THE CASE

A healthy 6-month-old girl born via spontaneous vaginal delivery to a 33-year-old mother presented to her family physician (FP) for a routine well-child examination. The mother’s prenatal anatomy scan, delivery, and personal and family history were unremarkable. The patient was not firstborn or breech, and there was no family history of hip dysplasia. On prior infant well-child examinations, Ortolani and Barlow maneuvers were negative, and the patient demonstrated spontaneous movement of both legs. There was no evidence of hip dysplasia, lower extremity weakness, musculoskeletal abnormalities, or abnormal skin markings. The patient had normal growth and development (50th percentile for height and weight, average Ages & Stages Questionnaire scores) and no history of infection or trauma.

At the current presentation, the FP noted a leg-length discrepancy while palpating the bony (patellar and malleolar) landmarks of the lower extremities, but the right and left anterior superior iliac spine was symmetrical. The gluteal folds and popliteal fossae were asymmetric, a Galeazzi test was positive, and the right leg measured approximately 2 cm shorter than the left leg. There was no evidence of scoliosis or pelvic abnormalities. Physical examination revealed no ecchymosis or trauma. Orthopedic evaluation by the FP of the hips, knees, and ankles was normal, including negative repeat Ortolani and Barlow maneuvers and normal range of motion. We obtained x-rays of the lower extremities and ordered an orthopedic consultation.

THE DIAGNOSIS

The differential diagnosis included congenital, traumatic, infectious, inflammatory, idiopathic, and neurologic causes.^1-3 The most common etiologies of leg-length discrepancies are summarized in TABLE 1.^1-3 Radiographic imaging showed a femur length discrepancy, which was determined to be congenital without indication of trauma or disease; therefore, a diagnosis of congenital femoral bowing was made.

Initial orthopedic evaluation revealed a femur length discrepancy of approximately 2 cm. Plain films showed lateral femoral bowing (FIGURE 1A). Regular interval imaging performed at routine well-child examinations at 19 months, 3 years, and 5 years of age showed progression of the femoral length discrepancy from 2 cm to nearly 5 cm, remaining proportionally constant, as well as increasing genu valgum of the right leg up to 12 degrees (FIGURE 1B-D).

DISCUSSION

Congenital femoral bowing, which can present as a leg-length discrepancy in infants, is a relatively rare finding with an incidence of 1 per 52,000 births.⁴ Our patient presented with an isolated limb deformity, but congenital femoral bowing is recognized as a clinical feature of several skeletal dysplasias (TABLE 2).⁵

What’s recommended

The American Academy of Pediatrics recommends routine age-appropriate physical examination without specifying leg-length assessment.⁶ There is insufficient evidence, according to the US Preventive Services Task Force and the American Academy of Pediatrics, regarding the value of routine infant hip and leg-length assessment for developmental dysplasia of the hip and other musculoskeletal abnormalities; however, both agree that abnormal findings require follow-up and management.^6-8

Congenital femoral bowing requires plain film diagnosis

Following physical examination, diagnosis of congenital femoral bowing should be confirmed by plain films. Plain radiography remains the main imaging modality for proximal focal femoral deficiency and fibular hemimelia, and appropriate identification of the osseous abnormalities seen on radiographs allows for accurate classification of congenital femoral bowing, prognosis, and surgical planning. (Minor malformations associated with congenital leg-length discrepancies are not typically identified as being part of a larger syndromic diagnosis.⁴) The patient should subsequently be referred to an orthopedist for monitoring and to establish a long-term management plan.

Continue to: Early diagnosis can improve treatment outcome

Early diagnosis can improve treatment outcome

Both early diagnosis of congenital femoral bowing and prediction of leg-length discrepancy at skeletal maturity can influence potential treatment options, which range from conservative management (eg, watchful waiting, physical therapy, shoe lifts, orthotics, bracing) to surgical intervention. Several models have been used to predict skeletal growth, including the Moseley straight line graph, Green and Anderson growth curve, Amstutz method, and Paley’s multiplier method.^4,9-14

Congenital femoral bowing may present clinically as a leg-length discrepancy with no indication of trauma or disease.

Intervention for leg-length discrepancy generally is dictated by the magnitude of the inequality and the presence of functional deficits and/or pain.² If the degree of femur angulation begins to affect structural development, surgical intervention should be considered to align development and/or correct the discrepancy. Physical therapy, shoe lifts, orthotics, and bracing are treatment options for managing smaller discrepancies.^2,15

Our patient. The physician (CP) reviewed treatment options with the family that included watchful waiting, use of a shoe lift and/or orthotics, and bracing. The family chose watchful waiting due to the structural integrity of the patient’s other major joints and her relatively preserved function. The patient demonstrated mild gross motor delay at routine well-child visits at 9, 12, and 15 months, but was walking by 19 months. Her development was otherwise normal as documented via regular developmental screenings at routine well-child examinations. The patient participated in home physical therapy to maintain strength, flexibility, and functional mobility, and she was able to ambulate by walking on her right toes.

Surgery. Ultimately the patient underwent medial distal femoral hemiepiphysiodesis of the right lower extremity at 6 years of age due to increasing leg-length discrepancy and lateralization of the patella from the valgus deformity. The patient’s mother reported that she did well postoperatively, with increased range of motion, improved physical capabilities, and reduced discomfort in the right leg. She continued to participate in physical therapy and had routine follow-up with her physical therapist, her FP, and orthopedist.

A second surgery. At approximately 8 years and 9 months of age, the orthopedist noted that the patient’s leg-length discrepancy had increased, and she had right extensor mechanism malalignment and severe patellar subluxation. The patient subsequently underwent surgery to remove the existing hardware, including right extensor mechanism realignment via a Roux-Goldthwait procedure (with reconstruction of the medial patellofemoral ligament and anterior cruciate ligament), as well as left distal femoral epiphysiodesis. She did very well postoperatively and continues to participate in physical therapy approximately once weekly. She has had an improvement in her gait and stability using shoe lifts.

Continue to: THE TAKEAWAY

A routine well-child examination can be an opportunity to identify congenital musculoskeletal problems. Congenital femoral bowing is a relatively rare finding⁴ that may present as a leg-length discrepancy. With proper evaluation, including visual inspection, palpation, range-of-motion testing, and special tests as needed (eg, Galeazzi test, Ortolani and Barlow maneuvers), early intervention is possible if a leg-length discrepancy is noted. Close monitoring of gait abnormalities at routine well-child visits is essential.

Physical therapy, shoe lift therapy, and surgical approaches are treatment options for leg-length discrepancy,² and early intervention can improve treatment outcomes.¹⁴ Understanding how to manage congenital femoral bowing over time is important in providing options and counselling patients and their families.¹⁵

Treatment of leg-length discrepancy in pediatric patients requires long-term management with a team approach that includes patients and their families. The goal of intervention is to reduce physical and emotional trauma, while addressing complications and maintaining function of the affected limb, as well as the whole body.¹⁵

CORRESPONDENCE
Beth P. Davis, DPT, MBA, FNAP, Emory University School of Medicine, Department of Rehabilitation Medicine, Division of Physical Therapy, 1462 Clifton Road NE, Suite 312, Atlanta, GA 30342; [email protected].

THE CASE

A healthy 6-month-old girl born via spontaneous vaginal delivery to a 33-year-old mother presented to her family physician (FP) for a routine well-child examination. The mother’s prenatal anatomy scan, delivery, and personal and family history were unremarkable. The patient was not firstborn or breech, and there was no family history of hip dysplasia. On prior infant well-child examinations, Ortolani and Barlow maneuvers were negative, and the patient demonstrated spontaneous movement of both legs. There was no evidence of hip dysplasia, lower extremity weakness, musculoskeletal abnormalities, or abnormal skin markings. The patient had normal growth and development (50th percentile for height and weight, average Ages & Stages Questionnaire scores) and no history of infection or trauma.

At the current presentation, the FP noted a leg-length discrepancy while palpating the bony (patellar and malleolar) landmarks of the lower extremities, but the right and left anterior superior iliac spine was symmetrical. The gluteal folds and popliteal fossae were asymmetric, a Galeazzi test was positive, and the right leg measured approximately 2 cm shorter than the left leg. There was no evidence of scoliosis or pelvic abnormalities. Physical examination revealed no ecchymosis or trauma. Orthopedic evaluation by the FP of the hips, knees, and ankles was normal, including negative repeat Ortolani and Barlow maneuvers and normal range of motion. We obtained x-rays of the lower extremities and ordered an orthopedic consultation.

THE DIAGNOSIS

The differential diagnosis included congenital, traumatic, infectious, inflammatory, idiopathic, and neurologic causes.^1-3 The most common etiologies of leg-length discrepancies are summarized in TABLE 1.^1-3 Radiographic imaging showed a femur length discrepancy, which was determined to be congenital without indication of trauma or disease; therefore, a diagnosis of congenital femoral bowing was made.

Initial orthopedic evaluation revealed a femur length discrepancy of approximately 2 cm. Plain films showed lateral femoral bowing (FIGURE 1A). Regular interval imaging performed at routine well-child examinations at 19 months, 3 years, and 5 years of age showed progression of the femoral length discrepancy from 2 cm to nearly 5 cm, remaining proportionally constant, as well as increasing genu valgum of the right leg up to 12 degrees (FIGURE 1B-D).

DISCUSSION

Congenital femoral bowing, which can present as a leg-length discrepancy in infants, is a relatively rare finding with an incidence of 1 per 52,000 births.⁴ Our patient presented with an isolated limb deformity, but congenital femoral bowing is recognized as a clinical feature of several skeletal dysplasias (TABLE 2).⁵

What’s recommended

The American Academy of Pediatrics recommends routine age-appropriate physical examination without specifying leg-length assessment.⁶ There is insufficient evidence, according to the US Preventive Services Task Force and the American Academy of Pediatrics, regarding the value of routine infant hip and leg-length assessment for developmental dysplasia of the hip and other musculoskeletal abnormalities; however, both agree that abnormal findings require follow-up and management.^6-8

Congenital femoral bowing requires plain film diagnosis

Following physical examination, diagnosis of congenital femoral bowing should be confirmed by plain films. Plain radiography remains the main imaging modality for proximal focal femoral deficiency and fibular hemimelia, and appropriate identification of the osseous abnormalities seen on radiographs allows for accurate classification of congenital femoral bowing, prognosis, and surgical planning. (Minor malformations associated with congenital leg-length discrepancies are not typically identified as being part of a larger syndromic diagnosis.⁴) The patient should subsequently be referred to an orthopedist for monitoring and to establish a long-term management plan.

Continue to: Early diagnosis can improve treatment outcome

Early diagnosis can improve treatment outcome

Both early diagnosis of congenital femoral bowing and prediction of leg-length discrepancy at skeletal maturity can influence potential treatment options, which range from conservative management (eg, watchful waiting, physical therapy, shoe lifts, orthotics, bracing) to surgical intervention. Several models have been used to predict skeletal growth, including the Moseley straight line graph, Green and Anderson growth curve, Amstutz method, and Paley’s multiplier method.^4,9-14

Congenital femoral bowing may present clinically as a leg-length discrepancy with no indication of trauma or disease.

Intervention for leg-length discrepancy generally is dictated by the magnitude of the inequality and the presence of functional deficits and/or pain.² If the degree of femur angulation begins to affect structural development, surgical intervention should be considered to align development and/or correct the discrepancy. Physical therapy, shoe lifts, orthotics, and bracing are treatment options for managing smaller discrepancies.^2,15

Our patient. The physician (CP) reviewed treatment options with the family that included watchful waiting, use of a shoe lift and/or orthotics, and bracing. The family chose watchful waiting due to the structural integrity of the patient’s other major joints and her relatively preserved function. The patient demonstrated mild gross motor delay at routine well-child visits at 9, 12, and 15 months, but was walking by 19 months. Her development was otherwise normal as documented via regular developmental screenings at routine well-child examinations. The patient participated in home physical therapy to maintain strength, flexibility, and functional mobility, and she was able to ambulate by walking on her right toes.

Surgery. Ultimately the patient underwent medial distal femoral hemiepiphysiodesis of the right lower extremity at 6 years of age due to increasing leg-length discrepancy and lateralization of the patella from the valgus deformity. The patient’s mother reported that she did well postoperatively, with increased range of motion, improved physical capabilities, and reduced discomfort in the right leg. She continued to participate in physical therapy and had routine follow-up with her physical therapist, her FP, and orthopedist.

A second surgery. At approximately 8 years and 9 months of age, the orthopedist noted that the patient’s leg-length discrepancy had increased, and she had right extensor mechanism malalignment and severe patellar subluxation. The patient subsequently underwent surgery to remove the existing hardware, including right extensor mechanism realignment via a Roux-Goldthwait procedure (with reconstruction of the medial patellofemoral ligament and anterior cruciate ligament), as well as left distal femoral epiphysiodesis. She did very well postoperatively and continues to participate in physical therapy approximately once weekly. She has had an improvement in her gait and stability using shoe lifts.

Continue to: THE TAKEAWAY

A routine well-child examination can be an opportunity to identify congenital musculoskeletal problems. Congenital femoral bowing is a relatively rare finding⁴ that may present as a leg-length discrepancy. With proper evaluation, including visual inspection, palpation, range-of-motion testing, and special tests as needed (eg, Galeazzi test, Ortolani and Barlow maneuvers), early intervention is possible if a leg-length discrepancy is noted. Close monitoring of gait abnormalities at routine well-child visits is essential.

Physical therapy, shoe lift therapy, and surgical approaches are treatment options for leg-length discrepancy,² and early intervention can improve treatment outcomes.¹⁴ Understanding how to manage congenital femoral bowing over time is important in providing options and counselling patients and their families.¹⁵

Treatment of leg-length discrepancy in pediatric patients requires long-term management with a team approach that includes patients and their families. The goal of intervention is to reduce physical and emotional trauma, while addressing complications and maintaining function of the affected limb, as well as the whole body.¹⁵

CORRESPONDENCE
Beth P. Davis, DPT, MBA, FNAP, Emory University School of Medicine, Department of Rehabilitation Medicine, Division of Physical Therapy, 1462 Clifton Road NE, Suite 312, Atlanta, GA 30342; [email protected].

THE CASE

A healthy 6-month-old girl born via spontaneous vaginal delivery to a 33-year-old mother presented to her family physician (FP) for a routine well-child examination. The mother’s prenatal anatomy scan, delivery, and personal and family history were unremarkable. The patient was not firstborn or breech, and there was no family history of hip dysplasia. On prior infant well-child examinations, Ortolani and Barlow maneuvers were negative, and the patient demonstrated spontaneous movement of both legs. There was no evidence of hip dysplasia, lower extremity weakness, musculoskeletal abnormalities, or abnormal skin markings. The patient had normal growth and development (50th percentile for height and weight, average Ages & Stages Questionnaire scores) and no history of infection or trauma.

At the current presentation, the FP noted a leg-length discrepancy while palpating the bony (patellar and malleolar) landmarks of the lower extremities, but the right and left anterior superior iliac spine was symmetrical. The gluteal folds and popliteal fossae were asymmetric, a Galeazzi test was positive, and the right leg measured approximately 2 cm shorter than the left leg. There was no evidence of scoliosis or pelvic abnormalities. Physical examination revealed no ecchymosis or trauma. Orthopedic evaluation by the FP of the hips, knees, and ankles was normal, including negative repeat Ortolani and Barlow maneuvers and normal range of motion. We obtained x-rays of the lower extremities and ordered an orthopedic consultation.

THE DIAGNOSIS

The differential diagnosis included congenital, traumatic, infectious, inflammatory, idiopathic, and neurologic causes.^1-3 The most common etiologies of leg-length discrepancies are summarized in TABLE 1.^1-3 Radiographic imaging showed a femur length discrepancy, which was determined to be congenital without indication of trauma or disease; therefore, a diagnosis of congenital femoral bowing was made.

Initial orthopedic evaluation revealed a femur length discrepancy of approximately 2 cm. Plain films showed lateral femoral bowing (FIGURE 1A). Regular interval imaging performed at routine well-child examinations at 19 months, 3 years, and 5 years of age showed progression of the femoral length discrepancy from 2 cm to nearly 5 cm, remaining proportionally constant, as well as increasing genu valgum of the right leg up to 12 degrees (FIGURE 1B-D).

DISCUSSION

Congenital femoral bowing, which can present as a leg-length discrepancy in infants, is a relatively rare finding with an incidence of 1 per 52,000 births.⁴ Our patient presented with an isolated limb deformity, but congenital femoral bowing is recognized as a clinical feature of several skeletal dysplasias (TABLE 2).⁵

What’s recommended

The American Academy of Pediatrics recommends routine age-appropriate physical examination without specifying leg-length assessment.⁶ There is insufficient evidence, according to the US Preventive Services Task Force and the American Academy of Pediatrics, regarding the value of routine infant hip and leg-length assessment for developmental dysplasia of the hip and other musculoskeletal abnormalities; however, both agree that abnormal findings require follow-up and management.^6-8

Congenital femoral bowing requires plain film diagnosis

Following physical examination, diagnosis of congenital femoral bowing should be confirmed by plain films. Plain radiography remains the main imaging modality for proximal focal femoral deficiency and fibular hemimelia, and appropriate identification of the osseous abnormalities seen on radiographs allows for accurate classification of congenital femoral bowing, prognosis, and surgical planning. (Minor malformations associated with congenital leg-length discrepancies are not typically identified as being part of a larger syndromic diagnosis.⁴) The patient should subsequently be referred to an orthopedist for monitoring and to establish a long-term management plan.

Continue to: Early diagnosis can improve treatment outcome

Early diagnosis can improve treatment outcome

Both early diagnosis of congenital femoral bowing and prediction of leg-length discrepancy at skeletal maturity can influence potential treatment options, which range from conservative management (eg, watchful waiting, physical therapy, shoe lifts, orthotics, bracing) to surgical intervention. Several models have been used to predict skeletal growth, including the Moseley straight line graph, Green and Anderson growth curve, Amstutz method, and Paley’s multiplier method.^4,9-14

Congenital femoral bowing may present clinically as a leg-length discrepancy with no indication of trauma or disease.

Intervention for leg-length discrepancy generally is dictated by the magnitude of the inequality and the presence of functional deficits and/or pain.² If the degree of femur angulation begins to affect structural development, surgical intervention should be considered to align development and/or correct the discrepancy. Physical therapy, shoe lifts, orthotics, and bracing are treatment options for managing smaller discrepancies.^2,15

Our patient. The physician (CP) reviewed treatment options with the family that included watchful waiting, use of a shoe lift and/or orthotics, and bracing. The family chose watchful waiting due to the structural integrity of the patient’s other major joints and her relatively preserved function. The patient demonstrated mild gross motor delay at routine well-child visits at 9, 12, and 15 months, but was walking by 19 months. Her development was otherwise normal as documented via regular developmental screenings at routine well-child examinations. The patient participated in home physical therapy to maintain strength, flexibility, and functional mobility, and she was able to ambulate by walking on her right toes.

Surgery. Ultimately the patient underwent medial distal femoral hemiepiphysiodesis of the right lower extremity at 6 years of age due to increasing leg-length discrepancy and lateralization of the patella from the valgus deformity. The patient’s mother reported that she did well postoperatively, with increased range of motion, improved physical capabilities, and reduced discomfort in the right leg. She continued to participate in physical therapy and had routine follow-up with her physical therapist, her FP, and orthopedist.

