia nervosa is far less common in men than in women.^37,38 Elements in the history that suggest this disorder include excessive exercise and a low body mass index. Chronic malnutrition (cachexia), regardless of the cause, can result in secondary hypogonadism.

Acute illness (gonadotroph sick syndrome). Hypogonadism is a relatively common finding in any critical illness (analogous to euthyroid sick syndrome with respect to the hypothalamic-pituitary-thyroid axis).⁸ Testosterone levels are invariably low, so that assessment of testosterone status is not recommended in this setting. The low testosterone phase is usually transient and resolves with resolution or improvement of the underlying medical condition, such as sepsis or myocardial infarction.

HIV. Human immunodeficiency virus (HIV) infection can result in primary or secondary hypogonadism. It can occur with active HIV infection, in patients in whom control of viral replication has been achieved with highly active antiretroviral therapy, and even in patients who have normalized CD4+ cell counts.³⁹ Hypogonadism in HIV patients is multifactorial and may be related to weight loss, opportunistic infections of the pituitary-hypothalamus or testes, or medications such as opioids (licit or illicit), ganciclovir (Cytovene), ketoconazole, the appetite stimulant megestrol (Megace), or cyclophosphamide (Cytoxan). Testosterone replacement therapy does not adversely affect the HIV disease process and in fact may help to avoid complications.

Chronic medical conditions such as cirrhosis, renal failure, and rheumatoid arthritis commonly result in hypogonadism, the pathogenesis of which may involve dysfunction at all levels of the hypothalamic-pituitary-go-nadal axis.^40–45 Hypogonadism in the setting of chronic disease is multifactorial, being due not only to the metabolic disturbances seen with these illnesses (uremia in renal failure, elevated circulating estrogens in liver cirrhosis), but also to recurrent acute illness and hospitalization for infection in these immuno-compromised hosts, either from the underlying medical condition or as a result of medications (corticosteroids).

Alcohol abuse. Alcohol can have adverse effects at all levels of the hypothalamic-pituitary-gonadal axis, resulting in low serum testosterone and reduced spermatogenesis.⁴⁶

Severe chronic primary hypothyroidism, manifested by an extreme elevation of serum thyroid-stimulating hormone (TSH), can result in hypopituitarism. Pituitary function usually recovers with restoration of euthyroidism.^47,48

Pubertal delay. Depending on the age of presentation, differentiating pubertal delay from permanent hypogonadotropic hypogonadism can be challenging.

• Sellar mass or cyst—pituitary adenoma, craniopharyngioma, Rathke cleft cyst, meningioma
• Infiltrative lesion—lymphocytic hypophysitis, Langerhans cell histiocytosis, hemochromatosis, sarcoidosis, infection
• Metastatic lesion
• Trauma (head injury)
• Radiation exposure
• Surgery
• Stalk severance
• Pituitary apoplexy.

See Table 1 for a summary of the causes of male hypogonadism.

WHEN IS MRI INDICATED IN EVALUATING SECONDARY HYPOGONADISM?

The yield of pituitary-hypothalamic imaging in older men with secondary hypogonadism is fairly low in the absence of other pituitary hormone abnormalities and deficiencies. There are limited data regarding appropriate criteria for performing hypothalamic-pituitary imaging studies. However, a patient who has multiple anterior pituitary abnormalities on laboratory evaluation should undergo dedicated hypothalamic-pituitary magnetic resonance imaging (MRI).

The Endocrine Society Clinical Practice Guidelines¹¹ recommend that MRI be performed to exclude a pituitary or hypothalamic tumor or infiltrative disease if the patient has severe secondary hypogonadism (serum testosterone < 150 ng/dL), panhypopituitarism, persistent hyperprolactinemia, or symptoms or signs of tumor mass effect such as headache, visual impairment, or a visual field defect.

WHO SHOULD UNDERGO ASSESSMENT OF TESTOSTERONE STATUS?

Screening for androgen deficiency in the asymptomatic general population is not recommended.¹¹ The nonspecific nature of many of the signs and symptoms of androgen deficiency makes it difficult to give concrete recommendations as to who should have testosterone levels measured. Clinicians should consider testing if there is evidence of certain clinical disorders that are associated with low testosterone levels (see earlier discussion on the specific causes of primary and secondary hypogonadism).

When a male patient complains of erectile dysfunction, the investigation should include an assessment of serum testosterone. However, if a man who has a constellation of nonspecific symptoms asks for his testosterone level to be assessed (which is common, given the aggressive marketing of testosterone replacement by the pharmaceutical industry), we would recommend a basic evaluation that includes a comprehensive metabolic panel, complete blood count, and TSH level. Further testing should be determined by the history and physical examination. If no obvious explanation has been found for the patient’s symptoms at that point, assessment of serum testosterone may be warranted. More often than not the patient’s weight and limited physical activity are the driving forces behind the nonspecific symptoms, and counseling a patient on a life-style change can provide much benefit if the patient follows through with the physician’s recommendations.

Men whom we believe should not undergo assessment for testosterone deficiency are those who are acutely ill and hospitalized and those who are severely obese and are complaining of fatigue. Testosterone levels should be assessed only after the acute illness has resolved and, in a severely obese patient with fatigue, only after a thorough evaluation for sleep apnea has been undertaken.

TREAT THE UNDERLYING CAUSE, IF ONE CAN BE FOUND

If the evaluation of low testosterone leads to the diagnosis of a clear underlying condition that is amenable to treatment, such as prolactin elevation or sleep apnea, then treatment should be directed at the underlying cause, with subsequent monitoring of the patient’s symptoms and response in serum testosterone levels. In general, the use of dopamine agonist therapy in the management of hyperprolactinemia and, in cases of panhypopituitarism, of replacement therapy with levothyroxine (Synthroid), hydrocortisone, and possibly growth hormone and desmopressin (DDAVP), fall best under the purview of an endocrinologist. A caveat: serum TSH cannot be used to monitor levothyroxine replacement therapy in cases of secondary hypothyroidism. The clinical picture and serum free T₄ and free T₃ levels are used instead.

In the absence of a correctable (or immediately correctable) cause, testosterone supplementation can be initiated on an individualized basis in select patients who have clinical signs and symptoms of androgen deficiency if the benefits of treatment appear to outweigh the potential risks, and only after a thorough discussion with the patient.¹¹ The Endocrine Society recommends against offering testosterone therapy to all older men with low testosterone.¹¹

INFERTILITY

In men presenting with low serum testosterone, semen analysis is not routine. It is usually reserved for patients presenting with the primary complaint of infertility.

If an endocrine disorder such as prolactin elevation or hypothyroidism is the suspected cause of infertility, the patient should be referred to an endocrinologist for further evaluation and management. Treatment of male infertility should be directed at the underlying cause, but often requires exogenous human chorionic gonadotropin, FSH, GnRH (via a pulsatile pump), and possibly sperm harvesting from the testis with subsequent in vitro fertilization with intracytoplasmic sperm injection. It is critical that the partner be included in the evaluation of infertility.

These patients should be referred to a urologic or fertility center specializing in the diagnosis and treatment of infertility. For further information regarding male infertility, patients can be directed to www.fertilitylifelines.com.

CASE CONCLUDED

The patient’s low serum testosterone was confirmed on subsequent measurements at 8 am, with levels of 128 and 182 ng/dL (reference range 249–836). Other laboratory values:

• LH 1.4 mIU/mL (reference range 1.2–8.6)
• FSH 2.7 mIU/mL (1.3–9.9 mIU/mL)

(Both of these values are inappropriately normal in the setting of the low testosterone.)

• TSH 248 μIU/mL (0.4–5.5)
• Prolactin 24.6 ng/mL (1.6–18.8).

The patient was started on levothyroxine replacement therapy and after 3 months was noted to be euthyroid (TSH 1.8 μIU/mL) and to have a normal serum prolactin level. Testosterone levels (8 am) at this time were 350 ng/dL and 420 ng/dL.

Therefore, the cause of this patient’s hypogonadism was severe hypothyroidism and associated mild hyperprolactinemia. This case shows that a thorough evaluation is warranted before initiating testosterone therapy.

