Ms. E, age 23, presents to your office for a routine visit for management of bipolar I disorder and posttraumatic stress disorder with comorbid type 2 diabetes mellitus. She currently is taking risperidone, 3 mg/d, lamotrigine, 200 mg/d, metformin, 2,000 mg/d, medroxyprogesterone, 150 mg every 3 months, and prazosin, 8 mg/d. Her mood has been stabilized for the last 3 years with this medication regimen.

Ms. E has a history of self-discontinuing medication when adverse events occur. She has been hospitalized twice for psychosis and suicide attempts. Past psychotropic medications that have been discontinued due to adverse effects include ziprasidone (mild abnormal lip movement), olanzapine (ineffective and drowsy), valproic acid (tremor and abdominal discomfort), lithium (rash), and aripiprazole (increased fasting blood sugar and labile mood).

At her appointment today, Ms. E says she is concerned because she has been experiencing galactorrhea for the past 4 weeks. Her prolactin level is 14.4 ng/mL; a normal level for a woman who is not pregnant is <25 ng/mL. However, a repeat prolactin level is obtained, and is found to be elevated at 38 ng/mL.

Prolactin, a polypeptide hormone that is secreted from the pituitary gland, has many functions, including involvement in the synthesis and maintenance of breast milk production, in reproductive behavior, and in luteal function.^1,2 Hyperprolactinemia—an elevated prolactin level—is a common endocrinologic disorder of the hypothalamic–pituitary–axis.³ Children, adolescents, premenopausal women, and women in the perinatal period are more vulnerable to medication-induced hyperprolactinemia.⁴ If not asymptomatic, patients with hyperprolactinemia may experience amenorrhea, galactorrhea, hypogonadism, sexual dysfunction, or infertility.^1,4 Chronic hyperprolactinemia may increase the risk for long-term complications, such as decreased bone mineral density and osteoporosis, although available evidence has conflicting findings.¹

Hyperprolactinemia is diagnosed by a prolactin concentration above the upper reference range.³ Various hormones and neurotransmitters can impact inhibition or stimulation of prolactin release.⁵ For example, dopamine tonically inhibits prolactin release and synthesis, whereas estrogen stimulates prolactin secretion.^1,5 Prolactin also can be elevated under several physiologic and pathologic conditions, such as during stressful situations, meals, or sexual activity.^1,5 A prolactin level >250 ng/mL is usually indicative of a prolactinoma; however, some medications, such as strong D2 receptor antagonists (eg, risperidone, haloperidol), can cause significant elevation without evidence of prolactinoma.³ In the absence of a tumor, medications are often identified as the cause of hyperprolactinemia.³ According to the Endocrinology Society clinical practice guideline, medication-induced elevated prolactin levels are typically between 25 to 100 ng/mL.³

Medication-induced hyperprolactinemia

Antipsychotics, antidepressants, hormonal preparations, antihypertensives, and gastrointestinal agents have been associated with hyperprolactinemia (Table 1^1,3,5-11). These medication classes increase prolactin by decreasing dopamine, which facilitates disinhibition of prolactin synthesis and release, or increasing prolactin stimulating hormones, such as serotonin or estrogen.⁵

Antipsychotics are the most common medication-related cause of hyperprolactinemia.³ Typical antipsychotics are more likely to cause hyperprolactinemia than atypical antipsychotics; the incidence among patients taking typical antipsychotics is 40% to 90%.³ Atypical antipsychotics, except risperidone and paliperidone, are considered to cause less endocrinologic effects than typical antipsychotics through various mechanisms: serotonergic receptor antagonism, fast dissociation from D2 receptors, D2 receptor partial agonism, and preferential binding of D3 vs D2 receptors.^1,5 By having transient D2 receptor association, clozapine and quetiapine are considered to have less risk of hyperprolactinemia compared with other atypical antipsychotics.^1,5 Aripiprazole, brexpiprazole, and cariprazine are partial D2 receptor agonists, and cariprazine is the only agent that exhibits preferential binding to D3 receptors.^12,13 Based on limited data, brexpiprazole and cariprazine may have prolactin-sparing properties given their partial D2 receptor agonism.^12,13 However, one study found increased prolactin levels in some patients after treatment with brexpiprazole, 4 mg/d.¹⁴ Similarly, another study found that cariprazine could increase prolactin levels as much as 4.1 ng/mL, depending on the dose.¹⁵ Except for aripiprazole, brexpiprazole, cariprazine, and clozapine, all other atypical antipsychotics marketed in the United States have a standard warning in the package insert regarding prolactin elevations.^1,16,17

Because antidepressants are less well-studied as a cause of medication-induced hyperprolactinemia, drawing definitive conclusions regarding incidence rates is limited, but the incidence seems to be fairly low.^6,18 A French pharmacovigilance study found that of 182,836 spontaneous adverse drug events reported between 1985 and 2009, there were 159 reports of selective serotonin reuptake inhibitors (SSRIs) inducing hyper­prolactinemia.⁶ Fluoxetine and paroxetine represented about one-half of the cases; however, there were also cases associated with citalopram, escitalopram, sertraline, fluvoxamine, milnacipran, and venlafaxine. In comparison, there were only 11 reports of hyperprolactinemia associated with tricyclic antidepressants or monoamine oxidase inhibitors. Although patients were not always symptomatic, the most commonly reported symptoms were galactorrhea (55%), gynecomastia (29%), amenorrhea (11%), mastodynia (11%), and sexual disorders (4%).⁶ Another study of 5,920 patients treated with fluoxetine found mastodynia in 0.25%, gynecomastia in 0.08%, and galactorrhea in 0.07% of patients.¹⁸ Symptoms occurred in an extremely low percentage of patients, and the study is >20 years old.¹⁸

Mirtazapine and bupropion have been found to be prolactin-neutral.⁵ Bupropion also has been reported to decrease prolactin levels, potentially via its ability to block dopamine reuptake.¹⁹

Managing medication-induced hyperprolactinemia

Screening for and identifying clinically significant hyperprolactinemia is critical, because adverse effects of medications can lead to nonadherence and clinical decompensation.²⁰ Patients must be informed of potential symptoms of hyperprolactinemia, and clinicians should inquire about such symptoms at each visit. Routine monitoring of prolactin levels in asymptomatic patients is not necessary, because the Endocrine Society Clinical Practice Guideline does not recommend treating patients with asymptomatic medication-induced hyperprolactinemia.³

In patients who report hyperprolactinemia symptoms, clinicians should review the patient’s prescribed medications and past medical history (eg, chronic renal failure, hypothyroidism) for potential causes or exacerbations, and address these factors accordingly.³ Order a measurement of prolactin level. A patient with a prolactin level >100 ng/mL should be referred to Endocrinology to rule out prolactinoma.¹

If a patient’s prolactin level is between 25 and 100 ng/mL, review the patient’s medications (Table 1^1,3,5-11), because prolactin levels within this range usually signal a medication-induced cause.³ For patients with antipsychotic-induced hyperprolactinemia, there are several management strategies (Table 2^{1,3,4,9,16,17,21-27}):

• Watch and wait may be warranted when the patient is experiencing mild hyperprolactinemia symptoms.
• Discontinue. If the patient can be maintained without an antipsychotic, discontinuing the antipsychotic would be a first-line option.³
• Reduce the dose. Reducing the antipsychotic dose may be the preferred strategy for patients with moderate to severe hyperprolactinemia symptoms who responded to the antipsychotic and do not wish to start adjunctive therapy.⁴
• Switching to a prolactin-sparing antipsychotic may help normalize prolactin levels and may be preferred when the risk of relapse is low.³ Dopamine agonists can treat medication-induced hyperprolactinemia, but may worsen psychiatric symptoms.^28,29 Therefore, this may be the preferred strategy if the offending medication cannot be discontinued or switched, or if the patient has a comorbid prolactinoma.

Less data exist on managing hyperprolactinemia that is induced by a medication other than an antipsychotic; however, it seems reasonable that the same strategies could be implemented. Specifically, for SSRI–induced hyperprolactinemia, if clinically appropriate, switching to or adding an alternative antidepressant that may be prolactin-sparing, such as mirtazapine or bupropion, could be attempted.⁸ One study found that fluoxetine-induced galactorrhea ceased within 10 days of discontinuing the medication.³⁰

CASE CONTINUED

Because Ms. E has been on the same medication regimen for 3 years and recently developed galactorrhea, it seems unlikely that her hyperprolactinemia is medication-induced. However, a tumor-related cause is less likely because the prolactin level is <100 ng/mL. Based on the literature, the only possible medication-induced cause of her galactorrhea is risperidone. Ms. E agrees to a trial of adjunctive oral aripiprazole, 5 mg/d, with close monitoring of her type 2 diabetes mellitus. Because of the long elimination half-life of aripiprazole, 1 month is required to monitor for improvement in galactorrhea. Ms. E is advised to use breast pads as a nonpharmacologic strategy in the interim. After 1 month of treatment, Ms. E denies galactorrhea symptoms and no longer requires the use of breast pads.

Ms. E, age 23, presents to your office for a routine visit for management of bipolar I disorder and posttraumatic stress disorder with comorbid type 2 diabetes mellitus. She currently is taking risperidone, 3 mg/d, lamotrigine, 200 mg/d, metformin, 2,000 mg/d, medroxyprogesterone, 150 mg every 3 months, and prazosin, 8 mg/d. Her mood has been stabilized for the last 3 years with this medication regimen.

Ms. E has a history of self-discontinuing medication when adverse events occur. She has been hospitalized twice for psychosis and suicide attempts. Past psychotropic medications that have been discontinued due to adverse effects include ziprasidone (mild abnormal lip movement), olanzapine (ineffective and drowsy), valproic acid (tremor and abdominal discomfort), lithium (rash), and aripiprazole (increased fasting blood sugar and labile mood).

At her appointment today, Ms. E says she is concerned because she has been experiencing galactorrhea for the past 4 weeks. Her prolactin level is 14.4 ng/mL; a normal level for a woman who is not pregnant is <25 ng/mL. However, a repeat prolactin level is obtained, and is found to be elevated at 38 ng/mL.

Prolactin, a polypeptide hormone that is secreted from the pituitary gland, has many functions, including involvement in the synthesis and maintenance of breast milk production, in reproductive behavior, and in luteal function.^1,2 Hyperprolactinemia—an elevated prolactin level—is a common endocrinologic disorder of the hypothalamic–pituitary–axis.³ Children, adolescents, premenopausal women, and women in the perinatal period are more vulnerable to medication-induced hyperprolactinemia.⁴ If not asymptomatic, patients with hyperprolactinemia may experience amenorrhea, galactorrhea, hypogonadism, sexual dysfunction, or infertility.^1,4 Chronic hyperprolactinemia may increase the risk for long-term complications, such as decreased bone mineral density and osteoporosis, although available evidence has conflicting findings.¹

Hyperprolactinemia is diagnosed by a prolactin concentration above the upper reference range.³ Various hormones and neurotransmitters can impact inhibition or stimulation of prolactin release.⁵ For example, dopamine tonically inhibits prolactin release and synthesis, whereas estrogen stimulates prolactin secretion.^1,5 Prolactin also can be elevated under several physiologic and pathologic conditions, such as during stressful situations, meals, or sexual activity.^1,5 A prolactin level >250 ng/mL is usually indicative of a prolactinoma; however, some medications, such as strong D2 receptor antagonists (eg, risperidone, haloperidol), can cause significant elevation without evidence of prolactinoma.³ In the absence of a tumor, medications are often identified as the cause of hyperprolactinemia.³ According to the Endocrinology Society clinical practice guideline, medication-induced elevated prolactin levels are typically between 25 to 100 ng/mL.³

Medication-induced hyperprolactinemia

Antipsychotics, antidepressants, hormonal preparations, antihypertensives, and gastrointestinal agents have been associated with hyperprolactinemia (Table 1^1,3,5-11). These medication classes increase prolactin by decreasing dopamine, which facilitates disinhibition of prolactin synthesis and release, or increasing prolactin stimulating hormones, such as serotonin or estrogen.⁵

Antipsychotics are the most common medication-related cause of hyperprolactinemia.³ Typical antipsychotics are more likely to cause hyperprolactinemia than atypical antipsychotics; the incidence among patients taking typical antipsychotics is 40% to 90%.³ Atypical antipsychotics, except risperidone and paliperidone, are considered to cause less endocrinologic effects than typical antipsychotics through various mechanisms: serotonergic receptor antagonism, fast dissociation from D2 receptors, D2 receptor partial agonism, and preferential binding of D3 vs D2 receptors.^1,5 By having transient D2 receptor association, clozapine and quetiapine are considered to have less risk of hyperprolactinemia compared with other atypical antipsychotics.^1,5 Aripiprazole, brexpiprazole, and cariprazine are partial D2 receptor agonists, and cariprazine is the only agent that exhibits preferential binding to D3 receptors.^12,13 Based on limited data, brexpiprazole and cariprazine may have prolactin-sparing properties given their partial D2 receptor agonism.^12,13 However, one study found increased prolactin levels in some patients after treatment with brexpiprazole, 4 mg/d.¹⁴ Similarly, another study found that cariprazine could increase prolactin levels as much as 4.1 ng/mL, depending on the dose.¹⁵ Except for aripiprazole, brexpiprazole, cariprazine, and clozapine, all other atypical antipsychotics marketed in the United States have a standard warning in the package insert regarding prolactin elevations.^1,16,17

Because antidepressants are less well-studied as a cause of medication-induced hyperprolactinemia, drawing definitive conclusions regarding incidence rates is limited, but the incidence seems to be fairly low.^6,18 A French pharmacovigilance study found that of 182,836 spontaneous adverse drug events reported between 1985 and 2009, there were 159 reports of selective serotonin reuptake inhibitors (SSRIs) inducing hyper­prolactinemia.⁶ Fluoxetine and paroxetine represented about one-half of the cases; however, there were also cases associated with citalopram, escitalopram, sertraline, fluvoxamine, milnacipran, and venlafaxine. In comparison, there were only 11 reports of hyperprolactinemia associated with tricyclic antidepressants or monoamine oxidase inhibitors. Although patients were not always symptomatic, the most commonly reported symptoms were galactorrhea (55%), gynecomastia (29%), amenorrhea (11%), mastodynia (11%), and sexual disorders (4%).⁶ Another study of 5,920 patients treated with fluoxetine found mastodynia in 0.25%, gynecomastia in 0.08%, and galactorrhea in 0.07% of patients.¹⁸ Symptoms occurred in an extremely low percentage of patients, and the study is >20 years old.¹⁸

Mirtazapine and bupropion have been found to be prolactin-neutral.⁵ Bupropion also has been reported to decrease prolactin levels, potentially via its ability to block dopamine reuptake.¹⁹

Managing medication-induced hyperprolactinemia

Screening for and identifying clinically significant hyperprolactinemia is critical, because adverse effects of medications can lead to nonadherence and clinical decompensation.²⁰ Patients must be informed of potential symptoms of hyperprolactinemia, and clinicians should inquire about such symptoms at each visit. Routine monitoring of prolactin levels in asymptomatic patients is not necessary, because the Endocrine Society Clinical Practice Guideline does not recommend treating patients with asymptomatic medication-induced hyperprolactinemia.³

In patients who report hyperprolactinemia symptoms, clinicians should review the patient’s prescribed medications and past medical history (eg, chronic renal failure, hypothyroidism) for potential causes or exacerbations, and address these factors accordingly.³ Order a measurement of prolactin level. A patient with a prolactin level >100 ng/mL should be referred to Endocrinology to rule out prolactinoma.¹

If a patient’s prolactin level is between 25 and 100 ng/mL, review the patient’s medications (Table 1^1,3,5-11), because prolactin levels within this range usually signal a medication-induced cause.³ For patients with antipsychotic-induced hyperprolactinemia, there are several management strategies (Table 2^{1,3,4,9,16,17,21-27}):

• Watch and wait may be warranted when the patient is experiencing mild hyperprolactinemia symptoms.
• Discontinue. If the patient can be maintained without an antipsychotic, discontinuing the antipsychotic would be a first-line option.³
• Reduce the dose. Reducing the antipsychotic dose may be the preferred strategy for patients with moderate to severe hyperprolactinemia symptoms who responded to the antipsychotic and do not wish to start adjunctive therapy.⁴
• Switching to a prolactin-sparing antipsychotic may help normalize prolactin levels and may be preferred when the risk of relapse is low.³ Dopamine agonists can treat medication-induced hyperprolactinemia, but may worsen psychiatric symptoms.^28,29 Therefore, this may be the preferred strategy if the offending medication cannot be discontinued or switched, or if the patient has a comorbid prolactinoma.

Less data exist on managing hyperprolactinemia that is induced by a medication other than an antipsychotic; however, it seems reasonable that the same strategies could be implemented. Specifically, for SSRI–induced hyperprolactinemia, if clinically appropriate, switching to or adding an alternative antidepressant that may be prolactin-sparing, such as mirtazapine or bupropion, could be attempted.⁸ One study found that fluoxetine-induced galactorrhea ceased within 10 days of discontinuing the medication.³⁰

CASE CONTINUED

Because Ms. E has been on the same medication regimen for 3 years and recently developed galactorrhea, it seems unlikely that her hyperprolactinemia is medication-induced. However, a tumor-related cause is less likely because the prolactin level is <100 ng/mL. Based on the literature, the only possible medication-induced cause of her galactorrhea is risperidone. Ms. E agrees to a trial of adjunctive oral aripiprazole, 5 mg/d, with close monitoring of her type 2 diabetes mellitus. Because of the long elimination half-life of aripiprazole, 1 month is required to monitor for improvement in galactorrhea. Ms. E is advised to use breast pads as a nonpharmacologic strategy in the interim. After 1 month of treatment, Ms. E denies galactorrhea symptoms and no longer requires the use of breast pads.

Ms. E, age 23, presents to your office for a routine visit for management of bipolar I disorder and posttraumatic stress disorder with comorbid type 2 diabetes mellitus. She currently is taking risperidone, 3 mg/d, lamotrigine, 200 mg/d, metformin, 2,000 mg/d, medroxyprogesterone, 150 mg every 3 months, and prazosin, 8 mg/d. Her mood has been stabilized for the last 3 years with this medication regimen.

Ms. E has a history of self-discontinuing medication when adverse events occur. She has been hospitalized twice for psychosis and suicide attempts. Past psychotropic medications that have been discontinued due to adverse effects include ziprasidone (mild abnormal lip movement), olanzapine (ineffective and drowsy), valproic acid (tremor and abdominal discomfort), lithium (rash), and aripiprazole (increased fasting blood sugar and labile mood).

At her appointment today, Ms. E says she is concerned because she has been experiencing galactorrhea for the past 4 weeks. Her prolactin level is 14.4 ng/mL; a normal level for a woman who is not pregnant is <25 ng/mL. However, a repeat prolactin level is obtained, and is found to be elevated at 38 ng/mL.