A second surgery. At approximately 8 years and 9 months of age, the orthopedist noted that the patient’s leg-length discrepancy had increased, and she had right extensor mechanism malalignment and severe patellar subluxation. The patient subsequently underwent surgery to remove the existing hardware, including right extensor mechanism realignment via a Roux-Goldthwait procedure (with reconstruction of the medial patellofemoral ligament and anterior cruciate ligament), as well as left distal femoral epiphysiodesis. She did very well postoperatively and continues to participate in physical therapy approximately once weekly. She has had an improvement in her gait and stability using shoe lifts.

Continue to: THE TAKEAWAY

A routine well-child examination can be an opportunity to identify congenital musculoskeletal problems. Congenital femoral bowing is a relatively rare finding⁴ that may present as a leg-length discrepancy. With proper evaluation, including visual inspection, palpation, range-of-motion testing, and special tests as needed (eg, Galeazzi test, Ortolani and Barlow maneuvers), early intervention is possible if a leg-length discrepancy is noted. Close monitoring of gait abnormalities at routine well-child visits is essential.

Physical therapy, shoe lift therapy, and surgical approaches are treatment options for leg-length discrepancy,² and early intervention can improve treatment outcomes.¹⁴ Understanding how to manage congenital femoral bowing over time is important in providing options and counselling patients and their families.¹⁵

Treatment of leg-length discrepancy in pediatric patients requires long-term management with a team approach that includes patients and their families. The goal of intervention is to reduce physical and emotional trauma, while addressing complications and maintaining function of the affected limb, as well as the whole body.¹⁵

CORRESPONDENCE
Beth P. Davis, DPT, MBA, FNAP, Emory University School of Medicine, Department of Rehabilitation Medicine, Division of Physical Therapy, 1462 Clifton Road NE, Suite 312, Atlanta, GA 30342; [email protected].

More than 60% of newborns appear clinically jaundiced in the first few weeks of life,¹ most often due to physiologic jaundice. Mild hyperbilirubinemia peaks at Days 3 to 5 and returns to normal in the following weeks.¹ However, approximately 10% of term and 25% of late preterm infants will undergo phototherapy for hyperbilirubinemia in an effort to prevent acute bilirubin encephalopathy (ABE) and kernicterus.²

Heightened vigilance to prevent these rare but devastating outcomes has made hyperbilirubinemia the most common cause of hospital readmission in infants in the United States³ and one with significant health care costs. This article summarizes the evidence and recommendations for the screening, evaluation, and management of hyperbilirubinemia in term infants.

But first, we begin with a quick look at the causes of hyperbilirubinemia.

Causes of conjugated vs unconjugated hyperbilirubinemia

Bilirubin is generated when red blood cells break down and release heme, which is metabolized into biliverdin and then to bilirubin. Unconjugated bilirubin binds to albumin in the blood and is transported to hepatocytes where conjugation occurs, allowing it to be excreted through the gastrointestinal tract. In neonates, most of the conjugated bilirubin that reaches the gut is then unconjugated, resulting in its recirculation. Additionally, neonates have an increased volume of red blood cells and a slow conjugating system. These factors all contribute to excess unconjugated bilirubin, which manifests as physiologic, nonpathologic jaundice.⁴TABLE 1^4-6 lists causes of unconjugated hyperbilirubinemia.

Elevated conjugated hyperbilirubinemia (conjugated bilirubin level ≥20% of total serum bilirubin [TSB]) is always pathologic and occurs due to intrahepatic or extrahepatic obstruction. TABLE 2⁷ lists causes of conjugated hyperbilirubinemia. Infants found to have conjugated hyperbilirubinemia should undergo an additional work-up to determine the cause and identify potential complications of this disease.⁸

Given that the differential for conjugated hyperbilirubinemia is so broad and that it is often associated with severe disease requiring complicated and invasive treatments, infants with conjugated hyperbilirubinemia should be referred to a pediatric tertiary care facility with pediatric gastroenterologists, infectious disease specialists, and surgeons.⁷

What puts newborns at risk?

Major and minor risk factors for the development of severe hyperbilirubinemia in well newborns ≥35 weeks’ gestation are listed in TABLE 3.⁹ Those that carry the highest risk include gestational age <38 weeks, having a sibling who required phototherapy, visible jaundice by the time of discharge, and exclusive breastfeeding.⁹ Several more recent cohort studies, however, suggest that breastfeeding may not be a significant risk factor.¹⁰ The more risk factors present, the higher the risk. Infants who are formula fed, age ≥41 gestational weeks, or have no major or minor risk factors have a very low likelihood of developing severe hyperbilirubinemia.⁹

Continue to: The Bhutani curve...

The Bhutani curve¹¹ is a widely used, validated nomogram based on pre-discharge hour-specific serum bilirubin measurements. (Go to http://pediatrics.aappublications.org/content/114/1/297 and see Figure 2.) It is the most reliable way to assess the risk for subsequent development of significant hyperbilirubinemia requiring phototherapy.⁹ As such, it is the basis for several online calculators and apps such as BiliTool (bilitool.org).

An alternative nomogram developed by Varvarigou et al¹² is available for predicting significant hyperbilirubinemia based on transcutaneous bilirubin assessment. (Go to https://pdfs.semanticscholar.org/a9a6/5a988dba7a3442bcebc149ad5aea5e3c35d5.pdf and see Figure 3.) The American Academy of Pediatrics (AAP) supports the use of either bilirubin assessment for the screening and diagnosis of hyperbilirubinemia in infants ≥35 weeks’ gestation.⁹

Neurotoxicity risk factors. It is important to differentiate the major and minor risk factors for severe hyperbilirubinemia from neurotoxicity risk factors, also listed in TABLE 3.⁹ Neurotoxicity risk factors are indicative of conditions that may affect albumin binding of bilirubin and are thought to lower the threshold at which bilirubin may cross the blood-brain barrier and render the brain more susceptible to damage from bilirubin. These neurotoxicity risk factors should be applied to the AAP phototherapy nomogram (see Figure 3 at pediatrics.aappublications.org/content/114/1/297) to determine the threshold for initiation of phototherapy in infants with hyperbilirubinemia.⁹

Hyperbilirubinemia is the most common cause of hospital readmission of infants in the United States.

Few investigators have attempted to define risk factors for the development of poor neurologic outcomes associated with hyperbilirubinemia. Evidence to date has not allowed the determination of a specific bilirubin level at which subsequent development of kernicterus occurs.⁹ The limited data available suggest a poor correlation between TSB level and bilirubin-induced neurologic dysfunction.¹³

(For more on kernicterus, as well as ABE and bilirubin-induced neurologic dysfunction [BIND], see “Why do we worry about hyperbilirubinemia?”^9,14-16)

Continue to: Diagnosis relies on TSB and/or TcB

Diagnosis relies on TSB and/or TcB

TSB measurement is the traditional and most widely used method for screening and diagnosing neonatal hyperbilirubinemia, but the blood draw is invasive and carries a risk (albeit low) of infection and anemia.¹⁷ Transcutaneous bilirubin (TcB) assessment is a noninvasive alternative that generally correlates well with TSB values ≤15 mg/dL,^17-20 even in Hispanic, African, and multiethnic populations.^18,21,22

Diagnosis of hyperbilirubinemia is made with TSB or TcB measured at >95th percentile for age in hours. TcB levels measured at >15 mg/dL should be confirmed with TSB measurement. Visual assessment of jaundice should not be used for diagnosis, as it may lead to errors.^9-23

The total cost of testing is lower with TcB ($4-$15 per patient¹⁷) than with TSB when the cost of supplies and personnel are considered.²⁴ Although more recent evidence suggests that TcB is an acceptable way to measure bilirubin in premature infants, no professional society currently recommends the use of TcB for the diagnosis of hyperbilirubinemia in infants²⁵ <35 weeks’ gestation.

Screening recommendations lack consensus

There is a lack of consensus among professional societies on appropriate screening for neonatal hyperbilirubinemia, likely due to limited available data, necessitating expert-driven recommendations.

The AAP recommends universal screening of infants ≥35 weeks’ gestation prior to discharge with measurement of TSB/TcB and/or clinical assessment.⁹ The Canadian Pediatric Society recommends universal screening with TSB/TcB measurement in all infants in the first 72 hours of life.²⁶

Continue to: The US Preventive Services Task Force...

The US Preventative Services Task Force, however, found insufficient evidence to recommend universal screening for infants ≥35 weeks’ gestation.²⁷ The main rationale for their “I” recommendation was that although screening can identify infants at risk of developing severe hyperbilirubinemia, there is no clear evidence that identifying and treating elevated bilirubin levels results in the prevention of kernicterus.

The United Kingdom’s National Institute for Health and Care Excellence (NICE) guidelines do not support universal screening either.²⁸ NICE recommends risk factor assessment and visual inspection for jaundice in all newborns and also additional physical examination for newborns with risk factors. NICE recommends against routine monitoring of bilirubin levels in infants who do not appear jaundiced.

Several recent cohort studies suggest that breastfeeding may not be a significant risk factor for hyperbilirubinemia.

All infants who appear jaundiced should be evaluated with either risk factor assessment or bilirubin measurement (TSB or TcB). Infants born to mothers who are Rh-negative or have type O blood should have cord blood tested for blood type, Rh status, and other antibodies with a direct Coombs test, as ABO and Rh incompatibility are major risk factors for development of hyperbilirubinemia because of hemolysis.^8,9

A question of cost-efficacy? Data from a multicenter prospective clinical trial suggest a number needed to screen of 128,600 to prevent 1 case of kernicterus,²⁹ making cost another important factor in the discussion about screening for neonatal hyperbilirubinemia. Universal screening is associated not only with the cost of TSB and TcB measurements, but also with the cost of phototherapy, rates of which are increased with universal screening.^24,29,30 The cost of caring for 1 patient with kernicterus over a lifetime is estimated at $900,000, while the estimated cost to prevent 1 case of kernicterus with universal TSB/TcB screening is between $5.7 and $9.2 million.³¹

In Canada, universal screening was found to decrease emergency department visits for jaundice, but did not affect rates of readmission for hyperbilirubinemia, length of hospital stay, or rates of phototherapy after discharge.³⁰

Continue to: Phototherapy: What kind of light, when to initiate

Phototherapy: What kind of light, when to initiate

The initial management of hyperbilirubinemia is phototherapy. Light directed at the skin converts bilirubin to lumirubin—a compound that unlike bilirubin does not require conjugation in the liver and can be directly excreted in the urine or bile.⁸

No professional society currently recommends the use of TcB for the diagnosis of hyperbilirubinemia in infants <35 weeks’ gestation.

Light in the blue-green spectrum (460-490 nm) is most effective. Generally, phototherapy is more effective the closer the light is to the infant and the greater the surface area of skin the infant has exposed. There are many different types of lights used to provide phototherapy including fluorescent, halogen, light emitting diode (LED), and fiber optic lights, which are commonly used in home biliblankets.⁸ Fluorescent and halogen lights are the conventional methods, but newer LED systems are equally effective in terms of rate of decline of serum bilirubin levels, duration of phototherapy required, and need for exchange transfusion. Fiber optic lights work as well as other lights in preterm infants but are less effective in term infants. Using 2 fiber optic lights in term infants can increase efficacy to the level of a single conventional or LED source.³²

Phototherapy thresholds. The AAP phototherapy curve (see Figure 3 at http://pediatrics.aappublications.org/content/114/1/297) is commonly used to determine phototherapy thresholds for infants with hyperbilirubinemia. This nomogram applies TSB level and age in hours to a “low,” “medium,” or “high” risk curve that is determined by the presence of neurotoxicity risk factors and gestational age. Infants on the “medium” and “high” risk curves have lower thresholds for initiation of phototherapy.⁹ The majority of infants born at gestational age ≥38 weeks being cared for in a newborn nursery will be assigned to a low risk curve on the AAP phototherapy nomogram, as many of the neurotoxicity risk factors that elevate risk would also be reasons for infants to be in an intensive care unit.

Online calculators and apps based on the AAP phototherapy nomogram, such as BiliTool (bilitool.org), offer recommendations for phototherapy thresholds and may suggest a time interval at which to repeat bilirubin testing if phototherapy is not indicated.

The additional work-up for infants requiring phototherapy often includes neonatal blood type, direct Coombs test, complete blood count and smear, and conjugated bilirubin level.⁹ Besser et al,³³ however, found that 88% of infants requiring phototherapy had normal laboratory results. They also found that those infants with lab abnormalities often started phototherapy before 48 hours of age and did not have an appropriate decrease in bilirubin after initiation of phototherapy.

Continue to: Timing

Timing. Based on this data, it is reasonable to start phototherapy in term infants who develop jaundice at >48 to 72 hours of age without doing additional testing.

Bilirubin levels are expected to drop about 0.5 mg/dL per hour in the first 4 to 8 hours after starting phototherapy, but if the bilirubin measurement is not decreasing as expected or is increasing, additional work-up, with reticulocyte count, G6PD (glucose-6-phosphate dehydrogenase) concentration, end-tidal carbon dioxide determination (ETCO), and a bilirubin/albumin (B/A) ratio is warranted.⁸ Since unbound bilirubin can cross the blood-brain barrier, increased B/A ratio could theoretically be a predictor of bilirubin-induced neurologic dysfunction risk, but Iskander et al³⁴ found that it was not superior to TSB levels in predicting neurotoxicity. ETCO may help identify children with ongoing hemolysis.⁸

The ideal time to stop phototherapy is not clear. Expert recommendations for phototherapy discontinuation thresholds range from 4-5 mg/dL to 13-14 mg/dL,⁸ while other clinicians stop phototherapy when bilirubin falls 1 to 2 mg/dL below the phototherapy initiation threshold. Phototherapy should be continued for any infant with signs of acute bilirubin encephalopathy, even if the bilirubin level is decreasing.⁹ Rebound hyperbilirubinemia is rare, and checking rebound bilirubin levels is not recommended.⁸

Safety. Phototherapy is generally considered safe, but both short- and long-term adverse effects are possible. Immediate adverse effects include intestinal hypermobility/diarrhea and temperature instability. Long-term issues include increased risks of the development of childhood asthma (odds ratio=1.4) and type 1 diabetes (odds ratio=3.79).³⁵ Phototherapy can also be distressing for parents, as it requires frequent blood draws, physical separation, and possible disruption of breastfeeding.³⁶ One study found a number needed to harm of 4 for cessation of breastfeeding at 1 month in jaundiced infants.³⁷

Maintain breastfeeding. The AAP recommends breastfeeding be continued and promoted in infants who are jaundiced and receiving phototherapy.⁹ Maternal interaction with health care professionals who are encouraging of this practice was the best predictor of ongoing breastfeeding in a qualitative study of jaundiced infants and their families.³⁸ Interrupting phototherapy for up to 30 minutes to allow for breastfeeding without eye covers has not been shown to decrease the efficacy of phototherapy.³⁸

Continue to: Available evidence does not provide a clear answer...

Available evidence does not provide a clear answer regarding whether formula supplementation should be initiated in breastfed infants with hyperbilirubinemia. Cow’s milk formula supplementation decreases intestinal reabsorption of bilirubin, lowering serum bilirubin levels, but may interfere with successful breastfeeding.³⁹ The Academy of Breastfeeding Medicine recommends an individual discussion about formula supplementation in place of, or prior to, phototherapy if an infant’s bilirubin is approaching (within 2-3 mg/dL) or above the threshold for phototherapy.³⁹ Routine supplementation with intravenous fluids or other non–milk-based supplementation is not recommended for infants receiving phototherapy.⁹

Adjuvant therapies and exchange transfusion

Clofibrate, metalloporphyrins, and ursodiol have been studied in the management of unconjugated hyperbilirubinemia as augmentation to phototherapy. Honar et al⁴⁰ found that ursodiol added at the time of phototherapy initiation demonstrated a significant reduction in peak bilirubin levels and duration of phototherapy in term infants with unconjugated hyperbilirubinemia without any adverse effects. Cochrane reviews of clofibrat⁵ and metalloporphyrins⁴¹ found that when added to phototherapy, these medications significantly decreased serum bilirubin levels and duration of phototherapy. However, there was insufficient evidence to recommend their use due to inadequate data on safety and long-term outcomes.

Exchange transfusion. Infants with bilirubin levels >25 mg/dL, those who are not responding to phototherapy, and those with evidence of acute bilirubin encephalopathy should be treated with exchange transfusion, with initiation based on an infant’s age in hours and neurotoxicity risk factors.⁹ Exchange transfusion involves taking small aliquots of blood from the infant and replacing them with donor red cells until the infant’s blood volume has been replaced twice to remove bilirubin and antibodies that may be causing hemolysis. It should be carried out in a neonatal intensive care unit due to significant risks.

About 88% of infants requiring phototherapy have normal laboratory study results.

Approximately 12% of infants have a complication from exchange transfusion including infection, electrolyte imbalances, thrombosis, thrombocytopenia, and necrotizing enterocolitis.⁸ The mortality rate in neonates without hemolysis who undergo exchange transfusion is 3 to 4 per 1000 treated.⁴²

Post-discharge follow-up

Infants discharged before 72 hours of life should be seen within 2 days of discharge. Those infants with significant risk factors for development of severe hyperbilirubinemia should be seen within 1 day. Arrangements for follow-up should be made prior to discharge. Some infants discharged before 48 hours of life may require 2 follow-up visits. If follow-up cannot be ensured for an infant with risk factors for the development of severe hyperbilirubinemia, delay of discharge may be appropriate.⁹

CORRESPONDENCE
Katharine C. DeGeorge, MD, MS, Department of Family Medicine, University of Virginia, PO Box 800729, Charlottesville, VA, 22908-0729; [email protected].

More than 60% of newborns appear clinically jaundiced in the first few weeks of life,¹ most often due to physiologic jaundice. Mild hyperbilirubinemia peaks at Days 3 to 5 and returns to normal in the following weeks.¹ However, approximately 10% of term and 25% of late preterm infants will undergo phototherapy for hyperbilirubinemia in an effort to prevent acute bilirubin encephalopathy (ABE) and kernicterus.²

Heightened vigilance to prevent these rare but devastating outcomes has made hyperbilirubinemia the most common cause of hospital readmission in infants in the United States³ and one with significant health care costs. This article summarizes the evidence and recommendations for the screening, evaluation, and management of hyperbilirubinemia in term infants.

But first, we begin with a quick look at the causes of hyperbilirubinemia.

Causes of conjugated vs unconjugated hyperbilirubinemia

Bilirubin is generated when red blood cells break down and release heme, which is metabolized into biliverdin and then to bilirubin. Unconjugated bilirubin binds to albumin in the blood and is transported to hepatocytes where conjugation occurs, allowing it to be excreted through the gastrointestinal tract. In neonates, most of the conjugated bilirubin that reaches the gut is then unconjugated, resulting in its recirculation. Additionally, neonates have an increased volume of red blood cells and a slow conjugating system. These factors all contribute to excess unconjugated bilirubin, which manifests as physiologic, nonpathologic jaundice.⁴TABLE 1^4-6 lists causes of unconjugated hyperbilirubinemia.

Elevated conjugated hyperbilirubinemia (conjugated bilirubin level ≥20% of total serum bilirubin [TSB]) is always pathologic and occurs due to intrahepatic or extrahepatic obstruction. TABLE 2⁷ lists causes of conjugated hyperbilirubinemia. Infants found to have conjugated hyperbilirubinemia should undergo an additional work-up to determine the cause and identify potential complications of this disease.⁸

Given that the differential for conjugated hyperbilirubinemia is so broad and that it is often associated with severe disease requiring complicated and invasive treatments, infants with conjugated hyperbilirubinemia should be referred to a pediatric tertiary care facility with pediatric gastroenterologists, infectious disease specialists, and surgeons.⁷

What puts newborns at risk?