Intensive care medicine has dramatically evolved over the last 15 years, after reports from many landmark trials.¹ Updated strategies for mechanical ventilation² and “bundles” of strategies to optimize hemodynamic therapy³ have reduced the rates of morbidity and death from deadly critical conditions such as the adult respiratory distress syndrome (ARDS) and sepsis.

Despite these important improvements in short-term outcomes, it is increasingly recognized that intensive care unit (ICU) survivors suffer considerable long-term complications that affect their usual functioning.⁴ Recently, the Society of Critical Care Medicine convened a conference in which these long-term complications were named the “post-intensive care syndrome.”⁵

Quality of life, particularly its physical component, is considerably lower after a stay in the medical or surgical ICU.^6–8 Posttraumatic stress disorder, depression, and sexual dysfunction are consistently reported years after ICU discharge.^9–13

Perhaps the most frequently unrecognized complication in ICU survivors is cognitive impairment. Current data suggest that neurocognitive impairment after an ICU stay is common and that it persists 6 years or more after hospital discharge.

Hopkins et al^14,15 analyzed 10 cohort studies of long-term cognitive impairment after an ICU stay; 5 of them focused on patients with ARDS. The prevalence of cognitive impairment was as high as 78% at hospital discharge, 46% at 1 year, and 25% 6 years after discharge.^15,16 Of the cognitive domains compromised, memory was the most often affected, followed by executive function and attention.^14,17

Interestingly, data suggest that cognition may improve somewhat in the first 6 to 12 months after ICU discharge.¹⁵ Therefore, if we can detect it early on and promptly refer patients for cognitive therapy, we may eventually improve the prognosis of this disabling complication.

This review will focus on how to evaluate, prevent, and treat cognitive impairment in patients who survive an ICU stay.

COGNITIVE IMPAIRMENT AFTER A STAY IN THE ICU

The association between ICU stay and neurocognitive dysfunction is poorly understood. Potential causes include hypoxemia,¹⁸ hypotension, ¹⁹ hyperglycemia,¹⁴ and—an area of growing interest and evolving research—sedation and delirium.²⁰

Patients on mechanical ventilation are commonly given sedatives and analgesics to prevent anxiety and pain.²¹ However, these medications are strongly associated with delirium.²² In fact, recent studies found that benzodiazepines have an independent, dose-related, temporal association with delirium, with some reports describing a 20% increase in delirium per milligram of benzodiazepine.²³ In another study, which included medical and surgical ICU patients, use of morphine was the strongest predictor of delirium, with a sixfold increase in odds over a period of 5 months.²⁴

Delirium is important to prevent, diagnose, and treat, since it has a direct association with the development of long-term cognitive impairment.^22,25 A review of studies that included 1,885 medical and surgical patients found that those who developed delirium during an ICU stay were three times more likely to have cognitive dysfunction when assessed 3 years later.²⁰

Whether delirium is a primary disorder associated with cognitive impairment or if it only represents an underlying process leading to poor cognitive outcomes is unknown. As delirious patients are more likely to be older, to be mechanically ventilated, to require more sedation, and, in particular, to be sicker, the association between delirium and cognitive impairment may reflect the relationship between these risk factors and poor cognitive outcomes.²⁶

Glucose and its relationship with cognitive function is another topic of investigation. A secondary analysis of a study that included ARDS survivors revealed that blood glucose values higher than 153 mg/dL, higher glucose variability, and duration of mechanical ventilation were associated with cognitive sequelae.^27,28

Other studies focused on mechanical ventilation. In one study,²⁹ one-third of patients who had been mechanically ventilated showed signs of neurocognitive impairment when they were evaluated 6 months after hospital discharge.

Mild cognitive impairment differs from cognitive impairment after an ICU stay

Cognitive impairment after ICU discharge does not follow the same pattern as mild cognitive impairment, and some authors consider these two types of cognitive impairment to be unrelated.

While mild cognitive impairment is progressive and associated with aging, cognitive impairment in ICU survivors develops rapidly after acute illness and is usually related to numerous pathologic and neurochemical pathways.

For example, the neurotransmitter acetylcholine is thought to be involved in cognitive function as well as neuroplasticity of the motor cortex. In a model of cognitive impairment after stroke, activity of the cholinergic system was reduced.^30,31 Further, in a study in rats, Baskerville et al³² showed that experience-dependent plasticity could be completely blocked by damaging the cholinergic neurons in the nucleus basalis of Meynert, thereby affecting memory and other functions supported by this pathway.

Another implicated pathway involves dopamine. Of interest, dopamine augmentation has been shown to enhance simple motor memories and to improve procedural learning. Understanding of these neurochemical alterations opens opportunities for investigation of drug therapies.

ASSESSMENT TOOLS

Cognitive impairment is important to detect in ICU survivors because it predicts poor outcomes from rehabilitation. A study of stroke patients found that those with cognitive alterations immediately after the stroke were less likely to be discharged home or to be living at home 6 months after discharge.³³

A possible explanation may be that affected patients cannot fully participate in rehabilitation activities, owing to impairment in executive function, inability to remember therapy instructions, or disruption of implicit and explicit learning. Indeed, some authors consider cognitive impairment after acquired brain injury to be the most relevant surrogate marker of rehabilitation potential. Consequently, manipulation or enhancement of cognition may directly affect rehabilitation outcomes.³⁴

Disagreement about terminology and diagnostic criteria creates a problem for health care providers working with patients with potential cognitive impairment. Numerous systems have been proposed to define this condition; in fact, Stephan et al³⁵ reviewed the literature and found no fewer than 17. None of them is specific for cognitive impairment after an ICU stay.

Petersen et al³⁶ in 1999 proposed initial criteria for mild cognitive impairment that included the following:

• A memory complaint
• Normal general cognitive functioning
• Normal activities of daily living
• Memory impairment in relation to age and education
• No dementia.

Later, other areas of impairment besides memory were recognized, such as language, attention, perception, reasoning, and motor planning.³⁷ Therefore, mild cognitive impairment is currently classified into subtypes, which include amnestic (affecting single or multiple domains) and nonamnestic (also affecting single or multiple domains).³⁸

In clinical practice, impairment of specific cognitive domains may be challenging to detect, and neuropsychological testing is often needed. Cognitive screening tests can detect impairment across a restricted range of cognitive abilities, while more comprehensive assessments address each of the primary domains of cognition.³⁹ Formal testing provides normative and validated data on cognition performance and severity.

The Montreal Cognitive Assessment⁴⁰ is popular, comprehensive, used in a variety of professions in diverse types of facilities (acute care, rehabilitation, and skilled care facilities), and brief (taking 11 minutes to administer). It evaluates orientation, memory, language, attention, reasoning, and visual-constructional abilities. The maximum score is 30; cognitive impairment is defined as a score of less than 26. It has a sensitivity of 90% and a specificity of 87%.

The Folstein Mini-Mental State Examination (MMSE) is the most commonly used of the noncomprehensive tests in clinical practice.⁴¹ It assesses orientation, memory, language, attention, and praxis. It has a maximum score of 30 points; the cutoff score for cognitive impairment is 24 points or less.

A limitation of the MMSE is that its sensitivity is very low, ranging from 1% to 49%.^42,43 The MMSE scores of patients with cognitive impairment overlap considerably with those of age-matched healthy controls.³⁹ Conversely, the MMSE’s specificity is usually high, ranging from 85% to 100%.⁴²

Moreover, the MMSE poses copyright issues, an important consideration when selecting a test. In 2001, the authors of the MMSE transferred all intellectual property rights to Psychological Assessment Resources, which has exclusive rights to publish, license, and manage all intellectual property rights in all media and languages. Photocopying and using the MMSE without applying for permission from and paying this company ($1.23 per use) constitutes copyright infringement. Therefore, health care providers and researchers have been using other tests to evaluate cognition.

Other tests of cognition assess individual domains. Interestingly, studies of long-term cognitive impairment after ICU admission used these tests to define outcomes.²⁵ Specific tests include:

• The Digit Span and the Trailmaking Test A (used to assess attention and orientation)²⁵
• The Rey Auditory Verbal Learning Test (used to evaluate verbal memory)
• The Complex Figure Test (helpful in defining visual-spatial construction and delayed visual memory)
• The Trailmaking Test B (also included in the Montreal Cognitive Assessment; assesses executive functioning).