Prolactin, a polypeptide hormone that is secreted from the pituitary gland, has many functions, including involvement in the synthesis and maintenance of breast milk production, in reproductive behavior, and in luteal function.^1,2 Hyperprolactinemia—an elevated prolactin level—is a common endocrinologic disorder of the hypothalamic–pituitary–axis.³ Children, adolescents, premenopausal women, and women in the perinatal period are more vulnerable to medication-induced hyperprolactinemia.⁴ If not asymptomatic, patients with hyperprolactinemia may experience amenorrhea, galactorrhea, hypogonadism, sexual dysfunction, or infertility.^1,4 Chronic hyperprolactinemia may increase the risk for long-term complications, such as decreased bone mineral density and osteoporosis, although available evidence has conflicting findings.¹

Hyperprolactinemia is diagnosed by a prolactin concentration above the upper reference range.³ Various hormones and neurotransmitters can impact inhibition or stimulation of prolactin release.⁵ For example, dopamine tonically inhibits prolactin release and synthesis, whereas estrogen stimulates prolactin secretion.^1,5 Prolactin also can be elevated under several physiologic and pathologic conditions, such as during stressful situations, meals, or sexual activity.^1,5 A prolactin level >250 ng/mL is usually indicative of a prolactinoma; however, some medications, such as strong D2 receptor antagonists (eg, risperidone, haloperidol), can cause significant elevation without evidence of prolactinoma.³ In the absence of a tumor, medications are often identified as the cause of hyperprolactinemia.³ According to the Endocrinology Society clinical practice guideline, medication-induced elevated prolactin levels are typically between 25 to 100 ng/mL.³

Medication-induced hyperprolactinemia

Antipsychotics, antidepressants, hormonal preparations, antihypertensives, and gastrointestinal agents have been associated with hyperprolactinemia (Table 1^1,3,5-11). These medication classes increase prolactin by decreasing dopamine, which facilitates disinhibition of prolactin synthesis and release, or increasing prolactin stimulating hormones, such as serotonin or estrogen.⁵

Antipsychotics are the most common medication-related cause of hyperprolactinemia.³ Typical antipsychotics are more likely to cause hyperprolactinemia than atypical antipsychotics; the incidence among patients taking typical antipsychotics is 40% to 90%.³ Atypical antipsychotics, except risperidone and paliperidone, are considered to cause less endocrinologic effects than typical antipsychotics through various mechanisms: serotonergic receptor antagonism, fast dissociation from D2 receptors, D2 receptor partial agonism, and preferential binding of D3 vs D2 receptors.^1,5 By having transient D2 receptor association, clozapine and quetiapine are considered to have less risk of hyperprolactinemia compared with other atypical antipsychotics.^1,5 Aripiprazole, brexpiprazole, and cariprazine are partial D2 receptor agonists, and cariprazine is the only agent that exhibits preferential binding to D3 receptors.^12,13 Based on limited data, brexpiprazole and cariprazine may have prolactin-sparing properties given their partial D2 receptor agonism.^12,13 However, one study found increased prolactin levels in some patients after treatment with brexpiprazole, 4 mg/d.¹⁴ Similarly, another study found that cariprazine could increase prolactin levels as much as 4.1 ng/mL, depending on the dose.¹⁵ Except for aripiprazole, brexpiprazole, cariprazine, and clozapine, all other atypical antipsychotics marketed in the United States have a standard warning in the package insert regarding prolactin elevations.^1,16,17

Because antidepressants are less well-studied as a cause of medication-induced hyperprolactinemia, drawing definitive conclusions regarding incidence rates is limited, but the incidence seems to be fairly low.^6,18 A French pharmacovigilance study found that of 182,836 spontaneous adverse drug events reported between 1985 and 2009, there were 159 reports of selective serotonin reuptake inhibitors (SSRIs) inducing hyper­prolactinemia.⁶ Fluoxetine and paroxetine represented about one-half of the cases; however, there were also cases associated with citalopram, escitalopram, sertraline, fluvoxamine, milnacipran, and venlafaxine. In comparison, there were only 11 reports of hyperprolactinemia associated with tricyclic antidepressants or monoamine oxidase inhibitors. Although patients were not always symptomatic, the most commonly reported symptoms were galactorrhea (55%), gynecomastia (29%), amenorrhea (11%), mastodynia (11%), and sexual disorders (4%).⁶ Another study of 5,920 patients treated with fluoxetine found mastodynia in 0.25%, gynecomastia in 0.08%, and galactorrhea in 0.07% of patients.¹⁸ Symptoms occurred in an extremely low percentage of patients, and the study is >20 years old.¹⁸

Mirtazapine and bupropion have been found to be prolactin-neutral.⁵ Bupropion also has been reported to decrease prolactin levels, potentially via its ability to block dopamine reuptake.¹⁹

Managing medication-induced hyperprolactinemia

Screening for and identifying clinically significant hyperprolactinemia is critical, because adverse effects of medications can lead to nonadherence and clinical decompensation.²⁰ Patients must be informed of potential symptoms of hyperprolactinemia, and clinicians should inquire about such symptoms at each visit. Routine monitoring of prolactin levels in asymptomatic patients is not necessary, because the Endocrine Society Clinical Practice Guideline does not recommend treating patients with asymptomatic medication-induced hyperprolactinemia.³

In patients who report hyperprolactinemia symptoms, clinicians should review the patient’s prescribed medications and past medical history (eg, chronic renal failure, hypothyroidism) for potential causes or exacerbations, and address these factors accordingly.³ Order a measurement of prolactin level. A patient with a prolactin level >100 ng/mL should be referred to Endocrinology to rule out prolactinoma.¹

If a patient’s prolactin level is between 25 and 100 ng/mL, review the patient’s medications (Table 1^1,3,5-11), because prolactin levels within this range usually signal a medication-induced cause.³ For patients with antipsychotic-induced hyperprolactinemia, there are several management strategies (Table 2^{1,3,4,9,16,17,21-27}):

• Watch and wait may be warranted when the patient is experiencing mild hyperprolactinemia symptoms.
• Discontinue. If the patient can be maintained without an antipsychotic, discontinuing the antipsychotic would be a first-line option.³
• Reduce the dose. Reducing the antipsychotic dose may be the preferred strategy for patients with moderate to severe hyperprolactinemia symptoms who responded to the antipsychotic and do not wish to start adjunctive therapy.⁴
• Switching to a prolactin-sparing antipsychotic may help normalize prolactin levels and may be preferred when the risk of relapse is low.³ Dopamine agonists can treat medication-induced hyperprolactinemia, but may worsen psychiatric symptoms.^28,29 Therefore, this may be the preferred strategy if the offending medication cannot be discontinued or switched, or if the patient has a comorbid prolactinoma.

Less data exist on managing hyperprolactinemia that is induced by a medication other than an antipsychotic; however, it seems reasonable that the same strategies could be implemented. Specifically, for SSRI–induced hyperprolactinemia, if clinically appropriate, switching to or adding an alternative antidepressant that may be prolactin-sparing, such as mirtazapine or bupropion, could be attempted.⁸ One study found that fluoxetine-induced galactorrhea ceased within 10 days of discontinuing the medication.³⁰

CASE CONTINUED

Because Ms. E has been on the same medication regimen for 3 years and recently developed galactorrhea, it seems unlikely that her hyperprolactinemia is medication-induced. However, a tumor-related cause is less likely because the prolactin level is <100 ng/mL. Based on the literature, the only possible medication-induced cause of her galactorrhea is risperidone. Ms. E agrees to a trial of adjunctive oral aripiprazole, 5 mg/d, with close monitoring of her type 2 diabetes mellitus. Because of the long elimination half-life of aripiprazole, 1 month is required to monitor for improvement in galactorrhea. Ms. E is advised to use breast pads as a nonpharmacologic strategy in the interim. After 1 month of treatment, Ms. E denies galactorrhea symptoms and no longer requires the use of breast pads.

CASE Psychotic and reclusive

Ms. A, age 51, has schizophrenia and has been doing well living at a supervised residential facility. She was stable on haloperidol, 10 mg twice a day, for years but recently became agitated, threatening her roommate and yelling during the night. Ms. A begins to refuse to take her haloperidol. She also refuses to attend several outpatient appointments. As a result, Ms. A is admitted to the psychiatric unit on an involuntary basis.

In the hospital, Ms. A rarely comes out of her room. When she does come out, she usually sits in a chair, talking to herself and occasionally yelling or crying in apparent distress. Ms. A refuses to engage with her treatment team and lies mute in her bed when they attempt to interview her. Her records indicate that previous medication trials have included chlorpromazine, fluphenazine, haloperidol, paliperidone, ziprasidone, and quetiapine. Despite her present decompensation, discussion with the clinicians who had previously treated her reveals that she has done well on haloperidol and thus she is restarted on her outpatient dose.

Over the next week, Ms. A begins to interact more appropriately with nursing staff and can make her needs known; however, conversations are still extremely brief and based primarily around her requests. Although the frequency of her distressed outbursts has decreased, she is still responding to internal stimuli, loudly yelling and crying out at times. After 2 weeks, Ms. A still will not cooperate with her treatment team or social workers. She refuses to talk about planning her discharge, and often remains in bed for long periods during the day.

[polldaddy:9945425]

The authors’ observations

As a class, antipsychotics lead to symptom reduction in approximately 70% of patients.¹ However, the degree of response can vary markedly between individuals; although some patients may experience almost complete resolution of symptoms, others are still markedly impaired, as in Ms. A’s case.

A substantial amount of literature suggests that although the practice is common, use of >1 antipsychotic does not significantly increase efficacy but increases risk of adverse effects, such as type 2 diabetes mellitus, metabolic syndrome, cognitive impairment, and extrapyramidal symptoms.^2-4 One exception is augmentation of clozapine with a second anti­psychotic, which in certain cases appears to offer greater efficacy than clozapine alone.¹ Practice guidelines and evidence generally do not support the use of multiple antipsychotics, but 20% of patients take >1 antipsychotic.^5,6 Although antipsychotic polypharmacy may be appropriate for some patients, current literature suggests it is being done more often than recommended.

Clozapine is considered the most efficacious option for treatment-resistant schizophrenia.⁷ Because of Ms. A’s history of recurrent hospitalizations, her extensive list of trialed medications, and her ongoing symptoms despite a sufficient trial of haloperidol, the treatment team gives serious consideration to switching Ms. A to clozapine. However, Ms. A is not able to tolerate blood draws without significant support from nursing staff, and it is likely she would be unable to tolerate the frequent blood monitoring required of patients receiving clozapine.

Because many of Ms. A’s symptoms were negative or depressive, including hypersomnia, psychomotor retardation, sadness with frequent crying spells, and reduced interest in activities, adding an antidepressant to Ms. A’s medication regimen was considered. A recent systematic review and meta-analysis showed that adding an antidepressant to an antipsychotic in patients with schizophrenia had small but beneficial effects on depressive and negative symptoms and a low risk of adverse effects.⁸ However, Ms. A declined this option.

 

 

TREATMENT Adding long-acting haloperidol

Ms. A had previously achieved therapeutic blood levels⁹ with oral haloperidol. Data suggest that compared with the oral form, long-acting injectable antipsychotics can both improve compliance and decrease rehospitalization rates.^10-12 Because Ms. A previously had done well with haloperidol decanoate, 200 mg every 2 weeks, achieving a blood level of 16.2 ng/mL, and because she had a partial response to oral haloperidol, we add haloperidol decanoate, 100 mg every 2 weeks, to her regimen, with the intention of transitioning her to all-depot dosing. In addition, the treatment team tries to engage Ms. A in a discussion of potential psychological contributions to her current presentation. They note that Ms. A has her basic needs met on the unit and reports feeling safe there; thus, a fear of discharge may be contributing to her lack of engagement with the team. However, because of her limited communication, it is challenging to investigate this hypothesis or explore other possible psychological issues.

Despite increasing the dosing of haloperidol, Ms. A shows minimal improvement. She continues to stonewall her treatment team, and is unwilling or unable to engage in meaningful conversation. A review of her chart suggests that this hospital course is different from previous ones in which her average stay was a few weeks, and she generally was able to converse with the treatment team, participate in discussions about her care, and make decisions about her desire for discharge.

The team considers if additional factors could be impacting Ms. A’s current presentation. They raise the possibility that she could be going through menopause, and hormonal fluctuations may be contributing to her symptoms. Despite being on the unit for nearly 2 months, Ms. A has not required the use of sanitary products. She also reports to nursing staff that at times she feels flushed and sweaty, but she is afebrile and does not have other signs or symptoms of infection.

[polldaddy:9945428]

The authors’ observations

Evidence suggests that estrogen levels can influence the development and severity of symptoms of schizophrenia (Table 1^13,14). Rates of schizophrenia are lower in women, and women typically have a later onset of illness with less severe symptoms.¹³ Women also have a second peak incidence of schizophrenia between ages 45 and 50, corresponding with the hormonal changes associated with menopause and the associated drop in estrogen.¹⁴ Symptoms also fluctuate with hormonal cycles—women experience worsening symptoms during the premenstrual phase of the menstrual cycle, when estrogen levels are low, and an improvement of symptoms during high-estrogen phases of the cycle.¹⁴ Overall, low levels of estrogen also have been observed in women with schizophrenia relative to controls, although this may be partially attributable to treatment with antipsychotics.¹⁴

Estrogen affects various regions of the brain implicated in schizophrenia and likely imparts its behavioral effects through several different mechanisms. Estrogen can act on cells to directly impact intracellular signaling and to alter gene expression.¹⁵ Although most often thought of as being related to reproductive functions, estrogen receptors can be found in many cortical and subcortical regions of the brain, such as the hippocampus, substantia nigra, and prefrontal cortex. Estrogen receptor expression levels in certain brain regions have been found to be altered in individuals with schizophrenia.¹⁵ Estrogen also enhances neurogenesis and neuroplasticity, playing a role in learning and memory.¹⁶ Particularly relevant, estrogen has been shown to directly impact both the dopaminergic and serotonergic systems.^15,17 In animal models, estrogen has been shown to decrease the behavioral effects induced by dopamine agonists and decrease symptoms of schizophrenia.¹⁸ The underlying molecular mechanisms by which estrogen has these effects are uncertain.

Given estrogen’s potentially protective effects, clinical trials have explored the role of estrogen as an adjuvant to antipsychotics for treating schizophrenia. Studies have shown that estrogen can improve psychotic symptoms in patients with schizophrenia.^19,20 However, because estrogen administration can increase the risk of breast and uterine cancer, researchers are instead investigating selective estrogen receptor modulators (SERMs).¹⁴ These medications have mixed agonist and antagonist effects, with different effects on different tissues. Raloxifene is a SERM that acts as an estrogen agonist in some tissues, but an antagonist in uterine and breast tissue, which may minimize potential deleterious adverse effects (Table 2^21-24). Repeated randomized controlled trials have found promising results for use of raloxifene as an adjunctive treatment in peri- and postmenopausal women with schizophrenia, including those refractory to antipsychotic treatment.^13,25-27

TREATMENT Address symptoms

The treatment team takes steps to address Ms. A’s perimenopausal symptoms. For mild to moderate hot flashes, primary interventions are nonpharmacologic.²⁸ Because Ms. A primarily reports her hot flashes at night, she is given lightweight pajamas and moved to the coolest room on the unit. Both bring some relief, and her hot flashes appear to be less distressing. The treatment team decides to consult Endocrinology to further investigate the feasibility of starting raloxifene (Table 3) because of their experience using this medication to manage osteoporosis.

[polldaddy:9945429]

The authors’ observations

Raloxifene is FDA-approved for treating osteoporosis and preventing invasive breast cancer.²⁹ Because it is an estrogen antagonist in both breast and uterine tissues, raloxifene does not increase the risk of uterine or breast cancer. Large studies have shown rates of cardiovascular events are similar for raloxifene and placebo, and some studies have found that raloxifene treatment is associated with improvement in cardiovascular risk factors, including lower blood pressure, lower low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol.²⁹ Raloxifene does, however, increase risk of venous thromboembolism, including deep vein thrombosis and pulmonary embolism, and fatal stroke.^29,30 Overall, the risk remains relatively low, with an absolute risk increase of fatal stroke of 0.7 per 1,000 woman-years (number needed to harm [NNH]: 250) and an absolute risk increase of venous thromboembolic events of 1.88 per 1,000 women-years (NNH: 158).³¹ However, raloxifene may not be appropriate for patients with independent risk factors for these events. Despite this, a large meta-analysis found a 10% decrease in mortality for patients taking raloxifene compared with those receiving placebo.³² Raloxifene also can cause hot flashes, muscle cramps, and flu-like symptoms.²⁹

Diagnosis of menopause and perimenopause is largely clinical, with hormone testing generally recommended for women age <45 in whom the diagnosis may be unclear.²⁸ Thus, Ms. A’s vasomotor symptoms and absence of a menstrual cycle for at least 2 months were diagnostic of perimenopause; a 12-month cessation in menstrual cycles is required for a diagnosis of menopause.²⁸

OUTCOME Improvement with raloxifene

Because Ms. A is at relatively low risk for a thromboembolism or stroke, the benefit of raloxifene is thought to outweigh the risk, and she is started on raloxifene, 60 mg/d. Over the next 2 weeks, Ms. A becomes increasingly interactive, and is seen sitting at a table talking with other patients on multiple occasions. She spends time looking at fashion magazines, and engages in conversation about fashion with staff and other patients. She participates in group therapy for the first time during this hospital stay and begins to talk about discharge. She occasionally smiles and waves at her treatment team and participates more in the daily interview, although these interactions remain limited and on her terms. She maintains this improvement and is transferred to a psychiatric facility in her home county for ongoing care and discharge planning.

CASE Psychotic and reclusive

Ms. A, age 51, has schizophrenia and has been doing well living at a supervised residential facility. She was stable on haloperidol, 10 mg twice a day, for years but recently became agitated, threatening her roommate and yelling during the night. Ms. A begins to refuse to take her haloperidol. She also refuses to attend several outpatient appointments. As a result, Ms. A is admitted to the psychiatric unit on an involuntary basis.

In the hospital, Ms. A rarely comes out of her room. When she does come out, she usually sits in a chair, talking to herself and occasionally yelling or crying in apparent distress. Ms. A refuses to engage with her treatment team and lies mute in her bed when they attempt to interview her. Her records indicate that previous medication trials have included chlorpromazine, fluphenazine, haloperidol, paliperidone, ziprasidone, and quetiapine. Despite her present decompensation, discussion with the clinicians who had previously treated her reveals that she has done well on haloperidol and thus she is restarted on her outpatient dose.

Over the next week, Ms. A begins to interact more appropriately with nursing staff and can make her needs known; however, conversations are still extremely brief and based primarily around her requests. Although the frequency of her distressed outbursts has decreased, she is still responding to internal stimuli, loudly yelling and crying out at times. After 2 weeks, Ms. A still will not cooperate with her treatment team or social workers. She refuses to talk about planning her discharge, and often remains in bed for long periods during the day.

[polldaddy:9945425]

The authors’ observations

As a class, antipsychotics lead to symptom reduction in approximately 70% of patients.¹ However, the degree of response can vary markedly between individuals; although some patients may experience almost complete resolution of symptoms, others are still markedly impaired, as in Ms. A’s case.

