CASE 1 › Sally G, age 46, has been experiencing paresthesias for the past 3 months. She says that when she is cycling, the air on her legs feels much cooler than normal, with a similar feeling in her hands. Whenever her hands or legs are in cool water, she says it feels as if she’s dipped them into an ice bucket. Summer heat makes her skin feel as if it's on fire, and she’s noticed increased sweating on her lower legs. She complains of itching (although she has no rash) and she’s had intermittent tingling and burning in her toes. On neurologic exam, she demonstrates normal strength, sensation, reflexes, coordination, and cranial nerve function.

Case 2 › Jessica T, age 25, comes in to see her family physician because she’s been experiencing numbness in her right leg. It had begun with numbness of the right great toe about a year ago. Subsequently, the numbness extended up her foot to the lateral aspect of the lower leg with an accompanying burning sensation. Three months prior to this visit, she developed weakness in her right foot and toes. She denies any symptoms in her left leg, upper extremities, or face.

A neurologic exam of the upper extremities is normal. Ms. T also has normal cranial nerve function, and normal strength, sensation, and reflexes in the left leg. A motor exam of the right leg reveals normal strength in the hip flexors, hip adductors, hip abductors, and quadriceps. On the Medical Research Council scale, she has 4/5 strength in the hamstrings, 0/5 in the ankle dorsiflexors, 1/5 in the posterior tibialis, and 3/5 in the gastrocnemius. She has a normal right patellar reflex, and an ankle jerk reflex and Babinski sign are absent. She has reduced sensation on the posterior and lateral portions of the right leg and the entire foot. Sensation is preserved on the medial side of the right lower leg and anterior thigh. She has right-sided steppage gait.

Look for positive neuropathic symptoms such as cramping and tingling, negative symptoms such as numbness and weakness, and autonomic symptoms such as constipation, diarrhea, and sweating.

If these 2 women were your patients, how would you proceed with their care?

Paresthesias such as numbness and tingling in the lower extremities are common complaints in family medicine. These symptoms can be challenging to evaluate because they have multiple potential etiologies with varied clinical presentations.¹

A well-honed understanding of lower extremity anatomy and the location and characteristics of common complaints is essential to making an accurate diagnosis and treatment plan. This article discusses the tests to use when evaluating a patient who presents with lower extremity numbness and pain. It also describes the typical presentation and findings of several types of peripheral neuropathy, and how to manage them.

Parasthesias are often the result of peripheral neuropathy

While paresthesias can arise from disorders of the central or peripheral nervous system, this article focuses on paresthesias that are the result of peripheral neuropathy. Peripheral neuropathy can be classified as mononeuropathy, multiple mononeuropathy, or polyneuropathy:

• Mononeuropathy is focal involvement of a single nerve resulting from a localized process such as compression or entrapment, as in carpal tunnel syndrome.¹
• Multiple mononeuropathy (mononeuritis multiplex) results from damage to multiple noncontiguous nerves that can occur simultaneously or sequentially, as in vasculitic causes of neuropathy.¹
• Polyneuropathy involves 2 or more contiguous nerves, usually symmetric and length-dependent, creating a “stocking-glove” pattern of paresthesias.¹ Polyneuropathy affects longer nerves first, and thus, patients will initially complain of symptoms in their feet and legs, and later their hands. Polyneuropathy is most commonly seen in diabetes.

Possible causes of peripheral neuropathy include numerous anatomic, systemic, metabolic, and toxic conditions (TABLE 1).^1,2

What's causing the neuropathy? The search for telltale clues

While obtaining the history, ask the patient about the presence of positive, negative, or autonomic neuropathic symptoms. Positive symptoms, which usually present first, are due to excess or inappropriate nerve activity and include cramping, twitching, burning, and tingling.³ Negative symptoms are due to reduced nerve activity and include numbness, weakness, decreased balance, and poor sensation. Autonomic symptoms include early satiety, constipation or diarrhea, impotence, sweating abnormalities, and orthostasis.³ The timing of onset, progression, and duration of such symptoms can give important diagnostic clues. For example, an acute onset of painful foot drop may indicate an inflammatory cause such as vasculitis, whereas slowly progressive numbness in both feet points toward a distal sensorimotor polyneuropathy, likely from a metabolic cause. Symmetry or asymmetry at presentation, as well as speed of progression of symptoms, can also significantly narrow the differential (TABLE 2).

Determining the exact location of symptoms is important and usually requires prompting. For example, when a patient refers to “the legs,” he could mean anywhere from the foot to the hip. The presence of radiating pain can also help localize the lesion, generally pointing to a radiculopathy (disease at the root of a nerve). Bowel or bladder involvement could suggest involvement of the spinal cord or autonomic nervous system.

A thorough social history can help identify potentially treatable causes of neuropathy. The probability of a toxic, infectious, or vitamin deficiency etiology can be ascertained by inquiring about a patient’s occupation, sexual history, dietary habits, and drug, alcohol, and tobacco history.³ Personal and family medical history can suggest possible genetic or endocrine causes of neuropathy. A personal or family history of childhood “clumsiness” (suggestive of a hereditary neuropathy, such as Charcot-Marie-Tooth disease), diabetes mellitus, or thyroid, renal, hepatic, or autoimmune diseases would be significant. A personal or family history of cancer is also an important diagnostic clue.³

These tests help narrow the diagnostic possibilities

An acute onset of painful foot drop may indicate an inflammatory cause of neuropathic symptoms, such as vasculitis.

Motor and sensory testing are essential, as is testing of coordination and reflexes. Motor examination involves manual muscle testing. In many patients, pain can limit effort, so encourage patients to try hard during testing so you can determine the true severity of weakness. Sensory testing should include pinprick, temperature differentiation, vibration, and proprioception. Also examine the cranial nerves and upper extremities because abnormal findings could suggest a central nervous system (CNS) lesion or proximal progression of disease, with the patient unaware of subtle symptom worsening or spreading. The pattern of deficits as well as predominance of motor vs sensory nerve involvement can further narrow the differential. For example, unilateral symptoms typically suggest either a structural lesion or inflammatory lesion as the cause, while unilateral weakness without numbness could be significant for the onset of amyotrophic lateral sclerosis.¹ A careful skin, hair, and mucous membrane exam is useful because many infectious, toxic, autoimmune, and genetic causes of peripheral neuropathy also cause changes in these areas. High arches, hammer toes, and inverted champagne bottle legs suggest a hereditary neuropathy.³

In addition to the history and examination, electrodiagnostic testing (EDX) is often helpful, and judicious laboratory testing can further narrow diagnostic possibilities. (See “How best to use EDX and lab testing to evaluate peripheral neuropathy”.^1-3)

So what type of neuropathy are you dealing with?

The details of your patient’s history and findings from the exam and testing will point you toward any one of a number of different types of neuropathies. The list below covers a range—from the common (distal sensorimotor polyneuropathy) to the more rare (paraneoplastic neuropathies).

Distal sensorimotor polyneuropathy (DSP)

DSP is the most common type of neuropathy.⁴ The typical presentation of DSP is chronic, distal, symmetric, and predominantly sensory.⁵ Any variation on this suggests an atypical neuropathy.⁵ Patients with DSP present with loss of function (loss of sensation to pinprick, temperature, vibration, proprioception) and/or tingling, burning, and pain starting symmetrically in the lower extremities. Over the course of years, paresthesias move up the legs to the knees before symptoms begin in the arms.

While the disorder can be quite painful, it is not usually functionally limiting unless the loss of sensation is severe enough to cause falls from sensory ataxia. Weakness is rare. When it occurs, it is usually a mild weakness of the distal leg with foot atrophy.

The most common cause of DSP is diabetes or impaired glucose tolerance. Other common causes are vitamin deficiencies (vitamin B1, B6, B12), folate deficiency, paraproteinemia, and hypo/hyperthyroidism. Also consider alcohol abuse, human immunodeficiency virus (HIV) infection, gastric bypass, chemotherapy, chronic kidney disease, and autoimmune conditions such as Sjögren’s syndrome, lupus, and rheumatoid arthritis.¹

Testing. EDX can help confirm a diagnosis of DSP. A 2009 American Academy of Neurology review of lab testing for DSP found the tests with the highest diagnostic yield were fasting blood glucose, vitamin B12 level with methylmalonic acid, and serum protein electrophoresis and immunofixation electrophoresis (IFE).⁴ If the initial screen with a fasting blood sugar or hemoglobin A1c (HbA1c) is negative, further testing with a glucose tolerance test is recommended.

Treatment of DSP depends on the underlying etiology. Vitamin deficiencies should be corrected and metabolic or autoimmune etiologies addressed as appropriate. There are multiple pharmacologic options for treating persistent pain or discomfort. Best evidence (Level A) exists for pregabalin.⁶ Moderate evidence of effectiveness (Level B) exists for gabapentin, sodium valproate, amitriptyline, venlafaxine, and duloxetine.⁶

Small fiber neuropathy

Small fiber neuropathy can present similarly to DSP, with distal painful paresthesias, but can spread to the upper extremities within a few weeks or months from onset, while DSP spreads to the hands years after onset. Small fiber neuropathy is also associated with early autonomic dysfunction. Examination usually reveals decreased sensation distally, but reflexes and strength are normal.

Common causes of small fiber neuropathy are diabetes, glucose intolerance, metabolic syndrome, hypo/hyperthyroidism, monoclonal gammopathy, alcohol abuse, vitamin B12 deficiency, and hypertriglyceridemia.⁷ Less common causes include Sjögren’s syndrome, HIV, Lyme disease, sarcoidosis, heavy metal toxicity, amyloidosis, and celiac disease.⁷

Testing and treatment. Skin biopsy is used to confirm the diagnosis of small fiber neuropathy.⁷ (EDX results are normal.⁷) Persistent pain can be treated with the same agents discussed above for treating DSP.

Acquired demyelinating neuropathy

Acquired demyelinating neuropathy is a rare condition, but one in which prompt recognition and treatment can prevent significant neurologic decline. There are both acute and chronic types of acquired demyelinating neuropathies.

Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyradiculoneuropathy. Nearly two-thirds of patients with GBS report a previous respiratory or gastrointestinal illness; cytomegalovirus and Campylobacter jejuni are the most frequently associated infections.⁸

Small fiber neuropathy can look like distal sensorimotor polyneuropathy, but can spread to the upper extremities quicker and can cause autonomic dysfunction.

The onset of GBS often involves pain in the back or limbs, followed by a rapid progression of sensory loss and weakness (over days to a few weeks) that typically starts in the feet and moves upward.⁸ Though the typical presentation of GBS is “ascending,” there are frequent exceptions to this pattern.⁸ Physical exam shows weakness, sensory loss, and absent reflexes. Severe cases can result in complete paralysis, even of extraocular movements. Autonomic dysfunction is common.

Testing. EDX and lumbar puncture are needed to accurately diagnose GBS.⁸ EDX initially may be unremarkable, but over time, areas of demyelination become apparent. Lumbar puncture shows albuminocytologic dissociation (no white cells, elevated protein).

Treatment. Patients with GBS are initially managed as inpatients because 33% of cases lead to respiratory failure.⁹ Treatments include intravenous immunoglobulin (IVIg) or plasmapheresis; both have similar outcomes, speeding neurologic recovery time but not affecting overall long-term prognosis.¹⁰ Response to treatment is often not immediate, and some patients continue to worsen after treatment.⁸ Still, long-term prognosis is good, even for severely affected patients, as long as they receive good supportive care. The relapse rate is between 2% and 6%.⁸

In chronic inflammatory demyelinating polyneuropathy (CIDP), patients develop stepwise nerve dysfunction over many weeks to months. One nerve is affected, then another, usually in a different limb. There is generally no antecedent illness, and pain is infrequent.⁸ Progressive limb weakness is by far the most common presentation, and manifests as a foot drop or wrist drop. Patients may report difficulty getting up from a chair, walking up stairs, or opening jars.⁸ Facial or extraocular nerve involvement is uncommon, as is respiratory involvement.⁸ Neurologic exam shows absent reflexes, weakness, and loss of sensation in the distribution of a particular nerve or nerves.

Testing and treatment. Diagnosis of CIDP is made by a combination of EDX that shows demyelination and lumbar puncture that demonstrates albuminocytologic dissociation. Treatments include long-term immunosuppression with oral prednisone, IVIg, plasmapheresis, and rarely, agents such as mycophenolate mofetil, azathioprine, cyclosporine, and rituximab.⁹

Entrapment neuropathy

This is the result of compression or entrapment of a nerve by another anatomic structure. It can be caused by internal or external factors, including fluid retention.¹¹ Damage from compression or entrapment progresses in stages and, over time, can result in demyelination and distal degeneration of the nerve.¹¹ More interior nerve fibers, such as pain nerve fibers, are often the last to be affected.¹¹ Therefore, patients often first experience loss of motor function or loss of sensation to light touch.

Common fibular nerve (formerly known as common peroneal nerve) entrapment at the fibular head is the most common entrapment neuropathy in the lower extremities. It’s usually the result of direct trauma, such as prolonged positioning in debilitated patients or surgical patients, habitual leg-crossing, tight boots, or tight casts.^11,12 Uncoordinated gait due to poor dorsiflexion of the foot at the ankle (foot drop) is common while plantar flexion is preserved. Pain and sensory loss depend on the degree of compression and the exact location of compression.

Testing and treatment. EDX is useful for identifying the location of compression or entrapment and can guide further imaging, if needed. Conservative treatments aimed at modifying or correcting the underlying etiology, such as removing a tight-fitting cast or brace or instructing a patient to stop leg crossing, can be effective. Occasionally, surgery is required.

Anterior tarsal tunnel syndrome is compression of the deep fibular nerve as it passes through the inferior extensor retinaculum of the distal lower leg. Characteristic symptoms include pain and burning over the dorsum of the foot.¹¹ Paresthesias in the first dorsal web space are also common.¹¹ This can be seen in athletes who perform repetitive ankle plantar flexion, such as ballet dancers, soccer players, and runners.¹² It can also be caused by recurrent ankle sprains, ganglion cysts, and tight-fitting shoes or boots.^11,12 Chronic cases can result in toe extensor weakness or atrophy of the extensor digitorum brevis muscle.

Testing and treatment. Again, EDX is very useful in identifying the exact area of compression and involved nerve segments. Management requires correcting the underlying etiology, which can usually be done conservatively. Surgical decompression may be needed.

Suspect a paraneoplastic process if a patient presents with subacute progressive onset of neuropathic symptoms in the upper extremities.

Paraneoplastic neuropathies

Paraneoplastic neuropathies are exceptionally rare but often develop before cancer is diagnosed. Therefore, early suspicion and recognition can greatly affect cancer prognosis.¹³ Certain characteristics should increase suspicion of a paraneoplastic process. For example, symptoms with a subacute progressive onset that involve the upper extremities early in the disease are characteristic of a paraneoplastic process.¹³

Coexisting CNS symptoms and/or constitutional symptoms of malignancy should also increase suspicion.¹³ Consider a paraneo­plastic process in patients who have a past history of cancer or significant cancer risk factors, such as smoking.

Testing. When you suspect a paraneoplastic process, the work-up should include antibody testing for the most common or likely cancers according to patient characteristics. Panels of the most common paraneoplastic antibodies are available from many commercial labs. Obtain imaging to identify a possible underlying malignancy.

That said, it’s also important to perform a basic work-up for the more common causes of neuropathy in patients you suspect may have cancer. The reason: Paraneoplastic neuropathies are rare, and not all neuropathies in patients with cancer are paraneoplastic.¹³

CASE 1 › Ms. G describes diffuse paresthesias that are worse in her lower extremities, but she has a normal neurologic exam. Her physician suspects a neuropathic cause, and a normal exam makes small fiber neuropathy more likely. EDX is normal. The initial work-up includes an HbA1c, thyroid-stimulating hormone, vitamin B12 level, antinuclear antibody, erythrocyte sedimentation rate, IFE, and free light chain assay.

Testing reveals that Ms. G has a high free light chain ratio, which suggests a monoclonal gammopathy is the most likely etiology. Skin biopsy demonstrates decreased nerve fiber density consistent with a small fiber neuropathy. Her physician refers her to Hematology for bone marrow biopsy, and also prescribes gabapentin 300 mg/d at bedtime for symptomatic relief. Ms. G is currently being closely monitored for conversion to multiple myeloma.

CASE 2 › In Ms. T’s case, the exam helps localize the lesion. Areas supplied by the common fibular nerve, tibial nerve, and sural nerve are affected, while the area innervated by the femoral nerve and saphenous nerve and the proximal hip muscles are spared. This localizes a lesion to the sciatic nerve. EDX confirms a proximal sciatic lesion, but not the underlying etiology. Since the lesion had been precisely localized, her physician orders imaging.

Magnetic resonance imaging of Ms. T’s hip and upper leg shows a 10.7 cm x 7.8 cm x 13 cm heterogeneously enhancing mass in the expected location of the right sciatic nerve (FIGURE). Biopsy reveals a high grade, poorly differentiated synovial sarcoma. Her physician refers her to an oncologist for initiation of chemotherapy, radiation, and debulking surgery.

CORRESPONDENCE
Laura C. Mayans, MD, Department of Family and Community Medicine, University of Kansas School of Medicine-Wichita, 1010 N. Kansas, Wichita, KS 67214; [email protected].

CASE 1 › Sally G, age 46, has been experiencing paresthesias for the past 3 months. She says that when she is cycling, the air on her legs feels much cooler than normal, with a similar feeling in her hands. Whenever her hands or legs are in cool water, she says it feels as if she’s dipped them into an ice bucket. Summer heat makes her skin feel as if it's on fire, and she’s noticed increased sweating on her lower legs. She complains of itching (although she has no rash) and she’s had intermittent tingling and burning in her toes. On neurologic exam, she demonstrates normal strength, sensation, reflexes, coordination, and cranial nerve function.

Case 2 › Jessica T, age 25, comes in to see her family physician because she’s been experiencing numbness in her right leg. It had begun with numbness of the right great toe about a year ago. Subsequently, the numbness extended up her foot to the lateral aspect of the lower leg with an accompanying burning sensation. Three months prior to this visit, she developed weakness in her right foot and toes. She denies any symptoms in her left leg, upper extremities, or face.

A neurologic exam of the upper extremities is normal. Ms. T also has normal cranial nerve function, and normal strength, sensation, and reflexes in the left leg. A motor exam of the right leg reveals normal strength in the hip flexors, hip adductors, hip abductors, and quadriceps. On the Medical Research Council scale, she has 4/5 strength in the hamstrings, 0/5 in the ankle dorsiflexors, 1/5 in the posterior tibialis, and 3/5 in the gastrocnemius. She has a normal right patellar reflex, and an ankle jerk reflex and Babinski sign are absent. She has reduced sensation on the posterior and lateral portions of the right leg and the entire foot. Sensation is preserved on the medial side of the right lower leg and anterior thigh. She has right-sided steppage gait.

Look for positive neuropathic symptoms such as cramping and tingling, negative symptoms such as numbness and weakness, and autonomic symptoms such as constipation, diarrhea, and sweating.

If these 2 women were your patients, how would you proceed with their care?

Paresthesias such as numbness and tingling in the lower extremities are common complaints in family medicine. These symptoms can be challenging to evaluate because they have multiple potential etiologies with varied clinical presentations.¹

A well-honed understanding of lower extremity anatomy and the location and characteristics of common complaints is essential to making an accurate diagnosis and treatment plan. This article discusses the tests to use when evaluating a patient who presents with lower extremity numbness and pain. It also describes the typical presentation and findings of several types of peripheral neuropathy, and how to manage them.

Parasthesias are often the result of peripheral neuropathy

While paresthesias can arise from disorders of the central or peripheral nervous system, this article focuses on paresthesias that are the result of peripheral neuropathy. Peripheral neuropathy can be classified as mononeuropathy, multiple mononeuropathy, or polyneuropathy:

• Mononeuropathy is focal involvement of a single nerve resulting from a localized process such as compression or entrapment, as in carpal tunnel syndrome.¹
• Multiple mononeuropathy (mononeuritis multiplex) results from damage to multiple noncontiguous nerves that can occur simultaneously or sequentially, as in vasculitic causes of neuropathy.¹
• Polyneuropathy involves 2 or more contiguous nerves, usually symmetric and length-dependent, creating a “stocking-glove” pattern of paresthesias.¹ Polyneuropathy affects longer nerves first, and thus, patients will initially complain of symptoms in their feet and legs, and later their hands. Polyneuropathy is most commonly seen in diabetes.

Possible causes of peripheral neuropathy include numerous anatomic, systemic, metabolic, and toxic conditions (TABLE 1).^1,2

What's causing the neuropathy? The search for telltale clues

While obtaining the history, ask the patient about the presence of positive, negative, or autonomic neuropathic symptoms. Positive symptoms, which usually present first, are due to excess or inappropriate nerve activity and include cramping, twitching, burning, and tingling.³ Negative symptoms are due to reduced nerve activity and include numbness, weakness, decreased balance, and poor sensation. Autonomic symptoms include early satiety, constipation or diarrhea, impotence, sweating abnormalities, and orthostasis.³ The timing of onset, progression, and duration of such symptoms can give important diagnostic clues. For example, an acute onset of painful foot drop may indicate an inflammatory cause such as vasculitis, whereas slowly progressive numbness in both feet points toward a distal sensorimotor polyneuropathy, likely from a metabolic cause. Symmetry or asymmetry at presentation, as well as speed of progression of symptoms, can also significantly narrow the differential (TABLE 2).

Determining the exact location of symptoms is important and usually requires prompting. For example, when a patient refers to “the legs,” he could mean anywhere from the foot to the hip. The presence of radiating pain can also help localize the lesion, generally pointing to a radiculopathy (disease at the root of a nerve). Bowel or bladder involvement could suggest involvement of the spinal cord or autonomic nervous system.

A thorough social history can help identify potentially treatable causes of neuropathy. The probability of a toxic, infectious, or vitamin deficiency etiology can be ascertained by inquiring about a patient’s occupation, sexual history, dietary habits, and drug, alcohol, and tobacco history.³ Personal and family medical history can suggest possible genetic or endocrine causes of neuropathy. A personal or family history of childhood “clumsiness” (suggestive of a hereditary neuropathy, such as Charcot-Marie-Tooth disease), diabetes mellitus, or thyroid, renal, hepatic, or autoimmune diseases would be significant. A personal or family history of cancer is also an important diagnostic clue.³

These tests help narrow the diagnostic possibilities

An acute onset of painful foot drop may indicate an inflammatory cause of neuropathic symptoms, such as vasculitis.

Motor and sensory testing are essential, as is testing of coordination and reflexes. Motor examination involves manual muscle testing. In many patients, pain can limit effort, so encourage patients to try hard during testing so you can determine the true severity of weakness. Sensory testing should include pinprick, temperature differentiation, vibration, and proprioception. Also examine the cranial nerves and upper extremities because abnormal findings could suggest a central nervous system (CNS) lesion or proximal progression of disease, with the patient unaware of subtle symptom worsening or spreading. The pattern of deficits as well as predominance of motor vs sensory nerve involvement can further narrow the differential. For example, unilateral symptoms typically suggest either a structural lesion or inflammatory lesion as the cause, while unilateral weakness without numbness could be significant for the onset of amyotrophic lateral sclerosis.¹ A careful skin, hair, and mucous membrane exam is useful because many infectious, toxic, autoimmune, and genetic causes of peripheral neuropathy also cause changes in these areas. High arches, hammer toes, and inverted champagne bottle legs suggest a hereditary neuropathy.³

In addition to the history and examination, electrodiagnostic testing (EDX) is often helpful, and judicious laboratory testing can further narrow diagnostic possibilities. (See “How best to use EDX and lab testing to evaluate peripheral neuropathy”.^1-3)

So what type of neuropathy are you dealing with?

The details of your patient’s history and findings from the exam and testing will point you toward any one of a number of different types of neuropathies. The list below covers a range—from the common (distal sensorimotor polyneuropathy) to the more rare (paraneoplastic neuropathies).

Distal sensorimotor polyneuropathy (DSP)

DSP is the most common type of neuropathy.⁴ The typical presentation of DSP is chronic, distal, symmetric, and predominantly sensory.⁵ Any variation on this suggests an atypical neuropathy.⁵ Patients with DSP present with loss of function (loss of sensation to pinprick, temperature, vibration, proprioception) and/or tingling, burning, and pain starting symmetrically in the lower extremities. Over the course of years, paresthesias move up the legs to the knees before symptoms begin in the arms.

While the disorder can be quite painful, it is not usually functionally limiting unless the loss of sensation is severe enough to cause falls from sensory ataxia. Weakness is rare. When it occurs, it is usually a mild weakness of the distal leg with foot atrophy.

The most common cause of DSP is diabetes or impaired glucose tolerance. Other common causes are vitamin deficiencies (vitamin B1, B6, B12), folate deficiency, paraproteinemia, and hypo/hyperthyroidism. Also consider alcohol abuse, human immunodeficiency virus (HIV) infection, gastric bypass, chemotherapy, chronic kidney disease, and autoimmune conditions such as Sjögren’s syndrome, lupus, and rheumatoid arthritis.¹

Testing. EDX can help confirm a diagnosis of DSP. A 2009 American Academy of Neurology review of lab testing for DSP found the tests with the highest diagnostic yield were fasting blood glucose, vitamin B12 level with methylmalonic acid, and serum protein electrophoresis and immunofixation electrophoresis (IFE).⁴ If the initial screen with a fasting blood sugar or hemoglobin A1c (HbA1c) is negative, further testing with a glucose tolerance test is recommended.

Treatment of DSP depends on the underlying etiology. Vitamin deficiencies should be corrected and metabolic or autoimmune etiologies addressed as appropriate. There are multiple pharmacologic options for treating persistent pain or discomfort. Best evidence (Level A) exists for pregabalin.⁶ Moderate evidence of effectiveness (Level B) exists for gabapentin, sodium valproate, amitriptyline, venlafaxine, and duloxetine.⁶

Small fiber neuropathy

Small fiber neuropathy can present similarly to DSP, with distal painful paresthesias, but can spread to the upper extremities within a few weeks or months from onset, while DSP spreads to the hands years after onset. Small fiber neuropathy is also associated with early autonomic dysfunction. Examination usually reveals decreased sensation distally, but reflexes and strength are normal.

Common causes of small fiber neuropathy are diabetes, glucose intolerance, metabolic syndrome, hypo/hyperthyroidism, monoclonal gammopathy, alcohol abuse, vitamin B12 deficiency, and hypertriglyceridemia.⁷ Less common causes include Sjögren’s syndrome, HIV, Lyme disease, sarcoidosis, heavy metal toxicity, amyloidosis, and celiac disease.⁷

Testing and treatment. Skin biopsy is used to confirm the diagnosis of small fiber neuropathy.⁷ (EDX results are normal.⁷) Persistent pain can be treated with the same agents discussed above for treating DSP.

Acquired demyelinating neuropathy

Acquired demyelinating neuropathy is a rare condition, but one in which prompt recognition and treatment can prevent significant neurologic decline. There are both acute and chronic types of acquired demyelinating neuropathies.

Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyradiculoneuropathy. Nearly two-thirds of patients with GBS report a previous respiratory or gastrointestinal illness; cytomegalovirus and Campylobacter jejuni are the most frequently associated infections.⁸

Small fiber neuropathy can look like distal sensorimotor polyneuropathy, but can spread to the upper extremities quicker and can cause autonomic dysfunction.

The onset of GBS often involves pain in the back or limbs, followed by a rapid progression of sensory loss and weakness (over days to a few weeks) that typically starts in the feet and moves upward.⁸ Though the typical presentation of GBS is “ascending,” there are frequent exceptions to this pattern.⁸ Physical exam shows weakness, sensory loss, and absent reflexes. Severe cases can result in complete paralysis, even of extraocular movements. Autonomic dysfunction is common.

Testing. EDX and lumbar puncture are needed to accurately diagnose GBS.⁸ EDX initially may be unremarkable, but over time, areas of demyelination become apparent. Lumbar puncture shows albuminocytologic dissociation (no white cells, elevated protein).

Treatment. Patients with GBS are initially managed as inpatients because 33% of cases lead to respiratory failure.⁹ Treatments include intravenous immunoglobulin (IVIg) or plasmapheresis; both have similar outcomes, speeding neurologic recovery time but not affecting overall long-term prognosis.¹⁰ Response to treatment is often not immediate, and some patients continue to worsen after treatment.⁸ Still, long-term prognosis is good, even for severely affected patients, as long as they receive good supportive care. The relapse rate is between 2% and 6%.⁸

In chronic inflammatory demyelinating polyneuropathy (CIDP), patients develop stepwise nerve dysfunction over many weeks to months. One nerve is affected, then another, usually in a different limb. There is generally no antecedent illness, and pain is infrequent.⁸ Progressive limb weakness is by far the most common presentation, and manifests as a foot drop or wrist drop. Patients may report difficulty getting up from a chair, walking up stairs, or opening jars.⁸ Facial or extraocular nerve involvement is uncommon, as is respiratory involvement.⁸ Neurologic exam shows absent reflexes, weakness, and loss of sensation in the distribution of a particular nerve or nerves.

Testing and treatment. Diagnosis of CIDP is made by a combination of EDX that shows demyelination and lumbar puncture that demonstrates albuminocytologic dissociation. Treatments include long-term immunosuppression with oral prednisone, IVIg, plasmapheresis, and rarely, agents such as mycophenolate mofetil, azathioprine, cyclosporine, and rituximab.⁹

Entrapment neuropathy

This is the result of compression or entrapment of a nerve by another anatomic structure. It can be caused by internal or external factors, including fluid retention.¹¹ Damage from compression or entrapment progresses in stages and, over time, can result in demyelination and distal degeneration of the nerve.¹¹ More interior nerve fibers, such as pain nerve fibers, are often the last to be affected.¹¹ Therefore, patients often first experience loss of motor function or loss of sensation to light touch.

Common fibular nerve (formerly known as common peroneal nerve) entrapment at the fibular head is the most common entrapment neuropathy in the lower extremities. It’s usually the result of direct trauma, such as prolonged positioning in debilitated patients or surgical patients, habitual leg-crossing, tight boots, or tight casts.^11,12 Uncoordinated gait due to poor dorsiflexion of the foot at the ankle (foot drop) is common while plantar flexion is preserved. Pain and sensory loss depend on the degree of compression and the exact location of compression.

Testing and treatment. EDX is useful for identifying the location of compression or entrapment and can guide further imaging, if needed. Conservative treatments aimed at modifying or correcting the underlying etiology, such as removing a tight-fitting cast or brace or instructing a patient to stop leg crossing, can be effective. Occasionally, surgery is required.

Anterior tarsal tunnel syndrome is compression of the deep fibular nerve as it passes through the inferior extensor retinaculum of the distal lower leg. Characteristic symptoms include pain and burning over the dorsum of the foot.¹¹ Paresthesias in the first dorsal web space are also common.¹¹ This can be seen in athletes who perform repetitive ankle plantar flexion, such as ballet dancers, soccer players, and runners.¹² It can also be caused by recurrent ankle sprains, ganglion cysts, and tight-fitting shoes or boots.^11,12 Chronic cases can result in toe extensor weakness or atrophy of the extensor digitorum brevis muscle.

Testing and treatment. Again, EDX is very useful in identifying the exact area of compression and involved nerve segments. Management requires correcting the underlying etiology, which can usually be done conservatively. Surgical decompression may be needed.

Suspect a paraneoplastic process if a patient presents with subacute progressive onset of neuropathic symptoms in the upper extremities.

Paraneoplastic neuropathies

Paraneoplastic neuropathies are exceptionally rare but often develop before cancer is diagnosed. Therefore, early suspicion and recognition can greatly affect cancer prognosis.¹³ Certain characteristics should increase suspicion of a paraneoplastic process. For example, symptoms with a subacute progressive onset that involve the upper extremities early in the disease are characteristic of a paraneoplastic process.¹³

Coexisting CNS symptoms and/or constitutional symptoms of malignancy should also increase suspicion.¹³ Consider a paraneo­plastic process in patients who have a past history of cancer or significant cancer risk factors, such as smoking.

Testing. When you suspect a paraneoplastic process, the work-up should include antibody testing for the most common or likely cancers according to patient characteristics. Panels of the most common paraneoplastic antibodies are available from many commercial labs. Obtain imaging to identify a possible underlying malignancy.

That said, it’s also important to perform a basic work-up for the more common causes of neuropathy in patients you suspect may have cancer. The reason: Paraneoplastic neuropathies are rare, and not all neuropathies in patients with cancer are paraneoplastic.¹³

CASE 1 › Ms. G describes diffuse paresthesias that are worse in her lower extremities, but she has a normal neurologic exam. Her physician suspects a neuropathic cause, and a normal exam makes small fiber neuropathy more likely. EDX is normal. The initial work-up includes an HbA1c, thyroid-stimulating hormone, vitamin B12 level, antinuclear antibody, erythrocyte sedimentation rate, IFE, and free light chain assay.

Testing reveals that Ms. G has a high free light chain ratio, which suggests a monoclonal gammopathy is the most likely etiology. Skin biopsy demonstrates decreased nerve fiber density consistent with a small fiber neuropathy. Her physician refers her to Hematology for bone marrow biopsy, and also prescribes gabapentin 300 mg/d at bedtime for symptomatic relief. Ms. G is currently being closely monitored for conversion to multiple myeloma.

CASE 2 › In Ms. T’s case, the exam helps localize the lesion. Areas supplied by the common fibular nerve, tibial nerve, and sural nerve are affected, while the area innervated by the femoral nerve and saphenous nerve and the proximal hip muscles are spared. This localizes a lesion to the sciatic nerve. EDX confirms a proximal sciatic lesion, but not the underlying etiology. Since the lesion had been precisely localized, her physician orders imaging.

Magnetic resonance imaging of Ms. T’s hip and upper leg shows a 10.7 cm x 7.8 cm x 13 cm heterogeneously enhancing mass in the expected location of the right sciatic nerve (FIGURE). Biopsy reveals a high grade, poorly differentiated synovial sarcoma. Her physician refers her to an oncologist for initiation of chemotherapy, radiation, and debulking surgery.

CORRESPONDENCE
Laura C. Mayans, MD, Department of Family and Community Medicine, University of Kansas School of Medicine-Wichita, 1010 N. Kansas, Wichita, KS 67214; [email protected].

CASE 1 › Sally G, age 46, has been experiencing paresthesias for the past 3 months. She says that when she is cycling, the air on her legs feels much cooler than normal, with a similar feeling in her hands. Whenever her hands or legs are in cool water, she says it feels as if she’s dipped them into an ice bucket. Summer heat makes her skin feel as if it's on fire, and she’s noticed increased sweating on her lower legs. She complains of itching (although she has no rash) and she’s had intermittent tingling and burning in her toes. On neurologic exam, she demonstrates normal strength, sensation, reflexes, coordination, and cranial nerve function.

Case 2 › Jessica T, age 25, comes in to see her family physician because she’s been experiencing numbness in her right leg. It had begun with numbness of the right great toe about a year ago. Subsequently, the numbness extended up her foot to the lateral aspect of the lower leg with an accompanying burning sensation. Three months prior to this visit, she developed weakness in her right foot and toes. She denies any symptoms in her left leg, upper extremities, or face.

A neurologic exam of the upper extremities is normal. Ms. T also has normal cranial nerve function, and normal strength, sensation, and reflexes in the left leg. A motor exam of the right leg reveals normal strength in the hip flexors, hip adductors, hip abductors, and quadriceps. On the Medical Research Council scale, she has 4/5 strength in the hamstrings, 0/5 in the ankle dorsiflexors, 1/5 in the posterior tibialis, and 3/5 in the gastrocnemius. She has a normal right patellar reflex, and an ankle jerk reflex and Babinski sign are absent. She has reduced sensation on the posterior and lateral portions of the right leg and the entire foot. Sensation is preserved on the medial side of the right lower leg and anterior thigh. She has right-sided steppage gait.

Look for positive neuropathic symptoms such as cramping and tingling, negative symptoms such as numbness and weakness, and autonomic symptoms such as constipation, diarrhea, and sweating.

If these 2 women were your patients, how would you proceed with their care?

Paresthesias such as numbness and tingling in the lower extremities are common complaints in family medicine. These symptoms can be challenging to evaluate because they have multiple potential etiologies with varied clinical presentations.¹

A well-honed understanding of lower extremity anatomy and the location and characteristics of common complaints is essential to making an accurate diagnosis and treatment plan. This article discusses the tests to use when evaluating a patient who presents with lower extremity numbness and pain. It also describes the typical presentation and findings of several types of peripheral neuropathy, and how to manage them.

Parasthesias are often the result of peripheral neuropathy

While paresthesias can arise from disorders of the central or peripheral nervous system, this article focuses on paresthesias that are the result of peripheral neuropathy. Peripheral neuropathy can be classified as mononeuropathy, multiple mononeuropathy, or polyneuropathy:

• Mononeuropathy is focal involvement of a single nerve resulting from a localized process such as compression or entrapment, as in carpal tunnel syndrome.¹
• Multiple mononeuropathy (mononeuritis multiplex) results from damage to multiple noncontiguous nerves that can occur simultaneously or sequentially, as in vasculitic causes of neuropathy.¹
• Polyneuropathy involves 2 or more contiguous nerves, usually symmetric and length-dependent, creating a “stocking-glove” pattern of paresthesias.¹ Polyneuropathy affects longer nerves first, and thus, patients will initially complain of symptoms in their feet and legs, and later their hands. Polyneuropathy is most commonly seen in diabetes.

Possible causes of peripheral neuropathy include numerous anatomic, systemic, metabolic, and toxic conditions (TABLE 1).^1,2

What's causing the neuropathy? The search for telltale clues

While obtaining the history, ask the patient about the presence of positive, negative, or autonomic neuropathic symptoms. Positive symptoms, which usually present first, are due to excess or inappropriate nerve activity and include cramping, twitching, burning, and tingling.³ Negative symptoms are due to reduced nerve activity and include numbness, weakness, decreased balance, and poor sensation. Autonomic symptoms include early satiety, constipation or diarrhea, impotence, sweating abnormalities, and orthostasis.³ The timing of onset, progression, and duration of such symptoms can give important diagnostic clues. For example, an acute onset of painful foot drop may indicate an inflammatory cause such as vasculitis, whereas slowly progressive numbness in both feet points toward a distal sensorimotor polyneuropathy, likely from a metabolic cause. Symmetry or asymmetry at presentation, as well as speed of progression of symptoms, can also significantly narrow the differential (TABLE 2).

Determining the exact location of symptoms is important and usually requires prompting. For example, when a patient refers to “the legs,” he could mean anywhere from the foot to the hip. The presence of radiating pain can also help localize the lesion, generally pointing to a radiculopathy (disease at the root of a nerve). Bowel or bladder involvement could suggest involvement of the spinal cord or autonomic nervous system.

A thorough social history can help identify potentially treatable causes of neuropathy. The probability of a toxic, infectious, or vitamin deficiency etiology can be ascertained by inquiring about a patient’s occupation, sexual history, dietary habits, and drug, alcohol, and tobacco history.³ Personal and family medical history can suggest possible genetic or endocrine causes of neuropathy. A personal or family history of childhood “clumsiness” (suggestive of a hereditary neuropathy, such as Charcot-Marie-Tooth disease), diabetes mellitus, or thyroid, renal, hepatic, or autoimmune diseases would be significant. A personal or family history of cancer is also an important diagnostic clue.³

These tests help narrow the diagnostic possibilities

An acute onset of painful foot drop may indicate an inflammatory cause of neuropathic symptoms, such as vasculitis.

Motor and sensory testing are essential, as is testing of coordination and reflexes. Motor examination involves manual muscle testing. In many patients, pain can limit effort, so encourage patients to try hard during testing so you can determine the true severity of weakness. Sensory testing should include pinprick, temperature differentiation, vibration, and proprioception. Also examine the cranial nerves and upper extremities because abnormal findings could suggest a central nervous system (CNS) lesion or proximal progression of disease, with the patient unaware of subtle symptom worsening or spreading. The pattern of deficits as well as predominance of motor vs sensory nerve involvement can further narrow the differential. For example, unilateral symptoms typically suggest either a structural lesion or inflammatory lesion as the cause, while unilateral weakness without numbness could be significant for the onset of amyotrophic lateral sclerosis.¹ A careful skin, hair, and mucous membrane exam is useful because many infectious, toxic, autoimmune, and genetic causes of peripheral neuropathy also cause changes in these areas. High arches, hammer toes, and inverted champagne bottle legs suggest a hereditary neuropathy.³

In addition to the history and examination, electrodiagnostic testing (EDX) is often helpful, and judicious laboratory testing can further narrow diagnostic possibilities. (See “How best to use EDX and lab testing to evaluate peripheral neuropathy”.^1-3)

So what type of neuropathy are you dealing with?

