Prevention has the greatest potential to reduce the societal burden from stroke.1 Several therapies that specifically target the underlying atherosclerotic disease process have been shown in clinical trials to markedly lower the risk of recurrent vascular events including stroke.2 However, there is great variability in how clinical trial data are implemented in clinical practice for ischemic stroke prevention.35 This has led to a knowledge‐implementation‐practice gap, possibly because of the limited awareness of the scientific evidence supporting various treatments, as well as the lack of a systematic approach to hospital stroke care.3 Our review discusses the evidence for reducing vascular risk after ischemic stroke and successful models of systematic interventions initiated during stroke hospitalization, with the goal of narrowing the stroke hospitalization evidencepractice gap.

Societal Burden

Stroke is the third‐leading cause of death in the United States and the leading cause of serious long‐term disability.6 Approximately 700,000 Americans have a new stroke or recurrent strokes every year, whereas nearly 5 million live with the consequences of stroke; nearly all stroke survivors (90%) have some residual functional deficit, and approximately 40% experience moderate to severe impairment.6 Stroke mortality is substantial, with a 30‐day case fatality rate after first stroke (of any cause) of about 25%.7, 8 Indeed, four‐fifths of patients do not survive for 10 years after stroke, and approximately one‐third of all case fatalities occur in the first year after a stroke.8 The estimated economic impact in 2006, US$57.9 billion, further underscores the substantial mortality and morbidity of stroke.6 Given the limited options for acute stroke therapies,9 stroke prevention remains an important therapeutic goal, especially because fewer than 5% of acute stroke patients in the United States currently receive the only Food and Drug Administrationapproved treatmentintravenous tissue plasminogen activator.10 It is obvious that additional strategies are urgently needed to reduce the devastating consequences of stroke.

Why Involve the Hospitalist?

The Hospitalist system in the United States is rapidly growing.11 Tthe Society of Hospital Medicine projects that by 2010 there will be approximately 30,000 hospitalists in the United States.11 A member census conducted by the American Academy of Neurology in 2000 found 13,500 practicing neurologists, most of whom are concentrated in urban and metropolitan areas.12 As such, with more than 700,000 strokes occurring each year,6 most stroke patients in the United States will not be seen or evaluated by a neurologist. Indeed, one study indicated that only 11.3% of stroke patients are attended exclusively by a neurologist.13 Furthermore, it is not uncommon for stroke patients to have numerous other medical issues that require attention and multidisciplinary care coordination during the hospital stay, an area where hospitalists excel. Conceivably, the ability to promptly identify and treat these non‐neurological comorbidities, which account for at least 30% of the deaths from acute ischemic stroke,14 could go a long way toward improving stroke outcomes.

Hospitalists are in the forefront of developing strategies for improving the quality of acute care and patient satisfaction, reducing medical errors, and focusing on efficient resource utilization. Translating evidence‐based strategies for acute stroke care into actual practice is a mechanism for improving the quality of care, ensuring that basic care does not deviate from provider to provider or from day to day (weekdays compared to weekend days/holidays) while at the same time allowing for the individualization of care appropriate to a patient's unique needs.15 After the acute treatment of stroke or TIA, additional measures must be initiated as soon as it is safe to do so in order to begin the process of limiting stroke progression and preventing recurrence. Secondary prevention measures require a coordinated transition in order to ensure continuation of care and follow‐up as needed. After a thorough risk assessment is complete, hospitalists will need to consider a 3‐pronged approach to secondary prevention that follows the national guidelines described above: pharmacotherapy, behavior modification, and, in some cases, surgical intervention.

Secondary Stroke

Secondary or recurrent strokes are strokes that occur after a first stroke or TIA,2 and the single biggest risk factor for having a stroke is already having had one.2 Because hospitalists generally see patients after ischemic cerebrovascular events have already happened, their opportunities to intervene are mostly geared toward reducing the risk of secondary stroke (beyond enhancing the prevention of complications from the index event). Recent community‐based data indicate that the short‐term risk of secondary stroke is high.16, 17 After a minor stroke or TIA, the risk of recurrent stroke or TIA increases over time8%‐12% within 7 days, 12%‐15% within 30 days, and 17%‐19% within 90 days.18 In the largest study of short‐term risk following TIA,19 there was an 11% risk of stroke (51% of which occurred in the 48 hours after TIA), an 13% risk of TIA, and a 25% risk of any adverse event within 90 days of the TIA.

Overall, the risk of a second cerebrovascular event is highest in the first year after a stroke/TIA (12%), declining to about 5% annually thereafter.7 The effects of secondary stroke are more devastating than those of the primary stroke: the 30‐day fatality rate after a first recurrent stroke is almost double that after the first‐ever stroke (41% versus 22%).20 The pathological factors that lead to TIA and stroke, such as platelet aggregation and subsequent thrombosis or the systolic stroke of blood against stenotic carotid plaques, are one and the same. As such, the short‐ and long‐term risks of recurrent events after both first stroke or first TIA necessitate investigation into a patient's vascular risk and early initiation of appropriate stroke prevention strategies.21

Cross Risk

Because the atherothrombotic disease process is systemic in nature with a variety of manifestations, stroke patients with atherosclerosis frequently have coexistent coronary artery disease and peripheral artery disease,22 and as such, are at risk for vascular events emanating from any of these beds in addition to that of the cervicocephalic arterial tree.23, 24 For instance, in a study of individuals in a long‐term care facility, among the patients with ischemic stroke, 56% had overlapping coronary artery disease, 28% had peripheral artery disease,25 and 38% of the patients had at least 2 manifestations of their atherosclerotic disease. The take‐home message here is that hospitalists also have the opportunity while treating patients hospitalized following stroke to prevent other vascular events by identifying and treating stroke patients who have systemic atherosclerosis.

Risk Factors

The first step in any approach to stroke prevention is the identification of predisposing risk factors. Several of the known biological and lifestyle risk factors associated with cerebrovascular disease were identified decades ago from large longitudinal studies.2 Certain stroke risk factors are nonmodifiable and therefore cannot be the target of intervention. 26 Treatment of the various stroke risk factors could have a substantial impact on reducing the burden of stroke. Table 1 shows the number needed to treat to prevent one stroke per year by modification of the individual stroke risk factor.

Guidelines for Secondary Stroke Prevention

Several organizations have published guidelines for the prevention of secondary stroke based on clinical evidence and expert consensus. Key guidelines include those published by the American Stroke Association (ASA),2 American College of Chest Physicians (ACCP),27 and the National Stroke Association. Although these guidelines are broadaddressing many components of stroke prevention and careeach contains recommendations specifically applicable to secondary prevention in most stroke patients who the hospitalist will encounter. Some provide hospital‐based guidelines that focus on care protocols and systems processes (ie, ASA Stroke Systems Guidelines), whereas others are therapy‐based guidelines (i.e, ACCP Guidelines on Antithrombotic Therapy for Ischemic Stroke). In the next few sections, we discuss common risk factors for and causes of secondary stroke and the prevailing guideline recommendations for modifying them. Discussion of the management of rare causes of ischemic stroke such as arterial dissection, vasculitis, patent foramen ovale, and so forth is beyond the scope of this article.

Hypertension, Dyslipidemia, and Diabetes

Table 2 shows the current national guideline recommendations for the management of premier vascular risk factorshypertension, dyslipidemia, and diabetesin ischemic stroke and TIA patients.2 Antihypertensive therapy is recommended for the prevention of secondary stroke and other vascular events in patients who have experienced an ischemic stroke or TIA and are beyond the hyperacute period.28, 29 Such treatment should be considered for all ischemic stroke and TIA patients regardless of history of hypertension.28 Although available data support the use of diuretics and the combination of diuretics plus an angiotensin‐converting enzyme inhibitor,28, 30 selection of specific medications should be individualized according to a patient's comorbid conditions.29 It is also important to note that despite the proven benefit of beta blockers in the secondary prevention of recurrent cardiac events, current evidence shows no clear benefit from the use of beta blockers in the prevention of stroke.29, 31

For ischemic cerebrovascular disease patients with dyslipidemia or symptomatic atherosclerosis, cholesterol management should be according to the current Adult Treatment Panel (ATP) guidelines.32 Statins should be the first‐line treatment.33, 34 Ischemic stroke or TIA patients whose underlying stroke mechanism is presumed to be atherosclerosis should be considered for statin therapy even if they have normal cholesterol levels and no evidence of atherosclerosis.33, 34 The recent Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study was the first study to specifically investigate the effect of statins in patients with a prior stroke but with normal cholesterol levels and no evidence of coronary heart disease. It found that treatment with atorvastatin 80 mg/day (vs. placebo) was associated with a 16% reduction in relative risk of recurrent stroke.34

The care of an ischemic stroke or TIA patient who has diabetes warrants more rigorous control of blood pressure and lipids.35, 36 Such patients usually require more than one antihypertensive drug. ACEIs and angiotensin receptor blockers (ARBs) are more effective in reducing the progression of renal disease and are the recommended first‐choice medications for these patients.37, 38 The target for glucose control should be reaching near‐normoglycemic levels.39

Large‐Artery Atherosclerosis

In selected at‐risk stroke patients, surgical techniques (eg, carotid endarterectomy [CEA], carotid angioplasty and/or stenting [CAS]) may reduce the rate of recurrent stroke.4044 For patients who have had ischemic cerebrovascular events in the preceding 6 months and who have ipsilateral severe (70%‐99%) cervical carotid artery stenosis, CEA done by a surgeon is recommended; it has a perioperative morbidity and mortality of less than 6%.40 For those with ipsilateral moderate (50%‐69%) cervical carotid stenosis, CEA should be considered, and whether to operate should be decided on the basis of the patient's age, sex, comorbidities, and severity of initial symptoms.41 Analyses of endarterectomy trials indicated that the benefit from CEA is greatest if performed within 2 weeks of a patient's last ischemic event, the advantage it confers rapidly falling with increasing delay.45 From the hospitalist's standpoint, it is of prime importance to ensure that patients admitted to the hospital with a TIA or ischemic stroke are not discharged before it has been established whether have severe carotid stenosis that requires a revascularization procedure. If carotid stenosis is less than 50%, CEA is not recommended.41

A newer, less invasive form of carotid artery revascularization is CAS,46 which is performed by operators with established periprocedural morbidity and mortality rates of 4%‐6% and may be considered in those with:

• Symptomatic severe stenosis (>70%) that is difficult to access surgically.2

• Medical issues that greatly increase the risks of surgery, such as clinically significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal nerve palsy, radiation‐induced stenosis or restenosis after carotid endarterectomy, and more than 80 years old.43

Angioplasty and/or stenting may also be considered when patients with symptomatic extracranial vertebral stenosis are having symptoms despite optimal medical risk factor treatments.2 Among those with hemodynamically significant stenosis of the major intracranial vasculature (basilar, middle cerebrals, distal carotids, and vertebrals) experiencing symptoms despite optimal medical risk factor treatments, angioplasty and/or stenting is considered experimental.2

The degree of arterial stenosis can be assessed by ultrasound, magnetic resonance angiogram (MRA), computed tomography angiogram (CTA), and conventional catheter angiogram, the last of which remains the gold standard. A carotid ultrasound performed at a certified vascular laboratory or by an experienced radiology technologist that shows less than 50% stenosis need not be followed up with another neuroimaging test. Generally, MRA tends to overestimate the degree of arterial stenosis but is a useful screening tool. In the event that an MRA reveals more than 50% stenosis, another diagnostic modality such as a carotid duplex, CTA, or conventional catheter angiogram should be performed to confirm this finding.

Antithrombotic Treatment

Noncardioembolic Stroke Mechanism

For ischemic stroke or TIA patients who have no high‐risk source of cardiogenic embolism, antiplatelet agents rather than oral anticoagulation are generally recommended to reduce the risk of recurrent stroke and other cardiovascular events.4850 Acceptable options for initial therapy include:

• Aspirin (50 to 325 mg/day)48;

• Combination of aspirin (50 mg) and extended‐release dipyridamole (400 mg) daily49, 51;

• Clopidogrel (75 mg) daily.50

The combination of aspirin and extended‐release dipyridamole is suggested instead of aspirin alone, and clopidogrel may be considered instead of aspirin alone.49, 51 However, currently there is not enough data to make evidence‐based recommendations for choosing between antiplatelet drugs beyond aspirin.2 Furthermore, there is no evidence that increasing the dose of aspirin for patients who have had an ischemic stroke while taking aspirin provides additional benefit.2 The selection of an antiplatelet agent must be individualized, giving due consideration to a patient's presumed stroke mechanism, risk factor profile, and tolerance.

Other antiplatelet guidelines for noncardioembolic stroke/TIA patients include that:

• Adding aspirin to clopidogrel increases the risk of hemorrhage and should not be routinely recommended for ischemic stroke or TIA patients.52, 53

• Clopidogrel is a reasonable alternative for aspirin‐intolerant patients.50

Education for Behavior Modification

It is crucial to discharge patients with the tools they need to make important lifestyle changes. Patients can significantly reduce their stroke risk by making changes in their everyday patterns of behavior. As much education as possible about smoking cessation, exercise, diet, and the warning signs of stroke should be provided often as possible during hospitalization for a stroke and need not be left to nurses. Stroke education is extremely important so patients understand the need to call for emergency medical services immediately if they even suspect they are having stroke symptoms because of the very narrow window of opportunity for treatment of an acute stroke.54 All patients should be encouraged to make lifestyle adjustments such as ceasing smoking, reducing alcohol intake, and controlling weight. Smoking cessation appears to be effective in preventing secondary stroke (33% reduction in relative risk),44 and initiating smoking cessation counseling during hospitalization for stroke may result in a high rate of adherence to smoking cessation, at least in the short term.55 Table 3 displays current national guideline recommendations on lifestyle modification approaches.2

EvidencePractice Gap

There are now many secondary stroke prevention modalities, and there is a copious amount of data validating the efficacy of quite a few of them.2 Yet there is a large gap in implementing evidence‐based secondary prevention strategies.35 TIA and ischemic stroke patients are often discharged from the hospital without being prescribed any preventive medications, despite the data supporting the use of antiplatelet agents, anticoagulants, and antihypertensives for prevention of secondary stroke.4 In addition, several behavioral interventions could help patients to avoid stroke recurrence,2 but quite often stroke patients are not educated about them during the acute care period.4 Poor discharge treatment utilization limits the effectiveness of proven therapies, resulting in lost opportunities to reduce the burden of secondary stroke.

The reasons for these care gaps are multifactorial and can be traced to patient and provider issues as well as to health care delivery processes. Our understanding of the reasons for this gap is improving. Generally speaking, preventive services are used less frequently than those services or treatment modalities that provide immediate relief or economic benefit. The benefit of most preventive services is more readily seen at a population level than at a individual level and accrues slowly over time. It becomes more difficult to stress prevention in a health care system driven by technology‐based acute care.3

Current clinical management of acute stroke patients has stroke specialists and hospital physicians focusing on the acute management and diagnostic workup during hospitalization. Initiation of long‐term treatment is often deferred to after discharge, when the patient resumes long‐term primary care follow‐up.54 This deferred approach may result in therapy not being initiated or being initiated less efficiently and at a time (weeks or months after the initial presentation) when the stroke event and underlying atherosclerotic disease may no longer be the focus of either the patient or the primary care physician.54

Initiating medications during the acute stroke hospitalization phase sends the patient the message that these therapies are important for preventing recurrence and are an essential part of their treatment.54 More important, hospital initiation of secondary prevention therapies has been shown to be a strong predictor of these therapies continuing to be used after discharge56 and is associated with better clinical outcomes.5759 Table 4 shows some of the resources available to assist hospitalists in overcoming the evidencepractice gap in stroke treatment.

CONCLUSIONS

The acute stroke hospitalization setting provides the ideal opportunity for hospitalists to not only institute evidence‐based prevention therapies for recurrent stroke but also to have the undivided attention of patients and their families. Furthermore, it may be risky to assume that relevant therapy when deferred will be initiated in a timely fashion, if at all, after hospital discharge. As part of an effective continuum of care, hospitalists have an important role not just in the management of acute ischemic stroke, but also in long‐term reduction of vascular risk.

Prevention has the greatest potential to reduce the societal burden from stroke.1 Several therapies that specifically target the underlying atherosclerotic disease process have been shown in clinical trials to markedly lower the risk of recurrent vascular events including stroke.2 However, there is great variability in how clinical trial data are implemented in clinical practice for ischemic stroke prevention.35 This has led to a knowledge‐implementation‐practice gap, possibly because of the limited awareness of the scientific evidence supporting various treatments, as well as the lack of a systematic approach to hospital stroke care.3 Our review discusses the evidence for reducing vascular risk after ischemic stroke and successful models of systematic interventions initiated during stroke hospitalization, with the goal of narrowing the stroke hospitalization evidencepractice gap.