A substantial amount of literature suggests that although the practice is common, use of >1 antipsychotic does not significantly increase efficacy but increases risk of adverse effects, such as type 2 diabetes mellitus, metabolic syndrome, cognitive impairment, and extrapyramidal symptoms.^2-4 One exception is augmentation of clozapine with a second anti­psychotic, which in certain cases appears to offer greater efficacy than clozapine alone.¹ Practice guidelines and evidence generally do not support the use of multiple antipsychotics, but 20% of patients take >1 antipsychotic.^5,6 Although antipsychotic polypharmacy may be appropriate for some patients, current literature suggests it is being done more often than recommended.

Clozapine is considered the most efficacious option for treatment-resistant schizophrenia.⁷ Because of Ms. A’s history of recurrent hospitalizations, her extensive list of trialed medications, and her ongoing symptoms despite a sufficient trial of haloperidol, the treatment team gives serious consideration to switching Ms. A to clozapine. However, Ms. A is not able to tolerate blood draws without significant support from nursing staff, and it is likely she would be unable to tolerate the frequent blood monitoring required of patients receiving clozapine.

Because many of Ms. A’s symptoms were negative or depressive, including hypersomnia, psychomotor retardation, sadness with frequent crying spells, and reduced interest in activities, adding an antidepressant to Ms. A’s medication regimen was considered. A recent systematic review and meta-analysis showed that adding an antidepressant to an antipsychotic in patients with schizophrenia had small but beneficial effects on depressive and negative symptoms and a low risk of adverse effects.⁸ However, Ms. A declined this option.

 

 

TREATMENT Adding long-acting haloperidol

Ms. A had previously achieved therapeutic blood levels⁹ with oral haloperidol. Data suggest that compared with the oral form, long-acting injectable antipsychotics can both improve compliance and decrease rehospitalization rates.^10-12 Because Ms. A previously had done well with haloperidol decanoate, 200 mg every 2 weeks, achieving a blood level of 16.2 ng/mL, and because she had a partial response to oral haloperidol, we add haloperidol decanoate, 100 mg every 2 weeks, to her regimen, with the intention of transitioning her to all-depot dosing. In addition, the treatment team tries to engage Ms. A in a discussion of potential psychological contributions to her current presentation. They note that Ms. A has her basic needs met on the unit and reports feeling safe there; thus, a fear of discharge may be contributing to her lack of engagement with the team. However, because of her limited communication, it is challenging to investigate this hypothesis or explore other possible psychological issues.

Despite increasing the dosing of haloperidol, Ms. A shows minimal improvement. She continues to stonewall her treatment team, and is unwilling or unable to engage in meaningful conversation. A review of her chart suggests that this hospital course is different from previous ones in which her average stay was a few weeks, and she generally was able to converse with the treatment team, participate in discussions about her care, and make decisions about her desire for discharge.

The team considers if additional factors could be impacting Ms. A’s current presentation. They raise the possibility that she could be going through menopause, and hormonal fluctuations may be contributing to her symptoms. Despite being on the unit for nearly 2 months, Ms. A has not required the use of sanitary products. She also reports to nursing staff that at times she feels flushed and sweaty, but she is afebrile and does not have other signs or symptoms of infection.

[polldaddy:9945428]

The authors’ observations

Evidence suggests that estrogen levels can influence the development and severity of symptoms of schizophrenia (Table 1^13,14). Rates of schizophrenia are lower in women, and women typically have a later onset of illness with less severe symptoms.¹³ Women also have a second peak incidence of schizophrenia between ages 45 and 50, corresponding with the hormonal changes associated with menopause and the associated drop in estrogen.¹⁴ Symptoms also fluctuate with hormonal cycles—women experience worsening symptoms during the premenstrual phase of the menstrual cycle, when estrogen levels are low, and an improvement of symptoms during high-estrogen phases of the cycle.¹⁴ Overall, low levels of estrogen also have been observed in women with schizophrenia relative to controls, although this may be partially attributable to treatment with antipsychotics.¹⁴

Estrogen affects various regions of the brain implicated in schizophrenia and likely imparts its behavioral effects through several different mechanisms. Estrogen can act on cells to directly impact intracellular signaling and to alter gene expression.¹⁵ Although most often thought of as being related to reproductive functions, estrogen receptors can be found in many cortical and subcortical regions of the brain, such as the hippocampus, substantia nigra, and prefrontal cortex. Estrogen receptor expression levels in certain brain regions have been found to be altered in individuals with schizophrenia.¹⁵ Estrogen also enhances neurogenesis and neuroplasticity, playing a role in learning and memory.¹⁶ Particularly relevant, estrogen has been shown to directly impact both the dopaminergic and serotonergic systems.^15,17 In animal models, estrogen has been shown to decrease the behavioral effects induced by dopamine agonists and decrease symptoms of schizophrenia.¹⁸ The underlying molecular mechanisms by which estrogen has these effects are uncertain.

Given estrogen’s potentially protective effects, clinical trials have explored the role of estrogen as an adjuvant to antipsychotics for treating schizophrenia. Studies have shown that estrogen can improve psychotic symptoms in patients with schizophrenia.^19,20 However, because estrogen administration can increase the risk of breast and uterine cancer, researchers are instead investigating selective estrogen receptor modulators (SERMs).¹⁴ These medications have mixed agonist and antagonist effects, with different effects on different tissues. Raloxifene is a SERM that acts as an estrogen agonist in some tissues, but an antagonist in uterine and breast tissue, which may minimize potential deleterious adverse effects (Table 2^21-24). Repeated randomized controlled trials have found promising results for use of raloxifene as an adjunctive treatment in peri- and postmenopausal women with schizophrenia, including those refractory to antipsychotic treatment.^13,25-27

TREATMENT Address symptoms

The treatment team takes steps to address Ms. A’s perimenopausal symptoms. For mild to moderate hot flashes, primary interventions are nonpharmacologic.²⁸ Because Ms. A primarily reports her hot flashes at night, she is given lightweight pajamas and moved to the coolest room on the unit. Both bring some relief, and her hot flashes appear to be less distressing. The treatment team decides to consult Endocrinology to further investigate the feasibility of starting raloxifene (Table 3) because of their experience using this medication to manage osteoporosis.

[polldaddy:9945429]

The authors’ observations

Raloxifene is FDA-approved for treating osteoporosis and preventing invasive breast cancer.²⁹ Because it is an estrogen antagonist in both breast and uterine tissues, raloxifene does not increase the risk of uterine or breast cancer. Large studies have shown rates of cardiovascular events are similar for raloxifene and placebo, and some studies have found that raloxifene treatment is associated with improvement in cardiovascular risk factors, including lower blood pressure, lower low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol.²⁹ Raloxifene does, however, increase risk of venous thromboembolism, including deep vein thrombosis and pulmonary embolism, and fatal stroke.^29,30 Overall, the risk remains relatively low, with an absolute risk increase of fatal stroke of 0.7 per 1,000 woman-years (number needed to harm [NNH]: 250) and an absolute risk increase of venous thromboembolic events of 1.88 per 1,000 women-years (NNH: 158).³¹ However, raloxifene may not be appropriate for patients with independent risk factors for these events. Despite this, a large meta-analysis found a 10% decrease in mortality for patients taking raloxifene compared with those receiving placebo.³² Raloxifene also can cause hot flashes, muscle cramps, and flu-like symptoms.²⁹

Diagnosis of menopause and perimenopause is largely clinical, with hormone testing generally recommended for women age <45 in whom the diagnosis may be unclear.²⁸ Thus, Ms. A’s vasomotor symptoms and absence of a menstrual cycle for at least 2 months were diagnostic of perimenopause; a 12-month cessation in menstrual cycles is required for a diagnosis of menopause.²⁸

OUTCOME Improvement with raloxifene

Because Ms. A is at relatively low risk for a thromboembolism or stroke, the benefit of raloxifene is thought to outweigh the risk, and she is started on raloxifene, 60 mg/d. Over the next 2 weeks, Ms. A becomes increasingly interactive, and is seen sitting at a table talking with other patients on multiple occasions. She spends time looking at fashion magazines, and engages in conversation about fashion with staff and other patients. She participates in group therapy for the first time during this hospital stay and begins to talk about discharge. She occasionally smiles and waves at her treatment team and participates more in the daily interview, although these interactions remain limited and on her terms. She maintains this improvement and is transferred to a psychiatric facility in her home county for ongoing care and discharge planning.

CASE Psychotic and reclusive

Ms. A, age 51, has schizophrenia and has been doing well living at a supervised residential facility. She was stable on haloperidol, 10 mg twice a day, for years but recently became agitated, threatening her roommate and yelling during the night. Ms. A begins to refuse to take her haloperidol. She also refuses to attend several outpatient appointments. As a result, Ms. A is admitted to the psychiatric unit on an involuntary basis.

In the hospital, Ms. A rarely comes out of her room. When she does come out, she usually sits in a chair, talking to herself and occasionally yelling or crying in apparent distress. Ms. A refuses to engage with her treatment team and lies mute in her bed when they attempt to interview her. Her records indicate that previous medication trials have included chlorpromazine, fluphenazine, haloperidol, paliperidone, ziprasidone, and quetiapine. Despite her present decompensation, discussion with the clinicians who had previously treated her reveals that she has done well on haloperidol and thus she is restarted on her outpatient dose.

Over the next week, Ms. A begins to interact more appropriately with nursing staff and can make her needs known; however, conversations are still extremely brief and based primarily around her requests. Although the frequency of her distressed outbursts has decreased, she is still responding to internal stimuli, loudly yelling and crying out at times. After 2 weeks, Ms. A still will not cooperate with her treatment team or social workers. She refuses to talk about planning her discharge, and often remains in bed for long periods during the day.

[polldaddy:9945425]

The authors’ observations

As a class, antipsychotics lead to symptom reduction in approximately 70% of patients.¹ However, the degree of response can vary markedly between individuals; although some patients may experience almost complete resolution of symptoms, others are still markedly impaired, as in Ms. A’s case.

A substantial amount of literature suggests that although the practice is common, use of >1 antipsychotic does not significantly increase efficacy but increases risk of adverse effects, such as type 2 diabetes mellitus, metabolic syndrome, cognitive impairment, and extrapyramidal symptoms.^2-4 One exception is augmentation of clozapine with a second anti­psychotic, which in certain cases appears to offer greater efficacy than clozapine alone.¹ Practice guidelines and evidence generally do not support the use of multiple antipsychotics, but 20% of patients take >1 antipsychotic.^5,6 Although antipsychotic polypharmacy may be appropriate for some patients, current literature suggests it is being done more often than recommended.

Clozapine is considered the most efficacious option for treatment-resistant schizophrenia.⁷ Because of Ms. A’s history of recurrent hospitalizations, her extensive list of trialed medications, and her ongoing symptoms despite a sufficient trial of haloperidol, the treatment team gives serious consideration to switching Ms. A to clozapine. However, Ms. A is not able to tolerate blood draws without significant support from nursing staff, and it is likely she would be unable to tolerate the frequent blood monitoring required of patients receiving clozapine.

Because many of Ms. A’s symptoms were negative or depressive, including hypersomnia, psychomotor retardation, sadness with frequent crying spells, and reduced interest in activities, adding an antidepressant to Ms. A’s medication regimen was considered. A recent systematic review and meta-analysis showed that adding an antidepressant to an antipsychotic in patients with schizophrenia had small but beneficial effects on depressive and negative symptoms and a low risk of adverse effects.⁸ However, Ms. A declined this option.

 

 

TREATMENT Adding long-acting haloperidol

Ms. A had previously achieved therapeutic blood levels⁹ with oral haloperidol. Data suggest that compared with the oral form, long-acting injectable antipsychotics can both improve compliance and decrease rehospitalization rates.^10-12 Because Ms. A previously had done well with haloperidol decanoate, 200 mg every 2 weeks, achieving a blood level of 16.2 ng/mL, and because she had a partial response to oral haloperidol, we add haloperidol decanoate, 100 mg every 2 weeks, to her regimen, with the intention of transitioning her to all-depot dosing. In addition, the treatment team tries to engage Ms. A in a discussion of potential psychological contributions to her current presentation. They note that Ms. A has her basic needs met on the unit and reports feeling safe there; thus, a fear of discharge may be contributing to her lack of engagement with the team. However, because of her limited communication, it is challenging to investigate this hypothesis or explore other possible psychological issues.

Despite increasing the dosing of haloperidol, Ms. A shows minimal improvement. She continues to stonewall her treatment team, and is unwilling or unable to engage in meaningful conversation. A review of her chart suggests that this hospital course is different from previous ones in which her average stay was a few weeks, and she generally was able to converse with the treatment team, participate in discussions about her care, and make decisions about her desire for discharge.

The team considers if additional factors could be impacting Ms. A’s current presentation. They raise the possibility that she could be going through menopause, and hormonal fluctuations may be contributing to her symptoms. Despite being on the unit for nearly 2 months, Ms. A has not required the use of sanitary products. She also reports to nursing staff that at times she feels flushed and sweaty, but she is afebrile and does not have other signs or symptoms of infection.

[polldaddy:9945428]

The authors’ observations

Evidence suggests that estrogen levels can influence the development and severity of symptoms of schizophrenia (Table 1^13,14). Rates of schizophrenia are lower in women, and women typically have a later onset of illness with less severe symptoms.¹³ Women also have a second peak incidence of schizophrenia between ages 45 and 50, corresponding with the hormonal changes associated with menopause and the associated drop in estrogen.¹⁴ Symptoms also fluctuate with hormonal cycles—women experience worsening symptoms during the premenstrual phase of the menstrual cycle, when estrogen levels are low, and an improvement of symptoms during high-estrogen phases of the cycle.¹⁴ Overall, low levels of estrogen also have been observed in women with schizophrenia relative to controls, although this may be partially attributable to treatment with antipsychotics.¹⁴

Estrogen affects various regions of the brain implicated in schizophrenia and likely imparts its behavioral effects through several different mechanisms. Estrogen can act on cells to directly impact intracellular signaling and to alter gene expression.¹⁵ Although most often thought of as being related to reproductive functions, estrogen receptors can be found in many cortical and subcortical regions of the brain, such as the hippocampus, substantia nigra, and prefrontal cortex. Estrogen receptor expression levels in certain brain regions have been found to be altered in individuals with schizophrenia.¹⁵ Estrogen also enhances neurogenesis and neuroplasticity, playing a role in learning and memory.¹⁶ Particularly relevant, estrogen has been shown to directly impact both the dopaminergic and serotonergic systems.^15,17 In animal models, estrogen has been shown to decrease the behavioral effects induced by dopamine agonists and decrease symptoms of schizophrenia.¹⁸ The underlying molecular mechanisms by which estrogen has these effects are uncertain.

Given estrogen’s potentially protective effects, clinical trials have explored the role of estrogen as an adjuvant to antipsychotics for treating schizophrenia. Studies have shown that estrogen can improve psychotic symptoms in patients with schizophrenia.^19,20 However, because estrogen administration can increase the risk of breast and uterine cancer, researchers are instead investigating selective estrogen receptor modulators (SERMs).¹⁴ These medications have mixed agonist and antagonist effects, with different effects on different tissues. Raloxifene is a SERM that acts as an estrogen agonist in some tissues, but an antagonist in uterine and breast tissue, which may minimize potential deleterious adverse effects (Table 2^21-24). Repeated randomized controlled trials have found promising results for use of raloxifene as an adjunctive treatment in peri- and postmenopausal women with schizophrenia, including those refractory to antipsychotic treatment.^13,25-27

TREATMENT Address symptoms

The treatment team takes steps to address Ms. A’s perimenopausal symptoms. For mild to moderate hot flashes, primary interventions are nonpharmacologic.²⁸ Because Ms. A primarily reports her hot flashes at night, she is given lightweight pajamas and moved to the coolest room on the unit. Both bring some relief, and her hot flashes appear to be less distressing. The treatment team decides to consult Endocrinology to further investigate the feasibility of starting raloxifene (Table 3) because of their experience using this medication to manage osteoporosis.

[polldaddy:9945429]

The authors’ observations

Raloxifene is FDA-approved for treating osteoporosis and preventing invasive breast cancer.²⁹ Because it is an estrogen antagonist in both breast and uterine tissues, raloxifene does not increase the risk of uterine or breast cancer. Large studies have shown rates of cardiovascular events are similar for raloxifene and placebo, and some studies have found that raloxifene treatment is associated with improvement in cardiovascular risk factors, including lower blood pressure, lower low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol.²⁹ Raloxifene does, however, increase risk of venous thromboembolism, including deep vein thrombosis and pulmonary embolism, and fatal stroke.^29,30 Overall, the risk remains relatively low, with an absolute risk increase of fatal stroke of 0.7 per 1,000 woman-years (number needed to harm [NNH]: 250) and an absolute risk increase of venous thromboembolic events of 1.88 per 1,000 women-years (NNH: 158).³¹ However, raloxifene may not be appropriate for patients with independent risk factors for these events. Despite this, a large meta-analysis found a 10% decrease in mortality for patients taking raloxifene compared with those receiving placebo.³² Raloxifene also can cause hot flashes, muscle cramps, and flu-like symptoms.²⁹

Diagnosis of menopause and perimenopause is largely clinical, with hormone testing generally recommended for women age <45 in whom the diagnosis may be unclear.²⁸ Thus, Ms. A’s vasomotor symptoms and absence of a menstrual cycle for at least 2 months were diagnostic of perimenopause; a 12-month cessation in menstrual cycles is required for a diagnosis of menopause.²⁸

OUTCOME Improvement with raloxifene

Because Ms. A is at relatively low risk for a thromboembolism or stroke, the benefit of raloxifene is thought to outweigh the risk, and she is started on raloxifene, 60 mg/d. Over the next 2 weeks, Ms. A becomes increasingly interactive, and is seen sitting at a table talking with other patients on multiple occasions. She spends time looking at fashion magazines, and engages in conversation about fashion with staff and other patients. She participates in group therapy for the first time during this hospital stay and begins to talk about discharge. She occasionally smiles and waves at her treatment team and participates more in the daily interview, although these interactions remain limited and on her terms. She maintains this improvement and is transferred to a psychiatric facility in her home county for ongoing care and discharge planning.

Hospital psychiatrists often are asked whether a patient with comorbid medical and psychiatric illnesses should be admitted to an inpatient psychiatry unit or to a medical unit. Psychiatric units vary widely in their capacity to manage patients’ medical conditions. Medical comorbidity also is associated with longer psychiatric hospitalizations.¹ The decision of where to admit may be particularly challenging when presented with a patient with delirium, which often mimics primary psychiatric illnesses such as depression but will not resolve without treatment of the underlying illness. While diagnosis and treatment of delirium typically occur in the hospital setting, 1 study found that approximately 15% of 199 psychiatric inpatients were delirious and that these patients had hospital stays that were approximately 62% longer than those without delirium.²

When you need to determine whether a patient should be admitted to an inpatient psychiatry unit with a medical consult or vice versa, consider the following 3 Ms and 3 Ps.

Medications. Can medications, including those that are given intravenously or require serum monitoring, be administered on the psychiatric unit? Can the medical unit administer involuntary psychotropics?

Mobility. Does the patient require assistance with mobility? Does the patient pose a fall risk? A physical therapy consult may be helpful.

