Applied Evidence

CASE › Your patient, Amy Z, age 58, was given a diagnosis of hypertension 10 years ago and since then has been maintained on hydrochlorothiazide 50 mg/d and lisinopril 10 mg/d. In the office today, she reports intermittent chest tightness and heaviness. She has no history of coronary artery disease (CAD), cerebrovascular disease, or peripheral vascular disease. She attributes her chest discomfort to emotional stress. She recently started a job after having been unemployed, but still has no health insurance and is concerned about losing her house.

She denies orthopnea and resting or exertional dyspnea, and says she never gets chest pain while climbing stairs. Her blood pressure is elevated at 180/110 mm Hg, but her other vital signs are normal (pulse, 70 beats per minute; respiratory rate, 18 breaths per minute). On physical examination, she has no venous distension in her neck and her lungs are clear. A cardiac exam reveals a regular rate and rhythm, with a normally split S1 and S2 and no murmurs, rubs, or gallops. Palpation of the chest does not reproduce her chest pain.

You are concerned that your patient’s chest pain could be from heart disease, but she wants to defer additional testing because of the cost, stating, “It’s all due to my stress.”

How would you proceed?

Musculoskeletal chest wall pain is the most common cause of chest pain in patients who seek treatment in the office, followed by GI disease and stable heart disease.

Whether they go to the emergency department (ED) or to their family physician’s office, most patients who seek treatment for chest pain don’t have life-threatening cardiac illness. Of the 8 million patients who visit an ED for chest pain each year, only 13% are diagnosed with acute coronary syndrome (ACS).^1,2 Among those seen for chest pain in a primary care office, only a minority (approximately 1.5%) have unstable heart disease.^3-5 Cross-sectional studies indicate that musculoskeletal chest wall pain (or “chest wall syndrome [CWS]”) is the most common cause of chest pain in patients who seek treatment in the office, followed by gastrointestinal (GI) disease, stable heart disease, psychosocial or psychiatric conditions, pulmonary disease, and other cardiovascular conditions (TABLE 1).^3,6,7

When evaluating patients with chest pain in the office, the challenge is to appropriately evaluate and manage those who are at low risk of ACS, while at the same time identifying and arranging prompt transfer or referral for the minority of patients who are at high cardiac risk. This article describes how to determine which patients require emergency treatment, which tools to use to screen for ACS and other potential causes of chest pain, and how to proceed when initial evaluation and testing do not point to a clear diagnosis.

Start with the ABCs

When a patient presents in primary care with a chief complaint of chest pain, it’s of course critical that you quickly determine if he or she is stable by evaluating the “ABCs” (airway, breathing, and circulation). Any potentially unstable patient should be immediately transferred for emergency care.⁸ A patient who shows no signs of respiratory distress and whose vital signs are within a normal range is unlikely to be acutely unstable, and can be further evaluated in the office.

If the patient is stable, obtain a history of the onset and evolution of the chest pain, especially its location, quality, duration, and aggravating or alleviating factors. Also ask about a personal or family history of heart disease, hypertension, diabetes, or hypercholesterolemia, and about tobacco use. While the presence of any of these cardiac risk factors may increase suspicion for a cardiac cause for chest pain, the absence of such factors does not eliminate the need for a careful diagnostic evaluation.

Patients with “typical” chest pain have a higher risk of ACS. In a 2005 review of observational prospective and retrospective studies and systematic reviews, Swap et al⁹ corroborated the description of “typical” anginal chest pain, indicating that patients whose chest pain is exertional, radiating to one or both arms, similar to or worse than prior cardiac chest pain, or associated with nausea, vomiting, or diaphoresis are at high risk for ACS (TABLE 2).⁹ These researchers also found that chest pain that is stabbing, pleuritic, positional, or reproducible with palpation suggests that a patient is at low risk for ACS. Pain that is not exertional or that is in a small inframammary area of the chest also suggests a low risk for ACS.⁹

Marburg Heart Score and other tests can help rule out ACS

Patients with chest pain that is exertional, radiating to one or both arms, or associated with nausea are at high risk for acute coronary syndrome.As part of your initial physical examination, assess the patient’s overall condition and stability. Be aware, however, that an older literature review found that a physical exam is only minimally helpful in assessing ACS risk in a patient with chest pain. Findings that may increase the risk of ACS are a third heart sound (positive likelihood ratio [LR+] = 3.2; 95% confidence interval [CI], 1.6-6.5), systolic blood pressure <80 mm/Hg (LR+ = 3.1; 95% CI, 1.8-5.2), and pulmonary crackles on auscultation (LR+ = 2.1; 95% CI, 1.4–3.1); however, the absence of these findings does not exclude ACS.10 The most helpful sign or symptom in evaluating a patient with chest pain is chest wall tenderness on palpation, which largely rules out ACS in low-prevalence settings, such as a primary care office.¹¹

Bösner et al¹² developed the Marburg Heart Score (MHS) to help primary care physicians evaluate the risk of CAD in patients with chest pain (TABLE 3).^12,13 A subsequent validation study found that an MHS ≥3 had a sensitivity of 89.1% (95% CI, 81.1%-94%) and a specificity of 63.5% (95% CI, 60%-66.9%) for CAD.¹³ The test’s negative predictive value (NPV) of 97.9% (95% CI, 96.2%-98.9%) means that patients with an MHS ≤2 are very unlikely to have CAD; however, the low positive predictive value (PPV) of only 23.3% (95% CI, 19.2%-28.0%) means an MHS ≥3 is not particularly helpful in diagnosing CAD.^12,13

Unless it is clear that your patient’s chest pain is unlikely to have a cardiac cause (eg, pain is reproducible on palpation, or an MHS ≤2), order an electrocardiogram (EKG). If the EKG shows ST-segment elevation in 2 or more contiguous leads, presumed new left bundle branch block, ischemic ST-segment depression >.5 mm (.05 mV), or dynamic T-wave inversion with pain or discomfort, the patient needs urgent referral for emergency care.⁸ If the EKG is nondiagnostic but the chest pain is suspicious for CAD, then further testing with cardiac biomarkers (eg, troponin I or T) is recommended to evaluate for non-ST elevation myocardial infarction. Consider chest radiography if there is evidence of respiratory disease (cough, dyspnea, or a history of pulmonary disease).

Don’t overlook chest wall syndrome, GERD, or panic disorder

There are several conditions to consider in the differential diagnosis of patients whose chest pain does not appear to have a cardiac cause:

CWS is the most common cause of chest pain in primary care patients.^14,15 While there are several specific types of chest wall pain—including musculoskeletal pain, parietal or intercostal pain, Tietze’s syndrome, and costochondral pain—all are manifestations of a musculoskeletal disorder and associated with tenderness of the chest wall. CWS is not life threatening, but one study found high rates of anxiety (54%-93%) among patients with moderate to severe CWS.^14,15

Few trials have evaluated treatments for chest wall pain or costochondritis, though typical recommendations include nonsteroidal anti-inflammatory medications, use of heat or cold, physical therapy, or injection of local anesthetic.¹⁶ One study found that stretching exercises might benefit patients with costochondritis.¹⁷

GI disorders. Patients with esophagitis or gastroesophageal reflux disease (GERD) often report heartburn, chronic cough, chronic laryngitis, and asthma.¹⁸ However, the sensitivity and specificity of these symptoms are too low to allow diagnosis or exclusion of GERD based on history alone.¹⁸

Chest wall tenderness on palpation largely rules out acute coronary syndrome.Acid suppression therapy can be used to test for GERD. A 2005 meta-analysis of 6 studies found the sensitivity and specificity of a proton-pump inhibitor (PPI) acid suppression test for the diagnosis of GERD in patients with noncardiac chest pain were 80% (95% CI, 71%-87%) and 74% (95% CI, 64%-83%), respectively.¹⁹ One study demonstrated that relief of chest pain after a 14-day course of omeprazole 40 mg/d was more sensitive than endoscopy, manometry, or 24-hour esophageal pH monitoring in diagnosing GERD.²⁰ Another study found that in patients with noncardiac chest pain and normal upper endoscopy, symptomatic relief with lansoprazole 30 mg/d for 4 weeks can be used to diagnose endoscopy-negative GERD.²¹

It is appropriate to try a high-dose course of a PPI (ie, omeprazole 40 mg twice daily, lansoprazole 30 mg/d, or esomeprazole 40 mg twice daily) to evaluate for GERD as the cause of chest pain in patients who:^20-22
• do not initially describe typical reflux symptoms (eg, heartburn, chronic regurgitation, chronic cough, or a sore or burning throat)
• have no history of surgery in the upper GI tract, esophagus, or thorax, and
• have no signs or symptoms that indicate they have a serious or malignant disease (eg, weight loss, anemia, or dysphagia).

Panic disorder. Several tools have been proposed for screening for panic disorder (PD),^23,24 but none have been tested in patients with chest pain. Dammen et al²⁵ developed a 3-item questionnaire to assess for PD among patients with chest pain who were referred for cardiac evaluation (TABLE 4).²⁵ A score ≥5 on the Dammen questionnaire had 55% sensitivity and 86% specificity for PD, with a PPV of 71% and an NPV of 76%.²⁵ Although this instrument has not been subjected to validation studies, using it may help clarify whether further investigation for PD is warranted.

A 2-week course of high-dose proton pump inhibitor therapy can help identify patients whose chest pain may be caused by undiagnosed GERD.Psychotherapeutic interventions may be effective for patients whose chest pain is caused by PD. A Cochrane review of 15 randomized controlled trials of psychological interventions for chest pain in patients with normal coronary anatomy found that cognitive-behavior therapy, and possibly hypnotherapy, reduced patient reports of chest pain, reduced chest pain frequency, and increased the number of chest pain-free days, at least for 3 months.²⁶

What to do when the diagnosis remains unclear

When your initial evaluation and diagnostic testing yield no clear diagnosis, appropriate follow-up is vital because in the year after primary care patients first develop chest pain, they are 1.5 to 3 times more likely than the general population to be diagnosed with musculoskeletal, GI, psychological, or respiratory problems, nearly 5 times as likely to be diagnosed with heart failure, and nearly 15 times as likely to be diagnosed with coronary heart disease.^27,28

Consider ordering exercise or chemical stress testing within 3 to 7 days for a patient with chest pain that suggests ACS but who has normal results on EKG and biomarker testing.⁸ Interestingly, though, in a study of 4181 patients in an ED chest pain unit who had 2 sets of normal serum troponins during a 6-hour period followed by exercise or chemical stress testing, only 470 patients (11%) had abnormal stress test results and only 37 (.9%) had obstructive CAD that would have potentially benefited from revascularization.²⁹ Thus, testing troponin levels twice over 6 hours is a reasonable alternative to stress testing for a primary care patient with chest pain; stress testing would be unnecessary if both troponin values were normal.

CASE › Based on her current chest pain symptoms, Ms. Z’s MHS is a reassuringly low 1, so CAD is unlikely. However, she scores 5 on the Dammen panic disorder screen. Due to her financial concerns, you decide to forgo stress testing and instead draw a serum troponin now, with plans to repeat later in the afternoon at your clinic lab if the initial result is normal. You encourage her to try a high-dose PPI for 2 weeks to determine whether GERD may be contributing to her symptoms, and offer to help her explore counseling options to address her emotional stressors.

CORRESPONDENCE
William E. Cayley Jr, MD, MDiv, University of Wisconsin, UW Health Augusta Family Medicine Clinic, 207 West Lincoln, Augusta, WI 54722; [email protected]

CASE › Your patient, Amy Z, age 58, was given a diagnosis of hypertension 10 years ago and since then has been maintained on hydrochlorothiazide 50 mg/d and lisinopril 10 mg/d. In the office today, she reports intermittent chest tightness and heaviness. She has no history of coronary artery disease (CAD), cerebrovascular disease, or peripheral vascular disease. She attributes her chest discomfort to emotional stress. She recently started a job after having been unemployed, but still has no health insurance and is concerned about losing her house.

She denies orthopnea and resting or exertional dyspnea, and says she never gets chest pain while climbing stairs. Her blood pressure is elevated at 180/110 mm Hg, but her other vital signs are normal (pulse, 70 beats per minute; respiratory rate, 18 breaths per minute). On physical examination, she has no venous distension in her neck and her lungs are clear. A cardiac exam reveals a regular rate and rhythm, with a normally split S1 and S2 and no murmurs, rubs, or gallops. Palpation of the chest does not reproduce her chest pain.

You are concerned that your patient’s chest pain could be from heart disease, but she wants to defer additional testing because of the cost, stating, “It’s all due to my stress.”

How would you proceed?

Musculoskeletal chest wall pain is the most common cause of chest pain in patients who seek treatment in the office, followed by GI disease and stable heart disease.

Whether they go to the emergency department (ED) or to their family physician’s office, most patients who seek treatment for chest pain don’t have life-threatening cardiac illness. Of the 8 million patients who visit an ED for chest pain each year, only 13% are diagnosed with acute coronary syndrome (ACS).^1,2 Among those seen for chest pain in a primary care office, only a minority (approximately 1.5%) have unstable heart disease.^3-5 Cross-sectional studies indicate that musculoskeletal chest wall pain (or “chest wall syndrome [CWS]”) is the most common cause of chest pain in patients who seek treatment in the office, followed by gastrointestinal (GI) disease, stable heart disease, psychosocial or psychiatric conditions, pulmonary disease, and other cardiovascular conditions (TABLE 1).^3,6,7

When evaluating patients with chest pain in the office, the challenge is to appropriately evaluate and manage those who are at low risk of ACS, while at the same time identifying and arranging prompt transfer or referral for the minority of patients who are at high cardiac risk. This article describes how to determine which patients require emergency treatment, which tools to use to screen for ACS and other potential causes of chest pain, and how to proceed when initial evaluation and testing do not point to a clear diagnosis.

Start with the ABCs

When a patient presents in primary care with a chief complaint of chest pain, it’s of course critical that you quickly determine if he or she is stable by evaluating the “ABCs” (airway, breathing, and circulation). Any potentially unstable patient should be immediately transferred for emergency care.⁸ A patient who shows no signs of respiratory distress and whose vital signs are within a normal range is unlikely to be acutely unstable, and can be further evaluated in the office.

If the patient is stable, obtain a history of the onset and evolution of the chest pain, especially its location, quality, duration, and aggravating or alleviating factors. Also ask about a personal or family history of heart disease, hypertension, diabetes, or hypercholesterolemia, and about tobacco use. While the presence of any of these cardiac risk factors may increase suspicion for a cardiac cause for chest pain, the absence of such factors does not eliminate the need for a careful diagnostic evaluation.

Patients with “typical” chest pain have a higher risk of ACS. In a 2005 review of observational prospective and retrospective studies and systematic reviews, Swap et al⁹ corroborated the description of “typical” anginal chest pain, indicating that patients whose chest pain is exertional, radiating to one or both arms, similar to or worse than prior cardiac chest pain, or associated with nausea, vomiting, or diaphoresis are at high risk for ACS (TABLE 2).⁹ These researchers also found that chest pain that is stabbing, pleuritic, positional, or reproducible with palpation suggests that a patient is at low risk for ACS. Pain that is not exertional or that is in a small inframammary area of the chest also suggests a low risk for ACS.⁹

Marburg Heart Score and other tests can help rule out ACS

Patients with chest pain that is exertional, radiating to one or both arms, or associated with nausea are at high risk for acute coronary syndrome.As part of your initial physical examination, assess the patient’s overall condition and stability. Be aware, however, that an older literature review found that a physical exam is only minimally helpful in assessing ACS risk in a patient with chest pain. Findings that may increase the risk of ACS are a third heart sound (positive likelihood ratio [LR+] = 3.2; 95% confidence interval [CI], 1.6-6.5), systolic blood pressure <80 mm/Hg (LR+ = 3.1; 95% CI, 1.8-5.2), and pulmonary crackles on auscultation (LR+ = 2.1; 95% CI, 1.4–3.1); however, the absence of these findings does not exclude ACS.10 The most helpful sign or symptom in evaluating a patient with chest pain is chest wall tenderness on palpation, which largely rules out ACS in low-prevalence settings, such as a primary care office.¹¹

Bösner et al¹² developed the Marburg Heart Score (MHS) to help primary care physicians evaluate the risk of CAD in patients with chest pain (TABLE 3).^12,13 A subsequent validation study found that an MHS ≥3 had a sensitivity of 89.1% (95% CI, 81.1%-94%) and a specificity of 63.5% (95% CI, 60%-66.9%) for CAD.¹³ The test’s negative predictive value (NPV) of 97.9% (95% CI, 96.2%-98.9%) means that patients with an MHS ≤2 are very unlikely to have CAD; however, the low positive predictive value (PPV) of only 23.3% (95% CI, 19.2%-28.0%) means an MHS ≥3 is not particularly helpful in diagnosing CAD.^12,13

Unless it is clear that your patient’s chest pain is unlikely to have a cardiac cause (eg, pain is reproducible on palpation, or an MHS ≤2), order an electrocardiogram (EKG). If the EKG shows ST-segment elevation in 2 or more contiguous leads, presumed new left bundle branch block, ischemic ST-segment depression >.5 mm (.05 mV), or dynamic T-wave inversion with pain or discomfort, the patient needs urgent referral for emergency care.⁸ If the EKG is nondiagnostic but the chest pain is suspicious for CAD, then further testing with cardiac biomarkers (eg, troponin I or T) is recommended to evaluate for non-ST elevation myocardial infarction. Consider chest radiography if there is evidence of respiratory disease (cough, dyspnea, or a history of pulmonary disease).

Don’t overlook chest wall syndrome, GERD, or panic disorder

There are several conditions to consider in the differential diagnosis of patients whose chest pain does not appear to have a cardiac cause:

CWS is the most common cause of chest pain in primary care patients.^14,15 While there are several specific types of chest wall pain—including musculoskeletal pain, parietal or intercostal pain, Tietze’s syndrome, and costochondral pain—all are manifestations of a musculoskeletal disorder and associated with tenderness of the chest wall. CWS is not life threatening, but one study found high rates of anxiety (54%-93%) among patients with moderate to severe CWS.^14,15

Few trials have evaluated treatments for chest wall pain or costochondritis, though typical recommendations include nonsteroidal anti-inflammatory medications, use of heat or cold, physical therapy, or injection of local anesthetic.¹⁶ One study found that stretching exercises might benefit patients with costochondritis.¹⁷

GI disorders. Patients with esophagitis or gastroesophageal reflux disease (GERD) often report heartburn, chronic cough, chronic laryngitis, and asthma.¹⁸ However, the sensitivity and specificity of these symptoms are too low to allow diagnosis or exclusion of GERD based on history alone.¹⁸

Chest wall tenderness on palpation largely rules out acute coronary syndrome.Acid suppression therapy can be used to test for GERD. A 2005 meta-analysis of 6 studies found the sensitivity and specificity of a proton-pump inhibitor (PPI) acid suppression test for the diagnosis of GERD in patients with noncardiac chest pain were 80% (95% CI, 71%-87%) and 74% (95% CI, 64%-83%), respectively.¹⁹ One study demonstrated that relief of chest pain after a 14-day course of omeprazole 40 mg/d was more sensitive than endoscopy, manometry, or 24-hour esophageal pH monitoring in diagnosing GERD.²⁰ Another study found that in patients with noncardiac chest pain and normal upper endoscopy, symptomatic relief with lansoprazole 30 mg/d for 4 weeks can be used to diagnose endoscopy-negative GERD.²¹

It is appropriate to try a high-dose course of a PPI (ie, omeprazole 40 mg twice daily, lansoprazole 30 mg/d, or esomeprazole 40 mg twice daily) to evaluate for GERD as the cause of chest pain in patients who:^20-22
• do not initially describe typical reflux symptoms (eg, heartburn, chronic regurgitation, chronic cough, or a sore or burning throat)
• have no history of surgery in the upper GI tract, esophagus, or thorax, and
• have no signs or symptoms that indicate they have a serious or malignant disease (eg, weight loss, anemia, or dysphagia).

Panic disorder. Several tools have been proposed for screening for panic disorder (PD),^23,24 but none have been tested in patients with chest pain. Dammen et al²⁵ developed a 3-item questionnaire to assess for PD among patients with chest pain who were referred for cardiac evaluation (TABLE 4).²⁵ A score ≥5 on the Dammen questionnaire had 55% sensitivity and 86% specificity for PD, with a PPV of 71% and an NPV of 76%.²⁵ Although this instrument has not been subjected to validation studies, using it may help clarify whether further investigation for PD is warranted.

A 2-week course of high-dose proton pump inhibitor therapy can help identify patients whose chest pain may be caused by undiagnosed GERD.Psychotherapeutic interventions may be effective for patients whose chest pain is caused by PD. A Cochrane review of 15 randomized controlled trials of psychological interventions for chest pain in patients with normal coronary anatomy found that cognitive-behavior therapy, and possibly hypnotherapy, reduced patient reports of chest pain, reduced chest pain frequency, and increased the number of chest pain-free days, at least for 3 months.²⁶

What to do when the diagnosis remains unclear

When your initial evaluation and diagnostic testing yield no clear diagnosis, appropriate follow-up is vital because in the year after primary care patients first develop chest pain, they are 1.5 to 3 times more likely than the general population to be diagnosed with musculoskeletal, GI, psychological, or respiratory problems, nearly 5 times as likely to be diagnosed with heart failure, and nearly 15 times as likely to be diagnosed with coronary heart disease.^27,28

Consider ordering exercise or chemical stress testing within 3 to 7 days for a patient with chest pain that suggests ACS but who has normal results on EKG and biomarker testing.⁸ Interestingly, though, in a study of 4181 patients in an ED chest pain unit who had 2 sets of normal serum troponins during a 6-hour period followed by exercise or chemical stress testing, only 470 patients (11%) had abnormal stress test results and only 37 (.9%) had obstructive CAD that would have potentially benefited from revascularization.²⁹ Thus, testing troponin levels twice over 6 hours is a reasonable alternative to stress testing for a primary care patient with chest pain; stress testing would be unnecessary if both troponin values were normal.

CASE › Based on her current chest pain symptoms, Ms. Z’s MHS is a reassuringly low 1, so CAD is unlikely. However, she scores 5 on the Dammen panic disorder screen. Due to her financial concerns, you decide to forgo stress testing and instead draw a serum troponin now, with plans to repeat later in the afternoon at your clinic lab if the initial result is normal. You encourage her to try a high-dose PPI for 2 weeks to determine whether GERD may be contributing to her symptoms, and offer to help her explore counseling options to address her emotional stressors.

CORRESPONDENCE
William E. Cayley Jr, MD, MDiv, University of Wisconsin, UW Health Augusta Family Medicine Clinic, 207 West Lincoln, Augusta, WI 54722; [email protected]

CASE › Your patient, Amy Z, age 58, was given a diagnosis of hypertension 10 years ago and since then has been maintained on hydrochlorothiazide 50 mg/d and lisinopril 10 mg/d. In the office today, she reports intermittent chest tightness and heaviness. She has no history of coronary artery disease (CAD), cerebrovascular disease, or peripheral vascular disease. She attributes her chest discomfort to emotional stress. She recently started a job after having been unemployed, but still has no health insurance and is concerned about losing her house.

She denies orthopnea and resting or exertional dyspnea, and says she never gets chest pain while climbing stairs. Her blood pressure is elevated at 180/110 mm Hg, but her other vital signs are normal (pulse, 70 beats per minute; respiratory rate, 18 breaths per minute). On physical examination, she has no venous distension in her neck and her lungs are clear. A cardiac exam reveals a regular rate and rhythm, with a normally split S1 and S2 and no murmurs, rubs, or gallops. Palpation of the chest does not reproduce her chest pain.

You are concerned that your patient’s chest pain could be from heart disease, but she wants to defer additional testing because of the cost, stating, “It’s all due to my stress.”

How would you proceed?

Musculoskeletal chest wall pain is the most common cause of chest pain in patients who seek treatment in the office, followed by GI disease and stable heart disease.

Whether they go to the emergency department (ED) or to their family physician’s office, most patients who seek treatment for chest pain don’t have life-threatening cardiac illness. Of the 8 million patients who visit an ED for chest pain each year, only 13% are diagnosed with acute coronary syndrome (ACS).^1,2 Among those seen for chest pain in a primary care office, only a minority (approximately 1.5%) have unstable heart disease.^3-5 Cross-sectional studies indicate that musculoskeletal chest wall pain (or “chest wall syndrome [CWS]”) is the most common cause of chest pain in patients who seek treatment in the office, followed by gastrointestinal (GI) disease, stable heart disease, psychosocial or psychiatric conditions, pulmonary disease, and other cardiovascular conditions (TABLE 1).^3,6,7

When evaluating patients with chest pain in the office, the challenge is to appropriately evaluate and manage those who are at low risk of ACS, while at the same time identifying and arranging prompt transfer or referral for the minority of patients who are at high cardiac risk. This article describes how to determine which patients require emergency treatment, which tools to use to screen for ACS and other potential causes of chest pain, and how to proceed when initial evaluation and testing do not point to a clear diagnosis.

Start with the ABCs

When a patient presents in primary care with a chief complaint of chest pain, it’s of course critical that you quickly determine if he or she is stable by evaluating the “ABCs” (airway, breathing, and circulation). Any potentially unstable patient should be immediately transferred for emergency care.⁸ A patient who shows no signs of respiratory distress and whose vital signs are within a normal range is unlikely to be acutely unstable, and can be further evaluated in the office.

If the patient is stable, obtain a history of the onset and evolution of the chest pain, especially its location, quality, duration, and aggravating or alleviating factors. Also ask about a personal or family history of heart disease, hypertension, diabetes, or hypercholesterolemia, and about tobacco use. While the presence of any of these cardiac risk factors may increase suspicion for a cardiac cause for chest pain, the absence of such factors does not eliminate the need for a careful diagnostic evaluation.

Patients with “typical” chest pain have a higher risk of ACS. In a 2005 review of observational prospective and retrospective studies and systematic reviews, Swap et al⁹ corroborated the description of “typical” anginal chest pain, indicating that patients whose chest pain is exertional, radiating to one or both arms, similar to or worse than prior cardiac chest pain, or associated with nausea, vomiting, or diaphoresis are at high risk for ACS (TABLE 2).⁹ These researchers also found that chest pain that is stabbing, pleuritic, positional, or reproducible with palpation suggests that a patient is at low risk for ACS. Pain that is not exertional or that is in a small inframammary area of the chest also suggests a low risk for ACS.⁹

Marburg Heart Score and other tests can help rule out ACS

Patients with chest pain that is exertional, radiating to one or both arms, or associated with nausea are at high risk for acute coronary syndrome.As part of your initial physical examination, assess the patient’s overall condition and stability. Be aware, however, that an older literature review found that a physical exam is only minimally helpful in assessing ACS risk in a patient with chest pain. Findings that may increase the risk of ACS are a third heart sound (positive likelihood ratio [LR+] = 3.2; 95% confidence interval [CI], 1.6-6.5), systolic blood pressure <80 mm/Hg (LR+ = 3.1; 95% CI, 1.8-5.2), and pulmonary crackles on auscultation (LR+ = 2.1; 95% CI, 1.4–3.1); however, the absence of these findings does not exclude ACS.10 The most helpful sign or symptom in evaluating a patient with chest pain is chest wall tenderness on palpation, which largely rules out ACS in low-prevalence settings, such as a primary care office.¹¹

Bösner et al¹² developed the Marburg Heart Score (MHS) to help primary care physicians evaluate the risk of CAD in patients with chest pain (TABLE 3).^12,13 A subsequent validation study found that an MHS ≥3 had a sensitivity of 89.1% (95% CI, 81.1%-94%) and a specificity of 63.5% (95% CI, 60%-66.9%) for CAD.¹³ The test’s negative predictive value (NPV) of 97.9% (95% CI, 96.2%-98.9%) means that patients with an MHS ≤2 are very unlikely to have CAD; however, the low positive predictive value (PPV) of only 23.3% (95% CI, 19.2%-28.0%) means an MHS ≥3 is not particularly helpful in diagnosing CAD.^12,13

Unless it is clear that your patient’s chest pain is unlikely to have a cardiac cause (eg, pain is reproducible on palpation, or an MHS ≤2), order an electrocardiogram (EKG). If the EKG shows ST-segment elevation in 2 or more contiguous leads, presumed new left bundle branch block, ischemic ST-segment depression >.5 mm (.05 mV), or dynamic T-wave inversion with pain or discomfort, the patient needs urgent referral for emergency care.⁸ If the EKG is nondiagnostic but the chest pain is suspicious for CAD, then further testing with cardiac biomarkers (eg, troponin I or T) is recommended to evaluate for non-ST elevation myocardial infarction. Consider chest radiography if there is evidence of respiratory disease (cough, dyspnea, or a history of pulmonary disease).