Societal Burden

Stroke is the third‐leading cause of death in the United States and the leading cause of serious long‐term disability.6 Approximately 700,000 Americans have a new stroke or recurrent strokes every year, whereas nearly 5 million live with the consequences of stroke; nearly all stroke survivors (90%) have some residual functional deficit, and approximately 40% experience moderate to severe impairment.6 Stroke mortality is substantial, with a 30‐day case fatality rate after first stroke (of any cause) of about 25%.7, 8 Indeed, four‐fifths of patients do not survive for 10 years after stroke, and approximately one‐third of all case fatalities occur in the first year after a stroke.8 The estimated economic impact in 2006, US$57.9 billion, further underscores the substantial mortality and morbidity of stroke.6 Given the limited options for acute stroke therapies,9 stroke prevention remains an important therapeutic goal, especially because fewer than 5% of acute stroke patients in the United States currently receive the only Food and Drug Administrationapproved treatmentintravenous tissue plasminogen activator.10 It is obvious that additional strategies are urgently needed to reduce the devastating consequences of stroke.

Why Involve the Hospitalist?

The Hospitalist system in the United States is rapidly growing.11 Tthe Society of Hospital Medicine projects that by 2010 there will be approximately 30,000 hospitalists in the United States.11 A member census conducted by the American Academy of Neurology in 2000 found 13,500 practicing neurologists, most of whom are concentrated in urban and metropolitan areas.12 As such, with more than 700,000 strokes occurring each year,6 most stroke patients in the United States will not be seen or evaluated by a neurologist. Indeed, one study indicated that only 11.3% of stroke patients are attended exclusively by a neurologist.13 Furthermore, it is not uncommon for stroke patients to have numerous other medical issues that require attention and multidisciplinary care coordination during the hospital stay, an area where hospitalists excel. Conceivably, the ability to promptly identify and treat these non‐neurological comorbidities, which account for at least 30% of the deaths from acute ischemic stroke,14 could go a long way toward improving stroke outcomes.

Hospitalists are in the forefront of developing strategies for improving the quality of acute care and patient satisfaction, reducing medical errors, and focusing on efficient resource utilization. Translating evidence‐based strategies for acute stroke care into actual practice is a mechanism for improving the quality of care, ensuring that basic care does not deviate from provider to provider or from day to day (weekdays compared to weekend days/holidays) while at the same time allowing for the individualization of care appropriate to a patient's unique needs.15 After the acute treatment of stroke or TIA, additional measures must be initiated as soon as it is safe to do so in order to begin the process of limiting stroke progression and preventing recurrence. Secondary prevention measures require a coordinated transition in order to ensure continuation of care and follow‐up as needed. After a thorough risk assessment is complete, hospitalists will need to consider a 3‐pronged approach to secondary prevention that follows the national guidelines described above: pharmacotherapy, behavior modification, and, in some cases, surgical intervention.

Secondary Stroke

Secondary or recurrent strokes are strokes that occur after a first stroke or TIA,2 and the single biggest risk factor for having a stroke is already having had one.2 Because hospitalists generally see patients after ischemic cerebrovascular events have already happened, their opportunities to intervene are mostly geared toward reducing the risk of secondary stroke (beyond enhancing the prevention of complications from the index event). Recent community‐based data indicate that the short‐term risk of secondary stroke is high.16, 17 After a minor stroke or TIA, the risk of recurrent stroke or TIA increases over time8%‐12% within 7 days, 12%‐15% within 30 days, and 17%‐19% within 90 days.18 In the largest study of short‐term risk following TIA,19 there was an 11% risk of stroke (51% of which occurred in the 48 hours after TIA), an 13% risk of TIA, and a 25% risk of any adverse event within 90 days of the TIA.

Overall, the risk of a second cerebrovascular event is highest in the first year after a stroke/TIA (12%), declining to about 5% annually thereafter.7 The effects of secondary stroke are more devastating than those of the primary stroke: the 30‐day fatality rate after a first recurrent stroke is almost double that after the first‐ever stroke (41% versus 22%).20 The pathological factors that lead to TIA and stroke, such as platelet aggregation and subsequent thrombosis or the systolic stroke of blood against stenotic carotid plaques, are one and the same. As such, the short‐ and long‐term risks of recurrent events after both first stroke or first TIA necessitate investigation into a patient's vascular risk and early initiation of appropriate stroke prevention strategies.21

Cross Risk

Because the atherothrombotic disease process is systemic in nature with a variety of manifestations, stroke patients with atherosclerosis frequently have coexistent coronary artery disease and peripheral artery disease,22 and as such, are at risk for vascular events emanating from any of these beds in addition to that of the cervicocephalic arterial tree.23, 24 For instance, in a study of individuals in a long‐term care facility, among the patients with ischemic stroke, 56% had overlapping coronary artery disease, 28% had peripheral artery disease,25 and 38% of the patients had at least 2 manifestations of their atherosclerotic disease. The take‐home message here is that hospitalists also have the opportunity while treating patients hospitalized following stroke to prevent other vascular events by identifying and treating stroke patients who have systemic atherosclerosis.

Risk Factors

The first step in any approach to stroke prevention is the identification of predisposing risk factors. Several of the known biological and lifestyle risk factors associated with cerebrovascular disease were identified decades ago from large longitudinal studies.2 Certain stroke risk factors are nonmodifiable and therefore cannot be the target of intervention. 26 Treatment of the various stroke risk factors could have a substantial impact on reducing the burden of stroke. Table 1 shows the number needed to treat to prevent one stroke per year by modification of the individual stroke risk factor.

Guidelines for Secondary Stroke Prevention

Several organizations have published guidelines for the prevention of secondary stroke based on clinical evidence and expert consensus. Key guidelines include those published by the American Stroke Association (ASA),2 American College of Chest Physicians (ACCP),27 and the National Stroke Association. Although these guidelines are broadaddressing many components of stroke prevention and careeach contains recommendations specifically applicable to secondary prevention in most stroke patients who the hospitalist will encounter. Some provide hospital‐based guidelines that focus on care protocols and systems processes (ie, ASA Stroke Systems Guidelines), whereas others are therapy‐based guidelines (i.e, ACCP Guidelines on Antithrombotic Therapy for Ischemic Stroke). In the next few sections, we discuss common risk factors for and causes of secondary stroke and the prevailing guideline recommendations for modifying them. Discussion of the management of rare causes of ischemic stroke such as arterial dissection, vasculitis, patent foramen ovale, and so forth is beyond the scope of this article.

Hypertension, Dyslipidemia, and Diabetes

Table 2 shows the current national guideline recommendations for the management of premier vascular risk factorshypertension, dyslipidemia, and diabetesin ischemic stroke and TIA patients.2 Antihypertensive therapy is recommended for the prevention of secondary stroke and other vascular events in patients who have experienced an ischemic stroke or TIA and are beyond the hyperacute period.28, 29 Such treatment should be considered for all ischemic stroke and TIA patients regardless of history of hypertension.28 Although available data support the use of diuretics and the combination of diuretics plus an angiotensin‐converting enzyme inhibitor,28, 30 selection of specific medications should be individualized according to a patient's comorbid conditions.29 It is also important to note that despite the proven benefit of beta blockers in the secondary prevention of recurrent cardiac events, current evidence shows no clear benefit from the use of beta blockers in the prevention of stroke.29, 31

For ischemic cerebrovascular disease patients with dyslipidemia or symptomatic atherosclerosis, cholesterol management should be according to the current Adult Treatment Panel (ATP) guidelines.32 Statins should be the first‐line treatment.33, 34 Ischemic stroke or TIA patients whose underlying stroke mechanism is presumed to be atherosclerosis should be considered for statin therapy even if they have normal cholesterol levels and no evidence of atherosclerosis.33, 34 The recent Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study was the first study to specifically investigate the effect of statins in patients with a prior stroke but with normal cholesterol levels and no evidence of coronary heart disease. It found that treatment with atorvastatin 80 mg/day (vs. placebo) was associated with a 16% reduction in relative risk of recurrent stroke.34

The care of an ischemic stroke or TIA patient who has diabetes warrants more rigorous control of blood pressure and lipids.35, 36 Such patients usually require more than one antihypertensive drug. ACEIs and angiotensin receptor blockers (ARBs) are more effective in reducing the progression of renal disease and are the recommended first‐choice medications for these patients.37, 38 The target for glucose control should be reaching near‐normoglycemic levels.39

Large‐Artery Atherosclerosis

In selected at‐risk stroke patients, surgical techniques (eg, carotid endarterectomy [CEA], carotid angioplasty and/or stenting [CAS]) may reduce the rate of recurrent stroke.4044 For patients who have had ischemic cerebrovascular events in the preceding 6 months and who have ipsilateral severe (70%‐99%) cervical carotid artery stenosis, CEA done by a surgeon is recommended; it has a perioperative morbidity and mortality of less than 6%.40 For those with ipsilateral moderate (50%‐69%) cervical carotid stenosis, CEA should be considered, and whether to operate should be decided on the basis of the patient's age, sex, comorbidities, and severity of initial symptoms.41 Analyses of endarterectomy trials indicated that the benefit from CEA is greatest if performed within 2 weeks of a patient's last ischemic event, the advantage it confers rapidly falling with increasing delay.45 From the hospitalist's standpoint, it is of prime importance to ensure that patients admitted to the hospital with a TIA or ischemic stroke are not discharged before it has been established whether have severe carotid stenosis that requires a revascularization procedure. If carotid stenosis is less than 50%, CEA is not recommended.41

A newer, less invasive form of carotid artery revascularization is CAS,46 which is performed by operators with established periprocedural morbidity and mortality rates of 4%‐6% and may be considered in those with:

• Symptomatic severe stenosis (>70%) that is difficult to access surgically.2

• Medical issues that greatly increase the risks of surgery, such as clinically significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal nerve palsy, radiation‐induced stenosis or restenosis after carotid endarterectomy, and more than 80 years old.43

Angioplasty and/or stenting may also be considered when patients with symptomatic extracranial vertebral stenosis are having symptoms despite optimal medical risk factor treatments.2 Among those with hemodynamically significant stenosis of the major intracranial vasculature (basilar, middle cerebrals, distal carotids, and vertebrals) experiencing symptoms despite optimal medical risk factor treatments, angioplasty and/or stenting is considered experimental.2

The degree of arterial stenosis can be assessed by ultrasound, magnetic resonance angiogram (MRA), computed tomography angiogram (CTA), and conventional catheter angiogram, the last of which remains the gold standard. A carotid ultrasound performed at a certified vascular laboratory or by an experienced radiology technologist that shows less than 50% stenosis need not be followed up with another neuroimaging test. Generally, MRA tends to overestimate the degree of arterial stenosis but is a useful screening tool. In the event that an MRA reveals more than 50% stenosis, another diagnostic modality such as a carotid duplex, CTA, or conventional catheter angiogram should be performed to confirm this finding.

Antithrombotic Treatment

Noncardioembolic Stroke Mechanism

For ischemic stroke or TIA patients who have no high‐risk source of cardiogenic embolism, antiplatelet agents rather than oral anticoagulation are generally recommended to reduce the risk of recurrent stroke and other cardiovascular events.4850 Acceptable options for initial therapy include:

• Aspirin (50 to 325 mg/day)48;

• Combination of aspirin (50 mg) and extended‐release dipyridamole (400 mg) daily49, 51;

• Clopidogrel (75 mg) daily.50

The combination of aspirin and extended‐release dipyridamole is suggested instead of aspirin alone, and clopidogrel may be considered instead of aspirin alone.49, 51 However, currently there is not enough data to make evidence‐based recommendations for choosing between antiplatelet drugs beyond aspirin.2 Furthermore, there is no evidence that increasing the dose of aspirin for patients who have had an ischemic stroke while taking aspirin provides additional benefit.2 The selection of an antiplatelet agent must be individualized, giving due consideration to a patient's presumed stroke mechanism, risk factor profile, and tolerance.

Other antiplatelet guidelines for noncardioembolic stroke/TIA patients include that:

• Adding aspirin to clopidogrel increases the risk of hemorrhage and should not be routinely recommended for ischemic stroke or TIA patients.52, 53

• Clopidogrel is a reasonable alternative for aspirin‐intolerant patients.50

Education for Behavior Modification

It is crucial to discharge patients with the tools they need to make important lifestyle changes. Patients can significantly reduce their stroke risk by making changes in their everyday patterns of behavior. As much education as possible about smoking cessation, exercise, diet, and the warning signs of stroke should be provided often as possible during hospitalization for a stroke and need not be left to nurses. Stroke education is extremely important so patients understand the need to call for emergency medical services immediately if they even suspect they are having stroke symptoms because of the very narrow window of opportunity for treatment of an acute stroke.54 All patients should be encouraged to make lifestyle adjustments such as ceasing smoking, reducing alcohol intake, and controlling weight. Smoking cessation appears to be effective in preventing secondary stroke (33% reduction in relative risk),44 and initiating smoking cessation counseling during hospitalization for stroke may result in a high rate of adherence to smoking cessation, at least in the short term.55 Table 3 displays current national guideline recommendations on lifestyle modification approaches.2

EvidencePractice Gap

There are now many secondary stroke prevention modalities, and there is a copious amount of data validating the efficacy of quite a few of them.2 Yet there is a large gap in implementing evidence‐based secondary prevention strategies.35 TIA and ischemic stroke patients are often discharged from the hospital without being prescribed any preventive medications, despite the data supporting the use of antiplatelet agents, anticoagulants, and antihypertensives for prevention of secondary stroke.4 In addition, several behavioral interventions could help patients to avoid stroke recurrence,2 but quite often stroke patients are not educated about them during the acute care period.4 Poor discharge treatment utilization limits the effectiveness of proven therapies, resulting in lost opportunities to reduce the burden of secondary stroke.

The reasons for these care gaps are multifactorial and can be traced to patient and provider issues as well as to health care delivery processes. Our understanding of the reasons for this gap is improving. Generally speaking, preventive services are used less frequently than those services or treatment modalities that provide immediate relief or economic benefit. The benefit of most preventive services is more readily seen at a population level than at a individual level and accrues slowly over time. It becomes more difficult to stress prevention in a health care system driven by technology‐based acute care.3

Current clinical management of acute stroke patients has stroke specialists and hospital physicians focusing on the acute management and diagnostic workup during hospitalization. Initiation of long‐term treatment is often deferred to after discharge, when the patient resumes long‐term primary care follow‐up.54 This deferred approach may result in therapy not being initiated or being initiated less efficiently and at a time (weeks or months after the initial presentation) when the stroke event and underlying atherosclerotic disease may no longer be the focus of either the patient or the primary care physician.54

Initiating medications during the acute stroke hospitalization phase sends the patient the message that these therapies are important for preventing recurrence and are an essential part of their treatment.54 More important, hospital initiation of secondary prevention therapies has been shown to be a strong predictor of these therapies continuing to be used after discharge56 and is associated with better clinical outcomes.5759 Table 4 shows some of the resources available to assist hospitalists in overcoming the evidencepractice gap in stroke treatment.

CONCLUSIONS

The acute stroke hospitalization setting provides the ideal opportunity for hospitalists to not only institute evidence‐based prevention therapies for recurrent stroke but also to have the undivided attention of patients and their families. Furthermore, it may be risky to assume that relevant therapy when deferred will be initiated in a timely fashion, if at all, after hospital discharge. As part of an effective continuum of care, hospitalists have an important role not just in the management of acute ischemic stroke, but also in long‐term reduction of vascular risk.

Prevention has the greatest potential to reduce the societal burden from stroke.1 Several therapies that specifically target the underlying atherosclerotic disease process have been shown in clinical trials to markedly lower the risk of recurrent vascular events including stroke.2 However, there is great variability in how clinical trial data are implemented in clinical practice for ischemic stroke prevention.35 This has led to a knowledge‐implementation‐practice gap, possibly because of the limited awareness of the scientific evidence supporting various treatments, as well as the lack of a systematic approach to hospital stroke care.3 Our review discusses the evidence for reducing vascular risk after ischemic stroke and successful models of systematic interventions initiated during stroke hospitalization, with the goal of narrowing the stroke hospitalization evidencepractice gap.

Societal Burden

Stroke is the third‐leading cause of death in the United States and the leading cause of serious long‐term disability.6 Approximately 700,000 Americans have a new stroke or recurrent strokes every year, whereas nearly 5 million live with the consequences of stroke; nearly all stroke survivors (90%) have some residual functional deficit, and approximately 40% experience moderate to severe impairment.6 Stroke mortality is substantial, with a 30‐day case fatality rate after first stroke (of any cause) of about 25%.7, 8 Indeed, four‐fifths of patients do not survive for 10 years after stroke, and approximately one‐third of all case fatalities occur in the first year after a stroke.8 The estimated economic impact in 2006, US$57.9 billion, further underscores the substantial mortality and morbidity of stroke.6 Given the limited options for acute stroke therapies,9 stroke prevention remains an important therapeutic goal, especially because fewer than 5% of acute stroke patients in the United States currently receive the only Food and Drug Administrationapproved treatmentintravenous tissue plasminogen activator.10 It is obvious that additional strategies are urgently needed to reduce the devastating consequences of stroke.