Monitoring. Suicide risk is the most common indication for patient sitters.³ Would a patient sitter be needed for the patient? On the other hand, can the psychiatry unit manage telemetry, frequent vital signs, or infectious disease precautions?

People. Would the patient benefit from the therapeutic milieu and specialized staff of an inpatient psychiatry unit?

Prognosis. What ongoing medical and psychiatric management is required? What are the medical and psychiatric prognoses?

Placement. To where will the patient be transferred after hospitalization? How does admission to inpatient psychiatry vs medical impact the ultimate disposition?

Help the treatment team make the decision

Determining the ideal patient placement often evokes strong feelings among treatment teams. Psychiatrists can help facilitate the conversation by asking the questions outlined above, and by keep­ing in mind, “What is best for this patient?”

Hospital psychiatrists often are asked whether a patient with comorbid medical and psychiatric illnesses should be admitted to an inpatient psychiatry unit or to a medical unit. Psychiatric units vary widely in their capacity to manage patients’ medical conditions. Medical comorbidity also is associated with longer psychiatric hospitalizations.¹ The decision of where to admit may be particularly challenging when presented with a patient with delirium, which often mimics primary psychiatric illnesses such as depression but will not resolve without treatment of the underlying illness. While diagnosis and treatment of delirium typically occur in the hospital setting, 1 study found that approximately 15% of 199 psychiatric inpatients were delirious and that these patients had hospital stays that were approximately 62% longer than those without delirium.²

When you need to determine whether a patient should be admitted to an inpatient psychiatry unit with a medical consult or vice versa, consider the following 3 Ms and 3 Ps.

Medications. Can medications, including those that are given intravenously or require serum monitoring, be administered on the psychiatric unit? Can the medical unit administer involuntary psychotropics?

Mobility. Does the patient require assistance with mobility? Does the patient pose a fall risk? A physical therapy consult may be helpful.

Monitoring. Suicide risk is the most common indication for patient sitters.³ Would a patient sitter be needed for the patient? On the other hand, can the psychiatry unit manage telemetry, frequent vital signs, or infectious disease precautions?

People. Would the patient benefit from the therapeutic milieu and specialized staff of an inpatient psychiatry unit?

Prognosis. What ongoing medical and psychiatric management is required? What are the medical and psychiatric prognoses?

Placement. To where will the patient be transferred after hospitalization? How does admission to inpatient psychiatry vs medical impact the ultimate disposition?

Help the treatment team make the decision

Determining the ideal patient placement often evokes strong feelings among treatment teams. Psychiatrists can help facilitate the conversation by asking the questions outlined above, and by keep­ing in mind, “What is best for this patient?”

Hospital psychiatrists often are asked whether a patient with comorbid medical and psychiatric illnesses should be admitted to an inpatient psychiatry unit or to a medical unit. Psychiatric units vary widely in their capacity to manage patients’ medical conditions. Medical comorbidity also is associated with longer psychiatric hospitalizations.¹ The decision of where to admit may be particularly challenging when presented with a patient with delirium, which often mimics primary psychiatric illnesses such as depression but will not resolve without treatment of the underlying illness. While diagnosis and treatment of delirium typically occur in the hospital setting, 1 study found that approximately 15% of 199 psychiatric inpatients were delirious and that these patients had hospital stays that were approximately 62% longer than those without delirium.²

When you need to determine whether a patient should be admitted to an inpatient psychiatry unit with a medical consult or vice versa, consider the following 3 Ms and 3 Ps.

Medications. Can medications, including those that are given intravenously or require serum monitoring, be administered on the psychiatric unit? Can the medical unit administer involuntary psychotropics?

Mobility. Does the patient require assistance with mobility? Does the patient pose a fall risk? A physical therapy consult may be helpful.

Monitoring. Suicide risk is the most common indication for patient sitters.³ Would a patient sitter be needed for the patient? On the other hand, can the psychiatry unit manage telemetry, frequent vital signs, or infectious disease precautions?

People. Would the patient benefit from the therapeutic milieu and specialized staff of an inpatient psychiatry unit?

Prognosis. What ongoing medical and psychiatric management is required? What are the medical and psychiatric prognoses?

Placement. To where will the patient be transferred after hospitalization? How does admission to inpatient psychiatry vs medical impact the ultimate disposition?

Help the treatment team make the decision

Determining the ideal patient placement often evokes strong feelings among treatment teams. Psychiatrists can help facilitate the conversation by asking the questions outlined above, and by keep­ing in mind, “What is best for this patient?”

The ubiquitous use of e-mail has opened the proverbial “Pandora’s box” of access to psychiatrists. Our e-mail addresses are readily available online via search engines or on hospital Web sites. E-mail has become a convenient method of communicating with patients; however, it also has resulted in a proliferation of unsolicited e-mails sent to physicians from people they don’t know seeking professional advice.¹ If you publish medical literature or make media appearances, you may be contacted by such individuals requesting your expertise.

Unsolicited e-mails present psychiatrists with ethical and legal quandaries that force them to consider how they can balance the human reflex to offer assistance against the potential ramifications of replying. These conundrums include:

• whether the sender is an actual person, and whether he or she is asking for advice
• the risks of replying vs not replying
• the possibility that there is a plausible crisis or danger to the sender or others
• the potential for establishing a doctor–patient relationship by replying
• the legal liability that might be incurred by replying.²

Take preemptive measures

There is guidance on how to e-mail your patients and respond to solicited e-mails, but there is a dearth of literature on how to respond to unsolicited e-mails. Anecdotal reports and limited literature suggest several possible measures you could take for managing unsolicited e-mails:

• Establish a policy of never opening unsolicited e-mails
• Create a strict junk-mail filter to prevent unsolicited e-mails from being delivered to your inbox
• Set up an automatic reply stating that unwanted or unsolicited e-mails will not be read and/or that no reply will be provided
• Read unsolicited e-mails, but immediately delete them without replying
• Acknowledge the sender in a reply, but state that you are unable to assist and decline further contact
• Send a generic reply clarifying that you are unable to provide medical assistance, and encourage the sender to seek help locally.²

Despite the urge to help, consider the consequences

In addition to taking up valuable time, unsolicited e-mails create legal and ethical predicaments that could subject you to legal liability if you choose to reply. Even though your intentions may be altruistic and you want to be helpful, you may unknowingly create problems for yourself. Clinicians should carefully weigh the consequences of replying before clicking “send.”

The ubiquitous use of e-mail has opened the proverbial “Pandora’s box” of access to psychiatrists. Our e-mail addresses are readily available online via search engines or on hospital Web sites. E-mail has become a convenient method of communicating with patients; however, it also has resulted in a proliferation of unsolicited e-mails sent to physicians from people they don’t know seeking professional advice.¹ If you publish medical literature or make media appearances, you may be contacted by such individuals requesting your expertise.

Unsolicited e-mails present psychiatrists with ethical and legal quandaries that force them to consider how they can balance the human reflex to offer assistance against the potential ramifications of replying. These conundrums include:

• whether the sender is an actual person, and whether he or she is asking for advice
• the risks of replying vs not replying
• the possibility that there is a plausible crisis or danger to the sender or others
• the potential for establishing a doctor–patient relationship by replying
• the legal liability that might be incurred by replying.²

Take preemptive measures

There is guidance on how to e-mail your patients and respond to solicited e-mails, but there is a dearth of literature on how to respond to unsolicited e-mails. Anecdotal reports and limited literature suggest several possible measures you could take for managing unsolicited e-mails:

• Establish a policy of never opening unsolicited e-mails
• Create a strict junk-mail filter to prevent unsolicited e-mails from being delivered to your inbox
• Set up an automatic reply stating that unwanted or unsolicited e-mails will not be read and/or that no reply will be provided
• Read unsolicited e-mails, but immediately delete them without replying
• Acknowledge the sender in a reply, but state that you are unable to assist and decline further contact
• Send a generic reply clarifying that you are unable to provide medical assistance, and encourage the sender to seek help locally.²

Despite the urge to help, consider the consequences

In addition to taking up valuable time, unsolicited e-mails create legal and ethical predicaments that could subject you to legal liability if you choose to reply. Even though your intentions may be altruistic and you want to be helpful, you may unknowingly create problems for yourself. Clinicians should carefully weigh the consequences of replying before clicking “send.”

The ubiquitous use of e-mail has opened the proverbial “Pandora’s box” of access to psychiatrists. Our e-mail addresses are readily available online via search engines or on hospital Web sites. E-mail has become a convenient method of communicating with patients; however, it also has resulted in a proliferation of unsolicited e-mails sent to physicians from people they don’t know seeking professional advice.¹ If you publish medical literature or make media appearances, you may be contacted by such individuals requesting your expertise.

Unsolicited e-mails present psychiatrists with ethical and legal quandaries that force them to consider how they can balance the human reflex to offer assistance against the potential ramifications of replying. These conundrums include:

• whether the sender is an actual person, and whether he or she is asking for advice
• the risks of replying vs not replying
• the possibility that there is a plausible crisis or danger to the sender or others
• the potential for establishing a doctor–patient relationship by replying
• the legal liability that might be incurred by replying.²

Take preemptive measures

There is guidance on how to e-mail your patients and respond to solicited e-mails, but there is a dearth of literature on how to respond to unsolicited e-mails. Anecdotal reports and limited literature suggest several possible measures you could take for managing unsolicited e-mails:

• Establish a policy of never opening unsolicited e-mails
• Create a strict junk-mail filter to prevent unsolicited e-mails from being delivered to your inbox
• Set up an automatic reply stating that unwanted or unsolicited e-mails will not be read and/or that no reply will be provided
• Read unsolicited e-mails, but immediately delete them without replying
• Acknowledge the sender in a reply, but state that you are unable to assist and decline further contact
• Send a generic reply clarifying that you are unable to provide medical assistance, and encourage the sender to seek help locally.²

Despite the urge to help, consider the consequences

In addition to taking up valuable time, unsolicited e-mails create legal and ethical predicaments that could subject you to legal liability if you choose to reply. Even though your intentions may be altruistic and you want to be helpful, you may unknowingly create problems for yourself. Clinicians should carefully weigh the consequences of replying before clicking “send.”

Misuse of prescription opioids has led to a staggering number of patients developing addiction, which the National Institutes of Health (NIH) and Department of Health and Human Services (HHS) have identified as a health care crisis. In the United States, approximately 29% of patients prescribed an opioid misuse it, and approximately 80% of heroin users started with prescription opioids.^1,2 The NIH and HHS have outlined 5 priorities to help resolve this crisis:

1. Improve access to prevention, treatment, and recovery support services
2. Increase availability and distribution of overdose-reversing medications
3. As the epidemic changes, strengthen what we know with improved public health surveillance
4. Support research that advances the understanding of pain and addiction and that develops new treatments and interventions
5. Improve pain management by utilizing evidence-based practices and reducing opioid misuse and opiate-related harm.³

Treating chronic pain in patients with bipolar disorder

At the Missouri University Psychiatric Center, an inpatient psychiatric ward, we recently conducted a retrospective cohort study to identify effective alternatives for treating pain, and to decrease opioid-related harm. Our study focused on 73 inpatients experiencing exacerbation of bipolar I disorder who also had chronic pain. These patients were treated with mood stabilizers, including lithium and carbamazepine. Patients also were taking medications, as needed, for agitation and their home medications for various medical problems. Selection of mood stabilizer therapy was non-random by standard of care based on best clinical practices. Dosing was based on blood-level monitoring adjusted to maintain therapeutic levels while receiving inpatient care. The average duration of inpatient treatment was approximately 1 to 5 weeks.

Pain was measured at baseline and compared with daily pain scores after mood stabilizer therapy using a 10-point scale, with 0 for no pain to 10 for worse pain, for the duration of the admission As expected based on the findings of previous research, carbamazepine resulted in a decrease in average daily pain score by 1.25 points after treatment (P = .048; F value = 4.3; F-crit = 4.23; calculated by one-way analysis of variance). However, patients who received lithium experienced a greater decrease in average daily pain score, by 2.17 points after treatment (P = .00035; F value = 14.56; F-crit = 4.02).

To further characterize the relationship between bipolar disorder and chronic pain, we looked at change in pain scores for mixed, manic, and depressive episodes of bipolar disorder by Clinical Global Impressions—Improvement (CGI-I) Scale categories (Figure). Participants who experienced the greatest clinical improvement also experienced the highest degree of analgesia. Those in the “Very much improved” CGI-I category experienced an almost 3-point decrease in average daily pain scores, with significance well below threshold (P = .0000967; F value = 19.83; F-crit = 4.11). Participants who showed no change in their bipolar I disorder symptoms or experienced exacerbation of their symptoms showed a significant increase in pain scores (P = .037; F value = 6.24; F-crit = 5.32).

Our data show that lithium and carbamazepine provide clinically and statistically significant analgesia in patients with bipolar I disorder and chronic pain. Furthermore, exacerbation of bipolar I disorder symptoms was associated with an increase of approximately 4 points on a 10-point chronic pain scale. While lithium and carbamazepine already are frequently used to treat patients with bipolar disorder, these medications may be particularly helpful for those with comorbid chronic pain.
 

Acknowledgments

We would like to acknowledge contributions of Yajie Yu, MD, Sailaja Bysani, MD, Emily Leary, PhD, and Oluwole Popoola, MD, for their work in this study.

Misuse of prescription opioids has led to a staggering number of patients developing addiction, which the National Institutes of Health (NIH) and Department of Health and Human Services (HHS) have identified as a health care crisis. In the United States, approximately 29% of patients prescribed an opioid misuse it, and approximately 80% of heroin users started with prescription opioids.^1,2 The NIH and HHS have outlined 5 priorities to help resolve this crisis:

1. Improve access to prevention, treatment, and recovery support services
2. Increase availability and distribution of overdose-reversing medications
3. As the epidemic changes, strengthen what we know with improved public health surveillance
4. Support research that advances the understanding of pain and addiction and that develops new treatments and interventions
5. Improve pain management by utilizing evidence-based practices and reducing opioid misuse and opiate-related harm.³

Treating chronic pain in patients with bipolar disorder

At the Missouri University Psychiatric Center, an inpatient psychiatric ward, we recently conducted a retrospective cohort study to identify effective alternatives for treating pain, and to decrease opioid-related harm. Our study focused on 73 inpatients experiencing exacerbation of bipolar I disorder who also had chronic pain. These patients were treated with mood stabilizers, including lithium and carbamazepine. Patients also were taking medications, as needed, for agitation and their home medications for various medical problems. Selection of mood stabilizer therapy was non-random by standard of care based on best clinical practices. Dosing was based on blood-level monitoring adjusted to maintain therapeutic levels while receiving inpatient care. The average duration of inpatient treatment was approximately 1 to 5 weeks.

Pain was measured at baseline and compared with daily pain scores after mood stabilizer therapy using a 10-point scale, with 0 for no pain to 10 for worse pain, for the duration of the admission As expected based on the findings of previous research, carbamazepine resulted in a decrease in average daily pain score by 1.25 points after treatment (P = .048; F value = 4.3; F-crit = 4.23; calculated by one-way analysis of variance). However, patients who received lithium experienced a greater decrease in average daily pain score, by 2.17 points after treatment (P = .00035; F value = 14.56; F-crit = 4.02).

To further characterize the relationship between bipolar disorder and chronic pain, we looked at change in pain scores for mixed, manic, and depressive episodes of bipolar disorder by Clinical Global Impressions—Improvement (CGI-I) Scale categories (Figure). Participants who experienced the greatest clinical improvement also experienced the highest degree of analgesia. Those in the “Very much improved” CGI-I category experienced an almost 3-point decrease in average daily pain scores, with significance well below threshold (P = .0000967; F value = 19.83; F-crit = 4.11). Participants who showed no change in their bipolar I disorder symptoms or experienced exacerbation of their symptoms showed a significant increase in pain scores (P = .037; F value = 6.24; F-crit = 5.32).

Our data show that lithium and carbamazepine provide clinically and statistically significant analgesia in patients with bipolar I disorder and chronic pain. Furthermore, exacerbation of bipolar I disorder symptoms was associated with an increase of approximately 4 points on a 10-point chronic pain scale. While lithium and carbamazepine already are frequently used to treat patients with bipolar disorder, these medications may be particularly helpful for those with comorbid chronic pain.
 

Acknowledgments

We would like to acknowledge contributions of Yajie Yu, MD, Sailaja Bysani, MD, Emily Leary, PhD, and Oluwole Popoola, MD, for their work in this study.

Misuse of prescription opioids has led to a staggering number of patients developing addiction, which the National Institutes of Health (NIH) and Department of Health and Human Services (HHS) have identified as a health care crisis. In the United States, approximately 29% of patients prescribed an opioid misuse it, and approximately 80% of heroin users started with prescription opioids.^1,2 The NIH and HHS have outlined 5 priorities to help resolve this crisis:

1. Improve access to prevention, treatment, and recovery support services
2. Increase availability and distribution of overdose-reversing medications
3. As the epidemic changes, strengthen what we know with improved public health surveillance
4. Support research that advances the understanding of pain and addiction and that develops new treatments and interventions
5. Improve pain management by utilizing evidence-based practices and reducing opioid misuse and opiate-related harm.³

Treating chronic pain in patients with bipolar disorder

At the Missouri University Psychiatric Center, an inpatient psychiatric ward, we recently conducted a retrospective cohort study to identify effective alternatives for treating pain, and to decrease opioid-related harm. Our study focused on 73 inpatients experiencing exacerbation of bipolar I disorder who also had chronic pain. These patients were treated with mood stabilizers, including lithium and carbamazepine. Patients also were taking medications, as needed, for agitation and their home medications for various medical problems. Selection of mood stabilizer therapy was non-random by standard of care based on best clinical practices. Dosing was based on blood-level monitoring adjusted to maintain therapeutic levels while receiving inpatient care. The average duration of inpatient treatment was approximately 1 to 5 weeks.

Pain was measured at baseline and compared with daily pain scores after mood stabilizer therapy using a 10-point scale, with 0 for no pain to 10 for worse pain, for the duration of the admission As expected based on the findings of previous research, carbamazepine resulted in a decrease in average daily pain score by 1.25 points after treatment (P = .048; F value = 4.3; F-crit = 4.23; calculated by one-way analysis of variance). However, patients who received lithium experienced a greater decrease in average daily pain score, by 2.17 points after treatment (P = .00035; F value = 14.56; F-crit = 4.02).

To further characterize the relationship between bipolar disorder and chronic pain, we looked at change in pain scores for mixed, manic, and depressive episodes of bipolar disorder by Clinical Global Impressions—Improvement (CGI-I) Scale categories (Figure). Participants who experienced the greatest clinical improvement also experienced the highest degree of analgesia. Those in the “Very much improved” CGI-I category experienced an almost 3-point decrease in average daily pain scores, with significance well below threshold (P = .0000967; F value = 19.83; F-crit = 4.11). Participants who showed no change in their bipolar I disorder symptoms or experienced exacerbation of their symptoms showed a significant increase in pain scores (P = .037; F value = 6.24; F-crit = 5.32).