The details of your patient’s history and findings from the exam and testing will point you toward any one of a number of different types of neuropathies. The list below covers a range—from the common (distal sensorimotor polyneuropathy) to the more rare (paraneoplastic neuropathies).

Distal sensorimotor polyneuropathy (DSP)

DSP is the most common type of neuropathy.⁴ The typical presentation of DSP is chronic, distal, symmetric, and predominantly sensory.⁵ Any variation on this suggests an atypical neuropathy.⁵ Patients with DSP present with loss of function (loss of sensation to pinprick, temperature, vibration, proprioception) and/or tingling, burning, and pain starting symmetrically in the lower extremities. Over the course of years, paresthesias move up the legs to the knees before symptoms begin in the arms.

While the disorder can be quite painful, it is not usually functionally limiting unless the loss of sensation is severe enough to cause falls from sensory ataxia. Weakness is rare. When it occurs, it is usually a mild weakness of the distal leg with foot atrophy.

The most common cause of DSP is diabetes or impaired glucose tolerance. Other common causes are vitamin deficiencies (vitamin B1, B6, B12), folate deficiency, paraproteinemia, and hypo/hyperthyroidism. Also consider alcohol abuse, human immunodeficiency virus (HIV) infection, gastric bypass, chemotherapy, chronic kidney disease, and autoimmune conditions such as Sjögren’s syndrome, lupus, and rheumatoid arthritis.¹

Testing. EDX can help confirm a diagnosis of DSP. A 2009 American Academy of Neurology review of lab testing for DSP found the tests with the highest diagnostic yield were fasting blood glucose, vitamin B12 level with methylmalonic acid, and serum protein electrophoresis and immunofixation electrophoresis (IFE).⁴ If the initial screen with a fasting blood sugar or hemoglobin A1c (HbA1c) is negative, further testing with a glucose tolerance test is recommended.

Treatment of DSP depends on the underlying etiology. Vitamin deficiencies should be corrected and metabolic or autoimmune etiologies addressed as appropriate. There are multiple pharmacologic options for treating persistent pain or discomfort. Best evidence (Level A) exists for pregabalin.⁶ Moderate evidence of effectiveness (Level B) exists for gabapentin, sodium valproate, amitriptyline, venlafaxine, and duloxetine.⁶

Small fiber neuropathy

Small fiber neuropathy can present similarly to DSP, with distal painful paresthesias, but can spread to the upper extremities within a few weeks or months from onset, while DSP spreads to the hands years after onset. Small fiber neuropathy is also associated with early autonomic dysfunction. Examination usually reveals decreased sensation distally, but reflexes and strength are normal.

Common causes of small fiber neuropathy are diabetes, glucose intolerance, metabolic syndrome, hypo/hyperthyroidism, monoclonal gammopathy, alcohol abuse, vitamin B12 deficiency, and hypertriglyceridemia.⁷ Less common causes include Sjögren’s syndrome, HIV, Lyme disease, sarcoidosis, heavy metal toxicity, amyloidosis, and celiac disease.⁷

Testing and treatment. Skin biopsy is used to confirm the diagnosis of small fiber neuropathy.⁷ (EDX results are normal.⁷) Persistent pain can be treated with the same agents discussed above for treating DSP.

Acquired demyelinating neuropathy

Acquired demyelinating neuropathy is a rare condition, but one in which prompt recognition and treatment can prevent significant neurologic decline. There are both acute and chronic types of acquired demyelinating neuropathies.

Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyradiculoneuropathy. Nearly two-thirds of patients with GBS report a previous respiratory or gastrointestinal illness; cytomegalovirus and Campylobacter jejuni are the most frequently associated infections.⁸

Small fiber neuropathy can look like distal sensorimotor polyneuropathy, but can spread to the upper extremities quicker and can cause autonomic dysfunction.

The onset of GBS often involves pain in the back or limbs, followed by a rapid progression of sensory loss and weakness (over days to a few weeks) that typically starts in the feet and moves upward.⁸ Though the typical presentation of GBS is “ascending,” there are frequent exceptions to this pattern.⁸ Physical exam shows weakness, sensory loss, and absent reflexes. Severe cases can result in complete paralysis, even of extraocular movements. Autonomic dysfunction is common.

Testing. EDX and lumbar puncture are needed to accurately diagnose GBS.⁸ EDX initially may be unremarkable, but over time, areas of demyelination become apparent. Lumbar puncture shows albuminocytologic dissociation (no white cells, elevated protein).

Treatment. Patients with GBS are initially managed as inpatients because 33% of cases lead to respiratory failure.⁹ Treatments include intravenous immunoglobulin (IVIg) or plasmapheresis; both have similar outcomes, speeding neurologic recovery time but not affecting overall long-term prognosis.¹⁰ Response to treatment is often not immediate, and some patients continue to worsen after treatment.⁸ Still, long-term prognosis is good, even for severely affected patients, as long as they receive good supportive care. The relapse rate is between 2% and 6%.⁸

In chronic inflammatory demyelinating polyneuropathy (CIDP), patients develop stepwise nerve dysfunction over many weeks to months. One nerve is affected, then another, usually in a different limb. There is generally no antecedent illness, and pain is infrequent.⁸ Progressive limb weakness is by far the most common presentation, and manifests as a foot drop or wrist drop. Patients may report difficulty getting up from a chair, walking up stairs, or opening jars.⁸ Facial or extraocular nerve involvement is uncommon, as is respiratory involvement.⁸ Neurologic exam shows absent reflexes, weakness, and loss of sensation in the distribution of a particular nerve or nerves.

Testing and treatment. Diagnosis of CIDP is made by a combination of EDX that shows demyelination and lumbar puncture that demonstrates albuminocytologic dissociation. Treatments include long-term immunosuppression with oral prednisone, IVIg, plasmapheresis, and rarely, agents such as mycophenolate mofetil, azathioprine, cyclosporine, and rituximab.⁹

Entrapment neuropathy

This is the result of compression or entrapment of a nerve by another anatomic structure. It can be caused by internal or external factors, including fluid retention.¹¹ Damage from compression or entrapment progresses in stages and, over time, can result in demyelination and distal degeneration of the nerve.¹¹ More interior nerve fibers, such as pain nerve fibers, are often the last to be affected.¹¹ Therefore, patients often first experience loss of motor function or loss of sensation to light touch.

Common fibular nerve (formerly known as common peroneal nerve) entrapment at the fibular head is the most common entrapment neuropathy in the lower extremities. It’s usually the result of direct trauma, such as prolonged positioning in debilitated patients or surgical patients, habitual leg-crossing, tight boots, or tight casts.^11,12 Uncoordinated gait due to poor dorsiflexion of the foot at the ankle (foot drop) is common while plantar flexion is preserved. Pain and sensory loss depend on the degree of compression and the exact location of compression.

Testing and treatment. EDX is useful for identifying the location of compression or entrapment and can guide further imaging, if needed. Conservative treatments aimed at modifying or correcting the underlying etiology, such as removing a tight-fitting cast or brace or instructing a patient to stop leg crossing, can be effective. Occasionally, surgery is required.

Anterior tarsal tunnel syndrome is compression of the deep fibular nerve as it passes through the inferior extensor retinaculum of the distal lower leg. Characteristic symptoms include pain and burning over the dorsum of the foot.¹¹ Paresthesias in the first dorsal web space are also common.¹¹ This can be seen in athletes who perform repetitive ankle plantar flexion, such as ballet dancers, soccer players, and runners.¹² It can also be caused by recurrent ankle sprains, ganglion cysts, and tight-fitting shoes or boots.^11,12 Chronic cases can result in toe extensor weakness or atrophy of the extensor digitorum brevis muscle.

Testing and treatment. Again, EDX is very useful in identifying the exact area of compression and involved nerve segments. Management requires correcting the underlying etiology, which can usually be done conservatively. Surgical decompression may be needed.

Suspect a paraneoplastic process if a patient presents with subacute progressive onset of neuropathic symptoms in the upper extremities.

Paraneoplastic neuropathies

Paraneoplastic neuropathies are exceptionally rare but often develop before cancer is diagnosed. Therefore, early suspicion and recognition can greatly affect cancer prognosis.¹³ Certain characteristics should increase suspicion of a paraneoplastic process. For example, symptoms with a subacute progressive onset that involve the upper extremities early in the disease are characteristic of a paraneoplastic process.¹³

Coexisting CNS symptoms and/or constitutional symptoms of malignancy should also increase suspicion.¹³ Consider a paraneo­plastic process in patients who have a past history of cancer or significant cancer risk factors, such as smoking.

Testing. When you suspect a paraneoplastic process, the work-up should include antibody testing for the most common or likely cancers according to patient characteristics. Panels of the most common paraneoplastic antibodies are available from many commercial labs. Obtain imaging to identify a possible underlying malignancy.

That said, it’s also important to perform a basic work-up for the more common causes of neuropathy in patients you suspect may have cancer. The reason: Paraneoplastic neuropathies are rare, and not all neuropathies in patients with cancer are paraneoplastic.¹³

CASE 1 › Ms. G describes diffuse paresthesias that are worse in her lower extremities, but she has a normal neurologic exam. Her physician suspects a neuropathic cause, and a normal exam makes small fiber neuropathy more likely. EDX is normal. The initial work-up includes an HbA1c, thyroid-stimulating hormone, vitamin B12 level, antinuclear antibody, erythrocyte sedimentation rate, IFE, and free light chain assay.

Testing reveals that Ms. G has a high free light chain ratio, which suggests a monoclonal gammopathy is the most likely etiology. Skin biopsy demonstrates decreased nerve fiber density consistent with a small fiber neuropathy. Her physician refers her to Hematology for bone marrow biopsy, and also prescribes gabapentin 300 mg/d at bedtime for symptomatic relief. Ms. G is currently being closely monitored for conversion to multiple myeloma.

CASE 2 › In Ms. T’s case, the exam helps localize the lesion. Areas supplied by the common fibular nerve, tibial nerve, and sural nerve are affected, while the area innervated by the femoral nerve and saphenous nerve and the proximal hip muscles are spared. This localizes a lesion to the sciatic nerve. EDX confirms a proximal sciatic lesion, but not the underlying etiology. Since the lesion had been precisely localized, her physician orders imaging.

Magnetic resonance imaging of Ms. T’s hip and upper leg shows a 10.7 cm x 7.8 cm x 13 cm heterogeneously enhancing mass in the expected location of the right sciatic nerve (FIGURE). Biopsy reveals a high grade, poorly differentiated synovial sarcoma. Her physician refers her to an oncologist for initiation of chemotherapy, radiation, and debulking surgery.

CORRESPONDENCE
Laura C. Mayans, MD, Department of Family and Community Medicine, University of Kansas School of Medicine-Wichita, 1010 N. Kansas, Wichita, KS 67214; [email protected].

Each year, more than one in every 100 infants are born at less than 32 weeks postmenstrual age.¹ In industrialized countries, many of these infants are discharged from the neonatal intensive care unit (NICU) with home apnea monitors,¹ which alert caregivers to episodes of apnea and bradycardia, while also capturing and storing data surrounding significant events for later analysis.²

Evidence supporting the use of home apnea monitoring is sparse, and recommendations highlight the need to use this technology sparingly and to discontinue use once it is no longer necessary (TABLE).³ Counseling parents is critical. It’s important to explain that home apnea monitoring can be used to help reduce the likelihood that a child will die in his or her sleep, but it affords users no “guarantees.” In addition, home apnea monitoring can adversely affect parents. Parents who use home apnea monitoring for their infants have been shown to have higher stress scores, greater levels of fatigue, and poorer health than parents of infants without home apnea monitors.^4-8

As a family physician, you are likely to encounter home apnea monitoring in one of 3 scenarios: at the first visit after discharge by a premature infant who experienced apnea while hospitalized, at a follow-up visit after discharge from the hospital by an infant who experienced an apparent life-threatening event (ALTE), and at a follow-up visit by an infant whose sibling had died from sudden infant death syndrome (SIDS). This article presents case studies that illustrate each of these scenarios, and explains what to tell parents who ask about how long they should continue home apnea monitoring.

CASE 1 › Apnea of prematurity

Jacob is a newborn who is brought in to your clinic by his parents for an initial visit. The infant was born prematurely at 32 weeks and required a prolonged NICU stay. His mother says that Jacob spent 4 weeks there and was discharged home with home apnea monitoring. On exam, the infant has a monitor attached via a chest band. Jacob appears healthy and his exam is normal. The mother asks you how long her son should use the home monitor.

Pathologic apnea is a respiratory pause that lasts at least 20 seconds or is associated with cyanosis; abrupt, marked pallor or hypotonia; or bradycardia.² Apnea of prematurity is present in almost all infants born at <29 weeks postmenstrual age or who weigh <1000 g.⁹ It is found in 54% of infants born at 30 to 31 weeks, 15% born at 32 to 33 weeks, and 7% of infants born at 34 to 35 weeks.¹⁰

Apnea of prematurity is primarily due to an immature respiratory control system, which results in impaired breathing regulation, immature respiratory responses to hypercapnia and hypoxia, and an exaggerated inhibitory response to stimulation of airway receptors.^11-13 Although apnea of prematurity usually resolves by 36 to 40 weeks postmenstrual age, it often persists beyond 38 to 40 weeks in infants born before 28 weeks.¹⁰ In these infants, by 43 to 44 weeks postmenstrual age, the frequency of apneic episodes decreases to that of full-term infants.¹⁴

Apnea of prematurity is not associated with an increased risk of sudden infant death syndrome.

The differences in long-term outcomes of infants with apnea of prematurity vs infants without it are subtle, if present at all.^14,15 There does seem to be a correlation between the number of days with apnea and poor outcomes. Neurodevelopmental impairment and death are more likely in neonates who experience a greater number of days with apnea episodes.^16,17 However, apnea of prematurity is not associated with an increased risk of SIDS.¹⁸

According to the American Academy of Pediatrics (AAP), home apnea monitoring may be warranted for premature infants who are at high risk of recurrent episodes of apnea, bradycardia, and hypoxemia after hospital discharge.³ While there is general consensus that all infants born prior to 29 weeks meet this criterion, the use of home apnea monitors in older preterm infants varies significantly, and the decision to initiate monitoring in these patients is made by the discharging physician.³ Once initiated, the AAP recommends that the use of home apnea monitoring in this population be discontinued after approximately 43 weeks postmenstrual age or after the cessation of extreme episodes, whichever comes last.³

In Jacob’s case, the monitoring should be discontinued at approximately week 12 of life, or about age 3 months.

CASE 2 › Apparent life-threatening event

Sarah is brought to your office after being hospitalized for an ALTE. Her mother reports that she had witnessed her 13-day-old daughter not breathing for “about a minute.” Upon realizing what was happening, she “blew into the baby’s face,” whereupon Sarah awakened. The mother then called 911 and they went by ambulance to the emergency room. The newborn was admitted for observation overnight and received a thorough evaluation. She was discharged with a home apnea monitor.

You review the work-up and find nothing worrisome. Sarah is in a car seat attached to the apnea monitor with a chest strap. An examination of the child is normal. The mother asks you when they should stop using the home monitor.

An ALTE is “an event that is frightening to the observer and ... is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, or gagging.”² ALTE is a descriptive term, and not a definitive diagnosis.

The true incidence of ALTE is unknown, but is reported to be 0.5% to 6%; most events occur in children younger than age 1.^19,20 The risk for ALTE is increased for premature infants, particularly those with respiratory syncytial virus or who had undergone general anesthesia; infants who feed rapidly, cough frequently, or choke during feeding; and male infants.^19,21

The most common causes of ALTE (in descending order) are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.²² The etiology is unknown for about half of patients with ALTE.²³

Tell parents that if their infant experiences an ALTE, they should seek medical attention without delay. The fear is that failing to respond to this concern will ultimately result in a sudden unexpected infant death, specifically as a result of SIDS.²⁴

SIDS is very rare, occurring in only 40 per 100,000 births. One analysis found that children who die from SIDS and those who experience ALTE have very similar histories and clinical factors.²⁵ Approximately 7% of infants who die from SIDS have had an ALTE.² Overall, the long-term prognosis for infants who have had an ALTE is very good, although it depends on seriousness of the underlying etiology.^8,26-28

Guidance on the effective use of home apnea monitors in infants who experience an ALTE is sparse. Despite this, the National Institutes of Health (NIH) Consensus Statement on Infantile Apnea and Home Monitoring² and the American Academy of Pediatrics policy statement on apnea, sudden infant death syndrome, and home monitoring³ recommend the use of home apnea monitoring for certain infants who’ve had an ALTE. The NIH Consensus Statement specifies home monitoring for infants with one or more severe episodes of ALTEs that require mouth-to-mouth resuscitation or vigorous stimulation.² There are no specific guidelines regarding the duration of monitoring.^2,3

In Sarah’s case, home monitoring should be discontinued as soon as the mother is comfortable with the decision.

CASE 3 › Sudden infant death syndrome

The parents of a 2-month-old boy, Stephen, come to your office to establish care. They recently relocated and their previous care provider had prescribed a home apnea monitor because a child they’d had 3 years ago had died of SIDS. Stephen is in a car seat attached to the apnea monitor with a chest strap. Your examination of him is normal. Stephen’s parents would like to stop using the home monitor, and ask you if it’s safe to do so.

The most common causes of an apparent life-threatening event in an infant are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.

SIDS is the death of an infant or young child that is unexplained by history and in which postmortem examination fails to find an adequate explanation of cause of death.² Since the introduction of the Back to Sleep campaign in the early 1990s, the incidence of SIDS has decreased by more than 50%.⁸ In 2013, approximately 1500 infant deaths were attributed to SIDS.²⁴ Three-quarters of deaths due to SIDS occur between 2 to 4 months of age, and 95% of deaths occur before 9 months of age.²⁹ Risk factors for SIDS include sleep environment (prone and side sleeping, bed sharing, soft bedding), prenatal and postnatal maternal tobacco use, exposure to tobacco smoke, maternal mental illness or substance abuse, male sex, poverty, prematurity, low birth weight (less than 2500 g), and no or poor prenatal care.³⁰

The etiology of SIDS is unclear.³¹ The leading hypothesis is the “triple-risk model,” which proposes that death from SIDS is due to 3 overlapping factors: a vulnerable infant, a critical developmental period in homeostatic control, and an exogenous stressor.³²

Although the NIH Consensus Statement suggests home apnea monitoring is indicated for infants who are siblings of 2 or more SIDS victims,² more recent policy statements from the AAP recommend against using home apnea monitors to reduce the incidence of SIDS due to a lack of evidence.^3,8

With this in mind, Stephen’s monitor should be discontinued and his parents should be educated on proven methods of preventing SIDS, including placing him on his back to sleep, breastfeeding him, letting him use a pacifier during sleep, and not sleeping in the same bed with him or overdressing him when putting him to sleep.^3,8

CORRESPONDENCE
Allen Perkins, MD, MPH, Department of Family Medicine, University of South Alabama, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604; [email protected].

Each year, more than one in every 100 infants are born at less than 32 weeks postmenstrual age.¹ In industrialized countries, many of these infants are discharged from the neonatal intensive care unit (NICU) with home apnea monitors,¹ which alert caregivers to episodes of apnea and bradycardia, while also capturing and storing data surrounding significant events for later analysis.²

Evidence supporting the use of home apnea monitoring is sparse, and recommendations highlight the need to use this technology sparingly and to discontinue use once it is no longer necessary (TABLE).³ Counseling parents is critical. It’s important to explain that home apnea monitoring can be used to help reduce the likelihood that a child will die in his or her sleep, but it affords users no “guarantees.” In addition, home apnea monitoring can adversely affect parents. Parents who use home apnea monitoring for their infants have been shown to have higher stress scores, greater levels of fatigue, and poorer health than parents of infants without home apnea monitors.^4-8

As a family physician, you are likely to encounter home apnea monitoring in one of 3 scenarios: at the first visit after discharge by a premature infant who experienced apnea while hospitalized, at a follow-up visit after discharge from the hospital by an infant who experienced an apparent life-threatening event (ALTE), and at a follow-up visit by an infant whose sibling had died from sudden infant death syndrome (SIDS). This article presents case studies that illustrate each of these scenarios, and explains what to tell parents who ask about how long they should continue home apnea monitoring.

CASE 1 › Apnea of prematurity

Jacob is a newborn who is brought in to your clinic by his parents for an initial visit. The infant was born prematurely at 32 weeks and required a prolonged NICU stay. His mother says that Jacob spent 4 weeks there and was discharged home with home apnea monitoring. On exam, the infant has a monitor attached via a chest band. Jacob appears healthy and his exam is normal. The mother asks you how long her son should use the home monitor.

Pathologic apnea is a respiratory pause that lasts at least 20 seconds or is associated with cyanosis; abrupt, marked pallor or hypotonia; or bradycardia.² Apnea of prematurity is present in almost all infants born at <29 weeks postmenstrual age or who weigh <1000 g.⁹ It is found in 54% of infants born at 30 to 31 weeks, 15% born at 32 to 33 weeks, and 7% of infants born at 34 to 35 weeks.¹⁰

Apnea of prematurity is primarily due to an immature respiratory control system, which results in impaired breathing regulation, immature respiratory responses to hypercapnia and hypoxia, and an exaggerated inhibitory response to stimulation of airway receptors.^11-13 Although apnea of prematurity usually resolves by 36 to 40 weeks postmenstrual age, it often persists beyond 38 to 40 weeks in infants born before 28 weeks.¹⁰ In these infants, by 43 to 44 weeks postmenstrual age, the frequency of apneic episodes decreases to that of full-term infants.¹⁴

Apnea of prematurity is not associated with an increased risk of sudden infant death syndrome.

The differences in long-term outcomes of infants with apnea of prematurity vs infants without it are subtle, if present at all.^14,15 There does seem to be a correlation between the number of days with apnea and poor outcomes. Neurodevelopmental impairment and death are more likely in neonates who experience a greater number of days with apnea episodes.^16,17 However, apnea of prematurity is not associated with an increased risk of SIDS.¹⁸

According to the American Academy of Pediatrics (AAP), home apnea monitoring may be warranted for premature infants who are at high risk of recurrent episodes of apnea, bradycardia, and hypoxemia after hospital discharge.³ While there is general consensus that all infants born prior to 29 weeks meet this criterion, the use of home apnea monitors in older preterm infants varies significantly, and the decision to initiate monitoring in these patients is made by the discharging physician.³ Once initiated, the AAP recommends that the use of home apnea monitoring in this population be discontinued after approximately 43 weeks postmenstrual age or after the cessation of extreme episodes, whichever comes last.³

In Jacob’s case, the monitoring should be discontinued at approximately week 12 of life, or about age 3 months.

CASE 2 › Apparent life-threatening event

Sarah is brought to your office after being hospitalized for an ALTE. Her mother reports that she had witnessed her 13-day-old daughter not breathing for “about a minute.” Upon realizing what was happening, she “blew into the baby’s face,” whereupon Sarah awakened. The mother then called 911 and they went by ambulance to the emergency room. The newborn was admitted for observation overnight and received a thorough evaluation. She was discharged with a home apnea monitor.

You review the work-up and find nothing worrisome. Sarah is in a car seat attached to the apnea monitor with a chest strap. An examination of the child is normal. The mother asks you when they should stop using the home monitor.

An ALTE is “an event that is frightening to the observer and ... is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, or gagging.”² ALTE is a descriptive term, and not a definitive diagnosis.

The true incidence of ALTE is unknown, but is reported to be 0.5% to 6%; most events occur in children younger than age 1.^19,20 The risk for ALTE is increased for premature infants, particularly those with respiratory syncytial virus or who had undergone general anesthesia; infants who feed rapidly, cough frequently, or choke during feeding; and male infants.^19,21

The most common causes of ALTE (in descending order) are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.²² The etiology is unknown for about half of patients with ALTE.²³

Tell parents that if their infant experiences an ALTE, they should seek medical attention without delay. The fear is that failing to respond to this concern will ultimately result in a sudden unexpected infant death, specifically as a result of SIDS.²⁴

SIDS is very rare, occurring in only 40 per 100,000 births. One analysis found that children who die from SIDS and those who experience ALTE have very similar histories and clinical factors.²⁵ Approximately 7% of infants who die from SIDS have had an ALTE.² Overall, the long-term prognosis for infants who have had an ALTE is very good, although it depends on seriousness of the underlying etiology.^8,26-28

Guidance on the effective use of home apnea monitors in infants who experience an ALTE is sparse. Despite this, the National Institutes of Health (NIH) Consensus Statement on Infantile Apnea and Home Monitoring² and the American Academy of Pediatrics policy statement on apnea, sudden infant death syndrome, and home monitoring³ recommend the use of home apnea monitoring for certain infants who’ve had an ALTE. The NIH Consensus Statement specifies home monitoring for infants with one or more severe episodes of ALTEs that require mouth-to-mouth resuscitation or vigorous stimulation.² There are no specific guidelines regarding the duration of monitoring.^2,3

In Sarah’s case, home monitoring should be discontinued as soon as the mother is comfortable with the decision.

CASE 3 › Sudden infant death syndrome

The parents of a 2-month-old boy, Stephen, come to your office to establish care. They recently relocated and their previous care provider had prescribed a home apnea monitor because a child they’d had 3 years ago had died of SIDS. Stephen is in a car seat attached to the apnea monitor with a chest strap. Your examination of him is normal. Stephen’s parents would like to stop using the home monitor, and ask you if it’s safe to do so.

The most common causes of an apparent life-threatening event in an infant are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.

SIDS is the death of an infant or young child that is unexplained by history and in which postmortem examination fails to find an adequate explanation of cause of death.² Since the introduction of the Back to Sleep campaign in the early 1990s, the incidence of SIDS has decreased by more than 50%.⁸ In 2013, approximately 1500 infant deaths were attributed to SIDS.²⁴ Three-quarters of deaths due to SIDS occur between 2 to 4 months of age, and 95% of deaths occur before 9 months of age.²⁹ Risk factors for SIDS include sleep environment (prone and side sleeping, bed sharing, soft bedding), prenatal and postnatal maternal tobacco use, exposure to tobacco smoke, maternal mental illness or substance abuse, male sex, poverty, prematurity, low birth weight (less than 2500 g), and no or poor prenatal care.³⁰

The etiology of SIDS is unclear.³¹ The leading hypothesis is the “triple-risk model,” which proposes that death from SIDS is due to 3 overlapping factors: a vulnerable infant, a critical developmental period in homeostatic control, and an exogenous stressor.³²

Although the NIH Consensus Statement suggests home apnea monitoring is indicated for infants who are siblings of 2 or more SIDS victims,² more recent policy statements from the AAP recommend against using home apnea monitors to reduce the incidence of SIDS due to a lack of evidence.^3,8

With this in mind, Stephen’s monitor should be discontinued and his parents should be educated on proven methods of preventing SIDS, including placing him on his back to sleep, breastfeeding him, letting him use a pacifier during sleep, and not sleeping in the same bed with him or overdressing him when putting him to sleep.^3,8

CORRESPONDENCE
Allen Perkins, MD, MPH, Department of Family Medicine, University of South Alabama, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604; [email protected].

Each year, more than one in every 100 infants are born at less than 32 weeks postmenstrual age.¹ In industrialized countries, many of these infants are discharged from the neonatal intensive care unit (NICU) with home apnea monitors,¹ which alert caregivers to episodes of apnea and bradycardia, while also capturing and storing data surrounding significant events for later analysis.²

Evidence supporting the use of home apnea monitoring is sparse, and recommendations highlight the need to use this technology sparingly and to discontinue use once it is no longer necessary (TABLE).³ Counseling parents is critical. It’s important to explain that home apnea monitoring can be used to help reduce the likelihood that a child will die in his or her sleep, but it affords users no “guarantees.” In addition, home apnea monitoring can adversely affect parents. Parents who use home apnea monitoring for their infants have been shown to have higher stress scores, greater levels of fatigue, and poorer health than parents of infants without home apnea monitors.^4-8

As a family physician, you are likely to encounter home apnea monitoring in one of 3 scenarios: at the first visit after discharge by a premature infant who experienced apnea while hospitalized, at a follow-up visit after discharge from the hospital by an infant who experienced an apparent life-threatening event (ALTE), and at a follow-up visit by an infant whose sibling had died from sudden infant death syndrome (SIDS). This article presents case studies that illustrate each of these scenarios, and explains what to tell parents who ask about how long they should continue home apnea monitoring.

CASE 1 › Apnea of prematurity

Jacob is a newborn who is brought in to your clinic by his parents for an initial visit. The infant was born prematurely at 32 weeks and required a prolonged NICU stay. His mother says that Jacob spent 4 weeks there and was discharged home with home apnea monitoring. On exam, the infant has a monitor attached via a chest band. Jacob appears healthy and his exam is normal. The mother asks you how long her son should use the home monitor.

Pathologic apnea is a respiratory pause that lasts at least 20 seconds or is associated with cyanosis; abrupt, marked pallor or hypotonia; or bradycardia.² Apnea of prematurity is present in almost all infants born at <29 weeks postmenstrual age or who weigh <1000 g.⁹ It is found in 54% of infants born at 30 to 31 weeks, 15% born at 32 to 33 weeks, and 7% of infants born at 34 to 35 weeks.¹⁰

Apnea of prematurity is primarily due to an immature respiratory control system, which results in impaired breathing regulation, immature respiratory responses to hypercapnia and hypoxia, and an exaggerated inhibitory response to stimulation of airway receptors.^11-13 Although apnea of prematurity usually resolves by 36 to 40 weeks postmenstrual age, it often persists beyond 38 to 40 weeks in infants born before 28 weeks.¹⁰ In these infants, by 43 to 44 weeks postmenstrual age, the frequency of apneic episodes decreases to that of full-term infants.¹⁴

Apnea of prematurity is not associated with an increased risk of sudden infant death syndrome.

The differences in long-term outcomes of infants with apnea of prematurity vs infants without it are subtle, if present at all.^14,15 There does seem to be a correlation between the number of days with apnea and poor outcomes. Neurodevelopmental impairment and death are more likely in neonates who experience a greater number of days with apnea episodes.^16,17 However, apnea of prematurity is not associated with an increased risk of SIDS.¹⁸

According to the American Academy of Pediatrics (AAP), home apnea monitoring may be warranted for premature infants who are at high risk of recurrent episodes of apnea, bradycardia, and hypoxemia after hospital discharge.³ While there is general consensus that all infants born prior to 29 weeks meet this criterion, the use of home apnea monitors in older preterm infants varies significantly, and the decision to initiate monitoring in these patients is made by the discharging physician.³ Once initiated, the AAP recommends that the use of home apnea monitoring in this population be discontinued after approximately 43 weeks postmenstrual age or after the cessation of extreme episodes, whichever comes last.³

In Jacob’s case, the monitoring should be discontinued at approximately week 12 of life, or about age 3 months.

CASE 2 › Apparent life-threatening event

Sarah is brought to your office after being hospitalized for an ALTE. Her mother reports that she had witnessed her 13-day-old daughter not breathing for “about a minute.” Upon realizing what was happening, she “blew into the baby’s face,” whereupon Sarah awakened. The mother then called 911 and they went by ambulance to the emergency room. The newborn was admitted for observation overnight and received a thorough evaluation. She was discharged with a home apnea monitor.

You review the work-up and find nothing worrisome. Sarah is in a car seat attached to the apnea monitor with a chest strap. An examination of the child is normal. The mother asks you when they should stop using the home monitor.

An ALTE is “an event that is frightening to the observer and ... is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, or gagging.”² ALTE is a descriptive term, and not a definitive diagnosis.

The true incidence of ALTE is unknown, but is reported to be 0.5% to 6%; most events occur in children younger than age 1.^19,20 The risk for ALTE is increased for premature infants, particularly those with respiratory syncytial virus or who had undergone general anesthesia; infants who feed rapidly, cough frequently, or choke during feeding; and male infants.^19,21

The most common causes of ALTE (in descending order) are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.²² The etiology is unknown for about half of patients with ALTE.²³

Tell parents that if their infant experiences an ALTE, they should seek medical attention without delay. The fear is that failing to respond to this concern will ultimately result in a sudden unexpected infant death, specifically as a result of SIDS.²⁴

SIDS is very rare, occurring in only 40 per 100,000 births. One analysis found that children who die from SIDS and those who experience ALTE have very similar histories and clinical factors.²⁵ Approximately 7% of infants who die from SIDS have had an ALTE.² Overall, the long-term prognosis for infants who have had an ALTE is very good, although it depends on seriousness of the underlying etiology.^8,26-28

Guidance on the effective use of home apnea monitors in infants who experience an ALTE is sparse. Despite this, the National Institutes of Health (NIH) Consensus Statement on Infantile Apnea and Home Monitoring² and the American Academy of Pediatrics policy statement on apnea, sudden infant death syndrome, and home monitoring³ recommend the use of home apnea monitoring for certain infants who’ve had an ALTE. The NIH Consensus Statement specifies home monitoring for infants with one or more severe episodes of ALTEs that require mouth-to-mouth resuscitation or vigorous stimulation.² There are no specific guidelines regarding the duration of monitoring.^2,3

In Sarah’s case, home monitoring should be discontinued as soon as the mother is comfortable with the decision.

CASE 3 › Sudden infant death syndrome

The parents of a 2-month-old boy, Stephen, come to your office to establish care. They recently relocated and their previous care provider had prescribed a home apnea monitor because a child they’d had 3 years ago had died of SIDS. Stephen is in a car seat attached to the apnea monitor with a chest strap. Your examination of him is normal. Stephen’s parents would like to stop using the home monitor, and ask you if it’s safe to do so.

The most common causes of an apparent life-threatening event in an infant are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.

SIDS is the death of an infant or young child that is unexplained by history and in which postmortem examination fails to find an adequate explanation of cause of death.² Since the introduction of the Back to Sleep campaign in the early 1990s, the incidence of SIDS has decreased by more than 50%.⁸ In 2013, approximately 1500 infant deaths were attributed to SIDS.²⁴ Three-quarters of deaths due to SIDS occur between 2 to 4 months of age, and 95% of deaths occur before 9 months of age.²⁹ Risk factors for SIDS include sleep environment (prone and side sleeping, bed sharing, soft bedding), prenatal and postnatal maternal tobacco use, exposure to tobacco smoke, maternal mental illness or substance abuse, male sex, poverty, prematurity, low birth weight (less than 2500 g), and no or poor prenatal care.³⁰

The etiology of SIDS is unclear.³¹ The leading hypothesis is the “triple-risk model,” which proposes that death from SIDS is due to 3 overlapping factors: a vulnerable infant, a critical developmental period in homeostatic control, and an exogenous stressor.³²

Although the NIH Consensus Statement suggests home apnea monitoring is indicated for infants who are siblings of 2 or more SIDS victims,² more recent policy statements from the AAP recommend against using home apnea monitors to reduce the incidence of SIDS due to a lack of evidence.^3,8

With this in mind, Stephen’s monitor should be discontinued and his parents should be educated on proven methods of preventing SIDS, including placing him on his back to sleep, breastfeeding him, letting him use a pacifier during sleep, and not sleeping in the same bed with him or overdressing him when putting him to sleep.^3,8

CORRESPONDENCE
Allen Perkins, MD, MPH, Department of Family Medicine, University of South Alabama, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604; [email protected].

A 23-year-old man presents to the emergency department with the sudden onset of palpitations, lightheadedness, and dyspnea, accompanied by weakness and nausea, which started earlier in the evening. He estimates that he has experienced 15 similar episodes, lasting minutes to hours, since the age of 16, with the last one 3 years ago. These episodes typically end by themselves or with self-induced vomiting and lying supine. The current episode did not resolve with these maneuvers.

He has never received medical attention for these symptoms. He has no chest pain, orthopnea, paroxysmal nocturnal dyspnea, lower extremity edema, or syncope. He has had no recent illness, contacts with sick people, or travel.

The patient’s history includes a “childhood heart murmur,” which resolved, and also mild asthma. He is otherwise healthy but has not received regular medical care. He used to play competitive soccer but quit because playing made his symptoms of dyspnea on exertion and palpitations much worse.

He uses marijuana frequently and alcohol occasionally. He does not smoke tobacco or use other recreational drugs. Other than infrequent use of albuterol, he does not take any prescription or over-the-counter medications. He has no allergies. He knows of no family history of arrhythmia or sudden cardiac death.

Physical examination. On initial examination, his temperature is 36.4°C (97.5°F), heart rate 230 bpm, systolic blood pressure 60 mm Hg, respiratory rate 30 breaths per minute, oxygen saturation 100% while breathing room air, and body mass index 25 kg/m².

He is awake, anxious, and appears ill. He speaks only in short sentences. A focused cardiac examination reveals a regular tachycardia with no appreciable murmur or extra heart sounds; the apical impulse is not displaced. His lungs are clear. His abdomen is soft and nontender. He has 2+ pulses on a scale of 0 to 4+, with no peripheral edema.

His initial electrocardiogram (ECG) (Figure 1) shows a heart rate of 260 bpm and a regular wide complex tachycardia, defined as a rate greater than 100 bpm and a QRS complex wider than 0.12 seconds.

FOCUS ON REGULAR WIDE COMPLEX TACHYCARDIA

1. Which of the following is not in the differential diagnosis of regular wide complex tachycardia?

• Monomorphic ventricular tachycardia
• Orthodromic atrioventricular reentrant tachycardia 
• Antidromic atrioventricular reentrant tachycardia
• Sinus tachycardia with bundle branch block

Orthodromic atrioventricular reentrant tachycardia is not in the differential diagnosis.

Wide complex tachycardia can occur when the impulse originates outside the normal conduction system or when there is abnormal ventricular activation through the atrioventricular (AV) node and His-Purkinje system.

The main distinction to make when diagnosing the cause of a wide complex tachycardia is between the following:

Monomorphic ventricular tachycardia, which originates from a single ventricular focus that depolarizes the adjacent myocardium in a stepwise fashion, causing a wide QRS complex that does not begin in the native conduction system, and

Sinus tachycardia with bundle branch block, ie, supraventricular tachycardia with aberrant conduction within the normal conduction system. 

Three different conduction patterns are seen with atrioventricular reentrant tachycardia (Figure 2):

Sinus depolarization (Figure 2), in which the atrial impulse travels down the AV node, and the accessory pathway can be hidden and not contribute to the surface ECG.

Orthodromic atrioventricular reentrant tachycardia (Figure2), in which the depolarizing impulse travels antegrade down the AV node, then propagates from the ventricle back to the atria via the accessory pathway, resulting in a narrow QRS.

Antidromic atrioventricular reentrant tachycardia (Figure 2), in which the depolarization travels antegrade down the accessory pathway then propagates from the ventricle back to the atria via the AV node, resulting in a wide complex QRS with a delta wave.

Important features of the patient’s electrocardiogram (Figure 1) are consistent with antidromic atrioventricular reentrant tachycardia:

• “Buried” retrograde P waves, which are best seen in the continuous strip of lead II as a positive deflection notching in the negative nadir of the wave
• The PR segment is short, suggesting retrograde atrial depolarization
• The P wave is followed by a slow slurred upstroke (delta wave), best seen in lead I.

Treatment depends on diagnosis

Distinguishing supraventricular tachycardia from ventricular tachycardia is important, as the treatments differ. Supraventricular tachycardia is treated with adenosine, calcium channel blockers, and beta-blockers, which are not only ineffective for ventricular tachycardia, but rarely may precipitate hemodynamic deterioration.