Besides formal testing, an informal battery is often recommended to provide additional information. An informal evaluation includes word definition, reading and verbal fluency, reading comprehension, and performance of instrumental activities of daily living. Observing as patients perform tasks of daily living provides therapists with a vast amount of information, as these tasks require using multiple cognitive processes. Therefore, if a functional breakdown occurs during this assessment, the clinician needs to identify the domain or specific level of cognitive dysfunction involved in that deficit.⁴⁴

PREVENTIVE STRATEGIES

Strategies for minimizing the long-term effects of cognitive impairment have mostly focused on preventing it.

During the ICU stay, optimizing hemodynamic, glucose, and oxygenation levels may prevent future long-term complications.¹⁸

Also, the association between sedation, delirium, and consequent cognitive impairment (see above) has led many investigators to apply the “ABCDE” bundle of strategies.^25,45,46 Specifically, ABCDE stands for awakening and breathing, choice of sedatives with fewer adverse effects, daily delirium monitoring, and early mobility exercise. These strategies have been shown in randomized controlled trials to prevent delirium; however, they have not been proved to prevent cognitive impairment.

Awakening and breathing

In the Awakening and Breathing Controlled Trial,⁴⁷ patients in the intervention group (ie, those who had their sedatives interrupted every morning to see if they would awaken, and if so, if they could breathe on their own) were extubated 3 days sooner than those in the control group (who underwent daily trials of spontaneous breathing, if deemed safe). Also, ICU and hospital length of stay were shorter by 4 days. Best of all, over 1 year, the mortality rate was lower by 14 absolute percentage points.

Choice of sedatives

Often, mechanically ventilated patients are given benzodiazepines, opiates, and propofol (Diprivan).²¹ Dexmedetomidine (Precedex), a newer agent, is an alpha-2 agonist and may offer advantages over the others.

To date, three randomized controlled trials have assessed the effect of dexmedetomidine in terms of outcomes associated with delirium, and one trial evaluated its association with intellectual capacity in ICU patients.

The Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) trial randomized patients on mechanical ventilation to receive either dexmedetomidine or lorazepam (Ativan).⁴⁸ Dexmedetomidine-treated patients had 4 more days alive without delirium or coma (7 vs 3 days, P = .01).

Subsequently, the Safety and Efficacy of Dexmedetomidine Compared With Midazolam (SEDCOM) trial compared dexmedetomidine and midazolam (Versed) in mechanically ventilated patients. Those who received dexmedetomidine had a lower incidence of delirium (54% vs 76%, P < .001), and 2 fewer days on mechanical ventilation.⁴⁹

Reade et al⁵⁰ evaluated time to extubation in already delirious patients randomized to receive either dexmedetomidine or haloperidol (Haldol). Those receiving dexmedetomidine had a shorter time to extubation as well as a shorter ICU length of stay.

The Acute Neuroscience Intensive Care Sedation Trial⁵¹ evaluated intellectual capacity in neurological ICU patients sedated with either dexmedetomidine or propofol. This randomized, double-blind trial included 18 brain-injured and 12 non-brain-injured intubated patients. In a crossover protocol, each received the combination of fentanyl (Sublimaze) and propofol and the combination of fentanyl and dexmedetomidine.

Cognition was evaluated using the Adapted Cognitive Exam (ACE), which assesses intellectual capacity through orientation, language, registration, attention, calculation, and recall. This 10-minute examination does not require verbal communication, as it relies on the ability to respond to yes-or-no questions and perform simple motor tasks. The maximum possible score is 100 points.

Interestingly, while on propofol, the patients’ adjusted ACE scores went down by a mean of 12.4 points, whereas they went up by 6.8 points while on dexmedetomidine. Even though brain-injured patients required less sedation than non-brain-injured patients, the effect of dexmedetomidine and propofol did not change.⁵¹

In summary, these studies suggest that all sedatives are not the same in their short-term and intermediate-term outcomes.

In our practice, we use dexmedetomidine as our first-line sedation therapy. In patients with hemodynamic instability, we use benzodiazepines. We reserve propofol for very short periods of intubation or for hemodynamically stable patients who cannot be sedated with dexmedetomidine.

Daily delirium monitoring

As mentioned above, delirium affects many patients on mechanical ventilation, and it is highly underrecognized if valid tests are not used.⁵² Therefore, it is critically important to be familiar with the tests for assessing delirium. Of these, the Confusion Assessment Method for the ICU is probably the one with the best performance, with a sensitivity of 93% to 100% and a specificity of 98% to 100%.^53,54

Early mobilization

A landmark study paired the awakening and breathing strategy with early mobilization through physical and occupational therapy in the ICU.⁵⁵ Patients in the intervention group had a higher rate of return to independent functional status upon hospital discharge and a shorter duration of mechanical ventilation and delirium.

In conclusion, even though direct prevention of cognitive dysfunction is a challenging task, the ABCDE approach targets individual risk factors for delirium, which is an important contributor to cognitive impairment. Whether the ABCDE bundle directly affects the development of cognitive impairment requires further investigation.

COGNITIVE THERAPIES

The cognition-focused intervention most often described is cognitive training. Cognitive training is delivered in individual or group sessions in which the patient practices tasks targeting different domains, such as memory, language, and attention. Outcomes are often assessed in terms of improvement in test scores or effects on everyday functioning. Unfortunately, because of heterogeneity among cognitive training interventions and studied populations, we cannot yet make strong evidence-based recommendations for clinical practice.

Martin et al⁵⁶ in 2011 reviewed cognition-based interventions for healthy older people and people with mild cognitive impairment and found 36 relevant studies. Of these, only 3 were in patients with mild cognitive impairment, while the rest were in healthy older people.^56–58 Overall, the only available data were related to the memory domain, and outcomes were mostly associated with immediate recall of words, paragraphs, and stories. Based on this, cognitive therapy is currently considered justified, as most patients with cognitive impairment after an ICU stay have memory problems.

Zelinski et al⁵⁹ conducted a randomized, controlled, double-blind study comparing outcomes in an intervention group that underwent a computerized cognitive training program with those in a control group that viewed videos on a variety of topics such as literature, art, and history. The intervention, based on brain plasticity, aimed to improve the speed and accuracy of auditory information processing and to engage neuromodulatory systems. Some of the secondary outcomes favored the intervention group. These outcomes were related mostly to measures of overall memory, such as immediate and delayed recall, but also to a composite outcome that included letter-number sequencing and the digit span backwards test.

Despite these encouraging results, it is worth mentioning that these studies were not performed in patients with cognitive impairment associated with ICU admission. Therefore, the applicability and effectiveness of such therapies in post-ICU patients remains unknown.

Patients with posttraumatic brain injury and stroke have also been extensively studied in regard to the development of cognitive impairment.³⁴ These patients probably represent a better standard for comparison, as their cognitive impairment does not necessarily progress.

The effect of cognitive rehabilitation on the recovery in these patients depends on adaptation and remediation. Adaptation describes a patient’s ability to compensate for functional impairment.³⁴ This can be divided into internal and external adaptation. Internal adaptation requires the patient to recognize his or her cognitive limitation in order to adapt the to the environment accordingly. External adaptation entails getting help from devices or relatives (eg, phone calls) to achieve desired goals (eg, taking medication at scheduled times). Again, to adapt, the patient needs to be able to recognize his or her affected cognitive domain. Unfortunately, this is not always the case.

Remediation refers to the actual regaining of a lost ability. To stimulate neural plasticity, the patient is required to experience and repeat targeted skill-building activities.³⁸ There is evidence that patients are more likely to regain lost ability by repeating the practice frequently during a short period of time.⁶⁰

From the physician’s perspective, evaluating and identifying deficits in particular cognitive domains may help in designing a remediation plan in partnership with a cognitive therapist.

Cognitive rehabilitation in ICU survivors

The Returning to Everyday Tasks Utilizing Rehabilitation Networks (RETURN) study focused on cognitive and physical rehabilitation in post-ICU patients.⁶¹ This pilot study included 21 ICU survivors with cognitive or functional impairment at hospital discharge. Eight patients received usual care and 13 received a combination of in-home cognitive, physical, and functional rehabilitation over a 3-month period with a social worker or a master’s-level psychology technician.

