A 58-year-old-man with a history of intravenous drug abuse, chronic hepatitis C, and anxiety presented to our emergency department twice in 4 weeks with progressive dyspnea and night sweats. He was a nonsmoker and had been an electrician for 15 years.

The first time he came in, chest radiography revealed bilateral reticulonodular infiltrates in the lung bases. He was treated with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax) for presumed community-acquired pneumonia and was then sent home on a 10-day course of oral amoxicillin-clavulanate (Augmentin). The antibiotics did not improve his symptoms, and 3 weeks later he presented again to the emergency department.

On his second presentation, he was in respiratory distress (oxygen saturation 78% on room air) and was afebrile and tachypneic. Physical examination revealed numerous injection marks or “tracks” on the skin of both arms, and auscultation revealed diminished intensity of breath sounds in both lung bases.

Repeat chest radiography demonstrated that the infiltrates were still there. Computed tomography was ordered and showed mild centrilobular emphysematous changes in both lungs, bibasilar opacifications, and a mass-like lesion (3.3 × 1.9 cm) in the right lower lobe (Figure 1).

He subsequently underwent bronchoscopy, which showed no endobronchial abnormalities. Transbronchial lung biopsy was performed, and histopathologic analysis of the specimen (Figure 2) revealed rodlike, birefringent crystals under polarized light, with an extensive foreign-body giant-cell reaction outside pulmonary capillaries, suggestive of intravascular pulmonary talcosis. Blood and sputum cultures were negative for pathologic organisms. Bronchoalveolar lavage samples were negative for pathologic organisms and malignant cells.

On further questioning, the patient revealed that he intravenously injected various drugs intended for oral use, such as crushed meperidine (Demerol), methylphenidate (Ritalin), and methadone tablets.

Pulmonary function tests indicated a severe obstructive pattern. The predicted forced expiratory volume in the first second of expiration (FEV₁) was 25%, and the ratio of FEV₁ to forced vital capacity was 27%.

Transthoracic echocardiography revealed mild pulmonary hypertension with a right ventricular systolic pressure of 28 mm Hg at rest.

Based on the results of the histologic examination, a diagnosis of intravascular pulmonary talcosis was made. Antibiotics were discontinued, and treatment with albuterol and ipratropium bromide (Combivent) inhalers was started. The patient remained oxygen-dependent at the time of hospital discharge.

INTRAVASCULAR PULMONARY TALCOSIS

Intravascular pulmonary talcosis is seen predominantly in those who chronically inject intravenous drugs intended for oral use.^1,2

Many oral medications contain talc as a filler and lubricant to prevent the tablet from sticking to equipment during the manufacturing process. When oral medications containing talc are crushed, dissolved in water, and injected intravenously, the talc crystals and other particles lodge in the pulmonary vascular bed, resulting in microscopic pulmonary embolizations.

Over time, these particles migrate to the pulmonary interstitium and incite a foreign-body granulomatous reaction, which may be associated with progressive pulmonary fibrosis. The severity of this immune reaction and fibrosis may vary; hence, some patients remain asymptomatic, whereas some present with dyspnea from extensive fibrosis and pulmonary hypertension.

Persistent dyspnea along with persistent infiltrates on chest imaging in an intravenous drug abuser should prompt suspicion for intravascular pulmonary talcosis as well as consideration of other diagnoses, such as pneumonia, malignancy, and septic pulmonary emboli.

There is no established treatment for intravascular pulmonary talcosis; treatment is often supportive. A few studies and case reports have indicated varied success with systemic and inhaled corticosteroids.^3–5 In extreme cases, lung transplantation may be necessary; however, this would require a comprehensive psychiatric assessment to minimize the risk of addiction relapse after transplantation.

A 58-year-old-man with a history of intravenous drug abuse, chronic hepatitis C, and anxiety presented to our emergency department twice in 4 weeks with progressive dyspnea and night sweats. He was a nonsmoker and had been an electrician for 15 years.

The first time he came in, chest radiography revealed bilateral reticulonodular infiltrates in the lung bases. He was treated with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax) for presumed community-acquired pneumonia and was then sent home on a 10-day course of oral amoxicillin-clavulanate (Augmentin). The antibiotics did not improve his symptoms, and 3 weeks later he presented again to the emergency department.

On his second presentation, he was in respiratory distress (oxygen saturation 78% on room air) and was afebrile and tachypneic. Physical examination revealed numerous injection marks or “tracks” on the skin of both arms, and auscultation revealed diminished intensity of breath sounds in both lung bases.

Repeat chest radiography demonstrated that the infiltrates were still there. Computed tomography was ordered and showed mild centrilobular emphysematous changes in both lungs, bibasilar opacifications, and a mass-like lesion (3.3 × 1.9 cm) in the right lower lobe (Figure 1).

He subsequently underwent bronchoscopy, which showed no endobronchial abnormalities. Transbronchial lung biopsy was performed, and histopathologic analysis of the specimen (Figure 2) revealed rodlike, birefringent crystals under polarized light, with an extensive foreign-body giant-cell reaction outside pulmonary capillaries, suggestive of intravascular pulmonary talcosis. Blood and sputum cultures were negative for pathologic organisms. Bronchoalveolar lavage samples were negative for pathologic organisms and malignant cells.

On further questioning, the patient revealed that he intravenously injected various drugs intended for oral use, such as crushed meperidine (Demerol), methylphenidate (Ritalin), and methadone tablets.

Pulmonary function tests indicated a severe obstructive pattern. The predicted forced expiratory volume in the first second of expiration (FEV₁) was 25%, and the ratio of FEV₁ to forced vital capacity was 27%.

Transthoracic echocardiography revealed mild pulmonary hypertension with a right ventricular systolic pressure of 28 mm Hg at rest.

Based on the results of the histologic examination, a diagnosis of intravascular pulmonary talcosis was made. Antibiotics were discontinued, and treatment with albuterol and ipratropium bromide (Combivent) inhalers was started. The patient remained oxygen-dependent at the time of hospital discharge.

INTRAVASCULAR PULMONARY TALCOSIS

Intravascular pulmonary talcosis is seen predominantly in those who chronically inject intravenous drugs intended for oral use.^1,2

Many oral medications contain talc as a filler and lubricant to prevent the tablet from sticking to equipment during the manufacturing process. When oral medications containing talc are crushed, dissolved in water, and injected intravenously, the talc crystals and other particles lodge in the pulmonary vascular bed, resulting in microscopic pulmonary embolizations.

Over time, these particles migrate to the pulmonary interstitium and incite a foreign-body granulomatous reaction, which may be associated with progressive pulmonary fibrosis. The severity of this immune reaction and fibrosis may vary; hence, some patients remain asymptomatic, whereas some present with dyspnea from extensive fibrosis and pulmonary hypertension.

Persistent dyspnea along with persistent infiltrates on chest imaging in an intravenous drug abuser should prompt suspicion for intravascular pulmonary talcosis as well as consideration of other diagnoses, such as pneumonia, malignancy, and septic pulmonary emboli.

There is no established treatment for intravascular pulmonary talcosis; treatment is often supportive. A few studies and case reports have indicated varied success with systemic and inhaled corticosteroids.^3–5 In extreme cases, lung transplantation may be necessary; however, this would require a comprehensive psychiatric assessment to minimize the risk of addiction relapse after transplantation.

A 58-year-old-man with a history of intravenous drug abuse, chronic hepatitis C, and anxiety presented to our emergency department twice in 4 weeks with progressive dyspnea and night sweats. He was a nonsmoker and had been an electrician for 15 years.

The first time he came in, chest radiography revealed bilateral reticulonodular infiltrates in the lung bases. He was treated with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax) for presumed community-acquired pneumonia and was then sent home on a 10-day course of oral amoxicillin-clavulanate (Augmentin). The antibiotics did not improve his symptoms, and 3 weeks later he presented again to the emergency department.

On his second presentation, he was in respiratory distress (oxygen saturation 78% on room air) and was afebrile and tachypneic. Physical examination revealed numerous injection marks or “tracks” on the skin of both arms, and auscultation revealed diminished intensity of breath sounds in both lung bases.

Repeat chest radiography demonstrated that the infiltrates were still there. Computed tomography was ordered and showed mild centrilobular emphysematous changes in both lungs, bibasilar opacifications, and a mass-like lesion (3.3 × 1.9 cm) in the right lower lobe (Figure 1).

He subsequently underwent bronchoscopy, which showed no endobronchial abnormalities. Transbronchial lung biopsy was performed, and histopathologic analysis of the specimen (Figure 2) revealed rodlike, birefringent crystals under polarized light, with an extensive foreign-body giant-cell reaction outside pulmonary capillaries, suggestive of intravascular pulmonary talcosis. Blood and sputum cultures were negative for pathologic organisms. Bronchoalveolar lavage samples were negative for pathologic organisms and malignant cells.

On further questioning, the patient revealed that he intravenously injected various drugs intended for oral use, such as crushed meperidine (Demerol), methylphenidate (Ritalin), and methadone tablets.

Pulmonary function tests indicated a severe obstructive pattern. The predicted forced expiratory volume in the first second of expiration (FEV₁) was 25%, and the ratio of FEV₁ to forced vital capacity was 27%.

Transthoracic echocardiography revealed mild pulmonary hypertension with a right ventricular systolic pressure of 28 mm Hg at rest.

Based on the results of the histologic examination, a diagnosis of intravascular pulmonary talcosis was made. Antibiotics were discontinued, and treatment with albuterol and ipratropium bromide (Combivent) inhalers was started. The patient remained oxygen-dependent at the time of hospital discharge.

INTRAVASCULAR PULMONARY TALCOSIS

Intravascular pulmonary talcosis is seen predominantly in those who chronically inject intravenous drugs intended for oral use.^1,2

Many oral medications contain talc as a filler and lubricant to prevent the tablet from sticking to equipment during the manufacturing process. When oral medications containing talc are crushed, dissolved in water, and injected intravenously, the talc crystals and other particles lodge in the pulmonary vascular bed, resulting in microscopic pulmonary embolizations.

Over time, these particles migrate to the pulmonary interstitium and incite a foreign-body granulomatous reaction, which may be associated with progressive pulmonary fibrosis. The severity of this immune reaction and fibrosis may vary; hence, some patients remain asymptomatic, whereas some present with dyspnea from extensive fibrosis and pulmonary hypertension.

Persistent dyspnea along with persistent infiltrates on chest imaging in an intravenous drug abuser should prompt suspicion for intravascular pulmonary talcosis as well as consideration of other diagnoses, such as pneumonia, malignancy, and septic pulmonary emboli.

There is no established treatment for intravascular pulmonary talcosis; treatment is often supportive. A few studies and case reports have indicated varied success with systemic and inhaled corticosteroids.^3–5 In extreme cases, lung transplantation may be necessary; however, this would require a comprehensive psychiatric assessment to minimize the risk of addiction relapse after transplantation.

In many ways, vascular disease in the leg is similar to that in the heart. The risk factors, underlying conditions, and pathogenetic processes are the same, and in many cases, patients have both conditions. And just as cardiologists and emergency physicians have learned that in acute myocardial infarction “time is muscle,” we are coming to appreciate that in many cases of limb ischemia, “time is limb.”

Most physicians well understand the clinical spectrum of coronary artery disease, which ranges from stable angina to ST-elevation myocardial infarction. In the leg, the same situation exists: at the more benign end of the spectrum, patients experience no symptoms, but often that is because they lead a sedentary lifestyle, modifying their activity level to avoid pain. As the disease worsens, they can develop claudication and critical leg ischemia, comparable to non-ST-elevation myocardial infarction. The most severe condition is acute limb ischemia, analagous to ST-elevation myocardial infarction.

Distinguishing acute from critical limb ischemia is essential in patients who present with leg problems, whether it be leg pain or ulcers. The farther along the clinical spectrum the patient’s condition is, the more important it is to be aggressive in diagnosis and treatment. The history and physical examination are the most important first steps, focusing on the onset of symptoms, history, risk factors, and past interventions.

Peripheral artery disease is increasingly becoming a worldwide problem that is now being emphasized by the World Health Organization. Unfortunately, not enough attention is paid to the problem, not only in less-developed countries but also in the United States. Patients with peripheral artery disease tend to be elderly, in the lowest economic classes, and uninsured, and they often do not understand the impact of the disease on their health.

LEG ULCERS: CAUSES AND COSTS

Finding the underlying cause of leg ulcers is important, and the differential diagnosis is large (Table 1). However, knowing the cause does not necessarily lead to healing; it is still essential to assess perfusion, infection, and wound care, and to arrest edema.

Causes of leg and foot ulcers include venous insufficiency (with an estimated 2.5 million cases annually),^1,2 diabetes (nearly 1 million cases),³ and pressure (ie, bedsores, occurring in up to 28% of patients in extended care),⁴ all at a cost in the billions of dollars.^5–7

In general, peripheral artery disease itself does not cause ulcers; it is an inciting factor. It is important to find what started the process. Ill-fitting shoes, poor sensation because of diabetes, or a cut when trimming toenails can all contribute to a wound, and peripheral artery disease makes it unable to heal. The healing process requires more nutrients and oxygen than poor circulation can provide.

ACUTE LIMB ISCHEMIA

Acute limb ischemia is defined as any sudden decrease in limb perfusion causing a potential threat to limb viability.⁸ Although it comes on suddenly, it does not imply that the patient has not had long-standing peripheral artery disease. It is important to determine what suddenly changed to cause the onset of symptoms.

History and physical examination: The six Ps

A good history includes a thorough evaluation of the present illness, including the pain’s time of onset, abruptness, location, intensity, and change over time, and whether it is present at rest. The medical history should focus on claudication, diabetes, smoking, heart disease, palpitations, atrial fibrillation, and previous ischemic symptoms.⁸

The physical examination should focus on the “six Ps”:

• Pain
• Pulselessness
• Paresthesia (numbness occurs in about half of patients)
• Pallor (obstruction is typically one joint above the level of demarcation of pallor)
• Paralysis (a bad sign, particularly if the calf is tight)
• Poikilothermia (inability to regulate temperature).

A good pulse examination includes measuring the ankle-brachial index and a Doppler examination of both legs. A neurologic examination focusing on sensory and motor function is critical for determining the level of ischemia and the urgency of intervention.

Classification of acute limb ischemia

If it is determined that a patient has acute leg ischemia, it is important to categorize the condition using the classification system devised by the Society of Vascular Surgery and International Society of Cardiovascular Surgery (Table 2).⁹ The category establishes the type and urgency of treatment. This classification system is simple and depends on factors that can be assessed easily by nonspecialists:

• Pulses—arterial and venous pulses assessed by Doppler ultrasonography
• Sensation—the patient closes the eyes and answers if he or she can feel the examiner’s touch
• Motor function—can the patient move his or her toes?

Venous pulses can be difficult to assess. However, if the arterial pulse is present, the venous pulse should be next to it. Knowing the other criteria can determine the category, so not being certain of the venous pulse should not deter a clinician from assessing the other factors.

Category I is “viable.” Patients have intact sensory and motor functions and audible pulses. Patients in this category should be admitted and possibly started on anticoagulation therapy and referred to a vascular specialist within hours.

Category IIa is “threatened.” Sensation is starting to be lost but motor function is still present. These patients are considered to have reversible ischemia, analogous to myocardial infarction of the leg, and they require immediate attention.

Category IIb is similar and it also requires immediate attention.

Category III is usually irreversible, with loss of motor function and sensation.

CAUSES OF ACUTE LIMB ISCHEMIA

Thrombosis accounts for about 50% of cases. Underlying causes of the thrombosis are artherosclerosis (native or bypass), aneurysm, trauma, vasculitis (eg, in a rheumatologic disease such as lupus), and hypercoagulable states (particularly in patients with cancer).

Embolism accounts for about 30% of cases. Emboli usually arise from plaque rupture in atherosclerotic arteries or a clot breaking off from an aneurysm or from within the heart in patients with atrial fibrillation or another underlying heart disease. Paradoxical embolism, caused by an embolism crossing the heart through an opening such as a patent foramen ovale, is rare.

Uncommon causes include arterial dissection following trauma, adventitial cystic disease, popliteal artery entrapment, ergotism (from consuming fungus-contaminated grains), and human immunodeficiency virus arteriopathy.

The physical examination provides clues to the origin: livedo reticularis (purple discoloration in a mottled pattern) and blue nail beds indicate that an embolus is likely. Tests, including electrocardiography, echocardiography, and computed tomography of the chest and abdomen to look for an aneurysm, can help identify the cause. Ultrasonography of the popliteal arteries should also be considered to search for an aneurysm.

CRITICAL LIMB ISCHEMIA

Critical limb ischemia is more likely than acute limb ischemia to be seen in a general practice. Many aspects need to be addressed simultaneously, by different specialists: vascular and endocrine systems, infection, and wound care. The most successful management strategy is a dynamic approach using every piece of information.¹⁰

The Rutherford classification of peripheral artery disease has six categories based on the clinical presentation, with categories I through III being mild to severe claudication. We discuss here only the more severe categories: IV (pain at rest), V (tissue loss), and VI (gangrene).

Strong indicators of pain at rest are that the patient has to get up at night to dangle the leg over the bed or walk a few steps, or sleeps in a chair, or refuses to elevate the leg because of pain. The affected leg tends to appear red when the patient is standing (dependent rubor), but pale when the foot is elevated (elevation pallor).

Confirming that a patient has dependent rubor can be challenging, especially in people with dark skin. Classically, redness is seen when the leg is down and disappears with elevation, but in cellulitis, redness can also be reduced by elevating the leg. A foot that is hot to the touch is an indication of infection and not lack of perfusion alone.

The hemodynamic definition of critical limb ischemia is¹¹:

• Ankle-brachial pressure index less than 0.4
• Reduced toebrachial pressure index, ie, less than 0.7
• Reduced transcutaneous pressure of oxygen (Tcpo₂), ie, less than 40 mm Hg.

From 15% to 20% of patients with claudication will progress to critical ischemia over their lifetime, and in patients with claudication who also have diabetes, the risk is nearly 10 times higher. Without revascularization, the risk of amputation within 1 year is 73% for patients in Rutherford class IV and 95% for patients in class V or VI.

Revascularization and limb preservation

Preserving the limb is a prime goal. For patients who have an amputation, the mortality rate is 40% within 2 years.⁸ These patients tend to be elderly, and after an amputation, most will not learn to use a prosthesis and resume their previous level of activity. Other treatment objectives are to relieve pain, reduce cardiovascular risk, and minimize procedural complications.

Although limb preservation is not a controversial goal, best practices to preserve limbs are not universally available. Goodney et al¹² studied variation in the United States in the use of lower-extremity vascular procedures for critical limb ischemia. They defined “low-intensity” to “high-intensity” regions of the country depending on the proportion of patients who underwent a vascular procedure in the year before amputation. They found considerable variation, but even in the region of highest intensity, more than 40% of patients did not have a vascular procedure in the year before amputation.

Similarly, Jones et al¹³ mapped amputation rates by US state and found significant variation even after adjusting for risk factors such as tobacco use and obesity.

Controversy surrounds the specifics of revascularization treatment, as in many fields in vascular medicine. However, most experts agree that improved perfusion is the goal.

The Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Artery Disease recommends revascularization as the best treatment for patients with critical limb ischemia.⁸ In addition, the American College of Cardiology and American Heart Association Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic) state that the tibial or pedal artery that is capable of providing continuous and uncompromised outflow to the foot should be used as the site of distal anastomosis.¹⁴ These guidelines do not yet mention endovascular therapy.

Angiosomes guide revascularization

In the past few years, the ability to facilitate healing of foot ulcers has improved. Angiosomes—regions of vascularization supplied by specific arteries—can be mapped on the skin, similar to the way dermatomes are mapped for neural innervation (Figure 1). The foot and lower leg region has six angiosomes perfused by three arteries that branch off the popliteal artery after it passes behind the knee:

• The anterior tibial artery supplies the dorsum of the foot and the front of the lower limb.
• The posterior tibial artery supplies the plantar surface of the foot via three branches—the medial plantar, lateral plantar, and calcaneal branches.
• The peroneal artery supplies the lateral part of the foot with collaterals to the anterior and posterior tibial arteries if they are compromised.

Studies have compared angiosome-based treatment vs revascularizing the best available artery (thus depending on collateral flow to compensate to surrounding areas). They have found that regardless of whether an endovascular or bypass method of revascularization was used, an angiosome-based approach led to significantly higher amputation-free survival rates.^15–17

Patients typically do not have blockage of only a single tibial artery. Graziani et al¹⁸ assessed the vascular lesions in 417 patients with critical limb ischemia and found that multiple below-knee arteries were frequently involved. This makes it difficult to decide where to target revascularization efforts, and the angiosome concept helps with that.

ASSESSING WOUND PERFUSION

Ankle- and toe-brachial indices assess perfusion

The ankle-brachial index¹⁹ is a good superficial assessment of perfusion. Multiple epidemiologic studies have shown the prognostic value of the ankle brachial index beyond the traditional risk factors and even the Framingham risk score.¹⁹ Values:

• Normal 1.1–1.30 (> 1.31 is abnormal and consistent with calcified vessels, and is an unreliable measure)
• Low normal 0.91–1.00
• Mild disease 0.71–0.90
• Moderate disease 0.41–0.70
• Severe disease ≤ 0.40.