Don’t overlook chest wall syndrome, GERD, or panic disorder

There are several conditions to consider in the differential diagnosis of patients whose chest pain does not appear to have a cardiac cause:

CWS is the most common cause of chest pain in primary care patients.^14,15 While there are several specific types of chest wall pain—including musculoskeletal pain, parietal or intercostal pain, Tietze’s syndrome, and costochondral pain—all are manifestations of a musculoskeletal disorder and associated with tenderness of the chest wall. CWS is not life threatening, but one study found high rates of anxiety (54%-93%) among patients with moderate to severe CWS.^14,15

Few trials have evaluated treatments for chest wall pain or costochondritis, though typical recommendations include nonsteroidal anti-inflammatory medications, use of heat or cold, physical therapy, or injection of local anesthetic.¹⁶ One study found that stretching exercises might benefit patients with costochondritis.¹⁷

GI disorders. Patients with esophagitis or gastroesophageal reflux disease (GERD) often report heartburn, chronic cough, chronic laryngitis, and asthma.¹⁸ However, the sensitivity and specificity of these symptoms are too low to allow diagnosis or exclusion of GERD based on history alone.¹⁸

Chest wall tenderness on palpation largely rules out acute coronary syndrome.Acid suppression therapy can be used to test for GERD. A 2005 meta-analysis of 6 studies found the sensitivity and specificity of a proton-pump inhibitor (PPI) acid suppression test for the diagnosis of GERD in patients with noncardiac chest pain were 80% (95% CI, 71%-87%) and 74% (95% CI, 64%-83%), respectively.¹⁹ One study demonstrated that relief of chest pain after a 14-day course of omeprazole 40 mg/d was more sensitive than endoscopy, manometry, or 24-hour esophageal pH monitoring in diagnosing GERD.²⁰ Another study found that in patients with noncardiac chest pain and normal upper endoscopy, symptomatic relief with lansoprazole 30 mg/d for 4 weeks can be used to diagnose endoscopy-negative GERD.²¹

It is appropriate to try a high-dose course of a PPI (ie, omeprazole 40 mg twice daily, lansoprazole 30 mg/d, or esomeprazole 40 mg twice daily) to evaluate for GERD as the cause of chest pain in patients who:^20-22
• do not initially describe typical reflux symptoms (eg, heartburn, chronic regurgitation, chronic cough, or a sore or burning throat)
• have no history of surgery in the upper GI tract, esophagus, or thorax, and
• have no signs or symptoms that indicate they have a serious or malignant disease (eg, weight loss, anemia, or dysphagia).

Panic disorder. Several tools have been proposed for screening for panic disorder (PD),^23,24 but none have been tested in patients with chest pain. Dammen et al²⁵ developed a 3-item questionnaire to assess for PD among patients with chest pain who were referred for cardiac evaluation (TABLE 4).²⁵ A score ≥5 on the Dammen questionnaire had 55% sensitivity and 86% specificity for PD, with a PPV of 71% and an NPV of 76%.²⁵ Although this instrument has not been subjected to validation studies, using it may help clarify whether further investigation for PD is warranted.

A 2-week course of high-dose proton pump inhibitor therapy can help identify patients whose chest pain may be caused by undiagnosed GERD.Psychotherapeutic interventions may be effective for patients whose chest pain is caused by PD. A Cochrane review of 15 randomized controlled trials of psychological interventions for chest pain in patients with normal coronary anatomy found that cognitive-behavior therapy, and possibly hypnotherapy, reduced patient reports of chest pain, reduced chest pain frequency, and increased the number of chest pain-free days, at least for 3 months.²⁶

What to do when the diagnosis remains unclear

When your initial evaluation and diagnostic testing yield no clear diagnosis, appropriate follow-up is vital because in the year after primary care patients first develop chest pain, they are 1.5 to 3 times more likely than the general population to be diagnosed with musculoskeletal, GI, psychological, or respiratory problems, nearly 5 times as likely to be diagnosed with heart failure, and nearly 15 times as likely to be diagnosed with coronary heart disease.^27,28

Consider ordering exercise or chemical stress testing within 3 to 7 days for a patient with chest pain that suggests ACS but who has normal results on EKG and biomarker testing.⁸ Interestingly, though, in a study of 4181 patients in an ED chest pain unit who had 2 sets of normal serum troponins during a 6-hour period followed by exercise or chemical stress testing, only 470 patients (11%) had abnormal stress test results and only 37 (.9%) had obstructive CAD that would have potentially benefited from revascularization.²⁹ Thus, testing troponin levels twice over 6 hours is a reasonable alternative to stress testing for a primary care patient with chest pain; stress testing would be unnecessary if both troponin values were normal.

CASE › Based on her current chest pain symptoms, Ms. Z’s MHS is a reassuringly low 1, so CAD is unlikely. However, she scores 5 on the Dammen panic disorder screen. Due to her financial concerns, you decide to forgo stress testing and instead draw a serum troponin now, with plans to repeat later in the afternoon at your clinic lab if the initial result is normal. You encourage her to try a high-dose PPI for 2 weeks to determine whether GERD may be contributing to her symptoms, and offer to help her explore counseling options to address her emotional stressors.

CORRESPONDENCE
William E. Cayley Jr, MD, MDiv, University of Wisconsin, UW Health Augusta Family Medicine Clinic, 207 West Lincoln, Augusta, WI 54722; [email protected]

Primary care physicians often have the lead role in caring for patients with chronic pain from a myriad of causes, including arthritis, low back injury, migraine, neuropathic pain, and more.¹ To ensure optimal outcomes for such patients, understanding chronic pain syndromes and their negative effect on sleep, mood, and daily functioning is key.

Studies of the interaction of chronic pain, insomnia, and psychiatric disorders are increasing awareness of the way patients with this constellation of comorbidities respond to treatment. What they show is that optimal outcomes are possible only if we treat these co-occurring disorders simultaneously.

Pain affects multiple functions

While pain is thought to originate from a primary dysfunction in the nervous system, the mind and body are involved in the constellation of pain, sleep disturbances, depression, anxiety disorders, and substance abuse/dependence. Patients with chronic pain typically report a higher degree of impairment in all dimensions of quality of life and sleep, and have higher scores on anxiety or depression screens than those without chronic pain.²

Sleep. About two-thirds (65%) of patients with chronic pain and the vast majority (96%) of those with fibromyalgia report sleep disturbances, with difficulty falling asleep, staying asleep, or both.^3,4 Sleep deprivation has a hyperalgesic effect, which leads to decreased pain tolerance and greater severity and pain-related disability.^5,6 While there does not appear to be a causal link between poor sleep and the onset of new pain symptoms, treatment directed toward improving sleep may help to reduce pain severity.

Depression. In primary care settings, more than 27% of patients with chronic pain meet diagnostic criteria for comorbid depression.⁷ The relationship between pain and depression is bidirectional, whereby chronic pain predicts the onset of new depressive episodes and depression predicts the onset of chronic pain.⁸ Having both conditions is associated with greater pain intensity, greater interference with usual activities, and a lower likelihood of responding to treatment.⁸ That finding highlights the importance of screening for depression in patients who present with somatic complaints, such as fatigue and headache, and in treating both depression and the pain simultaneously.

Anxiety. The relationship between pain and anxiety also appears to be bidirectional. The prevalence of anxiety disorders—including generalized anxiety disorder (GAD), panic disorder, and social phobia—is about twice as high among patients with chronic pain than in the general population.⁹

In primary care settings, anxiety disorders often are unrecognized and untreated. What’s more, anxiety can cause or exacerbate pain symptoms¹⁰; higher prevalence rates for arthritis, migraines, and back pain have been found in patients with a GAD diagnosis than in those without it.⁹ In older adults, pain conditions such as arthritis and migraines are associated with significantly higher rates of anxiety.¹¹

Substance-related disorders. Substance abuse and dependence are an increasing problem worldwide, especially in developed countries. In North America, according to a 2012 report from the International Narcotics Control Board, approximately one in every 20 deaths of individuals ages 15 to 64 years is related to substance abuse.¹² Canada has been found to have the world’s highest per capita consumption of high-potency opioids.¹³ In the United States, prescription drug abuse has been targeted as a public health epidemic.¹⁴ Also of note: Chronic pain affects 24% to 67% of patients with substance use disorders.¹⁵

Because of their analgesic effect, opioids often are given to patients with chronic noncancer pain, but substance misuse is common. Patients with a history of substance abuse or dependence are 4 times more likely to receive a prescription for opioids than those without such a history, and often are given higher potency opioids at higher doses.¹⁶ What’s more, individuals with chronic pain and a history of substance abuse/dependence generally have poorer outcomes, typically because they require more intensive treatment but rarely get it.¹⁷ These findings highlight the need to develop strategies to manage the symptoms of chronic pain in individuals who have a history of substance abuse or dependence—and to prevent addiction in patients without such a history.

Take aim at most—or all—of the patient's symptoms

In treating a patient with multiple comorbidities, it is best to initiate treatment with an agent that will address most—or all—of his or her symptoms. Using one drug whenever possible will reduce costs, prevent drug-drug interactions, and limit the likelihood of adverse effects. The American Psychiatric Association recommends the use of tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for treating chronic pain and comorbid depression.¹⁸ There is evidence of the effectiveness of “unconventional” analgesics, including anticonvulsants and antidepressants, for the treatment of chronic pain, as well. Opioids are, of course, an option too. In addition, nonpharmacologic treatments, such as cognitive-behavioral therapy (CBT), are recommended.¹⁹

Start with an anticonvulsant?

The anticonvulsants gabapentin and pregabalin have been shown to be effective in reducing certain types of neuropathic pain and alleviating insomnia.^20,21 In studies investigating the use of these drugs in patients with GAD, both gabapentin and pregabalin led to improvement in anxiety symptoms, as well as in pain and sleep.^20,21 At a dose of about 600 mg/d, pregabalin has been shown to significantly reduce pain levels in patients diagnosed with diabetic peripheral pain syndrome²²; it has also been found to help prevent relapse²³ and reduce sleep disturbances associated with GAD.²⁴

The most common adverse effects of pregabalin are mild-to-moderate somnolence, dry mouth, headache, dizziness, and peripheral edema^20,22; dizziness, somnolence, peripheral edema, and gait disturbance are most commonly associated with gabapentin treatment.²⁵ These tend to stabilize over time, but occasionally the dose must be lowered or the drug discontinued.

Lamotrigine has been shown to reduce pain in patients with diabetic and sensory neuropathy compared with placebo,²⁶ but was not effective in treating patients with pain due to spinal cord injury. The drug should be initiated at a low dose and slowly titrated to minimize the risk of serious adverse effects such as Stevens-Johnson syndrome.²⁶

Try a tricyclic or an SNRI

TCAs, including amitriptyline, nortriptyline, desipramine, and imipramine, are recommended by the Canadian Pain Society as first-line therapy for chronic pain and often have benefit in the treatment of comorbid mood or anxiety disorders.²⁷ Noradrenergic antidepressants—including TCAs—appear to have particular efficacy in treating moderate to severe neuropathic pain in patients with a comorbid substance disorder who take the drugs regularly, while undergoing frequent assessments.¹⁵

Avoid prescribing TCAs for depressed patients until you carefully assess their risk of overdose.Overdose is a risk associated with TCAs, which have higher toxicity than other classes of antidepressants.²⁸ Thus, it is essential to avoid prescribing TCAs for depressed patients until you carefully assess their risk of overdose. TCAs should not be prescribed for any patient at increased risk for cardiac arrhythmias.²⁹

If you do prescribe a TCA… The doses of TCAs used to treat mood and anxiety symptoms often are much higher than doses needed for pain relief. As a result patients are often at risk of experiencing side effects.

What about an SNRI? In general, SNRIs, which target both serotonin and norepinephrine, have a greater analgesic effect than antidepressants targeting either neurotransmitter alone.³⁰ Duloxetine, an SNRI, has been shown to effectively reduce symptoms in patients with pain disorders and comorbid depression.³¹ Other SNRIs studied in the treatment of pain and associated symptoms include venlafaxine, which has been effective in treating patients in a primary care setting who had both pain and depression,³² and milnacipran, which has been used successfully to treat pain associated with fibromyalgia.³³

SNRIs may interfere with sleep. SNRIs have been associated with an increase in arousal and in rapid eye movement sleep suppression.³⁴ Thus, another type of medication may be preferable for patients with pain and a sleep disturbance or, if an SNRI is prescribed, it may be necessary to lower the dose or add a sleep aid.

The role of SSRIs

Despite the recognized utility and widespread use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depressive and anxiety disorders, their role in managing neuropathic pain is less clear. Although some agents, such as escitalopram, have demonstrated mild pain-relieving effects in patients with painful polyneuropathy, the magnitude of the effect was clinically relevant at best for only a small number of patients.³⁵ The effectiveness of other SSRIs in painful diabetic neuropathy has been shown to be less than that of TCAs.³⁶ SSRIs generally are not recommended for the treatment of chronic neuropathic pain, even when it is associated with mood and anxiety symptoms.²⁷

Opioids for which patients?

Chronic pain often is treated with opioids. Particular caution is required, however, when treating patients with pain and substance abuse or dependence.^15,37 In order to prevent relapse in such individuals when they’re suffering from chronic pain, opioids should be used only if:^15,38
• the pain is moderate to severe and has a significant impact on the patient’s functioning and overall quality of life;
• nonopioid medications have been tried but were unsuccessful; and
• the patient agrees to be closely monitored while taking opioids.

The opioids tramadol and methadone are recommended as third-line therapy, along with nonopioid medications such as cannabinoids, lamotrigine, topiramate, and valproic acid.²⁷

Use a comprehensive pain scale, such as the Brief Pain Inventory, to assess the pain of any patient with a history of a substance-related disorder rather than asking him or her to rate the pain level on a general Likert-type scale.¹⁵

Long-acting opioids, such as sustained-release morphine, oxycodone, or fentanyl patch, are preferable to short-acting immediate-release opioids, which have a higher addictive profile because of their fast onset of action.¹⁵ Keep in mind, however, that long-acting opioids also have the potential for abuse, and patients taking them must be carefully monitored, as well.

Nonpharmacologic therapy often helps, too

Instead of using a Likert-type scale, use a comprehensive pain scale, such as the Brief Pain Inventory, to assess pain in patients with a history of a substance-related disorder.Evidence suggests that even the most potent drugs significantly decrease pain in only about half of those taking them.³⁹ And whether or not adequate pain relief is achieved, patients with the constellation of pain and sleep, mood, anxiety, and/or substance disorders can benefit from nonpharmacologic interventions, as well. Let patients know that CBT, in particular, has been shown to have a positive effect on psychological function and comorbid psychological disorders, particularly when it is combined with pharmacologic therapy.⁴⁰ In addition, other nonpharmacologic treatments, including biofeedback^41-44 and meditation,^45-47 have shown preliminary value in managing pain.

Further research is needed to understand the effectiveness of CBT in the management of chronic pain; however, it appears that CBT may have a positive effect on psychological functioning and comorbid psychological disorders.

The bottom line: Don’t overlook mood, anxiety symptoms in pain patients

In epidemiological studies of chronic pain, it is apparent that sleep, depressive, substance abuse/dependence, and anxiety syndromes often occur together, which supports the necessity of considering psychosocial dynamics to understand pain. Although there has been some inconsistency observed across findings (eg, Romano and Turner),⁴⁸ clarifying the relationships amongst these disorders may be an avenue for future research. The literature to date suggests that mood- and anxiety-related symptoms should not be overlooked in pain patients, as there is a negative effect on prognosis when these disorders co-occur.⁶

CBT has a positive effect on psychological comorbidities, especially when combined with medication. Treatment should be based on individual patient factors, such as presenting symptoms and potential for drug side effects. Some pharmacologic agents have been shown to be effective in treating several symptoms of this pyramid. Such drugs offer the best success and relapse rates, and reduce the likelihood of drug interactions. CBT appears to offer added benefits, especially if combined with pharmacology. However, few controlled trials have been conducted in this area and further research is required to appropriately guide clinical management.

CORRESPONDENCE
Martin A. Katzman, MD, FRCPC, START Clinic for Mood and Anxiety Disorders, 32 Park Road, Toronto, Ontario, Canada M4W 2N4; [email protected]

Primary care physicians often have the lead role in caring for patients with chronic pain from a myriad of causes, including arthritis, low back injury, migraine, neuropathic pain, and more.¹ To ensure optimal outcomes for such patients, understanding chronic pain syndromes and their negative effect on sleep, mood, and daily functioning is key.

Studies of the interaction of chronic pain, insomnia, and psychiatric disorders are increasing awareness of the way patients with this constellation of comorbidities respond to treatment. What they show is that optimal outcomes are possible only if we treat these co-occurring disorders simultaneously.

Pain affects multiple functions

While pain is thought to originate from a primary dysfunction in the nervous system, the mind and body are involved in the constellation of pain, sleep disturbances, depression, anxiety disorders, and substance abuse/dependence. Patients with chronic pain typically report a higher degree of impairment in all dimensions of quality of life and sleep, and have higher scores on anxiety or depression screens than those without chronic pain.²

Sleep. About two-thirds (65%) of patients with chronic pain and the vast majority (96%) of those with fibromyalgia report sleep disturbances, with difficulty falling asleep, staying asleep, or both.^3,4 Sleep deprivation has a hyperalgesic effect, which leads to decreased pain tolerance and greater severity and pain-related disability.^5,6 While there does not appear to be a causal link between poor sleep and the onset of new pain symptoms, treatment directed toward improving sleep may help to reduce pain severity.

Depression. In primary care settings, more than 27% of patients with chronic pain meet diagnostic criteria for comorbid depression.⁷ The relationship between pain and depression is bidirectional, whereby chronic pain predicts the onset of new depressive episodes and depression predicts the onset of chronic pain.⁸ Having both conditions is associated with greater pain intensity, greater interference with usual activities, and a lower likelihood of responding to treatment.⁸ That finding highlights the importance of screening for depression in patients who present with somatic complaints, such as fatigue and headache, and in treating both depression and the pain simultaneously.

Anxiety. The relationship between pain and anxiety also appears to be bidirectional. The prevalence of anxiety disorders—including generalized anxiety disorder (GAD), panic disorder, and social phobia—is about twice as high among patients with chronic pain than in the general population.⁹

In primary care settings, anxiety disorders often are unrecognized and untreated. What’s more, anxiety can cause or exacerbate pain symptoms¹⁰; higher prevalence rates for arthritis, migraines, and back pain have been found in patients with a GAD diagnosis than in those without it.⁹ In older adults, pain conditions such as arthritis and migraines are associated with significantly higher rates of anxiety.¹¹

Substance-related disorders. Substance abuse and dependence are an increasing problem worldwide, especially in developed countries. In North America, according to a 2012 report from the International Narcotics Control Board, approximately one in every 20 deaths of individuals ages 15 to 64 years is related to substance abuse.¹² Canada has been found to have the world’s highest per capita consumption of high-potency opioids.¹³ In the United States, prescription drug abuse has been targeted as a public health epidemic.¹⁴ Also of note: Chronic pain affects 24% to 67% of patients with substance use disorders.¹⁵

Because of their analgesic effect, opioids often are given to patients with chronic noncancer pain, but substance misuse is common. Patients with a history of substance abuse or dependence are 4 times more likely to receive a prescription for opioids than those without such a history, and often are given higher potency opioids at higher doses.¹⁶ What’s more, individuals with chronic pain and a history of substance abuse/dependence generally have poorer outcomes, typically because they require more intensive treatment but rarely get it.¹⁷ These findings highlight the need to develop strategies to manage the symptoms of chronic pain in individuals who have a history of substance abuse or dependence—and to prevent addiction in patients without such a history.

Take aim at most—or all—of the patient's symptoms

In treating a patient with multiple comorbidities, it is best to initiate treatment with an agent that will address most—or all—of his or her symptoms. Using one drug whenever possible will reduce costs, prevent drug-drug interactions, and limit the likelihood of adverse effects. The American Psychiatric Association recommends the use of tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for treating chronic pain and comorbid depression.¹⁸ There is evidence of the effectiveness of “unconventional” analgesics, including anticonvulsants and antidepressants, for the treatment of chronic pain, as well. Opioids are, of course, an option too. In addition, nonpharmacologic treatments, such as cognitive-behavioral therapy (CBT), are recommended.¹⁹

Start with an anticonvulsant?

The anticonvulsants gabapentin and pregabalin have been shown to be effective in reducing certain types of neuropathic pain and alleviating insomnia.^20,21 In studies investigating the use of these drugs in patients with GAD, both gabapentin and pregabalin led to improvement in anxiety symptoms, as well as in pain and sleep.^20,21 At a dose of about 600 mg/d, pregabalin has been shown to significantly reduce pain levels in patients diagnosed with diabetic peripheral pain syndrome²²; it has also been found to help prevent relapse²³ and reduce sleep disturbances associated with GAD.²⁴

The most common adverse effects of pregabalin are mild-to-moderate somnolence, dry mouth, headache, dizziness, and peripheral edema^20,22; dizziness, somnolence, peripheral edema, and gait disturbance are most commonly associated with gabapentin treatment.²⁵ These tend to stabilize over time, but occasionally the dose must be lowered or the drug discontinued.

Lamotrigine has been shown to reduce pain in patients with diabetic and sensory neuropathy compared with placebo,²⁶ but was not effective in treating patients with pain due to spinal cord injury. The drug should be initiated at a low dose and slowly titrated to minimize the risk of serious adverse effects such as Stevens-Johnson syndrome.²⁶

Try a tricyclic or an SNRI

TCAs, including amitriptyline, nortriptyline, desipramine, and imipramine, are recommended by the Canadian Pain Society as first-line therapy for chronic pain and often have benefit in the treatment of comorbid mood or anxiety disorders.²⁷ Noradrenergic antidepressants—including TCAs—appear to have particular efficacy in treating moderate to severe neuropathic pain in patients with a comorbid substance disorder who take the drugs regularly, while undergoing frequent assessments.¹⁵

Avoid prescribing TCAs for depressed patients until you carefully assess their risk of overdose.Overdose is a risk associated with TCAs, which have higher toxicity than other classes of antidepressants.²⁸ Thus, it is essential to avoid prescribing TCAs for depressed patients until you carefully assess their risk of overdose. TCAs should not be prescribed for any patient at increased risk for cardiac arrhythmias.²⁹

If you do prescribe a TCA… The doses of TCAs used to treat mood and anxiety symptoms often are much higher than doses needed for pain relief. As a result patients are often at risk of experiencing side effects.

What about an SNRI? In general, SNRIs, which target both serotonin and norepinephrine, have a greater analgesic effect than antidepressants targeting either neurotransmitter alone.³⁰ Duloxetine, an SNRI, has been shown to effectively reduce symptoms in patients with pain disorders and comorbid depression.³¹ Other SNRIs studied in the treatment of pain and associated symptoms include venlafaxine, which has been effective in treating patients in a primary care setting who had both pain and depression,³² and milnacipran, which has been used successfully to treat pain associated with fibromyalgia.³³

SNRIs may interfere with sleep. SNRIs have been associated with an increase in arousal and in rapid eye movement sleep suppression.³⁴ Thus, another type of medication may be preferable for patients with pain and a sleep disturbance or, if an SNRI is prescribed, it may be necessary to lower the dose or add a sleep aid.

The role of SSRIs

Despite the recognized utility and widespread use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depressive and anxiety disorders, their role in managing neuropathic pain is less clear. Although some agents, such as escitalopram, have demonstrated mild pain-relieving effects in patients with painful polyneuropathy, the magnitude of the effect was clinically relevant at best for only a small number of patients.³⁵ The effectiveness of other SSRIs in painful diabetic neuropathy has been shown to be less than that of TCAs.³⁶ SSRIs generally are not recommended for the treatment of chronic neuropathic pain, even when it is associated with mood and anxiety symptoms.²⁷

Opioids for which patients?

Chronic pain often is treated with opioids. Particular caution is required, however, when treating patients with pain and substance abuse or dependence.^15,37 In order to prevent relapse in such individuals when they’re suffering from chronic pain, opioids should be used only if:^15,38
• the pain is moderate to severe and has a significant impact on the patient’s functioning and overall quality of life;
• nonopioid medications have been tried but were unsuccessful; and
• the patient agrees to be closely monitored while taking opioids.

The opioids tramadol and methadone are recommended as third-line therapy, along with nonopioid medications such as cannabinoids, lamotrigine, topiramate, and valproic acid.²⁷

Use a comprehensive pain scale, such as the Brief Pain Inventory, to assess the pain of any patient with a history of a substance-related disorder rather than asking him or her to rate the pain level on a general Likert-type scale.¹⁵

Long-acting opioids, such as sustained-release morphine, oxycodone, or fentanyl patch, are preferable to short-acting immediate-release opioids, which have a higher addictive profile because of their fast onset of action.¹⁵ Keep in mind, however, that long-acting opioids also have the potential for abuse, and patients taking them must be carefully monitored, as well.

Nonpharmacologic therapy often helps, too

Instead of using a Likert-type scale, use a comprehensive pain scale, such as the Brief Pain Inventory, to assess pain in patients with a history of a substance-related disorder.Evidence suggests that even the most potent drugs significantly decrease pain in only about half of those taking them.³⁹ And whether or not adequate pain relief is achieved, patients with the constellation of pain and sleep, mood, anxiety, and/or substance disorders can benefit from nonpharmacologic interventions, as well. Let patients know that CBT, in particular, has been shown to have a positive effect on psychological function and comorbid psychological disorders, particularly when it is combined with pharmacologic therapy.⁴⁰ In addition, other nonpharmacologic treatments, including biofeedback^41-44 and meditation,^45-47 have shown preliminary value in managing pain.

Further research is needed to understand the effectiveness of CBT in the management of chronic pain; however, it appears that CBT may have a positive effect on psychological functioning and comorbid psychological disorders.

The bottom line: Don’t overlook mood, anxiety symptoms in pain patients

In epidemiological studies of chronic pain, it is apparent that sleep, depressive, substance abuse/dependence, and anxiety syndromes often occur together, which supports the necessity of considering psychosocial dynamics to understand pain. Although there has been some inconsistency observed across findings (eg, Romano and Turner),⁴⁸ clarifying the relationships amongst these disorders may be an avenue for future research. The literature to date suggests that mood- and anxiety-related symptoms should not be overlooked in pain patients, as there is a negative effect on prognosis when these disorders co-occur.⁶

CBT has a positive effect on psychological comorbidities, especially when combined with medication. Treatment should be based on individual patient factors, such as presenting symptoms and potential for drug side effects. Some pharmacologic agents have been shown to be effective in treating several symptoms of this pyramid. Such drugs offer the best success and relapse rates, and reduce the likelihood of drug interactions. CBT appears to offer added benefits, especially if combined with pharmacology. However, few controlled trials have been conducted in this area and further research is required to appropriately guide clinical management.

CORRESPONDENCE
Martin A. Katzman, MD, FRCPC, START Clinic for Mood and Anxiety Disorders, 32 Park Road, Toronto, Ontario, Canada M4W 2N4; [email protected]

Primary care physicians often have the lead role in caring for patients with chronic pain from a myriad of causes, including arthritis, low back injury, migraine, neuropathic pain, and more.¹ To ensure optimal outcomes for such patients, understanding chronic pain syndromes and their negative effect on sleep, mood, and daily functioning is key.

Studies of the interaction of chronic pain, insomnia, and psychiatric disorders are increasing awareness of the way patients with this constellation of comorbidities respond to treatment. What they show is that optimal outcomes are possible only if we treat these co-occurring disorders simultaneously.

Pain affects multiple functions

While pain is thought to originate from a primary dysfunction in the nervous system, the mind and body are involved in the constellation of pain, sleep disturbances, depression, anxiety disorders, and substance abuse/dependence. Patients with chronic pain typically report a higher degree of impairment in all dimensions of quality of life and sleep, and have higher scores on anxiety or depression screens than those without chronic pain.²

Sleep. About two-thirds (65%) of patients with chronic pain and the vast majority (96%) of those with fibromyalgia report sleep disturbances, with difficulty falling asleep, staying asleep, or both.^3,4 Sleep deprivation has a hyperalgesic effect, which leads to decreased pain tolerance and greater severity and pain-related disability.^5,6 While there does not appear to be a causal link between poor sleep and the onset of new pain symptoms, treatment directed toward improving sleep may help to reduce pain severity.

Depression. In primary care settings, more than 27% of patients with chronic pain meet diagnostic criteria for comorbid depression.⁷ The relationship between pain and depression is bidirectional, whereby chronic pain predicts the onset of new depressive episodes and depression predicts the onset of chronic pain.⁸ Having both conditions is associated with greater pain intensity, greater interference with usual activities, and a lower likelihood of responding to treatment.⁸ That finding highlights the importance of screening for depression in patients who present with somatic complaints, such as fatigue and headache, and in treating both depression and the pain simultaneously.

Anxiety. The relationship between pain and anxiety also appears to be bidirectional. The prevalence of anxiety disorders—including generalized anxiety disorder (GAD), panic disorder, and social phobia—is about twice as high among patients with chronic pain than in the general population.⁹

In primary care settings, anxiety disorders often are unrecognized and untreated. What’s more, anxiety can cause or exacerbate pain symptoms¹⁰; higher prevalence rates for arthritis, migraines, and back pain have been found in patients with a GAD diagnosis than in those without it.⁹ In older adults, pain conditions such as arthritis and migraines are associated with significantly higher rates of anxiety.¹¹

Substance-related disorders. Substance abuse and dependence are an increasing problem worldwide, especially in developed countries. In North America, according to a 2012 report from the International Narcotics Control Board, approximately one in every 20 deaths of individuals ages 15 to 64 years is related to substance abuse.¹² Canada has been found to have the world’s highest per capita consumption of high-potency opioids.¹³ In the United States, prescription drug abuse has been targeted as a public health epidemic.¹⁴ Also of note: Chronic pain affects 24% to 67% of patients with substance use disorders.¹⁵

Because of their analgesic effect, opioids often are given to patients with chronic noncancer pain, but substance misuse is common. Patients with a history of substance abuse or dependence are 4 times more likely to receive a prescription for opioids than those without such a history, and often are given higher potency opioids at higher doses.¹⁶ What’s more, individuals with chronic pain and a history of substance abuse/dependence generally have poorer outcomes, typically because they require more intensive treatment but rarely get it.¹⁷ These findings highlight the need to develop strategies to manage the symptoms of chronic pain in individuals who have a history of substance abuse or dependence—and to prevent addiction in patients without such a history.