Also important is distinguishing pre-excitation atrial fibrillation from other types of supraventricular tachycardia with aberrancy, because the nodal blockade used to treat other causes of the condition may worsen the tachycardia via the accessory pathway. If pre-excitation atrial fibrillation is suspected on the basis of an irregular wide complex tachycardia with delta waves on ECG, then procainamide—a sodium channel blocker that affects the cardiac action potential and prolongs the refractory period of the accessory pathway—can be used to help control the arrhythmia.¹

Brugada criteria aid diagnosis

Adapted from Brugada P, et al. A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex. Circulation 1991; 83:1649–1659, with permission from Lippincott Williams &amp; Wilkins.

In 1991, Brugada et al² devised an algorithm to differentiate ventricular tachycardia from supraventricular tachycardia with aberrancy in the setting of regular wide complex tachycardia (Figure 3). It has a sensitivity of 98.7% and a specificity of 96.5% for diagnosing ventricular tachycardia and 96.5% sensitivity and 98.7% specificity for diagnosing supraventricular tachycardia with aberrant conduction. Using the algorithm, only 11 (ie, 2%) of the 544 tachycardias in their study were misclassified.^2–4

The Brugada algorithm consists of four criteria, with the presence of any leading to a diagnosis of ventricular tachycardia:

• Absence of an RS complex in all precordial leads (the QRS complexes in precordial leads have all negative or all positive deflections).
• An RS interval in at least one precordial lead of at least 100 ms (the interval is measured from the onset of R to the nadir of the S wave).
• AV dissociation, as determined by the existence of P waves marching out independent of the QRS complexes, capture beats (narrow QRS complexes resulting from the rare occasion when an intrinsic P wave conducts down the native pathway), or fusion beats (combined capture beat and ventricular beat, resulting in a different morphology than most of the wide QRS complexes present).
• Leads V₁, V₂, and V₆ satisfying the classic morphologic criteria for ventricular tachycardia.

If none of these criteria are met, supraventricular tachycardia is diagnosed.

In our patient, we can further confirm the diagnosis of antidromic atrioventricular reentrant tachycardia by using Brugada criteria to exclude ventricular tachycardia (Figure 3): the ECG (Figure 1) shows an RS complex in multiple precordial leads, the maximum RS interval is less than 100 ms in the precordial leads, there is no evidence of AV dissociation (lead II in the continuous strip shows buried P waves associated with QRS), and morphologic criteria are not met for ventricular tachycardia in leads V₁, V₂, and V₆. 

IS CARDIOVERSION NEEDED?

According to the American Heart Association guidelines for advanced cardiopulmonary life support, patients with tachyarrhythmias who are hemodynamically unstable should undergo cardioversion immediately.⁵

Our patient, who has a heart rate faster than 200 bpm and a systolic blood pressure of only 60 mm Hg, undergoes synchronized cardioversion in the emergency department. Immediately afterward, his ECG (Figure 4) demonstrates sinus rhythm with pre-excitation consistent with type B Wolff-Parkinson-White syndrome.

Once he is hemodynamically stable, a more thorough physical examination is performed. Examination of the head, ears, eyes, nose, and throat is unremarkable. He has no jugular venous distention or carotid bruits. His lungs are clear to auscultation bilaterally, without wheezes. His cardiac examination shows a regular rate and rhythm, normal first and second heart sounds, and no murmurs, rubs, or gallops.

WHICH DIAGNOSTIC STUDIES ARE NEEDED?

Laboratory tests

In an otherwise healthy young patient presenting with an arrhythmia, the initial laboratory workup should focus on a precipitating illness or a disease state that may incite an arrhythmia.

Our patient is evaluated for infection or septic shock (white blood cell count with differential), anemia (hemoglobin), thyrotoxicosis (thyroid-stimulating hormone and free thyroxine levels), drug abuse (urine toxicology screen), and cardiac syndromes including structural heart disease and myocardial injury (cardiac enzymes and B-type natriuretic peptide).⁶

His initial laboratory tests show normal electrolyte levels and renal function, leukocytosis with a white blood cell count of 15.6 × 10⁹/L (normal 4.0–10.0), mildly elevated thyroid-stimulating hormone, and a negative urine toxicology screen.

Transthoracic echocardiography

For a young patient presenting with pre-excitation on ECG and hemodynamic instability, transthoracic echocardiography to evaluate chamber size and look for structural abnormalities is a reasonable option.

Our patient undergoes transthoracic echocardiography, which demonstrates normal left ventricular size and function with a left ventricular ejection fraction of 69%, moderate right atrial enlargement, and mild right ventricular enlargement (Figure 5). The septal leaflet of the tricuspid valve is apically displaced, and there is mild regurgitation.

DIAGNOSIS: EBSTEIN ANOMALY

These findings are consistent with Ebstein anomaly. It can be recognized on transthoracic echocardiography as adherence of the septal and posterior tricuspid valve leaflets to the myocardium due to failure of the tissue to detach during embryogenesis, apical displacement of the annulus, right atrial enlargement, and right ventricular enlargement.^7–10 Apical displacement of the tricuspid valve is a hallmark finding and must be more than 20 mm or 8 mm/m² of body surface area to make the diagnosis.^11–13 ECG often demonstrates right atrial enlargement, first-degree atrial ventricular block, and right bundle branch block.

Ebstein anomaly is a rare embryonic developmental abnormality of the tricuspid valve. It occurs in 1 to 5 of 200,000 live births, accounting for approximately 0.5% of all congenital heart disease.^14,15 Most cases are sporadic and result from failure of the ventricle to delaminate during embryogenesis of the tricuspid valve, resulting in apical displacement of either the septal, posterior, or, very rarely, anterior leaflet of the tricuspid valve.^7,8 The prevalence is higher in infants whose mothers took lithium during early pregnancy.¹⁶

2. Which of the following is not a common finding associated with Ebstein anomaly?

• Apical displacement of the septal leaflet of the tricuspid valve
• Wolff-Parkinson-White syndrome
• Accessory bypass tract
• Tachyarrhythmias
• Increased risk of sudden death
• Left-sided heart failure

The answer is left-sided heart failure. Ebstein anomaly is associated with increased risk of tachyarrhythmias, right-sided heart failure, and sudden death.^7,8,17,18 In Ebstein anomaly, the tricuspid valve forms closer to the apex, so the part of the right ventricle that is superior to the displaced tricuspid valve functions as the right atrium, thus the term “atrialized” right ventricle. These abnormalities create an environment for accessory pathways, most commonly type B Wolff-Parkinson-White syndrome.¹⁹ Biventricular dysfunction can occur in rare severe cases.^7,8,18

Our patient is found to have an accessory tract-mediated antidromic atrioventricular reentrant tachycardia in the setting of Wolff-Parkinson-White syndrome and Ebstein anomaly. This is further confirmed with an electrophysiology study demonstrating a right posterior accessory pathway.

TREATMENT FOR EBSTEIN ANOMALY

3. Which treatment is advised for Ebstein anomaly?

• Observation alone
• Standard heart failure medications
• Radiofrequency catheter ablation
• Tricuspid valve repair or replacement
• Biventricular reconstruction
• Heart transplant

The answer is all of the above. Observation alone is advised for patients with mild symptoms, no evidence of right-to-left shunting, and only mild cardiomegaly. Medical management includes an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, a beta-blocker, and diuretics. Radiofrequency catheter ablation is the first-line therapy for patients with symptomatic Wolff-Parkinson-White syndrome.²⁰ A patient who develops worsening right-sided heart failure, cyanosis, paradoxical emboli, or frequent tachyarrhythmias should be considered for corrective surgery, which may include tricuspid valve repair or replacement, or biventricular reconstruction.^7,8,21 Cardiac transplant is reserved for severe cases.⁸

On hospital day 4, our patient undergoes successful radiofrequency catheter ablation without complications. At follow-up 3 months later, he continues to do well, with resolution of his symptoms and no further evidence of pre-excitation. His postprocedure ECG no longer shows delta waves.

TAKE-HOME POINTS

• For a patient with regular wide complex tachycardia, the first step is to assess hemodynamic stability. If the patient is hemodynamically unstable, emergent cardioversion is indicated.
• The differential diagnosis for regular wide complex tachycardia includes supraventricular tachycardia with aberrancy (orthodromic atrioventricular reentrant tachycardia, antidromic atrioventricular reentrant tachycardia, atrial tachycardia), and ventricular tachycardia.
• When pre-excited atrial fibrillation is suspected, AV nodal blocking agents should be avoided, as they may worsen tachyarrhythmia. Sodium channel blockers such as procainamide can help slow down the conduction of the accessory pathway.
• Ebstein anomaly is diagnosed on transthoracic echocardiography as apical displacement of the tricuspid valve resulting in atrialization of the right ventricle.
• Patients with Ebstein anomaly have a higher risk of death from right-sided heart failure and tachyarrhythmias, most commonly type B Wolff-Parkinson-White syndrome.
• Ebstein anomaly is medically managed with standard heart failure medications, including neurohormonal blockade therapies.
• Patients with Ebstein anomaly and cyanosis require surgical intervention with either valve repair or replacement.
   

Acknowledgment: We thank Dr. William Collins for his contribution in reviewing the manuscript and his technical expertise in developing some of the figures.

A 23-year-old man presents to the emergency department with the sudden onset of palpitations, lightheadedness, and dyspnea, accompanied by weakness and nausea, which started earlier in the evening. He estimates that he has experienced 15 similar episodes, lasting minutes to hours, since the age of 16, with the last one 3 years ago. These episodes typically end by themselves or with self-induced vomiting and lying supine. The current episode did not resolve with these maneuvers.

He has never received medical attention for these symptoms. He has no chest pain, orthopnea, paroxysmal nocturnal dyspnea, lower extremity edema, or syncope. He has had no recent illness, contacts with sick people, or travel.

The patient’s history includes a “childhood heart murmur,” which resolved, and also mild asthma. He is otherwise healthy but has not received regular medical care. He used to play competitive soccer but quit because playing made his symptoms of dyspnea on exertion and palpitations much worse.

He uses marijuana frequently and alcohol occasionally. He does not smoke tobacco or use other recreational drugs. Other than infrequent use of albuterol, he does not take any prescription or over-the-counter medications. He has no allergies. He knows of no family history of arrhythmia or sudden cardiac death.

Physical examination. On initial examination, his temperature is 36.4°C (97.5°F), heart rate 230 bpm, systolic blood pressure 60 mm Hg, respiratory rate 30 breaths per minute, oxygen saturation 100% while breathing room air, and body mass index 25 kg/m².

He is awake, anxious, and appears ill. He speaks only in short sentences. A focused cardiac examination reveals a regular tachycardia with no appreciable murmur or extra heart sounds; the apical impulse is not displaced. His lungs are clear. His abdomen is soft and nontender. He has 2+ pulses on a scale of 0 to 4+, with no peripheral edema.

His initial electrocardiogram (ECG) (Figure 1) shows a heart rate of 260 bpm and a regular wide complex tachycardia, defined as a rate greater than 100 bpm and a QRS complex wider than 0.12 seconds.

FOCUS ON REGULAR WIDE COMPLEX TACHYCARDIA

1. Which of the following is not in the differential diagnosis of regular wide complex tachycardia?

• Monomorphic ventricular tachycardia
• Orthodromic atrioventricular reentrant tachycardia 
• Antidromic atrioventricular reentrant tachycardia
• Sinus tachycardia with bundle branch block

Orthodromic atrioventricular reentrant tachycardia is not in the differential diagnosis.

Wide complex tachycardia can occur when the impulse originates outside the normal conduction system or when there is abnormal ventricular activation through the atrioventricular (AV) node and His-Purkinje system.

The main distinction to make when diagnosing the cause of a wide complex tachycardia is between the following:

Monomorphic ventricular tachycardia, which originates from a single ventricular focus that depolarizes the adjacent myocardium in a stepwise fashion, causing a wide QRS complex that does not begin in the native conduction system, and

Sinus tachycardia with bundle branch block, ie, supraventricular tachycardia with aberrant conduction within the normal conduction system. 

Three different conduction patterns are seen with atrioventricular reentrant tachycardia (Figure 2):

Sinus depolarization (Figure 2), in which the atrial impulse travels down the AV node, and the accessory pathway can be hidden and not contribute to the surface ECG.

Orthodromic atrioventricular reentrant tachycardia (Figure2), in which the depolarizing impulse travels antegrade down the AV node, then propagates from the ventricle back to the atria via the accessory pathway, resulting in a narrow QRS.

Antidromic atrioventricular reentrant tachycardia (Figure 2), in which the depolarization travels antegrade down the accessory pathway then propagates from the ventricle back to the atria via the AV node, resulting in a wide complex QRS with a delta wave.

Important features of the patient’s electrocardiogram (Figure 1) are consistent with antidromic atrioventricular reentrant tachycardia:

• “Buried” retrograde P waves, which are best seen in the continuous strip of lead II as a positive deflection notching in the negative nadir of the wave
• The PR segment is short, suggesting retrograde atrial depolarization
• The P wave is followed by a slow slurred upstroke (delta wave), best seen in lead I.

Treatment depends on diagnosis

Distinguishing supraventricular tachycardia from ventricular tachycardia is important, as the treatments differ. Supraventricular tachycardia is treated with adenosine, calcium channel blockers, and beta-blockers, which are not only ineffective for ventricular tachycardia, but rarely may precipitate hemodynamic deterioration.

Also important is distinguishing pre-excitation atrial fibrillation from other types of supraventricular tachycardia with aberrancy, because the nodal blockade used to treat other causes of the condition may worsen the tachycardia via the accessory pathway. If pre-excitation atrial fibrillation is suspected on the basis of an irregular wide complex tachycardia with delta waves on ECG, then procainamide—a sodium channel blocker that affects the cardiac action potential and prolongs the refractory period of the accessory pathway—can be used to help control the arrhythmia.¹

Brugada criteria aid diagnosis

Adapted from Brugada P, et al. A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex. Circulation 1991; 83:1649–1659, with permission from Lippincott Williams &amp; Wilkins.

In 1991, Brugada et al² devised an algorithm to differentiate ventricular tachycardia from supraventricular tachycardia with aberrancy in the setting of regular wide complex tachycardia (Figure 3). It has a sensitivity of 98.7% and a specificity of 96.5% for diagnosing ventricular tachycardia and 96.5% sensitivity and 98.7% specificity for diagnosing supraventricular tachycardia with aberrant conduction. Using the algorithm, only 11 (ie, 2%) of the 544 tachycardias in their study were misclassified.^2–4

The Brugada algorithm consists of four criteria, with the presence of any leading to a diagnosis of ventricular tachycardia:

• Absence of an RS complex in all precordial leads (the QRS complexes in precordial leads have all negative or all positive deflections).
• An RS interval in at least one precordial lead of at least 100 ms (the interval is measured from the onset of R to the nadir of the S wave).
• AV dissociation, as determined by the existence of P waves marching out independent of the QRS complexes, capture beats (narrow QRS complexes resulting from the rare occasion when an intrinsic P wave conducts down the native pathway), or fusion beats (combined capture beat and ventricular beat, resulting in a different morphology than most of the wide QRS complexes present).
• Leads V₁, V₂, and V₆ satisfying the classic morphologic criteria for ventricular tachycardia.

If none of these criteria are met, supraventricular tachycardia is diagnosed.

In our patient, we can further confirm the diagnosis of antidromic atrioventricular reentrant tachycardia by using Brugada criteria to exclude ventricular tachycardia (Figure 3): the ECG (Figure 1) shows an RS complex in multiple precordial leads, the maximum RS interval is less than 100 ms in the precordial leads, there is no evidence of AV dissociation (lead II in the continuous strip shows buried P waves associated with QRS), and morphologic criteria are not met for ventricular tachycardia in leads V₁, V₂, and V₆. 

IS CARDIOVERSION NEEDED?

According to the American Heart Association guidelines for advanced cardiopulmonary life support, patients with tachyarrhythmias who are hemodynamically unstable should undergo cardioversion immediately.⁵

Our patient, who has a heart rate faster than 200 bpm and a systolic blood pressure of only 60 mm Hg, undergoes synchronized cardioversion in the emergency department. Immediately afterward, his ECG (Figure 4) demonstrates sinus rhythm with pre-excitation consistent with type B Wolff-Parkinson-White syndrome.

Once he is hemodynamically stable, a more thorough physical examination is performed. Examination of the head, ears, eyes, nose, and throat is unremarkable. He has no jugular venous distention or carotid bruits. His lungs are clear to auscultation bilaterally, without wheezes. His cardiac examination shows a regular rate and rhythm, normal first and second heart sounds, and no murmurs, rubs, or gallops.

WHICH DIAGNOSTIC STUDIES ARE NEEDED?

Laboratory tests

In an otherwise healthy young patient presenting with an arrhythmia, the initial laboratory workup should focus on a precipitating illness or a disease state that may incite an arrhythmia.

Our patient is evaluated for infection or septic shock (white blood cell count with differential), anemia (hemoglobin), thyrotoxicosis (thyroid-stimulating hormone and free thyroxine levels), drug abuse (urine toxicology screen), and cardiac syndromes including structural heart disease and myocardial injury (cardiac enzymes and B-type natriuretic peptide).⁶

His initial laboratory tests show normal electrolyte levels and renal function, leukocytosis with a white blood cell count of 15.6 × 10⁹/L (normal 4.0–10.0), mildly elevated thyroid-stimulating hormone, and a negative urine toxicology screen.

Transthoracic echocardiography

For a young patient presenting with pre-excitation on ECG and hemodynamic instability, transthoracic echocardiography to evaluate chamber size and look for structural abnormalities is a reasonable option.

Our patient undergoes transthoracic echocardiography, which demonstrates normal left ventricular size and function with a left ventricular ejection fraction of 69%, moderate right atrial enlargement, and mild right ventricular enlargement (Figure 5). The septal leaflet of the tricuspid valve is apically displaced, and there is mild regurgitation.

DIAGNOSIS: EBSTEIN ANOMALY

These findings are consistent with Ebstein anomaly. It can be recognized on transthoracic echocardiography as adherence of the septal and posterior tricuspid valve leaflets to the myocardium due to failure of the tissue to detach during embryogenesis, apical displacement of the annulus, right atrial enlargement, and right ventricular enlargement.^7–10 Apical displacement of the tricuspid valve is a hallmark finding and must be more than 20 mm or 8 mm/m² of body surface area to make the diagnosis.^11–13 ECG often demonstrates right atrial enlargement, first-degree atrial ventricular block, and right bundle branch block.

Ebstein anomaly is a rare embryonic developmental abnormality of the tricuspid valve. It occurs in 1 to 5 of 200,000 live births, accounting for approximately 0.5% of all congenital heart disease.^14,15 Most cases are sporadic and result from failure of the ventricle to delaminate during embryogenesis of the tricuspid valve, resulting in apical displacement of either the septal, posterior, or, very rarely, anterior leaflet of the tricuspid valve.^7,8 The prevalence is higher in infants whose mothers took lithium during early pregnancy.¹⁶

2. Which of the following is not a common finding associated with Ebstein anomaly?

• Apical displacement of the septal leaflet of the tricuspid valve
• Wolff-Parkinson-White syndrome
• Accessory bypass tract
• Tachyarrhythmias
• Increased risk of sudden death
• Left-sided heart failure

The answer is left-sided heart failure. Ebstein anomaly is associated with increased risk of tachyarrhythmias, right-sided heart failure, and sudden death.^7,8,17,18 In Ebstein anomaly, the tricuspid valve forms closer to the apex, so the part of the right ventricle that is superior to the displaced tricuspid valve functions as the right atrium, thus the term “atrialized” right ventricle. These abnormalities create an environment for accessory pathways, most commonly type B Wolff-Parkinson-White syndrome.¹⁹ Biventricular dysfunction can occur in rare severe cases.^7,8,18

Our patient is found to have an accessory tract-mediated antidromic atrioventricular reentrant tachycardia in the setting of Wolff-Parkinson-White syndrome and Ebstein anomaly. This is further confirmed with an electrophysiology study demonstrating a right posterior accessory pathway.

TREATMENT FOR EBSTEIN ANOMALY

3. Which treatment is advised for Ebstein anomaly?

• Observation alone
• Standard heart failure medications
• Radiofrequency catheter ablation
• Tricuspid valve repair or replacement
• Biventricular reconstruction
• Heart transplant

The answer is all of the above. Observation alone is advised for patients with mild symptoms, no evidence of right-to-left shunting, and only mild cardiomegaly. Medical management includes an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, a beta-blocker, and diuretics. Radiofrequency catheter ablation is the first-line therapy for patients with symptomatic Wolff-Parkinson-White syndrome.²⁰ A patient who develops worsening right-sided heart failure, cyanosis, paradoxical emboli, or frequent tachyarrhythmias should be considered for corrective surgery, which may include tricuspid valve repair or replacement, or biventricular reconstruction.^7,8,21 Cardiac transplant is reserved for severe cases.⁸

On hospital day 4, our patient undergoes successful radiofrequency catheter ablation without complications. At follow-up 3 months later, he continues to do well, with resolution of his symptoms and no further evidence of pre-excitation. His postprocedure ECG no longer shows delta waves.

TAKE-HOME POINTS

• For a patient with regular wide complex tachycardia, the first step is to assess hemodynamic stability. If the patient is hemodynamically unstable, emergent cardioversion is indicated.
• The differential diagnosis for regular wide complex tachycardia includes supraventricular tachycardia with aberrancy (orthodromic atrioventricular reentrant tachycardia, antidromic atrioventricular reentrant tachycardia, atrial tachycardia), and ventricular tachycardia.
• When pre-excited atrial fibrillation is suspected, AV nodal blocking agents should be avoided, as they may worsen tachyarrhythmia. Sodium channel blockers such as procainamide can help slow down the conduction of the accessory pathway.
• Ebstein anomaly is diagnosed on transthoracic echocardiography as apical displacement of the tricuspid valve resulting in atrialization of the right ventricle.
• Patients with Ebstein anomaly have a higher risk of death from right-sided heart failure and tachyarrhythmias, most commonly type B Wolff-Parkinson-White syndrome.
• Ebstein anomaly is medically managed with standard heart failure medications, including neurohormonal blockade therapies.
• Patients with Ebstein anomaly and cyanosis require surgical intervention with either valve repair or replacement.
   

Acknowledgment: We thank Dr. William Collins for his contribution in reviewing the manuscript and his technical expertise in developing some of the figures.

A 23-year-old man presents to the emergency department with the sudden onset of palpitations, lightheadedness, and dyspnea, accompanied by weakness and nausea, which started earlier in the evening. He estimates that he has experienced 15 similar episodes, lasting minutes to hours, since the age of 16, with the last one 3 years ago. These episodes typically end by themselves or with self-induced vomiting and lying supine. The current episode did not resolve with these maneuvers.

He has never received medical attention for these symptoms. He has no chest pain, orthopnea, paroxysmal nocturnal dyspnea, lower extremity edema, or syncope. He has had no recent illness, contacts with sick people, or travel.

The patient’s history includes a “childhood heart murmur,” which resolved, and also mild asthma. He is otherwise healthy but has not received regular medical care. He used to play competitive soccer but quit because playing made his symptoms of dyspnea on exertion and palpitations much worse.

He uses marijuana frequently and alcohol occasionally. He does not smoke tobacco or use other recreational drugs. Other than infrequent use of albuterol, he does not take any prescription or over-the-counter medications. He has no allergies. He knows of no family history of arrhythmia or sudden cardiac death.

Physical examination. On initial examination, his temperature is 36.4°C (97.5°F), heart rate 230 bpm, systolic blood pressure 60 mm Hg, respiratory rate 30 breaths per minute, oxygen saturation 100% while breathing room air, and body mass index 25 kg/m².

He is awake, anxious, and appears ill. He speaks only in short sentences. A focused cardiac examination reveals a regular tachycardia with no appreciable murmur or extra heart sounds; the apical impulse is not displaced. His lungs are clear. His abdomen is soft and nontender. He has 2+ pulses on a scale of 0 to 4+, with no peripheral edema.

His initial electrocardiogram (ECG) (Figure 1) shows a heart rate of 260 bpm and a regular wide complex tachycardia, defined as a rate greater than 100 bpm and a QRS complex wider than 0.12 seconds.

FOCUS ON REGULAR WIDE COMPLEX TACHYCARDIA

1. Which of the following is not in the differential diagnosis of regular wide complex tachycardia?

• Monomorphic ventricular tachycardia
• Orthodromic atrioventricular reentrant tachycardia 
• Antidromic atrioventricular reentrant tachycardia
• Sinus tachycardia with bundle branch block

Orthodromic atrioventricular reentrant tachycardia is not in the differential diagnosis.

Wide complex tachycardia can occur when the impulse originates outside the normal conduction system or when there is abnormal ventricular activation through the atrioventricular (AV) node and His-Purkinje system.

The main distinction to make when diagnosing the cause of a wide complex tachycardia is between the following:

Monomorphic ventricular tachycardia, which originates from a single ventricular focus that depolarizes the adjacent myocardium in a stepwise fashion, causing a wide QRS complex that does not begin in the native conduction system, and

Sinus tachycardia with bundle branch block, ie, supraventricular tachycardia with aberrant conduction within the normal conduction system. 

Three different conduction patterns are seen with atrioventricular reentrant tachycardia (Figure 2):

Sinus depolarization (Figure 2), in which the atrial impulse travels down the AV node, and the accessory pathway can be hidden and not contribute to the surface ECG.

Orthodromic atrioventricular reentrant tachycardia (Figure2), in which the depolarizing impulse travels antegrade down the AV node, then propagates from the ventricle back to the atria via the accessory pathway, resulting in a narrow QRS.

Antidromic atrioventricular reentrant tachycardia (Figure 2), in which the depolarization travels antegrade down the accessory pathway then propagates from the ventricle back to the atria via the AV node, resulting in a wide complex QRS with a delta wave.

Important features of the patient’s electrocardiogram (Figure 1) are consistent with antidromic atrioventricular reentrant tachycardia:

• “Buried” retrograde P waves, which are best seen in the continuous strip of lead II as a positive deflection notching in the negative nadir of the wave
• The PR segment is short, suggesting retrograde atrial depolarization
• The P wave is followed by a slow slurred upstroke (delta wave), best seen in lead I.

Treatment depends on diagnosis

Distinguishing supraventricular tachycardia from ventricular tachycardia is important, as the treatments differ. Supraventricular tachycardia is treated with adenosine, calcium channel blockers, and beta-blockers, which are not only ineffective for ventricular tachycardia, but rarely may precipitate hemodynamic deterioration.

Also important is distinguishing pre-excitation atrial fibrillation from other types of supraventricular tachycardia with aberrancy, because the nodal blockade used to treat other causes of the condition may worsen the tachycardia via the accessory pathway. If pre-excitation atrial fibrillation is suspected on the basis of an irregular wide complex tachycardia with delta waves on ECG, then procainamide—a sodium channel blocker that affects the cardiac action potential and prolongs the refractory period of the accessory pathway—can be used to help control the arrhythmia.¹

Brugada criteria aid diagnosis

Adapted from Brugada P, et al. A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex. Circulation 1991; 83:1649–1659, with permission from Lippincott Williams &amp; Wilkins.

In 1991, Brugada et al² devised an algorithm to differentiate ventricular tachycardia from supraventricular tachycardia with aberrancy in the setting of regular wide complex tachycardia (Figure 3). It has a sensitivity of 98.7% and a specificity of 96.5% for diagnosing ventricular tachycardia and 96.5% sensitivity and 98.7% specificity for diagnosing supraventricular tachycardia with aberrant conduction. Using the algorithm, only 11 (ie, 2%) of the 544 tachycardias in their study were misclassified.^2–4

The Brugada algorithm consists of four criteria, with the presence of any leading to a diagnosis of ventricular tachycardia:

• Absence of an RS complex in all precordial leads (the QRS complexes in precordial leads have all negative or all positive deflections).
• An RS interval in at least one precordial lead of at least 100 ms (the interval is measured from the onset of R to the nadir of the S wave).
• AV dissociation, as determined by the existence of P waves marching out independent of the QRS complexes, capture beats (narrow QRS complexes resulting from the rare occasion when an intrinsic P wave conducts down the native pathway), or fusion beats (combined capture beat and ventricular beat, resulting in a different morphology than most of the wide QRS complexes present).
• Leads V₁, V₂, and V₆ satisfying the classic morphologic criteria for ventricular tachycardia.

If none of these criteria are met, supraventricular tachycardia is diagnosed.

In our patient, we can further confirm the diagnosis of antidromic atrioventricular reentrant tachycardia by using Brugada criteria to exclude ventricular tachycardia (Figure 3): the ECG (Figure 1) shows an RS complex in multiple precordial leads, the maximum RS interval is less than 100 ms in the precordial leads, there is no evidence of AV dissociation (lead II in the continuous strip shows buried P waves associated with QRS), and morphologic criteria are not met for ventricular tachycardia in leads V₁, V₂, and V₆. 

IS CARDIOVERSION NEEDED?

According to the American Heart Association guidelines for advanced cardiopulmonary life support, patients with tachyarrhythmias who are hemodynamically unstable should undergo cardioversion immediately.⁵

Our patient, who has a heart rate faster than 200 bpm and a systolic blood pressure of only 60 mm Hg, undergoes synchronized cardioversion in the emergency department. Immediately afterward, his ECG (Figure 4) demonstrates sinus rhythm with pre-excitation consistent with type B Wolff-Parkinson-White syndrome.

Once he is hemodynamically stable, a more thorough physical examination is performed. Examination of the head, ears, eyes, nose, and throat is unremarkable. He has no jugular venous distention or carotid bruits. His lungs are clear to auscultation bilaterally, without wheezes. His cardiac examination shows a regular rate and rhythm, normal first and second heart sounds, and no murmurs, rubs, or gallops.

WHICH DIAGNOSTIC STUDIES ARE NEEDED?

Laboratory tests

In an otherwise healthy young patient presenting with an arrhythmia, the initial laboratory workup should focus on a precipitating illness or a disease state that may incite an arrhythmia.

Our patient is evaluated for infection or septic shock (white blood cell count with differential), anemia (hemoglobin), thyrotoxicosis (thyroid-stimulating hormone and free thyroxine levels), drug abuse (urine toxicology screen), and cardiac syndromes including structural heart disease and myocardial injury (cardiac enzymes and B-type natriuretic peptide).⁶

His initial laboratory tests show normal electrolyte levels and renal function, leukocytosis with a white blood cell count of 15.6 × 10⁹/L (normal 4.0–10.0), mildly elevated thyroid-stimulating hormone, and a negative urine toxicology screen.

Transthoracic echocardiography

For a young patient presenting with pre-excitation on ECG and hemodynamic instability, transthoracic echocardiography to evaluate chamber size and look for structural abnormalities is a reasonable option.

Our patient undergoes transthoracic echocardiography, which demonstrates normal left ventricular size and function with a left ventricular ejection fraction of 69%, moderate right atrial enlargement, and mild right ventricular enlargement (Figure 5). The septal leaflet of the tricuspid valve is apically displaced, and there is mild regurgitation.

DIAGNOSIS: EBSTEIN ANOMALY

These findings are consistent with Ebstein anomaly. It can be recognized on transthoracic echocardiography as adherence of the septal and posterior tricuspid valve leaflets to the myocardium due to failure of the tissue to detach during embryogenesis, apical displacement of the annulus, right atrial enlargement, and right ventricular enlargement.^7–10 Apical displacement of the tricuspid valve is a hallmark finding and must be more than 20 mm or 8 mm/m² of body surface area to make the diagnosis.^11–13 ECG often demonstrates right atrial enlargement, first-degree atrial ventricular block, and right bundle branch block.

Ebstein anomaly is a rare embryonic developmental abnormality of the tricuspid valve. It occurs in 1 to 5 of 200,000 live births, accounting for approximately 0.5% of all congenital heart disease.^14,15 Most cases are sporadic and result from failure of the ventricle to delaminate during embryogenesis of the tricuspid valve, resulting in apical displacement of either the septal, posterior, or, very rarely, anterior leaflet of the tricuspid valve.^7,8 The prevalence is higher in infants whose mothers took lithium during early pregnancy.¹⁶

2. Which of the following is not a common finding associated with Ebstein anomaly?

• Apical displacement of the septal leaflet of the tricuspid valve
• Wolff-Parkinson-White syndrome
• Accessory bypass tract
• Tachyarrhythmias
• Increased risk of sudden death
• Left-sided heart failure

The answer is left-sided heart failure. Ebstein anomaly is associated with increased risk of tachyarrhythmias, right-sided heart failure, and sudden death.^7,8,17,18 In Ebstein anomaly, the tricuspid valve forms closer to the apex, so the part of the right ventricle that is superior to the displaced tricuspid valve functions as the right atrium, thus the term “atrialized” right ventricle. These abnormalities create an environment for accessory pathways, most commonly type B Wolff-Parkinson-White syndrome.¹⁹ Biventricular dysfunction can occur in rare severe cases.^7,8,18

Our patient is found to have an accessory tract-mediated antidromic atrioventricular reentrant tachycardia in the setting of Wolff-Parkinson-White syndrome and Ebstein anomaly. This is further confirmed with an electrophysiology study demonstrating a right posterior accessory pathway.

TREATMENT FOR EBSTEIN ANOMALY

3. Which treatment is advised for Ebstein anomaly?

• Observation alone
• Standard heart failure medications
• Radiofrequency catheter ablation
• Tricuspid valve repair or replacement
• Biventricular reconstruction
• Heart transplant

The answer is all of the above. Observation alone is advised for patients with mild symptoms, no evidence of right-to-left shunting, and only mild cardiomegaly. Medical management includes an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, a beta-blocker, and diuretics. Radiofrequency catheter ablation is the first-line therapy for patients with symptomatic Wolff-Parkinson-White syndrome.²⁰ A patient who develops worsening right-sided heart failure, cyanosis, paradoxical emboli, or frequent tachyarrhythmias should be considered for corrective surgery, which may include tricuspid valve repair or replacement, or biventricular reconstruction.^7,8,21 Cardiac transplant is reserved for severe cases.⁸

On hospital day 4, our patient undergoes successful radiofrequency catheter ablation without complications. At follow-up 3 months later, he continues to do well, with resolution of his symptoms and no further evidence of pre-excitation. His postprocedure ECG no longer shows delta waves.

TAKE-HOME POINTS

• For a patient with regular wide complex tachycardia, the first step is to assess hemodynamic stability. If the patient is hemodynamically unstable, emergent cardioversion is indicated.
• The differential diagnosis for regular wide complex tachycardia includes supraventricular tachycardia with aberrancy (orthodromic atrioventricular reentrant tachycardia, antidromic atrioventricular reentrant tachycardia, atrial tachycardia), and ventricular tachycardia.
• When pre-excited atrial fibrillation is suspected, AV nodal blocking agents should be avoided, as they may worsen tachyarrhythmia. Sodium channel blockers such as procainamide can help slow down the conduction of the accessory pathway.
• Ebstein anomaly is diagnosed on transthoracic echocardiography as apical displacement of the tricuspid valve resulting in atrialization of the right ventricle.
• Patients with Ebstein anomaly have a higher risk of death from right-sided heart failure and tachyarrhythmias, most commonly type B Wolff-Parkinson-White syndrome.
• Ebstein anomaly is medically managed with standard heart failure medications, including neurohormonal blockade therapies.
• Patients with Ebstein anomaly and cyanosis require surgical intervention with either valve repair or replacement.
   

Acknowledgment: We thank Dr. William Collins for his contribution in reviewing the manuscript and his technical expertise in developing some of the figures.

For decades, vitamin K antagonists such as warfarin, acenocoumarol, phenindione, and phenprocoumon have been the only available oral anticoagulants. These drugs have similar pharmacologic profiles and share significant drawbacks in clinical use: a narrow therapeutic window, food and drug interactions, and the need for repeated blood testing to ensure the desired international normalized ratio.

Such problems have fostered research in the field of coagulation, and new oral agents that selectively target coagulation factors have become available. At least three such products are already available in most countries: dabigatran (a thrombin or factor IIa inhibitor) and rivaroxaban and apixaban (factor Xa inhibitors).^1,2 Other factor Xa inhibitors, including edoxaban³ (available in the United States and Japan) and betrixaban,⁴ may also soon become available worldwide. 

The new oral anticoagulants are more effective than vitamin K antagonists in preventing several thromboembolic conditions, have fewer drug interactions, and likely have fewer side effects.⁵ Indications for these new agents are expected to expand as new clinical trial results become available.^6,7

This review summarizes the clinically relevant characteristics of the new oral anticoagulants (Table 1) and provides guidance on their usage (Table 2).

THROMBIN (FACTOR IIa) INHIBITORS

Dabigatran

Dabigatran etexilate is a prodrug that is rapidly and completely converted by esterases in the plasma and liver into its active metabolite, dabigatran. It competitively and reversibly binds to freely circulating and clot-bound thrombin, thereby blocking thrombin’s pro­coagulant properties (Figure 1).

Clinical trials have shown dabigatran to be similar to warfarin and enoxaparin in efficacy and safety in preventing and treating thromboembolic disease.^8–10

Indications. Dabigatran is approved by the US Food and Drug Administration (FDA) for:

• Preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treating deep vein thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5 to 10 days
• Preventing recurrence of deep vein thrombosis and pulmonary embolism in patients who have previously been treated with other medications.

Precautions. Dabigatran should not be used, or should be used only in a reduced dosage, in patients with renal failure. It can be used in patients with moderate liver impairment but should be avoided in patients with advanced liver disease (cirrhosis), especially if they have coagulopathy. Its use in pregnant and nursing women is not recommended.

Adverse effects. Bleeding, including gastrointestinal and intracranial hemorrhage, is the most important adverse effect,¹¹ but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.^1,12 Dyspepsia is common and may be severe enough to require stopping treatment.¹³ Other possible effects are pain or burning in the throat, skin rash, and syncope. The risk of acute coronary syndrome is slightly increased but is outweighed by the benefit of ischemic stroke prevention.^14,15

Drug interactions. Normally, permeability (P)-glycoprotein intestinal transporter extrudes substrate drugs back into the gut lumen after initial absorption, thereby interfering with drug bioavailability. Strong P-glycoprotein inhibitors (eg, ketoconazole, cyclosporine, tacrolimus, dronedarone, amiodarone, verapamil, clarithromycin) increase the plasma concentration of dabigatran. Despite that, giving these drugs with dabigatran is generally safe except in patients with renal failure (and especially with ketoconazole and dronedarone). To reduce interaction with verapamil, dabigatran should be taken at least 2 hours before this drug.

Potent P-glycoprotein transporter inducers such as rifampicin, carbamazepine, and phenytoin reduce the plasma concentration of dabigatran, and concomitant use of dabigatran with these drugs should be avoided.¹

Another selective thrombin inhibitor

Ximelagatran was extensively investigated and approved in several countries in 2006. However, it was withdrawn after reports of severe hepatotoxicity.¹⁶ No other selective thrombin inhibitors are currently in an advanced stage of development.

FACTOR Xa INHIBITORS

Factor Xa is an ideal target for anticoagulants because of its important role in thrombin formation (Figure 1). Selective or direct factor Xa inhibitors significantly reduce the number of strokes and systemic embolic events compared with warfarin in patients with atrial fibrillation. They also may cause fewer major bleeding events than warfarin, although evidence supporting this is less robust.¹⁷ These agents have shown an advantage over enoxaparin for thromboprophylaxis after elective hip or knee replacement surgery and after hip fracture surgery without increasing the rate of bleeding events.¹⁸

Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor. It  reversibly binds to factor Xa with high specificity and inhibits free and clot-bound factor Xa as well as factor Xa in the prothrombinase complex (which catalyzes the conversion of prothrombin to thrombin).¹⁹

Indications. Clinical trials have shown rivaroxaban to have suitable efficacy and safety in several clinical situations.^20–23 It is FDA-approved for:

• Reducing the risk of stroke and systemic embolism in nonvalvular atrial fibrillation
• Preventing deep vein thrombosis after hip or knee replacement surgery
• Treating deep vein thrombosis and pulmonary embolism
• Reducing the risk of recurrence of deep vein thrombosis and pulmonary embolism.

In addition, the European Medicines Agency has approved the use of rivaroxaban together with antiplatelet medications to prevent atherothrombotic events after an acute coronary syndrome with elevated cardiac biomarkers.

Precautions. Rivaroxaban should be taken with food to maximize its absorption. Like dabigatran, it should be avoided or used cautiously in patients with renal failure and liver disease, and it is not recommended for pregnant and nursing women. 