Why Involve the Hospitalist?

The Hospitalist system in the United States is rapidly growing.11 Tthe Society of Hospital Medicine projects that by 2010 there will be approximately 30,000 hospitalists in the United States.11 A member census conducted by the American Academy of Neurology in 2000 found 13,500 practicing neurologists, most of whom are concentrated in urban and metropolitan areas.12 As such, with more than 700,000 strokes occurring each year,6 most stroke patients in the United States will not be seen or evaluated by a neurologist. Indeed, one study indicated that only 11.3% of stroke patients are attended exclusively by a neurologist.13 Furthermore, it is not uncommon for stroke patients to have numerous other medical issues that require attention and multidisciplinary care coordination during the hospital stay, an area where hospitalists excel. Conceivably, the ability to promptly identify and treat these non‐neurological comorbidities, which account for at least 30% of the deaths from acute ischemic stroke,14 could go a long way toward improving stroke outcomes.

Hospitalists are in the forefront of developing strategies for improving the quality of acute care and patient satisfaction, reducing medical errors, and focusing on efficient resource utilization. Translating evidence‐based strategies for acute stroke care into actual practice is a mechanism for improving the quality of care, ensuring that basic care does not deviate from provider to provider or from day to day (weekdays compared to weekend days/holidays) while at the same time allowing for the individualization of care appropriate to a patient's unique needs.15 After the acute treatment of stroke or TIA, additional measures must be initiated as soon as it is safe to do so in order to begin the process of limiting stroke progression and preventing recurrence. Secondary prevention measures require a coordinated transition in order to ensure continuation of care and follow‐up as needed. After a thorough risk assessment is complete, hospitalists will need to consider a 3‐pronged approach to secondary prevention that follows the national guidelines described above: pharmacotherapy, behavior modification, and, in some cases, surgical intervention.

Secondary Stroke

Secondary or recurrent strokes are strokes that occur after a first stroke or TIA,2 and the single biggest risk factor for having a stroke is already having had one.2 Because hospitalists generally see patients after ischemic cerebrovascular events have already happened, their opportunities to intervene are mostly geared toward reducing the risk of secondary stroke (beyond enhancing the prevention of complications from the index event). Recent community‐based data indicate that the short‐term risk of secondary stroke is high.16, 17 After a minor stroke or TIA, the risk of recurrent stroke or TIA increases over time8%‐12% within 7 days, 12%‐15% within 30 days, and 17%‐19% within 90 days.18 In the largest study of short‐term risk following TIA,19 there was an 11% risk of stroke (51% of which occurred in the 48 hours after TIA), an 13% risk of TIA, and a 25% risk of any adverse event within 90 days of the TIA.

Overall, the risk of a second cerebrovascular event is highest in the first year after a stroke/TIA (12%), declining to about 5% annually thereafter.7 The effects of secondary stroke are more devastating than those of the primary stroke: the 30‐day fatality rate after a first recurrent stroke is almost double that after the first‐ever stroke (41% versus 22%).20 The pathological factors that lead to TIA and stroke, such as platelet aggregation and subsequent thrombosis or the systolic stroke of blood against stenotic carotid plaques, are one and the same. As such, the short‐ and long‐term risks of recurrent events after both first stroke or first TIA necessitate investigation into a patient's vascular risk and early initiation of appropriate stroke prevention strategies.21

Cross Risk

Because the atherothrombotic disease process is systemic in nature with a variety of manifestations, stroke patients with atherosclerosis frequently have coexistent coronary artery disease and peripheral artery disease,22 and as such, are at risk for vascular events emanating from any of these beds in addition to that of the cervicocephalic arterial tree.23, 24 For instance, in a study of individuals in a long‐term care facility, among the patients with ischemic stroke, 56% had overlapping coronary artery disease, 28% had peripheral artery disease,25 and 38% of the patients had at least 2 manifestations of their atherosclerotic disease. The take‐home message here is that hospitalists also have the opportunity while treating patients hospitalized following stroke to prevent other vascular events by identifying and treating stroke patients who have systemic atherosclerosis.

Risk Factors

The first step in any approach to stroke prevention is the identification of predisposing risk factors. Several of the known biological and lifestyle risk factors associated with cerebrovascular disease were identified decades ago from large longitudinal studies.2 Certain stroke risk factors are nonmodifiable and therefore cannot be the target of intervention. 26 Treatment of the various stroke risk factors could have a substantial impact on reducing the burden of stroke. Table 1 shows the number needed to treat to prevent one stroke per year by modification of the individual stroke risk factor.

Guidelines for Secondary Stroke Prevention

Several organizations have published guidelines for the prevention of secondary stroke based on clinical evidence and expert consensus. Key guidelines include those published by the American Stroke Association (ASA),2 American College of Chest Physicians (ACCP),27 and the National Stroke Association. Although these guidelines are broadaddressing many components of stroke prevention and careeach contains recommendations specifically applicable to secondary prevention in most stroke patients who the hospitalist will encounter. Some provide hospital‐based guidelines that focus on care protocols and systems processes (ie, ASA Stroke Systems Guidelines), whereas others are therapy‐based guidelines (i.e, ACCP Guidelines on Antithrombotic Therapy for Ischemic Stroke). In the next few sections, we discuss common risk factors for and causes of secondary stroke and the prevailing guideline recommendations for modifying them. Discussion of the management of rare causes of ischemic stroke such as arterial dissection, vasculitis, patent foramen ovale, and so forth is beyond the scope of this article.

Hypertension, Dyslipidemia, and Diabetes

Table 2 shows the current national guideline recommendations for the management of premier vascular risk factorshypertension, dyslipidemia, and diabetesin ischemic stroke and TIA patients.2 Antihypertensive therapy is recommended for the prevention of secondary stroke and other vascular events in patients who have experienced an ischemic stroke or TIA and are beyond the hyperacute period.28, 29 Such treatment should be considered for all ischemic stroke and TIA patients regardless of history of hypertension.28 Although available data support the use of diuretics and the combination of diuretics plus an angiotensin‐converting enzyme inhibitor,28, 30 selection of specific medications should be individualized according to a patient's comorbid conditions.29 It is also important to note that despite the proven benefit of beta blockers in the secondary prevention of recurrent cardiac events, current evidence shows no clear benefit from the use of beta blockers in the prevention of stroke.29, 31

For ischemic cerebrovascular disease patients with dyslipidemia or symptomatic atherosclerosis, cholesterol management should be according to the current Adult Treatment Panel (ATP) guidelines.32 Statins should be the first‐line treatment.33, 34 Ischemic stroke or TIA patients whose underlying stroke mechanism is presumed to be atherosclerosis should be considered for statin therapy even if they have normal cholesterol levels and no evidence of atherosclerosis.33, 34 The recent Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study was the first study to specifically investigate the effect of statins in patients with a prior stroke but with normal cholesterol levels and no evidence of coronary heart disease. It found that treatment with atorvastatin 80 mg/day (vs. placebo) was associated with a 16% reduction in relative risk of recurrent stroke.34

The care of an ischemic stroke or TIA patient who has diabetes warrants more rigorous control of blood pressure and lipids.35, 36 Such patients usually require more than one antihypertensive drug. ACEIs and angiotensin receptor blockers (ARBs) are more effective in reducing the progression of renal disease and are the recommended first‐choice medications for these patients.37, 38 The target for glucose control should be reaching near‐normoglycemic levels.39

Large‐Artery Atherosclerosis

In selected at‐risk stroke patients, surgical techniques (eg, carotid endarterectomy [CEA], carotid angioplasty and/or stenting [CAS]) may reduce the rate of recurrent stroke.4044 For patients who have had ischemic cerebrovascular events in the preceding 6 months and who have ipsilateral severe (70%‐99%) cervical carotid artery stenosis, CEA done by a surgeon is recommended; it has a perioperative morbidity and mortality of less than 6%.40 For those with ipsilateral moderate (50%‐69%) cervical carotid stenosis, CEA should be considered, and whether to operate should be decided on the basis of the patient's age, sex, comorbidities, and severity of initial symptoms.41 Analyses of endarterectomy trials indicated that the benefit from CEA is greatest if performed within 2 weeks of a patient's last ischemic event, the advantage it confers rapidly falling with increasing delay.45 From the hospitalist's standpoint, it is of prime importance to ensure that patients admitted to the hospital with a TIA or ischemic stroke are not discharged before it has been established whether have severe carotid stenosis that requires a revascularization procedure. If carotid stenosis is less than 50%, CEA is not recommended.41

A newer, less invasive form of carotid artery revascularization is CAS,46 which is performed by operators with established periprocedural morbidity and mortality rates of 4%‐6% and may be considered in those with:

• Symptomatic severe stenosis (>70%) that is difficult to access surgically.2

• Medical issues that greatly increase the risks of surgery, such as clinically significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal nerve palsy, radiation‐induced stenosis or restenosis after carotid endarterectomy, and more than 80 years old.43

Angioplasty and/or stenting may also be considered when patients with symptomatic extracranial vertebral stenosis are having symptoms despite optimal medical risk factor treatments.2 Among those with hemodynamically significant stenosis of the major intracranial vasculature (basilar, middle cerebrals, distal carotids, and vertebrals) experiencing symptoms despite optimal medical risk factor treatments, angioplasty and/or stenting is considered experimental.2

The degree of arterial stenosis can be assessed by ultrasound, magnetic resonance angiogram (MRA), computed tomography angiogram (CTA), and conventional catheter angiogram, the last of which remains the gold standard. A carotid ultrasound performed at a certified vascular laboratory or by an experienced radiology technologist that shows less than 50% stenosis need not be followed up with another neuroimaging test. Generally, MRA tends to overestimate the degree of arterial stenosis but is a useful screening tool. In the event that an MRA reveals more than 50% stenosis, another diagnostic modality such as a carotid duplex, CTA, or conventional catheter angiogram should be performed to confirm this finding.

Antithrombotic Treatment

Noncardioembolic Stroke Mechanism

For ischemic stroke or TIA patients who have no high‐risk source of cardiogenic embolism, antiplatelet agents rather than oral anticoagulation are generally recommended to reduce the risk of recurrent stroke and other cardiovascular events.4850 Acceptable options for initial therapy include:

• Aspirin (50 to 325 mg/day)48;

• Combination of aspirin (50 mg) and extended‐release dipyridamole (400 mg) daily49, 51;

• Clopidogrel (75 mg) daily.50

The combination of aspirin and extended‐release dipyridamole is suggested instead of aspirin alone, and clopidogrel may be considered instead of aspirin alone.49, 51 However, currently there is not enough data to make evidence‐based recommendations for choosing between antiplatelet drugs beyond aspirin.2 Furthermore, there is no evidence that increasing the dose of aspirin for patients who have had an ischemic stroke while taking aspirin provides additional benefit.2 The selection of an antiplatelet agent must be individualized, giving due consideration to a patient's presumed stroke mechanism, risk factor profile, and tolerance.

Other antiplatelet guidelines for noncardioembolic stroke/TIA patients include that:

• Adding aspirin to clopidogrel increases the risk of hemorrhage and should not be routinely recommended for ischemic stroke or TIA patients.52, 53

• Clopidogrel is a reasonable alternative for aspirin‐intolerant patients.50

Education for Behavior Modification

It is crucial to discharge patients with the tools they need to make important lifestyle changes. Patients can significantly reduce their stroke risk by making changes in their everyday patterns of behavior. As much education as possible about smoking cessation, exercise, diet, and the warning signs of stroke should be provided often as possible during hospitalization for a stroke and need not be left to nurses. Stroke education is extremely important so patients understand the need to call for emergency medical services immediately if they even suspect they are having stroke symptoms because of the very narrow window of opportunity for treatment of an acute stroke.54 All patients should be encouraged to make lifestyle adjustments such as ceasing smoking, reducing alcohol intake, and controlling weight. Smoking cessation appears to be effective in preventing secondary stroke (33% reduction in relative risk),44 and initiating smoking cessation counseling during hospitalization for stroke may result in a high rate of adherence to smoking cessation, at least in the short term.55 Table 3 displays current national guideline recommendations on lifestyle modification approaches.2

EvidencePractice Gap

There are now many secondary stroke prevention modalities, and there is a copious amount of data validating the efficacy of quite a few of them.2 Yet there is a large gap in implementing evidence‐based secondary prevention strategies.35 TIA and ischemic stroke patients are often discharged from the hospital without being prescribed any preventive medications, despite the data supporting the use of antiplatelet agents, anticoagulants, and antihypertensives for prevention of secondary stroke.4 In addition, several behavioral interventions could help patients to avoid stroke recurrence,2 but quite often stroke patients are not educated about them during the acute care period.4 Poor discharge treatment utilization limits the effectiveness of proven therapies, resulting in lost opportunities to reduce the burden of secondary stroke.

The reasons for these care gaps are multifactorial and can be traced to patient and provider issues as well as to health care delivery processes. Our understanding of the reasons for this gap is improving. Generally speaking, preventive services are used less frequently than those services or treatment modalities that provide immediate relief or economic benefit. The benefit of most preventive services is more readily seen at a population level than at a individual level and accrues slowly over time. It becomes more difficult to stress prevention in a health care system driven by technology‐based acute care.3

Current clinical management of acute stroke patients has stroke specialists and hospital physicians focusing on the acute management and diagnostic workup during hospitalization. Initiation of long‐term treatment is often deferred to after discharge, when the patient resumes long‐term primary care follow‐up.54 This deferred approach may result in therapy not being initiated or being initiated less efficiently and at a time (weeks or months after the initial presentation) when the stroke event and underlying atherosclerotic disease may no longer be the focus of either the patient or the primary care physician.54

Initiating medications during the acute stroke hospitalization phase sends the patient the message that these therapies are important for preventing recurrence and are an essential part of their treatment.54 More important, hospital initiation of secondary prevention therapies has been shown to be a strong predictor of these therapies continuing to be used after discharge56 and is associated with better clinical outcomes.5759 Table 4 shows some of the resources available to assist hospitalists in overcoming the evidencepractice gap in stroke treatment.

CONCLUSIONS

The acute stroke hospitalization setting provides the ideal opportunity for hospitalists to not only institute evidence‐based prevention therapies for recurrent stroke but also to have the undivided attention of patients and their families. Furthermore, it may be risky to assume that relevant therapy when deferred will be initiated in a timely fashion, if at all, after hospital discharge. As part of an effective continuum of care, hospitalists have an important role not just in the management of acute ischemic stroke, but also in long‐term reduction of vascular risk.

Embracing, with strengthened spirits

Shades of Her Life

Embracing, with strengthened spirits

Shades of Her Life

Embracing, with strengthened spirits

Shades of Her Life

• CLINICAL QUESTION: Which interventions are effective for the prevention of pressure ulcers?

• BOTTOM LINE: Effective strategies for preventing pressure ulcers include the use of support surfaces (mattresses, beds, and cushions), mattress overlays on operating tables, and specialized foam and sheepskin overlays. Frequent repositioning is effective, but the optimal schedule for turning is uncertain. Nutritional supplements are beneficial in patients with impaired nutrition. Simple skin moisturizers, specifically to the sacral area, are also effective. (LOE = 1a‐)

• REFERENCE: Reddy M, Gill SS. Rochon PA. Preventing pressure ulcers: a systematic review. JAMA 2006;296:974‐984.

• STUDY DESIGN: Systematic review

• FUNDING: Government

• SETTING: Various (meta‐analysis)

• SYNOPSIS: Multiple preventive approaches are used in the management of pressure ulcers. These authors systematically searched multiple evidence‐based databases including the Cochrane Registry, bibliographies of identified articles, and scientific meeting abstracts for randomized controlled trials (RCTs) evaluating preventive measures for pressure ulcers. No language restrictions were applied. They used standard methods to critically appraise individual RCTs. The search strategy identified 763 citations, from which 59 trials meeting eligibility criteria were selected. The methodologic quality of the RCTs was generally suboptimal. Interventions were grouped into 3 categories: those addressing impairments in (1) mobility, (2) nutrition, and (3) skin health. Effective strategies for those with impaired mobility included the use of support surfaces (mattresses, beds, and cushions), mattress overlays on operating tables, and specialized foam and sheepskin overlays. Frequent repositioning is effective, but the optimal schedule for turning (every 2 vs every 4 hours) is uncertain. Nutritional supplements are beneficial in patients with impaired nutrition. Simple skin moisturizers, specifically to the sacral area, were helpful, but the incremental benefit of other specific topical agents is minimal.

• CLINICAL QUESTION: Which interventions are effective for the prevention of pressure ulcers?