Take aim at most—or all—of the patient's symptoms

In treating a patient with multiple comorbidities, it is best to initiate treatment with an agent that will address most—or all—of his or her symptoms. Using one drug whenever possible will reduce costs, prevent drug-drug interactions, and limit the likelihood of adverse effects. The American Psychiatric Association recommends the use of tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for treating chronic pain and comorbid depression.¹⁸ There is evidence of the effectiveness of “unconventional” analgesics, including anticonvulsants and antidepressants, for the treatment of chronic pain, as well. Opioids are, of course, an option too. In addition, nonpharmacologic treatments, such as cognitive-behavioral therapy (CBT), are recommended.¹⁹

Start with an anticonvulsant?

The anticonvulsants gabapentin and pregabalin have been shown to be effective in reducing certain types of neuropathic pain and alleviating insomnia.^20,21 In studies investigating the use of these drugs in patients with GAD, both gabapentin and pregabalin led to improvement in anxiety symptoms, as well as in pain and sleep.^20,21 At a dose of about 600 mg/d, pregabalin has been shown to significantly reduce pain levels in patients diagnosed with diabetic peripheral pain syndrome²²; it has also been found to help prevent relapse²³ and reduce sleep disturbances associated with GAD.²⁴

The most common adverse effects of pregabalin are mild-to-moderate somnolence, dry mouth, headache, dizziness, and peripheral edema^20,22; dizziness, somnolence, peripheral edema, and gait disturbance are most commonly associated with gabapentin treatment.²⁵ These tend to stabilize over time, but occasionally the dose must be lowered or the drug discontinued.

Lamotrigine has been shown to reduce pain in patients with diabetic and sensory neuropathy compared with placebo,²⁶ but was not effective in treating patients with pain due to spinal cord injury. The drug should be initiated at a low dose and slowly titrated to minimize the risk of serious adverse effects such as Stevens-Johnson syndrome.²⁶

Try a tricyclic or an SNRI

TCAs, including amitriptyline, nortriptyline, desipramine, and imipramine, are recommended by the Canadian Pain Society as first-line therapy for chronic pain and often have benefit in the treatment of comorbid mood or anxiety disorders.²⁷ Noradrenergic antidepressants—including TCAs—appear to have particular efficacy in treating moderate to severe neuropathic pain in patients with a comorbid substance disorder who take the drugs regularly, while undergoing frequent assessments.¹⁵

Avoid prescribing TCAs for depressed patients until you carefully assess their risk of overdose.Overdose is a risk associated with TCAs, which have higher toxicity than other classes of antidepressants.²⁸ Thus, it is essential to avoid prescribing TCAs for depressed patients until you carefully assess their risk of overdose. TCAs should not be prescribed for any patient at increased risk for cardiac arrhythmias.²⁹

If you do prescribe a TCA… The doses of TCAs used to treat mood and anxiety symptoms often are much higher than doses needed for pain relief. As a result patients are often at risk of experiencing side effects.

What about an SNRI? In general, SNRIs, which target both serotonin and norepinephrine, have a greater analgesic effect than antidepressants targeting either neurotransmitter alone.³⁰ Duloxetine, an SNRI, has been shown to effectively reduce symptoms in patients with pain disorders and comorbid depression.³¹ Other SNRIs studied in the treatment of pain and associated symptoms include venlafaxine, which has been effective in treating patients in a primary care setting who had both pain and depression,³² and milnacipran, which has been used successfully to treat pain associated with fibromyalgia.³³

SNRIs may interfere with sleep. SNRIs have been associated with an increase in arousal and in rapid eye movement sleep suppression.³⁴ Thus, another type of medication may be preferable for patients with pain and a sleep disturbance or, if an SNRI is prescribed, it may be necessary to lower the dose or add a sleep aid.

The role of SSRIs

Despite the recognized utility and widespread use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depressive and anxiety disorders, their role in managing neuropathic pain is less clear. Although some agents, such as escitalopram, have demonstrated mild pain-relieving effects in patients with painful polyneuropathy, the magnitude of the effect was clinically relevant at best for only a small number of patients.³⁵ The effectiveness of other SSRIs in painful diabetic neuropathy has been shown to be less than that of TCAs.³⁶ SSRIs generally are not recommended for the treatment of chronic neuropathic pain, even when it is associated with mood and anxiety symptoms.²⁷

Opioids for which patients?

Chronic pain often is treated with opioids. Particular caution is required, however, when treating patients with pain and substance abuse or dependence.^15,37 In order to prevent relapse in such individuals when they’re suffering from chronic pain, opioids should be used only if:^15,38
• the pain is moderate to severe and has a significant impact on the patient’s functioning and overall quality of life;
• nonopioid medications have been tried but were unsuccessful; and
• the patient agrees to be closely monitored while taking opioids.

The opioids tramadol and methadone are recommended as third-line therapy, along with nonopioid medications such as cannabinoids, lamotrigine, topiramate, and valproic acid.²⁷

Use a comprehensive pain scale, such as the Brief Pain Inventory, to assess the pain of any patient with a history of a substance-related disorder rather than asking him or her to rate the pain level on a general Likert-type scale.¹⁵

Long-acting opioids, such as sustained-release morphine, oxycodone, or fentanyl patch, are preferable to short-acting immediate-release opioids, which have a higher addictive profile because of their fast onset of action.¹⁵ Keep in mind, however, that long-acting opioids also have the potential for abuse, and patients taking them must be carefully monitored, as well.

Nonpharmacologic therapy often helps, too

Instead of using a Likert-type scale, use a comprehensive pain scale, such as the Brief Pain Inventory, to assess pain in patients with a history of a substance-related disorder.Evidence suggests that even the most potent drugs significantly decrease pain in only about half of those taking them.³⁹ And whether or not adequate pain relief is achieved, patients with the constellation of pain and sleep, mood, anxiety, and/or substance disorders can benefit from nonpharmacologic interventions, as well. Let patients know that CBT, in particular, has been shown to have a positive effect on psychological function and comorbid psychological disorders, particularly when it is combined with pharmacologic therapy.⁴⁰ In addition, other nonpharmacologic treatments, including biofeedback^41-44 and meditation,^45-47 have shown preliminary value in managing pain.

Further research is needed to understand the effectiveness of CBT in the management of chronic pain; however, it appears that CBT may have a positive effect on psychological functioning and comorbid psychological disorders.

The bottom line: Don’t overlook mood, anxiety symptoms in pain patients

In epidemiological studies of chronic pain, it is apparent that sleep, depressive, substance abuse/dependence, and anxiety syndromes often occur together, which supports the necessity of considering psychosocial dynamics to understand pain. Although there has been some inconsistency observed across findings (eg, Romano and Turner),⁴⁸ clarifying the relationships amongst these disorders may be an avenue for future research. The literature to date suggests that mood- and anxiety-related symptoms should not be overlooked in pain patients, as there is a negative effect on prognosis when these disorders co-occur.⁶

CBT has a positive effect on psychological comorbidities, especially when combined with medication. Treatment should be based on individual patient factors, such as presenting symptoms and potential for drug side effects. Some pharmacologic agents have been shown to be effective in treating several symptoms of this pyramid. Such drugs offer the best success and relapse rates, and reduce the likelihood of drug interactions. CBT appears to offer added benefits, especially if combined with pharmacology. However, few controlled trials have been conducted in this area and further research is required to appropriately guide clinical management.

CORRESPONDENCE
Martin A. Katzman, MD, FRCPC, START Clinic for Mood and Anxiety Disorders, 32 Park Road, Toronto, Ontario, Canada M4W 2N4; [email protected]

CASE › Cassidy, age 14, comes to you for a physical in preparation for track and field tryouts. If she makes the team, she will practice 90 minutes every afternoon with optional practices 2 mornings a week.

She says that her period has been irregular since it started a year ago, and she complains of knee and shin pain that her mother attributes to “growing pains.” She says she usually skips breakfast due to a lack of time in the morning, but eats the school lunches. She is considering becoming a vegetarian. You suspect that the female athlete triad is at work here. How would you proceed?

The female athlete triad (“the triad”) is considered a spectrum of 3 interrelated disorders: low energy availability, menstrual dysfunction, and altered bone mineral density.¹ Low energy availability—total dietary energy in (calories in) minus total exercise energy expended (calories out)—is considered the key cause. Previously, the triad was described as disordered eating, amenorrhea (having no menstruation for >3 sequential months), and osteoporosis.² However, this definition has been expanded to encourage detection before clinical problems progress. In most instances, an athlete will develop only one or 2 of the 3 components of the triad.^3,4 This article describes the clinical manifestations of the triad, how to screen patients for it, and indications for referring affected athletes.

How common is the triad?

The prevalence of the triad is difficult to determine because published studies often feature poor standardization of definitions and scales, small sample sizes, and no control groups. In limited studies, the estimated prevalence of female athletes with the complete triad ranges from 1.3% to 4.3%.^3,4 Many studies, however, focus on just one of the following 3 components:

Low energy availability. Few studies have specifically evaluated the prevalence of low energy availability among female athletes. The prevalence of disordered eating among females ranges from 25% to 31% of those in “thin build” sports (eg, running, gymnastics, and figure skating) vs 5% to 9% of nonathletes.^5,6

Menstrual dysfunction. The prevalence of menstrual dysfunction in female athletes is reported to be as high as 79%.¹ Primary amenorrhea (a delay in the age of menarche past age 15) has been reported in 22% of gymnasts, cheerleaders, and divers vs <1% of the general population.⁷ Subclinical menstrual dysfunction is highly prevalent. For example, one study found 78% of normally menstruating recreational runners had luteal deficiency or anovulation in one-third of their cycles.⁸

In most instances, an athlete will develop only one or 2 of the 3 components of the triad.Altered bone mineral density (BMD). BMD is increased in most athletes compared to sedentary controls, but low BMD often is seen in amenorrheic athletes. One review found 22% to 50% of amenorrheic athletes had osteopenia vs 12% of controls.⁹ The prevalence of osteoporosis in this group was as high as 13% vs 2.3% of controls.⁹

Three interrelated problems

As noted earlier, low energy availability is believed to be the key underlying etiology of the triad. Energy availability is the dietary energy left in the body after exercise is completed, or total dietary energy in (calories in) minus total exercise energy expended (calories out).^10,11

Low energy availability is not synonymous with disordered eating. Low energy availability may be the result of either decreased caloric intake or increased output. For example, athletes who increase their training requirements (increased output) need to increase their caloric intake or they will suffer an energy imbalance. Disordered eating also can result in decreased caloric intake. Disordered eating ranges from poor eating habits such as skipping meals to psychiatric conditions such as anorexia nervosa, bulimia, or binge eating disorder. Behaviors may include restricting calories, purging, or using diet pills, diuretics, or laxatives. For a summary of the most recent changes to eating disorder diagnoses, go to http://www.dsm5.org/documents/eating%20disorders%20fact%20sheet.pdf.

Low energy availability leads to hormonal abnormalities that may exacerbate other triad symptoms. When energy is restricted, the body conserves energy by altering metabolism by several methods, including suppressing usual hormonal cycling. For example, inadequate energy availability results in suppression of gonadotropin-releasing hormone pulsatility and disruption of the number of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) pulses, which results in decreased estrogen levels.¹²

When an athlete has decreased body fat as a result of low energy availability, she may have decreased adipokines, particularly leptin, which is believed to play a role in the ovulatory (normal) menstrual cycle. Abnormal eating also can suppress ghrelin, a short-term hormonal regulator of eating cycles/food intake and a long-term regulator of energy balance. Thus, short-term ghrelin dysregulation can self-perpetuate and have long-term consequences.

In anorexia nervosa, the intestinally derived anorexigen peptide YY is elevated,¹³ which may contribute to bone loss. Patients with anorexia nervosa also have androgen deficiency and elevated cortisol, both of which are factors in energy metabolism and maintenance of bone density.¹⁴

Menstrual dysfunction. Female athletes may experience amenorrhea, oligomenorrhea (menstrual periods with intervals >35 days), or subclinical menstrual dysfunction. Amenorrhea that occurs after menarche is considered secondary amenorrhea. Brancaccio et al¹⁵ found the incidence of secondary amenorrhea was significantly higher in high school athletes (30%) than in controls (15%). The researchers noted that “strenuous training alone has not been shown to alter menstrual cycles; it is necessary for dietary restriction to occur.”¹⁵

Altered BMD. Osteoporosis is characterized by compromised bone strength that increases the risk of fracture,¹⁶ and BMD is an aspect of bone strength. Osteoporosis may be caused by inadequate accumulation of optimal BMD during childhood and adolescence. A diagnosis of osteoporosis in patients ages 5 to 19 requires the presence of low bone mass and a clinically significant fracture history.¹⁷

BMD is assessed by dual-energy x-ray absorptiometry (DXA). DXA results are reported as a T-score, in which a patient’s bone density is compared with that of a healthy 30-year-old woman, or Z-score, which compares patients’ BMD with age- and sex-matched controls. The International Society of Clinical Densitometry recommends using Z-scores instead of T-scores when screening for osteoporosis in premenopausal women and in children.¹⁸

Z-scores are expressed as the number of standard deviations above or below the average value of the reference group. For every reduction by one standard deviation in BMD, the patient’s fracture risk doubles. The American College of Sports Medicine defines “low BMD” as a Z-score between -1 and -2.0 and osteoporosis as a Z-score ≤-2.0.¹ For both definitions, the patient must have at least one secondary clinical risk factor for fracture, such as low estrogen, history of stress fracture, or nutritional deficiencies.

Screening for the triad: What to ask, what to look for

Screen all adolescent female athletes at preparticipation physicals or whenever they present with any of the triad’s signs and symptoms. Look for risk factors such as calorie restriction practices, vegetarianism, a history of injuries, extended exercise periods, or increased training, particularly sport-specific training.¹ Also consider social, genetic, and psychiatric issues, such as abuse and family dysfunction.

Strenuous training alone is not enough to alter menstrual cycles; dietary restriction must occur.If you believe a patient is at risk, ask her about her exercise and eating habits, menstrual cycles, and fracture history (TABLE 1).¹⁹ During the physical exam, look for signs that suggest the triad, including lanugo, enlarged parotid glands, and bradycardia (TABLE 2).¹ Be sure to calculate the patient’s body mass index or body fat percentage.

Based on the history and physical findings, consider laboratory testing for a complete blood count with differential, ferritin, serum iron, B12, folate, comprehensive metabolic panel, thyroid function tests, erythrocyte sedimentation rate, and a urinalysis.²⁰ For an athlete in whom you highly suspect the triad, order urine electrolytes, salivary amylase, and stool guaiac tests, as well as an electrocardiogram.¹⁹

If your patient is amenorrheic, be aware that functional amenorrhea is a diagnosis of exclusion. Other diagnoses to consider include pregnancy, polycystic ovary syndrome, prolactinoma, anatomic defect, and ovarian failure. A pregnancy test, FSH and LH levels, prolactin, and thyroid-stimulating hormone testing should all be considered during evaluation for amenorrhea.

All patients with a history of stress fracture should undergo a DXA scan, whether or not they have comorbid amenorrhea, oligomenorrhea, or disordered eating.²⁰ In patients with amenorrhea, the DXA may need to be repeated in one year if menses does not resume.

For patients who screen positive for disordered eating, amenorrhea, or decreased BMD, the International Olympic Committee (IOC) guidelines are an excellent starting point for further evaluation.¹⁹ The IOC has “decision trees” for female athletes with disordered eating, amenorrhea, and osteoporosis that are available at http://www.olympic.org/Documents/Reports/EN/en_report_917.pdf.¹⁹

In addition to screening female athletes for the triad, consider addressing eating attitudes, menses, and fracture history in routine office physicals for all female patients. Also, be aware that triad symptoms are not limited to female athletes; male athletes, particularly those in sports that focus on leanness, physique, or weight classes (eg, wrestling) also are at risk for low energy availability, disordered eating, and low BMD.

Tx: First, restore sufficient nutrition

When treating a patient with the triad, consider consulting with a sports medicine specialist because these physicians typically are trained in diagnosing and treating this condition. Because low energy availability is the cornerstone of the triad, the priority in treating an affected athlete is to restore sufficient nutrition for caloric needs. Referral to a registered dietitian for full nutritional assessment and meal planning is recommended. If your athlete is unwilling or unable to follow dietary recommendations, refer her to an eating disorder specialist team. Ideally, this specialist team would consist of a registered sport nutritionist, a physician, and a psychologist or psychiatrist who specializes in eating disorders.

Drugs that can augment your efforts

Although they play a small role in treating the triad, pharmacologic therapies may be used to augment nutrition counseling. The selective serotonin reuptake inhibitor fluoxetine is the only medication approved by the US Food and Drug Administration for treating patients with bulimia; it is not approved for those with anorexia nervosa._²¹

Oral contraceptives may help women return to monthly menses, but they do not normalize the metabolic factors that impair bone formation and bone health. They can be used as a last measure in athletes who will not follow dietary or exercise recommendations, or those who, despite following recommendations, do not have a return to normal menses after 6 months.

Nasal calcitonin may be used to treat low BMD; order a follow-up DXA scan in 12 months to monitor improvement. However, prolonged use of nasal calcitonin may increase the risk for cancer, and in October 2013 nasal calcitonin was withdrawn from the Canadian market.²² For amenorrheic athletes, recommend oral calcium, 1000 to 1300 mg/d, and vitamin D, 400 to 800 IU/d. Ideally, patients should receive these levels of nutrients via dietary intake, but if that is not realistic, supplements may be considered.^1,23 Bisphosphonates and selective estrogen receptor modulators are contraindicated for premenopausal athletes.¹⁹

Can the patient return to play?

The athlete will need to be medically and psychologically cleared before being allowed to return to play (RTP). If she has menstrual dysfunction or low BMD, these conditions should be addressed as a prerequisite for RTP. If the treating physician, nutritionist, and/or eating disorder specialist team recommends specific treatments or other interventions, the athlete should agree to the treatment plan in order to RTP. The physician or assessment team should determine the time frame for RTP on an individual basis. Athletes who do not comply with treatment regimens should, for their health and safety, be prohibited from return to sports participation.

Athletes who do not comply with treatment regimens should be prohibited from return to sports participation.Focus on prevention

Primary prevention should focus on educating female (and male) athletes about regarding food as fuel, discouraging unhealthy weight loss, and enlisting the support of coaches and governing bodies. An athlete’s coaches may be the first to notice symptoms of the triad as changes in performance or behavior, but coaches should not encourage athletes to lose weight or be involved in determining an athlete’s weight.¹⁹

CORRESPONDENCE
Jennifer Payne, MD, Family Medicine Residency Program, Lancaster General Hospital, 555 N Duke Street, Lancaster, PA 17604; [email protected]

CASE › Cassidy, age 14, comes to you for a physical in preparation for track and field tryouts. If she makes the team, she will practice 90 minutes every afternoon with optional practices 2 mornings a week.

She says that her period has been irregular since it started a year ago, and she complains of knee and shin pain that her mother attributes to “growing pains.” She says she usually skips breakfast due to a lack of time in the morning, but eats the school lunches. She is considering becoming a vegetarian. You suspect that the female athlete triad is at work here. How would you proceed?

The female athlete triad (“the triad”) is considered a spectrum of 3 interrelated disorders: low energy availability, menstrual dysfunction, and altered bone mineral density.¹ Low energy availability—total dietary energy in (calories in) minus total exercise energy expended (calories out)—is considered the key cause. Previously, the triad was described as disordered eating, amenorrhea (having no menstruation for >3 sequential months), and osteoporosis.² However, this definition has been expanded to encourage detection before clinical problems progress. In most instances, an athlete will develop only one or 2 of the 3 components of the triad.^3,4 This article describes the clinical manifestations of the triad, how to screen patients for it, and indications for referring affected athletes.

How common is the triad?

The prevalence of the triad is difficult to determine because published studies often feature poor standardization of definitions and scales, small sample sizes, and no control groups. In limited studies, the estimated prevalence of female athletes with the complete triad ranges from 1.3% to 4.3%.^3,4 Many studies, however, focus on just one of the following 3 components:

Low energy availability. Few studies have specifically evaluated the prevalence of low energy availability among female athletes. The prevalence of disordered eating among females ranges from 25% to 31% of those in “thin build” sports (eg, running, gymnastics, and figure skating) vs 5% to 9% of nonathletes.^5,6

Menstrual dysfunction. The prevalence of menstrual dysfunction in female athletes is reported to be as high as 79%.¹ Primary amenorrhea (a delay in the age of menarche past age 15) has been reported in 22% of gymnasts, cheerleaders, and divers vs <1% of the general population.⁷ Subclinical menstrual dysfunction is highly prevalent. For example, one study found 78% of normally menstruating recreational runners had luteal deficiency or anovulation in one-third of their cycles.⁸

In most instances, an athlete will develop only one or 2 of the 3 components of the triad.Altered bone mineral density (BMD). BMD is increased in most athletes compared to sedentary controls, but low BMD often is seen in amenorrheic athletes. One review found 22% to 50% of amenorrheic athletes had osteopenia vs 12% of controls.⁹ The prevalence of osteoporosis in this group was as high as 13% vs 2.3% of controls.⁹

Three interrelated problems

As noted earlier, low energy availability is believed to be the key underlying etiology of the triad. Energy availability is the dietary energy left in the body after exercise is completed, or total dietary energy in (calories in) minus total exercise energy expended (calories out).^10,11

Low energy availability is not synonymous with disordered eating. Low energy availability may be the result of either decreased caloric intake or increased output. For example, athletes who increase their training requirements (increased output) need to increase their caloric intake or they will suffer an energy imbalance. Disordered eating also can result in decreased caloric intake. Disordered eating ranges from poor eating habits such as skipping meals to psychiatric conditions such as anorexia nervosa, bulimia, or binge eating disorder. Behaviors may include restricting calories, purging, or using diet pills, diuretics, or laxatives. For a summary of the most recent changes to eating disorder diagnoses, go to http://www.dsm5.org/documents/eating%20disorders%20fact%20sheet.pdf.

Low energy availability leads to hormonal abnormalities that may exacerbate other triad symptoms. When energy is restricted, the body conserves energy by altering metabolism by several methods, including suppressing usual hormonal cycling. For example, inadequate energy availability results in suppression of gonadotropin-releasing hormone pulsatility and disruption of the number of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) pulses, which results in decreased estrogen levels.¹²

When an athlete has decreased body fat as a result of low energy availability, she may have decreased adipokines, particularly leptin, which is believed to play a role in the ovulatory (normal) menstrual cycle. Abnormal eating also can suppress ghrelin, a short-term hormonal regulator of eating cycles/food intake and a long-term regulator of energy balance. Thus, short-term ghrelin dysregulation can self-perpetuate and have long-term consequences.

In anorexia nervosa, the intestinally derived anorexigen peptide YY is elevated,¹³ which may contribute to bone loss. Patients with anorexia nervosa also have androgen deficiency and elevated cortisol, both of which are factors in energy metabolism and maintenance of bone density.¹⁴

Menstrual dysfunction. Female athletes may experience amenorrhea, oligomenorrhea (menstrual periods with intervals >35 days), or subclinical menstrual dysfunction. Amenorrhea that occurs after menarche is considered secondary amenorrhea. Brancaccio et al¹⁵ found the incidence of secondary amenorrhea was significantly higher in high school athletes (30%) than in controls (15%). The researchers noted that “strenuous training alone has not been shown to alter menstrual cycles; it is necessary for dietary restriction to occur.”¹⁵

Altered BMD. Osteoporosis is characterized by compromised bone strength that increases the risk of fracture,¹⁶ and BMD is an aspect of bone strength. Osteoporosis may be caused by inadequate accumulation of optimal BMD during childhood and adolescence. A diagnosis of osteoporosis in patients ages 5 to 19 requires the presence of low bone mass and a clinically significant fracture history.¹⁷

BMD is assessed by dual-energy x-ray absorptiometry (DXA). DXA results are reported as a T-score, in which a patient’s bone density is compared with that of a healthy 30-year-old woman, or Z-score, which compares patients’ BMD with age- and sex-matched controls. The International Society of Clinical Densitometry recommends using Z-scores instead of T-scores when screening for osteoporosis in premenopausal women and in children.¹⁸

Z-scores are expressed as the number of standard deviations above or below the average value of the reference group. For every reduction by one standard deviation in BMD, the patient’s fracture risk doubles. The American College of Sports Medicine defines “low BMD” as a Z-score between -1 and -2.0 and osteoporosis as a Z-score ≤-2.0.¹ For both definitions, the patient must have at least one secondary clinical risk factor for fracture, such as low estrogen, history of stress fracture, or nutritional deficiencies.

Screening for the triad: What to ask, what to look for

Screen all adolescent female athletes at preparticipation physicals or whenever they present with any of the triad’s signs and symptoms. Look for risk factors such as calorie restriction practices, vegetarianism, a history of injuries, extended exercise periods, or increased training, particularly sport-specific training.¹ Also consider social, genetic, and psychiatric issues, such as abuse and family dysfunction.

Strenuous training alone is not enough to alter menstrual cycles; dietary restriction must occur.If you believe a patient is at risk, ask her about her exercise and eating habits, menstrual cycles, and fracture history (TABLE 1).¹⁹ During the physical exam, look for signs that suggest the triad, including lanugo, enlarged parotid glands, and bradycardia (TABLE 2).¹ Be sure to calculate the patient’s body mass index or body fat percentage.

Based on the history and physical findings, consider laboratory testing for a complete blood count with differential, ferritin, serum iron, B12, folate, comprehensive metabolic panel, thyroid function tests, erythrocyte sedimentation rate, and a urinalysis.²⁰ For an athlete in whom you highly suspect the triad, order urine electrolytes, salivary amylase, and stool guaiac tests, as well as an electrocardiogram.¹⁹

If your patient is amenorrheic, be aware that functional amenorrhea is a diagnosis of exclusion. Other diagnoses to consider include pregnancy, polycystic ovary syndrome, prolactinoma, anatomic defect, and ovarian failure. A pregnancy test, FSH and LH levels, prolactin, and thyroid-stimulating hormone testing should all be considered during evaluation for amenorrhea.

All patients with a history of stress fracture should undergo a DXA scan, whether or not they have comorbid amenorrhea, oligomenorrhea, or disordered eating.²⁰ In patients with amenorrhea, the DXA may need to be repeated in one year if menses does not resume.

For patients who screen positive for disordered eating, amenorrhea, or decreased BMD, the International Olympic Committee (IOC) guidelines are an excellent starting point for further evaluation.¹⁹ The IOC has “decision trees” for female athletes with disordered eating, amenorrhea, and osteoporosis that are available at http://www.olympic.org/Documents/Reports/EN/en_report_917.pdf.¹⁹

In addition to screening female athletes for the triad, consider addressing eating attitudes, menses, and fracture history in routine office physicals for all female patients. Also, be aware that triad symptoms are not limited to female athletes; male athletes, particularly those in sports that focus on leanness, physique, or weight classes (eg, wrestling) also are at risk for low energy availability, disordered eating, and low BMD.

Tx: First, restore sufficient nutrition

When treating a patient with the triad, consider consulting with a sports medicine specialist because these physicians typically are trained in diagnosing and treating this condition. Because low energy availability is the cornerstone of the triad, the priority in treating an affected athlete is to restore sufficient nutrition for caloric needs. Referral to a registered dietitian for full nutritional assessment and meal planning is recommended. If your athlete is unwilling or unable to follow dietary recommendations, refer her to an eating disorder specialist team. Ideally, this specialist team would consist of a registered sport nutritionist, a physician, and a psychologist or psychiatrist who specializes in eating disorders.

Drugs that can augment your efforts

Although they play a small role in treating the triad, pharmacologic therapies may be used to augment nutrition counseling. The selective serotonin reuptake inhibitor fluoxetine is the only medication approved by the US Food and Drug Administration for treating patients with bulimia; it is not approved for those with anorexia nervosa._²¹

Oral contraceptives may help women return to monthly menses, but they do not normalize the metabolic factors that impair bone formation and bone health. They can be used as a last measure in athletes who will not follow dietary or exercise recommendations, or those who, despite following recommendations, do not have a return to normal menses after 6 months.

Nasal calcitonin may be used to treat low BMD; order a follow-up DXA scan in 12 months to monitor improvement. However, prolonged use of nasal calcitonin may increase the risk for cancer, and in October 2013 nasal calcitonin was withdrawn from the Canadian market.²² For amenorrheic athletes, recommend oral calcium, 1000 to 1300 mg/d, and vitamin D, 400 to 800 IU/d. Ideally, patients should receive these levels of nutrients via dietary intake, but if that is not realistic, supplements may be considered.^1,23 Bisphosphonates and selective estrogen receptor modulators are contraindicated for premenopausal athletes.¹⁹

Can the patient return to play?