Our data show that lithium and carbamazepine provide clinically and statistically significant analgesia in patients with bipolar I disorder and chronic pain. Furthermore, exacerbation of bipolar I disorder symptoms was associated with an increase of approximately 4 points on a 10-point chronic pain scale. While lithium and carbamazepine already are frequently used to treat patients with bipolar disorder, these medications may be particularly helpful for those with comorbid chronic pain.
 

Acknowledgments

We would like to acknowledge contributions of Yajie Yu, MD, Sailaja Bysani, MD, Emily Leary, PhD, and Oluwole Popoola, MD, for their work in this study.

A 39-year-old woman presented to the emergency department for evaluation of diffuse redness, itching, and tenderness of her skin. The patient said the eruption began 4 months earlier as localized plaques on her scalp, elbows, and beneath both breasts. Over the course of a few days, the redness became more diffuse, affecting most of her body. She also noticed swelling and skin desquamation on her lower extremities.

The patient had visited multiple urgent care clinics and underwent several courses of prednisone with initial improvement of symptoms, but experienced recurrence shortly after finishing the tapers.

On physical examination, more than 95% of the patient’s skin was bright red and tender to the touch, with associated exfoliation (FIGURES 1A-1B). Her lower extremities had pitting edema with superficial erosions that were weeping serous fluid. She was afebrile and normotensive, but had shaking chills and was tachycardic, with a heart rate of 115 bpm. There was no nail pitting, pustules, or lymphadenopathy. Lab tests revealed a low albumin level of 2.2 g/dL (normal: 3.5-5.5 g/dL), an elevated white blood cell count of 14,700 cells/mcL (normal: 4500-11,000 cells/mcL), and normocytic anemia (low hemoglobin of 8.7 g/dL; normal: 12-15.5 g/dL). The patient was admitted.

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

 

 

Diagnosis: Erythroderma

Based on the patient’s clinical presentation, we diagnosed severe erythroderma secondary to psoriasis. A punch biopsy was performed, and pathology demonstrated subacute spongiotic dermatitis with superficial neutrophilic infiltrates, consistent with psoriasis.

Erythroderma is widespread reddening of the skin associated with desquamation, typically involving more than 90% of the body’s surface area.¹ In most instances, erythroderma is a clinical presentation of an existing dermatosis. The most common causative conditions include primary skin disorders (such as psoriasis or atopic dermatitis), idiopathic erythroderma, and drug eruptions. Less common causes include cutaneous T-cell lymphoma, pityriasis rubra pilaris, and contact dermatitis.¹

Erythroderma is usually a clinical presentation of an existing dermatosis, such as psoriasis or atopic dermatitis.

It’s unclear why some skin diseases progress to erythroderma; the pathogenesis is complicated and involves keratinocytes and lymphocytes interacting with adhesion molecules and cytokines. Erythroderma can arise at any age and occurs in all races, but is more common in males and older adults, with a mean age of 42 to 61 years.² The annual incidence of erythroderma is estimated to be one per 100,000 adults.³

A complete picture of the patient is essential to making the diagnosis

Diagnosis can be difficult and hinges on historical and physical exam findings, as well as lab evaluations and skin biopsies. The history should focus on current and former medications, while the physical exam should hone in on clinical manifestations of existing dermatoses. The most common extracutaneous finding is generalized lymphadenopathy, which if prominent, may warrant lymph node biopsy, with studies for evaluation of underlying lymphoma.

Tachycardia develops in 40% of patients, secondary to increased blood flow to the skin and fluid loss, with risk of high-output cardiac failure.² Patients often have chills because their skin is not able to regulate their body temperature normally.⁴

The lab evaluation should include a complete blood count with differential and a comprehensive metabolic panel, as well as blood, skin, and urine cultures if infection is suspected as an inciting factor. Typical findings include mild anemia, leukocytosis, eosinophilia, and an elevated erythrocyte sedimentation rate.⁵ In addition, patients with chronic erythroderma commonly have low albumin.⁶ Unfortunately, lab studies don’t always reveal the underlying cause of the erythroderma.

Biopsies are commonly performed. However, the underlying etiology is often not clearly reflected in the result. Histology is typically nonspecific; findings frequently include hyperkeratosis, acanthosis, spongiosis, and perivascular inflammatory infiltrate. Additionally, the prominence of histologic features may vary depending on the stage of disease and the severity of inflammation. More specific findings may become evident later in the disease as the erythroderma clears, so repeated skin biopsies over time may be needed for diagnosis.⁷

Consider these conditions, which can lead to erythroderma

First and foremost, it is important to get a thorough history, particularly about prior skin conditions and symptoms that may indicate the presence of undiagnosed skin conditions.

Psoriasis is one of the most common causes of erythroderma. A history of pre-existing psoriasis is very helpful, but when this is not present, a biopsy can help confirm a clinical suspicion for psoriasis. It also helps to look for clues of psoriasis like nail changes or a history of plaques over the elbows and knees.

Atopic dermatitis is another common cause of erythroderma, and the history might include scaling and erythematous patches or plaques involving flexural surfaces before erythroderma occurs. Patients may have a history of atopic dermatitis from childhood and/or a history of other atopic conditions such as asthma and allergic rhinitis.

Drug eruptions occur following the administration of a new medication and can mimic a myriad of dermatoses.

Cutaneous T-cell lymphoma can lead to erythroderma and be differentiated with skin biopsy; pathology may show atypical lymphocytes, and Pautrier’s microabscesses may be seen.⁸

Pityriasis rubra pilaris is a relatively rare condition that presents with red-orange scaling patches and thickened yellowish palms and soles.⁹

Tx targets underlying etiology and associated complications

When treating a patient with erythroderma, it’s important to prevent hypothermia and secondary infections. If symptoms are severe, hospitalization should be considered. Nutrition should be assessed, and any fluid or electrolyte imbalances should be corrected.

Hospitalization should be considered to prevent hypothermia and secondary infections, as well as to assess nutrition and correct any fluid or electrolyte imbalances.

Oral antihistamines are commonly administered to suppress associated pruritus. Topical treatment usually consists of corticosteroids under occlusion with bland emollients. Depending upon the underlying disease, the following systemic medications may be started: methotrexate 7.5 to 15 mg once/week; acitretin 10 to 25 mg/d; or cyclosporine 2.5 to 5  mg/kg/d; in addition to topical treatment.⁴

Our patient. Pathology for our patient was indicative of psoriasis. She was started on a regimen of cyclosporine 4 to 5 mg/kg/d, diphenhydramine 25 to 50 mg as needed for itching, triamcinolone 0.1% ointment under wet wraps to her trunk and extremities, and hydrocortisone 2.5% ointment to be applied to her face daily. She was released after 5 days in the hospital. At outpatient follow-up one week later, her erythroderma was resolving. One month later, her erythroderma was resolved (FIGURE 2), although she did have psoriatic plaques on her lower legs.

CORRESPONDENCE
Richard P. Usatine, MD, University of Texas Health San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229; Usatine@uthscsa.edu.

A 39-year-old woman presented to the emergency department for evaluation of diffuse redness, itching, and tenderness of her skin. The patient said the eruption began 4 months earlier as localized plaques on her scalp, elbows, and beneath both breasts. Over the course of a few days, the redness became more diffuse, affecting most of her body. She also noticed swelling and skin desquamation on her lower extremities.

The patient had visited multiple urgent care clinics and underwent several courses of prednisone with initial improvement of symptoms, but experienced recurrence shortly after finishing the tapers.

On physical examination, more than 95% of the patient’s skin was bright red and tender to the touch, with associated exfoliation (FIGURES 1A-1B). Her lower extremities had pitting edema with superficial erosions that were weeping serous fluid. She was afebrile and normotensive, but had shaking chills and was tachycardic, with a heart rate of 115 bpm. There was no nail pitting, pustules, or lymphadenopathy. Lab tests revealed a low albumin level of 2.2 g/dL (normal: 3.5-5.5 g/dL), an elevated white blood cell count of 14,700 cells/mcL (normal: 4500-11,000 cells/mcL), and normocytic anemia (low hemoglobin of 8.7 g/dL; normal: 12-15.5 g/dL). The patient was admitted.

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

 

 

Diagnosis: Erythroderma

Based on the patient’s clinical presentation, we diagnosed severe erythroderma secondary to psoriasis. A punch biopsy was performed, and pathology demonstrated subacute spongiotic dermatitis with superficial neutrophilic infiltrates, consistent with psoriasis.

Erythroderma is widespread reddening of the skin associated with desquamation, typically involving more than 90% of the body’s surface area.¹ In most instances, erythroderma is a clinical presentation of an existing dermatosis. The most common causative conditions include primary skin disorders (such as psoriasis or atopic dermatitis), idiopathic erythroderma, and drug eruptions. Less common causes include cutaneous T-cell lymphoma, pityriasis rubra pilaris, and contact dermatitis.¹

Erythroderma is usually a clinical presentation of an existing dermatosis, such as psoriasis or atopic dermatitis.

It’s unclear why some skin diseases progress to erythroderma; the pathogenesis is complicated and involves keratinocytes and lymphocytes interacting with adhesion molecules and cytokines. Erythroderma can arise at any age and occurs in all races, but is more common in males and older adults, with a mean age of 42 to 61 years.² The annual incidence of erythroderma is estimated to be one per 100,000 adults.³

A complete picture of the patient is essential to making the diagnosis

Diagnosis can be difficult and hinges on historical and physical exam findings, as well as lab evaluations and skin biopsies. The history should focus on current and former medications, while the physical exam should hone in on clinical manifestations of existing dermatoses. The most common extracutaneous finding is generalized lymphadenopathy, which if prominent, may warrant lymph node biopsy, with studies for evaluation of underlying lymphoma.

Tachycardia develops in 40% of patients, secondary to increased blood flow to the skin and fluid loss, with risk of high-output cardiac failure.² Patients often have chills because their skin is not able to regulate their body temperature normally.⁴

The lab evaluation should include a complete blood count with differential and a comprehensive metabolic panel, as well as blood, skin, and urine cultures if infection is suspected as an inciting factor. Typical findings include mild anemia, leukocytosis, eosinophilia, and an elevated erythrocyte sedimentation rate.⁵ In addition, patients with chronic erythroderma commonly have low albumin.⁶ Unfortunately, lab studies don’t always reveal the underlying cause of the erythroderma.

Biopsies are commonly performed. However, the underlying etiology is often not clearly reflected in the result. Histology is typically nonspecific; findings frequently include hyperkeratosis, acanthosis, spongiosis, and perivascular inflammatory infiltrate. Additionally, the prominence of histologic features may vary depending on the stage of disease and the severity of inflammation. More specific findings may become evident later in the disease as the erythroderma clears, so repeated skin biopsies over time may be needed for diagnosis.⁷

Consider these conditions, which can lead to erythroderma

First and foremost, it is important to get a thorough history, particularly about prior skin conditions and symptoms that may indicate the presence of undiagnosed skin conditions.

Psoriasis is one of the most common causes of erythroderma. A history of pre-existing psoriasis is very helpful, but when this is not present, a biopsy can help confirm a clinical suspicion for psoriasis. It also helps to look for clues of psoriasis like nail changes or a history of plaques over the elbows and knees.

Atopic dermatitis is another common cause of erythroderma, and the history might include scaling and erythematous patches or plaques involving flexural surfaces before erythroderma occurs. Patients may have a history of atopic dermatitis from childhood and/or a history of other atopic conditions such as asthma and allergic rhinitis.

Drug eruptions occur following the administration of a new medication and can mimic a myriad of dermatoses.

Cutaneous T-cell lymphoma can lead to erythroderma and be differentiated with skin biopsy; pathology may show atypical lymphocytes, and Pautrier’s microabscesses may be seen.⁸

Pityriasis rubra pilaris is a relatively rare condition that presents with red-orange scaling patches and thickened yellowish palms and soles.⁹

Tx targets underlying etiology and associated complications

When treating a patient with erythroderma, it’s important to prevent hypothermia and secondary infections. If symptoms are severe, hospitalization should be considered. Nutrition should be assessed, and any fluid or electrolyte imbalances should be corrected.

Hospitalization should be considered to prevent hypothermia and secondary infections, as well as to assess nutrition and correct any fluid or electrolyte imbalances.

Oral antihistamines are commonly administered to suppress associated pruritus. Topical treatment usually consists of corticosteroids under occlusion with bland emollients. Depending upon the underlying disease, the following systemic medications may be started: methotrexate 7.5 to 15 mg once/week; acitretin 10 to 25 mg/d; or cyclosporine 2.5 to 5  mg/kg/d; in addition to topical treatment.⁴

Our patient. Pathology for our patient was indicative of psoriasis. She was started on a regimen of cyclosporine 4 to 5 mg/kg/d, diphenhydramine 25 to 50 mg as needed for itching, triamcinolone 0.1% ointment under wet wraps to her trunk and extremities, and hydrocortisone 2.5% ointment to be applied to her face daily. She was released after 5 days in the hospital. At outpatient follow-up one week later, her erythroderma was resolving. One month later, her erythroderma was resolved (FIGURE 2), although she did have psoriatic plaques on her lower legs.

CORRESPONDENCE
Richard P. Usatine, MD, University of Texas Health San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229; Usatine@uthscsa.edu.

A 39-year-old woman presented to the emergency department for evaluation of diffuse redness, itching, and tenderness of her skin. The patient said the eruption began 4 months earlier as localized plaques on her scalp, elbows, and beneath both breasts. Over the course of a few days, the redness became more diffuse, affecting most of her body. She also noticed swelling and skin desquamation on her lower extremities.

The patient had visited multiple urgent care clinics and underwent several courses of prednisone with initial improvement of symptoms, but experienced recurrence shortly after finishing the tapers.

On physical examination, more than 95% of the patient’s skin was bright red and tender to the touch, with associated exfoliation (FIGURES 1A-1B). Her lower extremities had pitting edema with superficial erosions that were weeping serous fluid. She was afebrile and normotensive, but had shaking chills and was tachycardic, with a heart rate of 115 bpm. There was no nail pitting, pustules, or lymphadenopathy. Lab tests revealed a low albumin level of 2.2 g/dL (normal: 3.5-5.5 g/dL), an elevated white blood cell count of 14,700 cells/mcL (normal: 4500-11,000 cells/mcL), and normocytic anemia (low hemoglobin of 8.7 g/dL; normal: 12-15.5 g/dL). The patient was admitted.

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

 

 

Diagnosis: Erythroderma

Based on the patient’s clinical presentation, we diagnosed severe erythroderma secondary to psoriasis. A punch biopsy was performed, and pathology demonstrated subacute spongiotic dermatitis with superficial neutrophilic infiltrates, consistent with psoriasis.

Erythroderma is widespread reddening of the skin associated with desquamation, typically involving more than 90% of the body’s surface area.¹ In most instances, erythroderma is a clinical presentation of an existing dermatosis. The most common causative conditions include primary skin disorders (such as psoriasis or atopic dermatitis), idiopathic erythroderma, and drug eruptions. Less common causes include cutaneous T-cell lymphoma, pityriasis rubra pilaris, and contact dermatitis.¹

Erythroderma is usually a clinical presentation of an existing dermatosis, such as psoriasis or atopic dermatitis.

It’s unclear why some skin diseases progress to erythroderma; the pathogenesis is complicated and involves keratinocytes and lymphocytes interacting with adhesion molecules and cytokines. Erythroderma can arise at any age and occurs in all races, but is more common in males and older adults, with a mean age of 42 to 61 years.² The annual incidence of erythroderma is estimated to be one per 100,000 adults.³

A complete picture of the patient is essential to making the diagnosis

Diagnosis can be difficult and hinges on historical and physical exam findings, as well as lab evaluations and skin biopsies. The history should focus on current and former medications, while the physical exam should hone in on clinical manifestations of existing dermatoses. The most common extracutaneous finding is generalized lymphadenopathy, which if prominent, may warrant lymph node biopsy, with studies for evaluation of underlying lymphoma.

Tachycardia develops in 40% of patients, secondary to increased blood flow to the skin and fluid loss, with risk of high-output cardiac failure.² Patients often have chills because their skin is not able to regulate their body temperature normally.⁴

The lab evaluation should include a complete blood count with differential and a comprehensive metabolic panel, as well as blood, skin, and urine cultures if infection is suspected as an inciting factor. Typical findings include mild anemia, leukocytosis, eosinophilia, and an elevated erythrocyte sedimentation rate.⁵ In addition, patients with chronic erythroderma commonly have low albumin.⁶ Unfortunately, lab studies don’t always reveal the underlying cause of the erythroderma.

Biopsies are commonly performed. However, the underlying etiology is often not clearly reflected in the result. Histology is typically nonspecific; findings frequently include hyperkeratosis, acanthosis, spongiosis, and perivascular inflammatory infiltrate. Additionally, the prominence of histologic features may vary depending on the stage of disease and the severity of inflammation. More specific findings may become evident later in the disease as the erythroderma clears, so repeated skin biopsies over time may be needed for diagnosis.⁷

Consider these conditions, which can lead to erythroderma

First and foremost, it is important to get a thorough history, particularly about prior skin conditions and symptoms that may indicate the presence of undiagnosed skin conditions.

Psoriasis is one of the most common causes of erythroderma. A history of pre-existing psoriasis is very helpful, but when this is not present, a biopsy can help confirm a clinical suspicion for psoriasis. It also helps to look for clues of psoriasis like nail changes or a history of plaques over the elbows and knees.

Atopic dermatitis is another common cause of erythroderma, and the history might include scaling and erythematous patches or plaques involving flexural surfaces before erythroderma occurs. Patients may have a history of atopic dermatitis from childhood and/or a history of other atopic conditions such as asthma and allergic rhinitis.

Drug eruptions occur following the administration of a new medication and can mimic a myriad of dermatoses.

Cutaneous T-cell lymphoma can lead to erythroderma and be differentiated with skin biopsy; pathology may show atypical lymphocytes, and Pautrier’s microabscesses may be seen.⁸

Pityriasis rubra pilaris is a relatively rare condition that presents with red-orange scaling patches and thickened yellowish palms and soles.⁹

Tx targets underlying etiology and associated complications

When treating a patient with erythroderma, it’s important to prevent hypothermia and secondary infections. If symptoms are severe, hospitalization should be considered. Nutrition should be assessed, and any fluid or electrolyte imbalances should be corrected.

Hospitalization should be considered to prevent hypothermia and secondary infections, as well as to assess nutrition and correct any fluid or electrolyte imbalances.

Oral antihistamines are commonly administered to suppress associated pruritus. Topical treatment usually consists of corticosteroids under occlusion with bland emollients. Depending upon the underlying disease, the following systemic medications may be started: methotrexate 7.5 to 15 mg once/week; acitretin 10 to 25 mg/d; or cyclosporine 2.5 to 5  mg/kg/d; in addition to topical treatment.⁴

Our patient. Pathology for our patient was indicative of psoriasis. She was started on a regimen of cyclosporine 4 to 5 mg/kg/d, diphenhydramine 25 to 50 mg as needed for itching, triamcinolone 0.1% ointment under wet wraps to her trunk and extremities, and hydrocortisone 2.5% ointment to be applied to her face daily. She was released after 5 days in the hospital. At outpatient follow-up one week later, her erythroderma was resolving. One month later, her erythroderma was resolved (FIGURE 2), although she did have psoriatic plaques on her lower legs.