However, the ankle-brachial index assesses perfusion only to the ankle, and many patients have ulcers in the toes and distal foot. The toe-brachial index must be specifically ordered in most institutions (if the first toe has an ulcer, the second toe should be assessed). The toe-brachial index is also important if the ankle-brachial index cannot be obtained because of calcified, noncompressible arteries in the ankle. A normal toe-brachial index is greater than 0.7.

The segmental blood pressure examination compares blood pressure measurements at multiple sites in the lower extremity. A drop of more than 20 mm Hg between segments indicates obstruction at that location. The test is simple and noninvasive and often can replace computed tomography.²⁰

Transcutaneous oximetry

Transcutaneous oximetry measures the Tcpo₂ from 1 to 2 mm deep in the skin from local capillaries. Measured adjacent to an ulcer, it is useful to predict wound healing and to assess the response to hyperbaric oxygen therapy.²¹ The values are:

• Normal > 70 mm Hg
• Impaired wound healing < 40 mm Hg
• Critical limb ischemia < 30 mm Hg.

Although most agree that a Tcpo₂ below 40 mm Hg requires revascularization, low values can arise from many causes other than peripheral artery disease, including high altitude, pulmonary disease, heart failure, edema, inflammation, callus, and skin diseases such as scleroderma.

Skin perfusion pressure better predicts healing

Skin perfusion pressure is a measure of the capillary opening pressure after occlusion and is another way to assess perfusion. This test is not routinely done and must be specially requested.

The test is performed by inflating a blood pressure cuff on the leg until blood flow is occluded, then using laser Doppler to determine reactive hyperemia, ie, the gradual return of blood flow during controlled pressure release. The pressure at which movement is detected is the skin perfusion pressure.²²

The laser Doppler probe emits and detects light scattered in the tissue. Light hitting moving blood cells undergoes a change in frequency, ie, a Doppler shift. An algorithm converts the optical information in the skin perfusion pressure by capturing the onset of capillary flow return and determining the pressure at which flow returns. Categories of results:

• > 50 mm Hg—normal
• 40–50 mm Hg—mild ischemia (wound healing probable)
• 30–40 mm Hg—moderate ischemia (wound healing uncertain)
• < 30 mm Hg—critical limb ischemia (wound healing unlikely).

Skin perfusion pressure testing has the advantages of not being affected by vessel calcification, thickened skin, or edema. It can be used on the plantar aspect of the foot and on digits. Recent small studies indicate that it is more sensitive for predicting wound healing than Tcpo₂ measures.

On the other hand, skin perfusion pressure testing is not useful for predicting response to hyperbaric oxygen therapy. Also, blood flow occlusion by the cuff may be painful.

Intraoperative fluorescence angiography

Intraoperative fluorescence angiography is used to assess flap viability during reconstructive surgery and is being studied to determine its usefulness for assessing tissue viability in limb ischemia.

The test provides real-time assessment of capillary perfusion, determining surface tissue viability. The imaging head contains a digital camera, a laser light source, and a distance sensor. The test requires intravenous administration of indocyanine green, which binds to plasma proteins and is cleared through the liver, making it safe for patients with renal dysfunction. It cannot be used in patients with allergies to iodine contrast, penicillin, or sulfa.²³

PREVENTION TARGETS CARDIOVASCULAR RISK FACTORS

Preventive measures are the same as for cardiovascular disease, ie, aggressive risk-factor modification: quitting smoking, lowering low-density lipoprotein cholesterol, reducing blood pressure, controlling diabetes, and managing heart failure.

Dual antiplatelet therapy should be instituted with aspirin and clopidogrel (Plavix) in patients undergoing revascularization. One can also consider cilostazol (Pletal); however, the role of this agent in patients with critical limb ischemia is less defined.

BYPASS OR ANGIOPLASTY?

The Bypass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial²⁴ randomly assigned 452 patients with severe limb ischemia due to infrainguinal atherosclerosis to receive either surgery-first or angioplasty-first care and followed them for 5.5 years.

No significant differences between the two groups were found in amputation-free survival, deaths, or health-related quality of life. However, hospital costs associated with the surgery-first strategy were about one-third higher. As expected, more patients in the surgery group developed a wound infection, and more patients in the angioplasty group required bypass surgery at some point.

The conclusion that can be reached from this study is that patients presenting with severe limb ischemia due to infrainguinal atherosclerotic occlusive disease who are suitable for both surgical and interventional procedures can be treated with either method. However, most experts consider endovascular therapy as the first option in many patients. The National Institutes of Health recently funded a study to compare contemporary endovascular therapy vs surgery in patients with critical limb ischemia.

TAKE-HOME POINTS

In the last decade, significant endovascular advances have been made. New devices and techniques have enhanced our ability to treat high-risk patients who have critical limb ischemia. The combination of risk factor modification, accurate diagnosis, and aggressive revascularization should prevent limb loss in many of these patients. For the primary care physician, a low threshold for assessing perfusion in patients with critical limb ischemia is important using a screening ankle-brachial index and toe-brachial index. These patients should promptly be referred to a vascular specialist for further evaluation and treatment.

In many ways, vascular disease in the leg is similar to that in the heart. The risk factors, underlying conditions, and pathogenetic processes are the same, and in many cases, patients have both conditions. And just as cardiologists and emergency physicians have learned that in acute myocardial infarction “time is muscle,” we are coming to appreciate that in many cases of limb ischemia, “time is limb.”

Most physicians well understand the clinical spectrum of coronary artery disease, which ranges from stable angina to ST-elevation myocardial infarction. In the leg, the same situation exists: at the more benign end of the spectrum, patients experience no symptoms, but often that is because they lead a sedentary lifestyle, modifying their activity level to avoid pain. As the disease worsens, they can develop claudication and critical leg ischemia, comparable to non-ST-elevation myocardial infarction. The most severe condition is acute limb ischemia, analagous to ST-elevation myocardial infarction.

Distinguishing acute from critical limb ischemia is essential in patients who present with leg problems, whether it be leg pain or ulcers. The farther along the clinical spectrum the patient’s condition is, the more important it is to be aggressive in diagnosis and treatment. The history and physical examination are the most important first steps, focusing on the onset of symptoms, history, risk factors, and past interventions.

Peripheral artery disease is increasingly becoming a worldwide problem that is now being emphasized by the World Health Organization. Unfortunately, not enough attention is paid to the problem, not only in less-developed countries but also in the United States. Patients with peripheral artery disease tend to be elderly, in the lowest economic classes, and uninsured, and they often do not understand the impact of the disease on their health.

LEG ULCERS: CAUSES AND COSTS

Finding the underlying cause of leg ulcers is important, and the differential diagnosis is large (Table 1). However, knowing the cause does not necessarily lead to healing; it is still essential to assess perfusion, infection, and wound care, and to arrest edema.

Causes of leg and foot ulcers include venous insufficiency (with an estimated 2.5 million cases annually),^1,2 diabetes (nearly 1 million cases),³ and pressure (ie, bedsores, occurring in up to 28% of patients in extended care),⁴ all at a cost in the billions of dollars.^5–7

In general, peripheral artery disease itself does not cause ulcers; it is an inciting factor. It is important to find what started the process. Ill-fitting shoes, poor sensation because of diabetes, or a cut when trimming toenails can all contribute to a wound, and peripheral artery disease makes it unable to heal. The healing process requires more nutrients and oxygen than poor circulation can provide.

ACUTE LIMB ISCHEMIA

Acute limb ischemia is defined as any sudden decrease in limb perfusion causing a potential threat to limb viability.⁸ Although it comes on suddenly, it does not imply that the patient has not had long-standing peripheral artery disease. It is important to determine what suddenly changed to cause the onset of symptoms.

History and physical examination: The six Ps

A good history includes a thorough evaluation of the present illness, including the pain’s time of onset, abruptness, location, intensity, and change over time, and whether it is present at rest. The medical history should focus on claudication, diabetes, smoking, heart disease, palpitations, atrial fibrillation, and previous ischemic symptoms.⁸

The physical examination should focus on the “six Ps”:

• Pain
• Pulselessness
• Paresthesia (numbness occurs in about half of patients)
• Pallor (obstruction is typically one joint above the level of demarcation of pallor)
• Paralysis (a bad sign, particularly if the calf is tight)
• Poikilothermia (inability to regulate temperature).

A good pulse examination includes measuring the ankle-brachial index and a Doppler examination of both legs. A neurologic examination focusing on sensory and motor function is critical for determining the level of ischemia and the urgency of intervention.

Classification of acute limb ischemia

If it is determined that a patient has acute leg ischemia, it is important to categorize the condition using the classification system devised by the Society of Vascular Surgery and International Society of Cardiovascular Surgery (Table 2).⁹ The category establishes the type and urgency of treatment. This classification system is simple and depends on factors that can be assessed easily by nonspecialists:

• Pulses—arterial and venous pulses assessed by Doppler ultrasonography
• Sensation—the patient closes the eyes and answers if he or she can feel the examiner’s touch
• Motor function—can the patient move his or her toes?

Venous pulses can be difficult to assess. However, if the arterial pulse is present, the venous pulse should be next to it. Knowing the other criteria can determine the category, so not being certain of the venous pulse should not deter a clinician from assessing the other factors.

Category I is “viable.” Patients have intact sensory and motor functions and audible pulses. Patients in this category should be admitted and possibly started on anticoagulation therapy and referred to a vascular specialist within hours.

Category IIa is “threatened.” Sensation is starting to be lost but motor function is still present. These patients are considered to have reversible ischemia, analogous to myocardial infarction of the leg, and they require immediate attention.

Category IIb is similar and it also requires immediate attention.

Category III is usually irreversible, with loss of motor function and sensation.

CAUSES OF ACUTE LIMB ISCHEMIA

Thrombosis accounts for about 50% of cases. Underlying causes of the thrombosis are artherosclerosis (native or bypass), aneurysm, trauma, vasculitis (eg, in a rheumatologic disease such as lupus), and hypercoagulable states (particularly in patients with cancer).

Embolism accounts for about 30% of cases. Emboli usually arise from plaque rupture in atherosclerotic arteries or a clot breaking off from an aneurysm or from within the heart in patients with atrial fibrillation or another underlying heart disease. Paradoxical embolism, caused by an embolism crossing the heart through an opening such as a patent foramen ovale, is rare.

Uncommon causes include arterial dissection following trauma, adventitial cystic disease, popliteal artery entrapment, ergotism (from consuming fungus-contaminated grains), and human immunodeficiency virus arteriopathy.

The physical examination provides clues to the origin: livedo reticularis (purple discoloration in a mottled pattern) and blue nail beds indicate that an embolus is likely. Tests, including electrocardiography, echocardiography, and computed tomography of the chest and abdomen to look for an aneurysm, can help identify the cause. Ultrasonography of the popliteal arteries should also be considered to search for an aneurysm.

CRITICAL LIMB ISCHEMIA

Critical limb ischemia is more likely than acute limb ischemia to be seen in a general practice. Many aspects need to be addressed simultaneously, by different specialists: vascular and endocrine systems, infection, and wound care. The most successful management strategy is a dynamic approach using every piece of information.¹⁰

The Rutherford classification of peripheral artery disease has six categories based on the clinical presentation, with categories I through III being mild to severe claudication. We discuss here only the more severe categories: IV (pain at rest), V (tissue loss), and VI (gangrene).

Strong indicators of pain at rest are that the patient has to get up at night to dangle the leg over the bed or walk a few steps, or sleeps in a chair, or refuses to elevate the leg because of pain. The affected leg tends to appear red when the patient is standing (dependent rubor), but pale when the foot is elevated (elevation pallor).

Confirming that a patient has dependent rubor can be challenging, especially in people with dark skin. Classically, redness is seen when the leg is down and disappears with elevation, but in cellulitis, redness can also be reduced by elevating the leg. A foot that is hot to the touch is an indication of infection and not lack of perfusion alone.

The hemodynamic definition of critical limb ischemia is¹¹:

• Ankle-brachial pressure index less than 0.4
• Reduced toebrachial pressure index, ie, less than 0.7
• Reduced transcutaneous pressure of oxygen (Tcpo₂), ie, less than 40 mm Hg.

From 15% to 20% of patients with claudication will progress to critical ischemia over their lifetime, and in patients with claudication who also have diabetes, the risk is nearly 10 times higher. Without revascularization, the risk of amputation within 1 year is 73% for patients in Rutherford class IV and 95% for patients in class V or VI.

Revascularization and limb preservation

Preserving the limb is a prime goal. For patients who have an amputation, the mortality rate is 40% within 2 years.⁸ These patients tend to be elderly, and after an amputation, most will not learn to use a prosthesis and resume their previous level of activity. Other treatment objectives are to relieve pain, reduce cardiovascular risk, and minimize procedural complications.

Although limb preservation is not a controversial goal, best practices to preserve limbs are not universally available. Goodney et al¹² studied variation in the United States in the use of lower-extremity vascular procedures for critical limb ischemia. They defined “low-intensity” to “high-intensity” regions of the country depending on the proportion of patients who underwent a vascular procedure in the year before amputation. They found considerable variation, but even in the region of highest intensity, more than 40% of patients did not have a vascular procedure in the year before amputation.

Similarly, Jones et al¹³ mapped amputation rates by US state and found significant variation even after adjusting for risk factors such as tobacco use and obesity.

Controversy surrounds the specifics of revascularization treatment, as in many fields in vascular medicine. However, most experts agree that improved perfusion is the goal.

The Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Artery Disease recommends revascularization as the best treatment for patients with critical limb ischemia.⁸ In addition, the American College of Cardiology and American Heart Association Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic) state that the tibial or pedal artery that is capable of providing continuous and uncompromised outflow to the foot should be used as the site of distal anastomosis.¹⁴ These guidelines do not yet mention endovascular therapy.

Angiosomes guide revascularization

In the past few years, the ability to facilitate healing of foot ulcers has improved. Angiosomes—regions of vascularization supplied by specific arteries—can be mapped on the skin, similar to the way dermatomes are mapped for neural innervation (Figure 1). The foot and lower leg region has six angiosomes perfused by three arteries that branch off the popliteal artery after it passes behind the knee:

• The anterior tibial artery supplies the dorsum of the foot and the front of the lower limb.
• The posterior tibial artery supplies the plantar surface of the foot via three branches—the medial plantar, lateral plantar, and calcaneal branches.
• The peroneal artery supplies the lateral part of the foot with collaterals to the anterior and posterior tibial arteries if they are compromised.

Studies have compared angiosome-based treatment vs revascularizing the best available artery (thus depending on collateral flow to compensate to surrounding areas). They have found that regardless of whether an endovascular or bypass method of revascularization was used, an angiosome-based approach led to significantly higher amputation-free survival rates.^15–17

Patients typically do not have blockage of only a single tibial artery. Graziani et al¹⁸ assessed the vascular lesions in 417 patients with critical limb ischemia and found that multiple below-knee arteries were frequently involved. This makes it difficult to decide where to target revascularization efforts, and the angiosome concept helps with that.

ASSESSING WOUND PERFUSION

Ankle- and toe-brachial indices assess perfusion

The ankle-brachial index¹⁹ is a good superficial assessment of perfusion. Multiple epidemiologic studies have shown the prognostic value of the ankle brachial index beyond the traditional risk factors and even the Framingham risk score.¹⁹ Values:

• Normal 1.1–1.30 (> 1.31 is abnormal and consistent with calcified vessels, and is an unreliable measure)
• Low normal 0.91–1.00
• Mild disease 0.71–0.90
• Moderate disease 0.41–0.70
• Severe disease ≤ 0.40.

However, the ankle-brachial index assesses perfusion only to the ankle, and many patients have ulcers in the toes and distal foot. The toe-brachial index must be specifically ordered in most institutions (if the first toe has an ulcer, the second toe should be assessed). The toe-brachial index is also important if the ankle-brachial index cannot be obtained because of calcified, noncompressible arteries in the ankle. A normal toe-brachial index is greater than 0.7.

The segmental blood pressure examination compares blood pressure measurements at multiple sites in the lower extremity. A drop of more than 20 mm Hg between segments indicates obstruction at that location. The test is simple and noninvasive and often can replace computed tomography.²⁰

Transcutaneous oximetry

Transcutaneous oximetry measures the Tcpo₂ from 1 to 2 mm deep in the skin from local capillaries. Measured adjacent to an ulcer, it is useful to predict wound healing and to assess the response to hyperbaric oxygen therapy.²¹ The values are:

• Normal > 70 mm Hg
• Impaired wound healing < 40 mm Hg
• Critical limb ischemia < 30 mm Hg.

Although most agree that a Tcpo₂ below 40 mm Hg requires revascularization, low values can arise from many causes other than peripheral artery disease, including high altitude, pulmonary disease, heart failure, edema, inflammation, callus, and skin diseases such as scleroderma.

Skin perfusion pressure better predicts healing

Skin perfusion pressure is a measure of the capillary opening pressure after occlusion and is another way to assess perfusion. This test is not routinely done and must be specially requested.

The test is performed by inflating a blood pressure cuff on the leg until blood flow is occluded, then using laser Doppler to determine reactive hyperemia, ie, the gradual return of blood flow during controlled pressure release. The pressure at which movement is detected is the skin perfusion pressure.²²

The laser Doppler probe emits and detects light scattered in the tissue. Light hitting moving blood cells undergoes a change in frequency, ie, a Doppler shift. An algorithm converts the optical information in the skin perfusion pressure by capturing the onset of capillary flow return and determining the pressure at which flow returns. Categories of results:

• > 50 mm Hg—normal
• 40–50 mm Hg—mild ischemia (wound healing probable)
• 30–40 mm Hg—moderate ischemia (wound healing uncertain)
• < 30 mm Hg—critical limb ischemia (wound healing unlikely).

Skin perfusion pressure testing has the advantages of not being affected by vessel calcification, thickened skin, or edema. It can be used on the plantar aspect of the foot and on digits. Recent small studies indicate that it is more sensitive for predicting wound healing than Tcpo₂ measures.

On the other hand, skin perfusion pressure testing is not useful for predicting response to hyperbaric oxygen therapy. Also, blood flow occlusion by the cuff may be painful.

Intraoperative fluorescence angiography

Intraoperative fluorescence angiography is used to assess flap viability during reconstructive surgery and is being studied to determine its usefulness for assessing tissue viability in limb ischemia.

The test provides real-time assessment of capillary perfusion, determining surface tissue viability. The imaging head contains a digital camera, a laser light source, and a distance sensor. The test requires intravenous administration of indocyanine green, which binds to plasma proteins and is cleared through the liver, making it safe for patients with renal dysfunction. It cannot be used in patients with allergies to iodine contrast, penicillin, or sulfa.²³

PREVENTION TARGETS CARDIOVASCULAR RISK FACTORS

Preventive measures are the same as for cardiovascular disease, ie, aggressive risk-factor modification: quitting smoking, lowering low-density lipoprotein cholesterol, reducing blood pressure, controlling diabetes, and managing heart failure.

Dual antiplatelet therapy should be instituted with aspirin and clopidogrel (Plavix) in patients undergoing revascularization. One can also consider cilostazol (Pletal); however, the role of this agent in patients with critical limb ischemia is less defined.

BYPASS OR ANGIOPLASTY?

The Bypass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial²⁴ randomly assigned 452 patients with severe limb ischemia due to infrainguinal atherosclerosis to receive either surgery-first or angioplasty-first care and followed them for 5.5 years.

No significant differences between the two groups were found in amputation-free survival, deaths, or health-related quality of life. However, hospital costs associated with the surgery-first strategy were about one-third higher. As expected, more patients in the surgery group developed a wound infection, and more patients in the angioplasty group required bypass surgery at some point.

The conclusion that can be reached from this study is that patients presenting with severe limb ischemia due to infrainguinal atherosclerotic occlusive disease who are suitable for both surgical and interventional procedures can be treated with either method. However, most experts consider endovascular therapy as the first option in many patients. The National Institutes of Health recently funded a study to compare contemporary endovascular therapy vs surgery in patients with critical limb ischemia.

TAKE-HOME POINTS

In the last decade, significant endovascular advances have been made. New devices and techniques have enhanced our ability to treat high-risk patients who have critical limb ischemia. The combination of risk factor modification, accurate diagnosis, and aggressive revascularization should prevent limb loss in many of these patients. For the primary care physician, a low threshold for assessing perfusion in patients with critical limb ischemia is important using a screening ankle-brachial index and toe-brachial index. These patients should promptly be referred to a vascular specialist for further evaluation and treatment.

In many ways, vascular disease in the leg is similar to that in the heart. The risk factors, underlying conditions, and pathogenetic processes are the same, and in many cases, patients have both conditions. And just as cardiologists and emergency physicians have learned that in acute myocardial infarction “time is muscle,” we are coming to appreciate that in many cases of limb ischemia, “time is limb.”

Most physicians well understand the clinical spectrum of coronary artery disease, which ranges from stable angina to ST-elevation myocardial infarction. In the leg, the same situation exists: at the more benign end of the spectrum, patients experience no symptoms, but often that is because they lead a sedentary lifestyle, modifying their activity level to avoid pain. As the disease worsens, they can develop claudication and critical leg ischemia, comparable to non-ST-elevation myocardial infarction. The most severe condition is acute limb ischemia, analagous to ST-elevation myocardial infarction.

Distinguishing acute from critical limb ischemia is essential in patients who present with leg problems, whether it be leg pain or ulcers. The farther along the clinical spectrum the patient’s condition is, the more important it is to be aggressive in diagnosis and treatment. The history and physical examination are the most important first steps, focusing on the onset of symptoms, history, risk factors, and past interventions.