The athlete will need to be medically and psychologically cleared before being allowed to return to play (RTP). If she has menstrual dysfunction or low BMD, these conditions should be addressed as a prerequisite for RTP. If the treating physician, nutritionist, and/or eating disorder specialist team recommends specific treatments or other interventions, the athlete should agree to the treatment plan in order to RTP. The physician or assessment team should determine the time frame for RTP on an individual basis. Athletes who do not comply with treatment regimens should, for their health and safety, be prohibited from return to sports participation.

Athletes who do not comply with treatment regimens should be prohibited from return to sports participation.Focus on prevention

Primary prevention should focus on educating female (and male) athletes about regarding food as fuel, discouraging unhealthy weight loss, and enlisting the support of coaches and governing bodies. An athlete’s coaches may be the first to notice symptoms of the triad as changes in performance or behavior, but coaches should not encourage athletes to lose weight or be involved in determining an athlete’s weight.¹⁹

CORRESPONDENCE
Jennifer Payne, MD, Family Medicine Residency Program, Lancaster General Hospital, 555 N Duke Street, Lancaster, PA 17604; [email protected]

CASE › Cassidy, age 14, comes to you for a physical in preparation for track and field tryouts. If she makes the team, she will practice 90 minutes every afternoon with optional practices 2 mornings a week.

She says that her period has been irregular since it started a year ago, and she complains of knee and shin pain that her mother attributes to “growing pains.” She says she usually skips breakfast due to a lack of time in the morning, but eats the school lunches. She is considering becoming a vegetarian. You suspect that the female athlete triad is at work here. How would you proceed?

The female athlete triad (“the triad”) is considered a spectrum of 3 interrelated disorders: low energy availability, menstrual dysfunction, and altered bone mineral density.¹ Low energy availability—total dietary energy in (calories in) minus total exercise energy expended (calories out)—is considered the key cause. Previously, the triad was described as disordered eating, amenorrhea (having no menstruation for >3 sequential months), and osteoporosis.² However, this definition has been expanded to encourage detection before clinical problems progress. In most instances, an athlete will develop only one or 2 of the 3 components of the triad.^3,4 This article describes the clinical manifestations of the triad, how to screen patients for it, and indications for referring affected athletes.

How common is the triad?

The prevalence of the triad is difficult to determine because published studies often feature poor standardization of definitions and scales, small sample sizes, and no control groups. In limited studies, the estimated prevalence of female athletes with the complete triad ranges from 1.3% to 4.3%.^3,4 Many studies, however, focus on just one of the following 3 components:

Low energy availability. Few studies have specifically evaluated the prevalence of low energy availability among female athletes. The prevalence of disordered eating among females ranges from 25% to 31% of those in “thin build” sports (eg, running, gymnastics, and figure skating) vs 5% to 9% of nonathletes.^5,6

Menstrual dysfunction. The prevalence of menstrual dysfunction in female athletes is reported to be as high as 79%.¹ Primary amenorrhea (a delay in the age of menarche past age 15) has been reported in 22% of gymnasts, cheerleaders, and divers vs <1% of the general population.⁷ Subclinical menstrual dysfunction is highly prevalent. For example, one study found 78% of normally menstruating recreational runners had luteal deficiency or anovulation in one-third of their cycles.⁸

In most instances, an athlete will develop only one or 2 of the 3 components of the triad.Altered bone mineral density (BMD). BMD is increased in most athletes compared to sedentary controls, but low BMD often is seen in amenorrheic athletes. One review found 22% to 50% of amenorrheic athletes had osteopenia vs 12% of controls.⁹ The prevalence of osteoporosis in this group was as high as 13% vs 2.3% of controls.⁹

Three interrelated problems

As noted earlier, low energy availability is believed to be the key underlying etiology of the triad. Energy availability is the dietary energy left in the body after exercise is completed, or total dietary energy in (calories in) minus total exercise energy expended (calories out).^10,11

Low energy availability is not synonymous with disordered eating. Low energy availability may be the result of either decreased caloric intake or increased output. For example, athletes who increase their training requirements (increased output) need to increase their caloric intake or they will suffer an energy imbalance. Disordered eating also can result in decreased caloric intake. Disordered eating ranges from poor eating habits such as skipping meals to psychiatric conditions such as anorexia nervosa, bulimia, or binge eating disorder. Behaviors may include restricting calories, purging, or using diet pills, diuretics, or laxatives. For a summary of the most recent changes to eating disorder diagnoses, go to http://www.dsm5.org/documents/eating%20disorders%20fact%20sheet.pdf.

Low energy availability leads to hormonal abnormalities that may exacerbate other triad symptoms. When energy is restricted, the body conserves energy by altering metabolism by several methods, including suppressing usual hormonal cycling. For example, inadequate energy availability results in suppression of gonadotropin-releasing hormone pulsatility and disruption of the number of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) pulses, which results in decreased estrogen levels.¹²

When an athlete has decreased body fat as a result of low energy availability, she may have decreased adipokines, particularly leptin, which is believed to play a role in the ovulatory (normal) menstrual cycle. Abnormal eating also can suppress ghrelin, a short-term hormonal regulator of eating cycles/food intake and a long-term regulator of energy balance. Thus, short-term ghrelin dysregulation can self-perpetuate and have long-term consequences.

In anorexia nervosa, the intestinally derived anorexigen peptide YY is elevated,¹³ which may contribute to bone loss. Patients with anorexia nervosa also have androgen deficiency and elevated cortisol, both of which are factors in energy metabolism and maintenance of bone density.¹⁴

Menstrual dysfunction. Female athletes may experience amenorrhea, oligomenorrhea (menstrual periods with intervals >35 days), or subclinical menstrual dysfunction. Amenorrhea that occurs after menarche is considered secondary amenorrhea. Brancaccio et al¹⁵ found the incidence of secondary amenorrhea was significantly higher in high school athletes (30%) than in controls (15%). The researchers noted that “strenuous training alone has not been shown to alter menstrual cycles; it is necessary for dietary restriction to occur.”¹⁵

Altered BMD. Osteoporosis is characterized by compromised bone strength that increases the risk of fracture,¹⁶ and BMD is an aspect of bone strength. Osteoporosis may be caused by inadequate accumulation of optimal BMD during childhood and adolescence. A diagnosis of osteoporosis in patients ages 5 to 19 requires the presence of low bone mass and a clinically significant fracture history.¹⁷

BMD is assessed by dual-energy x-ray absorptiometry (DXA). DXA results are reported as a T-score, in which a patient’s bone density is compared with that of a healthy 30-year-old woman, or Z-score, which compares patients’ BMD with age- and sex-matched controls. The International Society of Clinical Densitometry recommends using Z-scores instead of T-scores when screening for osteoporosis in premenopausal women and in children.¹⁸

Z-scores are expressed as the number of standard deviations above or below the average value of the reference group. For every reduction by one standard deviation in BMD, the patient’s fracture risk doubles. The American College of Sports Medicine defines “low BMD” as a Z-score between -1 and -2.0 and osteoporosis as a Z-score ≤-2.0.¹ For both definitions, the patient must have at least one secondary clinical risk factor for fracture, such as low estrogen, history of stress fracture, or nutritional deficiencies.

Screening for the triad: What to ask, what to look for

Screen all adolescent female athletes at preparticipation physicals or whenever they present with any of the triad’s signs and symptoms. Look for risk factors such as calorie restriction practices, vegetarianism, a history of injuries, extended exercise periods, or increased training, particularly sport-specific training.¹ Also consider social, genetic, and psychiatric issues, such as abuse and family dysfunction.

Strenuous training alone is not enough to alter menstrual cycles; dietary restriction must occur.If you believe a patient is at risk, ask her about her exercise and eating habits, menstrual cycles, and fracture history (TABLE 1).¹⁹ During the physical exam, look for signs that suggest the triad, including lanugo, enlarged parotid glands, and bradycardia (TABLE 2).¹ Be sure to calculate the patient’s body mass index or body fat percentage.

Based on the history and physical findings, consider laboratory testing for a complete blood count with differential, ferritin, serum iron, B12, folate, comprehensive metabolic panel, thyroid function tests, erythrocyte sedimentation rate, and a urinalysis.²⁰ For an athlete in whom you highly suspect the triad, order urine electrolytes, salivary amylase, and stool guaiac tests, as well as an electrocardiogram.¹⁹

If your patient is amenorrheic, be aware that functional amenorrhea is a diagnosis of exclusion. Other diagnoses to consider include pregnancy, polycystic ovary syndrome, prolactinoma, anatomic defect, and ovarian failure. A pregnancy test, FSH and LH levels, prolactin, and thyroid-stimulating hormone testing should all be considered during evaluation for amenorrhea.

All patients with a history of stress fracture should undergo a DXA scan, whether or not they have comorbid amenorrhea, oligomenorrhea, or disordered eating.²⁰ In patients with amenorrhea, the DXA may need to be repeated in one year if menses does not resume.

For patients who screen positive for disordered eating, amenorrhea, or decreased BMD, the International Olympic Committee (IOC) guidelines are an excellent starting point for further evaluation.¹⁹ The IOC has “decision trees” for female athletes with disordered eating, amenorrhea, and osteoporosis that are available at http://www.olympic.org/Documents/Reports/EN/en_report_917.pdf.¹⁹

In addition to screening female athletes for the triad, consider addressing eating attitudes, menses, and fracture history in routine office physicals for all female patients. Also, be aware that triad symptoms are not limited to female athletes; male athletes, particularly those in sports that focus on leanness, physique, or weight classes (eg, wrestling) also are at risk for low energy availability, disordered eating, and low BMD.

Tx: First, restore sufficient nutrition

When treating a patient with the triad, consider consulting with a sports medicine specialist because these physicians typically are trained in diagnosing and treating this condition. Because low energy availability is the cornerstone of the triad, the priority in treating an affected athlete is to restore sufficient nutrition for caloric needs. Referral to a registered dietitian for full nutritional assessment and meal planning is recommended. If your athlete is unwilling or unable to follow dietary recommendations, refer her to an eating disorder specialist team. Ideally, this specialist team would consist of a registered sport nutritionist, a physician, and a psychologist or psychiatrist who specializes in eating disorders.

Drugs that can augment your efforts

Although they play a small role in treating the triad, pharmacologic therapies may be used to augment nutrition counseling. The selective serotonin reuptake inhibitor fluoxetine is the only medication approved by the US Food and Drug Administration for treating patients with bulimia; it is not approved for those with anorexia nervosa._²¹

Oral contraceptives may help women return to monthly menses, but they do not normalize the metabolic factors that impair bone formation and bone health. They can be used as a last measure in athletes who will not follow dietary or exercise recommendations, or those who, despite following recommendations, do not have a return to normal menses after 6 months.

Nasal calcitonin may be used to treat low BMD; order a follow-up DXA scan in 12 months to monitor improvement. However, prolonged use of nasal calcitonin may increase the risk for cancer, and in October 2013 nasal calcitonin was withdrawn from the Canadian market.²² For amenorrheic athletes, recommend oral calcium, 1000 to 1300 mg/d, and vitamin D, 400 to 800 IU/d. Ideally, patients should receive these levels of nutrients via dietary intake, but if that is not realistic, supplements may be considered.^1,23 Bisphosphonates and selective estrogen receptor modulators are contraindicated for premenopausal athletes.¹⁹

Can the patient return to play?

The athlete will need to be medically and psychologically cleared before being allowed to return to play (RTP). If she has menstrual dysfunction or low BMD, these conditions should be addressed as a prerequisite for RTP. If the treating physician, nutritionist, and/or eating disorder specialist team recommends specific treatments or other interventions, the athlete should agree to the treatment plan in order to RTP. The physician or assessment team should determine the time frame for RTP on an individual basis. Athletes who do not comply with treatment regimens should, for their health and safety, be prohibited from return to sports participation.

Athletes who do not comply with treatment regimens should be prohibited from return to sports participation.Focus on prevention

Primary prevention should focus on educating female (and male) athletes about regarding food as fuel, discouraging unhealthy weight loss, and enlisting the support of coaches and governing bodies. An athlete’s coaches may be the first to notice symptoms of the triad as changes in performance or behavior, but coaches should not encourage athletes to lose weight or be involved in determining an athlete’s weight.¹⁹

CORRESPONDENCE
Jennifer Payne, MD, Family Medicine Residency Program, Lancaster General Hospital, 555 N Duke Street, Lancaster, PA 17604; [email protected]

Skin procedures such as closing wounds and removing neoplasms are an integral part of most family medicine practices. While closure of simple lacerations and small surgical procedures are relatively straightforward, some lesions require extra techniques and attention to achieve the best outcomes.

This article describes some steps you can take to achieve the best outcomes for wound healing and cosmesis. Although suturing basics are important for successful wound closure, that information is not covered in this article. Forsch,¹ however, provides an excellent discussion of basic wound skin preparation and suturing techniques.

Before beginning, visualize the ending

Before beginning any skin repair—whether it is a planned surgical procedure or a more urgent wound closure—review the patient’s medical record for conditions or medications that may adversely affect wound healing. Key in on patients with poorly controlled diabetes or those taking anticoagulants or antiplatelet drugs. Good diabetes control before surgery improves healing² and drugs that promote bleeding sometimes may be temporarily discontinued before a procedure. If a patient’s diabetes is poorly controlled, an elective procedure can be postponed. If a patient is taking an anticoagulant and the international normalized ratio is within the therapeutic window, the procedure can be performed, but the physician must be ready to address bleeding by having electrical or chemical cautery available.

During your initial evaluation of the patient, assess and document the condition of the joints, muscles, tendons, and ligaments in the area in question before the procedure. Being aware of the local anatomy will help you avoid inadvertently damaging nerves, tendons, vessels, and other vital structures. Also, any time a procedure is beyond your comfort level, ask for help or refer the patient to a subspecialist. For example, if a lesion is on a patient’s neck near the carotid artery, the procedure is better left to an ear, nose, and throat specialist.

On the day of the procedure, plan how you will close the wound before you make the first cut, and include this information in your informed consent. Mentally review the anatomy of the area before starting a procedure to anticipate obstacles or structures that may be inadvertently injured. Visualize how the skin will fit together and how it will heal before making an incision. Reassure the patient that you will use techniques to minimize pain and scarring. Consider taking photos both before and after the procedure for documentation.

The best cosmetic results usually are achieved when the final closure line (and therefore the scar) lies parallel to the lines of least skin tension.The best cosmetic results usually are achieved when the final closure line (and therefore the scar) lies parallel to the lines of least skin tension. When doing an excision, start choosing possible closures by considering layouts that produce this result. Eliminate from consideration any closures that would pull skin tension from areas that are immobile or that would cause cosmetic problems (such as a closure on or near the eyebrows or mouth, since this would change the contours of these structures). For such closures, a skin rearrangement flap may offer a cosmetically better outcome, especially on the face.

Tips for irrigating the wound and prepping the skin

If you are repairing a wound that is the result of an injury, you will need to clean the laceration gently but thoroughly. Avoid using products on open wounds that can damage regenerative tissue, such as organified iodines or hydrogen peroxide.^3,4 Before irrigating a wound with normal saline, thoroughly examine it for foreign bodies, which may promote infection and impede healing. Consider giving local anesthesia before irrigation. Typically, irrigation pressure of approximately 8 pounds per square inch (psi) is considered ideal.⁵ Using irrigation pressures of <4 psi only moistens the wound, and >15 psi can damage the wound and drive bacteria deeper into tissue.6 Pressures of 8 to 11 psi can be achieved using a 18- to 19-gauge needle or angiocatheter with a 30 cc to 35 cc syringe.

Consider snipping off the tip of the cap and leaving it snugly on the needle. This will help prevent needle sticks and allow for thorough and safer irrigation. If commercial irrigation equipment is available, use it as directed by the manufacturer. Always be aware of potential splashback while irrigating and use appropriate personal protective equipment.

For wounds that result from a surgical procedure, employ appropriate site preparation and sterile technique. Iodophors provide broad-spectrum coverage, are not associated with microbial resistance, and provide a bacteriostatic effect as long as they remain on the skin. They require at least 2 minutes of contact to release free iodine, which exerts antibacterial activity.

Chlorhexidine gluconate offers broad-spectrum coverage against bacteria, yeast, and molds. It appears to provide greater reduction in skin microflora than povidone-iodine, and remains active for hours after application.⁷ Use it with caution around the eyes because of the risk for conjunctival irritation, keratitis, or corneal ulceration.⁸ Make sure to apply the prep solution to an area larger than the area exposed by the fenestrated drape because the drape may move around during the procedure, inadvertently contaminating the surgical field.

When excising a neoplasm, consider the margin

When performing a surgical procedure such as removing a cutaneous neoplasm, don’t resect excessive tissue, but do excise adequate margins. (For adequate margins of various cutaneous neoplasms, see TABLE 1.^9-11) Mark the outlines of the visible tumor and the excision margin and show them to the patient, because some patients mistakenly assume that only the visible tumor will be removed.

Keep in mind when treating basal cell carcinomas (BCC) or squamous cell carcinomas (SCC) that the presence of high-risk characteristics may require larger surgical margins. The cure rates are lower for higher-risk BCCs, such as lesions that have morpheaform morphology or aggressive histologic features, or those that are ≥2 cm, recurrent, or located on the lips or paranasal or periocular regions.^10-12

Cure rates for these higher-risk BCCs can be improved substantially by using intraoperative margin evaluation (frozen sections) or Mohs micrographic surgery. (For more on Mohs surgery, see “When to consider Mohs surgery,” J Fam Pract. 2013;62:558.)

Primary SCCs that are ≥2 cm in diameter, poorly differentiated on histology, in high-risk sites, or invading subcutaneous tissues require larger margins.¹³ The approach to a suspicious pigmented cutaneous neoplasm consists of an initial biopsy or excision with 1 to 2 mm margins and pathologic evaluation.¹⁴

Because hematoma formation inhibits wound healing, pay special attention to hemostasis when excising a neoplasm. Use pressure for minor bleeding. Use mosquito forceps to clamp a bleeder followed by ligation with an absorbable suture for larger bleeders. Other techniques for hemostasis include electrical or chemical cauterization and hemostatic solutions.

Positioning of edges is key to minimize scarring

When suturing a wound—whether it is from an injury or a procedure—take care to evert the skin edges; the underlying dermis from both edges should touch. This is to compensate for future contracture of the wound and thus, to produce a flat scar. It is difficult to evert the edges when they are too far apart or under tension, and excess skin tends to invert the skin edges, which is undesirable. If the pressure generated by the suture is greater than the closing pressure of the skin capillaries, the result will be local necrosis.

Irrigation pressure of approximately 8 psi is considered ideal.Before placing the suture, gently pinch the skin edges together. If the skin edges require pressure to approximate, consider undermining the skin edges, that is, cutting the fibrous septae that connect the skin to the underlying fascia so you can more easily pull the wound edges together. Undermining can be performed with a scalpel blade, scissors, or by bluntly using a hemostat. Use skin hooks or forceps to lift the wound edge. The safest level of undermining is in the fat, just below the dermal-fat junction. It usually takes 2 to 3 cm of undermining to free up 1 cm of tissue. Periodically check to see how much tissue has been released and undermine the minimum amount necessary.

Buried dermal sutures do not increase the risk of infection in clean, uncontaminated lacerations.Use the recommended size suture for the area of the body and remove sutures at recommended times (TABLE 2).⁷ In general, use the thinnest suture for the least amount of time possible. When giving the patient wound care instructions, emphasize the importance of having the sutures removed on time. Delay may cause local irritation and increased scarring. To prevent suture marks, consider earlier removal of a single suture that causes extra tension (such as a vertical mattress suture, which is described on page 186) within a line of simple sutures. Infection or patient factors such as age, presence of vascular or chronic disease, and nutritional status may influence healing times and suture removal times, so carefully assess wound healing; it may be necessary to remove sutures earlier or later than the recommended time.

Avoid dog ears. Dog ears (bunching of skin at one end of a wound closure) usually are the result of unequal amounts of opposing tissue. Causes range from ragged lacerations and flap procedures to uneven apportion of tissue when suturing.

If the difference in the lengths of the 2 sides of a wound is ≤15%, the halving technique (placing the first suture in the center of the wound, the next suture in the center of each remaining segment, and so on) works well to avoid dog ears. Otherwise, a Burow triangle repair—a procedure that slightly extends the wound but removes the excess tissue and results in a better cosmetic outcome—may be required.

If while in the process of repairing a relatively small wound you notice that dog ears occur as the result of poor technique, consider removing and redoing the sutures.

Deep suturing reduces tension, improves outcomes

To achieve the best possible cosmetic outcomes when closing a particularly deep wound, consider placing deep sutures. Because scars remodel for about a year post-repair, tension across the wound area may produce a wider and more unsightly scar as time goes by. Deep closure of a wound with dissolvable sutures can:¹⁵
• reduce or eliminate wound tension when suturing the epidermis
• close potential space below the skin
• stop subcutaneous bleeding
• reduce hematoma and seroma formation.

The technique for deep suture placement is shown in FIGURES 1A to 1D. The decreased tension in the healing scar that results from placing deep-buried sutures will reduce the final width of the scar. Buried dermal sutures do not increase the risk of infection in clean, uncontaminated lacerations. However, animal studies suggest that deep sutures should be avoided in highly contaminated wounds.¹⁶

For deep lacerations with potential space remaining, use vertical mattress sutures to approximate the wound edges.¹⁵ The vertical mattress suture technique is shown in FIGURES 2A to 2C. This technique incorporates a large amount of tissue within the passage of the suture loops and provides good tensile strength in closing wound edges over a distance or under tension. It also is used for wounds in locations where wound edges tend to invert, such as on the posterior neck, behind the ear, in the groin, in the inframammary crease, or on concave body surfaces. Early removal (half of the generally recommended days) of vertical mattress sutures can help prevent suture marks, especially if nearby simple interrupted sutures can remain in place for the recommended duration.

When to consider tape, staples, or adhesive

Don’t overlook wound closure tapes for superficial wounds. Even if tape is a poor candidate for the primary wound closure, it still may be used during the early stages of wound healing to support other closures by spreading tension over a larger area than just the suture area. Apply one strip at a time on one side of the wound, then pull the tape across, everting the edges of the wound. This can help eliminate the “railroad track” scars sometimes caused by tight sutures.

Carefully assess wound healing; it may be necessary to remove sutures earlier or later than the recommended time.Often, the tip of a triangular flap will refuse to nudge up to the corner, even with a well-placed corner suture. Tape applied and then pulled over the tip can help approximate the tissue for this type of wound. An alternative use of tape is to strengthen fragile skin to allow for suturing. The tape can be applied to either side of a wound and the suture needle can be driven though the tape and skin so you can close as usual. To improve adhesion, use tincture of benzoin over the areas on which you want to apply tape.

When using staples for closure, be certain to approximate the tissue carefully. When possible, have an assistant approximate the edges. Hold the stapler with the center mark at the middle of the skin edges. Squeeze the handle completely while keeping the stapler still during application. Properly applied staples are much less painful to remove, which your patients will appreciate.

The vertical mattress suture technique provides good tensile strength in closing wound edges over a distance or under tension.Using tissue adhesives can save time because the procedure is quick and does not require suture or staple removal. Clean, low-tension wounds on the face tend to do well with adhesives. When on the fence about whether to suture or use adhesive, choose suture. Any wound for which you would consider using adhesive should be small enough to suture in just a few minutes.

CORRESPONDENCE
Luke M. Baudoin, MD, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130; [email protected]

Skin procedures such as closing wounds and removing neoplasms are an integral part of most family medicine practices. While closure of simple lacerations and small surgical procedures are relatively straightforward, some lesions require extra techniques and attention to achieve the best outcomes.

This article describes some steps you can take to achieve the best outcomes for wound healing and cosmesis. Although suturing basics are important for successful wound closure, that information is not covered in this article. Forsch,¹ however, provides an excellent discussion of basic wound skin preparation and suturing techniques.

Before beginning, visualize the ending

Before beginning any skin repair—whether it is a planned surgical procedure or a more urgent wound closure—review the patient’s medical record for conditions or medications that may adversely affect wound healing. Key in on patients with poorly controlled diabetes or those taking anticoagulants or antiplatelet drugs. Good diabetes control before surgery improves healing² and drugs that promote bleeding sometimes may be temporarily discontinued before a procedure. If a patient’s diabetes is poorly controlled, an elective procedure can be postponed. If a patient is taking an anticoagulant and the international normalized ratio is within the therapeutic window, the procedure can be performed, but the physician must be ready to address bleeding by having electrical or chemical cautery available.

During your initial evaluation of the patient, assess and document the condition of the joints, muscles, tendons, and ligaments in the area in question before the procedure. Being aware of the local anatomy will help you avoid inadvertently damaging nerves, tendons, vessels, and other vital structures. Also, any time a procedure is beyond your comfort level, ask for help or refer the patient to a subspecialist. For example, if a lesion is on a patient’s neck near the carotid artery, the procedure is better left to an ear, nose, and throat specialist.

On the day of the procedure, plan how you will close the wound before you make the first cut, and include this information in your informed consent. Mentally review the anatomy of the area before starting a procedure to anticipate obstacles or structures that may be inadvertently injured. Visualize how the skin will fit together and how it will heal before making an incision. Reassure the patient that you will use techniques to minimize pain and scarring. Consider taking photos both before and after the procedure for documentation.

The best cosmetic results usually are achieved when the final closure line (and therefore the scar) lies parallel to the lines of least skin tension.The best cosmetic results usually are achieved when the final closure line (and therefore the scar) lies parallel to the lines of least skin tension. When doing an excision, start choosing possible closures by considering layouts that produce this result. Eliminate from consideration any closures that would pull skin tension from areas that are immobile or that would cause cosmetic problems (such as a closure on or near the eyebrows or mouth, since this would change the contours of these structures). For such closures, a skin rearrangement flap may offer a cosmetically better outcome, especially on the face.

Tips for irrigating the wound and prepping the skin

If you are repairing a wound that is the result of an injury, you will need to clean the laceration gently but thoroughly. Avoid using products on open wounds that can damage regenerative tissue, such as organified iodines or hydrogen peroxide.^3,4 Before irrigating a wound with normal saline, thoroughly examine it for foreign bodies, which may promote infection and impede healing. Consider giving local anesthesia before irrigation. Typically, irrigation pressure of approximately 8 pounds per square inch (psi) is considered ideal.⁵ Using irrigation pressures of <4 psi only moistens the wound, and >15 psi can damage the wound and drive bacteria deeper into tissue.6 Pressures of 8 to 11 psi can be achieved using a 18- to 19-gauge needle or angiocatheter with a 30 cc to 35 cc syringe.

Consider snipping off the tip of the cap and leaving it snugly on the needle. This will help prevent needle sticks and allow for thorough and safer irrigation. If commercial irrigation equipment is available, use it as directed by the manufacturer. Always be aware of potential splashback while irrigating and use appropriate personal protective equipment.

For wounds that result from a surgical procedure, employ appropriate site preparation and sterile technique. Iodophors provide broad-spectrum coverage, are not associated with microbial resistance, and provide a bacteriostatic effect as long as they remain on the skin. They require at least 2 minutes of contact to release free iodine, which exerts antibacterial activity.

Chlorhexidine gluconate offers broad-spectrum coverage against bacteria, yeast, and molds. It appears to provide greater reduction in skin microflora than povidone-iodine, and remains active for hours after application.⁷ Use it with caution around the eyes because of the risk for conjunctival irritation, keratitis, or corneal ulceration.⁸ Make sure to apply the prep solution to an area larger than the area exposed by the fenestrated drape because the drape may move around during the procedure, inadvertently contaminating the surgical field.

When excising a neoplasm, consider the margin

When performing a surgical procedure such as removing a cutaneous neoplasm, don’t resect excessive tissue, but do excise adequate margins. (For adequate margins of various cutaneous neoplasms, see TABLE 1.^9-11) Mark the outlines of the visible tumor and the excision margin and show them to the patient, because some patients mistakenly assume that only the visible tumor will be removed.

Keep in mind when treating basal cell carcinomas (BCC) or squamous cell carcinomas (SCC) that the presence of high-risk characteristics may require larger surgical margins. The cure rates are lower for higher-risk BCCs, such as lesions that have morpheaform morphology or aggressive histologic features, or those that are ≥2 cm, recurrent, or located on the lips or paranasal or periocular regions.^10-12

Cure rates for these higher-risk BCCs can be improved substantially by using intraoperative margin evaluation (frozen sections) or Mohs micrographic surgery. (For more on Mohs surgery, see “When to consider Mohs surgery,” J Fam Pract. 2013;62:558.)

Primary SCCs that are ≥2 cm in diameter, poorly differentiated on histology, in high-risk sites, or invading subcutaneous tissues require larger margins.¹³ The approach to a suspicious pigmented cutaneous neoplasm consists of an initial biopsy or excision with 1 to 2 mm margins and pathologic evaluation.¹⁴

Because hematoma formation inhibits wound healing, pay special attention to hemostasis when excising a neoplasm. Use pressure for minor bleeding. Use mosquito forceps to clamp a bleeder followed by ligation with an absorbable suture for larger bleeders. Other techniques for hemostasis include electrical or chemical cauterization and hemostatic solutions.