Interventions included six in-person visits for cognitive rehabilitation and six televisits for physical and functional rehabilitation. Cognitive training was based on the goal-management training (GMT) protocol.⁶² This strategy attempts to improve executive function by increasing goal-directed behavior and by helping patients learn to be reflective before making decisions and executing tasks. The GMT model consists of sessions that build on one another to increase the rehabilitation intensity. During each session, goals are explained and participants perform increasingly challenging cognitive tasks.

Cognitive outcomes were evaluated using the Delis-Kaplan Tower Test to evaluate executive function by assessing the ability to plan and strategize efficiently. The patient is required to move disks across three pegs until a tower is built. The object is to use the fewest moves possible while adhering to two rules: larger disks cannot be placed on top of smaller ones, and disks must be moved one at a time, using only one hand.

At 3 months there was a significant difference between groups, with the intervention group earning higher tower test scores than controls did (median of 13 vs 7.5).

The Activity and Cognitive Therapy in the Intensive Care Unit (ACT-ICU) trial is another pilot study that will attempt to assess the feasibility of early cognitive rehabilitation in ICU survivors. This study will combine early mobilization with a cognitive intervention, and its primary outcome is executive function (with the tower test) at 3 months after discharge.⁶³

DRUG THERAPY

Some medications have been tested to assess whether they reduce the risk of progression from adult traumatic brain injury to cognitive impairment. These drugs augment dopamine and acetylcholine activity.

Methylphenidate (Ritalin), a dopaminergic drug, was studied in two trials. The first was a double-blind trial in 18 patients with posttraumatic brain injury. Memory was found to improve, based on the Working Memory Task Test. However, due to the small number of participants, no further conclusions were obtained.⁶⁴

The second trial, in 19 patients with posttraumatic brain injury, had a double-blind crossover design. Attention, evaluated by the Distraction Task Test, improved with the use of methylphenidate.⁶⁵ Again, the small number of patients precludes generalization of these results.

Donepezil (Aricept), a cholinergic drug, was evaluated in four clinical trials in posttraumatic brain injury patients^66–69; each trial included 21 to 180 patients. The trials evaluated the drug’s effect on memory and attention through a variety of tools (Paced Auditory Serial Addition Test; Wechsler Memory Scale; Boston Naming Test; Rey Auditory Verbal Learning Test; Complex Figure Test; and Reaction Time–Dual Task). Interestingly, donepezil was associated with large improvements in objective assessments of attention and memory. Despite methodologic flaws, such as a lack of blinding in one of these studies⁶⁹ and an open-label design in two of them,^66,68 of the drugs available, donepezil presents the strongest evidence for use in cognitive impairment after traumatic brain injury.⁷⁰

Intensive care medicine has dramatically evolved over the last 15 years, after reports from many landmark trials.¹ Updated strategies for mechanical ventilation² and “bundles” of strategies to optimize hemodynamic therapy³ have reduced the rates of morbidity and death from deadly critical conditions such as the adult respiratory distress syndrome (ARDS) and sepsis.

Despite these important improvements in short-term outcomes, it is increasingly recognized that intensive care unit (ICU) survivors suffer considerable long-term complications that affect their usual functioning.⁴ Recently, the Society of Critical Care Medicine convened a conference in which these long-term complications were named the “post-intensive care syndrome.”⁵

Quality of life, particularly its physical component, is considerably lower after a stay in the medical or surgical ICU.^6–8 Posttraumatic stress disorder, depression, and sexual dysfunction are consistently reported years after ICU discharge.^9–13

Perhaps the most frequently unrecognized complication in ICU survivors is cognitive impairment. Current data suggest that neurocognitive impairment after an ICU stay is common and that it persists 6 years or more after hospital discharge.

Hopkins et al^14,15 analyzed 10 cohort studies of long-term cognitive impairment after an ICU stay; 5 of them focused on patients with ARDS. The prevalence of cognitive impairment was as high as 78% at hospital discharge, 46% at 1 year, and 25% 6 years after discharge.^15,16 Of the cognitive domains compromised, memory was the most often affected, followed by executive function and attention.^14,17

Interestingly, data suggest that cognition may improve somewhat in the first 6 to 12 months after ICU discharge.¹⁵ Therefore, if we can detect it early on and promptly refer patients for cognitive therapy, we may eventually improve the prognosis of this disabling complication.

This review will focus on how to evaluate, prevent, and treat cognitive impairment in patients who survive an ICU stay.

COGNITIVE IMPAIRMENT AFTER A STAY IN THE ICU

The association between ICU stay and neurocognitive dysfunction is poorly understood. Potential causes include hypoxemia,¹⁸ hypotension, ¹⁹ hyperglycemia,¹⁴ and—an area of growing interest and evolving research—sedation and delirium.²⁰

Patients on mechanical ventilation are commonly given sedatives and analgesics to prevent anxiety and pain.²¹ However, these medications are strongly associated with delirium.²² In fact, recent studies found that benzodiazepines have an independent, dose-related, temporal association with delirium, with some reports describing a 20% increase in delirium per milligram of benzodiazepine.²³ In another study, which included medical and surgical ICU patients, use of morphine was the strongest predictor of delirium, with a sixfold increase in odds over a period of 5 months.²⁴

Delirium is important to prevent, diagnose, and treat, since it has a direct association with the development of long-term cognitive impairment.^22,25 A review of studies that included 1,885 medical and surgical patients found that those who developed delirium during an ICU stay were three times more likely to have cognitive dysfunction when assessed 3 years later.²⁰

Whether delirium is a primary disorder associated with cognitive impairment or if it only represents an underlying process leading to poor cognitive outcomes is unknown. As delirious patients are more likely to be older, to be mechanically ventilated, to require more sedation, and, in particular, to be sicker, the association between delirium and cognitive impairment may reflect the relationship between these risk factors and poor cognitive outcomes.²⁶

Glucose and its relationship with cognitive function is another topic of investigation. A secondary analysis of a study that included ARDS survivors revealed that blood glucose values higher than 153 mg/dL, higher glucose variability, and duration of mechanical ventilation were associated with cognitive sequelae.^27,28

Other studies focused on mechanical ventilation. In one study,²⁹ one-third of patients who had been mechanically ventilated showed signs of neurocognitive impairment when they were evaluated 6 months after hospital discharge.

Mild cognitive impairment differs from cognitive impairment after an ICU stay

Cognitive impairment after ICU discharge does not follow the same pattern as mild cognitive impairment, and some authors consider these two types of cognitive impairment to be unrelated.

While mild cognitive impairment is progressive and associated with aging, cognitive impairment in ICU survivors develops rapidly after acute illness and is usually related to numerous pathologic and neurochemical pathways.

For example, the neurotransmitter acetylcholine is thought to be involved in cognitive function as well as neuroplasticity of the motor cortex. In a model of cognitive impairment after stroke, activity of the cholinergic system was reduced.^30,31 Further, in a study in rats, Baskerville et al³² showed that experience-dependent plasticity could be completely blocked by damaging the cholinergic neurons in the nucleus basalis of Meynert, thereby affecting memory and other functions supported by this pathway.

Another implicated pathway involves dopamine. Of interest, dopamine augmentation has been shown to enhance simple motor memories and to improve procedural learning. Understanding of these neurochemical alterations opens opportunities for investigation of drug therapies.

ASSESSMENT TOOLS

Cognitive impairment is important to detect in ICU survivors because it predicts poor outcomes from rehabilitation. A study of stroke patients found that those with cognitive alterations immediately after the stroke were less likely to be discharged home or to be living at home 6 months after discharge.³³

A possible explanation may be that affected patients cannot fully participate in rehabilitation activities, owing to impairment in executive function, inability to remember therapy instructions, or disruption of implicit and explicit learning. Indeed, some authors consider cognitive impairment after acquired brain injury to be the most relevant surrogate marker of rehabilitation potential. Consequently, manipulation or enhancement of cognition may directly affect rehabilitation outcomes.³⁴

Disagreement about terminology and diagnostic criteria creates a problem for health care providers working with patients with potential cognitive impairment. Numerous systems have been proposed to define this condition; in fact, Stephan et al³⁵ reviewed the literature and found no fewer than 17. None of them is specific for cognitive impairment after an ICU stay.

