Pediatrics

LJUBLJANA, SLOVENIA – An expanded indication for the meningococcal group B vaccine known as Trumenba in patients aged 1-9 years is being considered by the Food and Drug Administration under the agency’s Breakthrough Therapy designation.

Breakthrough Therapy status is reserved for accelerated review of therapies considered to show substantial preliminary promise of effectively targeting a major unmet medical need.

The unmet need here is that there is no meningococcal group B vaccine approved for use in children under age 10 years. Yet infants and children under 5 years of age are at greatest risk of invasive meningococcal B disease, with reported case fatality rates of 8%-9%, Jason D. Maguire, MD, noted at the annual meeting of the European Society for Paediatric Infectious Diseases.

Trumenba has been approved in the United States for patients aged 10-25 years and in the European Union for individuals aged 10 years or older.

Dr. Maguire, of Pfizer’s vaccine clinical research and development program, presented the results of the two phase 2 randomized safety and immunogenicity trials conducted in patients aged 1- 9 years that the company has submitted to the FDA in support of the expanded indication. One study was carried out in 352 1-year-old toddlers, the other in 400 children aged 2-9 years, whose mean age was 4 years. The studies were carried out in Australia, Finland, Poland, and the Czech Republic.

In a pooled analysis of the vaccine’s immunogenicity when administered in a three-dose schedule of 120 mcg at 0, 2, and 6 months to 193 toddlers and 274 of the children aged 2-9 years, robust bactericidal antibody responses were seen against the four major Neisseria meningitidis group B strains that cause invasive disease. In fact, at least a fourfold rise in titers from baseline to 1 month after dose three was documented in the same high proportion of 1- to 9-year-olds as previously seen in the phase 3 trials that led to vaccine licensure in adolescents and young adults.

“These results support that the use of Trumenba, when given to children ages 1 to less than 10 years at the same dose and schedule that is currently approved in adolescents and young adults, can afford a high degree of protective antibody responses that correlate with immunity in this population,” Dr. Maguire said.

The safety and tolerability analysis included all 752 children in the two phase 2 studies, including the 110 toddlers randomized to three 60-mcg doses of the vaccine, although it has subsequently become clear that 120 mcg is the dose that provides the best immunogenicity with an acceptable safety profile, according to the physician.

Across the age groups, local reactions, including redness and swelling, were more common in Trumenba recipients than in controls who received hepatitis A vaccine and saline injections. So were systemic adverse events. Fever – a systemic event of particular interest to parents and clinicians – occurred in 37% of toddlers after vaccination, compared with 25% of 2- to 9-year-olds and 10%-12% of controls. Of note, prophylactic antipyretics weren’t allowed in the study.

“There’s somewhat of an inverse relationship between age and temperature. So as we go down in age, the rate of fever rises. But after each subsequent dose, regardless of age, there’s a reduction in the incidence of fever,” Dr. Maguire observed.

Most fevers were less than 39.0° C. Only 3 of 752 (less than 1%) patients experienced fever in excess of 40.0° C.

Two children withdrew from the study after developing hip synovitis, which was transient. Another withdrew because of prolonged irritability, fatigue, and decreased appetite.

“Although Trumenba had an acceptable safety and tolerability profile in 1- to 9-year-olds, this analysis wasn’t powered enough to detect uncommon adverse events, so we’ll continue to monitor safety for things like synovitis,” he said.

In 10- to 25-year-olds, the meningococcal vaccine can be given concomitantly with other vaccines without interference. There are plans to study concurrent vaccination with MMR and pneumococcal vaccines in 1- to 9-year-olds as well, according to Dr. Maguire.

Pfizer also now is planning clinical trials of the vaccine in infants, another important group currently unprotected against meningococcal group B disease, he added.

Dr. Maguire is an employee of Pfizer, who funded the studies.

[email protected]

LJUBLJANA, SLOVENIA – An expanded indication for the meningococcal group B vaccine known as Trumenba in patients aged 1-9 years is being considered by the Food and Drug Administration under the agency’s Breakthrough Therapy designation.

Breakthrough Therapy status is reserved for accelerated review of therapies considered to show substantial preliminary promise of effectively targeting a major unmet medical need.

The unmet need here is that there is no meningococcal group B vaccine approved for use in children under age 10 years. Yet infants and children under 5 years of age are at greatest risk of invasive meningococcal B disease, with reported case fatality rates of 8%-9%, Jason D. Maguire, MD, noted at the annual meeting of the European Society for Paediatric Infectious Diseases.

Trumenba has been approved in the United States for patients aged 10-25 years and in the European Union for individuals aged 10 years or older.

Dr. Maguire, of Pfizer’s vaccine clinical research and development program, presented the results of the two phase 2 randomized safety and immunogenicity trials conducted in patients aged 1- 9 years that the company has submitted to the FDA in support of the expanded indication. One study was carried out in 352 1-year-old toddlers, the other in 400 children aged 2-9 years, whose mean age was 4 years. The studies were carried out in Australia, Finland, Poland, and the Czech Republic.

In a pooled analysis of the vaccine’s immunogenicity when administered in a three-dose schedule of 120 mcg at 0, 2, and 6 months to 193 toddlers and 274 of the children aged 2-9 years, robust bactericidal antibody responses were seen against the four major Neisseria meningitidis group B strains that cause invasive disease. In fact, at least a fourfold rise in titers from baseline to 1 month after dose three was documented in the same high proportion of 1- to 9-year-olds as previously seen in the phase 3 trials that led to vaccine licensure in adolescents and young adults.

“These results support that the use of Trumenba, when given to children ages 1 to less than 10 years at the same dose and schedule that is currently approved in adolescents and young adults, can afford a high degree of protective antibody responses that correlate with immunity in this population,” Dr. Maguire said.

The safety and tolerability analysis included all 752 children in the two phase 2 studies, including the 110 toddlers randomized to three 60-mcg doses of the vaccine, although it has subsequently become clear that 120 mcg is the dose that provides the best immunogenicity with an acceptable safety profile, according to the physician.

Across the age groups, local reactions, including redness and swelling, were more common in Trumenba recipients than in controls who received hepatitis A vaccine and saline injections. So were systemic adverse events. Fever – a systemic event of particular interest to parents and clinicians – occurred in 37% of toddlers after vaccination, compared with 25% of 2- to 9-year-olds and 10%-12% of controls. Of note, prophylactic antipyretics weren’t allowed in the study.

“There’s somewhat of an inverse relationship between age and temperature. So as we go down in age, the rate of fever rises. But after each subsequent dose, regardless of age, there’s a reduction in the incidence of fever,” Dr. Maguire observed.

Most fevers were less than 39.0° C. Only 3 of 752 (less than 1%) patients experienced fever in excess of 40.0° C.

Two children withdrew from the study after developing hip synovitis, which was transient. Another withdrew because of prolonged irritability, fatigue, and decreased appetite.

“Although Trumenba had an acceptable safety and tolerability profile in 1- to 9-year-olds, this analysis wasn’t powered enough to detect uncommon adverse events, so we’ll continue to monitor safety for things like synovitis,” he said.

In 10- to 25-year-olds, the meningococcal vaccine can be given concomitantly with other vaccines without interference. There are plans to study concurrent vaccination with MMR and pneumococcal vaccines in 1- to 9-year-olds as well, according to Dr. Maguire.

Pfizer also now is planning clinical trials of the vaccine in infants, another important group currently unprotected against meningococcal group B disease, he added.

Dr. Maguire is an employee of Pfizer, who funded the studies.

[email protected]

LJUBLJANA, SLOVENIA – An expanded indication for the meningococcal group B vaccine known as Trumenba in patients aged 1-9 years is being considered by the Food and Drug Administration under the agency’s Breakthrough Therapy designation.

Breakthrough Therapy status is reserved for accelerated review of therapies considered to show substantial preliminary promise of effectively targeting a major unmet medical need.

The unmet need here is that there is no meningococcal group B vaccine approved for use in children under age 10 years. Yet infants and children under 5 years of age are at greatest risk of invasive meningococcal B disease, with reported case fatality rates of 8%-9%, Jason D. Maguire, MD, noted at the annual meeting of the European Society for Paediatric Infectious Diseases.

Trumenba has been approved in the United States for patients aged 10-25 years and in the European Union for individuals aged 10 years or older.

Dr. Maguire, of Pfizer’s vaccine clinical research and development program, presented the results of the two phase 2 randomized safety and immunogenicity trials conducted in patients aged 1- 9 years that the company has submitted to the FDA in support of the expanded indication. One study was carried out in 352 1-year-old toddlers, the other in 400 children aged 2-9 years, whose mean age was 4 years. The studies were carried out in Australia, Finland, Poland, and the Czech Republic.

In a pooled analysis of the vaccine’s immunogenicity when administered in a three-dose schedule of 120 mcg at 0, 2, and 6 months to 193 toddlers and 274 of the children aged 2-9 years, robust bactericidal antibody responses were seen against the four major Neisseria meningitidis group B strains that cause invasive disease. In fact, at least a fourfold rise in titers from baseline to 1 month after dose three was documented in the same high proportion of 1- to 9-year-olds as previously seen in the phase 3 trials that led to vaccine licensure in adolescents and young adults.

“These results support that the use of Trumenba, when given to children ages 1 to less than 10 years at the same dose and schedule that is currently approved in adolescents and young adults, can afford a high degree of protective antibody responses that correlate with immunity in this population,” Dr. Maguire said.

The safety and tolerability analysis included all 752 children in the two phase 2 studies, including the 110 toddlers randomized to three 60-mcg doses of the vaccine, although it has subsequently become clear that 120 mcg is the dose that provides the best immunogenicity with an acceptable safety profile, according to the physician.

Across the age groups, local reactions, including redness and swelling, were more common in Trumenba recipients than in controls who received hepatitis A vaccine and saline injections. So were systemic adverse events. Fever – a systemic event of particular interest to parents and clinicians – occurred in 37% of toddlers after vaccination, compared with 25% of 2- to 9-year-olds and 10%-12% of controls. Of note, prophylactic antipyretics weren’t allowed in the study.

“There’s somewhat of an inverse relationship between age and temperature. So as we go down in age, the rate of fever rises. But after each subsequent dose, regardless of age, there’s a reduction in the incidence of fever,” Dr. Maguire observed.

Most fevers were less than 39.0° C. Only 3 of 752 (less than 1%) patients experienced fever in excess of 40.0° C.

Two children withdrew from the study after developing hip synovitis, which was transient. Another withdrew because of prolonged irritability, fatigue, and decreased appetite.

“Although Trumenba had an acceptable safety and tolerability profile in 1- to 9-year-olds, this analysis wasn’t powered enough to detect uncommon adverse events, so we’ll continue to monitor safety for things like synovitis,” he said.

In 10- to 25-year-olds, the meningococcal vaccine can be given concomitantly with other vaccines without interference. There are plans to study concurrent vaccination with MMR and pneumococcal vaccines in 1- to 9-year-olds as well, according to Dr. Maguire.

Pfizer also now is planning clinical trials of the vaccine in infants, another important group currently unprotected against meningococcal group B disease, he added.

Dr. Maguire is an employee of Pfizer, who funded the studies.

[email protected]

Gastroesophageal reflux (GER) is common in infants and often presents a challenge to doctors who try to balance changing evidence with concerns about complications and parents’ concerns about their infant’s discomfort. In a 2018 guideline, the writing committee defined GER as reflux of stomach contents to the esophagus. GER is considered pathologic and, therefore, gastroesophageal reflux disease (GERD) when it is associated with troublesome symptoms and/or complications that can include esophagitis and aspiration.

Infants

GERD is difficult to diagnose in infants. The symptoms of GERD, such as crying after feeds, regurgitation, and irritability, occur commonly in all infants and in any individual infant may not be reflective of GERD. Regurgitation is common, frequent and normal in infants up to 6 months of age. A common challenge occurs when families request treatment for infants with irritability, back arching, and/or regurgitation who are otherwise doing well. In this group of infants it is important to recognize that neither testing nor therapy is indicated unless there is difficulty with feeding, growth, acquisition of milestones, or red flag signs.

In infants with recurrent regurgitation history, physical exam is usually sufficient to distinguish uncomplicated GER from GERD and other more worrisome diagnoses. Red flag symptoms raise the possibility of a different diagnosis. Red flag symptoms include weight loss; lethargy; excessive irritability/pain; onset of vomiting for more than 6 months or persisting past 12-18 months of age; rapidly increasing head circumference; persistent forceful, nocturnal, bloody, or bilious vomiting; abdominal distention; rectal bleeding; and chronic diarrhea. GERD that starts after 6 months of age or which persists after 12 months of age warrants further evaluation, often with referral to a pediatric gastroenterologist.

When GERD is suspected, the first therapeutic steps are to institute behavioral changes. Caregivers should avoid overfeeding and modify the feeding pattern to more frequent feedings consisting of less volume at each feed. The addition of thickeners to feeds does reduce regurgitation, although it may not affect other GERD signs and symptoms. Formula can be thickened with rice cereal, which tends to be an affordable choice that doesn’t clog nipples. Enzymes present in breast milk digest cereal thickeners, so breast milk can be thickened with xanthum gum (after 1 year of age) or carob bean–based products (after 42 weeks gestation).

If these modifications do not improve symptoms, the next step is to change the type of feeds. Some infants in whom GERD is suspected actually have cow’s milk protein allergy (CMPA), so a trial of cow’s milk elimination is warranted. A breastfeeding mother can eliminate all dairy from her diet including casein and whey. Caregivers can switch to an extensively hydrolyzed formula or an amino acid–based formula. The guideline do not recommend soy-based formulas because they are not available in Europe and because a significant percentage of infants with CMPA also develop allergy to soy, and they do not recommend rice hydrolysate formula because of a lack of evidence. Dairy can be reintroduced at a later point. While positional changes including elevating the head of the crib or placing the infant in the left lateral position can help decrease GERD, the American Academy of Pediatrics strongly discourages these positions because of safety concerns, so the guidelines do not recommend positional change.

If a 2-4 week trial of nonpharmacologic interventions fails, the next step is referral to a pediatric gastroenterologist. If a pediatric gastroenterologist is not available, a 4-8 week trial of acid suppressive medication may be given. No trial has shown utility of a trial of acid suppression as a diagnostic test for GERD. Medication should only be used in infants with strongly suspected GERD and, per the guidelines, “should not be used for the treatment of visible regurgitation in otherwise healthy infants.” Medications to treat GER do not have evidence of efficacy, and there is evidence of an increased risk of infection with use of acid suppression, including an increased risk of necrotizing enterocolitis, pneumonia, upper respiratory tract infections, sepsis, urinary tract infections, and Clostridium difficile. If used, proton-pump inhibitors are preferred over histamine-2 receptor blockers. Antacids and alginates are not recommended.
 

Older children

In children with heartburn or regurgitation without red flag symptoms, a trial of lifestyle changes and dietary education may be initiated. If a child is overweight, it is important to inform the patient and parents that excess body weight is associated with GERD. The head of the bed can be elevated along with left lateral positioning. The guidelines do not support any probiotics or herbal medicines.

If bothersome symptoms persist, a trial of acid-suppressing medication for 4-8 weeks is reasonable. A PPI is preferred to a histamine-2 receptor blocker. PPI safety studies are lacking, but case studies suggest an increase in infections in children taking acid-suppressing medications. Therefore, as with infants, if medications are used they should be prescribed at the lowest dose and for the shortest period of time possible. If medications are not helping, or need to be used long term, referral to a pediatric gastroenterologist can be considered. Of note, the guidelines do support a 4-8 week trial of PPIs in older children as a diagnostic test; this differs from the recommendations for infants, in whom a trial for diagnostic purposes is discouraged.
 

Diagnostic testing

Refer to a gastroenterologist for endoscopy in cases of persistent symptoms despite PPI use or failure to wean off medication. If there are no erosions, pH monitoring with pH-impedance monitoring or pH-metry can help distinguish between nonerosive reflux disease (NERD), reflux hypersensitivity, and functional heartburn. If it is performed when a child is off of PPIs, endoscopy can also diagnose PPI-responsive eosinophilic esophagitis. Barium contrast, abdominal ultrasonography, and manometry may be considered during the course of a search for an alternative diagnosis, but they should not be used to diagnose or confirm GERD.

The bottom line

Most GER is physiologic and does not need treatment. First-line treatment for GERD in infants and children is nonpharmacologic intervention.
 

Reference

Rosen R et al. Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2018 Mar;66(3):516-554.

Dr. Oh is a third year resident in the Family Medicine Residency at Abington-Jefferson Health. Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington - Jefferson Health.

Gastroesophageal reflux (GER) is common in infants and often presents a challenge to doctors who try to balance changing evidence with concerns about complications and parents’ concerns about their infant’s discomfort. In a 2018 guideline, the writing committee defined GER as reflux of stomach contents to the esophagus. GER is considered pathologic and, therefore, gastroesophageal reflux disease (GERD) when it is associated with troublesome symptoms and/or complications that can include esophagitis and aspiration.

Infants

GERD is difficult to diagnose in infants. The symptoms of GERD, such as crying after feeds, regurgitation, and irritability, occur commonly in all infants and in any individual infant may not be reflective of GERD. Regurgitation is common, frequent and normal in infants up to 6 months of age. A common challenge occurs when families request treatment for infants with irritability, back arching, and/or regurgitation who are otherwise doing well. In this group of infants it is important to recognize that neither testing nor therapy is indicated unless there is difficulty with feeding, growth, acquisition of milestones, or red flag signs.

In infants with recurrent regurgitation history, physical exam is usually sufficient to distinguish uncomplicated GER from GERD and other more worrisome diagnoses. Red flag symptoms raise the possibility of a different diagnosis. Red flag symptoms include weight loss; lethargy; excessive irritability/pain; onset of vomiting for more than 6 months or persisting past 12-18 months of age; rapidly increasing head circumference; persistent forceful, nocturnal, bloody, or bilious vomiting; abdominal distention; rectal bleeding; and chronic diarrhea. GERD that starts after 6 months of age or which persists after 12 months of age warrants further evaluation, often with referral to a pediatric gastroenterologist.

When GERD is suspected, the first therapeutic steps are to institute behavioral changes. Caregivers should avoid overfeeding and modify the feeding pattern to more frequent feedings consisting of less volume at each feed. The addition of thickeners to feeds does reduce regurgitation, although it may not affect other GERD signs and symptoms. Formula can be thickened with rice cereal, which tends to be an affordable choice that doesn’t clog nipples. Enzymes present in breast milk digest cereal thickeners, so breast milk can be thickened with xanthum gum (after 1 year of age) or carob bean–based products (after 42 weeks gestation).