Peripheral artery disease is increasingly becoming a worldwide problem that is now being emphasized by the World Health Organization. Unfortunately, not enough attention is paid to the problem, not only in less-developed countries but also in the United States. Patients with peripheral artery disease tend to be elderly, in the lowest economic classes, and uninsured, and they often do not understand the impact of the disease on their health.

LEG ULCERS: CAUSES AND COSTS

Finding the underlying cause of leg ulcers is important, and the differential diagnosis is large (Table 1). However, knowing the cause does not necessarily lead to healing; it is still essential to assess perfusion, infection, and wound care, and to arrest edema.

Causes of leg and foot ulcers include venous insufficiency (with an estimated 2.5 million cases annually),^1,2 diabetes (nearly 1 million cases),³ and pressure (ie, bedsores, occurring in up to 28% of patients in extended care),⁴ all at a cost in the billions of dollars.^5–7

In general, peripheral artery disease itself does not cause ulcers; it is an inciting factor. It is important to find what started the process. Ill-fitting shoes, poor sensation because of diabetes, or a cut when trimming toenails can all contribute to a wound, and peripheral artery disease makes it unable to heal. The healing process requires more nutrients and oxygen than poor circulation can provide.

ACUTE LIMB ISCHEMIA

Acute limb ischemia is defined as any sudden decrease in limb perfusion causing a potential threat to limb viability.⁸ Although it comes on suddenly, it does not imply that the patient has not had long-standing peripheral artery disease. It is important to determine what suddenly changed to cause the onset of symptoms.

History and physical examination: The six Ps

A good history includes a thorough evaluation of the present illness, including the pain’s time of onset, abruptness, location, intensity, and change over time, and whether it is present at rest. The medical history should focus on claudication, diabetes, smoking, heart disease, palpitations, atrial fibrillation, and previous ischemic symptoms.⁸

The physical examination should focus on the “six Ps”:

• Pain
• Pulselessness
• Paresthesia (numbness occurs in about half of patients)
• Pallor (obstruction is typically one joint above the level of demarcation of pallor)
• Paralysis (a bad sign, particularly if the calf is tight)
• Poikilothermia (inability to regulate temperature).

A good pulse examination includes measuring the ankle-brachial index and a Doppler examination of both legs. A neurologic examination focusing on sensory and motor function is critical for determining the level of ischemia and the urgency of intervention.

Classification of acute limb ischemia

If it is determined that a patient has acute leg ischemia, it is important to categorize the condition using the classification system devised by the Society of Vascular Surgery and International Society of Cardiovascular Surgery (Table 2).⁹ The category establishes the type and urgency of treatment. This classification system is simple and depends on factors that can be assessed easily by nonspecialists:

• Pulses—arterial and venous pulses assessed by Doppler ultrasonography
• Sensation—the patient closes the eyes and answers if he or she can feel the examiner’s touch
• Motor function—can the patient move his or her toes?

Venous pulses can be difficult to assess. However, if the arterial pulse is present, the venous pulse should be next to it. Knowing the other criteria can determine the category, so not being certain of the venous pulse should not deter a clinician from assessing the other factors.

Category I is “viable.” Patients have intact sensory and motor functions and audible pulses. Patients in this category should be admitted and possibly started on anticoagulation therapy and referred to a vascular specialist within hours.

Category IIa is “threatened.” Sensation is starting to be lost but motor function is still present. These patients are considered to have reversible ischemia, analogous to myocardial infarction of the leg, and they require immediate attention.

Category IIb is similar and it also requires immediate attention.

Category III is usually irreversible, with loss of motor function and sensation.

CAUSES OF ACUTE LIMB ISCHEMIA

Thrombosis accounts for about 50% of cases. Underlying causes of the thrombosis are artherosclerosis (native or bypass), aneurysm, trauma, vasculitis (eg, in a rheumatologic disease such as lupus), and hypercoagulable states (particularly in patients with cancer).

Embolism accounts for about 30% of cases. Emboli usually arise from plaque rupture in atherosclerotic arteries or a clot breaking off from an aneurysm or from within the heart in patients with atrial fibrillation or another underlying heart disease. Paradoxical embolism, caused by an embolism crossing the heart through an opening such as a patent foramen ovale, is rare.

Uncommon causes include arterial dissection following trauma, adventitial cystic disease, popliteal artery entrapment, ergotism (from consuming fungus-contaminated grains), and human immunodeficiency virus arteriopathy.

The physical examination provides clues to the origin: livedo reticularis (purple discoloration in a mottled pattern) and blue nail beds indicate that an embolus is likely. Tests, including electrocardiography, echocardiography, and computed tomography of the chest and abdomen to look for an aneurysm, can help identify the cause. Ultrasonography of the popliteal arteries should also be considered to search for an aneurysm.

CRITICAL LIMB ISCHEMIA

Critical limb ischemia is more likely than acute limb ischemia to be seen in a general practice. Many aspects need to be addressed simultaneously, by different specialists: vascular and endocrine systems, infection, and wound care. The most successful management strategy is a dynamic approach using every piece of information.¹⁰

The Rutherford classification of peripheral artery disease has six categories based on the clinical presentation, with categories I through III being mild to severe claudication. We discuss here only the more severe categories: IV (pain at rest), V (tissue loss), and VI (gangrene).

Strong indicators of pain at rest are that the patient has to get up at night to dangle the leg over the bed or walk a few steps, or sleeps in a chair, or refuses to elevate the leg because of pain. The affected leg tends to appear red when the patient is standing (dependent rubor), but pale when the foot is elevated (elevation pallor).

Confirming that a patient has dependent rubor can be challenging, especially in people with dark skin. Classically, redness is seen when the leg is down and disappears with elevation, but in cellulitis, redness can also be reduced by elevating the leg. A foot that is hot to the touch is an indication of infection and not lack of perfusion alone.

The hemodynamic definition of critical limb ischemia is¹¹:

• Ankle-brachial pressure index less than 0.4
• Reduced toebrachial pressure index, ie, less than 0.7
• Reduced transcutaneous pressure of oxygen (Tcpo₂), ie, less than 40 mm Hg.

From 15% to 20% of patients with claudication will progress to critical ischemia over their lifetime, and in patients with claudication who also have diabetes, the risk is nearly 10 times higher. Without revascularization, the risk of amputation within 1 year is 73% for patients in Rutherford class IV and 95% for patients in class V or VI.

Revascularization and limb preservation

Preserving the limb is a prime goal. For patients who have an amputation, the mortality rate is 40% within 2 years.⁸ These patients tend to be elderly, and after an amputation, most will not learn to use a prosthesis and resume their previous level of activity. Other treatment objectives are to relieve pain, reduce cardiovascular risk, and minimize procedural complications.

Although limb preservation is not a controversial goal, best practices to preserve limbs are not universally available. Goodney et al¹² studied variation in the United States in the use of lower-extremity vascular procedures for critical limb ischemia. They defined “low-intensity” to “high-intensity” regions of the country depending on the proportion of patients who underwent a vascular procedure in the year before amputation. They found considerable variation, but even in the region of highest intensity, more than 40% of patients did not have a vascular procedure in the year before amputation.

Similarly, Jones et al¹³ mapped amputation rates by US state and found significant variation even after adjusting for risk factors such as tobacco use and obesity.

Controversy surrounds the specifics of revascularization treatment, as in many fields in vascular medicine. However, most experts agree that improved perfusion is the goal.

The Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Artery Disease recommends revascularization as the best treatment for patients with critical limb ischemia.⁸ In addition, the American College of Cardiology and American Heart Association Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic) state that the tibial or pedal artery that is capable of providing continuous and uncompromised outflow to the foot should be used as the site of distal anastomosis.¹⁴ These guidelines do not yet mention endovascular therapy.

Angiosomes guide revascularization

In the past few years, the ability to facilitate healing of foot ulcers has improved. Angiosomes—regions of vascularization supplied by specific arteries—can be mapped on the skin, similar to the way dermatomes are mapped for neural innervation (Figure 1). The foot and lower leg region has six angiosomes perfused by three arteries that branch off the popliteal artery after it passes behind the knee:

• The anterior tibial artery supplies the dorsum of the foot and the front of the lower limb.
• The posterior tibial artery supplies the plantar surface of the foot via three branches—the medial plantar, lateral plantar, and calcaneal branches.
• The peroneal artery supplies the lateral part of the foot with collaterals to the anterior and posterior tibial arteries if they are compromised.

Studies have compared angiosome-based treatment vs revascularizing the best available artery (thus depending on collateral flow to compensate to surrounding areas). They have found that regardless of whether an endovascular or bypass method of revascularization was used, an angiosome-based approach led to significantly higher amputation-free survival rates.^15–17

Patients typically do not have blockage of only a single tibial artery. Graziani et al¹⁸ assessed the vascular lesions in 417 patients with critical limb ischemia and found that multiple below-knee arteries were frequently involved. This makes it difficult to decide where to target revascularization efforts, and the angiosome concept helps with that.

ASSESSING WOUND PERFUSION

Ankle- and toe-brachial indices assess perfusion

The ankle-brachial index¹⁹ is a good superficial assessment of perfusion. Multiple epidemiologic studies have shown the prognostic value of the ankle brachial index beyond the traditional risk factors and even the Framingham risk score.¹⁹ Values:

• Normal 1.1–1.30 (> 1.31 is abnormal and consistent with calcified vessels, and is an unreliable measure)
• Low normal 0.91–1.00
• Mild disease 0.71–0.90
• Moderate disease 0.41–0.70
• Severe disease ≤ 0.40.

However, the ankle-brachial index assesses perfusion only to the ankle, and many patients have ulcers in the toes and distal foot. The toe-brachial index must be specifically ordered in most institutions (if the first toe has an ulcer, the second toe should be assessed). The toe-brachial index is also important if the ankle-brachial index cannot be obtained because of calcified, noncompressible arteries in the ankle. A normal toe-brachial index is greater than 0.7.

The segmental blood pressure examination compares blood pressure measurements at multiple sites in the lower extremity. A drop of more than 20 mm Hg between segments indicates obstruction at that location. The test is simple and noninvasive and often can replace computed tomography.²⁰

Transcutaneous oximetry

Transcutaneous oximetry measures the Tcpo₂ from 1 to 2 mm deep in the skin from local capillaries. Measured adjacent to an ulcer, it is useful to predict wound healing and to assess the response to hyperbaric oxygen therapy.²¹ The values are:

• Normal > 70 mm Hg
• Impaired wound healing < 40 mm Hg
• Critical limb ischemia < 30 mm Hg.

Although most agree that a Tcpo₂ below 40 mm Hg requires revascularization, low values can arise from many causes other than peripheral artery disease, including high altitude, pulmonary disease, heart failure, edema, inflammation, callus, and skin diseases such as scleroderma.

Skin perfusion pressure better predicts healing

Skin perfusion pressure is a measure of the capillary opening pressure after occlusion and is another way to assess perfusion. This test is not routinely done and must be specially requested.

The test is performed by inflating a blood pressure cuff on the leg until blood flow is occluded, then using laser Doppler to determine reactive hyperemia, ie, the gradual return of blood flow during controlled pressure release. The pressure at which movement is detected is the skin perfusion pressure.²²

The laser Doppler probe emits and detects light scattered in the tissue. Light hitting moving blood cells undergoes a change in frequency, ie, a Doppler shift. An algorithm converts the optical information in the skin perfusion pressure by capturing the onset of capillary flow return and determining the pressure at which flow returns. Categories of results:

• > 50 mm Hg—normal
• 40–50 mm Hg—mild ischemia (wound healing probable)
• 30–40 mm Hg—moderate ischemia (wound healing uncertain)
• < 30 mm Hg—critical limb ischemia (wound healing unlikely).

Skin perfusion pressure testing has the advantages of not being affected by vessel calcification, thickened skin, or edema. It can be used on the plantar aspect of the foot and on digits. Recent small studies indicate that it is more sensitive for predicting wound healing than Tcpo₂ measures.

On the other hand, skin perfusion pressure testing is not useful for predicting response to hyperbaric oxygen therapy. Also, blood flow occlusion by the cuff may be painful.

Intraoperative fluorescence angiography

Intraoperative fluorescence angiography is used to assess flap viability during reconstructive surgery and is being studied to determine its usefulness for assessing tissue viability in limb ischemia.

The test provides real-time assessment of capillary perfusion, determining surface tissue viability. The imaging head contains a digital camera, a laser light source, and a distance sensor. The test requires intravenous administration of indocyanine green, which binds to plasma proteins and is cleared through the liver, making it safe for patients with renal dysfunction. It cannot be used in patients with allergies to iodine contrast, penicillin, or sulfa.²³

PREVENTION TARGETS CARDIOVASCULAR RISK FACTORS

Preventive measures are the same as for cardiovascular disease, ie, aggressive risk-factor modification: quitting smoking, lowering low-density lipoprotein cholesterol, reducing blood pressure, controlling diabetes, and managing heart failure.

Dual antiplatelet therapy should be instituted with aspirin and clopidogrel (Plavix) in patients undergoing revascularization. One can also consider cilostazol (Pletal); however, the role of this agent in patients with critical limb ischemia is less defined.

BYPASS OR ANGIOPLASTY?

The Bypass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial²⁴ randomly assigned 452 patients with severe limb ischemia due to infrainguinal atherosclerosis to receive either surgery-first or angioplasty-first care and followed them for 5.5 years.

No significant differences between the two groups were found in amputation-free survival, deaths, or health-related quality of life. However, hospital costs associated with the surgery-first strategy were about one-third higher. As expected, more patients in the surgery group developed a wound infection, and more patients in the angioplasty group required bypass surgery at some point.

The conclusion that can be reached from this study is that patients presenting with severe limb ischemia due to infrainguinal atherosclerotic occlusive disease who are suitable for both surgical and interventional procedures can be treated with either method. However, most experts consider endovascular therapy as the first option in many patients. The National Institutes of Health recently funded a study to compare contemporary endovascular therapy vs surgery in patients with critical limb ischemia.

TAKE-HOME POINTS

In the last decade, significant endovascular advances have been made. New devices and techniques have enhanced our ability to treat high-risk patients who have critical limb ischemia. The combination of risk factor modification, accurate diagnosis, and aggressive revascularization should prevent limb loss in many of these patients. For the primary care physician, a low threshold for assessing perfusion in patients with critical limb ischemia is important using a screening ankle-brachial index and toe-brachial index. These patients should promptly be referred to a vascular specialist for further evaluation and treatment.

The article by Dickstein et al on eating disorders in this issue of the Journal made me think about my experience long ago as an internist comanaging patients who had severe eating disorders.

As a rheumatologist, I noticed that these young women had a very high prevalence of fibromyalgia and associated visceral pain syndromes such as irritable bowel syndrome and interstitial cystitis. Because they had been experiencing fatigue and generalized pain, many of them had been tested for lupus. Since about 20% of young women may have a low-positive antinuclear antibody titer, some of these patients had been diagnosed with lupus, and some had been offered therapy.

Other factors reinforced their physicians’ appropriate concerns about possible connective tissue disease. For example, modest leukopenia is not infrequent in malnourished patients, and Raynaud phenomenon is common in young women. Bulimia is associated with gastroesophageal dysmotility, and some of these women had slightly elevated creatine kinase levels. These abnormalities were generally the result of over-vigorous exercise, ipecac use, emesis, and hypokalemia. However, myositis or scleroderma overlap syndromes had occasionally been diagnosed in some patients, especially when the severity of the primary eating disorder was unappreciated.

Many, including myself, have written about the strengths and limitations of evidence-based medicine. We routinely make both evidence- and experience-based clinical decisions, often with little time to reflect on the exact reason for each decision. As I think back on my stint in the eating disorders clinic, recalling individual patients and lessons learned, I am struck by how observation-based my management of those patients was and how those experiences have stuck with me.

Reflective clinical care (also known as anecdotal experience) can have a lasting impact on the way we practice. Twenty-five years later, I still think about eating disorders when I evaluate young women who have severe fibromyalgia.

The article by Dickstein et al on eating disorders in this issue of the Journal made me think about my experience long ago as an internist comanaging patients who had severe eating disorders.

As a rheumatologist, I noticed that these young women had a very high prevalence of fibromyalgia and associated visceral pain syndromes such as irritable bowel syndrome and interstitial cystitis. Because they had been experiencing fatigue and generalized pain, many of them had been tested for lupus. Since about 20% of young women may have a low-positive antinuclear antibody titer, some of these patients had been diagnosed with lupus, and some had been offered therapy.

Other factors reinforced their physicians’ appropriate concerns about possible connective tissue disease. For example, modest leukopenia is not infrequent in malnourished patients, and Raynaud phenomenon is common in young women. Bulimia is associated with gastroesophageal dysmotility, and some of these women had slightly elevated creatine kinase levels. These abnormalities were generally the result of over-vigorous exercise, ipecac use, emesis, and hypokalemia. However, myositis or scleroderma overlap syndromes had occasionally been diagnosed in some patients, especially when the severity of the primary eating disorder was unappreciated.

Many, including myself, have written about the strengths and limitations of evidence-based medicine. We routinely make both evidence- and experience-based clinical decisions, often with little time to reflect on the exact reason for each decision. As I think back on my stint in the eating disorders clinic, recalling individual patients and lessons learned, I am struck by how observation-based my management of those patients was and how those experiences have stuck with me.

Reflective clinical care (also known as anecdotal experience) can have a lasting impact on the way we practice. Twenty-five years later, I still think about eating disorders when I evaluate young women who have severe fibromyalgia.

The article by Dickstein et al on eating disorders in this issue of the Journal made me think about my experience long ago as an internist comanaging patients who had severe eating disorders.

As a rheumatologist, I noticed that these young women had a very high prevalence of fibromyalgia and associated visceral pain syndromes such as irritable bowel syndrome and interstitial cystitis. Because they had been experiencing fatigue and generalized pain, many of them had been tested for lupus. Since about 20% of young women may have a low-positive antinuclear antibody titer, some of these patients had been diagnosed with lupus, and some had been offered therapy.

Other factors reinforced their physicians’ appropriate concerns about possible connective tissue disease. For example, modest leukopenia is not infrequent in malnourished patients, and Raynaud phenomenon is common in young women. Bulimia is associated with gastroesophageal dysmotility, and some of these women had slightly elevated creatine kinase levels. These abnormalities were generally the result of over-vigorous exercise, ipecac use, emesis, and hypokalemia. However, myositis or scleroderma overlap syndromes had occasionally been diagnosed in some patients, especially when the severity of the primary eating disorder was unappreciated.

Many, including myself, have written about the strengths and limitations of evidence-based medicine. We routinely make both evidence- and experience-based clinical decisions, often with little time to reflect on the exact reason for each decision. As I think back on my stint in the eating disorders clinic, recalling individual patients and lessons learned, I am struck by how observation-based my management of those patients was and how those experiences have stuck with me.

Reflective clinical care (also known as anecdotal experience) can have a lasting impact on the way we practice. Twenty-five years later, I still think about eating disorders when I evaluate young women who have severe fibromyalgia.

Eating disorders are debilitating biopsychosocial illnesses associated with serious medical illness and a high risk of death.¹

Primary care physicians are often the first to see young women who have these problems, diagnose them, and start their evaluation and treatment.^2–4 Many patients require acute medical interventions as well as long-term care for chronic medical issues. Therefore, primary care physicians play essential front-line and long-term roles in the multidisciplinary treatment team.

DEFINITIONS OF EATING DISORDERS HAVE CHANGED

Several problems existed in the category of eating disorders in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-4) and in the DSM-4 Text Revision (DSM-4-TR). These problems have been addressed in the fifth edition (DSM-5), released in 2013.⁵

One problem in the earlier editions was that many patients referred for treatment of eating disorders—more than 50% in one study⁶—did not meet the criteria for anorexia nervosa or bulimia nervosa and thus had to be categorized as having “eating disorder not otherwise specified.” Further, the earlier editions did not recognize that young children and adolescent males can be affected.⁷

Eating disorders are now recognized as an equal-opportunity disease, with all ethnic and socioeconomic groups affected. Children can run into medical trouble with even a small amount of weight loss or falling off the growth curve. Moreover, children and adolescents do not “experience” their bodies in the same way adults do; they may lack the vocabulary for eating-disorder thoughts.

For these reasons, the definitions of eating disorders have changed in the DSM-5.⁵

Anorexia nervosa. Older editions of the DSM listed amenorrhea as a criterion. This has been eliminated in DSM-5, since amenorrhea does not necessarily predict medical risk or treatment outcome; also, it is not applicable to males or premenorrheal girls and postmenopausal women.⁸ In addition, the requirement of low weight is now defined in the context of “age, sex, developmental trajectory, and physical health,” rather than the old threshold of 85% of expected weight.⁹

What remains unchanged is that anorexia nervosa is still characterized by self-starvation in order to maintain an abnormally low body weight, along with an intense fear of being fat and a disturbed self-image.