Petersen et al³⁶ in 1999 proposed initial criteria for mild cognitive impairment that included the following:

• A memory complaint
• Normal general cognitive functioning
• Normal activities of daily living
• Memory impairment in relation to age and education
• No dementia.

Later, other areas of impairment besides memory were recognized, such as language, attention, perception, reasoning, and motor planning.³⁷ Therefore, mild cognitive impairment is currently classified into subtypes, which include amnestic (affecting single or multiple domains) and nonamnestic (also affecting single or multiple domains).³⁸

In clinical practice, impairment of specific cognitive domains may be challenging to detect, and neuropsychological testing is often needed. Cognitive screening tests can detect impairment across a restricted range of cognitive abilities, while more comprehensive assessments address each of the primary domains of cognition.³⁹ Formal testing provides normative and validated data on cognition performance and severity.

The Montreal Cognitive Assessment⁴⁰ is popular, comprehensive, used in a variety of professions in diverse types of facilities (acute care, rehabilitation, and skilled care facilities), and brief (taking 11 minutes to administer). It evaluates orientation, memory, language, attention, reasoning, and visual-constructional abilities. The maximum score is 30; cognitive impairment is defined as a score of less than 26. It has a sensitivity of 90% and a specificity of 87%.

The Folstein Mini-Mental State Examination (MMSE) is the most commonly used of the noncomprehensive tests in clinical practice.⁴¹ It assesses orientation, memory, language, attention, and praxis. It has a maximum score of 30 points; the cutoff score for cognitive impairment is 24 points or less.

A limitation of the MMSE is that its sensitivity is very low, ranging from 1% to 49%.^42,43 The MMSE scores of patients with cognitive impairment overlap considerably with those of age-matched healthy controls.³⁹ Conversely, the MMSE’s specificity is usually high, ranging from 85% to 100%.⁴²

Moreover, the MMSE poses copyright issues, an important consideration when selecting a test. In 2001, the authors of the MMSE transferred all intellectual property rights to Psychological Assessment Resources, which has exclusive rights to publish, license, and manage all intellectual property rights in all media and languages. Photocopying and using the MMSE without applying for permission from and paying this company ($1.23 per use) constitutes copyright infringement. Therefore, health care providers and researchers have been using other tests to evaluate cognition.

Other tests of cognition assess individual domains. Interestingly, studies of long-term cognitive impairment after ICU admission used these tests to define outcomes.²⁵ Specific tests include:

• The Digit Span and the Trailmaking Test A (used to assess attention and orientation)²⁵
• The Rey Auditory Verbal Learning Test (used to evaluate verbal memory)
• The Complex Figure Test (helpful in defining visual-spatial construction and delayed visual memory)
• The Trailmaking Test B (also included in the Montreal Cognitive Assessment; assesses executive functioning).

Besides formal testing, an informal battery is often recommended to provide additional information. An informal evaluation includes word definition, reading and verbal fluency, reading comprehension, and performance of instrumental activities of daily living. Observing as patients perform tasks of daily living provides therapists with a vast amount of information, as these tasks require using multiple cognitive processes. Therefore, if a functional breakdown occurs during this assessment, the clinician needs to identify the domain or specific level of cognitive dysfunction involved in that deficit.⁴⁴

PREVENTIVE STRATEGIES

Strategies for minimizing the long-term effects of cognitive impairment have mostly focused on preventing it.

During the ICU stay, optimizing hemodynamic, glucose, and oxygenation levels may prevent future long-term complications.¹⁸

Also, the association between sedation, delirium, and consequent cognitive impairment (see above) has led many investigators to apply the “ABCDE” bundle of strategies.^25,45,46 Specifically, ABCDE stands for awakening and breathing, choice of sedatives with fewer adverse effects, daily delirium monitoring, and early mobility exercise. These strategies have been shown in randomized controlled trials to prevent delirium; however, they have not been proved to prevent cognitive impairment.

Awakening and breathing

In the Awakening and Breathing Controlled Trial,⁴⁷ patients in the intervention group (ie, those who had their sedatives interrupted every morning to see if they would awaken, and if so, if they could breathe on their own) were extubated 3 days sooner than those in the control group (who underwent daily trials of spontaneous breathing, if deemed safe). Also, ICU and hospital length of stay were shorter by 4 days. Best of all, over 1 year, the mortality rate was lower by 14 absolute percentage points.

Choice of sedatives

Often, mechanically ventilated patients are given benzodiazepines, opiates, and propofol (Diprivan).²¹ Dexmedetomidine (Precedex), a newer agent, is an alpha-2 agonist and may offer advantages over the others.

To date, three randomized controlled trials have assessed the effect of dexmedetomidine in terms of outcomes associated with delirium, and one trial evaluated its association with intellectual capacity in ICU patients.

The Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) trial randomized patients on mechanical ventilation to receive either dexmedetomidine or lorazepam (Ativan).⁴⁸ Dexmedetomidine-treated patients had 4 more days alive without delirium or coma (7 vs 3 days, P = .01).

Subsequently, the Safety and Efficacy of Dexmedetomidine Compared With Midazolam (SEDCOM) trial compared dexmedetomidine and midazolam (Versed) in mechanically ventilated patients. Those who received dexmedetomidine had a lower incidence of delirium (54% vs 76%, P < .001), and 2 fewer days on mechanical ventilation.⁴⁹

Reade et al⁵⁰ evaluated time to extubation in already delirious patients randomized to receive either dexmedetomidine or haloperidol (Haldol). Those receiving dexmedetomidine had a shorter time to extubation as well as a shorter ICU length of stay.

The Acute Neuroscience Intensive Care Sedation Trial⁵¹ evaluated intellectual capacity in neurological ICU patients sedated with either dexmedetomidine or propofol. This randomized, double-blind trial included 18 brain-injured and 12 non-brain-injured intubated patients. In a crossover protocol, each received the combination of fentanyl (Sublimaze) and propofol and the combination of fentanyl and dexmedetomidine.

Cognition was evaluated using the Adapted Cognitive Exam (ACE), which assesses intellectual capacity through orientation, language, registration, attention, calculation, and recall. This 10-minute examination does not require verbal communication, as it relies on the ability to respond to yes-or-no questions and perform simple motor tasks. The maximum possible score is 100 points.

Interestingly, while on propofol, the patients’ adjusted ACE scores went down by a mean of 12.4 points, whereas they went up by 6.8 points while on dexmedetomidine. Even though brain-injured patients required less sedation than non-brain-injured patients, the effect of dexmedetomidine and propofol did not change.⁵¹

In summary, these studies suggest that all sedatives are not the same in their short-term and intermediate-term outcomes.

In our practice, we use dexmedetomidine as our first-line sedation therapy. In patients with hemodynamic instability, we use benzodiazepines. We reserve propofol for very short periods of intubation or for hemodynamically stable patients who cannot be sedated with dexmedetomidine.

Daily delirium monitoring

As mentioned above, delirium affects many patients on mechanical ventilation, and it is highly underrecognized if valid tests are not used.⁵² Therefore, it is critically important to be familiar with the tests for assessing delirium. Of these, the Confusion Assessment Method for the ICU is probably the one with the best performance, with a sensitivity of 93% to 100% and a specificity of 98% to 100%.^53,54

Early mobilization

A landmark study paired the awakening and breathing strategy with early mobilization through physical and occupational therapy in the ICU.⁵⁵ Patients in the intervention group had a higher rate of return to independent functional status upon hospital discharge and a shorter duration of mechanical ventilation and delirium.

In conclusion, even though direct prevention of cognitive dysfunction is a challenging task, the ABCDE approach targets individual risk factors for delirium, which is an important contributor to cognitive impairment. Whether the ABCDE bundle directly affects the development of cognitive impairment requires further investigation.

COGNITIVE THERAPIES

The cognition-focused intervention most often described is cognitive training. Cognitive training is delivered in individual or group sessions in which the patient practices tasks targeting different domains, such as memory, language, and attention. Outcomes are often assessed in terms of improvement in test scores or effects on everyday functioning. Unfortunately, because of heterogeneity among cognitive training interventions and studied populations, we cannot yet make strong evidence-based recommendations for clinical practice.

