Emergency Medicine

A 5-day-old infant was referred to the pediatric orthopedic clinic for evaluation of a left hip “clunk.” She is a firstborn child, born at full term (39 weeks) via cesarean delivery secondary to breech presentation. Her weight at birth was 7 lb 6 oz. The infant was noted to have a left hip clunk during a routine physical examination by her pediatrician, who made a referral to the pediatric orthopedic clinic for possible hip dysplasia. This is the patient’s first visit to the clinic.

There is no family history of hip dysplasia or other orthopedic abnormalities. The infant is a well-appearing, alert female measuring 20.5” in length and weighing 7 lb 4 oz. Vital signs are stable with no abnormality detected. The heart is regular in rate and rhythm, and the chest is clear bilaterally.

No cutaneous abnormalities are noted. The patient is able to move all her extremities spontaneously, and her spine is straight and normal with no evidence of spinal dysraphism. Her feet are normal bilaterally, with full range of motion and no equinovarus or metatarsus adductus deformity.

The neurologic examination is also unremarkable, with normal neonatal reflexes and excellent muscle tone throughout. 

Examination of the infant’s hips reveals a positive result on the Barlow test on the left side (the hip can be dislocated). There is also a positive Ortolani sign (the hip can be reduced), with asymmetric thigh skin folds noted (see Figures 1A and 1B, respectively).

Based on these positive physical examination findings, the patient was diagnosed with developmental dysplasia of the hip (DDH). Initial ultrasonography to confirm the diagnosis was not considered necessary, as the physical examination demonstrated obvious instability.1 The infant was placed in a Pavlik harness, which her parents were instructed should be worn full-time (see Figures 2A and 2B). She was scheduled for weekly follow-up visits for adjustments to the harness and serial hip examinations.

At the second follow-up visit, ultrasonography was performed, confirming the presence of dysplasia with decreased femoral head coverage and a steep socket (acetabulum). Use of the Pavlik harness was continued full-time for six weeks.

At age 6 weeks, the infant underwent a follow-up ultrasound to assess for improvement in the degree of dysplasia. The test revealed normal hips bilaterally with no evidence of DDH. Therefore, use of the Pavlik harness was discontinued. The parents were instructed to bring the child back in six months for a repeat clinical examination and an anteroposterior x-ray of the pelvis.¹

Discussion
The term developmental dysplasia of the hip (DDH) has replaced the more traditional term congenital hip dislocation because DDH more accurately reflects the variable characteristics that can be seen with this condition. As DDH may not be present at birth, the term congenital is misleading. We now know that DDH may occur in utero, perinatally, or during infancy and childhood.^2,3

Generally, DDH is used to describe an abnormal relationship between the femoral head and the acetabulum (see Figure 3⁴). The term represents a wide spectrum of abnormality, as shown in the Graf classification of hips in infants: type I refers to a normal hip; type II, immature development to mild dysplasia; type III, subluxation of the femoral head; and type 4, frank dislocation with severe instability.⁵

Diagnosing and managing DDH correctly requires the clinician to have a thorough understanding of the normal growth and development that occurs in the hip joint. Embryologically, the joint (including the femoral head and acetabulum) develops from the same primitive mesenchymal cells.⁶ By 11 to 12 weeks’ gestation, the initial structures of the hip joint are fully formed; theoretically, this is the earliest time at which a dislocation can occur.^2,7 DDH that develops at this stage would be called teratologic; this condition is seen most frequently in patients who have underlying neuromuscular conditions, such as myelodysplasia (spina bifida) or arthrogryposis. A typical dislocation takes place during the perinatal period in an infant who is otherwise healthy.²

Etiology
DDH occurs in about 11 of every 1,000 infants, with frank dislocations occurring in one to two infants per 10,000.⁸ The left hip is involved in approximately 60% of cases, the right in 20%, and both hips in about 20%. In the most common intrauterine fetal position, the left hip is lower than the right (usually abutting the mother’s sacrum) and is often in adduction. This is likely the reason that the left hip is more commonly affected by DDH.

DDH is believed to be multifactorial, with physiologic, genetic, and mechanical factors implicated in the etiology.³ The incidence of DDH varies with factors such as the patient’s age, race, and gender, the experience and training of the examiner, and the diagnostic criteria that are used.

Known risk factors for a positive newborn screening are shown in the table.^9,10 It is often helpful for clinicians to remember the “4F” mnemonic associated with DDH: female, firstborn, foot first, and family history.⁹

There is also an increased risk for DDH in patients with other conditions that are associated with intrauterine crowding. These include congenital muscular torticollis, metatarsus adductus, and congenital dislocation of the knee.²

Physical Examination
All newborn infants should be screened for DDH as part of the initial physical examination, with ultrasonography recommended for infants deemed at high risk for DDH and for those with inconclusive results on examination.^1,10,11 Providers should be aware that the newborn hip examination requires a considerable amount of practice and expertise.

A thorough medical history should always be obtained first, including gestational age, presentation (breech vs vertex), type of delivery (cesarean vs vaginal), gender, birth order, family history of DDH, ligamentous laxity, or myopathy.⁸

The examining clinician begins by placing the infant on a firm, flat surface. The infant should be as relaxed as possible. Next, the clinician observes both lower extremities for asymmetric thigh or buttock skin folds. Bilateral DDH can be very difficult to diagnose on the basis of this examination due to the lack of asymmetry (hips will have symmetric abnormality).

The Galeazzi sign is elicited by placing the infant supine with the hips and knees flexed to 90°.¹² With the hips in neutral abduction, the provider should determine whether the knees are at the same height. Unequal knee heights—a positive result for the Galeazzi sign—suggest femoral shortening (apparent leg length discrepancy), which may be explained by a hip dislocation. If both hips are dislocated, a false-negative result will often occur, since both will appear short and there will be no discrepancy.^2,12

Among physical examination techniques, the Ortolani and Barlow maneuvers are considered most reliable to detect hip instability in newborns and infants younger than 6 months^2,13,14 (review Figures 1A and 1B). The Ortolani test is used to detect the sensation of the dislocated hip reducing into the acetabulum, and the Barlow test elicits the unstable hip dislocating.² A palpable and occasionally audible clunk is considered a positive result on the Barlow test and usually indicates a diagnosis of DDH.¹⁴ High-pitched clicks or snaps frequently occur with hip range-of-motion maneuvers and during Ortolani and Barlow testing. These sounds are often attributed to snapping of the iliotibial band over the greater trochanter and do not usually signify dysplasia.¹⁵

Because DDH is a dynamic and evolving process, the physical findings on clinical examination change significantly, depending on the age of the infant or child. As an infant approaches age 3 months, limited hip abduction (especially when asymmetric) is often the most reliable physical examination finding in patients with DDH.¹² After age 3 to 4 months, Ortolani and Barlow testing will often produce negative results as progressive soft tissue contractures evolve.

Once a child begins to walk, gait abnormalities (eg, a short-limbed or waddling gait pattern) may raise suspicion for a diagnosis of DDH.⁷ It has been recommended that evaluation for DDH be performed at each routine office examination until the child is 12 months of age.¹

Treatment
The Pavlik harness is considered first-line treatment for DDH in infants younger than 6 months. The harness is a dynamic splint that allows the infant to engage in a sphere of active motion that encourages stabilization and deepening of the socket. The harness is applied with the knees flexed to about 90° and the hips in about 70° of abduction and 100° to 110° of flexion (as shown in Figures 2A and 2B).⁹

The duration of treatment depends on the infant’s age at presentation and the severity of DDH. Progress is judged by serial examinations and dynamic ultrasounds. The harness is worn full-time until clinical and radiographic examinations both yield normal results. After six weeks of treatment, the hips are examined out of the harness, and a repeat ultrasound is usually obtained. If findings are normal, use of the harness is ordinarily discontinued. Some patients will require harness use for a longer period in cases of delayed development of the acetabulum and/or severe laxity of the ligaments.⁹

The Pavlik harness is successful more than 90% of the time in newborns with DDH.⁸ Success rates have been reported as greatest in infants younger than 8 weeks at the time of treatment initiation, those with only one affected hip, and those with less severe disease (Graf types II or III).¹⁶

If ultrasonography shows no improvement after two to three weeks, it is usually recommended that the harness be discontinued; most orthopedic surgeons will then proceed with a closed or open reduction and spica body casting. Similarly, when the diagnosis of DDH is delayed until after ages 6 to 8 months, a closed reduction under anesthesia and placement of a spica body cast is usually the recommended treatment to maintain the hip in the reduced position.^17,18 Some older children (ages 1 to 5 years) may require bracing, traction, open reduction, and/or femoral or pelvic osteotomy.^17,18 It is believed that undiagnosed, untreated DDH can lead to early-onset degenerative hip disease (arthritis).¹

Patient/Family Education
The Pavlik harness is most effective when a consistent support system exists to educate parents about the importance of the harness, its care and maintenance, and the consequences of failure. Close monitoring of the infant’s progress is also essential to promoting adherence. Application and removal of the harness should be demonstrated to the parent or caregiver, as well as diapering, dressing, and undressing the infant; they should then be encouraged to practice immediately in the clinic or office.

During visits for harness adjustment, the strap position should be marked with indelible ink, allowing parents to reapply the device correctly, should removal be required (eg, for bathing).⁹ Ten percent of parents reportedly find reapplying the harness difficult during the first weeks of use. Difficulty in dressing and carrying an infant in a harness, feet slipping out of the harness, and skin irritation have been reported by about one-third of parents.¹⁹

Treatment adherence and subsequent success with the Pavlik harness is reported greatest (95%) in patients whose parents engage in demonstrations of harness use and follow instructions precisely.¹⁹ By providing a contact name and office number and following up with a phone call a few days after the harness is first applied, clinicians can significantly decrease parents’ anxiety and increase overall compliance.⁹

Conclusion
Despite recent increased awareness of DDH and the importance of thorough screening programs, hip dysplasia continues to be a frequently missed diagnosis in pediatrics. It is often up to the primary care clinician to screen for, assess, and potentially diagnose DDH. Therefore, a thorough understanding of this condition can promote early detection and diagnosis, with less invasive treatment and a more favorable outcome.

A proper hip examination should be a standard component of all newborn and infant well-child examinations. If DDH is suspected, appropriate referral to a pediatric orthopedic surgeon must be made so that timely treatment can be initiated. Early use of the Pavlik harness is significantly easier than the invasive surgery and prolonged immobilization necessitated by a delayed diagnosis. Whatever the course of treatment required, it is important for clinicians to support the patient and family: training and anticipatory guidance are essential components of DDH management.

A 5-day-old infant was referred to the pediatric orthopedic clinic for evaluation of a left hip “clunk.” She is a firstborn child, born at full term (39 weeks) via cesarean delivery secondary to breech presentation. Her weight at birth was 7 lb 6 oz. The infant was noted to have a left hip clunk during a routine physical examination by her pediatrician, who made a referral to the pediatric orthopedic clinic for possible hip dysplasia. This is the patient’s first visit to the clinic.

There is no family history of hip dysplasia or other orthopedic abnormalities. The infant is a well-appearing, alert female measuring 20.5” in length and weighing 7 lb 4 oz. Vital signs are stable with no abnormality detected. The heart is regular in rate and rhythm, and the chest is clear bilaterally.

No cutaneous abnormalities are noted. The patient is able to move all her extremities spontaneously, and her spine is straight and normal with no evidence of spinal dysraphism. Her feet are normal bilaterally, with full range of motion and no equinovarus or metatarsus adductus deformity.

The neurologic examination is also unremarkable, with normal neonatal reflexes and excellent muscle tone throughout. 

Examination of the infant’s hips reveals a positive result on the Barlow test on the left side (the hip can be dislocated). There is also a positive Ortolani sign (the hip can be reduced), with asymmetric thigh skin folds noted (see Figures 1A and 1B, respectively).

Based on these positive physical examination findings, the patient was diagnosed with developmental dysplasia of the hip (DDH). Initial ultrasonography to confirm the diagnosis was not considered necessary, as the physical examination demonstrated obvious instability.1 The infant was placed in a Pavlik harness, which her parents were instructed should be worn full-time (see Figures 2A and 2B). She was scheduled for weekly follow-up visits for adjustments to the harness and serial hip examinations.

At the second follow-up visit, ultrasonography was performed, confirming the presence of dysplasia with decreased femoral head coverage and a steep socket (acetabulum). Use of the Pavlik harness was continued full-time for six weeks.

At age 6 weeks, the infant underwent a follow-up ultrasound to assess for improvement in the degree of dysplasia. The test revealed normal hips bilaterally with no evidence of DDH. Therefore, use of the Pavlik harness was discontinued. The parents were instructed to bring the child back in six months for a repeat clinical examination and an anteroposterior x-ray of the pelvis.¹

Discussion
The term developmental dysplasia of the hip (DDH) has replaced the more traditional term congenital hip dislocation because DDH more accurately reflects the variable characteristics that can be seen with this condition. As DDH may not be present at birth, the term congenital is misleading. We now know that DDH may occur in utero, perinatally, or during infancy and childhood.^2,3

Generally, DDH is used to describe an abnormal relationship between the femoral head and the acetabulum (see Figure 3⁴). The term represents a wide spectrum of abnormality, as shown in the Graf classification of hips in infants: type I refers to a normal hip; type II, immature development to mild dysplasia; type III, subluxation of the femoral head; and type 4, frank dislocation with severe instability.⁵

Diagnosing and managing DDH correctly requires the clinician to have a thorough understanding of the normal growth and development that occurs in the hip joint. Embryologically, the joint (including the femoral head and acetabulum) develops from the same primitive mesenchymal cells.⁶ By 11 to 12 weeks’ gestation, the initial structures of the hip joint are fully formed; theoretically, this is the earliest time at which a dislocation can occur.^2,7 DDH that develops at this stage would be called teratologic; this condition is seen most frequently in patients who have underlying neuromuscular conditions, such as myelodysplasia (spina bifida) or arthrogryposis. A typical dislocation takes place during the perinatal period in an infant who is otherwise healthy.²

Etiology
DDH occurs in about 11 of every 1,000 infants, with frank dislocations occurring in one to two infants per 10,000.⁸ The left hip is involved in approximately 60% of cases, the right in 20%, and both hips in about 20%. In the most common intrauterine fetal position, the left hip is lower than the right (usually abutting the mother’s sacrum) and is often in adduction. This is likely the reason that the left hip is more commonly affected by DDH.

DDH is believed to be multifactorial, with physiologic, genetic, and mechanical factors implicated in the etiology.³ The incidence of DDH varies with factors such as the patient’s age, race, and gender, the experience and training of the examiner, and the diagnostic criteria that are used.

Known risk factors for a positive newborn screening are shown in the table.^9,10 It is often helpful for clinicians to remember the “4F” mnemonic associated with DDH: female, firstborn, foot first, and family history.⁹

There is also an increased risk for DDH in patients with other conditions that are associated with intrauterine crowding. These include congenital muscular torticollis, metatarsus adductus, and congenital dislocation of the knee.²

Physical Examination
All newborn infants should be screened for DDH as part of the initial physical examination, with ultrasonography recommended for infants deemed at high risk for DDH and for those with inconclusive results on examination.^1,10,11 Providers should be aware that the newborn hip examination requires a considerable amount of practice and expertise.

A thorough medical history should always be obtained first, including gestational age, presentation (breech vs vertex), type of delivery (cesarean vs vaginal), gender, birth order, family history of DDH, ligamentous laxity, or myopathy.⁸

The examining clinician begins by placing the infant on a firm, flat surface. The infant should be as relaxed as possible. Next, the clinician observes both lower extremities for asymmetric thigh or buttock skin folds. Bilateral DDH can be very difficult to diagnose on the basis of this examination due to the lack of asymmetry (hips will have symmetric abnormality).

The Galeazzi sign is elicited by placing the infant supine with the hips and knees flexed to 90°.¹² With the hips in neutral abduction, the provider should determine whether the knees are at the same height. Unequal knee heights—a positive result for the Galeazzi sign—suggest femoral shortening (apparent leg length discrepancy), which may be explained by a hip dislocation. If both hips are dislocated, a false-negative result will often occur, since both will appear short and there will be no discrepancy.^2,12

Among physical examination techniques, the Ortolani and Barlow maneuvers are considered most reliable to detect hip instability in newborns and infants younger than 6 months^2,13,14 (review Figures 1A and 1B). The Ortolani test is used to detect the sensation of the dislocated hip reducing into the acetabulum, and the Barlow test elicits the unstable hip dislocating.² A palpable and occasionally audible clunk is considered a positive result on the Barlow test and usually indicates a diagnosis of DDH.¹⁴ High-pitched clicks or snaps frequently occur with hip range-of-motion maneuvers and during Ortolani and Barlow testing. These sounds are often attributed to snapping of the iliotibial band over the greater trochanter and do not usually signify dysplasia.¹⁵

Because DDH is a dynamic and evolving process, the physical findings on clinical examination change significantly, depending on the age of the infant or child. As an infant approaches age 3 months, limited hip abduction (especially when asymmetric) is often the most reliable physical examination finding in patients with DDH.¹² After age 3 to 4 months, Ortolani and Barlow testing will often produce negative results as progressive soft tissue contractures evolve.

Once a child begins to walk, gait abnormalities (eg, a short-limbed or waddling gait pattern) may raise suspicion for a diagnosis of DDH.⁷ It has been recommended that evaluation for DDH be performed at each routine office examination until the child is 12 months of age.¹

Treatment
The Pavlik harness is considered first-line treatment for DDH in infants younger than 6 months. The harness is a dynamic splint that allows the infant to engage in a sphere of active motion that encourages stabilization and deepening of the socket. The harness is applied with the knees flexed to about 90° and the hips in about 70° of abduction and 100° to 110° of flexion (as shown in Figures 2A and 2B).⁹

The duration of treatment depends on the infant’s age at presentation and the severity of DDH. Progress is judged by serial examinations and dynamic ultrasounds. The harness is worn full-time until clinical and radiographic examinations both yield normal results. After six weeks of treatment, the hips are examined out of the harness, and a repeat ultrasound is usually obtained. If findings are normal, use of the harness is ordinarily discontinued. Some patients will require harness use for a longer period in cases of delayed development of the acetabulum and/or severe laxity of the ligaments.⁹

The Pavlik harness is successful more than 90% of the time in newborns with DDH.⁸ Success rates have been reported as greatest in infants younger than 8 weeks at the time of treatment initiation, those with only one affected hip, and those with less severe disease (Graf types II or III).¹⁶

If ultrasonography shows no improvement after two to three weeks, it is usually recommended that the harness be discontinued; most orthopedic surgeons will then proceed with a closed or open reduction and spica body casting. Similarly, when the diagnosis of DDH is delayed until after ages 6 to 8 months, a closed reduction under anesthesia and placement of a spica body cast is usually the recommended treatment to maintain the hip in the reduced position.^17,18 Some older children (ages 1 to 5 years) may require bracing, traction, open reduction, and/or femoral or pelvic osteotomy.^17,18 It is believed that undiagnosed, untreated DDH can lead to early-onset degenerative hip disease (arthritis).¹

Patient/Family Education
The Pavlik harness is most effective when a consistent support system exists to educate parents about the importance of the harness, its care and maintenance, and the consequences of failure. Close monitoring of the infant’s progress is also essential to promoting adherence. Application and removal of the harness should be demonstrated to the parent or caregiver, as well as diapering, dressing, and undressing the infant; they should then be encouraged to practice immediately in the clinic or office.

During visits for harness adjustment, the strap position should be marked with indelible ink, allowing parents to reapply the device correctly, should removal be required (eg, for bathing).⁹ Ten percent of parents reportedly find reapplying the harness difficult during the first weeks of use. Difficulty in dressing and carrying an infant in a harness, feet slipping out of the harness, and skin irritation have been reported by about one-third of parents.¹⁹

Treatment adherence and subsequent success with the Pavlik harness is reported greatest (95%) in patients whose parents engage in demonstrations of harness use and follow instructions precisely.¹⁹ By providing a contact name and office number and following up with a phone call a few days after the harness is first applied, clinicians can significantly decrease parents’ anxiety and increase overall compliance.⁹

Conclusion
Despite recent increased awareness of DDH and the importance of thorough screening programs, hip dysplasia continues to be a frequently missed diagnosis in pediatrics. It is often up to the primary care clinician to screen for, assess, and potentially diagnose DDH. Therefore, a thorough understanding of this condition can promote early detection and diagnosis, with less invasive treatment and a more favorable outcome.

A proper hip examination should be a standard component of all newborn and infant well-child examinations. If DDH is suspected, appropriate referral to a pediatric orthopedic surgeon must be made so that timely treatment can be initiated. Early use of the Pavlik harness is significantly easier than the invasive surgery and prolonged immobilization necessitated by a delayed diagnosis. Whatever the course of treatment required, it is important for clinicians to support the patient and family: training and anticipatory guidance are essential components of DDH management.

A 5-day-old infant was referred to the pediatric orthopedic clinic for evaluation of a left hip “clunk.” She is a firstborn child, born at full term (39 weeks) via cesarean delivery secondary to breech presentation. Her weight at birth was 7 lb 6 oz. The infant was noted to have a left hip clunk during a routine physical examination by her pediatrician, who made a referral to the pediatric orthopedic clinic for possible hip dysplasia. This is the patient’s first visit to the clinic.

There is no family history of hip dysplasia or other orthopedic abnormalities. The infant is a well-appearing, alert female measuring 20.5” in length and weighing 7 lb 4 oz. Vital signs are stable with no abnormality detected. The heart is regular in rate and rhythm, and the chest is clear bilaterally.