Major and minor risk factors for the development of severe hyperbilirubinemia in well newborns ≥35 weeks’ gestation are listed in TABLE 3.⁹ Those that carry the highest risk include gestational age <38 weeks, having a sibling who required phototherapy, visible jaundice by the time of discharge, and exclusive breastfeeding.⁹ Several more recent cohort studies, however, suggest that breastfeeding may not be a significant risk factor.¹⁰ The more risk factors present, the higher the risk. Infants who are formula fed, age ≥41 gestational weeks, or have no major or minor risk factors have a very low likelihood of developing severe hyperbilirubinemia.⁹

Continue to: The Bhutani curve...

The Bhutani curve¹¹ is a widely used, validated nomogram based on pre-discharge hour-specific serum bilirubin measurements. (Go to http://pediatrics.aappublications.org/content/114/1/297 and see Figure 2.) It is the most reliable way to assess the risk for subsequent development of significant hyperbilirubinemia requiring phototherapy.⁹ As such, it is the basis for several online calculators and apps such as BiliTool (bilitool.org).

An alternative nomogram developed by Varvarigou et al¹² is available for predicting significant hyperbilirubinemia based on transcutaneous bilirubin assessment. (Go to https://pdfs.semanticscholar.org/a9a6/5a988dba7a3442bcebc149ad5aea5e3c35d5.pdf and see Figure 3.) The American Academy of Pediatrics (AAP) supports the use of either bilirubin assessment for the screening and diagnosis of hyperbilirubinemia in infants ≥35 weeks’ gestation.⁹

Neurotoxicity risk factors. It is important to differentiate the major and minor risk factors for severe hyperbilirubinemia from neurotoxicity risk factors, also listed in TABLE 3.⁹ Neurotoxicity risk factors are indicative of conditions that may affect albumin binding of bilirubin and are thought to lower the threshold at which bilirubin may cross the blood-brain barrier and render the brain more susceptible to damage from bilirubin. These neurotoxicity risk factors should be applied to the AAP phototherapy nomogram (see Figure 3 at pediatrics.aappublications.org/content/114/1/297) to determine the threshold for initiation of phototherapy in infants with hyperbilirubinemia.⁹

Hyperbilirubinemia is the most common cause of hospital readmission of infants in the United States.

Few investigators have attempted to define risk factors for the development of poor neurologic outcomes associated with hyperbilirubinemia. Evidence to date has not allowed the determination of a specific bilirubin level at which subsequent development of kernicterus occurs.⁹ The limited data available suggest a poor correlation between TSB level and bilirubin-induced neurologic dysfunction.¹³

(For more on kernicterus, as well as ABE and bilirubin-induced neurologic dysfunction [BIND], see “Why do we worry about hyperbilirubinemia?”^9,14-16)

Continue to: Diagnosis relies on TSB and/or TcB

Diagnosis relies on TSB and/or TcB

TSB measurement is the traditional and most widely used method for screening and diagnosing neonatal hyperbilirubinemia, but the blood draw is invasive and carries a risk (albeit low) of infection and anemia.¹⁷ Transcutaneous bilirubin (TcB) assessment is a noninvasive alternative that generally correlates well with TSB values ≤15 mg/dL,^17-20 even in Hispanic, African, and multiethnic populations.^18,21,22

Diagnosis of hyperbilirubinemia is made with TSB or TcB measured at >95th percentile for age in hours. TcB levels measured at >15 mg/dL should be confirmed with TSB measurement. Visual assessment of jaundice should not be used for diagnosis, as it may lead to errors.^9-23

The total cost of testing is lower with TcB ($4-$15 per patient¹⁷) than with TSB when the cost of supplies and personnel are considered.²⁴ Although more recent evidence suggests that TcB is an acceptable way to measure bilirubin in premature infants, no professional society currently recommends the use of TcB for the diagnosis of hyperbilirubinemia in infants²⁵ <35 weeks’ gestation.

Screening recommendations lack consensus

There is a lack of consensus among professional societies on appropriate screening for neonatal hyperbilirubinemia, likely due to limited available data, necessitating expert-driven recommendations.

The AAP recommends universal screening of infants ≥35 weeks’ gestation prior to discharge with measurement of TSB/TcB and/or clinical assessment.⁹ The Canadian Pediatric Society recommends universal screening with TSB/TcB measurement in all infants in the first 72 hours of life.²⁶

Continue to: The US Preventive Services Task Force...

The US Preventative Services Task Force, however, found insufficient evidence to recommend universal screening for infants ≥35 weeks’ gestation.²⁷ The main rationale for their “I” recommendation was that although screening can identify infants at risk of developing severe hyperbilirubinemia, there is no clear evidence that identifying and treating elevated bilirubin levels results in the prevention of kernicterus.

The United Kingdom’s National Institute for Health and Care Excellence (NICE) guidelines do not support universal screening either.²⁸ NICE recommends risk factor assessment and visual inspection for jaundice in all newborns and also additional physical examination for newborns with risk factors. NICE recommends against routine monitoring of bilirubin levels in infants who do not appear jaundiced.

Several recent cohort studies suggest that breastfeeding may not be a significant risk factor for hyperbilirubinemia.

All infants who appear jaundiced should be evaluated with either risk factor assessment or bilirubin measurement (TSB or TcB). Infants born to mothers who are Rh-negative or have type O blood should have cord blood tested for blood type, Rh status, and other antibodies with a direct Coombs test, as ABO and Rh incompatibility are major risk factors for development of hyperbilirubinemia because of hemolysis.^8,9

A question of cost-efficacy? Data from a multicenter prospective clinical trial suggest a number needed to screen of 128,600 to prevent 1 case of kernicterus,²⁹ making cost another important factor in the discussion about screening for neonatal hyperbilirubinemia. Universal screening is associated not only with the cost of TSB and TcB measurements, but also with the cost of phototherapy, rates of which are increased with universal screening.^24,29,30 The cost of caring for 1 patient with kernicterus over a lifetime is estimated at $900,000, while the estimated cost to prevent 1 case of kernicterus with universal TSB/TcB screening is between $5.7 and $9.2 million.³¹

In Canada, universal screening was found to decrease emergency department visits for jaundice, but did not affect rates of readmission for hyperbilirubinemia, length of hospital stay, or rates of phototherapy after discharge.³⁰

Continue to: Phototherapy: What kind of light, when to initiate

Phototherapy: What kind of light, when to initiate

The initial management of hyperbilirubinemia is phototherapy. Light directed at the skin converts bilirubin to lumirubin—a compound that unlike bilirubin does not require conjugation in the liver and can be directly excreted in the urine or bile.⁸

No professional society currently recommends the use of TcB for the diagnosis of hyperbilirubinemia in infants <35 weeks’ gestation.

Light in the blue-green spectrum (460-490 nm) is most effective. Generally, phototherapy is more effective the closer the light is to the infant and the greater the surface area of skin the infant has exposed. There are many different types of lights used to provide phototherapy including fluorescent, halogen, light emitting diode (LED), and fiber optic lights, which are commonly used in home biliblankets.⁸ Fluorescent and halogen lights are the conventional methods, but newer LED systems are equally effective in terms of rate of decline of serum bilirubin levels, duration of phototherapy required, and need for exchange transfusion. Fiber optic lights work as well as other lights in preterm infants but are less effective in term infants. Using 2 fiber optic lights in term infants can increase efficacy to the level of a single conventional or LED source.³²

Phototherapy thresholds. The AAP phototherapy curve (see Figure 3 at http://pediatrics.aappublications.org/content/114/1/297) is commonly used to determine phototherapy thresholds for infants with hyperbilirubinemia. This nomogram applies TSB level and age in hours to a “low,” “medium,” or “high” risk curve that is determined by the presence of neurotoxicity risk factors and gestational age. Infants on the “medium” and “high” risk curves have lower thresholds for initiation of phototherapy.⁹ The majority of infants born at gestational age ≥38 weeks being cared for in a newborn nursery will be assigned to a low risk curve on the AAP phototherapy nomogram, as many of the neurotoxicity risk factors that elevate risk would also be reasons for infants to be in an intensive care unit.

Online calculators and apps based on the AAP phototherapy nomogram, such as BiliTool (bilitool.org), offer recommendations for phototherapy thresholds and may suggest a time interval at which to repeat bilirubin testing if phototherapy is not indicated.

The additional work-up for infants requiring phototherapy often includes neonatal blood type, direct Coombs test, complete blood count and smear, and conjugated bilirubin level.⁹ Besser et al,³³ however, found that 88% of infants requiring phototherapy had normal laboratory results. They also found that those infants with lab abnormalities often started phototherapy before 48 hours of age and did not have an appropriate decrease in bilirubin after initiation of phototherapy.

Continue to: Timing

Timing. Based on this data, it is reasonable to start phototherapy in term infants who develop jaundice at >48 to 72 hours of age without doing additional testing.

Bilirubin levels are expected to drop about 0.5 mg/dL per hour in the first 4 to 8 hours after starting phototherapy, but if the bilirubin measurement is not decreasing as expected or is increasing, additional work-up, with reticulocyte count, G6PD (glucose-6-phosphate dehydrogenase) concentration, end-tidal carbon dioxide determination (ETCO), and a bilirubin/albumin (B/A) ratio is warranted.⁸ Since unbound bilirubin can cross the blood-brain barrier, increased B/A ratio could theoretically be a predictor of bilirubin-induced neurologic dysfunction risk, but Iskander et al³⁴ found that it was not superior to TSB levels in predicting neurotoxicity. ETCO may help identify children with ongoing hemolysis.⁸

The ideal time to stop phototherapy is not clear. Expert recommendations for phototherapy discontinuation thresholds range from 4-5 mg/dL to 13-14 mg/dL,⁸ while other clinicians stop phototherapy when bilirubin falls 1 to 2 mg/dL below the phototherapy initiation threshold. Phototherapy should be continued for any infant with signs of acute bilirubin encephalopathy, even if the bilirubin level is decreasing.⁹ Rebound hyperbilirubinemia is rare, and checking rebound bilirubin levels is not recommended.⁸

Safety. Phototherapy is generally considered safe, but both short- and long-term adverse effects are possible. Immediate adverse effects include intestinal hypermobility/diarrhea and temperature instability. Long-term issues include increased risks of the development of childhood asthma (odds ratio=1.4) and type 1 diabetes (odds ratio=3.79).³⁵ Phototherapy can also be distressing for parents, as it requires frequent blood draws, physical separation, and possible disruption of breastfeeding.³⁶ One study found a number needed to harm of 4 for cessation of breastfeeding at 1 month in jaundiced infants.³⁷

Maintain breastfeeding. The AAP recommends breastfeeding be continued and promoted in infants who are jaundiced and receiving phototherapy.⁹ Maternal interaction with health care professionals who are encouraging of this practice was the best predictor of ongoing breastfeeding in a qualitative study of jaundiced infants and their families.³⁸ Interrupting phototherapy for up to 30 minutes to allow for breastfeeding without eye covers has not been shown to decrease the efficacy of phototherapy.³⁸

Continue to: Available evidence does not provide a clear answer...

Available evidence does not provide a clear answer regarding whether formula supplementation should be initiated in breastfed infants with hyperbilirubinemia. Cow’s milk formula supplementation decreases intestinal reabsorption of bilirubin, lowering serum bilirubin levels, but may interfere with successful breastfeeding.³⁹ The Academy of Breastfeeding Medicine recommends an individual discussion about formula supplementation in place of, or prior to, phototherapy if an infant’s bilirubin is approaching (within 2-3 mg/dL) or above the threshold for phototherapy.³⁹ Routine supplementation with intravenous fluids or other non–milk-based supplementation is not recommended for infants receiving phototherapy.⁹

Adjuvant therapies and exchange transfusion

Clofibrate, metalloporphyrins, and ursodiol have been studied in the management of unconjugated hyperbilirubinemia as augmentation to phototherapy. Honar et al⁴⁰ found that ursodiol added at the time of phototherapy initiation demonstrated a significant reduction in peak bilirubin levels and duration of phototherapy in term infants with unconjugated hyperbilirubinemia without any adverse effects. Cochrane reviews of clofibrat⁵ and metalloporphyrins⁴¹ found that when added to phototherapy, these medications significantly decreased serum bilirubin levels and duration of phototherapy. However, there was insufficient evidence to recommend their use due to inadequate data on safety and long-term outcomes.

Exchange transfusion. Infants with bilirubin levels >25 mg/dL, those who are not responding to phototherapy, and those with evidence of acute bilirubin encephalopathy should be treated with exchange transfusion, with initiation based on an infant’s age in hours and neurotoxicity risk factors.⁹ Exchange transfusion involves taking small aliquots of blood from the infant and replacing them with donor red cells until the infant’s blood volume has been replaced twice to remove bilirubin and antibodies that may be causing hemolysis. It should be carried out in a neonatal intensive care unit due to significant risks.

About 88% of infants requiring phototherapy have normal laboratory study results.

Approximately 12% of infants have a complication from exchange transfusion including infection, electrolyte imbalances, thrombosis, thrombocytopenia, and necrotizing enterocolitis.⁸ The mortality rate in neonates without hemolysis who undergo exchange transfusion is 3 to 4 per 1000 treated.⁴²

Post-discharge follow-up

Infants discharged before 72 hours of life should be seen within 2 days of discharge. Those infants with significant risk factors for development of severe hyperbilirubinemia should be seen within 1 day. Arrangements for follow-up should be made prior to discharge. Some infants discharged before 48 hours of life may require 2 follow-up visits. If follow-up cannot be ensured for an infant with risk factors for the development of severe hyperbilirubinemia, delay of discharge may be appropriate.⁹

CORRESPONDENCE
Katharine C. DeGeorge, MD, MS, Department of Family Medicine, University of Virginia, PO Box 800729, Charlottesville, VA, 22908-0729; [email protected].

More than 60% of newborns appear clinically jaundiced in the first few weeks of life,¹ most often due to physiologic jaundice. Mild hyperbilirubinemia peaks at Days 3 to 5 and returns to normal in the following weeks.¹ However, approximately 10% of term and 25% of late preterm infants will undergo phototherapy for hyperbilirubinemia in an effort to prevent acute bilirubin encephalopathy (ABE) and kernicterus.²

Heightened vigilance to prevent these rare but devastating outcomes has made hyperbilirubinemia the most common cause of hospital readmission in infants in the United States³ and one with significant health care costs. This article summarizes the evidence and recommendations for the screening, evaluation, and management of hyperbilirubinemia in term infants.

But first, we begin with a quick look at the causes of hyperbilirubinemia.

Causes of conjugated vs unconjugated hyperbilirubinemia

Bilirubin is generated when red blood cells break down and release heme, which is metabolized into biliverdin and then to bilirubin. Unconjugated bilirubin binds to albumin in the blood and is transported to hepatocytes where conjugation occurs, allowing it to be excreted through the gastrointestinal tract. In neonates, most of the conjugated bilirubin that reaches the gut is then unconjugated, resulting in its recirculation. Additionally, neonates have an increased volume of red blood cells and a slow conjugating system. These factors all contribute to excess unconjugated bilirubin, which manifests as physiologic, nonpathologic jaundice.⁴TABLE 1^4-6 lists causes of unconjugated hyperbilirubinemia.

Elevated conjugated hyperbilirubinemia (conjugated bilirubin level ≥20% of total serum bilirubin [TSB]) is always pathologic and occurs due to intrahepatic or extrahepatic obstruction. TABLE 2⁷ lists causes of conjugated hyperbilirubinemia. Infants found to have conjugated hyperbilirubinemia should undergo an additional work-up to determine the cause and identify potential complications of this disease.⁸

Given that the differential for conjugated hyperbilirubinemia is so broad and that it is often associated with severe disease requiring complicated and invasive treatments, infants with conjugated hyperbilirubinemia should be referred to a pediatric tertiary care facility with pediatric gastroenterologists, infectious disease specialists, and surgeons.⁷

What puts newborns at risk?

Major and minor risk factors for the development of severe hyperbilirubinemia in well newborns ≥35 weeks’ gestation are listed in TABLE 3.⁹ Those that carry the highest risk include gestational age <38 weeks, having a sibling who required phototherapy, visible jaundice by the time of discharge, and exclusive breastfeeding.⁹ Several more recent cohort studies, however, suggest that breastfeeding may not be a significant risk factor.¹⁰ The more risk factors present, the higher the risk. Infants who are formula fed, age ≥41 gestational weeks, or have no major or minor risk factors have a very low likelihood of developing severe hyperbilirubinemia.⁹

Continue to: The Bhutani curve...

The Bhutani curve¹¹ is a widely used, validated nomogram based on pre-discharge hour-specific serum bilirubin measurements. (Go to http://pediatrics.aappublications.org/content/114/1/297 and see Figure 2.) It is the most reliable way to assess the risk for subsequent development of significant hyperbilirubinemia requiring phototherapy.⁹ As such, it is the basis for several online calculators and apps such as BiliTool (bilitool.org).

An alternative nomogram developed by Varvarigou et al¹² is available for predicting significant hyperbilirubinemia based on transcutaneous bilirubin assessment. (Go to https://pdfs.semanticscholar.org/a9a6/5a988dba7a3442bcebc149ad5aea5e3c35d5.pdf and see Figure 3.) The American Academy of Pediatrics (AAP) supports the use of either bilirubin assessment for the screening and diagnosis of hyperbilirubinemia in infants ≥35 weeks’ gestation.⁹

Neurotoxicity risk factors. It is important to differentiate the major and minor risk factors for severe hyperbilirubinemia from neurotoxicity risk factors, also listed in TABLE 3.⁹ Neurotoxicity risk factors are indicative of conditions that may affect albumin binding of bilirubin and are thought to lower the threshold at which bilirubin may cross the blood-brain barrier and render the brain more susceptible to damage from bilirubin. These neurotoxicity risk factors should be applied to the AAP phototherapy nomogram (see Figure 3 at pediatrics.aappublications.org/content/114/1/297) to determine the threshold for initiation of phototherapy in infants with hyperbilirubinemia.⁹

Hyperbilirubinemia is the most common cause of hospital readmission of infants in the United States.

Few investigators have attempted to define risk factors for the development of poor neurologic outcomes associated with hyperbilirubinemia. Evidence to date has not allowed the determination of a specific bilirubin level at which subsequent development of kernicterus occurs.⁹ The limited data available suggest a poor correlation between TSB level and bilirubin-induced neurologic dysfunction.¹³

(For more on kernicterus, as well as ABE and bilirubin-induced neurologic dysfunction [BIND], see “Why do we worry about hyperbilirubinemia?”^9,14-16)

Continue to: Diagnosis relies on TSB and/or TcB

Diagnosis relies on TSB and/or TcB

TSB measurement is the traditional and most widely used method for screening and diagnosing neonatal hyperbilirubinemia, but the blood draw is invasive and carries a risk (albeit low) of infection and anemia.¹⁷ Transcutaneous bilirubin (TcB) assessment is a noninvasive alternative that generally correlates well with TSB values ≤15 mg/dL,^17-20 even in Hispanic, African, and multiethnic populations.^18,21,22

Diagnosis of hyperbilirubinemia is made with TSB or TcB measured at >95th percentile for age in hours. TcB levels measured at >15 mg/dL should be confirmed with TSB measurement. Visual assessment of jaundice should not be used for diagnosis, as it may lead to errors.^9-23

The total cost of testing is lower with TcB ($4-$15 per patient¹⁷) than with TSB when the cost of supplies and personnel are considered.²⁴ Although more recent evidence suggests that TcB is an acceptable way to measure bilirubin in premature infants, no professional society currently recommends the use of TcB for the diagnosis of hyperbilirubinemia in infants²⁵ <35 weeks’ gestation.