• BOTTOM LINE: Effective strategies for preventing pressure ulcers include the use of support surfaces (mattresses, beds, and cushions), mattress overlays on operating tables, and specialized foam and sheepskin overlays. Frequent repositioning is effective, but the optimal schedule for turning is uncertain. Nutritional supplements are beneficial in patients with impaired nutrition. Simple skin moisturizers, specifically to the sacral area, are also effective. (LOE = 1a‐)

• REFERENCE: Reddy M, Gill SS. Rochon PA. Preventing pressure ulcers: a systematic review. JAMA 2006;296:974‐984.

• STUDY DESIGN: Systematic review

• FUNDING: Government

• SETTING: Various (meta‐analysis)

• SYNOPSIS: Multiple preventive approaches are used in the management of pressure ulcers. These authors systematically searched multiple evidence‐based databases including the Cochrane Registry, bibliographies of identified articles, and scientific meeting abstracts for randomized controlled trials (RCTs) evaluating preventive measures for pressure ulcers. No language restrictions were applied. They used standard methods to critically appraise individual RCTs. The search strategy identified 763 citations, from which 59 trials meeting eligibility criteria were selected. The methodologic quality of the RCTs was generally suboptimal. Interventions were grouped into 3 categories: those addressing impairments in (1) mobility, (2) nutrition, and (3) skin health. Effective strategies for those with impaired mobility included the use of support surfaces (mattresses, beds, and cushions), mattress overlays on operating tables, and specialized foam and sheepskin overlays. Frequent repositioning is effective, but the optimal schedule for turning (every 2 vs every 4 hours) is uncertain. Nutritional supplements are beneficial in patients with impaired nutrition. Simple skin moisturizers, specifically to the sacral area, were helpful, but the incremental benefit of other specific topical agents is minimal.

• CLINICAL QUESTION: Which interventions are effective for the prevention of pressure ulcers?

• BOTTOM LINE: Effective strategies for preventing pressure ulcers include the use of support surfaces (mattresses, beds, and cushions), mattress overlays on operating tables, and specialized foam and sheepskin overlays. Frequent repositioning is effective, but the optimal schedule for turning is uncertain. Nutritional supplements are beneficial in patients with impaired nutrition. Simple skin moisturizers, specifically to the sacral area, are also effective. (LOE = 1a‐)

• REFERENCE: Reddy M, Gill SS. Rochon PA. Preventing pressure ulcers: a systematic review. JAMA 2006;296:974‐984.

• STUDY DESIGN: Systematic review

• FUNDING: Government

• SETTING: Various (meta‐analysis)

• SYNOPSIS: Multiple preventive approaches are used in the management of pressure ulcers. These authors systematically searched multiple evidence‐based databases including the Cochrane Registry, bibliographies of identified articles, and scientific meeting abstracts for randomized controlled trials (RCTs) evaluating preventive measures for pressure ulcers. No language restrictions were applied. They used standard methods to critically appraise individual RCTs. The search strategy identified 763 citations, from which 59 trials meeting eligibility criteria were selected. The methodologic quality of the RCTs was generally suboptimal. Interventions were grouped into 3 categories: those addressing impairments in (1) mobility, (2) nutrition, and (3) skin health. Effective strategies for those with impaired mobility included the use of support surfaces (mattresses, beds, and cushions), mattress overlays on operating tables, and specialized foam and sheepskin overlays. Frequent repositioning is effective, but the optimal schedule for turning (every 2 vs every 4 hours) is uncertain. Nutritional supplements are beneficial in patients with impaired nutrition. Simple skin moisturizers, specifically to the sacral area, were helpful, but the incremental benefit of other specific topical agents is minimal.

56‐year‐old man with a history of chronic liver disease of unknown etiology was referred for evaluation of intermittent low‐grade fevers, constipation, and an unintentional weight loss of 20‐kg during the previous 9 months. Three weeks prior to presentation, he was admitted to his local hospital for these symptoms and was treated empirically with cefotaxime for 6 days, but his symptoms persisted.

The patient's age and sex make him statistically at risk for vascular disease as well as malignancy. The history of chronic liver disease of unknown etiology is intriguing. In evaluating a patient with chronic liver disease, I want to know about alcohol consumption, intravenous drug use, family history, viral hepatitis serology, and antinuclear antibody testing. Chronic liver disease places this patient at increased risk for infection because portal hypertension causes blood to bypass a large part of the reticuloendothelial system (liver and spleen), therefore increasing the risk of sustained bacteremia.

Regarding his chronic low‐grade fever, I would like to know about his country of origin, travel history, occupational history, risk factors for human immunodeficiency virus (HIV) and tuberculosis, and any symptoms or signs of rheumatologic disease. Constipation and weight loss can be a result of malignancy (eg, hepatocellular carcinoma, colorectal cancer), vascular disease (eg, mesenteric thrombosis), or metabolic derangement (eg, hypercalcemia).

The patient had a history of recurrent episodes of ascites and low‐grade fevers. He first developed ascites, abdominal pain, low‐grade fevers, and pedal edema 20 years ago. These signs and symptoms resolved spontaneously, but similar episodes have recurred every 46 years since. Each time, diagnostic evaluation failed to reveal a specific etiology.

Twelve years prior to presentation, the patient was evaluated for chronic liver disease. Diagnostic tests at that time included viral hepatitis serology, ceruloplasmin, ferritin, alpha‐1‐antitrypsin, antimitochondrial antibody, and antinuclear antibody testing, all the results of which were within the normal range. The patient denied consumption of alcohol, medications, or toxic substances. Percutaneous liver biopsy demonstrated focal parenchymal scarring interspersed with areas of normal parenchyma, consistent with focal ischemic injury (Fig. 1).

Figure 1

The duration of the patient's symptoms is striking. A unifying diagnosis for this patient must explain his chronic liver disease, periodic fevers, ascites, and abdominal pain that started at a relatively young age. Conditions to consider include hepatitis B or C, hemochromatosis, Wilson's disease, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, alpha‐1‐antitrypsin deficiency, and drug or toxin exposure. Venoocclusive disease of the liver and chronic congestive hepatopathy (from heart failure or constrictive pericarditis) are especially attractive possibilities, given the findings of focal ischemic injury on liver biopsy.

Recurrent fever and abdominal pain can occur because of familial Mediterranean fever, which results from a genetic abnormality and causes recurrent peritoneal inflammation associated with fever and ascites. Although unlikely in this case, familial Mediterranean fever can cause secondary amyloidosis with liver involvement.

The patient reported episodic, vague abdominal pain, nausea, anorexia, night sweats, hair thinning, extreme fatigue, and lightheadedness. He had no known allergies, and his medications included propranolol, lactulose, docusate, and omeprazole. He was white, born in the United States, and a lawyer, but he had not worked during the previous 4 months. He was married and monogamous, and an HIV antibody test 4 months prior was negative. He had a remote history of tobacco and alcohol use between the 1960s and the 1980s. He denied intravenous drug use. His family history was only remarkable for a father with coronary artery disease.

With fever, the hypothalamic set point for temperature increases. Night sweats usually indicate an exaggeration of the normal diurnal drop in the hypothalamic set point for temperature, with dissipation of increased heat (caused by fever) through evaporation of perspiration. Unfortunately, night sweats are not specific to any particular cause of fever. Fatigue is equally nonspecific but could result from anemia, hypothyroidism, or adrenal insufficiency or could be a side effect of the propranolol. The lack of a family history makes hereditary periodic fevers unlikely.

The patient appeared chronically ill. His temperature was 35.2C, blood pressure 71/53 mm Hg, heart rate 84 beats per minute, respiratory rate 14 breaths per minute, and oxygen saturation 99% while breathing room air. His weight was 47 kg. Examination of the patient's head and neck revealed bitemporal wasting but no scleral icterus, and the oropharynx was clear. There was no thyromegaly or lymphadenopathy. The findings of the cardiopulmonary examination was normal. The abdomen was soft with mild diffuse tenderness. There was no organomegaly or obvious ascites. His extremities were warm and without edema or cyanosis. He was dark‐skinned and had rare spider angiomas. The results of his neurological examination were normal.

Sepsis, drug ingestion (particularly vasodilators), environmental exposure, and endocrine abnormalities such as adrenal insufficiency and hypothyroidism can all cause both hypothermia and hypotension. Adrenal insufficiency is especially intriguing becauase it is also associated with malaise, abdominal pain, and hyperpigmentation. Explaining both adrenal insufficiency and chronic liver disease is more difficult. Hemochromatosis can cause cirrhotic liver disease, adrenal and thyroid insufficiency, and dark skin, but the patient's normal ferritin and liver biopsy findings make this disease unlikely.

The results of the laboratory studies were: white‐cell count, 4900/mm³, with a normal differential count; hemoglobin, 11.0 g/dL; platelet count, 52,000/mm³; mean corpuscular volume, 89 m³; sodium, 131 mmol/L; potassium, 5.0 mmol/L; chloride, 101 mmol/L; bicarbonate, 21 mmol/L; blood urea nitrogen, 31 mg/dL; creatinine, 1.8 mg/dL; aspartate aminotransferase, 45 U/L (normal range 1641 U/L); alanine aminotransferase, 30 U/L (normal range 1259 U/L); alkaline phosphatase, 587 U/L (normal range 29111 U/L); total bilirubin, 1.1 mg/dL (normal range 0.31.3 mg/dL); gamma‐glutamyl transferase, 169 U/L (normal range 771 U/L); lactate dehydrogenase, 127 IU/L (normal range 91185 IU/L); thyroid‐stimulating hormone, 3.1 mIU/L (normal range 0.54.7 mIU/L). Coagulation studies revealed a prothrombin time of 12 seconds (international normalized ratio [INR] 1.1) and an activated partial thromboplastin time (aPTT) of greater than 100 seconds. Urinalysis and chest radiography were unremarkable.

The low sodium, high potassium, and relatively low bicarbonate levels are all compatible with adrenal insufficiency. When present, the combination of hyponatremia (primarily from glucocorticoid deficiency) and hyperkalemia (from mineralocorticoid deficiency) suggests the adrenal insufficiency is primary, rather than from the pituitary. The differential diagnosis of primary adrenal insufficiency includes autoimmune disease, granulomatous disease, and tumor.

Most interesting is the isolated prolongation of the aPTT, making adrenal hemorrhage another possibility as a cause of the adrenal insufficiency. Isolated elevation of the aPTT suggests deficiency or inhibition of the factors involved in the intrinsic pathway (factors VIII, IX, XI, and XII) or the presence of an antiphospholipid antibody, which would interfere with the test. Heparin administration (which may not be immediately obvious, as in the case of a heparin lock of an intravenous line) and von Willebrand disease (from loss of the normal von Willebrand factorassociated prevention of factor VIII proteolysis) can also cause isolated prolongation of the aPTT.

Tumor, perhaps hepatocellular cancer, remains a possible explanation for the elevated alkaline phosphatase, with possible adrenal involvement. Amyloidosis and diffuse granulomatous disease (either infectious or noninfectious, such as sarcoidosis) can cause elevation in alkaline phosphatase. At this time, I would rule out adrenal insufficiency, further evaluate the elevated aPTT, and image the liver and adrenal glands.

The patient was hospitalized and given intravenous fluids. His blood pressure increased to 90/54 mm Hg. Further testing revealed an alpha‐fetoprotein of 1.5 g/dL (normal range < 6.4 g/dL), an erythrocyte sedimentation rate of greater than 100 mm/s, and normal results of an antinuclear antibody test. Serum cortisol, drawn at 6 a.m., was 3 ng/dL; 60 minutes after cosyntropin stimulation, serum cortisol was 1 ng/dL. An ultrasound of the liver revealed chronic hepatic vein thrombosis.

The low absolute values and the failure of serum cortisol to respond to cosyntropin confirm the diagnosis of adrenal glucocorticoid deficiency. Hepatic vein thrombosis (Budd‐Chiari syndrome) is an unusual occurrence, often associated with a hypercoagulable state or tumor. How can we put these new findings together with the rest of the patient's abnormalities?

Primary antiphospholipid antibody syndrome is the most attractive unifying diagnosis because it appears to explain the most abnormalities with the fewest diagnoses. This syndrome includes arterial and venous thrombosis, thrombocytopenia, and isolated elevation of the aPTT and has been associated with hepatic vein thrombosis (acute and chronic) and adrenal insufficiency (from adrenal hemorrhage as a result of adrenal vein thrombosis). The histological findings of focal ischemic injury, seen on the patient's liver biopsy, are likely explained by hepatic venoocclusive disease.

Magnetic resonance imaging (MRI) of the abdomen (Fig. 2) demonstrated adrenal hemorrhage in the right adrenal gland. The patient's aPTT remained elevated even after his serum was mixed with normal serum, thereby excluding a factor deficiency. The results of a dilute Russell's viper venom time test (which tests the phospholipid‐dependent portion of the coagulation cascade) also showed elevation. The addition of phospholipids to the patient's serum corrected the aPTT, and a screen for factor inhibitors was negative. An anticardiolipin antibody (IgG) test was positive at 59.0 U (normal 0.42.3 U). These findings confirmed the presence of antiphospholipid antibodies.

Figure 2

The findings of a bone marrow biopsy, performed to exclude infiltrative diseases, were normal. The patient was diagnosed with primary antiphospholipid syndrome. Hydrocortisone and fludrocortisone were initiated, with the intention to continue them indefinitely. The patient was also started on intravenous heparin, which continued until he achieved a goal INR of 2.03.0 on warfarin. The patient was counseled on the importance of lifelong warfarin therapy given his diagnosis of antiphospholipid syndrome with hepatic vein and adrenal vein thromboses. On follow‐up 6 months after discharge, the patient's hypotension and fatigue had resolved, his alkaline phosphatase level had decreased substantially, and he had returned to work as a lawyer.

COMMENTARY

The diagnosis of a complex case with numerous clinical and laboratory abnormalities can be very difficult. The discussant successfully came to the correct diagnosis because he carefully evaluated each piece of evidence and did not fall prey to faulty triggering, the generation of diagnostic hypotheses based on selected pieces of clinical data.1 In the diagnostic process, physicians trigger new diagnostic possibilities and discard initial hypotheses as new findings emerge. Often, because of heuristic (analytic) biases, physicians fall victim to faulty triggering when evaluating patients.2 When confronted with a trigger feature such as night sweats, many physicians increase their consideration of tuberculosis or lymphoma at the expense of more common diagnoses, even though, as the discussant pointed out, any patient with fever can have this symptom.3 Whereas faulty use of trigger features may make physicians inappropriately consider uncommon diseases, a distinguishing feature limits the number of diagnostic possibilities and significantly changesincreases or decreasesthe likelihood of there being a rare disease.4 By correctly using the distinguishing feature of an elevated aPTT in the context of the patient's diverse clinical features, the discussant was able to arrive at a single, unifying diagnosis of antiphospholipid syndrome.

Antiphospholipid syndrome is arterial or venous thrombosis associated with significantly elevated antiphospholipid antibodies. Isolated prolongation of the aPTT is often the first clue to the presence of antiphospholipid antibodies, which interfere with phospholipid‐dependent coagulation assays.5 Antiphospholipid syndrome is considered primary if it is not associated with a known underlying disease or medication. Antiphospholipid syndrome is secondary if it is associated with certain diseases such as systemic lupus erythematosus and malignancy or with an adverse effect of medication. Although the prevalence of antiphospholipid antibodies is 1%5% in young, apparently healthy control subjects, it is higher in elderly patients with chronic diseases.6 It remains unclear why only certain patients with antiphospholipid antibodies manifest the syndrome, though having vascular risk factors may increase the risk of developing thrombosis in the presence of antiphospholipid antibodies.7

Three types of antiphospholipid antibody tests are currently in clinical use: lupus anticoagulants (measured by prolonged clotting time in a phospholipid‐dependent clotting test, such as the aPTT), anticardiolipin antibodies, and anti‐₂‐glycoprotein I antibodies. All 3 tests are plagued by not being standardized between hospitals and laboratories and have limited sensitivity and specificity.8, 9 Lupus anticoagulants are most closely associated with thrombosis. Although a prolonged aPTT in the presence of thrombosis is often the first clue to the presence of lupus anticoagulants, only 30%40% of patients with the syndrome have this laboratory abnormality.10 Therefore, a normal aPTT result does not rule out the presence of antiphospholipid antibodies, and other tests of lupus anticoagulants, such as the dilute Russell viper venom time, should be performed.8, 9 There are many types of anticardiolipin antibodies of varying immunoglobulin isotypes, which all share the ability to bind cardiolipin in vitro. The IgG isotypes (as in our patient) are thought to be most closely associated with thrombosis, and it is known that high titers of anticardiolipin antibodies have much better discriminatory value than low titers.810 There is little data on the anti‐₂‐glycoprotein I antibodies, but preliminary data suggest these antibodies may be more specific for the antiphospholipid syndrome.11

The antiphospholipid syndrome has classically been associated with lower‐extremity deep venous thrombosis, recurrent fetal loss, thrombocytopenia, and livedo reticularis.10 However, depending on the size and distribution of the vasculature involved and the extent and chronicity of involvement, antiphospholipid syndrome can result in manifestation of a wide range of diseases. Acute presentations such as thrombotic disease of the gastrointestinal, cardiac, and central nervous systems can be rapid and catastrophic. A more chronic and indolent course can lead to progressive organ dysfunction, as in this patient, with chronic liver disease resulting from recurrent episodes of hepatic venoocclusive disease and chronic hepatic vein thrombosis, a rare but well‐described complication of antiphospholipid syndrome.12, 13 It is unclear why the course of our patient's hepatic vein thrombosis waxed and waned so much. We hypothesized that he had episodes of microvascular hepatic venous thrombosis that led to transient hepatic dysfunction, with subsequent recovery upon spontaneous recanalization of hepatic veins or with healing and regeneration of liver tissue.