No cutaneous abnormalities are noted. The patient is able to move all her extremities spontaneously, and her spine is straight and normal with no evidence of spinal dysraphism. Her feet are normal bilaterally, with full range of motion and no equinovarus or metatarsus adductus deformity.

The neurologic examination is also unremarkable, with normal neonatal reflexes and excellent muscle tone throughout. 

Examination of the infant’s hips reveals a positive result on the Barlow test on the left side (the hip can be dislocated). There is also a positive Ortolani sign (the hip can be reduced), with asymmetric thigh skin folds noted (see Figures 1A and 1B, respectively).

Based on these positive physical examination findings, the patient was diagnosed with developmental dysplasia of the hip (DDH). Initial ultrasonography to confirm the diagnosis was not considered necessary, as the physical examination demonstrated obvious instability.1 The infant was placed in a Pavlik harness, which her parents were instructed should be worn full-time (see Figures 2A and 2B). She was scheduled for weekly follow-up visits for adjustments to the harness and serial hip examinations.

At the second follow-up visit, ultrasonography was performed, confirming the presence of dysplasia with decreased femoral head coverage and a steep socket (acetabulum). Use of the Pavlik harness was continued full-time for six weeks.

At age 6 weeks, the infant underwent a follow-up ultrasound to assess for improvement in the degree of dysplasia. The test revealed normal hips bilaterally with no evidence of DDH. Therefore, use of the Pavlik harness was discontinued. The parents were instructed to bring the child back in six months for a repeat clinical examination and an anteroposterior x-ray of the pelvis.¹

Discussion
The term developmental dysplasia of the hip (DDH) has replaced the more traditional term congenital hip dislocation because DDH more accurately reflects the variable characteristics that can be seen with this condition. As DDH may not be present at birth, the term congenital is misleading. We now know that DDH may occur in utero, perinatally, or during infancy and childhood.^2,3

Generally, DDH is used to describe an abnormal relationship between the femoral head and the acetabulum (see Figure 3⁴). The term represents a wide spectrum of abnormality, as shown in the Graf classification of hips in infants: type I refers to a normal hip; type II, immature development to mild dysplasia; type III, subluxation of the femoral head; and type 4, frank dislocation with severe instability.⁵

Diagnosing and managing DDH correctly requires the clinician to have a thorough understanding of the normal growth and development that occurs in the hip joint. Embryologically, the joint (including the femoral head and acetabulum) develops from the same primitive mesenchymal cells.⁶ By 11 to 12 weeks’ gestation, the initial structures of the hip joint are fully formed; theoretically, this is the earliest time at which a dislocation can occur.^2,7 DDH that develops at this stage would be called teratologic; this condition is seen most frequently in patients who have underlying neuromuscular conditions, such as myelodysplasia (spina bifida) or arthrogryposis. A typical dislocation takes place during the perinatal period in an infant who is otherwise healthy.²

Etiology
DDH occurs in about 11 of every 1,000 infants, with frank dislocations occurring in one to two infants per 10,000.⁸ The left hip is involved in approximately 60% of cases, the right in 20%, and both hips in about 20%. In the most common intrauterine fetal position, the left hip is lower than the right (usually abutting the mother’s sacrum) and is often in adduction. This is likely the reason that the left hip is more commonly affected by DDH.

DDH is believed to be multifactorial, with physiologic, genetic, and mechanical factors implicated in the etiology.³ The incidence of DDH varies with factors such as the patient’s age, race, and gender, the experience and training of the examiner, and the diagnostic criteria that are used.

Known risk factors for a positive newborn screening are shown in the table.^9,10 It is often helpful for clinicians to remember the “4F” mnemonic associated with DDH: female, firstborn, foot first, and family history.⁹

There is also an increased risk for DDH in patients with other conditions that are associated with intrauterine crowding. These include congenital muscular torticollis, metatarsus adductus, and congenital dislocation of the knee.²

Physical Examination
All newborn infants should be screened for DDH as part of the initial physical examination, with ultrasonography recommended for infants deemed at high risk for DDH and for those with inconclusive results on examination.^1,10,11 Providers should be aware that the newborn hip examination requires a considerable amount of practice and expertise.

A thorough medical history should always be obtained first, including gestational age, presentation (breech vs vertex), type of delivery (cesarean vs vaginal), gender, birth order, family history of DDH, ligamentous laxity, or myopathy.⁸

The examining clinician begins by placing the infant on a firm, flat surface. The infant should be as relaxed as possible. Next, the clinician observes both lower extremities for asymmetric thigh or buttock skin folds. Bilateral DDH can be very difficult to diagnose on the basis of this examination due to the lack of asymmetry (hips will have symmetric abnormality).

The Galeazzi sign is elicited by placing the infant supine with the hips and knees flexed to 90°.¹² With the hips in neutral abduction, the provider should determine whether the knees are at the same height. Unequal knee heights—a positive result for the Galeazzi sign—suggest femoral shortening (apparent leg length discrepancy), which may be explained by a hip dislocation. If both hips are dislocated, a false-negative result will often occur, since both will appear short and there will be no discrepancy.^2,12

Among physical examination techniques, the Ortolani and Barlow maneuvers are considered most reliable to detect hip instability in newborns and infants younger than 6 months^2,13,14 (review Figures 1A and 1B). The Ortolani test is used to detect the sensation of the dislocated hip reducing into the acetabulum, and the Barlow test elicits the unstable hip dislocating.² A palpable and occasionally audible clunk is considered a positive result on the Barlow test and usually indicates a diagnosis of DDH.¹⁴ High-pitched clicks or snaps frequently occur with hip range-of-motion maneuvers and during Ortolani and Barlow testing. These sounds are often attributed to snapping of the iliotibial band over the greater trochanter and do not usually signify dysplasia.¹⁵

Because DDH is a dynamic and evolving process, the physical findings on clinical examination change significantly, depending on the age of the infant or child. As an infant approaches age 3 months, limited hip abduction (especially when asymmetric) is often the most reliable physical examination finding in patients with DDH.¹² After age 3 to 4 months, Ortolani and Barlow testing will often produce negative results as progressive soft tissue contractures evolve.

Once a child begins to walk, gait abnormalities (eg, a short-limbed or waddling gait pattern) may raise suspicion for a diagnosis of DDH.⁷ It has been recommended that evaluation for DDH be performed at each routine office examination until the child is 12 months of age.¹

Treatment
The Pavlik harness is considered first-line treatment for DDH in infants younger than 6 months. The harness is a dynamic splint that allows the infant to engage in a sphere of active motion that encourages stabilization and deepening of the socket. The harness is applied with the knees flexed to about 90° and the hips in about 70° of abduction and 100° to 110° of flexion (as shown in Figures 2A and 2B).⁹

The duration of treatment depends on the infant’s age at presentation and the severity of DDH. Progress is judged by serial examinations and dynamic ultrasounds. The harness is worn full-time until clinical and radiographic examinations both yield normal results. After six weeks of treatment, the hips are examined out of the harness, and a repeat ultrasound is usually obtained. If findings are normal, use of the harness is ordinarily discontinued. Some patients will require harness use for a longer period in cases of delayed development of the acetabulum and/or severe laxity of the ligaments.⁹

The Pavlik harness is successful more than 90% of the time in newborns with DDH.⁸ Success rates have been reported as greatest in infants younger than 8 weeks at the time of treatment initiation, those with only one affected hip, and those with less severe disease (Graf types II or III).¹⁶

If ultrasonography shows no improvement after two to three weeks, it is usually recommended that the harness be discontinued; most orthopedic surgeons will then proceed with a closed or open reduction and spica body casting. Similarly, when the diagnosis of DDH is delayed until after ages 6 to 8 months, a closed reduction under anesthesia and placement of a spica body cast is usually the recommended treatment to maintain the hip in the reduced position.^17,18 Some older children (ages 1 to 5 years) may require bracing, traction, open reduction, and/or femoral or pelvic osteotomy.^17,18 It is believed that undiagnosed, untreated DDH can lead to early-onset degenerative hip disease (arthritis).¹

Patient/Family Education
The Pavlik harness is most effective when a consistent support system exists to educate parents about the importance of the harness, its care and maintenance, and the consequences of failure. Close monitoring of the infant’s progress is also essential to promoting adherence. Application and removal of the harness should be demonstrated to the parent or caregiver, as well as diapering, dressing, and undressing the infant; they should then be encouraged to practice immediately in the clinic or office.

During visits for harness adjustment, the strap position should be marked with indelible ink, allowing parents to reapply the device correctly, should removal be required (eg, for bathing).⁹ Ten percent of parents reportedly find reapplying the harness difficult during the first weeks of use. Difficulty in dressing and carrying an infant in a harness, feet slipping out of the harness, and skin irritation have been reported by about one-third of parents.¹⁹

Treatment adherence and subsequent success with the Pavlik harness is reported greatest (95%) in patients whose parents engage in demonstrations of harness use and follow instructions precisely.¹⁹ By providing a contact name and office number and following up with a phone call a few days after the harness is first applied, clinicians can significantly decrease parents’ anxiety and increase overall compliance.⁹

Conclusion
Despite recent increased awareness of DDH and the importance of thorough screening programs, hip dysplasia continues to be a frequently missed diagnosis in pediatrics. It is often up to the primary care clinician to screen for, assess, and potentially diagnose DDH. Therefore, a thorough understanding of this condition can promote early detection and diagnosis, with less invasive treatment and a more favorable outcome.

A proper hip examination should be a standard component of all newborn and infant well-child examinations. If DDH is suspected, appropriate referral to a pediatric orthopedic surgeon must be made so that timely treatment can be initiated. Early use of the Pavlik harness is significantly easier than the invasive surgery and prolonged immobilization necessitated by a delayed diagnosis. Whatever the course of treatment required, it is important for clinicians to support the patient and family: training and anticipatory guidance are essential components of DDH management.

Despite all the attention paid to ST-segment-elevation myocardial infarction (MI), in terms of sheer numbers, non-ST-elevation MI and unstable angina are where the action is. Acute coronary syndromes account for 2.43 million hospital discharges per year. Of these, 0.46 million are for ST-elevation MI and 1.97 million are for non-ST-elevation MI and unstable angina.^1,2

A number of recent studies have begun to answer some of the pressing questions about treating these types of acute coronary syndromes. In this article, I update the reader on these studies, along with recent findings regarding stenting and antiplatelet agents. As you will see, they are all interconnected.

TO CATHETERIZE IS BETTER THAN NOT TO CATHETERIZE

In the 1990s, a topic of debate was whether patients presenting with unstable angina or non-ST-elevation MI should routinely undergo catheterization or whether they would do just as well with a conservative approach, ie, undergoing catheterization only if they developed recurrent, spontaneous, or stress-induced ischemia. Now, the data are reasonably clear and favor an aggressive strategy.³

Mehta et al⁴ performed a meta-analysis of seven randomized controlled trials (N = 9,212 patients) of aggressive vs conservative angiography and revascularization for non-ST-elevation MI or unstable angina. The results favored the aggressive strategy. At 17 months of follow-up, death or MI had occurred in 7.4% of patients who received the aggressive therapy compared with 11.0% of those who received the conservative therapy, for an odds ratio of 0.82 (P = .001).

The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implemention of the ACC/AHA Guidelines?) Quality Improvement Initiative⁵ analyzed data from a registry of 17,926 patients with non-ST-elevation acute coronary syndrome who were at high risk because of positive cardiac markers or ischemic electrocardiographic changes. Overall, 2.0% of patients who received early invasive care (catheterization within the first 48 hours) died in the hospital compared with 6.2% of those who got no early invasive care, for an adjusted odds ratio of 0.63 (95% confidence interval [CI] 0.52–0.77).

The investigators also stratified the patients into those at low, medium, and high risk, using the criteria of the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin [eptifibatide] Therapy) risk score. There were fewer deaths with early invasive therapy in each risk group, and the risk reduction was greatest in the high-risk group.⁵

Bavry et al⁶ performed an updated meta-analysis of randomized trials. At a mean follow-up of 24 months, the relative risk of death from any cause was 0.75 in patients who received early invasive therapy.

In another meta-analysis, O’Donoghue et al⁷ found that the odds ratio of death, MI, or rehospitalization with acute coronary syndromes was 0.73 (95% CI 0.55–0.98) in men who received invasive vs conservative therapy; in women it was 0.81 (95% CI 0.65–1.01). In women, the benefit was statistically significant in those who had elevations of creatine kinase MB or troponin but not in those who did not, though the benefit in men appeared to be less dependent on the presence of biomarker abnormalities.

MUST ANGIOGRAPHY BE DONE IN THE FIRST 24 HOURS?

Although a number of trials showed that a routine invasive strategy leads to better outcomes than a conservative strategy, until recently we had no information as to whether the catheterization needed to be done early (eg, within the first 24 hours) or if it could be delayed a day or two while the patient received medical therapy.

Mehta et al⁸ conducted a trial to find out: the Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial. Patients were included if they had unstable angina or non-ST-elevation MI, presented to a hospital within 24 hours of the onset of symptoms, and had two of three high-risk features: age 60 years or older, elevated cardiac biomarkers, or electrocardiographic findings compatible with ischemia. All received standard medical therapy, and 3,031 were randomly assigned to undergo angiography either within 24 hours after randomization or 36 or more hours after randomization.

At 6 months, the primary outcome of death, new MI, or stroke had occurred in 9.6% of the patients in the early-intervention group and in 11.3% of those in the delayed-intervention group, but the difference was not statistically significant. However, the difference in the rate of a secondary end point, death, MI, or refractory ischemia, was statistically significant: 9.5% vs 12.9%, P = .003, owing mainly to less refractory ischemia with early intervention.

The patients were also stratified into two groups by baseline risk. The rate of the primary outcome was significantly lower with early intervention in high-risk patients, but not in those at intermediate or low risk. Thus, early intervention may be beneficial in patients at high risk, such as those with ongoing chest pain, but not necessarily in those at low risk.

LEAVE NO LESION BEHIND?

Coronary artery disease often affects more than one segment. Until recently, it was not known whether we should stent all stenotic segments in patients presenting with non-ST-elevation MI or unstable angina, or only the “culprit lesion.”

Shishehbor et al⁹ examined data from a Cleveland Clinic registry of 1,240 patients with acute coronary syndrome and multivessel coronary artery disease who underwent bare-metal stenting. The median follow-up was 2.3 years. Using a propensity model to match patients in the two groups with similar baseline characteristics, they found that the rate of repeat revascularization was less with multivessel intervention than with culprit-only stenting, as was the rate of the combined end point of death, MI, or revascularization, but not that of all-cause mortality or the composite of death or MI.

BARE-METAL VS DRUG-ELUTING STENTS: BALANCING THE RISKS AND BENEFITS

After a patient receives a stent, two bad things can happen: the artery can close up again either gradually, in a process called restenosis, or suddenly, via thrombosis.

Drug-eluting stents were invented to solve the problem of restenosis, and they work very well. Stone et al¹⁰ pooled the data from four double-blind trials of sirolimus (Rapamune) stents and five double-blind trials of paclitaxel (Taxol) stents and found that, at 4 years, the rates of target-lesion revascularization (for restenosis) were 7.8% with sirolimus stents vs 23.6% with bare-metal stents (P < .001), and 10.1% with paclitaxel stents vs 20.0% with bare-metal stents (P < .001).

Thrombosis was much less common in these studies, occurring in 1.2% of the sirolimus stent groups vs 0.6% of the bare-metal stent groups (P = .20), and in 1.3% of the paclitaxel stent groups vs 0.9% of the bare-metal stent groups (P = .30).¹⁰

However, drug-eluting stents appear to increase the risk of thrombosis later on, ie, after 1 year. Bavry et al,¹¹ in a meta-analysis, calculated that when stent thrombosis occurred, the median time after implantation was 15.5 months with sirolimus stents vs 4 months with bare-metal stents (P = .0052), and 18 months with paclitaxel stents vs 3.5 months with bare-metal stents (P = .04). The absolute risk of very late stent thrombosis after 1 year was very low, with five events per 1,000 patients with drug-eluting stents vs no events with bare-metal stents (P = .02). Nevertheless, this finding has practical implications. How long must patients continue dual antiplatelet therapy? And what if a patient needs surgery a year later?

Restenosis is not always so gradual

Although stent thrombosis is serious and often fatal, bare-metal stent restenosis is not always benign either, despite the classic view that stent restenosis is a gradual process that results in exertional angina. Reviewing 1,186 cases of bare-metal stent restenosis in 984 patients at Cleveland Clinic, Chen et al¹² reported that 9.5% of cases presented as acute MI (2.2% as ST-elevation MI and 7.3% as non-ST-elevation MI), and 26.4% as unstable angina requiring hospitalization.

A Mayo Clinic study¹³ corroborated these findings. The 10-year incidence of clinical bare-metal stent restenosis was 18.1%, and the incidence of MI was 2.1%. The 10-year rate of bare-metal stent thrombosis was 2%. Off-label use, primarily in saphenous vein grafts, increased the incidence; other correlates were prior MI, peripheral arterial disease, and ulcerated lesions.

Furthermore, bare-metal stent thrombosis can also occur later. We saw a case that occurred 13 years after the procedure, 3 days after the patient stopped taking aspirin because he was experiencing flu-like symptoms, ran out of aspirin, and felt too sick to go out and buy more. The presentation was with ST-elevation MI. The patient recovered after treatment with intracoronary abciximab (ReoPro), percutaneous thrombectomy, balloon angioplasty, and, eventually, bypass surgery.¹⁴

No difference in risk of death with drug-eluting vs bare-metal stents

Even though drug-eluting stents pose a slightly higher risk of thrombosis than bare-metal stents, the risk of death is no higher.¹⁵

I believe the reason is that there are competing risks, and that the higher risk of thrombosis with first-generation drug-eluting stents and the higher risk of restenosis with bare-metal stents essentially cancel each other out. For most patients, there is an absolute benefit with drug-eluting stents, which reduce the need for revascularization with no effect in terms of either increasing or decreasing the risk of MI or death. Second-generation drug-eluting stents may have advantages in reducing rates of death or MI compared with first-generation drug-eluting stents, though this remains to be proven conclusively.

The right revascularization for the right patient

Bavry and I¹⁶ developed an algorithm for deciding on revascularization, posing a series of questions:

• Does the patient need any form of revascularization?
• Is he or she at higher risk of both stent thrombosis and restenosis, as in patients with diabetes, diffuse multivessel disease with bifurcation lesions, or chronic total occlusions? If so, coronary artery bypass grafting remains an excellent option.
• Does he or she have a low risk of restenosis, as in patients without diabetes with focal lesions in large vessels? If so, one could consider a bare-metal stent, which would probably be more cost-effective than a drug-eluting stent in this situation.
• Does the patient have relative contraindications to drug-eluting stents? Examples are a history of noncompliance with medical therapy, financial issues such as lack of insurance that would make buying clopidogrel (Plavix) a problem, long-term anticoagulation, or anticipated need for surgery in the next few years.

If a drug-eluting stent is used, certain measures can help ensure that it is used optimally. It should often be placed under high pressure with a noncompliant balloon so that it achieves contact with the artery wall all around. One should consider intravascular ultrasonographic guidance to make sure the stent is well opposed if it is in a very calcified lesion. Dual antiplatelet therapy with clopidogrel and aspirin should be given for at least 1 year, and if there is no bleeding, perhaps longer, pending further data.¹⁶

LEAVE NO PLATELET ACTIVATED?

Platelets have several types of receptors that, when bound by their respective ligands, lead to platelet activation and aggregation and, ultimately, thrombus formation. Antagonists to some of these receptors are available or are being developed.¹⁷

For long-term therapy, blocking the process “upstream,” ie, preventing platelet activation, is better than blocking it “downstream,” ie, preventing aggregation. For example, clopidogrel, ticlopipine (Ticlid), and prasugrel (Effient) have active metabolites that bind to a subtype of the adenosine diphosphate receptor and prevent platelet activation, whereas the glycoprotein IIb/IIIa inhibitors such as abciximab work downstream, binding to a different receptor and preventing aggregation.¹⁸

The evidence for using dual antiplatelet therapy (ie, aspirin plus clopidogrel) in patients with acute coronary syndromes without ST-elevation is very well established.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,¹⁹ published in 2001, found a 20% relative risk reduction and a 2% absolute risk reduction in the incidence of MI, stroke, or cardiovascular death in patients randomly assigned to receive clopidogrel plus aspirin for 1 year vs aspirin alone for 1 year (P < .001). In the subgroup of patients who underwent percutaneous coronary intervention, the relative risk reduction in the incidence of MI or cardiovascular death at 1 year of follow-up was 31% (P = .002).²⁰

As a result of these findings, the cardiology society guidelines²¹ recommend a year of dual antiplatelet therapy after acute coronary syndromes, regardless of whether the patient is treated medically, percutaneously, or surgically.

But what happens after clopidogrel is withdrawn? Ho et al²² retrospectively analyzed data from Veterans Affairs hospitals and found a spike in the incidence of death or MI in the first 90 days after stopping clopidogrel treatment. This was true in medically treated patients as well as in those treated with percutaneous coronary interventions, in those with or without diabetes mellitus, in those who received a drug-eluting stent or a bare-metal stent, and in those treated longer than 9 months.

The investigators concluded that there might be a “clopidogrel rebound effect.” However, I believe that a true rebound effect, such as after withdrawal of heparin or warfarin, is biologically unlikely with clopidogrel, since clopidogrel irreversibly binds to its receptor for the 7- to 10-day life span of the platelet. Rather, I believe the phenomenon must be due to withdrawal of protection in patients at risk.