If these modifications do not improve symptoms, the next step is to change the type of feeds. Some infants in whom GERD is suspected actually have cow’s milk protein allergy (CMPA), so a trial of cow’s milk elimination is warranted. A breastfeeding mother can eliminate all dairy from her diet including casein and whey. Caregivers can switch to an extensively hydrolyzed formula or an amino acid–based formula. The guideline do not recommend soy-based formulas because they are not available in Europe and because a significant percentage of infants with CMPA also develop allergy to soy, and they do not recommend rice hydrolysate formula because of a lack of evidence. Dairy can be reintroduced at a later point. While positional changes including elevating the head of the crib or placing the infant in the left lateral position can help decrease GERD, the American Academy of Pediatrics strongly discourages these positions because of safety concerns, so the guidelines do not recommend positional change.

If a 2-4 week trial of nonpharmacologic interventions fails, the next step is referral to a pediatric gastroenterologist. If a pediatric gastroenterologist is not available, a 4-8 week trial of acid suppressive medication may be given. No trial has shown utility of a trial of acid suppression as a diagnostic test for GERD. Medication should only be used in infants with strongly suspected GERD and, per the guidelines, “should not be used for the treatment of visible regurgitation in otherwise healthy infants.” Medications to treat GER do not have evidence of efficacy, and there is evidence of an increased risk of infection with use of acid suppression, including an increased risk of necrotizing enterocolitis, pneumonia, upper respiratory tract infections, sepsis, urinary tract infections, and Clostridium difficile. If used, proton-pump inhibitors are preferred over histamine-2 receptor blockers. Antacids and alginates are not recommended.
 

Older children

In children with heartburn or regurgitation without red flag symptoms, a trial of lifestyle changes and dietary education may be initiated. If a child is overweight, it is important to inform the patient and parents that excess body weight is associated with GERD. The head of the bed can be elevated along with left lateral positioning. The guidelines do not support any probiotics or herbal medicines.

If bothersome symptoms persist, a trial of acid-suppressing medication for 4-8 weeks is reasonable. A PPI is preferred to a histamine-2 receptor blocker. PPI safety studies are lacking, but case studies suggest an increase in infections in children taking acid-suppressing medications. Therefore, as with infants, if medications are used they should be prescribed at the lowest dose and for the shortest period of time possible. If medications are not helping, or need to be used long term, referral to a pediatric gastroenterologist can be considered. Of note, the guidelines do support a 4-8 week trial of PPIs in older children as a diagnostic test; this differs from the recommendations for infants, in whom a trial for diagnostic purposes is discouraged.
 

Diagnostic testing

Refer to a gastroenterologist for endoscopy in cases of persistent symptoms despite PPI use or failure to wean off medication. If there are no erosions, pH monitoring with pH-impedance monitoring or pH-metry can help distinguish between nonerosive reflux disease (NERD), reflux hypersensitivity, and functional heartburn. If it is performed when a child is off of PPIs, endoscopy can also diagnose PPI-responsive eosinophilic esophagitis. Barium contrast, abdominal ultrasonography, and manometry may be considered during the course of a search for an alternative diagnosis, but they should not be used to diagnose or confirm GERD.

The bottom line

Most GER is physiologic and does not need treatment. First-line treatment for GERD in infants and children is nonpharmacologic intervention.
 

Reference

Rosen R et al. Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2018 Mar;66(3):516-554.

Dr. Oh is a third year resident in the Family Medicine Residency at Abington-Jefferson Health. Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington - Jefferson Health.

Gastroesophageal reflux (GER) is common in infants and often presents a challenge to doctors who try to balance changing evidence with concerns about complications and parents’ concerns about their infant’s discomfort. In a 2018 guideline, the writing committee defined GER as reflux of stomach contents to the esophagus. GER is considered pathologic and, therefore, gastroesophageal reflux disease (GERD) when it is associated with troublesome symptoms and/or complications that can include esophagitis and aspiration.

Infants

GERD is difficult to diagnose in infants. The symptoms of GERD, such as crying after feeds, regurgitation, and irritability, occur commonly in all infants and in any individual infant may not be reflective of GERD. Regurgitation is common, frequent and normal in infants up to 6 months of age. A common challenge occurs when families request treatment for infants with irritability, back arching, and/or regurgitation who are otherwise doing well. In this group of infants it is important to recognize that neither testing nor therapy is indicated unless there is difficulty with feeding, growth, acquisition of milestones, or red flag signs.

In infants with recurrent regurgitation history, physical exam is usually sufficient to distinguish uncomplicated GER from GERD and other more worrisome diagnoses. Red flag symptoms raise the possibility of a different diagnosis. Red flag symptoms include weight loss; lethargy; excessive irritability/pain; onset of vomiting for more than 6 months or persisting past 12-18 months of age; rapidly increasing head circumference; persistent forceful, nocturnal, bloody, or bilious vomiting; abdominal distention; rectal bleeding; and chronic diarrhea. GERD that starts after 6 months of age or which persists after 12 months of age warrants further evaluation, often with referral to a pediatric gastroenterologist.

When GERD is suspected, the first therapeutic steps are to institute behavioral changes. Caregivers should avoid overfeeding and modify the feeding pattern to more frequent feedings consisting of less volume at each feed. The addition of thickeners to feeds does reduce regurgitation, although it may not affect other GERD signs and symptoms. Formula can be thickened with rice cereal, which tends to be an affordable choice that doesn’t clog nipples. Enzymes present in breast milk digest cereal thickeners, so breast milk can be thickened with xanthum gum (after 1 year of age) or carob bean–based products (after 42 weeks gestation).

If these modifications do not improve symptoms, the next step is to change the type of feeds. Some infants in whom GERD is suspected actually have cow’s milk protein allergy (CMPA), so a trial of cow’s milk elimination is warranted. A breastfeeding mother can eliminate all dairy from her diet including casein and whey. Caregivers can switch to an extensively hydrolyzed formula or an amino acid–based formula. The guideline do not recommend soy-based formulas because they are not available in Europe and because a significant percentage of infants with CMPA also develop allergy to soy, and they do not recommend rice hydrolysate formula because of a lack of evidence. Dairy can be reintroduced at a later point. While positional changes including elevating the head of the crib or placing the infant in the left lateral position can help decrease GERD, the American Academy of Pediatrics strongly discourages these positions because of safety concerns, so the guidelines do not recommend positional change.

If a 2-4 week trial of nonpharmacologic interventions fails, the next step is referral to a pediatric gastroenterologist. If a pediatric gastroenterologist is not available, a 4-8 week trial of acid suppressive medication may be given. No trial has shown utility of a trial of acid suppression as a diagnostic test for GERD. Medication should only be used in infants with strongly suspected GERD and, per the guidelines, “should not be used for the treatment of visible regurgitation in otherwise healthy infants.” Medications to treat GER do not have evidence of efficacy, and there is evidence of an increased risk of infection with use of acid suppression, including an increased risk of necrotizing enterocolitis, pneumonia, upper respiratory tract infections, sepsis, urinary tract infections, and Clostridium difficile. If used, proton-pump inhibitors are preferred over histamine-2 receptor blockers. Antacids and alginates are not recommended.
 

Older children

In children with heartburn or regurgitation without red flag symptoms, a trial of lifestyle changes and dietary education may be initiated. If a child is overweight, it is important to inform the patient and parents that excess body weight is associated with GERD. The head of the bed can be elevated along with left lateral positioning. The guidelines do not support any probiotics or herbal medicines.

If bothersome symptoms persist, a trial of acid-suppressing medication for 4-8 weeks is reasonable. A PPI is preferred to a histamine-2 receptor blocker. PPI safety studies are lacking, but case studies suggest an increase in infections in children taking acid-suppressing medications. Therefore, as with infants, if medications are used they should be prescribed at the lowest dose and for the shortest period of time possible. If medications are not helping, or need to be used long term, referral to a pediatric gastroenterologist can be considered. Of note, the guidelines do support a 4-8 week trial of PPIs in older children as a diagnostic test; this differs from the recommendations for infants, in whom a trial for diagnostic purposes is discouraged.
 

Diagnostic testing

Refer to a gastroenterologist for endoscopy in cases of persistent symptoms despite PPI use or failure to wean off medication. If there are no erosions, pH monitoring with pH-impedance monitoring or pH-metry can help distinguish between nonerosive reflux disease (NERD), reflux hypersensitivity, and functional heartburn. If it is performed when a child is off of PPIs, endoscopy can also diagnose PPI-responsive eosinophilic esophagitis. Barium contrast, abdominal ultrasonography, and manometry may be considered during the course of a search for an alternative diagnosis, but they should not be used to diagnose or confirm GERD.

The bottom line

Most GER is physiologic and does not need treatment. First-line treatment for GERD in infants and children is nonpharmacologic intervention.
 

Reference

Rosen R et al. Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2018 Mar;66(3):516-554.

Dr. Oh is a third year resident in the Family Medicine Residency at Abington-Jefferson Health. Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington - Jefferson Health.

Oral immunotherapy reduced sensitivity to peanuts in allergic individuals, but at the cost of increased risk of anaphylaxis and other reactions, based on a meta-analysis from more than 1,000 patients published in the Lancet.

copyright mates/Fotolia.com

In the Peanut Allergen immunotherapy, Clarifying the Evidence (PACE) systematic review and meta-analysis, Derek K. Chu, MD, of McMaster University, Hamilton, Ont., and colleagues reviewed 12 trials conducted between 2011 and 2018 with a total of 1,041 patients (median age, 9 years).

Overall, the risk of anaphylaxis was significantly higher among children who received oral immunotherapy, compared with no therapy (risk ratio, 3.12) as was anaphylaxis frequency (incidence rate ratio, 2.72) and use of epinephrine (RR, 2.21).

In addition, oral immunotherapy increased serious adverse events, compared with no therapy (RR, 1.92). Nonanaphylactic reactions also went up among oral immunotherapy patients, with increased risk for vomiting (RR, 1.79), angioedema (RR, 2.25), upper respiratory tract reactions (RR, 1.36), and lower respiratory tract infections (RR, 1.55).

Quality of life scores were not significantly different between patients who did and did not receive oral immunotherapy, the researchers noted.

The oral immunotherapy consisted of defatted, lightly roasted peanut flour in 10 studies, and a combination of peanut paste, peanut extract, or ground and defatted peanut in the other studies.

The oral immunotherapy did induce desensitization to peanuts in support of earlier studies including the subcutaneous immunotherapy trial, but “this outcome does not translate into achieving the clinical and patient-desired aim of less allergic reactions and anaphylaxis,” Dr. Chu and associates wrote.

However, “rather than take the view that these data denounce current research in oral immunotherapy as not successful, we instead suggest that this research has reached an important milestone in mechanistic but not clinical efficacy. From a clinical or biological perspective, the apparently paradoxical desensitization versus longitudinal clinical findings show the lability and unreliability of allergen thresholds identified during oral food challenges because patients often unpredictably reacted to previously tolerated doses outside of clinic,” they emphasized.

The findings were limited by several factors including the small sample size, compared with similar studies for asthma or cardiovascular conditions, and by incomplete or inconsistent data reporting, the researchers noted. However, the results are the most comprehensive to date, and support the need for food allergy treatments with better safety profiles, using peanut allergy immunotherapy as a model for other food allergies.

Dr. Chu and two other authors reported being investigators on a federally funded ongoing peanut oral immunotherapy trial. Two authors reported receiving a variety of grants from organizations such as the National Institutes of Health; the American Academy of Allergy, Asthma, & Immunology; or pharmaceutical companies.

SOURCE: Chu DK et al. Lancet. 2019 June 1;393:2222-32.

Oral immunotherapy reduced sensitivity to peanuts in allergic individuals, but at the cost of increased risk of anaphylaxis and other reactions, based on a meta-analysis from more than 1,000 patients published in the Lancet.

copyright mates/Fotolia.com

In the Peanut Allergen immunotherapy, Clarifying the Evidence (PACE) systematic review and meta-analysis, Derek K. Chu, MD, of McMaster University, Hamilton, Ont., and colleagues reviewed 12 trials conducted between 2011 and 2018 with a total of 1,041 patients (median age, 9 years).

Overall, the risk of anaphylaxis was significantly higher among children who received oral immunotherapy, compared with no therapy (risk ratio, 3.12) as was anaphylaxis frequency (incidence rate ratio, 2.72) and use of epinephrine (RR, 2.21).

In addition, oral immunotherapy increased serious adverse events, compared with no therapy (RR, 1.92). Nonanaphylactic reactions also went up among oral immunotherapy patients, with increased risk for vomiting (RR, 1.79), angioedema (RR, 2.25), upper respiratory tract reactions (RR, 1.36), and lower respiratory tract infections (RR, 1.55).

Quality of life scores were not significantly different between patients who did and did not receive oral immunotherapy, the researchers noted.

The oral immunotherapy consisted of defatted, lightly roasted peanut flour in 10 studies, and a combination of peanut paste, peanut extract, or ground and defatted peanut in the other studies.

The oral immunotherapy did induce desensitization to peanuts in support of earlier studies including the subcutaneous immunotherapy trial, but “this outcome does not translate into achieving the clinical and patient-desired aim of less allergic reactions and anaphylaxis,” Dr. Chu and associates wrote.

However, “rather than take the view that these data denounce current research in oral immunotherapy as not successful, we instead suggest that this research has reached an important milestone in mechanistic but not clinical efficacy. From a clinical or biological perspective, the apparently paradoxical desensitization versus longitudinal clinical findings show the lability and unreliability of allergen thresholds identified during oral food challenges because patients often unpredictably reacted to previously tolerated doses outside of clinic,” they emphasized.

The findings were limited by several factors including the small sample size, compared with similar studies for asthma or cardiovascular conditions, and by incomplete or inconsistent data reporting, the researchers noted. However, the results are the most comprehensive to date, and support the need for food allergy treatments with better safety profiles, using peanut allergy immunotherapy as a model for other food allergies.

Dr. Chu and two other authors reported being investigators on a federally funded ongoing peanut oral immunotherapy trial. Two authors reported receiving a variety of grants from organizations such as the National Institutes of Health; the American Academy of Allergy, Asthma, & Immunology; or pharmaceutical companies.

SOURCE: Chu DK et al. Lancet. 2019 June 1;393:2222-32.

Oral immunotherapy reduced sensitivity to peanuts in allergic individuals, but at the cost of increased risk of anaphylaxis and other reactions, based on a meta-analysis from more than 1,000 patients published in the Lancet.

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In the Peanut Allergen immunotherapy, Clarifying the Evidence (PACE) systematic review and meta-analysis, Derek K. Chu, MD, of McMaster University, Hamilton, Ont., and colleagues reviewed 12 trials conducted between 2011 and 2018 with a total of 1,041 patients (median age, 9 years).

Overall, the risk of anaphylaxis was significantly higher among children who received oral immunotherapy, compared with no therapy (risk ratio, 3.12) as was anaphylaxis frequency (incidence rate ratio, 2.72) and use of epinephrine (RR, 2.21).

In addition, oral immunotherapy increased serious adverse events, compared with no therapy (RR, 1.92). Nonanaphylactic reactions also went up among oral immunotherapy patients, with increased risk for vomiting (RR, 1.79), angioedema (RR, 2.25), upper respiratory tract reactions (RR, 1.36), and lower respiratory tract infections (RR, 1.55).

Quality of life scores were not significantly different between patients who did and did not receive oral immunotherapy, the researchers noted.

The oral immunotherapy consisted of defatted, lightly roasted peanut flour in 10 studies, and a combination of peanut paste, peanut extract, or ground and defatted peanut in the other studies.

The oral immunotherapy did induce desensitization to peanuts in support of earlier studies including the subcutaneous immunotherapy trial, but “this outcome does not translate into achieving the clinical and patient-desired aim of less allergic reactions and anaphylaxis,” Dr. Chu and associates wrote.

However, “rather than take the view that these data denounce current research in oral immunotherapy as not successful, we instead suggest that this research has reached an important milestone in mechanistic but not clinical efficacy. From a clinical or biological perspective, the apparently paradoxical desensitization versus longitudinal clinical findings show the lability and unreliability of allergen thresholds identified during oral food challenges because patients often unpredictably reacted to previously tolerated doses outside of clinic,” they emphasized.

The findings were limited by several factors including the small sample size, compared with similar studies for asthma or cardiovascular conditions, and by incomplete or inconsistent data reporting, the researchers noted. However, the results are the most comprehensive to date, and support the need for food allergy treatments with better safety profiles, using peanut allergy immunotherapy as a model for other food allergies.

Dr. Chu and two other authors reported being investigators on a federally funded ongoing peanut oral immunotherapy trial. Two authors reported receiving a variety of grants from organizations such as the National Institutes of Health; the American Academy of Allergy, Asthma, & Immunology; or pharmaceutical companies.

SOURCE: Chu DK et al. Lancet. 2019 June 1;393:2222-32.

SAN FRANCISCO – Children with autism often struggle with repairing “messy” interactions with others, and this can impair their ability to communicate and develop properly. The interactive mismatch and repair technique, developed by Ed Tronick, PhD, when he was a researcher at Harvard Medical School and Children’s Hospital, Boston, may be able to guide communication development between an adult and a child with autism.

At the annual meeting of the American Psychiatric Association, Alexandra Harrison, MD, assistant professor of psychiatry at Harvard Medical School, described her experiences applying the technique to her work with autism patients, and showed a video of an awkward interaction she had with a 3-year-old boy with autism. By working to synchronize body movements with “Hal,” as well as inserting 1-second gaps between her statements, she helped him resolve an awkward moment, and Hal ultimately defused the tension by making a joke.

Hal managed to regulate his own uncertainty in the moment and navigate through tension. That small triumph has the potential to grow. “Once they’ve been able to secure some form of regulation with one or two or three individuals who are devoted to them, the hope is that this will spread and they will be able to regulate with individuals who are not as adjusted to them,” Gisele Apter, MD, PhD, a colleague of Dr. Harrison’s and professor of child psychiatry at Normandy Medical School, France, said in an interview. Dr. Apter moderated the session where the video was shown.

Dr. Tronick believes that the infant and caretaker grow together, making meanings together that are increasingly complex and coherent. That growth occurs in part through mismatch and repair interactions. Communication between infants and caregivers is nearly always a messy dance, with waxing and waning attention, changing intentions, and other dynamic factors leading to stops and starts, and awkward moments that the two must find a way to repair before carrying on.