Positioning of edges is key to minimize scarring

When suturing a wound—whether it is from an injury or a procedure—take care to evert the skin edges; the underlying dermis from both edges should touch. This is to compensate for future contracture of the wound and thus, to produce a flat scar. It is difficult to evert the edges when they are too far apart or under tension, and excess skin tends to invert the skin edges, which is undesirable. If the pressure generated by the suture is greater than the closing pressure of the skin capillaries, the result will be local necrosis.

Irrigation pressure of approximately 8 psi is considered ideal.Before placing the suture, gently pinch the skin edges together. If the skin edges require pressure to approximate, consider undermining the skin edges, that is, cutting the fibrous septae that connect the skin to the underlying fascia so you can more easily pull the wound edges together. Undermining can be performed with a scalpel blade, scissors, or by bluntly using a hemostat. Use skin hooks or forceps to lift the wound edge. The safest level of undermining is in the fat, just below the dermal-fat junction. It usually takes 2 to 3 cm of undermining to free up 1 cm of tissue. Periodically check to see how much tissue has been released and undermine the minimum amount necessary.

Buried dermal sutures do not increase the risk of infection in clean, uncontaminated lacerations.Use the recommended size suture for the area of the body and remove sutures at recommended times (TABLE 2).⁷ In general, use the thinnest suture for the least amount of time possible. When giving the patient wound care instructions, emphasize the importance of having the sutures removed on time. Delay may cause local irritation and increased scarring. To prevent suture marks, consider earlier removal of a single suture that causes extra tension (such as a vertical mattress suture, which is described on page 186) within a line of simple sutures. Infection or patient factors such as age, presence of vascular or chronic disease, and nutritional status may influence healing times and suture removal times, so carefully assess wound healing; it may be necessary to remove sutures earlier or later than the recommended time.

Avoid dog ears. Dog ears (bunching of skin at one end of a wound closure) usually are the result of unequal amounts of opposing tissue. Causes range from ragged lacerations and flap procedures to uneven apportion of tissue when suturing.

If the difference in the lengths of the 2 sides of a wound is ≤15%, the halving technique (placing the first suture in the center of the wound, the next suture in the center of each remaining segment, and so on) works well to avoid dog ears. Otherwise, a Burow triangle repair—a procedure that slightly extends the wound but removes the excess tissue and results in a better cosmetic outcome—may be required.

If while in the process of repairing a relatively small wound you notice that dog ears occur as the result of poor technique, consider removing and redoing the sutures.

Deep suturing reduces tension, improves outcomes

To achieve the best possible cosmetic outcomes when closing a particularly deep wound, consider placing deep sutures. Because scars remodel for about a year post-repair, tension across the wound area may produce a wider and more unsightly scar as time goes by. Deep closure of a wound with dissolvable sutures can:¹⁵
• reduce or eliminate wound tension when suturing the epidermis
• close potential space below the skin
• stop subcutaneous bleeding
• reduce hematoma and seroma formation.

The technique for deep suture placement is shown in FIGURES 1A to 1D. The decreased tension in the healing scar that results from placing deep-buried sutures will reduce the final width of the scar. Buried dermal sutures do not increase the risk of infection in clean, uncontaminated lacerations. However, animal studies suggest that deep sutures should be avoided in highly contaminated wounds.¹⁶

For deep lacerations with potential space remaining, use vertical mattress sutures to approximate the wound edges.¹⁵ The vertical mattress suture technique is shown in FIGURES 2A to 2C. This technique incorporates a large amount of tissue within the passage of the suture loops and provides good tensile strength in closing wound edges over a distance or under tension. It also is used for wounds in locations where wound edges tend to invert, such as on the posterior neck, behind the ear, in the groin, in the inframammary crease, or on concave body surfaces. Early removal (half of the generally recommended days) of vertical mattress sutures can help prevent suture marks, especially if nearby simple interrupted sutures can remain in place for the recommended duration.

When to consider tape, staples, or adhesive

Don’t overlook wound closure tapes for superficial wounds. Even if tape is a poor candidate for the primary wound closure, it still may be used during the early stages of wound healing to support other closures by spreading tension over a larger area than just the suture area. Apply one strip at a time on one side of the wound, then pull the tape across, everting the edges of the wound. This can help eliminate the “railroad track” scars sometimes caused by tight sutures.

Carefully assess wound healing; it may be necessary to remove sutures earlier or later than the recommended time.Often, the tip of a triangular flap will refuse to nudge up to the corner, even with a well-placed corner suture. Tape applied and then pulled over the tip can help approximate the tissue for this type of wound. An alternative use of tape is to strengthen fragile skin to allow for suturing. The tape can be applied to either side of a wound and the suture needle can be driven though the tape and skin so you can close as usual. To improve adhesion, use tincture of benzoin over the areas on which you want to apply tape.

When using staples for closure, be certain to approximate the tissue carefully. When possible, have an assistant approximate the edges. Hold the stapler with the center mark at the middle of the skin edges. Squeeze the handle completely while keeping the stapler still during application. Properly applied staples are much less painful to remove, which your patients will appreciate.

The vertical mattress suture technique provides good tensile strength in closing wound edges over a distance or under tension.Using tissue adhesives can save time because the procedure is quick and does not require suture or staple removal. Clean, low-tension wounds on the face tend to do well with adhesives. When on the fence about whether to suture or use adhesive, choose suture. Any wound for which you would consider using adhesive should be small enough to suture in just a few minutes.

CORRESPONDENCE
Luke M. Baudoin, MD, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130; [email protected]

Skin procedures such as closing wounds and removing neoplasms are an integral part of most family medicine practices. While closure of simple lacerations and small surgical procedures are relatively straightforward, some lesions require extra techniques and attention to achieve the best outcomes.

This article describes some steps you can take to achieve the best outcomes for wound healing and cosmesis. Although suturing basics are important for successful wound closure, that information is not covered in this article. Forsch,¹ however, provides an excellent discussion of basic wound skin preparation and suturing techniques.

Before beginning, visualize the ending

Before beginning any skin repair—whether it is a planned surgical procedure or a more urgent wound closure—review the patient’s medical record for conditions or medications that may adversely affect wound healing. Key in on patients with poorly controlled diabetes or those taking anticoagulants or antiplatelet drugs. Good diabetes control before surgery improves healing² and drugs that promote bleeding sometimes may be temporarily discontinued before a procedure. If a patient’s diabetes is poorly controlled, an elective procedure can be postponed. If a patient is taking an anticoagulant and the international normalized ratio is within the therapeutic window, the procedure can be performed, but the physician must be ready to address bleeding by having electrical or chemical cautery available.

During your initial evaluation of the patient, assess and document the condition of the joints, muscles, tendons, and ligaments in the area in question before the procedure. Being aware of the local anatomy will help you avoid inadvertently damaging nerves, tendons, vessels, and other vital structures. Also, any time a procedure is beyond your comfort level, ask for help or refer the patient to a subspecialist. For example, if a lesion is on a patient’s neck near the carotid artery, the procedure is better left to an ear, nose, and throat specialist.

On the day of the procedure, plan how you will close the wound before you make the first cut, and include this information in your informed consent. Mentally review the anatomy of the area before starting a procedure to anticipate obstacles or structures that may be inadvertently injured. Visualize how the skin will fit together and how it will heal before making an incision. Reassure the patient that you will use techniques to minimize pain and scarring. Consider taking photos both before and after the procedure for documentation.

The best cosmetic results usually are achieved when the final closure line (and therefore the scar) lies parallel to the lines of least skin tension.The best cosmetic results usually are achieved when the final closure line (and therefore the scar) lies parallel to the lines of least skin tension. When doing an excision, start choosing possible closures by considering layouts that produce this result. Eliminate from consideration any closures that would pull skin tension from areas that are immobile or that would cause cosmetic problems (such as a closure on or near the eyebrows or mouth, since this would change the contours of these structures). For such closures, a skin rearrangement flap may offer a cosmetically better outcome, especially on the face.

Tips for irrigating the wound and prepping the skin

If you are repairing a wound that is the result of an injury, you will need to clean the laceration gently but thoroughly. Avoid using products on open wounds that can damage regenerative tissue, such as organified iodines or hydrogen peroxide.^3,4 Before irrigating a wound with normal saline, thoroughly examine it for foreign bodies, which may promote infection and impede healing. Consider giving local anesthesia before irrigation. Typically, irrigation pressure of approximately 8 pounds per square inch (psi) is considered ideal.⁵ Using irrigation pressures of <4 psi only moistens the wound, and >15 psi can damage the wound and drive bacteria deeper into tissue.6 Pressures of 8 to 11 psi can be achieved using a 18- to 19-gauge needle or angiocatheter with a 30 cc to 35 cc syringe.

Consider snipping off the tip of the cap and leaving it snugly on the needle. This will help prevent needle sticks and allow for thorough and safer irrigation. If commercial irrigation equipment is available, use it as directed by the manufacturer. Always be aware of potential splashback while irrigating and use appropriate personal protective equipment.

For wounds that result from a surgical procedure, employ appropriate site preparation and sterile technique. Iodophors provide broad-spectrum coverage, are not associated with microbial resistance, and provide a bacteriostatic effect as long as they remain on the skin. They require at least 2 minutes of contact to release free iodine, which exerts antibacterial activity.

Chlorhexidine gluconate offers broad-spectrum coverage against bacteria, yeast, and molds. It appears to provide greater reduction in skin microflora than povidone-iodine, and remains active for hours after application.⁷ Use it with caution around the eyes because of the risk for conjunctival irritation, keratitis, or corneal ulceration.⁸ Make sure to apply the prep solution to an area larger than the area exposed by the fenestrated drape because the drape may move around during the procedure, inadvertently contaminating the surgical field.

When excising a neoplasm, consider the margin

When performing a surgical procedure such as removing a cutaneous neoplasm, don’t resect excessive tissue, but do excise adequate margins. (For adequate margins of various cutaneous neoplasms, see TABLE 1.^9-11) Mark the outlines of the visible tumor and the excision margin and show them to the patient, because some patients mistakenly assume that only the visible tumor will be removed.

Keep in mind when treating basal cell carcinomas (BCC) or squamous cell carcinomas (SCC) that the presence of high-risk characteristics may require larger surgical margins. The cure rates are lower for higher-risk BCCs, such as lesions that have morpheaform morphology or aggressive histologic features, or those that are ≥2 cm, recurrent, or located on the lips or paranasal or periocular regions.^10-12

Cure rates for these higher-risk BCCs can be improved substantially by using intraoperative margin evaluation (frozen sections) or Mohs micrographic surgery. (For more on Mohs surgery, see “When to consider Mohs surgery,” J Fam Pract. 2013;62:558.)

Primary SCCs that are ≥2 cm in diameter, poorly differentiated on histology, in high-risk sites, or invading subcutaneous tissues require larger margins.¹³ The approach to a suspicious pigmented cutaneous neoplasm consists of an initial biopsy or excision with 1 to 2 mm margins and pathologic evaluation.¹⁴

Because hematoma formation inhibits wound healing, pay special attention to hemostasis when excising a neoplasm. Use pressure for minor bleeding. Use mosquito forceps to clamp a bleeder followed by ligation with an absorbable suture for larger bleeders. Other techniques for hemostasis include electrical or chemical cauterization and hemostatic solutions.

Positioning of edges is key to minimize scarring

When suturing a wound—whether it is from an injury or a procedure—take care to evert the skin edges; the underlying dermis from both edges should touch. This is to compensate for future contracture of the wound and thus, to produce a flat scar. It is difficult to evert the edges when they are too far apart or under tension, and excess skin tends to invert the skin edges, which is undesirable. If the pressure generated by the suture is greater than the closing pressure of the skin capillaries, the result will be local necrosis.

Irrigation pressure of approximately 8 psi is considered ideal.Before placing the suture, gently pinch the skin edges together. If the skin edges require pressure to approximate, consider undermining the skin edges, that is, cutting the fibrous septae that connect the skin to the underlying fascia so you can more easily pull the wound edges together. Undermining can be performed with a scalpel blade, scissors, or by bluntly using a hemostat. Use skin hooks or forceps to lift the wound edge. The safest level of undermining is in the fat, just below the dermal-fat junction. It usually takes 2 to 3 cm of undermining to free up 1 cm of tissue. Periodically check to see how much tissue has been released and undermine the minimum amount necessary.

Buried dermal sutures do not increase the risk of infection in clean, uncontaminated lacerations.Use the recommended size suture for the area of the body and remove sutures at recommended times (TABLE 2).⁷ In general, use the thinnest suture for the least amount of time possible. When giving the patient wound care instructions, emphasize the importance of having the sutures removed on time. Delay may cause local irritation and increased scarring. To prevent suture marks, consider earlier removal of a single suture that causes extra tension (such as a vertical mattress suture, which is described on page 186) within a line of simple sutures. Infection or patient factors such as age, presence of vascular or chronic disease, and nutritional status may influence healing times and suture removal times, so carefully assess wound healing; it may be necessary to remove sutures earlier or later than the recommended time.

Avoid dog ears. Dog ears (bunching of skin at one end of a wound closure) usually are the result of unequal amounts of opposing tissue. Causes range from ragged lacerations and flap procedures to uneven apportion of tissue when suturing.

If the difference in the lengths of the 2 sides of a wound is ≤15%, the halving technique (placing the first suture in the center of the wound, the next suture in the center of each remaining segment, and so on) works well to avoid dog ears. Otherwise, a Burow triangle repair—a procedure that slightly extends the wound but removes the excess tissue and results in a better cosmetic outcome—may be required.

If while in the process of repairing a relatively small wound you notice that dog ears occur as the result of poor technique, consider removing and redoing the sutures.

Deep suturing reduces tension, improves outcomes

To achieve the best possible cosmetic outcomes when closing a particularly deep wound, consider placing deep sutures. Because scars remodel for about a year post-repair, tension across the wound area may produce a wider and more unsightly scar as time goes by. Deep closure of a wound with dissolvable sutures can:¹⁵
• reduce or eliminate wound tension when suturing the epidermis
• close potential space below the skin
• stop subcutaneous bleeding
• reduce hematoma and seroma formation.

The technique for deep suture placement is shown in FIGURES 1A to 1D. The decreased tension in the healing scar that results from placing deep-buried sutures will reduce the final width of the scar. Buried dermal sutures do not increase the risk of infection in clean, uncontaminated lacerations. However, animal studies suggest that deep sutures should be avoided in highly contaminated wounds.¹⁶

For deep lacerations with potential space remaining, use vertical mattress sutures to approximate the wound edges.¹⁵ The vertical mattress suture technique is shown in FIGURES 2A to 2C. This technique incorporates a large amount of tissue within the passage of the suture loops and provides good tensile strength in closing wound edges over a distance or under tension. It also is used for wounds in locations where wound edges tend to invert, such as on the posterior neck, behind the ear, in the groin, in the inframammary crease, or on concave body surfaces. Early removal (half of the generally recommended days) of vertical mattress sutures can help prevent suture marks, especially if nearby simple interrupted sutures can remain in place for the recommended duration.

When to consider tape, staples, or adhesive

Don’t overlook wound closure tapes for superficial wounds. Even if tape is a poor candidate for the primary wound closure, it still may be used during the early stages of wound healing to support other closures by spreading tension over a larger area than just the suture area. Apply one strip at a time on one side of the wound, then pull the tape across, everting the edges of the wound. This can help eliminate the “railroad track” scars sometimes caused by tight sutures.

Carefully assess wound healing; it may be necessary to remove sutures earlier or later than the recommended time.Often, the tip of a triangular flap will refuse to nudge up to the corner, even with a well-placed corner suture. Tape applied and then pulled over the tip can help approximate the tissue for this type of wound. An alternative use of tape is to strengthen fragile skin to allow for suturing. The tape can be applied to either side of a wound and the suture needle can be driven though the tape and skin so you can close as usual. To improve adhesion, use tincture of benzoin over the areas on which you want to apply tape.

When using staples for closure, be certain to approximate the tissue carefully. When possible, have an assistant approximate the edges. Hold the stapler with the center mark at the middle of the skin edges. Squeeze the handle completely while keeping the stapler still during application. Properly applied staples are much less painful to remove, which your patients will appreciate.

The vertical mattress suture technique provides good tensile strength in closing wound edges over a distance or under tension.Using tissue adhesives can save time because the procedure is quick and does not require suture or staple removal. Clean, low-tension wounds on the face tend to do well with adhesives. When on the fence about whether to suture or use adhesive, choose suture. Any wound for which you would consider using adhesive should be small enough to suture in just a few minutes.

CORRESPONDENCE
Luke M. Baudoin, MD, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130; [email protected]

CASE › 38-year-old, previously healthy G2 P2 woman arrives at your office with sudden-onset epigastric pain, chills, and nausea, but no vomiting. She has had no fever, shortness of breath, or pruritis. Her appetite is good and her weight is stable. Three days earlier, she gave birth to a healthy baby. The course of pregnancy had been uncomplicated, and delivery was vaginal at 35 weeks gestation without any complications. Her blood pressure (BP) was normal throughout pregnancy, and she had no signs of preeclampsia.

She does not smoke. Although she usually drinks 1 beer daily, she avoided alcohol during her pregnancy. She does not use illicit drugs. She has received no blood transfusions and has no history of viral hepatitis.

On examination she is alert and oriented. She is afebrile and anicteric. Her vital signs are normal with a BP of 116/80 mm Hg and a pulse rate of 86/min. Respiratory rate is 20/min, and oxygen saturation is 98% while breathing ambient air. On palpation, her abdomen is soft and nontender without organomegaly. There is no ascites and bowel sounds are audible.

Initial laboratory investigation yields the following results:
• alkaline phosphatase 436 U/L (normal, 40-135)
• alanine aminotransferase 685 U/L (4-55)
• total bilirubin 27 mcmol/L (2-20)
• serum albumin 25 g/L (35-55)
• international normalized ratio 0.9 (0.9-1.3)
• amylase 47 U/L (20-110)
• hemoglobin 146 g/L (140-180)
• platelets 296 3 109/L (150-400)
• white blood cell count 9.7 3 109/L (4.0-10.0)
• urinalysis reveals no proteins
• transferrin 4.58 g/L (1.32-3.02)
• iron saturation 29% (15-50)
• ferritin 70 mcg/L (10-200)
• serum copper 43.9 mcmol/L (9.0-27.0)
• ceruloplasmin 594 mg/L (200-600)
• Alpha-1-antitrypsin levels 2.05 g/L (1.06-1.58).

What is the differential diagnosis of abnormally elevated liver enzymes in the peripartum period?

Possible underlying causes of the patient’s findings include pregnancy-related liver diseases such as hyperemesis gravidarum (HG), intrahepatic cholestasis of pregnancy, preeclampsia, eclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), and acute fatty liver of pregnancy (AFLP); or liver diseases unrelated to pregnancy such as viral hepatitis, autoimmune liver disease, Wilson’s disease, Budd-Chiari syndrome, cholecystitis, and drug-induced hepatotoxicity.

Narrowing the field. HG usually presents between 4 to 13 weeks of the start of pregnancy and is characterized by severe nausea, vomiting, weight loss, and electrolyte disturbances, none of which are present in this patient. The patient does not have neuropsychiatric symptoms and signs typical of Wilson’s disease, and the high-normal ceruloplasmin level despite above-normal serum copper also weighs against this diagnosis.

Our patient was not taking any hepatotoxic drugs or over-the-counter medications that cause liver damage.

With intrahepatic cholestasis of pregnancy, aminotransferase levels can be as high as 20 times the upper limit of normal. However, with this disorder, elevated serum bile acids during the second half of pregnancy cause pruritis. Absence of pruritis, jaundice, and features of obstructive jaundice, including pale stools and dark urine, makes intrahepatic cholestasis of pregnancy unlikely. Moreover, patients with this disorder do not have constitutional symptoms.¹

Absence of jaundice, ascites, and hepatic vein thrombosis on ultrasound excludes Budd-Chiari syndrome.Preeclampsia is characterized by hypertension and proteinuria after 20 weeks of gestation or within 48 hours of delivery. Absence of seizures differentiates it from eclampsia. Right upper quadrant pain, nausea, and vomiting may be the presenting features. Aminotransferase levels can be up to 10 times the upper limit of normal. Bilirubin concentrations are usually normal. These abnormalities typically resolve within 2 weeks of delivery. Though atypical clinical presentations have been known with preeclampsia—particularly as extremes of maternal childbearing age have been associated with preeclampsia²—the patient’s normal BP and an absence of proteinuria make both preeclampsia and eclampsia unlikely.

HELLP syndrome usually arises in the second or third trimester of pregnancy but also can develop after delivery. Right upper quadrant and epigastric pain, nausea, and vomiting are usual presenting symptoms. Hypertension and proteinuria are found in 85% of cases.³ Absence of hypertension and proteinuria and normal microangiopathic blood smear and platelet count make HELLP syndrome unlikely in the patient.

AFLP usually presents in the third trimester of pregnancy with nausea, abdominal pain, jaundice, and hepatic encephalopathy. Hypoglycemia, lactic acidosis, hyperammonemia, and disseminated intravascular coagulation may complicate the clinical picture. Leukocytosis occurs in 98% of patients.⁴ Elevated concentrations of bilirubin, aminotransferases, and uric acid are commonly found. The biochemical picture in our patient does not match that of AFLP and makes this diagnosis unlikely.

Remaining potential diagnoses. Hepatitis B and C are possibilities and must be excluded by appropriate serologic tests. Hepatitis E viral infection usually follows a more severe course in pregnancy. Pregnant women are more likely to acquire hepatitis E in the second or third trimester. Also, though it is rare for autoimmune hepatitis to first appear during pregnancy, it too, must be ruled out.

Pregnancy is a prothrombotic state, so you must exclude Budd-Chiari syndrome. Up to 20% of cases of Budd-Chiari syndrome occur in women who are on oral contraceptives or are pregnant or 2 months postpartum.⁵ Right upper quadrant pain, jaundice, and ascites are the common clinical features.

Gallstones are strongly associated with higher parity in women. Pre-pregnancy obesity and high serum leptin levels are strong risk factors for pregnancy-associated gallbladder disease. Gallbladder sludge and stones are common in pregnancy and the postpartum period, and cholecystectomy is frequently done within the first year postpartum.⁶ Serum alkaline phosphatase is less helpful in diagnosing cholecystitis in pregnancy because of elevated levels from the placenta.

With hepatitis, Budd-Chiari syndrome, and gallstones remaining in the differential, what other investigations would you pursue to narrow the differential?

A test for hepatitis A virus immunoglobulin M (IgM) proves negative. Hepatitis B surface antigen is negative, and hepatitis B surface antibody is 11.5 mIU/L, suggesting borderline protective level of antibody. Hepatitis C virus antibody also is negative. Hepatitis E occurs in the Indian subcontinent, Africa, and the Middle East, and is therefore unlikely in this patient. Serologies for cytomegalovirus IgG and Epstein-Barr virus IgM are negative. Herpes simplex type-1 specific IgG antibody is present. These serologic results exclude viral causes of hepatitis.

Antinuclear (ANA) and antimitochondrial antibodies are negative. Antismooth muscle antibody (ASMA) is positive at a titer of 1:20. Quantitative IgG is 7.23 g/L (normal, 5.52-17.24), IgA is 1.36 g/L (0.87-3.94), and IgM is 1.19 g/L (0.44-2.47). Negative ANA, weakly positive ASMA, and normal levels of immunoglobulins in our patient do not support a diagnosis of autoimmune liver disease.

Imaging is the next step for this patient. Even during pregnancy, ultrasound and magnetic resonance imaging are safe and readily available. The diagnostic accuracy of ultrasound for detecting gallstones is 95%. When ultrasound findings are equivocal in a pregnant patient, magnetic resonance cholangiopancreatography provides an accurate evaluation of the biliary system and can substitute for endoscopic retrograde cholangiopancreatography (ERCP).⁷

An ultrasound examination of the patient shows a normal liver with no significant fatty infiltration. The gallbladder, however, is packed with calculi. The common hepatic duct measures 4.6 mm and the common bile duct measures 8.5 mm. The intrahepatic ducts are not dilated. Doppler ultrasound of the hepatic and portal veins demonstrates normal flow without evidence of thromboses. Absence of jaundice, ascites, and hepatic vein thrombosis on ultrasound excludes Budd-Chiari syndrome.

The diagnosis

History of sudden-onset epigastric pain, chills, and nausea in the postpartum period, no history of liver disease, and an uneventful pregnancy makes cholecystitis the most likely diagnosis for the patient.

Gallstones are common in pregnancy and more than 4% of pregnant women have incident gallbladder sludge or stones persisting to the early postpartum. Cholesterol secretion is increased in the second and third trimester of pregnancy, thus increasing the lithogenicity of the bile.⁸

The outcome

We performed a papillotomy and removed 15 pale, almost white-faced stones.ERCP showed several stones in the common bile duct. We performed a papillotomy and removed 15 pale, almost white-faced, stones. Subsequent laparoscopic cholecystectomy removed a large gallbladder with multiple remaining stones. Microscopic examination of the gallbladder wall showed thickened muscularis propria and fibrosis of the subserosa, findings consistent with chronic cholecystitis.

CORRESPONDENCE
H.U. Rehman, MBBS, Clinical Associate Professor, Department of Medicine, Regina General Hospital, 1440 14th Avenue, Regina, SK, S4P 0W5, Canada; [email protected]

CASE › 38-year-old, previously healthy G2 P2 woman arrives at your office with sudden-onset epigastric pain, chills, and nausea, but no vomiting. She has had no fever, shortness of breath, or pruritis. Her appetite is good and her weight is stable. Three days earlier, she gave birth to a healthy baby. The course of pregnancy had been uncomplicated, and delivery was vaginal at 35 weeks gestation without any complications. Her blood pressure (BP) was normal throughout pregnancy, and she had no signs of preeclampsia.

She does not smoke. Although she usually drinks 1 beer daily, she avoided alcohol during her pregnancy. She does not use illicit drugs. She has received no blood transfusions and has no history of viral hepatitis.

On examination she is alert and oriented. She is afebrile and anicteric. Her vital signs are normal with a BP of 116/80 mm Hg and a pulse rate of 86/min. Respiratory rate is 20/min, and oxygen saturation is 98% while breathing ambient air. On palpation, her abdomen is soft and nontender without organomegaly. There is no ascites and bowel sounds are audible.

Initial laboratory investigation yields the following results:
• alkaline phosphatase 436 U/L (normal, 40-135)
• alanine aminotransferase 685 U/L (4-55)
• total bilirubin 27 mcmol/L (2-20)
• serum albumin 25 g/L (35-55)
• international normalized ratio 0.9 (0.9-1.3)
• amylase 47 U/L (20-110)
• hemoglobin 146 g/L (140-180)
• platelets 296 3 109/L (150-400)
• white blood cell count 9.7 3 109/L (4.0-10.0)
• urinalysis reveals no proteins
• transferrin 4.58 g/L (1.32-3.02)
• iron saturation 29% (15-50)
• ferritin 70 mcg/L (10-200)
• serum copper 43.9 mcmol/L (9.0-27.0)
• ceruloplasmin 594 mg/L (200-600)
• Alpha-1-antitrypsin levels 2.05 g/L (1.06-1.58).

What is the differential diagnosis of abnormally elevated liver enzymes in the peripartum period?

Possible underlying causes of the patient’s findings include pregnancy-related liver diseases such as hyperemesis gravidarum (HG), intrahepatic cholestasis of pregnancy, preeclampsia, eclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), and acute fatty liver of pregnancy (AFLP); or liver diseases unrelated to pregnancy such as viral hepatitis, autoimmune liver disease, Wilson’s disease, Budd-Chiari syndrome, cholecystitis, and drug-induced hepatotoxicity.

Narrowing the field. HG usually presents between 4 to 13 weeks of the start of pregnancy and is characterized by severe nausea, vomiting, weight loss, and electrolyte disturbances, none of which are present in this patient. The patient does not have neuropsychiatric symptoms and signs typical of Wilson’s disease, and the high-normal ceruloplasmin level despite above-normal serum copper also weighs against this diagnosis.

Our patient was not taking any hepatotoxic drugs or over-the-counter medications that cause liver damage.

With intrahepatic cholestasis of pregnancy, aminotransferase levels can be as high as 20 times the upper limit of normal. However, with this disorder, elevated serum bile acids during the second half of pregnancy cause pruritis. Absence of pruritis, jaundice, and features of obstructive jaundice, including pale stools and dark urine, makes intrahepatic cholestasis of pregnancy unlikely. Moreover, patients with this disorder do not have constitutional symptoms.¹

Absence of jaundice, ascites, and hepatic vein thrombosis on ultrasound excludes Budd-Chiari syndrome.Preeclampsia is characterized by hypertension and proteinuria after 20 weeks of gestation or within 48 hours of delivery. Absence of seizures differentiates it from eclampsia. Right upper quadrant pain, nausea, and vomiting may be the presenting features. Aminotransferase levels can be up to 10 times the upper limit of normal. Bilirubin concentrations are usually normal. These abnormalities typically resolve within 2 weeks of delivery. Though atypical clinical presentations have been known with preeclampsia—particularly as extremes of maternal childbearing age have been associated with preeclampsia²—the patient’s normal BP and an absence of proteinuria make both preeclampsia and eclampsia unlikely.