Adverse effects. The most common adverse event is bleeding, although the incidence of major hemorrhage is similar to that with vitamin K antagonists and low-molecular-weight heparins.¹ Other effects include osteoarticular pain, weakness, wound secretion, skin rash, pruritus, abdominal pain, and syncope.

Drug interactions. Inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes can alter the metabolism of rivaroxaban, making its levels too high. Rivaroxaban is not recommended for patients receiving systemic treatment with azole-antimycotics (eg, ketoconazole) or protease inhibitors to treat human immunodeficiency virus (HIV) infection (eg, ritonavir), as these drugs are strong inhibitors of both systems and may considerably increase plasma rivaroxaban concentrations.²⁴ Interactions of rivaroxaban with most other inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes are considered clinically inconsequential, but caution is still recommended, especially in patients already at risk of bleeding (eg, those taking antiplatelet agents).²⁵  

Strong inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes (eg, rifampicin, phenytoin) can reduce plasma rivaroxaban concentrations and thus decrease its efficacy. Caution is needed if rivaroxaban is taken with these drugs.

Apixaban

Apixaban also selectively and reversibly inhibits free and clot-bound factor Xa, as well as factor Xa in the prothrombinase complex.

Indications. Apixaban has a suitable efficacy and safety profile, and in clinical trials fewer patients died while taking it than those taking warfarin.^26–28 It is FDA-approved for:

• Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Prophylaxis of deep vein thrombosis and pulmonary embolism in patients who have undergone hip or knee replacement
• Treating deep vein thrombosis and pulmonary embolism
• Reducing the risk of recurrent deep vein thrombosis and pulmonary embolism after initial therapy.

Precautions. Apixaban can be used in most patients with renal failure, but at a lower dosage in some circumstances (Table 2). It can be used without dosage adjustment for patients with mild hepatic impairment but should be avoided in those with moderate or advanced liver failure. It is contraindicated in pregnant and nursing women.

Adverse effects. As with other anticoagulants, the most common adverse effect is bleeding, but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.^1,26–28 Other adverse reactions, such as nausea, skin rash, and liver enzyme elevation, are uncommon.

Drug interactions are similar to those of rivaroxaban but are generally less intense. Concomitant use with strong dual inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes, especially azole-antimycotics and HIV protease inhibitors, should be avoided, but if used, the apixaban dosage may be halved. Caution is also recommended if using apixaban with dual inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes.²⁹

Edoxaban

Edoxaban, another direct factor Xa inhibitor, has a rapid onset of action. It is taken orally once daily and has antithrombotic efficacy similar to other agents in this group.^1,30

Indications. Edoxaban has been approved by the Japanese Pharmaceuticals and Medical Devices Agency and the FDA for:

• Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treating deep vein thrombosis and pulmonary embolism after 10 days of initial therapy with a parenteral anticoagulant.

Precautions. Edoxaban should not be used in patients with creatinine clearance above 95 mL/min because patients with this excellent level of renal function may clear the drug too well and therefore have a higher risk of ische­mic stroke than those receiving warfarin.³¹

Adverse effects and drug interactions are similar to those of other factor Xa inhibitors.

Other factor Xa inhibitors

Betrixaban is similar to other factor Xa inhibitors but has some unique pharmacokinetic characteristics, including minimal metabolism through the cytochrome P450 system, limited renal excretion, and a long half-life. This profile may have the advantages of fewer drug interactions and greater flexibility for use in patients with poor renal function, as well as the convenience of once-daily dosing.^4,32 The drug has not yet been approved for clinical use by the FDA or the European Medicines Agency.

Additional oral factor Xa inhibitors, including letaxaban, darexaban, and eribaxaban, are being developed with the aim of overcoming the limitations of available drugs in the group.³³

COAGULATION MONITORING

Given their rapid onset of action, stable pharmacokinetic properties, and few significant drug interactions, the new oral anticoagulants do not generally require coagulation monitoring. However, these drugs may produce alterations in coagulation tests: thrombin inhibitors tend to prolong the activated partial thromboplastin time, and factor Xa inhibitors tend to prolong the prothrombin time. These alterations vary from laboratory to laboratory, depending on the reagents used.^34,35

The new agents have also been reported to cause false-positive results on lupus anticoagulant assays and falsely elevated activated protein C ratio assays, misclassifying patients with the factor V Leiden mutation as normal.^36,37

Anticoagulation from dabigatran therapy can be monitored with the ecarin clotting time test, which yields a dose-dependent prolongation of clotting time.³⁸ Rivaroxaban, apixaban, and edoxaban can be monitored using modified chromogenic anti-Xa assays.²⁵ These tests may help manage overdoses, bleeding events, and emergency perioperative situations, but their usefulness in clinical practice is limited at this time because they are not widely available and they are not validated for this use.

SWITCHING FROM VITAMIN K ANTAGONISTS TO THE NEW AGENTS

Important issues to consider when switching anticoagulant agents are the delayed onset of action after initiating treatment and the persistent anticoagulant effect after stopping it. In both cases, the international normalized ratio can be used to monitor the anticoagulant effect of the drugs. Renal failure should also be considered, as it can prolong the plasma half-life of the agents.^1,39

MANAGING BLEEDING

Dabigatran is the only new anticoagulant with an antidote commercially available: idaruciz­umab can completely reverse the anticoagulant effect of dabigatran within minutes.

The other new oral anticoagulants lack antidotes, which can present a major problem if a patient has a major bleed or needs emergency surgery. Giving vitamin K is probably useless in this situation. In general, patients taking one of the new oral anticoagulants who present with bleeding should be treated with traditional measures—eg, oral activated charcoal to retard absorption of recently ingested drugs and cauterization and packing of localized bleeding sites. Dialysis may be useful for patients taking dabigatran⁴⁰ but probably not the other drugs, because they are more highly protein-bound.

Other measures to consider include giving:

• Fresh frozen plasma, which may have some potential for reversing the action of thrombin inhibitors and factor Xa inhibitors but lacks data in humans⁴¹
• Activated prothrombin complex concentrate for reversing thrombin inhibitors
• Nonactivated prothrombin complex concentrates and factor Xa analogues for reversing anti-factor Xa agents^42–44
• Recombinant factor VIIa, but serious adverse effects—disseminated intravascular coagulation and systemic thrombosis— limit its usefulness.⁴⁵

More research is needed to assess the efficacy and safety of these measures.^46,47

STOPPING THERAPY BEFORE SURGERY

How long to withhold a new oral anticoagulant before patients undergo surgery depends on the type and urgency of the procedure, the indication for anticoagulation, the patient’s renal function, and the drug used.

For procedures with a low risk of bleeding (eg, laparoscopy, colonoscopy), dabigatran should be stopped at least 48 hours before the procedure, and factor Xa inhibitors at least 24 hours before. More time should be allowed for patients with renal failure to clear the drug, according to creatinine clearance.

For procedures entailing a high bleeding risk (eg, major surgery, insertion of pacemaker or defibrillator, neurosurgery, spinal puncture), any new oral anticoagulant should be stopped at least 48 hours before the procedure, with a longer time needed for patients with renal failure.

If urgent surgery is needed and performed within a few hours after the last dose of a drug, bleeding complications should be anticipated.

Resuming anticoagulation therapy after surgery should also be individualized depending on the procedure, the indication for anticoagulation, and renal function. In most patients, if good hemostasis is achieved, the drug may be resumed 4 to 6 hours after surgery. Generally, the first dose should be reduced by 50%, after which the usual maintenance dose can be resumed.³⁹

OTHER POSSIBLE USES

Cardioversion. Anticoagulation with da­big­­atran before and after cardioversion in patients with atrial fibrillation⁴⁸ appears as effective and safe as anticoagulation with warfarin.⁴⁹ There are insufficient data for the other new oral anticoagulants.

Heparin-induced thrombocytopenia. The new oral anticoagulants do not affect the interaction of platelets with platelet factor 4 or antibodies to the platelet factor 4-heparin complex, indicating that they may be an appropriate option for anticoagulation in patients with heparin-induced thrombocytopenia.^50–53

Other conditions. The new oral anticoagulants have demonstrated efficacy in preventing or treating thromboembolic disease in patients with cancer⁵⁴ and critical illnesses,⁵⁵ and in treating acute coronary syndrome^56–58 and other conditions.⁵⁹ However, their role in these settings is not well established.^60,61

SITUATIONS TO AVOID

Valvular heart disease. The new oral anticoagulants should not be prescribed for patients with a prosthetic heart valve or other significant valvular heart disease because of an increased risk of thrombotic complications with dabigatran and the lack of evidence of efficacy and safety of factor Xa inhibitors.^62–64

Concurrent thrombolytic therapy along with any of the new oral anticoagulants poses a very high risk of bleeding. Some cases in which dabigatran was used successfully in this situation have been reported, but definitive recommendations are lacking.⁶⁵

Elderly patients. The safety of the new oral anticoagulants in the elderly is of concern because of the high prevalence of renal failure and other comorbidities and the underrepresentation of this population in many clinical trials assessing these drugs. Data on interactions with foods or other drugs in this population are also scant.⁶⁶

CHOOSING AN ORAL ANTICOAGULANT

New oral anticoagulants are now a viable alternative to vitamin K antagonists for preventing and treating thromboembolic disease.^67,68

When oral anticoagulation is indicated, the choice of drug should be individualized. Cost is an important consideration: direct costs of the new drugs are substantially higher than those of vitamin K antagonists and heparin, but their cost-effectiveness may be comparable or superior to that of warfarin or enoxaparin when clinical efficacy and savings in avoiding coagulation tests are considered.¹⁸

Many experts estimate that the new oral anticoagulants are not remarkably superior to vitamin K antagonists, and thus patients whose coagulation is well controlled and stable on a traditional drug would probably not benefit much from changing.^1,18

There is currently no conclusive evidence to determine which new oral anticoagulant drug is more effective and safe for long-term treatment, as head-to-head studies of the different medications have not yet been performed.^17,69,70 However, there are factors to consider when choosing a drug:

• Rivaroxaban and edoxaban can be taken once daily and so may be better choices for patients who may have difficulties with compliance.
• Dabigatran should be avoided in patients with dyspepsia because of gastrointestinal adverse effects.¹³
• Dabigatran should be avoided in patients at risk of myocardial infarction because of a possible additional increase in risk.^1,71

For decades, vitamin K antagonists such as warfarin, acenocoumarol, phenindione, and phenprocoumon have been the only available oral anticoagulants. These drugs have similar pharmacologic profiles and share significant drawbacks in clinical use: a narrow therapeutic window, food and drug interactions, and the need for repeated blood testing to ensure the desired international normalized ratio.

Such problems have fostered research in the field of coagulation, and new oral agents that selectively target coagulation factors have become available. At least three such products are already available in most countries: dabigatran (a thrombin or factor IIa inhibitor) and rivaroxaban and apixaban (factor Xa inhibitors).^1,2 Other factor Xa inhibitors, including edoxaban³ (available in the United States and Japan) and betrixaban,⁴ may also soon become available worldwide. 

The new oral anticoagulants are more effective than vitamin K antagonists in preventing several thromboembolic conditions, have fewer drug interactions, and likely have fewer side effects.⁵ Indications for these new agents are expected to expand as new clinical trial results become available.^6,7

This review summarizes the clinically relevant characteristics of the new oral anticoagulants (Table 1) and provides guidance on their usage (Table 2).

THROMBIN (FACTOR IIa) INHIBITORS

Dabigatran

Dabigatran etexilate is a prodrug that is rapidly and completely converted by esterases in the plasma and liver into its active metabolite, dabigatran. It competitively and reversibly binds to freely circulating and clot-bound thrombin, thereby blocking thrombin’s pro­coagulant properties (Figure 1).

Clinical trials have shown dabigatran to be similar to warfarin and enoxaparin in efficacy and safety in preventing and treating thromboembolic disease.^8–10

Indications. Dabigatran is approved by the US Food and Drug Administration (FDA) for:

• Preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treating deep vein thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5 to 10 days
• Preventing recurrence of deep vein thrombosis and pulmonary embolism in patients who have previously been treated with other medications.

Precautions. Dabigatran should not be used, or should be used only in a reduced dosage, in patients with renal failure. It can be used in patients with moderate liver impairment but should be avoided in patients with advanced liver disease (cirrhosis), especially if they have coagulopathy. Its use in pregnant and nursing women is not recommended.

Adverse effects. Bleeding, including gastrointestinal and intracranial hemorrhage, is the most important adverse effect,¹¹ but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.^1,12 Dyspepsia is common and may be severe enough to require stopping treatment.¹³ Other possible effects are pain or burning in the throat, skin rash, and syncope. The risk of acute coronary syndrome is slightly increased but is outweighed by the benefit of ischemic stroke prevention.^14,15

Drug interactions. Normally, permeability (P)-glycoprotein intestinal transporter extrudes substrate drugs back into the gut lumen after initial absorption, thereby interfering with drug bioavailability. Strong P-glycoprotein inhibitors (eg, ketoconazole, cyclosporine, tacrolimus, dronedarone, amiodarone, verapamil, clarithromycin) increase the plasma concentration of dabigatran. Despite that, giving these drugs with dabigatran is generally safe except in patients with renal failure (and especially with ketoconazole and dronedarone). To reduce interaction with verapamil, dabigatran should be taken at least 2 hours before this drug.

Potent P-glycoprotein transporter inducers such as rifampicin, carbamazepine, and phenytoin reduce the plasma concentration of dabigatran, and concomitant use of dabigatran with these drugs should be avoided.¹

Another selective thrombin inhibitor

Ximelagatran was extensively investigated and approved in several countries in 2006. However, it was withdrawn after reports of severe hepatotoxicity.¹⁶ No other selective thrombin inhibitors are currently in an advanced stage of development.

FACTOR Xa INHIBITORS

Factor Xa is an ideal target for anticoagulants because of its important role in thrombin formation (Figure 1). Selective or direct factor Xa inhibitors significantly reduce the number of strokes and systemic embolic events compared with warfarin in patients with atrial fibrillation. They also may cause fewer major bleeding events than warfarin, although evidence supporting this is less robust.¹⁷ These agents have shown an advantage over enoxaparin for thromboprophylaxis after elective hip or knee replacement surgery and after hip fracture surgery without increasing the rate of bleeding events.¹⁸

Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor. It  reversibly binds to factor Xa with high specificity and inhibits free and clot-bound factor Xa as well as factor Xa in the prothrombinase complex (which catalyzes the conversion of prothrombin to thrombin).¹⁹

Indications. Clinical trials have shown rivaroxaban to have suitable efficacy and safety in several clinical situations.^20–23 It is FDA-approved for:

• Reducing the risk of stroke and systemic embolism in nonvalvular atrial fibrillation
• Preventing deep vein thrombosis after hip or knee replacement surgery
• Treating deep vein thrombosis and pulmonary embolism
• Reducing the risk of recurrence of deep vein thrombosis and pulmonary embolism.

In addition, the European Medicines Agency has approved the use of rivaroxaban together with antiplatelet medications to prevent atherothrombotic events after an acute coronary syndrome with elevated cardiac biomarkers.

Precautions. Rivaroxaban should be taken with food to maximize its absorption. Like dabigatran, it should be avoided or used cautiously in patients with renal failure and liver disease, and it is not recommended for pregnant and nursing women. 

Adverse effects. The most common adverse event is bleeding, although the incidence of major hemorrhage is similar to that with vitamin K antagonists and low-molecular-weight heparins.¹ Other effects include osteoarticular pain, weakness, wound secretion, skin rash, pruritus, abdominal pain, and syncope.

Drug interactions. Inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes can alter the metabolism of rivaroxaban, making its levels too high. Rivaroxaban is not recommended for patients receiving systemic treatment with azole-antimycotics (eg, ketoconazole) or protease inhibitors to treat human immunodeficiency virus (HIV) infection (eg, ritonavir), as these drugs are strong inhibitors of both systems and may considerably increase plasma rivaroxaban concentrations.²⁴ Interactions of rivaroxaban with most other inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes are considered clinically inconsequential, but caution is still recommended, especially in patients already at risk of bleeding (eg, those taking antiplatelet agents).²⁵  

Strong inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes (eg, rifampicin, phenytoin) can reduce plasma rivaroxaban concentrations and thus decrease its efficacy. Caution is needed if rivaroxaban is taken with these drugs.

Apixaban

Apixaban also selectively and reversibly inhibits free and clot-bound factor Xa, as well as factor Xa in the prothrombinase complex.

Indications. Apixaban has a suitable efficacy and safety profile, and in clinical trials fewer patients died while taking it than those taking warfarin.^26–28 It is FDA-approved for:

• Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Prophylaxis of deep vein thrombosis and pulmonary embolism in patients who have undergone hip or knee replacement
• Treating deep vein thrombosis and pulmonary embolism
• Reducing the risk of recurrent deep vein thrombosis and pulmonary embolism after initial therapy.

Precautions. Apixaban can be used in most patients with renal failure, but at a lower dosage in some circumstances (Table 2). It can be used without dosage adjustment for patients with mild hepatic impairment but should be avoided in those with moderate or advanced liver failure. It is contraindicated in pregnant and nursing women.

Adverse effects. As with other anticoagulants, the most common adverse effect is bleeding, but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.^1,26–28 Other adverse reactions, such as nausea, skin rash, and liver enzyme elevation, are uncommon.

Drug interactions are similar to those of rivaroxaban but are generally less intense. Concomitant use with strong dual inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes, especially azole-antimycotics and HIV protease inhibitors, should be avoided, but if used, the apixaban dosage may be halved. Caution is also recommended if using apixaban with dual inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes.²⁹

Edoxaban

Edoxaban, another direct factor Xa inhibitor, has a rapid onset of action. It is taken orally once daily and has antithrombotic efficacy similar to other agents in this group.^1,30

Indications. Edoxaban has been approved by the Japanese Pharmaceuticals and Medical Devices Agency and the FDA for:

• Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treating deep vein thrombosis and pulmonary embolism after 10 days of initial therapy with a parenteral anticoagulant.

Precautions. Edoxaban should not be used in patients with creatinine clearance above 95 mL/min because patients with this excellent level of renal function may clear the drug too well and therefore have a higher risk of ische­mic stroke than those receiving warfarin.³¹

Adverse effects and drug interactions are similar to those of other factor Xa inhibitors.

Other factor Xa inhibitors

Betrixaban is similar to other factor Xa inhibitors but has some unique pharmacokinetic characteristics, including minimal metabolism through the cytochrome P450 system, limited renal excretion, and a long half-life. This profile may have the advantages of fewer drug interactions and greater flexibility for use in patients with poor renal function, as well as the convenience of once-daily dosing.^4,32 The drug has not yet been approved for clinical use by the FDA or the European Medicines Agency.

Additional oral factor Xa inhibitors, including letaxaban, darexaban, and eribaxaban, are being developed with the aim of overcoming the limitations of available drugs in the group.³³

COAGULATION MONITORING

Given their rapid onset of action, stable pharmacokinetic properties, and few significant drug interactions, the new oral anticoagulants do not generally require coagulation monitoring. However, these drugs may produce alterations in coagulation tests: thrombin inhibitors tend to prolong the activated partial thromboplastin time, and factor Xa inhibitors tend to prolong the prothrombin time. These alterations vary from laboratory to laboratory, depending on the reagents used.^34,35

The new agents have also been reported to cause false-positive results on lupus anticoagulant assays and falsely elevated activated protein C ratio assays, misclassifying patients with the factor V Leiden mutation as normal.^36,37

Anticoagulation from dabigatran therapy can be monitored with the ecarin clotting time test, which yields a dose-dependent prolongation of clotting time.³⁸ Rivaroxaban, apixaban, and edoxaban can be monitored using modified chromogenic anti-Xa assays.²⁵ These tests may help manage overdoses, bleeding events, and emergency perioperative situations, but their usefulness in clinical practice is limited at this time because they are not widely available and they are not validated for this use.

SWITCHING FROM VITAMIN K ANTAGONISTS TO THE NEW AGENTS

Important issues to consider when switching anticoagulant agents are the delayed onset of action after initiating treatment and the persistent anticoagulant effect after stopping it. In both cases, the international normalized ratio can be used to monitor the anticoagulant effect of the drugs. Renal failure should also be considered, as it can prolong the plasma half-life of the agents.^1,39

MANAGING BLEEDING

Dabigatran is the only new anticoagulant with an antidote commercially available: idaruciz­umab can completely reverse the anticoagulant effect of dabigatran within minutes.

The other new oral anticoagulants lack antidotes, which can present a major problem if a patient has a major bleed or needs emergency surgery. Giving vitamin K is probably useless in this situation. In general, patients taking one of the new oral anticoagulants who present with bleeding should be treated with traditional measures—eg, oral activated charcoal to retard absorption of recently ingested drugs and cauterization and packing of localized bleeding sites. Dialysis may be useful for patients taking dabigatran⁴⁰ but probably not the other drugs, because they are more highly protein-bound.

Other measures to consider include giving:

• Fresh frozen plasma, which may have some potential for reversing the action of thrombin inhibitors and factor Xa inhibitors but lacks data in humans⁴¹
• Activated prothrombin complex concentrate for reversing thrombin inhibitors
• Nonactivated prothrombin complex concentrates and factor Xa analogues for reversing anti-factor Xa agents^42–44
• Recombinant factor VIIa, but serious adverse effects—disseminated intravascular coagulation and systemic thrombosis— limit its usefulness.⁴⁵

More research is needed to assess the efficacy and safety of these measures.^46,47

STOPPING THERAPY BEFORE SURGERY

How long to withhold a new oral anticoagulant before patients undergo surgery depends on the type and urgency of the procedure, the indication for anticoagulation, the patient’s renal function, and the drug used.

For procedures with a low risk of bleeding (eg, laparoscopy, colonoscopy), dabigatran should be stopped at least 48 hours before the procedure, and factor Xa inhibitors at least 24 hours before. More time should be allowed for patients with renal failure to clear the drug, according to creatinine clearance.

For procedures entailing a high bleeding risk (eg, major surgery, insertion of pacemaker or defibrillator, neurosurgery, spinal puncture), any new oral anticoagulant should be stopped at least 48 hours before the procedure, with a longer time needed for patients with renal failure.

If urgent surgery is needed and performed within a few hours after the last dose of a drug, bleeding complications should be anticipated.

Resuming anticoagulation therapy after surgery should also be individualized depending on the procedure, the indication for anticoagulation, and renal function. In most patients, if good hemostasis is achieved, the drug may be resumed 4 to 6 hours after surgery. Generally, the first dose should be reduced by 50%, after which the usual maintenance dose can be resumed.³⁹

OTHER POSSIBLE USES

Cardioversion. Anticoagulation with da­big­­atran before and after cardioversion in patients with atrial fibrillation⁴⁸ appears as effective and safe as anticoagulation with warfarin.⁴⁹ There are insufficient data for the other new oral anticoagulants.

Heparin-induced thrombocytopenia. The new oral anticoagulants do not affect the interaction of platelets with platelet factor 4 or antibodies to the platelet factor 4-heparin complex, indicating that they may be an appropriate option for anticoagulation in patients with heparin-induced thrombocytopenia.^50–53

Other conditions. The new oral anticoagulants have demonstrated efficacy in preventing or treating thromboembolic disease in patients with cancer⁵⁴ and critical illnesses,⁵⁵ and in treating acute coronary syndrome^56–58 and other conditions.⁵⁹ However, their role in these settings is not well established.^60,61

SITUATIONS TO AVOID

Valvular heart disease. The new oral anticoagulants should not be prescribed for patients with a prosthetic heart valve or other significant valvular heart disease because of an increased risk of thrombotic complications with dabigatran and the lack of evidence of efficacy and safety of factor Xa inhibitors.^62–64

Concurrent thrombolytic therapy along with any of the new oral anticoagulants poses a very high risk of bleeding. Some cases in which dabigatran was used successfully in this situation have been reported, but definitive recommendations are lacking.⁶⁵

Elderly patients. The safety of the new oral anticoagulants in the elderly is of concern because of the high prevalence of renal failure and other comorbidities and the underrepresentation of this population in many clinical trials assessing these drugs. Data on interactions with foods or other drugs in this population are also scant.⁶⁶

CHOOSING AN ORAL ANTICOAGULANT

New oral anticoagulants are now a viable alternative to vitamin K antagonists for preventing and treating thromboembolic disease.^67,68

When oral anticoagulation is indicated, the choice of drug should be individualized. Cost is an important consideration: direct costs of the new drugs are substantially higher than those of vitamin K antagonists and heparin, but their cost-effectiveness may be comparable or superior to that of warfarin or enoxaparin when clinical efficacy and savings in avoiding coagulation tests are considered.¹⁸

Many experts estimate that the new oral anticoagulants are not remarkably superior to vitamin K antagonists, and thus patients whose coagulation is well controlled and stable on a traditional drug would probably not benefit much from changing.^1,18

There is currently no conclusive evidence to determine which new oral anticoagulant drug is more effective and safe for long-term treatment, as head-to-head studies of the different medications have not yet been performed.^17,69,70 However, there are factors to consider when choosing a drug:

• Rivaroxaban and edoxaban can be taken once daily and so may be better choices for patients who may have difficulties with compliance.
• Dabigatran should be avoided in patients with dyspepsia because of gastrointestinal adverse effects.¹³
• Dabigatran should be avoided in patients at risk of myocardial infarction because of a possible additional increase in risk.^1,71

For decades, vitamin K antagonists such as warfarin, acenocoumarol, phenindione, and phenprocoumon have been the only available oral anticoagulants. These drugs have similar pharmacologic profiles and share significant drawbacks in clinical use: a narrow therapeutic window, food and drug interactions, and the need for repeated blood testing to ensure the desired international normalized ratio.

Such problems have fostered research in the field of coagulation, and new oral agents that selectively target coagulation factors have become available. At least three such products are already available in most countries: dabigatran (a thrombin or factor IIa inhibitor) and rivaroxaban and apixaban (factor Xa inhibitors).^1,2 Other factor Xa inhibitors, including edoxaban³ (available in the United States and Japan) and betrixaban,⁴ may also soon become available worldwide. 

The new oral anticoagulants are more effective than vitamin K antagonists in preventing several thromboembolic conditions, have fewer drug interactions, and likely have fewer side effects.⁵ Indications for these new agents are expected to expand as new clinical trial results become available.^6,7

This review summarizes the clinically relevant characteristics of the new oral anticoagulants (Table 1) and provides guidance on their usage (Table 2).

THROMBIN (FACTOR IIa) INHIBITORS

Dabigatran

Dabigatran etexilate is a prodrug that is rapidly and completely converted by esterases in the plasma and liver into its active metabolite, dabigatran. It competitively and reversibly binds to freely circulating and clot-bound thrombin, thereby blocking thrombin’s pro­coagulant properties (Figure 1).

Clinical trials have shown dabigatran to be similar to warfarin and enoxaparin in efficacy and safety in preventing and treating thromboembolic disease.^8–10

Indications. Dabigatran is approved by the US Food and Drug Administration (FDA) for:

• Preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treating deep vein thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5 to 10 days
• Preventing recurrence of deep vein thrombosis and pulmonary embolism in patients who have previously been treated with other medications.

Precautions. Dabigatran should not be used, or should be used only in a reduced dosage, in patients with renal failure. It can be used in patients with moderate liver impairment but should be avoided in patients with advanced liver disease (cirrhosis), especially if they have coagulopathy. Its use in pregnant and nursing women is not recommended.

Adverse effects. Bleeding, including gastrointestinal and intracranial hemorrhage, is the most important adverse effect,¹¹ but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.^1,12 Dyspepsia is common and may be severe enough to require stopping treatment.¹³ Other possible effects are pain or burning in the throat, skin rash, and syncope. The risk of acute coronary syndrome is slightly increased but is outweighed by the benefit of ischemic stroke prevention.^14,15

Drug interactions. Normally, permeability (P)-glycoprotein intestinal transporter extrudes substrate drugs back into the gut lumen after initial absorption, thereby interfering with drug bioavailability. Strong P-glycoprotein inhibitors (eg, ketoconazole, cyclosporine, tacrolimus, dronedarone, amiodarone, verapamil, clarithromycin) increase the plasma concentration of dabigatran. Despite that, giving these drugs with dabigatran is generally safe except in patients with renal failure (and especially with ketoconazole and dronedarone). To reduce interaction with verapamil, dabigatran should be taken at least 2 hours before this drug.

Potent P-glycoprotein transporter inducers such as rifampicin, carbamazepine, and phenytoin reduce the plasma concentration of dabigatran, and concomitant use of dabigatran with these drugs should be avoided.¹

Another selective thrombin inhibitor

Ximelagatran was extensively investigated and approved in several countries in 2006. However, it was withdrawn after reports of severe hepatotoxicity.¹⁶ No other selective thrombin inhibitors are currently in an advanced stage of development.

FACTOR Xa INHIBITORS

Factor Xa is an ideal target for anticoagulants because of its important role in thrombin formation (Figure 1). Selective or direct factor Xa inhibitors significantly reduce the number of strokes and systemic embolic events compared with warfarin in patients with atrial fibrillation. They also may cause fewer major bleeding events than warfarin, although evidence supporting this is less robust.¹⁷ These agents have shown an advantage over enoxaparin for thromboprophylaxis after elective hip or knee replacement surgery and after hip fracture surgery without increasing the rate of bleeding events.¹⁸

Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor. It  reversibly binds to factor Xa with high specificity and inhibits free and clot-bound factor Xa as well as factor Xa in the prothrombinase complex (which catalyzes the conversion of prothrombin to thrombin).¹⁹

Indications. Clinical trials have shown rivaroxaban to have suitable efficacy and safety in several clinical situations.^20–23 It is FDA-approved for:

• Reducing the risk of stroke and systemic embolism in nonvalvular atrial fibrillation
• Preventing deep vein thrombosis after hip or knee replacement surgery
• Treating deep vein thrombosis and pulmonary embolism
• Reducing the risk of recurrence of deep vein thrombosis and pulmonary embolism.

In addition, the European Medicines Agency has approved the use of rivaroxaban together with antiplatelet medications to prevent atherothrombotic events after an acute coronary syndrome with elevated cardiac biomarkers.

Precautions. Rivaroxaban should be taken with food to maximize its absorption. Like dabigatran, it should be avoided or used cautiously in patients with renal failure and liver disease, and it is not recommended for pregnant and nursing women. 

Adverse effects. The most common adverse event is bleeding, although the incidence of major hemorrhage is similar to that with vitamin K antagonists and low-molecular-weight heparins.¹ Other effects include osteoarticular pain, weakness, wound secretion, skin rash, pruritus, abdominal pain, and syncope.

Drug interactions. Inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes can alter the metabolism of rivaroxaban, making its levels too high. Rivaroxaban is not recommended for patients receiving systemic treatment with azole-antimycotics (eg, ketoconazole) or protease inhibitors to treat human immunodeficiency virus (HIV) infection (eg, ritonavir), as these drugs are strong inhibitors of both systems and may considerably increase plasma rivaroxaban concentrations.²⁴ Interactions of rivaroxaban with most other inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes are considered clinically inconsequential, but caution is still recommended, especially in patients already at risk of bleeding (eg, those taking antiplatelet agents).²⁵  

Strong inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes (eg, rifampicin, phenytoin) can reduce plasma rivaroxaban concentrations and thus decrease its efficacy. Caution is needed if rivaroxaban is taken with these drugs.

Apixaban

Apixaban also selectively and reversibly inhibits free and clot-bound factor Xa, as well as factor Xa in the prothrombinase complex.

Indications. Apixaban has a suitable efficacy and safety profile, and in clinical trials fewer patients died while taking it than those taking warfarin.^26–28 It is FDA-approved for:

• Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Prophylaxis of deep vein thrombosis and pulmonary embolism in patients who have undergone hip or knee replacement
• Treating deep vein thrombosis and pulmonary embolism
• Reducing the risk of recurrent deep vein thrombosis and pulmonary embolism after initial therapy.

Precautions. Apixaban can be used in most patients with renal failure, but at a lower dosage in some circumstances (Table 2). It can be used without dosage adjustment for patients with mild hepatic impairment but should be avoided in those with moderate or advanced liver failure. It is contraindicated in pregnant and nursing women.

Adverse effects. As with other anticoagulants, the most common adverse effect is bleeding, but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.^1,26–28 Other adverse reactions, such as nausea, skin rash, and liver enzyme elevation, are uncommon.

Drug interactions are similar to those of rivaroxaban but are generally less intense. Concomitant use with strong dual inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes, especially azole-antimycotics and HIV protease inhibitors, should be avoided, but if used, the apixaban dosage may be halved. Caution is also recommended if using apixaban with dual inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes.²⁹

Edoxaban

Edoxaban, another direct factor Xa inhibitor, has a rapid onset of action. It is taken orally once daily and has antithrombotic efficacy similar to other agents in this group.^1,30

Indications. Edoxaban has been approved by the Japanese Pharmaceuticals and Medical Devices Agency and the FDA for:

• Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treating deep vein thrombosis and pulmonary embolism after 10 days of initial therapy with a parenteral anticoagulant.

Precautions. Edoxaban should not be used in patients with creatinine clearance above 95 mL/min because patients with this excellent level of renal function may clear the drug too well and therefore have a higher risk of ische­mic stroke than those receiving warfarin.³¹

Adverse effects and drug interactions are similar to those of other factor Xa inhibitors.

Other factor Xa inhibitors

Betrixaban is similar to other factor Xa inhibitors but has some unique pharmacokinetic characteristics, including minimal metabolism through the cytochrome P450 system, limited renal excretion, and a long half-life. This profile may have the advantages of fewer drug interactions and greater flexibility for use in patients with poor renal function, as well as the convenience of once-daily dosing.^4,32 The drug has not yet been approved for clinical use by the FDA or the European Medicines Agency.

Additional oral factor Xa inhibitors, including letaxaban, darexaban, and eribaxaban, are being developed with the aim of overcoming the limitations of available drugs in the group.³³

COAGULATION MONITORING

Given their rapid onset of action, stable pharmacokinetic properties, and few significant drug interactions, the new oral anticoagulants do not generally require coagulation monitoring. However, these drugs may produce alterations in coagulation tests: thrombin inhibitors tend to prolong the activated partial thromboplastin time, and factor Xa inhibitors tend to prolong the prothrombin time. These alterations vary from laboratory to laboratory, depending on the reagents used.^34,35

The new agents have also been reported to cause false-positive results on lupus anticoagulant assays and falsely elevated activated protein C ratio assays, misclassifying patients with the factor V Leiden mutation as normal.^36,37

Anticoagulation from dabigatran therapy can be monitored with the ecarin clotting time test, which yields a dose-dependent prolongation of clotting time.³⁸ Rivaroxaban, apixaban, and edoxaban can be monitored using modified chromogenic anti-Xa assays.²⁵ These tests may help manage overdoses, bleeding events, and emergency perioperative situations, but their usefulness in clinical practice is limited at this time because they are not widely available and they are not validated for this use.

SWITCHING FROM VITAMIN K ANTAGONISTS TO THE NEW AGENTS

Important issues to consider when switching anticoagulant agents are the delayed onset of action after initiating treatment and the persistent anticoagulant effect after stopping it. In both cases, the international normalized ratio can be used to monitor the anticoagulant effect of the drugs. Renal failure should also be considered, as it can prolong the plasma half-life of the agents.^1,39

MANAGING BLEEDING

Dabigatran is the only new anticoagulant with an antidote commercially available: idaruciz­umab can completely reverse the anticoagulant effect of dabigatran within minutes.

The other new oral anticoagulants lack antidotes, which can present a major problem if a patient has a major bleed or needs emergency surgery. Giving vitamin K is probably useless in this situation. In general, patients taking one of the new oral anticoagulants who present with bleeding should be treated with traditional measures—eg, oral activated charcoal to retard absorption of recently ingested drugs and cauterization and packing of localized bleeding sites. Dialysis may be useful for patients taking dabigatran⁴⁰ but probably not the other drugs, because they are more highly protein-bound.

Other measures to consider include giving:

• Fresh frozen plasma, which may have some potential for reversing the action of thrombin inhibitors and factor Xa inhibitors but lacks data in humans⁴¹
• Activated prothrombin complex concentrate for reversing thrombin inhibitors
• Nonactivated prothrombin complex concentrates and factor Xa analogues for reversing anti-factor Xa agents^42–44
• Recombinant factor VIIa, but serious adverse effects—disseminated intravascular coagulation and systemic thrombosis— limit its usefulness.⁴⁵

More research is needed to assess the efficacy and safety of these measures.^46,47

STOPPING THERAPY BEFORE SURGERY

How long to withhold a new oral anticoagulant before patients undergo surgery depends on the type and urgency of the procedure, the indication for anticoagulation, the patient’s renal function, and the drug used.

For procedures with a low risk of bleeding (eg, laparoscopy, colonoscopy), dabigatran should be stopped at least 48 hours before the procedure, and factor Xa inhibitors at least 24 hours before. More time should be allowed for patients with renal failure to clear the drug, according to creatinine clearance.

For procedures entailing a high bleeding risk (eg, major surgery, insertion of pacemaker or defibrillator, neurosurgery, spinal puncture), any new oral anticoagulant should be stopped at least 48 hours before the procedure, with a longer time needed for patients with renal failure.

If urgent surgery is needed and performed within a few hours after the last dose of a drug, bleeding complications should be anticipated.

Resuming anticoagulation therapy after surgery should also be individualized depending on the procedure, the indication for anticoagulation, and renal function. In most patients, if good hemostasis is achieved, the drug may be resumed 4 to 6 hours after surgery. Generally, the first dose should be reduced by 50%, after which the usual maintenance dose can be resumed.³⁹

OTHER POSSIBLE USES

Cardioversion. Anticoagulation with da­big­­atran before and after cardioversion in patients with atrial fibrillation⁴⁸ appears as effective and safe as anticoagulation with warfarin.⁴⁹ There are insufficient data for the other new oral anticoagulants.

Heparin-induced thrombocytopenia. The new oral anticoagulants do not affect the interaction of platelets with platelet factor 4 or antibodies to the platelet factor 4-heparin complex, indicating that they may be an appropriate option for anticoagulation in patients with heparin-induced thrombocytopenia.^50–53

Other conditions. The new oral anticoagulants have demonstrated efficacy in preventing or treating thromboembolic disease in patients with cancer⁵⁴ and critical illnesses,⁵⁵ and in treating acute coronary syndrome^56–58 and other conditions.⁵⁹ However, their role in these settings is not well established.^60,61

SITUATIONS TO AVOID

Valvular heart disease. The new oral anticoagulants should not be prescribed for patients with a prosthetic heart valve or other significant valvular heart disease because of an increased risk of thrombotic complications with dabigatran and the lack of evidence of efficacy and safety of factor Xa inhibitors.^62–64

Concurrent thrombolytic therapy along with any of the new oral anticoagulants poses a very high risk of bleeding. Some cases in which dabigatran was used successfully in this situation have been reported, but definitive recommendations are lacking.⁶⁵

Elderly patients. The safety of the new oral anticoagulants in the elderly is of concern because of the high prevalence of renal failure and other comorbidities and the underrepresentation of this population in many clinical trials assessing these drugs. Data on interactions with foods or other drugs in this population are also scant.⁶⁶

CHOOSING AN ORAL ANTICOAGULANT

New oral anticoagulants are now a viable alternative to vitamin K antagonists for preventing and treating thromboembolic disease.^67,68

When oral anticoagulation is indicated, the choice of drug should be individualized. Cost is an important consideration: direct costs of the new drugs are substantially higher than those of vitamin K antagonists and heparin, but their cost-effectiveness may be comparable or superior to that of warfarin or enoxaparin when clinical efficacy and savings in avoiding coagulation tests are considered.¹⁸

Many experts estimate that the new oral anticoagulants are not remarkably superior to vitamin K antagonists, and thus patients whose coagulation is well controlled and stable on a traditional drug would probably not benefit much from changing.^1,18

There is currently no conclusive evidence to determine which new oral anticoagulant drug is more effective and safe for long-term treatment, as head-to-head studies of the different medications have not yet been performed.^17,69,70 However, there are factors to consider when choosing a drug:

• Rivaroxaban and edoxaban can be taken once daily and so may be better choices for patients who may have difficulties with compliance.
• Dabigatran should be avoided in patients with dyspepsia because of gastrointestinal adverse effects.¹³
• Dabigatran should be avoided in patients at risk of myocardial infarction because of a possible additional increase in risk.^1,71

The advent of the insulin pump in the late 1970s was a step forward in diabetes treatment,¹ and recent improvements make these devices easier to use in intensive insulin management. Today, more than 400,000 people in the United States are thought to be using an insulin pump.²

See related editorial

With a pump, patients can adjust the dosage and discreetly give themselves boluses by simply pushing a button instead of giving themselves multiple daily injections. Also, pump therapy can be tailored to correct for hepatic glucose production in a way that injections cannot.