Treatment of antiphospholipid syndrome is controversial. Although prior reports suggested that patients with this syndrome were at higher risk for recurrent thrombosis when treated with the usual dose of warfarin (target INR 2.03.0), 2 randomized trial showed there was no difference in the recurrence of thrombosis between moderate‐intensity treatment with warfarin and high‐intensity treatment with warfarin.14, 15 Our patient was treated with warfarin to a moderate‐intensity target INR of 2.03.0 because he had liver disease and adrenal hemorrhage. Although he has done well, it is important that he be continuously reassessed, as should all patients with similar conditions, for the risk and recurrence of thrombosis weighed against the risk of bleeding.

Adrenal insufficiency is another rare complication of antiphospholipid syndrome. It was first described as such in 198016 and has since been reported in both children and adults.1719 Abdominal pain and hypotension were the most common findings (55% and 54%, respectively) in one case series of 86 patients with adrenal insufficiency from antiphospholipid syndrome.20 Fever, nausea, vomiting, weakness, fatigue, lethargy, and altered mental status were also variably present. Loss of adrenal function is most often a result of adrenal hemorrhage, which is best detected by MRI of the adrenal glands.21

The vascular anatomy of the adrenal gland is unusual. Multiple arteries supply the gland, but only one central vein provides drainage, making the gland relatively vulnerable to hemorrhagic infarction.22 Most cases of adrenal insufficiency from antiphospholipid syndrome are thought to be a result of adrenal vein thrombosis. The MRI showed that only the right adrenal gland of our patient had evidence of hemorrhage. Because both adrenal glands must be damaged before adrenal insufficiency results, it is probable that the left adrenal gland was damaged because of prior episodes of infarction and/or hemorrhage, but remote damage could not be detected by MRI. Of note, antiphospholipid antibodies directed against cholesterol‐rich proteins in the adrenal gland can also cause a locally active procoagulant state with microvascular venous thrombosis and subsequent postinfarction hemorrhage, which is another way in which the left adrenal gland could have been damaged without showing up radiographically.23

As for other types of adrenal insufficiency, the primary treatment for adrenal insufficiency from antiphospholipid syndrome is rapid corticosteroid replacement, with the addition of anticoagulants to treat the hypercoagulable state of the antiphospholipid syndrome. Adrenal insufficiency is temporary in some cases.24 Mortality from adrenal insufficiency due to antiphospholipid syndrome may be higher than that from other forms of adrenal insufficiency.22 Therefore, screening for adrenal insufficiency is critical for any patient with suspected or documented antiphospholipid syndrome who presents with abdominal pain, weakness, electrolyte abnormalities, or unexplained hypotension.

This case illustrates the importance, as the key to diagnosis, of determining a distinguishing feature such as a prolonged aPTT from among the multitude of abnormalities that could have led the diagnostic process astray. Occasionally, a single clinical or laboratory abnormality, such as the elevated aPTT in our patient, is so valuable in the assessment of a difficult case that it significantly increases the likelihood of an uncommon condition and leads to the correct final diagnosis, thereby becoming the pivotal distinguishing feature.

56‐year‐old man with a history of chronic liver disease of unknown etiology was referred for evaluation of intermittent low‐grade fevers, constipation, and an unintentional weight loss of 20‐kg during the previous 9 months. Three weeks prior to presentation, he was admitted to his local hospital for these symptoms and was treated empirically with cefotaxime for 6 days, but his symptoms persisted.

The patient's age and sex make him statistically at risk for vascular disease as well as malignancy. The history of chronic liver disease of unknown etiology is intriguing. In evaluating a patient with chronic liver disease, I want to know about alcohol consumption, intravenous drug use, family history, viral hepatitis serology, and antinuclear antibody testing. Chronic liver disease places this patient at increased risk for infection because portal hypertension causes blood to bypass a large part of the reticuloendothelial system (liver and spleen), therefore increasing the risk of sustained bacteremia.

Regarding his chronic low‐grade fever, I would like to know about his country of origin, travel history, occupational history, risk factors for human immunodeficiency virus (HIV) and tuberculosis, and any symptoms or signs of rheumatologic disease. Constipation and weight loss can be a result of malignancy (eg, hepatocellular carcinoma, colorectal cancer), vascular disease (eg, mesenteric thrombosis), or metabolic derangement (eg, hypercalcemia).

The patient had a history of recurrent episodes of ascites and low‐grade fevers. He first developed ascites, abdominal pain, low‐grade fevers, and pedal edema 20 years ago. These signs and symptoms resolved spontaneously, but similar episodes have recurred every 46 years since. Each time, diagnostic evaluation failed to reveal a specific etiology.

Twelve years prior to presentation, the patient was evaluated for chronic liver disease. Diagnostic tests at that time included viral hepatitis serology, ceruloplasmin, ferritin, alpha‐1‐antitrypsin, antimitochondrial antibody, and antinuclear antibody testing, all the results of which were within the normal range. The patient denied consumption of alcohol, medications, or toxic substances. Percutaneous liver biopsy demonstrated focal parenchymal scarring interspersed with areas of normal parenchyma, consistent with focal ischemic injury (Fig. 1).

Figure 1

The duration of the patient's symptoms is striking. A unifying diagnosis for this patient must explain his chronic liver disease, periodic fevers, ascites, and abdominal pain that started at a relatively young age. Conditions to consider include hepatitis B or C, hemochromatosis, Wilson's disease, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, alpha‐1‐antitrypsin deficiency, and drug or toxin exposure. Venoocclusive disease of the liver and chronic congestive hepatopathy (from heart failure or constrictive pericarditis) are especially attractive possibilities, given the findings of focal ischemic injury on liver biopsy.

Recurrent fever and abdominal pain can occur because of familial Mediterranean fever, which results from a genetic abnormality and causes recurrent peritoneal inflammation associated with fever and ascites. Although unlikely in this case, familial Mediterranean fever can cause secondary amyloidosis with liver involvement.

The patient reported episodic, vague abdominal pain, nausea, anorexia, night sweats, hair thinning, extreme fatigue, and lightheadedness. He had no known allergies, and his medications included propranolol, lactulose, docusate, and omeprazole. He was white, born in the United States, and a lawyer, but he had not worked during the previous 4 months. He was married and monogamous, and an HIV antibody test 4 months prior was negative. He had a remote history of tobacco and alcohol use between the 1960s and the 1980s. He denied intravenous drug use. His family history was only remarkable for a father with coronary artery disease.

With fever, the hypothalamic set point for temperature increases. Night sweats usually indicate an exaggeration of the normal diurnal drop in the hypothalamic set point for temperature, with dissipation of increased heat (caused by fever) through evaporation of perspiration. Unfortunately, night sweats are not specific to any particular cause of fever. Fatigue is equally nonspecific but could result from anemia, hypothyroidism, or adrenal insufficiency or could be a side effect of the propranolol. The lack of a family history makes hereditary periodic fevers unlikely.

The patient appeared chronically ill. His temperature was 35.2C, blood pressure 71/53 mm Hg, heart rate 84 beats per minute, respiratory rate 14 breaths per minute, and oxygen saturation 99% while breathing room air. His weight was 47 kg. Examination of the patient's head and neck revealed bitemporal wasting but no scleral icterus, and the oropharynx was clear. There was no thyromegaly or lymphadenopathy. The findings of the cardiopulmonary examination was normal. The abdomen was soft with mild diffuse tenderness. There was no organomegaly or obvious ascites. His extremities were warm and without edema or cyanosis. He was dark‐skinned and had rare spider angiomas. The results of his neurological examination were normal.

Sepsis, drug ingestion (particularly vasodilators), environmental exposure, and endocrine abnormalities such as adrenal insufficiency and hypothyroidism can all cause both hypothermia and hypotension. Adrenal insufficiency is especially intriguing becauase it is also associated with malaise, abdominal pain, and hyperpigmentation. Explaining both adrenal insufficiency and chronic liver disease is more difficult. Hemochromatosis can cause cirrhotic liver disease, adrenal and thyroid insufficiency, and dark skin, but the patient's normal ferritin and liver biopsy findings make this disease unlikely.

The results of the laboratory studies were: white‐cell count, 4900/mm³, with a normal differential count; hemoglobin, 11.0 g/dL; platelet count, 52,000/mm³; mean corpuscular volume, 89 m³; sodium, 131 mmol/L; potassium, 5.0 mmol/L; chloride, 101 mmol/L; bicarbonate, 21 mmol/L; blood urea nitrogen, 31 mg/dL; creatinine, 1.8 mg/dL; aspartate aminotransferase, 45 U/L (normal range 1641 U/L); alanine aminotransferase, 30 U/L (normal range 1259 U/L); alkaline phosphatase, 587 U/L (normal range 29111 U/L); total bilirubin, 1.1 mg/dL (normal range 0.31.3 mg/dL); gamma‐glutamyl transferase, 169 U/L (normal range 771 U/L); lactate dehydrogenase, 127 IU/L (normal range 91185 IU/L); thyroid‐stimulating hormone, 3.1 mIU/L (normal range 0.54.7 mIU/L). Coagulation studies revealed a prothrombin time of 12 seconds (international normalized ratio [INR] 1.1) and an activated partial thromboplastin time (aPTT) of greater than 100 seconds. Urinalysis and chest radiography were unremarkable.

The low sodium, high potassium, and relatively low bicarbonate levels are all compatible with adrenal insufficiency. When present, the combination of hyponatremia (primarily from glucocorticoid deficiency) and hyperkalemia (from mineralocorticoid deficiency) suggests the adrenal insufficiency is primary, rather than from the pituitary. The differential diagnosis of primary adrenal insufficiency includes autoimmune disease, granulomatous disease, and tumor.

Most interesting is the isolated prolongation of the aPTT, making adrenal hemorrhage another possibility as a cause of the adrenal insufficiency. Isolated elevation of the aPTT suggests deficiency or inhibition of the factors involved in the intrinsic pathway (factors VIII, IX, XI, and XII) or the presence of an antiphospholipid antibody, which would interfere with the test. Heparin administration (which may not be immediately obvious, as in the case of a heparin lock of an intravenous line) and von Willebrand disease (from loss of the normal von Willebrand factorassociated prevention of factor VIII proteolysis) can also cause isolated prolongation of the aPTT.

Tumor, perhaps hepatocellular cancer, remains a possible explanation for the elevated alkaline phosphatase, with possible adrenal involvement. Amyloidosis and diffuse granulomatous disease (either infectious or noninfectious, such as sarcoidosis) can cause elevation in alkaline phosphatase. At this time, I would rule out adrenal insufficiency, further evaluate the elevated aPTT, and image the liver and adrenal glands.

The patient was hospitalized and given intravenous fluids. His blood pressure increased to 90/54 mm Hg. Further testing revealed an alpha‐fetoprotein of 1.5 g/dL (normal range < 6.4 g/dL), an erythrocyte sedimentation rate of greater than 100 mm/s, and normal results of an antinuclear antibody test. Serum cortisol, drawn at 6 a.m., was 3 ng/dL; 60 minutes after cosyntropin stimulation, serum cortisol was 1 ng/dL. An ultrasound of the liver revealed chronic hepatic vein thrombosis.

The low absolute values and the failure of serum cortisol to respond to cosyntropin confirm the diagnosis of adrenal glucocorticoid deficiency. Hepatic vein thrombosis (Budd‐Chiari syndrome) is an unusual occurrence, often associated with a hypercoagulable state or tumor. How can we put these new findings together with the rest of the patient's abnormalities?

Primary antiphospholipid antibody syndrome is the most attractive unifying diagnosis because it appears to explain the most abnormalities with the fewest diagnoses. This syndrome includes arterial and venous thrombosis, thrombocytopenia, and isolated elevation of the aPTT and has been associated with hepatic vein thrombosis (acute and chronic) and adrenal insufficiency (from adrenal hemorrhage as a result of adrenal vein thrombosis). The histological findings of focal ischemic injury, seen on the patient's liver biopsy, are likely explained by hepatic venoocclusive disease.

Magnetic resonance imaging (MRI) of the abdomen (Fig. 2) demonstrated adrenal hemorrhage in the right adrenal gland. The patient's aPTT remained elevated even after his serum was mixed with normal serum, thereby excluding a factor deficiency. The results of a dilute Russell's viper venom time test (which tests the phospholipid‐dependent portion of the coagulation cascade) also showed elevation. The addition of phospholipids to the patient's serum corrected the aPTT, and a screen for factor inhibitors was negative. An anticardiolipin antibody (IgG) test was positive at 59.0 U (normal 0.42.3 U). These findings confirmed the presence of antiphospholipid antibodies.

Figure 2

The findings of a bone marrow biopsy, performed to exclude infiltrative diseases, were normal. The patient was diagnosed with primary antiphospholipid syndrome. Hydrocortisone and fludrocortisone were initiated, with the intention to continue them indefinitely. The patient was also started on intravenous heparin, which continued until he achieved a goal INR of 2.03.0 on warfarin. The patient was counseled on the importance of lifelong warfarin therapy given his diagnosis of antiphospholipid syndrome with hepatic vein and adrenal vein thromboses. On follow‐up 6 months after discharge, the patient's hypotension and fatigue had resolved, his alkaline phosphatase level had decreased substantially, and he had returned to work as a lawyer.

COMMENTARY

The diagnosis of a complex case with numerous clinical and laboratory abnormalities can be very difficult. The discussant successfully came to the correct diagnosis because he carefully evaluated each piece of evidence and did not fall prey to faulty triggering, the generation of diagnostic hypotheses based on selected pieces of clinical data.1 In the diagnostic process, physicians trigger new diagnostic possibilities and discard initial hypotheses as new findings emerge. Often, because of heuristic (analytic) biases, physicians fall victim to faulty triggering when evaluating patients.2 When confronted with a trigger feature such as night sweats, many physicians increase their consideration of tuberculosis or lymphoma at the expense of more common diagnoses, even though, as the discussant pointed out, any patient with fever can have this symptom.3 Whereas faulty use of trigger features may make physicians inappropriately consider uncommon diseases, a distinguishing feature limits the number of diagnostic possibilities and significantly changesincreases or decreasesthe likelihood of there being a rare disease.4 By correctly using the distinguishing feature of an elevated aPTT in the context of the patient's diverse clinical features, the discussant was able to arrive at a single, unifying diagnosis of antiphospholipid syndrome.