HELLP syndrome usually arises in the second or third trimester of pregnancy but also can develop after delivery. Right upper quadrant and epigastric pain, nausea, and vomiting are usual presenting symptoms. Hypertension and proteinuria are found in 85% of cases.³ Absence of hypertension and proteinuria and normal microangiopathic blood smear and platelet count make HELLP syndrome unlikely in the patient.

AFLP usually presents in the third trimester of pregnancy with nausea, abdominal pain, jaundice, and hepatic encephalopathy. Hypoglycemia, lactic acidosis, hyperammonemia, and disseminated intravascular coagulation may complicate the clinical picture. Leukocytosis occurs in 98% of patients.⁴ Elevated concentrations of bilirubin, aminotransferases, and uric acid are commonly found. The biochemical picture in our patient does not match that of AFLP and makes this diagnosis unlikely.

Remaining potential diagnoses. Hepatitis B and C are possibilities and must be excluded by appropriate serologic tests. Hepatitis E viral infection usually follows a more severe course in pregnancy. Pregnant women are more likely to acquire hepatitis E in the second or third trimester. Also, though it is rare for autoimmune hepatitis to first appear during pregnancy, it too, must be ruled out.

Pregnancy is a prothrombotic state, so you must exclude Budd-Chiari syndrome. Up to 20% of cases of Budd-Chiari syndrome occur in women who are on oral contraceptives or are pregnant or 2 months postpartum.⁵ Right upper quadrant pain, jaundice, and ascites are the common clinical features.

Gallstones are strongly associated with higher parity in women. Pre-pregnancy obesity and high serum leptin levels are strong risk factors for pregnancy-associated gallbladder disease. Gallbladder sludge and stones are common in pregnancy and the postpartum period, and cholecystectomy is frequently done within the first year postpartum.⁶ Serum alkaline phosphatase is less helpful in diagnosing cholecystitis in pregnancy because of elevated levels from the placenta.

With hepatitis, Budd-Chiari syndrome, and gallstones remaining in the differential, what other investigations would you pursue to narrow the differential?

A test for hepatitis A virus immunoglobulin M (IgM) proves negative. Hepatitis B surface antigen is negative, and hepatitis B surface antibody is 11.5 mIU/L, suggesting borderline protective level of antibody. Hepatitis C virus antibody also is negative. Hepatitis E occurs in the Indian subcontinent, Africa, and the Middle East, and is therefore unlikely in this patient. Serologies for cytomegalovirus IgG and Epstein-Barr virus IgM are negative. Herpes simplex type-1 specific IgG antibody is present. These serologic results exclude viral causes of hepatitis.

Antinuclear (ANA) and antimitochondrial antibodies are negative. Antismooth muscle antibody (ASMA) is positive at a titer of 1:20. Quantitative IgG is 7.23 g/L (normal, 5.52-17.24), IgA is 1.36 g/L (0.87-3.94), and IgM is 1.19 g/L (0.44-2.47). Negative ANA, weakly positive ASMA, and normal levels of immunoglobulins in our patient do not support a diagnosis of autoimmune liver disease.

Imaging is the next step for this patient. Even during pregnancy, ultrasound and magnetic resonance imaging are safe and readily available. The diagnostic accuracy of ultrasound for detecting gallstones is 95%. When ultrasound findings are equivocal in a pregnant patient, magnetic resonance cholangiopancreatography provides an accurate evaluation of the biliary system and can substitute for endoscopic retrograde cholangiopancreatography (ERCP).⁷

An ultrasound examination of the patient shows a normal liver with no significant fatty infiltration. The gallbladder, however, is packed with calculi. The common hepatic duct measures 4.6 mm and the common bile duct measures 8.5 mm. The intrahepatic ducts are not dilated. Doppler ultrasound of the hepatic and portal veins demonstrates normal flow without evidence of thromboses. Absence of jaundice, ascites, and hepatic vein thrombosis on ultrasound excludes Budd-Chiari syndrome.

The diagnosis

History of sudden-onset epigastric pain, chills, and nausea in the postpartum period, no history of liver disease, and an uneventful pregnancy makes cholecystitis the most likely diagnosis for the patient.

Gallstones are common in pregnancy and more than 4% of pregnant women have incident gallbladder sludge or stones persisting to the early postpartum. Cholesterol secretion is increased in the second and third trimester of pregnancy, thus increasing the lithogenicity of the bile.⁸

The outcome

We performed a papillotomy and removed 15 pale, almost white-faced stones.ERCP showed several stones in the common bile duct. We performed a papillotomy and removed 15 pale, almost white-faced, stones. Subsequent laparoscopic cholecystectomy removed a large gallbladder with multiple remaining stones. Microscopic examination of the gallbladder wall showed thickened muscularis propria and fibrosis of the subserosa, findings consistent with chronic cholecystitis.

CORRESPONDENCE
H.U. Rehman, MBBS, Clinical Associate Professor, Department of Medicine, Regina General Hospital, 1440 14th Avenue, Regina, SK, S4P 0W5, Canada; [email protected]

CASE › 38-year-old, previously healthy G2 P2 woman arrives at your office with sudden-onset epigastric pain, chills, and nausea, but no vomiting. She has had no fever, shortness of breath, or pruritis. Her appetite is good and her weight is stable. Three days earlier, she gave birth to a healthy baby. The course of pregnancy had been uncomplicated, and delivery was vaginal at 35 weeks gestation without any complications. Her blood pressure (BP) was normal throughout pregnancy, and she had no signs of preeclampsia.

She does not smoke. Although she usually drinks 1 beer daily, she avoided alcohol during her pregnancy. She does not use illicit drugs. She has received no blood transfusions and has no history of viral hepatitis.

On examination she is alert and oriented. She is afebrile and anicteric. Her vital signs are normal with a BP of 116/80 mm Hg and a pulse rate of 86/min. Respiratory rate is 20/min, and oxygen saturation is 98% while breathing ambient air. On palpation, her abdomen is soft and nontender without organomegaly. There is no ascites and bowel sounds are audible.

Initial laboratory investigation yields the following results:
• alkaline phosphatase 436 U/L (normal, 40-135)
• alanine aminotransferase 685 U/L (4-55)
• total bilirubin 27 mcmol/L (2-20)
• serum albumin 25 g/L (35-55)
• international normalized ratio 0.9 (0.9-1.3)
• amylase 47 U/L (20-110)
• hemoglobin 146 g/L (140-180)
• platelets 296 3 109/L (150-400)
• white blood cell count 9.7 3 109/L (4.0-10.0)
• urinalysis reveals no proteins
• transferrin 4.58 g/L (1.32-3.02)
• iron saturation 29% (15-50)
• ferritin 70 mcg/L (10-200)
• serum copper 43.9 mcmol/L (9.0-27.0)
• ceruloplasmin 594 mg/L (200-600)
• Alpha-1-antitrypsin levels 2.05 g/L (1.06-1.58).

What is the differential diagnosis of abnormally elevated liver enzymes in the peripartum period?

Possible underlying causes of the patient’s findings include pregnancy-related liver diseases such as hyperemesis gravidarum (HG), intrahepatic cholestasis of pregnancy, preeclampsia, eclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), and acute fatty liver of pregnancy (AFLP); or liver diseases unrelated to pregnancy such as viral hepatitis, autoimmune liver disease, Wilson’s disease, Budd-Chiari syndrome, cholecystitis, and drug-induced hepatotoxicity.

Narrowing the field. HG usually presents between 4 to 13 weeks of the start of pregnancy and is characterized by severe nausea, vomiting, weight loss, and electrolyte disturbances, none of which are present in this patient. The patient does not have neuropsychiatric symptoms and signs typical of Wilson’s disease, and the high-normal ceruloplasmin level despite above-normal serum copper also weighs against this diagnosis.

Our patient was not taking any hepatotoxic drugs or over-the-counter medications that cause liver damage.

With intrahepatic cholestasis of pregnancy, aminotransferase levels can be as high as 20 times the upper limit of normal. However, with this disorder, elevated serum bile acids during the second half of pregnancy cause pruritis. Absence of pruritis, jaundice, and features of obstructive jaundice, including pale stools and dark urine, makes intrahepatic cholestasis of pregnancy unlikely. Moreover, patients with this disorder do not have constitutional symptoms.¹

Absence of jaundice, ascites, and hepatic vein thrombosis on ultrasound excludes Budd-Chiari syndrome.Preeclampsia is characterized by hypertension and proteinuria after 20 weeks of gestation or within 48 hours of delivery. Absence of seizures differentiates it from eclampsia. Right upper quadrant pain, nausea, and vomiting may be the presenting features. Aminotransferase levels can be up to 10 times the upper limit of normal. Bilirubin concentrations are usually normal. These abnormalities typically resolve within 2 weeks of delivery. Though atypical clinical presentations have been known with preeclampsia—particularly as extremes of maternal childbearing age have been associated with preeclampsia²—the patient’s normal BP and an absence of proteinuria make both preeclampsia and eclampsia unlikely.

HELLP syndrome usually arises in the second or third trimester of pregnancy but also can develop after delivery. Right upper quadrant and epigastric pain, nausea, and vomiting are usual presenting symptoms. Hypertension and proteinuria are found in 85% of cases.³ Absence of hypertension and proteinuria and normal microangiopathic blood smear and platelet count make HELLP syndrome unlikely in the patient.

AFLP usually presents in the third trimester of pregnancy with nausea, abdominal pain, jaundice, and hepatic encephalopathy. Hypoglycemia, lactic acidosis, hyperammonemia, and disseminated intravascular coagulation may complicate the clinical picture. Leukocytosis occurs in 98% of patients.⁴ Elevated concentrations of bilirubin, aminotransferases, and uric acid are commonly found. The biochemical picture in our patient does not match that of AFLP and makes this diagnosis unlikely.

Remaining potential diagnoses. Hepatitis B and C are possibilities and must be excluded by appropriate serologic tests. Hepatitis E viral infection usually follows a more severe course in pregnancy. Pregnant women are more likely to acquire hepatitis E in the second or third trimester. Also, though it is rare for autoimmune hepatitis to first appear during pregnancy, it too, must be ruled out.

Pregnancy is a prothrombotic state, so you must exclude Budd-Chiari syndrome. Up to 20% of cases of Budd-Chiari syndrome occur in women who are on oral contraceptives or are pregnant or 2 months postpartum.⁵ Right upper quadrant pain, jaundice, and ascites are the common clinical features.

Gallstones are strongly associated with higher parity in women. Pre-pregnancy obesity and high serum leptin levels are strong risk factors for pregnancy-associated gallbladder disease. Gallbladder sludge and stones are common in pregnancy and the postpartum period, and cholecystectomy is frequently done within the first year postpartum.⁶ Serum alkaline phosphatase is less helpful in diagnosing cholecystitis in pregnancy because of elevated levels from the placenta.

With hepatitis, Budd-Chiari syndrome, and gallstones remaining in the differential, what other investigations would you pursue to narrow the differential?

A test for hepatitis A virus immunoglobulin M (IgM) proves negative. Hepatitis B surface antigen is negative, and hepatitis B surface antibody is 11.5 mIU/L, suggesting borderline protective level of antibody. Hepatitis C virus antibody also is negative. Hepatitis E occurs in the Indian subcontinent, Africa, and the Middle East, and is therefore unlikely in this patient. Serologies for cytomegalovirus IgG and Epstein-Barr virus IgM are negative. Herpes simplex type-1 specific IgG antibody is present. These serologic results exclude viral causes of hepatitis.

Antinuclear (ANA) and antimitochondrial antibodies are negative. Antismooth muscle antibody (ASMA) is positive at a titer of 1:20. Quantitative IgG is 7.23 g/L (normal, 5.52-17.24), IgA is 1.36 g/L (0.87-3.94), and IgM is 1.19 g/L (0.44-2.47). Negative ANA, weakly positive ASMA, and normal levels of immunoglobulins in our patient do not support a diagnosis of autoimmune liver disease.

Imaging is the next step for this patient. Even during pregnancy, ultrasound and magnetic resonance imaging are safe and readily available. The diagnostic accuracy of ultrasound for detecting gallstones is 95%. When ultrasound findings are equivocal in a pregnant patient, magnetic resonance cholangiopancreatography provides an accurate evaluation of the biliary system and can substitute for endoscopic retrograde cholangiopancreatography (ERCP).⁷

An ultrasound examination of the patient shows a normal liver with no significant fatty infiltration. The gallbladder, however, is packed with calculi. The common hepatic duct measures 4.6 mm and the common bile duct measures 8.5 mm. The intrahepatic ducts are not dilated. Doppler ultrasound of the hepatic and portal veins demonstrates normal flow without evidence of thromboses. Absence of jaundice, ascites, and hepatic vein thrombosis on ultrasound excludes Budd-Chiari syndrome.

The diagnosis

History of sudden-onset epigastric pain, chills, and nausea in the postpartum period, no history of liver disease, and an uneventful pregnancy makes cholecystitis the most likely diagnosis for the patient.

Gallstones are common in pregnancy and more than 4% of pregnant women have incident gallbladder sludge or stones persisting to the early postpartum. Cholesterol secretion is increased in the second and third trimester of pregnancy, thus increasing the lithogenicity of the bile.⁸

The outcome

We performed a papillotomy and removed 15 pale, almost white-faced stones.ERCP showed several stones in the common bile duct. We performed a papillotomy and removed 15 pale, almost white-faced, stones. Subsequent laparoscopic cholecystectomy removed a large gallbladder with multiple remaining stones. Microscopic examination of the gallbladder wall showed thickened muscularis propria and fibrosis of the subserosa, findings consistent with chronic cholecystitis.

CORRESPONDENCE
H.U. Rehman, MBBS, Clinical Associate Professor, Department of Medicine, Regina General Hospital, 1440 14th Avenue, Regina, SK, S4P 0W5, Canada; [email protected]

CASE 1 › Steve B is a 43-year-old patient with bipolar disorder and a history of hypertension and high cholesterol. His body mass index (BMI) is 29. During a checkup, he tells you his psychiatrist recently started him on olanzapine. He reports that the medication is working, but he’s concerned about adverse effects, and asks whether he should be monitored for signs of diabetes.

CASE 2 › Mary F, an 83-year-old with Alzheimer’s disease and a history of stable coronary artery disease, is a resident in a long-term care facility, where staff members report that she is increasingly combative. The floor nurse says Ms. F has been striking out at the nurses’ aides who attempt to dress her and asks that you prescribe an antipsychotic to “calm her down.”

If Mr. B and Ms. F were your patients, what would you do?

In 1951, the chance discovery of an anesthetic’s calming properties was the first step in the development of the medications that came to be known as antipsychotics.¹ In recent years, we have seen an expansion in both the number of antipsychotic agents on the market and the scope of their use, for conditions as varied as chronic pain, dementia, nausea and vomiting, and Tourette syndrome.

While antipsychotics often are prescribed by psychiatrists or other specialists, primary care physicians are increasingly likely to be involved in the management of patients who take them—and, at times, to prescribe antipsychotic agents themselves. We developed this guide to increase awareness of safe prescribing practices and principles guiding the initiation and management of antipsychotic agents. We start with a review of the mechanism of action of first- and second-generation antipsychotics (SGAs).

In the last decade, research has called into question whether second-generation antipsychotics really are more effective than first-generation agents

First- and second-generation agents: How they work and differ

Antipsychotics act at the level of the dopaminergic pathways in the central nervous system by blocking the D2 receptors. Action on the mesolimbic pathway is thought to be responsible for their effects on schizophrenia symptoms,² while action at receptor sites in other dopaminergic pathways leads to common adverse effects, primarily the extrapyramidal symptoms (EPS) associated with first-generation antipsychotics (FGAs).

The distinction between first- and second-generation agents relates to SGAs’ blockage of serotonin receptors (thought to better relieve schizophrenia symptoms) and increased specificity for the mesolimbic pathway (which reduces the action on other dopamine pathways and is less likely to produce EPS).³ These differences largely accounted for the belief that SGAs were more effective and provided the rationale for their designation as atypical antipsychotics.

Are SGAs really better?

In the last decade, research has called such claims into question. Trials such as the Clinical Antipsychotic Trials of Intervention Effectiveness4 and Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia study,⁵ as well as a meta-analysis,6 found that SGAs as a class are no more effective than FGAs. That said, 2 SGAs—clozapine and olanzapine—were found to be superior to FGAs for the treatment of schizophrenia. The studies also raised doubts about SGAs’ advantages regarding tolerability, as the time to discontinuation due to intolerable adverse effects was similar for first- and second-generation drugs.^4-6

Approved and off-label indications: A look at the evidence

In addition to schizophrenia, many antipsychotics have US Food and Drug Administration (FDA) approval to treat various psychiatric and nonpsychiatric conditions (TABLE 1).⁷ Several are approved for use in bipolar disorder, 2 are approved as adjunctive treatment of major depressive disorder (MDD), and one is approved for the short-term treatment of generalized anxiety disorder (GAD). Porphyria, tetanus, and intractable hiccups are among the nonpsychiatric conditions for which some antipsychotics are approved.⁷

Antipsychotics' efficacy in controlling dementia-related agitation, aggression, and psychosis has consistently shown a modest but statistically significant benefit.Evidence ranging from anecdotal to randomized controlled trials (RCTs) is steadily emerging about off-label uses of antipsychotics, with risperidone, quetiapine, and olanzapine foremost among them.^8,9 Use of antipsychotics in the treatment of neuropsychiatric symptoms (NPS) of dementia has become particularly widespread, with off-label use of antipsychotics more prevalent in long-term care facilities than in outpatient settings.⁹

NPS. Antipsychotics’ efficacy in controlling dementia-related agitation, aggression, and psychosis has consistently shown a modest but statistically significant benefit. A Cochrane review found evidence that the use of risperidone and olanzapine resulted in improvements in agitation scale scores; risperidone was linked to improved scores on a psychosis scale, as well.¹⁰ A second meta-analysis showed small but statistically significant improvements in NPS with risperidone, olanzapine, and aripiprazole.⁸ Another study showed that nearly half (48%) of patients who had a positive response to risperidone relapsed when they stopped taking the drug.¹¹

A rapidly aging population is expected to further increase the need for pharmacologic interventions to control NPS. Yet safety concerns about the use of antipsychotics in the elderly (more on this in a bit) call this practice into question.

Chronic pain. A 2008 Cochrane review analyzed the efficacy of antipsychotics for acute and chronic pain, pooling results of 11 studies of the treatment of conditions such as postherpetic neuralgia, tension headache, acute myocardial infarction (MI), and terminal cancer. Results from the pooled trials were described as mixed, although an overall statistically significant decrease in pain intensity was found.¹²

Polypharmacy. The simultaneous use of 2 or more antipsychotic agents is also increasingly prevalent,¹³ with levels exceeding 50% in one study of patients with schizophrenia.¹⁴ Because there is little data on the safety and efficacy of antipsychotic polypharmacy, this off-label approach should be considered only as a last resort.¹⁵

Off-label treatment of psychiatric conditions

GAD. In comparative effectiveness trials, quetiapine was found to be equal to both paroxetine and escitalopram for the treatment of GAD, with a favorable effect on symptoms 8 weeks after its initiation.⁸ Trials of other antipsychotics for the treatment of GAD have not demonstrated clear efficacy. Trifluoperazine is approved for GAD, as a short-term treatment.

MDD. Antipsychotics have been shown to be beneficial in the treatment of MDD, although only quetiapine and aripiprazole are approved (and only as adjunctive treatment). Evidence supports the use of both agents, as well as risperidone, as augmentation to selective serotonin reuptake inhibitors (SSRIs), and in pooled results from 5 placebo-controlled trials, quetiapine was found to be effective as monotherapy for MDD.⁹

Obsessive-compulsive disorder (OCD). Compared with placebo, risperidone showed a 4-fold increase in the likelihood of a favorable response (number needed to treat [NNT]=4) in patients with OCD,⁸ but the drug remains off-label for this purpose.

Posttraumatic stress disorder (PTSD). A meta-analysis of 7 studies demonstrated risperidone’s efficacy in the treatment of combat-related PTSD.⁹ In a large Veterans Administration study of patients with combat-related PTSD resistant to treatment with SSRIs, however, risperidone showed no benefit after 6 months of therapy.¹⁶ Antipsychotics have not been found beneficial for substance abuse, eating disorders, or insomnia.⁹

Identifying risk factos, monitoring for adverse effects

While FGAs carry an increased risk of EPS, SGAs increase the risk of obesity, hyperlipidemia, hypertension, and diabetes mellitus. The average life expectancy of patients with schizophrenia is 2 to 3 decades lower than that of age-matched controls,¹⁷ a finding largely attributed to the increased rate of cardiovascular disease. While this can be partly explained by differences in lifestyle and access to care, the metabolic effects of SGAs are a likely contributing factor.

Check a patient's weight before starting him or her on a second-generation antipsychotic and regularly once treatment has begun; an increase in BMI ≥1 point warrants a referral to a nutritionist. Because of the adverse effects of FGAs and SGAs, the American Diabetes Association and American Psychiatric Association jointly issued guidelines addressing both the type and optimal frequency of monitoring for patients on antipsychotics (TABLE 2).^18,19 Following them is critical, as both the initiation of an antipsychotic agent and any change in regimen can lead to the development—or exacerbation—of a number of diseases.

Before initiating antipsychotic therapy—or the first time you see a patient like Mr. B, whose care you will be monitoring—a thorough assessment of risk factors is needed. Foremost among them are overweight or obesity, insulin resistance or diabetes, a history of heart disease, and EPS.

In some cases, preexisting conditions and the potential harm of a specific drug must be weighed in determining which antipsychotic to prescribe. When adverse effects develop after drug therapy has been initiated, decisions about further actions should be based on both the degree of the unfavorable response and the availability of other treatments—and made, as appropriate, in consultation with the specialist who prescribed the drug.

CASE 1 › You tell Mr. B that metabolic side effects like weight gain, impaired glucose tolerance, and increased low-density lipoprotein cholesterol are common with SGAs like the one he is taking, and that you will monitor his fasting glucose levels to evaluate his risk for developing diabetes—starting with this visit. (Olanzapine, the drug he is taking, is 4 times more likely than an FGA to lead to diabetes.¹⁸)

You talk to him, too, about the importance of weight control and note that if his BMI increases by ≥1 point you will refer him to a nutritionist and recommend a structured exercise program. Finally, you schedule an appointment in 3 months.

Risks associated with older age and dementia

In 2010, there were 84,842 visits to US emergency departments (EDs) due to adverse drug events involving antipsychotic agents—a 110% increase since 2005. Nearly 30% of these ED visits involved patients 65 years or older.²⁰

On a regular basis, review your patient's medications for potential drug-drug interactions and assess the efficacy of the antipsychotic he or she is taking.Among patients with dementia, use of antipsychotics has been found to dramatically increase the risk of stroke (rate ratio, 3.26 for FGAs and 5.86 for SGAs).²¹ The risk was greatest in the first 35 days of treatment, but persisted throughout the 175-day study period.

The rate of MI also was elevated in dementia patients (hazard ratio of 2.19 for the first 30 days of treatment, then falling to 1.15 for the first year).²² The risk of pulmonary embolism and deep vein thrombosis also rose for patients who had been on antipsychotics during the previous 24 months (odds ratio=1.32), with the highest risk within the first 90 days of treatment.²³

Risk of death varies with agent and dose. Multiple studies have shown that the mortality risk associated with antipsychotics varies greatly among individual drugs, with haloperidol carrying the highest risk and quetiapine the lowest.^24-26 The hazard ratio for death within the first 30 days was 3.2 for haloperidol, 1.6 for risperidone, and 1.5 for olanzapine; quetiapine had no statistically significant increase. The increased mortality risk was statistically significant only at higher doses.²⁴

The FDA weighs in

Evidence of the elevated risk of death led the FDA to require black-box warnings on SGAs (in 2005)27 and FGAs (in 2008),²⁸ stating that “antipsychotics are not indicated for the treatment of dementia-related psychosis.”²⁸ More recently (in 2012), the American Geriatrics Society (AGS) published a guide on the management of NPS in patients with dementia.²⁹ In it, the AGS acknowledges that despite FDA warnings, antipsychotics may be necessary for the treatment of NPS.

The AGS stresses the importance of nonpharmacologic interventions (eg, positive reinforcement, orientation to time and place, music, light exercise, pet therapy) as a first-line approach. If these measures fail and antipsychotics are necessary, the AGS calls for obtaining informed consent from a family member, using the lowest effective dose, and regularly attempting to wean the patient off the antipsychotic as the standard of care.²⁸

CASE 2 › New or worsening aggressive behavior in an elderly patient with dementia requires a prompt assessment. You start with a complete medical evaluation of Ms. F, ruling out common causes of agitation such as infection, pain, constipation, and an adverse reaction to medication.

You also ask about the incidents of aggression: Does the same aide dress Ms. F daily? Does the aide introduce herself and explain what she’s about to do before attempting to dress the patient?

Next, you recommend nonpharmacologic therapies, such as calming music, participation in group activities, and pet therapy. You tell the floor nurse that if these measures fail and Ms. F’s threatening behavior continues, an antipsychotic may be considered.

Guard against abuse of antipsychotics

As antipsychotic use increases, so, too, does misuse and abuse, particularly of quetiapine. The drug has a reported street value of $3 to $8 for a 25- to 100-mg dose and is known as “quell,” “Susie-Q,” “and “baby heroin”; “Q-ball” is the name used for a combination of cocaine and quetiapine.^30,31

The Drug Abuse Warning Network reported a 115% increase in ED visits related to the misuse or abuse of pharmaceuticals between 2004 and 2010.³² In 2010, 57,199 drug abuse cases—including 28,618 suicide attempts—were linked to antipsychotics.²⁰

To optimize the benefit of antipsychotics and minimize the likelihood of abuse, ensure that every patient taking them has a clearly documented indication for an antipsychotic and a single responsible prescriber of the antipsychotic, often a psychiatrist. Your responsibilities: Schedule visits for monitoring, do a medication review to identify potential drug-drug interactions, and assess efficacy, all on a regular basis.

CASE 1 › At Mr. B’s next visit, you retest his fasting glucose (which is now 105 mg/dL) and recheck his BMI, which has climbed to 30. You tell him you will speak with his psychiatrist about his weight gain and your concern about the development of insulin resistance.

To minimize the likelihood of abuse, ensure that every patient taking an antipsychotic has a single responsible prescriber. Meanwhile, you refer the patient to a nutritionist and encourage a healthy lifestyle. Because the medication has been effective, you schedule a follow-up visit in 6 weeks to see if the lifestyle interventions have been successful before consulting with the patient’s psychiatrist about a change in medication.

CASE 2 › When you return to the long-term care facility one week later, you find that Ms. F’s NPS have not abated. You realize an antipsychotic agent may be needed. Because she has a history of heart disease, however, she has a higher risk for cardiovascular events.

You meet with her son to review the benefits and risks of antipsychotic therapy, explaining that risperidone is a reasonable agent and that a low starting dose (0.25-0.5 mg) will reduce the risk. You obtain his informed consent, document your treatment goals—a decrease in threatening behavior and the ability of the staff to work with Ms. F to get her up and out of bed—and establish a plan to review in 2 weeks.

CORRESPONDENCE
Daniel DeJoseph, MD, Drexel Family Medicine, 3401 Market Street, Suite 105-B, Philadelphia, PA 19104; [email protected]

CASE 1 › Steve B is a 43-year-old patient with bipolar disorder and a history of hypertension and high cholesterol. His body mass index (BMI) is 29. During a checkup, he tells you his psychiatrist recently started him on olanzapine. He reports that the medication is working, but he’s concerned about adverse effects, and asks whether he should be monitored for signs of diabetes.

CASE 2 › Mary F, an 83-year-old with Alzheimer’s disease and a history of stable coronary artery disease, is a resident in a long-term care facility, where staff members report that she is increasingly combative. The floor nurse says Ms. F has been striking out at the nurses’ aides who attempt to dress her and asks that you prescribe an antipsychotic to “calm her down.”

If Mr. B and Ms. F were your patients, what would you do?

In 1951, the chance discovery of an anesthetic’s calming properties was the first step in the development of the medications that came to be known as antipsychotics.¹ In recent years, we have seen an expansion in both the number of antipsychotic agents on the market and the scope of their use, for conditions as varied as chronic pain, dementia, nausea and vomiting, and Tourette syndrome.

While antipsychotics often are prescribed by psychiatrists or other specialists, primary care physicians are increasingly likely to be involved in the management of patients who take them—and, at times, to prescribe antipsychotic agents themselves. We developed this guide to increase awareness of safe prescribing practices and principles guiding the initiation and management of antipsychotic agents. We start with a review of the mechanism of action of first- and second-generation antipsychotics (SGAs).

In the last decade, research has called into question whether second-generation antipsychotics really are more effective than first-generation agents

First- and second-generation agents: How they work and differ

Antipsychotics act at the level of the dopaminergic pathways in the central nervous system by blocking the D2 receptors. Action on the mesolimbic pathway is thought to be responsible for their effects on schizophrenia symptoms,² while action at receptor sites in other dopaminergic pathways leads to common adverse effects, primarily the extrapyramidal symptoms (EPS) associated with first-generation antipsychotics (FGAs).