CORRESPONDENCE
Richard P. Usatine, MD, University of Texas Health San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229; Usatine@uthscsa.edu.

“Good morning, Mr. Harris. What can I do for you today?”

“Dr. Hickner, I need an MRI of my right knee. I hurt it last week, and I need to find out if I tore something.”

We all know that too many patients request—and often get—costly (and unnecessary) magnetic resonance imaging (MRI) and computed tomography (CT) scans of their joints and backs. That’s why such imaging is targeted in the Choosing Wisely campaign, which aims to eliminate needless testing.¹

But how can we confidently tell Mr. Harris that he doesn’t need an MRI or CT scan? One approach is to explain that imaging is generally reserved for those considering surgery, as it serves to inform the surgeon of the exact procedure needed. Another approach is to be skilled in physical exam techniques that increase our confidence in the clinical diagnosis.

Applying this to acute knee injuries. In this issue of JFP, Koster and colleagues explain that the Lachman test (and possibly the newer lever sign test) are maneuvers that have a high probability of ruling out complete anterior cruciate ligament (ACL) tears when performed properly. The Lachman test, for example, has a 96% sensitivity for complete ACL ruptures.² (The anterior drawer test has too low a sensitivity to rule out ACL injuries, and the pivot shift test is a bit too challenging to be performed reliably.)

A thorough physical exam and selective plain x-rays are all that is needed for the initial evaluation of most knee injuries.

This is important information because early surgery for ACL tears leads to better outcomes for athletes, and a reliable physical exam to rule out an ACL tear reduces the need for imaging. Moreover, other than fractures near the knee, no other knee injuries require early surgery. So a thorough physical exam and selective plain x-rays are all that is needed for the initial evaluation of most knee injuries.

The same is true for back and shoulder injuries, where acute imaging with MRI or CT is rarely called for. A thorough and accurate physical examination is usually sufficient, supplemented with plain X-rays on a selective basis.

Going one step further, consider taking a look at the JAMA series called, “The Rational Clinical Examination,” which has been compiled into a single publication by the same name.³ It is an excellent guide to the sensitivity, specificity, and positive and negative likelihood ratios of a host of clinical findings and tests. It can help to greatly improve clinical skills and reduce unnecessary testing.

“Good morning, Mr. Harris. What can I do for you today?”

“Dr. Hickner, I need an MRI of my right knee. I hurt it last week, and I need to find out if I tore something.”

We all know that too many patients request—and often get—costly (and unnecessary) magnetic resonance imaging (MRI) and computed tomography (CT) scans of their joints and backs. That’s why such imaging is targeted in the Choosing Wisely campaign, which aims to eliminate needless testing.¹

But how can we confidently tell Mr. Harris that he doesn’t need an MRI or CT scan? One approach is to explain that imaging is generally reserved for those considering surgery, as it serves to inform the surgeon of the exact procedure needed. Another approach is to be skilled in physical exam techniques that increase our confidence in the clinical diagnosis.

Applying this to acute knee injuries. In this issue of JFP, Koster and colleagues explain that the Lachman test (and possibly the newer lever sign test) are maneuvers that have a high probability of ruling out complete anterior cruciate ligament (ACL) tears when performed properly. The Lachman test, for example, has a 96% sensitivity for complete ACL ruptures.² (The anterior drawer test has too low a sensitivity to rule out ACL injuries, and the pivot shift test is a bit too challenging to be performed reliably.)

A thorough physical exam and selective plain x-rays are all that is needed for the initial evaluation of most knee injuries.

This is important information because early surgery for ACL tears leads to better outcomes for athletes, and a reliable physical exam to rule out an ACL tear reduces the need for imaging. Moreover, other than fractures near the knee, no other knee injuries require early surgery. So a thorough physical exam and selective plain x-rays are all that is needed for the initial evaluation of most knee injuries.

The same is true for back and shoulder injuries, where acute imaging with MRI or CT is rarely called for. A thorough and accurate physical examination is usually sufficient, supplemented with plain X-rays on a selective basis.

Going one step further, consider taking a look at the JAMA series called, “The Rational Clinical Examination,” which has been compiled into a single publication by the same name.³ It is an excellent guide to the sensitivity, specificity, and positive and negative likelihood ratios of a host of clinical findings and tests. It can help to greatly improve clinical skills and reduce unnecessary testing.

“Good morning, Mr. Harris. What can I do for you today?”

“Dr. Hickner, I need an MRI of my right knee. I hurt it last week, and I need to find out if I tore something.”

We all know that too many patients request—and often get—costly (and unnecessary) magnetic resonance imaging (MRI) and computed tomography (CT) scans of their joints and backs. That’s why such imaging is targeted in the Choosing Wisely campaign, which aims to eliminate needless testing.¹

But how can we confidently tell Mr. Harris that he doesn’t need an MRI or CT scan? One approach is to explain that imaging is generally reserved for those considering surgery, as it serves to inform the surgeon of the exact procedure needed. Another approach is to be skilled in physical exam techniques that increase our confidence in the clinical diagnosis.

Applying this to acute knee injuries. In this issue of JFP, Koster and colleagues explain that the Lachman test (and possibly the newer lever sign test) are maneuvers that have a high probability of ruling out complete anterior cruciate ligament (ACL) tears when performed properly. The Lachman test, for example, has a 96% sensitivity for complete ACL ruptures.² (The anterior drawer test has too low a sensitivity to rule out ACL injuries, and the pivot shift test is a bit too challenging to be performed reliably.)

A thorough physical exam and selective plain x-rays are all that is needed for the initial evaluation of most knee injuries.

This is important information because early surgery for ACL tears leads to better outcomes for athletes, and a reliable physical exam to rule out an ACL tear reduces the need for imaging. Moreover, other than fractures near the knee, no other knee injuries require early surgery. So a thorough physical exam and selective plain x-rays are all that is needed for the initial evaluation of most knee injuries.

The same is true for back and shoulder injuries, where acute imaging with MRI or CT is rarely called for. A thorough and accurate physical examination is usually sufficient, supplemented with plain X-rays on a selective basis.

Going one step further, consider taking a look at the JAMA series called, “The Rational Clinical Examination,” which has been compiled into a single publication by the same name.³ It is an excellent guide to the sensitivity, specificity, and positive and negative likelihood ratios of a host of clinical findings and tests. It can help to greatly improve clinical skills and reduce unnecessary testing.

THE CASE

A 12-year-old girl presented to my office (JH) with bilateral wrist pain. She had fallen on both wrists palmar-flexed and then, while trying to get up, landed on both wrists dorsi-flexed. The patient did not hear any “pops,” but felt immediate pain when her wrists hyperextended. Hand, wrist, and forearm x-rays were negative bilaterally for fractures. She was placed in bilateral thumb spica splints.

At follow-up one week later, the patient reported 6/10 pain in her left wrist and 7/10 pain in her right wrist. The pain increased to 10/10 bilaterally with movement and was not relieved by icing or nonsteroidal anti-inflammatory drugs. On physical exam, there was bilateral swelling of the wrists without ecchymosis or erythema. The patient had limited passive and active range of motion, especially during wrist extension. She also had tenderness to palpation over the anatomical snuff box, extending proximally to the distal radius bilaterally. She had no tenderness over the ulna or metacarpals, no loss of sensation in any area nerves, and she was neurovascularly intact bilaterally.

Based on the mechanism of injury, undetected fracture or full thickness ligament tear were both possible. Because of this, and because magnetic resonance imaging (MRI) entails no radiation exposure, MRI was chosen for additional imaging of both wrists.

THE DIAGNOSIS

The MRI revealed bilateral, nondisplaced, extra-articular fractures extending through the scaphoid waist, with surrounding bone marrow edema. In the right wrist, the patient also had a low-grade partial tear of the membranous portion of the scapholunate interosseous ligament (SLIL) at the scaphoid attachment (FIGURE 1). In the left wrist, she also had a low-grade sprain of the SLIL without tear (FIGURE 2).

DISCUSSION

Carpal fractures account for 6% of all fractures.¹ Scaphoid fractures are the most common carpal bone fracture among all age groups, but account for only 0.4% of all pediatric fractures.^1-3 They’re commonly missed on x-rays because they are usually nondisplaced and hidden by other structures superimposed on the image.^1,2,4 Undetected, scaphoid fractures can cause prolonged interruption to the bone’s architecture, leading to avascular necrosis of the proximal portion of the scaphoid bone.^5,6

Bilateral scaphoid fractures are extremely rare and account for less than 1% of all scaphoid fractures.⁷ Very few of these cases have been published in the literature, and those that have been published have talked about the fractures being secondary to chronic stress fractures and as being treated with internal fixation (regardless of whether the fractures were nondisplaced or if the ligaments were intact).^6-9

Our patient was placed in bilateral fiberglass short-arm thumb spica casts. We tried conservative treatment measures first because she had help with her activities of daily living (ADLs). At a follow-up visit 2 weeks later, we switched the casts to long-arm thumb spica casts because of the patient’s ability to pronate and supinate her wrists in the short-arm versions. After one month of wearing the long-arm casts, we placed her back in bilateral short-arm casts for 2 weeks. Eight weeks after the fall, we removed the short-arm casts for reevaluation.

We obtained x-rays to assess for any new changes to the wrist and specifically the scaphoid bones. The x-rays showed almost completely healed scaphoid bones with good alignment, but the patient still had 5/10 pain in the left wrist and 8/10 pain in the right wrist with movement. We placed her in adjustable thermoformable polymer braces, which were removed when she bathed.

Scaphoid fractures are commonly missed on x-rays because they are usually nondisplaced and hidden by other structures superimposed on the image.

Due to the uniqueness of her injuries, our patient had weekly visits with her primary care provider (PCP) for the first 2 months of treatment, followed by bimonthly visits for the remainder. At 10 weeks after the fall, her pain with movement was almost gone and she began physical therapy. She also began removing the braces during sedentary activity in order to practice range-of-motion exercises to prevent excessive stiffness in her wrists. Our patient regained full strength and range of motion one month later.

One other published case report describes the successful union of bilateral scaphoid fractures using bilateral long-arm casts followed by short-arm casts.⁷ Similar to our patient’s case, full union of the scaphoid bones was achieved within 12 weeks.⁷ Together, these cases suggest that conservative treatment methods are a viable alternative to surgery.

TAKEAWAY

For patients presenting with wrist pain after trauma to the wrists, assess anatomical snuffbox tenderness and obtain x-rays. Do not be falsely reassured by negative x-rays in the presence of a positive physical exam, however, as scaphoid fractures are often hidden on x-rays. If tenderness at the anatomical snuffbox is present and doesn’t subside within a few days, apply a short-arm thumb splint and obtain subsequent imaging.

If tenderness at the anatomical snuffbox is present and doesn't subside within a few days, apply a short-arm thumb splint and obtain subsequent imaging.

If bilateral, nondisplaced, stable scaphoid fractures are diagnosed, conservative treatment with long-arm and short-arm casts is a viable alternative to surgery. This treatment decision should be made on an individual basis, however, as it requires the patient to have frequent PCP visits, assistance with ADLs, and complete adherence to the treatment plan.

THE CASE

A 12-year-old girl presented to my office (JH) with bilateral wrist pain. She had fallen on both wrists palmar-flexed and then, while trying to get up, landed on both wrists dorsi-flexed. The patient did not hear any “pops,” but felt immediate pain when her wrists hyperextended. Hand, wrist, and forearm x-rays were negative bilaterally for fractures. She was placed in bilateral thumb spica splints.

At follow-up one week later, the patient reported 6/10 pain in her left wrist and 7/10 pain in her right wrist. The pain increased to 10/10 bilaterally with movement and was not relieved by icing or nonsteroidal anti-inflammatory drugs. On physical exam, there was bilateral swelling of the wrists without ecchymosis or erythema. The patient had limited passive and active range of motion, especially during wrist extension. She also had tenderness to palpation over the anatomical snuff box, extending proximally to the distal radius bilaterally. She had no tenderness over the ulna or metacarpals, no loss of sensation in any area nerves, and she was neurovascularly intact bilaterally.

Based on the mechanism of injury, undetected fracture or full thickness ligament tear were both possible. Because of this, and because magnetic resonance imaging (MRI) entails no radiation exposure, MRI was chosen for additional imaging of both wrists.

THE DIAGNOSIS

The MRI revealed bilateral, nondisplaced, extra-articular fractures extending through the scaphoid waist, with surrounding bone marrow edema. In the right wrist, the patient also had a low-grade partial tear of the membranous portion of the scapholunate interosseous ligament (SLIL) at the scaphoid attachment (FIGURE 1). In the left wrist, she also had a low-grade sprain of the SLIL without tear (FIGURE 2).

DISCUSSION

Carpal fractures account for 6% of all fractures.¹ Scaphoid fractures are the most common carpal bone fracture among all age groups, but account for only 0.4% of all pediatric fractures.^1-3 They’re commonly missed on x-rays because they are usually nondisplaced and hidden by other structures superimposed on the image.^1,2,4 Undetected, scaphoid fractures can cause prolonged interruption to the bone’s architecture, leading to avascular necrosis of the proximal portion of the scaphoid bone.^5,6

Bilateral scaphoid fractures are extremely rare and account for less than 1% of all scaphoid fractures.⁷ Very few of these cases have been published in the literature, and those that have been published have talked about the fractures being secondary to chronic stress fractures and as being treated with internal fixation (regardless of whether the fractures were nondisplaced or if the ligaments were intact).^6-9

Our patient was placed in bilateral fiberglass short-arm thumb spica casts. We tried conservative treatment measures first because she had help with her activities of daily living (ADLs). At a follow-up visit 2 weeks later, we switched the casts to long-arm thumb spica casts because of the patient’s ability to pronate and supinate her wrists in the short-arm versions. After one month of wearing the long-arm casts, we placed her back in bilateral short-arm casts for 2 weeks. Eight weeks after the fall, we removed the short-arm casts for reevaluation.

We obtained x-rays to assess for any new changes to the wrist and specifically the scaphoid bones. The x-rays showed almost completely healed scaphoid bones with good alignment, but the patient still had 5/10 pain in the left wrist and 8/10 pain in the right wrist with movement. We placed her in adjustable thermoformable polymer braces, which were removed when she bathed.

Scaphoid fractures are commonly missed on x-rays because they are usually nondisplaced and hidden by other structures superimposed on the image.

Due to the uniqueness of her injuries, our patient had weekly visits with her primary care provider (PCP) for the first 2 months of treatment, followed by bimonthly visits for the remainder. At 10 weeks after the fall, her pain with movement was almost gone and she began physical therapy. She also began removing the braces during sedentary activity in order to practice range-of-motion exercises to prevent excessive stiffness in her wrists. Our patient regained full strength and range of motion one month later.

One other published case report describes the successful union of bilateral scaphoid fractures using bilateral long-arm casts followed by short-arm casts.⁷ Similar to our patient’s case, full union of the scaphoid bones was achieved within 12 weeks.⁷ Together, these cases suggest that conservative treatment methods are a viable alternative to surgery.

TAKEAWAY

For patients presenting with wrist pain after trauma to the wrists, assess anatomical snuffbox tenderness and obtain x-rays. Do not be falsely reassured by negative x-rays in the presence of a positive physical exam, however, as scaphoid fractures are often hidden on x-rays. If tenderness at the anatomical snuffbox is present and doesn’t subside within a few days, apply a short-arm thumb splint and obtain subsequent imaging.

If tenderness at the anatomical snuffbox is present and doesn't subside within a few days, apply a short-arm thumb splint and obtain subsequent imaging.

If bilateral, nondisplaced, stable scaphoid fractures are diagnosed, conservative treatment with long-arm and short-arm casts is a viable alternative to surgery. This treatment decision should be made on an individual basis, however, as it requires the patient to have frequent PCP visits, assistance with ADLs, and complete adherence to the treatment plan.

THE CASE

A 12-year-old girl presented to my office (JH) with bilateral wrist pain. She had fallen on both wrists palmar-flexed and then, while trying to get up, landed on both wrists dorsi-flexed. The patient did not hear any “pops,” but felt immediate pain when her wrists hyperextended. Hand, wrist, and forearm x-rays were negative bilaterally for fractures. She was placed in bilateral thumb spica splints.

At follow-up one week later, the patient reported 6/10 pain in her left wrist and 7/10 pain in her right wrist. The pain increased to 10/10 bilaterally with movement and was not relieved by icing or nonsteroidal anti-inflammatory drugs. On physical exam, there was bilateral swelling of the wrists without ecchymosis or erythema. The patient had limited passive and active range of motion, especially during wrist extension. She also had tenderness to palpation over the anatomical snuff box, extending proximally to the distal radius bilaterally. She had no tenderness over the ulna or metacarpals, no loss of sensation in any area nerves, and she was neurovascularly intact bilaterally.

Based on the mechanism of injury, undetected fracture or full thickness ligament tear were both possible. Because of this, and because magnetic resonance imaging (MRI) entails no radiation exposure, MRI was chosen for additional imaging of both wrists.

THE DIAGNOSIS

The MRI revealed bilateral, nondisplaced, extra-articular fractures extending through the scaphoid waist, with surrounding bone marrow edema. In the right wrist, the patient also had a low-grade partial tear of the membranous portion of the scapholunate interosseous ligament (SLIL) at the scaphoid attachment (FIGURE 1). In the left wrist, she also had a low-grade sprain of the SLIL without tear (FIGURE 2).

DISCUSSION

Carpal fractures account for 6% of all fractures.¹ Scaphoid fractures are the most common carpal bone fracture among all age groups, but account for only 0.4% of all pediatric fractures.^1-3 They’re commonly missed on x-rays because they are usually nondisplaced and hidden by other structures superimposed on the image.^1,2,4 Undetected, scaphoid fractures can cause prolonged interruption to the bone’s architecture, leading to avascular necrosis of the proximal portion of the scaphoid bone.^5,6

Bilateral scaphoid fractures are extremely rare and account for less than 1% of all scaphoid fractures.⁷ Very few of these cases have been published in the literature, and those that have been published have talked about the fractures being secondary to chronic stress fractures and as being treated with internal fixation (regardless of whether the fractures were nondisplaced or if the ligaments were intact).^6-9

Our patient was placed in bilateral fiberglass short-arm thumb spica casts. We tried conservative treatment measures first because she had help with her activities of daily living (ADLs). At a follow-up visit 2 weeks later, we switched the casts to long-arm thumb spica casts because of the patient’s ability to pronate and supinate her wrists in the short-arm versions. After one month of wearing the long-arm casts, we placed her back in bilateral short-arm casts for 2 weeks. Eight weeks after the fall, we removed the short-arm casts for reevaluation.

We obtained x-rays to assess for any new changes to the wrist and specifically the scaphoid bones. The x-rays showed almost completely healed scaphoid bones with good alignment, but the patient still had 5/10 pain in the left wrist and 8/10 pain in the right wrist with movement. We placed her in adjustable thermoformable polymer braces, which were removed when she bathed.