Antiphospholipid syndrome is arterial or venous thrombosis associated with significantly elevated antiphospholipid antibodies. Isolated prolongation of the aPTT is often the first clue to the presence of antiphospholipid antibodies, which interfere with phospholipid‐dependent coagulation assays.5 Antiphospholipid syndrome is considered primary if it is not associated with a known underlying disease or medication. Antiphospholipid syndrome is secondary if it is associated with certain diseases such as systemic lupus erythematosus and malignancy or with an adverse effect of medication. Although the prevalence of antiphospholipid antibodies is 1%5% in young, apparently healthy control subjects, it is higher in elderly patients with chronic diseases.6 It remains unclear why only certain patients with antiphospholipid antibodies manifest the syndrome, though having vascular risk factors may increase the risk of developing thrombosis in the presence of antiphospholipid antibodies.7

Three types of antiphospholipid antibody tests are currently in clinical use: lupus anticoagulants (measured by prolonged clotting time in a phospholipid‐dependent clotting test, such as the aPTT), anticardiolipin antibodies, and anti‐₂‐glycoprotein I antibodies. All 3 tests are plagued by not being standardized between hospitals and laboratories and have limited sensitivity and specificity.8, 9 Lupus anticoagulants are most closely associated with thrombosis. Although a prolonged aPTT in the presence of thrombosis is often the first clue to the presence of lupus anticoagulants, only 30%40% of patients with the syndrome have this laboratory abnormality.10 Therefore, a normal aPTT result does not rule out the presence of antiphospholipid antibodies, and other tests of lupus anticoagulants, such as the dilute Russell viper venom time, should be performed.8, 9 There are many types of anticardiolipin antibodies of varying immunoglobulin isotypes, which all share the ability to bind cardiolipin in vitro. The IgG isotypes (as in our patient) are thought to be most closely associated with thrombosis, and it is known that high titers of anticardiolipin antibodies have much better discriminatory value than low titers.810 There is little data on the anti‐₂‐glycoprotein I antibodies, but preliminary data suggest these antibodies may be more specific for the antiphospholipid syndrome.11

The antiphospholipid syndrome has classically been associated with lower‐extremity deep venous thrombosis, recurrent fetal loss, thrombocytopenia, and livedo reticularis.10 However, depending on the size and distribution of the vasculature involved and the extent and chronicity of involvement, antiphospholipid syndrome can result in manifestation of a wide range of diseases. Acute presentations such as thrombotic disease of the gastrointestinal, cardiac, and central nervous systems can be rapid and catastrophic. A more chronic and indolent course can lead to progressive organ dysfunction, as in this patient, with chronic liver disease resulting from recurrent episodes of hepatic venoocclusive disease and chronic hepatic vein thrombosis, a rare but well‐described complication of antiphospholipid syndrome.12, 13 It is unclear why the course of our patient's hepatic vein thrombosis waxed and waned so much. We hypothesized that he had episodes of microvascular hepatic venous thrombosis that led to transient hepatic dysfunction, with subsequent recovery upon spontaneous recanalization of hepatic veins or with healing and regeneration of liver tissue.

Treatment of antiphospholipid syndrome is controversial. Although prior reports suggested that patients with this syndrome were at higher risk for recurrent thrombosis when treated with the usual dose of warfarin (target INR 2.03.0), 2 randomized trial showed there was no difference in the recurrence of thrombosis between moderate‐intensity treatment with warfarin and high‐intensity treatment with warfarin.14, 15 Our patient was treated with warfarin to a moderate‐intensity target INR of 2.03.0 because he had liver disease and adrenal hemorrhage. Although he has done well, it is important that he be continuously reassessed, as should all patients with similar conditions, for the risk and recurrence of thrombosis weighed against the risk of bleeding.

Adrenal insufficiency is another rare complication of antiphospholipid syndrome. It was first described as such in 198016 and has since been reported in both children and adults.1719 Abdominal pain and hypotension were the most common findings (55% and 54%, respectively) in one case series of 86 patients with adrenal insufficiency from antiphospholipid syndrome.20 Fever, nausea, vomiting, weakness, fatigue, lethargy, and altered mental status were also variably present. Loss of adrenal function is most often a result of adrenal hemorrhage, which is best detected by MRI of the adrenal glands.21

The vascular anatomy of the adrenal gland is unusual. Multiple arteries supply the gland, but only one central vein provides drainage, making the gland relatively vulnerable to hemorrhagic infarction.22 Most cases of adrenal insufficiency from antiphospholipid syndrome are thought to be a result of adrenal vein thrombosis. The MRI showed that only the right adrenal gland of our patient had evidence of hemorrhage. Because both adrenal glands must be damaged before adrenal insufficiency results, it is probable that the left adrenal gland was damaged because of prior episodes of infarction and/or hemorrhage, but remote damage could not be detected by MRI. Of note, antiphospholipid antibodies directed against cholesterol‐rich proteins in the adrenal gland can also cause a locally active procoagulant state with microvascular venous thrombosis and subsequent postinfarction hemorrhage, which is another way in which the left adrenal gland could have been damaged without showing up radiographically.23

As for other types of adrenal insufficiency, the primary treatment for adrenal insufficiency from antiphospholipid syndrome is rapid corticosteroid replacement, with the addition of anticoagulants to treat the hypercoagulable state of the antiphospholipid syndrome. Adrenal insufficiency is temporary in some cases.24 Mortality from adrenal insufficiency due to antiphospholipid syndrome may be higher than that from other forms of adrenal insufficiency.22 Therefore, screening for adrenal insufficiency is critical for any patient with suspected or documented antiphospholipid syndrome who presents with abdominal pain, weakness, electrolyte abnormalities, or unexplained hypotension.

This case illustrates the importance, as the key to diagnosis, of determining a distinguishing feature such as a prolonged aPTT from among the multitude of abnormalities that could have led the diagnostic process astray. Occasionally, a single clinical or laboratory abnormality, such as the elevated aPTT in our patient, is so valuable in the assessment of a difficult case that it significantly increases the likelihood of an uncommon condition and leads to the correct final diagnosis, thereby becoming the pivotal distinguishing feature.

56‐year‐old man with a history of chronic liver disease of unknown etiology was referred for evaluation of intermittent low‐grade fevers, constipation, and an unintentional weight loss of 20‐kg during the previous 9 months. Three weeks prior to presentation, he was admitted to his local hospital for these symptoms and was treated empirically with cefotaxime for 6 days, but his symptoms persisted.

The patient's age and sex make him statistically at risk for vascular disease as well as malignancy. The history of chronic liver disease of unknown etiology is intriguing. In evaluating a patient with chronic liver disease, I want to know about alcohol consumption, intravenous drug use, family history, viral hepatitis serology, and antinuclear antibody testing. Chronic liver disease places this patient at increased risk for infection because portal hypertension causes blood to bypass a large part of the reticuloendothelial system (liver and spleen), therefore increasing the risk of sustained bacteremia.

Regarding his chronic low‐grade fever, I would like to know about his country of origin, travel history, occupational history, risk factors for human immunodeficiency virus (HIV) and tuberculosis, and any symptoms or signs of rheumatologic disease. Constipation and weight loss can be a result of malignancy (eg, hepatocellular carcinoma, colorectal cancer), vascular disease (eg, mesenteric thrombosis), or metabolic derangement (eg, hypercalcemia).

The patient had a history of recurrent episodes of ascites and low‐grade fevers. He first developed ascites, abdominal pain, low‐grade fevers, and pedal edema 20 years ago. These signs and symptoms resolved spontaneously, but similar episodes have recurred every 46 years since. Each time, diagnostic evaluation failed to reveal a specific etiology.

Twelve years prior to presentation, the patient was evaluated for chronic liver disease. Diagnostic tests at that time included viral hepatitis serology, ceruloplasmin, ferritin, alpha‐1‐antitrypsin, antimitochondrial antibody, and antinuclear antibody testing, all the results of which were within the normal range. The patient denied consumption of alcohol, medications, or toxic substances. Percutaneous liver biopsy demonstrated focal parenchymal scarring interspersed with areas of normal parenchyma, consistent with focal ischemic injury (Fig. 1).

Figure 1

The duration of the patient's symptoms is striking. A unifying diagnosis for this patient must explain his chronic liver disease, periodic fevers, ascites, and abdominal pain that started at a relatively young age. Conditions to consider include hepatitis B or C, hemochromatosis, Wilson's disease, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, alpha‐1‐antitrypsin deficiency, and drug or toxin exposure. Venoocclusive disease of the liver and chronic congestive hepatopathy (from heart failure or constrictive pericarditis) are especially attractive possibilities, given the findings of focal ischemic injury on liver biopsy.

Recurrent fever and abdominal pain can occur because of familial Mediterranean fever, which results from a genetic abnormality and causes recurrent peritoneal inflammation associated with fever and ascites. Although unlikely in this case, familial Mediterranean fever can cause secondary amyloidosis with liver involvement.

The patient reported episodic, vague abdominal pain, nausea, anorexia, night sweats, hair thinning, extreme fatigue, and lightheadedness. He had no known allergies, and his medications included propranolol, lactulose, docusate, and omeprazole. He was white, born in the United States, and a lawyer, but he had not worked during the previous 4 months. He was married and monogamous, and an HIV antibody test 4 months prior was negative. He had a remote history of tobacco and alcohol use between the 1960s and the 1980s. He denied intravenous drug use. His family history was only remarkable for a father with coronary artery disease.

With fever, the hypothalamic set point for temperature increases. Night sweats usually indicate an exaggeration of the normal diurnal drop in the hypothalamic set point for temperature, with dissipation of increased heat (caused by fever) through evaporation of perspiration. Unfortunately, night sweats are not specific to any particular cause of fever. Fatigue is equally nonspecific but could result from anemia, hypothyroidism, or adrenal insufficiency or could be a side effect of the propranolol. The lack of a family history makes hereditary periodic fevers unlikely.

The patient appeared chronically ill. His temperature was 35.2C, blood pressure 71/53 mm Hg, heart rate 84 beats per minute, respiratory rate 14 breaths per minute, and oxygen saturation 99% while breathing room air. His weight was 47 kg. Examination of the patient's head and neck revealed bitemporal wasting but no scleral icterus, and the oropharynx was clear. There was no thyromegaly or lymphadenopathy. The findings of the cardiopulmonary examination was normal. The abdomen was soft with mild diffuse tenderness. There was no organomegaly or obvious ascites. His extremities were warm and without edema or cyanosis. He was dark‐skinned and had rare spider angiomas. The results of his neurological examination were normal.

Sepsis, drug ingestion (particularly vasodilators), environmental exposure, and endocrine abnormalities such as adrenal insufficiency and hypothyroidism can all cause both hypothermia and hypotension. Adrenal insufficiency is especially intriguing becauase it is also associated with malaise, abdominal pain, and hyperpigmentation. Explaining both adrenal insufficiency and chronic liver disease is more difficult. Hemochromatosis can cause cirrhotic liver disease, adrenal and thyroid insufficiency, and dark skin, but the patient's normal ferritin and liver biopsy findings make this disease unlikely.

The results of the laboratory studies were: white‐cell count, 4900/mm³, with a normal differential count; hemoglobin, 11.0 g/dL; platelet count, 52,000/mm³; mean corpuscular volume, 89 m³; sodium, 131 mmol/L; potassium, 5.0 mmol/L; chloride, 101 mmol/L; bicarbonate, 21 mmol/L; blood urea nitrogen, 31 mg/dL; creatinine, 1.8 mg/dL; aspartate aminotransferase, 45 U/L (normal range 1641 U/L); alanine aminotransferase, 30 U/L (normal range 1259 U/L); alkaline phosphatase, 587 U/L (normal range 29111 U/L); total bilirubin, 1.1 mg/dL (normal range 0.31.3 mg/dL); gamma‐glutamyl transferase, 169 U/L (normal range 771 U/L); lactate dehydrogenase, 127 IU/L (normal range 91185 IU/L); thyroid‐stimulating hormone, 3.1 mIU/L (normal range 0.54.7 mIU/L). Coagulation studies revealed a prothrombin time of 12 seconds (international normalized ratio [INR] 1.1) and an activated partial thromboplastin time (aPTT) of greater than 100 seconds. Urinalysis and chest radiography were unremarkable.

The low sodium, high potassium, and relatively low bicarbonate levels are all compatible with adrenal insufficiency. When present, the combination of hyponatremia (primarily from glucocorticoid deficiency) and hyperkalemia (from mineralocorticoid deficiency) suggests the adrenal insufficiency is primary, rather than from the pituitary. The differential diagnosis of primary adrenal insufficiency includes autoimmune disease, granulomatous disease, and tumor.

Most interesting is the isolated prolongation of the aPTT, making adrenal hemorrhage another possibility as a cause of the adrenal insufficiency. Isolated elevation of the aPTT suggests deficiency or inhibition of the factors involved in the intrinsic pathway (factors VIII, IX, XI, and XII) or the presence of an antiphospholipid antibody, which would interfere with the test. Heparin administration (which may not be immediately obvious, as in the case of a heparin lock of an intravenous line) and von Willebrand disease (from loss of the normal von Willebrand factorassociated prevention of factor VIII proteolysis) can also cause isolated prolongation of the aPTT.

Tumor, perhaps hepatocellular cancer, remains a possible explanation for the elevated alkaline phosphatase, with possible adrenal involvement. Amyloidosis and diffuse granulomatous disease (either infectious or noninfectious, such as sarcoidosis) can cause elevation in alkaline phosphatase. At this time, I would rule out adrenal insufficiency, further evaluate the elevated aPTT, and image the liver and adrenal glands.

The patient was hospitalized and given intravenous fluids. His blood pressure increased to 90/54 mm Hg. Further testing revealed an alpha‐fetoprotein of 1.5 g/dL (normal range < 6.4 g/dL), an erythrocyte sedimentation rate of greater than 100 mm/s, and normal results of an antinuclear antibody test. Serum cortisol, drawn at 6 a.m., was 3 ng/dL; 60 minutes after cosyntropin stimulation, serum cortisol was 1 ng/dL. An ultrasound of the liver revealed chronic hepatic vein thrombosis.

The low absolute values and the failure of serum cortisol to respond to cosyntropin confirm the diagnosis of adrenal glucocorticoid deficiency. Hepatic vein thrombosis (Budd‐Chiari syndrome) is an unusual occurrence, often associated with a hypercoagulable state or tumor. How can we put these new findings together with the rest of the patient's abnormalities?

Primary antiphospholipid antibody syndrome is the most attractive unifying diagnosis because it appears to explain the most abnormalities with the fewest diagnoses. This syndrome includes arterial and venous thrombosis, thrombocytopenia, and isolated elevation of the aPTT and has been associated with hepatic vein thrombosis (acute and chronic) and adrenal insufficiency (from adrenal hemorrhage as a result of adrenal vein thrombosis). The histological findings of focal ischemic injury, seen on the patient's liver biopsy, are likely explained by hepatic venoocclusive disease.

Magnetic resonance imaging (MRI) of the abdomen (Fig. 2) demonstrated adrenal hemorrhage in the right adrenal gland. The patient's aPTT remained elevated even after his serum was mixed with normal serum, thereby excluding a factor deficiency. The results of a dilute Russell's viper venom time test (which tests the phospholipid‐dependent portion of the coagulation cascade) also showed elevation. The addition of phospholipids to the patient's serum corrected the aPTT, and a screen for factor inhibitors was negative. An anticardiolipin antibody (IgG) test was positive at 59.0 U (normal 0.42.3 U). These findings confirmed the presence of antiphospholipid antibodies.

Figure 2

The findings of a bone marrow biopsy, performed to exclude infiltrative diseases, were normal. The patient was diagnosed with primary antiphospholipid syndrome. Hydrocortisone and fludrocortisone were initiated, with the intention to continue them indefinitely. The patient was also started on intravenous heparin, which continued until he achieved a goal INR of 2.03.0 on warfarin. The patient was counseled on the importance of lifelong warfarin therapy given his diagnosis of antiphospholipid syndrome with hepatic vein and adrenal vein thromboses. On follow‐up 6 months after discharge, the patient's hypotension and fatigue had resolved, his alkaline phosphatase level had decreased substantially, and he had returned to work as a lawyer.

COMMENTARY

The diagnosis of a complex case with numerous clinical and laboratory abnormalities can be very difficult. The discussant successfully came to the correct diagnosis because he carefully evaluated each piece of evidence and did not fall prey to faulty triggering, the generation of diagnostic hypotheses based on selected pieces of clinical data.1 In the diagnostic process, physicians trigger new diagnostic possibilities and discard initial hypotheses as new findings emerge. Often, because of heuristic (analytic) biases, physicians fall victim to faulty triggering when evaluating patients.2 When confronted with a trigger feature such as night sweats, many physicians increase their consideration of tuberculosis or lymphoma at the expense of more common diagnoses, even though, as the discussant pointed out, any patient with fever can have this symptom.3 Whereas faulty use of trigger features may make physicians inappropriately consider uncommon diseases, a distinguishing feature limits the number of diagnostic possibilities and significantly changesincreases or decreasesthe likelihood of there being a rare disease.4 By correctly using the distinguishing feature of an elevated aPTT in the context of the patient's diverse clinical features, the discussant was able to arrive at a single, unifying diagnosis of antiphospholipid syndrome.