This article reviews the clinical application of continuous subcutaneous insulin therapy—ie, the insulin pump—and provides recommendations for patient selection and management.

INDICATIONS FOR AN INSULIN PUMP

The American Association of Clinical Endocrinologists³ recommends considering an insulin pump for patients with type 1 or 2 diabetes mellitus who have a clear indication:

• Suboptimal control on basal-bolus injections, ie, not achieving glycemic goals despite maximal adherence to multiple daily injections
• Wide and erratic glycemic excursions
• Frequent severe hypoglycemia, or hypoglycemia unawareness
• A marked “dawn phenomenon” (spike in blood glucose level early in the morning)
• Pregnancy or planning for pregnancy
• Erratic lifestyle
• Personal preference.

WHO IS A GOOD CANDIDATE FOR AN INSULIN PUMP?

Good candidates for a pump are patients with type 1 diabetes (and some with type 2) who are well versed in taking multiple daily injections, are already checking their glucose four or more times daily, “counting carbs” (estimating or, preferably, measuring how much carbohydrate they are eating, and limiting their intake accordingly), and demonstrate the ability to adjust their dosing appropriately (Table 1).

A pump is not a shortcut to checking glucose less frequently or making fewer decisions. However, for those who actively manage their diabetes, it provides more real-time flexibility and some important safety features, as discussed below.

IS A PUMP BETTER THAN INJECTIONS?

Several studies have compared insulin pump therapy and multiple daily injections.^4–7 While some found no difference in glucose control in terms of hemoglobin A_1c or hypoglycemia, others showed improved glucose control with pumps in patients who had higher baseline hemoglobin A_1c levels (> 10%).⁶ In this subgroup, a pump lowered hemoglobin A_1c an additional estimated 0.65% compared with multiple daily injections.⁶ Fructosamine levels also improved in pump users.⁶

Using continuous glucose monitoring for 3 days in a study in children with type 1 diabetes, Schreiver et al⁸ found lower insulin requirements and less-severe glycemic excursions with a pump than with multiple daily injections.

A 2013 study⁹ of 57 patients ages 13 to 71 with type 2 diabetes who were struggling to control their blood sugar with multiple daily injections found that they achieved better control with less insulin using a pump.

A meta-analysis found pump therapy to be more effective than multiple daily injections for those who used it more than 1 year.¹⁰

ADVANTAGES AND DISADVANTAGES OF INSULIN PUMP THERAPY

Intensive glucose control reduces microvascular complications in type 1 diabetes.^11–14 The advantages of using a pump include better adherence, more accurate dosing, greater lifestyle flexibility, control of the dawn phenomenon without induction of nocturnal hypoglycemia, and the ability to suspend or temporarily reduce basal insulin to compensate for increased physical activity.¹⁵

Disadvantages include the high degree of technical aptitude required, the need for high-level engagement, skin reactions to tape, a higher risk of diabetic ketoacidosis from pump malfunction, infusion-site problems such as “tunneling” of insulin (leakage of insulin along the outside of the cannula and back to the skin surface) and clogging of the infusion set, and a risk of inactivation of insulin from exposure to heat, which can lead to ketoacidosis in a few hours if not addressed promptly.¹⁵

IS IT COST-EFFECTIVE?

There is evidence that continuous subcutaneous insulin infusion is cost-effective, both in general and compared with multiple daily injections for children and adults with type 1 diabetes mellitus. Cohen and Shaw¹⁶ found that life expectancy and quality-adjusted life-years increased in pump users, although the price per life-year gained varied greatly depending on the model used.

And this therapy is expensive. Most pumps cost more than $6,000, and supplies cost about $300 per month. Most insurance providers cover this therapy for patients with type 1 diabetes (Table 2) but less often for those with type 2. Further, many insurance policies have copayments, and patients may find a 20% co-payment a significant financial burden. Physicians need to obtain preapproval for insulin pumps from the insurance company. Typically, prescriptions for supplies are written annually. Despite these significant costs, most patients with type 1 diabetes who use an insulin pump find that the benefits of improved control and greater independence justify the cost.

An annual review of currently available insulin pumps and other diabetes-related equipment is published in Diabetes Forecast.¹⁷

PATIENT PERSPECTIVE ON INSULIN PUMP USE

Many patients who use a pump find that it gives them greater flexibility to adjust to day-to-day changes in schedules and routines. For example, consuming an extra serving at a meal could necessitate another injection for a patient on multiple daily injections, but a pump user would need only to push a few buttons. With cell phone apps available to control some pumps, many people find that an insulin pump is more discreet and easier to manage than carrying around injection supplies. Further, the complex calculations of carbohydrate ratios and correction factors are easier and more accurate with a pump.

In an open-label randomized study,¹⁸ 29 of 41 patients with type 1 diabetes said they preferred a pump to multiple daily injections.

Conversely, some people do not want a pump because it is attached all the time and identifies them to others as having an illness. Other patients do not trust a machine and want control in their own hands. (Actually, machines typically are much more reliable and less mistake-prone than humans.)

HOW DOES A PUMP WORK COMPARED WITH MULTIPLE DAILY INJECTIONS?

Patients taking multiple daily injections must use two types of insulin: a long-acting one that reaches a steady level in the blood without a peak and lasts from 12 to 24 hours, and a rapid-acting one taken with meals, usually having a peak of action and an effect lasting 3 to 5 hours. The idea is to approximate normal insulin patterns, with a basal level in the background and peaks (boluses) of insulin with carbohydrate intake.

Insulin pumps use only one kind of insulin—a rapid-acting one, ie, lispro, aspart, or glulisine. They preserve the basal-bolus concept, but with many refinements (discussed below).¹⁵

Most pumps are attached to the patient by plastic tubing that connects the reservoir to a subcutaneous cannula or steel needle. However, some pumps have a reservoir directly attached to a subcutaneous cannula without the tubing. This type of pump is controlled with a remote device.

The infusion set and the site should be changed every 3 days

The infusion set (cannula or needle and tubing) and the site should be changed every third day to minimize the risk of infection and abnormal delivery due to protein buildup on the cannula os, epithelial healing, and irritation around the site. Failure to do so often results in higher blood glucose concentrations.¹⁹

The patient and healthcare team work together to calculate the patient’s daily insulin needs, and the pump is programmed based on the patient’s requirements, lifestyle, and sensitivity to insulin. Once the pump is started, the patient operates it to deliver the insulin dose according to carbohydrate intake and blood glucose level.

PUMP SETTINGS

Basal rate

The basal rate is programmed by the physician and is intended to mimic physiologic insulin release. The pump can be set to a number of basal rates within any 24-hour period. This provides more physiologic matching of insulin delivery to hourly insulin needs based on the patient’s daily schedule.

If the patient has been taking multiple daily injections, the hourly basal rate can be calculated by dividing the daily basal dose by 24. However, lower rates are usually used after midnight, and rates are increased early in the morning to counteract the dawn phenomenon.

The rates can also be adjusted temporarily (for up to 24 hours), with a feature called the temporary basal rate. People tend to have higher blood glucose levels when they have a respiratory illness, are under significant stress, or are menstruating. Thus, a person with influenza could increase the basal rate by 25%, or a student could run a temporary basal rate of 150% for 4 hours before taking a final exam.

Conversely, exercising increases insulin’s effectiveness at the muscle level, and insulin requirements drop. To counteract this, one would temporarily decrease the basal rate in the pump before exercising.

Many factors affect the bolus dose

A pump is not a shortcut to checking glucose less frequently, or to making fewer decisions

A bolus of insulin is given for meals and to correct hyperglycemia, as with multiple daily injections. A pump calculates the bolus based on the carbohydrate ratio, correction factor, or both. These ratios are programmed into the pump by the physician. A benefit of the insulin pump is that the patient just has to input the amount of carbohydrates to be eaten or record a blood glucose level and the pump will calculate the bolus dose of insulin to be given.

The carbohydrate ratio is the amount of insulin that should be taken per amount of carbohydrate. A typical ratio is 1:15, meaning that the patient should take 1 unit of insulin for every 15 g of carbohydrates to be eaten. This varies by patient depending on insulin sensitivity.

The correction factor describes how much the glucose level is expected to drop per unit of insulin given. For example, if the target glucose level is 100 mg/dL and the correction factor is 25, then the patient will get 1 unit of correction of insulin if his or her glucose level is 125 mg/dL, 2 units if it is 150 mg/dL, and so on. A pump can dispense fractions of a unit.

The target glucose level or range is set by the physician and patient and is one of the factors the pump uses in calculating a bolus dose. Insulin pumps allow for multiple target glucose levels. Commonly, to minimize the risk of hypoglycemia, a higher (less strict) target is set for bedtime and overnight than for daytime.

Active insulin time defines how soon the patient can take another bolus.

Often, people eat more than they thought they would. They may also find that the glucose level did not increase or decrease as much as expected. Many patients who actively manage their glucose take additional boluses of insulin after a meal if their glucose is higher than they thought it would be. A patient taking injections cannot know how much of the insulin from the before-meal bolus is still working and has to guess.

Insulin pumps use a logarithmic formula to calculate this and prevent the user from “stacking” insulin boluses and lowering the glucose level too much. For example, if the active insulin time is 4 hours and the patient took a bolus for lunch at noon, he or she would be unable to take a full insulin correction dose until 4:00 pm. The patient can override this feature. Although the active insulin time varies from patient to patient, it is rarely more than 4 hours.

Additional safety features

Suspend. When a person who is taking insulin injections starts to experience hypoglycemia, he or she has one option—to eat something to treat the low blood glucose. The insulin injection has already been taken and cannot be reversed. However, with an insulin pump the patient can first suspend the pump so that no additional insulin is infused until it is safe again, and then eat to treat the low sugar level. This allows the patient to eat less, prevent overtreating, and, hopefully, prevent rebound hyperglycemia.

Reverse correction. When patients take insulin for an upcoming meal, they estimate the amount needed for the carbohydrates that they are about to eat as well as how much correction is needed. If their glucose level is below the target range, they may or may not subtract insulin from the dose to achieve the glucose target. The pump does this automatically, resulting in a lower dose of insulin for that bolus. This allows the patient to take a bolus for a meal even if he or she is below the target, and thus prevent hyperglycemia.

CAN INSULIN PUMPS BE USED IN THE HOSPITAL?

Patients can keep using their insulin pump in the hospital under the right conditions.

Inpatient hypoglycemia increases the risk of death, and although not all patients require tight glycemic control, there is still benefit in avoiding extremes in blood sugar levels,²⁰ including at night.^20–22 Insulin pump therapy, when used in the hospital, results in fewer episodes of severe hyperglycemia (glucose levels > 300 mg/dL) and hypoglycemia (levels < 40 mg/dL) than multiple daily injections.²² Moreover, most pump users feel more comfortable when they can manage their own therapy. Using the pump in the hospital has the additional benefit that patients can treat themselves before and after meals easily with less staff time and effort.

Bailon et al²³ retrospectively studied 35 patients with insulin pumps in 50 hospitalizations. More than half of the patients were allowed to continue using their pump in the hospital. Reasons for discontinuing the pump included lack of access to supplies, unfamiliarity with the pump, attempted suicide, malfunctioning hardware, diabetic ketoacidosis, and altered mental status. Patients using their pump had fewer episodes of hypoglycemia (glucose levels < 70 mg/dL) than patients who removed their pump. In patients who continued using the pump throughout their hospitalization, no adverse events (eg, site infection or mechanical failure) were noted.

Leonhardi et al²⁴ reviewed 25 hospital admissions, and the outcomes were similar to those reported by Bailon et al,²³ with no adverse outcomes related to the pumps.

When using an insulin pump in the hospital

Most insulin pumps cost more than $6,000, plus about $300 per month for supplies

When a physician wants a patient to continue using an insulin pump in the hospital, a number of things must happen. The nursing staff must be informed that the patient is wearing a pump and can self-administer insulin. Most facilities will still follow routine protocols for checking blood glucose but will document that the patient is administering his or her own insulin. The patient must be well enough to manage the pump. If the infusion site needs to be changed, the patient would be expected to do so with his or her own supplies.

Imaging and insulin pumps

Advice differs on what to do if a patient with an insulin pump needs to undergo radiographic imaging. For example, the University of Wisconsin radiology department says it is safe to keep an insulin pump in place if the x-ray beam will be on for less than 3 seconds at a time and if the device is covered by a lead apron.²⁵ However, radiation can induce electrical currents in the circuitry, which can alter the function of the pump. For this reason, some manufacturers recommend removing the device before the patient enters any room in which radiation or magnetic resonance imaging will be used.^26–31

Insulin pumps and surgery

Insulin pumps have been used in the perioperative and intraoperative periods, with positive outcomes.³² An analysis of 20 patients on pumps undergoing a total of 23 surgeries (mostly orthopedic procedures) found that 13 of the 20 patients wore their pump during surgery. No adverse events were noted in any of these cases, although the sample size was small.³³

Corney et al³⁴ retrospectively compared insulin pumps with alternative methods of perioperative glucose management. Multiple surgical specialties were included. No significant difference in mean blood glucose levels was found between those who continued to use their pump and those who used other methods. In those who continued to use their pump, there were no episodes of intraoperative technical difficulties related to the pump.

Any patient who may be undergoing a procedure or surgery must let the surgeon and anesthesiologist know that he or she has a pump. If the infusion site is too close to the site of the surgery or procedure, it must be moved.

Concerns during surgery include catheter or site disconnection or loss, crystallization within the tubing (a potential problem not limited to surgery), and pump malfunction. If the procedure involves imaging, the pump should probably be disconnected or covered by lead shielding as directed in the pump manufacturer’s manual. The surgeon and anesthesiologist must decide whether to continue use of a pump during a surgical procedure. However, the study by Corney et al³⁴ shows it is possible.

Most office-based procedures can be done with the insulin pump in place, as the patient is not under general anesthesia and so can adjust the insulin regimen as needed.

Abdelmalak et al,³⁵ in a comprehensive review of insulin pump use in noncardiac surgery, commented that the type of surgery may play a role in determining the best approach to perioperative glucose management. Major surgery causes a large inflammatory response that makes it difficult to control blood sugar, especially when steroids or beta agonists are given, whereas minor surgery does not affect blood glucose nearly as much. The authors offered recommendations on pump use during various surgical procedures depending on the length of the procedure:

• If surgery is anticipated to last less than 1 hour, then keep the insulin pump on, and have the patient manage corrections preoperatively and postoperatively.
• For surgery of intermediate length (1–3 hours), have the patient take a bolus of 1 hour’s worth of insulin (based on the basal rate for that time period) before the procedure, then remove the insulin pump. Do this only if blood sugar is normal or close to normal. If the patient is severely hyperglycemic, remove the insulin pump and start an intravenous insulin infusion.
• If the procedure will take more than 3 hours, remove the pump and start an insulin infusion regardless of the blood sugar level.³⁵

AIR TRAVEL AND INSULIN PUMPS

Insulin pumps can be easy to manage during airline travel if the user is prepared (Table 3).

First, it is important to have a letter from the treating physician stating that the pump is a necessary medical device. All supplies should be carried on and in a separate bag for easy inspection. The more forthcoming the user is at the security checkpoint, the easier the process.

According to the Transportation Security Administration, insulin pump users can keep their pump on during screening, and the metal detectors and full-body scanners will not harm the device.³⁶

However, manufacturer recommendations differ. Medtronic recommends that patients not expose their insulin pump to x-rays, and that instead of going through a full-body scanner the patient should request a pat-down.³⁷ Animas recommends the same.³⁸ OmniPod states that their system can be worn through airport imaging, making it the only approved continuous insulin delivery system that can be taken through airport imaging.³⁹

Another potential problem is the change in atmospheric pressure during takeoff and landing. Bubbles can form in the insulin reservoir as air pressure decreases with ascent, thereby displacing insulin from the pump to the patient. The opposite happens during descent. King et al⁴⁰ corroborated this phenomenon with Animas and Medtronic pumps. Asante recommends removing their pump tubing during takeoff and landing.³⁰

If PROBLEMS ARISE

Like any machine, an insulin pump can fail. Most failures result in lack of insulin delivery—the patient does not get excess insulin from insulin pump failure. Excess insulin delivery is most often due to operator error. All insulin is either preprogrammed (basal by provider or patient) or must be confirmed by the patient at the time of delivery (meal or correction boluses).

Pump manufacturers have 24-hour support programs and hotlines, with experts who will either walk the patient through the problem or send a replacement pump—often within 24 hours.

EVOLVING TECHNOLOGY

Pump technology is evolving quickly. On the way are “smart” pumps that interact with other systems, smaller pumps with advanced touch-screen features, and patch pumps that do not have tubing but operate similarly to pumps with tubing (ie, a cannula is still required for insulin delivery).

Some insulin pumps can be linked to an external glucose sensor. These systems provide a great amount of information to the patient and provider. Often, there is increased awareness of fluctuations in glucose, allowing earlier intervention to prevent high and low glucose excursions. Sensor-augmented pumps may further improve safety by suspending infusion during hypoglycemia.^41,42

Researchers continue to strive for closed-loop systems that would allow the pump to automatically respond to circulating glucose and thus provide truly physiologic control.⁴³ A recent study showed the effectiveness of the outpatient use of a bihormonal (insulin and glucagon) “bionic pancreas,” which provided improved glucose control and similar or less hypoglycemia in adults and adolescents who had been using a traditional insulin pump.⁴⁴

The advent of the insulin pump in the late 1970s was a step forward in diabetes treatment,¹ and recent improvements make these devices easier to use in intensive insulin management. Today, more than 400,000 people in the United States are thought to be using an insulin pump.²

See related editorial

With a pump, patients can adjust the dosage and discreetly give themselves boluses by simply pushing a button instead of giving themselves multiple daily injections. Also, pump therapy can be tailored to correct for hepatic glucose production in a way that injections cannot.

This article reviews the clinical application of continuous subcutaneous insulin therapy—ie, the insulin pump—and provides recommendations for patient selection and management.

INDICATIONS FOR AN INSULIN PUMP

The American Association of Clinical Endocrinologists³ recommends considering an insulin pump for patients with type 1 or 2 diabetes mellitus who have a clear indication:

• Suboptimal control on basal-bolus injections, ie, not achieving glycemic goals despite maximal adherence to multiple daily injections
• Wide and erratic glycemic excursions
• Frequent severe hypoglycemia, or hypoglycemia unawareness
• A marked “dawn phenomenon” (spike in blood glucose level early in the morning)
• Pregnancy or planning for pregnancy
• Erratic lifestyle
• Personal preference.

WHO IS A GOOD CANDIDATE FOR AN INSULIN PUMP?

Good candidates for a pump are patients with type 1 diabetes (and some with type 2) who are well versed in taking multiple daily injections, are already checking their glucose four or more times daily, “counting carbs” (estimating or, preferably, measuring how much carbohydrate they are eating, and limiting their intake accordingly), and demonstrate the ability to adjust their dosing appropriately (Table 1).

A pump is not a shortcut to checking glucose less frequently or making fewer decisions. However, for those who actively manage their diabetes, it provides more real-time flexibility and some important safety features, as discussed below.

IS A PUMP BETTER THAN INJECTIONS?

Several studies have compared insulin pump therapy and multiple daily injections.^4–7 While some found no difference in glucose control in terms of hemoglobin A_1c or hypoglycemia, others showed improved glucose control with pumps in patients who had higher baseline hemoglobin A_1c levels (> 10%).⁶ In this subgroup, a pump lowered hemoglobin A_1c an additional estimated 0.65% compared with multiple daily injections.⁶ Fructosamine levels also improved in pump users.⁶

Using continuous glucose monitoring for 3 days in a study in children with type 1 diabetes, Schreiver et al⁸ found lower insulin requirements and less-severe glycemic excursions with a pump than with multiple daily injections.

A 2013 study⁹ of 57 patients ages 13 to 71 with type 2 diabetes who were struggling to control their blood sugar with multiple daily injections found that they achieved better control with less insulin using a pump.

A meta-analysis found pump therapy to be more effective than multiple daily injections for those who used it more than 1 year.¹⁰

ADVANTAGES AND DISADVANTAGES OF INSULIN PUMP THERAPY

Intensive glucose control reduces microvascular complications in type 1 diabetes.^11–14 The advantages of using a pump include better adherence, more accurate dosing, greater lifestyle flexibility, control of the dawn phenomenon without induction of nocturnal hypoglycemia, and the ability to suspend or temporarily reduce basal insulin to compensate for increased physical activity.¹⁵

Disadvantages include the high degree of technical aptitude required, the need for high-level engagement, skin reactions to tape, a higher risk of diabetic ketoacidosis from pump malfunction, infusion-site problems such as “tunneling” of insulin (leakage of insulin along the outside of the cannula and back to the skin surface) and clogging of the infusion set, and a risk of inactivation of insulin from exposure to heat, which can lead to ketoacidosis in a few hours if not addressed promptly.¹⁵

IS IT COST-EFFECTIVE?

There is evidence that continuous subcutaneous insulin infusion is cost-effective, both in general and compared with multiple daily injections for children and adults with type 1 diabetes mellitus. Cohen and Shaw¹⁶ found that life expectancy and quality-adjusted life-years increased in pump users, although the price per life-year gained varied greatly depending on the model used.

And this therapy is expensive. Most pumps cost more than $6,000, and supplies cost about $300 per month. Most insurance providers cover this therapy for patients with type 1 diabetes (Table 2) but less often for those with type 2. Further, many insurance policies have copayments, and patients may find a 20% co-payment a significant financial burden. Physicians need to obtain preapproval for insulin pumps from the insurance company. Typically, prescriptions for supplies are written annually. Despite these significant costs, most patients with type 1 diabetes who use an insulin pump find that the benefits of improved control and greater independence justify the cost.

An annual review of currently available insulin pumps and other diabetes-related equipment is published in Diabetes Forecast.¹⁷

PATIENT PERSPECTIVE ON INSULIN PUMP USE

Many patients who use a pump find that it gives them greater flexibility to adjust to day-to-day changes in schedules and routines. For example, consuming an extra serving at a meal could necessitate another injection for a patient on multiple daily injections, but a pump user would need only to push a few buttons. With cell phone apps available to control some pumps, many people find that an insulin pump is more discreet and easier to manage than carrying around injection supplies. Further, the complex calculations of carbohydrate ratios and correction factors are easier and more accurate with a pump.

In an open-label randomized study,¹⁸ 29 of 41 patients with type 1 diabetes said they preferred a pump to multiple daily injections.

Conversely, some people do not want a pump because it is attached all the time and identifies them to others as having an illness. Other patients do not trust a machine and want control in their own hands. (Actually, machines typically are much more reliable and less mistake-prone than humans.)

HOW DOES A PUMP WORK COMPARED WITH MULTIPLE DAILY INJECTIONS?

Patients taking multiple daily injections must use two types of insulin: a long-acting one that reaches a steady level in the blood without a peak and lasts from 12 to 24 hours, and a rapid-acting one taken with meals, usually having a peak of action and an effect lasting 3 to 5 hours. The idea is to approximate normal insulin patterns, with a basal level in the background and peaks (boluses) of insulin with carbohydrate intake.

Insulin pumps use only one kind of insulin—a rapid-acting one, ie, lispro, aspart, or glulisine. They preserve the basal-bolus concept, but with many refinements (discussed below).¹⁵

Most pumps are attached to the patient by plastic tubing that connects the reservoir to a subcutaneous cannula or steel needle. However, some pumps have a reservoir directly attached to a subcutaneous cannula without the tubing. This type of pump is controlled with a remote device.

The infusion set and the site should be changed every 3 days

The infusion set (cannula or needle and tubing) and the site should be changed every third day to minimize the risk of infection and abnormal delivery due to protein buildup on the cannula os, epithelial healing, and irritation around the site. Failure to do so often results in higher blood glucose concentrations.¹⁹

The patient and healthcare team work together to calculate the patient’s daily insulin needs, and the pump is programmed based on the patient’s requirements, lifestyle, and sensitivity to insulin. Once the pump is started, the patient operates it to deliver the insulin dose according to carbohydrate intake and blood glucose level.

PUMP SETTINGS

Basal rate

The basal rate is programmed by the physician and is intended to mimic physiologic insulin release. The pump can be set to a number of basal rates within any 24-hour period. This provides more physiologic matching of insulin delivery to hourly insulin needs based on the patient’s daily schedule.

If the patient has been taking multiple daily injections, the hourly basal rate can be calculated by dividing the daily basal dose by 24. However, lower rates are usually used after midnight, and rates are increased early in the morning to counteract the dawn phenomenon.

The rates can also be adjusted temporarily (for up to 24 hours), with a feature called the temporary basal rate. People tend to have higher blood glucose levels when they have a respiratory illness, are under significant stress, or are menstruating. Thus, a person with influenza could increase the basal rate by 25%, or a student could run a temporary basal rate of 150% for 4 hours before taking a final exam.

Conversely, exercising increases insulin’s effectiveness at the muscle level, and insulin requirements drop. To counteract this, one would temporarily decrease the basal rate in the pump before exercising.

Many factors affect the bolus dose

A pump is not a shortcut to checking glucose less frequently, or to making fewer decisions

A bolus of insulin is given for meals and to correct hyperglycemia, as with multiple daily injections. A pump calculates the bolus based on the carbohydrate ratio, correction factor, or both. These ratios are programmed into the pump by the physician. A benefit of the insulin pump is that the patient just has to input the amount of carbohydrates to be eaten or record a blood glucose level and the pump will calculate the bolus dose of insulin to be given.

The carbohydrate ratio is the amount of insulin that should be taken per amount of carbohydrate. A typical ratio is 1:15, meaning that the patient should take 1 unit of insulin for every 15 g of carbohydrates to be eaten. This varies by patient depending on insulin sensitivity.

The correction factor describes how much the glucose level is expected to drop per unit of insulin given. For example, if the target glucose level is 100 mg/dL and the correction factor is 25, then the patient will get 1 unit of correction of insulin if his or her glucose level is 125 mg/dL, 2 units if it is 150 mg/dL, and so on. A pump can dispense fractions of a unit.

The target glucose level or range is set by the physician and patient and is one of the factors the pump uses in calculating a bolus dose. Insulin pumps allow for multiple target glucose levels. Commonly, to minimize the risk of hypoglycemia, a higher (less strict) target is set for bedtime and overnight than for daytime.

Active insulin time defines how soon the patient can take another bolus.

Often, people eat more than they thought they would. They may also find that the glucose level did not increase or decrease as much as expected. Many patients who actively manage their glucose take additional boluses of insulin after a meal if their glucose is higher than they thought it would be. A patient taking injections cannot know how much of the insulin from the before-meal bolus is still working and has to guess.

Insulin pumps use a logarithmic formula to calculate this and prevent the user from “stacking” insulin boluses and lowering the glucose level too much. For example, if the active insulin time is 4 hours and the patient took a bolus for lunch at noon, he or she would be unable to take a full insulin correction dose until 4:00 pm. The patient can override this feature. Although the active insulin time varies from patient to patient, it is rarely more than 4 hours.

Additional safety features

Suspend. When a person who is taking insulin injections starts to experience hypoglycemia, he or she has one option—to eat something to treat the low blood glucose. The insulin injection has already been taken and cannot be reversed. However, with an insulin pump the patient can first suspend the pump so that no additional insulin is infused until it is safe again, and then eat to treat the low sugar level. This allows the patient to eat less, prevent overtreating, and, hopefully, prevent rebound hyperglycemia.

Reverse correction. When patients take insulin for an upcoming meal, they estimate the amount needed for the carbohydrates that they are about to eat as well as how much correction is needed. If their glucose level is below the target range, they may or may not subtract insulin from the dose to achieve the glucose target. The pump does this automatically, resulting in a lower dose of insulin for that bolus. This allows the patient to take a bolus for a meal even if he or she is below the target, and thus prevent hyperglycemia.

CAN INSULIN PUMPS BE USED IN THE HOSPITAL?

Patients can keep using their insulin pump in the hospital under the right conditions.

Inpatient hypoglycemia increases the risk of death, and although not all patients require tight glycemic control, there is still benefit in avoiding extremes in blood sugar levels,²⁰ including at night.^20–22 Insulin pump therapy, when used in the hospital, results in fewer episodes of severe hyperglycemia (glucose levels > 300 mg/dL) and hypoglycemia (levels < 40 mg/dL) than multiple daily injections.²² Moreover, most pump users feel more comfortable when they can manage their own therapy. Using the pump in the hospital has the additional benefit that patients can treat themselves before and after meals easily with less staff time and effort.

Bailon et al²³ retrospectively studied 35 patients with insulin pumps in 50 hospitalizations. More than half of the patients were allowed to continue using their pump in the hospital. Reasons for discontinuing the pump included lack of access to supplies, unfamiliarity with the pump, attempted suicide, malfunctioning hardware, diabetic ketoacidosis, and altered mental status. Patients using their pump had fewer episodes of hypoglycemia (glucose levels < 70 mg/dL) than patients who removed their pump. In patients who continued using the pump throughout their hospitalization, no adverse events (eg, site infection or mechanical failure) were noted.

Leonhardi et al²⁴ reviewed 25 hospital admissions, and the outcomes were similar to those reported by Bailon et al,²³ with no adverse outcomes related to the pumps.

When using an insulin pump in the hospital

Most insulin pumps cost more than $6,000, plus about $300 per month for supplies

When a physician wants a patient to continue using an insulin pump in the hospital, a number of things must happen. The nursing staff must be informed that the patient is wearing a pump and can self-administer insulin. Most facilities will still follow routine protocols for checking blood glucose but will document that the patient is administering his or her own insulin. The patient must be well enough to manage the pump. If the infusion site needs to be changed, the patient would be expected to do so with his or her own supplies.

Imaging and insulin pumps

Advice differs on what to do if a patient with an insulin pump needs to undergo radiographic imaging. For example, the University of Wisconsin radiology department says it is safe to keep an insulin pump in place if the x-ray beam will be on for less than 3 seconds at a time and if the device is covered by a lead apron.²⁵ However, radiation can induce electrical currents in the circuitry, which can alter the function of the pump. For this reason, some manufacturers recommend removing the device before the patient enters any room in which radiation or magnetic resonance imaging will be used.^26–31

Insulin pumps and surgery

Insulin pumps have been used in the perioperative and intraoperative periods, with positive outcomes.³² An analysis of 20 patients on pumps undergoing a total of 23 surgeries (mostly orthopedic procedures) found that 13 of the 20 patients wore their pump during surgery. No adverse events were noted in any of these cases, although the sample size was small.³³

Corney et al³⁴ retrospectively compared insulin pumps with alternative methods of perioperative glucose management. Multiple surgical specialties were included. No significant difference in mean blood glucose levels was found between those who continued to use their pump and those who used other methods. In those who continued to use their pump, there were no episodes of intraoperative technical difficulties related to the pump.

Any patient who may be undergoing a procedure or surgery must let the surgeon and anesthesiologist know that he or she has a pump. If the infusion site is too close to the site of the surgery or procedure, it must be moved.

Concerns during surgery include catheter or site disconnection or loss, crystallization within the tubing (a potential problem not limited to surgery), and pump malfunction. If the procedure involves imaging, the pump should probably be disconnected or covered by lead shielding as directed in the pump manufacturer’s manual. The surgeon and anesthesiologist must decide whether to continue use of a pump during a surgical procedure. However, the study by Corney et al³⁴ shows it is possible.

Most office-based procedures can be done with the insulin pump in place, as the patient is not under general anesthesia and so can adjust the insulin regimen as needed.

Abdelmalak et al,³⁵ in a comprehensive review of insulin pump use in noncardiac surgery, commented that the type of surgery may play a role in determining the best approach to perioperative glucose management. Major surgery causes a large inflammatory response that makes it difficult to control blood sugar, especially when steroids or beta agonists are given, whereas minor surgery does not affect blood glucose nearly as much. The authors offered recommendations on pump use during various surgical procedures depending on the length of the procedure:

• If surgery is anticipated to last less than 1 hour, then keep the insulin pump on, and have the patient manage corrections preoperatively and postoperatively.
• For surgery of intermediate length (1–3 hours), have the patient take a bolus of 1 hour’s worth of insulin (based on the basal rate for that time period) before the procedure, then remove the insulin pump. Do this only if blood sugar is normal or close to normal. If the patient is severely hyperglycemic, remove the insulin pump and start an intravenous insulin infusion.
• If the procedure will take more than 3 hours, remove the pump and start an insulin infusion regardless of the blood sugar level.³⁵

AIR TRAVEL AND INSULIN PUMPS

Insulin pumps can be easy to manage during airline travel if the user is prepared (Table 3).

First, it is important to have a letter from the treating physician stating that the pump is a necessary medical device. All supplies should be carried on and in a separate bag for easy inspection. The more forthcoming the user is at the security checkpoint, the easier the process.

According to the Transportation Security Administration, insulin pump users can keep their pump on during screening, and the metal detectors and full-body scanners will not harm the device.³⁶

However, manufacturer recommendations differ. Medtronic recommends that patients not expose their insulin pump to x-rays, and that instead of going through a full-body scanner the patient should request a pat-down.³⁷ Animas recommends the same.³⁸ OmniPod states that their system can be worn through airport imaging, making it the only approved continuous insulin delivery system that can be taken through airport imaging.³⁹

Another potential problem is the change in atmospheric pressure during takeoff and landing. Bubbles can form in the insulin reservoir as air pressure decreases with ascent, thereby displacing insulin from the pump to the patient. The opposite happens during descent. King et al⁴⁰ corroborated this phenomenon with Animas and Medtronic pumps. Asante recommends removing their pump tubing during takeoff and landing.³⁰

If PROBLEMS ARISE

Like any machine, an insulin pump can fail. Most failures result in lack of insulin delivery—the patient does not get excess insulin from insulin pump failure. Excess insulin delivery is most often due to operator error. All insulin is either preprogrammed (basal by provider or patient) or must be confirmed by the patient at the time of delivery (meal or correction boluses).

Pump manufacturers have 24-hour support programs and hotlines, with experts who will either walk the patient through the problem or send a replacement pump—often within 24 hours.

EVOLVING TECHNOLOGY

Pump technology is evolving quickly. On the way are “smart” pumps that interact with other systems, smaller pumps with advanced touch-screen features, and patch pumps that do not have tubing but operate similarly to pumps with tubing (ie, a cannula is still required for insulin delivery).

Some insulin pumps can be linked to an external glucose sensor. These systems provide a great amount of information to the patient and provider. Often, there is increased awareness of fluctuations in glucose, allowing earlier intervention to prevent high and low glucose excursions. Sensor-augmented pumps may further improve safety by suspending infusion during hypoglycemia.^41,42

Researchers continue to strive for closed-loop systems that would allow the pump to automatically respond to circulating glucose and thus provide truly physiologic control.⁴³ A recent study showed the effectiveness of the outpatient use of a bihormonal (insulin and glucagon) “bionic pancreas,” which provided improved glucose control and similar or less hypoglycemia in adults and adolescents who had been using a traditional insulin pump.⁴⁴

The advent of the insulin pump in the late 1970s was a step forward in diabetes treatment,¹ and recent improvements make these devices easier to use in intensive insulin management. Today, more than 400,000 people in the United States are thought to be using an insulin pump.²

See related editorial

With a pump, patients can adjust the dosage and discreetly give themselves boluses by simply pushing a button instead of giving themselves multiple daily injections. Also, pump therapy can be tailored to correct for hepatic glucose production in a way that injections cannot.

This article reviews the clinical application of continuous subcutaneous insulin therapy—ie, the insulin pump—and provides recommendations for patient selection and management.

INDICATIONS FOR AN INSULIN PUMP

The American Association of Clinical Endocrinologists³ recommends considering an insulin pump for patients with type 1 or 2 diabetes mellitus who have a clear indication:

• Suboptimal control on basal-bolus injections, ie, not achieving glycemic goals despite maximal adherence to multiple daily injections
• Wide and erratic glycemic excursions
• Frequent severe hypoglycemia, or hypoglycemia unawareness
• A marked “dawn phenomenon” (spike in blood glucose level early in the morning)
• Pregnancy or planning for pregnancy
• Erratic lifestyle
• Personal preference.

WHO IS A GOOD CANDIDATE FOR AN INSULIN PUMP?

Good candidates for a pump are patients with type 1 diabetes (and some with type 2) who are well versed in taking multiple daily injections, are already checking their glucose four or more times daily, “counting carbs” (estimating or, preferably, measuring how much carbohydrate they are eating, and limiting their intake accordingly), and demonstrate the ability to adjust their dosing appropriately (Table 1).

A pump is not a shortcut to checking glucose less frequently or making fewer decisions. However, for those who actively manage their diabetes, it provides more real-time flexibility and some important safety features, as discussed below.

IS A PUMP BETTER THAN INJECTIONS?

Several studies have compared insulin pump therapy and multiple daily injections.^4–7 While some found no difference in glucose control in terms of hemoglobin A_1c or hypoglycemia, others showed improved glucose control with pumps in patients who had higher baseline hemoglobin A_1c levels (> 10%).⁶ In this subgroup, a pump lowered hemoglobin A_1c an additional estimated 0.65% compared with multiple daily injections.⁶ Fructosamine levels also improved in pump users.⁶

Using continuous glucose monitoring for 3 days in a study in children with type 1 diabetes, Schreiver et al⁸ found lower insulin requirements and less-severe glycemic excursions with a pump than with multiple daily injections.

A 2013 study⁹ of 57 patients ages 13 to 71 with type 2 diabetes who were struggling to control their blood sugar with multiple daily injections found that they achieved better control with less insulin using a pump.

A meta-analysis found pump therapy to be more effective than multiple daily injections for those who used it more than 1 year.¹⁰

ADVANTAGES AND DISADVANTAGES OF INSULIN PUMP THERAPY

Intensive glucose control reduces microvascular complications in type 1 diabetes.^11–14 The advantages of using a pump include better adherence, more accurate dosing, greater lifestyle flexibility, control of the dawn phenomenon without induction of nocturnal hypoglycemia, and the ability to suspend or temporarily reduce basal insulin to compensate for increased physical activity.¹⁵

Disadvantages include the high degree of technical aptitude required, the need for high-level engagement, skin reactions to tape, a higher risk of diabetic ketoacidosis from pump malfunction, infusion-site problems such as “tunneling” of insulin (leakage of insulin along the outside of the cannula and back to the skin surface) and clogging of the infusion set, and a risk of inactivation of insulin from exposure to heat, which can lead to ketoacidosis in a few hours if not addressed promptly.¹⁵

IS IT COST-EFFECTIVE?

There is evidence that continuous subcutaneous insulin infusion is cost-effective, both in general and compared with multiple daily injections for children and adults with type 1 diabetes mellitus. Cohen and Shaw¹⁶ found that life expectancy and quality-adjusted life-years increased in pump users, although the price per life-year gained varied greatly depending on the model used.

And this therapy is expensive. Most pumps cost more than $6,000, and supplies cost about $300 per month. Most insurance providers cover this therapy for patients with type 1 diabetes (Table 2) but less often for those with type 2. Further, many insurance policies have copayments, and patients may find a 20% co-payment a significant financial burden. Physicians need to obtain preapproval for insulin pumps from the insurance company. Typically, prescriptions for supplies are written annually. Despite these significant costs, most patients with type 1 diabetes who use an insulin pump find that the benefits of improved control and greater independence justify the cost.

An annual review of currently available insulin pumps and other diabetes-related equipment is published in Diabetes Forecast.¹⁷

PATIENT PERSPECTIVE ON INSULIN PUMP USE

Many patients who use a pump find that it gives them greater flexibility to adjust to day-to-day changes in schedules and routines. For example, consuming an extra serving at a meal could necessitate another injection for a patient on multiple daily injections, but a pump user would need only to push a few buttons. With cell phone apps available to control some pumps, many people find that an insulin pump is more discreet and easier to manage than carrying around injection supplies. Further, the complex calculations of carbohydrate ratios and correction factors are easier and more accurate with a pump.