Bulimia nervosa. In both the old and the new editions of the DSM, bulimia nervosa is characterized by episodes of binge eating followed by inappropriate compensatory behaviors to avoid weight gain, such as vomiting, laxative abuse, diuretic abuse, and overexercise. In DSM-5, bulimia nervosa no longer has subtypes and requires only one binge per week with compensatory behavior, for at least 3 months. This change was based on the finding that there is no clear difference in psychopathology or treatment outcome between patients with one and two binge-purge episodes a week.¹⁰

“Eating disorder not otherwise specified” was a wastebasket category, lumping all those who did not meet the criteria for anorexia nervosa or bulimia nervosa or who did not neatly fit into a specific category.¹⁰ In DSM-5, subcategories were designed to help distinguish different treatment needs and outcomes between various subtypes.

Binge-eating disorder, one of the new subcategories, is characterized by binge eating without inappropriate compensatory behaviors.⁹ Patients with binge-eating disorder are often obese, have greater functional impairment, and are more likely to develop components of metabolic syndrome than obese patients without eating disorders.¹¹

Avoidant/restrictive food intake disorder is another new DSM-5 diagnosis, characterized by failure to meet nutritional needs for reasons other than weight control. Reasons include disinterest in eating, dislike of sensory characteristics of food, or avoidance of consequences of eating. This disorder replaces the category “feeding disorder of infancy or early childhood,” since the condition can also occur in adolescents and adults.¹²

Other new diagnoses are:

• Atypical anorexia nervosa (if the patient is not underweight)
• Purging disorder
• Subthreshold bulimia nervosa (if the patient has < 1 episode per week or has had them for < 3 months)
• Subthreshold binge eating disorder (< 1 time a week or < 3 months)
• Night eating syndrome
• Pica and rumination disorder.

Regardless of the diagnostic label, the medical evaluation and treatment of anyone with an eating disorder should be tailored to the specific behaviors of the eating disorder. Medical complications can be subdivided into those from starvation, from purging, and from refeeding.

MEDICAL COMPLICATIONS OF STARVATION

Cardiovascular effects of starvation

Malnutrition and starvation have multiple adverse effects on the heart.

Electrophysiologic effects. Sinus bradycardia (< 60 bpm) and hypotension are common cardiac manifestations of starvation.¹³ Bradycardia has been attributed to an adaptive increase in parasympathetic vagal tone.¹⁴ QTc prolongation is also seen in patients with malnutrition.¹⁵

Together, these electrocardiographic abnormalities predispose the patient to ventricular arrhythmia and sudden cardiac death.¹⁶ The risk of ventricular arrhythmia is particularly relevant when treating psychiatric symptoms, since antipsychotics and tricyclic antidepressants are among several drug classes that can cause further QTc prolongation (Table 1).^17,18

In patients with QTc prolongation, bradycardia, or both, the standard of care involves acute hospitalization for refeeding using continuous telemetric monitoring until normal rhythm is restored and the heart rate is above 40 at night and 50 by day.^4,19

Structural changes. Starvation also causes structural changes in the heart. Loss of lean body mass can reduce cardiac muscle mass, compromise cardiac output, and lead to mitral valve prolapse.²⁰ These changes are fully reversible with restored nutrition and regaining of heart mass.^21,22

Effects of starvation on the brain

Starvation can affect brain structure and cognitive function. Undernourished patients have reduced volumes of white and gray matter, a change that can occur within months. Cortical volumes may increase with weight gain, but a reduction in gray matter volume may not be completely reversible.²³

Furthermore, starvation impairs cognitive functions that are needed to stop eating-disorder behaviors; namely, decision-making, emotional control, regulation of appetite, and reward path-ways. Therefore, undernourished patients may not have sufficient insight into the disease to be able to make the best choices for recovery. This finding lends support for using the Maudsley method in adolescents, in which parents take control of their child’s eating until the child can maintain a healthy weight.²⁴

Gastrointestinal consequences of starvation

Patients with malnutrition have prolonged gastric emptying and colonic transit time with solid foods.²⁵ They often complain of early satiety, abdominal pain, bloating, and constipation, all symptoms that complicate the refeeding process. A prokinetic such as metoclopramide (Reglan), given 1 hour before meals and at bedtime, may provide some relief from gastrointestinal symptoms.²⁶

Patients may also experience transient lactose or fructose intolerance after prolonged starvation. Taking a lactase supplement (eg, Lactaid 1–10 tabs) before consuming dairy products and dextrose (contained in candies such as Smarties) before eating fruit or fructose-containing foods can sometimes partially relieve symptoms. In general, gastrointestinal function returns over time as nutritional status improves.

Patients with severe or prolonged starvation can develop steatosis accompanied by elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In reports of starvation-induced steatosis, liver enzyme levels rapidly normalize with nutritional rehabilitation.²⁷

Endocrine consequences of starvation

Amenorrhea. Dysregulation of the hypothalamic-pituitary-gonadal axis is a major endocrine complication of nutritional in-sufficiency. Weight loss disrupts the normal pulsatile secretion of gonadotropin-releasing hormone, reduces secretion of luteinizing hormone and follicle-stimulating hormone, and decreases estrogen levels.²⁸ Leptin deficiency likely plays a role in suppressing gonadotropin secretion with subsequent development of amenorrhea. With weight gain, levels of leptin and gonadotropins normalize and menstruation eventually returns.^29,30

Hypothyroidism. Starvation can also lead to dysregulation of the hypothalamic-pituitary-thyroid axis. Typically, the concentration of triiodothyronine (T3) is reduced, the ratio of thyroxine (T4) to T3 is elevated, and thyroid-stimulating hormone (TSH) is close to or within the normal range, creating a euthyroid sick syndrome. In eating disorders, this thyroid disturbance is a result of starvation and resolves with weight restoration. Therefore, thyroid hormone replacement therapy is not medically indicated.²⁸

Osteoporosis. Amenorrhea resulting from low estrogen levels in undernourished patients can raise the risk of osteoporosis and fractures, particularly in patients with a low body mass index. Osteopenia results from a negative balance between bone deposition and resorption.

Lack of bone deposition can be especially problematic when disordered eating occurs during peak bone mass development, ie, ages 11 to 14 for girls, and ages 15 to 17 for boys.^31,32 Even a 5% to 10% decrease in bone deposition can result in significant risk of osteopenia.³³ However, after age 30, bone resorption is a greater contributor.³⁴

Does hormone therapy correct bone loss? Given the association between estrogen deficiency and bone loss, estrogen supplementation was expected to be an effective treatment for bone loss in patients with eating disorders.³⁵ Also, the restoration of menses through hormone replacement may give underweight patients a false sense of achieving a “healthy” weight.³⁶

Golden et al³⁷ prospectively studied 50 adolescents and found no significant difference in bone mineral density at 1 year of follow-up between patients treated with estrogen and those who received only standard nutritional therapy. However, increased bone mineral density was achieved in adolescents with anorexia nervosa treated with transdermally administered estrogen dosed to mimic physiologic pubertal levels.³⁸

Klibanski et al³⁹ found that hormone therapy resulted in a 4% gain in bone density in an extremely low-weight subset of women with anorexia nervosa (< 70% of ideal body weight), whereas similar patients in the control group lost 20%. However, in all groups, only weight gain correlated with bone gain in women who were within 70% of their ideal body weight.

Divasta et al⁴⁰ evaluated 60 girls and women ages 13 to 27 with anorexia nervosa, randomized to receive either placebo or dehydroepiandrosterone combined with an estrogen-progestin oral contraceptive, and followed for 18 months. As in the study by Klibanski et al,³⁹ bone loss was prevented in the treatment group, but significant bone gain occurred only in the context of weight gain.

The bottom line is that only weight gain has resulted in significant increases in bone density in patients with anorexia nervosa, and hormone therapy without weight gain has not been shown to increase bone density effectively in this population. Although calcium and vitamin D in oral therapeutic doses through foods or through supplementation are required for bone gain, the combination is not enough to augment bone density in the absence of weight gain.³⁷ Although not curative, weight gain is currently the best option for treating bone loss, and no single pharmacologic treatment is effective.

COMPLICATIONS OF PURGING

Oral complications of purging

Patients who purge by vomiting are at risk of complications from exposure of the esophagus, pharynx, and mouth to acidic gastric contents.

Dental problems. Over time, contact with gastric acid wears down enamel on the lingual and occlusal surfaces of teeth, resulting in dental caries and periodontal disease. Until they can give up purging, patients should be instructed to rinse with mouthwash or water immediately after vomiting to reduce the acidity in the mouth.^41,42 We recommend that patients not brush their teeth after vomiting, because brushing can deliver acid to otherwise unreachable surfaces and thus worsen tooth erosion. For patients who are determined to brush after vomiting, a bicarbonate toothpaste might mitigate harm.⁴²

Sialadenosis (hypertrophy of the salivary glands) is another consequence of repeated vomiting, with elevated salivary amylase. Both the size of the glands and the salivary amylase level generally normalize on their own after vomiting is stopped, but parotitis can take up to a year to resolve. Similar to smoker’s cough, parotitis may acutely worsen when the patient abruptly stops vomiting and may worsen before it improves.

To reduce discomfort, patients can use hot compresses or sugarless hard candies.⁴⁴ However, the latter should not be substituted as a chronic habit in a patient with disordered eating. Patients need to be reassured that the swelling is not permanent, since they often interpret it as having fat cheeks (the “chipmunk sign”).

Hypokalemia, metabolic alkalosis, renal dysfunction

Chronic vomiting can cause electrolyte and acid-base imbalances, the most worrisome of which is hypokalemia. With repeated vomiting, loss of potassium and gastric acid causes metabolic alkalosis with hypokalemia, hypochloremia, and hypomagnesemia. Loss of water and the resultant volume contraction activates the renin-angiotensin-aldosterone system, and elevated aldosterone further decreases serum potassium.

In patients with eating disorders, who often have other factors contributing to electrolyte imbalance, vomiting-induced hypokalemia heightens the risk of cardiac arrhythmias.⁴³

Hypokalemia can also cause rhabdomyolysis and kidney damage.^41,43 Prolonged hypokalemia and reduced kidney perfusion in the setting of volume depletion causes acute kidney injury and impaired concentrating ability of the renal tubules. Hypovolemia can cause prerenal azotemia and increases the risk for nephrolithiasis and nephrocalcinosis.^44,45

When a patient stops vomiting, elevated aldosterone from prior hypovolemia results in water retention and can manifest in significant edema associated with hypochloremic alkalosis. This condition, known as pseudo-Bartter syndrome, usually resolves without treatment. In the meantime, salt restriction and leg elevation can help reduce edema.²⁶

Laxative abuse: A mode of purging

Many patients with eating disorders abuse laxatives to lose weight or to prevent weight gain. Believing that laxatives will prevent calorie absorption, patients commonly take them to compensate for caloric intake (eg, during a binge episode). The immediate weight loss, albeit artificial, is highly reinforcing for an eating-disorder patient. In some cases, patients with eating disorders also abuse laxatives to self-treat the constipation that results from chronic starvation.⁴⁶

Over time, tolerance to laxatives develops, and patients use increasingly larger doses. This can lead to activation of the renin-angiotensin-aldosterone system.⁴⁷ Patients interpret the resultant edema as true weight gain and again take laxatives to get rid of it. If laxatives are stopped abruptly, the patient may need inpatient and outpatient support for the resultant fluid shifts.

Gastrointestinal complications of laxative abuse include reflex hypofunction of the bowel, malabsorption, steatorrhea, and gastrointestinal bleeding.⁴⁷ Reflex hypofunction during laxative withdrawal is a consequence of the bowel becoming tolerant of laxatives.⁴⁸ Cathartic colon syndrome is a rare complication characterized by loss of the normal haustral markings and slowed or absent peristalsis in segments of the colon.⁴⁹

Systemically, the major risk of laxative abuse relates to electrolyte and acid-base imbalance. Loss of potassium and water in the stool can cause hypokalemia and metabolic alkalosis.⁴⁸ The disturbances caused by laxative abuse are similar to those caused by vomiting and diuretic use and have the same treatment.

The most important component of treating laxative abuse is giving patients realistic expectations to help them tolerate temporary discomfort and to help manage the edema and fluid shifts that can happen acutely with shifting of fluid into the intracellular space. In extreme cases, this may need to be managed in the hospital. To help relieve the initial anxiety, doctors should emphasize that any bloating the patient experiences is not true weight gain and will go away within a few days to weeks. In addition, explaining that laxatives reduce nutrient absorption only minimally may lessen the temptation to resume taking them.⁴⁸

Diuretic abuse: Another form of purging

Diuretic abuse is yet another mode of purging, with its own set of medical complications. Like laxatives, diuretics are not effective weight-loss agents, and the weight reduction they cause is only temporary.

As with vomiting, there is a compensatory activation of the renin-angiotensin-aldosterone system, and therefore subsequent fluid intake will lead to water retention, which encourages further diuretic use.⁴¹ Diuretics can also contribute to hypokalemia, hypomagnesemia, hypochloremia, and metabolic alkalosis.

Ipecac abuse can lead to heart failure

Ipecac syrup has long been used to induce vomiting, but this practice has become much less common since ipecac has become harder to obtain in the United States.⁵⁰ The emetine base contained in ipecac binds irreversibly to cardiac and skeletal muscle. With continued use, irreversible cardiomyopathy develops and can lead to heart failure. Treatment should include supportive care and immediate cessation of ipecac use.

Diabetic patients may skip insulin to lose weight

Patients with diabetes, especially those with type 1 that begins in childhood, are at greater risk of eating disorders over time.⁵¹ They may withhold insulin to lose weight, a practice referred to in the nonmedical literature as “diabulimia,” and they seem particularly more likely to develop bulimia nervosa than those without diabetes.⁵²

The medical prognosis is poor for patients with diabetes who develop eating disorders and do not receive intensive treatment.⁵¹ In addition, if a diabetic patient on an insulin pump becomes depressed in addition to having an eating disorder, careful monitoring for suicidal thoughts and a rapid follow-up with mental health services are in order.

REFEEDING SYNDROME

When refeeding is started, a high glucose load stimulates insulin secretion, resulting in cellular uptake of phosphorus along with potassium, magnesium, and glucose. In addition, total body phosphorus is depleted by the increased demand for adenosine triphosphate and 2,3-diphosphoglycerate for cellular metabolism.

When liver enzyme levels increase, the astute clinician will closely monitor the patient for evidence of refeeding syndrome. In a child, adolescent, or young adult, the standard of care is inpatient monitoring for acute stabilization.^4,19

Hypophosphatemia is the hallmark of refeeding syndrome, although hypomagnesemia, hypokalemia, and hypoglycemia can also occur.⁵³ In addition, sodium and water retention can lead to fluid overload, with shifting of fluid into the intracellular space, resulting in dependent edema.

Cardiovascular complications are the most worrisome manifestations of refeeding syndrome. Electrolyte shifts and increased fluid volume can cause arrhythmias and heart failure. Furthermore, severely undernourished patients may have reduced myocardial mass as well as electrocardiographic abnormalities associated with starvation, which further increase their vulnerability to electrolyte shifts and fluid retention during refeeding.¹⁵

Other manifestations of refeeding syndrome include delirium, seizures, rhabdomyolysis, and respiratory failure. In the most extreme cases, refeeding syndrome causes sudden death.⁵³

Fortunately, refeeding syndrome is easily preventable and treatable when recognized early. Electrolytes and cardiovascular and renal function must be carefully monitored, especially during the first week of nutritional restoration.⁵³ In patients with extremely low body mass (< 70% of ideal body weight) or with precipitous weight loss, close monitoring of the complete metabolic panel including electrolytes, AST, ALT, calcium, magnesium, and phosphorus may be required to detect changes that can affect cardiac status. Specific suggestions for refeeding are discussed below and in Table 2.⁴⁵

ACUTE CARE OF PATIENTS WITH EATING DISORDERS

Refeeding in the inpatient setting

The decision to hospitalize an eating-disorder patient is based on the current or potential risk of serious medical complications and the likelihood of success at home. Medical criteria for hospital admission are outlined in Table 3.^4,54

In refeeding undernourished patients, the challenge is to maximize weight gain while preventing refeeding syndrome. Undernourished patients are generally hypometabolic at baseline but become hypermetabolic once refeeding begins.

How many calories should refeeding start with? The traditional principle of “start low and go slow” has been recently challenged.⁵⁵ Starting at 1,200 kcal/day or less in the typical patient can result in failure to gain weight or even in weight loss in the first week of refeeding.⁵⁶ The goal is to achieve a weight gain of 0.2 kg/day while the patient is in the hospital. Thus, we start higher, and to date we have seen no cases of life-threatening refeeding syndrome. In all patients who need hospitalization or who are beginning the refeeding process as outpatients, caloric intake should be started at 1,500 to 2,000 kcal/day.^45,57 However, for exceptionally low-weight patients, intake may be started lower.

In Australia, patients are started at 1,900 kcal/day.⁵⁶ All patients in one program there receive nasogastric feeding initially in an intensive care unit and then are moved to a regular nursing floor where they graduate to full oral feeding as they improve cardiovascularly and behaviorally. In the United States, some programs use nasogastric feeding at night for caloric restoration; our program and others use nasogastric feeding as a behavioral modification strategy for patients who refuse food or supplements by mouth.

Phosphorus supplementation. Many centers give phosphorus supplements preventively. In our center, we give potassium phosphate (Neutra-Phos) 500 mg orally twice daily for 5 days, and we have seen no life-threatening cases of refeeding syndrome with that regimen. Other centers give phosphorus supplements in a dose of 250 mg orally twice a day for 5 days, while still others only supplement phosphorus reactively once a deficit has been identified. The latter method requires daily blood draws for monitoring and is reactive rather than proactive. Further studies can help clarify the optimal dosing and timing of phosphorus supplementation.

Managing fluid balance. Fluid-loading these patients may tip them over the edge into refeeding syndrome. Except in cases of shock, patients with eating disorders should not be given intravenous fluids, as it is safer to rehydrate and feed them orally. Electrolyte imbalances can be corrected orally with no need for intravenous supplementation. To avoid fluid overload, fluids can be started at 1,500 mL to 2,000 mL per day, with strict monitoring of intake and output. Fluids are liberalized if ALT and AST levels remain normal and to gradually correct orthostatic hypotension; caloric fluids are ideal to help address energy needs and improve bradycardia.

Laboratory monitoring. On admission, a urinalysis, complete blood cell count, complete metabolic panel, TSH, erythrocyte sedimentation rate, serum magnesium, and phosphorus should be obtained.²⁶ In addition, continuous electrocardiographic recording should begin on admission.⁴⁵ Inpatient use of a telemetry bed helps identify extreme tachycardia with arrhythmia, as well as profound bradycardia.^45,56

Some protocols call for daily laboratory monitoring, although that degree of testing is less cost-effective. If initial results are normal, clinical judgment can be used on when to repeat laboratory evaluation. For instance, patients with edema require repeat complete metabolic panels to assess for elevated ALT and AST, electrolyte imbalances, and other abnormalities.

Signs of refeeding syndrome include tachycardia, hepatosplenomegaly, peripheral edema, altered mental status, and electrolyte disturbances, specifically, acute or severe hypophosphatemia or hypokalemia.^26,45 If refeeding syndrome is suspected, the rate of caloric intake should be reduced or not advanced, fluid intake should be urgently reassessed for volume overload, and supportive care with close monitoring should be provided.

KNOWLEDGE SAVES LIVES

Eating disorders can lead to potentially life-threatening medical complications that require attentive care by the primary care clinician and subspecialist. Without thoughtful consideration, it is easy for even a caring medical team to unintentionally enable patients with these illnesses or to cause active harm in the case of underrecognized pathology.⁵⁸

Acute medical stabilization on an inpatient unit trained to recognize pathology and treat sequelae can be lifesaving. Arming patients and families with medical knowledge, as provided in the Academy for Eating Disorders’ brochure, “Critical Points for Early Recognition and Medical Risk Management in the Care of Individuals with Eating Disorders”⁵⁹ can help save patients’ lives.

Eating disorders are debilitating biopsychosocial illnesses associated with serious medical illness and a high risk of death.¹

Primary care physicians are often the first to see young women who have these problems, diagnose them, and start their evaluation and treatment.^2–4 Many patients require acute medical interventions as well as long-term care for chronic medical issues. Therefore, primary care physicians play essential front-line and long-term roles in the multidisciplinary treatment team.

DEFINITIONS OF EATING DISORDERS HAVE CHANGED

Several problems existed in the category of eating disorders in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-4) and in the DSM-4 Text Revision (DSM-4-TR). These problems have been addressed in the fifth edition (DSM-5), released in 2013.⁵

One problem in the earlier editions was that many patients referred for treatment of eating disorders—more than 50% in one study⁶—did not meet the criteria for anorexia nervosa or bulimia nervosa and thus had to be categorized as having “eating disorder not otherwise specified.” Further, the earlier editions did not recognize that young children and adolescent males can be affected.⁷

Eating disorders are now recognized as an equal-opportunity disease, with all ethnic and socioeconomic groups affected. Children can run into medical trouble with even a small amount of weight loss or falling off the growth curve. Moreover, children and adolescents do not “experience” their bodies in the same way adults do; they may lack the vocabulary for eating-disorder thoughts.

For these reasons, the definitions of eating disorders have changed in the DSM-5.⁵

Anorexia nervosa. Older editions of the DSM listed amenorrhea as a criterion. This has been eliminated in DSM-5, since amenorrhea does not necessarily predict medical risk or treatment outcome; also, it is not applicable to males or premenorrheal girls and postmenopausal women.⁸ In addition, the requirement of low weight is now defined in the context of “age, sex, developmental trajectory, and physical health,” rather than the old threshold of 85% of expected weight.⁹

What remains unchanged is that anorexia nervosa is still characterized by self-starvation in order to maintain an abnormally low body weight, along with an intense fear of being fat and a disturbed self-image.