Screening recommendations lack consensus

There is a lack of consensus among professional societies on appropriate screening for neonatal hyperbilirubinemia, likely due to limited available data, necessitating expert-driven recommendations.

The AAP recommends universal screening of infants ≥35 weeks’ gestation prior to discharge with measurement of TSB/TcB and/or clinical assessment.⁹ The Canadian Pediatric Society recommends universal screening with TSB/TcB measurement in all infants in the first 72 hours of life.²⁶

Continue to: The US Preventive Services Task Force...

The US Preventative Services Task Force, however, found insufficient evidence to recommend universal screening for infants ≥35 weeks’ gestation.²⁷ The main rationale for their “I” recommendation was that although screening can identify infants at risk of developing severe hyperbilirubinemia, there is no clear evidence that identifying and treating elevated bilirubin levels results in the prevention of kernicterus.

The United Kingdom’s National Institute for Health and Care Excellence (NICE) guidelines do not support universal screening either.²⁸ NICE recommends risk factor assessment and visual inspection for jaundice in all newborns and also additional physical examination for newborns with risk factors. NICE recommends against routine monitoring of bilirubin levels in infants who do not appear jaundiced.

Several recent cohort studies suggest that breastfeeding may not be a significant risk factor for hyperbilirubinemia.

All infants who appear jaundiced should be evaluated with either risk factor assessment or bilirubin measurement (TSB or TcB). Infants born to mothers who are Rh-negative or have type O blood should have cord blood tested for blood type, Rh status, and other antibodies with a direct Coombs test, as ABO and Rh incompatibility are major risk factors for development of hyperbilirubinemia because of hemolysis.^8,9

A question of cost-efficacy? Data from a multicenter prospective clinical trial suggest a number needed to screen of 128,600 to prevent 1 case of kernicterus,²⁹ making cost another important factor in the discussion about screening for neonatal hyperbilirubinemia. Universal screening is associated not only with the cost of TSB and TcB measurements, but also with the cost of phototherapy, rates of which are increased with universal screening.^24,29,30 The cost of caring for 1 patient with kernicterus over a lifetime is estimated at $900,000, while the estimated cost to prevent 1 case of kernicterus with universal TSB/TcB screening is between $5.7 and $9.2 million.³¹

In Canada, universal screening was found to decrease emergency department visits for jaundice, but did not affect rates of readmission for hyperbilirubinemia, length of hospital stay, or rates of phototherapy after discharge.³⁰

Continue to: Phototherapy: What kind of light, when to initiate

Phototherapy: What kind of light, when to initiate

The initial management of hyperbilirubinemia is phototherapy. Light directed at the skin converts bilirubin to lumirubin—a compound that unlike bilirubin does not require conjugation in the liver and can be directly excreted in the urine or bile.⁸

No professional society currently recommends the use of TcB for the diagnosis of hyperbilirubinemia in infants <35 weeks’ gestation.

Light in the blue-green spectrum (460-490 nm) is most effective. Generally, phototherapy is more effective the closer the light is to the infant and the greater the surface area of skin the infant has exposed. There are many different types of lights used to provide phototherapy including fluorescent, halogen, light emitting diode (LED), and fiber optic lights, which are commonly used in home biliblankets.⁸ Fluorescent and halogen lights are the conventional methods, but newer LED systems are equally effective in terms of rate of decline of serum bilirubin levels, duration of phototherapy required, and need for exchange transfusion. Fiber optic lights work as well as other lights in preterm infants but are less effective in term infants. Using 2 fiber optic lights in term infants can increase efficacy to the level of a single conventional or LED source.³²

Phototherapy thresholds. The AAP phototherapy curve (see Figure 3 at http://pediatrics.aappublications.org/content/114/1/297) is commonly used to determine phototherapy thresholds for infants with hyperbilirubinemia. This nomogram applies TSB level and age in hours to a “low,” “medium,” or “high” risk curve that is determined by the presence of neurotoxicity risk factors and gestational age. Infants on the “medium” and “high” risk curves have lower thresholds for initiation of phototherapy.⁹ The majority of infants born at gestational age ≥38 weeks being cared for in a newborn nursery will be assigned to a low risk curve on the AAP phototherapy nomogram, as many of the neurotoxicity risk factors that elevate risk would also be reasons for infants to be in an intensive care unit.

Online calculators and apps based on the AAP phototherapy nomogram, such as BiliTool (bilitool.org), offer recommendations for phototherapy thresholds and may suggest a time interval at which to repeat bilirubin testing if phototherapy is not indicated.

The additional work-up for infants requiring phototherapy often includes neonatal blood type, direct Coombs test, complete blood count and smear, and conjugated bilirubin level.⁹ Besser et al,³³ however, found that 88% of infants requiring phototherapy had normal laboratory results. They also found that those infants with lab abnormalities often started phototherapy before 48 hours of age and did not have an appropriate decrease in bilirubin after initiation of phototherapy.

Continue to: Timing

Timing. Based on this data, it is reasonable to start phototherapy in term infants who develop jaundice at >48 to 72 hours of age without doing additional testing.

Bilirubin levels are expected to drop about 0.5 mg/dL per hour in the first 4 to 8 hours after starting phototherapy, but if the bilirubin measurement is not decreasing as expected or is increasing, additional work-up, with reticulocyte count, G6PD (glucose-6-phosphate dehydrogenase) concentration, end-tidal carbon dioxide determination (ETCO), and a bilirubin/albumin (B/A) ratio is warranted.⁸ Since unbound bilirubin can cross the blood-brain barrier, increased B/A ratio could theoretically be a predictor of bilirubin-induced neurologic dysfunction risk, but Iskander et al³⁴ found that it was not superior to TSB levels in predicting neurotoxicity. ETCO may help identify children with ongoing hemolysis.⁸

The ideal time to stop phototherapy is not clear. Expert recommendations for phototherapy discontinuation thresholds range from 4-5 mg/dL to 13-14 mg/dL,⁸ while other clinicians stop phototherapy when bilirubin falls 1 to 2 mg/dL below the phototherapy initiation threshold. Phototherapy should be continued for any infant with signs of acute bilirubin encephalopathy, even if the bilirubin level is decreasing.⁹ Rebound hyperbilirubinemia is rare, and checking rebound bilirubin levels is not recommended.⁸

Safety. Phototherapy is generally considered safe, but both short- and long-term adverse effects are possible. Immediate adverse effects include intestinal hypermobility/diarrhea and temperature instability. Long-term issues include increased risks of the development of childhood asthma (odds ratio=1.4) and type 1 diabetes (odds ratio=3.79).³⁵ Phototherapy can also be distressing for parents, as it requires frequent blood draws, physical separation, and possible disruption of breastfeeding.³⁶ One study found a number needed to harm of 4 for cessation of breastfeeding at 1 month in jaundiced infants.³⁷

Maintain breastfeeding. The AAP recommends breastfeeding be continued and promoted in infants who are jaundiced and receiving phototherapy.⁹ Maternal interaction with health care professionals who are encouraging of this practice was the best predictor of ongoing breastfeeding in a qualitative study of jaundiced infants and their families.³⁸ Interrupting phototherapy for up to 30 minutes to allow for breastfeeding without eye covers has not been shown to decrease the efficacy of phototherapy.³⁸

Continue to: Available evidence does not provide a clear answer...

Available evidence does not provide a clear answer regarding whether formula supplementation should be initiated in breastfed infants with hyperbilirubinemia. Cow’s milk formula supplementation decreases intestinal reabsorption of bilirubin, lowering serum bilirubin levels, but may interfere with successful breastfeeding.³⁹ The Academy of Breastfeeding Medicine recommends an individual discussion about formula supplementation in place of, or prior to, phototherapy if an infant’s bilirubin is approaching (within 2-3 mg/dL) or above the threshold for phototherapy.³⁹ Routine supplementation with intravenous fluids or other non–milk-based supplementation is not recommended for infants receiving phototherapy.⁹

Adjuvant therapies and exchange transfusion

Clofibrate, metalloporphyrins, and ursodiol have been studied in the management of unconjugated hyperbilirubinemia as augmentation to phototherapy. Honar et al⁴⁰ found that ursodiol added at the time of phototherapy initiation demonstrated a significant reduction in peak bilirubin levels and duration of phototherapy in term infants with unconjugated hyperbilirubinemia without any adverse effects. Cochrane reviews of clofibrat⁵ and metalloporphyrins⁴¹ found that when added to phototherapy, these medications significantly decreased serum bilirubin levels and duration of phototherapy. However, there was insufficient evidence to recommend their use due to inadequate data on safety and long-term outcomes.

Exchange transfusion. Infants with bilirubin levels >25 mg/dL, those who are not responding to phototherapy, and those with evidence of acute bilirubin encephalopathy should be treated with exchange transfusion, with initiation based on an infant’s age in hours and neurotoxicity risk factors.⁹ Exchange transfusion involves taking small aliquots of blood from the infant and replacing them with donor red cells until the infant’s blood volume has been replaced twice to remove bilirubin and antibodies that may be causing hemolysis. It should be carried out in a neonatal intensive care unit due to significant risks.

About 88% of infants requiring phototherapy have normal laboratory study results.

Approximately 12% of infants have a complication from exchange transfusion including infection, electrolyte imbalances, thrombosis, thrombocytopenia, and necrotizing enterocolitis.⁸ The mortality rate in neonates without hemolysis who undergo exchange transfusion is 3 to 4 per 1000 treated.⁴²

Post-discharge follow-up

Infants discharged before 72 hours of life should be seen within 2 days of discharge. Those infants with significant risk factors for development of severe hyperbilirubinemia should be seen within 1 day. Arrangements for follow-up should be made prior to discharge. Some infants discharged before 48 hours of life may require 2 follow-up visits. If follow-up cannot be ensured for an infant with risk factors for the development of severe hyperbilirubinemia, delay of discharge may be appropriate.⁹

CORRESPONDENCE
Katharine C. DeGeorge, MD, MS, Department of Family Medicine, University of Virginia, PO Box 800729, Charlottesville, VA, 22908-0729; [email protected].

Tobacco companies are marketing a new version of cigarettes dubbed heat-not-burn (HNB) cigarettes.^1,2 Offered as a “modified-risk tobacco product,” HNB cigarettes utilize a lithium battery-powered heating element and are available all over the world.^1,2 Like conventional smokes, they contain tobacco, but deliver nicotine by heating leaves at 350° C rather than burning them at 600° C.^1-3 Heating the tobacco produces an inhalable aerosol with tobacco flavor and nicotine, without smoke. These HNB cigarettes are also different from e-cigarettes that aerosolize a liquid.

Heat-not-burn aerosols deliver many of the same dangerous compounds as traditional cigarettes, including carbon monoxide, tar, and aromatic hydrocarbons.

Tobacco companies contend that HNB cigarettes are safer than smoking tobacco.¹ Consumers inhale a heated tobacco aerosol that reportedly contains less nicotine and fewer toxicities; yet, HNB are not independently substantiated as being healthier, nor proven safe.^1-5 Thermal decomposition, rather than combustion, may afford a less dangerous nicotine consumption; however, HNB aerosols deliver many of the same dangerous compounds as traditional cigarettes, including carbon monoxide, tar, and aromatic hydrocarbons.^2-6 Despite possible harm reduction in the short-run, long-term safety remains unconfirmed.

Safety in passive environmental inhalations is not established.² HNB cigarettes are contraindicated during pregnancy and/or lactation. Nicotine is provided in addictive quantities, enough to foster continued dependence. Exposure to HNB products can promote longer-term usage or lead to smoking traditional tobacco cigarettes. There is also an increased risk to non-smokers of exposure to HNB aerosols. Additionally, lithium batteries have been known to burn or explode. HNB devices may even lead to privacy concerns due micro-controller chips contained within that harvest information. These chips could inform manufacturers about device usage.⁷

Tobacco is a global health hazard and smoking is the number one preventable cause of disease.^1,5,8 Global smoking prevalence is nearing 19%.⁹ There are concerns about dual use, rather than HNB cigarettes alone as a substitute for conventional smoking. The ultimate hope is to abstain from all tobacco and nicotine. Although HNB inhalations contain fewer toxic chemicals than by smoking, evidence regarding mitigation of tobacco-related diseases is inconclusive.¹⁰

Physicians have an obligation to minimize tobacco and nicotine-related hazards.

Physicians have an obligation to minimize tobacco and nicotine-related hazards. Ongoing research and clinical exposure might better document the health impact of HNB cigarettes. Until the risks and benefits of HNB cigarettes are confirmed, health care professionals would be wise to counsel against their use.

Diksha Mohanty, MD; Steven Lippmann, MD
Louisville, Ky

Tobacco companies are marketing a new version of cigarettes dubbed heat-not-burn (HNB) cigarettes.^1,2 Offered as a “modified-risk tobacco product,” HNB cigarettes utilize a lithium battery-powered heating element and are available all over the world.^1,2 Like conventional smokes, they contain tobacco, but deliver nicotine by heating leaves at 350° C rather than burning them at 600° C.^1-3 Heating the tobacco produces an inhalable aerosol with tobacco flavor and nicotine, without smoke. These HNB cigarettes are also different from e-cigarettes that aerosolize a liquid.

Heat-not-burn aerosols deliver many of the same dangerous compounds as traditional cigarettes, including carbon monoxide, tar, and aromatic hydrocarbons.

Tobacco companies contend that HNB cigarettes are safer than smoking tobacco.¹ Consumers inhale a heated tobacco aerosol that reportedly contains less nicotine and fewer toxicities; yet, HNB are not independently substantiated as being healthier, nor proven safe.^1-5 Thermal decomposition, rather than combustion, may afford a less dangerous nicotine consumption; however, HNB aerosols deliver many of the same dangerous compounds as traditional cigarettes, including carbon monoxide, tar, and aromatic hydrocarbons.^2-6 Despite possible harm reduction in the short-run, long-term safety remains unconfirmed.

Safety in passive environmental inhalations is not established.² HNB cigarettes are contraindicated during pregnancy and/or lactation. Nicotine is provided in addictive quantities, enough to foster continued dependence. Exposure to HNB products can promote longer-term usage or lead to smoking traditional tobacco cigarettes. There is also an increased risk to non-smokers of exposure to HNB aerosols. Additionally, lithium batteries have been known to burn or explode. HNB devices may even lead to privacy concerns due micro-controller chips contained within that harvest information. These chips could inform manufacturers about device usage.⁷

Tobacco is a global health hazard and smoking is the number one preventable cause of disease.^1,5,8 Global smoking prevalence is nearing 19%.⁹ There are concerns about dual use, rather than HNB cigarettes alone as a substitute for conventional smoking. The ultimate hope is to abstain from all tobacco and nicotine. Although HNB inhalations contain fewer toxic chemicals than by smoking, evidence regarding mitigation of tobacco-related diseases is inconclusive.¹⁰

Physicians have an obligation to minimize tobacco and nicotine-related hazards.

Physicians have an obligation to minimize tobacco and nicotine-related hazards. Ongoing research and clinical exposure might better document the health impact of HNB cigarettes. Until the risks and benefits of HNB cigarettes are confirmed, health care professionals would be wise to counsel against their use.

Diksha Mohanty, MD; Steven Lippmann, MD
Louisville, Ky

Tobacco companies are marketing a new version of cigarettes dubbed heat-not-burn (HNB) cigarettes.^1,2 Offered as a “modified-risk tobacco product,” HNB cigarettes utilize a lithium battery-powered heating element and are available all over the world.^1,2 Like conventional smokes, they contain tobacco, but deliver nicotine by heating leaves at 350° C rather than burning them at 600° C.^1-3 Heating the tobacco produces an inhalable aerosol with tobacco flavor and nicotine, without smoke. These HNB cigarettes are also different from e-cigarettes that aerosolize a liquid.

Heat-not-burn aerosols deliver many of the same dangerous compounds as traditional cigarettes, including carbon monoxide, tar, and aromatic hydrocarbons.

Tobacco companies contend that HNB cigarettes are safer than smoking tobacco.¹ Consumers inhale a heated tobacco aerosol that reportedly contains less nicotine and fewer toxicities; yet, HNB are not independently substantiated as being healthier, nor proven safe.^1-5 Thermal decomposition, rather than combustion, may afford a less dangerous nicotine consumption; however, HNB aerosols deliver many of the same dangerous compounds as traditional cigarettes, including carbon monoxide, tar, and aromatic hydrocarbons.^2-6 Despite possible harm reduction in the short-run, long-term safety remains unconfirmed.

Safety in passive environmental inhalations is not established.² HNB cigarettes are contraindicated during pregnancy and/or lactation. Nicotine is provided in addictive quantities, enough to foster continued dependence. Exposure to HNB products can promote longer-term usage or lead to smoking traditional tobacco cigarettes. There is also an increased risk to non-smokers of exposure to HNB aerosols. Additionally, lithium batteries have been known to burn or explode. HNB devices may even lead to privacy concerns due micro-controller chips contained within that harvest information. These chips could inform manufacturers about device usage.⁷

Tobacco is a global health hazard and smoking is the number one preventable cause of disease.^1,5,8 Global smoking prevalence is nearing 19%.⁹ There are concerns about dual use, rather than HNB cigarettes alone as a substitute for conventional smoking. The ultimate hope is to abstain from all tobacco and nicotine. Although HNB inhalations contain fewer toxic chemicals than by smoking, evidence regarding mitigation of tobacco-related diseases is inconclusive.¹⁰

Physicians have an obligation to minimize tobacco and nicotine-related hazards.

Physicians have an obligation to minimize tobacco and nicotine-related hazards. Ongoing research and clinical exposure might better document the health impact of HNB cigarettes. Until the risks and benefits of HNB cigarettes are confirmed, health care professionals would be wise to counsel against their use.

Diksha Mohanty, MD; Steven Lippmann, MD
Louisville, Ky

Like JFP’s Editor-in-Chief, Dr. John Hickner, I have been skeptical about bariatric surgery (A [former] skeptic’s view of bariatric surgery. J Fam Pract. 2018;67:600), but I will recommend it for a select few patients who are unable or unwilling to undergo significant lifestyle changes. My experience in clinic has done nothing to change this skeptical view. I have many patients who opted for bariatric surgery, but did not change their lifestyle habits. These patients often regain weight and accumulate chronic diseases 2 to 7 years postop. In the end, if a patient does not change their lifestyle, bariatric surgery can push the consequences of obesity out 5 to 10 years, but at a very significant risk.

The most significant problem I see is that many primary care providers do not feel qualified to impart meaningful lifestyle recommendations to patients, which often leads to guidance that is inadequate and, in some cases, inaccurate. Furthermore, assuming patients have received evidence-based instructions, they often lack the support and means to apply these lifestyle changes. I would be very hesitant to recommend bariatric surgery before addressing all of these concerns.

An interesting study done by Lingvay et al¹ showed that postsurgical starvation (600 kcal/d) without the bariatric surgery had better short-term outcomes than surgery with calorie restriction, which suggests that a period of starvation is better than surgery.

It is more prudent to refer bariatric surgery candidates to someone who understands good nutrition and lifestyle changes.

In general, the results of evidence-based lifestyle changes far surpass any medical or surgical treatment for obesity and its associated chronic diseases. The evidence for this is overwhelming. (See books by Drs. Joel Fuhrman, Michael Greger, Neal Barnard, Dean Ornish, and Garth Davis, as well as the hundreds of peer-reviewed studies cited in these books.) Yet most patients under-going bariatric surgery never receive proper instructions or attempt any meaningful lifestyle changes.

I think it is far more prudent to refer potential surgical candidates to someone who understands good nutrition and lifestyle changes, such as a doctor certified by the American College of Lifestyle Medicine (lifestylemedicine.org). Surgery, in my opinion, is a very poor and dangerous second choice.