Antiphospholipid syndrome is arterial or venous thrombosis associated with significantly elevated antiphospholipid antibodies. Isolated prolongation of the aPTT is often the first clue to the presence of antiphospholipid antibodies, which interfere with phospholipid‐dependent coagulation assays.5 Antiphospholipid syndrome is considered primary if it is not associated with a known underlying disease or medication. Antiphospholipid syndrome is secondary if it is associated with certain diseases such as systemic lupus erythematosus and malignancy or with an adverse effect of medication. Although the prevalence of antiphospholipid antibodies is 1%5% in young, apparently healthy control subjects, it is higher in elderly patients with chronic diseases.6 It remains unclear why only certain patients with antiphospholipid antibodies manifest the syndrome, though having vascular risk factors may increase the risk of developing thrombosis in the presence of antiphospholipid antibodies.7

Three types of antiphospholipid antibody tests are currently in clinical use: lupus anticoagulants (measured by prolonged clotting time in a phospholipid‐dependent clotting test, such as the aPTT), anticardiolipin antibodies, and anti‐₂‐glycoprotein I antibodies. All 3 tests are plagued by not being standardized between hospitals and laboratories and have limited sensitivity and specificity.8, 9 Lupus anticoagulants are most closely associated with thrombosis. Although a prolonged aPTT in the presence of thrombosis is often the first clue to the presence of lupus anticoagulants, only 30%40% of patients with the syndrome have this laboratory abnormality.10 Therefore, a normal aPTT result does not rule out the presence of antiphospholipid antibodies, and other tests of lupus anticoagulants, such as the dilute Russell viper venom time, should be performed.8, 9 There are many types of anticardiolipin antibodies of varying immunoglobulin isotypes, which all share the ability to bind cardiolipin in vitro. The IgG isotypes (as in our patient) are thought to be most closely associated with thrombosis, and it is known that high titers of anticardiolipin antibodies have much better discriminatory value than low titers.810 There is little data on the anti‐₂‐glycoprotein I antibodies, but preliminary data suggest these antibodies may be more specific for the antiphospholipid syndrome.11

The antiphospholipid syndrome has classically been associated with lower‐extremity deep venous thrombosis, recurrent fetal loss, thrombocytopenia, and livedo reticularis.10 However, depending on the size and distribution of the vasculature involved and the extent and chronicity of involvement, antiphospholipid syndrome can result in manifestation of a wide range of diseases. Acute presentations such as thrombotic disease of the gastrointestinal, cardiac, and central nervous systems can be rapid and catastrophic. A more chronic and indolent course can lead to progressive organ dysfunction, as in this patient, with chronic liver disease resulting from recurrent episodes of hepatic venoocclusive disease and chronic hepatic vein thrombosis, a rare but well‐described complication of antiphospholipid syndrome.12, 13 It is unclear why the course of our patient's hepatic vein thrombosis waxed and waned so much. We hypothesized that he had episodes of microvascular hepatic venous thrombosis that led to transient hepatic dysfunction, with subsequent recovery upon spontaneous recanalization of hepatic veins or with healing and regeneration of liver tissue.

Treatment of antiphospholipid syndrome is controversial. Although prior reports suggested that patients with this syndrome were at higher risk for recurrent thrombosis when treated with the usual dose of warfarin (target INR 2.03.0), 2 randomized trial showed there was no difference in the recurrence of thrombosis between moderate‐intensity treatment with warfarin and high‐intensity treatment with warfarin.14, 15 Our patient was treated with warfarin to a moderate‐intensity target INR of 2.03.0 because he had liver disease and adrenal hemorrhage. Although he has done well, it is important that he be continuously reassessed, as should all patients with similar conditions, for the risk and recurrence of thrombosis weighed against the risk of bleeding.

Adrenal insufficiency is another rare complication of antiphospholipid syndrome. It was first described as such in 198016 and has since been reported in both children and adults.1719 Abdominal pain and hypotension were the most common findings (55% and 54%, respectively) in one case series of 86 patients with adrenal insufficiency from antiphospholipid syndrome.20 Fever, nausea, vomiting, weakness, fatigue, lethargy, and altered mental status were also variably present. Loss of adrenal function is most often a result of adrenal hemorrhage, which is best detected by MRI of the adrenal glands.21

The vascular anatomy of the adrenal gland is unusual. Multiple arteries supply the gland, but only one central vein provides drainage, making the gland relatively vulnerable to hemorrhagic infarction.22 Most cases of adrenal insufficiency from antiphospholipid syndrome are thought to be a result of adrenal vein thrombosis. The MRI showed that only the right adrenal gland of our patient had evidence of hemorrhage. Because both adrenal glands must be damaged before adrenal insufficiency results, it is probable that the left adrenal gland was damaged because of prior episodes of infarction and/or hemorrhage, but remote damage could not be detected by MRI. Of note, antiphospholipid antibodies directed against cholesterol‐rich proteins in the adrenal gland can also cause a locally active procoagulant state with microvascular venous thrombosis and subsequent postinfarction hemorrhage, which is another way in which the left adrenal gland could have been damaged without showing up radiographically.23

As for other types of adrenal insufficiency, the primary treatment for adrenal insufficiency from antiphospholipid syndrome is rapid corticosteroid replacement, with the addition of anticoagulants to treat the hypercoagulable state of the antiphospholipid syndrome. Adrenal insufficiency is temporary in some cases.24 Mortality from adrenal insufficiency due to antiphospholipid syndrome may be higher than that from other forms of adrenal insufficiency.22 Therefore, screening for adrenal insufficiency is critical for any patient with suspected or documented antiphospholipid syndrome who presents with abdominal pain, weakness, electrolyte abnormalities, or unexplained hypotension.

This case illustrates the importance, as the key to diagnosis, of determining a distinguishing feature such as a prolonged aPTT from among the multitude of abnormalities that could have led the diagnostic process astray. Occasionally, a single clinical or laboratory abnormality, such as the elevated aPTT in our patient, is so valuable in the assessment of a difficult case that it significantly increases the likelihood of an uncommon condition and leads to the correct final diagnosis, thereby becoming the pivotal distinguishing feature.

We deeply appreciate the involvement of our reviewers who made the Journal of Hospital Medicine so successful in its first year. Listed below are the many reviewers and volume of their contributions. They have our sincere gratitude.

Reviewed 4 or More Articles

Eric Alper (6)

David Anthony (4)

Vineet Arora (4)

Thomas E. Baudendistel (11)

Daniel J. Brotman (7)

Vincent W. Chiang (5)

Eugene Shu‐Sen Chu (5)

Gurpreet Dhaliwal (7)

Lorenzo Di Francesco (4)

Andras Fenyves (4)

Stacy Fischer (5)

Kathlyn Fletcher (5)

Philip H. Goodman (4)

Carolyn Gould (4)

Jeffrey L. Greenwald (6)

Lakshmi Halasyamani (4)

Brian Harte (13)

Christopher P. Landrigan (5)

Peter K. Lindenauer (4)

Greg Maynard (7)

Sylvia Cheney McKean (4)

Thomas Aquinas Murphy (4)

James C. Pile (9)

Thomas Price (4)

Sumant Ranji (8)

Bradley Allen Sharpe (4)

Jason Stein (7)

Robin Tricoles (9)

Guillermo E. Umpierrez (5)

Arpana Vidyarthi (6)

Heidi Wald (7)

David Wesorick (4)

Reviewed 3 Articles

Ron G. Angus

Paul Aronowitz

Vanitha Bala

Jennifer Best

Cynthia Jean Brown

Gregory Bump

Hugo Quinny Cheng

Eva Chittenden

Eric Coleman

Curtiss B. Cook

Edward Etchells

Alan John Forster

Roma Y. Gianchandani

Leslie W. Hall

Jennifer Hanrahan

Amir K. Jaffer

Peter John Kaboli

Jennifer Kapo

Dennis Manning

Constantine Manthous

Janet Nagamine

Kevin J. O'Leary

Brian Michael Pate

Robert C. Pendleton

Jeffrey Lawrence Schnipper

Hasan Shabbir

James Edwin Stone

Chad Whelan

Audrey Young

Reviewed 2 Articles

Drew Abernathy

Stephen J. Bekanich

Paul Cantey

Kerry Cho

Patrick Conway

Jasminka Criley

Catherine Curley

Jennifer Daru

Catherine F. Decker

Andrew Paul DeFilippis

Daniel J. DiBona

Mark Earnest

Douglas Einstadter

Margaret Fang

Jonathan M. Flacker

Bradley Evan Flansbaum

Michael Frankel

Jeffrey Glasheen

Amir H. Hamrahian

Karen E. Hauer

Eric Edwin Howell

Carlos Manuel Isada

Christopher Seoung Kim

Sunil Kripalani

Jean S. Kutner

Cindy Lai

Janet Larson

David Likosky

David Ling

Michelle Magee

Navneet Majhail

Michael Matheny

George Mathew

Govardhanan Nagaiah

James Newman

Christopher Ohl

Shawn Ralston

Daniel A. Rauch

John James Ross

Joel Rubenstein

David Schulman

Kaveh G. Shojania

Gregory Randall Smith Jr.

Peter Youngers Watson

Chad T. Whelan

Neil Winawer

Scott Wright

Reviewed 1 Article

Adebola Adesanya

Nasim Afsarmanesh

Richard Keith Albert

Mel L. Anderson, III

Wendy Artrong

Thomas W. Barrett

David Bar‐Shain

Marc Baskin

Brent Beasley

Thomas Bookwalter

Susan S. Braithwaite

Beril Caker

Douglas Carlson

Alison Chantal Caviness

Steven L. Cohn

Yvette Marie Cua

Russ Cucina

Ethan Ulysses Cumbler

Mellar Davis

Allan S. Detsky

Jeffrey Randolph Dichter

Thomas Donner

Daniel David Dressler

Erin Egan

Matthew Eisen

Kenneth Richard Epstein

Leslie Fall

Shaun Uiglas Frost

Michael Sebastian Galin

Matthew Garber

Rajesh Garg

Raminder Singh Gill

Jackie Glover

Adrienne Green

Paul Hain

Braden Hale

Sajeev Handa

Julie Hauer

Michael Heisler

Jeanne M. Huddleston

Alan J. Hunter

Kevin Hwang

Brian Jack

Ian Harold Jenkins

Kurien John

Daniel Johnson

Todd Joyner

Deepa Kabirdas

Allen Kachalia

Abel Ngo Kho

Steven Jay Kravet

Marco Aurelio Ladino

Robert Lash

Joshua Lee

Sei Lee

Arthur Jefferson Lesesne

Marcia Levetown

Luci Leykum

Joshua David Liberman

Jonathan Mansbach

Brian Markoff

David Meltzer

Anna Leco Merca

Barbara Messinger‐Rapport

Gregory Misky

William Moran

Brahmajee Nallamothu

Theore Elliott Nash

Heather Nye

Timothy O'Brien

Bruce Ovbiagele

Thomas Andrew Owens

Mary Pak

Steven Zvi Pantilat

Vikas Parekh

Kimberly Rask

Michael Rothberg

Hilary F. Ryder

Wael Saber

Sanjay Saint

Rene Salazar

Kaycee Sink

N. Smith

Malathi Srinivasin

Raj Srivastava

Erin Stucky

Alexander Turchin

Bobbak Vahid

Robert Wachter

Robert L. Wears

Howard Weitz

Winthrop Whitcomb

Mark V. Williams

Sherrie Williams

David Woods

We deeply appreciate the involvement of our reviewers who made the Journal of Hospital Medicine so successful in its first year. Listed below are the many reviewers and volume of their contributions. They have our sincere gratitude.

Reviewed 4 or More Articles

Eric Alper (6)

David Anthony (4)

Vineet Arora (4)

Thomas E. Baudendistel (11)

Daniel J. Brotman (7)

Vincent W. Chiang (5)

Eugene Shu‐Sen Chu (5)

Gurpreet Dhaliwal (7)

Lorenzo Di Francesco (4)

Andras Fenyves (4)

Stacy Fischer (5)

Kathlyn Fletcher (5)

Philip H. Goodman (4)

Carolyn Gould (4)

Jeffrey L. Greenwald (6)

Lakshmi Halasyamani (4)

Brian Harte (13)

Christopher P. Landrigan (5)

Peter K. Lindenauer (4)

Greg Maynard (7)

Sylvia Cheney McKean (4)

Thomas Aquinas Murphy (4)

James C. Pile (9)

Thomas Price (4)

Sumant Ranji (8)

Bradley Allen Sharpe (4)

Jason Stein (7)

Robin Tricoles (9)

Guillermo E. Umpierrez (5)

Arpana Vidyarthi (6)

Heidi Wald (7)

David Wesorick (4)

Reviewed 3 Articles

Ron G. Angus

Paul Aronowitz

Vanitha Bala

Jennifer Best

Cynthia Jean Brown

Gregory Bump

Hugo Quinny Cheng

Eva Chittenden

Eric Coleman

Curtiss B. Cook

Edward Etchells

Alan John Forster

Roma Y. Gianchandani

Leslie W. Hall

Jennifer Hanrahan

Amir K. Jaffer

Peter John Kaboli

Jennifer Kapo

Dennis Manning

Constantine Manthous

Janet Nagamine

Kevin J. O'Leary

Brian Michael Pate

Robert C. Pendleton

Jeffrey Lawrence Schnipper

Hasan Shabbir

James Edwin Stone

Chad Whelan

Audrey Young

Reviewed 2 Articles

Drew Abernathy

Stephen J. Bekanich

Paul Cantey

Kerry Cho

Patrick Conway

Jasminka Criley

Catherine Curley

Jennifer Daru

Catherine F. Decker

Andrew Paul DeFilippis

Daniel J. DiBona

Mark Earnest

Douglas Einstadter

Margaret Fang

Jonathan M. Flacker

Bradley Evan Flansbaum

Michael Frankel

Jeffrey Glasheen

Amir H. Hamrahian

Karen E. Hauer

Eric Edwin Howell

Carlos Manuel Isada

Christopher Seoung Kim

Sunil Kripalani

Jean S. Kutner

Cindy Lai

Janet Larson

David Likosky

David Ling

Michelle Magee

Navneet Majhail

Michael Matheny

George Mathew

Govardhanan Nagaiah

James Newman

Christopher Ohl

Shawn Ralston

Daniel A. Rauch

John James Ross

Joel Rubenstein

David Schulman

Kaveh G. Shojania

Gregory Randall Smith Jr.

Peter Youngers Watson

Chad T. Whelan

Neil Winawer

Scott Wright

Reviewed 1 Article

Adebola Adesanya

Nasim Afsarmanesh

Richard Keith Albert

Mel L. Anderson, III

Wendy Artrong

Thomas W. Barrett

David Bar‐Shain

Marc Baskin

Brent Beasley

Thomas Bookwalter

Susan S. Braithwaite

Beril Caker

Douglas Carlson

Alison Chantal Caviness

Steven L. Cohn

Yvette Marie Cua

Russ Cucina

Ethan Ulysses Cumbler

Mellar Davis

Allan S. Detsky

Jeffrey Randolph Dichter

Thomas Donner

Daniel David Dressler

Erin Egan

Matthew Eisen

Kenneth Richard Epstein

Leslie Fall

Shaun Uiglas Frost

Michael Sebastian Galin

Matthew Garber

Rajesh Garg

Raminder Singh Gill

Jackie Glover

Adrienne Green

Paul Hain

Braden Hale

Sajeev Handa

Julie Hauer

Michael Heisler

Jeanne M. Huddleston

Alan J. Hunter

Kevin Hwang

Brian Jack

Ian Harold Jenkins

Kurien John

Daniel Johnson

Todd Joyner

Deepa Kabirdas

Allen Kachalia

Abel Ngo Kho

Steven Jay Kravet

Marco Aurelio Ladino

Robert Lash

Joshua Lee

Sei Lee

Arthur Jefferson Lesesne

Marcia Levetown

Luci Leykum

Joshua David Liberman

Jonathan Mansbach

Brian Markoff

David Meltzer

Anna Leco Merca

Barbara Messinger‐Rapport

Gregory Misky

William Moran

Brahmajee Nallamothu

Theore Elliott Nash

Heather Nye

Timothy O'Brien

Bruce Ovbiagele

Thomas Andrew Owens

Mary Pak

Steven Zvi Pantilat

Vikas Parekh

Kimberly Rask

Michael Rothberg

Hilary F. Ryder

Wael Saber

Sanjay Saint

Rene Salazar

Kaycee Sink

N. Smith

Malathi Srinivasin

Raj Srivastava

Erin Stucky

Alexander Turchin

Bobbak Vahid

Robert Wachter

Robert L. Wears

Howard Weitz

Winthrop Whitcomb

Mark V. Williams

Sherrie Williams

David Woods

We deeply appreciate the involvement of our reviewers who made the Journal of Hospital Medicine so successful in its first year. Listed below are the many reviewers and volume of their contributions. They have our sincere gratitude.