Bulimia nervosa. In both the old and the new editions of the DSM, bulimia nervosa is characterized by episodes of binge eating followed by inappropriate compensatory behaviors to avoid weight gain, such as vomiting, laxative abuse, diuretic abuse, and overexercise. In DSM-5, bulimia nervosa no longer has subtypes and requires only one binge per week with compensatory behavior, for at least 3 months. This change was based on the finding that there is no clear difference in psychopathology or treatment outcome between patients with one and two binge-purge episodes a week.¹⁰

“Eating disorder not otherwise specified” was a wastebasket category, lumping all those who did not meet the criteria for anorexia nervosa or bulimia nervosa or who did not neatly fit into a specific category.¹⁰ In DSM-5, subcategories were designed to help distinguish different treatment needs and outcomes between various subtypes.

Binge-eating disorder, one of the new subcategories, is characterized by binge eating without inappropriate compensatory behaviors.⁹ Patients with binge-eating disorder are often obese, have greater functional impairment, and are more likely to develop components of metabolic syndrome than obese patients without eating disorders.¹¹

Avoidant/restrictive food intake disorder is another new DSM-5 diagnosis, characterized by failure to meet nutritional needs for reasons other than weight control. Reasons include disinterest in eating, dislike of sensory characteristics of food, or avoidance of consequences of eating. This disorder replaces the category “feeding disorder of infancy or early childhood,” since the condition can also occur in adolescents and adults.¹²

Other new diagnoses are:

• Atypical anorexia nervosa (if the patient is not underweight)
• Purging disorder
• Subthreshold bulimia nervosa (if the patient has < 1 episode per week or has had them for < 3 months)
• Subthreshold binge eating disorder (< 1 time a week or < 3 months)
• Night eating syndrome
• Pica and rumination disorder.

Regardless of the diagnostic label, the medical evaluation and treatment of anyone with an eating disorder should be tailored to the specific behaviors of the eating disorder. Medical complications can be subdivided into those from starvation, from purging, and from refeeding.

MEDICAL COMPLICATIONS OF STARVATION

Cardiovascular effects of starvation

Malnutrition and starvation have multiple adverse effects on the heart.

Electrophysiologic effects. Sinus bradycardia (< 60 bpm) and hypotension are common cardiac manifestations of starvation.¹³ Bradycardia has been attributed to an adaptive increase in parasympathetic vagal tone.¹⁴ QTc prolongation is also seen in patients with malnutrition.¹⁵

Together, these electrocardiographic abnormalities predispose the patient to ventricular arrhythmia and sudden cardiac death.¹⁶ The risk of ventricular arrhythmia is particularly relevant when treating psychiatric symptoms, since antipsychotics and tricyclic antidepressants are among several drug classes that can cause further QTc prolongation (Table 1).^17,18

In patients with QTc prolongation, bradycardia, or both, the standard of care involves acute hospitalization for refeeding using continuous telemetric monitoring until normal rhythm is restored and the heart rate is above 40 at night and 50 by day.^4,19

Structural changes. Starvation also causes structural changes in the heart. Loss of lean body mass can reduce cardiac muscle mass, compromise cardiac output, and lead to mitral valve prolapse.²⁰ These changes are fully reversible with restored nutrition and regaining of heart mass.^21,22

Effects of starvation on the brain

Starvation can affect brain structure and cognitive function. Undernourished patients have reduced volumes of white and gray matter, a change that can occur within months. Cortical volumes may increase with weight gain, but a reduction in gray matter volume may not be completely reversible.²³

Furthermore, starvation impairs cognitive functions that are needed to stop eating-disorder behaviors; namely, decision-making, emotional control, regulation of appetite, and reward path-ways. Therefore, undernourished patients may not have sufficient insight into the disease to be able to make the best choices for recovery. This finding lends support for using the Maudsley method in adolescents, in which parents take control of their child’s eating until the child can maintain a healthy weight.²⁴

Gastrointestinal consequences of starvation

Patients with malnutrition have prolonged gastric emptying and colonic transit time with solid foods.²⁵ They often complain of early satiety, abdominal pain, bloating, and constipation, all symptoms that complicate the refeeding process. A prokinetic such as metoclopramide (Reglan), given 1 hour before meals and at bedtime, may provide some relief from gastrointestinal symptoms.²⁶

Patients may also experience transient lactose or fructose intolerance after prolonged starvation. Taking a lactase supplement (eg, Lactaid 1–10 tabs) before consuming dairy products and dextrose (contained in candies such as Smarties) before eating fruit or fructose-containing foods can sometimes partially relieve symptoms. In general, gastrointestinal function returns over time as nutritional status improves.

Patients with severe or prolonged starvation can develop steatosis accompanied by elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In reports of starvation-induced steatosis, liver enzyme levels rapidly normalize with nutritional rehabilitation.²⁷

Endocrine consequences of starvation

Amenorrhea. Dysregulation of the hypothalamic-pituitary-gonadal axis is a major endocrine complication of nutritional in-sufficiency. Weight loss disrupts the normal pulsatile secretion of gonadotropin-releasing hormone, reduces secretion of luteinizing hormone and follicle-stimulating hormone, and decreases estrogen levels.²⁸ Leptin deficiency likely plays a role in suppressing gonadotropin secretion with subsequent development of amenorrhea. With weight gain, levels of leptin and gonadotropins normalize and menstruation eventually returns.^29,30

Hypothyroidism. Starvation can also lead to dysregulation of the hypothalamic-pituitary-thyroid axis. Typically, the concentration of triiodothyronine (T3) is reduced, the ratio of thyroxine (T4) to T3 is elevated, and thyroid-stimulating hormone (TSH) is close to or within the normal range, creating a euthyroid sick syndrome. In eating disorders, this thyroid disturbance is a result of starvation and resolves with weight restoration. Therefore, thyroid hormone replacement therapy is not medically indicated.²⁸

Osteoporosis. Amenorrhea resulting from low estrogen levels in undernourished patients can raise the risk of osteoporosis and fractures, particularly in patients with a low body mass index. Osteopenia results from a negative balance between bone deposition and resorption.

Lack of bone deposition can be especially problematic when disordered eating occurs during peak bone mass development, ie, ages 11 to 14 for girls, and ages 15 to 17 for boys.^31,32 Even a 5% to 10% decrease in bone deposition can result in significant risk of osteopenia.³³ However, after age 30, bone resorption is a greater contributor.³⁴

Does hormone therapy correct bone loss? Given the association between estrogen deficiency and bone loss, estrogen supplementation was expected to be an effective treatment for bone loss in patients with eating disorders.³⁵ Also, the restoration of menses through hormone replacement may give underweight patients a false sense of achieving a “healthy” weight.³⁶

Golden et al³⁷ prospectively studied 50 adolescents and found no significant difference in bone mineral density at 1 year of follow-up between patients treated with estrogen and those who received only standard nutritional therapy. However, increased bone mineral density was achieved in adolescents with anorexia nervosa treated with transdermally administered estrogen dosed to mimic physiologic pubertal levels.³⁸

Klibanski et al³⁹ found that hormone therapy resulted in a 4% gain in bone density in an extremely low-weight subset of women with anorexia nervosa (< 70% of ideal body weight), whereas similar patients in the control group lost 20%. However, in all groups, only weight gain correlated with bone gain in women who were within 70% of their ideal body weight.

Divasta et al⁴⁰ evaluated 60 girls and women ages 13 to 27 with anorexia nervosa, randomized to receive either placebo or dehydroepiandrosterone combined with an estrogen-progestin oral contraceptive, and followed for 18 months. As in the study by Klibanski et al,³⁹ bone loss was prevented in the treatment group, but significant bone gain occurred only in the context of weight gain.

The bottom line is that only weight gain has resulted in significant increases in bone density in patients with anorexia nervosa, and hormone therapy without weight gain has not been shown to increase bone density effectively in this population. Although calcium and vitamin D in oral therapeutic doses through foods or through supplementation are required for bone gain, the combination is not enough to augment bone density in the absence of weight gain.³⁷ Although not curative, weight gain is currently the best option for treating bone loss, and no single pharmacologic treatment is effective.

COMPLICATIONS OF PURGING

Oral complications of purging

Patients who purge by vomiting are at risk of complications from exposure of the esophagus, pharynx, and mouth to acidic gastric contents.

Dental problems. Over time, contact with gastric acid wears down enamel on the lingual and occlusal surfaces of teeth, resulting in dental caries and periodontal disease. Until they can give up purging, patients should be instructed to rinse with mouthwash or water immediately after vomiting to reduce the acidity in the mouth.^41,42 We recommend that patients not brush their teeth after vomiting, because brushing can deliver acid to otherwise unreachable surfaces and thus worsen tooth erosion. For patients who are determined to brush after vomiting, a bicarbonate toothpaste might mitigate harm.⁴²

Sialadenosis (hypertrophy of the salivary glands) is another consequence of repeated vomiting, with elevated salivary amylase. Both the size of the glands and the salivary amylase level generally normalize on their own after vomiting is stopped, but parotitis can take up to a year to resolve. Similar to smoker’s cough, parotitis may acutely worsen when the patient abruptly stops vomiting and may worsen before it improves.

To reduce discomfort, patients can use hot compresses or sugarless hard candies.⁴⁴ However, the latter should not be substituted as a chronic habit in a patient with disordered eating. Patients need to be reassured that the swelling is not permanent, since they often interpret it as having fat cheeks (the “chipmunk sign”).

Hypokalemia, metabolic alkalosis, renal dysfunction

Chronic vomiting can cause electrolyte and acid-base imbalances, the most worrisome of which is hypokalemia. With repeated vomiting, loss of potassium and gastric acid causes metabolic alkalosis with hypokalemia, hypochloremia, and hypomagnesemia. Loss of water and the resultant volume contraction activates the renin-angiotensin-aldosterone system, and elevated aldosterone further decreases serum potassium.

In patients with eating disorders, who often have other factors contributing to electrolyte imbalance, vomiting-induced hypokalemia heightens the risk of cardiac arrhythmias.⁴³

Hypokalemia can also cause rhabdomyolysis and kidney damage.^41,43 Prolonged hypokalemia and reduced kidney perfusion in the setting of volume depletion causes acute kidney injury and impaired concentrating ability of the renal tubules. Hypovolemia can cause prerenal azotemia and increases the risk for nephrolithiasis and nephrocalcinosis.^44,45

When a patient stops vomiting, elevated aldosterone from prior hypovolemia results in water retention and can manifest in significant edema associated with hypochloremic alkalosis. This condition, known as pseudo-Bartter syndrome, usually resolves without treatment. In the meantime, salt restriction and leg elevation can help reduce edema.²⁶

Laxative abuse: A mode of purging

Many patients with eating disorders abuse laxatives to lose weight or to prevent weight gain. Believing that laxatives will prevent calorie absorption, patients commonly take them to compensate for caloric intake (eg, during a binge episode). The immediate weight loss, albeit artificial, is highly reinforcing for an eating-disorder patient. In some cases, patients with eating disorders also abuse laxatives to self-treat the constipation that results from chronic starvation.⁴⁶

Over time, tolerance to laxatives develops, and patients use increasingly larger doses. This can lead to activation of the renin-angiotensin-aldosterone system.⁴⁷ Patients interpret the resultant edema as true weight gain and again take laxatives to get rid of it. If laxatives are stopped abruptly, the patient may need inpatient and outpatient support for the resultant fluid shifts.

Gastrointestinal complications of laxative abuse include reflex hypofunction of the bowel, malabsorption, steatorrhea, and gastrointestinal bleeding.⁴⁷ Reflex hypofunction during laxative withdrawal is a consequence of the bowel becoming tolerant of laxatives.⁴⁸ Cathartic colon syndrome is a rare complication characterized by loss of the normal haustral markings and slowed or absent peristalsis in segments of the colon.⁴⁹

Systemically, the major risk of laxative abuse relates to electrolyte and acid-base imbalance. Loss of potassium and water in the stool can cause hypokalemia and metabolic alkalosis.⁴⁸ The disturbances caused by laxative abuse are similar to those caused by vomiting and diuretic use and have the same treatment.

The most important component of treating laxative abuse is giving patients realistic expectations to help them tolerate temporary discomfort and to help manage the edema and fluid shifts that can happen acutely with shifting of fluid into the intracellular space. In extreme cases, this may need to be managed in the hospital. To help relieve the initial anxiety, doctors should emphasize that any bloating the patient experiences is not true weight gain and will go away within a few days to weeks. In addition, explaining that laxatives reduce nutrient absorption only minimally may lessen the temptation to resume taking them.⁴⁸

Diuretic abuse: Another form of purging

Diuretic abuse is yet another mode of purging, with its own set of medical complications. Like laxatives, diuretics are not effective weight-loss agents, and the weight reduction they cause is only temporary.

As with vomiting, there is a compensatory activation of the renin-angiotensin-aldosterone system, and therefore subsequent fluid intake will lead to water retention, which encourages further diuretic use.⁴¹ Diuretics can also contribute to hypokalemia, hypomagnesemia, hypochloremia, and metabolic alkalosis.

Ipecac abuse can lead to heart failure

Ipecac syrup has long been used to induce vomiting, but this practice has become much less common since ipecac has become harder to obtain in the United States.⁵⁰ The emetine base contained in ipecac binds irreversibly to cardiac and skeletal muscle. With continued use, irreversible cardiomyopathy develops and can lead to heart failure. Treatment should include supportive care and immediate cessation of ipecac use.

Diabetic patients may skip insulin to lose weight

Patients with diabetes, especially those with type 1 that begins in childhood, are at greater risk of eating disorders over time.⁵¹ They may withhold insulin to lose weight, a practice referred to in the nonmedical literature as “diabulimia,” and they seem particularly more likely to develop bulimia nervosa than those without diabetes.⁵²

The medical prognosis is poor for patients with diabetes who develop eating disorders and do not receive intensive treatment.⁵¹ In addition, if a diabetic patient on an insulin pump becomes depressed in addition to having an eating disorder, careful monitoring for suicidal thoughts and a rapid follow-up with mental health services are in order.

REFEEDING SYNDROME

When refeeding is started, a high glucose load stimulates insulin secretion, resulting in cellular uptake of phosphorus along with potassium, magnesium, and glucose. In addition, total body phosphorus is depleted by the increased demand for adenosine triphosphate and 2,3-diphosphoglycerate for cellular metabolism.

When liver enzyme levels increase, the astute clinician will closely monitor the patient for evidence of refeeding syndrome. In a child, adolescent, or young adult, the standard of care is inpatient monitoring for acute stabilization.^4,19

Hypophosphatemia is the hallmark of refeeding syndrome, although hypomagnesemia, hypokalemia, and hypoglycemia can also occur.⁵³ In addition, sodium and water retention can lead to fluid overload, with shifting of fluid into the intracellular space, resulting in dependent edema.

Cardiovascular complications are the most worrisome manifestations of refeeding syndrome. Electrolyte shifts and increased fluid volume can cause arrhythmias and heart failure. Furthermore, severely undernourished patients may have reduced myocardial mass as well as electrocardiographic abnormalities associated with starvation, which further increase their vulnerability to electrolyte shifts and fluid retention during refeeding.¹⁵

Other manifestations of refeeding syndrome include delirium, seizures, rhabdomyolysis, and respiratory failure. In the most extreme cases, refeeding syndrome causes sudden death.⁵³

Fortunately, refeeding syndrome is easily preventable and treatable when recognized early. Electrolytes and cardiovascular and renal function must be carefully monitored, especially during the first week of nutritional restoration.⁵³ In patients with extremely low body mass (< 70% of ideal body weight) or with precipitous weight loss, close monitoring of the complete metabolic panel including electrolytes, AST, ALT, calcium, magnesium, and phosphorus may be required to detect changes that can affect cardiac status. Specific suggestions for refeeding are discussed below and in Table 2.⁴⁵

ACUTE CARE OF PATIENTS WITH EATING DISORDERS

Refeeding in the inpatient setting

The decision to hospitalize an eating-disorder patient is based on the current or potential risk of serious medical complications and the likelihood of success at home. Medical criteria for hospital admission are outlined in Table 3.^4,54

In refeeding undernourished patients, the challenge is to maximize weight gain while preventing refeeding syndrome. Undernourished patients are generally hypometabolic at baseline but become hypermetabolic once refeeding begins.

How many calories should refeeding start with? The traditional principle of “start low and go slow” has been recently challenged.⁵⁵ Starting at 1,200 kcal/day or less in the typical patient can result in failure to gain weight or even in weight loss in the first week of refeeding.⁵⁶ The goal is to achieve a weight gain of 0.2 kg/day while the patient is in the hospital. Thus, we start higher, and to date we have seen no cases of life-threatening refeeding syndrome. In all patients who need hospitalization or who are beginning the refeeding process as outpatients, caloric intake should be started at 1,500 to 2,000 kcal/day.^45,57 However, for exceptionally low-weight patients, intake may be started lower.

In Australia, patients are started at 1,900 kcal/day.⁵⁶ All patients in one program there receive nasogastric feeding initially in an intensive care unit and then are moved to a regular nursing floor where they graduate to full oral feeding as they improve cardiovascularly and behaviorally. In the United States, some programs use nasogastric feeding at night for caloric restoration; our program and others use nasogastric feeding as a behavioral modification strategy for patients who refuse food or supplements by mouth.

Phosphorus supplementation. Many centers give phosphorus supplements preventively. In our center, we give potassium phosphate (Neutra-Phos) 500 mg orally twice daily for 5 days, and we have seen no life-threatening cases of refeeding syndrome with that regimen. Other centers give phosphorus supplements in a dose of 250 mg orally twice a day for 5 days, while still others only supplement phosphorus reactively once a deficit has been identified. The latter method requires daily blood draws for monitoring and is reactive rather than proactive. Further studies can help clarify the optimal dosing and timing of phosphorus supplementation.

Managing fluid balance. Fluid-loading these patients may tip them over the edge into refeeding syndrome. Except in cases of shock, patients with eating disorders should not be given intravenous fluids, as it is safer to rehydrate and feed them orally. Electrolyte imbalances can be corrected orally with no need for intravenous supplementation. To avoid fluid overload, fluids can be started at 1,500 mL to 2,000 mL per day, with strict monitoring of intake and output. Fluids are liberalized if ALT and AST levels remain normal and to gradually correct orthostatic hypotension; caloric fluids are ideal to help address energy needs and improve bradycardia.

Laboratory monitoring. On admission, a urinalysis, complete blood cell count, complete metabolic panel, TSH, erythrocyte sedimentation rate, serum magnesium, and phosphorus should be obtained.²⁶ In addition, continuous electrocardiographic recording should begin on admission.⁴⁵ Inpatient use of a telemetry bed helps identify extreme tachycardia with arrhythmia, as well as profound bradycardia.^45,56

Some protocols call for daily laboratory monitoring, although that degree of testing is less cost-effective. If initial results are normal, clinical judgment can be used on when to repeat laboratory evaluation. For instance, patients with edema require repeat complete metabolic panels to assess for elevated ALT and AST, electrolyte imbalances, and other abnormalities.

Signs of refeeding syndrome include tachycardia, hepatosplenomegaly, peripheral edema, altered mental status, and electrolyte disturbances, specifically, acute or severe hypophosphatemia or hypokalemia.^26,45 If refeeding syndrome is suspected, the rate of caloric intake should be reduced or not advanced, fluid intake should be urgently reassessed for volume overload, and supportive care with close monitoring should be provided.

KNOWLEDGE SAVES LIVES

Eating disorders can lead to potentially life-threatening medical complications that require attentive care by the primary care clinician and subspecialist. Without thoughtful consideration, it is easy for even a caring medical team to unintentionally enable patients with these illnesses or to cause active harm in the case of underrecognized pathology.⁵⁸

Acute medical stabilization on an inpatient unit trained to recognize pathology and treat sequelae can be lifesaving. Arming patients and families with medical knowledge, as provided in the Academy for Eating Disorders’ brochure, “Critical Points for Early Recognition and Medical Risk Management in the Care of Individuals with Eating Disorders”⁵⁹ can help save patients’ lives.

Eating disorders are debilitating biopsychosocial illnesses associated with serious medical illness and a high risk of death.¹

Primary care physicians are often the first to see young women who have these problems, diagnose them, and start their evaluation and treatment.^2–4 Many patients require acute medical interventions as well as long-term care for chronic medical issues. Therefore, primary care physicians play essential front-line and long-term roles in the multidisciplinary treatment team.

DEFINITIONS OF EATING DISORDERS HAVE CHANGED

Several problems existed in the category of eating disorders in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-4) and in the DSM-4 Text Revision (DSM-4-TR). These problems have been addressed in the fifth edition (DSM-5), released in 2013.⁵

One problem in the earlier editions was that many patients referred for treatment of eating disorders—more than 50% in one study⁶—did not meet the criteria for anorexia nervosa or bulimia nervosa and thus had to be categorized as having “eating disorder not otherwise specified.” Further, the earlier editions did not recognize that young children and adolescent males can be affected.⁷

Eating disorders are now recognized as an equal-opportunity disease, with all ethnic and socioeconomic groups affected. Children can run into medical trouble with even a small amount of weight loss or falling off the growth curve. Moreover, children and adolescents do not “experience” their bodies in the same way adults do; they may lack the vocabulary for eating-disorder thoughts.