Scaphoid fractures are commonly missed on x-rays because they are usually nondisplaced and hidden by other structures superimposed on the image.

Due to the uniqueness of her injuries, our patient had weekly visits with her primary care provider (PCP) for the first 2 months of treatment, followed by bimonthly visits for the remainder. At 10 weeks after the fall, her pain with movement was almost gone and she began physical therapy. She also began removing the braces during sedentary activity in order to practice range-of-motion exercises to prevent excessive stiffness in her wrists. Our patient regained full strength and range of motion one month later.

One other published case report describes the successful union of bilateral scaphoid fractures using bilateral long-arm casts followed by short-arm casts.⁷ Similar to our patient’s case, full union of the scaphoid bones was achieved within 12 weeks.⁷ Together, these cases suggest that conservative treatment methods are a viable alternative to surgery.

TAKEAWAY

For patients presenting with wrist pain after trauma to the wrists, assess anatomical snuffbox tenderness and obtain x-rays. Do not be falsely reassured by negative x-rays in the presence of a positive physical exam, however, as scaphoid fractures are often hidden on x-rays. If tenderness at the anatomical snuffbox is present and doesn’t subside within a few days, apply a short-arm thumb splint and obtain subsequent imaging.

If tenderness at the anatomical snuffbox is present and doesn't subside within a few days, apply a short-arm thumb splint and obtain subsequent imaging.

If bilateral, nondisplaced, stable scaphoid fractures are diagnosed, conservative treatment with long-arm and short-arm casts is a viable alternative to surgery. This treatment decision should be made on an individual basis, however, as it requires the patient to have frequent PCP visits, assistance with ADLs, and complete adherence to the treatment plan.

ILLUSTRATIVE CASE

A fussy 6-month-old infant is brought into the emergency department (ED) with a rectal temperature of 101.5° F. She is consolable, breathing normally, and appears well hydrated. You find no clear etiology for her fever and suspect that a urinary tract infection (UTI) may be the source of her illness. How do you proceed with obtaining a urine sample?

A febrile infant in the family physician’s office or ED is a familiar clinical situation that may require an invasive diagnostic work-up. Up to 7% of infants ages 2 to 24 months with fever of unknown origin may have a UTI.² Collecting a urine sample from pre-toilet-trained children can be time consuming. In fact, obtaining a clean-catch urine sample in this age group took an average of more than one hour in one randomized controlled trial (RCT).³ More convenient methods of urine collection, such as placing a cotton ball in the diaper or using a perineal collection bag, have contamination rates of up to 63%.⁴

The American Academy of Pediatrics (AAP) guidelines for evaluating possible UTI in a febrile child <2 years of age recommend obtaining a sample for urinalysis “through the most convenient means.”⁵ If urinalysis is positive, only urine obtained by catheterization or suprapubic aspiration should be cultured. Guidelines from the National Institute for Health and Care Excellence in the United Kingdom are similar, but allow for culture of clean-catch urine samples.⁶

A recent prospective cohort study examined a noninvasive alternating lumbar-bladder tapping method to stimulate voiding in infants ages 0 to 6 months.⁷ Within 5 minutes, 49% of the infants provided a clean-catch sample, with contamination rates similar to those of samples obtained using invasive methods.⁷ Younger infants were more likely to void within the time allotted. Another trial of bladder tapping conducted in hospitalized infants <30 days old showed similar results.⁸

There are, however, no previously reported randomized trials demonstrating the efficacy of a noninvasive urine collection technique in the outpatient setting.

Use of invasive collection methods requires skilled personnel and may cause significant discomfort for patients (and parents). Noninvasive methods, such as bag urine collection, have unacceptable contamination rates. In addition, waiting to catch a potentially cleaner urine sample is time-consuming, so better strategies to collect urine from infants are needed. This RCT is the first to examine the efficacy of a unique stimulation technique to obtain a clean-catch urine sample from infants ages 1 to 12 months.

STUDY SUMMARY

Noninvasive stimulation method triggers faster clean urine samples

A nonblinded, single-center RCT conducted in Australia compared 2 methods for obtaining a clean-catch urine sample within 5 minutes: the Quick-Wee method (suprapubic stimulation with gauze soaked in cold fluid) or usual care (waiting for spontaneous voiding with no stimulation).¹ Three hundred fifty-four infants (ages 1-12 months) who required urine sample collection were randomized in a 1:1 ratio; allocation was concealed. Infants with anatomic or neurologic abnormalities and those needing immediate antibiotic therapy were excluded.

Almost one-third of patients provided successful clean-catch samples within 5 minutes.

The most common reasons for obtaining the urine sample were fever of unknown origin and “unsettled baby,” followed by poor feeding and suspected UTI. The primary outcome was voiding within 5 minutes; secondary outcomes included time to void, whether urine was successfully caught, contamination rate, and parent/clinician satisfaction.

Study personnel removed the diaper, then cleaned the genitals of all patients with room temperature sterile water. A caregiver or clinician was ready and waiting to catch urine when the patient voided. In the Quick-Wee group, a clinician rubbed the patient’s suprapubic area in a circular fashion with gauze soaked in refrigerated saline (2.8° C). At 5 minutes, clinicians recorded the voiding status and decided how to proceed.

Using intention-to-treat analysis, 31% of the patients in the Quick-Wee group voided within 5 minutes, compared with 12% of the usual-care patients. Similarly, 30% of patients in the Quick-Wee group provided a successful clean-catch sample within 5 minutes compared with 9% in the usual-care group (P<.001; number needed to treat=4.7; 95% CI, 3.4-7.7). Contamination rates were no different between the Quick-Wee and usual-care samples. Both parents and clinicians were more satisfied with the Quick-Wee method than with usual care (median score of 2 vs 3 on a 5-point Likert scale, in which 1 is most satisfied; P<.001). There was no difference when results were adjusted for age or sex. No adverse events occurred.

WHAT’S NEW

New method could reduce the need for invasive sampling

A simple suprapubic stimulation technique increased the number of infants who provided a clean-catch voided urine sample within 5 minutes—a clinically relevant and satisfying outcome. In appropriate patients, use of the Quick-Wee method to obtain a clean-catch voided sample for initial urinalysis, rather than attempting methods with known high contamination rates, may potentially reduce the need for invasive sampling using catheterization or suprapubic aspiration.

CAVEATS

Complete age range and ideal storage temperature are unknown

Neonates and pre-continent children older than 12 months were not included in this trial, so these conclusions do not apply to those groups of patients. The intervention period lasted only 5 minutes, but other published studies suggest that this amount of time is adequate for voiding to occur.^6,7 Although this study used soaking fluid stored at 2.8° C, the ideal storage temperature is unknown.

CHALLENGES TO IMPLEMENTATION

AAP doesn’t endorse clean-catch urine samples for culture

The Quick-Wee method is simple and easy to implement, and requires no specialized training or equipment. AAP guidelines do not endorse the use of clean-catch voided urine for culture, which may be a barrier to changing urine collection practices in some settings.

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

A fussy 6-month-old infant is brought into the emergency department (ED) with a rectal temperature of 101.5° F. She is consolable, breathing normally, and appears well hydrated. You find no clear etiology for her fever and suspect that a urinary tract infection (UTI) may be the source of her illness. How do you proceed with obtaining a urine sample?

A febrile infant in the family physician’s office or ED is a familiar clinical situation that may require an invasive diagnostic work-up. Up to 7% of infants ages 2 to 24 months with fever of unknown origin may have a UTI.² Collecting a urine sample from pre-toilet-trained children can be time consuming. In fact, obtaining a clean-catch urine sample in this age group took an average of more than one hour in one randomized controlled trial (RCT).³ More convenient methods of urine collection, such as placing a cotton ball in the diaper or using a perineal collection bag, have contamination rates of up to 63%.⁴

The American Academy of Pediatrics (AAP) guidelines for evaluating possible UTI in a febrile child <2 years of age recommend obtaining a sample for urinalysis “through the most convenient means.”⁵ If urinalysis is positive, only urine obtained by catheterization or suprapubic aspiration should be cultured. Guidelines from the National Institute for Health and Care Excellence in the United Kingdom are similar, but allow for culture of clean-catch urine samples.⁶

A recent prospective cohort study examined a noninvasive alternating lumbar-bladder tapping method to stimulate voiding in infants ages 0 to 6 months.⁷ Within 5 minutes, 49% of the infants provided a clean-catch sample, with contamination rates similar to those of samples obtained using invasive methods.⁷ Younger infants were more likely to void within the time allotted. Another trial of bladder tapping conducted in hospitalized infants <30 days old showed similar results.⁸

There are, however, no previously reported randomized trials demonstrating the efficacy of a noninvasive urine collection technique in the outpatient setting.

Use of invasive collection methods requires skilled personnel and may cause significant discomfort for patients (and parents). Noninvasive methods, such as bag urine collection, have unacceptable contamination rates. In addition, waiting to catch a potentially cleaner urine sample is time-consuming, so better strategies to collect urine from infants are needed. This RCT is the first to examine the efficacy of a unique stimulation technique to obtain a clean-catch urine sample from infants ages 1 to 12 months.

STUDY SUMMARY

Noninvasive stimulation method triggers faster clean urine samples

A nonblinded, single-center RCT conducted in Australia compared 2 methods for obtaining a clean-catch urine sample within 5 minutes: the Quick-Wee method (suprapubic stimulation with gauze soaked in cold fluid) or usual care (waiting for spontaneous voiding with no stimulation).¹ Three hundred fifty-four infants (ages 1-12 months) who required urine sample collection were randomized in a 1:1 ratio; allocation was concealed. Infants with anatomic or neurologic abnormalities and those needing immediate antibiotic therapy were excluded.

Almost one-third of patients provided successful clean-catch samples within 5 minutes.

The most common reasons for obtaining the urine sample were fever of unknown origin and “unsettled baby,” followed by poor feeding and suspected UTI. The primary outcome was voiding within 5 minutes; secondary outcomes included time to void, whether urine was successfully caught, contamination rate, and parent/clinician satisfaction.

Study personnel removed the diaper, then cleaned the genitals of all patients with room temperature sterile water. A caregiver or clinician was ready and waiting to catch urine when the patient voided. In the Quick-Wee group, a clinician rubbed the patient’s suprapubic area in a circular fashion with gauze soaked in refrigerated saline (2.8° C). At 5 minutes, clinicians recorded the voiding status and decided how to proceed.

Using intention-to-treat analysis, 31% of the patients in the Quick-Wee group voided within 5 minutes, compared with 12% of the usual-care patients. Similarly, 30% of patients in the Quick-Wee group provided a successful clean-catch sample within 5 minutes compared with 9% in the usual-care group (P<.001; number needed to treat=4.7; 95% CI, 3.4-7.7). Contamination rates were no different between the Quick-Wee and usual-care samples. Both parents and clinicians were more satisfied with the Quick-Wee method than with usual care (median score of 2 vs 3 on a 5-point Likert scale, in which 1 is most satisfied; P<.001). There was no difference when results were adjusted for age or sex. No adverse events occurred.

WHAT’S NEW

New method could reduce the need for invasive sampling

A simple suprapubic stimulation technique increased the number of infants who provided a clean-catch voided urine sample within 5 minutes—a clinically relevant and satisfying outcome. In appropriate patients, use of the Quick-Wee method to obtain a clean-catch voided sample for initial urinalysis, rather than attempting methods with known high contamination rates, may potentially reduce the need for invasive sampling using catheterization or suprapubic aspiration.

CAVEATS

Complete age range and ideal storage temperature are unknown

Neonates and pre-continent children older than 12 months were not included in this trial, so these conclusions do not apply to those groups of patients. The intervention period lasted only 5 minutes, but other published studies suggest that this amount of time is adequate for voiding to occur.^6,7 Although this study used soaking fluid stored at 2.8° C, the ideal storage temperature is unknown.

CHALLENGES TO IMPLEMENTATION

AAP doesn’t endorse clean-catch urine samples for culture

The Quick-Wee method is simple and easy to implement, and requires no specialized training or equipment. AAP guidelines do not endorse the use of clean-catch voided urine for culture, which may be a barrier to changing urine collection practices in some settings.

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

A fussy 6-month-old infant is brought into the emergency department (ED) with a rectal temperature of 101.5° F. She is consolable, breathing normally, and appears well hydrated. You find no clear etiology for her fever and suspect that a urinary tract infection (UTI) may be the source of her illness. How do you proceed with obtaining a urine sample?

A febrile infant in the family physician’s office or ED is a familiar clinical situation that may require an invasive diagnostic work-up. Up to 7% of infants ages 2 to 24 months with fever of unknown origin may have a UTI.² Collecting a urine sample from pre-toilet-trained children can be time consuming. In fact, obtaining a clean-catch urine sample in this age group took an average of more than one hour in one randomized controlled trial (RCT).³ More convenient methods of urine collection, such as placing a cotton ball in the diaper or using a perineal collection bag, have contamination rates of up to 63%.⁴

The American Academy of Pediatrics (AAP) guidelines for evaluating possible UTI in a febrile child <2 years of age recommend obtaining a sample for urinalysis “through the most convenient means.”⁵ If urinalysis is positive, only urine obtained by catheterization or suprapubic aspiration should be cultured. Guidelines from the National Institute for Health and Care Excellence in the United Kingdom are similar, but allow for culture of clean-catch urine samples.⁶

A recent prospective cohort study examined a noninvasive alternating lumbar-bladder tapping method to stimulate voiding in infants ages 0 to 6 months.⁷ Within 5 minutes, 49% of the infants provided a clean-catch sample, with contamination rates similar to those of samples obtained using invasive methods.⁷ Younger infants were more likely to void within the time allotted. Another trial of bladder tapping conducted in hospitalized infants <30 days old showed similar results.⁸

There are, however, no previously reported randomized trials demonstrating the efficacy of a noninvasive urine collection technique in the outpatient setting.

Use of invasive collection methods requires skilled personnel and may cause significant discomfort for patients (and parents). Noninvasive methods, such as bag urine collection, have unacceptable contamination rates. In addition, waiting to catch a potentially cleaner urine sample is time-consuming, so better strategies to collect urine from infants are needed. This RCT is the first to examine the efficacy of a unique stimulation technique to obtain a clean-catch urine sample from infants ages 1 to 12 months.

STUDY SUMMARY

Noninvasive stimulation method triggers faster clean urine samples

A nonblinded, single-center RCT conducted in Australia compared 2 methods for obtaining a clean-catch urine sample within 5 minutes: the Quick-Wee method (suprapubic stimulation with gauze soaked in cold fluid) or usual care (waiting for spontaneous voiding with no stimulation).¹ Three hundred fifty-four infants (ages 1-12 months) who required urine sample collection were randomized in a 1:1 ratio; allocation was concealed. Infants with anatomic or neurologic abnormalities and those needing immediate antibiotic therapy were excluded.

Almost one-third of patients provided successful clean-catch samples within 5 minutes.

The most common reasons for obtaining the urine sample were fever of unknown origin and “unsettled baby,” followed by poor feeding and suspected UTI. The primary outcome was voiding within 5 minutes; secondary outcomes included time to void, whether urine was successfully caught, contamination rate, and parent/clinician satisfaction.

Study personnel removed the diaper, then cleaned the genitals of all patients with room temperature sterile water. A caregiver or clinician was ready and waiting to catch urine when the patient voided. In the Quick-Wee group, a clinician rubbed the patient’s suprapubic area in a circular fashion with gauze soaked in refrigerated saline (2.8° C). At 5 minutes, clinicians recorded the voiding status and decided how to proceed.

Using intention-to-treat analysis, 31% of the patients in the Quick-Wee group voided within 5 minutes, compared with 12% of the usual-care patients. Similarly, 30% of patients in the Quick-Wee group provided a successful clean-catch sample within 5 minutes compared with 9% in the usual-care group (P<.001; number needed to treat=4.7; 95% CI, 3.4-7.7). Contamination rates were no different between the Quick-Wee and usual-care samples. Both parents and clinicians were more satisfied with the Quick-Wee method than with usual care (median score of 2 vs 3 on a 5-point Likert scale, in which 1 is most satisfied; P<.001). There was no difference when results were adjusted for age or sex. No adverse events occurred.

WHAT’S NEW

New method could reduce the need for invasive sampling

A simple suprapubic stimulation technique increased the number of infants who provided a clean-catch voided urine sample within 5 minutes—a clinically relevant and satisfying outcome. In appropriate patients, use of the Quick-Wee method to obtain a clean-catch voided sample for initial urinalysis, rather than attempting methods with known high contamination rates, may potentially reduce the need for invasive sampling using catheterization or suprapubic aspiration.

CAVEATS

Complete age range and ideal storage temperature are unknown

Neonates and pre-continent children older than 12 months were not included in this trial, so these conclusions do not apply to those groups of patients. The intervention period lasted only 5 minutes, but other published studies suggest that this amount of time is adequate for voiding to occur.^6,7 Although this study used soaking fluid stored at 2.8° C, the ideal storage temperature is unknown.

CHALLENGES TO IMPLEMENTATION

AAP doesn’t endorse clean-catch urine samples for culture

The Quick-Wee method is simple and easy to implement, and requires no specialized training or equipment. AAP guidelines do not endorse the use of clean-catch voided urine for culture, which may be a barrier to changing urine collection practices in some settings.

ACKNOWLEDGEMENT

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

The Advisory Committee on Immunization Practices (ACIP) made relatively few new vaccine recommendations in 2017. One pertained to prevention of hepatitis B virus (HBV) infection in infants born to HBV-infected mothers. Another recommended a new vaccine to prevent shingles. A third advised considering an additional dose of mumps vaccine during an outbreak. This year’s recommendations pertaining to influenza vaccines were covered in a previous Practice Alert.¹

Perinatal HBV prevention: New strategy if revaccination is required

Hepatitis B prevention programs in the United States have decreased the incidence of HBV infections from 9.6 cases per 100,000 population in 1982 (the year the hepatitis B [HepB] vaccine was first available) to 1.1 cases per 100,000 population in 2015 (FIGURE 1).² One major route of HBV dissemination worldwide is perinatal transmission to infants by HBV-infected mothers. However, this route of infection has been greatly diminished in the United States because of widespread screening of pregnant women and because newborns of mothers with known active HBV infection receive prophylaxis with hepatitis B immune globulin and HBV vaccine.

Each year in the United States an estimated 25,000 infants are born to mothers who are positive for hepatitis B surface antigen (HBsAg).³ Without post-exposure prophylaxis, 85% of these infants would develop HBV infection if the mother is also hepatitis B e antigen (HBeAg) positive; 30% would develop HBV infection if the mother is HBeAg negative.² Eighty percent to 90% of infected infants develop chronic HBV infection and are at increased risk of chronic liver disease.² Of all infants receiving the recommended post-exposure prophylaxis, only about 1% develop infection.²

Available HepB vaccines. HepB vaccine consists of HBsAg derived from yeast using recombinant DNA technology, which is then purified by biochemical separation techniques. Three vaccine products are available for newborns and infants in the United States. Two are single-antigen vaccines—Engerix-B (GlaxoSmithKline Biologicals) and Recombivax HB (Merck & Co.)—and both can be used starting at birth. One combination vaccine, Pediarix (GlaxoSmithKline Biologicals) is used for children ages 6 weeks to 6 years. It contains HBsAg as do the other 2 vaccines, as well as diphtheria and tetanus toxoids, acellular pertussis adsorbed, and inactivated poliovirus (DTaP-HepB-IPV).