These momentary mismatches, which happen all the time, are in fact a key element of childhood development, according to Dr. Apter. “There’s a lack of synchrony, and we want to get back on track because we push to communicate again. To do that, we have to repair the interaction, and one of the most beautiful things about development with this unbalanced couple is that the adult is generally there to support, to scaffold the child, but just one small step ahead of the infant so that it will enrich its development,” she said. 

But a caregiver with depression or another mental illness, or a child with impaired communication development because of autism, can impede that natural process.

Dr. Tronick’s method aims to provide some structure to the interaction by likening the nonverbal part of the interaction to music and dance. There are vocal rhythms, tone, and pitch, and then there are coordinated patterns of movement, gaze, and facial expressions such as smiles or frowns. The idea is that developmental growth occurs when the infant and the adult create meanings through their interactions.

Such growth can occur in microprocesses – extended moments in which child and caregiver iron out a mismatch in intent or action. Resolving these situations, and then moving forward with the rest of the interaction, helps the child grow in complexity and development by acquiring new meanings.

One-second beats after each statement or sentence lead to predictability. “He can develop an expectancy, and he can anticipate my vocal turns, and that is going to be reassuring to him,” Dr. Harrison said during the presentation. It also allows the caregiver to think through a messy moment, to try something different if one action seems not to be working. “It’s very hard to know how to repair the messiness, because it’s actually not messy enough. It’s too black and white. Something works or it doesn’t work, whereas with most kids you can be a little messy and you have time to get back on track with them.

“With these children [with autism], it requires a level of awareness which is higher. It is helpful for the adult to try to adjust and learn to interact in a different way that is more attuned to the child,” Dr. Apter said.

In the video shown by Dr. Harrison, she and Hal are in the therapy/play area, and Hal’s mother has just left before he could say goodbye. He was very upset by this, but then turned to work building a “map” out of construction toys called H-links that he had been playing with, along with his mother, before she left. Throughout the video, Dr. Harrison attempts to synchronize her body movements with Hal’s, shifting her position when he shifts his, and these get out of alignment and come back in alignment at different times. Several times, body motion synchrony is followed by a statement from Hal.

Dr. Harrison sits on the floor next to him, with Hal faced away from her. At a loss for what to do, she makes a small pile of H-links next to her. Hal notices this, and then moves some of the H-links back to their original position.

Hal says, “The H-links don’t go together that much.”

“They don’t go together that much?” repeats Dr. Harrison.

“Yeah.” He takes more H-block pieces from her pile.

“You wanted to take my ones, too?”

At this point, there is an obvious mismatch, with Hal claiming Dr. Harrison’s H-blocks.

Hal smiles as he takes a few more H-blocks and then says, “Only for boys.”

Then his smile widens and he gazes directly at Dr. Harrison, who meets his with an expression of mock surprise.

“What?”

“Only for boys,” Hal repeats.

Dr. Harrison then strings a long a series of phrases, each separated by 1-second beats. Hal orients himself away from her, smiling slightly: “You mean only boys can play with these? ... Uh oh ... Guess that means ... I’m not allowed! ... Is that right? ... Oh, my gosh ... How did they ever make up that rule, I wonder?”

At this, Hal orients himself toward Dr. Harrison again and smiles widely this time. “You’re tricking me,” says Dr. Harrison, and he gazes downward, though toward her. “But I think you’re trying to tell me that you don’t want me to hand them to you ... You want to get them yourself. ... That right?”

“Yeah. No more giving me pieces,” says Hal.

“Oh, I’m glad I understood. ... I will not give you any more pieces.”

SAN FRANCISCO – Children with autism often struggle with repairing “messy” interactions with others, and this can impair their ability to communicate and develop properly. The interactive mismatch and repair technique, developed by Ed Tronick, PhD, when he was a researcher at Harvard Medical School and Children’s Hospital, Boston, may be able to guide communication development between an adult and a child with autism.

At the annual meeting of the American Psychiatric Association, Alexandra Harrison, MD, assistant professor of psychiatry at Harvard Medical School, described her experiences applying the technique to her work with autism patients, and showed a video of an awkward interaction she had with a 3-year-old boy with autism. By working to synchronize body movements with “Hal,” as well as inserting 1-second gaps between her statements, she helped him resolve an awkward moment, and Hal ultimately defused the tension by making a joke.

Hal managed to regulate his own uncertainty in the moment and navigate through tension. That small triumph has the potential to grow. “Once they’ve been able to secure some form of regulation with one or two or three individuals who are devoted to them, the hope is that this will spread and they will be able to regulate with individuals who are not as adjusted to them,” Gisele Apter, MD, PhD, a colleague of Dr. Harrison’s and professor of child psychiatry at Normandy Medical School, France, said in an interview. Dr. Apter moderated the session where the video was shown.

Dr. Tronick believes that the infant and caretaker grow together, making meanings together that are increasingly complex and coherent. That growth occurs in part through mismatch and repair interactions. Communication between infants and caregivers is nearly always a messy dance, with waxing and waning attention, changing intentions, and other dynamic factors leading to stops and starts, and awkward moments that the two must find a way to repair before carrying on.

These momentary mismatches, which happen all the time, are in fact a key element of childhood development, according to Dr. Apter. “There’s a lack of synchrony, and we want to get back on track because we push to communicate again. To do that, we have to repair the interaction, and one of the most beautiful things about development with this unbalanced couple is that the adult is generally there to support, to scaffold the child, but just one small step ahead of the infant so that it will enrich its development,” she said. 

But a caregiver with depression or another mental illness, or a child with impaired communication development because of autism, can impede that natural process.

Dr. Tronick’s method aims to provide some structure to the interaction by likening the nonverbal part of the interaction to music and dance. There are vocal rhythms, tone, and pitch, and then there are coordinated patterns of movement, gaze, and facial expressions such as smiles or frowns. The idea is that developmental growth occurs when the infant and the adult create meanings through their interactions.

Such growth can occur in microprocesses – extended moments in which child and caregiver iron out a mismatch in intent or action. Resolving these situations, and then moving forward with the rest of the interaction, helps the child grow in complexity and development by acquiring new meanings.

One-second beats after each statement or sentence lead to predictability. “He can develop an expectancy, and he can anticipate my vocal turns, and that is going to be reassuring to him,” Dr. Harrison said during the presentation. It also allows the caregiver to think through a messy moment, to try something different if one action seems not to be working. “It’s very hard to know how to repair the messiness, because it’s actually not messy enough. It’s too black and white. Something works or it doesn’t work, whereas with most kids you can be a little messy and you have time to get back on track with them.

“With these children [with autism], it requires a level of awareness which is higher. It is helpful for the adult to try to adjust and learn to interact in a different way that is more attuned to the child,” Dr. Apter said.

In the video shown by Dr. Harrison, she and Hal are in the therapy/play area, and Hal’s mother has just left before he could say goodbye. He was very upset by this, but then turned to work building a “map” out of construction toys called H-links that he had been playing with, along with his mother, before she left. Throughout the video, Dr. Harrison attempts to synchronize her body movements with Hal’s, shifting her position when he shifts his, and these get out of alignment and come back in alignment at different times. Several times, body motion synchrony is followed by a statement from Hal.

Dr. Harrison sits on the floor next to him, with Hal faced away from her. At a loss for what to do, she makes a small pile of H-links next to her. Hal notices this, and then moves some of the H-links back to their original position.

Hal says, “The H-links don’t go together that much.”

“They don’t go together that much?” repeats Dr. Harrison.

“Yeah.” He takes more H-block pieces from her pile.

“You wanted to take my ones, too?”

At this point, there is an obvious mismatch, with Hal claiming Dr. Harrison’s H-blocks.

Hal smiles as he takes a few more H-blocks and then says, “Only for boys.”

Then his smile widens and he gazes directly at Dr. Harrison, who meets his with an expression of mock surprise.

“What?”

“Only for boys,” Hal repeats.

Dr. Harrison then strings a long a series of phrases, each separated by 1-second beats. Hal orients himself away from her, smiling slightly: “You mean only boys can play with these? ... Uh oh ... Guess that means ... I’m not allowed! ... Is that right? ... Oh, my gosh ... How did they ever make up that rule, I wonder?”

At this, Hal orients himself toward Dr. Harrison again and smiles widely this time. “You’re tricking me,” says Dr. Harrison, and he gazes downward, though toward her. “But I think you’re trying to tell me that you don’t want me to hand them to you ... You want to get them yourself. ... That right?”

“Yeah. No more giving me pieces,” says Hal.

“Oh, I’m glad I understood. ... I will not give you any more pieces.”

SAN FRANCISCO – Children with autism often struggle with repairing “messy” interactions with others, and this can impair their ability to communicate and develop properly. The interactive mismatch and repair technique, developed by Ed Tronick, PhD, when he was a researcher at Harvard Medical School and Children’s Hospital, Boston, may be able to guide communication development between an adult and a child with autism.

At the annual meeting of the American Psychiatric Association, Alexandra Harrison, MD, assistant professor of psychiatry at Harvard Medical School, described her experiences applying the technique to her work with autism patients, and showed a video of an awkward interaction she had with a 3-year-old boy with autism. By working to synchronize body movements with “Hal,” as well as inserting 1-second gaps between her statements, she helped him resolve an awkward moment, and Hal ultimately defused the tension by making a joke.

Hal managed to regulate his own uncertainty in the moment and navigate through tension. That small triumph has the potential to grow. “Once they’ve been able to secure some form of regulation with one or two or three individuals who are devoted to them, the hope is that this will spread and they will be able to regulate with individuals who are not as adjusted to them,” Gisele Apter, MD, PhD, a colleague of Dr. Harrison’s and professor of child psychiatry at Normandy Medical School, France, said in an interview. Dr. Apter moderated the session where the video was shown.

Dr. Tronick believes that the infant and caretaker grow together, making meanings together that are increasingly complex and coherent. That growth occurs in part through mismatch and repair interactions. Communication between infants and caregivers is nearly always a messy dance, with waxing and waning attention, changing intentions, and other dynamic factors leading to stops and starts, and awkward moments that the two must find a way to repair before carrying on.

These momentary mismatches, which happen all the time, are in fact a key element of childhood development, according to Dr. Apter. “There’s a lack of synchrony, and we want to get back on track because we push to communicate again. To do that, we have to repair the interaction, and one of the most beautiful things about development with this unbalanced couple is that the adult is generally there to support, to scaffold the child, but just one small step ahead of the infant so that it will enrich its development,” she said. 

But a caregiver with depression or another mental illness, or a child with impaired communication development because of autism, can impede that natural process.

Dr. Tronick’s method aims to provide some structure to the interaction by likening the nonverbal part of the interaction to music and dance. There are vocal rhythms, tone, and pitch, and then there are coordinated patterns of movement, gaze, and facial expressions such as smiles or frowns. The idea is that developmental growth occurs when the infant and the adult create meanings through their interactions.

Such growth can occur in microprocesses – extended moments in which child and caregiver iron out a mismatch in intent or action. Resolving these situations, and then moving forward with the rest of the interaction, helps the child grow in complexity and development by acquiring new meanings.

One-second beats after each statement or sentence lead to predictability. “He can develop an expectancy, and he can anticipate my vocal turns, and that is going to be reassuring to him,” Dr. Harrison said during the presentation. It also allows the caregiver to think through a messy moment, to try something different if one action seems not to be working. “It’s very hard to know how to repair the messiness, because it’s actually not messy enough. It’s too black and white. Something works or it doesn’t work, whereas with most kids you can be a little messy and you have time to get back on track with them.

“With these children [with autism], it requires a level of awareness which is higher. It is helpful for the adult to try to adjust and learn to interact in a different way that is more attuned to the child,” Dr. Apter said.

In the video shown by Dr. Harrison, she and Hal are in the therapy/play area, and Hal’s mother has just left before he could say goodbye. He was very upset by this, but then turned to work building a “map” out of construction toys called H-links that he had been playing with, along with his mother, before she left. Throughout the video, Dr. Harrison attempts to synchronize her body movements with Hal’s, shifting her position when he shifts his, and these get out of alignment and come back in alignment at different times. Several times, body motion synchrony is followed by a statement from Hal.

Dr. Harrison sits on the floor next to him, with Hal faced away from her. At a loss for what to do, she makes a small pile of H-links next to her. Hal notices this, and then moves some of the H-links back to their original position.

Hal says, “The H-links don’t go together that much.”

“They don’t go together that much?” repeats Dr. Harrison.

“Yeah.” He takes more H-block pieces from her pile.

“You wanted to take my ones, too?”

At this point, there is an obvious mismatch, with Hal claiming Dr. Harrison’s H-blocks.

Hal smiles as he takes a few more H-blocks and then says, “Only for boys.”

Then his smile widens and he gazes directly at Dr. Harrison, who meets his with an expression of mock surprise.

“What?”

“Only for boys,” Hal repeats.

Dr. Harrison then strings a long a series of phrases, each separated by 1-second beats. Hal orients himself away from her, smiling slightly: “You mean only boys can play with these? ... Uh oh ... Guess that means ... I’m not allowed! ... Is that right? ... Oh, my gosh ... How did they ever make up that rule, I wonder?”

At this, Hal orients himself toward Dr. Harrison again and smiles widely this time. “You’re tricking me,” says Dr. Harrison, and he gazes downward, though toward her. “But I think you’re trying to tell me that you don’t want me to hand them to you ... You want to get them yourself. ... That right?”

“Yeah. No more giving me pieces,” says Hal.

“Oh, I’m glad I understood. ... I will not give you any more pieces.”

The National Comprehensive Cancer Network (NCCN) has issued new clinical practice guidelines for the treatment of pediatric acute lymphoblastic leukemia (ALL).

“The cure rate for pediatric ALL in the U.S. has risen from 0% in the 1960s to nearly 90% today. This is among the most profound medical success stories in history,” Patrick Brown, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, said in a statement announcing the guidelines. Dr. Brown chairs the NCCN Clinical Practice Guidelines for adult and pediatric ALL.

“Pediatric ALL survivors live a long time; we have to consider long-term effects as well,” Hiroto Inaba, MD, PhD, of St. Jude Children’s Research Hospital, Memphis, and vice chair of the guidelines committee, said in the statement.

The new recommendations highlight the importance of supportive care interventions in an effort to reduce the chances of patients experiencing severe adverse effects.

The pediatric ALL guidelines provide evidence-based recommendations about optimal treatment strategies for ALL to prolong survival in children affected, with a focus on treatment outside of clinical trials (Pediatric Acute Lymphoblastic Leukemia. NCCN.org, Version 1.2019, published May 30, 2019).

While treatment for ALL often includes long-term chemotherapy regimens that involve multiple stages, several novel treatment strategies are summarized in the guidelines, including various types of immunotherapy and targeted therapy.

The guidelines are intended to accompany the NCCN Guidelines for Adult ALL and integrate treatment recommendations for patients in overlapping age categories. The recommendations are organized based on risk level, which may also be associated with age.

“The highest risk [is] associated with those diagnosed within the first 12 months of life or between the ages 10 and 21 years old,” the guideline authors wrote.

Another unique aspect of the guidelines is the recognition of vulnerable populations, such as young infants or children with Down syndrome, who face distinct treatment challenges. The authors provide guidance on the best supportive care measures for these patients.

The NCCN is currently expanding the collection of clinical practice guidelines for additional pediatric malignancies. At present, they are planning to undertake a minimum of 90% of all incident pediatric cancers.

Upcoming guidelines include treatment recommendations for pediatric Burkitt lymphoma, and are scheduled for release later in 2019.

Future efforts include modifying the guidelines for use in low- and middle-income countries, with the goal of providing direction in resource-limited environments.

“We know that many, many children can be cured with inexpensive and widely-available therapies,” Dr. Brown said. “With the increasing global reach of the NCCN Guidelines, we can really pave the way for increasing the cure rates throughout the world.”
 

The National Comprehensive Cancer Network (NCCN) has issued new clinical practice guidelines for the treatment of pediatric acute lymphoblastic leukemia (ALL).

“The cure rate for pediatric ALL in the U.S. has risen from 0% in the 1960s to nearly 90% today. This is among the most profound medical success stories in history,” Patrick Brown, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, said in a statement announcing the guidelines. Dr. Brown chairs the NCCN Clinical Practice Guidelines for adult and pediatric ALL.

“Pediatric ALL survivors live a long time; we have to consider long-term effects as well,” Hiroto Inaba, MD, PhD, of St. Jude Children’s Research Hospital, Memphis, and vice chair of the guidelines committee, said in the statement.

The new recommendations highlight the importance of supportive care interventions in an effort to reduce the chances of patients experiencing severe adverse effects.

The pediatric ALL guidelines provide evidence-based recommendations about optimal treatment strategies for ALL to prolong survival in children affected, with a focus on treatment outside of clinical trials (Pediatric Acute Lymphoblastic Leukemia. NCCN.org, Version 1.2019, published May 30, 2019).

While treatment for ALL often includes long-term chemotherapy regimens that involve multiple stages, several novel treatment strategies are summarized in the guidelines, including various types of immunotherapy and targeted therapy.

The guidelines are intended to accompany the NCCN Guidelines for Adult ALL and integrate treatment recommendations for patients in overlapping age categories. The recommendations are organized based on risk level, which may also be associated with age.

“The highest risk [is] associated with those diagnosed within the first 12 months of life or between the ages 10 and 21 years old,” the guideline authors wrote.

Another unique aspect of the guidelines is the recognition of vulnerable populations, such as young infants or children with Down syndrome, who face distinct treatment challenges. The authors provide guidance on the best supportive care measures for these patients.

The NCCN is currently expanding the collection of clinical practice guidelines for additional pediatric malignancies. At present, they are planning to undertake a minimum of 90% of all incident pediatric cancers.

Upcoming guidelines include treatment recommendations for pediatric Burkitt lymphoma, and are scheduled for release later in 2019.

Future efforts include modifying the guidelines for use in low- and middle-income countries, with the goal of providing direction in resource-limited environments.

“We know that many, many children can be cured with inexpensive and widely-available therapies,” Dr. Brown said. “With the increasing global reach of the NCCN Guidelines, we can really pave the way for increasing the cure rates throughout the world.”
 

The National Comprehensive Cancer Network (NCCN) has issued new clinical practice guidelines for the treatment of pediatric acute lymphoblastic leukemia (ALL).