The distinction between first- and second-generation agents relates to SGAs’ blockage of serotonin receptors (thought to better relieve schizophrenia symptoms) and increased specificity for the mesolimbic pathway (which reduces the action on other dopamine pathways and is less likely to produce EPS).³ These differences largely accounted for the belief that SGAs were more effective and provided the rationale for their designation as atypical antipsychotics.

Are SGAs really better?

In the last decade, research has called such claims into question. Trials such as the Clinical Antipsychotic Trials of Intervention Effectiveness4 and Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia study,⁵ as well as a meta-analysis,6 found that SGAs as a class are no more effective than FGAs. That said, 2 SGAs—clozapine and olanzapine—were found to be superior to FGAs for the treatment of schizophrenia. The studies also raised doubts about SGAs’ advantages regarding tolerability, as the time to discontinuation due to intolerable adverse effects was similar for first- and second-generation drugs.^4-6

Approved and off-label indications: A look at the evidence

In addition to schizophrenia, many antipsychotics have US Food and Drug Administration (FDA) approval to treat various psychiatric and nonpsychiatric conditions (TABLE 1).⁷ Several are approved for use in bipolar disorder, 2 are approved as adjunctive treatment of major depressive disorder (MDD), and one is approved for the short-term treatment of generalized anxiety disorder (GAD). Porphyria, tetanus, and intractable hiccups are among the nonpsychiatric conditions for which some antipsychotics are approved.⁷

Antipsychotics' efficacy in controlling dementia-related agitation, aggression, and psychosis has consistently shown a modest but statistically significant benefit.Evidence ranging from anecdotal to randomized controlled trials (RCTs) is steadily emerging about off-label uses of antipsychotics, with risperidone, quetiapine, and olanzapine foremost among them.^8,9 Use of antipsychotics in the treatment of neuropsychiatric symptoms (NPS) of dementia has become particularly widespread, with off-label use of antipsychotics more prevalent in long-term care facilities than in outpatient settings.⁹

NPS. Antipsychotics’ efficacy in controlling dementia-related agitation, aggression, and psychosis has consistently shown a modest but statistically significant benefit. A Cochrane review found evidence that the use of risperidone and olanzapine resulted in improvements in agitation scale scores; risperidone was linked to improved scores on a psychosis scale, as well.¹⁰ A second meta-analysis showed small but statistically significant improvements in NPS with risperidone, olanzapine, and aripiprazole.⁸ Another study showed that nearly half (48%) of patients who had a positive response to risperidone relapsed when they stopped taking the drug.¹¹

A rapidly aging population is expected to further increase the need for pharmacologic interventions to control NPS. Yet safety concerns about the use of antipsychotics in the elderly (more on this in a bit) call this practice into question.

Chronic pain. A 2008 Cochrane review analyzed the efficacy of antipsychotics for acute and chronic pain, pooling results of 11 studies of the treatment of conditions such as postherpetic neuralgia, tension headache, acute myocardial infarction (MI), and terminal cancer. Results from the pooled trials were described as mixed, although an overall statistically significant decrease in pain intensity was found.¹²

Polypharmacy. The simultaneous use of 2 or more antipsychotic agents is also increasingly prevalent,¹³ with levels exceeding 50% in one study of patients with schizophrenia.¹⁴ Because there is little data on the safety and efficacy of antipsychotic polypharmacy, this off-label approach should be considered only as a last resort.¹⁵

Off-label treatment of psychiatric conditions

GAD. In comparative effectiveness trials, quetiapine was found to be equal to both paroxetine and escitalopram for the treatment of GAD, with a favorable effect on symptoms 8 weeks after its initiation.⁸ Trials of other antipsychotics for the treatment of GAD have not demonstrated clear efficacy. Trifluoperazine is approved for GAD, as a short-term treatment.

MDD. Antipsychotics have been shown to be beneficial in the treatment of MDD, although only quetiapine and aripiprazole are approved (and only as adjunctive treatment). Evidence supports the use of both agents, as well as risperidone, as augmentation to selective serotonin reuptake inhibitors (SSRIs), and in pooled results from 5 placebo-controlled trials, quetiapine was found to be effective as monotherapy for MDD.⁹

Obsessive-compulsive disorder (OCD). Compared with placebo, risperidone showed a 4-fold increase in the likelihood of a favorable response (number needed to treat [NNT]=4) in patients with OCD,⁸ but the drug remains off-label for this purpose.

Posttraumatic stress disorder (PTSD). A meta-analysis of 7 studies demonstrated risperidone’s efficacy in the treatment of combat-related PTSD.⁹ In a large Veterans Administration study of patients with combat-related PTSD resistant to treatment with SSRIs, however, risperidone showed no benefit after 6 months of therapy.¹⁶ Antipsychotics have not been found beneficial for substance abuse, eating disorders, or insomnia.⁹

Identifying risk factos, monitoring for adverse effects

While FGAs carry an increased risk of EPS, SGAs increase the risk of obesity, hyperlipidemia, hypertension, and diabetes mellitus. The average life expectancy of patients with schizophrenia is 2 to 3 decades lower than that of age-matched controls,¹⁷ a finding largely attributed to the increased rate of cardiovascular disease. While this can be partly explained by differences in lifestyle and access to care, the metabolic effects of SGAs are a likely contributing factor.

Check a patient's weight before starting him or her on a second-generation antipsychotic and regularly once treatment has begun; an increase in BMI ≥1 point warrants a referral to a nutritionist. Because of the adverse effects of FGAs and SGAs, the American Diabetes Association and American Psychiatric Association jointly issued guidelines addressing both the type and optimal frequency of monitoring for patients on antipsychotics (TABLE 2).^18,19 Following them is critical, as both the initiation of an antipsychotic agent and any change in regimen can lead to the development—or exacerbation—of a number of diseases.

Before initiating antipsychotic therapy—or the first time you see a patient like Mr. B, whose care you will be monitoring—a thorough assessment of risk factors is needed. Foremost among them are overweight or obesity, insulin resistance or diabetes, a history of heart disease, and EPS.

In some cases, preexisting conditions and the potential harm of a specific drug must be weighed in determining which antipsychotic to prescribe. When adverse effects develop after drug therapy has been initiated, decisions about further actions should be based on both the degree of the unfavorable response and the availability of other treatments—and made, as appropriate, in consultation with the specialist who prescribed the drug.

CASE 1 › You tell Mr. B that metabolic side effects like weight gain, impaired glucose tolerance, and increased low-density lipoprotein cholesterol are common with SGAs like the one he is taking, and that you will monitor his fasting glucose levels to evaluate his risk for developing diabetes—starting with this visit. (Olanzapine, the drug he is taking, is 4 times more likely than an FGA to lead to diabetes.¹⁸)

You talk to him, too, about the importance of weight control and note that if his BMI increases by ≥1 point you will refer him to a nutritionist and recommend a structured exercise program. Finally, you schedule an appointment in 3 months.

Risks associated with older age and dementia

In 2010, there were 84,842 visits to US emergency departments (EDs) due to adverse drug events involving antipsychotic agents—a 110% increase since 2005. Nearly 30% of these ED visits involved patients 65 years or older.²⁰

On a regular basis, review your patient's medications for potential drug-drug interactions and assess the efficacy of the antipsychotic he or she is taking.Among patients with dementia, use of antipsychotics has been found to dramatically increase the risk of stroke (rate ratio, 3.26 for FGAs and 5.86 for SGAs).²¹ The risk was greatest in the first 35 days of treatment, but persisted throughout the 175-day study period.

The rate of MI also was elevated in dementia patients (hazard ratio of 2.19 for the first 30 days of treatment, then falling to 1.15 for the first year).²² The risk of pulmonary embolism and deep vein thrombosis also rose for patients who had been on antipsychotics during the previous 24 months (odds ratio=1.32), with the highest risk within the first 90 days of treatment.²³

Risk of death varies with agent and dose. Multiple studies have shown that the mortality risk associated with antipsychotics varies greatly among individual drugs, with haloperidol carrying the highest risk and quetiapine the lowest.^24-26 The hazard ratio for death within the first 30 days was 3.2 for haloperidol, 1.6 for risperidone, and 1.5 for olanzapine; quetiapine had no statistically significant increase. The increased mortality risk was statistically significant only at higher doses.²⁴

The FDA weighs in

Evidence of the elevated risk of death led the FDA to require black-box warnings on SGAs (in 2005)27 and FGAs (in 2008),²⁸ stating that “antipsychotics are not indicated for the treatment of dementia-related psychosis.”²⁸ More recently (in 2012), the American Geriatrics Society (AGS) published a guide on the management of NPS in patients with dementia.²⁹ In it, the AGS acknowledges that despite FDA warnings, antipsychotics may be necessary for the treatment of NPS.

The AGS stresses the importance of nonpharmacologic interventions (eg, positive reinforcement, orientation to time and place, music, light exercise, pet therapy) as a first-line approach. If these measures fail and antipsychotics are necessary, the AGS calls for obtaining informed consent from a family member, using the lowest effective dose, and regularly attempting to wean the patient off the antipsychotic as the standard of care.²⁸

CASE 2 › New or worsening aggressive behavior in an elderly patient with dementia requires a prompt assessment. You start with a complete medical evaluation of Ms. F, ruling out common causes of agitation such as infection, pain, constipation, and an adverse reaction to medication.

You also ask about the incidents of aggression: Does the same aide dress Ms. F daily? Does the aide introduce herself and explain what she’s about to do before attempting to dress the patient?

Next, you recommend nonpharmacologic therapies, such as calming music, participation in group activities, and pet therapy. You tell the floor nurse that if these measures fail and Ms. F’s threatening behavior continues, an antipsychotic may be considered.

Guard against abuse of antipsychotics

As antipsychotic use increases, so, too, does misuse and abuse, particularly of quetiapine. The drug has a reported street value of $3 to $8 for a 25- to 100-mg dose and is known as “quell,” “Susie-Q,” “and “baby heroin”; “Q-ball” is the name used for a combination of cocaine and quetiapine.^30,31

The Drug Abuse Warning Network reported a 115% increase in ED visits related to the misuse or abuse of pharmaceuticals between 2004 and 2010.³² In 2010, 57,199 drug abuse cases—including 28,618 suicide attempts—were linked to antipsychotics.²⁰

To optimize the benefit of antipsychotics and minimize the likelihood of abuse, ensure that every patient taking them has a clearly documented indication for an antipsychotic and a single responsible prescriber of the antipsychotic, often a psychiatrist. Your responsibilities: Schedule visits for monitoring, do a medication review to identify potential drug-drug interactions, and assess efficacy, all on a regular basis.

CASE 1 › At Mr. B’s next visit, you retest his fasting glucose (which is now 105 mg/dL) and recheck his BMI, which has climbed to 30. You tell him you will speak with his psychiatrist about his weight gain and your concern about the development of insulin resistance.

To minimize the likelihood of abuse, ensure that every patient taking an antipsychotic has a single responsible prescriber. Meanwhile, you refer the patient to a nutritionist and encourage a healthy lifestyle. Because the medication has been effective, you schedule a follow-up visit in 6 weeks to see if the lifestyle interventions have been successful before consulting with the patient’s psychiatrist about a change in medication.

CASE 2 › When you return to the long-term care facility one week later, you find that Ms. F’s NPS have not abated. You realize an antipsychotic agent may be needed. Because she has a history of heart disease, however, she has a higher risk for cardiovascular events.

You meet with her son to review the benefits and risks of antipsychotic therapy, explaining that risperidone is a reasonable agent and that a low starting dose (0.25-0.5 mg) will reduce the risk. You obtain his informed consent, document your treatment goals—a decrease in threatening behavior and the ability of the staff to work with Ms. F to get her up and out of bed—and establish a plan to review in 2 weeks.

CORRESPONDENCE
Daniel DeJoseph, MD, Drexel Family Medicine, 3401 Market Street, Suite 105-B, Philadelphia, PA 19104; [email protected]

CASE 1 › Steve B is a 43-year-old patient with bipolar disorder and a history of hypertension and high cholesterol. His body mass index (BMI) is 29. During a checkup, he tells you his psychiatrist recently started him on olanzapine. He reports that the medication is working, but he’s concerned about adverse effects, and asks whether he should be monitored for signs of diabetes.

CASE 2 › Mary F, an 83-year-old with Alzheimer’s disease and a history of stable coronary artery disease, is a resident in a long-term care facility, where staff members report that she is increasingly combative. The floor nurse says Ms. F has been striking out at the nurses’ aides who attempt to dress her and asks that you prescribe an antipsychotic to “calm her down.”

If Mr. B and Ms. F were your patients, what would you do?

In 1951, the chance discovery of an anesthetic’s calming properties was the first step in the development of the medications that came to be known as antipsychotics.¹ In recent years, we have seen an expansion in both the number of antipsychotic agents on the market and the scope of their use, for conditions as varied as chronic pain, dementia, nausea and vomiting, and Tourette syndrome.

While antipsychotics often are prescribed by psychiatrists or other specialists, primary care physicians are increasingly likely to be involved in the management of patients who take them—and, at times, to prescribe antipsychotic agents themselves. We developed this guide to increase awareness of safe prescribing practices and principles guiding the initiation and management of antipsychotic agents. We start with a review of the mechanism of action of first- and second-generation antipsychotics (SGAs).

In the last decade, research has called into question whether second-generation antipsychotics really are more effective than first-generation agents

First- and second-generation agents: How they work and differ

Antipsychotics act at the level of the dopaminergic pathways in the central nervous system by blocking the D2 receptors. Action on the mesolimbic pathway is thought to be responsible for their effects on schizophrenia symptoms,² while action at receptor sites in other dopaminergic pathways leads to common adverse effects, primarily the extrapyramidal symptoms (EPS) associated with first-generation antipsychotics (FGAs).

The distinction between first- and second-generation agents relates to SGAs’ blockage of serotonin receptors (thought to better relieve schizophrenia symptoms) and increased specificity for the mesolimbic pathway (which reduces the action on other dopamine pathways and is less likely to produce EPS).³ These differences largely accounted for the belief that SGAs were more effective and provided the rationale for their designation as atypical antipsychotics.

Are SGAs really better?

In the last decade, research has called such claims into question. Trials such as the Clinical Antipsychotic Trials of Intervention Effectiveness4 and Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia study,⁵ as well as a meta-analysis,6 found that SGAs as a class are no more effective than FGAs. That said, 2 SGAs—clozapine and olanzapine—were found to be superior to FGAs for the treatment of schizophrenia. The studies also raised doubts about SGAs’ advantages regarding tolerability, as the time to discontinuation due to intolerable adverse effects was similar for first- and second-generation drugs.^4-6

Approved and off-label indications: A look at the evidence

In addition to schizophrenia, many antipsychotics have US Food and Drug Administration (FDA) approval to treat various psychiatric and nonpsychiatric conditions (TABLE 1).⁷ Several are approved for use in bipolar disorder, 2 are approved as adjunctive treatment of major depressive disorder (MDD), and one is approved for the short-term treatment of generalized anxiety disorder (GAD). Porphyria, tetanus, and intractable hiccups are among the nonpsychiatric conditions for which some antipsychotics are approved.⁷

Antipsychotics' efficacy in controlling dementia-related agitation, aggression, and psychosis has consistently shown a modest but statistically significant benefit.Evidence ranging from anecdotal to randomized controlled trials (RCTs) is steadily emerging about off-label uses of antipsychotics, with risperidone, quetiapine, and olanzapine foremost among them.^8,9 Use of antipsychotics in the treatment of neuropsychiatric symptoms (NPS) of dementia has become particularly widespread, with off-label use of antipsychotics more prevalent in long-term care facilities than in outpatient settings.⁹

NPS. Antipsychotics’ efficacy in controlling dementia-related agitation, aggression, and psychosis has consistently shown a modest but statistically significant benefit. A Cochrane review found evidence that the use of risperidone and olanzapine resulted in improvements in agitation scale scores; risperidone was linked to improved scores on a psychosis scale, as well.¹⁰ A second meta-analysis showed small but statistically significant improvements in NPS with risperidone, olanzapine, and aripiprazole.⁸ Another study showed that nearly half (48%) of patients who had a positive response to risperidone relapsed when they stopped taking the drug.¹¹

A rapidly aging population is expected to further increase the need for pharmacologic interventions to control NPS. Yet safety concerns about the use of antipsychotics in the elderly (more on this in a bit) call this practice into question.

Chronic pain. A 2008 Cochrane review analyzed the efficacy of antipsychotics for acute and chronic pain, pooling results of 11 studies of the treatment of conditions such as postherpetic neuralgia, tension headache, acute myocardial infarction (MI), and terminal cancer. Results from the pooled trials were described as mixed, although an overall statistically significant decrease in pain intensity was found.¹²

Polypharmacy. The simultaneous use of 2 or more antipsychotic agents is also increasingly prevalent,¹³ with levels exceeding 50% in one study of patients with schizophrenia.¹⁴ Because there is little data on the safety and efficacy of antipsychotic polypharmacy, this off-label approach should be considered only as a last resort.¹⁵

Off-label treatment of psychiatric conditions

GAD. In comparative effectiveness trials, quetiapine was found to be equal to both paroxetine and escitalopram for the treatment of GAD, with a favorable effect on symptoms 8 weeks after its initiation.⁸ Trials of other antipsychotics for the treatment of GAD have not demonstrated clear efficacy. Trifluoperazine is approved for GAD, as a short-term treatment.

MDD. Antipsychotics have been shown to be beneficial in the treatment of MDD, although only quetiapine and aripiprazole are approved (and only as adjunctive treatment). Evidence supports the use of both agents, as well as risperidone, as augmentation to selective serotonin reuptake inhibitors (SSRIs), and in pooled results from 5 placebo-controlled trials, quetiapine was found to be effective as monotherapy for MDD.⁹

Obsessive-compulsive disorder (OCD). Compared with placebo, risperidone showed a 4-fold increase in the likelihood of a favorable response (number needed to treat [NNT]=4) in patients with OCD,⁸ but the drug remains off-label for this purpose.

Posttraumatic stress disorder (PTSD). A meta-analysis of 7 studies demonstrated risperidone’s efficacy in the treatment of combat-related PTSD.⁹ In a large Veterans Administration study of patients with combat-related PTSD resistant to treatment with SSRIs, however, risperidone showed no benefit after 6 months of therapy.¹⁶ Antipsychotics have not been found beneficial for substance abuse, eating disorders, or insomnia.⁹

Identifying risk factos, monitoring for adverse effects

While FGAs carry an increased risk of EPS, SGAs increase the risk of obesity, hyperlipidemia, hypertension, and diabetes mellitus. The average life expectancy of patients with schizophrenia is 2 to 3 decades lower than that of age-matched controls,¹⁷ a finding largely attributed to the increased rate of cardiovascular disease. While this can be partly explained by differences in lifestyle and access to care, the metabolic effects of SGAs are a likely contributing factor.

Check a patient's weight before starting him or her on a second-generation antipsychotic and regularly once treatment has begun; an increase in BMI ≥1 point warrants a referral to a nutritionist. Because of the adverse effects of FGAs and SGAs, the American Diabetes Association and American Psychiatric Association jointly issued guidelines addressing both the type and optimal frequency of monitoring for patients on antipsychotics (TABLE 2).^18,19 Following them is critical, as both the initiation of an antipsychotic agent and any change in regimen can lead to the development—or exacerbation—of a number of diseases.

Before initiating antipsychotic therapy—or the first time you see a patient like Mr. B, whose care you will be monitoring—a thorough assessment of risk factors is needed. Foremost among them are overweight or obesity, insulin resistance or diabetes, a history of heart disease, and EPS.

In some cases, preexisting conditions and the potential harm of a specific drug must be weighed in determining which antipsychotic to prescribe. When adverse effects develop after drug therapy has been initiated, decisions about further actions should be based on both the degree of the unfavorable response and the availability of other treatments—and made, as appropriate, in consultation with the specialist who prescribed the drug.

CASE 1 › You tell Mr. B that metabolic side effects like weight gain, impaired glucose tolerance, and increased low-density lipoprotein cholesterol are common with SGAs like the one he is taking, and that you will monitor his fasting glucose levels to evaluate his risk for developing diabetes—starting with this visit. (Olanzapine, the drug he is taking, is 4 times more likely than an FGA to lead to diabetes.¹⁸)

You talk to him, too, about the importance of weight control and note that if his BMI increases by ≥1 point you will refer him to a nutritionist and recommend a structured exercise program. Finally, you schedule an appointment in 3 months.

Risks associated with older age and dementia

In 2010, there were 84,842 visits to US emergency departments (EDs) due to adverse drug events involving antipsychotic agents—a 110% increase since 2005. Nearly 30% of these ED visits involved patients 65 years or older.²⁰

On a regular basis, review your patient's medications for potential drug-drug interactions and assess the efficacy of the antipsychotic he or she is taking.Among patients with dementia, use of antipsychotics has been found to dramatically increase the risk of stroke (rate ratio, 3.26 for FGAs and 5.86 for SGAs).²¹ The risk was greatest in the first 35 days of treatment, but persisted throughout the 175-day study period.

The rate of MI also was elevated in dementia patients (hazard ratio of 2.19 for the first 30 days of treatment, then falling to 1.15 for the first year).²² The risk of pulmonary embolism and deep vein thrombosis also rose for patients who had been on antipsychotics during the previous 24 months (odds ratio=1.32), with the highest risk within the first 90 days of treatment.²³

Risk of death varies with agent and dose. Multiple studies have shown that the mortality risk associated with antipsychotics varies greatly among individual drugs, with haloperidol carrying the highest risk and quetiapine the lowest.^24-26 The hazard ratio for death within the first 30 days was 3.2 for haloperidol, 1.6 for risperidone, and 1.5 for olanzapine; quetiapine had no statistically significant increase. The increased mortality risk was statistically significant only at higher doses.²⁴

The FDA weighs in

Evidence of the elevated risk of death led the FDA to require black-box warnings on SGAs (in 2005)27 and FGAs (in 2008),²⁸ stating that “antipsychotics are not indicated for the treatment of dementia-related psychosis.”²⁸ More recently (in 2012), the American Geriatrics Society (AGS) published a guide on the management of NPS in patients with dementia.²⁹ In it, the AGS acknowledges that despite FDA warnings, antipsychotics may be necessary for the treatment of NPS.

The AGS stresses the importance of nonpharmacologic interventions (eg, positive reinforcement, orientation to time and place, music, light exercise, pet therapy) as a first-line approach. If these measures fail and antipsychotics are necessary, the AGS calls for obtaining informed consent from a family member, using the lowest effective dose, and regularly attempting to wean the patient off the antipsychotic as the standard of care.²⁸

CASE 2 › New or worsening aggressive behavior in an elderly patient with dementia requires a prompt assessment. You start with a complete medical evaluation of Ms. F, ruling out common causes of agitation such as infection, pain, constipation, and an adverse reaction to medication.

You also ask about the incidents of aggression: Does the same aide dress Ms. F daily? Does the aide introduce herself and explain what she’s about to do before attempting to dress the patient?

Next, you recommend nonpharmacologic therapies, such as calming music, participation in group activities, and pet therapy. You tell the floor nurse that if these measures fail and Ms. F’s threatening behavior continues, an antipsychotic may be considered.

Guard against abuse of antipsychotics

As antipsychotic use increases, so, too, does misuse and abuse, particularly of quetiapine. The drug has a reported street value of $3 to $8 for a 25- to 100-mg dose and is known as “quell,” “Susie-Q,” “and “baby heroin”; “Q-ball” is the name used for a combination of cocaine and quetiapine.^30,31

The Drug Abuse Warning Network reported a 115% increase in ED visits related to the misuse or abuse of pharmaceuticals between 2004 and 2010.³² In 2010, 57,199 drug abuse cases—including 28,618 suicide attempts—were linked to antipsychotics.²⁰

To optimize the benefit of antipsychotics and minimize the likelihood of abuse, ensure that every patient taking them has a clearly documented indication for an antipsychotic and a single responsible prescriber of the antipsychotic, often a psychiatrist. Your responsibilities: Schedule visits for monitoring, do a medication review to identify potential drug-drug interactions, and assess efficacy, all on a regular basis.

CASE 1 › At Mr. B’s next visit, you retest his fasting glucose (which is now 105 mg/dL) and recheck his BMI, which has climbed to 30. You tell him you will speak with his psychiatrist about his weight gain and your concern about the development of insulin resistance.

To minimize the likelihood of abuse, ensure that every patient taking an antipsychotic has a single responsible prescriber. Meanwhile, you refer the patient to a nutritionist and encourage a healthy lifestyle. Because the medication has been effective, you schedule a follow-up visit in 6 weeks to see if the lifestyle interventions have been successful before consulting with the patient’s psychiatrist about a change in medication.

CASE 2 › When you return to the long-term care facility one week later, you find that Ms. F’s NPS have not abated. You realize an antipsychotic agent may be needed. Because she has a history of heart disease, however, she has a higher risk for cardiovascular events.

You meet with her son to review the benefits and risks of antipsychotic therapy, explaining that risperidone is a reasonable agent and that a low starting dose (0.25-0.5 mg) will reduce the risk. You obtain his informed consent, document your treatment goals—a decrease in threatening behavior and the ability of the staff to work with Ms. F to get her up and out of bed—and establish a plan to review in 2 weeks.

CORRESPONDENCE
Daniel DeJoseph, MD, Drexel Family Medicine, 3401 Market Street, Suite 105-B, Philadelphia, PA 19104; [email protected]

Childhood hypertension is on the rise: Recent data from the National Health and Nutrition Survey suggest 10% of children and adolescents have prehypertension and 4% have hypertension.^1-4 Unfortunately, the condition often is missed. In a study of 14,187 children and adolescents who had at least 3 well-child visits at an outpatient academic medical center, 507 patients met the criteria for hypertension, yet only 131 (26%) had this diagnosis documented in their electronic health record.⁵

In a survey of 89 pediatricians, >50% of respondents said they were not familiar with the most current published recommendations for diagnosing and treating pediatric hypertension.⁶ Respondents also indicated that the most common reason for not initiating pharmacotherapy for children with hypertension was a lack of familiarity with appropriate antihypertensive agents (54%), followed by concern for adverse medication effects. Delayed diagnosis, evaluation, and treatment of hypertension in young patients can increase the likelihood of serious consequences, including target-organ damage such as left ventricular hypertrophy (LVH). In this review, we’ll describe the factors that put children and adolescents at risk for hypertension, and offer an evidence-based approach to diagnosis and treatment.

Obesity is a key risk factor

An estimated 17% of children aged 2 to 19 are obese.⁷ Obesity increases a child’s risk for hypertension by approximately 3- to 5-fold, and body mass index (BMI) is greater in children with primary hypertension compared with those with secondary hypertension.⁸ Hypertension is more common among Hispanic and non-Hispanic black male children and adolescents compared with their white counterparts; these ethnic disparities are not found in females.^9,10 Poor diets and physical inactivity further contribute to obesity and hypertension risk. Children who were born preterm or had a very low birth weight also are at increased risk.¹¹

Unchecked hypertension can lead to cardiac, vascular damage

Some children and adolescents with undiagnosed and untreated hypertension have evidence of target-organ damage, including cardiac dysfunction and pathologic vascular abnormalities. LVH is present in 20% to 41% of children and adolescents with hypertension.^12,13 Carotid intima-media thickness, an established surrogate marker for atherosclerosis, is abnormally increased in children with hypertension, even after adjusting for BMI.¹⁴ Other target organ effects include impaired cognitive function, reduced glomerular filtration rate, microalbuminuria, and retinal arteriolar narrowing.^15-17

Normal BP standards for children and adolescents are based on gender, age, and height percentile.Pediatric hypertension may persist into adulthood. A meta-analysis of more than 50 studies found that elevated blood pressure (BP) in childhood increases the risk for hypertension as an adult.¹⁸

NHLBI recommendations call for a BP check at every visit

The National Heart, Lung, and Blood Institute (NHLBI) Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents (“the 4th Report”) recommends measuring BP in all children over age 3 during every health care visit.¹² Children under age 3 should have their BP checked in certain circumstances, including preterm delivery, congenital heart disease, recurrent urinary tract infections, renal/urologic disease, organ transplantation, malignancy, and systemic illnesses associated with hypertension.¹² The 4th Report is endorsed by the American Academy of Pediatrics (AAP); however, the American Academy of Family Physicians and the US Preventive Services Task Force have concluded that the evidence is insufficient to recommend for or against routine screening for hypertension in children and adolescents to reduce the risk of cardiovascular disease (CVD).^19,20

Does the child have hypertension? That depends on several factors

Determining whether a child has hypertension requires that you consult national BP standards to determine if he or she is within the normal range. Normal BP standards for children and adolescents are based on gender, age, and height percentile, and provide a precise classification based on body size.¹² These tables are available from the NHLBI Web site at http://www.nhlbi.nih.gov/guidelines/hypertension/child_tbl.htm. Height percentiles in these tables correspond with the Centers for Disease Control and Prevention (CDC) growth charts published in 2000.²¹ The Baylor College of Medicine Children’s Nutrition Research Center has a web-based calculator to help physicians determine BP percentiles in children and adolescents; it is available at http://www.bcm.edu/bodycomplab/Flashapps/BPVAgeChartpage.html. The International Pediatric Hypertension Association also offers BP charts and calculators at http://www.iphapediatrichypertension.org.