In stable patients, dual therapy is not as beneficial

Would dual antiplatelet therapy with clopidogrel and aspirin also benefit patients at risk of atherothrombotic events but without acute coronary syndromes?

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial²³ included 15,603 patients with either clinically evident but stable cardiovascular disease or multiple risk factors for athero-thrombosis. They were randomly assigned to receive either clopidogrel 75 mg/day plus aspirin 75 to 162 mg/day or placebo plus aspirin. At a median of 28 months, the groups did not differ significantly in the rate of MI, stroke, or death from cardiovascular causes.

However, the subgroup of patients who had documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease did appear to derive significant benefit from dual therapy.²⁴ In this subgroup, the rate of MI, stroke, or cardiovascular death at a median follow-up of 27.6 months was 8.8% with placebo plus aspirin compared with 7.3% with clopidogrel plus aspirin, for a hazard ratio of 0.83 (95% CI 0.72–0.96, P = .01). Unstented patients with stable coronary artery disease but without prior MI derived no benefit.

Bleeding and thrombosis: The Scylla and Charybdis of antiplatelet therapy

However, with dual antiplatelet therapy, we steer between the Scylla of bleeding and the Charybdis of thrombosis.²⁵

In the CHARISMA subgroup who had prior MI, ischemic stroke, or symptomatic peripheral arterial disease, the incidence of moderate or severe bleeding was higher with dual therapy than with aspirin alone, but the rates converged after about 1 year of treatment.²⁴ Further, there was no difference in fatal bleeding or intracranial bleeding, although the rate of moderate bleeding (defined as the need for transfusion) was higher with dual therapy (2.0% vs 1.3%, P = .004).

I believe the data indicate that if a patient can tolerate dual antiplatelet therapy for 9 to 12 months without any bleeding issues, he or she is unlikely to have a major bleeding episode if dual therapy is continued beyond this time.

About half of bleeding events in patients on chronic antiplatelet therapy are gastrointestinal. To address this risk, in 2008 an expert committee from the American College of Cardiology, American College of Gastroenterology, and American Heart Association issued a consensus document²⁶ in which they recommended assessing gastrointestinal risk factors in patients on antiplatelet therapy, such as history of ulcers (and testing for and treating Helicobacter pylori infection if present), history of gastrointestinal bleeding, concomitant anticoagulant therapy, and dual antiplatelet therapy. If any of these were present, the committee recommended considering a proton pump inhibitor. The committee also recommended a proton pump inhibitor for patients on antiplatelet therapy who have more than one of the following: age 60 years or more, corticosteroid use, or dyspepsia or gastroesophageal reflux symptoms.

Some ex vivo platelet studies and observational analyses have suggested that there might be an adverse interaction between clopidogrel and proton pump inhibitors due to a blunting of clopidogrel’s antiplatelet effect. A large randomized clinical trial was designed and launched to determine if a single-pill combination of the proton pump inhibitor omeprazole (Prilosec) and clopidogrel would be safer than clopidogrel alone when added to aspirin. Called COGENT-1 (Clopidogrel and the Optimization of GI Events Trial), it was halted early in 2009 when it lost its funding. However, preliminary data did not show an adverse interaction between clopidogrel and omeprazole.

What is the right dose of aspirin?

Steinhubl et al²⁷ performed a post hoc observational analysis of data from the CHARISMA trial. Their findings suggested that higher doses of aspirin are not more effective than lower doses for chronic therapy. Furthermore, in the group receiving clopidogrel plus aspirin, the incidence of severe or life-threatening bleeding was significantly greater with aspirin doses higher than 100 mg than with doses lower than 100 mg, 2.6% vs 1.7%, P = .040.

A randomized, controlled trial called Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS 7)²⁸ recently reported that higher-dose aspirin (ie, 325 mg) may be better than lower dose aspirin (ie, 81 mg) in patients with acute coronary syndromes undergoing percutaneous coronary intervention and receiving clopidogrel. During this 30-day study, there was no increase in overall bleeding with the higher dose of aspirin, though gastrointestinal bleeding was slightly increased.²⁹ In a factorial design, the second part of this trial found that a higher-dose clopidogrel regimen reduced stent thrombosis.²⁹

In vitro, response to clopidogrel shows a normal bell-shaped distribution.³⁰ In theory, therefore, patients who are hyperresponders may be at higher risk of bleeding, and those who are hyporesponders may be at risk of ischemic events.

A clinical trial is under way to examine whether hyporesponders should get higher doses. Called GRAVITAS (Gauging Responsiveness With a VerifyNow Assay Impact on Thrombosis and Safety), it will use a point-of-care platelet assay and then allocate patients to receive either standard therapy or double the dose of clopidogrel. The primary end point will be the rate of cardiovascular death, nonfatal MI, or stent thrombosis at 6 months.

Is prasugrel better than clopidogrel?

Prasugrel (Effient) is a new drug of the same class as clopidogrel, ie, a thienopyridine, with its active metabolite binding to the same platelet receptor as clopidogrel and inhibiting platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel. Prasugrel was recently approved by the Food and Drug Administration. But is it better?³¹

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) compared prasugrel and clopidogrel in 13,608 patients with moderate- to high-risk acute coronary syndromes who were scheduled to undergo percutaneous coronary intervention.³²

Overall, prasugrel was better. At 15 months, the incidence of the primary end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) was significantly lower with prasugrel therapy than with clopidogrel in the entire cohort (9.9% vs 12.1%, hazard ratio 0.81, 95% CI 0.73–0.90, P < .001), in the subgroup with ST-segment elevation MI, and in the subgroup with unstable angina or non-ST-elevation MI.

However, there was a price to pay. The rate of major bleeding was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% CI 1.03–1.68, P = .03). Assessing the balance between the risk and the benefit, the investigators identified three subgroups who did not derive a net clinical benefit from prasugrel: patients who had had a previous stroke or transient ischemic attack (this group actually had a net harm from prasugrel), patients 75 years of age or older, and patients weighing less than 60 kg (132 pounds).

More work is needed to determine which patients are best served by standard-dose clopidogrel, higher doses of clopidogrel, platelet-assay-guided dosing of clopidogrel, or prasugrel.²⁴

Short-acting, potent intravenous platelet blockade with an agent such as cangrelor is theoretically appealing, but further research is necessary.^33,34 Ticagrelor, a reversible adenosine diphosphate receptor antagonist, provides yet another potential option in antiplatelet therapy for acute coronary syndromes. In the recent PLATO trial (Study of Platelet Inhibition and Patient Outcomes), compared with clopidogrel, ticagrelor reduced the risk of ischemic events, including death.^35,36 Here, too, there was more major bleeding (unrelated to coronary artery bypass grafting) with ticagrelor.

Thus, clinical assessment of an individual patient’s ischemic and bleeding risks will continue to be critical as therapeutic strategies evolve.

Despite all the attention paid to ST-segment-elevation myocardial infarction (MI), in terms of sheer numbers, non-ST-elevation MI and unstable angina are where the action is. Acute coronary syndromes account for 2.43 million hospital discharges per year. Of these, 0.46 million are for ST-elevation MI and 1.97 million are for non-ST-elevation MI and unstable angina.^1,2

A number of recent studies have begun to answer some of the pressing questions about treating these types of acute coronary syndromes. In this article, I update the reader on these studies, along with recent findings regarding stenting and antiplatelet agents. As you will see, they are all interconnected.

TO CATHETERIZE IS BETTER THAN NOT TO CATHETERIZE

In the 1990s, a topic of debate was whether patients presenting with unstable angina or non-ST-elevation MI should routinely undergo catheterization or whether they would do just as well with a conservative approach, ie, undergoing catheterization only if they developed recurrent, spontaneous, or stress-induced ischemia. Now, the data are reasonably clear and favor an aggressive strategy.³

Mehta et al⁴ performed a meta-analysis of seven randomized controlled trials (N = 9,212 patients) of aggressive vs conservative angiography and revascularization for non-ST-elevation MI or unstable angina. The results favored the aggressive strategy. At 17 months of follow-up, death or MI had occurred in 7.4% of patients who received the aggressive therapy compared with 11.0% of those who received the conservative therapy, for an odds ratio of 0.82 (P = .001).

The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implemention of the ACC/AHA Guidelines?) Quality Improvement Initiative⁵ analyzed data from a registry of 17,926 patients with non-ST-elevation acute coronary syndrome who were at high risk because of positive cardiac markers or ischemic electrocardiographic changes. Overall, 2.0% of patients who received early invasive care (catheterization within the first 48 hours) died in the hospital compared with 6.2% of those who got no early invasive care, for an adjusted odds ratio of 0.63 (95% confidence interval [CI] 0.52–0.77).

The investigators also stratified the patients into those at low, medium, and high risk, using the criteria of the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin [eptifibatide] Therapy) risk score. There were fewer deaths with early invasive therapy in each risk group, and the risk reduction was greatest in the high-risk group.⁵

Bavry et al⁶ performed an updated meta-analysis of randomized trials. At a mean follow-up of 24 months, the relative risk of death from any cause was 0.75 in patients who received early invasive therapy.

In another meta-analysis, O’Donoghue et al⁷ found that the odds ratio of death, MI, or rehospitalization with acute coronary syndromes was 0.73 (95% CI 0.55–0.98) in men who received invasive vs conservative therapy; in women it was 0.81 (95% CI 0.65–1.01). In women, the benefit was statistically significant in those who had elevations of creatine kinase MB or troponin but not in those who did not, though the benefit in men appeared to be less dependent on the presence of biomarker abnormalities.

MUST ANGIOGRAPHY BE DONE IN THE FIRST 24 HOURS?

Although a number of trials showed that a routine invasive strategy leads to better outcomes than a conservative strategy, until recently we had no information as to whether the catheterization needed to be done early (eg, within the first 24 hours) or if it could be delayed a day or two while the patient received medical therapy.

Mehta et al⁸ conducted a trial to find out: the Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial. Patients were included if they had unstable angina or non-ST-elevation MI, presented to a hospital within 24 hours of the onset of symptoms, and had two of three high-risk features: age 60 years or older, elevated cardiac biomarkers, or electrocardiographic findings compatible with ischemia. All received standard medical therapy, and 3,031 were randomly assigned to undergo angiography either within 24 hours after randomization or 36 or more hours after randomization.

At 6 months, the primary outcome of death, new MI, or stroke had occurred in 9.6% of the patients in the early-intervention group and in 11.3% of those in the delayed-intervention group, but the difference was not statistically significant. However, the difference in the rate of a secondary end point, death, MI, or refractory ischemia, was statistically significant: 9.5% vs 12.9%, P = .003, owing mainly to less refractory ischemia with early intervention.

The patients were also stratified into two groups by baseline risk. The rate of the primary outcome was significantly lower with early intervention in high-risk patients, but not in those at intermediate or low risk. Thus, early intervention may be beneficial in patients at high risk, such as those with ongoing chest pain, but not necessarily in those at low risk.

LEAVE NO LESION BEHIND?

Coronary artery disease often affects more than one segment. Until recently, it was not known whether we should stent all stenotic segments in patients presenting with non-ST-elevation MI or unstable angina, or only the “culprit lesion.”

Shishehbor et al⁹ examined data from a Cleveland Clinic registry of 1,240 patients with acute coronary syndrome and multivessel coronary artery disease who underwent bare-metal stenting. The median follow-up was 2.3 years. Using a propensity model to match patients in the two groups with similar baseline characteristics, they found that the rate of repeat revascularization was less with multivessel intervention than with culprit-only stenting, as was the rate of the combined end point of death, MI, or revascularization, but not that of all-cause mortality or the composite of death or MI.

BARE-METAL VS DRUG-ELUTING STENTS: BALANCING THE RISKS AND BENEFITS

After a patient receives a stent, two bad things can happen: the artery can close up again either gradually, in a process called restenosis, or suddenly, via thrombosis.

Drug-eluting stents were invented to solve the problem of restenosis, and they work very well. Stone et al¹⁰ pooled the data from four double-blind trials of sirolimus (Rapamune) stents and five double-blind trials of paclitaxel (Taxol) stents and found that, at 4 years, the rates of target-lesion revascularization (for restenosis) were 7.8% with sirolimus stents vs 23.6% with bare-metal stents (P < .001), and 10.1% with paclitaxel stents vs 20.0% with bare-metal stents (P < .001).

Thrombosis was much less common in these studies, occurring in 1.2% of the sirolimus stent groups vs 0.6% of the bare-metal stent groups (P = .20), and in 1.3% of the paclitaxel stent groups vs 0.9% of the bare-metal stent groups (P = .30).¹⁰

However, drug-eluting stents appear to increase the risk of thrombosis later on, ie, after 1 year. Bavry et al,¹¹ in a meta-analysis, calculated that when stent thrombosis occurred, the median time after implantation was 15.5 months with sirolimus stents vs 4 months with bare-metal stents (P = .0052), and 18 months with paclitaxel stents vs 3.5 months with bare-metal stents (P = .04). The absolute risk of very late stent thrombosis after 1 year was very low, with five events per 1,000 patients with drug-eluting stents vs no events with bare-metal stents (P = .02). Nevertheless, this finding has practical implications. How long must patients continue dual antiplatelet therapy? And what if a patient needs surgery a year later?

Restenosis is not always so gradual

Although stent thrombosis is serious and often fatal, bare-metal stent restenosis is not always benign either, despite the classic view that stent restenosis is a gradual process that results in exertional angina. Reviewing 1,186 cases of bare-metal stent restenosis in 984 patients at Cleveland Clinic, Chen et al¹² reported that 9.5% of cases presented as acute MI (2.2% as ST-elevation MI and 7.3% as non-ST-elevation MI), and 26.4% as unstable angina requiring hospitalization.

A Mayo Clinic study¹³ corroborated these findings. The 10-year incidence of clinical bare-metal stent restenosis was 18.1%, and the incidence of MI was 2.1%. The 10-year rate of bare-metal stent thrombosis was 2%. Off-label use, primarily in saphenous vein grafts, increased the incidence; other correlates were prior MI, peripheral arterial disease, and ulcerated lesions.

Furthermore, bare-metal stent thrombosis can also occur later. We saw a case that occurred 13 years after the procedure, 3 days after the patient stopped taking aspirin because he was experiencing flu-like symptoms, ran out of aspirin, and felt too sick to go out and buy more. The presentation was with ST-elevation MI. The patient recovered after treatment with intracoronary abciximab (ReoPro), percutaneous thrombectomy, balloon angioplasty, and, eventually, bypass surgery.¹⁴

No difference in risk of death with drug-eluting vs bare-metal stents

Even though drug-eluting stents pose a slightly higher risk of thrombosis than bare-metal stents, the risk of death is no higher.¹⁵

I believe the reason is that there are competing risks, and that the higher risk of thrombosis with first-generation drug-eluting stents and the higher risk of restenosis with bare-metal stents essentially cancel each other out. For most patients, there is an absolute benefit with drug-eluting stents, which reduce the need for revascularization with no effect in terms of either increasing or decreasing the risk of MI or death. Second-generation drug-eluting stents may have advantages in reducing rates of death or MI compared with first-generation drug-eluting stents, though this remains to be proven conclusively.

The right revascularization for the right patient

Bavry and I¹⁶ developed an algorithm for deciding on revascularization, posing a series of questions:

• Does the patient need any form of revascularization?
• Is he or she at higher risk of both stent thrombosis and restenosis, as in patients with diabetes, diffuse multivessel disease with bifurcation lesions, or chronic total occlusions? If so, coronary artery bypass grafting remains an excellent option.
• Does he or she have a low risk of restenosis, as in patients without diabetes with focal lesions in large vessels? If so, one could consider a bare-metal stent, which would probably be more cost-effective than a drug-eluting stent in this situation.
• Does the patient have relative contraindications to drug-eluting stents? Examples are a history of noncompliance with medical therapy, financial issues such as lack of insurance that would make buying clopidogrel (Plavix) a problem, long-term anticoagulation, or anticipated need for surgery in the next few years.

If a drug-eluting stent is used, certain measures can help ensure that it is used optimally. It should often be placed under high pressure with a noncompliant balloon so that it achieves contact with the artery wall all around. One should consider intravascular ultrasonographic guidance to make sure the stent is well opposed if it is in a very calcified lesion. Dual antiplatelet therapy with clopidogrel and aspirin should be given for at least 1 year, and if there is no bleeding, perhaps longer, pending further data.¹⁶

LEAVE NO PLATELET ACTIVATED?

Platelets have several types of receptors that, when bound by their respective ligands, lead to platelet activation and aggregation and, ultimately, thrombus formation. Antagonists to some of these receptors are available or are being developed.¹⁷

For long-term therapy, blocking the process “upstream,” ie, preventing platelet activation, is better than blocking it “downstream,” ie, preventing aggregation. For example, clopidogrel, ticlopipine (Ticlid), and prasugrel (Effient) have active metabolites that bind to a subtype of the adenosine diphosphate receptor and prevent platelet activation, whereas the glycoprotein IIb/IIIa inhibitors such as abciximab work downstream, binding to a different receptor and preventing aggregation.¹⁸

The evidence for using dual antiplatelet therapy (ie, aspirin plus clopidogrel) in patients with acute coronary syndromes without ST-elevation is very well established.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,¹⁹ published in 2001, found a 20% relative risk reduction and a 2% absolute risk reduction in the incidence of MI, stroke, or cardiovascular death in patients randomly assigned to receive clopidogrel plus aspirin for 1 year vs aspirin alone for 1 year (P < .001). In the subgroup of patients who underwent percutaneous coronary intervention, the relative risk reduction in the incidence of MI or cardiovascular death at 1 year of follow-up was 31% (P = .002).²⁰

As a result of these findings, the cardiology society guidelines²¹ recommend a year of dual antiplatelet therapy after acute coronary syndromes, regardless of whether the patient is treated medically, percutaneously, or surgically.

But what happens after clopidogrel is withdrawn? Ho et al²² retrospectively analyzed data from Veterans Affairs hospitals and found a spike in the incidence of death or MI in the first 90 days after stopping clopidogrel treatment. This was true in medically treated patients as well as in those treated with percutaneous coronary interventions, in those with or without diabetes mellitus, in those who received a drug-eluting stent or a bare-metal stent, and in those treated longer than 9 months.

The investigators concluded that there might be a “clopidogrel rebound effect.” However, I believe that a true rebound effect, such as after withdrawal of heparin or warfarin, is biologically unlikely with clopidogrel, since clopidogrel irreversibly binds to its receptor for the 7- to 10-day life span of the platelet. Rather, I believe the phenomenon must be due to withdrawal of protection in patients at risk.

In stable patients, dual therapy is not as beneficial

Would dual antiplatelet therapy with clopidogrel and aspirin also benefit patients at risk of atherothrombotic events but without acute coronary syndromes?

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial²³ included 15,603 patients with either clinically evident but stable cardiovascular disease or multiple risk factors for athero-thrombosis. They were randomly assigned to receive either clopidogrel 75 mg/day plus aspirin 75 to 162 mg/day or placebo plus aspirin. At a median of 28 months, the groups did not differ significantly in the rate of MI, stroke, or death from cardiovascular causes.

However, the subgroup of patients who had documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease did appear to derive significant benefit from dual therapy.²⁴ In this subgroup, the rate of MI, stroke, or cardiovascular death at a median follow-up of 27.6 months was 8.8% with placebo plus aspirin compared with 7.3% with clopidogrel plus aspirin, for a hazard ratio of 0.83 (95% CI 0.72–0.96, P = .01). Unstented patients with stable coronary artery disease but without prior MI derived no benefit.

Bleeding and thrombosis: The Scylla and Charybdis of antiplatelet therapy

However, with dual antiplatelet therapy, we steer between the Scylla of bleeding and the Charybdis of thrombosis.²⁵

In the CHARISMA subgroup who had prior MI, ischemic stroke, or symptomatic peripheral arterial disease, the incidence of moderate or severe bleeding was higher with dual therapy than with aspirin alone, but the rates converged after about 1 year of treatment.²⁴ Further, there was no difference in fatal bleeding or intracranial bleeding, although the rate of moderate bleeding (defined as the need for transfusion) was higher with dual therapy (2.0% vs 1.3%, P = .004).

I believe the data indicate that if a patient can tolerate dual antiplatelet therapy for 9 to 12 months without any bleeding issues, he or she is unlikely to have a major bleeding episode if dual therapy is continued beyond this time.

About half of bleeding events in patients on chronic antiplatelet therapy are gastrointestinal. To address this risk, in 2008 an expert committee from the American College of Cardiology, American College of Gastroenterology, and American Heart Association issued a consensus document²⁶ in which they recommended assessing gastrointestinal risk factors in patients on antiplatelet therapy, such as history of ulcers (and testing for and treating Helicobacter pylori infection if present), history of gastrointestinal bleeding, concomitant anticoagulant therapy, and dual antiplatelet therapy. If any of these were present, the committee recommended considering a proton pump inhibitor. The committee also recommended a proton pump inhibitor for patients on antiplatelet therapy who have more than one of the following: age 60 years or more, corticosteroid use, or dyspepsia or gastroesophageal reflux symptoms.

Some ex vivo platelet studies and observational analyses have suggested that there might be an adverse interaction between clopidogrel and proton pump inhibitors due to a blunting of clopidogrel’s antiplatelet effect. A large randomized clinical trial was designed and launched to determine if a single-pill combination of the proton pump inhibitor omeprazole (Prilosec) and clopidogrel would be safer than clopidogrel alone when added to aspirin. Called COGENT-1 (Clopidogrel and the Optimization of GI Events Trial), it was halted early in 2009 when it lost its funding. However, preliminary data did not show an adverse interaction between clopidogrel and omeprazole.