“The cure rate for pediatric ALL in the U.S. has risen from 0% in the 1960s to nearly 90% today. This is among the most profound medical success stories in history,” Patrick Brown, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, said in a statement announcing the guidelines. Dr. Brown chairs the NCCN Clinical Practice Guidelines for adult and pediatric ALL.

“Pediatric ALL survivors live a long time; we have to consider long-term effects as well,” Hiroto Inaba, MD, PhD, of St. Jude Children’s Research Hospital, Memphis, and vice chair of the guidelines committee, said in the statement.

The new recommendations highlight the importance of supportive care interventions in an effort to reduce the chances of patients experiencing severe adverse effects.

The pediatric ALL guidelines provide evidence-based recommendations about optimal treatment strategies for ALL to prolong survival in children affected, with a focus on treatment outside of clinical trials (Pediatric Acute Lymphoblastic Leukemia. NCCN.org, Version 1.2019, published May 30, 2019).

While treatment for ALL often includes long-term chemotherapy regimens that involve multiple stages, several novel treatment strategies are summarized in the guidelines, including various types of immunotherapy and targeted therapy.

The guidelines are intended to accompany the NCCN Guidelines for Adult ALL and integrate treatment recommendations for patients in overlapping age categories. The recommendations are organized based on risk level, which may also be associated with age.

“The highest risk [is] associated with those diagnosed within the first 12 months of life or between the ages 10 and 21 years old,” the guideline authors wrote.

Another unique aspect of the guidelines is the recognition of vulnerable populations, such as young infants or children with Down syndrome, who face distinct treatment challenges. The authors provide guidance on the best supportive care measures for these patients.

The NCCN is currently expanding the collection of clinical practice guidelines for additional pediatric malignancies. At present, they are planning to undertake a minimum of 90% of all incident pediatric cancers.

Upcoming guidelines include treatment recommendations for pediatric Burkitt lymphoma, and are scheduled for release later in 2019.

Future efforts include modifying the guidelines for use in low- and middle-income countries, with the goal of providing direction in resource-limited environments.

“We know that many, many children can be cured with inexpensive and widely-available therapies,” Dr. Brown said. “With the increasing global reach of the NCCN Guidelines, we can really pave the way for increasing the cure rates throughout the world.”
 

LAS VEGAS – The Melody transcatheter pulmonary valve showed durable efficacy out to 5 years after placement in a mandated U.S. postapproval study that followed 65 patients, a majority of whom were children or teenagers.

Mitchel L. Zoler/MDedge News

After 5 years, 69% of the replacement valve recipients had no valvular hemodynamic dysfunction, compared with a 67% rate among patients enrolled in the original Investigational Device Exemption (IDE) study that led to Food and Drug Administration marketing approval for the Melody valve in 2010 under a humanitarian device exemption. (Full approval followed in 2017.)

The 5-year rate of any reintervention, including explants, was 78% in the postapproval study, again similar to the 76% rate reported in the IDE study after a median 4.5 year follow-up (Circulation. 2015 Jun 2;131[22]:1960-70), Aimee K. Armstrong, MD, said at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.

The new 5-year postapproval study findings “confirm that the hemodynamic effectiveness achieved by real-world providers is equivalent to the historical control established in the IDE study,” concluded Dr. Armstrong, professor of pediatrics at the Ohio State University and director of cardiac catheterization and interventional therapies at Nationwide Children’s Hospital, both in Columbus.

The postapproval study ran at 10 U.S. centers, none of which were among the five U.S. centers that ran the IDE study. Today, the Melody transcatheter pulmonary valve “is very commonly used” at many additional U.S. sites, Dr. Armstrong said in an interview. And the outcomes achieved using the valve likely surpass those seen in the IDE and postapproval studies because of innovations in technique, such as more routine use of “prestenting,” placing a stent in the vascular site where the pulmonary valve conduit will sit to address stenosis at this location and prevent subsequent conduit fracture (JACC Cardiovasc Interv. 2017 Sep;10[17]:1760-2).

“In 2010 [when the postapproval study began], we didn’t understand the importance of prestenting the way we do now. In 2010, I did not prestent every patient; now I do,” she said. The results reported by Dr. Armstrong included a 5% cumulative rate of major stent fractures in the Melody devices.

The postapproval study results also documented a concerning 4.5% annualized incidence of endocarditis among pulmonary valve recipients, with a nearly 300% increased rate of endocarditis among patients aged 12 years or younger, compared with older patients. Dr. Armstrong cautioned that this age association may be confounded by other factors, such as a residual pressure gradient in the right ventricular outflow tract of 15 mm Hg or greater. “We are discovering that we need to reduce the pressure gradient as much as we can, to perhaps less than 15 mm Hg, to reduce endocarditis, and that is something we did not know even a year ago. Practice is still evolving.”

The Melody Transcatheter Pulmonary Valve Postapproval Study performed cardiac catheterization for valve placement in 121 patients, and successfully implanted the valve for at least 24 hours in 99 of these patients. Patient age ranged from 5 to 45 years, with a median of 17 years; two-thirds were boys or men. The median age of the patients in the postapproval study was about 2 years younger than in the IDE study. Dr. Armstrong and her associates had previously published the 1-year outcomes from the postapproval study (JACC Cardiovasc Interv. 2014 Nov;7[11]:1254-62).

The enrolled patients usually needed a new right ventricular outflow tract because of a congenital heart defect, such as tetralogy of Fallot with pulmonary atresia and truncus arteriosus. Patients also included those who underwent a Ross operation. These patients often receive surgical placement of a right ventricular-to-pulmonary artery conduit, which can over time develop stenosis, insufficiency, or both because of calcification, intimal proliferation, and graft degeneration.

Multiple conduit reoperations to restore right ventricular outflow tract function are usually needed over a patient’s lifetime because of conduit degeneration. This makes a transcatheter procedure in a child or adolescent an attractive option because the prosthetic conduit will need replacement relatively quickly, and the transcatheter approach avoids an episode of open-heart surgery.

The Melody system is not the only transcatheter option for treating a leak or stenosis in a right ventricular outflow tract. The Sapien XT Transcatheter Heart Valve, marketed by Edwards, has FDA labeling for replacement of a dysfunctional right ventricular outflow tract.

Because the Sapien XT system was designed for replacing an aortic valve it’s challenging to place the conduit in the pulmonary valve position, Dr. Armstrong said. Operators find the Sapien 3 valve, a more modern design of the XT model that’s also primarily intended for aortic valve replacement, easier to position than the XT for pulmonary valve replacement, but Sapien 3 does not have FDA labeling for the right ventricular outflow tract indication. The Sapien valves are attractive because they don’t fracture, but Melody is easier to place and operators can reduce the fracture risk by prestenting, she noted.

Overall, the 5-year results from the postapproval study represented success, because 78% of patients who received the Melody device avoided any further interventions during follow-up. “That’s a big deal to a 12, 15, or 18 year old,” said Dr. Armstrong. “A surgically placed valve won’t last long in a teen, so it’s nice to do something noninvasively. It’s great if you can delay surgery for a few years” and avoid having the patient grow out of a surgically placed conduit or developing lots of calcification in the conduit during a growth spurt.

The postapproval study was funded by Medtronic, the company that sells the Melody valve. Dr. Armstrong has received research funding from Medtronic as well as Abbott, Edwards, and Siemens, and she has been a consultant to Abbott.

[email protected]

LAS VEGAS – The Melody transcatheter pulmonary valve showed durable efficacy out to 5 years after placement in a mandated U.S. postapproval study that followed 65 patients, a majority of whom were children or teenagers.

Mitchel L. Zoler/MDedge News

After 5 years, 69% of the replacement valve recipients had no valvular hemodynamic dysfunction, compared with a 67% rate among patients enrolled in the original Investigational Device Exemption (IDE) study that led to Food and Drug Administration marketing approval for the Melody valve in 2010 under a humanitarian device exemption. (Full approval followed in 2017.)

The 5-year rate of any reintervention, including explants, was 78% in the postapproval study, again similar to the 76% rate reported in the IDE study after a median 4.5 year follow-up (Circulation. 2015 Jun 2;131[22]:1960-70), Aimee K. Armstrong, MD, said at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.

The new 5-year postapproval study findings “confirm that the hemodynamic effectiveness achieved by real-world providers is equivalent to the historical control established in the IDE study,” concluded Dr. Armstrong, professor of pediatrics at the Ohio State University and director of cardiac catheterization and interventional therapies at Nationwide Children’s Hospital, both in Columbus.

The postapproval study ran at 10 U.S. centers, none of which were among the five U.S. centers that ran the IDE study. Today, the Melody transcatheter pulmonary valve “is very commonly used” at many additional U.S. sites, Dr. Armstrong said in an interview. And the outcomes achieved using the valve likely surpass those seen in the IDE and postapproval studies because of innovations in technique, such as more routine use of “prestenting,” placing a stent in the vascular site where the pulmonary valve conduit will sit to address stenosis at this location and prevent subsequent conduit fracture (JACC Cardiovasc Interv. 2017 Sep;10[17]:1760-2).

“In 2010 [when the postapproval study began], we didn’t understand the importance of prestenting the way we do now. In 2010, I did not prestent every patient; now I do,” she said. The results reported by Dr. Armstrong included a 5% cumulative rate of major stent fractures in the Melody devices.

The postapproval study results also documented a concerning 4.5% annualized incidence of endocarditis among pulmonary valve recipients, with a nearly 300% increased rate of endocarditis among patients aged 12 years or younger, compared with older patients. Dr. Armstrong cautioned that this age association may be confounded by other factors, such as a residual pressure gradient in the right ventricular outflow tract of 15 mm Hg or greater. “We are discovering that we need to reduce the pressure gradient as much as we can, to perhaps less than 15 mm Hg, to reduce endocarditis, and that is something we did not know even a year ago. Practice is still evolving.”

The Melody Transcatheter Pulmonary Valve Postapproval Study performed cardiac catheterization for valve placement in 121 patients, and successfully implanted the valve for at least 24 hours in 99 of these patients. Patient age ranged from 5 to 45 years, with a median of 17 years; two-thirds were boys or men. The median age of the patients in the postapproval study was about 2 years younger than in the IDE study. Dr. Armstrong and her associates had previously published the 1-year outcomes from the postapproval study (JACC Cardiovasc Interv. 2014 Nov;7[11]:1254-62).

The enrolled patients usually needed a new right ventricular outflow tract because of a congenital heart defect, such as tetralogy of Fallot with pulmonary atresia and truncus arteriosus. Patients also included those who underwent a Ross operation. These patients often receive surgical placement of a right ventricular-to-pulmonary artery conduit, which can over time develop stenosis, insufficiency, or both because of calcification, intimal proliferation, and graft degeneration.

Multiple conduit reoperations to restore right ventricular outflow tract function are usually needed over a patient’s lifetime because of conduit degeneration. This makes a transcatheter procedure in a child or adolescent an attractive option because the prosthetic conduit will need replacement relatively quickly, and the transcatheter approach avoids an episode of open-heart surgery.

The Melody system is not the only transcatheter option for treating a leak or stenosis in a right ventricular outflow tract. The Sapien XT Transcatheter Heart Valve, marketed by Edwards, has FDA labeling for replacement of a dysfunctional right ventricular outflow tract.

Because the Sapien XT system was designed for replacing an aortic valve it’s challenging to place the conduit in the pulmonary valve position, Dr. Armstrong said. Operators find the Sapien 3 valve, a more modern design of the XT model that’s also primarily intended for aortic valve replacement, easier to position than the XT for pulmonary valve replacement, but Sapien 3 does not have FDA labeling for the right ventricular outflow tract indication. The Sapien valves are attractive because they don’t fracture, but Melody is easier to place and operators can reduce the fracture risk by prestenting, she noted.

Overall, the 5-year results from the postapproval study represented success, because 78% of patients who received the Melody device avoided any further interventions during follow-up. “That’s a big deal to a 12, 15, or 18 year old,” said Dr. Armstrong. “A surgically placed valve won’t last long in a teen, so it’s nice to do something noninvasively. It’s great if you can delay surgery for a few years” and avoid having the patient grow out of a surgically placed conduit or developing lots of calcification in the conduit during a growth spurt.

The postapproval study was funded by Medtronic, the company that sells the Melody valve. Dr. Armstrong has received research funding from Medtronic as well as Abbott, Edwards, and Siemens, and she has been a consultant to Abbott.

[email protected]

LAS VEGAS – The Melody transcatheter pulmonary valve showed durable efficacy out to 5 years after placement in a mandated U.S. postapproval study that followed 65 patients, a majority of whom were children or teenagers.

Mitchel L. Zoler/MDedge News

After 5 years, 69% of the replacement valve recipients had no valvular hemodynamic dysfunction, compared with a 67% rate among patients enrolled in the original Investigational Device Exemption (IDE) study that led to Food and Drug Administration marketing approval for the Melody valve in 2010 under a humanitarian device exemption. (Full approval followed in 2017.)

The 5-year rate of any reintervention, including explants, was 78% in the postapproval study, again similar to the 76% rate reported in the IDE study after a median 4.5 year follow-up (Circulation. 2015 Jun 2;131[22]:1960-70), Aimee K. Armstrong, MD, said at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.

The new 5-year postapproval study findings “confirm that the hemodynamic effectiveness achieved by real-world providers is equivalent to the historical control established in the IDE study,” concluded Dr. Armstrong, professor of pediatrics at the Ohio State University and director of cardiac catheterization and interventional therapies at Nationwide Children’s Hospital, both in Columbus.

The postapproval study ran at 10 U.S. centers, none of which were among the five U.S. centers that ran the IDE study. Today, the Melody transcatheter pulmonary valve “is very commonly used” at many additional U.S. sites, Dr. Armstrong said in an interview. And the outcomes achieved using the valve likely surpass those seen in the IDE and postapproval studies because of innovations in technique, such as more routine use of “prestenting,” placing a stent in the vascular site where the pulmonary valve conduit will sit to address stenosis at this location and prevent subsequent conduit fracture (JACC Cardiovasc Interv. 2017 Sep;10[17]:1760-2).

“In 2010 [when the postapproval study began], we didn’t understand the importance of prestenting the way we do now. In 2010, I did not prestent every patient; now I do,” she said. The results reported by Dr. Armstrong included a 5% cumulative rate of major stent fractures in the Melody devices.

The postapproval study results also documented a concerning 4.5% annualized incidence of endocarditis among pulmonary valve recipients, with a nearly 300% increased rate of endocarditis among patients aged 12 years or younger, compared with older patients. Dr. Armstrong cautioned that this age association may be confounded by other factors, such as a residual pressure gradient in the right ventricular outflow tract of 15 mm Hg or greater. “We are discovering that we need to reduce the pressure gradient as much as we can, to perhaps less than 15 mm Hg, to reduce endocarditis, and that is something we did not know even a year ago. Practice is still evolving.”

The Melody Transcatheter Pulmonary Valve Postapproval Study performed cardiac catheterization for valve placement in 121 patients, and successfully implanted the valve for at least 24 hours in 99 of these patients. Patient age ranged from 5 to 45 years, with a median of 17 years; two-thirds were boys or men. The median age of the patients in the postapproval study was about 2 years younger than in the IDE study. Dr. Armstrong and her associates had previously published the 1-year outcomes from the postapproval study (JACC Cardiovasc Interv. 2014 Nov;7[11]:1254-62).

The enrolled patients usually needed a new right ventricular outflow tract because of a congenital heart defect, such as tetralogy of Fallot with pulmonary atresia and truncus arteriosus. Patients also included those who underwent a Ross operation. These patients often receive surgical placement of a right ventricular-to-pulmonary artery conduit, which can over time develop stenosis, insufficiency, or both because of calcification, intimal proliferation, and graft degeneration.

Multiple conduit reoperations to restore right ventricular outflow tract function are usually needed over a patient’s lifetime because of conduit degeneration. This makes a transcatheter procedure in a child or adolescent an attractive option because the prosthetic conduit will need replacement relatively quickly, and the transcatheter approach avoids an episode of open-heart surgery.

The Melody system is not the only transcatheter option for treating a leak or stenosis in a right ventricular outflow tract. The Sapien XT Transcatheter Heart Valve, marketed by Edwards, has FDA labeling for replacement of a dysfunctional right ventricular outflow tract.

Because the Sapien XT system was designed for replacing an aortic valve it’s challenging to place the conduit in the pulmonary valve position, Dr. Armstrong said. Operators find the Sapien 3 valve, a more modern design of the XT model that’s also primarily intended for aortic valve replacement, easier to position than the XT for pulmonary valve replacement, but Sapien 3 does not have FDA labeling for the right ventricular outflow tract indication. The Sapien valves are attractive because they don’t fracture, but Melody is easier to place and operators can reduce the fracture risk by prestenting, she noted.

Overall, the 5-year results from the postapproval study represented success, because 78% of patients who received the Melody device avoided any further interventions during follow-up. “That’s a big deal to a 12, 15, or 18 year old,” said Dr. Armstrong. “A surgically placed valve won’t last long in a teen, so it’s nice to do something noninvasively. It’s great if you can delay surgery for a few years” and avoid having the patient grow out of a surgically placed conduit or developing lots of calcification in the conduit during a growth spurt.

The postapproval study was funded by Medtronic, the company that sells the Melody valve. Dr. Armstrong has received research funding from Medtronic as well as Abbott, Edwards, and Siemens, and she has been a consultant to Abbott.