For these reasons, the definitions of eating disorders have changed in the DSM-5.⁵

Anorexia nervosa. Older editions of the DSM listed amenorrhea as a criterion. This has been eliminated in DSM-5, since amenorrhea does not necessarily predict medical risk or treatment outcome; also, it is not applicable to males or premenorrheal girls and postmenopausal women.⁸ In addition, the requirement of low weight is now defined in the context of “age, sex, developmental trajectory, and physical health,” rather than the old threshold of 85% of expected weight.⁹

What remains unchanged is that anorexia nervosa is still characterized by self-starvation in order to maintain an abnormally low body weight, along with an intense fear of being fat and a disturbed self-image.

Bulimia nervosa. In both the old and the new editions of the DSM, bulimia nervosa is characterized by episodes of binge eating followed by inappropriate compensatory behaviors to avoid weight gain, such as vomiting, laxative abuse, diuretic abuse, and overexercise. In DSM-5, bulimia nervosa no longer has subtypes and requires only one binge per week with compensatory behavior, for at least 3 months. This change was based on the finding that there is no clear difference in psychopathology or treatment outcome between patients with one and two binge-purge episodes a week.¹⁰

“Eating disorder not otherwise specified” was a wastebasket category, lumping all those who did not meet the criteria for anorexia nervosa or bulimia nervosa or who did not neatly fit into a specific category.¹⁰ In DSM-5, subcategories were designed to help distinguish different treatment needs and outcomes between various subtypes.

Binge-eating disorder, one of the new subcategories, is characterized by binge eating without inappropriate compensatory behaviors.⁹ Patients with binge-eating disorder are often obese, have greater functional impairment, and are more likely to develop components of metabolic syndrome than obese patients without eating disorders.¹¹

Avoidant/restrictive food intake disorder is another new DSM-5 diagnosis, characterized by failure to meet nutritional needs for reasons other than weight control. Reasons include disinterest in eating, dislike of sensory characteristics of food, or avoidance of consequences of eating. This disorder replaces the category “feeding disorder of infancy or early childhood,” since the condition can also occur in adolescents and adults.¹²

Other new diagnoses are:

• Atypical anorexia nervosa (if the patient is not underweight)
• Purging disorder
• Subthreshold bulimia nervosa (if the patient has < 1 episode per week or has had them for < 3 months)
• Subthreshold binge eating disorder (< 1 time a week or < 3 months)
• Night eating syndrome
• Pica and rumination disorder.

Regardless of the diagnostic label, the medical evaluation and treatment of anyone with an eating disorder should be tailored to the specific behaviors of the eating disorder. Medical complications can be subdivided into those from starvation, from purging, and from refeeding.

MEDICAL COMPLICATIONS OF STARVATION

Cardiovascular effects of starvation

Malnutrition and starvation have multiple adverse effects on the heart.

Electrophysiologic effects. Sinus bradycardia (< 60 bpm) and hypotension are common cardiac manifestations of starvation.¹³ Bradycardia has been attributed to an adaptive increase in parasympathetic vagal tone.¹⁴ QTc prolongation is also seen in patients with malnutrition.¹⁵

Together, these electrocardiographic abnormalities predispose the patient to ventricular arrhythmia and sudden cardiac death.¹⁶ The risk of ventricular arrhythmia is particularly relevant when treating psychiatric symptoms, since antipsychotics and tricyclic antidepressants are among several drug classes that can cause further QTc prolongation (Table 1).^17,18

In patients with QTc prolongation, bradycardia, or both, the standard of care involves acute hospitalization for refeeding using continuous telemetric monitoring until normal rhythm is restored and the heart rate is above 40 at night and 50 by day.^4,19

Structural changes. Starvation also causes structural changes in the heart. Loss of lean body mass can reduce cardiac muscle mass, compromise cardiac output, and lead to mitral valve prolapse.²⁰ These changes are fully reversible with restored nutrition and regaining of heart mass.^21,22

Effects of starvation on the brain

Starvation can affect brain structure and cognitive function. Undernourished patients have reduced volumes of white and gray matter, a change that can occur within months. Cortical volumes may increase with weight gain, but a reduction in gray matter volume may not be completely reversible.²³

Furthermore, starvation impairs cognitive functions that are needed to stop eating-disorder behaviors; namely, decision-making, emotional control, regulation of appetite, and reward path-ways. Therefore, undernourished patients may not have sufficient insight into the disease to be able to make the best choices for recovery. This finding lends support for using the Maudsley method in adolescents, in which parents take control of their child’s eating until the child can maintain a healthy weight.²⁴

Gastrointestinal consequences of starvation

Patients with malnutrition have prolonged gastric emptying and colonic transit time with solid foods.²⁵ They often complain of early satiety, abdominal pain, bloating, and constipation, all symptoms that complicate the refeeding process. A prokinetic such as metoclopramide (Reglan), given 1 hour before meals and at bedtime, may provide some relief from gastrointestinal symptoms.²⁶

Patients may also experience transient lactose or fructose intolerance after prolonged starvation. Taking a lactase supplement (eg, Lactaid 1–10 tabs) before consuming dairy products and dextrose (contained in candies such as Smarties) before eating fruit or fructose-containing foods can sometimes partially relieve symptoms. In general, gastrointestinal function returns over time as nutritional status improves.

Patients with severe or prolonged starvation can develop steatosis accompanied by elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In reports of starvation-induced steatosis, liver enzyme levels rapidly normalize with nutritional rehabilitation.²⁷

Endocrine consequences of starvation

Amenorrhea. Dysregulation of the hypothalamic-pituitary-gonadal axis is a major endocrine complication of nutritional in-sufficiency. Weight loss disrupts the normal pulsatile secretion of gonadotropin-releasing hormone, reduces secretion of luteinizing hormone and follicle-stimulating hormone, and decreases estrogen levels.²⁸ Leptin deficiency likely plays a role in suppressing gonadotropin secretion with subsequent development of amenorrhea. With weight gain, levels of leptin and gonadotropins normalize and menstruation eventually returns.^29,30

Hypothyroidism. Starvation can also lead to dysregulation of the hypothalamic-pituitary-thyroid axis. Typically, the concentration of triiodothyronine (T3) is reduced, the ratio of thyroxine (T4) to T3 is elevated, and thyroid-stimulating hormone (TSH) is close to or within the normal range, creating a euthyroid sick syndrome. In eating disorders, this thyroid disturbance is a result of starvation and resolves with weight restoration. Therefore, thyroid hormone replacement therapy is not medically indicated.²⁸

Osteoporosis. Amenorrhea resulting from low estrogen levels in undernourished patients can raise the risk of osteoporosis and fractures, particularly in patients with a low body mass index. Osteopenia results from a negative balance between bone deposition and resorption.

Lack of bone deposition can be especially problematic when disordered eating occurs during peak bone mass development, ie, ages 11 to 14 for girls, and ages 15 to 17 for boys.^31,32 Even a 5% to 10% decrease in bone deposition can result in significant risk of osteopenia.³³ However, after age 30, bone resorption is a greater contributor.³⁴

Does hormone therapy correct bone loss? Given the association between estrogen deficiency and bone loss, estrogen supplementation was expected to be an effective treatment for bone loss in patients with eating disorders.³⁵ Also, the restoration of menses through hormone replacement may give underweight patients a false sense of achieving a “healthy” weight.³⁶

Golden et al³⁷ prospectively studied 50 adolescents and found no significant difference in bone mineral density at 1 year of follow-up between patients treated with estrogen and those who received only standard nutritional therapy. However, increased bone mineral density was achieved in adolescents with anorexia nervosa treated with transdermally administered estrogen dosed to mimic physiologic pubertal levels.³⁸

Klibanski et al³⁹ found that hormone therapy resulted in a 4% gain in bone density in an extremely low-weight subset of women with anorexia nervosa (< 70% of ideal body weight), whereas similar patients in the control group lost 20%. However, in all groups, only weight gain correlated with bone gain in women who were within 70% of their ideal body weight.

Divasta et al⁴⁰ evaluated 60 girls and women ages 13 to 27 with anorexia nervosa, randomized to receive either placebo or dehydroepiandrosterone combined with an estrogen-progestin oral contraceptive, and followed for 18 months. As in the study by Klibanski et al,³⁹ bone loss was prevented in the treatment group, but significant bone gain occurred only in the context of weight gain.

The bottom line is that only weight gain has resulted in significant increases in bone density in patients with anorexia nervosa, and hormone therapy without weight gain has not been shown to increase bone density effectively in this population. Although calcium and vitamin D in oral therapeutic doses through foods or through supplementation are required for bone gain, the combination is not enough to augment bone density in the absence of weight gain.³⁷ Although not curative, weight gain is currently the best option for treating bone loss, and no single pharmacologic treatment is effective.

COMPLICATIONS OF PURGING

Oral complications of purging

Patients who purge by vomiting are at risk of complications from exposure of the esophagus, pharynx, and mouth to acidic gastric contents.

Dental problems. Over time, contact with gastric acid wears down enamel on the lingual and occlusal surfaces of teeth, resulting in dental caries and periodontal disease. Until they can give up purging, patients should be instructed to rinse with mouthwash or water immediately after vomiting to reduce the acidity in the mouth.^41,42 We recommend that patients not brush their teeth after vomiting, because brushing can deliver acid to otherwise unreachable surfaces and thus worsen tooth erosion. For patients who are determined to brush after vomiting, a bicarbonate toothpaste might mitigate harm.⁴²

Sialadenosis (hypertrophy of the salivary glands) is another consequence of repeated vomiting, with elevated salivary amylase. Both the size of the glands and the salivary amylase level generally normalize on their own after vomiting is stopped, but parotitis can take up to a year to resolve. Similar to smoker’s cough, parotitis may acutely worsen when the patient abruptly stops vomiting and may worsen before it improves.

To reduce discomfort, patients can use hot compresses or sugarless hard candies.⁴⁴ However, the latter should not be substituted as a chronic habit in a patient with disordered eating. Patients need to be reassured that the swelling is not permanent, since they often interpret it as having fat cheeks (the “chipmunk sign”).

Hypokalemia, metabolic alkalosis, renal dysfunction

Chronic vomiting can cause electrolyte and acid-base imbalances, the most worrisome of which is hypokalemia. With repeated vomiting, loss of potassium and gastric acid causes metabolic alkalosis with hypokalemia, hypochloremia, and hypomagnesemia. Loss of water and the resultant volume contraction activates the renin-angiotensin-aldosterone system, and elevated aldosterone further decreases serum potassium.

In patients with eating disorders, who often have other factors contributing to electrolyte imbalance, vomiting-induced hypokalemia heightens the risk of cardiac arrhythmias.⁴³

Hypokalemia can also cause rhabdomyolysis and kidney damage.^41,43 Prolonged hypokalemia and reduced kidney perfusion in the setting of volume depletion causes acute kidney injury and impaired concentrating ability of the renal tubules. Hypovolemia can cause prerenal azotemia and increases the risk for nephrolithiasis and nephrocalcinosis.^44,45

When a patient stops vomiting, elevated aldosterone from prior hypovolemia results in water retention and can manifest in significant edema associated with hypochloremic alkalosis. This condition, known as pseudo-Bartter syndrome, usually resolves without treatment. In the meantime, salt restriction and leg elevation can help reduce edema.²⁶

Laxative abuse: A mode of purging

Many patients with eating disorders abuse laxatives to lose weight or to prevent weight gain. Believing that laxatives will prevent calorie absorption, patients commonly take them to compensate for caloric intake (eg, during a binge episode). The immediate weight loss, albeit artificial, is highly reinforcing for an eating-disorder patient. In some cases, patients with eating disorders also abuse laxatives to self-treat the constipation that results from chronic starvation.⁴⁶

Over time, tolerance to laxatives develops, and patients use increasingly larger doses. This can lead to activation of the renin-angiotensin-aldosterone system.⁴⁷ Patients interpret the resultant edema as true weight gain and again take laxatives to get rid of it. If laxatives are stopped abruptly, the patient may need inpatient and outpatient support for the resultant fluid shifts.

Gastrointestinal complications of laxative abuse include reflex hypofunction of the bowel, malabsorption, steatorrhea, and gastrointestinal bleeding.⁴⁷ Reflex hypofunction during laxative withdrawal is a consequence of the bowel becoming tolerant of laxatives.⁴⁸ Cathartic colon syndrome is a rare complication characterized by loss of the normal haustral markings and slowed or absent peristalsis in segments of the colon.⁴⁹

Systemically, the major risk of laxative abuse relates to electrolyte and acid-base imbalance. Loss of potassium and water in the stool can cause hypokalemia and metabolic alkalosis.⁴⁸ The disturbances caused by laxative abuse are similar to those caused by vomiting and diuretic use and have the same treatment.

The most important component of treating laxative abuse is giving patients realistic expectations to help them tolerate temporary discomfort and to help manage the edema and fluid shifts that can happen acutely with shifting of fluid into the intracellular space. In extreme cases, this may need to be managed in the hospital. To help relieve the initial anxiety, doctors should emphasize that any bloating the patient experiences is not true weight gain and will go away within a few days to weeks. In addition, explaining that laxatives reduce nutrient absorption only minimally may lessen the temptation to resume taking them.⁴⁸

Diuretic abuse: Another form of purging

Diuretic abuse is yet another mode of purging, with its own set of medical complications. Like laxatives, diuretics are not effective weight-loss agents, and the weight reduction they cause is only temporary.

As with vomiting, there is a compensatory activation of the renin-angiotensin-aldosterone system, and therefore subsequent fluid intake will lead to water retention, which encourages further diuretic use.⁴¹ Diuretics can also contribute to hypokalemia, hypomagnesemia, hypochloremia, and metabolic alkalosis.

Ipecac abuse can lead to heart failure

Ipecac syrup has long been used to induce vomiting, but this practice has become much less common since ipecac has become harder to obtain in the United States.⁵⁰ The emetine base contained in ipecac binds irreversibly to cardiac and skeletal muscle. With continued use, irreversible cardiomyopathy develops and can lead to heart failure. Treatment should include supportive care and immediate cessation of ipecac use.

Diabetic patients may skip insulin to lose weight

Patients with diabetes, especially those with type 1 that begins in childhood, are at greater risk of eating disorders over time.⁵¹ They may withhold insulin to lose weight, a practice referred to in the nonmedical literature as “diabulimia,” and they seem particularly more likely to develop bulimia nervosa than those without diabetes.⁵²

The medical prognosis is poor for patients with diabetes who develop eating disorders and do not receive intensive treatment.⁵¹ In addition, if a diabetic patient on an insulin pump becomes depressed in addition to having an eating disorder, careful monitoring for suicidal thoughts and a rapid follow-up with mental health services are in order.

REFEEDING SYNDROME

When refeeding is started, a high glucose load stimulates insulin secretion, resulting in cellular uptake of phosphorus along with potassium, magnesium, and glucose. In addition, total body phosphorus is depleted by the increased demand for adenosine triphosphate and 2,3-diphosphoglycerate for cellular metabolism.

When liver enzyme levels increase, the astute clinician will closely monitor the patient for evidence of refeeding syndrome. In a child, adolescent, or young adult, the standard of care is inpatient monitoring for acute stabilization.^4,19

Hypophosphatemia is the hallmark of refeeding syndrome, although hypomagnesemia, hypokalemia, and hypoglycemia can also occur.⁵³ In addition, sodium and water retention can lead to fluid overload, with shifting of fluid into the intracellular space, resulting in dependent edema.

Cardiovascular complications are the most worrisome manifestations of refeeding syndrome. Electrolyte shifts and increased fluid volume can cause arrhythmias and heart failure. Furthermore, severely undernourished patients may have reduced myocardial mass as well as electrocardiographic abnormalities associated with starvation, which further increase their vulnerability to electrolyte shifts and fluid retention during refeeding.¹⁵

Other manifestations of refeeding syndrome include delirium, seizures, rhabdomyolysis, and respiratory failure. In the most extreme cases, refeeding syndrome causes sudden death.⁵³

Fortunately, refeeding syndrome is easily preventable and treatable when recognized early. Electrolytes and cardiovascular and renal function must be carefully monitored, especially during the first week of nutritional restoration.⁵³ In patients with extremely low body mass (< 70% of ideal body weight) or with precipitous weight loss, close monitoring of the complete metabolic panel including electrolytes, AST, ALT, calcium, magnesium, and phosphorus may be required to detect changes that can affect cardiac status. Specific suggestions for refeeding are discussed below and in Table 2.⁴⁵

ACUTE CARE OF PATIENTS WITH EATING DISORDERS

Refeeding in the inpatient setting

The decision to hospitalize an eating-disorder patient is based on the current or potential risk of serious medical complications and the likelihood of success at home. Medical criteria for hospital admission are outlined in Table 3.^4,54

In refeeding undernourished patients, the challenge is to maximize weight gain while preventing refeeding syndrome. Undernourished patients are generally hypometabolic at baseline but become hypermetabolic once refeeding begins.

How many calories should refeeding start with? The traditional principle of “start low and go slow” has been recently challenged.⁵⁵ Starting at 1,200 kcal/day or less in the typical patient can result in failure to gain weight or even in weight loss in the first week of refeeding.⁵⁶ The goal is to achieve a weight gain of 0.2 kg/day while the patient is in the hospital. Thus, we start higher, and to date we have seen no cases of life-threatening refeeding syndrome. In all patients who need hospitalization or who are beginning the refeeding process as outpatients, caloric intake should be started at 1,500 to 2,000 kcal/day.^45,57 However, for exceptionally low-weight patients, intake may be started lower.

In Australia, patients are started at 1,900 kcal/day.⁵⁶ All patients in one program there receive nasogastric feeding initially in an intensive care unit and then are moved to a regular nursing floor where they graduate to full oral feeding as they improve cardiovascularly and behaviorally. In the United States, some programs use nasogastric feeding at night for caloric restoration; our program and others use nasogastric feeding as a behavioral modification strategy for patients who refuse food or supplements by mouth.

Phosphorus supplementation. Many centers give phosphorus supplements preventively. In our center, we give potassium phosphate (Neutra-Phos) 500 mg orally twice daily for 5 days, and we have seen no life-threatening cases of refeeding syndrome with that regimen. Other centers give phosphorus supplements in a dose of 250 mg orally twice a day for 5 days, while still others only supplement phosphorus reactively once a deficit has been identified. The latter method requires daily blood draws for monitoring and is reactive rather than proactive. Further studies can help clarify the optimal dosing and timing of phosphorus supplementation.

Managing fluid balance. Fluid-loading these patients may tip them over the edge into refeeding syndrome. Except in cases of shock, patients with eating disorders should not be given intravenous fluids, as it is safer to rehydrate and feed them orally. Electrolyte imbalances can be corrected orally with no need for intravenous supplementation. To avoid fluid overload, fluids can be started at 1,500 mL to 2,000 mL per day, with strict monitoring of intake and output. Fluids are liberalized if ALT and AST levels remain normal and to gradually correct orthostatic hypotension; caloric fluids are ideal to help address energy needs and improve bradycardia.

Laboratory monitoring. On admission, a urinalysis, complete blood cell count, complete metabolic panel, TSH, erythrocyte sedimentation rate, serum magnesium, and phosphorus should be obtained.²⁶ In addition, continuous electrocardiographic recording should begin on admission.⁴⁵ Inpatient use of a telemetry bed helps identify extreme tachycardia with arrhythmia, as well as profound bradycardia.^45,56

Some protocols call for daily laboratory monitoring, although that degree of testing is less cost-effective. If initial results are normal, clinical judgment can be used on when to repeat laboratory evaluation. For instance, patients with edema require repeat complete metabolic panels to assess for elevated ALT and AST, electrolyte imbalances, and other abnormalities.

Signs of refeeding syndrome include tachycardia, hepatosplenomegaly, peripheral edema, altered mental status, and electrolyte disturbances, specifically, acute or severe hypophosphatemia or hypokalemia.^26,45 If refeeding syndrome is suspected, the rate of caloric intake should be reduced or not advanced, fluid intake should be urgently reassessed for volume overload, and supportive care with close monitoring should be provided.

KNOWLEDGE SAVES LIVES

Eating disorders can lead to potentially life-threatening medical complications that require attentive care by the primary care clinician and subspecialist. Without thoughtful consideration, it is easy for even a caring medical team to unintentionally enable patients with these illnesses or to cause active harm in the case of underrecognized pathology.⁵⁸

Acute medical stabilization on an inpatient unit trained to recognize pathology and treat sequelae can be lifesaving. Arming patients and families with medical knowledge, as provided in the Academy for Eating Disorders’ brochure, “Critical Points for Early Recognition and Medical Risk Management in the Care of Individuals with Eating Disorders”⁵⁹ can help save patients’ lives.

Quality improvement (QI) is about system change for the entire organization. In a session at HM14, Michelle Mourad, MD, and Nasim Afsar, MD, SFHM, outlined QI principles and a systematic step-wise process that can create and sustain change successfully in our hospitals.

QI principles include creating a sense of urgency, implementation, and sustainability. The seven steps for a successful QI project are as follows: understand the problem, convince others there is a problem, identify areas of improvement, prioritize a small test of change, devise a measurement strategy, measure change, and sustain change.

Understanding the problem includes creating a fishbone diagram that helps you identify the causes of your problem. Convincing others requires presentation of inspiring data and telling your story.