John Reed, MD
Fishersville, Va

Like JFP’s Editor-in-Chief, Dr. John Hickner, I have been skeptical about bariatric surgery (A [former] skeptic’s view of bariatric surgery. J Fam Pract. 2018;67:600), but I will recommend it for a select few patients who are unable or unwilling to undergo significant lifestyle changes. My experience in clinic has done nothing to change this skeptical view. I have many patients who opted for bariatric surgery, but did not change their lifestyle habits. These patients often regain weight and accumulate chronic diseases 2 to 7 years postop. In the end, if a patient does not change their lifestyle, bariatric surgery can push the consequences of obesity out 5 to 10 years, but at a very significant risk.

The most significant problem I see is that many primary care providers do not feel qualified to impart meaningful lifestyle recommendations to patients, which often leads to guidance that is inadequate and, in some cases, inaccurate. Furthermore, assuming patients have received evidence-based instructions, they often lack the support and means to apply these lifestyle changes. I would be very hesitant to recommend bariatric surgery before addressing all of these concerns.

An interesting study done by Lingvay et al¹ showed that postsurgical starvation (600 kcal/d) without the bariatric surgery had better short-term outcomes than surgery with calorie restriction, which suggests that a period of starvation is better than surgery.

It is more prudent to refer bariatric surgery candidates to someone who understands good nutrition and lifestyle changes.

In general, the results of evidence-based lifestyle changes far surpass any medical or surgical treatment for obesity and its associated chronic diseases. The evidence for this is overwhelming. (See books by Drs. Joel Fuhrman, Michael Greger, Neal Barnard, Dean Ornish, and Garth Davis, as well as the hundreds of peer-reviewed studies cited in these books.) Yet most patients under-going bariatric surgery never receive proper instructions or attempt any meaningful lifestyle changes.

I think it is far more prudent to refer potential surgical candidates to someone who understands good nutrition and lifestyle changes, such as a doctor certified by the American College of Lifestyle Medicine (lifestylemedicine.org). Surgery, in my opinion, is a very poor and dangerous second choice.

John Reed, MD
Fishersville, Va

Like JFP’s Editor-in-Chief, Dr. John Hickner, I have been skeptical about bariatric surgery (A [former] skeptic’s view of bariatric surgery. J Fam Pract. 2018;67:600), but I will recommend it for a select few patients who are unable or unwilling to undergo significant lifestyle changes. My experience in clinic has done nothing to change this skeptical view. I have many patients who opted for bariatric surgery, but did not change their lifestyle habits. These patients often regain weight and accumulate chronic diseases 2 to 7 years postop. In the end, if a patient does not change their lifestyle, bariatric surgery can push the consequences of obesity out 5 to 10 years, but at a very significant risk.

The most significant problem I see is that many primary care providers do not feel qualified to impart meaningful lifestyle recommendations to patients, which often leads to guidance that is inadequate and, in some cases, inaccurate. Furthermore, assuming patients have received evidence-based instructions, they often lack the support and means to apply these lifestyle changes. I would be very hesitant to recommend bariatric surgery before addressing all of these concerns.

An interesting study done by Lingvay et al¹ showed that postsurgical starvation (600 kcal/d) without the bariatric surgery had better short-term outcomes than surgery with calorie restriction, which suggests that a period of starvation is better than surgery.

It is more prudent to refer bariatric surgery candidates to someone who understands good nutrition and lifestyle changes.

In general, the results of evidence-based lifestyle changes far surpass any medical or surgical treatment for obesity and its associated chronic diseases. The evidence for this is overwhelming. (See books by Drs. Joel Fuhrman, Michael Greger, Neal Barnard, Dean Ornish, and Garth Davis, as well as the hundreds of peer-reviewed studies cited in these books.) Yet most patients under-going bariatric surgery never receive proper instructions or attempt any meaningful lifestyle changes.

I think it is far more prudent to refer potential surgical candidates to someone who understands good nutrition and lifestyle changes, such as a doctor certified by the American College of Lifestyle Medicine (lifestylemedicine.org). Surgery, in my opinion, is a very poor and dangerous second choice.

John Reed, MD
Fishersville, Va

I appreciated the PURL, “Should you reassess your patient’s asthma diagnosis?” (J Fam Pract. 2018;67:704-707) that reminded clinicians to taper asthma controller medications in asymptomatic patients. The articles cited^1,2 by Drs. Stevermer and Hayes documented that one-third of the adults enrolled in the respective study with physician-diagnosed asthma did not have objective evidence for asthma and were either over-diagnosed or had remitted. These articles also contained evidence that: 1) over-diagnosis was likely much more common than remission,¹ and 2) there was a significant temporal trend towards increasing over-diagnosis/remission during the last several decades. The authors of the cited article¹ suggested that the temporal trend could be explained by increased public awareness of respiratory symptoms, more aggressive marketing of asthma medications, and a lack of objective measurement of reversible airway obstruction in primary care. These assertions deserve careful consideration as we strive to diagnose asthma appropriately.

Over-diagnosis/remission is almost certainly not as prevalent (33%) as the authors of the cited articles^1,2 reported. The reason is simple selection bias: 1) the cited study² excluded asthma patients who smoked >10 pack-years (it enrolled 701 asthma patients and excluded 812 asthma patients with a >10 pack-year smoking history), and 2) this study likely did not include asthma patients with the asthma-COPD overlap syndrome, which is treated as asthma and comprises an additional 30% of our patients with chronic airflow limitation (the asthma-COPD spectrum).³ Asthma patients who smoke and/or have the overlap syndrome are prone to severe asthma that is refractory to inhaled corticosteroids.^3,4

In addition to making the correct diagnosis, it is equally important to be aware of efficacious therapies for severe refractory asthma that primary care clinicians can easily use. There is now good evidence that azithromycin is efficacious for severe refractory asthma⁵ and should be considered prior to referral for immunomodulatory asthma therapies.⁶

David L. Hahn, MD, MS
Madison, Wis

1. Aaron SD, Vandemheen KL, Boulet LP, et al; Canadian Respiratory Clinical Research Consortium. Overdiagnosis of asthma in obese and nonobese adults. CMAJ. 2008;179:1121-1131.

2. Aaron SD, Vandemheen KL, FitzGerald JM, et al; Canadian Respiratory Research Network. Reevaluation of diagnosis in adults with physician-diagnosed asthma. JAMA. 2017;317:269-279.

3. Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: what are its features and how important is it? Thorax. 2009;64:728-735.

4. Stapleton M, Howard-Thompson A, George C, et al. Smoking and asthma. J Am Board Fam Med. 2011;24;313-322.

5. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017:390659-668.

6. Hahn DL, Grasmick M, Hetzel S, et al; AZMATICS (AZithroMycin-Asthma Trial In Community Settings) Study Group. Azithromycin for bronchial asthma in adults: an effectiveness trial. J Am Board Fam Med. 2012;25:442-459.

Continue to: Authors' response...

Authors’ response:

We appreciate Dr. Hahn’s observations about the PURL¹ on overdiagnosis of asthma. This article focused on the results of a prospective, multicenter cohort study² that evaluated the feasibility of tapering, and in many patients, stopping asthma medications. We agree that if the study had included people diagnosed with asthma who also had smoked at least 10 pack-years or who also had COPD, the proportion of those who would eventually no longer meet diagnostic criteria for asthma would be lower than in this study. We are uncertain of the relative proportion of cases that were overdiagnosis, when compared with true remission of disease, as only 43% of those no longer meeting the diagnostic criteria for asthma had evidence of prior lung function testing, whether by formal spirometry, serial peak function testing, or bronchial challenge testing.

We agree that using efficacious therapies for severe refractory asthma is essential, but the selection of those therapies was outside the scope of this PURL.

James J. Stevermer, MD, MSPH; Alisa Hayes, MD
Columbia, Mo

1. Stevermer JJ, Hayes A. Should you reassess your patient’s asthma diagnosis? J Fam Pract. 2018;67:704-707.

2. Aaron SD, Vandemheen KL, FitzGerald JM, et al; Canadian Respiratory Research Network. Reevaluation of diagnosis in adults with physician-diagnosed asthma. JAMA. 2017;317:269-279.

I appreciated the PURL, “Should you reassess your patient’s asthma diagnosis?” (J Fam Pract. 2018;67:704-707) that reminded clinicians to taper asthma controller medications in asymptomatic patients. The articles cited^1,2 by Drs. Stevermer and Hayes documented that one-third of the adults enrolled in the respective study with physician-diagnosed asthma did not have objective evidence for asthma and were either over-diagnosed or had remitted. These articles also contained evidence that: 1) over-diagnosis was likely much more common than remission,¹ and 2) there was a significant temporal trend towards increasing over-diagnosis/remission during the last several decades. The authors of the cited article¹ suggested that the temporal trend could be explained by increased public awareness of respiratory symptoms, more aggressive marketing of asthma medications, and a lack of objective measurement of reversible airway obstruction in primary care. These assertions deserve careful consideration as we strive to diagnose asthma appropriately.

Over-diagnosis/remission is almost certainly not as prevalent (33%) as the authors of the cited articles^1,2 reported. The reason is simple selection bias: 1) the cited study² excluded asthma patients who smoked >10 pack-years (it enrolled 701 asthma patients and excluded 812 asthma patients with a >10 pack-year smoking history), and 2) this study likely did not include asthma patients with the asthma-COPD overlap syndrome, which is treated as asthma and comprises an additional 30% of our patients with chronic airflow limitation (the asthma-COPD spectrum).³ Asthma patients who smoke and/or have the overlap syndrome are prone to severe asthma that is refractory to inhaled corticosteroids.^3,4

In addition to making the correct diagnosis, it is equally important to be aware of efficacious therapies for severe refractory asthma that primary care clinicians can easily use. There is now good evidence that azithromycin is efficacious for severe refractory asthma⁵ and should be considered prior to referral for immunomodulatory asthma therapies.⁶

David L. Hahn, MD, MS
Madison, Wis

1. Aaron SD, Vandemheen KL, Boulet LP, et al; Canadian Respiratory Clinical Research Consortium. Overdiagnosis of asthma in obese and nonobese adults. CMAJ. 2008;179:1121-1131.

2. Aaron SD, Vandemheen KL, FitzGerald JM, et al; Canadian Respiratory Research Network. Reevaluation of diagnosis in adults with physician-diagnosed asthma. JAMA. 2017;317:269-279.

3. Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: what are its features and how important is it? Thorax. 2009;64:728-735.

4. Stapleton M, Howard-Thompson A, George C, et al. Smoking and asthma. J Am Board Fam Med. 2011;24;313-322.

5. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017:390659-668.

6. Hahn DL, Grasmick M, Hetzel S, et al; AZMATICS (AZithroMycin-Asthma Trial In Community Settings) Study Group. Azithromycin for bronchial asthma in adults: an effectiveness trial. J Am Board Fam Med. 2012;25:442-459.

Continue to: Authors' response...

Authors’ response:

We appreciate Dr. Hahn’s observations about the PURL¹ on overdiagnosis of asthma. This article focused on the results of a prospective, multicenter cohort study² that evaluated the feasibility of tapering, and in many patients, stopping asthma medications. We agree that if the study had included people diagnosed with asthma who also had smoked at least 10 pack-years or who also had COPD, the proportion of those who would eventually no longer meet diagnostic criteria for asthma would be lower than in this study. We are uncertain of the relative proportion of cases that were overdiagnosis, when compared with true remission of disease, as only 43% of those no longer meeting the diagnostic criteria for asthma had evidence of prior lung function testing, whether by formal spirometry, serial peak function testing, or bronchial challenge testing.

We agree that using efficacious therapies for severe refractory asthma is essential, but the selection of those therapies was outside the scope of this PURL.

James J. Stevermer, MD, MSPH; Alisa Hayes, MD
Columbia, Mo

1. Stevermer JJ, Hayes A. Should you reassess your patient’s asthma diagnosis? J Fam Pract. 2018;67:704-707.

2. Aaron SD, Vandemheen KL, FitzGerald JM, et al; Canadian Respiratory Research Network. Reevaluation of diagnosis in adults with physician-diagnosed asthma. JAMA. 2017;317:269-279.

I appreciated the PURL, “Should you reassess your patient’s asthma diagnosis?” (J Fam Pract. 2018;67:704-707) that reminded clinicians to taper asthma controller medications in asymptomatic patients. The articles cited^1,2 by Drs. Stevermer and Hayes documented that one-third of the adults enrolled in the respective study with physician-diagnosed asthma did not have objective evidence for asthma and were either over-diagnosed or had remitted. These articles also contained evidence that: 1) over-diagnosis was likely much more common than remission,¹ and 2) there was a significant temporal trend towards increasing over-diagnosis/remission during the last several decades. The authors of the cited article¹ suggested that the temporal trend could be explained by increased public awareness of respiratory symptoms, more aggressive marketing of asthma medications, and a lack of objective measurement of reversible airway obstruction in primary care. These assertions deserve careful consideration as we strive to diagnose asthma appropriately.

Over-diagnosis/remission is almost certainly not as prevalent (33%) as the authors of the cited articles^1,2 reported. The reason is simple selection bias: 1) the cited study² excluded asthma patients who smoked >10 pack-years (it enrolled 701 asthma patients and excluded 812 asthma patients with a >10 pack-year smoking history), and 2) this study likely did not include asthma patients with the asthma-COPD overlap syndrome, which is treated as asthma and comprises an additional 30% of our patients with chronic airflow limitation (the asthma-COPD spectrum).³ Asthma patients who smoke and/or have the overlap syndrome are prone to severe asthma that is refractory to inhaled corticosteroids.^3,4

In addition to making the correct diagnosis, it is equally important to be aware of efficacious therapies for severe refractory asthma that primary care clinicians can easily use. There is now good evidence that azithromycin is efficacious for severe refractory asthma⁵ and should be considered prior to referral for immunomodulatory asthma therapies.⁶

David L. Hahn, MD, MS
Madison, Wis

1. Aaron SD, Vandemheen KL, Boulet LP, et al; Canadian Respiratory Clinical Research Consortium. Overdiagnosis of asthma in obese and nonobese adults. CMAJ. 2008;179:1121-1131.

2. Aaron SD, Vandemheen KL, FitzGerald JM, et al; Canadian Respiratory Research Network. Reevaluation of diagnosis in adults with physician-diagnosed asthma. JAMA. 2017;317:269-279.

3. Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: what are its features and how important is it? Thorax. 2009;64:728-735.

4. Stapleton M, Howard-Thompson A, George C, et al. Smoking and asthma. J Am Board Fam Med. 2011;24;313-322.

5. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017:390659-668.

6. Hahn DL, Grasmick M, Hetzel S, et al; AZMATICS (AZithroMycin-Asthma Trial In Community Settings) Study Group. Azithromycin for bronchial asthma in adults: an effectiveness trial. J Am Board Fam Med. 2012;25:442-459.

Continue to: Authors' response...

Authors’ response:

We appreciate Dr. Hahn’s observations about the PURL¹ on overdiagnosis of asthma. This article focused on the results of a prospective, multicenter cohort study² that evaluated the feasibility of tapering, and in many patients, stopping asthma medications. We agree that if the study had included people diagnosed with asthma who also had smoked at least 10 pack-years or who also had COPD, the proportion of those who would eventually no longer meet diagnostic criteria for asthma would be lower than in this study. We are uncertain of the relative proportion of cases that were overdiagnosis, when compared with true remission of disease, as only 43% of those no longer meeting the diagnostic criteria for asthma had evidence of prior lung function testing, whether by formal spirometry, serial peak function testing, or bronchial challenge testing.

We agree that using efficacious therapies for severe refractory asthma is essential, but the selection of those therapies was outside the scope of this PURL.

James J. Stevermer, MD, MSPH; Alisa Hayes, MD
Columbia, Mo

1. Stevermer JJ, Hayes A. Should you reassess your patient’s asthma diagnosis? J Fam Pract. 2018;67:704-707.

2. Aaron SD, Vandemheen KL, FitzGerald JM, et al; Canadian Respiratory Research Network. Reevaluation of diagnosis in adults with physician-diagnosed asthma. JAMA. 2017;317:269-279.

EVIDENCE SUMMARY

A 2017 network meta-analysis included 19 RCTs and 87,831 patients receiving anticoagulation, antiplatelet therapy, or LAAC for NVAF.¹ LAAC was superior to antiplatelet therapy (hazard ratio [HR]=0.44; 95% confidence interval [CI], 0.23-0.86; P<.05) and similar to NOACs (HR=1.01; 95% CI, 0.53-1.92; P=.969) for reducing risk of stroke.

LAAC and NOACs found “most effective”

A network meta-analysis of 21 RCTs, which included data from 96,017 patients, examined the effectiveness of 7 interventions to prevent stroke in patients with NVAF: 4 NOACs, VKA, aspirin, and LAAC; the analysis compared VKA with the other interventions.² The 2 trials that investigated LAAC accounted for only 1114 patients.

When the 7 interventions were ranked simultaneously on 2 efficacy outcomes (stroke/systemic embolism and all-cause mortality), all 4 NOACs and LAAC clustered together as “the most effective and lifesaving.”

Fewer hemorrhagic strokes with LAAC than VKA

A 2016 meta-analysis of 6 RCTs compared risk of stroke for adults with NVAF who received LAAC, VKA, or NOACs.³ No significant differences were found between NOACs and VKA or LAAC and VKA. The LAAC group had a significantly smaller number of patients.

A 2015 meta-analysis of 2406 patients with NVAF found that patients who received LAAC had significantly fewer hemorrhagic strokes (HR=0.22; P<.05) than patients who received VKA.⁴ No differences in all-cause stroke were found between the 2 groups during an average follow-up of 2.69 years.

LAAC found superior to warfarin for stroke prevention in one trial

A 2014 multicenter, randomized study (PROTECT-AF) of 707 patients with NVAF plus 1 additional stroke risk factor compared LAAC with VKA (warfarin).⁵ LAAC met criteria at 3.8 years for both noninferiority and superiority in preventing stroke, based on 2.3 events per 100 patient-years compared with 3.8 events per 100 patient-years for VKA. The number needed to treat with LAAC was 67 to result in 1 less event per patient-year.

A 2014 RCT (PREVAIL) evaluated patients with NVAF plus 1 additional stroke risk factor. LAAC was noninferior to warfarin for ischemic stroke prevention.⁶

Continue to: RECOMMENDATIONS

The American College of Cardiology (ACC) recommends LAAC for patients with NVAF who are not candidates for long-term anticoagulation.⁷ Similarly, the 2016 European Society of Cardiology guidelines issued a Class IIb recommendation for LAAC for stroke prevention in those with contraindications for long-term anticoagulation.⁸ Lastly, in a 2014 guideline, the American Heart Association, ACC, and the Heart Rhythm Society issued a Class IIb recommendation for surgical excision of the left atrial appendage in patients with atrial fibrillation undergoing cardiac surgery, but did not provide recommendations regarding LAAC.⁹

EVIDENCE SUMMARY

A 2017 network meta-analysis included 19 RCTs and 87,831 patients receiving anticoagulation, antiplatelet therapy, or LAAC for NVAF.¹ LAAC was superior to antiplatelet therapy (hazard ratio [HR]=0.44; 95% confidence interval [CI], 0.23-0.86; P<.05) and similar to NOACs (HR=1.01; 95% CI, 0.53-1.92; P=.969) for reducing risk of stroke.

LAAC and NOACs found “most effective”

A network meta-analysis of 21 RCTs, which included data from 96,017 patients, examined the effectiveness of 7 interventions to prevent stroke in patients with NVAF: 4 NOACs, VKA, aspirin, and LAAC; the analysis compared VKA with the other interventions.² The 2 trials that investigated LAAC accounted for only 1114 patients.