In an open-label randomized study,¹⁸ 29 of 41 patients with type 1 diabetes said they preferred a pump to multiple daily injections.

Conversely, some people do not want a pump because it is attached all the time and identifies them to others as having an illness. Other patients do not trust a machine and want control in their own hands. (Actually, machines typically are much more reliable and less mistake-prone than humans.)

HOW DOES A PUMP WORK COMPARED WITH MULTIPLE DAILY INJECTIONS?

Patients taking multiple daily injections must use two types of insulin: a long-acting one that reaches a steady level in the blood without a peak and lasts from 12 to 24 hours, and a rapid-acting one taken with meals, usually having a peak of action and an effect lasting 3 to 5 hours. The idea is to approximate normal insulin patterns, with a basal level in the background and peaks (boluses) of insulin with carbohydrate intake.

Insulin pumps use only one kind of insulin—a rapid-acting one, ie, lispro, aspart, or glulisine. They preserve the basal-bolus concept, but with many refinements (discussed below).¹⁵

Most pumps are attached to the patient by plastic tubing that connects the reservoir to a subcutaneous cannula or steel needle. However, some pumps have a reservoir directly attached to a subcutaneous cannula without the tubing. This type of pump is controlled with a remote device.

The infusion set and the site should be changed every 3 days

The infusion set (cannula or needle and tubing) and the site should be changed every third day to minimize the risk of infection and abnormal delivery due to protein buildup on the cannula os, epithelial healing, and irritation around the site. Failure to do so often results in higher blood glucose concentrations.¹⁹

The patient and healthcare team work together to calculate the patient’s daily insulin needs, and the pump is programmed based on the patient’s requirements, lifestyle, and sensitivity to insulin. Once the pump is started, the patient operates it to deliver the insulin dose according to carbohydrate intake and blood glucose level.

PUMP SETTINGS

Basal rate

The basal rate is programmed by the physician and is intended to mimic physiologic insulin release. The pump can be set to a number of basal rates within any 24-hour period. This provides more physiologic matching of insulin delivery to hourly insulin needs based on the patient’s daily schedule.

If the patient has been taking multiple daily injections, the hourly basal rate can be calculated by dividing the daily basal dose by 24. However, lower rates are usually used after midnight, and rates are increased early in the morning to counteract the dawn phenomenon.

The rates can also be adjusted temporarily (for up to 24 hours), with a feature called the temporary basal rate. People tend to have higher blood glucose levels when they have a respiratory illness, are under significant stress, or are menstruating. Thus, a person with influenza could increase the basal rate by 25%, or a student could run a temporary basal rate of 150% for 4 hours before taking a final exam.

Conversely, exercising increases insulin’s effectiveness at the muscle level, and insulin requirements drop. To counteract this, one would temporarily decrease the basal rate in the pump before exercising.

Many factors affect the bolus dose

A pump is not a shortcut to checking glucose less frequently, or to making fewer decisions

A bolus of insulin is given for meals and to correct hyperglycemia, as with multiple daily injections. A pump calculates the bolus based on the carbohydrate ratio, correction factor, or both. These ratios are programmed into the pump by the physician. A benefit of the insulin pump is that the patient just has to input the amount of carbohydrates to be eaten or record a blood glucose level and the pump will calculate the bolus dose of insulin to be given.

The carbohydrate ratio is the amount of insulin that should be taken per amount of carbohydrate. A typical ratio is 1:15, meaning that the patient should take 1 unit of insulin for every 15 g of carbohydrates to be eaten. This varies by patient depending on insulin sensitivity.

The correction factor describes how much the glucose level is expected to drop per unit of insulin given. For example, if the target glucose level is 100 mg/dL and the correction factor is 25, then the patient will get 1 unit of correction of insulin if his or her glucose level is 125 mg/dL, 2 units if it is 150 mg/dL, and so on. A pump can dispense fractions of a unit.

The target glucose level or range is set by the physician and patient and is one of the factors the pump uses in calculating a bolus dose. Insulin pumps allow for multiple target glucose levels. Commonly, to minimize the risk of hypoglycemia, a higher (less strict) target is set for bedtime and overnight than for daytime.

Active insulin time defines how soon the patient can take another bolus.

Often, people eat more than they thought they would. They may also find that the glucose level did not increase or decrease as much as expected. Many patients who actively manage their glucose take additional boluses of insulin after a meal if their glucose is higher than they thought it would be. A patient taking injections cannot know how much of the insulin from the before-meal bolus is still working and has to guess.

Insulin pumps use a logarithmic formula to calculate this and prevent the user from “stacking” insulin boluses and lowering the glucose level too much. For example, if the active insulin time is 4 hours and the patient took a bolus for lunch at noon, he or she would be unable to take a full insulin correction dose until 4:00 pm. The patient can override this feature. Although the active insulin time varies from patient to patient, it is rarely more than 4 hours.

Additional safety features

Suspend. When a person who is taking insulin injections starts to experience hypoglycemia, he or she has one option—to eat something to treat the low blood glucose. The insulin injection has already been taken and cannot be reversed. However, with an insulin pump the patient can first suspend the pump so that no additional insulin is infused until it is safe again, and then eat to treat the low sugar level. This allows the patient to eat less, prevent overtreating, and, hopefully, prevent rebound hyperglycemia.

Reverse correction. When patients take insulin for an upcoming meal, they estimate the amount needed for the carbohydrates that they are about to eat as well as how much correction is needed. If their glucose level is below the target range, they may or may not subtract insulin from the dose to achieve the glucose target. The pump does this automatically, resulting in a lower dose of insulin for that bolus. This allows the patient to take a bolus for a meal even if he or she is below the target, and thus prevent hyperglycemia.

CAN INSULIN PUMPS BE USED IN THE HOSPITAL?

Patients can keep using their insulin pump in the hospital under the right conditions.

Inpatient hypoglycemia increases the risk of death, and although not all patients require tight glycemic control, there is still benefit in avoiding extremes in blood sugar levels,²⁰ including at night.^20–22 Insulin pump therapy, when used in the hospital, results in fewer episodes of severe hyperglycemia (glucose levels > 300 mg/dL) and hypoglycemia (levels < 40 mg/dL) than multiple daily injections.²² Moreover, most pump users feel more comfortable when they can manage their own therapy. Using the pump in the hospital has the additional benefit that patients can treat themselves before and after meals easily with less staff time and effort.

Bailon et al²³ retrospectively studied 35 patients with insulin pumps in 50 hospitalizations. More than half of the patients were allowed to continue using their pump in the hospital. Reasons for discontinuing the pump included lack of access to supplies, unfamiliarity with the pump, attempted suicide, malfunctioning hardware, diabetic ketoacidosis, and altered mental status. Patients using their pump had fewer episodes of hypoglycemia (glucose levels < 70 mg/dL) than patients who removed their pump. In patients who continued using the pump throughout their hospitalization, no adverse events (eg, site infection or mechanical failure) were noted.

Leonhardi et al²⁴ reviewed 25 hospital admissions, and the outcomes were similar to those reported by Bailon et al,²³ with no adverse outcomes related to the pumps.

When using an insulin pump in the hospital

Most insulin pumps cost more than $6,000, plus about $300 per month for supplies

When a physician wants a patient to continue using an insulin pump in the hospital, a number of things must happen. The nursing staff must be informed that the patient is wearing a pump and can self-administer insulin. Most facilities will still follow routine protocols for checking blood glucose but will document that the patient is administering his or her own insulin. The patient must be well enough to manage the pump. If the infusion site needs to be changed, the patient would be expected to do so with his or her own supplies.

Imaging and insulin pumps

Advice differs on what to do if a patient with an insulin pump needs to undergo radiographic imaging. For example, the University of Wisconsin radiology department says it is safe to keep an insulin pump in place if the x-ray beam will be on for less than 3 seconds at a time and if the device is covered by a lead apron.²⁵ However, radiation can induce electrical currents in the circuitry, which can alter the function of the pump. For this reason, some manufacturers recommend removing the device before the patient enters any room in which radiation or magnetic resonance imaging will be used.^26–31

Insulin pumps and surgery

Insulin pumps have been used in the perioperative and intraoperative periods, with positive outcomes.³² An analysis of 20 patients on pumps undergoing a total of 23 surgeries (mostly orthopedic procedures) found that 13 of the 20 patients wore their pump during surgery. No adverse events were noted in any of these cases, although the sample size was small.³³

Corney et al³⁴ retrospectively compared insulin pumps with alternative methods of perioperative glucose management. Multiple surgical specialties were included. No significant difference in mean blood glucose levels was found between those who continued to use their pump and those who used other methods. In those who continued to use their pump, there were no episodes of intraoperative technical difficulties related to the pump.

Any patient who may be undergoing a procedure or surgery must let the surgeon and anesthesiologist know that he or she has a pump. If the infusion site is too close to the site of the surgery or procedure, it must be moved.

Concerns during surgery include catheter or site disconnection or loss, crystallization within the tubing (a potential problem not limited to surgery), and pump malfunction. If the procedure involves imaging, the pump should probably be disconnected or covered by lead shielding as directed in the pump manufacturer’s manual. The surgeon and anesthesiologist must decide whether to continue use of a pump during a surgical procedure. However, the study by Corney et al³⁴ shows it is possible.

Most office-based procedures can be done with the insulin pump in place, as the patient is not under general anesthesia and so can adjust the insulin regimen as needed.

Abdelmalak et al,³⁵ in a comprehensive review of insulin pump use in noncardiac surgery, commented that the type of surgery may play a role in determining the best approach to perioperative glucose management. Major surgery causes a large inflammatory response that makes it difficult to control blood sugar, especially when steroids or beta agonists are given, whereas minor surgery does not affect blood glucose nearly as much. The authors offered recommendations on pump use during various surgical procedures depending on the length of the procedure:

• If surgery is anticipated to last less than 1 hour, then keep the insulin pump on, and have the patient manage corrections preoperatively and postoperatively.
• For surgery of intermediate length (1–3 hours), have the patient take a bolus of 1 hour’s worth of insulin (based on the basal rate for that time period) before the procedure, then remove the insulin pump. Do this only if blood sugar is normal or close to normal. If the patient is severely hyperglycemic, remove the insulin pump and start an intravenous insulin infusion.
• If the procedure will take more than 3 hours, remove the pump and start an insulin infusion regardless of the blood sugar level.³⁵

AIR TRAVEL AND INSULIN PUMPS

Insulin pumps can be easy to manage during airline travel if the user is prepared (Table 3).

First, it is important to have a letter from the treating physician stating that the pump is a necessary medical device. All supplies should be carried on and in a separate bag for easy inspection. The more forthcoming the user is at the security checkpoint, the easier the process.

According to the Transportation Security Administration, insulin pump users can keep their pump on during screening, and the metal detectors and full-body scanners will not harm the device.³⁶

However, manufacturer recommendations differ. Medtronic recommends that patients not expose their insulin pump to x-rays, and that instead of going through a full-body scanner the patient should request a pat-down.³⁷ Animas recommends the same.³⁸ OmniPod states that their system can be worn through airport imaging, making it the only approved continuous insulin delivery system that can be taken through airport imaging.³⁹

Another potential problem is the change in atmospheric pressure during takeoff and landing. Bubbles can form in the insulin reservoir as air pressure decreases with ascent, thereby displacing insulin from the pump to the patient. The opposite happens during descent. King et al⁴⁰ corroborated this phenomenon with Animas and Medtronic pumps. Asante recommends removing their pump tubing during takeoff and landing.³⁰

If PROBLEMS ARISE

Like any machine, an insulin pump can fail. Most failures result in lack of insulin delivery—the patient does not get excess insulin from insulin pump failure. Excess insulin delivery is most often due to operator error. All insulin is either preprogrammed (basal by provider or patient) or must be confirmed by the patient at the time of delivery (meal or correction boluses).

Pump manufacturers have 24-hour support programs and hotlines, with experts who will either walk the patient through the problem or send a replacement pump—often within 24 hours.

EVOLVING TECHNOLOGY

Pump technology is evolving quickly. On the way are “smart” pumps that interact with other systems, smaller pumps with advanced touch-screen features, and patch pumps that do not have tubing but operate similarly to pumps with tubing (ie, a cannula is still required for insulin delivery).

Some insulin pumps can be linked to an external glucose sensor. These systems provide a great amount of information to the patient and provider. Often, there is increased awareness of fluctuations in glucose, allowing earlier intervention to prevent high and low glucose excursions. Sensor-augmented pumps may further improve safety by suspending infusion during hypoglycemia.^41,42

Researchers continue to strive for closed-loop systems that would allow the pump to automatically respond to circulating glucose and thus provide truly physiologic control.⁴³ A recent study showed the effectiveness of the outpatient use of a bihormonal (insulin and glucagon) “bionic pancreas,” which provided improved glucose control and similar or less hypoglycemia in adults and adolescents who had been using a traditional insulin pump.⁴⁴

In this issue of the Journal, Millstein et al provide an elegant, practical, and up-to-date review of insulin pump therapy (also known as continuous subcutaneous insulin infusion), emphasizing its benefits and comparing it with multiple daily insulin injections.¹

See related article

NOT FOR EVERYONE

While insulin pumps make the lives of many patients much easier, we should be careful when generalizing their indications. These devices have been with us for 4 decades, during which they have progressively been made more precise and more intelligent—and smaller. The technology may be attractive to some patients but undesirable to others (Table 1).

Many healthcare providers are unfamiliar with pump technology, and some are intimidated by it because it involves a dynamic device-user interface that is more complex than that of other concealed programmed devices such as pacemakers. Inadequate glycemic management is complex and may result from factors such as fear of hypoglycemia, difficulty with insulin dose adjustment, and poor math skills.²

Unfortunately, some patients are given a pump without proper screening and education, and they tend to call the pump manufacturer’s help line or their provider often for help with technical problems. Selecting the right patient for this technology is more important than the converse.

Indications for an insulin pump vary by country. In some countries, a pump is started as soon as type 1 diabetes is diagnosed. In the United States, the indications are very rigorous and restrictive, especially for patients with type 2 diabetes, in whom a lack of endogenous insulin production must first be proved.

There is no question that a pump should be offered to every patient with type 1 diabetes who demonstrates good motivation to improve his or her glucose control, but only after a rigorous education program. This option is too costly to be tried just to see if the patient likes it.

ADVERSE EVENTS WITH INSULIN PUMPS: MORE DATA NEEDED

A worrisome aspect of continuous subcutaneous insulin infusion at a population level is a lack of information on the root causes of adverse events (diabetic ketoacidosis or severe hypoglycemia) in patients who use it. These events may be serious and sometimes even fatal.

Outside of a controlled environment, it is difficult to ascertain whether an adverse event represents device error or user error, since pumps contain different components (electronic, mechanical, and pharmacologic) that interface with the human user.³ How adverse events are tracked or categorized is unclear, and given the risks associated with this technology, better postmarketing evaluation is needed. Furthermore, we do not know if the precision of insulin delivery decreases over the life of a pump.

While most pump manufacturers have good customer service and make every effort to provide the patient with a replacement pump in case of failure, we do not know if anyone maintains a database of such failures or adverse events, and if those failures can be analyzed to improve safety.³

INTERFACES ARE NOT STANDARD

When one buys a new car, little time is needed to learn how to operate it because most cars use the same basic features.

The situation is different with insulin pumps. To compete with each other, pump manufacturers create different looks, different insulin delivery methods, and different ways of administering a bolus. Switching from one pump to another is difficult without detailed education on the “bells and whistles” of the new pump.

Most patients use just a few features of the pump. They look at it as more of a convenience. They sometimes forget they are wearing it, and even forget to take a bolus before a meal.

PATIENT SATISFACTION DEPENDS ON THE PATIENT

For years, we thought insulin pumps were better at improving hypoglycemia awareness. But in a prospective study, multiple daily injections with frequent self-monitoring of blood glucose provided identical outcomes without worsening hemoglobin A_1c compared with continuous infusion with real-time continuous glucose monitoring, although satisfaction with treatment was better in the latter group.⁴

Patients’ satisfaction with continuous subcutaneous insulin infusion depends on their baseline hemoglobin A_1c level. Patients with relatively low hemoglobin A_1c tend to take an active approach to self-care, describe the pump as a tool for meeting glycemic goals, and say the pump makes them feel more normal. Patients with high hemoglobin A_1c tend to have a more passive approach to their self-care and have more negative experiences with the pump. Women are more concerned than men with the effect of the pump on body image and social acceptance.⁵

DOLLARS AND CENTS

According to 2012 estimates, 29 million Americans had diabetes mellitus, of whom 1.25 million had type 1. The direct medical costs of diabetes are estimated at $176 billion, of which 12% covers overall pharmacy costs.⁶ About 31% of adults with diabetes use insulin.⁷

For a device that costs $6,000, has a life span of only 4 years, and requires supplies that cost $300 per month, rigorous interpretation of superiority data would be needed to confirm that this technology would have a positive impact on public health if every insulin-using patient with diabetes were to say yes to it. It is true that switching from multiple daily injections to a pump leads to a significant reduction in insulin expenditures in patients with type 2 diabetes, according to a retrospective analysis of claims data.⁸

However, not all studies comparing pumps and multiple daily injections in type 2 diabetes have shown an advantage of one over the other in terms of a reduction in fasting glucose, hemoglobin A_1c, or incidence of hypoglycemia.⁹ A meta-analysis¹⁰ found that the two therapies had similar effects on glycemic control and hypoglycemia. Continuous infusion had a more favorable effect in adults with type 1 diabetes.¹⁰

Neither continuous infusion nor multiple daily injections can mimic physiologic endogenous insulin secretion. Endogenous insulin is secreted into the portal system, and its main site of action is the liver. As a result, there is more hepatic glucose uptake and thus a lower peripheral plasma insulin concentration with endogenous secretion than with systemic administration. Endogenous insulin secretion also suppresses hepatic glucose production and reduces the risk of hypoglycemia.¹¹

PROGRESS, BUT NOT PERFECTION

Diabetes mellitus constitutes a big burden on patients and on society. The discovery of insulin was a giant leap forward; the insulin pump was another great advance. We are getting closer to an integrated bionic pancreas. We are far from achieving a perfect system, but we are much better off than we were 50 or 80 years ago. And although insulin pump technology is sophisticated and precise, it still interfaces with a human user, and the human user still must press its buttons.

In this issue of the Journal, Millstein et al provide an elegant, practical, and up-to-date review of insulin pump therapy (also known as continuous subcutaneous insulin infusion), emphasizing its benefits and comparing it with multiple daily insulin injections.¹

See related article

NOT FOR EVERYONE

While insulin pumps make the lives of many patients much easier, we should be careful when generalizing their indications. These devices have been with us for 4 decades, during which they have progressively been made more precise and more intelligent—and smaller. The technology may be attractive to some patients but undesirable to others (Table 1).

Many healthcare providers are unfamiliar with pump technology, and some are intimidated by it because it involves a dynamic device-user interface that is more complex than that of other concealed programmed devices such as pacemakers. Inadequate glycemic management is complex and may result from factors such as fear of hypoglycemia, difficulty with insulin dose adjustment, and poor math skills.²

Unfortunately, some patients are given a pump without proper screening and education, and they tend to call the pump manufacturer’s help line or their provider often for help with technical problems. Selecting the right patient for this technology is more important than the converse.

Indications for an insulin pump vary by country. In some countries, a pump is started as soon as type 1 diabetes is diagnosed. In the United States, the indications are very rigorous and restrictive, especially for patients with type 2 diabetes, in whom a lack of endogenous insulin production must first be proved.

There is no question that a pump should be offered to every patient with type 1 diabetes who demonstrates good motivation to improve his or her glucose control, but only after a rigorous education program. This option is too costly to be tried just to see if the patient likes it.

ADVERSE EVENTS WITH INSULIN PUMPS: MORE DATA NEEDED

A worrisome aspect of continuous subcutaneous insulin infusion at a population level is a lack of information on the root causes of adverse events (diabetic ketoacidosis or severe hypoglycemia) in patients who use it. These events may be serious and sometimes even fatal.

Outside of a controlled environment, it is difficult to ascertain whether an adverse event represents device error or user error, since pumps contain different components (electronic, mechanical, and pharmacologic) that interface with the human user.³ How adverse events are tracked or categorized is unclear, and given the risks associated with this technology, better postmarketing evaluation is needed. Furthermore, we do not know if the precision of insulin delivery decreases over the life of a pump.

While most pump manufacturers have good customer service and make every effort to provide the patient with a replacement pump in case of failure, we do not know if anyone maintains a database of such failures or adverse events, and if those failures can be analyzed to improve safety.³

INTERFACES ARE NOT STANDARD

When one buys a new car, little time is needed to learn how to operate it because most cars use the same basic features.

The situation is different with insulin pumps. To compete with each other, pump manufacturers create different looks, different insulin delivery methods, and different ways of administering a bolus. Switching from one pump to another is difficult without detailed education on the “bells and whistles” of the new pump.

Most patients use just a few features of the pump. They look at it as more of a convenience. They sometimes forget they are wearing it, and even forget to take a bolus before a meal.

PATIENT SATISFACTION DEPENDS ON THE PATIENT

For years, we thought insulin pumps were better at improving hypoglycemia awareness. But in a prospective study, multiple daily injections with frequent self-monitoring of blood glucose provided identical outcomes without worsening hemoglobin A_1c compared with continuous infusion with real-time continuous glucose monitoring, although satisfaction with treatment was better in the latter group.⁴

Patients’ satisfaction with continuous subcutaneous insulin infusion depends on their baseline hemoglobin A_1c level. Patients with relatively low hemoglobin A_1c tend to take an active approach to self-care, describe the pump as a tool for meeting glycemic goals, and say the pump makes them feel more normal. Patients with high hemoglobin A_1c tend to have a more passive approach to their self-care and have more negative experiences with the pump. Women are more concerned than men with the effect of the pump on body image and social acceptance.⁵

DOLLARS AND CENTS

According to 2012 estimates, 29 million Americans had diabetes mellitus, of whom 1.25 million had type 1. The direct medical costs of diabetes are estimated at $176 billion, of which 12% covers overall pharmacy costs.⁶ About 31% of adults with diabetes use insulin.⁷

For a device that costs $6,000, has a life span of only 4 years, and requires supplies that cost $300 per month, rigorous interpretation of superiority data would be needed to confirm that this technology would have a positive impact on public health if every insulin-using patient with diabetes were to say yes to it. It is true that switching from multiple daily injections to a pump leads to a significant reduction in insulin expenditures in patients with type 2 diabetes, according to a retrospective analysis of claims data.⁸

However, not all studies comparing pumps and multiple daily injections in type 2 diabetes have shown an advantage of one over the other in terms of a reduction in fasting glucose, hemoglobin A_1c, or incidence of hypoglycemia.⁹ A meta-analysis¹⁰ found that the two therapies had similar effects on glycemic control and hypoglycemia. Continuous infusion had a more favorable effect in adults with type 1 diabetes.¹⁰

Neither continuous infusion nor multiple daily injections can mimic physiologic endogenous insulin secretion. Endogenous insulin is secreted into the portal system, and its main site of action is the liver. As a result, there is more hepatic glucose uptake and thus a lower peripheral plasma insulin concentration with endogenous secretion than with systemic administration. Endogenous insulin secretion also suppresses hepatic glucose production and reduces the risk of hypoglycemia.¹¹

PROGRESS, BUT NOT PERFECTION

Diabetes mellitus constitutes a big burden on patients and on society. The discovery of insulin was a giant leap forward; the insulin pump was another great advance. We are getting closer to an integrated bionic pancreas. We are far from achieving a perfect system, but we are much better off than we were 50 or 80 years ago. And although insulin pump technology is sophisticated and precise, it still interfaces with a human user, and the human user still must press its buttons.

In this issue of the Journal, Millstein et al provide an elegant, practical, and up-to-date review of insulin pump therapy (also known as continuous subcutaneous insulin infusion), emphasizing its benefits and comparing it with multiple daily insulin injections.¹

See related article

NOT FOR EVERYONE

While insulin pumps make the lives of many patients much easier, we should be careful when generalizing their indications. These devices have been with us for 4 decades, during which they have progressively been made more precise and more intelligent—and smaller. The technology may be attractive to some patients but undesirable to others (Table 1).

Many healthcare providers are unfamiliar with pump technology, and some are intimidated by it because it involves a dynamic device-user interface that is more complex than that of other concealed programmed devices such as pacemakers. Inadequate glycemic management is complex and may result from factors such as fear of hypoglycemia, difficulty with insulin dose adjustment, and poor math skills.²

Unfortunately, some patients are given a pump without proper screening and education, and they tend to call the pump manufacturer’s help line or their provider often for help with technical problems. Selecting the right patient for this technology is more important than the converse.

Indications for an insulin pump vary by country. In some countries, a pump is started as soon as type 1 diabetes is diagnosed. In the United States, the indications are very rigorous and restrictive, especially for patients with type 2 diabetes, in whom a lack of endogenous insulin production must first be proved.

There is no question that a pump should be offered to every patient with type 1 diabetes who demonstrates good motivation to improve his or her glucose control, but only after a rigorous education program. This option is too costly to be tried just to see if the patient likes it.

ADVERSE EVENTS WITH INSULIN PUMPS: MORE DATA NEEDED

A worrisome aspect of continuous subcutaneous insulin infusion at a population level is a lack of information on the root causes of adverse events (diabetic ketoacidosis or severe hypoglycemia) in patients who use it. These events may be serious and sometimes even fatal.

Outside of a controlled environment, it is difficult to ascertain whether an adverse event represents device error or user error, since pumps contain different components (electronic, mechanical, and pharmacologic) that interface with the human user.³ How adverse events are tracked or categorized is unclear, and given the risks associated with this technology, better postmarketing evaluation is needed. Furthermore, we do not know if the precision of insulin delivery decreases over the life of a pump.

While most pump manufacturers have good customer service and make every effort to provide the patient with a replacement pump in case of failure, we do not know if anyone maintains a database of such failures or adverse events, and if those failures can be analyzed to improve safety.³

INTERFACES ARE NOT STANDARD

When one buys a new car, little time is needed to learn how to operate it because most cars use the same basic features.

The situation is different with insulin pumps. To compete with each other, pump manufacturers create different looks, different insulin delivery methods, and different ways of administering a bolus. Switching from one pump to another is difficult without detailed education on the “bells and whistles” of the new pump.

Most patients use just a few features of the pump. They look at it as more of a convenience. They sometimes forget they are wearing it, and even forget to take a bolus before a meal.

PATIENT SATISFACTION DEPENDS ON THE PATIENT

For years, we thought insulin pumps were better at improving hypoglycemia awareness. But in a prospective study, multiple daily injections with frequent self-monitoring of blood glucose provided identical outcomes without worsening hemoglobin A_1c compared with continuous infusion with real-time continuous glucose monitoring, although satisfaction with treatment was better in the latter group.⁴

Patients’ satisfaction with continuous subcutaneous insulin infusion depends on their baseline hemoglobin A_1c level. Patients with relatively low hemoglobin A_1c tend to take an active approach to self-care, describe the pump as a tool for meeting glycemic goals, and say the pump makes them feel more normal. Patients with high hemoglobin A_1c tend to have a more passive approach to their self-care and have more negative experiences with the pump. Women are more concerned than men with the effect of the pump on body image and social acceptance.⁵

DOLLARS AND CENTS

According to 2012 estimates, 29 million Americans had diabetes mellitus, of whom 1.25 million had type 1. The direct medical costs of diabetes are estimated at $176 billion, of which 12% covers overall pharmacy costs.⁶ About 31% of adults with diabetes use insulin.⁷

For a device that costs $6,000, has a life span of only 4 years, and requires supplies that cost $300 per month, rigorous interpretation of superiority data would be needed to confirm that this technology would have a positive impact on public health if every insulin-using patient with diabetes were to say yes to it. It is true that switching from multiple daily injections to a pump leads to a significant reduction in insulin expenditures in patients with type 2 diabetes, according to a retrospective analysis of claims data.⁸

However, not all studies comparing pumps and multiple daily injections in type 2 diabetes have shown an advantage of one over the other in terms of a reduction in fasting glucose, hemoglobin A_1c, or incidence of hypoglycemia.⁹ A meta-analysis¹⁰ found that the two therapies had similar effects on glycemic control and hypoglycemia. Continuous infusion had a more favorable effect in adults with type 1 diabetes.¹⁰

Neither continuous infusion nor multiple daily injections can mimic physiologic endogenous insulin secretion. Endogenous insulin is secreted into the portal system, and its main site of action is the liver. As a result, there is more hepatic glucose uptake and thus a lower peripheral plasma insulin concentration with endogenous secretion than with systemic administration. Endogenous insulin secretion also suppresses hepatic glucose production and reduces the risk of hypoglycemia.¹¹

PROGRESS, BUT NOT PERFECTION

Diabetes mellitus constitutes a big burden on patients and on society. The discovery of insulin was a giant leap forward; the insulin pump was another great advance. We are getting closer to an integrated bionic pancreas. We are far from achieving a perfect system, but we are much better off than we were 50 or 80 years ago. And although insulin pump technology is sophisticated and precise, it still interfaces with a human user, and the human user still must press its buttons.

Liver cancer is increasing in prevalence; from 2000 to 2010, the prevalence increased from 7.1 per 100,000 to 8.4 per 100,000 people.¹ This increase is due in part to an increase in chronic liver diseases such as hepatitis B and C and nonalcoholic steatohepatitis.² In addition, liver metastases, especially from colorectal cancer and breast cancer, are also on the rise worldwide. More than 60% of patients with colorectal cancer will have a liver metastasis at some point in the course of their disease.

However, only 10% to 15% of patients with hepatocellular carcinoma are candidates for surgical resection.^3,4 And for patients who are not surgical candidates, there are currently no accepted guidelines on treatment.⁵ Treatment of metastatic liver cancer has consisted mainly of systemic chemotherapy, but if standard treatments fail, other options need to be considered.

A number of minimally invasive treatments are available for primary and metastatic liver cancer.⁶ These treatments are for the most part palliative, but in rare instances they are curative. They can be divided into percutaneous imaging-guided therapy (eg, radiofrequency ablation, microwave ablation) and four catheter-based transarterial therapies:

• Bland embolization
• Chemoembolization
• Chemoembolization with drug-eluting microspheres
• Yttrium-90 radioembolization.

In this article, we focus only on the four catheter-based transarterial therapies, providing a brief description of each and a discussion of potential postprocedural complications and the key elements of postprocedural care.

The rationale for catheter-based transarterial therapy

Primary and metastatic liver malignancies depend mainly on the hepatic arterial blood supply for their survival and growth, whereas normal liver tissue is supplied mainly by the portal vein. Therapy applied through the hepatic arterial system is distributed directly to malignant tissue and spares healthy liver tissue. (Note: The leg is the route of access for all catheter-based transarterial therapies.)

BLAND EMBOLIZATION

In transarterial bland embolization, tiny spheres of a neutral (ie, bland) material are injected into the distal branches of the arteries that supply the tumor. These microemboli, 45 to 150 µm in diameter,⁷ permanently occlude the blood vessels.

Bland embolization carries a risk of pulmonary embolism if there is shunting between the pulmonary and hepatic circulation via the hepatic vein.^8,9 Fortunately, this serious complication is rare. Technetium-99m macroaggregated albumin (Tc-99m MAA) scanning is done before the procedure to assess the risk.

Posttreatment care and follow-up

Patients require follow-up with contrast-enhanced computed tomography (CT) 6 to 8 weeks after the procedure to evaluate tumor regression.

Further treatment

If follow-up CT shows that the lesion or lesions have not regressed or have increased in size, the embolization procedure can be repeated about 12 weeks after the initial treatment. The most likely cause of a poor response to therapy is failure to adequately identify all tumor-supplying vessels.¹⁰

CHEMOEMBOLIZATION

Transarterial chemoembolization targets the blood supply of the tumor with a combination of chemotherapeutic drugs and an embolizing agent. Standard chemotherapy agents used include doxorubicin, cisplatin, and mitomycin-C. A microcatheter is advanced into the vessel supplying the tumor, and the combination drug is injected as close to the tumor as possible.¹¹

Transarterial chemoembolization is the most commonly performed hepatic artery-directed therapy for liver cancer. It has been used to treat solitary tumors as well as multifocal disease. It allows for maximum embolization potential while preserving liver function.

Posttreatment care and follow-up

Postembolization syndrome, characterized by low-grade fever, mild leukocytosis, and pain, is common after transarterial chemoembolization. Therefore, the patient is usually admitted to the hospital overnight for monitoring and control of symptoms such as pain and nausea. Mild abdominal pain is common and should resolve within several days; severe abdominal pain should be evaluated, as chemical and ischemic cholecystitis have been reported. Severe abdominal pain also raises concern for possible tumor rupture or liver infarction.

At discharge after chemoembolization, patients are instructed to report high fever, jaundice, or abdominal swelling

At the time of discharge, patients should be instructed to contact their clinician if they experience high fever, jaundice, or abdominal swelling. Liver function testing is not recommended within 7 to 10 days of treatment, as the expected rise in aminotransferase levels could prompt an unnecessary workup. Barring additional complications, patients should be seen in the office 2 weeks after the procedure.¹²

Lesions should be followed by serial contrast-enhanced CT to determine response to therapy. The current recommendation for stable patients is CT every 3 months for 2 years, and then every 6 months until active disease recurs.¹³

Safety concerns

A rare but serious concern after this procedure is fulminant hepatic failure, which has a high death rate. It has been reported in fewer than 1% of patients. Less severe complications include liver failure and infection.¹³

Further treatment

Patients with multifocal disease may require further treatment, usually 4 to 6 weeks after the initial procedure. If a transjugular intrahepatic portosystemic shunt is already in place, the patient can undergo chemoembolization as long as liver function is preserved. However, these patients generally have a poorer prognosis.

CHEMOEMBOLIZATION WITH DRUG-ELUTING MICROSPHERES

In transarterial chemoembolization with drug-eluting microspheres, beads loaded with chemotherapeutic drugs provide controlled delivery, resulting in both ischemia of the tumor and slow release of chemotherapy.

Several types of beads are currently available, with different degrees of affinity for chemotherapy agents. An advantage of the beads is that they can be used in patients with tumors that show aggressive shunting or in tumors that have vascular invasion. The technique for delivering the beads is similar to that used in standard chemoembolization.¹⁴

Posttreatment care and follow-up

Postembolization syndrome is common. Treatment usually consists of hydration and control of pain and nausea. Follow-up includes serial CT to evaluate tumor response.

Safety concerns

Overall, this procedure is safe. A phase 1 and 2 trial¹⁵ showed adverse effects similar to those seen in chemoembolization. The most common adverse effect was a transient increase in liver enzymes. Serious complications such as tumor rupture, spontaneous bacterial peritonitis, and liver failure were rare.

YTTRIUM-90 RADIOEMBOLIZATION

In yttrium-90 radioembolization, radioactive microspheres are injected into the hepatic arterial supply. The procedure involves careful planning and is usually completed in stages.

The first stage involves angiography to map the hepatic vascular anatomy, as well as prophylactic embolization to protect against unintended delivery of the radioactive drug to vessels of the gastrointestinal tract (such as a branch of the hepatic artery that may supply the duodenum), causing tissue necrosis. Another reason for mapping is to look for any potential shunt between the tumor’s blood supply and the lung^16,17 and thus prevent pulmonary embolism from the embolization procedure. The gastric mucosa and the salivary glands are also studied, as isolated gastric mucosal uptake indicates gastrointestinal vascular shunting.

The mapping stage involves injecting radioactive particles of technetium-99m microaggregated albumin, which are close in size to the yttrium-90 particles used during the actual procedure. The dose injected is usually 4 to 5 mCi (much lower than the typical tumor-therapy dose of 100–120 Gy), and imaging is done with either planar or single-photon emission CT. The patient is usually admitted for overnight observation after angiography.

In the second stage, 1 or 2 weeks later, the patient undergoes injection of the radiopharmaceuticals into the hepatic artery supplying the tumor. If disease burden is high or there is bilobar disease, the treatment is repeated in another 6 to 8 weeks. After the procedure, the patient is admitted to the hospital for observation by an inpatient team.

Posttreatment care and follow-up

The major concern after yttrium-90 radioembolization is reflux of the microspheres through unrecognized gastrointestinal channels,¹⁸ particularly into the mucosa of the stomach and proximal duodenum, causing the formation of nonhealing ulcers, which can cause major morbidity and even death. Antiulcer medications can be started immediately after the procedure.

Postembolization syndrome is frequently seen, and the fever usually responds to acet­a­minophen. Nausea and vomiting can be managed conservatively.¹⁹

The patient returns for a follow-up visit within 4 to 6 weeks of the injection procedure, mainly for assessment of liver function. A transient increase in liver enzymes and tumor markers may be seen at this time. A massive increase in liver enzyme levels should be investigated further.

Safety concerns

The postprocedural radiation exposure from the patient is within the acceptable safety range; therefore, no special precautions are necessary. However, since resin spheres are excreted in the urine, precautions are needed for urine disposal during the first 24 hours.^20,21

Further treatments

If there is multifocal disease or a poor response to the initial treatment, a second session can be done 6 to 8 weeks after the first one. Before the second session, the liver tumor is imaged.²² For hepatocellular carcinoma, imaging may show shrinkage and necrosis of the tumor. For metastatic tumors, this imaging is important as it may show either failure or progression of disease.²³ For this reason, functional imaging such as positron-emission tomography is important as it may show the extrahepatic spread of tumor, thereby halting further treatment. A complete blood cell count may also be done at 30 days to look for radiation-related cytopenia. A scrupulous log of the radiation dose received by the patient should be maintained.

PUNCTURE-SITE COMPLICATIONS

Hematoma

Hematoma at the puncture site is the most common complication of arterial access, with an incidence of 5% to 23%. The main clinical findings are erythema and swelling at the puncture site, with a palpable hardening of the skin. Pain and decreased range of motion in the affected extremity can also occur.

Simple hematomas exhibit a stable size and hemoglobin count and are managed conservatively. Initial management involves marking the site and checking frequently for a change in size, as well as applying pressure. Strict bed rest is recommended, with the affected leg kept straight for 4 to 6 hours. The hemoglobin concentration and hematocrit should be monitored for acute blood loss. Simple hematomas usually resolve in 2 to 4 weeks.

Complicated hematoma is characterized by continuous blood loss and can be compounded by a coagulopathy coexistent with underlying liver disease. Severe blood loss can result in hypotension and tachycardia with an acute drop in the hemoglobin concentration.

Of note, a complicated hematoma can manifest superficially in the groin and may not change size over time, as most of the bleeding is intrapelvic.

Complicated hematomas require management by an interventional radiologist, including urgent noncontrast CT of the pelvis to evaluate for bleeding. In severe cases, embolization or stent graft placement by the interventional radiologist may be necessary. Open surgical evacuation is usually done only when compartment syndrome is a concern.^24–26

Pseudoaneurysm

Pseudoaneurysm occurs in 0.5% to 9% of patients who undergo arterial puncture. It primarily arises from difficulty with cannulation of the artery and from inadequate compression after removal of the vascular sheath.

The signs of pseudoaneurysm are similar to those of hematoma, but it presents with a palpable thrill or bruit on auscultation. Ultrasonography is used for diagnosis.

As with hematoma treatment, bed rest and close monitoring are important. Mild pseudoaneurysm usually responds to manual compression for 20 to 30 minutes. More severe cases may require surgical intervention or percutaneous thrombin injection under ultrasonographic guidance.^25,27

Infection

Infection of the puncture site is rare, with an incidence of about 1%. However, with the advent of closure devices such as Angio-Seal (St. Jude Medical), the incidence of infection has been on the rise, as these devices leave a tract from the skin to the vessel, providing a nidus for infection.^25,28

The hallmarks of infection are straightforward and include pain, swelling, erythema, fever, and leukocytosis, and treatment involves antibiotics.