What is the right dose of aspirin?

Steinhubl et al²⁷ performed a post hoc observational analysis of data from the CHARISMA trial. Their findings suggested that higher doses of aspirin are not more effective than lower doses for chronic therapy. Furthermore, in the group receiving clopidogrel plus aspirin, the incidence of severe or life-threatening bleeding was significantly greater with aspirin doses higher than 100 mg than with doses lower than 100 mg, 2.6% vs 1.7%, P = .040.

A randomized, controlled trial called Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS 7)²⁸ recently reported that higher-dose aspirin (ie, 325 mg) may be better than lower dose aspirin (ie, 81 mg) in patients with acute coronary syndromes undergoing percutaneous coronary intervention and receiving clopidogrel. During this 30-day study, there was no increase in overall bleeding with the higher dose of aspirin, though gastrointestinal bleeding was slightly increased.²⁹ In a factorial design, the second part of this trial found that a higher-dose clopidogrel regimen reduced stent thrombosis.²⁹

In vitro, response to clopidogrel shows a normal bell-shaped distribution.³⁰ In theory, therefore, patients who are hyperresponders may be at higher risk of bleeding, and those who are hyporesponders may be at risk of ischemic events.

A clinical trial is under way to examine whether hyporesponders should get higher doses. Called GRAVITAS (Gauging Responsiveness With a VerifyNow Assay Impact on Thrombosis and Safety), it will use a point-of-care platelet assay and then allocate patients to receive either standard therapy or double the dose of clopidogrel. The primary end point will be the rate of cardiovascular death, nonfatal MI, or stent thrombosis at 6 months.

Is prasugrel better than clopidogrel?

Prasugrel (Effient) is a new drug of the same class as clopidogrel, ie, a thienopyridine, with its active metabolite binding to the same platelet receptor as clopidogrel and inhibiting platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel. Prasugrel was recently approved by the Food and Drug Administration. But is it better?³¹

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) compared prasugrel and clopidogrel in 13,608 patients with moderate- to high-risk acute coronary syndromes who were scheduled to undergo percutaneous coronary intervention.³²

Overall, prasugrel was better. At 15 months, the incidence of the primary end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) was significantly lower with prasugrel therapy than with clopidogrel in the entire cohort (9.9% vs 12.1%, hazard ratio 0.81, 95% CI 0.73–0.90, P < .001), in the subgroup with ST-segment elevation MI, and in the subgroup with unstable angina or non-ST-elevation MI.

However, there was a price to pay. The rate of major bleeding was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% CI 1.03–1.68, P = .03). Assessing the balance between the risk and the benefit, the investigators identified three subgroups who did not derive a net clinical benefit from prasugrel: patients who had had a previous stroke or transient ischemic attack (this group actually had a net harm from prasugrel), patients 75 years of age or older, and patients weighing less than 60 kg (132 pounds).

More work is needed to determine which patients are best served by standard-dose clopidogrel, higher doses of clopidogrel, platelet-assay-guided dosing of clopidogrel, or prasugrel.²⁴

Short-acting, potent intravenous platelet blockade with an agent such as cangrelor is theoretically appealing, but further research is necessary.^33,34 Ticagrelor, a reversible adenosine diphosphate receptor antagonist, provides yet another potential option in antiplatelet therapy for acute coronary syndromes. In the recent PLATO trial (Study of Platelet Inhibition and Patient Outcomes), compared with clopidogrel, ticagrelor reduced the risk of ischemic events, including death.^35,36 Here, too, there was more major bleeding (unrelated to coronary artery bypass grafting) with ticagrelor.

Thus, clinical assessment of an individual patient’s ischemic and bleeding risks will continue to be critical as therapeutic strategies evolve.

Despite all the attention paid to ST-segment-elevation myocardial infarction (MI), in terms of sheer numbers, non-ST-elevation MI and unstable angina are where the action is. Acute coronary syndromes account for 2.43 million hospital discharges per year. Of these, 0.46 million are for ST-elevation MI and 1.97 million are for non-ST-elevation MI and unstable angina.^1,2

A number of recent studies have begun to answer some of the pressing questions about treating these types of acute coronary syndromes. In this article, I update the reader on these studies, along with recent findings regarding stenting and antiplatelet agents. As you will see, they are all interconnected.

TO CATHETERIZE IS BETTER THAN NOT TO CATHETERIZE

In the 1990s, a topic of debate was whether patients presenting with unstable angina or non-ST-elevation MI should routinely undergo catheterization or whether they would do just as well with a conservative approach, ie, undergoing catheterization only if they developed recurrent, spontaneous, or stress-induced ischemia. Now, the data are reasonably clear and favor an aggressive strategy.³

Mehta et al⁴ performed a meta-analysis of seven randomized controlled trials (N = 9,212 patients) of aggressive vs conservative angiography and revascularization for non-ST-elevation MI or unstable angina. The results favored the aggressive strategy. At 17 months of follow-up, death or MI had occurred in 7.4% of patients who received the aggressive therapy compared with 11.0% of those who received the conservative therapy, for an odds ratio of 0.82 (P = .001).

The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implemention of the ACC/AHA Guidelines?) Quality Improvement Initiative⁵ analyzed data from a registry of 17,926 patients with non-ST-elevation acute coronary syndrome who were at high risk because of positive cardiac markers or ischemic electrocardiographic changes. Overall, 2.0% of patients who received early invasive care (catheterization within the first 48 hours) died in the hospital compared with 6.2% of those who got no early invasive care, for an adjusted odds ratio of 0.63 (95% confidence interval [CI] 0.52–0.77).

The investigators also stratified the patients into those at low, medium, and high risk, using the criteria of the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin [eptifibatide] Therapy) risk score. There were fewer deaths with early invasive therapy in each risk group, and the risk reduction was greatest in the high-risk group.⁵

Bavry et al⁶ performed an updated meta-analysis of randomized trials. At a mean follow-up of 24 months, the relative risk of death from any cause was 0.75 in patients who received early invasive therapy.

In another meta-analysis, O’Donoghue et al⁷ found that the odds ratio of death, MI, or rehospitalization with acute coronary syndromes was 0.73 (95% CI 0.55–0.98) in men who received invasive vs conservative therapy; in women it was 0.81 (95% CI 0.65–1.01). In women, the benefit was statistically significant in those who had elevations of creatine kinase MB or troponin but not in those who did not, though the benefit in men appeared to be less dependent on the presence of biomarker abnormalities.

MUST ANGIOGRAPHY BE DONE IN THE FIRST 24 HOURS?

Although a number of trials showed that a routine invasive strategy leads to better outcomes than a conservative strategy, until recently we had no information as to whether the catheterization needed to be done early (eg, within the first 24 hours) or if it could be delayed a day or two while the patient received medical therapy.

Mehta et al⁸ conducted a trial to find out: the Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial. Patients were included if they had unstable angina or non-ST-elevation MI, presented to a hospital within 24 hours of the onset of symptoms, and had two of three high-risk features: age 60 years or older, elevated cardiac biomarkers, or electrocardiographic findings compatible with ischemia. All received standard medical therapy, and 3,031 were randomly assigned to undergo angiography either within 24 hours after randomization or 36 or more hours after randomization.

At 6 months, the primary outcome of death, new MI, or stroke had occurred in 9.6% of the patients in the early-intervention group and in 11.3% of those in the delayed-intervention group, but the difference was not statistically significant. However, the difference in the rate of a secondary end point, death, MI, or refractory ischemia, was statistically significant: 9.5% vs 12.9%, P = .003, owing mainly to less refractory ischemia with early intervention.

The patients were also stratified into two groups by baseline risk. The rate of the primary outcome was significantly lower with early intervention in high-risk patients, but not in those at intermediate or low risk. Thus, early intervention may be beneficial in patients at high risk, such as those with ongoing chest pain, but not necessarily in those at low risk.

LEAVE NO LESION BEHIND?

Coronary artery disease often affects more than one segment. Until recently, it was not known whether we should stent all stenotic segments in patients presenting with non-ST-elevation MI or unstable angina, or only the “culprit lesion.”

Shishehbor et al⁹ examined data from a Cleveland Clinic registry of 1,240 patients with acute coronary syndrome and multivessel coronary artery disease who underwent bare-metal stenting. The median follow-up was 2.3 years. Using a propensity model to match patients in the two groups with similar baseline characteristics, they found that the rate of repeat revascularization was less with multivessel intervention than with culprit-only stenting, as was the rate of the combined end point of death, MI, or revascularization, but not that of all-cause mortality or the composite of death or MI.

BARE-METAL VS DRUG-ELUTING STENTS: BALANCING THE RISKS AND BENEFITS

After a patient receives a stent, two bad things can happen: the artery can close up again either gradually, in a process called restenosis, or suddenly, via thrombosis.

Drug-eluting stents were invented to solve the problem of restenosis, and they work very well. Stone et al¹⁰ pooled the data from four double-blind trials of sirolimus (Rapamune) stents and five double-blind trials of paclitaxel (Taxol) stents and found that, at 4 years, the rates of target-lesion revascularization (for restenosis) were 7.8% with sirolimus stents vs 23.6% with bare-metal stents (P < .001), and 10.1% with paclitaxel stents vs 20.0% with bare-metal stents (P < .001).

Thrombosis was much less common in these studies, occurring in 1.2% of the sirolimus stent groups vs 0.6% of the bare-metal stent groups (P = .20), and in 1.3% of the paclitaxel stent groups vs 0.9% of the bare-metal stent groups (P = .30).¹⁰

However, drug-eluting stents appear to increase the risk of thrombosis later on, ie, after 1 year. Bavry et al,¹¹ in a meta-analysis, calculated that when stent thrombosis occurred, the median time after implantation was 15.5 months with sirolimus stents vs 4 months with bare-metal stents (P = .0052), and 18 months with paclitaxel stents vs 3.5 months with bare-metal stents (P = .04). The absolute risk of very late stent thrombosis after 1 year was very low, with five events per 1,000 patients with drug-eluting stents vs no events with bare-metal stents (P = .02). Nevertheless, this finding has practical implications. How long must patients continue dual antiplatelet therapy? And what if a patient needs surgery a year later?

Restenosis is not always so gradual

Although stent thrombosis is serious and often fatal, bare-metal stent restenosis is not always benign either, despite the classic view that stent restenosis is a gradual process that results in exertional angina. Reviewing 1,186 cases of bare-metal stent restenosis in 984 patients at Cleveland Clinic, Chen et al¹² reported that 9.5% of cases presented as acute MI (2.2% as ST-elevation MI and 7.3% as non-ST-elevation MI), and 26.4% as unstable angina requiring hospitalization.

A Mayo Clinic study¹³ corroborated these findings. The 10-year incidence of clinical bare-metal stent restenosis was 18.1%, and the incidence of MI was 2.1%. The 10-year rate of bare-metal stent thrombosis was 2%. Off-label use, primarily in saphenous vein grafts, increased the incidence; other correlates were prior MI, peripheral arterial disease, and ulcerated lesions.

Furthermore, bare-metal stent thrombosis can also occur later. We saw a case that occurred 13 years after the procedure, 3 days after the patient stopped taking aspirin because he was experiencing flu-like symptoms, ran out of aspirin, and felt too sick to go out and buy more. The presentation was with ST-elevation MI. The patient recovered after treatment with intracoronary abciximab (ReoPro), percutaneous thrombectomy, balloon angioplasty, and, eventually, bypass surgery.¹⁴

No difference in risk of death with drug-eluting vs bare-metal stents

Even though drug-eluting stents pose a slightly higher risk of thrombosis than bare-metal stents, the risk of death is no higher.¹⁵

I believe the reason is that there are competing risks, and that the higher risk of thrombosis with first-generation drug-eluting stents and the higher risk of restenosis with bare-metal stents essentially cancel each other out. For most patients, there is an absolute benefit with drug-eluting stents, which reduce the need for revascularization with no effect in terms of either increasing or decreasing the risk of MI or death. Second-generation drug-eluting stents may have advantages in reducing rates of death or MI compared with first-generation drug-eluting stents, though this remains to be proven conclusively.

The right revascularization for the right patient

Bavry and I¹⁶ developed an algorithm for deciding on revascularization, posing a series of questions:

• Does the patient need any form of revascularization?
• Is he or she at higher risk of both stent thrombosis and restenosis, as in patients with diabetes, diffuse multivessel disease with bifurcation lesions, or chronic total occlusions? If so, coronary artery bypass grafting remains an excellent option.
• Does he or she have a low risk of restenosis, as in patients without diabetes with focal lesions in large vessels? If so, one could consider a bare-metal stent, which would probably be more cost-effective than a drug-eluting stent in this situation.
• Does the patient have relative contraindications to drug-eluting stents? Examples are a history of noncompliance with medical therapy, financial issues such as lack of insurance that would make buying clopidogrel (Plavix) a problem, long-term anticoagulation, or anticipated need for surgery in the next few years.

If a drug-eluting stent is used, certain measures can help ensure that it is used optimally. It should often be placed under high pressure with a noncompliant balloon so that it achieves contact with the artery wall all around. One should consider intravascular ultrasonographic guidance to make sure the stent is well opposed if it is in a very calcified lesion. Dual antiplatelet therapy with clopidogrel and aspirin should be given for at least 1 year, and if there is no bleeding, perhaps longer, pending further data.¹⁶

LEAVE NO PLATELET ACTIVATED?

Platelets have several types of receptors that, when bound by their respective ligands, lead to platelet activation and aggregation and, ultimately, thrombus formation. Antagonists to some of these receptors are available or are being developed.¹⁷

For long-term therapy, blocking the process “upstream,” ie, preventing platelet activation, is better than blocking it “downstream,” ie, preventing aggregation. For example, clopidogrel, ticlopipine (Ticlid), and prasugrel (Effient) have active metabolites that bind to a subtype of the adenosine diphosphate receptor and prevent platelet activation, whereas the glycoprotein IIb/IIIa inhibitors such as abciximab work downstream, binding to a different receptor and preventing aggregation.¹⁸

The evidence for using dual antiplatelet therapy (ie, aspirin plus clopidogrel) in patients with acute coronary syndromes without ST-elevation is very well established.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,¹⁹ published in 2001, found a 20% relative risk reduction and a 2% absolute risk reduction in the incidence of MI, stroke, or cardiovascular death in patients randomly assigned to receive clopidogrel plus aspirin for 1 year vs aspirin alone for 1 year (P < .001). In the subgroup of patients who underwent percutaneous coronary intervention, the relative risk reduction in the incidence of MI or cardiovascular death at 1 year of follow-up was 31% (P = .002).²⁰

As a result of these findings, the cardiology society guidelines²¹ recommend a year of dual antiplatelet therapy after acute coronary syndromes, regardless of whether the patient is treated medically, percutaneously, or surgically.

But what happens after clopidogrel is withdrawn? Ho et al²² retrospectively analyzed data from Veterans Affairs hospitals and found a spike in the incidence of death or MI in the first 90 days after stopping clopidogrel treatment. This was true in medically treated patients as well as in those treated with percutaneous coronary interventions, in those with or without diabetes mellitus, in those who received a drug-eluting stent or a bare-metal stent, and in those treated longer than 9 months.

The investigators concluded that there might be a “clopidogrel rebound effect.” However, I believe that a true rebound effect, such as after withdrawal of heparin or warfarin, is biologically unlikely with clopidogrel, since clopidogrel irreversibly binds to its receptor for the 7- to 10-day life span of the platelet. Rather, I believe the phenomenon must be due to withdrawal of protection in patients at risk.

In stable patients, dual therapy is not as beneficial

Would dual antiplatelet therapy with clopidogrel and aspirin also benefit patients at risk of atherothrombotic events but without acute coronary syndromes?

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial²³ included 15,603 patients with either clinically evident but stable cardiovascular disease or multiple risk factors for athero-thrombosis. They were randomly assigned to receive either clopidogrel 75 mg/day plus aspirin 75 to 162 mg/day or placebo plus aspirin. At a median of 28 months, the groups did not differ significantly in the rate of MI, stroke, or death from cardiovascular causes.

However, the subgroup of patients who had documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease did appear to derive significant benefit from dual therapy.²⁴ In this subgroup, the rate of MI, stroke, or cardiovascular death at a median follow-up of 27.6 months was 8.8% with placebo plus aspirin compared with 7.3% with clopidogrel plus aspirin, for a hazard ratio of 0.83 (95% CI 0.72–0.96, P = .01). Unstented patients with stable coronary artery disease but without prior MI derived no benefit.

Bleeding and thrombosis: The Scylla and Charybdis of antiplatelet therapy

However, with dual antiplatelet therapy, we steer between the Scylla of bleeding and the Charybdis of thrombosis.²⁵

In the CHARISMA subgroup who had prior MI, ischemic stroke, or symptomatic peripheral arterial disease, the incidence of moderate or severe bleeding was higher with dual therapy than with aspirin alone, but the rates converged after about 1 year of treatment.²⁴ Further, there was no difference in fatal bleeding or intracranial bleeding, although the rate of moderate bleeding (defined as the need for transfusion) was higher with dual therapy (2.0% vs 1.3%, P = .004).

I believe the data indicate that if a patient can tolerate dual antiplatelet therapy for 9 to 12 months without any bleeding issues, he or she is unlikely to have a major bleeding episode if dual therapy is continued beyond this time.

About half of bleeding events in patients on chronic antiplatelet therapy are gastrointestinal. To address this risk, in 2008 an expert committee from the American College of Cardiology, American College of Gastroenterology, and American Heart Association issued a consensus document²⁶ in which they recommended assessing gastrointestinal risk factors in patients on antiplatelet therapy, such as history of ulcers (and testing for and treating Helicobacter pylori infection if present), history of gastrointestinal bleeding, concomitant anticoagulant therapy, and dual antiplatelet therapy. If any of these were present, the committee recommended considering a proton pump inhibitor. The committee also recommended a proton pump inhibitor for patients on antiplatelet therapy who have more than one of the following: age 60 years or more, corticosteroid use, or dyspepsia or gastroesophageal reflux symptoms.

Some ex vivo platelet studies and observational analyses have suggested that there might be an adverse interaction between clopidogrel and proton pump inhibitors due to a blunting of clopidogrel’s antiplatelet effect. A large randomized clinical trial was designed and launched to determine if a single-pill combination of the proton pump inhibitor omeprazole (Prilosec) and clopidogrel would be safer than clopidogrel alone when added to aspirin. Called COGENT-1 (Clopidogrel and the Optimization of GI Events Trial), it was halted early in 2009 when it lost its funding. However, preliminary data did not show an adverse interaction between clopidogrel and omeprazole.

What is the right dose of aspirin?

Steinhubl et al²⁷ performed a post hoc observational analysis of data from the CHARISMA trial. Their findings suggested that higher doses of aspirin are not more effective than lower doses for chronic therapy. Furthermore, in the group receiving clopidogrel plus aspirin, the incidence of severe or life-threatening bleeding was significantly greater with aspirin doses higher than 100 mg than with doses lower than 100 mg, 2.6% vs 1.7%, P = .040.

A randomized, controlled trial called Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS 7)²⁸ recently reported that higher-dose aspirin (ie, 325 mg) may be better than lower dose aspirin (ie, 81 mg) in patients with acute coronary syndromes undergoing percutaneous coronary intervention and receiving clopidogrel. During this 30-day study, there was no increase in overall bleeding with the higher dose of aspirin, though gastrointestinal bleeding was slightly increased.²⁹ In a factorial design, the second part of this trial found that a higher-dose clopidogrel regimen reduced stent thrombosis.²⁹

In vitro, response to clopidogrel shows a normal bell-shaped distribution.³⁰ In theory, therefore, patients who are hyperresponders may be at higher risk of bleeding, and those who are hyporesponders may be at risk of ischemic events.

A clinical trial is under way to examine whether hyporesponders should get higher doses. Called GRAVITAS (Gauging Responsiveness With a VerifyNow Assay Impact on Thrombosis and Safety), it will use a point-of-care platelet assay and then allocate patients to receive either standard therapy or double the dose of clopidogrel. The primary end point will be the rate of cardiovascular death, nonfatal MI, or stent thrombosis at 6 months.

Is prasugrel better than clopidogrel?

Prasugrel (Effient) is a new drug of the same class as clopidogrel, ie, a thienopyridine, with its active metabolite binding to the same platelet receptor as clopidogrel and inhibiting platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel. Prasugrel was recently approved by the Food and Drug Administration. But is it better?³¹

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) compared prasugrel and clopidogrel in 13,608 patients with moderate- to high-risk acute coronary syndromes who were scheduled to undergo percutaneous coronary intervention.³²

Overall, prasugrel was better. At 15 months, the incidence of the primary end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) was significantly lower with prasugrel therapy than with clopidogrel in the entire cohort (9.9% vs 12.1%, hazard ratio 0.81, 95% CI 0.73–0.90, P < .001), in the subgroup with ST-segment elevation MI, and in the subgroup with unstable angina or non-ST-elevation MI.

However, there was a price to pay. The rate of major bleeding was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% CI 1.03–1.68, P = .03). Assessing the balance between the risk and the benefit, the investigators identified three subgroups who did not derive a net clinical benefit from prasugrel: patients who had had a previous stroke or transient ischemic attack (this group actually had a net harm from prasugrel), patients 75 years of age or older, and patients weighing less than 60 kg (132 pounds).