[email protected]

Here are 5 articles from the June issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Expert: There’s no single treatment for fibromyalgia

To take the posttest, go to: https://bit.ly/2EAI5v1
Expires February 3, 2020

2. Mood and behavior are different targets for irritability in children

To take the posttest, go to: https://bit.ly/2wpLS9X
Expires February 6, 2020

3. Biomarkers predict VTE risk with menopausal oral hormone therapy

To take the posttest, go to: https://bit.ly/2JKEQFC
Expires February 6, 2020

4. Mild aerobic exercise speeds sports concussion recovery

To take the posttest, go to: https://bit.ly/30RuYiE
Expires February 4, 2020

5. For CABG, multiple and single arterial grafts show no survival difference

To take the posttest, go to: https://bit.ly/2wtiCiF
Expires January 31, 2020

Here are 5 articles from the June issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Expert: There’s no single treatment for fibromyalgia

To take the posttest, go to: https://bit.ly/2EAI5v1
Expires February 3, 2020

2. Mood and behavior are different targets for irritability in children

To take the posttest, go to: https://bit.ly/2wpLS9X
Expires February 6, 2020

3. Biomarkers predict VTE risk with menopausal oral hormone therapy

To take the posttest, go to: https://bit.ly/2JKEQFC
Expires February 6, 2020

4. Mild aerobic exercise speeds sports concussion recovery

To take the posttest, go to: https://bit.ly/30RuYiE
Expires February 4, 2020

5. For CABG, multiple and single arterial grafts show no survival difference

To take the posttest, go to: https://bit.ly/2wtiCiF
Expires January 31, 2020

Here are 5 articles from the June issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Expert: There’s no single treatment for fibromyalgia

To take the posttest, go to: https://bit.ly/2EAI5v1
Expires February 3, 2020

2. Mood and behavior are different targets for irritability in children

To take the posttest, go to: https://bit.ly/2wpLS9X
Expires February 6, 2020

3. Biomarkers predict VTE risk with menopausal oral hormone therapy

To take the posttest, go to: https://bit.ly/2JKEQFC
Expires February 6, 2020

4. Mild aerobic exercise speeds sports concussion recovery

To take the posttest, go to: https://bit.ly/30RuYiE
Expires February 4, 2020

5. For CABG, multiple and single arterial grafts show no survival difference

To take the posttest, go to: https://bit.ly/2wtiCiF
Expires January 31, 2020

CHICAGO – Administering CPX-351 prior to a three-drug regimen produced a high response rate in pediatric patients with acute myeloid leukemia (AML) in first relapse.

Jennifer Smith/MDedge News

In a phase 1/2 trial, CPX-351 followed by fludarabine, cytarabine, and filgrastim (FLAG) produced an overall response rate of 81%, and 70% of responders had their best response while receiving CPX-351.

“This is the best response rate published in North America for those [pediatric AML patients] in first relapse,” said Todd Cooper, DO, of Seattle Children’s Hospital in Washington.

Dr. Cooper presented results from the phase 1/2 AAML1421 trial (NCT02642965) at the annual meeting of the American Society of Clinical Oncology.

The primary objective of phase 1 was to determine the recommended phase 2 dose and toxicities of CPX-351, a liposomal preparation of cytarabine and daunorubicin. The primary objective of phase 2 was to assess the best response in patients who received CPX-351 in cycle 1 and FLAG in cycle 2.

The trial enrolled 38 AML patients, 6 in the dose-finding phase and 32 in the efficacy phase. The patients’ median age at study entry was 11.91 years (range, 1.81-21.5). Most patients (88.9%) had CNS 1 disease, and most (73.7%) had not received a transplant.

Half of patients had a first complete response (CR) that lasted 180 to 365 days, 13.2% had a first CR lasting less than 180 days, and 36.8% had a first CR lasting more than 1 year.

Dosing and toxicity

During the dose-finding portion of the study, the first dose level of CPX-351 was 135 units/m² on days 1, 3, and 5. There was one dose-limiting toxicity — grade 3 decrease in ejection fraction — so 135 units/m² was deemed the recommended phase 2 dose.

The most common grade 3 or higher adverse events observed with CPX-351 in cycle 1 were infections and infestations (47.4%), febrile neutropenia (44.7%), maculopapular rash (39.5%), and prolonged QT interval (18.4%).

The most common grade 3 or higher adverse events observed with FLAG in cycle 2 were febrile neutropenia (23.1%), prolonged QT interval (23.1%), and infections and infestations (19.2%).

Response and survival

There were 37 patients evaluable for response. The overall response rate was defined as CR plus CR without platelet recovery (CRp) plus CR with incomplete hematologic recovery (CRi).

The overall response rate was 81.1% (n = 30), which included 20 CRs (54.1%), 5 CRps (13.5%), and 5 CRis (13.5%). Five patients had a partial response (13.5%), and two patients had treatment failure (5.4%).

During CPX-351 treatment (n = 37), the CR rate was 37.8% (n = 14), the CRp rate was 5.4% (n = 2), and the CRi rate was 32.4% (n = 12).

During FLAG treatment (n = 27), the CR rate was 48.1% (n = 13), the CRp rate was 25.9% (n = 7), and the CRi rate was 7.4% (n = 2).

Of the 25 patients who achieved a CR or CRp at any time, 21 (84%) were minimal residual disease negative by flow cytometry. Twelve patients were minimal residual disease negative after cycle 1.

Most patients who achieved a CRi or better (83.3%) went on to hematopoietic stem cell transplant.

The 2-year overall survival was 47% for all patients and 60% for responders. None of the non-responders were still alive 2 years after therapy.

“The results certainly warrant a phase 3 study of CPX-351,” Dr. Cooper said. “In fact, it is the lead molecule that’s going to be incorporated into the next COG phase 3 study.”

AAML1421 was sponsored by the Children’s Oncology Group in collaboration with the National Cancer Institute. Dr. Cooper disclosed relationships with Juno Therapeutics and Celgene.

[email protected]

SOURCE: Cooper TM et al. ASCO 2019. Abstract 10003.

CHICAGO – Administering CPX-351 prior to a three-drug regimen produced a high response rate in pediatric patients with acute myeloid leukemia (AML) in first relapse.

Jennifer Smith/MDedge News

In a phase 1/2 trial, CPX-351 followed by fludarabine, cytarabine, and filgrastim (FLAG) produced an overall response rate of 81%, and 70% of responders had their best response while receiving CPX-351.

“This is the best response rate published in North America for those [pediatric AML patients] in first relapse,” said Todd Cooper, DO, of Seattle Children’s Hospital in Washington.

Dr. Cooper presented results from the phase 1/2 AAML1421 trial (NCT02642965) at the annual meeting of the American Society of Clinical Oncology.

The primary objective of phase 1 was to determine the recommended phase 2 dose and toxicities of CPX-351, a liposomal preparation of cytarabine and daunorubicin. The primary objective of phase 2 was to assess the best response in patients who received CPX-351 in cycle 1 and FLAG in cycle 2.

The trial enrolled 38 AML patients, 6 in the dose-finding phase and 32 in the efficacy phase. The patients’ median age at study entry was 11.91 years (range, 1.81-21.5). Most patients (88.9%) had CNS 1 disease, and most (73.7%) had not received a transplant.

Half of patients had a first complete response (CR) that lasted 180 to 365 days, 13.2% had a first CR lasting less than 180 days, and 36.8% had a first CR lasting more than 1 year.

Dosing and toxicity

During the dose-finding portion of the study, the first dose level of CPX-351 was 135 units/m² on days 1, 3, and 5. There was one dose-limiting toxicity — grade 3 decrease in ejection fraction — so 135 units/m² was deemed the recommended phase 2 dose.

The most common grade 3 or higher adverse events observed with CPX-351 in cycle 1 were infections and infestations (47.4%), febrile neutropenia (44.7%), maculopapular rash (39.5%), and prolonged QT interval (18.4%).

The most common grade 3 or higher adverse events observed with FLAG in cycle 2 were febrile neutropenia (23.1%), prolonged QT interval (23.1%), and infections and infestations (19.2%).

Response and survival

There were 37 patients evaluable for response. The overall response rate was defined as CR plus CR without platelet recovery (CRp) plus CR with incomplete hematologic recovery (CRi).

The overall response rate was 81.1% (n = 30), which included 20 CRs (54.1%), 5 CRps (13.5%), and 5 CRis (13.5%). Five patients had a partial response (13.5%), and two patients had treatment failure (5.4%).

During CPX-351 treatment (n = 37), the CR rate was 37.8% (n = 14), the CRp rate was 5.4% (n = 2), and the CRi rate was 32.4% (n = 12).

During FLAG treatment (n = 27), the CR rate was 48.1% (n = 13), the CRp rate was 25.9% (n = 7), and the CRi rate was 7.4% (n = 2).

Of the 25 patients who achieved a CR or CRp at any time, 21 (84%) were minimal residual disease negative by flow cytometry. Twelve patients were minimal residual disease negative after cycle 1.

Most patients who achieved a CRi or better (83.3%) went on to hematopoietic stem cell transplant.

The 2-year overall survival was 47% for all patients and 60% for responders. None of the non-responders were still alive 2 years after therapy.

“The results certainly warrant a phase 3 study of CPX-351,” Dr. Cooper said. “In fact, it is the lead molecule that’s going to be incorporated into the next COG phase 3 study.”

AAML1421 was sponsored by the Children’s Oncology Group in collaboration with the National Cancer Institute. Dr. Cooper disclosed relationships with Juno Therapeutics and Celgene.

[email protected]

SOURCE: Cooper TM et al. ASCO 2019. Abstract 10003.

CHICAGO – Administering CPX-351 prior to a three-drug regimen produced a high response rate in pediatric patients with acute myeloid leukemia (AML) in first relapse.

Jennifer Smith/MDedge News

In a phase 1/2 trial, CPX-351 followed by fludarabine, cytarabine, and filgrastim (FLAG) produced an overall response rate of 81%, and 70% of responders had their best response while receiving CPX-351.

“This is the best response rate published in North America for those [pediatric AML patients] in first relapse,” said Todd Cooper, DO, of Seattle Children’s Hospital in Washington.

Dr. Cooper presented results from the phase 1/2 AAML1421 trial (NCT02642965) at the annual meeting of the American Society of Clinical Oncology.

The primary objective of phase 1 was to determine the recommended phase 2 dose and toxicities of CPX-351, a liposomal preparation of cytarabine and daunorubicin. The primary objective of phase 2 was to assess the best response in patients who received CPX-351 in cycle 1 and FLAG in cycle 2.

The trial enrolled 38 AML patients, 6 in the dose-finding phase and 32 in the efficacy phase. The patients’ median age at study entry was 11.91 years (range, 1.81-21.5). Most patients (88.9%) had CNS 1 disease, and most (73.7%) had not received a transplant.

Half of patients had a first complete response (CR) that lasted 180 to 365 days, 13.2% had a first CR lasting less than 180 days, and 36.8% had a first CR lasting more than 1 year.

Dosing and toxicity

During the dose-finding portion of the study, the first dose level of CPX-351 was 135 units/m² on days 1, 3, and 5. There was one dose-limiting toxicity — grade 3 decrease in ejection fraction — so 135 units/m² was deemed the recommended phase 2 dose.

The most common grade 3 or higher adverse events observed with CPX-351 in cycle 1 were infections and infestations (47.4%), febrile neutropenia (44.7%), maculopapular rash (39.5%), and prolonged QT interval (18.4%).

The most common grade 3 or higher adverse events observed with FLAG in cycle 2 were febrile neutropenia (23.1%), prolonged QT interval (23.1%), and infections and infestations (19.2%).

Response and survival

There were 37 patients evaluable for response. The overall response rate was defined as CR plus CR without platelet recovery (CRp) plus CR with incomplete hematologic recovery (CRi).

The overall response rate was 81.1% (n = 30), which included 20 CRs (54.1%), 5 CRps (13.5%), and 5 CRis (13.5%). Five patients had a partial response (13.5%), and two patients had treatment failure (5.4%).

During CPX-351 treatment (n = 37), the CR rate was 37.8% (n = 14), the CRp rate was 5.4% (n = 2), and the CRi rate was 32.4% (n = 12).

During FLAG treatment (n = 27), the CR rate was 48.1% (n = 13), the CRp rate was 25.9% (n = 7), and the CRi rate was 7.4% (n = 2).

Of the 25 patients who achieved a CR or CRp at any time, 21 (84%) were minimal residual disease negative by flow cytometry. Twelve patients were minimal residual disease negative after cycle 1.

Most patients who achieved a CRi or better (83.3%) went on to hematopoietic stem cell transplant.

The 2-year overall survival was 47% for all patients and 60% for responders. None of the non-responders were still alive 2 years after therapy.

“The results certainly warrant a phase 3 study of CPX-351,” Dr. Cooper said. “In fact, it is the lead molecule that’s going to be incorporated into the next COG phase 3 study.”

AAML1421 was sponsored by the Children’s Oncology Group in collaboration with the National Cancer Institute. Dr. Cooper disclosed relationships with Juno Therapeutics and Celgene.

[email protected]

SOURCE: Cooper TM et al. ASCO 2019. Abstract 10003.

Managing agitation—verbal and/or motor restlessness that often is accompanied by irritability and a predisposition to aggression or violence—can be challenging in any patient, but particularly so in children and adolescents. In the United States, the prevalence of children and adolescents presenting to an emergency department (ED) for treatment of psychiatric symptoms, including agitation, has been on the rise.^1,2

Similar to the multitude of causes of fever, agitation among children and adolescents has many possible causes.³ Because agitation can pose a risk for harm to others and/or self, it is important to manage it proactively. Other than studies that focus on agitation in pediatric anesthesia, there is a dearth of studies examining agitation and its treatment in children and adolescents. There is also a scarcity of training in the management of acute agitation in children and adolescents. In a 2017 survey of pediatric hospitalists and consultation-liaison psychiatrists at 38 academic children’s hospitals in North America, approximately 60% of respondents indicated that they had received no training in the evaluation or management of pediatric acute agitation.⁴ In addition, approximately 54% of participants said they did not screen for risk factors for pediatric agitation, even though 84% encountered the condition at least once a month, and as often as weekly.⁴

This article reviews evidence on the causes and treatments of agitation in children and adolescents. For the purposes of this review, child refers to a patient age 6 to 12, and adolescent refers to a patient age 13 to 17.

Identifying the cause

Addressing the underlying cause of agitation is essential. It’s also important to manage acute agitation while the underlying cause is being investigated in a way that does not jeopardize the patient’s emotional or physical safety.

Agitation in children or teens can be due to psychiatric causes such as autism, attention-deficit/hyperactivity disorder (ADHD), or posttraumatic stress disorder (PTSD), or due to medical conditions such as delirium, traumatic brain injury, or other conditions (Table 1).

In a 2005 study of 194 children with agitation in a pediatric post-anesthesia care unit, pain (27%) and anxiety (25%) were found to be the most common causes of agitation.³ Anesthesia-related agitation was a less common cause (11%). Physiologic anomalies were found to be the underlying cause of agitation in only 3 children in this study, but were undiagnosed for a prolonged period in 2 of these 3 children, which highlights the importance of a thorough differential diagnosis in the management of agitation in children.³

Assessment of an agitated child should include a comprehensive history, physical exam, and laboratory testing as indicated. When a pediatric patient comes to the ED with a chief presentation of agitation, a thorough medical and psychiatric assessment should be performed. For patients with a history of psychiatric diagnoses, do not assume that the cause of agitation is psychiatric.

Continue to: Psychiatric causes

 

 

Psychiatric causes

Autism spectrum disorder. Children and teens with autism often feel overwhelmed due to transitions, changes, and/or sensory overload. This sensory overload may be in response to relatively subtle sensory stimuli, so it may not always be apparent to parents or others around them.

Research suggests that in general, the ability to cope effectively with emotions is difficult without optimal language development. Due to cognitive/language delays and a related lack of emotional attunement and limited skills in recognizing, expressing, or coping with emotions, difficult emotions in children and adolescents with autism can manifest as agitation.

Attention-deficit/hyperactivity disorder. Children with ADHD may be at a higher risk for agitation, in part due to poor impulse control and limited coping skills. In addition, chronic negative feedback (from parents, teachers, or both) may contribute to low self-esteem, mood symptoms, defiance, and/or other behavioral difficulties. In addition to standard pharmacotherapy for ADHD, treatment involves parent behavior modification training. Setting firm yet empathic limits, “picking battles,” and implementing a developmentally appropriate behavioral plan to manage disruptive behavior in children or adolescents with ADHD can go a long way in helping to prevent the emergence of agitation.

Posttraumatic stress disorder. In some young children, new-onset, unexplained agitation may be the only sign of abuse or trauma. Children who have undergone trauma tend to experience confusion and distress. This may manifest as agitation or aggression, or other symptoms such as increased anxiety or nightmares.⁵ Trauma may be in the form of witnessing violence (domestic or other); experiencing physical, sexual, and/or emotional abuse; or witnessing/experiencing other significant threats to the safety of self and/or loved ones. Re-establishing (or establishing) a sense of psychological and physical safety is paramount in such patients.⁶ Psychotherapy is the first-line modality of treatment in children and adolescents with PTSD.⁶ In general, there is a scarcity of research on medication treatments for PTSD symptoms among children and adolescents.⁶

Oppositional defiant disorder/conduct disorder. Oppositional defiant disorder (ODD) can be comorbid with ADHD. The diagnosis of ODD requires a pervasive pattern of anger, defiance, vindictiveness, and hostility, particularly towards authority figures. However, these symptoms need to be differentiated from the normal range of childhood behavior. Occasionally, children learn to cope maladaptively through disruptive behavior or agitation. Although a parent or caregiver may see this behavior as intentionally malevolent, in a child with limited coping skills (whether due to young age, developmental/cognitive/language/learning delays, or social communication deficits) or one who has witnessed frequent agitation or aggression in the family environment, agitation and disruptive behavior may be a maladaptive form of coping. Thus, diligence needs to be exercised in the diagnosis of ODD and in understanding the psychosocial factors affecting the child, particularly because impulsiveness and uncooperativeness on their own have been found to be linked to greater likelihood of prescription of psychotropic medications from multiple classes.⁷ Family-based interventions, particularly parent training, family therapy, and age-appropriate child skills training, are of prime importance in managing this condition.⁸ Research shows that a shortage of resources, system issues, and cultural roadblocks in implementing family-based psychosocial interventions also can contribute to the increased use of psychotropic medications for aggression in children and teens with ODD, conduct disorder, or ADHD.⁸ The astute clinician needs to be cognizant of this before prescribing.