When the 7 interventions were ranked simultaneously on 2 efficacy outcomes (stroke/systemic embolism and all-cause mortality), all 4 NOACs and LAAC clustered together as “the most effective and lifesaving.”

Fewer hemorrhagic strokes with LAAC than VKA

A 2016 meta-analysis of 6 RCTs compared risk of stroke for adults with NVAF who received LAAC, VKA, or NOACs.³ No significant differences were found between NOACs and VKA or LAAC and VKA. The LAAC group had a significantly smaller number of patients.

A 2015 meta-analysis of 2406 patients with NVAF found that patients who received LAAC had significantly fewer hemorrhagic strokes (HR=0.22; P<.05) than patients who received VKA.⁴ No differences in all-cause stroke were found between the 2 groups during an average follow-up of 2.69 years.

LAAC found superior to warfarin for stroke prevention in one trial

A 2014 multicenter, randomized study (PROTECT-AF) of 707 patients with NVAF plus 1 additional stroke risk factor compared LAAC with VKA (warfarin).⁵ LAAC met criteria at 3.8 years for both noninferiority and superiority in preventing stroke, based on 2.3 events per 100 patient-years compared with 3.8 events per 100 patient-years for VKA. The number needed to treat with LAAC was 67 to result in 1 less event per patient-year.

A 2014 RCT (PREVAIL) evaluated patients with NVAF plus 1 additional stroke risk factor. LAAC was noninferior to warfarin for ischemic stroke prevention.⁶

Continue to: RECOMMENDATIONS

The American College of Cardiology (ACC) recommends LAAC for patients with NVAF who are not candidates for long-term anticoagulation.⁷ Similarly, the 2016 European Society of Cardiology guidelines issued a Class IIb recommendation for LAAC for stroke prevention in those with contraindications for long-term anticoagulation.⁸ Lastly, in a 2014 guideline, the American Heart Association, ACC, and the Heart Rhythm Society issued a Class IIb recommendation for surgical excision of the left atrial appendage in patients with atrial fibrillation undergoing cardiac surgery, but did not provide recommendations regarding LAAC.⁹

EVIDENCE SUMMARY

A 2017 network meta-analysis included 19 RCTs and 87,831 patients receiving anticoagulation, antiplatelet therapy, or LAAC for NVAF.¹ LAAC was superior to antiplatelet therapy (hazard ratio [HR]=0.44; 95% confidence interval [CI], 0.23-0.86; P<.05) and similar to NOACs (HR=1.01; 95% CI, 0.53-1.92; P=.969) for reducing risk of stroke.

LAAC and NOACs found “most effective”

A network meta-analysis of 21 RCTs, which included data from 96,017 patients, examined the effectiveness of 7 interventions to prevent stroke in patients with NVAF: 4 NOACs, VKA, aspirin, and LAAC; the analysis compared VKA with the other interventions.² The 2 trials that investigated LAAC accounted for only 1114 patients.

When the 7 interventions were ranked simultaneously on 2 efficacy outcomes (stroke/systemic embolism and all-cause mortality), all 4 NOACs and LAAC clustered together as “the most effective and lifesaving.”

Fewer hemorrhagic strokes with LAAC than VKA

A 2016 meta-analysis of 6 RCTs compared risk of stroke for adults with NVAF who received LAAC, VKA, or NOACs.³ No significant differences were found between NOACs and VKA or LAAC and VKA. The LAAC group had a significantly smaller number of patients.

A 2015 meta-analysis of 2406 patients with NVAF found that patients who received LAAC had significantly fewer hemorrhagic strokes (HR=0.22; P<.05) than patients who received VKA.⁴ No differences in all-cause stroke were found between the 2 groups during an average follow-up of 2.69 years.

LAAC found superior to warfarin for stroke prevention in one trial

A 2014 multicenter, randomized study (PROTECT-AF) of 707 patients with NVAF plus 1 additional stroke risk factor compared LAAC with VKA (warfarin).⁵ LAAC met criteria at 3.8 years for both noninferiority and superiority in preventing stroke, based on 2.3 events per 100 patient-years compared with 3.8 events per 100 patient-years for VKA. The number needed to treat with LAAC was 67 to result in 1 less event per patient-year.

A 2014 RCT (PREVAIL) evaluated patients with NVAF plus 1 additional stroke risk factor. LAAC was noninferior to warfarin for ischemic stroke prevention.⁶

Continue to: RECOMMENDATIONS

The American College of Cardiology (ACC) recommends LAAC for patients with NVAF who are not candidates for long-term anticoagulation.⁷ Similarly, the 2016 European Society of Cardiology guidelines issued a Class IIb recommendation for LAAC for stroke prevention in those with contraindications for long-term anticoagulation.⁸ Lastly, in a 2014 guideline, the American Heart Association, ACC, and the Heart Rhythm Society issued a Class IIb recommendation for surgical excision of the left atrial appendage in patients with atrial fibrillation undergoing cardiac surgery, but did not provide recommendations regarding LAAC.⁹

When I was training to become a family physician, my mentor often told me that a competent family physician should be able to manage about 80% of patients’ office visits without consultation. I am not sure where that figure came from, but my 40 years of experience in family medicine supports that prediction. Of course, the flip-side of that coin is having the wisdom to make those referrals for patients who really need a specialist’s diagnostic or treatment skills. The “rub,” of course, is that when I do need a specialist’s help, the wait for an appointment is often unacceptably long—both for me and my patients.

One way to help alleviate the logjam of referrals is to manage more medical problems ourselves. Now I don’t mean holding on to patients who definitely need a referral. But I do think we should avoid being too quick to hand off a patient. Let me explain.

When I was Chair of Family Medicine at Cleveland Clinic, I asked my specialty colleagues what percentage of the referred patients they saw in their offices could be managed competently by a well-trained family physician. The usual answer—from a variety of specialists—was “about 30%.” If we took care of that 30% of patients ourselves, it would go a long way toward freeing up specialists’ schedules to see the patients who truly require their expertise.

My mentor often told me that a competent family physician should be able to manage about 80% of patients’ office visits without consultation.

Some public health systems, such as the University of California San Francisco Medical Center,¹ have implemented successful triage systems to alleviate the referral backlog. Patients are triaged by a specialist and assigned to 1 of 3 categories: 1) urgent—the patient will be seen right away, 2) non-urgent—the patient will be seen as soon as possible (usually within 2 weeks), or 3) phone/email consultation—the specialist provides diagnostic and management advice electronically, or by phone, but does not see the patient.

Continue to: The issue of referral comes to mind...

The issue of referral comes to mind this month in light of our cover story on migraine headache management. Migraine is one of those conditions that is often referred for specialist care, but can, in many cases, be competently managed by family physicians. The diagnosis of migraine is made almost entirely by history and physical exam, and there are many treatments for acute attacks and prevention that are effective and can be prescribed by family physicians and other primary health care professionals.

Yes, patients with more severe migraine may need a specialist consultation. But let’s remain cognizant of the fact that a good percentage of our patients will be best served staying right where they are—in the office of their family physician.

When I was training to become a family physician, my mentor often told me that a competent family physician should be able to manage about 80% of patients’ office visits without consultation. I am not sure where that figure came from, but my 40 years of experience in family medicine supports that prediction. Of course, the flip-side of that coin is having the wisdom to make those referrals for patients who really need a specialist’s diagnostic or treatment skills. The “rub,” of course, is that when I do need a specialist’s help, the wait for an appointment is often unacceptably long—both for me and my patients.

One way to help alleviate the logjam of referrals is to manage more medical problems ourselves. Now I don’t mean holding on to patients who definitely need a referral. But I do think we should avoid being too quick to hand off a patient. Let me explain.

When I was Chair of Family Medicine at Cleveland Clinic, I asked my specialty colleagues what percentage of the referred patients they saw in their offices could be managed competently by a well-trained family physician. The usual answer—from a variety of specialists—was “about 30%.” If we took care of that 30% of patients ourselves, it would go a long way toward freeing up specialists’ schedules to see the patients who truly require their expertise.

My mentor often told me that a competent family physician should be able to manage about 80% of patients’ office visits without consultation.

Some public health systems, such as the University of California San Francisco Medical Center,¹ have implemented successful triage systems to alleviate the referral backlog. Patients are triaged by a specialist and assigned to 1 of 3 categories: 1) urgent—the patient will be seen right away, 2) non-urgent—the patient will be seen as soon as possible (usually within 2 weeks), or 3) phone/email consultation—the specialist provides diagnostic and management advice electronically, or by phone, but does not see the patient.

Continue to: The issue of referral comes to mind...

The issue of referral comes to mind this month in light of our cover story on migraine headache management. Migraine is one of those conditions that is often referred for specialist care, but can, in many cases, be competently managed by family physicians. The diagnosis of migraine is made almost entirely by history and physical exam, and there are many treatments for acute attacks and prevention that are effective and can be prescribed by family physicians and other primary health care professionals.

Yes, patients with more severe migraine may need a specialist consultation. But let’s remain cognizant of the fact that a good percentage of our patients will be best served staying right where they are—in the office of their family physician.

When I was training to become a family physician, my mentor often told me that a competent family physician should be able to manage about 80% of patients’ office visits without consultation. I am not sure where that figure came from, but my 40 years of experience in family medicine supports that prediction. Of course, the flip-side of that coin is having the wisdom to make those referrals for patients who really need a specialist’s diagnostic or treatment skills. The “rub,” of course, is that when I do need a specialist’s help, the wait for an appointment is often unacceptably long—both for me and my patients.

One way to help alleviate the logjam of referrals is to manage more medical problems ourselves. Now I don’t mean holding on to patients who definitely need a referral. But I do think we should avoid being too quick to hand off a patient. Let me explain.

When I was Chair of Family Medicine at Cleveland Clinic, I asked my specialty colleagues what percentage of the referred patients they saw in their offices could be managed competently by a well-trained family physician. The usual answer—from a variety of specialists—was “about 30%.” If we took care of that 30% of patients ourselves, it would go a long way toward freeing up specialists’ schedules to see the patients who truly require their expertise.

My mentor often told me that a competent family physician should be able to manage about 80% of patients’ office visits without consultation.

Some public health systems, such as the University of California San Francisco Medical Center,¹ have implemented successful triage systems to alleviate the referral backlog. Patients are triaged by a specialist and assigned to 1 of 3 categories: 1) urgent—the patient will be seen right away, 2) non-urgent—the patient will be seen as soon as possible (usually within 2 weeks), or 3) phone/email consultation—the specialist provides diagnostic and management advice electronically, or by phone, but does not see the patient.

Continue to: The issue of referral comes to mind...

The issue of referral comes to mind this month in light of our cover story on migraine headache management. Migraine is one of those conditions that is often referred for specialist care, but can, in many cases, be competently managed by family physicians. The diagnosis of migraine is made almost entirely by history and physical exam, and there are many treatments for acute attacks and prevention that are effective and can be prescribed by family physicians and other primary health care professionals.

Yes, patients with more severe migraine may need a specialist consultation. But let’s remain cognizant of the fact that a good percentage of our patients will be best served staying right where they are—in the office of their family physician.

A 59-year-old woman presented to a dermatology clinic with an asymptomatic brown facial hyperpigmentation that had developed several years earlier, and had persisted, despite regular face washing. Physicians who previously treated this patient interpreted this as melasma and advised her to wear sunscreen. The condition was not aggravated by sun exposure. The patient reported that she was otherwise healthy.

Physical examination revealed a brown discoloration with a slightly rough texture. Upon rubbing the affected area with a 70% isopropyl alcohol pad, normal skin was revealed (FIGURE 1A) and brown flakes were apparent on the gauze (FIGURE 1B). 

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The physician diagnosed terra firma-forme dermatosis (TFFD) in this patient, noting the “dirty brown coloration” and distribution that did not suggest post-inflammatory hyperpigmentation or melasma. TFFD is a rare and benign form of acquired hyperpigmentation characterized by “velvety, pigmented patches or plaques.”¹ A simple bedside test, known as an “alcohol wipe test,” both confirms and treats TFFD; it involves rubbing the affected area with a 70% isopropyl alcohol pad.¹

TFFD is not a consequence of poor hygiene, but may be a result of “sticky” sebum that produces a buildup of keratin debris, sebum, and bacteria.

TFFD typically affects the face, neck, trunk, or ankles, but the scalp, axilla, back, and pubis also can be affected.¹ Histopathology will show negligible amounts of dermal inflammation, hyperkeratosis with mild acanthosis, and hyperkeratosis and papillomatosis.¹ Most patients diagnosed with TFFD report that the hyperpigmentation does not improve despite washing with soap and water.²

Hygiene is not a factor

In 2015, Greywal and Cohen followed the case presentations of 10 Caucasian patients with TFFD who presented with “brown and/or black plaques or papules or both.”² Many of the individuals followed in this case series reported “[practicing] good hygiene and showered a minimum of every other day or daily.”² The same was reported by the patient in this case. This suggests that TFFD is not a consequence of poor hygiene but perhaps a result of “sticky” sebum that produces a buildup of keratin debris, sebum, and bacteria on the skin.³ This produces the hyperpigmentation seen clinically.

Differential includes post-inflammatory hyperpigmentation

Several other hyperpigmentation disorders were considered on the initial differential diagnosis for this case, including melasma and post-inflammatory hyperpigmentation. However, these 2 conditions are macular, whereas this hyperpigmented condition had a rough, mildly papular texture. Additionally, melasma flares up in the summer with UV exposure, and post-inflammatory hyperpigmentation presents with pruritus and/or a pre-existing rash.⁴ This patient reported that the condition did not itch nor change with increased sunlight, thus making melasma and post-inflammatory hyperpigmentation unlikely diagnoses.

Acanthosis nigricans also was considered because it presents with a velvety brown pigmentation similar to what was seen with this patient. Acanthosis nigricans, however, primarily affects flexural areas, not the face, making it improbable.

Continue to: Our patient

Our patient. A “wipe test” was performed on the patient. This removed the brown flaky scaling and revealed the underlying normal skin. We instructed the patient to wash daily with a soapy wash cloth and scrub with 70% isopropyl alcohol should the hyperpigmentation recur. The patient did not return.

CORRESPONDENCE
Robert T. Brodell, MD, Department of Dermatology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216; [email protected]

A 59-year-old woman presented to a dermatology clinic with an asymptomatic brown facial hyperpigmentation that had developed several years earlier, and had persisted, despite regular face washing. Physicians who previously treated this patient interpreted this as melasma and advised her to wear sunscreen. The condition was not aggravated by sun exposure. The patient reported that she was otherwise healthy.

Physical examination revealed a brown discoloration with a slightly rough texture. Upon rubbing the affected area with a 70% isopropyl alcohol pad, normal skin was revealed (FIGURE 1A) and brown flakes were apparent on the gauze (FIGURE 1B). 

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The physician diagnosed terra firma-forme dermatosis (TFFD) in this patient, noting the “dirty brown coloration” and distribution that did not suggest post-inflammatory hyperpigmentation or melasma. TFFD is a rare and benign form of acquired hyperpigmentation characterized by “velvety, pigmented patches or plaques.”¹ A simple bedside test, known as an “alcohol wipe test,” both confirms and treats TFFD; it involves rubbing the affected area with a 70% isopropyl alcohol pad.¹

TFFD is not a consequence of poor hygiene, but may be a result of “sticky” sebum that produces a buildup of keratin debris, sebum, and bacteria.

TFFD typically affects the face, neck, trunk, or ankles, but the scalp, axilla, back, and pubis also can be affected.¹ Histopathology will show negligible amounts of dermal inflammation, hyperkeratosis with mild acanthosis, and hyperkeratosis and papillomatosis.¹ Most patients diagnosed with TFFD report that the hyperpigmentation does not improve despite washing with soap and water.²

Hygiene is not a factor

In 2015, Greywal and Cohen followed the case presentations of 10 Caucasian patients with TFFD who presented with “brown and/or black plaques or papules or both.”² Many of the individuals followed in this case series reported “[practicing] good hygiene and showered a minimum of every other day or daily.”² The same was reported by the patient in this case. This suggests that TFFD is not a consequence of poor hygiene but perhaps a result of “sticky” sebum that produces a buildup of keratin debris, sebum, and bacteria on the skin.³ This produces the hyperpigmentation seen clinically.

Differential includes post-inflammatory hyperpigmentation

Several other hyperpigmentation disorders were considered on the initial differential diagnosis for this case, including melasma and post-inflammatory hyperpigmentation. However, these 2 conditions are macular, whereas this hyperpigmented condition had a rough, mildly papular texture. Additionally, melasma flares up in the summer with UV exposure, and post-inflammatory hyperpigmentation presents with pruritus and/or a pre-existing rash.⁴ This patient reported that the condition did not itch nor change with increased sunlight, thus making melasma and post-inflammatory hyperpigmentation unlikely diagnoses.

Acanthosis nigricans also was considered because it presents with a velvety brown pigmentation similar to what was seen with this patient. Acanthosis nigricans, however, primarily affects flexural areas, not the face, making it improbable.

Continue to: Our patient

Our patient. A “wipe test” was performed on the patient. This removed the brown flaky scaling and revealed the underlying normal skin. We instructed the patient to wash daily with a soapy wash cloth and scrub with 70% isopropyl alcohol should the hyperpigmentation recur. The patient did not return.

CORRESPONDENCE
Robert T. Brodell, MD, Department of Dermatology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216; [email protected]

A 59-year-old woman presented to a dermatology clinic with an asymptomatic brown facial hyperpigmentation that had developed several years earlier, and had persisted, despite regular face washing. Physicians who previously treated this patient interpreted this as melasma and advised her to wear sunscreen. The condition was not aggravated by sun exposure. The patient reported that she was otherwise healthy.

Physical examination revealed a brown discoloration with a slightly rough texture. Upon rubbing the affected area with a 70% isopropyl alcohol pad, normal skin was revealed (FIGURE 1A) and brown flakes were apparent on the gauze (FIGURE 1B). 

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The physician diagnosed terra firma-forme dermatosis (TFFD) in this patient, noting the “dirty brown coloration” and distribution that did not suggest post-inflammatory hyperpigmentation or melasma. TFFD is a rare and benign form of acquired hyperpigmentation characterized by “velvety, pigmented patches or plaques.”¹ A simple bedside test, known as an “alcohol wipe test,” both confirms and treats TFFD; it involves rubbing the affected area with a 70% isopropyl alcohol pad.¹

TFFD is not a consequence of poor hygiene, but may be a result of “sticky” sebum that produces a buildup of keratin debris, sebum, and bacteria.

TFFD typically affects the face, neck, trunk, or ankles, but the scalp, axilla, back, and pubis also can be affected.¹ Histopathology will show negligible amounts of dermal inflammation, hyperkeratosis with mild acanthosis, and hyperkeratosis and papillomatosis.¹ Most patients diagnosed with TFFD report that the hyperpigmentation does not improve despite washing with soap and water.²

Hygiene is not a factor

In 2015, Greywal and Cohen followed the case presentations of 10 Caucasian patients with TFFD who presented with “brown and/or black plaques or papules or both.”² Many of the individuals followed in this case series reported “[practicing] good hygiene and showered a minimum of every other day or daily.”² The same was reported by the patient in this case. This suggests that TFFD is not a consequence of poor hygiene but perhaps a result of “sticky” sebum that produces a buildup of keratin debris, sebum, and bacteria on the skin.³ This produces the hyperpigmentation seen clinically.