More work is needed to determine which patients are best served by standard-dose clopidogrel, higher doses of clopidogrel, platelet-assay-guided dosing of clopidogrel, or prasugrel.²⁴

Short-acting, potent intravenous platelet blockade with an agent such as cangrelor is theoretically appealing, but further research is necessary.^33,34 Ticagrelor, a reversible adenosine diphosphate receptor antagonist, provides yet another potential option in antiplatelet therapy for acute coronary syndromes. In the recent PLATO trial (Study of Platelet Inhibition and Patient Outcomes), compared with clopidogrel, ticagrelor reduced the risk of ischemic events, including death.^35,36 Here, too, there was more major bleeding (unrelated to coronary artery bypass grafting) with ticagrelor.

Thus, clinical assessment of an individual patient’s ischemic and bleeding risks will continue to be critical as therapeutic strategies evolve.

A 6-year-old girl was brought by her parents to the emergency department (ED) with an elevated heart rate. According to the parents, the girl was carrying her younger sister when they both fell, landing on their buttocks. The child told them that her heart was beating fast, and the parents said she appeared to be on the verge of fainting.

They stated that their daughter was healthy and active; they denied previous episodes of shortness of breath, headache, weakness, tachycardia, syncope, or fatigue with exercise. Her caffeine intake, they claimed, was limited to one small cup of soda they allowed her each week.

Initial evaluation in the ED revealed an anxious child with tachycardia and shortness of breath. She presented with a temperature of 98.3°F (36.8°C); pulse, 210 beats/min; respirations, 33 breaths/min; blood pressure, 100/72 mm Hg; weight, 78 lb; height, 45 in; and BMI, 27.1. ECG revealed a heart rate exceeding 210 beats/min, and a pediatric cardiologist made a diagnosis of supraventricular tachycardia (SVT).

The pediatric cardiologist prescribed an adenosine IV drip, which successfully stabilized the child’s heart to sinus rhythm. After three hours in the ED, the patient was discharged with a stable heart rate of 100 beats/min. (It is well known that heart rate regulation changes significantly during development; this is most obvious in higher basal rates in infants and children, compared with adults.¹)

The parents were advised to administer atenolol 12.5 mg (one tablet) twice daily and to make a follow-up appointment with a pediatric electrophysiologist. (Although atenolol is not currently FDA approved for this use, a multicenter prospective randomized controlled trial comparing digoxin with beta-blockers for the treatment of SVT in children is presently under way.²)

At that appointment, the pediatric electrophysiologist provided information to the parents regarding the therapeutic options for SVT. The parents continued to administer atenolol to the child, as was deemed necessary until any accessory electrical pathway could be identified and, if so, an ablation procedure could be performed. They were uncertain how to proceed so long as their daughter experienced no recurrent episodes of SVT while receiving pharmacologic therapy.

However, six months after the initial episode, the child (then age 7) presented to the ED once again with recurrent SVT. The pediatric cardiologist ordered an adenosine IV drip, which resulted in successful conversion to sinus rhythm. The parents were instructed to increase the child’s atenolol dosage to 25 mg twice a day.

Six months later, after extensive research and consultation, the parents agreed to an ablation procedure in order to prevent further episodes of SVT. Upon their informed consent, the child was sent to a cardiac catheterization laboratory for an electrophysiology study (EPS), which confirmed the presence of an accessory pathway, as well as the diagnosis of atrioventricular reciprocating tachycardia (AVRT). The procedure was followed by radiofrequency catheter ablation to correct the 7-year-old patient’s accessory pathway–mediated reentry tachycardia.

Discussion
SVT, also known as paroxysmal supraventricular tachycardia (PSVT), is one of the most common symptomatic pediatric arrhythmias, affecting between one in 25,000 and one in 250 children.³ It is defined as rapid heart rhythm (140 to 240 beats/min) that is caused by the presence of additional electrical connections and/or congenital muscle fibers between the atrium and the ventricle or within the atrioventricular (AV) node that did not, for unknown reasons, separate completely during development.⁴ SVT can be triggered by physical or psychological stress automaticity.³

Approximately 50% of children with SVT present with a first episode before age 1. SVT usually occurs in early childhood, between ages 6 and 9.⁴ Almost 90% of pediatric patients with SVT are diagnosed with a reentry mechanism.³ The symptoms experienced may be resolved pharmacologically or by means of an invasive therapy. Serious sequelae associated with SVT include heart failure and cardiac arrest.

For children with rare and mildly symptomatic episodes in whom SVT is easily terminated, the SVT may not warrant treatment. However, it may be advisable to offer medical therapy or transcatheter ablation as therapeutic options for children with episodes that are difficult to terminate, occur frequently, or occur during participation in athletics.⁴

Pathophysiology
SVT generally presents as one of three types: AVRT, which is also known as Wolff-Parkinson-White syndrome; atrioventricular nodal reentry tachycardia (AVNRT); and automatic tachycardia (AT).

AVRT, the most common type of SVT, comprises about 90% of pediatric cases. It is defined by the presence of one or more accessory conduction pathways that are anatomically separated from the normal cardiac conduction system.5 AVRT may be orthodromic (that is, the arrhythmia circuit proceeds down the AV node and retrograde up the accessory conduction pathway) or antedromic (ie, proceeding down the accessory pathway and up the AV node⁵; see figure.^6,7)

AVNRT, considered the second most common type of SVT in children, accounts for about 10% of pediatric cases. AVNRT is caused by an interaction between the two types of pathways within the AV node—one with a fast conduction time and a short refractory period, and the other with a slow conduction time and a long refractory period. AVNRT occurs when the antegrade conduction block in the fast pathway results in conduction over the slow pathway and back up the fast pathway, forming a microreentrant circuit.⁵

AT is the result of rapid depolarization from an automatic focus originating within the atria but outside the sinus node.³

Patient Presentation and History
The typical presentation of AVRT in children of school age includes palpitations, chest pain or tightness, dizziness, anxiety, decrease in exercise tolerance, easy fatigability, and/or shortness of breath.³ Onset is described as abrupt, while termination of SVT is described as slower because the catecholamine levels are typically elevated.⁴

The frequency and duration of SVT can vary greatly, from a few minutes to a few hours; it can occur as regularly as daily or as uncommonly as once or twice per year.⁴ Additionally, SVT symptoms can go unrecognized until a cardiac dysfunction develops. As for the patient in the case study, no apparent factor in her history was identified that may have induced SVT.

The differential diagnosis for SVT is broad, including sinus tachycardia, multifocal atrial tachycardia, and SVT with aberrancy.⁸ Additional considerations include stress, anxiety, hyperthyroidism, electrolyte abnormalities, and dehydration—any of which can present with a tachycardia response.⁴ Furthermore, clinicians are often unlikely to diagnose a child with any cardiac problem because chest pain is more commonly a presenting symptom of a pulmonary or musculoskeletal condition than a cardiac problem.³

Physical Examination
SVT can be diagnosed based on medical history and physical examination. During the physical examination, providers will assess the patient’s blood pressure and pulse, auscultate heart and lung sounds, assess the veins in the patient’s neck for different types of pulsations, and conduct cardiac maneuvers, including the Valsalva maneuver and carotid sinus massage.^9,10

Laboratory Work-up and Diagnosis
Three specific tests help clinicians monitor and evaluate a patient’s conduction system. ECG is important to assess the heart rhythm both at baseline and when symptoms are occurring, if possible.³ Ambulatory ECG (ie, Holter monitoring, event recorders) record the patient’s heart rhythm on a continuous basis.

An EPS, which is performed to classify the mechanism of SVT, is conducted by inserting one or more electrocatheters into the heart by way of the femoral vein or other peripheral vessel.³ Pacing and sensing electrodes at the ends of the catheters record local intracardiac electrical activity and timing information, providing a detailed analysis of the heart’s electrical activity. The EPS is critical to determine the presence of one or more extra electrical pathways within the heart and to localize it by region.^3,11 An ablation procedure may follow.

Management Options
SVT can be treated pharmacologically or nonpharmacologically. First-line pharmacologic options include certain beta-blockers (including atenolol and propranolol), digoxin, and calcium channel blockers. Second-line pharmacologic treatments include amiodarone, flecainide, and sotalol,⁴ all of which are contraindicated in children younger than 1 year because of these patients’ hemodynamic dependency on the heart and inability to generate stroke volume.³ Pharmacologic treatment of SVT is associated with a 68% success rate in children⁴ (see Table 1⁴).

For children in whom pharmacologic treatment is ineffective, an ablation procedure may be performed. Radiofrequency catheter ablation is currently considered first-line therapy for AVRT and AVNRT.¹² In this invasive procedure, intracardiac electrical mapping is performed and the initiating focus of the arrhythmia or the accessory electrical pathway that has been identified within the heart is destroyed by radiofrequency energy, delivered by electrocatheter. Ablations performed during the acute phase of SVT have a 95% success rate.^3,13

Cryoablation is a relatively new treatment in which liquid nitrous oxide is used to cool the catheter to subfreezing temperatures, enabling it to destroy the myocardial tissue by freezing.^3,14 The advantage of cryoablation is the option of reversible cooling, which allows the electrophysiologist to test the area first, confirming the accuracy of the apparent location accessory pathway.¹⁵

Noninvasive, nonpharmacologic interventions that increase the refractoriness of the AV node may be successful in terminating the tachyarrhythmia during episodes of SVT (see Table 2^3,9,13,16). They are used to terminate and diagnose tachydysrhythmias, increase parasympathetic tone, and slow conduction through the AV node.³

Patient Education
It is very important for health care providers to relieve parents’ and caregivers’ stress, anxiety, and uncertainty by educating them about the child’s cardiac condition of SVT. Information to convey include an understanding of what SVT is, what may cause it, what triggers the patient should avoid, what treatments are available and appropriate (including the maneuvers shown in Table 2), and what outcomes may be expected. An excellent patient/family education handout from the Children’s Hospitals and Clinics of Minnesota¹⁷ is available at www.childrensmn.org/Manuals/PFS/Condill/018303.pdf.

Follow-Up
Primary care providers must emphasize the importance of monitoring the patient’s progress, based on the severity of his or her SVT symptoms. The provider may choose to monitor the patient for a few weeks or a few months, assessing the frequency of arrhythmia recurrence and the heart rate, to adjust or substitute medications based on repeat ECG or Holter evaluations, and to plan further therapy, should the condition worsen.⁵

The Case Patient
One month after undergoing radiofrequency catheter ablation, the child presented to the pediatric cardiologist for follow-up. Since the procedure, she had been without any symptoms referable to the cardiovascular system. She denied experiencing any fast heart rate, palpitations, chest pain, shortness of breath, or dizziness. ECG demonstrated normal sinus rhythm.

Two years after undergoing radiofrequency ablation, the child is functioning at a normal activity level with no recurrence of SVT episodes.

Conclusion
The purpose of this case study is to improve primary care providers’ understanding of SVT in children and to convey the importance of identifying the condition in a timely manner and referring patients to a pediatric cardiologist or electrophysiologist. For most children affected by SVT, a regimen of pharmacologic and/or nonpharmacologic treatment—supported by detailed education for their parents and caregivers—can allow them to live a healthy, normal life.

A 6-year-old girl was brought by her parents to the emergency department (ED) with an elevated heart rate. According to the parents, the girl was carrying her younger sister when they both fell, landing on their buttocks. The child told them that her heart was beating fast, and the parents said she appeared to be on the verge of fainting.

They stated that their daughter was healthy and active; they denied previous episodes of shortness of breath, headache, weakness, tachycardia, syncope, or fatigue with exercise. Her caffeine intake, they claimed, was limited to one small cup of soda they allowed her each week.

Initial evaluation in the ED revealed an anxious child with tachycardia and shortness of breath. She presented with a temperature of 98.3°F (36.8°C); pulse, 210 beats/min; respirations, 33 breaths/min; blood pressure, 100/72 mm Hg; weight, 78 lb; height, 45 in; and BMI, 27.1. ECG revealed a heart rate exceeding 210 beats/min, and a pediatric cardiologist made a diagnosis of supraventricular tachycardia (SVT).

The pediatric cardiologist prescribed an adenosine IV drip, which successfully stabilized the child’s heart to sinus rhythm. After three hours in the ED, the patient was discharged with a stable heart rate of 100 beats/min. (It is well known that heart rate regulation changes significantly during development; this is most obvious in higher basal rates in infants and children, compared with adults.¹)

The parents were advised to administer atenolol 12.5 mg (one tablet) twice daily and to make a follow-up appointment with a pediatric electrophysiologist. (Although atenolol is not currently FDA approved for this use, a multicenter prospective randomized controlled trial comparing digoxin with beta-blockers for the treatment of SVT in children is presently under way.²)

At that appointment, the pediatric electrophysiologist provided information to the parents regarding the therapeutic options for SVT. The parents continued to administer atenolol to the child, as was deemed necessary until any accessory electrical pathway could be identified and, if so, an ablation procedure could be performed. They were uncertain how to proceed so long as their daughter experienced no recurrent episodes of SVT while receiving pharmacologic therapy.

However, six months after the initial episode, the child (then age 7) presented to the ED once again with recurrent SVT. The pediatric cardiologist ordered an adenosine IV drip, which resulted in successful conversion to sinus rhythm. The parents were instructed to increase the child’s atenolol dosage to 25 mg twice a day.

Six months later, after extensive research and consultation, the parents agreed to an ablation procedure in order to prevent further episodes of SVT. Upon their informed consent, the child was sent to a cardiac catheterization laboratory for an electrophysiology study (EPS), which confirmed the presence of an accessory pathway, as well as the diagnosis of atrioventricular reciprocating tachycardia (AVRT). The procedure was followed by radiofrequency catheter ablation to correct the 7-year-old patient’s accessory pathway–mediated reentry tachycardia.

Discussion
SVT, also known as paroxysmal supraventricular tachycardia (PSVT), is one of the most common symptomatic pediatric arrhythmias, affecting between one in 25,000 and one in 250 children.³ It is defined as rapid heart rhythm (140 to 240 beats/min) that is caused by the presence of additional electrical connections and/or congenital muscle fibers between the atrium and the ventricle or within the atrioventricular (AV) node that did not, for unknown reasons, separate completely during development.⁴ SVT can be triggered by physical or psychological stress automaticity.³

Approximately 50% of children with SVT present with a first episode before age 1. SVT usually occurs in early childhood, between ages 6 and 9.⁴ Almost 90% of pediatric patients with SVT are diagnosed with a reentry mechanism.³ The symptoms experienced may be resolved pharmacologically or by means of an invasive therapy. Serious sequelae associated with SVT include heart failure and cardiac arrest.

For children with rare and mildly symptomatic episodes in whom SVT is easily terminated, the SVT may not warrant treatment. However, it may be advisable to offer medical therapy or transcatheter ablation as therapeutic options for children with episodes that are difficult to terminate, occur frequently, or occur during participation in athletics.⁴

Pathophysiology
SVT generally presents as one of three types: AVRT, which is also known as Wolff-Parkinson-White syndrome; atrioventricular nodal reentry tachycardia (AVNRT); and automatic tachycardia (AT).

AVRT, the most common type of SVT, comprises about 90% of pediatric cases. It is defined by the presence of one or more accessory conduction pathways that are anatomically separated from the normal cardiac conduction system.5 AVRT may be orthodromic (that is, the arrhythmia circuit proceeds down the AV node and retrograde up the accessory conduction pathway) or antedromic (ie, proceeding down the accessory pathway and up the AV node⁵; see figure.^6,7)

AVNRT, considered the second most common type of SVT in children, accounts for about 10% of pediatric cases. AVNRT is caused by an interaction between the two types of pathways within the AV node—one with a fast conduction time and a short refractory period, and the other with a slow conduction time and a long refractory period. AVNRT occurs when the antegrade conduction block in the fast pathway results in conduction over the slow pathway and back up the fast pathway, forming a microreentrant circuit.⁵

AT is the result of rapid depolarization from an automatic focus originating within the atria but outside the sinus node.³

Patient Presentation and History
The typical presentation of AVRT in children of school age includes palpitations, chest pain or tightness, dizziness, anxiety, decrease in exercise tolerance, easy fatigability, and/or shortness of breath.³ Onset is described as abrupt, while termination of SVT is described as slower because the catecholamine levels are typically elevated.⁴

The frequency and duration of SVT can vary greatly, from a few minutes to a few hours; it can occur as regularly as daily or as uncommonly as once or twice per year.⁴ Additionally, SVT symptoms can go unrecognized until a cardiac dysfunction develops. As for the patient in the case study, no apparent factor in her history was identified that may have induced SVT.

The differential diagnosis for SVT is broad, including sinus tachycardia, multifocal atrial tachycardia, and SVT with aberrancy.⁸ Additional considerations include stress, anxiety, hyperthyroidism, electrolyte abnormalities, and dehydration—any of which can present with a tachycardia response.⁴ Furthermore, clinicians are often unlikely to diagnose a child with any cardiac problem because chest pain is more commonly a presenting symptom of a pulmonary or musculoskeletal condition than a cardiac problem.³

Physical Examination
SVT can be diagnosed based on medical history and physical examination. During the physical examination, providers will assess the patient’s blood pressure and pulse, auscultate heart and lung sounds, assess the veins in the patient’s neck for different types of pulsations, and conduct cardiac maneuvers, including the Valsalva maneuver and carotid sinus massage.^9,10

Laboratory Work-up and Diagnosis
Three specific tests help clinicians monitor and evaluate a patient’s conduction system. ECG is important to assess the heart rhythm both at baseline and when symptoms are occurring, if possible.³ Ambulatory ECG (ie, Holter monitoring, event recorders) record the patient’s heart rhythm on a continuous basis.

An EPS, which is performed to classify the mechanism of SVT, is conducted by inserting one or more electrocatheters into the heart by way of the femoral vein or other peripheral vessel.³ Pacing and sensing electrodes at the ends of the catheters record local intracardiac electrical activity and timing information, providing a detailed analysis of the heart’s electrical activity. The EPS is critical to determine the presence of one or more extra electrical pathways within the heart and to localize it by region.^3,11 An ablation procedure may follow.

Management Options
SVT can be treated pharmacologically or nonpharmacologically. First-line pharmacologic options include certain beta-blockers (including atenolol and propranolol), digoxin, and calcium channel blockers. Second-line pharmacologic treatments include amiodarone, flecainide, and sotalol,⁴ all of which are contraindicated in children younger than 1 year because of these patients’ hemodynamic dependency on the heart and inability to generate stroke volume.³ Pharmacologic treatment of SVT is associated with a 68% success rate in children⁴ (see Table 1⁴).

For children in whom pharmacologic treatment is ineffective, an ablation procedure may be performed. Radiofrequency catheter ablation is currently considered first-line therapy for AVRT and AVNRT.¹² In this invasive procedure, intracardiac electrical mapping is performed and the initiating focus of the arrhythmia or the accessory electrical pathway that has been identified within the heart is destroyed by radiofrequency energy, delivered by electrocatheter. Ablations performed during the acute phase of SVT have a 95% success rate.^3,13

Cryoablation is a relatively new treatment in which liquid nitrous oxide is used to cool the catheter to subfreezing temperatures, enabling it to destroy the myocardial tissue by freezing.^3,14 The advantage of cryoablation is the option of reversible cooling, which allows the electrophysiologist to test the area first, confirming the accuracy of the apparent location accessory pathway.¹⁵

Noninvasive, nonpharmacologic interventions that increase the refractoriness of the AV node may be successful in terminating the tachyarrhythmia during episodes of SVT (see Table 2^3,9,13,16). They are used to terminate and diagnose tachydysrhythmias, increase parasympathetic tone, and slow conduction through the AV node.³

Patient Education
It is very important for health care providers to relieve parents’ and caregivers’ stress, anxiety, and uncertainty by educating them about the child’s cardiac condition of SVT. Information to convey include an understanding of what SVT is, what may cause it, what triggers the patient should avoid, what treatments are available and appropriate (including the maneuvers shown in Table 2), and what outcomes may be expected. An excellent patient/family education handout from the Children’s Hospitals and Clinics of Minnesota¹⁷ is available at www.childrensmn.org/Manuals/PFS/Condill/018303.pdf.

Follow-Up
Primary care providers must emphasize the importance of monitoring the patient’s progress, based on the severity of his or her SVT symptoms. The provider may choose to monitor the patient for a few weeks or a few months, assessing the frequency of arrhythmia recurrence and the heart rate, to adjust or substitute medications based on repeat ECG or Holter evaluations, and to plan further therapy, should the condition worsen.⁵

The Case Patient
One month after undergoing radiofrequency catheter ablation, the child presented to the pediatric cardiologist for follow-up. Since the procedure, she had been without any symptoms referable to the cardiovascular system. She denied experiencing any fast heart rate, palpitations, chest pain, shortness of breath, or dizziness. ECG demonstrated normal sinus rhythm.

Two years after undergoing radiofrequency ablation, the child is functioning at a normal activity level with no recurrence of SVT episodes.

Conclusion
The purpose of this case study is to improve primary care providers’ understanding of SVT in children and to convey the importance of identifying the condition in a timely manner and referring patients to a pediatric cardiologist or electrophysiologist. For most children affected by SVT, a regimen of pharmacologic and/or nonpharmacologic treatment—supported by detailed education for their parents and caregivers—can allow them to live a healthy, normal life.

A 6-year-old girl was brought by her parents to the emergency department (ED) with an elevated heart rate. According to the parents, the girl was carrying her younger sister when they both fell, landing on their buttocks. The child told them that her heart was beating fast, and the parents said she appeared to be on the verge of fainting.

They stated that their daughter was healthy and active; they denied previous episodes of shortness of breath, headache, weakness, tachycardia, syncope, or fatigue with exercise. Her caffeine intake, they claimed, was limited to one small cup of soda they allowed her each week.