Nerve damage

In rare cases, puncture or postprocedural compression can damage surrounding nerves. The incidence of nerve damage is less than 0.5%. Symptoms include numbness and tingling at the access site and limb weakness. Treatment involves symptomatic management and physical therapy. Nerve damage can also result from nerve sheath compression by a hematoma.^25,29

Arterial thrombosis

Arterial thrombosis can occur at the site of sheath entry, but this can be avoided by administering anticoagulation during the procedure. Classic symptoms include the “5 P’s”: pain, pallor, paresthesia, pulselessness, and paralysis. Treatment depends on the clot burden, with small clots potentially dissolving and larger clots requiring possible thrombolysis, embolectomy, or surgery.^25,30

SYSTEMIC CONSIDERATIONS

Postembolization syndrome

Postembolization syndrome is characterized by low-grade fever, mild leukocytosis, and pain. Although not a true complication of the procedure, it is an expected event in postprocedural care and should not be confused with systemic infection.

Symptoms of postembolization syndrome peak within 5 days and can last up to 10 days

The pathophysiology of postembolization syndrome is not completely understood, but it is believed to be a sequela of liver necrosis and resulting inflammatory reaction.³¹ The incidence has been reported to be as high as 90% to 95%, with 81% of patients reporting nausea, vomiting, malaise, and myalgias; 42% of patients experience low-grade fever.³² Higher doses of chemotherapy and inadvertent embolization of the gallbladder have been associated with a higher incidence of postembolization syndrome.³²

Symptoms typically peak within 5 days of the procedure and can last up to 10 days. If symptoms do not resolve during this time, infection should be ruled out. Blood cultures and aspirates from infarcted liver tissue remain sterile in postembolization syndrome, thus helping to rule out infection.³²

Treatment with corticosteroids, analgesics, antinausea drugs, and intravenous fluids have all been used individually or in combination, with varying success rates. Prophylactic anti­biotic treatment does not appear to play a role.³³

Tumor lysis syndrome

Tumor lysis syndrome—a complex of severe metabolic disturbances potentially resulting in nephropathy and kidney failure—is extremely rare, with only a handful of individual case reports. It can occur with any embolization technique. Hsieh et al³⁴ reported two cases arising 24 hours to 3 days after treatment. Hsieh et al,³⁴ Burney,³⁵ and Sakamoto et al³⁶ reported tumor lysis syndrome in patients with tumors larger than 5 cm, suggesting that these patients may be at higher risk.

Tumor lysis syndrome typically presents with oliguria and subsequently progresses to electrolyte abnormalities, defined by Cairo and Bishop³⁷ as a 25% increase or decrease in the serum concentration of two of the following within 7 days after tumor therapy: uric acid, potassium, calcium, or phosphate. Treatment involves correction of electrolyte disturbances, as well as aggressive rehydration and allopurinol for high uric acid levels.

Hypersensitivity to iodinated contrast

Contrast reactions range from immediate (within 1 hour) to delayed (from 1 hour to several days after administration). The most common symptoms of an immediate reaction are pruritus, flushing, angioedema, bronchospasm, wheezing, hypotension, and shock. Delayed reactions typically involve mild to moderate skin rash, mild angioedema, minor erythema multiforme, and, rarely, Stevens-Johnson syndrome.³⁸ Dermatology consultation should always be considered for delayed reactions, particularly for severe skin manifestations.

Immediate reactions should be treated with intravenous (IV) fluid support and bronchodilators, and in life-threatening situations, epinephrine. Treatment of delayed reaction is guided by the symptoms. If the reaction is mild (pruritus or rash), secure IV access, have oxygen on standby, begin IV fluids, and consider giving diphenhydramine 50 mg IV or by mouth. Hydrocortisone 200 mg IV can be substituted if the patient has a diphen-hydramine allergy. For severe reactions, epinephrine (1:1,000 intramuscularly or 1:10,000 IV) should be given immediately.³⁹

Ideally, high-risk patients (ie, those with known contrast allergies) should avoid contrast medium if possible. However, if contrast is necessary, premedication should be provided. The American College of Radiology recommends the following preprocedural regimen: prednisone 50 mg by mouth 13 hours, 7 hours, and 1 hour before contrast administration, then 50 mg of diphenhydramine (IV, intramuscular, or oral) 1 hour before the procedure. Methylprednisolone 32 mg by mouth 12 hours and 2 hours before the procedure is an alternative to prednisone; 200 mg of IV hydrocortisone can be used if the patient cannot take oral medication.^40–42

Hypersensitivity to embolizing agents

In chemoembolization procedures, ethiodized oil is used as both a contrast medium and an occluding agent. This lipiodol suspension is combined and injected with the chemotherapy drug. Hypersensitivity reactions have been reported, but the mechanism is not well understood.

One study⁴³ showed a 3.2% occurrence of hypersensitivity to lipiodol combined with cisplatin, a frequently used combination. The most common reaction was dyspnea and urticaria (observed in 57% of patients); bronchospasm, altered mental status, and pruritus were also observed in lower frequencies. Treatment involved corticosteroids and antihistamines; blood pressure support with vasopressors was used as needed.⁴³

Contrast-induced nephropathy

Contrast-induced nephropathy is defined as a 25% rise in serum creatinine from baseline after exposure to iodinated contrast agents. Patients particularly at risk include those with preexisting renal impairment, diabetes mellitus, or acute renal failure due to dehydration. Other risk factors include age, preexisting cardiovascular disease, and hepatic impairment.

Prophylactic strategies rely primarily on intravenous hydration before exposure. The use of N-acetylcysteine can also be considered, but its effectiveness is controversial and it is not routinely recommended in the United States.

Managing acute renal failure, whether new or due to chronic renal impairment, should first involve rehydration. In cases of a severe rise in creatinine or uremia, dialysis should be considered as well as a nephrology consultation.^44,45

Liver cancer is increasing in prevalence; from 2000 to 2010, the prevalence increased from 7.1 per 100,000 to 8.4 per 100,000 people.¹ This increase is due in part to an increase in chronic liver diseases such as hepatitis B and C and nonalcoholic steatohepatitis.² In addition, liver metastases, especially from colorectal cancer and breast cancer, are also on the rise worldwide. More than 60% of patients with colorectal cancer will have a liver metastasis at some point in the course of their disease.

However, only 10% to 15% of patients with hepatocellular carcinoma are candidates for surgical resection.^3,4 And for patients who are not surgical candidates, there are currently no accepted guidelines on treatment.⁵ Treatment of metastatic liver cancer has consisted mainly of systemic chemotherapy, but if standard treatments fail, other options need to be considered.

A number of minimally invasive treatments are available for primary and metastatic liver cancer.⁶ These treatments are for the most part palliative, but in rare instances they are curative. They can be divided into percutaneous imaging-guided therapy (eg, radiofrequency ablation, microwave ablation) and four catheter-based transarterial therapies:

• Bland embolization
• Chemoembolization
• Chemoembolization with drug-eluting microspheres
• Yttrium-90 radioembolization.

In this article, we focus only on the four catheter-based transarterial therapies, providing a brief description of each and a discussion of potential postprocedural complications and the key elements of postprocedural care.

The rationale for catheter-based transarterial therapy

Primary and metastatic liver malignancies depend mainly on the hepatic arterial blood supply for their survival and growth, whereas normal liver tissue is supplied mainly by the portal vein. Therapy applied through the hepatic arterial system is distributed directly to malignant tissue and spares healthy liver tissue. (Note: The leg is the route of access for all catheter-based transarterial therapies.)

BLAND EMBOLIZATION

In transarterial bland embolization, tiny spheres of a neutral (ie, bland) material are injected into the distal branches of the arteries that supply the tumor. These microemboli, 45 to 150 µm in diameter,⁷ permanently occlude the blood vessels.

Bland embolization carries a risk of pulmonary embolism if there is shunting between the pulmonary and hepatic circulation via the hepatic vein.^8,9 Fortunately, this serious complication is rare. Technetium-99m macroaggregated albumin (Tc-99m MAA) scanning is done before the procedure to assess the risk.

Posttreatment care and follow-up

Patients require follow-up with contrast-enhanced computed tomography (CT) 6 to 8 weeks after the procedure to evaluate tumor regression.

Further treatment

If follow-up CT shows that the lesion or lesions have not regressed or have increased in size, the embolization procedure can be repeated about 12 weeks after the initial treatment. The most likely cause of a poor response to therapy is failure to adequately identify all tumor-supplying vessels.¹⁰

CHEMOEMBOLIZATION

Transarterial chemoembolization targets the blood supply of the tumor with a combination of chemotherapeutic drugs and an embolizing agent. Standard chemotherapy agents used include doxorubicin, cisplatin, and mitomycin-C. A microcatheter is advanced into the vessel supplying the tumor, and the combination drug is injected as close to the tumor as possible.¹¹

Transarterial chemoembolization is the most commonly performed hepatic artery-directed therapy for liver cancer. It has been used to treat solitary tumors as well as multifocal disease. It allows for maximum embolization potential while preserving liver function.

Posttreatment care and follow-up

Postembolization syndrome, characterized by low-grade fever, mild leukocytosis, and pain, is common after transarterial chemoembolization. Therefore, the patient is usually admitted to the hospital overnight for monitoring and control of symptoms such as pain and nausea. Mild abdominal pain is common and should resolve within several days; severe abdominal pain should be evaluated, as chemical and ischemic cholecystitis have been reported. Severe abdominal pain also raises concern for possible tumor rupture or liver infarction.

At discharge after chemoembolization, patients are instructed to report high fever, jaundice, or abdominal swelling

At the time of discharge, patients should be instructed to contact their clinician if they experience high fever, jaundice, or abdominal swelling. Liver function testing is not recommended within 7 to 10 days of treatment, as the expected rise in aminotransferase levels could prompt an unnecessary workup. Barring additional complications, patients should be seen in the office 2 weeks after the procedure.¹²

Lesions should be followed by serial contrast-enhanced CT to determine response to therapy. The current recommendation for stable patients is CT every 3 months for 2 years, and then every 6 months until active disease recurs.¹³

Safety concerns

A rare but serious concern after this procedure is fulminant hepatic failure, which has a high death rate. It has been reported in fewer than 1% of patients. Less severe complications include liver failure and infection.¹³

Further treatment

Patients with multifocal disease may require further treatment, usually 4 to 6 weeks after the initial procedure. If a transjugular intrahepatic portosystemic shunt is already in place, the patient can undergo chemoembolization as long as liver function is preserved. However, these patients generally have a poorer prognosis.

CHEMOEMBOLIZATION WITH DRUG-ELUTING MICROSPHERES

In transarterial chemoembolization with drug-eluting microspheres, beads loaded with chemotherapeutic drugs provide controlled delivery, resulting in both ischemia of the tumor and slow release of chemotherapy.

Several types of beads are currently available, with different degrees of affinity for chemotherapy agents. An advantage of the beads is that they can be used in patients with tumors that show aggressive shunting or in tumors that have vascular invasion. The technique for delivering the beads is similar to that used in standard chemoembolization.¹⁴

Posttreatment care and follow-up

Postembolization syndrome is common. Treatment usually consists of hydration and control of pain and nausea. Follow-up includes serial CT to evaluate tumor response.

Safety concerns

Overall, this procedure is safe. A phase 1 and 2 trial¹⁵ showed adverse effects similar to those seen in chemoembolization. The most common adverse effect was a transient increase in liver enzymes. Serious complications such as tumor rupture, spontaneous bacterial peritonitis, and liver failure were rare.

YTTRIUM-90 RADIOEMBOLIZATION

In yttrium-90 radioembolization, radioactive microspheres are injected into the hepatic arterial supply. The procedure involves careful planning and is usually completed in stages.

The first stage involves angiography to map the hepatic vascular anatomy, as well as prophylactic embolization to protect against unintended delivery of the radioactive drug to vessels of the gastrointestinal tract (such as a branch of the hepatic artery that may supply the duodenum), causing tissue necrosis. Another reason for mapping is to look for any potential shunt between the tumor’s blood supply and the lung^16,17 and thus prevent pulmonary embolism from the embolization procedure. The gastric mucosa and the salivary glands are also studied, as isolated gastric mucosal uptake indicates gastrointestinal vascular shunting.

The mapping stage involves injecting radioactive particles of technetium-99m microaggregated albumin, which are close in size to the yttrium-90 particles used during the actual procedure. The dose injected is usually 4 to 5 mCi (much lower than the typical tumor-therapy dose of 100–120 Gy), and imaging is done with either planar or single-photon emission CT. The patient is usually admitted for overnight observation after angiography.

In the second stage, 1 or 2 weeks later, the patient undergoes injection of the radiopharmaceuticals into the hepatic artery supplying the tumor. If disease burden is high or there is bilobar disease, the treatment is repeated in another 6 to 8 weeks. After the procedure, the patient is admitted to the hospital for observation by an inpatient team.

Posttreatment care and follow-up

The major concern after yttrium-90 radioembolization is reflux of the microspheres through unrecognized gastrointestinal channels,¹⁸ particularly into the mucosa of the stomach and proximal duodenum, causing the formation of nonhealing ulcers, which can cause major morbidity and even death. Antiulcer medications can be started immediately after the procedure.

Postembolization syndrome is frequently seen, and the fever usually responds to acet­a­minophen. Nausea and vomiting can be managed conservatively.¹⁹

The patient returns for a follow-up visit within 4 to 6 weeks of the injection procedure, mainly for assessment of liver function. A transient increase in liver enzymes and tumor markers may be seen at this time. A massive increase in liver enzyme levels should be investigated further.

Safety concerns

The postprocedural radiation exposure from the patient is within the acceptable safety range; therefore, no special precautions are necessary. However, since resin spheres are excreted in the urine, precautions are needed for urine disposal during the first 24 hours.^20,21

Further treatments

If there is multifocal disease or a poor response to the initial treatment, a second session can be done 6 to 8 weeks after the first one. Before the second session, the liver tumor is imaged.²² For hepatocellular carcinoma, imaging may show shrinkage and necrosis of the tumor. For metastatic tumors, this imaging is important as it may show either failure or progression of disease.²³ For this reason, functional imaging such as positron-emission tomography is important as it may show the extrahepatic spread of tumor, thereby halting further treatment. A complete blood cell count may also be done at 30 days to look for radiation-related cytopenia. A scrupulous log of the radiation dose received by the patient should be maintained.

PUNCTURE-SITE COMPLICATIONS

Hematoma

Hematoma at the puncture site is the most common complication of arterial access, with an incidence of 5% to 23%. The main clinical findings are erythema and swelling at the puncture site, with a palpable hardening of the skin. Pain and decreased range of motion in the affected extremity can also occur.

Simple hematomas exhibit a stable size and hemoglobin count and are managed conservatively. Initial management involves marking the site and checking frequently for a change in size, as well as applying pressure. Strict bed rest is recommended, with the affected leg kept straight for 4 to 6 hours. The hemoglobin concentration and hematocrit should be monitored for acute blood loss. Simple hematomas usually resolve in 2 to 4 weeks.

Complicated hematoma is characterized by continuous blood loss and can be compounded by a coagulopathy coexistent with underlying liver disease. Severe blood loss can result in hypotension and tachycardia with an acute drop in the hemoglobin concentration.

Of note, a complicated hematoma can manifest superficially in the groin and may not change size over time, as most of the bleeding is intrapelvic.

Complicated hematomas require management by an interventional radiologist, including urgent noncontrast CT of the pelvis to evaluate for bleeding. In severe cases, embolization or stent graft placement by the interventional radiologist may be necessary. Open surgical evacuation is usually done only when compartment syndrome is a concern.^24–26

Pseudoaneurysm

Pseudoaneurysm occurs in 0.5% to 9% of patients who undergo arterial puncture. It primarily arises from difficulty with cannulation of the artery and from inadequate compression after removal of the vascular sheath.

The signs of pseudoaneurysm are similar to those of hematoma, but it presents with a palpable thrill or bruit on auscultation. Ultrasonography is used for diagnosis.

As with hematoma treatment, bed rest and close monitoring are important. Mild pseudoaneurysm usually responds to manual compression for 20 to 30 minutes. More severe cases may require surgical intervention or percutaneous thrombin injection under ultrasonographic guidance.^25,27

Infection

Infection of the puncture site is rare, with an incidence of about 1%. However, with the advent of closure devices such as Angio-Seal (St. Jude Medical), the incidence of infection has been on the rise, as these devices leave a tract from the skin to the vessel, providing a nidus for infection.^25,28

The hallmarks of infection are straightforward and include pain, swelling, erythema, fever, and leukocytosis, and treatment involves antibiotics.

Nerve damage

In rare cases, puncture or postprocedural compression can damage surrounding nerves. The incidence of nerve damage is less than 0.5%. Symptoms include numbness and tingling at the access site and limb weakness. Treatment involves symptomatic management and physical therapy. Nerve damage can also result from nerve sheath compression by a hematoma.^25,29

Arterial thrombosis

Arterial thrombosis can occur at the site of sheath entry, but this can be avoided by administering anticoagulation during the procedure. Classic symptoms include the “5 P’s”: pain, pallor, paresthesia, pulselessness, and paralysis. Treatment depends on the clot burden, with small clots potentially dissolving and larger clots requiring possible thrombolysis, embolectomy, or surgery.^25,30

SYSTEMIC CONSIDERATIONS

Postembolization syndrome

Postembolization syndrome is characterized by low-grade fever, mild leukocytosis, and pain. Although not a true complication of the procedure, it is an expected event in postprocedural care and should not be confused with systemic infection.

Symptoms of postembolization syndrome peak within 5 days and can last up to 10 days

The pathophysiology of postembolization syndrome is not completely understood, but it is believed to be a sequela of liver necrosis and resulting inflammatory reaction.³¹ The incidence has been reported to be as high as 90% to 95%, with 81% of patients reporting nausea, vomiting, malaise, and myalgias; 42% of patients experience low-grade fever.³² Higher doses of chemotherapy and inadvertent embolization of the gallbladder have been associated with a higher incidence of postembolization syndrome.³²

Symptoms typically peak within 5 days of the procedure and can last up to 10 days. If symptoms do not resolve during this time, infection should be ruled out. Blood cultures and aspirates from infarcted liver tissue remain sterile in postembolization syndrome, thus helping to rule out infection.³²

Treatment with corticosteroids, analgesics, antinausea drugs, and intravenous fluids have all been used individually or in combination, with varying success rates. Prophylactic anti­biotic treatment does not appear to play a role.³³

Tumor lysis syndrome

Tumor lysis syndrome—a complex of severe metabolic disturbances potentially resulting in nephropathy and kidney failure—is extremely rare, with only a handful of individual case reports. It can occur with any embolization technique. Hsieh et al³⁴ reported two cases arising 24 hours to 3 days after treatment. Hsieh et al,³⁴ Burney,³⁵ and Sakamoto et al³⁶ reported tumor lysis syndrome in patients with tumors larger than 5 cm, suggesting that these patients may be at higher risk.

Tumor lysis syndrome typically presents with oliguria and subsequently progresses to electrolyte abnormalities, defined by Cairo and Bishop³⁷ as a 25% increase or decrease in the serum concentration of two of the following within 7 days after tumor therapy: uric acid, potassium, calcium, or phosphate. Treatment involves correction of electrolyte disturbances, as well as aggressive rehydration and allopurinol for high uric acid levels.

Hypersensitivity to iodinated contrast

Contrast reactions range from immediate (within 1 hour) to delayed (from 1 hour to several days after administration). The most common symptoms of an immediate reaction are pruritus, flushing, angioedema, bronchospasm, wheezing, hypotension, and shock. Delayed reactions typically involve mild to moderate skin rash, mild angioedema, minor erythema multiforme, and, rarely, Stevens-Johnson syndrome.³⁸ Dermatology consultation should always be considered for delayed reactions, particularly for severe skin manifestations.

Immediate reactions should be treated with intravenous (IV) fluid support and bronchodilators, and in life-threatening situations, epinephrine. Treatment of delayed reaction is guided by the symptoms. If the reaction is mild (pruritus or rash), secure IV access, have oxygen on standby, begin IV fluids, and consider giving diphenhydramine 50 mg IV or by mouth. Hydrocortisone 200 mg IV can be substituted if the patient has a diphen-hydramine allergy. For severe reactions, epinephrine (1:1,000 intramuscularly or 1:10,000 IV) should be given immediately.³⁹

Ideally, high-risk patients (ie, those with known contrast allergies) should avoid contrast medium if possible. However, if contrast is necessary, premedication should be provided. The American College of Radiology recommends the following preprocedural regimen: prednisone 50 mg by mouth 13 hours, 7 hours, and 1 hour before contrast administration, then 50 mg of diphenhydramine (IV, intramuscular, or oral) 1 hour before the procedure. Methylprednisolone 32 mg by mouth 12 hours and 2 hours before the procedure is an alternative to prednisone; 200 mg of IV hydrocortisone can be used if the patient cannot take oral medication.^40–42

Hypersensitivity to embolizing agents

In chemoembolization procedures, ethiodized oil is used as both a contrast medium and an occluding agent. This lipiodol suspension is combined and injected with the chemotherapy drug. Hypersensitivity reactions have been reported, but the mechanism is not well understood.

One study⁴³ showed a 3.2% occurrence of hypersensitivity to lipiodol combined with cisplatin, a frequently used combination. The most common reaction was dyspnea and urticaria (observed in 57% of patients); bronchospasm, altered mental status, and pruritus were also observed in lower frequencies. Treatment involved corticosteroids and antihistamines; blood pressure support with vasopressors was used as needed.⁴³

Contrast-induced nephropathy

Contrast-induced nephropathy is defined as a 25% rise in serum creatinine from baseline after exposure to iodinated contrast agents. Patients particularly at risk include those with preexisting renal impairment, diabetes mellitus, or acute renal failure due to dehydration. Other risk factors include age, preexisting cardiovascular disease, and hepatic impairment.

Prophylactic strategies rely primarily on intravenous hydration before exposure. The use of N-acetylcysteine can also be considered, but its effectiveness is controversial and it is not routinely recommended in the United States.

Managing acute renal failure, whether new or due to chronic renal impairment, should first involve rehydration. In cases of a severe rise in creatinine or uremia, dialysis should be considered as well as a nephrology consultation.^44,45

Liver cancer is increasing in prevalence; from 2000 to 2010, the prevalence increased from 7.1 per 100,000 to 8.4 per 100,000 people.¹ This increase is due in part to an increase in chronic liver diseases such as hepatitis B and C and nonalcoholic steatohepatitis.² In addition, liver metastases, especially from colorectal cancer and breast cancer, are also on the rise worldwide. More than 60% of patients with colorectal cancer will have a liver metastasis at some point in the course of their disease.

However, only 10% to 15% of patients with hepatocellular carcinoma are candidates for surgical resection.^3,4 And for patients who are not surgical candidates, there are currently no accepted guidelines on treatment.⁵ Treatment of metastatic liver cancer has consisted mainly of systemic chemotherapy, but if standard treatments fail, other options need to be considered.

A number of minimally invasive treatments are available for primary and metastatic liver cancer.⁶ These treatments are for the most part palliative, but in rare instances they are curative. They can be divided into percutaneous imaging-guided therapy (eg, radiofrequency ablation, microwave ablation) and four catheter-based transarterial therapies:

• Bland embolization
• Chemoembolization
• Chemoembolization with drug-eluting microspheres
• Yttrium-90 radioembolization.

In this article, we focus only on the four catheter-based transarterial therapies, providing a brief description of each and a discussion of potential postprocedural complications and the key elements of postprocedural care.

The rationale for catheter-based transarterial therapy

Primary and metastatic liver malignancies depend mainly on the hepatic arterial blood supply for their survival and growth, whereas normal liver tissue is supplied mainly by the portal vein. Therapy applied through the hepatic arterial system is distributed directly to malignant tissue and spares healthy liver tissue. (Note: The leg is the route of access for all catheter-based transarterial therapies.)

BLAND EMBOLIZATION

In transarterial bland embolization, tiny spheres of a neutral (ie, bland) material are injected into the distal branches of the arteries that supply the tumor. These microemboli, 45 to 150 µm in diameter,⁷ permanently occlude the blood vessels.

Bland embolization carries a risk of pulmonary embolism if there is shunting between the pulmonary and hepatic circulation via the hepatic vein.^8,9 Fortunately, this serious complication is rare. Technetium-99m macroaggregated albumin (Tc-99m MAA) scanning is done before the procedure to assess the risk.

Posttreatment care and follow-up

Patients require follow-up with contrast-enhanced computed tomography (CT) 6 to 8 weeks after the procedure to evaluate tumor regression.

Further treatment

If follow-up CT shows that the lesion or lesions have not regressed or have increased in size, the embolization procedure can be repeated about 12 weeks after the initial treatment. The most likely cause of a poor response to therapy is failure to adequately identify all tumor-supplying vessels.¹⁰

CHEMOEMBOLIZATION

Transarterial chemoembolization targets the blood supply of the tumor with a combination of chemotherapeutic drugs and an embolizing agent. Standard chemotherapy agents used include doxorubicin, cisplatin, and mitomycin-C. A microcatheter is advanced into the vessel supplying the tumor, and the combination drug is injected as close to the tumor as possible.¹¹

Transarterial chemoembolization is the most commonly performed hepatic artery-directed therapy for liver cancer. It has been used to treat solitary tumors as well as multifocal disease. It allows for maximum embolization potential while preserving liver function.

Posttreatment care and follow-up

Postembolization syndrome, characterized by low-grade fever, mild leukocytosis, and pain, is common after transarterial chemoembolization. Therefore, the patient is usually admitted to the hospital overnight for monitoring and control of symptoms such as pain and nausea. Mild abdominal pain is common and should resolve within several days; severe abdominal pain should be evaluated, as chemical and ischemic cholecystitis have been reported. Severe abdominal pain also raises concern for possible tumor rupture or liver infarction.

At discharge after chemoembolization, patients are instructed to report high fever, jaundice, or abdominal swelling

At the time of discharge, patients should be instructed to contact their clinician if they experience high fever, jaundice, or abdominal swelling. Liver function testing is not recommended within 7 to 10 days of treatment, as the expected rise in aminotransferase levels could prompt an unnecessary workup. Barring additional complications, patients should be seen in the office 2 weeks after the procedure.¹²

Lesions should be followed by serial contrast-enhanced CT to determine response to therapy. The current recommendation for stable patients is CT every 3 months for 2 years, and then every 6 months until active disease recurs.¹³

Safety concerns

A rare but serious concern after this procedure is fulminant hepatic failure, which has a high death rate. It has been reported in fewer than 1% of patients. Less severe complications include liver failure and infection.¹³

Further treatment

Patients with multifocal disease may require further treatment, usually 4 to 6 weeks after the initial procedure. If a transjugular intrahepatic portosystemic shunt is already in place, the patient can undergo chemoembolization as long as liver function is preserved. However, these patients generally have a poorer prognosis.

CHEMOEMBOLIZATION WITH DRUG-ELUTING MICROSPHERES

In transarterial chemoembolization with drug-eluting microspheres, beads loaded with chemotherapeutic drugs provide controlled delivery, resulting in both ischemia of the tumor and slow release of chemotherapy.

Several types of beads are currently available, with different degrees of affinity for chemotherapy agents. An advantage of the beads is that they can be used in patients with tumors that show aggressive shunting or in tumors that have vascular invasion. The technique for delivering the beads is similar to that used in standard chemoembolization.¹⁴

Posttreatment care and follow-up

Postembolization syndrome is common. Treatment usually consists of hydration and control of pain and nausea. Follow-up includes serial CT to evaluate tumor response.

Safety concerns

Overall, this procedure is safe. A phase 1 and 2 trial¹⁵ showed adverse effects similar to those seen in chemoembolization. The most common adverse effect was a transient increase in liver enzymes. Serious complications such as tumor rupture, spontaneous bacterial peritonitis, and liver failure were rare.

YTTRIUM-90 RADIOEMBOLIZATION

In yttrium-90 radioembolization, radioactive microspheres are injected into the hepatic arterial supply. The procedure involves careful planning and is usually completed in stages.

The first stage involves angiography to map the hepatic vascular anatomy, as well as prophylactic embolization to protect against unintended delivery of the radioactive drug to vessels of the gastrointestinal tract (such as a branch of the hepatic artery that may supply the duodenum), causing tissue necrosis. Another reason for mapping is to look for any potential shunt between the tumor’s blood supply and the lung^16,17 and thus prevent pulmonary embolism from the embolization procedure. The gastric mucosa and the salivary glands are also studied, as isolated gastric mucosal uptake indicates gastrointestinal vascular shunting.

The mapping stage involves injecting radioactive particles of technetium-99m microaggregated albumin, which are close in size to the yttrium-90 particles used during the actual procedure. The dose injected is usually 4 to 5 mCi (much lower than the typical tumor-therapy dose of 100–120 Gy), and imaging is done with either planar or single-photon emission CT. The patient is usually admitted for overnight observation after angiography.

In the second stage, 1 or 2 weeks later, the patient undergoes injection of the radiopharmaceuticals into the hepatic artery supplying the tumor. If disease burden is high or there is bilobar disease, the treatment is repeated in another 6 to 8 weeks. After the procedure, the patient is admitted to the hospital for observation by an inpatient team.

Posttreatment care and follow-up

The major concern after yttrium-90 radioembolization is reflux of the microspheres through unrecognized gastrointestinal channels,¹⁸ particularly into the mucosa of the stomach and proximal duodenum, causing the formation of nonhealing ulcers, which can cause major morbidity and even death. Antiulcer medications can be started immediately after the procedure.

Postembolization syndrome is frequently seen, and the fever usually responds to acet­a­minophen. Nausea and vomiting can be managed conservatively.¹⁹

The patient returns for a follow-up visit within 4 to 6 weeks of the injection procedure, mainly for assessment of liver function. A transient increase in liver enzymes and tumor markers may be seen at this time. A massive increase in liver enzyme levels should be investigated further.

Safety concerns

The postprocedural radiation exposure from the patient is within the acceptable safety range; therefore, no special precautions are necessary. However, since resin spheres are excreted in the urine, precautions are needed for urine disposal during the first 24 hours.^20,21

Further treatments

If there is multifocal disease or a poor response to the initial treatment, a second session can be done 6 to 8 weeks after the first one. Before the second session, the liver tumor is imaged.²² For hepatocellular carcinoma, imaging may show shrinkage and necrosis of the tumor. For metastatic tumors, this imaging is important as it may show either failure or progression of disease.²³ For this reason, functional imaging such as positron-emission tomography is important as it may show the extrahepatic spread of tumor, thereby halting further treatment. A complete blood cell count may also be done at 30 days to look for radiation-related cytopenia. A scrupulous log of the radiation dose received by the patient should be maintained.

PUNCTURE-SITE COMPLICATIONS

Hematoma

Hematoma at the puncture site is the most common complication of arterial access, with an incidence of 5% to 23%. The main clinical findings are erythema and swelling at the puncture site, with a palpable hardening of the skin. Pain and decreased range of motion in the affected extremity can also occur.

Simple hematomas exhibit a stable size and hemoglobin count and are managed conservatively. Initial management involves marking the site and checking frequently for a change in size, as well as applying pressure. Strict bed rest is recommended, with the affected leg kept straight for 4 to 6 hours. The hemoglobin concentration and hematocrit should be monitored for acute blood loss. Simple hematomas usually resolve in 2 to 4 weeks.

Complicated hematoma is characterized by continuous blood loss and can be compounded by a coagulopathy coexistent with underlying liver disease. Severe blood loss can result in hypotension and tachycardia with an acute drop in the hemoglobin concentration.

Of note, a complicated hematoma can manifest superficially in the groin and may not change size over time, as most of the bleeding is intrapelvic.

Complicated hematomas require management by an interventional radiologist, including urgent noncontrast CT of the pelvis to evaluate for bleeding. In severe cases, embolization or stent graft placement by the interventional radiologist may be necessary. Open surgical evacuation is usually done only when compartment syndrome is a concern.^24–26

Pseudoaneurysm

Pseudoaneurysm occurs in 0.5% to 9% of patients who undergo arterial puncture. It primarily arises from difficulty with cannulation of the artery and from inadequate compression after removal of the vascular sheath.

The signs of pseudoaneurysm are similar to those of hematoma, but it presents with a palpable thrill or bruit on auscultation. Ultrasonography is used for diagnosis.

As with hematoma treatment, bed rest and close monitoring are important. Mild pseudoaneurysm usually responds to manual compression for 20 to 30 minutes. More severe cases may require surgical intervention or percutaneous thrombin injection under ultrasonographic guidance.^25,27

Infection

Infection of the puncture site is rare, with an incidence of about 1%. However, with the advent of closure devices such as Angio-Seal (St. Jude Medical), the incidence of infection has been on the rise, as these devices leave a tract from the skin to the vessel, providing a nidus for infection.^25,28

The hallmarks of infection are straightforward and include pain, swelling, erythema, fever, and leukocytosis, and treatment involves antibiotics.

Nerve damage

In rare cases, puncture or postprocedural compression can damage surrounding nerves. The incidence of nerve damage is less than 0.5%. Symptoms include numbness and tingling at the access site and limb weakness. Treatment involves symptomatic management and physical therapy. Nerve damage can also result from nerve sheath compression by a hematoma.^25,29

Arterial thrombosis

Arterial thrombosis can occur at the site of sheath entry, but this can be avoided by administering anticoagulation during the procedure. Classic symptoms include the “5 P’s”: pain, pallor, paresthesia, pulselessness, and paralysis. Treatment depends on the clot burden, with small clots potentially dissolving and larger clots requiring possible thrombolysis, embolectomy, or surgery.^25,30

SYSTEMIC CONSIDERATIONS

Postembolization syndrome

Postembolization syndrome is characterized by low-grade fever, mild leukocytosis, and pain. Although not a true complication of the procedure, it is an expected event in postprocedural care and should not be confused with systemic infection.

Symptoms of postembolization syndrome peak within 5 days and can last up to 10 days

The pathophysiology of postembolization syndrome is not completely understood, but it is believed to be a sequela of liver necrosis and resulting inflammatory reaction.³¹ The incidence has been reported to be as high as 90% to 95%, with 81% of patients reporting nausea, vomiting, malaise, and myalgias; 42% of patients experience low-grade fever.³² Higher doses of chemotherapy and inadvertent embolization of the gallbladder have been associated with a higher incidence of postembolization syndrome.³²

Symptoms typically peak within 5 days of the procedure and can last up to 10 days. If symptoms do not resolve during this time, infection should be ruled out. Blood cultures and aspirates from infarcted liver tissue remain sterile in postembolization syndrome, thus helping to rule out infection.³²

Treatment with corticosteroids, analgesics, antinausea drugs, and intravenous fluids have all been used individually or in combination, with varying success rates. Prophylactic anti­biotic treatment does not appear to play a role.³³

Tumor lysis syndrome

Tumor lysis syndrome—a complex of severe metabolic disturbances potentially resulting in nephropathy and kidney failure—is extremely rare, with only a handful of individual case reports. It can occur with any embolization technique. Hsieh et al³⁴ reported two cases arising 24 hours to 3 days after treatment. Hsieh et al,³⁴ Burney,³⁵ and Sakamoto et al³⁶ reported tumor lysis syndrome in patients with tumors larger than 5 cm, suggesting that these patients may be at higher risk.

Tumor lysis syndrome typically presents with oliguria and subsequently progresses to electrolyte abnormalities, defined by Cairo and Bishop³⁷ as a 25% increase or decrease in the serum concentration of two of the following within 7 days after tumor therapy: uric acid, potassium, calcium, or phosphate. Treatment involves correction of electrolyte disturbances, as well as aggressive rehydration and allopurinol for high uric acid levels.

Hypersensitivity to iodinated contrast

Contrast reactions range from immediate (within 1 hour) to delayed (from 1 hour to several days after administration). The most common symptoms of an immediate reaction are pruritus, flushing, angioedema, bronchospasm, wheezing, hypotension, and shock. Delayed reactions typically involve mild to moderate skin rash, mild angioedema, minor erythema multiforme, and, rarely, Stevens-Johnson syndrome.³⁸ Dermatology consultation should always be considered for delayed reactions, particularly for severe skin manifestations.

Immediate reactions should be treated with intravenous (IV) fluid support and bronchodilators, and in life-threatening situations, epinephrine. Treatment of delayed reaction is guided by the symptoms. If the reaction is mild (pruritus or rash), secure IV access, have oxygen on standby, begin IV fluids, and consider giving diphenhydramine 50 mg IV or by mouth. Hydrocortisone 200 mg IV can be substituted if the patient has a diphen-hydramine allergy. For severe reactions, epinephrine (1:1,000 intramuscularly or 1:10,000 IV) should be given immediately.³⁹

Ideally, high-risk patients (ie, those with known contrast allergies) should avoid contrast medium if possible. However, if contrast is necessary, premedication should be provided. The American College of Radiology recommends the following preprocedural regimen: prednisone 50 mg by mouth 13 hours, 7 hours, and 1 hour before contrast administration, then 50 mg of diphenhydramine (IV, intramuscular, or oral) 1 hour before the procedure. Methylprednisolone 32 mg by mouth 12 hours and 2 hours before the procedure is an alternative to prednisone; 200 mg of IV hydrocortisone can be used if the patient cannot take oral medication.^40–42

Hypersensitivity to embolizing agents

In chemoembolization procedures, ethiodized oil is used as both a contrast medium and an occluding agent. This lipiodol suspension is combined and injected with the chemotherapy drug. Hypersensitivity reactions have been reported, but the mechanism is not well understood.

One study⁴³ showed a 3.2% occurrence of hypersensitivity to lipiodol combined with cisplatin, a frequently used combination. The most common reaction was dyspnea and urticaria (observed in 57% of patients); bronchospasm, altered mental status, and pruritus were also observed in lower frequencies. Treatment involved corticosteroids and antihistamines; blood pressure support with vasopressors was used as needed.⁴³

Contrast-induced nephropathy

Contrast-induced nephropathy is defined as a 25% rise in serum creatinine from baseline after exposure to iodinated contrast agents. Patients particularly at risk include those with preexisting renal impairment, diabetes mellitus, or acute renal failure due to dehydration. Other risk factors include age, preexisting cardiovascular disease, and hepatic impairment.

Prophylactic strategies rely primarily on intravenous hydration before exposure. The use of N-acetylcysteine can also be considered, but its effectiveness is controversial and it is not routinely recommended in the United States.

Managing acute renal failure, whether new or due to chronic renal impairment, should first involve rehydration. In cases of a severe rise in creatinine or uremia, dialysis should be considered as well as a nephrology consultation.^44,45

No, not all patients with allergic conjunctivitis need prescription eyedrops.

For mild symptoms, basic nonpharmacologic eye care often suffices. Advise the patient to avoid rubbing the eyes, to use artificial tears as needed, to apply cold compresses, to limit or temporarily discontinue contact lens wear, and to avoid exposure to known allergens.

Topical therapy with an over-the-counter eyedrop that combines an antihistamine and a mast cell stabilizer is another first-line measure.

Prescription eyedrops are usually reserved for patients who have persistent bothersome symptoms despite use of over-the-counter eyedrops. Also, some patients have difficulty with the regimens for over-the-counter eyedrops, since most must be applied two to four times per day. In addition, patients with concomitant allergic rhinitis may benefit from an intranasal corticosteroid.

ALLERGIC CONJUNCTIVITIS: A BRIEF OVERVIEW

Allergic conjunctivitis, caused by exposure of the eye to airborne allergens, affects up to 40% of the US population, predominantly young adults.¹ Bilateral pruritus is the chief symptom. The absence of pruritus should prompt consideration of a more serious eye condition.

Other common symptoms of allergic conjunctivitis include redness, tearing (a clear, watery discharge), eyelid edema, burning, and mild photophobia. Some patients may have infraorbital edema and darkening around the eye, dubbed an “allergic shiner.”¹

Allergic conjunctivitis can be acute, with sudden onset of symptoms upon exposure to an isolated allergen. It can be seasonal, from exposure to pollen and with a more gradual onset. It can also be perennial, from year-round exposure to indoor allergens such as animal dander, dust mites, and mold.

Allergic conjunctivitis often occurs together with allergic rhinitis, which is also caused by exposure to aeroallergens and is characterized by nasal congestion, pruritus, rhinorrhea (anterior and posterior), and sneezing.²

Pollen is more commonly associated with rhinoconjunctivitis, whereas dust mite allergy is more likely to cause rhinitis alone.