Reviewed 4 or More Articles

Eric Alper (6)

David Anthony (4)

Vineet Arora (4)

Thomas E. Baudendistel (11)

Daniel J. Brotman (7)

Vincent W. Chiang (5)

Eugene Shu‐Sen Chu (5)

Gurpreet Dhaliwal (7)

Lorenzo Di Francesco (4)

Andras Fenyves (4)

Stacy Fischer (5)

Kathlyn Fletcher (5)

Philip H. Goodman (4)

Carolyn Gould (4)

Jeffrey L. Greenwald (6)

Lakshmi Halasyamani (4)

Brian Harte (13)

Christopher P. Landrigan (5)

Peter K. Lindenauer (4)

Greg Maynard (7)

Sylvia Cheney McKean (4)

Thomas Aquinas Murphy (4)

James C. Pile (9)

Thomas Price (4)

Sumant Ranji (8)

Bradley Allen Sharpe (4)

Jason Stein (7)

Robin Tricoles (9)

Guillermo E. Umpierrez (5)

Arpana Vidyarthi (6)

Heidi Wald (7)

David Wesorick (4)

Reviewed 3 Articles

Ron G. Angus

Paul Aronowitz

Vanitha Bala

Jennifer Best

Cynthia Jean Brown

Gregory Bump

Hugo Quinny Cheng

Eva Chittenden

Eric Coleman

Curtiss B. Cook

Edward Etchells

Alan John Forster

Roma Y. Gianchandani

Leslie W. Hall

Jennifer Hanrahan

Amir K. Jaffer

Peter John Kaboli

Jennifer Kapo

Dennis Manning

Constantine Manthous

Janet Nagamine

Kevin J. O'Leary

Brian Michael Pate

Robert C. Pendleton

Jeffrey Lawrence Schnipper

Hasan Shabbir

James Edwin Stone

Chad Whelan

Audrey Young

Reviewed 2 Articles

Drew Abernathy

Stephen J. Bekanich

Paul Cantey

Kerry Cho

Patrick Conway

Jasminka Criley

Catherine Curley

Jennifer Daru

Catherine F. Decker

Andrew Paul DeFilippis

Daniel J. DiBona

Mark Earnest

Douglas Einstadter

Margaret Fang

Jonathan M. Flacker

Bradley Evan Flansbaum

Michael Frankel

Jeffrey Glasheen

Amir H. Hamrahian

Karen E. Hauer

Eric Edwin Howell

Carlos Manuel Isada

Christopher Seoung Kim

Sunil Kripalani

Jean S. Kutner

Cindy Lai

Janet Larson

David Likosky

David Ling

Michelle Magee

Navneet Majhail

Michael Matheny

George Mathew

Govardhanan Nagaiah

James Newman

Christopher Ohl

Shawn Ralston

Daniel A. Rauch

John James Ross

Joel Rubenstein

David Schulman

Kaveh G. Shojania

Gregory Randall Smith Jr.

Peter Youngers Watson

Chad T. Whelan

Neil Winawer

Scott Wright

Reviewed 1 Article

Adebola Adesanya

Nasim Afsarmanesh

Richard Keith Albert

Mel L. Anderson, III

Wendy Artrong

Thomas W. Barrett

David Bar‐Shain

Marc Baskin

Brent Beasley

Thomas Bookwalter

Susan S. Braithwaite

Beril Caker

Douglas Carlson

Alison Chantal Caviness

Steven L. Cohn

Yvette Marie Cua

Russ Cucina

Ethan Ulysses Cumbler

Mellar Davis

Allan S. Detsky

Jeffrey Randolph Dichter

Thomas Donner

Daniel David Dressler

Erin Egan

Matthew Eisen

Kenneth Richard Epstein

Leslie Fall

Shaun Uiglas Frost

Michael Sebastian Galin

Matthew Garber

Rajesh Garg

Raminder Singh Gill

Jackie Glover

Adrienne Green

Paul Hain

Braden Hale

Sajeev Handa

Julie Hauer

Michael Heisler

Jeanne M. Huddleston

Alan J. Hunter

Kevin Hwang

Brian Jack

Ian Harold Jenkins

Kurien John

Daniel Johnson

Todd Joyner

Deepa Kabirdas

Allen Kachalia

Abel Ngo Kho

Steven Jay Kravet

Marco Aurelio Ladino

Robert Lash

Joshua Lee

Sei Lee

Arthur Jefferson Lesesne

Marcia Levetown

Luci Leykum

Joshua David Liberman

Jonathan Mansbach

Brian Markoff

David Meltzer

Anna Leco Merca

Barbara Messinger‐Rapport

Gregory Misky

William Moran

Brahmajee Nallamothu

Theore Elliott Nash

Heather Nye

Timothy O'Brien

Bruce Ovbiagele

Thomas Andrew Owens

Mary Pak

Steven Zvi Pantilat

Vikas Parekh

Kimberly Rask

Michael Rothberg

Hilary F. Ryder

Wael Saber

Sanjay Saint

Rene Salazar

Kaycee Sink

N. Smith

Malathi Srinivasin

Raj Srivastava

Erin Stucky

Alexander Turchin

Bobbak Vahid

Robert Wachter

Robert L. Wears

Howard Weitz

Winthrop Whitcomb

Mark V. Williams

Sherrie Williams

David Woods

• CLINICAL QUESTION: How safe and effective is fixed‐dose subcutaneous unfractionated heparin in the treatment of venous thromboembolism?

• BOTTOM LINE: In this study, fixed‐dose weight‐adjusted unfractionated heparin (UFH) administered subcutaneously was as safe and effective as low‐molecular‐weight heparin (LMWH) in the treatment of venous thromboembolism (VTE). Estimated drug costs for a 6‐day course are $712 for LMWH and $37 for UFH. Most clinicians will want to see similar results from at least 1 additional well‐done clinical trial, including more patients with symptomatic pulmonary embolism, before routinely treating VTE with subcutaneous UFH. (LOE = 1b)

• REFERENCE: Kearon C, Ginsberg JS, Julian JA, et al, for the Fixed‐Dose Heparin (FIDO) Investigators. Comparison of fixed‐dose weight‐adjusted unfractionated heparin and low‐molecular‐weight heparin for acute treatment of venous thromboembolism. JAMA 2006;296:935‐942.

• STUDY DESIGN: Randomized controlled trial (single‐blinded)

• FUNDING: Foundation

• SETTING: Outpatient (any)

• ALLOCATION: Concealed

• SYNOPSIS: These investigators randomly assigned (concealed allocation assignment) 708 patients, 18 years or older, with acute VTE to subcutaneous UFH (initial dose of 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours) or LMWH (dalteparin or enoxaparin, 100 IU/kg every 12 hours). The dose of subcutaneous UFH remained fixed for individual patients and was not changed during treatment as a result of anticoagulation profiles. The diagnosis of VTE included patients with acute deep vein thrombosis of the legs (81%) or symptomatic pulmonary embolism (19%). Oral warfarin was usually started on the same day as heparin in both groups and continued for a minimum of 3 months with doses adjusted to achieve an international normalized ratio (INR) of between 2.0 and 3.0. Heparin was continued for at least 5 days and until the INR was 2.0 or higher for 2 consecutive days. Individuals unaware of treatment group assignment assessed all outcomes, including study eligibility criteria. Follow‐up occurred for more than 98% of subjects for 3 months. All eligible and consenting patients underwent final data analysis. The risk of recurrent VTE in the first 3 months after treatment was not significantly different between patients in the UFH group (3.8%) and those in the LMWH group (3.4%). The risk of major bleeding during the first 10 days of treatment was also similar between the UFH group (1.1%) and LMWH group (1.4%). Approximately 70% of patients in both groups received treatment entirely out of hospital. Overall, there were 18 deaths in the UFH group and 22 deaths in the LMWH group (difference not significant). Adverse events were unrelated to whether subjects were subtherapeutic or supratherapeutic.

• CLINICAL QUESTION: How safe and effective is fixed‐dose subcutaneous unfractionated heparin in the treatment of venous thromboembolism?

• BOTTOM LINE: In this study, fixed‐dose weight‐adjusted unfractionated heparin (UFH) administered subcutaneously was as safe and effective as low‐molecular‐weight heparin (LMWH) in the treatment of venous thromboembolism (VTE). Estimated drug costs for a 6‐day course are $712 for LMWH and $37 for UFH. Most clinicians will want to see similar results from at least 1 additional well‐done clinical trial, including more patients with symptomatic pulmonary embolism, before routinely treating VTE with subcutaneous UFH. (LOE = 1b)

• REFERENCE: Kearon C, Ginsberg JS, Julian JA, et al, for the Fixed‐Dose Heparin (FIDO) Investigators. Comparison of fixed‐dose weight‐adjusted unfractionated heparin and low‐molecular‐weight heparin for acute treatment of venous thromboembolism. JAMA 2006;296:935‐942.

• STUDY DESIGN: Randomized controlled trial (single‐blinded)

• FUNDING: Foundation

• SETTING: Outpatient (any)

• ALLOCATION: Concealed

• SYNOPSIS: These investigators randomly assigned (concealed allocation assignment) 708 patients, 18 years or older, with acute VTE to subcutaneous UFH (initial dose of 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours) or LMWH (dalteparin or enoxaparin, 100 IU/kg every 12 hours). The dose of subcutaneous UFH remained fixed for individual patients and was not changed during treatment as a result of anticoagulation profiles. The diagnosis of VTE included patients with acute deep vein thrombosis of the legs (81%) or symptomatic pulmonary embolism (19%). Oral warfarin was usually started on the same day as heparin in both groups and continued for a minimum of 3 months with doses adjusted to achieve an international normalized ratio (INR) of between 2.0 and 3.0. Heparin was continued for at least 5 days and until the INR was 2.0 or higher for 2 consecutive days. Individuals unaware of treatment group assignment assessed all outcomes, including study eligibility criteria. Follow‐up occurred for more than 98% of subjects for 3 months. All eligible and consenting patients underwent final data analysis. The risk of recurrent VTE in the first 3 months after treatment was not significantly different between patients in the UFH group (3.8%) and those in the LMWH group (3.4%). The risk of major bleeding during the first 10 days of treatment was also similar between the UFH group (1.1%) and LMWH group (1.4%). Approximately 70% of patients in both groups received treatment entirely out of hospital. Overall, there were 18 deaths in the UFH group and 22 deaths in the LMWH group (difference not significant). Adverse events were unrelated to whether subjects were subtherapeutic or supratherapeutic.

• CLINICAL QUESTION: How safe and effective is fixed‐dose subcutaneous unfractionated heparin in the treatment of venous thromboembolism?

• BOTTOM LINE: In this study, fixed‐dose weight‐adjusted unfractionated heparin (UFH) administered subcutaneously was as safe and effective as low‐molecular‐weight heparin (LMWH) in the treatment of venous thromboembolism (VTE). Estimated drug costs for a 6‐day course are $712 for LMWH and $37 for UFH. Most clinicians will want to see similar results from at least 1 additional well‐done clinical trial, including more patients with symptomatic pulmonary embolism, before routinely treating VTE with subcutaneous UFH. (LOE = 1b)

• REFERENCE: Kearon C, Ginsberg JS, Julian JA, et al, for the Fixed‐Dose Heparin (FIDO) Investigators. Comparison of fixed‐dose weight‐adjusted unfractionated heparin and low‐molecular‐weight heparin for acute treatment of venous thromboembolism. JAMA 2006;296:935‐942.

• STUDY DESIGN: Randomized controlled trial (single‐blinded)

• FUNDING: Foundation

• SETTING: Outpatient (any)

• ALLOCATION: Concealed

• SYNOPSIS: These investigators randomly assigned (concealed allocation assignment) 708 patients, 18 years or older, with acute VTE to subcutaneous UFH (initial dose of 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours) or LMWH (dalteparin or enoxaparin, 100 IU/kg every 12 hours). The dose of subcutaneous UFH remained fixed for individual patients and was not changed during treatment as a result of anticoagulation profiles. The diagnosis of VTE included patients with acute deep vein thrombosis of the legs (81%) or symptomatic pulmonary embolism (19%). Oral warfarin was usually started on the same day as heparin in both groups and continued for a minimum of 3 months with doses adjusted to achieve an international normalized ratio (INR) of between 2.0 and 3.0. Heparin was continued for at least 5 days and until the INR was 2.0 or higher for 2 consecutive days. Individuals unaware of treatment group assignment assessed all outcomes, including study eligibility criteria. Follow‐up occurred for more than 98% of subjects for 3 months. All eligible and consenting patients underwent final data analysis. The risk of recurrent VTE in the first 3 months after treatment was not significantly different between patients in the UFH group (3.8%) and those in the LMWH group (3.4%). The risk of major bleeding during the first 10 days of treatment was also similar between the UFH group (1.1%) and LMWH group (1.4%). Approximately 70% of patients in both groups received treatment entirely out of hospital. Overall, there were 18 deaths in the UFH group and 22 deaths in the LMWH group (difference not significant). Adverse events were unrelated to whether subjects were subtherapeutic or supratherapeutic.

A previously healthy 27‐year‐old El Salvadoran immigrant presented with a 2‐week history of cough, fever, rigors, prostration, anorexia, weight loss, and scant hemoptysis. Physical examination revealed a thin, febrile, toxic‐appearing man in respiratory distress with bibasilar rales and scattered wheezes. Laboratory data showed a sodium of 126 mEq/L, lactate dehydrogenase of 617 U/L, ferritin of 3570 ng/mL, and liver test abnormalities suggestive of cholestasis. Chest film (Fig. 1) and computed tomography (Fig. 2) demonstrated a diffuse miliary air space pattern. Sputum smears for mycobacterium tuberculosis were negative. A urine histoplasmosis antigen level was markedly positive (7.6 EIA units), and bone marrow cultures eventually grew Histoplasma capsulatum. The HIV test result was positive, and his CD4 count was 34 cells/mm³. He was successfully treated with liposomal amphotericin B followed by itraconazole.

Figure 1

Figure 2

Histoplasmosis is the most prevalent endemic mycosis in Latin America. Most infections are asymptomatic or self‐limited, but immunodeficient individuals may develop acute pulmonary or severe, progressive disseminated infection, usually from reactivation of latent disease. Although nonspecific, the serum lactate dehydrogenase and ferritin levels are often markedly elevated. Chest imaging may be normal or show a diffuse reticulonodular pattern (with nodules less than 3 mm in diameter), indistinguishable from miliary tuberculosis. In HIV‐infected individuals, disseminated histoplasmosis usually develops when the CD4 count is less than 75 cells/mm³. Treatment is generally lifelong.

A previously healthy 27‐year‐old El Salvadoran immigrant presented with a 2‐week history of cough, fever, rigors, prostration, anorexia, weight loss, and scant hemoptysis. Physical examination revealed a thin, febrile, toxic‐appearing man in respiratory distress with bibasilar rales and scattered wheezes. Laboratory data showed a sodium of 126 mEq/L, lactate dehydrogenase of 617 U/L, ferritin of 3570 ng/mL, and liver test abnormalities suggestive of cholestasis. Chest film (Fig. 1) and computed tomography (Fig. 2) demonstrated a diffuse miliary air space pattern. Sputum smears for mycobacterium tuberculosis were negative. A urine histoplasmosis antigen level was markedly positive (7.6 EIA units), and bone marrow cultures eventually grew Histoplasma capsulatum. The HIV test result was positive, and his CD4 count was 34 cells/mm³. He was successfully treated with liposomal amphotericin B followed by itraconazole.

Figure 1

Figure 2

Histoplasmosis is the most prevalent endemic mycosis in Latin America. Most infections are asymptomatic or self‐limited, but immunodeficient individuals may develop acute pulmonary or severe, progressive disseminated infection, usually from reactivation of latent disease. Although nonspecific, the serum lactate dehydrogenase and ferritin levels are often markedly elevated. Chest imaging may be normal or show a diffuse reticulonodular pattern (with nodules less than 3 mm in diameter), indistinguishable from miliary tuberculosis. In HIV‐infected individuals, disseminated histoplasmosis usually develops when the CD4 count is less than 75 cells/mm³. Treatment is generally lifelong.

A previously healthy 27‐year‐old El Salvadoran immigrant presented with a 2‐week history of cough, fever, rigors, prostration, anorexia, weight loss, and scant hemoptysis. Physical examination revealed a thin, febrile, toxic‐appearing man in respiratory distress with bibasilar rales and scattered wheezes. Laboratory data showed a sodium of 126 mEq/L, lactate dehydrogenase of 617 U/L, ferritin of 3570 ng/mL, and liver test abnormalities suggestive of cholestasis. Chest film (Fig. 1) and computed tomography (Fig. 2) demonstrated a diffuse miliary air space pattern. Sputum smears for mycobacterium tuberculosis were negative. A urine histoplasmosis antigen level was markedly positive (7.6 EIA units), and bone marrow cultures eventually grew Histoplasma capsulatum. The HIV test result was positive, and his CD4 count was 34 cells/mm³. He was successfully treated with liposomal amphotericin B followed by itraconazole.

Figure 1

Figure 2

Histoplasmosis is the most prevalent endemic mycosis in Latin America. Most infections are asymptomatic or self‐limited, but immunodeficient individuals may develop acute pulmonary or severe, progressive disseminated infection, usually from reactivation of latent disease. Although nonspecific, the serum lactate dehydrogenase and ferritin levels are often markedly elevated. Chest imaging may be normal or show a diffuse reticulonodular pattern (with nodules less than 3 mm in diameter), indistinguishable from miliary tuberculosis. In HIV‐infected individuals, disseminated histoplasmosis usually develops when the CD4 count is less than 75 cells/mm³. Treatment is generally lifelong.