Initial evaluation in the ED revealed an anxious child with tachycardia and shortness of breath. She presented with a temperature of 98.3°F (36.8°C); pulse, 210 beats/min; respirations, 33 breaths/min; blood pressure, 100/72 mm Hg; weight, 78 lb; height, 45 in; and BMI, 27.1. ECG revealed a heart rate exceeding 210 beats/min, and a pediatric cardiologist made a diagnosis of supraventricular tachycardia (SVT).

The pediatric cardiologist prescribed an adenosine IV drip, which successfully stabilized the child’s heart to sinus rhythm. After three hours in the ED, the patient was discharged with a stable heart rate of 100 beats/min. (It is well known that heart rate regulation changes significantly during development; this is most obvious in higher basal rates in infants and children, compared with adults.¹)

The parents were advised to administer atenolol 12.5 mg (one tablet) twice daily and to make a follow-up appointment with a pediatric electrophysiologist. (Although atenolol is not currently FDA approved for this use, a multicenter prospective randomized controlled trial comparing digoxin with beta-blockers for the treatment of SVT in children is presently under way.²)

At that appointment, the pediatric electrophysiologist provided information to the parents regarding the therapeutic options for SVT. The parents continued to administer atenolol to the child, as was deemed necessary until any accessory electrical pathway could be identified and, if so, an ablation procedure could be performed. They were uncertain how to proceed so long as their daughter experienced no recurrent episodes of SVT while receiving pharmacologic therapy.

However, six months after the initial episode, the child (then age 7) presented to the ED once again with recurrent SVT. The pediatric cardiologist ordered an adenosine IV drip, which resulted in successful conversion to sinus rhythm. The parents were instructed to increase the child’s atenolol dosage to 25 mg twice a day.

Six months later, after extensive research and consultation, the parents agreed to an ablation procedure in order to prevent further episodes of SVT. Upon their informed consent, the child was sent to a cardiac catheterization laboratory for an electrophysiology study (EPS), which confirmed the presence of an accessory pathway, as well as the diagnosis of atrioventricular reciprocating tachycardia (AVRT). The procedure was followed by radiofrequency catheter ablation to correct the 7-year-old patient’s accessory pathway–mediated reentry tachycardia.

Discussion
SVT, also known as paroxysmal supraventricular tachycardia (PSVT), is one of the most common symptomatic pediatric arrhythmias, affecting between one in 25,000 and one in 250 children.³ It is defined as rapid heart rhythm (140 to 240 beats/min) that is caused by the presence of additional electrical connections and/or congenital muscle fibers between the atrium and the ventricle or within the atrioventricular (AV) node that did not, for unknown reasons, separate completely during development.⁴ SVT can be triggered by physical or psychological stress automaticity.³

Approximately 50% of children with SVT present with a first episode before age 1. SVT usually occurs in early childhood, between ages 6 and 9.⁴ Almost 90% of pediatric patients with SVT are diagnosed with a reentry mechanism.³ The symptoms experienced may be resolved pharmacologically or by means of an invasive therapy. Serious sequelae associated with SVT include heart failure and cardiac arrest.

For children with rare and mildly symptomatic episodes in whom SVT is easily terminated, the SVT may not warrant treatment. However, it may be advisable to offer medical therapy or transcatheter ablation as therapeutic options for children with episodes that are difficult to terminate, occur frequently, or occur during participation in athletics.⁴

Pathophysiology
SVT generally presents as one of three types: AVRT, which is also known as Wolff-Parkinson-White syndrome; atrioventricular nodal reentry tachycardia (AVNRT); and automatic tachycardia (AT).

AVRT, the most common type of SVT, comprises about 90% of pediatric cases. It is defined by the presence of one or more accessory conduction pathways that are anatomically separated from the normal cardiac conduction system.5 AVRT may be orthodromic (that is, the arrhythmia circuit proceeds down the AV node and retrograde up the accessory conduction pathway) or antedromic (ie, proceeding down the accessory pathway and up the AV node⁵; see figure.^6,7)

AVNRT, considered the second most common type of SVT in children, accounts for about 10% of pediatric cases. AVNRT is caused by an interaction between the two types of pathways within the AV node—one with a fast conduction time and a short refractory period, and the other with a slow conduction time and a long refractory period. AVNRT occurs when the antegrade conduction block in the fast pathway results in conduction over the slow pathway and back up the fast pathway, forming a microreentrant circuit.⁵

AT is the result of rapid depolarization from an automatic focus originating within the atria but outside the sinus node.³

Patient Presentation and History
The typical presentation of AVRT in children of school age includes palpitations, chest pain or tightness, dizziness, anxiety, decrease in exercise tolerance, easy fatigability, and/or shortness of breath.³ Onset is described as abrupt, while termination of SVT is described as slower because the catecholamine levels are typically elevated.⁴

The frequency and duration of SVT can vary greatly, from a few minutes to a few hours; it can occur as regularly as daily or as uncommonly as once or twice per year.⁴ Additionally, SVT symptoms can go unrecognized until a cardiac dysfunction develops. As for the patient in the case study, no apparent factor in her history was identified that may have induced SVT.

The differential diagnosis for SVT is broad, including sinus tachycardia, multifocal atrial tachycardia, and SVT with aberrancy.⁸ Additional considerations include stress, anxiety, hyperthyroidism, electrolyte abnormalities, and dehydration—any of which can present with a tachycardia response.⁴ Furthermore, clinicians are often unlikely to diagnose a child with any cardiac problem because chest pain is more commonly a presenting symptom of a pulmonary or musculoskeletal condition than a cardiac problem.³

Physical Examination
SVT can be diagnosed based on medical history and physical examination. During the physical examination, providers will assess the patient’s blood pressure and pulse, auscultate heart and lung sounds, assess the veins in the patient’s neck for different types of pulsations, and conduct cardiac maneuvers, including the Valsalva maneuver and carotid sinus massage.^9,10

Laboratory Work-up and Diagnosis
Three specific tests help clinicians monitor and evaluate a patient’s conduction system. ECG is important to assess the heart rhythm both at baseline and when symptoms are occurring, if possible.³ Ambulatory ECG (ie, Holter monitoring, event recorders) record the patient’s heart rhythm on a continuous basis.

An EPS, which is performed to classify the mechanism of SVT, is conducted by inserting one or more electrocatheters into the heart by way of the femoral vein or other peripheral vessel.³ Pacing and sensing electrodes at the ends of the catheters record local intracardiac electrical activity and timing information, providing a detailed analysis of the heart’s electrical activity. The EPS is critical to determine the presence of one or more extra electrical pathways within the heart and to localize it by region.^3,11 An ablation procedure may follow.

Management Options
SVT can be treated pharmacologically or nonpharmacologically. First-line pharmacologic options include certain beta-blockers (including atenolol and propranolol), digoxin, and calcium channel blockers. Second-line pharmacologic treatments include amiodarone, flecainide, and sotalol,⁴ all of which are contraindicated in children younger than 1 year because of these patients’ hemodynamic dependency on the heart and inability to generate stroke volume.³ Pharmacologic treatment of SVT is associated with a 68% success rate in children⁴ (see Table 1⁴).

For children in whom pharmacologic treatment is ineffective, an ablation procedure may be performed. Radiofrequency catheter ablation is currently considered first-line therapy for AVRT and AVNRT.¹² In this invasive procedure, intracardiac electrical mapping is performed and the initiating focus of the arrhythmia or the accessory electrical pathway that has been identified within the heart is destroyed by radiofrequency energy, delivered by electrocatheter. Ablations performed during the acute phase of SVT have a 95% success rate.^3,13

Cryoablation is a relatively new treatment in which liquid nitrous oxide is used to cool the catheter to subfreezing temperatures, enabling it to destroy the myocardial tissue by freezing.^3,14 The advantage of cryoablation is the option of reversible cooling, which allows the electrophysiologist to test the area first, confirming the accuracy of the apparent location accessory pathway.¹⁵

Noninvasive, nonpharmacologic interventions that increase the refractoriness of the AV node may be successful in terminating the tachyarrhythmia during episodes of SVT (see Table 2^3,9,13,16). They are used to terminate and diagnose tachydysrhythmias, increase parasympathetic tone, and slow conduction through the AV node.³

Patient Education
It is very important for health care providers to relieve parents’ and caregivers’ stress, anxiety, and uncertainty by educating them about the child’s cardiac condition of SVT. Information to convey include an understanding of what SVT is, what may cause it, what triggers the patient should avoid, what treatments are available and appropriate (including the maneuvers shown in Table 2), and what outcomes may be expected. An excellent patient/family education handout from the Children’s Hospitals and Clinics of Minnesota¹⁷ is available at www.childrensmn.org/Manuals/PFS/Condill/018303.pdf.

Follow-Up
Primary care providers must emphasize the importance of monitoring the patient’s progress, based on the severity of his or her SVT symptoms. The provider may choose to monitor the patient for a few weeks or a few months, assessing the frequency of arrhythmia recurrence and the heart rate, to adjust or substitute medications based on repeat ECG or Holter evaluations, and to plan further therapy, should the condition worsen.⁵

The Case Patient
One month after undergoing radiofrequency catheter ablation, the child presented to the pediatric cardiologist for follow-up. Since the procedure, she had been without any symptoms referable to the cardiovascular system. She denied experiencing any fast heart rate, palpitations, chest pain, shortness of breath, or dizziness. ECG demonstrated normal sinus rhythm.

Two years after undergoing radiofrequency ablation, the child is functioning at a normal activity level with no recurrence of SVT episodes.

Conclusion
The purpose of this case study is to improve primary care providers’ understanding of SVT in children and to convey the importance of identifying the condition in a timely manner and referring patients to a pediatric cardiologist or electrophysiologist. For most children affected by SVT, a regimen of pharmacologic and/or nonpharmacologic treatment—supported by detailed education for their parents and caregivers—can allow them to live a healthy, normal life.

A 39-year-old woman presented to the emergency department (ED) with a chief complaint of muscle aches and pain. She stated that three days earlier, she had begun exercising in a 45-minute “spinning” class (ie, riding a stationary bicycle with a weighted front wheel). The patient had not engaged in any aerobic exercise for at least six months before the spinning class. She mentioned that much older participants in the class were outperforming her, but she did not feel the need to keep up with them.

After dismounting, the woman said, she experienced weakness in her legs and had great difficulty ambulating. She went home, took 400 mg of ibuprofen, and went to bed. She awoke with pain and swelling in both thighs and continued to take ibuprofen, in addition to applying a topical mentholated preparation to her thighs. She took an Epsom salts bath two days later.

On the morning of the third day after the spinning class, she voided black urine and presented to the ED.

The patient had no significant medical history. Surgical history was limited to removal of a ganglion cyst on her wrist. She denied any history of seizure disorder, thyroid disease, hepatitis, heart disease, or hyperlipidemia.

The patient had been taking ibuprofen as needed since the spinning class. She was taking no other medications. She denied any allergies to drugs or food.

The patient admitted to smoking one pack of cigarettes per week and to occasional alcohol consumption but denied use of illicit drugs. She was employed as an executive officer for a large business association.

On physical examination, the patient’s vital signs were blood pressure, 134/73 mm/Hg; pulse, 86 beats/min; and respirations, 16 breaths/min. She was afebrile, alert, and oriented. Her sclera were nonicteric. Her neck was supple with no anterior cervical lymphadenopathy. There was no thyroid enlargement, her lungs were clear to auscultation, and her heart sounds were regular. There was no peripheral edema, and dorsalis pedis pulses were present bilaterally. Her thighs appeared swollen but were not tender to palpation.

The patient’s history, combined with an extremely high level of serum creatine phosphokinase (CPK; ie, 123,800 U/L [reference range, 45 to 260 U/L¹]), confirmed a diagnosis of rhabdomyolysis. She was admitted for close observation. The patient’s urinalysis revealed 2 to 5 red blood cells and 6 to 10 white blood cells per high-power field. Moderate occult blood was detected, with no casts or protein noted. A urine myoglobin test was not performed.

The patient underwent IV hydration with dextrose 5% in water and three ampules of sodium bicarbonate after being given a 2.0-L saline bolus. Ibuprofen was discontinued. IV hydration with bicarbonate solution was continued until the patient’s CPK level declined significantly. She underwent daily laboratory testing (see Table 1). Her renal function remained stable, and she was discharged on hospital day 7.

DISCUSSION
Rhabdomyolysis is a clinical condition defined as muscle necrosis resulting from the release of intracellular skeletal muscle components (including myoglobin, CPK, potassium, phosphorus, and aldolase) into the extracellular compartment.^1-3 The condition was first described during the bombing of London in World War II, with high incidence of crush injuries, shock, and associated kidney damage.⁴ The preponderance of such injuries during a 1988 earthquake in Armenia led the International Society of Nephrology to form its Renal Disaster Relief Task Force, which has provided support at numerous other disaster scenes since then.⁵

Rhabdomyolysis has been identified with a variety of pathologic events: those that cause muscle trauma, those associated with muscle use or overuse, and other etiologies involving genetic, metabolic, infectious, or pharmaceutical factors.¹ Many of the reported causes of rhabdomyolysis are listed in Table 2.^1,2

For patients with muscle trauma, the etiology of rhabdomyolysis is clear, but for those with other disease states, diagnosis may be more elusive. Patients who present with rhabdomyolysis after excessive exercise, for example, may have underlying metabolic disorders that predispose them to exertional rhabdomyolysis, such as chronic hypokalemia resulting from primary hyperaldosteronism.¹ Others may have a muscle enzyme deficiency, as in McArdle’s syndrome or carnitine deficiency.⁶

Alterations in blood chemistries can also contribute to development of rhabdomyolysis, even when more obvious etiologies for muscle necrosis are evident. Hypokalemia interferes with the vasodilation that normally occurs during exercise to increase muscle blood flow.^1,7,8 Continued exercise can lead to muscle necrosis, raising a concern for athletes who take diuretics.¹ Hypophosphatemia leads to a state of muscle necrosis; this is of particular concern for alcoholic patients who receive hyperalimentation without repletion of phosphates.⁹

Diagnosis
Patients with rhabdomyolysis usually present with myalgias, darkened urine (red, brown, or black), and a clinical scenario that corroborates the diagnosis (ie, history of trauma, excessive exercise, use of an offending medication).¹ Some patients may have minimal to absent symptoms or symptoms that occur only after exercise.³

A careful history is key. While traumatic causes are obvious, it is important to ask a patient with rhabdomyolysis after exertion about previous history of excessive weakness during or immediately after exercise, excessive cramping, or discoloration of urine after exercise. The family history may point to a genetic abnormality. A thorough understanding of the patient’s use of medications, including OTC agents, is also important. Rhabdomyolysis has been reported in patients who use herbal remedies, including those taken to facilitate weight loss or to improve lipid profiles.^10,11

For patients suspected of having rhabdomyolysis, a serum CPK level should be obtained; results exceeding normal values by five times confirm the diagnosis.³ Measurements for potassium, phosphorus, and calcium are also important to determine, as is renal function. A high level of serum aldolase (an enzyme that breaks down glucose in muscle tissue) can also support a diagnosis of rhabdomyolysis.^1,12 Urinalysis and urine myoglobin testing are also warranted, although a negative urine myoglobin test result does not rule out rhabdomyolysis in the presence of an elevated CPK level. Myoglobin is cleared rapidly by the kidneys, whereas serum CPK levels change slowly.¹

Any patient who presents with acute rhabdomyolysis and low to normal values for potassium or phosphate should be evaluated further for hypokalemia and hypophosphatemia as contributing or etiologic factors. Hypocalcemia may occur in the early course of rhabdomyolysis as calcium salt is deposited in muscle tissue. Patients recovering from rhabdomyolysis may experience rebound hypercalcemia as the damaged muscle releases the deposited calcium.^7,13

In most cases of rhabdomyolysis, only laboratory values are needed to make the diagnosis and follow the course of the episode.¹ However, when the etiology appears to involve metabolic deficiencies or genetic etiologies, it may become necessary to order additional diagnostic tests. These may include tests for thyroid function, a carnitine level to screen for glycogen storage diseases, and toxin screening (eg, for illicit drugs, such as cocaine).^2,6

Treatment and Management
Effective treatment of rhabdomyolysis relies on recognizing the underlying disorder.¹ For patients with muscle trauma (eg, crush injury) or muscle overuse, the mainstay of treatment is aggressive fluid resuscitation and prevention of acute injury to the kidneys.¹³ As for patients with an injury induced by a pharmaceutical agent or a toxin, removal of the offending agent is required, followed by hydration and prevention of renal damage. Supportive care during an infectious illness is also essential.¹⁴

Additionally, treatment must address the complications inherent with rhabdomyolysis.¹ In addition to CPK, potassium, phosphorus, and myoglobin are also released from skeletal muscle tissue. Hyperkalemia can be fatal, and potassium levels must be monitored closely to avert this condition.^7,8,13 During an episode of rhabdomyolysis, normal levels of both potassium and phosphorus should raise the clinician’s suspicion for underlying hypokalemia and hypophosphatemia—conditions that may have contributed to the episode of rhabdomyolysis. Hypocalcemia may also develop.¹³

Released myoglobin may cause acute kidney injury, as is the case in 33% to 50% of patients with rhabdomyolysis.³ In early studies, it was determined that alkalinizing the urine with IV isotonic bicarbonate might thwart onset of acute kidney injury.^1,2,15 Time is critical, and even on the battlefield or at the scene of a recent disaster, most attempts at resuscitation are begun immediately. IV access may be problematic, but administration of oral bicarbonate solutions has also proven effective.¹⁵ Close follow-up of the serum urea and creatinine levels and measurement of the urine pH during alkalinization is warranted throughout the course of the episode.

Unfortunately, some patients respond poorly to these conservative measures, and the released myoglobin can cause renal tubular blockage and necrosis, resulting in acute kidney injury.¹ Renal replacement therapy may be required.¹⁶ However, most episodes of dialysis-dependent acute renal injury do subside with time.

For patients with less elusive causes of rhabdomyolysis, treatment will hinge on a workup of the possible etiologies and follow-up treatment to target the apparent cause. For example, carnitine may be administered to patients with carnitine deficiency, and hypokalemic patients may be given potassium.^1,6,7 These patients will also need counseling before they consider engaging in an exercise program.

Patient’s Outcome
The case patient presented with exertional rhabdomyolysis; improper hydration, severe deconditioning, and a relatively low serum potassium level may all have contributed to the muscle necrosis she experienced. She was given IV alkaline solutions and did not develop acute kidney injury. She was discharged from the hospital and at the time of this writing was awaiting outpatient follow-up.

It should be interesting to see whether the case patient experiences any further episodes of severe weakness after engaging in exercise. Her low-normal potassium level (reference range, 3.5 to 5.3 mmol/L¹⁷) warrants further follow-up, as does her mildly elevated thyroid-stimulating hormone level (reference range, 0.5 to 4.7 mcIU/mL¹⁷).

CONCLUSION
Patients with rhabdomyolysis may present with muscle aches, darkened urine, and/or weakness; an elevated CPK level confirms the diagnosis. Management is mainly conservative, with IV hydration accompanied by alkalinizing the urine and correcting any metabolic abnormalities, such as potassium deficiencies. For the few patients who experience severe acute kidney injury, renal replacement therapy may be necessary.

While most causes of rhabdomyolysis have obvious clinical scenarios, such as a crush injury, a search for muscle enzyme deficiencies, disorders of potassium homeostasis, and thyroid abnormalities is also warranted in patients who present with exertional rhabdomyolysis.

A 39-year-old woman presented to the emergency department (ED) with a chief complaint of muscle aches and pain. She stated that three days earlier, she had begun exercising in a 45-minute “spinning” class (ie, riding a stationary bicycle with a weighted front wheel). The patient had not engaged in any aerobic exercise for at least six months before the spinning class. She mentioned that much older participants in the class were outperforming her, but she did not feel the need to keep up with them.

After dismounting, the woman said, she experienced weakness in her legs and had great difficulty ambulating. She went home, took 400 mg of ibuprofen, and went to bed. She awoke with pain and swelling in both thighs and continued to take ibuprofen, in addition to applying a topical mentholated preparation to her thighs. She took an Epsom salts bath two days later.

On the morning of the third day after the spinning class, she voided black urine and presented to the ED.

The patient had no significant medical history. Surgical history was limited to removal of a ganglion cyst on her wrist. She denied any history of seizure disorder, thyroid disease, hepatitis, heart disease, or hyperlipidemia.

The patient had been taking ibuprofen as needed since the spinning class. She was taking no other medications. She denied any allergies to drugs or food.

The patient admitted to smoking one pack of cigarettes per week and to occasional alcohol consumption but denied use of illicit drugs. She was employed as an executive officer for a large business association.

On physical examination, the patient’s vital signs were blood pressure, 134/73 mm/Hg; pulse, 86 beats/min; and respirations, 16 breaths/min. She was afebrile, alert, and oriented. Her sclera were nonicteric. Her neck was supple with no anterior cervical lymphadenopathy. There was no thyroid enlargement, her lungs were clear to auscultation, and her heart sounds were regular. There was no peripheral edema, and dorsalis pedis pulses were present bilaterally. Her thighs appeared swollen but were not tender to palpation.

The patient’s history, combined with an extremely high level of serum creatine phosphokinase (CPK; ie, 123,800 U/L [reference range, 45 to 260 U/L¹]), confirmed a diagnosis of rhabdomyolysis. She was admitted for close observation. The patient’s urinalysis revealed 2 to 5 red blood cells and 6 to 10 white blood cells per high-power field. Moderate occult blood was detected, with no casts or protein noted. A urine myoglobin test was not performed.