Continue to: Hallucinations/psychosis

Hallucinations/psychosis. Hallucinations (whether from psychiatric or medical causes) are significantly associated with agitation.⁹ In particular, auditory command hallucinations have been linked to agitation. Command hallucinations in children and adolescents may be secondary to early-onset schizophrenia; however, this diagnosis is rare.¹⁰ Hallucinations can also be an adverse effect of amphetamine-based stimulant medications in children and adolescents. Visual hallucinations are most often a sign of an underlying medical disorder such as delirium, occipital lobe mass/infection, or drug intoxication or withdrawal. Hallucinations need to be distinguished from the normal, imaginative play of a young child.¹⁰

Bipolar mania. In adults, bipolar disorder is a primary psychiatric cause of agitation. In children and adolescents, the diagnosis of bipolar disorder can be complex and requires careful and nuanced history-taking. The risks of agitation are greater with bipolar disorder than with unipolar depression.^11,12

Disruptive mood dysregulation disorder. Prior to DSM-5, many children and adolescents with chronic, non-episodic irritability and severe outbursts out of proportion to the situation or stimuli were given a diagnosis of bipolar disorder. These symptoms, in combination with other symptoms, are now considered part of disruptive mood dysregulation disorder when severe outbursts in a child or adolescent occur 3 to 4 times a week consistently, for at least 1 year. The diagnosis of disruptive mood dysregulation disorder requires ruling out other psychiatric and medical conditions, particularly ADHD.¹³

Substance intoxication/withdrawal. Intoxication or withdrawal from substances such as alcohol, stimulant medications, opioids, methamphetamines, and other agents can lead to agitation. This is more likely to occur among adolescents than children.¹⁴

Adjustment disorder. Parental divorce, especially if it is conflictual, or other life stressors, such as experiencing a move or frequent moves, may contribute to the development of agitation in children and adolescents.

Continue to: Depression

Depression. In children and adolescents, depression can manifest as anger or irritability, and occasionally as agitation.

Medical causes

Delirium. Refractory agitation is often a manifestation of delirium in children and adolescents.¹⁵ If unrecognized and untreated, delirium can be fatal.¹⁶ Therefore, it is imperative that clinicians routinely assess for delirium in any patient who presents with agitation.

Because a patient with delirium often presents with agitation and visual or auditory hallucinations, the medical team may tend to assume these symptoms are secondary to a psychiatric disorder. In this case, the role of the consultation-liaison psychiatrist is critical for guiding the medical team, particularly to continue a thorough exploration of underlying causes while avoiding polypharmacy. Noise, bright lights, frequent changes in nursing staff or caregivers, anticholinergic or benzodiazepine medications, and frequent changes in schedules should be avoided to prevent delirium from occurring or getting worse.¹⁷ A multidisciplinary team approach is key in identifying the underlying cause and managing delirium in pediatric patients.

Traumatic brain injury. Agitation may be a presenting symptom in youth with traumatic brain injury (TBI).¹⁸ Agitation may present often in the acute recovery phase.¹⁹ There is limited evidence on the efficacy and safety of pharmacotherapy for agitation in pediatric patients with TBI.¹⁸

Autoimmune conditions. In a study of 27 patients with anti-N-methyl-d-aspartate receptor encephalitis, Mohammad et al²⁰ found that agitation was a common symptom.

Continue to: Medication-induced/iatrogenic

Medication-induced/iatrogenic. Agitation can be an adverse effect of medications such as amantadine (often used for TBI),¹⁸ atypical antipsychotics,²¹ selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors.

Infection. Agitation can be a result of encephalitis, meningitis, or other infectious processes.²²

Metabolic conditions. Hepatic or renal failure, diabetic ketoacidosis, and thyroid toxicosis may cause agitation in children or adolescents.²²

Start with nonpharmacologic interventions

Few studies have examined de-escalation techniques in agitated children and adolescents. However, verbal de-escalation is generally viewed as the first-line technique for managing agitation in children and adolescents. When feasible, teaching and modeling developmentally appropriate stress management skills for children and teens can be a beneficial preventative strategy to reduce the incidence and worsening of agitation.²³

Clinicians should refrain from using coercion.²⁴ Coercion could harm the therapeutic alliance, thereby impeding assessment of the underlying causes of agitation, and can be particularly harmful for patients who have a history of trauma or abuse. Even in pediatric patients with no such history, coercion is discouraged due to its punitive connotations and potential to adversely impact a vulnerable child or teen.

Continue to: Establishing a therapeutic rapport...

Establishing a therapeutic rapport with the patient, when feasible, can facilitate smoother de-escalation by offering the patient an outlet to air his/her frustrations and emotions, and by helping the patient feel understood.²⁴ To facilitate this, ensure that the patient’s basic comforts and needs are met, such as access to a warm bed, food, and safety.²⁵

The psychiatrist’s role is to help uncover and address the underlying reason for the patient’s agony or distress. Once the child or adolescent has calmed, explore potential triggers or causes of the agitation.

There has been a significant move away from the use of restraints for managing agitation in children and adolescents.²⁶ Restraints have a psychologically traumatizing effect,²⁷ and have been linked to life-threatening injuries and death in children.²⁴

Pharmacotherapy: Proceed with caution

There are no FDA-approved medications for the treatment of agitation in the general pediatric population, and any medication use in this population is off-label. There is also a dearth of research examining the safety and efficacy of using psychotropic medications for agitation in pediatric patients. Because children and adolescents are more susceptible to adverse effects and risks associated with the use of psychotropic medications, special caution is warranted. In general, pharmacologic interventions are not recommended without the use of psychotherapy-based modalities.

In the past, the aim of using medications to treat patients with agitation was to put the patient to sleep.²⁵ This practice did not help clinicians to assess for underlying causes, and was often accompanied by a greater risk of adverse effects and reactions.²⁴ Therefore, the goal of medication treatment for agitation is to help calm the patient instead of inducing sleep.²⁵

Continue to: Pharmacotherapy should...

Pharmacotherapy should be used only when behavioral interventions have been unsuccessful. Key considerations for using psychotropic medications to address agitation in children and adolescents are summarized in Table 2.²⁵

Antipsychotics, particularly second-generation antipsychotics (SGAs), have been commonly used to manage acute agitation in children and adolescents, and there has been an upswing in the use of these medications in the United States in the last several years.²⁸ Research indicates that males, children and adolescents in foster care, and those with Medicaid have been the more frequent youth recipients of SGAs.²⁹ Of particular concern is the prevalence of antipsychotic use among children younger than age 6. In the last few decades, there has been an increase in the prescription of antipsychotics for children younger than age 6, particularly for disruptive behavior and aggression.³⁰ In a study of preschool-age Medicaid patients in Kentucky, 70,777 prescriptions for SGAs were given to 6,915 children <6 years of age; 73% of these prescriptions were for male patients.³⁰ Because there is a lack of controlled studies examining the safety and efficacy of SGAs among children and adolescents, especially with long-term use, further research is needed and caution is warranted.²⁸

The FDA has approved risperidone (for patients age 5 to 16) and oral aripiprazole (for patients age 6 to 17) for treating irritability related to autism spectrum disorder; irritability can contribute to or exacerbate agitation. The FDA has also approved several antipsychotic medications for treating schizophrenia or bipolar disorder in adolescents of varying ages. However, SGAs have also been found to be used commonly among young patients who do not meet criteria for autism, schizophrenia, or bipolar disorder. Aggression is the most common symptom for which SGAs are used among the pediatric population.²⁹ Careful and judicious weighing of the risks and benefits is warranted before using antipsychotic medications in a child or adolescent.

Externalizing disorders among children and adolescents tend to get treated with antipsychotics.²⁸ A Canadian study examining records of 6,916 children found that most children who had been prescribed risperidone received it for ADHD or conduct disorder, and most patients had not received laboratory testing for monitoring the antipsychotic medication they were taking.³¹ In a 2018 study examining medical records of 120 pediatric patients who presented to an ED in British Columbia with agitation, antipsychotics were the most commonly used medications for patients with autism spectrum disorder; most patients received at least 1 dose.¹⁴

For children and adolescents with agitation or aggression who were admitted to inpatient units, IM olanzapine and ziprasidone were found to exhibit similar efficacy when used to treat agitation.^14,21,32

Continue to: In case reports...

In case reports, a combination of olanzapine with CNS-suppressing agents has resulted in death. Therefore, do not combine olanzapine with agents such as benzodiazepines.²⁵ In a patient with a likely medical source of agitation, insufficient evidence exists to support the use of olanzapine, and additional research is needed.²⁵

Low-dose haloperidol has been found to be effective for delirium-related agitation in pediatric studies.¹⁵ Before initiating an antipsychotic for any child or adolescent, review the patient’s family history for reports of early cardiac death and the patient’s own history of cardiac symptoms, palpitations, syncope, or prolonged QT interval. Monitor for QT prolongation. Among commonly used antipsychotics, the risk of QT prolongation is higher with IV administration of haloperidol and with ziprasidone. Studies show that compared with oral or IM haloperidol, the IV formulation has a higher risk of increased QTc interval, torsades de pointes, and sudden death.³³ The FDA recommends continuous cardiac monitoring in adults receiving IV haloperidol. Data for its safety in children and adolescents are insufficient.

A few studies have found risperidone to be efficacious for treating ODD and conduct disorder; however, this use is off-label, and its considerable adverse effect and risk profile needs to be weighed against the potential benefit.⁸

Antipsychotic polypharmacy should be avoided because of the higher risk of adverse effects and interactions, and a lack of robust, controlled studies evaluating the safety of using antipsychotics for non-FDA-approved indications in children and adolescents.⁷ All patients who receive antipsychotics require monitoring for extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome, orthostatic hypotension, sedation, metabolic syndrome, and other potential adverse effects. Patients receiving risperidone need to have their prolactin levels monitored periodically, and their parents should be made aware of the potential for hyperprolactinemia and other adverse effects. Aripiprazole and quetiapine may increase the risk of suicidality.

Antiepileptics. A meta-analysis of 7 randomized controlled trials examining the use of antiepileptic medications (valproate, lamotrigine, levetiracetam, and topiramate) in children with autism spectrum disorder found no significant difference between placebo and these medications for addressing agitation.³⁴

Continue to: In a retrospective case series...

In a retrospective case series of 30 pedi­atric patients with autism spectrum disorder who were given oxcarbazepine, Douglas et al³⁵ found that 47% of participants experienced significant improvement in irritability/agitation. However, 23% of patients reported significant adverse effects leading to discontinuation. Insufficient evidence exists for the safety and efficacy of oxcarbazepine in this population.³⁵

Benzodiazepines. The use of benzodiazepines in pediatric patients has been associated with paradoxical disinhibition reactions, particularly in children with autism and other developmental or cognitive disabilities or delays.²¹ There is a lack of data on the safety and efficacy of long-term use of benzodiazepines in children, especially in light of these patients’ developing brains, the risk of cognitive impairment, and the potential for dependence with long-term use. Despite this, some studies show that the use of benzodiazepines is fairly common among pediatric patients who present to the ED with agitation.¹⁴ In a recent retrospective study, Kendrick et al¹⁴ found that among pediatric patients with agitation who were brought to the ED, benzodiazepines were the most commonly prescribed medications.

Other medications. Clonidine and guanfacine have been used off-label to treat agitation in children and adolescents, particularly among those with ADHD or autism. Some small pediatric trials have also shown their benefit in decreasing symptoms of aggression, impulsivity, and hyper-arousal in PTSD.³⁶ In addition to adverse effects that include but are not limited to lowered blood pressure, bradycardia, and risk of atrioventricular block, clinicians need to be vigilant for potentially serious rebound hypertension that may occur if doses of these medications are missed; this risk is greater with clonidine.

Diphenhydramine, in both oral and IM forms, has been used to treat agitation in children,³² but has also been associated with a paradoxical disinhibition reaction in pediatric patients²¹ and therefore should be used only sparingly and with caution. Diphenhydramine has anticholinergic properties, and may worsen delirium.¹⁵ Stimulant medications can help aggressive behavior in children and adolescents with ADHD.³⁷

Bottom Line

Agitation among children and adolescents has many possible causes. A combination of a comprehensive assessment and evidence-based, judicious treatment interventions can help prevent and manage agitation in this vulnerable population.

Related Resources

• Baker M, Carlson GA. What do we really know about PRN use in agitated children with mental health conditions: a clinical review. Evid Based Ment Health. 2018;21(4):166-170.
• Gerson R, Malas N, Mroczkowski MM. Crisis in the emergency department: the evaluation and management of acute agitation in children and adolescents. Child Adolesc Psychiatr Clin N Am. 2018;27(3):367-386.

Drug Brand Names

Amantadine • Symmetrel
Aripiprazole • Abilify
Clonidine • Catapres
Guanfacine • Intuniv, Tenex
Haloperidol • Haldol
Lamotrigine • Lamictal
Levetiracetam • Keppra, Spritam
Olanzapine • Zyprexa
Oxcarbazepine • Trileptal
Quetiapine • Seroquel
Topiramate • Topamax
Risperidone • Risperdal
Valproate • Depakene
Ziprasidone • Geodon

Managing agitation—verbal and/or motor restlessness that often is accompanied by irritability and a predisposition to aggression or violence—can be challenging in any patient, but particularly so in children and adolescents. In the United States, the prevalence of children and adolescents presenting to an emergency department (ED) for treatment of psychiatric symptoms, including agitation, has been on the rise.^1,2

Similar to the multitude of causes of fever, agitation among children and adolescents has many possible causes.³ Because agitation can pose a risk for harm to others and/or self, it is important to manage it proactively. Other than studies that focus on agitation in pediatric anesthesia, there is a dearth of studies examining agitation and its treatment in children and adolescents. There is also a scarcity of training in the management of acute agitation in children and adolescents. In a 2017 survey of pediatric hospitalists and consultation-liaison psychiatrists at 38 academic children’s hospitals in North America, approximately 60% of respondents indicated that they had received no training in the evaluation or management of pediatric acute agitation.⁴ In addition, approximately 54% of participants said they did not screen for risk factors for pediatric agitation, even though 84% encountered the condition at least once a month, and as often as weekly.⁴

This article reviews evidence on the causes and treatments of agitation in children and adolescents. For the purposes of this review, child refers to a patient age 6 to 12, and adolescent refers to a patient age 13 to 17.

Identifying the cause

Addressing the underlying cause of agitation is essential. It’s also important to manage acute agitation while the underlying cause is being investigated in a way that does not jeopardize the patient’s emotional or physical safety.

Agitation in children or teens can be due to psychiatric causes such as autism, attention-deficit/hyperactivity disorder (ADHD), or posttraumatic stress disorder (PTSD), or due to medical conditions such as delirium, traumatic brain injury, or other conditions (Table 1).

In a 2005 study of 194 children with agitation in a pediatric post-anesthesia care unit, pain (27%) and anxiety (25%) were found to be the most common causes of agitation.³ Anesthesia-related agitation was a less common cause (11%). Physiologic anomalies were found to be the underlying cause of agitation in only 3 children in this study, but were undiagnosed for a prolonged period in 2 of these 3 children, which highlights the importance of a thorough differential diagnosis in the management of agitation in children.³

Assessment of an agitated child should include a comprehensive history, physical exam, and laboratory testing as indicated. When a pediatric patient comes to the ED with a chief presentation of agitation, a thorough medical and psychiatric assessment should be performed. For patients with a history of psychiatric diagnoses, do not assume that the cause of agitation is psychiatric.

Continue to: Psychiatric causes

 

 

Psychiatric causes

Autism spectrum disorder. Children and teens with autism often feel overwhelmed due to transitions, changes, and/or sensory overload. This sensory overload may be in response to relatively subtle sensory stimuli, so it may not always be apparent to parents or others around them.

Research suggests that in general, the ability to cope effectively with emotions is difficult without optimal language development. Due to cognitive/language delays and a related lack of emotional attunement and limited skills in recognizing, expressing, or coping with emotions, difficult emotions in children and adolescents with autism can manifest as agitation.

Attention-deficit/hyperactivity disorder. Children with ADHD may be at a higher risk for agitation, in part due to poor impulse control and limited coping skills. In addition, chronic negative feedback (from parents, teachers, or both) may contribute to low self-esteem, mood symptoms, defiance, and/or other behavioral difficulties. In addition to standard pharmacotherapy for ADHD, treatment involves parent behavior modification training. Setting firm yet empathic limits, “picking battles,” and implementing a developmentally appropriate behavioral plan to manage disruptive behavior in children or adolescents with ADHD can go a long way in helping to prevent the emergence of agitation.

Posttraumatic stress disorder. In some young children, new-onset, unexplained agitation may be the only sign of abuse or trauma. Children who have undergone trauma tend to experience confusion and distress. This may manifest as agitation or aggression, or other symptoms such as increased anxiety or nightmares.⁵ Trauma may be in the form of witnessing violence (domestic or other); experiencing physical, sexual, and/or emotional abuse; or witnessing/experiencing other significant threats to the safety of self and/or loved ones. Re-establishing (or establishing) a sense of psychological and physical safety is paramount in such patients.⁶ Psychotherapy is the first-line modality of treatment in children and adolescents with PTSD.⁶ In general, there is a scarcity of research on medication treatments for PTSD symptoms among children and adolescents.⁶

Oppositional defiant disorder/conduct disorder. Oppositional defiant disorder (ODD) can be comorbid with ADHD. The diagnosis of ODD requires a pervasive pattern of anger, defiance, vindictiveness, and hostility, particularly towards authority figures. However, these symptoms need to be differentiated from the normal range of childhood behavior. Occasionally, children learn to cope maladaptively through disruptive behavior or agitation. Although a parent or caregiver may see this behavior as intentionally malevolent, in a child with limited coping skills (whether due to young age, developmental/cognitive/language/learning delays, or social communication deficits) or one who has witnessed frequent agitation or aggression in the family environment, agitation and disruptive behavior may be a maladaptive form of coping. Thus, diligence needs to be exercised in the diagnosis of ODD and in understanding the psychosocial factors affecting the child, particularly because impulsiveness and uncooperativeness on their own have been found to be linked to greater likelihood of prescription of psychotropic medications from multiple classes.⁷ Family-based interventions, particularly parent training, family therapy, and age-appropriate child skills training, are of prime importance in managing this condition.⁸ Research shows that a shortage of resources, system issues, and cultural roadblocks in implementing family-based psychosocial interventions also can contribute to the increased use of psychotropic medications for aggression in children and teens with ODD, conduct disorder, or ADHD.⁸ The astute clinician needs to be cognizant of this before prescribing.