Martin et al⁵⁶ in 2011 reviewed cognition-based interventions for healthy older people and people with mild cognitive impairment and found 36 relevant studies. Of these, only 3 were in patients with mild cognitive impairment, while the rest were in healthy older people.^56–58 Overall, the only available data were related to the memory domain, and outcomes were mostly associated with immediate recall of words, paragraphs, and stories. Based on this, cognitive therapy is currently considered justified, as most patients with cognitive impairment after an ICU stay have memory problems.

Zelinski et al⁵⁹ conducted a randomized, controlled, double-blind study comparing outcomes in an intervention group that underwent a computerized cognitive training program with those in a control group that viewed videos on a variety of topics such as literature, art, and history. The intervention, based on brain plasticity, aimed to improve the speed and accuracy of auditory information processing and to engage neuromodulatory systems. Some of the secondary outcomes favored the intervention group. These outcomes were related mostly to measures of overall memory, such as immediate and delayed recall, but also to a composite outcome that included letter-number sequencing and the digit span backwards test.

Despite these encouraging results, it is worth mentioning that these studies were not performed in patients with cognitive impairment associated with ICU admission. Therefore, the applicability and effectiveness of such therapies in post-ICU patients remains unknown.

Patients with posttraumatic brain injury and stroke have also been extensively studied in regard to the development of cognitive impairment.³⁴ These patients probably represent a better standard for comparison, as their cognitive impairment does not necessarily progress.

The effect of cognitive rehabilitation on the recovery in these patients depends on adaptation and remediation. Adaptation describes a patient’s ability to compensate for functional impairment.³⁴ This can be divided into internal and external adaptation. Internal adaptation requires the patient to recognize his or her cognitive limitation in order to adapt the to the environment accordingly. External adaptation entails getting help from devices or relatives (eg, phone calls) to achieve desired goals (eg, taking medication at scheduled times). Again, to adapt, the patient needs to be able to recognize his or her affected cognitive domain. Unfortunately, this is not always the case.

Remediation refers to the actual regaining of a lost ability. To stimulate neural plasticity, the patient is required to experience and repeat targeted skill-building activities.³⁸ There is evidence that patients are more likely to regain lost ability by repeating the practice frequently during a short period of time.⁶⁰

From the physician’s perspective, evaluating and identifying deficits in particular cognitive domains may help in designing a remediation plan in partnership with a cognitive therapist.

Cognitive rehabilitation in ICU survivors

The Returning to Everyday Tasks Utilizing Rehabilitation Networks (RETURN) study focused on cognitive and physical rehabilitation in post-ICU patients.⁶¹ This pilot study included 21 ICU survivors with cognitive or functional impairment at hospital discharge. Eight patients received usual care and 13 received a combination of in-home cognitive, physical, and functional rehabilitation over a 3-month period with a social worker or a master’s-level psychology technician.

Interventions included six in-person visits for cognitive rehabilitation and six televisits for physical and functional rehabilitation. Cognitive training was based on the goal-management training (GMT) protocol.⁶² This strategy attempts to improve executive function by increasing goal-directed behavior and by helping patients learn to be reflective before making decisions and executing tasks. The GMT model consists of sessions that build on one another to increase the rehabilitation intensity. During each session, goals are explained and participants perform increasingly challenging cognitive tasks.

Cognitive outcomes were evaluated using the Delis-Kaplan Tower Test to evaluate executive function by assessing the ability to plan and strategize efficiently. The patient is required to move disks across three pegs until a tower is built. The object is to use the fewest moves possible while adhering to two rules: larger disks cannot be placed on top of smaller ones, and disks must be moved one at a time, using only one hand.

At 3 months there was a significant difference between groups, with the intervention group earning higher tower test scores than controls did (median of 13 vs 7.5).

The Activity and Cognitive Therapy in the Intensive Care Unit (ACT-ICU) trial is another pilot study that will attempt to assess the feasibility of early cognitive rehabilitation in ICU survivors. This study will combine early mobilization with a cognitive intervention, and its primary outcome is executive function (with the tower test) at 3 months after discharge.⁶³

DRUG THERAPY

Some medications have been tested to assess whether they reduce the risk of progression from adult traumatic brain injury to cognitive impairment. These drugs augment dopamine and acetylcholine activity.

Methylphenidate (Ritalin), a dopaminergic drug, was studied in two trials. The first was a double-blind trial in 18 patients with posttraumatic brain injury. Memory was found to improve, based on the Working Memory Task Test. However, due to the small number of participants, no further conclusions were obtained.⁶⁴

The second trial, in 19 patients with posttraumatic brain injury, had a double-blind crossover design. Attention, evaluated by the Distraction Task Test, improved with the use of methylphenidate.⁶⁵ Again, the small number of patients precludes generalization of these results.

Donepezil (Aricept), a cholinergic drug, was evaluated in four clinical trials in posttraumatic brain injury patients^66–69; each trial included 21 to 180 patients. The trials evaluated the drug’s effect on memory and attention through a variety of tools (Paced Auditory Serial Addition Test; Wechsler Memory Scale; Boston Naming Test; Rey Auditory Verbal Learning Test; Complex Figure Test; and Reaction Time–Dual Task). Interestingly, donepezil was associated with large improvements in objective assessments of attention and memory. Despite methodologic flaws, such as a lack of blinding in one of these studies⁶⁹ and an open-label design in two of them,^66,68 of the drugs available, donepezil presents the strongest evidence for use in cognitive impairment after traumatic brain injury.⁷⁰

Intensive care medicine has dramatically evolved over the last 15 years, after reports from many landmark trials.¹ Updated strategies for mechanical ventilation² and “bundles” of strategies to optimize hemodynamic therapy³ have reduced the rates of morbidity and death from deadly critical conditions such as the adult respiratory distress syndrome (ARDS) and sepsis.

Despite these important improvements in short-term outcomes, it is increasingly recognized that intensive care unit (ICU) survivors suffer considerable long-term complications that affect their usual functioning.⁴ Recently, the Society of Critical Care Medicine convened a conference in which these long-term complications were named the “post-intensive care syndrome.”⁵

Quality of life, particularly its physical component, is considerably lower after a stay in the medical or surgical ICU.^6–8 Posttraumatic stress disorder, depression, and sexual dysfunction are consistently reported years after ICU discharge.^9–13

Perhaps the most frequently unrecognized complication in ICU survivors is cognitive impairment. Current data suggest that neurocognitive impairment after an ICU stay is common and that it persists 6 years or more after hospital discharge.

Hopkins et al^14,15 analyzed 10 cohort studies of long-term cognitive impairment after an ICU stay; 5 of them focused on patients with ARDS. The prevalence of cognitive impairment was as high as 78% at hospital discharge, 46% at 1 year, and 25% 6 years after discharge.^15,16 Of the cognitive domains compromised, memory was the most often affected, followed by executive function and attention.^14,17

Interestingly, data suggest that cognition may improve somewhat in the first 6 to 12 months after ICU discharge.¹⁵ Therefore, if we can detect it early on and promptly refer patients for cognitive therapy, we may eventually improve the prognosis of this disabling complication.

This review will focus on how to evaluate, prevent, and treat cognitive impairment in patients who survive an ICU stay.

COGNITIVE IMPAIRMENT AFTER A STAY IN THE ICU

The association between ICU stay and neurocognitive dysfunction is poorly understood. Potential causes include hypoxemia,¹⁸ hypotension, ¹⁹ hyperglycemia,¹⁴ and—an area of growing interest and evolving research—sedation and delirium.²⁰

Patients on mechanical ventilation are commonly given sedatives and analgesics to prevent anxiety and pain.²¹ However, these medications are strongly associated with delirium.²² In fact, recent studies found that benzodiazepines have an independent, dose-related, temporal association with delirium, with some reports describing a 20% increase in delirium per milligram of benzodiazepine.²³ In another study, which included medical and surgical ICU patients, use of morphine was the strongest predictor of delirium, with a sixfold increase in odds over a period of 5 months.²⁴

Delirium is important to prevent, diagnose, and treat, since it has a direct association with the development of long-term cognitive impairment.^22,25 A review of studies that included 1,885 medical and surgical patients found that those who developed delirium during an ICU stay were three times more likely to have cognitive dysfunction when assessed 3 years later.²⁰

Whether delirium is a primary disorder associated with cognitive impairment or if it only represents an underlying process leading to poor cognitive outcomes is unknown. As delirious patients are more likely to be older, to be mechanically ventilated, to require more sedation, and, in particular, to be sicker, the association between delirium and cognitive impairment may reflect the relationship between these risk factors and poor cognitive outcomes.²⁶

Glucose and its relationship with cognitive function is another topic of investigation. A secondary analysis of a study that included ARDS survivors revealed that blood glucose values higher than 153 mg/dL, higher glucose variability, and duration of mechanical ventilation were associated with cognitive sequelae.^27,28

Other studies focused on mechanical ventilation. In one study,²⁹ one-third of patients who had been mechanically ventilated showed signs of neurocognitive impairment when they were evaluated 6 months after hospital discharge.