The patient underwent IV hydration with dextrose 5% in water and three ampules of sodium bicarbonate after being given a 2.0-L saline bolus. Ibuprofen was discontinued. IV hydration with bicarbonate solution was continued until the patient’s CPK level declined significantly. She underwent daily laboratory testing (see Table 1). Her renal function remained stable, and she was discharged on hospital day 7.

DISCUSSION
Rhabdomyolysis is a clinical condition defined as muscle necrosis resulting from the release of intracellular skeletal muscle components (including myoglobin, CPK, potassium, phosphorus, and aldolase) into the extracellular compartment.^1-3 The condition was first described during the bombing of London in World War II, with high incidence of crush injuries, shock, and associated kidney damage.⁴ The preponderance of such injuries during a 1988 earthquake in Armenia led the International Society of Nephrology to form its Renal Disaster Relief Task Force, which has provided support at numerous other disaster scenes since then.⁵

Rhabdomyolysis has been identified with a variety of pathologic events: those that cause muscle trauma, those associated with muscle use or overuse, and other etiologies involving genetic, metabolic, infectious, or pharmaceutical factors.¹ Many of the reported causes of rhabdomyolysis are listed in Table 2.^1,2

For patients with muscle trauma, the etiology of rhabdomyolysis is clear, but for those with other disease states, diagnosis may be more elusive. Patients who present with rhabdomyolysis after excessive exercise, for example, may have underlying metabolic disorders that predispose them to exertional rhabdomyolysis, such as chronic hypokalemia resulting from primary hyperaldosteronism.¹ Others may have a muscle enzyme deficiency, as in McArdle’s syndrome or carnitine deficiency.⁶

Alterations in blood chemistries can also contribute to development of rhabdomyolysis, even when more obvious etiologies for muscle necrosis are evident. Hypokalemia interferes with the vasodilation that normally occurs during exercise to increase muscle blood flow.^1,7,8 Continued exercise can lead to muscle necrosis, raising a concern for athletes who take diuretics.¹ Hypophosphatemia leads to a state of muscle necrosis; this is of particular concern for alcoholic patients who receive hyperalimentation without repletion of phosphates.⁹

Diagnosis
Patients with rhabdomyolysis usually present with myalgias, darkened urine (red, brown, or black), and a clinical scenario that corroborates the diagnosis (ie, history of trauma, excessive exercise, use of an offending medication).¹ Some patients may have minimal to absent symptoms or symptoms that occur only after exercise.³

A careful history is key. While traumatic causes are obvious, it is important to ask a patient with rhabdomyolysis after exertion about previous history of excessive weakness during or immediately after exercise, excessive cramping, or discoloration of urine after exercise. The family history may point to a genetic abnormality. A thorough understanding of the patient’s use of medications, including OTC agents, is also important. Rhabdomyolysis has been reported in patients who use herbal remedies, including those taken to facilitate weight loss or to improve lipid profiles.^10,11

For patients suspected of having rhabdomyolysis, a serum CPK level should be obtained; results exceeding normal values by five times confirm the diagnosis.³ Measurements for potassium, phosphorus, and calcium are also important to determine, as is renal function. A high level of serum aldolase (an enzyme that breaks down glucose in muscle tissue) can also support a diagnosis of rhabdomyolysis.^1,12 Urinalysis and urine myoglobin testing are also warranted, although a negative urine myoglobin test result does not rule out rhabdomyolysis in the presence of an elevated CPK level. Myoglobin is cleared rapidly by the kidneys, whereas serum CPK levels change slowly.¹

Any patient who presents with acute rhabdomyolysis and low to normal values for potassium or phosphate should be evaluated further for hypokalemia and hypophosphatemia as contributing or etiologic factors. Hypocalcemia may occur in the early course of rhabdomyolysis as calcium salt is deposited in muscle tissue. Patients recovering from rhabdomyolysis may experience rebound hypercalcemia as the damaged muscle releases the deposited calcium.^7,13

In most cases of rhabdomyolysis, only laboratory values are needed to make the diagnosis and follow the course of the episode.¹ However, when the etiology appears to involve metabolic deficiencies or genetic etiologies, it may become necessary to order additional diagnostic tests. These may include tests for thyroid function, a carnitine level to screen for glycogen storage diseases, and toxin screening (eg, for illicit drugs, such as cocaine).^2,6

Treatment and Management
Effective treatment of rhabdomyolysis relies on recognizing the underlying disorder.¹ For patients with muscle trauma (eg, crush injury) or muscle overuse, the mainstay of treatment is aggressive fluid resuscitation and prevention of acute injury to the kidneys.¹³ As for patients with an injury induced by a pharmaceutical agent or a toxin, removal of the offending agent is required, followed by hydration and prevention of renal damage. Supportive care during an infectious illness is also essential.¹⁴

Additionally, treatment must address the complications inherent with rhabdomyolysis.¹ In addition to CPK, potassium, phosphorus, and myoglobin are also released from skeletal muscle tissue. Hyperkalemia can be fatal, and potassium levels must be monitored closely to avert this condition.^7,8,13 During an episode of rhabdomyolysis, normal levels of both potassium and phosphorus should raise the clinician’s suspicion for underlying hypokalemia and hypophosphatemia—conditions that may have contributed to the episode of rhabdomyolysis. Hypocalcemia may also develop.¹³

Released myoglobin may cause acute kidney injury, as is the case in 33% to 50% of patients with rhabdomyolysis.³ In early studies, it was determined that alkalinizing the urine with IV isotonic bicarbonate might thwart onset of acute kidney injury.^1,2,15 Time is critical, and even on the battlefield or at the scene of a recent disaster, most attempts at resuscitation are begun immediately. IV access may be problematic, but administration of oral bicarbonate solutions has also proven effective.¹⁵ Close follow-up of the serum urea and creatinine levels and measurement of the urine pH during alkalinization is warranted throughout the course of the episode.

Unfortunately, some patients respond poorly to these conservative measures, and the released myoglobin can cause renal tubular blockage and necrosis, resulting in acute kidney injury.¹ Renal replacement therapy may be required.¹⁶ However, most episodes of dialysis-dependent acute renal injury do subside with time.

For patients with less elusive causes of rhabdomyolysis, treatment will hinge on a workup of the possible etiologies and follow-up treatment to target the apparent cause. For example, carnitine may be administered to patients with carnitine deficiency, and hypokalemic patients may be given potassium.^1,6,7 These patients will also need counseling before they consider engaging in an exercise program.

Patient’s Outcome
The case patient presented with exertional rhabdomyolysis; improper hydration, severe deconditioning, and a relatively low serum potassium level may all have contributed to the muscle necrosis she experienced. She was given IV alkaline solutions and did not develop acute kidney injury. She was discharged from the hospital and at the time of this writing was awaiting outpatient follow-up.

It should be interesting to see whether the case patient experiences any further episodes of severe weakness after engaging in exercise. Her low-normal potassium level (reference range, 3.5 to 5.3 mmol/L¹⁷) warrants further follow-up, as does her mildly elevated thyroid-stimulating hormone level (reference range, 0.5 to 4.7 mcIU/mL¹⁷).

CONCLUSION
Patients with rhabdomyolysis may present with muscle aches, darkened urine, and/or weakness; an elevated CPK level confirms the diagnosis. Management is mainly conservative, with IV hydration accompanied by alkalinizing the urine and correcting any metabolic abnormalities, such as potassium deficiencies. For the few patients who experience severe acute kidney injury, renal replacement therapy may be necessary.

While most causes of rhabdomyolysis have obvious clinical scenarios, such as a crush injury, a search for muscle enzyme deficiencies, disorders of potassium homeostasis, and thyroid abnormalities is also warranted in patients who present with exertional rhabdomyolysis.

A 39-year-old woman presented to the emergency department (ED) with a chief complaint of muscle aches and pain. She stated that three days earlier, she had begun exercising in a 45-minute “spinning” class (ie, riding a stationary bicycle with a weighted front wheel). The patient had not engaged in any aerobic exercise for at least six months before the spinning class. She mentioned that much older participants in the class were outperforming her, but she did not feel the need to keep up with them.

After dismounting, the woman said, she experienced weakness in her legs and had great difficulty ambulating. She went home, took 400 mg of ibuprofen, and went to bed. She awoke with pain and swelling in both thighs and continued to take ibuprofen, in addition to applying a topical mentholated preparation to her thighs. She took an Epsom salts bath two days later.

On the morning of the third day after the spinning class, she voided black urine and presented to the ED.

The patient had no significant medical history. Surgical history was limited to removal of a ganglion cyst on her wrist. She denied any history of seizure disorder, thyroid disease, hepatitis, heart disease, or hyperlipidemia.

The patient had been taking ibuprofen as needed since the spinning class. She was taking no other medications. She denied any allergies to drugs or food.

The patient admitted to smoking one pack of cigarettes per week and to occasional alcohol consumption but denied use of illicit drugs. She was employed as an executive officer for a large business association.

On physical examination, the patient’s vital signs were blood pressure, 134/73 mm/Hg; pulse, 86 beats/min; and respirations, 16 breaths/min. She was afebrile, alert, and oriented. Her sclera were nonicteric. Her neck was supple with no anterior cervical lymphadenopathy. There was no thyroid enlargement, her lungs were clear to auscultation, and her heart sounds were regular. There was no peripheral edema, and dorsalis pedis pulses were present bilaterally. Her thighs appeared swollen but were not tender to palpation.

The patient’s history, combined with an extremely high level of serum creatine phosphokinase (CPK; ie, 123,800 U/L [reference range, 45 to 260 U/L¹]), confirmed a diagnosis of rhabdomyolysis. She was admitted for close observation. The patient’s urinalysis revealed 2 to 5 red blood cells and 6 to 10 white blood cells per high-power field. Moderate occult blood was detected, with no casts or protein noted. A urine myoglobin test was not performed.

The patient underwent IV hydration with dextrose 5% in water and three ampules of sodium bicarbonate after being given a 2.0-L saline bolus. Ibuprofen was discontinued. IV hydration with bicarbonate solution was continued until the patient’s CPK level declined significantly. She underwent daily laboratory testing (see Table 1). Her renal function remained stable, and she was discharged on hospital day 7.

DISCUSSION
Rhabdomyolysis is a clinical condition defined as muscle necrosis resulting from the release of intracellular skeletal muscle components (including myoglobin, CPK, potassium, phosphorus, and aldolase) into the extracellular compartment.^1-3 The condition was first described during the bombing of London in World War II, with high incidence of crush injuries, shock, and associated kidney damage.⁴ The preponderance of such injuries during a 1988 earthquake in Armenia led the International Society of Nephrology to form its Renal Disaster Relief Task Force, which has provided support at numerous other disaster scenes since then.⁵

Rhabdomyolysis has been identified with a variety of pathologic events: those that cause muscle trauma, those associated with muscle use or overuse, and other etiologies involving genetic, metabolic, infectious, or pharmaceutical factors.¹ Many of the reported causes of rhabdomyolysis are listed in Table 2.^1,2

For patients with muscle trauma, the etiology of rhabdomyolysis is clear, but for those with other disease states, diagnosis may be more elusive. Patients who present with rhabdomyolysis after excessive exercise, for example, may have underlying metabolic disorders that predispose them to exertional rhabdomyolysis, such as chronic hypokalemia resulting from primary hyperaldosteronism.¹ Others may have a muscle enzyme deficiency, as in McArdle’s syndrome or carnitine deficiency.⁶

Alterations in blood chemistries can also contribute to development of rhabdomyolysis, even when more obvious etiologies for muscle necrosis are evident. Hypokalemia interferes with the vasodilation that normally occurs during exercise to increase muscle blood flow.^1,7,8 Continued exercise can lead to muscle necrosis, raising a concern for athletes who take diuretics.¹ Hypophosphatemia leads to a state of muscle necrosis; this is of particular concern for alcoholic patients who receive hyperalimentation without repletion of phosphates.⁹

Diagnosis
Patients with rhabdomyolysis usually present with myalgias, darkened urine (red, brown, or black), and a clinical scenario that corroborates the diagnosis (ie, history of trauma, excessive exercise, use of an offending medication).¹ Some patients may have minimal to absent symptoms or symptoms that occur only after exercise.³

A careful history is key. While traumatic causes are obvious, it is important to ask a patient with rhabdomyolysis after exertion about previous history of excessive weakness during or immediately after exercise, excessive cramping, or discoloration of urine after exercise. The family history may point to a genetic abnormality. A thorough understanding of the patient’s use of medications, including OTC agents, is also important. Rhabdomyolysis has been reported in patients who use herbal remedies, including those taken to facilitate weight loss or to improve lipid profiles.^10,11

For patients suspected of having rhabdomyolysis, a serum CPK level should be obtained; results exceeding normal values by five times confirm the diagnosis.³ Measurements for potassium, phosphorus, and calcium are also important to determine, as is renal function. A high level of serum aldolase (an enzyme that breaks down glucose in muscle tissue) can also support a diagnosis of rhabdomyolysis.^1,12 Urinalysis and urine myoglobin testing are also warranted, although a negative urine myoglobin test result does not rule out rhabdomyolysis in the presence of an elevated CPK level. Myoglobin is cleared rapidly by the kidneys, whereas serum CPK levels change slowly.¹

Any patient who presents with acute rhabdomyolysis and low to normal values for potassium or phosphate should be evaluated further for hypokalemia and hypophosphatemia as contributing or etiologic factors. Hypocalcemia may occur in the early course of rhabdomyolysis as calcium salt is deposited in muscle tissue. Patients recovering from rhabdomyolysis may experience rebound hypercalcemia as the damaged muscle releases the deposited calcium.^7,13

In most cases of rhabdomyolysis, only laboratory values are needed to make the diagnosis and follow the course of the episode.¹ However, when the etiology appears to involve metabolic deficiencies or genetic etiologies, it may become necessary to order additional diagnostic tests. These may include tests for thyroid function, a carnitine level to screen for glycogen storage diseases, and toxin screening (eg, for illicit drugs, such as cocaine).^2,6

Treatment and Management
Effective treatment of rhabdomyolysis relies on recognizing the underlying disorder.¹ For patients with muscle trauma (eg, crush injury) or muscle overuse, the mainstay of treatment is aggressive fluid resuscitation and prevention of acute injury to the kidneys.¹³ As for patients with an injury induced by a pharmaceutical agent or a toxin, removal of the offending agent is required, followed by hydration and prevention of renal damage. Supportive care during an infectious illness is also essential.¹⁴

Additionally, treatment must address the complications inherent with rhabdomyolysis.¹ In addition to CPK, potassium, phosphorus, and myoglobin are also released from skeletal muscle tissue. Hyperkalemia can be fatal, and potassium levels must be monitored closely to avert this condition.^7,8,13 During an episode of rhabdomyolysis, normal levels of both potassium and phosphorus should raise the clinician’s suspicion for underlying hypokalemia and hypophosphatemia—conditions that may have contributed to the episode of rhabdomyolysis. Hypocalcemia may also develop.¹³

Released myoglobin may cause acute kidney injury, as is the case in 33% to 50% of patients with rhabdomyolysis.³ In early studies, it was determined that alkalinizing the urine with IV isotonic bicarbonate might thwart onset of acute kidney injury.^1,2,15 Time is critical, and even on the battlefield or at the scene of a recent disaster, most attempts at resuscitation are begun immediately. IV access may be problematic, but administration of oral bicarbonate solutions has also proven effective.¹⁵ Close follow-up of the serum urea and creatinine levels and measurement of the urine pH during alkalinization is warranted throughout the course of the episode.

Unfortunately, some patients respond poorly to these conservative measures, and the released myoglobin can cause renal tubular blockage and necrosis, resulting in acute kidney injury.¹ Renal replacement therapy may be required.¹⁶ However, most episodes of dialysis-dependent acute renal injury do subside with time.

For patients with less elusive causes of rhabdomyolysis, treatment will hinge on a workup of the possible etiologies and follow-up treatment to target the apparent cause. For example, carnitine may be administered to patients with carnitine deficiency, and hypokalemic patients may be given potassium.^1,6,7 These patients will also need counseling before they consider engaging in an exercise program.

Patient’s Outcome
The case patient presented with exertional rhabdomyolysis; improper hydration, severe deconditioning, and a relatively low serum potassium level may all have contributed to the muscle necrosis she experienced. She was given IV alkaline solutions and did not develop acute kidney injury. She was discharged from the hospital and at the time of this writing was awaiting outpatient follow-up.

It should be interesting to see whether the case patient experiences any further episodes of severe weakness after engaging in exercise. Her low-normal potassium level (reference range, 3.5 to 5.3 mmol/L¹⁷) warrants further follow-up, as does her mildly elevated thyroid-stimulating hormone level (reference range, 0.5 to 4.7 mcIU/mL¹⁷).

CONCLUSION
Patients with rhabdomyolysis may present with muscle aches, darkened urine, and/or weakness; an elevated CPK level confirms the diagnosis. Management is mainly conservative, with IV hydration accompanied by alkalinizing the urine and correcting any metabolic abnormalities, such as potassium deficiencies. For the few patients who experience severe acute kidney injury, renal replacement therapy may be necessary.

While most causes of rhabdomyolysis have obvious clinical scenarios, such as a crush injury, a search for muscle enzyme deficiencies, disorders of potassium homeostasis, and thyroid abnormalities is also warranted in patients who present with exertional rhabdomyolysis.

A 29-year-old man presented to the emergency department (ED) with a chief complaint of food stuck in his throat. He reported that he had swallowed a piece of chicken and felt it get stuck. Drinking water to help it go down was unsuccessful.

The patient’s history was positive for childhood asthma and nine years of solid food dysphagia. There was no history of a caustic chemical ingestion or of drug-induced esophagitis. He denied having dyspepsia, heartburn, or chest pain. He was not taking any medications and had no allergies.

When his dysphagia symptoms began nine years ago, he was diagnosed with acid reflux disease, confirmed by an upper gastrointestinal (GI) tract x-ray. Since that time, he reported having to swallow liquid after every bite of food and said he suffered from severe anxiety over fear of choking.

Evaluation in the ED consisted of endoscopic examination by a gastroenterologist. In addition to dislodging a food bolus, the endoscope revealed a narrowed, ringed esophagus with mucosal changes throughout the length of the esophagus (see Figures 1 through 3). Esophageal biopsies were taken, and the esophagus was dilated successfully with a 40-Fr Maloney dilator. The endoscopist detected too much resistance to pass a larger dilator.

Biopsy results revealed eosinophilic esophagitis. The patient was given oral fluticasone propionate. At one-month follow-up, he reported feeling much better. Upper endoscopy revealed some improvement, and the gastroenterologist was able to pass both a 46- and a 48-Fr Maloney dilator with only mild resistance. (The largest Maloney dilator, a 60-Fr dilator, should easily pass through a normal esophagus, according to T. L. Sack, MD, oral communication, June 2009.)

Discussion
Eosinophilic esophagitis (EE) involves the infiltration of the esophageal mucosa with eosinophils, causing edema, inflammation, and eventually, thickening and stenotic changes of the esophageal mucosa.¹

The normal esophageal mucosa contains lymphocytes, mast cells, and dendritic cells, which protect the esophagus from invading toxins and microorganisms. Eosinophils are not usually present, but when they are, they can have toxic effects on the esophageal mucosa.² EE is associated with solid food dysphagia, a direct result of damage to the esophageal mucosa, and other causes that are not clearly understood.

Research findings suggest that symptoms of dysphagia may be caused by degranulating eosinophils and mast cells, which have an antagonistic effect on the muscarinic receptors and cause smooth muscle to contract.^3,4 The proposed triggering mechanism of EE is an immunoglobulin E (IgE) immune–mediated response to an allergen.² Based on results from IgE radioallergosorbent testing (RAST), aeroallergens are more likely than food to act as triggers.⁵

EE in the Adult Patient
Traditionally, EE has been a condition seen in the pediatric population, with symptoms of nausea, vomiting, and failure to thrive; however, it is becoming increasingly recognized among adults. The typical patient is a man in his 20s or 30s (although cases of EE have been reported among women and older adults) with acute and recurrent solid food dysphagia, with or without food impaction.⁴

Often the patient reports a history of environmental or food allergies, asthma, rhinitis, or eczema.^2,4-6 Researchers have reported the presence of allergic symptoms in at least 50% of patients diagnosed with EE,² and many patients experience exacerbations associated with seasonal changes.⁷

GERD may coexist with EE; however, no relationship has been identified between the two.⁸ EE should be considered in patients with gastrointestinal symptoms that persist despite at least four weeks’ treatment with a proton pump inhibitor (PPI).²

Dysphagia: Differential Diagnosis
Adult patients with esophageal dysphagia usually report the feeling of food getting stuck when they try to swallow.⁹ Dysphagia may result from a mechanical obstruction or a neuromuscular/motility condition. Patients with mechanical obstructions usually have difficulty swallowing solids, while those with motility disorders tend to have difficulty with both liquids and solids.^1,9

Mechanical obstructions may include carcinomas (intrinsic and extrinsic), strictures, or Schatzki rings (small thin mucosal rings of unknown etiology located at the gastroesophageal junction).^1,9 Progressive dysphagia to solids over a short period of time is often indicative of esophageal carcinoma. GERD, pill-induced trauma, previous ingestion of a caustic chemical, and radiation are common causes of esophageal stricture formation. For a list of medications that are particularly caustic to the esophageal mucosa, see the table.^9,10

Neuromuscular manifestations of dysphagia include achalasia, diffuse esophageal spasm, nutcracker esophagus, and scleroderma.¹ These are usually associated with progressive difficulty in swallowing.⁹

Evaluating the Patient
A thorough patient history can often reveal potential causes of dysphagia and eliminate others. This should include current medications, chronic medical conditions and details regarding their onset and duration, and symptoms associated with dysphagia.⁹

Physical examination should include palpation of the thyroid because of the potential for a thyroid mass to cause extrinsic compression of the esophagus, palpation of the abdomen for masses or organomegaly, and a complete neurologic evaluation.⁹

Laboratory tests should be ordered based on the information obtained from the history and physical. Testing may include thyroid studies to eliminate hypothyroid or hyperthyroid causes of dysphagia, and complete blood count (CBC) with differential to rule out inflammatory or infectious processes.⁹ While eosinophilia may be present in the differential, it is not a universally accepted marker for establishing the diagnosis of EE.^2,5 Stools should be checked for occult blood, because a positive finding may suggest esophageal carcinoma.⁹

Diagnosis
In the primary care setting, a barium esophagram may be used during the initial workup to evaluate the anatomic structures of the esophagus and to differentiate between a mechanical obstruction and a neuromuscular disorder.^1,9 This noninvasive test requires the patient to swallow a radiopaque liquid as x-rays are taken.