Continue to: Hallucinations/psychosis

Hallucinations/psychosis. Hallucinations (whether from psychiatric or medical causes) are significantly associated with agitation.⁹ In particular, auditory command hallucinations have been linked to agitation. Command hallucinations in children and adolescents may be secondary to early-onset schizophrenia; however, this diagnosis is rare.¹⁰ Hallucinations can also be an adverse effect of amphetamine-based stimulant medications in children and adolescents. Visual hallucinations are most often a sign of an underlying medical disorder such as delirium, occipital lobe mass/infection, or drug intoxication or withdrawal. Hallucinations need to be distinguished from the normal, imaginative play of a young child.¹⁰

Bipolar mania. In adults, bipolar disorder is a primary psychiatric cause of agitation. In children and adolescents, the diagnosis of bipolar disorder can be complex and requires careful and nuanced history-taking. The risks of agitation are greater with bipolar disorder than with unipolar depression.^11,12

Disruptive mood dysregulation disorder. Prior to DSM-5, many children and adolescents with chronic, non-episodic irritability and severe outbursts out of proportion to the situation or stimuli were given a diagnosis of bipolar disorder. These symptoms, in combination with other symptoms, are now considered part of disruptive mood dysregulation disorder when severe outbursts in a child or adolescent occur 3 to 4 times a week consistently, for at least 1 year. The diagnosis of disruptive mood dysregulation disorder requires ruling out other psychiatric and medical conditions, particularly ADHD.¹³

Substance intoxication/withdrawal. Intoxication or withdrawal from substances such as alcohol, stimulant medications, opioids, methamphetamines, and other agents can lead to agitation. This is more likely to occur among adolescents than children.¹⁴

Adjustment disorder. Parental divorce, especially if it is conflictual, or other life stressors, such as experiencing a move or frequent moves, may contribute to the development of agitation in children and adolescents.

Continue to: Depression

Depression. In children and adolescents, depression can manifest as anger or irritability, and occasionally as agitation.

Medical causes

Delirium. Refractory agitation is often a manifestation of delirium in children and adolescents.¹⁵ If unrecognized and untreated, delirium can be fatal.¹⁶ Therefore, it is imperative that clinicians routinely assess for delirium in any patient who presents with agitation.

Because a patient with delirium often presents with agitation and visual or auditory hallucinations, the medical team may tend to assume these symptoms are secondary to a psychiatric disorder. In this case, the role of the consultation-liaison psychiatrist is critical for guiding the medical team, particularly to continue a thorough exploration of underlying causes while avoiding polypharmacy. Noise, bright lights, frequent changes in nursing staff or caregivers, anticholinergic or benzodiazepine medications, and frequent changes in schedules should be avoided to prevent delirium from occurring or getting worse.¹⁷ A multidisciplinary team approach is key in identifying the underlying cause and managing delirium in pediatric patients.

Traumatic brain injury. Agitation may be a presenting symptom in youth with traumatic brain injury (TBI).¹⁸ Agitation may present often in the acute recovery phase.¹⁹ There is limited evidence on the efficacy and safety of pharmacotherapy for agitation in pediatric patients with TBI.¹⁸

Autoimmune conditions. In a study of 27 patients with anti-N-methyl-d-aspartate receptor encephalitis, Mohammad et al²⁰ found that agitation was a common symptom.

Continue to: Medication-induced/iatrogenic

Medication-induced/iatrogenic. Agitation can be an adverse effect of medications such as amantadine (often used for TBI),¹⁸ atypical antipsychotics,²¹ selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors.

Infection. Agitation can be a result of encephalitis, meningitis, or other infectious processes.²²

Metabolic conditions. Hepatic or renal failure, diabetic ketoacidosis, and thyroid toxicosis may cause agitation in children or adolescents.²²

Start with nonpharmacologic interventions

Few studies have examined de-escalation techniques in agitated children and adolescents. However, verbal de-escalation is generally viewed as the first-line technique for managing agitation in children and adolescents. When feasible, teaching and modeling developmentally appropriate stress management skills for children and teens can be a beneficial preventative strategy to reduce the incidence and worsening of agitation.²³

Clinicians should refrain from using coercion.²⁴ Coercion could harm the therapeutic alliance, thereby impeding assessment of the underlying causes of agitation, and can be particularly harmful for patients who have a history of trauma or abuse. Even in pediatric patients with no such history, coercion is discouraged due to its punitive connotations and potential to adversely impact a vulnerable child or teen.

Continue to: Establishing a therapeutic rapport...

Establishing a therapeutic rapport with the patient, when feasible, can facilitate smoother de-escalation by offering the patient an outlet to air his/her frustrations and emotions, and by helping the patient feel understood.²⁴ To facilitate this, ensure that the patient’s basic comforts and needs are met, such as access to a warm bed, food, and safety.²⁵

The psychiatrist’s role is to help uncover and address the underlying reason for the patient’s agony or distress. Once the child or adolescent has calmed, explore potential triggers or causes of the agitation.

There has been a significant move away from the use of restraints for managing agitation in children and adolescents.²⁶ Restraints have a psychologically traumatizing effect,²⁷ and have been linked to life-threatening injuries and death in children.²⁴

Pharmacotherapy: Proceed with caution

There are no FDA-approved medications for the treatment of agitation in the general pediatric population, and any medication use in this population is off-label. There is also a dearth of research examining the safety and efficacy of using psychotropic medications for agitation in pediatric patients. Because children and adolescents are more susceptible to adverse effects and risks associated with the use of psychotropic medications, special caution is warranted. In general, pharmacologic interventions are not recommended without the use of psychotherapy-based modalities.

In the past, the aim of using medications to treat patients with agitation was to put the patient to sleep.²⁵ This practice did not help clinicians to assess for underlying causes, and was often accompanied by a greater risk of adverse effects and reactions.²⁴ Therefore, the goal of medication treatment for agitation is to help calm the patient instead of inducing sleep.²⁵

Continue to: Pharmacotherapy should...

Pharmacotherapy should be used only when behavioral interventions have been unsuccessful. Key considerations for using psychotropic medications to address agitation in children and adolescents are summarized in Table 2.²⁵

Antipsychotics, particularly second-generation antipsychotics (SGAs), have been commonly used to manage acute agitation in children and adolescents, and there has been an upswing in the use of these medications in the United States in the last several years.²⁸ Research indicates that males, children and adolescents in foster care, and those with Medicaid have been the more frequent youth recipients of SGAs.²⁹ Of particular concern is the prevalence of antipsychotic use among children younger than age 6. In the last few decades, there has been an increase in the prescription of antipsychotics for children younger than age 6, particularly for disruptive behavior and aggression.³⁰ In a study of preschool-age Medicaid patients in Kentucky, 70,777 prescriptions for SGAs were given to 6,915 children <6 years of age; 73% of these prescriptions were for male patients.³⁰ Because there is a lack of controlled studies examining the safety and efficacy of SGAs among children and adolescents, especially with long-term use, further research is needed and caution is warranted.²⁸

The FDA has approved risperidone (for patients age 5 to 16) and oral aripiprazole (for patients age 6 to 17) for treating irritability related to autism spectrum disorder; irritability can contribute to or exacerbate agitation. The FDA has also approved several antipsychotic medications for treating schizophrenia or bipolar disorder in adolescents of varying ages. However, SGAs have also been found to be used commonly among young patients who do not meet criteria for autism, schizophrenia, or bipolar disorder. Aggression is the most common symptom for which SGAs are used among the pediatric population.²⁹ Careful and judicious weighing of the risks and benefits is warranted before using antipsychotic medications in a child or adolescent.

Externalizing disorders among children and adolescents tend to get treated with antipsychotics.²⁸ A Canadian study examining records of 6,916 children found that most children who had been prescribed risperidone received it for ADHD or conduct disorder, and most patients had not received laboratory testing for monitoring the antipsychotic medication they were taking.³¹ In a 2018 study examining medical records of 120 pediatric patients who presented to an ED in British Columbia with agitation, antipsychotics were the most commonly used medications for patients with autism spectrum disorder; most patients received at least 1 dose.¹⁴

For children and adolescents with agitation or aggression who were admitted to inpatient units, IM olanzapine and ziprasidone were found to exhibit similar efficacy when used to treat agitation.^14,21,32

Continue to: In case reports...

In case reports, a combination of olanzapine with CNS-suppressing agents has resulted in death. Therefore, do not combine olanzapine with agents such as benzodiazepines.²⁵ In a patient with a likely medical source of agitation, insufficient evidence exists to support the use of olanzapine, and additional research is needed.²⁵

Low-dose haloperidol has been found to be effective for delirium-related agitation in pediatric studies.¹⁵ Before initiating an antipsychotic for any child or adolescent, review the patient’s family history for reports of early cardiac death and the patient’s own history of cardiac symptoms, palpitations, syncope, or prolonged QT interval. Monitor for QT prolongation. Among commonly used antipsychotics, the risk of QT prolongation is higher with IV administration of haloperidol and with ziprasidone. Studies show that compared with oral or IM haloperidol, the IV formulation has a higher risk of increased QTc interval, torsades de pointes, and sudden death.³³ The FDA recommends continuous cardiac monitoring in adults receiving IV haloperidol. Data for its safety in children and adolescents are insufficient.

A few studies have found risperidone to be efficacious for treating ODD and conduct disorder; however, this use is off-label, and its considerable adverse effect and risk profile needs to be weighed against the potential benefit.⁸

Antipsychotic polypharmacy should be avoided because of the higher risk of adverse effects and interactions, and a lack of robust, controlled studies evaluating the safety of using antipsychotics for non-FDA-approved indications in children and adolescents.⁷ All patients who receive antipsychotics require monitoring for extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome, orthostatic hypotension, sedation, metabolic syndrome, and other potential adverse effects. Patients receiving risperidone need to have their prolactin levels monitored periodically, and their parents should be made aware of the potential for hyperprolactinemia and other adverse effects. Aripiprazole and quetiapine may increase the risk of suicidality.

Antiepileptics. A meta-analysis of 7 randomized controlled trials examining the use of antiepileptic medications (valproate, lamotrigine, levetiracetam, and topiramate) in children with autism spectrum disorder found no significant difference between placebo and these medications for addressing agitation.³⁴

Continue to: In a retrospective case series...

In a retrospective case series of 30 pedi­atric patients with autism spectrum disorder who were given oxcarbazepine, Douglas et al³⁵ found that 47% of participants experienced significant improvement in irritability/agitation. However, 23% of patients reported significant adverse effects leading to discontinuation. Insufficient evidence exists for the safety and efficacy of oxcarbazepine in this population.³⁵

Benzodiazepines. The use of benzodiazepines in pediatric patients has been associated with paradoxical disinhibition reactions, particularly in children with autism and other developmental or cognitive disabilities or delays.²¹ There is a lack of data on the safety and efficacy of long-term use of benzodiazepines in children, especially in light of these patients’ developing brains, the risk of cognitive impairment, and the potential for dependence with long-term use. Despite this, some studies show that the use of benzodiazepines is fairly common among pediatric patients who present to the ED with agitation.¹⁴ In a recent retrospective study, Kendrick et al¹⁴ found that among pediatric patients with agitation who were brought to the ED, benzodiazepines were the most commonly prescribed medications.

Other medications. Clonidine and guanfacine have been used off-label to treat agitation in children and adolescents, particularly among those with ADHD or autism. Some small pediatric trials have also shown their benefit in decreasing symptoms of aggression, impulsivity, and hyper-arousal in PTSD.³⁶ In addition to adverse effects that include but are not limited to lowered blood pressure, bradycardia, and risk of atrioventricular block, clinicians need to be vigilant for potentially serious rebound hypertension that may occur if doses of these medications are missed; this risk is greater with clonidine.

Diphenhydramine, in both oral and IM forms, has been used to treat agitation in children,³² but has also been associated with a paradoxical disinhibition reaction in pediatric patients²¹ and therefore should be used only sparingly and with caution. Diphenhydramine has anticholinergic properties, and may worsen delirium.¹⁵ Stimulant medications can help aggressive behavior in children and adolescents with ADHD.³⁷

Bottom Line

Agitation among children and adolescents has many possible causes. A combination of a comprehensive assessment and evidence-based, judicious treatment interventions can help prevent and manage agitation in this vulnerable population.

Related Resources

• Baker M, Carlson GA. What do we really know about PRN use in agitated children with mental health conditions: a clinical review. Evid Based Ment Health. 2018;21(4):166-170.
• Gerson R, Malas N, Mroczkowski MM. Crisis in the emergency department: the evaluation and management of acute agitation in children and adolescents. Child Adolesc Psychiatr Clin N Am. 2018;27(3):367-386.

Drug Brand Names

Amantadine • Symmetrel
Aripiprazole • Abilify
Clonidine • Catapres
Guanfacine • Intuniv, Tenex
Haloperidol • Haldol
Lamotrigine • Lamictal
Levetiracetam • Keppra, Spritam
Olanzapine • Zyprexa
Oxcarbazepine • Trileptal
Quetiapine • Seroquel
Topiramate • Topamax
Risperidone • Risperdal
Valproate • Depakene
Ziprasidone • Geodon

Managing agitation—verbal and/or motor restlessness that often is accompanied by irritability and a predisposition to aggression or violence—can be challenging in any patient, but particularly so in children and adolescents. In the United States, the prevalence of children and adolescents presenting to an emergency department (ED) for treatment of psychiatric symptoms, including agitation, has been on the rise.^1,2

Similar to the multitude of causes of fever, agitation among children and adolescents has many possible causes.³ Because agitation can pose a risk for harm to others and/or self, it is important to manage it proactively. Other than studies that focus on agitation in pediatric anesthesia, there is a dearth of studies examining agitation and its treatment in children and adolescents. There is also a scarcity of training in the management of acute agitation in children and adolescents. In a 2017 survey of pediatric hospitalists and consultation-liaison psychiatrists at 38 academic children’s hospitals in North America, approximately 60% of respondents indicated that they had received no training in the evaluation or management of pediatric acute agitation.⁴ In addition, approximately 54% of participants said they did not screen for risk factors for pediatric agitation, even though 84% encountered the condition at least once a month, and as often as weekly.⁴

This article reviews evidence on the causes and treatments of agitation in children and adolescents. For the purposes of this review, child refers to a patient age 6 to 12, and adolescent refers to a patient age 13 to 17.

Identifying the cause

Addressing the underlying cause of agitation is essential. It’s also important to manage acute agitation while the underlying cause is being investigated in a way that does not jeopardize the patient’s emotional or physical safety.

Agitation in children or teens can be due to psychiatric causes such as autism, attention-deficit/hyperactivity disorder (ADHD), or posttraumatic stress disorder (PTSD), or due to medical conditions such as delirium, traumatic brain injury, or other conditions (Table 1).

In a 2005 study of 194 children with agitation in a pediatric post-anesthesia care unit, pain (27%) and anxiety (25%) were found to be the most common causes of agitation.³ Anesthesia-related agitation was a less common cause (11%). Physiologic anomalies were found to be the underlying cause of agitation in only 3 children in this study, but were undiagnosed for a prolonged period in 2 of these 3 children, which highlights the importance of a thorough differential diagnosis in the management of agitation in children.³

Assessment of an agitated child should include a comprehensive history, physical exam, and laboratory testing as indicated. When a pediatric patient comes to the ED with a chief presentation of agitation, a thorough medical and psychiatric assessment should be performed. For patients with a history of psychiatric diagnoses, do not assume that the cause of agitation is psychiatric.

Continue to: Psychiatric causes

 

 

Psychiatric causes

Autism spectrum disorder. Children and teens with autism often feel overwhelmed due to transitions, changes, and/or sensory overload. This sensory overload may be in response to relatively subtle sensory stimuli, so it may not always be apparent to parents or others around them.

Research suggests that in general, the ability to cope effectively with emotions is difficult without optimal language development. Due to cognitive/language delays and a related lack of emotional attunement and limited skills in recognizing, expressing, or coping with emotions, difficult emotions in children and adolescents with autism can manifest as agitation.

Attention-deficit/hyperactivity disorder. Children with ADHD may be at a higher risk for agitation, in part due to poor impulse control and limited coping skills. In addition, chronic negative feedback (from parents, teachers, or both) may contribute to low self-esteem, mood symptoms, defiance, and/or other behavioral difficulties. In addition to standard pharmacotherapy for ADHD, treatment involves parent behavior modification training. Setting firm yet empathic limits, “picking battles,” and implementing a developmentally appropriate behavioral plan to manage disruptive behavior in children or adolescents with ADHD can go a long way in helping to prevent the emergence of agitation.

Posttraumatic stress disorder. In some young children, new-onset, unexplained agitation may be the only sign of abuse or trauma. Children who have undergone trauma tend to experience confusion and distress. This may manifest as agitation or aggression, or other symptoms such as increased anxiety or nightmares.⁵ Trauma may be in the form of witnessing violence (domestic or other); experiencing physical, sexual, and/or emotional abuse; or witnessing/experiencing other significant threats to the safety of self and/or loved ones. Re-establishing (or establishing) a sense of psychological and physical safety is paramount in such patients.⁶ Psychotherapy is the first-line modality of treatment in children and adolescents with PTSD.⁶ In general, there is a scarcity of research on medication treatments for PTSD symptoms among children and adolescents.⁶

Oppositional defiant disorder/conduct disorder. Oppositional defiant disorder (ODD) can be comorbid with ADHD. The diagnosis of ODD requires a pervasive pattern of anger, defiance, vindictiveness, and hostility, particularly towards authority figures. However, these symptoms need to be differentiated from the normal range of childhood behavior. Occasionally, children learn to cope maladaptively through disruptive behavior or agitation. Although a parent or caregiver may see this behavior as intentionally malevolent, in a child with limited coping skills (whether due to young age, developmental/cognitive/language/learning delays, or social communication deficits) or one who has witnessed frequent agitation or aggression in the family environment, agitation and disruptive behavior may be a maladaptive form of coping. Thus, diligence needs to be exercised in the diagnosis of ODD and in understanding the psychosocial factors affecting the child, particularly because impulsiveness and uncooperativeness on their own have been found to be linked to greater likelihood of prescription of psychotropic medications from multiple classes.⁷ Family-based interventions, particularly parent training, family therapy, and age-appropriate child skills training, are of prime importance in managing this condition.⁸ Research shows that a shortage of resources, system issues, and cultural roadblocks in implementing family-based psychosocial interventions also can contribute to the increased use of psychotropic medications for aggression in children and teens with ODD, conduct disorder, or ADHD.⁸ The astute clinician needs to be cognizant of this before prescribing.