Differential includes post-inflammatory hyperpigmentation

Several other hyperpigmentation disorders were considered on the initial differential diagnosis for this case, including melasma and post-inflammatory hyperpigmentation. However, these 2 conditions are macular, whereas this hyperpigmented condition had a rough, mildly papular texture. Additionally, melasma flares up in the summer with UV exposure, and post-inflammatory hyperpigmentation presents with pruritus and/or a pre-existing rash.⁴ This patient reported that the condition did not itch nor change with increased sunlight, thus making melasma and post-inflammatory hyperpigmentation unlikely diagnoses.

Acanthosis nigricans also was considered because it presents with a velvety brown pigmentation similar to what was seen with this patient. Acanthosis nigricans, however, primarily affects flexural areas, not the face, making it improbable.

Continue to: Our patient

Our patient. A “wipe test” was performed on the patient. This removed the brown flaky scaling and revealed the underlying normal skin. We instructed the patient to wash daily with a soapy wash cloth and scrub with 70% isopropyl alcohol should the hyperpigmentation recur. The patient did not return.

CORRESPONDENCE
Robert T. Brodell, MD, Department of Dermatology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216; [email protected]

THE CASE

A 61-year-old Caucasian woman presented with acute right shoulder pain that began after she received an influenza vaccination at a local pharmacy 2 weeks earlier. She pointed to the proximal-most aspect of her lateral right upper arm as the vaccination site. Her pain intensified with shoulder abduction, forward flexion, and reaching movements. She denied recent and past injury to her shoulder, fever, chills, rash, or skin changes at the injection site. She said her left shoulder did not bother her.

The patient had continued to participate in her aerobics class, despite the discomfort. Her medical history included hypertension and myocardial infarction, and the medications she was taking included lisinopril 20 mg/d, atenolol 50 mg/d, and aspirin 81 mg/d.

The physical exam revealed a thin female with no visible rashes or erythema on her right shoulder. While there was no deltoid atrophy in comparison to her unaffected shoulder, she generally had low muscle mass in both arms. A painful arc of abduction was present, as was pain with palpation of the supraspinatus insertion. No pain was appreciated over the short or long head of the biceps tendon or the sternoclavicular or acromioclavicular joints. Strength was 5/5 for all movements of the rotator cuff, but pain was reproduced with resisted shoulder abduction. A Hawkin’s test was positive, while Speed’s, Yergason’s, cross-arm abduction, and O’Brien’s tests were all negative.

THE DIAGNOSIS

Anteroposterior, Grashey, Y-view, and axillary view radiographs of the right shoulder were normal without any calcific tendinopathy, degenerative changes, or acute fractures. The patient’s history and physical exam were consistent with a rotator cuff tendinitis secondary to an immune response to an influenza vaccination that infiltrated the supraspinatus tendon.

DISCUSSION

Soreness, redness and swelling at the injection site, fever, body aches, and headache are common adverse effects of the influenza vaccine.¹Although rare, acute brachial neuritis, infection, rotator cuff injuries, and contusions of the humeral head have also been reported. ^2-5 Collectively, these conditions are referred to as shoulder injuries related to vaccination administration (SIRVA). There have been multiple SIRVA cases reported in the United States, and the US Court of Federal Claims has compensated >100 patients for SIRVA since 2011.⁶ There is currently no listing of SIRVA as a potential adverse reaction to the influenza vaccine on the package inserts or on the Centers for Disease Control and Prevention (CDC) Web site.

Shoulder soreness lasting <72 hours without functional impairment is likely due to soreness at the injection site. If symptoms do not resolve within 72 to 96 hours, consider a more thorough workup, with SIRVA being a possible diagnosis.^1,7 The etiology of SIRVA remains uncertain, but an inflammatory reaction from a vaccine mistakenly administered into the subacromial/subdeltoid bursa has been suggested. Whether this reaction is dependent on the nonantigenic or antigenic components of the vaccine has yet to be determined.

Symptoms of SIRVA include pain with arm movement, pain that is worse at night or awakens the patient from sleep, restricted range of motion, or arm weakness. Examination will reveal pain when resisting rotator cuff movements, particularly shoulder abduction. Advanced imaging can be considered when the diagnosis is in question. In previous cases of vaccine-associated rotator cuff tendinopathy in the authors’ practice, T2 magnetic resonance imaging (MRI) has shown focal inflammatory signal within the supraspinatus tendon and subacromial bursa.

Continue to: With support from the CDC...

With support from the CDC, the Immunization Action Coalition (IAC), a source of immunization information for health care professionals, recommends that vaccines be administered into the deltoid or vastus lateralis for individuals between the ages of 3 and 18 years and recommends the deltoid as the preferred location in adults ≥19 years. The IAC suggests increasing the needle length for intramuscular (IM) immunizations (depending on the weight of the patient), although in the authors’ experience, the adjustment of needle length may often be overlooked (TABLE⁷).

The majority of reported SIRVA cases caused by overpenetration have occurred in individuals weighing <140 lb or those who had little deltoid muscle bulk. An MRI study to evaluate optimal intramuscular needle length in pediatric patients found that the IAC-recommended needle lengths still allowed penetration of the subdeltoid space in a substantial number of patients.⁸ Classic teaching of IM deltoid injection landmarks is 3 fingerbreadths distal to the acromion, and a more proximal administration of a vaccine would allow penetration of the rotator cuff structures below.

How to manage the patient

Patients who develop SIRVA should be managed similarly to patients with tendinopathy from other causes. Treatment options include: physical therapy, anti-inflammatory medications, and subacromial corticosteroid injections. Given the significant discomfort and nighttime pain associated with rotator cuff tendinopathy, corticosteroid injections can offer rapid relief.

Limited data exist on the effect of corticosteroids on the suppression of the immune response in immunocompetent patients. Vaccinations are generally thought to stimulate an adequate immune response 14 days following administration, so our suggestion would be to re-vaccinate patients if a corticosteroid injection to treat SIRVA is completed prior to this.⁹

Our patient’s outcome

We talked to the patient about treatment options, which included physical therapy and nonsteroidal anti-inflammatory drugs (NSAIDs), but the patient elected to go forward with a corticosteroid injection. We administered 2 cc of Depo-Medrol 40 mg/mL with 2 cc of 1% lidocaine without epinephrine and 2 cc of 0.5% ropivacaine into her right shoulder subacromial space using a posterior approach. The patient noticed a 70% improvement in her pain immediately following the injection.

Continue to: Considering her influenza vaccine...

Considering her influenza vaccine was administered more than 14 days prior to her corticosteroid injection, we felt that she had mounted enough of an immune response for the vaccination to have been adequate for protection.⁹ Therefore, we told her that she didn’t need to be revaccinated for influenza this season. The case was reported to the Vaccine Adverse Event Reporting System (VAERS).

In previous cases of vaccine-associated rotator cuff tendonopathy, T2 MRI images have shown focal inflammatory signal within the supraspinatous tendon and subacromial bursa.

At the patient’s 2-month follow up, she reported an overall 80% improvement in pain. She continued to have occasional discomfort with certain movements, although the pain was relieved with over-the-counter anti-inflammatory medication. On physical exam she had an intact arc of abduction of the right shoulder to 150° without pain. Forward flexion and external and internal rotation were normal and pain free. She had mild pain with resisted abduction and a positive Hawkin’s test. The patient agreed to go to physical therapy to work on rotator cuff strengthening. She denied any known influenza infection up to that time.

THE TAKEAWAY

It’s important to consider rotator cuff injuries or SIRVA as a potential adverse effect of influenza vaccination administration. Thin patients and those with low deltoid muscle mass are at risk of vaccine over-penetration, and proximally placed deltoid vaccines may reach the rotator cuff structures below. Staff should be trained on appropriate techniques for administering influenza vaccinations to avoid causing SIRVA. Specifically:

• Intramuscular vaccines injected into the deltoid muscle should be 3 fingerbreadths distal to the acromion. A more proximal approach could potentially contact the rotator cuff muscles.
• Vaccine administration should mirror the position of the patient (eg, if the patient is sitting, the administrator should be sitting; if the patient is standing, the administrator should be standing).
• Needle length for vaccine administration should be adjusted according to the patient’s weight (TABLE⁷).

Following vaccination, it is important to keep 2 other points in mind. First, if a subacromial corticosteroid injection is used for treatment of SIRVA within the first 2 weeks of vaccine administration, consider revaccination. Second, be sure to use the VAERS to report any clinically significant medical event that occurs after vaccination. VAERS is a national vaccine safety surveillance program that is supported by the CDC and the US Food and Drug Administration. The VAERS reporting system can be accessed through www.vaers.hhhs.gov.

CORRESPONDENCE
Dusty Marie Narducci, MD, 5290 Big Island Drive, Unit 1303, Jacksonville, FL 32246; [email protected]

THE CASE

A 61-year-old Caucasian woman presented with acute right shoulder pain that began after she received an influenza vaccination at a local pharmacy 2 weeks earlier. She pointed to the proximal-most aspect of her lateral right upper arm as the vaccination site. Her pain intensified with shoulder abduction, forward flexion, and reaching movements. She denied recent and past injury to her shoulder, fever, chills, rash, or skin changes at the injection site. She said her left shoulder did not bother her.

The patient had continued to participate in her aerobics class, despite the discomfort. Her medical history included hypertension and myocardial infarction, and the medications she was taking included lisinopril 20 mg/d, atenolol 50 mg/d, and aspirin 81 mg/d.

The physical exam revealed a thin female with no visible rashes or erythema on her right shoulder. While there was no deltoid atrophy in comparison to her unaffected shoulder, she generally had low muscle mass in both arms. A painful arc of abduction was present, as was pain with palpation of the supraspinatus insertion. No pain was appreciated over the short or long head of the biceps tendon or the sternoclavicular or acromioclavicular joints. Strength was 5/5 for all movements of the rotator cuff, but pain was reproduced with resisted shoulder abduction. A Hawkin’s test was positive, while Speed’s, Yergason’s, cross-arm abduction, and O’Brien’s tests were all negative.

THE DIAGNOSIS

Anteroposterior, Grashey, Y-view, and axillary view radiographs of the right shoulder were normal without any calcific tendinopathy, degenerative changes, or acute fractures. The patient’s history and physical exam were consistent with a rotator cuff tendinitis secondary to an immune response to an influenza vaccination that infiltrated the supraspinatus tendon.

DISCUSSION

Soreness, redness and swelling at the injection site, fever, body aches, and headache are common adverse effects of the influenza vaccine.¹Although rare, acute brachial neuritis, infection, rotator cuff injuries, and contusions of the humeral head have also been reported. ^2-5 Collectively, these conditions are referred to as shoulder injuries related to vaccination administration (SIRVA). There have been multiple SIRVA cases reported in the United States, and the US Court of Federal Claims has compensated >100 patients for SIRVA since 2011.⁶ There is currently no listing of SIRVA as a potential adverse reaction to the influenza vaccine on the package inserts or on the Centers for Disease Control and Prevention (CDC) Web site.

Shoulder soreness lasting <72 hours without functional impairment is likely due to soreness at the injection site. If symptoms do not resolve within 72 to 96 hours, consider a more thorough workup, with SIRVA being a possible diagnosis.^1,7 The etiology of SIRVA remains uncertain, but an inflammatory reaction from a vaccine mistakenly administered into the subacromial/subdeltoid bursa has been suggested. Whether this reaction is dependent on the nonantigenic or antigenic components of the vaccine has yet to be determined.

Symptoms of SIRVA include pain with arm movement, pain that is worse at night or awakens the patient from sleep, restricted range of motion, or arm weakness. Examination will reveal pain when resisting rotator cuff movements, particularly shoulder abduction. Advanced imaging can be considered when the diagnosis is in question. In previous cases of vaccine-associated rotator cuff tendinopathy in the authors’ practice, T2 magnetic resonance imaging (MRI) has shown focal inflammatory signal within the supraspinatus tendon and subacromial bursa.

Continue to: With support from the CDC...

With support from the CDC, the Immunization Action Coalition (IAC), a source of immunization information for health care professionals, recommends that vaccines be administered into the deltoid or vastus lateralis for individuals between the ages of 3 and 18 years and recommends the deltoid as the preferred location in adults ≥19 years. The IAC suggests increasing the needle length for intramuscular (IM) immunizations (depending on the weight of the patient), although in the authors’ experience, the adjustment of needle length may often be overlooked (TABLE⁷).

The majority of reported SIRVA cases caused by overpenetration have occurred in individuals weighing <140 lb or those who had little deltoid muscle bulk. An MRI study to evaluate optimal intramuscular needle length in pediatric patients found that the IAC-recommended needle lengths still allowed penetration of the subdeltoid space in a substantial number of patients.⁸ Classic teaching of IM deltoid injection landmarks is 3 fingerbreadths distal to the acromion, and a more proximal administration of a vaccine would allow penetration of the rotator cuff structures below.

How to manage the patient

Patients who develop SIRVA should be managed similarly to patients with tendinopathy from other causes. Treatment options include: physical therapy, anti-inflammatory medications, and subacromial corticosteroid injections. Given the significant discomfort and nighttime pain associated with rotator cuff tendinopathy, corticosteroid injections can offer rapid relief.

Limited data exist on the effect of corticosteroids on the suppression of the immune response in immunocompetent patients. Vaccinations are generally thought to stimulate an adequate immune response 14 days following administration, so our suggestion would be to re-vaccinate patients if a corticosteroid injection to treat SIRVA is completed prior to this.⁹

Our patient’s outcome

We talked to the patient about treatment options, which included physical therapy and nonsteroidal anti-inflammatory drugs (NSAIDs), but the patient elected to go forward with a corticosteroid injection. We administered 2 cc of Depo-Medrol 40 mg/mL with 2 cc of 1% lidocaine without epinephrine and 2 cc of 0.5% ropivacaine into her right shoulder subacromial space using a posterior approach. The patient noticed a 70% improvement in her pain immediately following the injection.

Continue to: Considering her influenza vaccine...

Considering her influenza vaccine was administered more than 14 days prior to her corticosteroid injection, we felt that she had mounted enough of an immune response for the vaccination to have been adequate for protection.⁹ Therefore, we told her that she didn’t need to be revaccinated for influenza this season. The case was reported to the Vaccine Adverse Event Reporting System (VAERS).

In previous cases of vaccine-associated rotator cuff tendonopathy, T2 MRI images have shown focal inflammatory signal within the supraspinatous tendon and subacromial bursa.

At the patient’s 2-month follow up, she reported an overall 80% improvement in pain. She continued to have occasional discomfort with certain movements, although the pain was relieved with over-the-counter anti-inflammatory medication. On physical exam she had an intact arc of abduction of the right shoulder to 150° without pain. Forward flexion and external and internal rotation were normal and pain free. She had mild pain with resisted abduction and a positive Hawkin’s test. The patient agreed to go to physical therapy to work on rotator cuff strengthening. She denied any known influenza infection up to that time.

THE TAKEAWAY

It’s important to consider rotator cuff injuries or SIRVA as a potential adverse effect of influenza vaccination administration. Thin patients and those with low deltoid muscle mass are at risk of vaccine over-penetration, and proximally placed deltoid vaccines may reach the rotator cuff structures below. Staff should be trained on appropriate techniques for administering influenza vaccinations to avoid causing SIRVA. Specifically:

• Intramuscular vaccines injected into the deltoid muscle should be 3 fingerbreadths distal to the acromion. A more proximal approach could potentially contact the rotator cuff muscles.
• Vaccine administration should mirror the position of the patient (eg, if the patient is sitting, the administrator should be sitting; if the patient is standing, the administrator should be standing).
• Needle length for vaccine administration should be adjusted according to the patient’s weight (TABLE⁷).

Following vaccination, it is important to keep 2 other points in mind. First, if a subacromial corticosteroid injection is used for treatment of SIRVA within the first 2 weeks of vaccine administration, consider revaccination. Second, be sure to use the VAERS to report any clinically significant medical event that occurs after vaccination. VAERS is a national vaccine safety surveillance program that is supported by the CDC and the US Food and Drug Administration. The VAERS reporting system can be accessed through www.vaers.hhhs.gov.

CORRESPONDENCE
Dusty Marie Narducci, MD, 5290 Big Island Drive, Unit 1303, Jacksonville, FL 32246; [email protected]

THE CASE

A 61-year-old Caucasian woman presented with acute right shoulder pain that began after she received an influenza vaccination at a local pharmacy 2 weeks earlier. She pointed to the proximal-most aspect of her lateral right upper arm as the vaccination site. Her pain intensified with shoulder abduction, forward flexion, and reaching movements. She denied recent and past injury to her shoulder, fever, chills, rash, or skin changes at the injection site. She said her left shoulder did not bother her.

The patient had continued to participate in her aerobics class, despite the discomfort. Her medical history included hypertension and myocardial infarction, and the medications she was taking included lisinopril 20 mg/d, atenolol 50 mg/d, and aspirin 81 mg/d.

The physical exam revealed a thin female with no visible rashes or erythema on her right shoulder. While there was no deltoid atrophy in comparison to her unaffected shoulder, she generally had low muscle mass in both arms. A painful arc of abduction was present, as was pain with palpation of the supraspinatus insertion. No pain was appreciated over the short or long head of the biceps tendon or the sternoclavicular or acromioclavicular joints. Strength was 5/5 for all movements of the rotator cuff, but pain was reproduced with resisted shoulder abduction. A Hawkin’s test was positive, while Speed’s, Yergason’s, cross-arm abduction, and O’Brien’s tests were all negative.

THE DIAGNOSIS

Anteroposterior, Grashey, Y-view, and axillary view radiographs of the right shoulder were normal without any calcific tendinopathy, degenerative changes, or acute fractures. The patient’s history and physical exam were consistent with a rotator cuff tendinitis secondary to an immune response to an influenza vaccination that infiltrated the supraspinatus tendon.

DISCUSSION

Soreness, redness and swelling at the injection site, fever, body aches, and headache are common adverse effects of the influenza vaccine.¹Although rare, acute brachial neuritis, infection, rotator cuff injuries, and contusions of the humeral head have also been reported. ^2-5 Collectively, these conditions are referred to as shoulder injuries related to vaccination administration (SIRVA). There have been multiple SIRVA cases reported in the United States, and the US Court of Federal Claims has compensated >100 patients for SIRVA since 2011.⁶ There is currently no listing of SIRVA as a potential adverse reaction to the influenza vaccine on the package inserts or on the Centers for Disease Control and Prevention (CDC) Web site.

Shoulder soreness lasting <72 hours without functional impairment is likely due to soreness at the injection site. If symptoms do not resolve within 72 to 96 hours, consider a more thorough workup, with SIRVA being a possible diagnosis.^1,7 The etiology of SIRVA remains uncertain, but an inflammatory reaction from a vaccine mistakenly administered into the subacromial/subdeltoid bursa has been suggested. Whether this reaction is dependent on the nonantigenic or antigenic components of the vaccine has yet to be determined.

Symptoms of SIRVA include pain with arm movement, pain that is worse at night or awakens the patient from sleep, restricted range of motion, or arm weakness. Examination will reveal pain when resisting rotator cuff movements, particularly shoulder abduction. Advanced imaging can be considered when the diagnosis is in question. In previous cases of vaccine-associated rotator cuff tendinopathy in the authors’ practice, T2 magnetic resonance imaging (MRI) has shown focal inflammatory signal within the supraspinatus tendon and subacromial bursa.

Continue to: With support from the CDC...

With support from the CDC, the Immunization Action Coalition (IAC), a source of immunization information for health care professionals, recommends that vaccines be administered into the deltoid or vastus lateralis for individuals between the ages of 3 and 18 years and recommends the deltoid as the preferred location in adults ≥19 years. The IAC suggests increasing the needle length for intramuscular (IM) immunizations (depending on the weight of the patient), although in the authors’ experience, the adjustment of needle length may often be overlooked (TABLE⁷).