The gold standard for diagnosing EE, however, is upper endoscopy with biopsy of the esophageal mucosa.⁶ Endoscopic findings that indicate EE are atypical of GERD; they may include a narrowed, small-caliber esophagus, concentric mucosal rings, proximal stenosis, linear ulcerations, atrophic changes, and white papules associated with eosinophilic microabscesses.⁶

Although there is no consensus regarding the number of eosinophils that should be present for an accurate diagnosis of EE, microscopic interpretation of the biopsy from both the proximal and the distal esophageal epithelia⁵ usually shows 15 or more eosinophils per high-power field.^2,11 It has been suggested that mucosal biopsies be taken along the entire length of the esophagus, as eosinophilic infiltration may extend from the proximal to the distal esophagus.²

GERD and trauma induced by medication use may also be associated with esophageal eosinophilic infiltration5; however, eosinophils are usually present only in the distal esophageal mucosa³ and are not as abundant as in EE.⁷ If endoscopy reveals persistent eosinophilia despite four to eight weeks’ treatment with a PPI, the diagnosis of EE is confirmed.²

Treatment
Treatment for EE is still under investigation. Research has examined the association between EE and food allergies or aeroallergens.⁴ Evaluation by an allergist using skin prick tests or RAST is recommended in the adult patient to help determine the source of the underlying inflammation.^5,7 Eliminating any identified allergen should help alleviate symptoms.⁴

For patients in whom no source of inflammation can be identified, treatment with 1.0 to 2.0 mg/kg/d of oral prednisone for acute exacerbations has been shown to significantly improve symptoms and histology¹²; however, because of the associated risk for adverse systemic effects, long-term use is not recommended.

In many patients, the inhaled corticosteroid fluticasone has also proved successful in reducing EE—associated inflammation.⁶ Current evidence supports adult dosing between 880 and 1,760 mcg per day for six to eight weeks, administered with a metered-dose inhaler and no spacer. Fluticasone should be sprayed directly into the mouth and swallowed, after which the patient should take nothing by mouth for 30 minutes.¹³ Prolonged fluticasone use has been associated with esophageal candidiasis.² There are currently no recommendations regarding its use as maintenance therapy.

Montelukast, a leukotriene receptor antagonist, has also been shown in some studies to reduce the inflammatory process¹¹; however, one study team recently found it to have no therapeutic effect.¹³

PPIs may be effective for improving EE symptoms even in the absence of GERD because of the reduced gastric acid production,⁷ but they do not usually improve EE’s histologic features.³

Use of esophageal dilation in patients with EE is controversial because of an associated risk for perforation.¹⁴ If this intervention is to be performed, the patient should be treated in advance with oral corticosteroids to reduce esophageal inflammation.^15,16 In addition, the endoscopist should start with small-sized dilators and carefully proceed to larger sizes.¹¹ Critics of esophageal dilation argue that the procedure is only a temporary solution and does nothing for the underlying condition.^4,8

Regarding endoscopic surveillance, an interval of at least four weeks between interventions is recommended.¹³

Role of the Primary Care Clinician
Undiagnosed EE can cause the patient discomfort, frustration, and anxiety, as seen in the case study. Many patients with undiagnosed EE have been exposed to unnecessary medical therapy and antireflux surgery.³ Without proper diagnosis and treatment, EE may worsen, causing complications associated with chronic inflammation (ie, esophageal fibrosis and strictures).^2,6

The long-term prognosis of EE is unknown at this time.⁸ The disease is usually chronic, with periods of remission and exacerbation. With an understanding of EE and appropriate therapies, the primary care practitioner can team with the gastroenterologist to provide effective disease management through endoscopic surveillance and intervention for acute exacerbations. Guidelines recommend that patients be closely followed with regular office visits to reassess symptoms, compliance with therapy, and adverse effects, with the goal of preventing complications associated with EE.¹³

Conclusion
To effectively evaluate the patient who presents with dysphagia, the primary care provider should have a working knowledge of EE, as well as an understanding of the key elements in the history and physical examination to help ensure an accurate diagnosis. This will facilitate timely referral to a gastroenterologist for endoscopic evaluation, when indicated.         

A 29-year-old man presented to the emergency department (ED) with a chief complaint of food stuck in his throat. He reported that he had swallowed a piece of chicken and felt it get stuck. Drinking water to help it go down was unsuccessful.

The patient’s history was positive for childhood asthma and nine years of solid food dysphagia. There was no history of a caustic chemical ingestion or of drug-induced esophagitis. He denied having dyspepsia, heartburn, or chest pain. He was not taking any medications and had no allergies.

When his dysphagia symptoms began nine years ago, he was diagnosed with acid reflux disease, confirmed by an upper gastrointestinal (GI) tract x-ray. Since that time, he reported having to swallow liquid after every bite of food and said he suffered from severe anxiety over fear of choking.

Evaluation in the ED consisted of endoscopic examination by a gastroenterologist. In addition to dislodging a food bolus, the endoscope revealed a narrowed, ringed esophagus with mucosal changes throughout the length of the esophagus (see Figures 1 through 3). Esophageal biopsies were taken, and the esophagus was dilated successfully with a 40-Fr Maloney dilator. The endoscopist detected too much resistance to pass a larger dilator.

Biopsy results revealed eosinophilic esophagitis. The patient was given oral fluticasone propionate. At one-month follow-up, he reported feeling much better. Upper endoscopy revealed some improvement, and the gastroenterologist was able to pass both a 46- and a 48-Fr Maloney dilator with only mild resistance. (The largest Maloney dilator, a 60-Fr dilator, should easily pass through a normal esophagus, according to T. L. Sack, MD, oral communication, June 2009.)

Discussion
Eosinophilic esophagitis (EE) involves the infiltration of the esophageal mucosa with eosinophils, causing edema, inflammation, and eventually, thickening and stenotic changes of the esophageal mucosa.¹

The normal esophageal mucosa contains lymphocytes, mast cells, and dendritic cells, which protect the esophagus from invading toxins and microorganisms. Eosinophils are not usually present, but when they are, they can have toxic effects on the esophageal mucosa.² EE is associated with solid food dysphagia, a direct result of damage to the esophageal mucosa, and other causes that are not clearly understood.

Research findings suggest that symptoms of dysphagia may be caused by degranulating eosinophils and mast cells, which have an antagonistic effect on the muscarinic receptors and cause smooth muscle to contract.^3,4 The proposed triggering mechanism of EE is an immunoglobulin E (IgE) immune–mediated response to an allergen.² Based on results from IgE radioallergosorbent testing (RAST), aeroallergens are more likely than food to act as triggers.⁵

EE in the Adult Patient
Traditionally, EE has been a condition seen in the pediatric population, with symptoms of nausea, vomiting, and failure to thrive; however, it is becoming increasingly recognized among adults. The typical patient is a man in his 20s or 30s (although cases of EE have been reported among women and older adults) with acute and recurrent solid food dysphagia, with or without food impaction.⁴

Often the patient reports a history of environmental or food allergies, asthma, rhinitis, or eczema.^2,4-6 Researchers have reported the presence of allergic symptoms in at least 50% of patients diagnosed with EE,² and many patients experience exacerbations associated with seasonal changes.⁷

GERD may coexist with EE; however, no relationship has been identified between the two.⁸ EE should be considered in patients with gastrointestinal symptoms that persist despite at least four weeks’ treatment with a proton pump inhibitor (PPI).²

Dysphagia: Differential Diagnosis
Adult patients with esophageal dysphagia usually report the feeling of food getting stuck when they try to swallow.⁹ Dysphagia may result from a mechanical obstruction or a neuromuscular/motility condition. Patients with mechanical obstructions usually have difficulty swallowing solids, while those with motility disorders tend to have difficulty with both liquids and solids.^1,9

Mechanical obstructions may include carcinomas (intrinsic and extrinsic), strictures, or Schatzki rings (small thin mucosal rings of unknown etiology located at the gastroesophageal junction).^1,9 Progressive dysphagia to solids over a short period of time is often indicative of esophageal carcinoma. GERD, pill-induced trauma, previous ingestion of a caustic chemical, and radiation are common causes of esophageal stricture formation. For a list of medications that are particularly caustic to the esophageal mucosa, see the table.^9,10

Neuromuscular manifestations of dysphagia include achalasia, diffuse esophageal spasm, nutcracker esophagus, and scleroderma.¹ These are usually associated with progressive difficulty in swallowing.⁹

Evaluating the Patient
A thorough patient history can often reveal potential causes of dysphagia and eliminate others. This should include current medications, chronic medical conditions and details regarding their onset and duration, and symptoms associated with dysphagia.⁹

Physical examination should include palpation of the thyroid because of the potential for a thyroid mass to cause extrinsic compression of the esophagus, palpation of the abdomen for masses or organomegaly, and a complete neurologic evaluation.⁹

Laboratory tests should be ordered based on the information obtained from the history and physical. Testing may include thyroid studies to eliminate hypothyroid or hyperthyroid causes of dysphagia, and complete blood count (CBC) with differential to rule out inflammatory or infectious processes.⁹ While eosinophilia may be present in the differential, it is not a universally accepted marker for establishing the diagnosis of EE.^2,5 Stools should be checked for occult blood, because a positive finding may suggest esophageal carcinoma.⁹

Diagnosis
In the primary care setting, a barium esophagram may be used during the initial workup to evaluate the anatomic structures of the esophagus and to differentiate between a mechanical obstruction and a neuromuscular disorder.^1,9 This noninvasive test requires the patient to swallow a radiopaque liquid as x-rays are taken.

The gold standard for diagnosing EE, however, is upper endoscopy with biopsy of the esophageal mucosa.⁶ Endoscopic findings that indicate EE are atypical of GERD; they may include a narrowed, small-caliber esophagus, concentric mucosal rings, proximal stenosis, linear ulcerations, atrophic changes, and white papules associated with eosinophilic microabscesses.⁶

Although there is no consensus regarding the number of eosinophils that should be present for an accurate diagnosis of EE, microscopic interpretation of the biopsy from both the proximal and the distal esophageal epithelia⁵ usually shows 15 or more eosinophils per high-power field.^2,11 It has been suggested that mucosal biopsies be taken along the entire length of the esophagus, as eosinophilic infiltration may extend from the proximal to the distal esophagus.²

GERD and trauma induced by medication use may also be associated with esophageal eosinophilic infiltration5; however, eosinophils are usually present only in the distal esophageal mucosa³ and are not as abundant as in EE.⁷ If endoscopy reveals persistent eosinophilia despite four to eight weeks’ treatment with a PPI, the diagnosis of EE is confirmed.²

Treatment
Treatment for EE is still under investigation. Research has examined the association between EE and food allergies or aeroallergens.⁴ Evaluation by an allergist using skin prick tests or RAST is recommended in the adult patient to help determine the source of the underlying inflammation.^5,7 Eliminating any identified allergen should help alleviate symptoms.⁴

For patients in whom no source of inflammation can be identified, treatment with 1.0 to 2.0 mg/kg/d of oral prednisone for acute exacerbations has been shown to significantly improve symptoms and histology¹²; however, because of the associated risk for adverse systemic effects, long-term use is not recommended.

In many patients, the inhaled corticosteroid fluticasone has also proved successful in reducing EE—associated inflammation.⁶ Current evidence supports adult dosing between 880 and 1,760 mcg per day for six to eight weeks, administered with a metered-dose inhaler and no spacer. Fluticasone should be sprayed directly into the mouth and swallowed, after which the patient should take nothing by mouth for 30 minutes.¹³ Prolonged fluticasone use has been associated with esophageal candidiasis.² There are currently no recommendations regarding its use as maintenance therapy.

Montelukast, a leukotriene receptor antagonist, has also been shown in some studies to reduce the inflammatory process¹¹; however, one study team recently found it to have no therapeutic effect.¹³

PPIs may be effective for improving EE symptoms even in the absence of GERD because of the reduced gastric acid production,⁷ but they do not usually improve EE’s histologic features.³

Use of esophageal dilation in patients with EE is controversial because of an associated risk for perforation.¹⁴ If this intervention is to be performed, the patient should be treated in advance with oral corticosteroids to reduce esophageal inflammation.^15,16 In addition, the endoscopist should start with small-sized dilators and carefully proceed to larger sizes.¹¹ Critics of esophageal dilation argue that the procedure is only a temporary solution and does nothing for the underlying condition.^4,8

Regarding endoscopic surveillance, an interval of at least four weeks between interventions is recommended.¹³

Role of the Primary Care Clinician
Undiagnosed EE can cause the patient discomfort, frustration, and anxiety, as seen in the case study. Many patients with undiagnosed EE have been exposed to unnecessary medical therapy and antireflux surgery.³ Without proper diagnosis and treatment, EE may worsen, causing complications associated with chronic inflammation (ie, esophageal fibrosis and strictures).^2,6

The long-term prognosis of EE is unknown at this time.⁸ The disease is usually chronic, with periods of remission and exacerbation. With an understanding of EE and appropriate therapies, the primary care practitioner can team with the gastroenterologist to provide effective disease management through endoscopic surveillance and intervention for acute exacerbations. Guidelines recommend that patients be closely followed with regular office visits to reassess symptoms, compliance with therapy, and adverse effects, with the goal of preventing complications associated with EE.¹³

Conclusion
To effectively evaluate the patient who presents with dysphagia, the primary care provider should have a working knowledge of EE, as well as an understanding of the key elements in the history and physical examination to help ensure an accurate diagnosis. This will facilitate timely referral to a gastroenterologist for endoscopic evaluation, when indicated.         

A 29-year-old man presented to the emergency department (ED) with a chief complaint of food stuck in his throat. He reported that he had swallowed a piece of chicken and felt it get stuck. Drinking water to help it go down was unsuccessful.

The patient’s history was positive for childhood asthma and nine years of solid food dysphagia. There was no history of a caustic chemical ingestion or of drug-induced esophagitis. He denied having dyspepsia, heartburn, or chest pain. He was not taking any medications and had no allergies.

When his dysphagia symptoms began nine years ago, he was diagnosed with acid reflux disease, confirmed by an upper gastrointestinal (GI) tract x-ray. Since that time, he reported having to swallow liquid after every bite of food and said he suffered from severe anxiety over fear of choking.

Evaluation in the ED consisted of endoscopic examination by a gastroenterologist. In addition to dislodging a food bolus, the endoscope revealed a narrowed, ringed esophagus with mucosal changes throughout the length of the esophagus (see Figures 1 through 3). Esophageal biopsies were taken, and the esophagus was dilated successfully with a 40-Fr Maloney dilator. The endoscopist detected too much resistance to pass a larger dilator.

Biopsy results revealed eosinophilic esophagitis. The patient was given oral fluticasone propionate. At one-month follow-up, he reported feeling much better. Upper endoscopy revealed some improvement, and the gastroenterologist was able to pass both a 46- and a 48-Fr Maloney dilator with only mild resistance. (The largest Maloney dilator, a 60-Fr dilator, should easily pass through a normal esophagus, according to T. L. Sack, MD, oral communication, June 2009.)

Discussion
Eosinophilic esophagitis (EE) involves the infiltration of the esophageal mucosa with eosinophils, causing edema, inflammation, and eventually, thickening and stenotic changes of the esophageal mucosa.¹

The normal esophageal mucosa contains lymphocytes, mast cells, and dendritic cells, which protect the esophagus from invading toxins and microorganisms. Eosinophils are not usually present, but when they are, they can have toxic effects on the esophageal mucosa.² EE is associated with solid food dysphagia, a direct result of damage to the esophageal mucosa, and other causes that are not clearly understood.

Research findings suggest that symptoms of dysphagia may be caused by degranulating eosinophils and mast cells, which have an antagonistic effect on the muscarinic receptors and cause smooth muscle to contract.^3,4 The proposed triggering mechanism of EE is an immunoglobulin E (IgE) immune–mediated response to an allergen.² Based on results from IgE radioallergosorbent testing (RAST), aeroallergens are more likely than food to act as triggers.⁵

EE in the Adult Patient
Traditionally, EE has been a condition seen in the pediatric population, with symptoms of nausea, vomiting, and failure to thrive; however, it is becoming increasingly recognized among adults. The typical patient is a man in his 20s or 30s (although cases of EE have been reported among women and older adults) with acute and recurrent solid food dysphagia, with or without food impaction.⁴

Often the patient reports a history of environmental or food allergies, asthma, rhinitis, or eczema.^2,4-6 Researchers have reported the presence of allergic symptoms in at least 50% of patients diagnosed with EE,² and many patients experience exacerbations associated with seasonal changes.⁷

GERD may coexist with EE; however, no relationship has been identified between the two.⁸ EE should be considered in patients with gastrointestinal symptoms that persist despite at least four weeks’ treatment with a proton pump inhibitor (PPI).²

Dysphagia: Differential Diagnosis
Adult patients with esophageal dysphagia usually report the feeling of food getting stuck when they try to swallow.⁹ Dysphagia may result from a mechanical obstruction or a neuromuscular/motility condition. Patients with mechanical obstructions usually have difficulty swallowing solids, while those with motility disorders tend to have difficulty with both liquids and solids.^1,9

Mechanical obstructions may include carcinomas (intrinsic and extrinsic), strictures, or Schatzki rings (small thin mucosal rings of unknown etiology located at the gastroesophageal junction).^1,9 Progressive dysphagia to solids over a short period of time is often indicative of esophageal carcinoma. GERD, pill-induced trauma, previous ingestion of a caustic chemical, and radiation are common causes of esophageal stricture formation. For a list of medications that are particularly caustic to the esophageal mucosa, see the table.^9,10

Neuromuscular manifestations of dysphagia include achalasia, diffuse esophageal spasm, nutcracker esophagus, and scleroderma.¹ These are usually associated with progressive difficulty in swallowing.⁹

Evaluating the Patient
A thorough patient history can often reveal potential causes of dysphagia and eliminate others. This should include current medications, chronic medical conditions and details regarding their onset and duration, and symptoms associated with dysphagia.⁹

Physical examination should include palpation of the thyroid because of the potential for a thyroid mass to cause extrinsic compression of the esophagus, palpation of the abdomen for masses or organomegaly, and a complete neurologic evaluation.⁹

Laboratory tests should be ordered based on the information obtained from the history and physical. Testing may include thyroid studies to eliminate hypothyroid or hyperthyroid causes of dysphagia, and complete blood count (CBC) with differential to rule out inflammatory or infectious processes.⁹ While eosinophilia may be present in the differential, it is not a universally accepted marker for establishing the diagnosis of EE.^2,5 Stools should be checked for occult blood, because a positive finding may suggest esophageal carcinoma.⁹

Diagnosis
In the primary care setting, a barium esophagram may be used during the initial workup to evaluate the anatomic structures of the esophagus and to differentiate between a mechanical obstruction and a neuromuscular disorder.^1,9 This noninvasive test requires the patient to swallow a radiopaque liquid as x-rays are taken.

The gold standard for diagnosing EE, however, is upper endoscopy with biopsy of the esophageal mucosa.⁶ Endoscopic findings that indicate EE are atypical of GERD; they may include a narrowed, small-caliber esophagus, concentric mucosal rings, proximal stenosis, linear ulcerations, atrophic changes, and white papules associated with eosinophilic microabscesses.⁶

Although there is no consensus regarding the number of eosinophils that should be present for an accurate diagnosis of EE, microscopic interpretation of the biopsy from both the proximal and the distal esophageal epithelia⁵ usually shows 15 or more eosinophils per high-power field.^2,11 It has been suggested that mucosal biopsies be taken along the entire length of the esophagus, as eosinophilic infiltration may extend from the proximal to the distal esophagus.²

GERD and trauma induced by medication use may also be associated with esophageal eosinophilic infiltration5; however, eosinophils are usually present only in the distal esophageal mucosa³ and are not as abundant as in EE.⁷ If endoscopy reveals persistent eosinophilia despite four to eight weeks’ treatment with a PPI, the diagnosis of EE is confirmed.²

Treatment
Treatment for EE is still under investigation. Research has examined the association between EE and food allergies or aeroallergens.⁴ Evaluation by an allergist using skin prick tests or RAST is recommended in the adult patient to help determine the source of the underlying inflammation.^5,7 Eliminating any identified allergen should help alleviate symptoms.⁴

For patients in whom no source of inflammation can be identified, treatment with 1.0 to 2.0 mg/kg/d of oral prednisone for acute exacerbations has been shown to significantly improve symptoms and histology¹²; however, because of the associated risk for adverse systemic effects, long-term use is not recommended.