Continue to: Hallucinations/psychosis

Hallucinations/psychosis. Hallucinations (whether from psychiatric or medical causes) are significantly associated with agitation.⁹ In particular, auditory command hallucinations have been linked to agitation. Command hallucinations in children and adolescents may be secondary to early-onset schizophrenia; however, this diagnosis is rare.¹⁰ Hallucinations can also be an adverse effect of amphetamine-based stimulant medications in children and adolescents. Visual hallucinations are most often a sign of an underlying medical disorder such as delirium, occipital lobe mass/infection, or drug intoxication or withdrawal. Hallucinations need to be distinguished from the normal, imaginative play of a young child.¹⁰

Bipolar mania. In adults, bipolar disorder is a primary psychiatric cause of agitation. In children and adolescents, the diagnosis of bipolar disorder can be complex and requires careful and nuanced history-taking. The risks of agitation are greater with bipolar disorder than with unipolar depression.^11,12

Disruptive mood dysregulation disorder. Prior to DSM-5, many children and adolescents with chronic, non-episodic irritability and severe outbursts out of proportion to the situation or stimuli were given a diagnosis of bipolar disorder. These symptoms, in combination with other symptoms, are now considered part of disruptive mood dysregulation disorder when severe outbursts in a child or adolescent occur 3 to 4 times a week consistently, for at least 1 year. The diagnosis of disruptive mood dysregulation disorder requires ruling out other psychiatric and medical conditions, particularly ADHD.¹³

Substance intoxication/withdrawal. Intoxication or withdrawal from substances such as alcohol, stimulant medications, opioids, methamphetamines, and other agents can lead to agitation. This is more likely to occur among adolescents than children.¹⁴

Adjustment disorder. Parental divorce, especially if it is conflictual, or other life stressors, such as experiencing a move or frequent moves, may contribute to the development of agitation in children and adolescents.

Continue to: Depression

Depression. In children and adolescents, depression can manifest as anger or irritability, and occasionally as agitation.

Medical causes

Delirium. Refractory agitation is often a manifestation of delirium in children and adolescents.¹⁵ If unrecognized and untreated, delirium can be fatal.¹⁶ Therefore, it is imperative that clinicians routinely assess for delirium in any patient who presents with agitation.

Because a patient with delirium often presents with agitation and visual or auditory hallucinations, the medical team may tend to assume these symptoms are secondary to a psychiatric disorder. In this case, the role of the consultation-liaison psychiatrist is critical for guiding the medical team, particularly to continue a thorough exploration of underlying causes while avoiding polypharmacy. Noise, bright lights, frequent changes in nursing staff or caregivers, anticholinergic or benzodiazepine medications, and frequent changes in schedules should be avoided to prevent delirium from occurring or getting worse.¹⁷ A multidisciplinary team approach is key in identifying the underlying cause and managing delirium in pediatric patients.

Traumatic brain injury. Agitation may be a presenting symptom in youth with traumatic brain injury (TBI).¹⁸ Agitation may present often in the acute recovery phase.¹⁹ There is limited evidence on the efficacy and safety of pharmacotherapy for agitation in pediatric patients with TBI.¹⁸

Autoimmune conditions. In a study of 27 patients with anti-N-methyl-d-aspartate receptor encephalitis, Mohammad et al²⁰ found that agitation was a common symptom.

Continue to: Medication-induced/iatrogenic

Medication-induced/iatrogenic. Agitation can be an adverse effect of medications such as amantadine (often used for TBI),¹⁸ atypical antipsychotics,²¹ selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors.

Infection. Agitation can be a result of encephalitis, meningitis, or other infectious processes.²²

Metabolic conditions. Hepatic or renal failure, diabetic ketoacidosis, and thyroid toxicosis may cause agitation in children or adolescents.²²

Start with nonpharmacologic interventions

Few studies have examined de-escalation techniques in agitated children and adolescents. However, verbal de-escalation is generally viewed as the first-line technique for managing agitation in children and adolescents. When feasible, teaching and modeling developmentally appropriate stress management skills for children and teens can be a beneficial preventative strategy to reduce the incidence and worsening of agitation.²³

Clinicians should refrain from using coercion.²⁴ Coercion could harm the therapeutic alliance, thereby impeding assessment of the underlying causes of agitation, and can be particularly harmful for patients who have a history of trauma or abuse. Even in pediatric patients with no such history, coercion is discouraged due to its punitive connotations and potential to adversely impact a vulnerable child or teen.

Continue to: Establishing a therapeutic rapport...

Establishing a therapeutic rapport with the patient, when feasible, can facilitate smoother de-escalation by offering the patient an outlet to air his/her frustrations and emotions, and by helping the patient feel understood.²⁴ To facilitate this, ensure that the patient’s basic comforts and needs are met, such as access to a warm bed, food, and safety.²⁵

The psychiatrist’s role is to help uncover and address the underlying reason for the patient’s agony or distress. Once the child or adolescent has calmed, explore potential triggers or causes of the agitation.

There has been a significant move away from the use of restraints for managing agitation in children and adolescents.²⁶ Restraints have a psychologically traumatizing effect,²⁷ and have been linked to life-threatening injuries and death in children.²⁴

Pharmacotherapy: Proceed with caution

There are no FDA-approved medications for the treatment of agitation in the general pediatric population, and any medication use in this population is off-label. There is also a dearth of research examining the safety and efficacy of using psychotropic medications for agitation in pediatric patients. Because children and adolescents are more susceptible to adverse effects and risks associated with the use of psychotropic medications, special caution is warranted. In general, pharmacologic interventions are not recommended without the use of psychotherapy-based modalities.

In the past, the aim of using medications to treat patients with agitation was to put the patient to sleep.²⁵ This practice did not help clinicians to assess for underlying causes, and was often accompanied by a greater risk of adverse effects and reactions.²⁴ Therefore, the goal of medication treatment for agitation is to help calm the patient instead of inducing sleep.²⁵

Continue to: Pharmacotherapy should...

Pharmacotherapy should be used only when behavioral interventions have been unsuccessful. Key considerations for using psychotropic medications to address agitation in children and adolescents are summarized in Table 2.²⁵

Antipsychotics, particularly second-generation antipsychotics (SGAs), have been commonly used to manage acute agitation in children and adolescents, and there has been an upswing in the use of these medications in the United States in the last several years.²⁸ Research indicates that males, children and adolescents in foster care, and those with Medicaid have been the more frequent youth recipients of SGAs.²⁹ Of particular concern is the prevalence of antipsychotic use among children younger than age 6. In the last few decades, there has been an increase in the prescription of antipsychotics for children younger than age 6, particularly for disruptive behavior and aggression.³⁰ In a study of preschool-age Medicaid patients in Kentucky, 70,777 prescriptions for SGAs were given to 6,915 children <6 years of age; 73% of these prescriptions were for male patients.³⁰ Because there is a lack of controlled studies examining the safety and efficacy of SGAs among children and adolescents, especially with long-term use, further research is needed and caution is warranted.²⁸

The FDA has approved risperidone (for patients age 5 to 16) and oral aripiprazole (for patients age 6 to 17) for treating irritability related to autism spectrum disorder; irritability can contribute to or exacerbate agitation. The FDA has also approved several antipsychotic medications for treating schizophrenia or bipolar disorder in adolescents of varying ages. However, SGAs have also been found to be used commonly among young patients who do not meet criteria for autism, schizophrenia, or bipolar disorder. Aggression is the most common symptom for which SGAs are used among the pediatric population.²⁹ Careful and judicious weighing of the risks and benefits is warranted before using antipsychotic medications in a child or adolescent.

Externalizing disorders among children and adolescents tend to get treated with antipsychotics.²⁸ A Canadian study examining records of 6,916 children found that most children who had been prescribed risperidone received it for ADHD or conduct disorder, and most patients had not received laboratory testing for monitoring the antipsychotic medication they were taking.³¹ In a 2018 study examining medical records of 120 pediatric patients who presented to an ED in British Columbia with agitation, antipsychotics were the most commonly used medications for patients with autism spectrum disorder; most patients received at least 1 dose.¹⁴

For children and adolescents with agitation or aggression who were admitted to inpatient units, IM olanzapine and ziprasidone were found to exhibit similar efficacy when used to treat agitation.^14,21,32

Continue to: In case reports...

In case reports, a combination of olanzapine with CNS-suppressing agents has resulted in death. Therefore, do not combine olanzapine with agents such as benzodiazepines.²⁵ In a patient with a likely medical source of agitation, insufficient evidence exists to support the use of olanzapine, and additional research is needed.²⁵

Low-dose haloperidol has been found to be effective for delirium-related agitation in pediatric studies.¹⁵ Before initiating an antipsychotic for any child or adolescent, review the patient’s family history for reports of early cardiac death and the patient’s own history of cardiac symptoms, palpitations, syncope, or prolonged QT interval. Monitor for QT prolongation. Among commonly used antipsychotics, the risk of QT prolongation is higher with IV administration of haloperidol and with ziprasidone. Studies show that compared with oral or IM haloperidol, the IV formulation has a higher risk of increased QTc interval, torsades de pointes, and sudden death.³³ The FDA recommends continuous cardiac monitoring in adults receiving IV haloperidol. Data for its safety in children and adolescents are insufficient.

A few studies have found risperidone to be efficacious for treating ODD and conduct disorder; however, this use is off-label, and its considerable adverse effect and risk profile needs to be weighed against the potential benefit.⁸

Antipsychotic polypharmacy should be avoided because of the higher risk of adverse effects and interactions, and a lack of robust, controlled studies evaluating the safety of using antipsychotics for non-FDA-approved indications in children and adolescents.⁷ All patients who receive antipsychotics require monitoring for extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome, orthostatic hypotension, sedation, metabolic syndrome, and other potential adverse effects. Patients receiving risperidone need to have their prolactin levels monitored periodically, and their parents should be made aware of the potential for hyperprolactinemia and other adverse effects. Aripiprazole and quetiapine may increase the risk of suicidality.

Antiepileptics. A meta-analysis of 7 randomized controlled trials examining the use of antiepileptic medications (valproate, lamotrigine, levetiracetam, and topiramate) in children with autism spectrum disorder found no significant difference between placebo and these medications for addressing agitation.³⁴

Continue to: In a retrospective case series...

In a retrospective case series of 30 pedi­atric patients with autism spectrum disorder who were given oxcarbazepine, Douglas et al³⁵ found that 47% of participants experienced significant improvement in irritability/agitation. However, 23% of patients reported significant adverse effects leading to discontinuation. Insufficient evidence exists for the safety and efficacy of oxcarbazepine in this population.³⁵

Benzodiazepines. The use of benzodiazepines in pediatric patients has been associated with paradoxical disinhibition reactions, particularly in children with autism and other developmental or cognitive disabilities or delays.²¹ There is a lack of data on the safety and efficacy of long-term use of benzodiazepines in children, especially in light of these patients’ developing brains, the risk of cognitive impairment, and the potential for dependence with long-term use. Despite this, some studies show that the use of benzodiazepines is fairly common among pediatric patients who present to the ED with agitation.¹⁴ In a recent retrospective study, Kendrick et al¹⁴ found that among pediatric patients with agitation who were brought to the ED, benzodiazepines were the most commonly prescribed medications.

Other medications. Clonidine and guanfacine have been used off-label to treat agitation in children and adolescents, particularly among those with ADHD or autism. Some small pediatric trials have also shown their benefit in decreasing symptoms of aggression, impulsivity, and hyper-arousal in PTSD.³⁶ In addition to adverse effects that include but are not limited to lowered blood pressure, bradycardia, and risk of atrioventricular block, clinicians need to be vigilant for potentially serious rebound hypertension that may occur if doses of these medications are missed; this risk is greater with clonidine.

Diphenhydramine, in both oral and IM forms, has been used to treat agitation in children,³² but has also been associated with a paradoxical disinhibition reaction in pediatric patients²¹ and therefore should be used only sparingly and with caution. Diphenhydramine has anticholinergic properties, and may worsen delirium.¹⁵ Stimulant medications can help aggressive behavior in children and adolescents with ADHD.³⁷

Bottom Line

Agitation among children and adolescents has many possible causes. A combination of a comprehensive assessment and evidence-based, judicious treatment interventions can help prevent and manage agitation in this vulnerable population.

Related Resources

• Baker M, Carlson GA. What do we really know about PRN use in agitated children with mental health conditions: a clinical review. Evid Based Ment Health. 2018;21(4):166-170.
• Gerson R, Malas N, Mroczkowski MM. Crisis in the emergency department: the evaluation and management of acute agitation in children and adolescents. Child Adolesc Psychiatr Clin N Am. 2018;27(3):367-386.

Drug Brand Names

Amantadine • Symmetrel
Aripiprazole • Abilify
Clonidine • Catapres
Guanfacine • Intuniv, Tenex
Haloperidol • Haldol
Lamotrigine • Lamictal
Levetiracetam • Keppra, Spritam
Olanzapine • Zyprexa
Oxcarbazepine • Trileptal
Quetiapine • Seroquel
Topiramate • Topamax
Risperidone • Risperdal
Valproate • Depakene
Ziprasidone • Geodon

LJUBLJANA, SLOVENIA – A high body mass index in pregnant women who receive a seasonal influenza vaccine doesn’t impair their vaccine response; indeed, it might actually improve their seroconversion rate, Michelle Clarke reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

She presented a prospective cohort study of 90 women vaccinated against influenza during pregnancy, 24 of whom had a BMI of 30 kg/m² or more. The impetus for the study was the investigators’ understanding that influenza in pregnancy carries an increased risk of severe complications, obesity is a known risk factor for more severe episodes of influenza, and vaccine responses could potentially be adversely affected by obesity, either because of the associated inflammatory state and altered cytokine profile or inadequate vaccine delivery via the intramuscular route. Yet the impact of obesity on vaccine responses in pregnancy has been unclear.

Blood samples obtained before and 1 month after vaccination showed similarly high-titer postvaccination seropositivity rates against influenza B, H3N2, and H1N1 regardless of the women’s weight status. Indeed, the seropositivity rate against all three influenza viruses was higher in the obese subgroup, by a margin of 92%-74%. Also, postvaccination geometric mean antibody titers were significantly higher in the obese group. Particularly impressive was the difference in H1N1 seroconversion, defined as a fourfold increase in titer 28 days after vaccination: 79% versus 55%, noted Ms. Clarke of the University of Adelaide.

Of note, influenza vaccination in the first trimester resulted in a significantly lower seropositive antibody rate than vaccination in the second or third trimesters. The implication is that gestational age at vaccination, regardless of BMI, may be an important determinant of optimal vaccine protection for mothers and their newborns. However, this tentative conclusion requires confirmation in an independent larger sample, because the patient numbers in the study were small: Seropositive antibodies to all three vaccine antigens were documented in just 7 of 12 women (58%) vaccinated in the first trimester, compared with 47 of 53 (89%) vaccinated in the second trimester and 18 of 25 (72%) in the third.

Ms. Clarke reported having no financial conflicts regarding the study, which was supported by the Women’s and Children’s Hospital Research Foundation.

[email protected]

LJUBLJANA, SLOVENIA – A high body mass index in pregnant women who receive a seasonal influenza vaccine doesn’t impair their vaccine response; indeed, it might actually improve their seroconversion rate, Michelle Clarke reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

She presented a prospective cohort study of 90 women vaccinated against influenza during pregnancy, 24 of whom had a BMI of 30 kg/m² or more. The impetus for the study was the investigators’ understanding that influenza in pregnancy carries an increased risk of severe complications, obesity is a known risk factor for more severe episodes of influenza, and vaccine responses could potentially be adversely affected by obesity, either because of the associated inflammatory state and altered cytokine profile or inadequate vaccine delivery via the intramuscular route. Yet the impact of obesity on vaccine responses in pregnancy has been unclear.

Blood samples obtained before and 1 month after vaccination showed similarly high-titer postvaccination seropositivity rates against influenza B, H3N2, and H1N1 regardless of the women’s weight status. Indeed, the seropositivity rate against all three influenza viruses was higher in the obese subgroup, by a margin of 92%-74%. Also, postvaccination geometric mean antibody titers were significantly higher in the obese group. Particularly impressive was the difference in H1N1 seroconversion, defined as a fourfold increase in titer 28 days after vaccination: 79% versus 55%, noted Ms. Clarke of the University of Adelaide.

Of note, influenza vaccination in the first trimester resulted in a significantly lower seropositive antibody rate than vaccination in the second or third trimesters. The implication is that gestational age at vaccination, regardless of BMI, may be an important determinant of optimal vaccine protection for mothers and their newborns. However, this tentative conclusion requires confirmation in an independent larger sample, because the patient numbers in the study were small: Seropositive antibodies to all three vaccine antigens were documented in just 7 of 12 women (58%) vaccinated in the first trimester, compared with 47 of 53 (89%) vaccinated in the second trimester and 18 of 25 (72%) in the third.

Ms. Clarke reported having no financial conflicts regarding the study, which was supported by the Women’s and Children’s Hospital Research Foundation.

[email protected]

LJUBLJANA, SLOVENIA – A high body mass index in pregnant women who receive a seasonal influenza vaccine doesn’t impair their vaccine response; indeed, it might actually improve their seroconversion rate, Michelle Clarke reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

She presented a prospective cohort study of 90 women vaccinated against influenza during pregnancy, 24 of whom had a BMI of 30 kg/m² or more. The impetus for the study was the investigators’ understanding that influenza in pregnancy carries an increased risk of severe complications, obesity is a known risk factor for more severe episodes of influenza, and vaccine responses could potentially be adversely affected by obesity, either because of the associated inflammatory state and altered cytokine profile or inadequate vaccine delivery via the intramuscular route. Yet the impact of obesity on vaccine responses in pregnancy has been unclear.

Blood samples obtained before and 1 month after vaccination showed similarly high-titer postvaccination seropositivity rates against influenza B, H3N2, and H1N1 regardless of the women’s weight status. Indeed, the seropositivity rate against all three influenza viruses was higher in the obese subgroup, by a margin of 92%-74%. Also, postvaccination geometric mean antibody titers were significantly higher in the obese group. Particularly impressive was the difference in H1N1 seroconversion, defined as a fourfold increase in titer 28 days after vaccination: 79% versus 55%, noted Ms. Clarke of the University of Adelaide.

Of note, influenza vaccination in the first trimester resulted in a significantly lower seropositive antibody rate than vaccination in the second or third trimesters. The implication is that gestational age at vaccination, regardless of BMI, may be an important determinant of optimal vaccine protection for mothers and their newborns. However, this tentative conclusion requires confirmation in an independent larger sample, because the patient numbers in the study were small: Seropositive antibodies to all three vaccine antigens were documented in just 7 of 12 women (58%) vaccinated in the first trimester, compared with 47 of 53 (89%) vaccinated in the second trimester and 18 of 25 (72%) in the third.

Ms. Clarke reported having no financial conflicts regarding the study, which was supported by the Women’s and Children’s Hospital Research Foundation.

[email protected]