Mild cognitive impairment differs from cognitive impairment after an ICU stay

Cognitive impairment after ICU discharge does not follow the same pattern as mild cognitive impairment, and some authors consider these two types of cognitive impairment to be unrelated.

While mild cognitive impairment is progressive and associated with aging, cognitive impairment in ICU survivors develops rapidly after acute illness and is usually related to numerous pathologic and neurochemical pathways.

For example, the neurotransmitter acetylcholine is thought to be involved in cognitive function as well as neuroplasticity of the motor cortex. In a model of cognitive impairment after stroke, activity of the cholinergic system was reduced.^30,31 Further, in a study in rats, Baskerville et al³² showed that experience-dependent plasticity could be completely blocked by damaging the cholinergic neurons in the nucleus basalis of Meynert, thereby affecting memory and other functions supported by this pathway.

Another implicated pathway involves dopamine. Of interest, dopamine augmentation has been shown to enhance simple motor memories and to improve procedural learning. Understanding of these neurochemical alterations opens opportunities for investigation of drug therapies.

ASSESSMENT TOOLS

Cognitive impairment is important to detect in ICU survivors because it predicts poor outcomes from rehabilitation. A study of stroke patients found that those with cognitive alterations immediately after the stroke were less likely to be discharged home or to be living at home 6 months after discharge.³³

A possible explanation may be that affected patients cannot fully participate in rehabilitation activities, owing to impairment in executive function, inability to remember therapy instructions, or disruption of implicit and explicit learning. Indeed, some authors consider cognitive impairment after acquired brain injury to be the most relevant surrogate marker of rehabilitation potential. Consequently, manipulation or enhancement of cognition may directly affect rehabilitation outcomes.³⁴

Disagreement about terminology and diagnostic criteria creates a problem for health care providers working with patients with potential cognitive impairment. Numerous systems have been proposed to define this condition; in fact, Stephan et al³⁵ reviewed the literature and found no fewer than 17. None of them is specific for cognitive impairment after an ICU stay.

Petersen et al³⁶ in 1999 proposed initial criteria for mild cognitive impairment that included the following:

• A memory complaint
• Normal general cognitive functioning
• Normal activities of daily living
• Memory impairment in relation to age and education
• No dementia.

Later, other areas of impairment besides memory were recognized, such as language, attention, perception, reasoning, and motor planning.³⁷ Therefore, mild cognitive impairment is currently classified into subtypes, which include amnestic (affecting single or multiple domains) and nonamnestic (also affecting single or multiple domains).³⁸

In clinical practice, impairment of specific cognitive domains may be challenging to detect, and neuropsychological testing is often needed. Cognitive screening tests can detect impairment across a restricted range of cognitive abilities, while more comprehensive assessments address each of the primary domains of cognition.³⁹ Formal testing provides normative and validated data on cognition performance and severity.

The Montreal Cognitive Assessment⁴⁰ is popular, comprehensive, used in a variety of professions in diverse types of facilities (acute care, rehabilitation, and skilled care facilities), and brief (taking 11 minutes to administer). It evaluates orientation, memory, language, attention, reasoning, and visual-constructional abilities. The maximum score is 30; cognitive impairment is defined as a score of less than 26. It has a sensitivity of 90% and a specificity of 87%.

The Folstein Mini-Mental State Examination (MMSE) is the most commonly used of the noncomprehensive tests in clinical practice.⁴¹ It assesses orientation, memory, language, attention, and praxis. It has a maximum score of 30 points; the cutoff score for cognitive impairment is 24 points or less.

A limitation of the MMSE is that its sensitivity is very low, ranging from 1% to 49%.^42,43 The MMSE scores of patients with cognitive impairment overlap considerably with those of age-matched healthy controls.³⁹ Conversely, the MMSE’s specificity is usually high, ranging from 85% to 100%.⁴²

Moreover, the MMSE poses copyright issues, an important consideration when selecting a test. In 2001, the authors of the MMSE transferred all intellectual property rights to Psychological Assessment Resources, which has exclusive rights to publish, license, and manage all intellectual property rights in all media and languages. Photocopying and using the MMSE without applying for permission from and paying this company ($1.23 per use) constitutes copyright infringement. Therefore, health care providers and researchers have been using other tests to evaluate cognition.

Other tests of cognition assess individual domains. Interestingly, studies of long-term cognitive impairment after ICU admission used these tests to define outcomes.²⁵ Specific tests include:

• The Digit Span and the Trailmaking Test A (used to assess attention and orientation)²⁵
• The Rey Auditory Verbal Learning Test (used to evaluate verbal memory)
• The Complex Figure Test (helpful in defining visual-spatial construction and delayed visual memory)
• The Trailmaking Test B (also included in the Montreal Cognitive Assessment; assesses executive functioning).

Besides formal testing, an informal battery is often recommended to provide additional information. An informal evaluation includes word definition, reading and verbal fluency, reading comprehension, and performance of instrumental activities of daily living. Observing as patients perform tasks of daily living provides therapists with a vast amount of information, as these tasks require using multiple cognitive processes. Therefore, if a functional breakdown occurs during this assessment, the clinician needs to identify the domain or specific level of cognitive dysfunction involved in that deficit.⁴⁴

PREVENTIVE STRATEGIES

Strategies for minimizing the long-term effects of cognitive impairment have mostly focused on preventing it.

During the ICU stay, optimizing hemodynamic, glucose, and oxygenation levels may prevent future long-term complications.¹⁸

Also, the association between sedation, delirium, and consequent cognitive impairment (see above) has led many investigators to apply the “ABCDE” bundle of strategies.^25,45,46 Specifically, ABCDE stands for awakening and breathing, choice of sedatives with fewer adverse effects, daily delirium monitoring, and early mobility exercise. These strategies have been shown in randomized controlled trials to prevent delirium; however, they have not been proved to prevent cognitive impairment.

Awakening and breathing

In the Awakening and Breathing Controlled Trial,⁴⁷ patients in the intervention group (ie, those who had their sedatives interrupted every morning to see if they would awaken, and if so, if they could breathe on their own) were extubated 3 days sooner than those in the control group (who underwent daily trials of spontaneous breathing, if deemed safe). Also, ICU and hospital length of stay were shorter by 4 days. Best of all, over 1 year, the mortality rate was lower by 14 absolute percentage points.

Choice of sedatives

Often, mechanically ventilated patients are given benzodiazepines, opiates, and propofol (Diprivan).²¹ Dexmedetomidine (Precedex), a newer agent, is an alpha-2 agonist and may offer advantages over the others.

To date, three randomized controlled trials have assessed the effect of dexmedetomidine in terms of outcomes associated with delirium, and one trial evaluated its association with intellectual capacity in ICU patients.

The Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) trial randomized patients on mechanical ventilation to receive either dexmedetomidine or lorazepam (Ativan).⁴⁸ Dexmedetomidine-treated patients had 4 more days alive without delirium or coma (7 vs 3 days, P = .01).

Subsequently, the Safety and Efficacy of Dexmedetomidine Compared With Midazolam (SEDCOM) trial compared dexmedetomidine and midazolam (Versed) in mechanically ventilated patients. Those who received dexmedetomidine had a lower incidence of delirium (54% vs 76%, P < .001), and 2 fewer days on mechanical ventilation.⁴⁹

Reade et al⁵⁰ evaluated time to extubation in already delirious patients randomized to receive either dexmedetomidine or haloperidol (Haldol). Those receiving dexmedetomidine had a shorter time to extubation as well as a shorter ICU length of stay.