Dr. Mourad encouraged the audience to use personal anecdotes and focus on the ‘why,’ not the ‘what’ or ‘how’ to relate to others on a personal level. Identifying areas of improvement requires creation of a process map to identify obstacles that can be removed. “Your goal is to make systems work for people,” said Dr. Mourad. Ask people to tell you how the process will work better for them.

Prioritizing small tests of change requires identifying low-effort, high-impact tasks that will lead to easy wins. “Don’t do the thankless tasks that are high-effort with low impact,” said Dr. Afsar. She further encouraged physicians to perform small tests of change to help understand if their ideas are worthy of large scale implementation.

Plan-Do-Study-Act (PDSA) and A3 methodology are two methods by which a QI project can be organized for implementation. Devising a measurement strategy requires collecting data from appropriate sources in the hospital to ensure improved outcomes as a result of interventions performed. Outcomes, structure, and process are the areas in which results can be measured.

Coaching your team is an important part of motivating your team for continued progress. Change can be concretely measured and plotted over time via statistical process control charts (download SPC macros in Excel to plot graphs).

Lastly, sustaining change requires celebrating success. Dr. Afsar cautioned the audience to set appropriate expectations and goals to sustain system change. Further, once the change is set in motion, put the process ownership into the group (not on you). Creating data that is readily accessible and visible to the group helps them understand progress over time. Design the process to fit into natural workflow to make the process an easy transition that is sustainable long-term.

Key Points

• QI is a four legged stool: education, data audit and feedback, systems change, and culture change;

• Create a fishbone diagram to understand the cause and the effect;

• Create a sense of urgency by sharing inspirational data and finding your story and focusing on the why;

• Use process maps to identify areas of improvement;

• Prioritize those areas and implement small tests of change;

• Measure all outcomes and use statistical process control charts to demonstrate change;

• Motivate and coach people throughout the process change;

• Make data easily accessible to all members of the group to track progress; and

• Sustain change by setting realistic expectations and celebrating success.

Dr. Kanikkannan is Hospitalist Medical Director and Assistant Professor of Medicine at Rowan University School of Osteopathic Medicine and is a member of Team Hospitalist.

Quality improvement (QI) is about system change for the entire organization. In a session at HM14, Michelle Mourad, MD, and Nasim Afsar, MD, SFHM, outlined QI principles and a systematic step-wise process that can create and sustain change successfully in our hospitals.

QI principles include creating a sense of urgency, implementation, and sustainability. The seven steps for a successful QI project are as follows: understand the problem, convince others there is a problem, identify areas of improvement, prioritize a small test of change, devise a measurement strategy, measure change, and sustain change.

Understanding the problem includes creating a fishbone diagram that helps you identify the causes of your problem. Convincing others requires presentation of inspiring data and telling your story.

Dr. Mourad encouraged the audience to use personal anecdotes and focus on the ‘why,’ not the ‘what’ or ‘how’ to relate to others on a personal level. Identifying areas of improvement requires creation of a process map to identify obstacles that can be removed. “Your goal is to make systems work for people,” said Dr. Mourad. Ask people to tell you how the process will work better for them.

Prioritizing small tests of change requires identifying low-effort, high-impact tasks that will lead to easy wins. “Don’t do the thankless tasks that are high-effort with low impact,” said Dr. Afsar. She further encouraged physicians to perform small tests of change to help understand if their ideas are worthy of large scale implementation.

Plan-Do-Study-Act (PDSA) and A3 methodology are two methods by which a QI project can be organized for implementation. Devising a measurement strategy requires collecting data from appropriate sources in the hospital to ensure improved outcomes as a result of interventions performed. Outcomes, structure, and process are the areas in which results can be measured.

Coaching your team is an important part of motivating your team for continued progress. Change can be concretely measured and plotted over time via statistical process control charts (download SPC macros in Excel to plot graphs).

Lastly, sustaining change requires celebrating success. Dr. Afsar cautioned the audience to set appropriate expectations and goals to sustain system change. Further, once the change is set in motion, put the process ownership into the group (not on you). Creating data that is readily accessible and visible to the group helps them understand progress over time. Design the process to fit into natural workflow to make the process an easy transition that is sustainable long-term.

Key Points

• QI is a four legged stool: education, data audit and feedback, systems change, and culture change;

• Create a fishbone diagram to understand the cause and the effect;

• Create a sense of urgency by sharing inspirational data and finding your story and focusing on the why;

• Use process maps to identify areas of improvement;

• Prioritize those areas and implement small tests of change;

• Measure all outcomes and use statistical process control charts to demonstrate change;

• Motivate and coach people throughout the process change;

• Make data easily accessible to all members of the group to track progress; and

• Sustain change by setting realistic expectations and celebrating success.

Dr. Kanikkannan is Hospitalist Medical Director and Assistant Professor of Medicine at Rowan University School of Osteopathic Medicine and is a member of Team Hospitalist.

Quality improvement (QI) is about system change for the entire organization. In a session at HM14, Michelle Mourad, MD, and Nasim Afsar, MD, SFHM, outlined QI principles and a systematic step-wise process that can create and sustain change successfully in our hospitals.

QI principles include creating a sense of urgency, implementation, and sustainability. The seven steps for a successful QI project are as follows: understand the problem, convince others there is a problem, identify areas of improvement, prioritize a small test of change, devise a measurement strategy, measure change, and sustain change.

Understanding the problem includes creating a fishbone diagram that helps you identify the causes of your problem. Convincing others requires presentation of inspiring data and telling your story.

Dr. Mourad encouraged the audience to use personal anecdotes and focus on the ‘why,’ not the ‘what’ or ‘how’ to relate to others on a personal level. Identifying areas of improvement requires creation of a process map to identify obstacles that can be removed. “Your goal is to make systems work for people,” said Dr. Mourad. Ask people to tell you how the process will work better for them.

Prioritizing small tests of change requires identifying low-effort, high-impact tasks that will lead to easy wins. “Don’t do the thankless tasks that are high-effort with low impact,” said Dr. Afsar. She further encouraged physicians to perform small tests of change to help understand if their ideas are worthy of large scale implementation.

Plan-Do-Study-Act (PDSA) and A3 methodology are two methods by which a QI project can be organized for implementation. Devising a measurement strategy requires collecting data from appropriate sources in the hospital to ensure improved outcomes as a result of interventions performed. Outcomes, structure, and process are the areas in which results can be measured.

Coaching your team is an important part of motivating your team for continued progress. Change can be concretely measured and plotted over time via statistical process control charts (download SPC macros in Excel to plot graphs).

Lastly, sustaining change requires celebrating success. Dr. Afsar cautioned the audience to set appropriate expectations and goals to sustain system change. Further, once the change is set in motion, put the process ownership into the group (not on you). Creating data that is readily accessible and visible to the group helps them understand progress over time. Design the process to fit into natural workflow to make the process an easy transition that is sustainable long-term.

Key Points

• QI is a four legged stool: education, data audit and feedback, systems change, and culture change;

• Create a fishbone diagram to understand the cause and the effect;

• Create a sense of urgency by sharing inspirational data and finding your story and focusing on the why;

• Use process maps to identify areas of improvement;

• Prioritize those areas and implement small tests of change;

• Measure all outcomes and use statistical process control charts to demonstrate change;

• Motivate and coach people throughout the process change;

• Make data easily accessible to all members of the group to track progress; and

• Sustain change by setting realistic expectations and celebrating success.

Dr. Kanikkannan is Hospitalist Medical Director and Assistant Professor of Medicine at Rowan University School of Osteopathic Medicine and is a member of Team Hospitalist.

Each year, 60 million Americans experience mental illness. Across the United States, each year, regardless of race, age, religion, or economic status, mental illness affects the lives of one in four adults and one in 10 children. This means that someone in every family has mental illness.

Most of our patients probably don’t tell anyone that they or one of their family members has mental illness They probably are doing what most of us do: Pretend it’s not there. Why? Because the stigma of mental illness is pervasive and destructive. What can we do to decrease the stigma?

Mental illness accounts for increased morbidity and mortality as well as lifetime disability. The World Health Organization (WHO) estimates that neuropsychiatric disorders are the leading cause of disability in the United States, followed by cardiovascular and circulatory diseases, and neoplasms. The neuropsychiatric disorders category, which includes mental and behavioral disorders, accounts for 13.6% of total U.S. disability-adjusted life years (DALYs). Neurological disorders account for 5.1% of total U.S. DALYs.

Impact on the family

Not only does stigma affect individuals, it affects family members as well. Family members suffer from SBA, or stigma by association (Brit. J. Psych. 2002;181:494-8), also known as courtesy stigma (Social. Psychiatry Psychiatr. Epidemiol. 2003;38:593-602). Families share stigma because families share a genetic heritage. Families share stigma by assuming responsibility for their family members’ behaviors. Families share stigma because they are seen as having common motivations (J. Pers. Soc. Psychol. 2012;102:224-41).

SBA causes psychological distress in family members (Rehabil. Psychol. 2013;58:73-80; J. Nerv. Ment. Dis. 1987;175:4-11; Br. J. Psychiatry 2002;181:494-8; and Schizophr. Bull. 1998;24:115-126).

Psychological complaints, such as brooding, inner unrest, and irritability, and physical complaints, such as insomnia, fatigue, and neck and shoulder pain, have been attributed to the psychological distress of SBA. Family members may avoid social interactions and conceal their relationship to the family member who is mentally ill (Acad. Psychiatry 2008;32:87-91). They might psychologically distance themselves from a relative with mental illness.

SBA varies by disease type, family role, and age. The greatest SBA is associated with drug dependence. These family members are blamed for the illness, held responsible for relapse, and viewed as incompetent. In the study of Patrick W. Corrigan, Psy.D., (J. Fam. Psychol. 2006;20:239-46), family members report feelings of "contamination" and shame. Severe depression or panic and phobias engender less stigma. More educated people are less likely to report feelings of stigma.

According to Dr. Corrigan, SBA varies by family role: Parents are blamed for causing the child’s mental illness, siblings are blamed for not ensuring that relatives with mental illness adhere to treatment plans, and children are fearful of being "contaminated" with the mental illness of their parent. The closer the relationship, the less the stigma is perceived as defining the person. Family closeness can reduce stigma (The Gerontologist 2012;52:89-97). Regarding age, a British study showed that the highest stigma is reported in the 16- to 19-year-old age group (Br. J. Psychiatry 2000;177:4-7).

Psychiatry as a profession has not helped diminish stigma. It is not uncommon to hear psychiatrists assign blame to parents or spouses. Psychiatrists often believe that the family has a role in the patient’s illness. How many spouses have been told they are "codependent" with the implication that they have somehow "caused the illness"? What can we do diminish stigma?

Fighting stigma

Fighting stigma means confronting stigma (Advances in Psychiatric Treatment 2000;6:65-72). Most efforts worldwide have begun with the idea of educating people about mental illness. These efforts, focused on promoting mental illness as a biological illness, have had limited success and in some situations actually increased stigma (Acta Psychiatr. Scand. 2012; 125:440-52). The answer may lie in targeted education: specific facts for specific groups.

For example, young couples with children become less fearful after education targeted specifically for them (Br. J. Psychiatry 1996;168:191-8). Antistigma campaigns are common throughout the world. The websites of most professional psychiatric organizations, such as the American Psychiatric Association, the Royal College of Psychiatrists, and the College of Psychiatrists of Ireland, provide information about antistigma campaigns. Organizations often partner with mental health charities. Antistigma efforts also focus on publishing articles about stigma as the Lancet did in a series a few years ago (1998;352:1048). It is unclear whether these efforts reduce stigma. Dr. Corrigan suggests that meeting people who have mental illness weakens the tendency to link mental illness and violence (Psychiatric Rehabilitation Skills 2002;6: 312-34).

The current consensus is that antistigma campaigns should focus on the competence of people with mental illness. In this vein, the Scottish Mental Health Arts & Film Festival highlights the contributions that people with mental illness make to society. The festival, which began in 2007, also sponsors a contest for films that depict people with mental illness in realistic, holistic ways. In 2013, the festival drew 12,000 attendees and sparked 120 newspaper articles that emphasized the fact that people with mental illness are generally active, useful members of society.

Meanwhile, a Canadian antistigma campaign tells the stories of people with mental illness and provides evidence of the competence of these people. The APA’s public service video series, "A Healthy Minds Minute," features celebrities and prominent figures calling for equal access to quality care, and insurance coverage for people with mental illness and substance use disorders.

What do we do to reduce stigma? Psychiatrists such as William Beardslee have written about their personal experience of a family member with mental illness. A member of the Association of Family Psychiatrists, Julie Totten, lost her brother to suicide and in response, she developed an organization called Families for Depression Awareness, which is devoted to reducing the stigma of mental illness. For me, it is my personal campaign to say: "One in four means that someone in everyone’s family has mental illness."

What more can we do?

• Speak up when you hear or see stigma.

• Stress the normalcy of people who have mental illness.

• Come out of the closet on behalf of yourself or a family member.

• Include people who acknowledge they suffer from mental illness in antistigma campaigns.

• Discuss the role of stigma with patients and their families. Ask "How has stigma affected you as a family? In what ways has your family helped reduce the stigma of your mental illness?"

• Encourage attendance at support groups, such as NAMI (the National Alliance on Mental Illness).

• Embrace your family member or yourself: Look for personal qualities that wipe out stigma.

• Don’t allow people to stigmatize patients: It might be your family member they are talking about.

• Talk positively about respecting our patients.

• Start a conversation to reduce stigma.

• Remember that fighting stigma means confronting stigma.

Dr. Heru is an associate professor of psychiatry at the University of Colorado at Denver, Aurora. She has been a member of the Association of Family Psychiatrists since 2002 and currently serves as the organization’s treasurer. She is the author of a new book, "Working With Families in Medical Settings" (New York: Routledge, 2013).

Each year, 60 million Americans experience mental illness. Across the United States, each year, regardless of race, age, religion, or economic status, mental illness affects the lives of one in four adults and one in 10 children. This means that someone in every family has mental illness.

Most of our patients probably don’t tell anyone that they or one of their family members has mental illness They probably are doing what most of us do: Pretend it’s not there. Why? Because the stigma of mental illness is pervasive and destructive. What can we do to decrease the stigma?

Mental illness accounts for increased morbidity and mortality as well as lifetime disability. The World Health Organization (WHO) estimates that neuropsychiatric disorders are the leading cause of disability in the United States, followed by cardiovascular and circulatory diseases, and neoplasms. The neuropsychiatric disorders category, which includes mental and behavioral disorders, accounts for 13.6% of total U.S. disability-adjusted life years (DALYs). Neurological disorders account for 5.1% of total U.S. DALYs.

Impact on the family

Not only does stigma affect individuals, it affects family members as well. Family members suffer from SBA, or stigma by association (Brit. J. Psych. 2002;181:494-8), also known as courtesy stigma (Social. Psychiatry Psychiatr. Epidemiol. 2003;38:593-602). Families share stigma because families share a genetic heritage. Families share stigma by assuming responsibility for their family members’ behaviors. Families share stigma because they are seen as having common motivations (J. Pers. Soc. Psychol. 2012;102:224-41).

SBA causes psychological distress in family members (Rehabil. Psychol. 2013;58:73-80; J. Nerv. Ment. Dis. 1987;175:4-11; Br. J. Psychiatry 2002;181:494-8; and Schizophr. Bull. 1998;24:115-126).

Psychological complaints, such as brooding, inner unrest, and irritability, and physical complaints, such as insomnia, fatigue, and neck and shoulder pain, have been attributed to the psychological distress of SBA. Family members may avoid social interactions and conceal their relationship to the family member who is mentally ill (Acad. Psychiatry 2008;32:87-91). They might psychologically distance themselves from a relative with mental illness.

SBA varies by disease type, family role, and age. The greatest SBA is associated with drug dependence. These family members are blamed for the illness, held responsible for relapse, and viewed as incompetent. In the study of Patrick W. Corrigan, Psy.D., (J. Fam. Psychol. 2006;20:239-46), family members report feelings of "contamination" and shame. Severe depression or panic and phobias engender less stigma. More educated people are less likely to report feelings of stigma.

According to Dr. Corrigan, SBA varies by family role: Parents are blamed for causing the child’s mental illness, siblings are blamed for not ensuring that relatives with mental illness adhere to treatment plans, and children are fearful of being "contaminated" with the mental illness of their parent. The closer the relationship, the less the stigma is perceived as defining the person. Family closeness can reduce stigma (The Gerontologist 2012;52:89-97). Regarding age, a British study showed that the highest stigma is reported in the 16- to 19-year-old age group (Br. J. Psychiatry 2000;177:4-7).

Psychiatry as a profession has not helped diminish stigma. It is not uncommon to hear psychiatrists assign blame to parents or spouses. Psychiatrists often believe that the family has a role in the patient’s illness. How many spouses have been told they are "codependent" with the implication that they have somehow "caused the illness"? What can we do diminish stigma?

Fighting stigma

Fighting stigma means confronting stigma (Advances in Psychiatric Treatment 2000;6:65-72). Most efforts worldwide have begun with the idea of educating people about mental illness. These efforts, focused on promoting mental illness as a biological illness, have had limited success and in some situations actually increased stigma (Acta Psychiatr. Scand. 2012; 125:440-52). The answer may lie in targeted education: specific facts for specific groups.

For example, young couples with children become less fearful after education targeted specifically for them (Br. J. Psychiatry 1996;168:191-8). Antistigma campaigns are common throughout the world. The websites of most professional psychiatric organizations, such as the American Psychiatric Association, the Royal College of Psychiatrists, and the College of Psychiatrists of Ireland, provide information about antistigma campaigns. Organizations often partner with mental health charities. Antistigma efforts also focus on publishing articles about stigma as the Lancet did in a series a few years ago (1998;352:1048). It is unclear whether these efforts reduce stigma. Dr. Corrigan suggests that meeting people who have mental illness weakens the tendency to link mental illness and violence (Psychiatric Rehabilitation Skills 2002;6: 312-34).

The current consensus is that antistigma campaigns should focus on the competence of people with mental illness. In this vein, the Scottish Mental Health Arts & Film Festival highlights the contributions that people with mental illness make to society. The festival, which began in 2007, also sponsors a contest for films that depict people with mental illness in realistic, holistic ways. In 2013, the festival drew 12,000 attendees and sparked 120 newspaper articles that emphasized the fact that people with mental illness are generally active, useful members of society.

Meanwhile, a Canadian antistigma campaign tells the stories of people with mental illness and provides evidence of the competence of these people. The APA’s public service video series, "A Healthy Minds Minute," features celebrities and prominent figures calling for equal access to quality care, and insurance coverage for people with mental illness and substance use disorders.

What do we do to reduce stigma? Psychiatrists such as William Beardslee have written about their personal experience of a family member with mental illness. A member of the Association of Family Psychiatrists, Julie Totten, lost her brother to suicide and in response, she developed an organization called Families for Depression Awareness, which is devoted to reducing the stigma of mental illness. For me, it is my personal campaign to say: "One in four means that someone in everyone’s family has mental illness."

What more can we do?

• Speak up when you hear or see stigma.

• Stress the normalcy of people who have mental illness.

• Come out of the closet on behalf of yourself or a family member.

• Include people who acknowledge they suffer from mental illness in antistigma campaigns.

• Discuss the role of stigma with patients and their families. Ask "How has stigma affected you as a family? In what ways has your family helped reduce the stigma of your mental illness?"

• Encourage attendance at support groups, such as NAMI (the National Alliance on Mental Illness).

• Embrace your family member or yourself: Look for personal qualities that wipe out stigma.

• Don’t allow people to stigmatize patients: It might be your family member they are talking about.

• Talk positively about respecting our patients.

• Start a conversation to reduce stigma.

• Remember that fighting stigma means confronting stigma.

Dr. Heru is an associate professor of psychiatry at the University of Colorado at Denver, Aurora. She has been a member of the Association of Family Psychiatrists since 2002 and currently serves as the organization’s treasurer. She is the author of a new book, "Working With Families in Medical Settings" (New York: Routledge, 2013).

Each year, 60 million Americans experience mental illness. Across the United States, each year, regardless of race, age, religion, or economic status, mental illness affects the lives of one in four adults and one in 10 children. This means that someone in every family has mental illness.

Most of our patients probably don’t tell anyone that they or one of their family members has mental illness They probably are doing what most of us do: Pretend it’s not there. Why? Because the stigma of mental illness is pervasive and destructive. What can we do to decrease the stigma?

Mental illness accounts for increased morbidity and mortality as well as lifetime disability. The World Health Organization (WHO) estimates that neuropsychiatric disorders are the leading cause of disability in the United States, followed by cardiovascular and circulatory diseases, and neoplasms. The neuropsychiatric disorders category, which includes mental and behavioral disorders, accounts for 13.6% of total U.S. disability-adjusted life years (DALYs). Neurological disorders account for 5.1% of total U.S. DALYs.

Impact on the family

Not only does stigma affect individuals, it affects family members as well. Family members suffer from SBA, or stigma by association (Brit. J. Psych. 2002;181:494-8), also known as courtesy stigma (Social. Psychiatry Psychiatr. Epidemiol. 2003;38:593-602). Families share stigma because families share a genetic heritage. Families share stigma by assuming responsibility for their family members’ behaviors. Families share stigma because they are seen as having common motivations (J. Pers. Soc. Psychol. 2012;102:224-41).