Until December 31, 2014, a vaccine combining HBsAg and haemophilus-B antigen, Comvax (Merck and Co.), was available for infants 6 weeks or older. Comvax is no longer produced.

Factors affecting the dosing schedule. For infants born to HBsAg-positive mothers, the final dose of the HepB series should be completed at age 6 months with either one of the monovalent HepB vaccines or the DTaP-HepB-IPV vaccine. When the now-discontinued Comvax was used to complete the series, the final dose was administered at 12 to 15 months. The timing of HepB vaccine at birth and at subsequent intervals, and a decision on whether to give hepatitis B immune globulin, depend on the baby’s birth weight, the mother’s HBsAg status, and type of vaccine used.²

Post-vaccination assessment. ACIP recommends that babies born to HBsAg-positive mothers and having received the final dose of the vaccine series be serologically tested for immunity to HBV at age 9 to 12 months; or if the series is delayed, at one to 2 months after the final dose.⁴ Infants without evidence of active infection (ie, HBsAg negative) and with levels of antibody to HBsAg ≥10 mIU/mL are considered protected and need no further vaccinations.⁴ Revaccination is advised for those with antibody levels <10 mIU/mL—who account for only about 2% of infants having received the recommended schedule.⁴

New revaccination strategy. The previous recommendation on revaccination advised a second 3-dose series with repeat serologic testing one to 2 months after the final dose of vaccine. Although this strategy is still acceptable, the new recommendation for infants with antibody levels <10 mIU/mL favors (for cost savings and convenience) administration of a single dose of HepB vaccine with retesting one to 2 months later.²

Several studies presented at the ACIP meeting in February 2017 showed that more than 90% of infants revaccinated with the single dose will develop a protective antibody level.⁴ Infants whose anti-HBs remain <10 mIU/mL following the single-dose re-vaccination should receive 2 additional doses of HepB vaccine, followed by testing one to 2 months after the last dose⁴ (FIGURE 2²).

(A new HepB vaccine, HEPLISAV-B [Dynavax Technologies Corp]), has been approved for use in adults. More on this in a bit.)

 

 

Herpes zoster vaccine: Data guidance on product selection

In 2017, the US Food and Drug Administration (FDA) approved a new vaccine against shingles, an adjuvanted herpes zoster subunit (HZ/su) vaccine, Shingrix (GlaxoSmithKline Biologicals). It is now an alternative to the live attenuated virus (ZVL) vaccine, Zostavax (Merck & Co.), licensed in 2006. ZVL is approved for use in adults ages 50 to 59 years, but ACIP recommends it only for adults 60 and older.⁵ It is given as a single dose, while HZ/su is given as a 2-dose series at 0 and at 2 to 6 months. By ACIP’s analysis, HZ/su is more effective than ZVL. In a comparison model looking at health outcomes over a lifetime among one million patients 60 to 69 years of age, HZ/su would prevent 53,000 more cases of shingles and 4000 more cases of postherpetic neuralgia than would ZVL.⁶

At its October 2017 meeting, ACIP voted to recommend HZ/su for adults ages 50 and older (including those previously vaccinated with ZVL), and to recommend HZ/su preferentially over the use of ZVL.⁷ More details on the ACIP considerations are contained in a recent JFP audiocast.⁸

Additional mumps vaccine is warranted in an outbreak

While use of mumps-containing vaccine in the United States has led to markedly lower disease incidence rates than existed in the pre-vaccine era, in recent years there have been large mumps outbreaks among young adults at universities and other close-knit communities. These groups have had relatively high rates of completion of 2 doses of measles, mumps, and rubella (MMR) vaccine, and the cause of the outbreaks is not fully understood. Potential contributors include waning immunity following vaccination and antigenic differences between the virus strains circulating and those in the vaccine.

ACIP considered whether a third dose of MMR should be recommended to those fully vaccinated if they are at high risk due to an outbreak. Although the evidence to support the effectiveness of a third dose was scant and of very low quality, the evidence for vaccine safety was reassuring and ACIP voted to recommend the use of a third dose in outbreaks.⁹

One new vaccine and others on the horizon

ACIP is evaluating a new HepB vaccine, HEPLISAV-B, which was approved by the FDA in November 2017 for use in adults.^10,11 The vaccine contains the same antigen as other available HepB vaccines but a different adjuvant. It is administered in 2 doses one month apart, which is preferable to the current 3-dose, 6-month schedule. There is, however, some indication that it causes increased rates of cardiovascular complications.¹⁰ ACIP is evaluating the relative effectiveness and safety of HEPLISAV-B and other HepB vaccines, and recommendations are expected this spring.

Other vaccines in various stages of development, but not ready for ACIP evaluation, include those against Zika virus, norovirus, respiratory syncytial virus, and dengue virus.

ACIP is also retrospectively assessing whether adding the 13 valent pneumococcal conjugate vaccine to the schedule for those over the age of 65 has led to improved pneumonia outcomes. It will reconsider the previous recommendation based on the results of its assessment.

The Advisory Committee on Immunization Practices (ACIP) made relatively few new vaccine recommendations in 2017. One pertained to prevention of hepatitis B virus (HBV) infection in infants born to HBV-infected mothers. Another recommended a new vaccine to prevent shingles. A third advised considering an additional dose of mumps vaccine during an outbreak. This year’s recommendations pertaining to influenza vaccines were covered in a previous Practice Alert.¹

Perinatal HBV prevention: New strategy if revaccination is required

Hepatitis B prevention programs in the United States have decreased the incidence of HBV infections from 9.6 cases per 100,000 population in 1982 (the year the hepatitis B [HepB] vaccine was first available) to 1.1 cases per 100,000 population in 2015 (FIGURE 1).² One major route of HBV dissemination worldwide is perinatal transmission to infants by HBV-infected mothers. However, this route of infection has been greatly diminished in the United States because of widespread screening of pregnant women and because newborns of mothers with known active HBV infection receive prophylaxis with hepatitis B immune globulin and HBV vaccine.

Each year in the United States an estimated 25,000 infants are born to mothers who are positive for hepatitis B surface antigen (HBsAg).³ Without post-exposure prophylaxis, 85% of these infants would develop HBV infection if the mother is also hepatitis B e antigen (HBeAg) positive; 30% would develop HBV infection if the mother is HBeAg negative.² Eighty percent to 90% of infected infants develop chronic HBV infection and are at increased risk of chronic liver disease.² Of all infants receiving the recommended post-exposure prophylaxis, only about 1% develop infection.²

Available HepB vaccines. HepB vaccine consists of HBsAg derived from yeast using recombinant DNA technology, which is then purified by biochemical separation techniques. Three vaccine products are available for newborns and infants in the United States. Two are single-antigen vaccines—Engerix-B (GlaxoSmithKline Biologicals) and Recombivax HB (Merck & Co.)—and both can be used starting at birth. One combination vaccine, Pediarix (GlaxoSmithKline Biologicals) is used for children ages 6 weeks to 6 years. It contains HBsAg as do the other 2 vaccines, as well as diphtheria and tetanus toxoids, acellular pertussis adsorbed, and inactivated poliovirus (DTaP-HepB-IPV).

Until December 31, 2014, a vaccine combining HBsAg and haemophilus-B antigen, Comvax (Merck and Co.), was available for infants 6 weeks or older. Comvax is no longer produced.

Factors affecting the dosing schedule. For infants born to HBsAg-positive mothers, the final dose of the HepB series should be completed at age 6 months with either one of the monovalent HepB vaccines or the DTaP-HepB-IPV vaccine. When the now-discontinued Comvax was used to complete the series, the final dose was administered at 12 to 15 months. The timing of HepB vaccine at birth and at subsequent intervals, and a decision on whether to give hepatitis B immune globulin, depend on the baby’s birth weight, the mother’s HBsAg status, and type of vaccine used.²

Post-vaccination assessment. ACIP recommends that babies born to HBsAg-positive mothers and having received the final dose of the vaccine series be serologically tested for immunity to HBV at age 9 to 12 months; or if the series is delayed, at one to 2 months after the final dose.⁴ Infants without evidence of active infection (ie, HBsAg negative) and with levels of antibody to HBsAg ≥10 mIU/mL are considered protected and need no further vaccinations.⁴ Revaccination is advised for those with antibody levels <10 mIU/mL—who account for only about 2% of infants having received the recommended schedule.⁴

New revaccination strategy. The previous recommendation on revaccination advised a second 3-dose series with repeat serologic testing one to 2 months after the final dose of vaccine. Although this strategy is still acceptable, the new recommendation for infants with antibody levels <10 mIU/mL favors (for cost savings and convenience) administration of a single dose of HepB vaccine with retesting one to 2 months later.²

Several studies presented at the ACIP meeting in February 2017 showed that more than 90% of infants revaccinated with the single dose will develop a protective antibody level.⁴ Infants whose anti-HBs remain <10 mIU/mL following the single-dose re-vaccination should receive 2 additional doses of HepB vaccine, followed by testing one to 2 months after the last dose⁴ (FIGURE 2²).

(A new HepB vaccine, HEPLISAV-B [Dynavax Technologies Corp]), has been approved for use in adults. More on this in a bit.)

 

 

Herpes zoster vaccine: Data guidance on product selection

In 2017, the US Food and Drug Administration (FDA) approved a new vaccine against shingles, an adjuvanted herpes zoster subunit (HZ/su) vaccine, Shingrix (GlaxoSmithKline Biologicals). It is now an alternative to the live attenuated virus (ZVL) vaccine, Zostavax (Merck & Co.), licensed in 2006. ZVL is approved for use in adults ages 50 to 59 years, but ACIP recommends it only for adults 60 and older.⁵ It is given as a single dose, while HZ/su is given as a 2-dose series at 0 and at 2 to 6 months. By ACIP’s analysis, HZ/su is more effective than ZVL. In a comparison model looking at health outcomes over a lifetime among one million patients 60 to 69 years of age, HZ/su would prevent 53,000 more cases of shingles and 4000 more cases of postherpetic neuralgia than would ZVL.⁶

At its October 2017 meeting, ACIP voted to recommend HZ/su for adults ages 50 and older (including those previously vaccinated with ZVL), and to recommend HZ/su preferentially over the use of ZVL.⁷ More details on the ACIP considerations are contained in a recent JFP audiocast.⁸

Additional mumps vaccine is warranted in an outbreak

While use of mumps-containing vaccine in the United States has led to markedly lower disease incidence rates than existed in the pre-vaccine era, in recent years there have been large mumps outbreaks among young adults at universities and other close-knit communities. These groups have had relatively high rates of completion of 2 doses of measles, mumps, and rubella (MMR) vaccine, and the cause of the outbreaks is not fully understood. Potential contributors include waning immunity following vaccination and antigenic differences between the virus strains circulating and those in the vaccine.

ACIP considered whether a third dose of MMR should be recommended to those fully vaccinated if they are at high risk due to an outbreak. Although the evidence to support the effectiveness of a third dose was scant and of very low quality, the evidence for vaccine safety was reassuring and ACIP voted to recommend the use of a third dose in outbreaks.⁹

One new vaccine and others on the horizon

ACIP is evaluating a new HepB vaccine, HEPLISAV-B, which was approved by the FDA in November 2017 for use in adults.^10,11 The vaccine contains the same antigen as other available HepB vaccines but a different adjuvant. It is administered in 2 doses one month apart, which is preferable to the current 3-dose, 6-month schedule. There is, however, some indication that it causes increased rates of cardiovascular complications.¹⁰ ACIP is evaluating the relative effectiveness and safety of HEPLISAV-B and other HepB vaccines, and recommendations are expected this spring.

Other vaccines in various stages of development, but not ready for ACIP evaluation, include those against Zika virus, norovirus, respiratory syncytial virus, and dengue virus.

ACIP is also retrospectively assessing whether adding the 13 valent pneumococcal conjugate vaccine to the schedule for those over the age of 65 has led to improved pneumonia outcomes. It will reconsider the previous recommendation based on the results of its assessment.

The Advisory Committee on Immunization Practices (ACIP) made relatively few new vaccine recommendations in 2017. One pertained to prevention of hepatitis B virus (HBV) infection in infants born to HBV-infected mothers. Another recommended a new vaccine to prevent shingles. A third advised considering an additional dose of mumps vaccine during an outbreak. This year’s recommendations pertaining to influenza vaccines were covered in a previous Practice Alert.¹

Perinatal HBV prevention: New strategy if revaccination is required

Hepatitis B prevention programs in the United States have decreased the incidence of HBV infections from 9.6 cases per 100,000 population in 1982 (the year the hepatitis B [HepB] vaccine was first available) to 1.1 cases per 100,000 population in 2015 (FIGURE 1).² One major route of HBV dissemination worldwide is perinatal transmission to infants by HBV-infected mothers. However, this route of infection has been greatly diminished in the United States because of widespread screening of pregnant women and because newborns of mothers with known active HBV infection receive prophylaxis with hepatitis B immune globulin and HBV vaccine.

Each year in the United States an estimated 25,000 infants are born to mothers who are positive for hepatitis B surface antigen (HBsAg).³ Without post-exposure prophylaxis, 85% of these infants would develop HBV infection if the mother is also hepatitis B e antigen (HBeAg) positive; 30% would develop HBV infection if the mother is HBeAg negative.² Eighty percent to 90% of infected infants develop chronic HBV infection and are at increased risk of chronic liver disease.² Of all infants receiving the recommended post-exposure prophylaxis, only about 1% develop infection.²

Available HepB vaccines. HepB vaccine consists of HBsAg derived from yeast using recombinant DNA technology, which is then purified by biochemical separation techniques. Three vaccine products are available for newborns and infants in the United States. Two are single-antigen vaccines—Engerix-B (GlaxoSmithKline Biologicals) and Recombivax HB (Merck & Co.)—and both can be used starting at birth. One combination vaccine, Pediarix (GlaxoSmithKline Biologicals) is used for children ages 6 weeks to 6 years. It contains HBsAg as do the other 2 vaccines, as well as diphtheria and tetanus toxoids, acellular pertussis adsorbed, and inactivated poliovirus (DTaP-HepB-IPV).

Until December 31, 2014, a vaccine combining HBsAg and haemophilus-B antigen, Comvax (Merck and Co.), was available for infants 6 weeks or older. Comvax is no longer produced.

Factors affecting the dosing schedule. For infants born to HBsAg-positive mothers, the final dose of the HepB series should be completed at age 6 months with either one of the monovalent HepB vaccines or the DTaP-HepB-IPV vaccine. When the now-discontinued Comvax was used to complete the series, the final dose was administered at 12 to 15 months. The timing of HepB vaccine at birth and at subsequent intervals, and a decision on whether to give hepatitis B immune globulin, depend on the baby’s birth weight, the mother’s HBsAg status, and type of vaccine used.²

Post-vaccination assessment. ACIP recommends that babies born to HBsAg-positive mothers and having received the final dose of the vaccine series be serologically tested for immunity to HBV at age 9 to 12 months; or if the series is delayed, at one to 2 months after the final dose.⁴ Infants without evidence of active infection (ie, HBsAg negative) and with levels of antibody to HBsAg ≥10 mIU/mL are considered protected and need no further vaccinations.⁴ Revaccination is advised for those with antibody levels <10 mIU/mL—who account for only about 2% of infants having received the recommended schedule.⁴

New revaccination strategy. The previous recommendation on revaccination advised a second 3-dose series with repeat serologic testing one to 2 months after the final dose of vaccine. Although this strategy is still acceptable, the new recommendation for infants with antibody levels <10 mIU/mL favors (for cost savings and convenience) administration of a single dose of HepB vaccine with retesting one to 2 months later.²

Several studies presented at the ACIP meeting in February 2017 showed that more than 90% of infants revaccinated with the single dose will develop a protective antibody level.⁴ Infants whose anti-HBs remain <10 mIU/mL following the single-dose re-vaccination should receive 2 additional doses of HepB vaccine, followed by testing one to 2 months after the last dose⁴ (FIGURE 2²).

(A new HepB vaccine, HEPLISAV-B [Dynavax Technologies Corp]), has been approved for use in adults. More on this in a bit.)

 

 

Herpes zoster vaccine: Data guidance on product selection

In 2017, the US Food and Drug Administration (FDA) approved a new vaccine against shingles, an adjuvanted herpes zoster subunit (HZ/su) vaccine, Shingrix (GlaxoSmithKline Biologicals). It is now an alternative to the live attenuated virus (ZVL) vaccine, Zostavax (Merck & Co.), licensed in 2006. ZVL is approved for use in adults ages 50 to 59 years, but ACIP recommends it only for adults 60 and older.⁵ It is given as a single dose, while HZ/su is given as a 2-dose series at 0 and at 2 to 6 months. By ACIP’s analysis, HZ/su is more effective than ZVL. In a comparison model looking at health outcomes over a lifetime among one million patients 60 to 69 years of age, HZ/su would prevent 53,000 more cases of shingles and 4000 more cases of postherpetic neuralgia than would ZVL.⁶

At its October 2017 meeting, ACIP voted to recommend HZ/su for adults ages 50 and older (including those previously vaccinated with ZVL), and to recommend HZ/su preferentially over the use of ZVL.⁷ More details on the ACIP considerations are contained in a recent JFP audiocast.⁸

Additional mumps vaccine is warranted in an outbreak

While use of mumps-containing vaccine in the United States has led to markedly lower disease incidence rates than existed in the pre-vaccine era, in recent years there have been large mumps outbreaks among young adults at universities and other close-knit communities. These groups have had relatively high rates of completion of 2 doses of measles, mumps, and rubella (MMR) vaccine, and the cause of the outbreaks is not fully understood. Potential contributors include waning immunity following vaccination and antigenic differences between the virus strains circulating and those in the vaccine.

ACIP considered whether a third dose of MMR should be recommended to those fully vaccinated if they are at high risk due to an outbreak. Although the evidence to support the effectiveness of a third dose was scant and of very low quality, the evidence for vaccine safety was reassuring and ACIP voted to recommend the use of a third dose in outbreaks.⁹

One new vaccine and others on the horizon

ACIP is evaluating a new HepB vaccine, HEPLISAV-B, which was approved by the FDA in November 2017 for use in adults.^10,11 The vaccine contains the same antigen as other available HepB vaccines but a different adjuvant. It is administered in 2 doses one month apart, which is preferable to the current 3-dose, 6-month schedule. There is, however, some indication that it causes increased rates of cardiovascular complications.¹⁰ ACIP is evaluating the relative effectiveness and safety of HEPLISAV-B and other HepB vaccines, and recommendations are expected this spring.

Other vaccines in various stages of development, but not ready for ACIP evaluation, include those against Zika virus, norovirus, respiratory syncytial virus, and dengue virus.

ACIP is also retrospectively assessing whether adding the 13 valent pneumococcal conjugate vaccine to the schedule for those over the age of 65 has led to improved pneumonia outcomes. It will reconsider the previous recommendation based on the results of its assessment.