The Acute Neuroscience Intensive Care Sedation Trial⁵¹ evaluated intellectual capacity in neurological ICU patients sedated with either dexmedetomidine or propofol. This randomized, double-blind trial included 18 brain-injured and 12 non-brain-injured intubated patients. In a crossover protocol, each received the combination of fentanyl (Sublimaze) and propofol and the combination of fentanyl and dexmedetomidine.

Cognition was evaluated using the Adapted Cognitive Exam (ACE), which assesses intellectual capacity through orientation, language, registration, attention, calculation, and recall. This 10-minute examination does not require verbal communication, as it relies on the ability to respond to yes-or-no questions and perform simple motor tasks. The maximum possible score is 100 points.

Interestingly, while on propofol, the patients’ adjusted ACE scores went down by a mean of 12.4 points, whereas they went up by 6.8 points while on dexmedetomidine. Even though brain-injured patients required less sedation than non-brain-injured patients, the effect of dexmedetomidine and propofol did not change.⁵¹

In summary, these studies suggest that all sedatives are not the same in their short-term and intermediate-term outcomes.

In our practice, we use dexmedetomidine as our first-line sedation therapy. In patients with hemodynamic instability, we use benzodiazepines. We reserve propofol for very short periods of intubation or for hemodynamically stable patients who cannot be sedated with dexmedetomidine.

Daily delirium monitoring

As mentioned above, delirium affects many patients on mechanical ventilation, and it is highly underrecognized if valid tests are not used.⁵² Therefore, it is critically important to be familiar with the tests for assessing delirium. Of these, the Confusion Assessment Method for the ICU is probably the one with the best performance, with a sensitivity of 93% to 100% and a specificity of 98% to 100%.^53,54

Early mobilization

A landmark study paired the awakening and breathing strategy with early mobilization through physical and occupational therapy in the ICU.⁵⁵ Patients in the intervention group had a higher rate of return to independent functional status upon hospital discharge and a shorter duration of mechanical ventilation and delirium.

In conclusion, even though direct prevention of cognitive dysfunction is a challenging task, the ABCDE approach targets individual risk factors for delirium, which is an important contributor to cognitive impairment. Whether the ABCDE bundle directly affects the development of cognitive impairment requires further investigation.

COGNITIVE THERAPIES

The cognition-focused intervention most often described is cognitive training. Cognitive training is delivered in individual or group sessions in which the patient practices tasks targeting different domains, such as memory, language, and attention. Outcomes are often assessed in terms of improvement in test scores or effects on everyday functioning. Unfortunately, because of heterogeneity among cognitive training interventions and studied populations, we cannot yet make strong evidence-based recommendations for clinical practice.

Martin et al⁵⁶ in 2011 reviewed cognition-based interventions for healthy older people and people with mild cognitive impairment and found 36 relevant studies. Of these, only 3 were in patients with mild cognitive impairment, while the rest were in healthy older people.^56–58 Overall, the only available data were related to the memory domain, and outcomes were mostly associated with immediate recall of words, paragraphs, and stories. Based on this, cognitive therapy is currently considered justified, as most patients with cognitive impairment after an ICU stay have memory problems.

Zelinski et al⁵⁹ conducted a randomized, controlled, double-blind study comparing outcomes in an intervention group that underwent a computerized cognitive training program with those in a control group that viewed videos on a variety of topics such as literature, art, and history. The intervention, based on brain plasticity, aimed to improve the speed and accuracy of auditory information processing and to engage neuromodulatory systems. Some of the secondary outcomes favored the intervention group. These outcomes were related mostly to measures of overall memory, such as immediate and delayed recall, but also to a composite outcome that included letter-number sequencing and the digit span backwards test.

Despite these encouraging results, it is worth mentioning that these studies were not performed in patients with cognitive impairment associated with ICU admission. Therefore, the applicability and effectiveness of such therapies in post-ICU patients remains unknown.

Patients with posttraumatic brain injury and stroke have also been extensively studied in regard to the development of cognitive impairment.³⁴ These patients probably represent a better standard for comparison, as their cognitive impairment does not necessarily progress.

The effect of cognitive rehabilitation on the recovery in these patients depends on adaptation and remediation. Adaptation describes a patient’s ability to compensate for functional impairment.³⁴ This can be divided into internal and external adaptation. Internal adaptation requires the patient to recognize his or her cognitive limitation in order to adapt the to the environment accordingly. External adaptation entails getting help from devices or relatives (eg, phone calls) to achieve desired goals (eg, taking medication at scheduled times). Again, to adapt, the patient needs to be able to recognize his or her affected cognitive domain. Unfortunately, this is not always the case.

Remediation refers to the actual regaining of a lost ability. To stimulate neural plasticity, the patient is required to experience and repeat targeted skill-building activities.³⁸ There is evidence that patients are more likely to regain lost ability by repeating the practice frequently during a short period of time.⁶⁰

From the physician’s perspective, evaluating and identifying deficits in particular cognitive domains may help in designing a remediation plan in partnership with a cognitive therapist.

Cognitive rehabilitation in ICU survivors

The Returning to Everyday Tasks Utilizing Rehabilitation Networks (RETURN) study focused on cognitive and physical rehabilitation in post-ICU patients.⁶¹ This pilot study included 21 ICU survivors with cognitive or functional impairment at hospital discharge. Eight patients received usual care and 13 received a combination of in-home cognitive, physical, and functional rehabilitation over a 3-month period with a social worker or a master’s-level psychology technician.

Interventions included six in-person visits for cognitive rehabilitation and six televisits for physical and functional rehabilitation. Cognitive training was based on the goal-management training (GMT) protocol.⁶² This strategy attempts to improve executive function by increasing goal-directed behavior and by helping patients learn to be reflective before making decisions and executing tasks. The GMT model consists of sessions that build on one another to increase the rehabilitation intensity. During each session, goals are explained and participants perform increasingly challenging cognitive tasks.

Cognitive outcomes were evaluated using the Delis-Kaplan Tower Test to evaluate executive function by assessing the ability to plan and strategize efficiently. The patient is required to move disks across three pegs until a tower is built. The object is to use the fewest moves possible while adhering to two rules: larger disks cannot be placed on top of smaller ones, and disks must be moved one at a time, using only one hand.

At 3 months there was a significant difference between groups, with the intervention group earning higher tower test scores than controls did (median of 13 vs 7.5).

The Activity and Cognitive Therapy in the Intensive Care Unit (ACT-ICU) trial is another pilot study that will attempt to assess the feasibility of early cognitive rehabilitation in ICU survivors. This study will combine early mobilization with a cognitive intervention, and its primary outcome is executive function (with the tower test) at 3 months after discharge.⁶³

DRUG THERAPY

Some medications have been tested to assess whether they reduce the risk of progression from adult traumatic brain injury to cognitive impairment. These drugs augment dopamine and acetylcholine activity.

Methylphenidate (Ritalin), a dopaminergic drug, was studied in two trials. The first was a double-blind trial in 18 patients with posttraumatic brain injury. Memory was found to improve, based on the Working Memory Task Test. However, due to the small number of participants, no further conclusions were obtained.⁶⁴

The second trial, in 19 patients with posttraumatic brain injury, had a double-blind crossover design. Attention, evaluated by the Distraction Task Test, improved with the use of methylphenidate.⁶⁵ Again, the small number of patients precludes generalization of these results.

Donepezil (Aricept), a cholinergic drug, was evaluated in four clinical trials in posttraumatic brain injury patients^66–69; each trial included 21 to 180 patients. The trials evaluated the drug’s effect on memory and attention through a variety of tools (Paced Auditory Serial Addition Test; Wechsler Memory Scale; Boston Naming Test; Rey Auditory Verbal Learning Test; Complex Figure Test; and Reaction Time–Dual Task). Interestingly, donepezil was associated with large improvements in objective assessments of attention and memory. Despite methodologic flaws, such as a lack of blinding in one of these studies⁶⁹ and an open-label design in two of them,^66,68 of the drugs available, donepezil presents the strongest evidence for use in cognitive impairment after traumatic brain injury.⁷⁰