SBA causes psychological distress in family members (Rehabil. Psychol. 2013;58:73-80; J. Nerv. Ment. Dis. 1987;175:4-11; Br. J. Psychiatry 2002;181:494-8; and Schizophr. Bull. 1998;24:115-126).

Psychological complaints, such as brooding, inner unrest, and irritability, and physical complaints, such as insomnia, fatigue, and neck and shoulder pain, have been attributed to the psychological distress of SBA. Family members may avoid social interactions and conceal their relationship to the family member who is mentally ill (Acad. Psychiatry 2008;32:87-91). They might psychologically distance themselves from a relative with mental illness.

SBA varies by disease type, family role, and age. The greatest SBA is associated with drug dependence. These family members are blamed for the illness, held responsible for relapse, and viewed as incompetent. In the study of Patrick W. Corrigan, Psy.D., (J. Fam. Psychol. 2006;20:239-46), family members report feelings of "contamination" and shame. Severe depression or panic and phobias engender less stigma. More educated people are less likely to report feelings of stigma.

According to Dr. Corrigan, SBA varies by family role: Parents are blamed for causing the child’s mental illness, siblings are blamed for not ensuring that relatives with mental illness adhere to treatment plans, and children are fearful of being "contaminated" with the mental illness of their parent. The closer the relationship, the less the stigma is perceived as defining the person. Family closeness can reduce stigma (The Gerontologist 2012;52:89-97). Regarding age, a British study showed that the highest stigma is reported in the 16- to 19-year-old age group (Br. J. Psychiatry 2000;177:4-7).

Psychiatry as a profession has not helped diminish stigma. It is not uncommon to hear psychiatrists assign blame to parents or spouses. Psychiatrists often believe that the family has a role in the patient’s illness. How many spouses have been told they are "codependent" with the implication that they have somehow "caused the illness"? What can we do diminish stigma?

Fighting stigma

Fighting stigma means confronting stigma (Advances in Psychiatric Treatment 2000;6:65-72). Most efforts worldwide have begun with the idea of educating people about mental illness. These efforts, focused on promoting mental illness as a biological illness, have had limited success and in some situations actually increased stigma (Acta Psychiatr. Scand. 2012; 125:440-52). The answer may lie in targeted education: specific facts for specific groups.

For example, young couples with children become less fearful after education targeted specifically for them (Br. J. Psychiatry 1996;168:191-8). Antistigma campaigns are common throughout the world. The websites of most professional psychiatric organizations, such as the American Psychiatric Association, the Royal College of Psychiatrists, and the College of Psychiatrists of Ireland, provide information about antistigma campaigns. Organizations often partner with mental health charities. Antistigma efforts also focus on publishing articles about stigma as the Lancet did in a series a few years ago (1998;352:1048). It is unclear whether these efforts reduce stigma. Dr. Corrigan suggests that meeting people who have mental illness weakens the tendency to link mental illness and violence (Psychiatric Rehabilitation Skills 2002;6: 312-34).

The current consensus is that antistigma campaigns should focus on the competence of people with mental illness. In this vein, the Scottish Mental Health Arts & Film Festival highlights the contributions that people with mental illness make to society. The festival, which began in 2007, also sponsors a contest for films that depict people with mental illness in realistic, holistic ways. In 2013, the festival drew 12,000 attendees and sparked 120 newspaper articles that emphasized the fact that people with mental illness are generally active, useful members of society.

Meanwhile, a Canadian antistigma campaign tells the stories of people with mental illness and provides evidence of the competence of these people. The APA’s public service video series, "A Healthy Minds Minute," features celebrities and prominent figures calling for equal access to quality care, and insurance coverage for people with mental illness and substance use disorders.

What do we do to reduce stigma? Psychiatrists such as William Beardslee have written about their personal experience of a family member with mental illness. A member of the Association of Family Psychiatrists, Julie Totten, lost her brother to suicide and in response, she developed an organization called Families for Depression Awareness, which is devoted to reducing the stigma of mental illness. For me, it is my personal campaign to say: "One in four means that someone in everyone’s family has mental illness."

What more can we do?

• Speak up when you hear or see stigma.

• Stress the normalcy of people who have mental illness.

• Come out of the closet on behalf of yourself or a family member.

• Include people who acknowledge they suffer from mental illness in antistigma campaigns.

• Discuss the role of stigma with patients and their families. Ask "How has stigma affected you as a family? In what ways has your family helped reduce the stigma of your mental illness?"

• Encourage attendance at support groups, such as NAMI (the National Alliance on Mental Illness).

• Embrace your family member or yourself: Look for personal qualities that wipe out stigma.

• Don’t allow people to stigmatize patients: It might be your family member they are talking about.

• Talk positively about respecting our patients.

• Start a conversation to reduce stigma.

• Remember that fighting stigma means confronting stigma.

Dr. Heru is an associate professor of psychiatry at the University of Colorado at Denver, Aurora. She has been a member of the Association of Family Psychiatrists since 2002 and currently serves as the organization’s treasurer. She is the author of a new book, "Working With Families in Medical Settings" (New York: Routledge, 2013).

Monosomal karyotype and high prognostic risk according to the revised International Prognostic Scoring System are independent predictors of relapse and mortality in patients with myelodysplastic syndrome or oligoblastic acute myeloid leukemia who undergo allogeneic hematopoietic stem cell transplantation, according to findings from the GITMO (Gruppo Italiano Trapianto di Midollo Osseo) registry.

Treatment failure after allogeneic hematopoietic stem cell transplantation may be from transplant complications or relapse. To understand the predictors of failure, investigators studied outcomes in 519 patients with myelodysplastic syndrome or oligoblastic acute myeloid leukemia who underwent hematopoietic stem cell transplantation between 2000 and 2011.

Those with monosomal karyotype had a 49% relapse rate and a 10% 5-year overall survival rate; both rates were significantly worse, compared with patients without monosomal karyotype (P less than .001 for each). Those considered high or very-high risk based on the International Prognostic Scoring System (IPSS-R), had 39% and 23% 5-year overall survival, respectively, and 23% and 39% relapse rates, respectively (P less than .001 in all cases vs. patients not at high or very-high risk), Dr. Matteo G. Della Porta of Fondazione IRCCS Policlinico San Matteo, Pavia, Italy and colleagues reported on behalf of the GITMO.

Age of 50 years or older and high hematopoietic cell transplantation-comorbidity index scores were independent predictors of nonrelapse mortality (P = .02; P = .017, respectively), they found (Blood 2014 [doi:10.1182/blood-2013-12-542720]).

Accounting for various combinations of patients’ ages, IPSS-R category, monosomal karyotype, and high hematopoietic cell transplantation–comorbidity index, the 5-year probability of survival after allogeneic hematopoietic stem cell transplantation ranged from 0 to 94%. The analyses performed reinforce the concept that allogenic hematopoietic stem cell transplantation – the only potentially curative treatment for MDS – "offers optimal eradication of myelodysplastic hematopoiesis when the procedure is performed before MDS patients progress to advanced disease stages," the investigators concluded.

The investigators reported having no disclosures.

Monosomal karyotype and high prognostic risk according to the revised International Prognostic Scoring System are independent predictors of relapse and mortality in patients with myelodysplastic syndrome or oligoblastic acute myeloid leukemia who undergo allogeneic hematopoietic stem cell transplantation, according to findings from the GITMO (Gruppo Italiano Trapianto di Midollo Osseo) registry.

Treatment failure after allogeneic hematopoietic stem cell transplantation may be from transplant complications or relapse. To understand the predictors of failure, investigators studied outcomes in 519 patients with myelodysplastic syndrome or oligoblastic acute myeloid leukemia who underwent hematopoietic stem cell transplantation between 2000 and 2011.

Those with monosomal karyotype had a 49% relapse rate and a 10% 5-year overall survival rate; both rates were significantly worse, compared with patients without monosomal karyotype (P less than .001 for each). Those considered high or very-high risk based on the International Prognostic Scoring System (IPSS-R), had 39% and 23% 5-year overall survival, respectively, and 23% and 39% relapse rates, respectively (P less than .001 in all cases vs. patients not at high or very-high risk), Dr. Matteo G. Della Porta of Fondazione IRCCS Policlinico San Matteo, Pavia, Italy and colleagues reported on behalf of the GITMO.

Age of 50 years or older and high hematopoietic cell transplantation-comorbidity index scores were independent predictors of nonrelapse mortality (P = .02; P = .017, respectively), they found (Blood 2014 [doi:10.1182/blood-2013-12-542720]).

Accounting for various combinations of patients’ ages, IPSS-R category, monosomal karyotype, and high hematopoietic cell transplantation–comorbidity index, the 5-year probability of survival after allogeneic hematopoietic stem cell transplantation ranged from 0 to 94%. The analyses performed reinforce the concept that allogenic hematopoietic stem cell transplantation – the only potentially curative treatment for MDS – "offers optimal eradication of myelodysplastic hematopoiesis when the procedure is performed before MDS patients progress to advanced disease stages," the investigators concluded.

The investigators reported having no disclosures.

Monosomal karyotype and high prognostic risk according to the revised International Prognostic Scoring System are independent predictors of relapse and mortality in patients with myelodysplastic syndrome or oligoblastic acute myeloid leukemia who undergo allogeneic hematopoietic stem cell transplantation, according to findings from the GITMO (Gruppo Italiano Trapianto di Midollo Osseo) registry.

Treatment failure after allogeneic hematopoietic stem cell transplantation may be from transplant complications or relapse. To understand the predictors of failure, investigators studied outcomes in 519 patients with myelodysplastic syndrome or oligoblastic acute myeloid leukemia who underwent hematopoietic stem cell transplantation between 2000 and 2011.

Those with monosomal karyotype had a 49% relapse rate and a 10% 5-year overall survival rate; both rates were significantly worse, compared with patients without monosomal karyotype (P less than .001 for each). Those considered high or very-high risk based on the International Prognostic Scoring System (IPSS-R), had 39% and 23% 5-year overall survival, respectively, and 23% and 39% relapse rates, respectively (P less than .001 in all cases vs. patients not at high or very-high risk), Dr. Matteo G. Della Porta of Fondazione IRCCS Policlinico San Matteo, Pavia, Italy and colleagues reported on behalf of the GITMO.

Age of 50 years or older and high hematopoietic cell transplantation-comorbidity index scores were independent predictors of nonrelapse mortality (P = .02; P = .017, respectively), they found (Blood 2014 [doi:10.1182/blood-2013-12-542720]).

Accounting for various combinations of patients’ ages, IPSS-R category, monosomal karyotype, and high hematopoietic cell transplantation–comorbidity index, the 5-year probability of survival after allogeneic hematopoietic stem cell transplantation ranged from 0 to 94%. The analyses performed reinforce the concept that allogenic hematopoietic stem cell transplantation – the only potentially curative treatment for MDS – "offers optimal eradication of myelodysplastic hematopoiesis when the procedure is performed before MDS patients progress to advanced disease stages," the investigators concluded.

The investigators reported having no disclosures.

Coadministration with entinostat – a cell-cycle inhibitor – appears to decrease hematologic responsiveness to azacitidine treatment for high-risk myelodysplastic syndrome, according to data from an open-label, phase II randomized trial.

An earlier, phase I pilot study had suggested that the combination was effective and tolerable, however this phase II study in 149 patients (97 patients with myelodysplastic syndrome and 52 patients with acute myeloid leukemia) showed a lower overall hematologic response and lower median overall survival in the combination arm, compared with the azacitidine-only arm, said Dr. Thomas Prebet, who was at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, when the work was done, but is now at Institut Paoli Calmettes, Marseille, France, and his colleagues.

They also performed genome-wide methylation studies on 99 specimens, finding that while demethylation in the combination arm was trending toward overall demethylation, it was significantly reduced, compared with the single agent arm, suggesting the entinostat was actually blocking the action of the azacitidine (J. Clin. Oncol. 2014 March 24 [doi:10.1200/JCO.2013.50.3102]).

The authors did note that the lower-dose, 10-day schedule of azacitidine, which was developed specifically for this phase II trial, appeared to double the rate of hematologic normalization, compared with that observed in a previous study using the standard 7-day schedule, suggesting that the longer schedule was more effective.

Some authors reported being consultants for and/or receiving research funding from various pharmaceutical companies. The study was partly supported by grants from the Leukemia and Lymphoma Society of America and Fulbright Franco-American Commission/Foundation.

tor@frontlinemedcom.com

Coadministration with entinostat – a cell-cycle inhibitor – appears to decrease hematologic responsiveness to azacitidine treatment for high-risk myelodysplastic syndrome, according to data from an open-label, phase II randomized trial.

An earlier, phase I pilot study had suggested that the combination was effective and tolerable, however this phase II study in 149 patients (97 patients with myelodysplastic syndrome and 52 patients with acute myeloid leukemia) showed a lower overall hematologic response and lower median overall survival in the combination arm, compared with the azacitidine-only arm, said Dr. Thomas Prebet, who was at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, when the work was done, but is now at Institut Paoli Calmettes, Marseille, France, and his colleagues.

They also performed genome-wide methylation studies on 99 specimens, finding that while demethylation in the combination arm was trending toward overall demethylation, it was significantly reduced, compared with the single agent arm, suggesting the entinostat was actually blocking the action of the azacitidine (J. Clin. Oncol. 2014 March 24 [doi:10.1200/JCO.2013.50.3102]).

The authors did note that the lower-dose, 10-day schedule of azacitidine, which was developed specifically for this phase II trial, appeared to double the rate of hematologic normalization, compared with that observed in a previous study using the standard 7-day schedule, suggesting that the longer schedule was more effective.

Some authors reported being consultants for and/or receiving research funding from various pharmaceutical companies. The study was partly supported by grants from the Leukemia and Lymphoma Society of America and Fulbright Franco-American Commission/Foundation.

tor@frontlinemedcom.com

Coadministration with entinostat – a cell-cycle inhibitor – appears to decrease hematologic responsiveness to azacitidine treatment for high-risk myelodysplastic syndrome, according to data from an open-label, phase II randomized trial.

An earlier, phase I pilot study had suggested that the combination was effective and tolerable, however this phase II study in 149 patients (97 patients with myelodysplastic syndrome and 52 patients with acute myeloid leukemia) showed a lower overall hematologic response and lower median overall survival in the combination arm, compared with the azacitidine-only arm, said Dr. Thomas Prebet, who was at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, when the work was done, but is now at Institut Paoli Calmettes, Marseille, France, and his colleagues.

They also performed genome-wide methylation studies on 99 specimens, finding that while demethylation in the combination arm was trending toward overall demethylation, it was significantly reduced, compared with the single agent arm, suggesting the entinostat was actually blocking the action of the azacitidine (J. Clin. Oncol. 2014 March 24 [doi:10.1200/JCO.2013.50.3102]).

The authors did note that the lower-dose, 10-day schedule of azacitidine, which was developed specifically for this phase II trial, appeared to double the rate of hematologic normalization, compared with that observed in a previous study using the standard 7-day schedule, suggesting that the longer schedule was more effective.

Some authors reported being consultants for and/or receiving research funding from various pharmaceutical companies. The study was partly supported by grants from the Leukemia and Lymphoma Society of America and Fulbright Franco-American Commission/Foundation.

tor@frontlinemedcom.com

 

 

Syringe

 

The European Commission (EC) has approved a subcutaneous (SC) formulation of rituximab (MabThera) to treat patients with follicular lymphoma or diffuse large B-cell lymphoma.

This formulation allows for 5-minute administration, a significant decrease over the 2.5-hour infusion time required to administer intravenous (IV) rituximab.

The drug’s maker, Roche, plans to begin launching SC rituximab in a number of European markets this year.

The EC’s approval of this formulation was primarily based on data from the SABRINA trial, which was recently published in The Lancet Oncology and funded by Roche.

In this phase 3 trial, researchers compared 3-week cycles of fixed-dose, SC rituximab to IV rituximab. They enrolled 127 patients with previously untreated, grade 1-3a, CD20-positive follicular lymphoma.

Patients were randomized to receive IV rituximab (375 mg/m²) or SC rituximab (1400 mg). After randomization, they received 1 induction dose of IV rituximab in cycle 1 and then their allocated treatment for cycles 2 through 8. Patients with a complete or partial response continued their treatment as maintenance every 8 weeks.

The study’s primary endpoint was the ratio of observed rituximab serum trough concentrations (C_trough) between the 2 groups at cycle 7.

Pharmacokinetic data were available for 75% of patients (48/64) in the IV arm and 86% of the patients (54/63) in the SC arm.

An analysis of these data suggested SC rituximab was non-inferior to the IV formulation. The geometric mean C_trough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio, 1.62).

The rate of adverse events was similar between the 2 arms, occurring in 88% (57/65) of patients in the IV arm and 92% (57/62) of patients in the SC arm. Grade 3 or higher adverse events occurred in 46% (n=30) and 47% (n=29) of patients, respectively.

The most common grade 3 or higher adverse event in both arms was neutropenia. It occurred in 22% (n=14) of patients in the IV arm and 26% (n=16) in the SC arm.

Adverse events related to administration were mostly grade 1-2. And they occurred more often in the SC arm than in the IV arm, in 50% (n=31) and 32% (n=21) of patients, respectively.

The researchers said these results suggest the SC formulation of rituximab is non-inferior to the IV formulation and poses no new safety concerns.

 

 

Syringe

 

The European Commission (EC) has approved a subcutaneous (SC) formulation of rituximab (MabThera) to treat patients with follicular lymphoma or diffuse large B-cell lymphoma.

This formulation allows for 5-minute administration, a significant decrease over the 2.5-hour infusion time required to administer intravenous (IV) rituximab.

The drug’s maker, Roche, plans to begin launching SC rituximab in a number of European markets this year.

The EC’s approval of this formulation was primarily based on data from the SABRINA trial, which was recently published in The Lancet Oncology and funded by Roche.

In this phase 3 trial, researchers compared 3-week cycles of fixed-dose, SC rituximab to IV rituximab. They enrolled 127 patients with previously untreated, grade 1-3a, CD20-positive follicular lymphoma.

Patients were randomized to receive IV rituximab (375 mg/m²) or SC rituximab (1400 mg). After randomization, they received 1 induction dose of IV rituximab in cycle 1 and then their allocated treatment for cycles 2 through 8. Patients with a complete or partial response continued their treatment as maintenance every 8 weeks.

The study’s primary endpoint was the ratio of observed rituximab serum trough concentrations (C_trough) between the 2 groups at cycle 7.

Pharmacokinetic data were available for 75% of patients (48/64) in the IV arm and 86% of the patients (54/63) in the SC arm.

An analysis of these data suggested SC rituximab was non-inferior to the IV formulation. The geometric mean C_trough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio, 1.62).

The rate of adverse events was similar between the 2 arms, occurring in 88% (57/65) of patients in the IV arm and 92% (57/62) of patients in the SC arm. Grade 3 or higher adverse events occurred in 46% (n=30) and 47% (n=29) of patients, respectively.

The most common grade 3 or higher adverse event in both arms was neutropenia. It occurred in 22% (n=14) of patients in the IV arm and 26% (n=16) in the SC arm.

Adverse events related to administration were mostly grade 1-2. And they occurred more often in the SC arm than in the IV arm, in 50% (n=31) and 32% (n=21) of patients, respectively.

The researchers said these results suggest the SC formulation of rituximab is non-inferior to the IV formulation and poses no new safety concerns.

 

 

Syringe

 

The European Commission (EC) has approved a subcutaneous (SC) formulation of rituximab (MabThera) to treat patients with follicular lymphoma or diffuse large B-cell lymphoma.

This formulation allows for 5-minute administration, a significant decrease over the 2.5-hour infusion time required to administer intravenous (IV) rituximab.

The drug’s maker, Roche, plans to begin launching SC rituximab in a number of European markets this year.

The EC’s approval of this formulation was primarily based on data from the SABRINA trial, which was recently published in The Lancet Oncology and funded by Roche.

In this phase 3 trial, researchers compared 3-week cycles of fixed-dose, SC rituximab to IV rituximab. They enrolled 127 patients with previously untreated, grade 1-3a, CD20-positive follicular lymphoma.

Patients were randomized to receive IV rituximab (375 mg/m²) or SC rituximab (1400 mg). After randomization, they received 1 induction dose of IV rituximab in cycle 1 and then their allocated treatment for cycles 2 through 8. Patients with a complete or partial response continued their treatment as maintenance every 8 weeks.

The study’s primary endpoint was the ratio of observed rituximab serum trough concentrations (C_trough) between the 2 groups at cycle 7.

Pharmacokinetic data were available for 75% of patients (48/64) in the IV arm and 86% of the patients (54/63) in the SC arm.

An analysis of these data suggested SC rituximab was non-inferior to the IV formulation. The geometric mean C_trough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio, 1.62).

The rate of adverse events was similar between the 2 arms, occurring in 88% (57/65) of patients in the IV arm and 92% (57/62) of patients in the SC arm. Grade 3 or higher adverse events occurred in 46% (n=30) and 47% (n=29) of patients, respectively.

The most common grade 3 or higher adverse event in both arms was neutropenia. It occurred in 22% (n=14) of patients in the IV arm and 26% (n=16) in the SC arm.

Adverse events related to administration were mostly grade 1-2. And they occurred more often in the SC arm than in the IV arm, in 50% (n=31) and 32% (n=21) of patients, respectively.

The researchers said these results suggest the SC formulation of rituximab is non-inferior to the IV formulation and poses no new safety concerns.