The majority of reported SIRVA cases caused by overpenetration have occurred in individuals weighing <140 lb or those who had little deltoid muscle bulk. An MRI study to evaluate optimal intramuscular needle length in pediatric patients found that the IAC-recommended needle lengths still allowed penetration of the subdeltoid space in a substantial number of patients.⁸ Classic teaching of IM deltoid injection landmarks is 3 fingerbreadths distal to the acromion, and a more proximal administration of a vaccine would allow penetration of the rotator cuff structures below.

How to manage the patient

Patients who develop SIRVA should be managed similarly to patients with tendinopathy from other causes. Treatment options include: physical therapy, anti-inflammatory medications, and subacromial corticosteroid injections. Given the significant discomfort and nighttime pain associated with rotator cuff tendinopathy, corticosteroid injections can offer rapid relief.

Limited data exist on the effect of corticosteroids on the suppression of the immune response in immunocompetent patients. Vaccinations are generally thought to stimulate an adequate immune response 14 days following administration, so our suggestion would be to re-vaccinate patients if a corticosteroid injection to treat SIRVA is completed prior to this.⁹

Our patient’s outcome

We talked to the patient about treatment options, which included physical therapy and nonsteroidal anti-inflammatory drugs (NSAIDs), but the patient elected to go forward with a corticosteroid injection. We administered 2 cc of Depo-Medrol 40 mg/mL with 2 cc of 1% lidocaine without epinephrine and 2 cc of 0.5% ropivacaine into her right shoulder subacromial space using a posterior approach. The patient noticed a 70% improvement in her pain immediately following the injection.

Continue to: Considering her influenza vaccine...

Considering her influenza vaccine was administered more than 14 days prior to her corticosteroid injection, we felt that she had mounted enough of an immune response for the vaccination to have been adequate for protection.⁹ Therefore, we told her that she didn’t need to be revaccinated for influenza this season. The case was reported to the Vaccine Adverse Event Reporting System (VAERS).

In previous cases of vaccine-associated rotator cuff tendonopathy, T2 MRI images have shown focal inflammatory signal within the supraspinatous tendon and subacromial bursa.

At the patient’s 2-month follow up, she reported an overall 80% improvement in pain. She continued to have occasional discomfort with certain movements, although the pain was relieved with over-the-counter anti-inflammatory medication. On physical exam she had an intact arc of abduction of the right shoulder to 150° without pain. Forward flexion and external and internal rotation were normal and pain free. She had mild pain with resisted abduction and a positive Hawkin’s test. The patient agreed to go to physical therapy to work on rotator cuff strengthening. She denied any known influenza infection up to that time.

THE TAKEAWAY

It’s important to consider rotator cuff injuries or SIRVA as a potential adverse effect of influenza vaccination administration. Thin patients and those with low deltoid muscle mass are at risk of vaccine over-penetration, and proximally placed deltoid vaccines may reach the rotator cuff structures below. Staff should be trained on appropriate techniques for administering influenza vaccinations to avoid causing SIRVA. Specifically:

• Intramuscular vaccines injected into the deltoid muscle should be 3 fingerbreadths distal to the acromion. A more proximal approach could potentially contact the rotator cuff muscles.
• Vaccine administration should mirror the position of the patient (eg, if the patient is sitting, the administrator should be sitting; if the patient is standing, the administrator should be standing).
• Needle length for vaccine administration should be adjusted according to the patient’s weight (TABLE⁷).

Following vaccination, it is important to keep 2 other points in mind. First, if a subacromial corticosteroid injection is used for treatment of SIRVA within the first 2 weeks of vaccine administration, consider revaccination. Second, be sure to use the VAERS to report any clinically significant medical event that occurs after vaccination. VAERS is a national vaccine safety surveillance program that is supported by the CDC and the US Food and Drug Administration. The VAERS reporting system can be accessed through www.vaers.hhhs.gov.

CORRESPONDENCE
Dusty Marie Narducci, MD, 5290 Big Island Drive, Unit 1303, Jacksonville, FL 32246; [email protected]

ILLUSTRATIVE CASE

A 46-year-old man with no significant past medical history presents to the emergency department (ED) with right flank pain and nausea. A computed tomography scan reveals a 5-mm ureteral stone with no obstruction or hydronephrosis. You are planning on starting him on intravenous (IV) ketorolac for pain. What is the most appropriate dose?

Ketorolac tromethamine is a highly effective nonsteroidal anti-inflammatory drug (NSAID). As a non-opiate analgesic, it is often the optimal first choice for the treatment of acute conditions such as flank, abdominal, musculoskeletal, and headache pains.² While it is not associated with euphoria, withdrawal effects, or respiratory depression (like its opiate analgesic counterparts), ketorolac carries a US Food and Drug Administration black box warning for gastrointestinal, cardiovascular, renal, and bleeding risks.³

NSAIDs are known to have a “ceiling dose,” a dose at which maximum analgesic benefit is achieved; higher doses will not provide further pain relief. Higher doses of ketorolac may be used when anti-inflammatory effects of NSAIDs are desired, but they are likely to cause more adverse effects.⁴ Available data describe the analgesic ceiling dose of ketorolac as 10 mg across dosage forms.^4,5 Yet, the majority of research and the majority of health care providers in current practice use higher doses of 20 to 60 mg. The US Food and Drug Administration label provides for a maximum dose of 60 mg/d.³

In one recent study, ketorolac was prescribed above its ceiling dose of 10 mg in atleast 97% of patients who received IV doses and in at least 96% of patients receiving intramuscular (IM) doses in a US emergency department.⁶ If ketorolac 10 mg is an effective analgesic dose, current practice exceeds the label recommendation to use the lowest effective dose. This study sought to determine the comparative efficacy of 3 different doses of IV ketorolac for acute pain management in an ED.

STUDY SUMMARY

Though often used at higher doses, 10 mg of ketorolac is enough for pain

This randomized double-blind trial evaluated the effectiveness of 3 different doses of IV ketorolac for acute pain in 240 adult patients, ages 18 to 65 years, presenting to an ED with acute flank, abdominal, musculoskeletal, or headache pain.¹ Acute pain was defined as onset ≤30 days.

Patients were randomized to receive either 10, 15, or 30 mg of IV ketorolac in 10 mL of normal saline. A pharmacist prepared the medication in identical syringes, and the syringes were delivered in a blinded manner to the nurses caring for the patients. Pain (measured using a 0 to 10 scale), vital signs, and adverse effects were assessed at baseline and at 15, 30, 60, 90, and 120 minutes. If patients were still in pain at 30 minutes, IV morphine 0.1 mg/kg was offered. The primary outcome was numerical pain score at 30 minutes after ketorolac administration; secondary outcomes included the occurrence of adverse events and the use of rescue medication.

The groups were similar in terms of demographics and baseline vital signs. The mean age of the participants was 39 to 42 years. Across the 3 groups, 36% to 40% of patients had abdominal pain, 26% to 39% had flank pain, 20% to 26% had musculoskeletal pain, and 1% to 11% had headache pain. Patients had pain for an average of 1.5 to 3.5 days.

Continue to: Baseline pain scores were similar...

Baseline pain scores were similar for all 3 groups (7.5-7.8 on a 10-point scale). In the intention-to-treat analysis, all 3 doses of ketorolac decreased pain significantly at 30 minutes, but there was no difference between the groups; for the 10- and 15-mg groups, the mean pain scores post-intervention were 5.1 (95% confidence interval [CI] 4.5-5.7 and 4.5-5.6, respectively); and for the 30-mg group, the mean pain score was 4.8 (95% CI, 4.2-5.5). No P values were provided. There was no difference between the groups at any other time intervals. There was also no difference in the number of patients who needed rescue medication (morphine) at 30 minutes between the groups (4 patients in the 10-mg group, 3 patients in the 15-mg group, and 4 patients in the 30-mg group; no P values were provided). In addition, adverse events (eg, dizziness, nausea, headache, itching, flushing) did not differ between the groups.

WHAT’S NEW

10 mg is just as effective as 30 mg

This trial confirms that a low dose (10 mg) of IV ketorolac is just as effective for acute pain control as higher 15- and 30-mg doses.

CAVEATS

A 2-hour time limit and no look at long-term effects

The ketorolac dose of 10 mg IV was specially prepared by the study pharmacist; it is unlikely this will be readily available in clinical settings. However, the 15-mg IV dose is also as effective as the higher 30-mg dose based on study results and is readily available.

A 10-mg dose of IV ketorolac is just as effective for acute pain control as a 15- or 30-mg IV dose.

It isn’t known whether the higher dose would have provided greater pain relief beyond the 120 minutes evaluated in this trial, or if alternative dosage forms (oral or IM) would result in different outcomes. This study was not designed to compare serious long-term adverse effects like bleeding, renal impairment, or cardiovascular events. Additionally, this study was not powered to look at specific therapeutic indications or anti-inflammatory response.

CHALLENGES TO IMPLEMENTATION

A 10-mg single-dose vial is not readily available

Ketorolac tromethamine for injection is available in the United States in 15-, 30-, and 60-mg single-dose vials. Because a 10-mg dose is not available as a single-dose vial, it would need to be specially prepared. However, this study should reassure providers that using the lowest available dose (eg, 15 mg IV if that is what is available) will relieve acute pain as well as higher doses.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 46-year-old man with no significant past medical history presents to the emergency department (ED) with right flank pain and nausea. A computed tomography scan reveals a 5-mm ureteral stone with no obstruction or hydronephrosis. You are planning on starting him on intravenous (IV) ketorolac for pain. What is the most appropriate dose?

Ketorolac tromethamine is a highly effective nonsteroidal anti-inflammatory drug (NSAID). As a non-opiate analgesic, it is often the optimal first choice for the treatment of acute conditions such as flank, abdominal, musculoskeletal, and headache pains.² While it is not associated with euphoria, withdrawal effects, or respiratory depression (like its opiate analgesic counterparts), ketorolac carries a US Food and Drug Administration black box warning for gastrointestinal, cardiovascular, renal, and bleeding risks.³

NSAIDs are known to have a “ceiling dose,” a dose at which maximum analgesic benefit is achieved; higher doses will not provide further pain relief. Higher doses of ketorolac may be used when anti-inflammatory effects of NSAIDs are desired, but they are likely to cause more adverse effects.⁴ Available data describe the analgesic ceiling dose of ketorolac as 10 mg across dosage forms.^4,5 Yet, the majority of research and the majority of health care providers in current practice use higher doses of 20 to 60 mg. The US Food and Drug Administration label provides for a maximum dose of 60 mg/d.³

In one recent study, ketorolac was prescribed above its ceiling dose of 10 mg in atleast 97% of patients who received IV doses and in at least 96% of patients receiving intramuscular (IM) doses in a US emergency department.⁶ If ketorolac 10 mg is an effective analgesic dose, current practice exceeds the label recommendation to use the lowest effective dose. This study sought to determine the comparative efficacy of 3 different doses of IV ketorolac for acute pain management in an ED.

STUDY SUMMARY

Though often used at higher doses, 10 mg of ketorolac is enough for pain

This randomized double-blind trial evaluated the effectiveness of 3 different doses of IV ketorolac for acute pain in 240 adult patients, ages 18 to 65 years, presenting to an ED with acute flank, abdominal, musculoskeletal, or headache pain.¹ Acute pain was defined as onset ≤30 days.

Patients were randomized to receive either 10, 15, or 30 mg of IV ketorolac in 10 mL of normal saline. A pharmacist prepared the medication in identical syringes, and the syringes were delivered in a blinded manner to the nurses caring for the patients. Pain (measured using a 0 to 10 scale), vital signs, and adverse effects were assessed at baseline and at 15, 30, 60, 90, and 120 minutes. If patients were still in pain at 30 minutes, IV morphine 0.1 mg/kg was offered. The primary outcome was numerical pain score at 30 minutes after ketorolac administration; secondary outcomes included the occurrence of adverse events and the use of rescue medication.

The groups were similar in terms of demographics and baseline vital signs. The mean age of the participants was 39 to 42 years. Across the 3 groups, 36% to 40% of patients had abdominal pain, 26% to 39% had flank pain, 20% to 26% had musculoskeletal pain, and 1% to 11% had headache pain. Patients had pain for an average of 1.5 to 3.5 days.

Continue to: Baseline pain scores were similar...

Baseline pain scores were similar for all 3 groups (7.5-7.8 on a 10-point scale). In the intention-to-treat analysis, all 3 doses of ketorolac decreased pain significantly at 30 minutes, but there was no difference between the groups; for the 10- and 15-mg groups, the mean pain scores post-intervention were 5.1 (95% confidence interval [CI] 4.5-5.7 and 4.5-5.6, respectively); and for the 30-mg group, the mean pain score was 4.8 (95% CI, 4.2-5.5). No P values were provided. There was no difference between the groups at any other time intervals. There was also no difference in the number of patients who needed rescue medication (morphine) at 30 minutes between the groups (4 patients in the 10-mg group, 3 patients in the 15-mg group, and 4 patients in the 30-mg group; no P values were provided). In addition, adverse events (eg, dizziness, nausea, headache, itching, flushing) did not differ between the groups.

WHAT’S NEW

10 mg is just as effective as 30 mg

This trial confirms that a low dose (10 mg) of IV ketorolac is just as effective for acute pain control as higher 15- and 30-mg doses.

CAVEATS

A 2-hour time limit and no look at long-term effects

The ketorolac dose of 10 mg IV was specially prepared by the study pharmacist; it is unlikely this will be readily available in clinical settings. However, the 15-mg IV dose is also as effective as the higher 30-mg dose based on study results and is readily available.

A 10-mg dose of IV ketorolac is just as effective for acute pain control as a 15- or 30-mg IV dose.

It isn’t known whether the higher dose would have provided greater pain relief beyond the 120 minutes evaluated in this trial, or if alternative dosage forms (oral or IM) would result in different outcomes. This study was not designed to compare serious long-term adverse effects like bleeding, renal impairment, or cardiovascular events. Additionally, this study was not powered to look at specific therapeutic indications or anti-inflammatory response.

CHALLENGES TO IMPLEMENTATION

A 10-mg single-dose vial is not readily available

Ketorolac tromethamine for injection is available in the United States in 15-, 30-, and 60-mg single-dose vials. Because a 10-mg dose is not available as a single-dose vial, it would need to be specially prepared. However, this study should reassure providers that using the lowest available dose (eg, 15 mg IV if that is what is available) will relieve acute pain as well as higher doses.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 46-year-old man with no significant past medical history presents to the emergency department (ED) with right flank pain and nausea. A computed tomography scan reveals a 5-mm ureteral stone with no obstruction or hydronephrosis. You are planning on starting him on intravenous (IV) ketorolac for pain. What is the most appropriate dose?

Ketorolac tromethamine is a highly effective nonsteroidal anti-inflammatory drug (NSAID). As a non-opiate analgesic, it is often the optimal first choice for the treatment of acute conditions such as flank, abdominal, musculoskeletal, and headache pains.² While it is not associated with euphoria, withdrawal effects, or respiratory depression (like its opiate analgesic counterparts), ketorolac carries a US Food and Drug Administration black box warning for gastrointestinal, cardiovascular, renal, and bleeding risks.³

NSAIDs are known to have a “ceiling dose,” a dose at which maximum analgesic benefit is achieved; higher doses will not provide further pain relief. Higher doses of ketorolac may be used when anti-inflammatory effects of NSAIDs are desired, but they are likely to cause more adverse effects.⁴ Available data describe the analgesic ceiling dose of ketorolac as 10 mg across dosage forms.^4,5 Yet, the majority of research and the majority of health care providers in current practice use higher doses of 20 to 60 mg. The US Food and Drug Administration label provides for a maximum dose of 60 mg/d.³

In one recent study, ketorolac was prescribed above its ceiling dose of 10 mg in atleast 97% of patients who received IV doses and in at least 96% of patients receiving intramuscular (IM) doses in a US emergency department.⁶ If ketorolac 10 mg is an effective analgesic dose, current practice exceeds the label recommendation to use the lowest effective dose. This study sought to determine the comparative efficacy of 3 different doses of IV ketorolac for acute pain management in an ED.

STUDY SUMMARY

Though often used at higher doses, 10 mg of ketorolac is enough for pain

This randomized double-blind trial evaluated the effectiveness of 3 different doses of IV ketorolac for acute pain in 240 adult patients, ages 18 to 65 years, presenting to an ED with acute flank, abdominal, musculoskeletal, or headache pain.¹ Acute pain was defined as onset ≤30 days.

Patients were randomized to receive either 10, 15, or 30 mg of IV ketorolac in 10 mL of normal saline. A pharmacist prepared the medication in identical syringes, and the syringes were delivered in a blinded manner to the nurses caring for the patients. Pain (measured using a 0 to 10 scale), vital signs, and adverse effects were assessed at baseline and at 15, 30, 60, 90, and 120 minutes. If patients were still in pain at 30 minutes, IV morphine 0.1 mg/kg was offered. The primary outcome was numerical pain score at 30 minutes after ketorolac administration; secondary outcomes included the occurrence of adverse events and the use of rescue medication.

The groups were similar in terms of demographics and baseline vital signs. The mean age of the participants was 39 to 42 years. Across the 3 groups, 36% to 40% of patients had abdominal pain, 26% to 39% had flank pain, 20% to 26% had musculoskeletal pain, and 1% to 11% had headache pain. Patients had pain for an average of 1.5 to 3.5 days.

Continue to: Baseline pain scores were similar...

Baseline pain scores were similar for all 3 groups (7.5-7.8 on a 10-point scale). In the intention-to-treat analysis, all 3 doses of ketorolac decreased pain significantly at 30 minutes, but there was no difference between the groups; for the 10- and 15-mg groups, the mean pain scores post-intervention were 5.1 (95% confidence interval [CI] 4.5-5.7 and 4.5-5.6, respectively); and for the 30-mg group, the mean pain score was 4.8 (95% CI, 4.2-5.5). No P values were provided. There was no difference between the groups at any other time intervals. There was also no difference in the number of patients who needed rescue medication (morphine) at 30 minutes between the groups (4 patients in the 10-mg group, 3 patients in the 15-mg group, and 4 patients in the 30-mg group; no P values were provided). In addition, adverse events (eg, dizziness, nausea, headache, itching, flushing) did not differ between the groups.

WHAT’S NEW

10 mg is just as effective as 30 mg

This trial confirms that a low dose (10 mg) of IV ketorolac is just as effective for acute pain control as higher 15- and 30-mg doses.

CAVEATS

A 2-hour time limit and no look at long-term effects

The ketorolac dose of 10 mg IV was specially prepared by the study pharmacist; it is unlikely this will be readily available in clinical settings. However, the 15-mg IV dose is also as effective as the higher 30-mg dose based on study results and is readily available.

A 10-mg dose of IV ketorolac is just as effective for acute pain control as a 15- or 30-mg IV dose.

It isn’t known whether the higher dose would have provided greater pain relief beyond the 120 minutes evaluated in this trial, or if alternative dosage forms (oral or IM) would result in different outcomes. This study was not designed to compare serious long-term adverse effects like bleeding, renal impairment, or cardiovascular events. Additionally, this study was not powered to look at specific therapeutic indications or anti-inflammatory response.

CHALLENGES TO IMPLEMENTATION

A 10-mg single-dose vial is not readily available

Ketorolac tromethamine for injection is available in the United States in 15-, 30-, and 60-mg single-dose vials. Because a 10-mg dose is not available as a single-dose vial, it would need to be specially prepared. However, this study should reassure providers that using the lowest available dose (eg, 15 mg IV if that is what is available) will relieve acute pain as well as higher doses.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.