An immunoglobulin E-mediated reaction

Allergic conjunctivitis is a type I immunoglobulin E-mediated immediate hypersensitivity reaction. In the early phase, ie, within minutes of allergen exposure, previously sensitized mast cells are exposed to an allergen, causing degranulation and release of inflammatory mediators, primarily histamine. The late phase, ie, 6 to 10 hours after the initial exposure, involves an influx of inflammatory cells such as eosinophils, basophils, and neutrophils.³

Differential diagnosis

For most patients, basic eye care measures are sufficient

The differential diagnosis of allergic conjunctivitis includes infectious conjunctivitis, chronic dry eye, preservative toxicity, giant papillary conjunctivitis, atopic keratoconjunctivitis, and vernal keratoconjunctivitis.³ Giant papillary conjunctivitis is an inflammatory reaction to a foreign substance, such as a contact lens. Atopic keratoconjunctivitis and vernal keratoconjunctivitis can be vision-threatening and require referral to an ophthalmologist. Atopic keratoconjunctivitis is associated with eczematous lesions of the lids and skin, and vernal keratoconjunctivitis involves chronic inflammation of the palpebral conjunctivae. Warning signs include photophobia, pain, abnormal findings on pupillary examination, blurred vision (unrelated to excessively watery eyes), unilateral eye complaints, and ciliary flush.²

Bacterial conjunctivitis is highly contagious and usually presents with hyperemia, “stuck eye” upon awakening, and thick, purulent discharge. It is usually unilateral. Symptoms include burning, foreign-body sensation, and discomfort rather than pruritus. Patients with allergic conjunctivitis may have concomitant bacterial conjunctivitis and so require a topical antibiotic as well as treatment for allergic conjunctivitis.

Viral conjunctivitis usually affects one eye, is self-limited, and typically presents with other symptoms of a viral syndrome.

MANAGEMENT OPTIONS

Management of allergic conjunctivitis consists of basic eye care, avoidance of allergy triggers, and over-the-counter and prescription topical and systemic therapies, as well as allergen immunotherapy.³

Avoidance

Triggers for the allergic reaction, such as pollen, can be identified with aeroallergen skin testing by an allergist. But simple avoidance measures are helpful, such as closing windows, using air conditioning, limiting exposure to the outdoors when pollen counts are high, wearing sunglasses, showering before bedtime, avoiding exposure to animal dander, and using zippered casings for bedding to minimize exposure to dust mites.³

Patients who wear contact lenses should reduce or discontinue their use, as allergens adhere to contact lens surfaces.

Topical therapies

If avoidance is not feasible or if symptoms persist despite avoidance measures, patients should be started on eyedrops.

Eyedrops for allergic conjunctivitis are classified by mechanism of action: topical anti­histamines, mast-cell stabilizers, and combination preparations of antihistamine and mast-cell stabilizer (Table 1). Algorithms for managing allergic conjunctivitis exist² but are based on expert consensus, since there are no randomized clinical trials with head-to-head comparisons of topical agents for allergic conjunctivitis.

In our practice, we use a three-step approach to treat allergic conjunctivitis (Table 2). Combination antihistamine and mast-cell stabilizer eyedrops are the first line, used as needed, daily, seasonally, or year-round, based on the patient’s symptoms and allergen profile. Antihistamine or combination eyedrops are preferred as they have a faster onset of action than mast-cell stabilizers alone,³ which have an onset of action of 3 to 5 days. The combination drops provide an effect on the late-phase response and a longer duration of action. 

Currently, the only over-the-counter eyedrops for allergic conjunctivitis are cromolyn (a mast-cell stabilizer) and ketotifen 0.025% (a combination antihistamine and mast-cell stabilizer). Most drops for allergic conjunctivitis are taken two to four times a day. Two once-daily eyedrop formulations for allergic conjunctivitis—available only by prescription—are olopatadine 0.2% and alcaftadine. However, these are very expensive (Table 1) and so may not be an appropriate choice for some patients. On the other hand, a study from the United Kingdom⁴ found that patients using olopatadine made fewer visits to their general practitioner than patients using cromolyn, resulting in lower overall cost of healthcare. Results of studies of patient preferences and efficacy of olopatadine 0.1% (twice-daily preparation) vs ketotifen 0.025% are mixed,^5–8 and no study has compared olopatadine 0.2% (once-daily preparation) with over-the-counter ketotifen.

Adverse effects of eyedrops

Common adverse effects include stinging and burning immediately after use; this effect may be reduced by keeping the eyedrops in the refrigerator. Patients who wear contact lenses should remove them before using eyedrops for allergic conjunctivitis, and wait at least 10 minutes to replace them if the eye is no longer red.² Antihistamine drops are contraindicated in patients at risk for angle-closure glaucoma.

Whenever possible, patients with seasonal allergic conjunctivitis should begin treatment 2 to 4 weeks before the relevant pollen season, as guided by the patient’s experience in past seasons or by the results of aeroallergen skin testing. This modifies the “priming” effect, in which the amount of allergen required to induce an immediate allergic response decreases with repeated exposure to the allergen.

OTHER TREATMENT OPTIONS

Vasoconstrictor or decongestant eyedrops are indicated to relieve eye redness but have little or no effect on pruritus, and prolonged use may lead to rebound hyperemia. Thus, they are not generally recommended for long-term treatment of allergic conjunctivitis.³ Also, patients with glaucoma should be advised against long-term use of over-the-counter vasoconstrictor eyedrops.

Corticosteroid eyedrops are reserved for refractory and severe cases. Their use requires close follow-up with an ophthalmologist to monitor for complications such as increased intraocular pressure, infection, and cataracts.²

Patients presenting with an acute severe episode of allergic conjunctivitis that has not responded to oral antihistamines or combination eyedrops may be treated with a short course of an oral corticosteroid, if the benefit outweighs the risk in that patient.

Oral antihistamines are generally less effective than topical ophthalmic agents in relieving ocular allergy symptoms and have a slower onset of action.² They are useful in patients who have an aversion to instilling eyedrops on a regular basis or who wear contact lenses.

For patients who have associated allergic rhinitis—ie, most patients with allergic conjunctivitis—intranasal corticosteroids and intranasal antihistamines are the most effective treatments for rhinitis and are also effective for allergic conjunctivitis. Monotherapy with an intranasal medication may provide sufficient relief of conjunctivitis symptoms or allow ocular medications to be used on a less frequent basis.

Allergen immunotherapy

Referral to an allergist for consideration of allergen immunotherapy is an option when avoidance measures are ineffective or unfeasible, when first-line treatments are ineffective, and when the patient does not wish to use medications.

Tailor treatment to symptoms, allergen profile, and patient preferences

Allergen immunotherapy is the only disease-modifying therapy available for allergic conjunctivitis. Two forms are available: traditional subcutaneous immunotherapy, and sublingual tablet immunotherapy, recently approved by the US Food and Drug Administration.⁹ Subcutaneous immunotherapy targets specific aeroallergens for patients allergic to multiple allergens. The new sublingual immunotherapy tablets target only grass pollen and ragweed pollen.⁹ Most patients in the United States are polysensitized.¹⁰ Both forms of immunotherapy can result in sustained effectiveness following discontinuation. Sub­lingual therapy may be administered year-round, before allergy season, or during allergy season (depending on the type of allergy).

TAILORING TREATMENT

We recommend a case-by-case approach to the management of patients with allergic conjunctivitis, tailoring treatment to the patient’s symptoms, allergen profile, and personal preferences.

For example, if adherence is a challenge we recommend a once-daily combination eyedrop (olopatadine 0.2%, or alcaftadine). If cost is a barrier, we recommend the combination over-the-counter drop (ketotifen).

Medications may be used during allergy season or year-round depending on the patient’s symptom and allergen profile. Patients whose symptoms are not relieved with these measures should be referred to an allergist for further evaluation and management, or to an ophthalmologist to monitor for complications of topical steroid use and other warning signs, as discussed earlier, or to weigh in on the differential diagnosis.

No, not all patients with allergic conjunctivitis need prescription eyedrops.

For mild symptoms, basic nonpharmacologic eye care often suffices. Advise the patient to avoid rubbing the eyes, to use artificial tears as needed, to apply cold compresses, to limit or temporarily discontinue contact lens wear, and to avoid exposure to known allergens.

Topical therapy with an over-the-counter eyedrop that combines an antihistamine and a mast cell stabilizer is another first-line measure.

Prescription eyedrops are usually reserved for patients who have persistent bothersome symptoms despite use of over-the-counter eyedrops. Also, some patients have difficulty with the regimens for over-the-counter eyedrops, since most must be applied two to four times per day. In addition, patients with concomitant allergic rhinitis may benefit from an intranasal corticosteroid.

ALLERGIC CONJUNCTIVITIS: A BRIEF OVERVIEW

Allergic conjunctivitis, caused by exposure of the eye to airborne allergens, affects up to 40% of the US population, predominantly young adults.¹ Bilateral pruritus is the chief symptom. The absence of pruritus should prompt consideration of a more serious eye condition.

Other common symptoms of allergic conjunctivitis include redness, tearing (a clear, watery discharge), eyelid edema, burning, and mild photophobia. Some patients may have infraorbital edema and darkening around the eye, dubbed an “allergic shiner.”¹

Allergic conjunctivitis can be acute, with sudden onset of symptoms upon exposure to an isolated allergen. It can be seasonal, from exposure to pollen and with a more gradual onset. It can also be perennial, from year-round exposure to indoor allergens such as animal dander, dust mites, and mold.

Allergic conjunctivitis often occurs together with allergic rhinitis, which is also caused by exposure to aeroallergens and is characterized by nasal congestion, pruritus, rhinorrhea (anterior and posterior), and sneezing.²

Pollen is more commonly associated with rhinoconjunctivitis, whereas dust mite allergy is more likely to cause rhinitis alone.

An immunoglobulin E-mediated reaction

Allergic conjunctivitis is a type I immunoglobulin E-mediated immediate hypersensitivity reaction. In the early phase, ie, within minutes of allergen exposure, previously sensitized mast cells are exposed to an allergen, causing degranulation and release of inflammatory mediators, primarily histamine. The late phase, ie, 6 to 10 hours after the initial exposure, involves an influx of inflammatory cells such as eosinophils, basophils, and neutrophils.³

Differential diagnosis

For most patients, basic eye care measures are sufficient

The differential diagnosis of allergic conjunctivitis includes infectious conjunctivitis, chronic dry eye, preservative toxicity, giant papillary conjunctivitis, atopic keratoconjunctivitis, and vernal keratoconjunctivitis.³ Giant papillary conjunctivitis is an inflammatory reaction to a foreign substance, such as a contact lens. Atopic keratoconjunctivitis and vernal keratoconjunctivitis can be vision-threatening and require referral to an ophthalmologist. Atopic keratoconjunctivitis is associated with eczematous lesions of the lids and skin, and vernal keratoconjunctivitis involves chronic inflammation of the palpebral conjunctivae. Warning signs include photophobia, pain, abnormal findings on pupillary examination, blurred vision (unrelated to excessively watery eyes), unilateral eye complaints, and ciliary flush.²

Bacterial conjunctivitis is highly contagious and usually presents with hyperemia, “stuck eye” upon awakening, and thick, purulent discharge. It is usually unilateral. Symptoms include burning, foreign-body sensation, and discomfort rather than pruritus. Patients with allergic conjunctivitis may have concomitant bacterial conjunctivitis and so require a topical antibiotic as well as treatment for allergic conjunctivitis.

Viral conjunctivitis usually affects one eye, is self-limited, and typically presents with other symptoms of a viral syndrome.

MANAGEMENT OPTIONS

Management of allergic conjunctivitis consists of basic eye care, avoidance of allergy triggers, and over-the-counter and prescription topical and systemic therapies, as well as allergen immunotherapy.³

Avoidance

Triggers for the allergic reaction, such as pollen, can be identified with aeroallergen skin testing by an allergist. But simple avoidance measures are helpful, such as closing windows, using air conditioning, limiting exposure to the outdoors when pollen counts are high, wearing sunglasses, showering before bedtime, avoiding exposure to animal dander, and using zippered casings for bedding to minimize exposure to dust mites.³

Patients who wear contact lenses should reduce or discontinue their use, as allergens adhere to contact lens surfaces.

Topical therapies

If avoidance is not feasible or if symptoms persist despite avoidance measures, patients should be started on eyedrops.

Eyedrops for allergic conjunctivitis are classified by mechanism of action: topical anti­histamines, mast-cell stabilizers, and combination preparations of antihistamine and mast-cell stabilizer (Table 1). Algorithms for managing allergic conjunctivitis exist² but are based on expert consensus, since there are no randomized clinical trials with head-to-head comparisons of topical agents for allergic conjunctivitis.

In our practice, we use a three-step approach to treat allergic conjunctivitis (Table 2). Combination antihistamine and mast-cell stabilizer eyedrops are the first line, used as needed, daily, seasonally, or year-round, based on the patient’s symptoms and allergen profile. Antihistamine or combination eyedrops are preferred as they have a faster onset of action than mast-cell stabilizers alone,³ which have an onset of action of 3 to 5 days. The combination drops provide an effect on the late-phase response and a longer duration of action. 

Currently, the only over-the-counter eyedrops for allergic conjunctivitis are cromolyn (a mast-cell stabilizer) and ketotifen 0.025% (a combination antihistamine and mast-cell stabilizer). Most drops for allergic conjunctivitis are taken two to four times a day. Two once-daily eyedrop formulations for allergic conjunctivitis—available only by prescription—are olopatadine 0.2% and alcaftadine. However, these are very expensive (Table 1) and so may not be an appropriate choice for some patients. On the other hand, a study from the United Kingdom⁴ found that patients using olopatadine made fewer visits to their general practitioner than patients using cromolyn, resulting in lower overall cost of healthcare. Results of studies of patient preferences and efficacy of olopatadine 0.1% (twice-daily preparation) vs ketotifen 0.025% are mixed,^5–8 and no study has compared olopatadine 0.2% (once-daily preparation) with over-the-counter ketotifen.

Adverse effects of eyedrops

Common adverse effects include stinging and burning immediately after use; this effect may be reduced by keeping the eyedrops in the refrigerator. Patients who wear contact lenses should remove them before using eyedrops for allergic conjunctivitis, and wait at least 10 minutes to replace them if the eye is no longer red.² Antihistamine drops are contraindicated in patients at risk for angle-closure glaucoma.

Whenever possible, patients with seasonal allergic conjunctivitis should begin treatment 2 to 4 weeks before the relevant pollen season, as guided by the patient’s experience in past seasons or by the results of aeroallergen skin testing. This modifies the “priming” effect, in which the amount of allergen required to induce an immediate allergic response decreases with repeated exposure to the allergen.

OTHER TREATMENT OPTIONS

Vasoconstrictor or decongestant eyedrops are indicated to relieve eye redness but have little or no effect on pruritus, and prolonged use may lead to rebound hyperemia. Thus, they are not generally recommended for long-term treatment of allergic conjunctivitis.³ Also, patients with glaucoma should be advised against long-term use of over-the-counter vasoconstrictor eyedrops.

Corticosteroid eyedrops are reserved for refractory and severe cases. Their use requires close follow-up with an ophthalmologist to monitor for complications such as increased intraocular pressure, infection, and cataracts.²

Patients presenting with an acute severe episode of allergic conjunctivitis that has not responded to oral antihistamines or combination eyedrops may be treated with a short course of an oral corticosteroid, if the benefit outweighs the risk in that patient.

Oral antihistamines are generally less effective than topical ophthalmic agents in relieving ocular allergy symptoms and have a slower onset of action.² They are useful in patients who have an aversion to instilling eyedrops on a regular basis or who wear contact lenses.

For patients who have associated allergic rhinitis—ie, most patients with allergic conjunctivitis—intranasal corticosteroids and intranasal antihistamines are the most effective treatments for rhinitis and are also effective for allergic conjunctivitis. Monotherapy with an intranasal medication may provide sufficient relief of conjunctivitis symptoms or allow ocular medications to be used on a less frequent basis.

Allergen immunotherapy

Referral to an allergist for consideration of allergen immunotherapy is an option when avoidance measures are ineffective or unfeasible, when first-line treatments are ineffective, and when the patient does not wish to use medications.

Tailor treatment to symptoms, allergen profile, and patient preferences

Allergen immunotherapy is the only disease-modifying therapy available for allergic conjunctivitis. Two forms are available: traditional subcutaneous immunotherapy, and sublingual tablet immunotherapy, recently approved by the US Food and Drug Administration.⁹ Subcutaneous immunotherapy targets specific aeroallergens for patients allergic to multiple allergens. The new sublingual immunotherapy tablets target only grass pollen and ragweed pollen.⁹ Most patients in the United States are polysensitized.¹⁰ Both forms of immunotherapy can result in sustained effectiveness following discontinuation. Sub­lingual therapy may be administered year-round, before allergy season, or during allergy season (depending on the type of allergy).

TAILORING TREATMENT

We recommend a case-by-case approach to the management of patients with allergic conjunctivitis, tailoring treatment to the patient’s symptoms, allergen profile, and personal preferences.

For example, if adherence is a challenge we recommend a once-daily combination eyedrop (olopatadine 0.2%, or alcaftadine). If cost is a barrier, we recommend the combination over-the-counter drop (ketotifen).

Medications may be used during allergy season or year-round depending on the patient’s symptom and allergen profile. Patients whose symptoms are not relieved with these measures should be referred to an allergist for further evaluation and management, or to an ophthalmologist to monitor for complications of topical steroid use and other warning signs, as discussed earlier, or to weigh in on the differential diagnosis.

No, not all patients with allergic conjunctivitis need prescription eyedrops.

For mild symptoms, basic nonpharmacologic eye care often suffices. Advise the patient to avoid rubbing the eyes, to use artificial tears as needed, to apply cold compresses, to limit or temporarily discontinue contact lens wear, and to avoid exposure to known allergens.

Topical therapy with an over-the-counter eyedrop that combines an antihistamine and a mast cell stabilizer is another first-line measure.

Prescription eyedrops are usually reserved for patients who have persistent bothersome symptoms despite use of over-the-counter eyedrops. Also, some patients have difficulty with the regimens for over-the-counter eyedrops, since most must be applied two to four times per day. In addition, patients with concomitant allergic rhinitis may benefit from an intranasal corticosteroid.

ALLERGIC CONJUNCTIVITIS: A BRIEF OVERVIEW

Allergic conjunctivitis, caused by exposure of the eye to airborne allergens, affects up to 40% of the US population, predominantly young adults.¹ Bilateral pruritus is the chief symptom. The absence of pruritus should prompt consideration of a more serious eye condition.

Other common symptoms of allergic conjunctivitis include redness, tearing (a clear, watery discharge), eyelid edema, burning, and mild photophobia. Some patients may have infraorbital edema and darkening around the eye, dubbed an “allergic shiner.”¹

Allergic conjunctivitis can be acute, with sudden onset of symptoms upon exposure to an isolated allergen. It can be seasonal, from exposure to pollen and with a more gradual onset. It can also be perennial, from year-round exposure to indoor allergens such as animal dander, dust mites, and mold.

Allergic conjunctivitis often occurs together with allergic rhinitis, which is also caused by exposure to aeroallergens and is characterized by nasal congestion, pruritus, rhinorrhea (anterior and posterior), and sneezing.²

Pollen is more commonly associated with rhinoconjunctivitis, whereas dust mite allergy is more likely to cause rhinitis alone.

An immunoglobulin E-mediated reaction

Allergic conjunctivitis is a type I immunoglobulin E-mediated immediate hypersensitivity reaction. In the early phase, ie, within minutes of allergen exposure, previously sensitized mast cells are exposed to an allergen, causing degranulation and release of inflammatory mediators, primarily histamine. The late phase, ie, 6 to 10 hours after the initial exposure, involves an influx of inflammatory cells such as eosinophils, basophils, and neutrophils.³

Differential diagnosis

For most patients, basic eye care measures are sufficient

The differential diagnosis of allergic conjunctivitis includes infectious conjunctivitis, chronic dry eye, preservative toxicity, giant papillary conjunctivitis, atopic keratoconjunctivitis, and vernal keratoconjunctivitis.³ Giant papillary conjunctivitis is an inflammatory reaction to a foreign substance, such as a contact lens. Atopic keratoconjunctivitis and vernal keratoconjunctivitis can be vision-threatening and require referral to an ophthalmologist. Atopic keratoconjunctivitis is associated with eczematous lesions of the lids and skin, and vernal keratoconjunctivitis involves chronic inflammation of the palpebral conjunctivae. Warning signs include photophobia, pain, abnormal findings on pupillary examination, blurred vision (unrelated to excessively watery eyes), unilateral eye complaints, and ciliary flush.²

Bacterial conjunctivitis is highly contagious and usually presents with hyperemia, “stuck eye” upon awakening, and thick, purulent discharge. It is usually unilateral. Symptoms include burning, foreign-body sensation, and discomfort rather than pruritus. Patients with allergic conjunctivitis may have concomitant bacterial conjunctivitis and so require a topical antibiotic as well as treatment for allergic conjunctivitis.

Viral conjunctivitis usually affects one eye, is self-limited, and typically presents with other symptoms of a viral syndrome.

MANAGEMENT OPTIONS

Management of allergic conjunctivitis consists of basic eye care, avoidance of allergy triggers, and over-the-counter and prescription topical and systemic therapies, as well as allergen immunotherapy.³

Avoidance

Triggers for the allergic reaction, such as pollen, can be identified with aeroallergen skin testing by an allergist. But simple avoidance measures are helpful, such as closing windows, using air conditioning, limiting exposure to the outdoors when pollen counts are high, wearing sunglasses, showering before bedtime, avoiding exposure to animal dander, and using zippered casings for bedding to minimize exposure to dust mites.³

Patients who wear contact lenses should reduce or discontinue their use, as allergens adhere to contact lens surfaces.

Topical therapies

If avoidance is not feasible or if symptoms persist despite avoidance measures, patients should be started on eyedrops.

Eyedrops for allergic conjunctivitis are classified by mechanism of action: topical anti­histamines, mast-cell stabilizers, and combination preparations of antihistamine and mast-cell stabilizer (Table 1). Algorithms for managing allergic conjunctivitis exist² but are based on expert consensus, since there are no randomized clinical trials with head-to-head comparisons of topical agents for allergic conjunctivitis.

In our practice, we use a three-step approach to treat allergic conjunctivitis (Table 2). Combination antihistamine and mast-cell stabilizer eyedrops are the first line, used as needed, daily, seasonally, or year-round, based on the patient’s symptoms and allergen profile. Antihistamine or combination eyedrops are preferred as they have a faster onset of action than mast-cell stabilizers alone,³ which have an onset of action of 3 to 5 days. The combination drops provide an effect on the late-phase response and a longer duration of action. 

Currently, the only over-the-counter eyedrops for allergic conjunctivitis are cromolyn (a mast-cell stabilizer) and ketotifen 0.025% (a combination antihistamine and mast-cell stabilizer). Most drops for allergic conjunctivitis are taken two to four times a day. Two once-daily eyedrop formulations for allergic conjunctivitis—available only by prescription—are olopatadine 0.2% and alcaftadine. However, these are very expensive (Table 1) and so may not be an appropriate choice for some patients. On the other hand, a study from the United Kingdom⁴ found that patients using olopatadine made fewer visits to their general practitioner than patients using cromolyn, resulting in lower overall cost of healthcare. Results of studies of patient preferences and efficacy of olopatadine 0.1% (twice-daily preparation) vs ketotifen 0.025% are mixed,^5–8 and no study has compared olopatadine 0.2% (once-daily preparation) with over-the-counter ketotifen.

Adverse effects of eyedrops

Common adverse effects include stinging and burning immediately after use; this effect may be reduced by keeping the eyedrops in the refrigerator. Patients who wear contact lenses should remove them before using eyedrops for allergic conjunctivitis, and wait at least 10 minutes to replace them if the eye is no longer red.² Antihistamine drops are contraindicated in patients at risk for angle-closure glaucoma.

Whenever possible, patients with seasonal allergic conjunctivitis should begin treatment 2 to 4 weeks before the relevant pollen season, as guided by the patient’s experience in past seasons or by the results of aeroallergen skin testing. This modifies the “priming” effect, in which the amount of allergen required to induce an immediate allergic response decreases with repeated exposure to the allergen.

OTHER TREATMENT OPTIONS

Vasoconstrictor or decongestant eyedrops are indicated to relieve eye redness but have little or no effect on pruritus, and prolonged use may lead to rebound hyperemia. Thus, they are not generally recommended for long-term treatment of allergic conjunctivitis.³ Also, patients with glaucoma should be advised against long-term use of over-the-counter vasoconstrictor eyedrops.

Corticosteroid eyedrops are reserved for refractory and severe cases. Their use requires close follow-up with an ophthalmologist to monitor for complications such as increased intraocular pressure, infection, and cataracts.²

Patients presenting with an acute severe episode of allergic conjunctivitis that has not responded to oral antihistamines or combination eyedrops may be treated with a short course of an oral corticosteroid, if the benefit outweighs the risk in that patient.

Oral antihistamines are generally less effective than topical ophthalmic agents in relieving ocular allergy symptoms and have a slower onset of action.² They are useful in patients who have an aversion to instilling eyedrops on a regular basis or who wear contact lenses.

For patients who have associated allergic rhinitis—ie, most patients with allergic conjunctivitis—intranasal corticosteroids and intranasal antihistamines are the most effective treatments for rhinitis and are also effective for allergic conjunctivitis. Monotherapy with an intranasal medication may provide sufficient relief of conjunctivitis symptoms or allow ocular medications to be used on a less frequent basis.

Allergen immunotherapy

Referral to an allergist for consideration of allergen immunotherapy is an option when avoidance measures are ineffective or unfeasible, when first-line treatments are ineffective, and when the patient does not wish to use medications.

Tailor treatment to symptoms, allergen profile, and patient preferences

Allergen immunotherapy is the only disease-modifying therapy available for allergic conjunctivitis. Two forms are available: traditional subcutaneous immunotherapy, and sublingual tablet immunotherapy, recently approved by the US Food and Drug Administration.⁹ Subcutaneous immunotherapy targets specific aeroallergens for patients allergic to multiple allergens. The new sublingual immunotherapy tablets target only grass pollen and ragweed pollen.⁹ Most patients in the United States are polysensitized.¹⁰ Both forms of immunotherapy can result in sustained effectiveness following discontinuation. Sub­lingual therapy may be administered year-round, before allergy season, or during allergy season (depending on the type of allergy).

TAILORING TREATMENT

We recommend a case-by-case approach to the management of patients with allergic conjunctivitis, tailoring treatment to the patient’s symptoms, allergen profile, and personal preferences.

For example, if adherence is a challenge we recommend a once-daily combination eyedrop (olopatadine 0.2%, or alcaftadine). If cost is a barrier, we recommend the combination over-the-counter drop (ketotifen).

Medications may be used during allergy season or year-round depending on the patient’s symptom and allergen profile. Patients whose symptoms are not relieved with these measures should be referred to an allergist for further evaluation and management, or to an ophthalmologist to monitor for complications of topical steroid use and other warning signs, as discussed earlier, or to weigh in on the differential diagnosis.

A 75-year-old woman with a history of hypertension and left-lung lobectomy for a carcinoid tumor 10 years ago presented with a 2-week history of progressive cough, dyspnea, and fatigue. Her heart rate was 159 beats per minute with an irregularly irregular rhythm, and her respiratory rate was 36 breaths per minute. Her blood pressure was 140/90 mm Hg. Examination revealed decreased breath sounds and dullness on percussion at the left lung base, jugular venous distention with a positive hepatojugular reflux sign, and an enlarged liver. Electrocardiography showed atrial fibrillation. Chest radiography (Figure 1) revealed enlargement of the cardiac silhouette, with a disproportionately increased transverse diameter, and an obscured left costophrenic angle. A radiograph taken 13 months earlier (Figure 1) had shown a normal cardiothoracic ratio.

EVALUATION OF PERICARDIAL EFFUSION

Pericardial effusion should be suspected in patients presenting with symptoms of impaired cardiac function such as fatigue, dyspnea, nausea, palpitations, lightheadedness, cough, and hoarseness. Patients may also present with chest pain, often decreased by sitting up and leaning forward and exacerbated by lying supine.

Physical examination may reveal distant heart sounds, an absent or displaced apical impulse, dullness and increased fremitus beneath the angle of the left scapula (the Ewart sign), pulsus paradoxus, and nonspecific findings such as tachycardia and hypotension. Jugular venous distention, hepatojugular reflux, and peripheral edema suggest impaired cardiac function.

A chest radiograph showing unexplained new symmetric cardiomegaly (which is often globe-shaped) without signs of pulmonary congestion¹ or with a left dominant pleural effusion is an indicator of pericardial effusion, as in our patient. Pericardial fluid may be seen outlining the heart between the epicardial and mediastinal fat, posterior to the sternum in a lateral view.

Other common causes of cardiomegaly include hypertension, congestive heart failure, valvular disease, cardiomyopathy, ischemic heart disease, and pulmonary disease.

Once pericardial effusion is suspected, the next step is to confirm its presence and determine its hemodynamic significance. Transthoracic echocardiography is the imaging test of choice to confirm effusion, as it can be done rapidly and in unstable patients.²

If transthoracic echocardiography is non­diagnostic but suspicion is high, further evaluation may include transesophageal echocardiography,³ computed tomography, or magnetic resonance imaging.

MAKING THE DIAGNOSIS

Pericardial effusion can occur as part of various diseases involving the pericardium, eg, acute pericarditis, myocarditis, autoimmune disease, postmyocardial infarction, malignancy, aortic dissection, and chest trauma. It can also be associated with certain drugs.

In our patient, echocardiography (Figure 2, Figure 3) demonstrated a large amount of pericardial fluid, and 820 mL of red fluid was aspirated by pericardiocentesis, resulting in relief of her respiratory symptoms. Subcostal two-dimensional echocardiography demonstrated rocking of the heart and intermittent right-ventricular collapse (watch video at www.ccjm.org). Flow cytometry demonstrated 10% kappa+ monoclonal cells. Bone marrow biopsy with immunohistochemical staining revealed infiltration by CD20+, CD5+, CD23+, and BCL1– cells, compatible with small lymphocytic lymphoma.

MALIGNANT PERICARDIAL EFFUSION

Pericardial disease can be the first manifestation of malignancy,⁴ more often when the patient presents with a large pericardial effusion or tamponade. Malignant tumors of the lung, breast, and esophagus—as well as lymphoma, leukemia, and melanoma—often spread to the pericardium directly or through the lymphatic vessels or bloodstream.⁴ In our patient, corticosteroid treatment was initiated, and echocardiography at a follow-up visit 2 months later showed no pericardial fluid.

A 75-year-old woman with a history of hypertension and left-lung lobectomy for a carcinoid tumor 10 years ago presented with a 2-week history of progressive cough, dyspnea, and fatigue. Her heart rate was 159 beats per minute with an irregularly irregular rhythm, and her respiratory rate was 36 breaths per minute. Her blood pressure was 140/90 mm Hg. Examination revealed decreased breath sounds and dullness on percussion at the left lung base, jugular venous distention with a positive hepatojugular reflux sign, and an enlarged liver. Electrocardiography showed atrial fibrillation. Chest radiography (Figure 1) revealed enlargement of the cardiac silhouette, with a disproportionately increased transverse diameter, and an obscured left costophrenic angle. A radiograph taken 13 months earlier (Figure 1) had shown a normal cardiothoracic ratio.

EVALUATION OF PERICARDIAL EFFUSION

Pericardial effusion should be suspected in patients presenting with symptoms of impaired cardiac function such as fatigue, dyspnea, nausea, palpitations, lightheadedness, cough, and hoarseness. Patients may also present with chest pain, often decreased by sitting up and leaning forward and exacerbated by lying supine.

Physical examination may reveal distant heart sounds, an absent or displaced apical impulse, dullness and increased fremitus beneath the angle of the left scapula (the Ewart sign), pulsus paradoxus, and nonspecific findings such as tachycardia and hypotension. Jugular venous distention, hepatojugular reflux, and peripheral edema suggest impaired cardiac function.

A chest radiograph showing unexplained new symmetric cardiomegaly (which is often globe-shaped) without signs of pulmonary congestion¹ or with a left dominant pleural effusion is an indicator of pericardial effusion, as in our patient. Pericardial fluid may be seen outlining the heart between the epicardial and mediastinal fat, posterior to the sternum in a lateral view.

Other common causes of cardiomegaly include hypertension, congestive heart failure, valvular disease, cardiomyopathy, ischemic heart disease, and pulmonary disease.

Once pericardial effusion is suspected, the next step is to confirm its presence and determine its hemodynamic significance. Transthoracic echocardiography is the imaging test of choice to confirm effusion, as it can be done rapidly and in unstable patients.²

If transthoracic echocardiography is non­diagnostic but suspicion is high, further evaluation may include transesophageal echocardiography,³ computed tomography, or magnetic resonance imaging.

MAKING THE DIAGNOSIS

Pericardial effusion can occur as part of various diseases involving the pericardium, eg, acute pericarditis, myocarditis, autoimmune disease, postmyocardial infarction, malignancy, aortic dissection, and chest trauma. It can also be associated with certain drugs.

In our patient, echocardiography (Figure 2, Figure 3) demonstrated a large amount of pericardial fluid, and 820 mL of red fluid was aspirated by pericardiocentesis, resulting in relief of her respiratory symptoms. Subcostal two-dimensional echocardiography demonstrated rocking of the heart and intermittent right-ventricular collapse (watch video at www.ccjm.org). Flow cytometry demonstrated 10% kappa+ monoclonal cells. Bone marrow biopsy with immunohistochemical staining revealed infiltration by CD20+, CD5+, CD23+, and BCL1– cells, compatible with small lymphocytic lymphoma.

MALIGNANT PERICARDIAL EFFUSION

Pericardial disease can be the first manifestation of malignancy,⁴ more often when the patient presents with a large pericardial effusion or tamponade. Malignant tumors of the lung, breast, and esophagus—as well as lymphoma, leukemia, and melanoma—often spread to the pericardium directly or through the lymphatic vessels or bloodstream.⁴ In our patient, corticosteroid treatment was initiated, and echocardiography at a follow-up visit 2 months later showed no pericardial fluid.

A 75-year-old woman with a history of hypertension and left-lung lobectomy for a carcinoid tumor 10 years ago presented with a 2-week history of progressive cough, dyspnea, and fatigue. Her heart rate was 159 beats per minute with an irregularly irregular rhythm, and her respiratory rate was 36 breaths per minute. Her blood pressure was 140/90 mm Hg. Examination revealed decreased breath sounds and dullness on percussion at the left lung base, jugular venous distention with a positive hepatojugular reflux sign, and an enlarged liver. Electrocardiography showed atrial fibrillation. Chest radiography (Figure 1) revealed enlargement of the cardiac silhouette, with a disproportionately increased transverse diameter, and an obscured left costophrenic angle. A radiograph taken 13 months earlier (Figure 1) had shown a normal cardiothoracic ratio.

EVALUATION OF PERICARDIAL EFFUSION

Pericardial effusion should be suspected in patients presenting with symptoms of impaired cardiac function such as fatigue, dyspnea, nausea, palpitations, lightheadedness, cough, and hoarseness. Patients may also present with chest pain, often decreased by sitting up and leaning forward and exacerbated by lying supine.

Physical examination may reveal distant heart sounds, an absent or displaced apical impulse, dullness and increased fremitus beneath the angle of the left scapula (the Ewart sign), pulsus paradoxus, and nonspecific findings such as tachycardia and hypotension. Jugular venous distention, hepatojugular reflux, and peripheral edema suggest impaired cardiac function.

A chest radiograph showing unexplained new symmetric cardiomegaly (which is often globe-shaped) without signs of pulmonary congestion¹ or with a left dominant pleural effusion is an indicator of pericardial effusion, as in our patient. Pericardial fluid may be seen outlining the heart between the epicardial and mediastinal fat, posterior to the sternum in a lateral view.

Other common causes of cardiomegaly include hypertension, congestive heart failure, valvular disease, cardiomyopathy, ischemic heart disease, and pulmonary disease.

Once pericardial effusion is suspected, the next step is to confirm its presence and determine its hemodynamic significance. Transthoracic echocardiography is the imaging test of choice to confirm effusion, as it can be done rapidly and in unstable patients.²

If transthoracic echocardiography is non­diagnostic but suspicion is high, further evaluation may include transesophageal echocardiography,³ computed tomography, or magnetic resonance imaging.

MAKING THE DIAGNOSIS

Pericardial effusion can occur as part of various diseases involving the pericardium, eg, acute pericarditis, myocarditis, autoimmune disease, postmyocardial infarction, malignancy, aortic dissection, and chest trauma. It can also be associated with certain drugs.

In our patient, echocardiography (Figure 2, Figure 3) demonstrated a large amount of pericardial fluid, and 820 mL of red fluid was aspirated by pericardiocentesis, resulting in relief of her respiratory symptoms. Subcostal two-dimensional echocardiography demonstrated rocking of the heart and intermittent right-ventricular collapse (watch video at www.ccjm.org). Flow cytometry demonstrated 10% kappa+ monoclonal cells. Bone marrow biopsy with immunohistochemical staining revealed infiltration by CD20+, CD5+, CD23+, and BCL1– cells, compatible with small lymphocytic lymphoma.

MALIGNANT PERICARDIAL EFFUSION

Pericardial disease can be the first manifestation of malignancy,⁴ more often when the patient presents with a large pericardial effusion or tamponade. Malignant tumors of the lung, breast, and esophagus—as well as lymphoma, leukemia, and melanoma—often spread to the pericardium directly or through the lymphatic vessels or bloodstream.⁴ In our patient, corticosteroid treatment was initiated, and echocardiography at a follow-up visit 2 months later showed no pericardial fluid.

A 39-year-old man presented with acute left hip pain and inability to bear weight following a minor trauma. The patient had a history of polycystic kidney disease and was on dialysis. Five years ago he had undergone bilateral nephrectomy and a renal transplantation that subsequently failed.

On examination, the active and passive range of motion of the left hip were limited due to pain. His serum laboratory values were:

• Parathyroid hormone 259.7 pmol/L (reference range 1.5–9.3)
• Calcium 2.32 mmol/L (1.15–1.32)
• Phosphate 3.26 mmol/L (0.8–1.45).

Computed tomography of the pelvis revealed an exophytic calcified lesion with multiple cystic spaces and fluid-fluid levels centered on the left pubis, extending medially into the right pubis and laterally into the left adductor muscle group. An acute pathologic fracture was documented in the left inferior pubic ramus (Figure 1). Other radiographic signs of long-standing hyperparathyroidism were present, including subperiosteal bone resorption at the radial side of the middle phalanges and the clavicle epiphysis.

The differential diagnosis of the pelvic lesion included giant cell tumor of bone with aneurysmal bone-cyst-like changes, osteitis fibrosa cystica, and, less likely, metastatic bone disease. Biopsy of the lesion showed clusters of osteoclast-type giant cells on a background of spindle cells and fibrous stroma that in this clinical context was consistent with the diagnosis of brown tumor (Figure 2).¹

BROWN TUMOR

Brown tumor has been reported in fewer than 2% of patients with primary hyperparathyroidism and in 1.5% to 1.7% of those with secondary hyperparathyroidism (ie, from chronic renal failure, malabsorption, vitamin D deficiency, or hypocalcemia).^2–4 An excess of parathyroid hormone increases the number and activity of osteoclasts, which are responsible for the lytic lesions. Brown tumor is the localized form of osteitis fibrosa cystica and is the most characteristic of the many skeletal changes that accompany secondary hyperparathyroidism.

Brown tumor is named for its color, which results from hemorrhages with accumulation of hemosiderin within the vascularized fibrous tissue. The tumor most commonly affects the pelvis, ribs, long-bone shafts, clavicle, and mandible.⁵ Clinical symptoms are nonspecific and depend on the size and location of the lesion.

Medical management of secondary hyperparathyroidism in dialysis patients involves some combination of phosphate binders (either calcium-containing or non-calcium-containing binders), calcitriol or synthetic vitamin D analogs, and a calcimimetic. Parathyroidectomy is required if drug therapy is ineffective. Surgical excision of brown tumor should be considered in patients who have large bone defects with spontaneous fracture risk or increasing pain. Our patient declined surgical intervention.