The diagnostic parameters for pediatric hypertension are listed in TABLE 1.¹² The higher systolic or diastolic BP percentile value is used to determine a child’s overall BP category. A child is considered normotensive if the BP is <90th percentile. Hypertension is an average systolic or diastolic BP that is ≥95th percentile on at least 3 separate occasions. Stage 1 hypertension is BP levels ranging from the 95th percentile to 5 mm Hg above the 99th percentile, and stage 2 hypertension is BP levels greater than 5 mm Hg above the 99th percentile.

For example, assume you are evaluating a 12-year-old boy who is 61 inches tall and has a BP of 129/87 mm Hg. According to the CDC growth charts, his height puts him in the 75th percentile for his age. Using the NHLBI chart, you determine that he falls in the 95th-99th percentile for BP, and thus, using the categories in TABLE 1, is given a diagnosis of Stage 1 hypertension.

Accurate BP measurement requires using an appropriate cuff size that covers 80% of the child’s upper arm. When the child is between cuff sizes, use the larger cuff because small cuffs overestimate BP readings. BP readings should be taken on the right arm with the arm supported at heart level after the child has been sitting quietly for at least 5 minutes.¹² One study showed that the initial BP readings taken in the triage area were significantly higher—often by >10 mm Hg—compared with follow-up measurements in the examination room.²²

The preferred method of BP measurement is auscultation; however, oscillometric devices also are acceptable. These devices are easier to use, help eliminate digit bias, and minimize observer variation, but they typically read approximately 6 to 9 mm Hg higher than auscultation.²³ For any BP measurement obtained by oscillometry that is >90th percentile, repeat the measurement by auscultation at least twice during the same office visit, and use an average of the repeated measurements.¹² Obtain measurements of a lower extremity when you suspect congenital heart disease (eg, aortic coarctation). For any patient in whom you confirm a BP measurement >95th percentile, repeat the measurement within 2 weeks; for BPs >99th percentile, reevaluation should occur within one week.

When the child is between cuff sizes, use the larger cuff because small cuffs overestimate BP readings.Ambulatory BP monitoring (ABPM). Because BP measurements have a circadian pattern (higher during the day and reduced by 10% during sleep²⁴) an ABPM device that provides 50 to 60 readings over 24 hours can be useful when evaluating children and adolescents for white-coat hypertension (elevated clinic BP with normal ambulatory BP), masked hypertension (normal clinic BP with elevated ambulatory BP), prehypertension and secondary hypertension (BP generally does not follow circadian patterns).²⁵ ABPM is more accurate than BP self-measurement, but usually is limited to children older than age 5

Steps to take for clinical evaluation

Start by conducting a thorough history and physical examination, looking for information that can help you select the most appropriate tests for the next phase of evaluation.^8,12 Calculate the patient’s BMI to screen for obesity, ask about a family history of hypertension or CVD, and determine if the patient is taking any medications that might cause hypertension, such as amphetamines, corticosteroids, or cyclosporine.⁸ Assess for signs and symptoms that suggest an underlying disease, such as renal disease (hematuria, edema, fatigue) or heart disease (chest pain, exertional dyspnea, palpitations).¹²

All children diagnosed with hypertension should be screened for secondary causes (TABLE 2). The recommended evaluation is to obtain a renal function panel, electrolytes, urinalysis, urine culture, complete blood count, renovascular imaging, and echocardiogram.¹² The most common etiologies for secondary hypertension are renal parenchymal disease (68%), renovascular abnormalities (10%), and endocrinopathies (10%).²⁶ Other causes, such as aortic coarctation, obstructive sleep apnea, iatrogenic factors (eg, toxins, medications, drugs of abuse), and genitourinary abnormalities, account for only a small percentage of cases and should be investigated as clinically indicated.²⁶

The most common etiology for secondary hypertension in children and adolescents is renal parenchymal disease.Renovascular assessment depends on facility expertise. Imaging options include renal ultrasound (with or without Doppler), computed tomography angiography, renal flow scan, and magnetic resonance angiography. These studies have similar sensitivities and specificities.²⁷ For patients in whom you strongly suspect renovascular disease, renal arteriography (digital subtraction angiography) provides the best images, although it is the most invasive study.²⁷

Refer children and adolescents who are found to have significant abnormalities during the initial evaluation to the appropriate specialist. BP measurements often improve when secondary causes are treated.

Which drugs for which patients?

Pharmacologic management is indicated for pediatric patients with stage 1 or stage 2 hypertension, secondary hypertension, and those with evidence of target-organ damage.¹² The goal of therapy is to reduce BP to <95th percentile. In patients with target organ damage, renal disease, or diabetes mellitus, the goal is <90th percentile.^12,15,28 Intensive management of BP (≤50th percentile) in children with chronic kidney disease has been shown to delay progression to renal failure,²⁹ but it is uncertain if lower BP goals can slow or prevent additional subclinical target organ damage. In patients with target-organ damage, renal disease, or diabetes, the goal of therapy is to reduce BP to <90th percentile.

Pharmacotherapy for hypertensive children or adolescents can be challenging because recommendations of which medication to use are based upon expert opinion and extrapolation from randomized trials of adults. The length of therapy (often lifelong), potential adverse effects, and unproven direct mortality benefit complicate this decision. Medication choice usually is based on physician preference or experience.¹² The most common antihypertensive drugs prescribed are angiotensin-converting enzyme (ACE) inhibitors (26%), followed by diuretics (20%), and beta-blockers (17%).^30,31 The starting doses and other details of medications commonly used to treat pediatric hypertension are listed in TABLE 3.^28,32-34

ARBs may be a more effective option than ACE inhibitors for African American children and adolescents.One approach to choosing an antihypertensive drug for children is to measure the patient’s ambulatory plasma renin activity (PRA) level before initiating therapy. Those with high PRA levels (>0.65 ng/mL/h), presumably due to peripheral vasoconstriction, may benefit more from ACE inhibitors, angiotensin receptor blockers (ARBs), or beta-adrenergic antagonists.³⁵ Individuals with low PRA levels (<0.65 ng/mL/h) maintain higher volume/sodium excess and may benefit more from diuretics or calcium channel blockers.³⁵

Ethnicity also may guide medication selection. African American adults do not respond well to ACE inhibitor monotherapy due to decreased PRA and increased salt hypersensitivity.³⁶ One meta-analysis found that African American children and adolescents had inadequate BP response to 6 individual ACE inhibitors, even at higher doses compared with white children and those of other ethnicities, who showed significant improvement in BP.³⁷ ARBs may be a more effective alternative for this population.

Most experts recommend initiating a single agent at a low dose.¹² A systematic review found that except for African American children, pediatric patients experienced comparable reductions in BP with ACE inhibitors (10.7/8.1 mm Hg), ARBs (10.5/6.9 mm Hg), and calcium channel blockers (9.3/7.2 mm Hg).³⁸ In addition, ACE inhibitors and ARBs significantly reduced proteinuria by 49% and 59%, respectively.³⁸

Schedule follow-up visits for 2 to 4 weeks (or sooner for patients with stage 2 Patients with prehypertension and stage 1 hypertension without target-organ damage generally can participate in competitive sports.hypertension) after initiating pharmacotherapy. If BP response is suboptimal, consider increasing the dose before adding a second agent. If the patient experiences significant adverse effects or has an inadequate BP response, changing to a drug from a different class is recommended.³⁹ Patients who do not adequately respond to these approaches may require combination therapy; in such cases, strongly consider consultation with pediatric nephrologist or cardiologist.³⁹ Medication compliance should be verified (eg, by pill counting, parental supervision) in patients who do not respond to therapy. Once BP control has been achieved, visits every 3 to 4 months are appropriate, with periodic laboratory monitoring, especially for children taking diuretics, ACE inhibitors, or ARBs or who have underlying renal disease.

Recommend exercise, but carefully monitor athlete's BP

Though the benefits of reducing sodium intake are small, doing so can be one of several lifestyles modifications to reduce BP in young patients.Encourage obese and overweight children and adolescents to lose weight to maintain a BMI <95th percentile. Current guidelines based on expert opinion recommend that children and adolescents should engage in 60 minutes of daily physical activity.¹² A meta-analysis found physical activity led to a 1% and 3% reduction in systolic and diastolic BP, respectively, although these results were not statistically significant.⁴⁰

Be aware, however, that children and adolescents with hypertension who engage in certain competitive sports can significantly increase their BP and may be at risk for complications.⁴¹ According to the AAP guidelines, patients with stage 2 hypertension should not engage in high-static sports (eg, gymnastics, weightlifting, wrestling, boxing, cycling, decathlon, triathlon) until BP is well controlled.⁴¹ Patients with target-organ damage, uncontrolled hypertension, or symptomatic hypertension should not participate until BP is well controlled. Patients with prehypertension and stage 1 hypertension without target-organ damage are eligible to participate in competitive athletics. Reassess BP every 6 months in patients who are prehypertensive and every one to 2 weeks for those with stage 1 hypertension. When the patient’s BP remains <90th percentile, routine surveillance every 3 to 6 months is recommended.

What about sodium? Encourage parents of pediatric patients with hypertension to limit their child’s salt intake to 1.2 g/d for those age 4 to 8 and 1.5 g/d for older children.⁴² A meta-analysis found salt reduction decreased systolic BP by 1.2 mm Hg and diastolic BP by 1.3 mm Hg.⁴³ Though these benefits are small, reducing sodium intake can be one of several lifestyle modifications, such as increased activity and quitting smoking, that can reduce young patients’ risk of hypertension and related cardiovascular sequelae.

CORRESPONDENCE
Robert Gauer, MD, Womack Army Medical Center, 2817 Reilly Road, Fort Bragg NC 28310; [email protected]

Childhood hypertension is on the rise: Recent data from the National Health and Nutrition Survey suggest 10% of children and adolescents have prehypertension and 4% have hypertension.^1-4 Unfortunately, the condition often is missed. In a study of 14,187 children and adolescents who had at least 3 well-child visits at an outpatient academic medical center, 507 patients met the criteria for hypertension, yet only 131 (26%) had this diagnosis documented in their electronic health record.⁵

In a survey of 89 pediatricians, >50% of respondents said they were not familiar with the most current published recommendations for diagnosing and treating pediatric hypertension.⁶ Respondents also indicated that the most common reason for not initiating pharmacotherapy for children with hypertension was a lack of familiarity with appropriate antihypertensive agents (54%), followed by concern for adverse medication effects. Delayed diagnosis, evaluation, and treatment of hypertension in young patients can increase the likelihood of serious consequences, including target-organ damage such as left ventricular hypertrophy (LVH). In this review, we’ll describe the factors that put children and adolescents at risk for hypertension, and offer an evidence-based approach to diagnosis and treatment.

Obesity is a key risk factor

An estimated 17% of children aged 2 to 19 are obese.⁷ Obesity increases a child’s risk for hypertension by approximately 3- to 5-fold, and body mass index (BMI) is greater in children with primary hypertension compared with those with secondary hypertension.⁸ Hypertension is more common among Hispanic and non-Hispanic black male children and adolescents compared with their white counterparts; these ethnic disparities are not found in females.^9,10 Poor diets and physical inactivity further contribute to obesity and hypertension risk. Children who were born preterm or had a very low birth weight also are at increased risk.¹¹

Unchecked hypertension can lead to cardiac, vascular damage

Some children and adolescents with undiagnosed and untreated hypertension have evidence of target-organ damage, including cardiac dysfunction and pathologic vascular abnormalities. LVH is present in 20% to 41% of children and adolescents with hypertension.^12,13 Carotid intima-media thickness, an established surrogate marker for atherosclerosis, is abnormally increased in children with hypertension, even after adjusting for BMI.¹⁴ Other target organ effects include impaired cognitive function, reduced glomerular filtration rate, microalbuminuria, and retinal arteriolar narrowing.^15-17

Normal BP standards for children and adolescents are based on gender, age, and height percentile.Pediatric hypertension may persist into adulthood. A meta-analysis of more than 50 studies found that elevated blood pressure (BP) in childhood increases the risk for hypertension as an adult.¹⁸

NHLBI recommendations call for a BP check at every visit

The National Heart, Lung, and Blood Institute (NHLBI) Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents (“the 4th Report”) recommends measuring BP in all children over age 3 during every health care visit.¹² Children under age 3 should have their BP checked in certain circumstances, including preterm delivery, congenital heart disease, recurrent urinary tract infections, renal/urologic disease, organ transplantation, malignancy, and systemic illnesses associated with hypertension.¹² The 4th Report is endorsed by the American Academy of Pediatrics (AAP); however, the American Academy of Family Physicians and the US Preventive Services Task Force have concluded that the evidence is insufficient to recommend for or against routine screening for hypertension in children and adolescents to reduce the risk of cardiovascular disease (CVD).^19,20

Does the child have hypertension? That depends on several factors

Determining whether a child has hypertension requires that you consult national BP standards to determine if he or she is within the normal range. Normal BP standards for children and adolescents are based on gender, age, and height percentile, and provide a precise classification based on body size.¹² These tables are available from the NHLBI Web site at http://www.nhlbi.nih.gov/guidelines/hypertension/child_tbl.htm. Height percentiles in these tables correspond with the Centers for Disease Control and Prevention (CDC) growth charts published in 2000.²¹ The Baylor College of Medicine Children’s Nutrition Research Center has a web-based calculator to help physicians determine BP percentiles in children and adolescents; it is available at http://www.bcm.edu/bodycomplab/Flashapps/BPVAgeChartpage.html. The International Pediatric Hypertension Association also offers BP charts and calculators at http://www.iphapediatrichypertension.org.

The diagnostic parameters for pediatric hypertension are listed in TABLE 1.¹² The higher systolic or diastolic BP percentile value is used to determine a child’s overall BP category. A child is considered normotensive if the BP is <90th percentile. Hypertension is an average systolic or diastolic BP that is ≥95th percentile on at least 3 separate occasions. Stage 1 hypertension is BP levels ranging from the 95th percentile to 5 mm Hg above the 99th percentile, and stage 2 hypertension is BP levels greater than 5 mm Hg above the 99th percentile.

For example, assume you are evaluating a 12-year-old boy who is 61 inches tall and has a BP of 129/87 mm Hg. According to the CDC growth charts, his height puts him in the 75th percentile for his age. Using the NHLBI chart, you determine that he falls in the 95th-99th percentile for BP, and thus, using the categories in TABLE 1, is given a diagnosis of Stage 1 hypertension.

Accurate BP measurement requires using an appropriate cuff size that covers 80% of the child’s upper arm. When the child is between cuff sizes, use the larger cuff because small cuffs overestimate BP readings. BP readings should be taken on the right arm with the arm supported at heart level after the child has been sitting quietly for at least 5 minutes.¹² One study showed that the initial BP readings taken in the triage area were significantly higher—often by >10 mm Hg—compared with follow-up measurements in the examination room.²²

The preferred method of BP measurement is auscultation; however, oscillometric devices also are acceptable. These devices are easier to use, help eliminate digit bias, and minimize observer variation, but they typically read approximately 6 to 9 mm Hg higher than auscultation.²³ For any BP measurement obtained by oscillometry that is >90th percentile, repeat the measurement by auscultation at least twice during the same office visit, and use an average of the repeated measurements.¹² Obtain measurements of a lower extremity when you suspect congenital heart disease (eg, aortic coarctation). For any patient in whom you confirm a BP measurement >95th percentile, repeat the measurement within 2 weeks; for BPs >99th percentile, reevaluation should occur within one week.

When the child is between cuff sizes, use the larger cuff because small cuffs overestimate BP readings.Ambulatory BP monitoring (ABPM). Because BP measurements have a circadian pattern (higher during the day and reduced by 10% during sleep²⁴) an ABPM device that provides 50 to 60 readings over 24 hours can be useful when evaluating children and adolescents for white-coat hypertension (elevated clinic BP with normal ambulatory BP), masked hypertension (normal clinic BP with elevated ambulatory BP), prehypertension and secondary hypertension (BP generally does not follow circadian patterns).²⁵ ABPM is more accurate than BP self-measurement, but usually is limited to children older than age 5

Steps to take for clinical evaluation

Start by conducting a thorough history and physical examination, looking for information that can help you select the most appropriate tests for the next phase of evaluation.^8,12 Calculate the patient’s BMI to screen for obesity, ask about a family history of hypertension or CVD, and determine if the patient is taking any medications that might cause hypertension, such as amphetamines, corticosteroids, or cyclosporine.⁸ Assess for signs and symptoms that suggest an underlying disease, such as renal disease (hematuria, edema, fatigue) or heart disease (chest pain, exertional dyspnea, palpitations).¹²

All children diagnosed with hypertension should be screened for secondary causes (TABLE 2). The recommended evaluation is to obtain a renal function panel, electrolytes, urinalysis, urine culture, complete blood count, renovascular imaging, and echocardiogram.¹² The most common etiologies for secondary hypertension are renal parenchymal disease (68%), renovascular abnormalities (10%), and endocrinopathies (10%).²⁶ Other causes, such as aortic coarctation, obstructive sleep apnea, iatrogenic factors (eg, toxins, medications, drugs of abuse), and genitourinary abnormalities, account for only a small percentage of cases and should be investigated as clinically indicated.²⁶

The most common etiology for secondary hypertension in children and adolescents is renal parenchymal disease.Renovascular assessment depends on facility expertise. Imaging options include renal ultrasound (with or without Doppler), computed tomography angiography, renal flow scan, and magnetic resonance angiography. These studies have similar sensitivities and specificities.²⁷ For patients in whom you strongly suspect renovascular disease, renal arteriography (digital subtraction angiography) provides the best images, although it is the most invasive study.²⁷

Refer children and adolescents who are found to have significant abnormalities during the initial evaluation to the appropriate specialist. BP measurements often improve when secondary causes are treated.

Which drugs for which patients?

Pharmacologic management is indicated for pediatric patients with stage 1 or stage 2 hypertension, secondary hypertension, and those with evidence of target-organ damage.¹² The goal of therapy is to reduce BP to <95th percentile. In patients with target organ damage, renal disease, or diabetes mellitus, the goal is <90th percentile.^12,15,28 Intensive management of BP (≤50th percentile) in children with chronic kidney disease has been shown to delay progression to renal failure,²⁹ but it is uncertain if lower BP goals can slow or prevent additional subclinical target organ damage. In patients with target-organ damage, renal disease, or diabetes, the goal of therapy is to reduce BP to <90th percentile.

Pharmacotherapy for hypertensive children or adolescents can be challenging because recommendations of which medication to use are based upon expert opinion and extrapolation from randomized trials of adults. The length of therapy (often lifelong), potential adverse effects, and unproven direct mortality benefit complicate this decision. Medication choice usually is based on physician preference or experience.¹² The most common antihypertensive drugs prescribed are angiotensin-converting enzyme (ACE) inhibitors (26%), followed by diuretics (20%), and beta-blockers (17%).^30,31 The starting doses and other details of medications commonly used to treat pediatric hypertension are listed in TABLE 3.^28,32-34

ARBs may be a more effective option than ACE inhibitors for African American children and adolescents.One approach to choosing an antihypertensive drug for children is to measure the patient’s ambulatory plasma renin activity (PRA) level before initiating therapy. Those with high PRA levels (>0.65 ng/mL/h), presumably due to peripheral vasoconstriction, may benefit more from ACE inhibitors, angiotensin receptor blockers (ARBs), or beta-adrenergic antagonists.³⁵ Individuals with low PRA levels (<0.65 ng/mL/h) maintain higher volume/sodium excess and may benefit more from diuretics or calcium channel blockers.³⁵

Ethnicity also may guide medication selection. African American adults do not respond well to ACE inhibitor monotherapy due to decreased PRA and increased salt hypersensitivity.³⁶ One meta-analysis found that African American children and adolescents had inadequate BP response to 6 individual ACE inhibitors, even at higher doses compared with white children and those of other ethnicities, who showed significant improvement in BP.³⁷ ARBs may be a more effective alternative for this population.

Most experts recommend initiating a single agent at a low dose.¹² A systematic review found that except for African American children, pediatric patients experienced comparable reductions in BP with ACE inhibitors (10.7/8.1 mm Hg), ARBs (10.5/6.9 mm Hg), and calcium channel blockers (9.3/7.2 mm Hg).³⁸ In addition, ACE inhibitors and ARBs significantly reduced proteinuria by 49% and 59%, respectively.³⁸

Schedule follow-up visits for 2 to 4 weeks (or sooner for patients with stage 2 Patients with prehypertension and stage 1 hypertension without target-organ damage generally can participate in competitive sports.hypertension) after initiating pharmacotherapy. If BP response is suboptimal, consider increasing the dose before adding a second agent. If the patient experiences significant adverse effects or has an inadequate BP response, changing to a drug from a different class is recommended.³⁹ Patients who do not adequately respond to these approaches may require combination therapy; in such cases, strongly consider consultation with pediatric nephrologist or cardiologist.³⁹ Medication compliance should be verified (eg, by pill counting, parental supervision) in patients who do not respond to therapy. Once BP control has been achieved, visits every 3 to 4 months are appropriate, with periodic laboratory monitoring, especially for children taking diuretics, ACE inhibitors, or ARBs or who have underlying renal disease.

Recommend exercise, but carefully monitor athlete's BP

Though the benefits of reducing sodium intake are small, doing so can be one of several lifestyles modifications to reduce BP in young patients.Encourage obese and overweight children and adolescents to lose weight to maintain a BMI <95th percentile. Current guidelines based on expert opinion recommend that children and adolescents should engage in 60 minutes of daily physical activity.¹² A meta-analysis found physical activity led to a 1% and 3% reduction in systolic and diastolic BP, respectively, although these results were not statistically significant.⁴⁰

Be aware, however, that children and adolescents with hypertension who engage in certain competitive sports can significantly increase their BP and may be at risk for complications.⁴¹ According to the AAP guidelines, patients with stage 2 hypertension should not engage in high-static sports (eg, gymnastics, weightlifting, wrestling, boxing, cycling, decathlon, triathlon) until BP is well controlled.⁴¹ Patients with target-organ damage, uncontrolled hypertension, or symptomatic hypertension should not participate until BP is well controlled. Patients with prehypertension and stage 1 hypertension without target-organ damage are eligible to participate in competitive athletics. Reassess BP every 6 months in patients who are prehypertensive and every one to 2 weeks for those with stage 1 hypertension. When the patient’s BP remains <90th percentile, routine surveillance every 3 to 6 months is recommended.

What about sodium? Encourage parents of pediatric patients with hypertension to limit their child’s salt intake to 1.2 g/d for those age 4 to 8 and 1.5 g/d for older children.⁴² A meta-analysis found salt reduction decreased systolic BP by 1.2 mm Hg and diastolic BP by 1.3 mm Hg.⁴³ Though these benefits are small, reducing sodium intake can be one of several lifestyle modifications, such as increased activity and quitting smoking, that can reduce young patients’ risk of hypertension and related cardiovascular sequelae.

CORRESPONDENCE
Robert Gauer, MD, Womack Army Medical Center, 2817 Reilly Road, Fort Bragg NC 28310; [email protected]

Childhood hypertension is on the rise: Recent data from the National Health and Nutrition Survey suggest 10% of children and adolescents have prehypertension and 4% have hypertension.^1-4 Unfortunately, the condition often is missed. In a study of 14,187 children and adolescents who had at least 3 well-child visits at an outpatient academic medical center, 507 patients met the criteria for hypertension, yet only 131 (26%) had this diagnosis documented in their electronic health record.⁵

In a survey of 89 pediatricians, >50% of respondents said they were not familiar with the most current published recommendations for diagnosing and treating pediatric hypertension.⁶ Respondents also indicated that the most common reason for not initiating pharmacotherapy for children with hypertension was a lack of familiarity with appropriate antihypertensive agents (54%), followed by concern for adverse medication effects. Delayed diagnosis, evaluation, and treatment of hypertension in young patients can increase the likelihood of serious consequences, including target-organ damage such as left ventricular hypertrophy (LVH). In this review, we’ll describe the factors that put children and adolescents at risk for hypertension, and offer an evidence-based approach to diagnosis and treatment.

Obesity is a key risk factor

An estimated 17% of children aged 2 to 19 are obese.⁷ Obesity increases a child’s risk for hypertension by approximately 3- to 5-fold, and body mass index (BMI) is greater in children with primary hypertension compared with those with secondary hypertension.⁸ Hypertension is more common among Hispanic and non-Hispanic black male children and adolescents compared with their white counterparts; these ethnic disparities are not found in females.^9,10 Poor diets and physical inactivity further contribute to obesity and hypertension risk. Children who were born preterm or had a very low birth weight also are at increased risk.¹¹

Unchecked hypertension can lead to cardiac, vascular damage

Some children and adolescents with undiagnosed and untreated hypertension have evidence of target-organ damage, including cardiac dysfunction and pathologic vascular abnormalities. LVH is present in 20% to 41% of children and adolescents with hypertension.^12,13 Carotid intima-media thickness, an established surrogate marker for atherosclerosis, is abnormally increased in children with hypertension, even after adjusting for BMI.¹⁴ Other target organ effects include impaired cognitive function, reduced glomerular filtration rate, microalbuminuria, and retinal arteriolar narrowing.^15-17

Normal BP standards for children and adolescents are based on gender, age, and height percentile.Pediatric hypertension may persist into adulthood. A meta-analysis of more than 50 studies found that elevated blood pressure (BP) in childhood increases the risk for hypertension as an adult.¹⁸

NHLBI recommendations call for a BP check at every visit

The National Heart, Lung, and Blood Institute (NHLBI) Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents (“the 4th Report”) recommends measuring BP in all children over age 3 during every health care visit.¹² Children under age 3 should have their BP checked in certain circumstances, including preterm delivery, congenital heart disease, recurrent urinary tract infections, renal/urologic disease, organ transplantation, malignancy, and systemic illnesses associated with hypertension.¹² The 4th Report is endorsed by the American Academy of Pediatrics (AAP); however, the American Academy of Family Physicians and the US Preventive Services Task Force have concluded that the evidence is insufficient to recommend for or against routine screening for hypertension in children and adolescents to reduce the risk of cardiovascular disease (CVD).^19,20

Does the child have hypertension? That depends on several factors

Determining whether a child has hypertension requires that you consult national BP standards to determine if he or she is within the normal range. Normal BP standards for children and adolescents are based on gender, age, and height percentile, and provide a precise classification based on body size.¹² These tables are available from the NHLBI Web site at http://www.nhlbi.nih.gov/guidelines/hypertension/child_tbl.htm. Height percentiles in these tables correspond with the Centers for Disease Control and Prevention (CDC) growth charts published in 2000.²¹ The Baylor College of Medicine Children’s Nutrition Research Center has a web-based calculator to help physicians determine BP percentiles in children and adolescents; it is available at http://www.bcm.edu/bodycomplab/Flashapps/BPVAgeChartpage.html. The International Pediatric Hypertension Association also offers BP charts and calculators at http://www.iphapediatrichypertension.org.

The diagnostic parameters for pediatric hypertension are listed in TABLE 1.¹² The higher systolic or diastolic BP percentile value is used to determine a child’s overall BP category. A child is considered normotensive if the BP is <90th percentile. Hypertension is an average systolic or diastolic BP that is ≥95th percentile on at least 3 separate occasions. Stage 1 hypertension is BP levels ranging from the 95th percentile to 5 mm Hg above the 99th percentile, and stage 2 hypertension is BP levels greater than 5 mm Hg above the 99th percentile.

For example, assume you are evaluating a 12-year-old boy who is 61 inches tall and has a BP of 129/87 mm Hg. According to the CDC growth charts, his height puts him in the 75th percentile for his age. Using the NHLBI chart, you determine that he falls in the 95th-99th percentile for BP, and thus, using the categories in TABLE 1, is given a diagnosis of Stage 1 hypertension.

Accurate BP measurement requires using an appropriate cuff size that covers 80% of the child’s upper arm. When the child is between cuff sizes, use the larger cuff because small cuffs overestimate BP readings. BP readings should be taken on the right arm with the arm supported at heart level after the child has been sitting quietly for at least 5 minutes.¹² One study showed that the initial BP readings taken in the triage area were significantly higher—often by >10 mm Hg—compared with follow-up measurements in the examination room.²²

The preferred method of BP measurement is auscultation; however, oscillometric devices also are acceptable. These devices are easier to use, help eliminate digit bias, and minimize observer variation, but they typically read approximately 6 to 9 mm Hg higher than auscultation.²³ For any BP measurement obtained by oscillometry that is >90th percentile, repeat the measurement by auscultation at least twice during the same office visit, and use an average of the repeated measurements.¹² Obtain measurements of a lower extremity when you suspect congenital heart disease (eg, aortic coarctation). For any patient in whom you confirm a BP measurement >95th percentile, repeat the measurement within 2 weeks; for BPs >99th percentile, reevaluation should occur within one week.

When the child is between cuff sizes, use the larger cuff because small cuffs overestimate BP readings.Ambulatory BP monitoring (ABPM). Because BP measurements have a circadian pattern (higher during the day and reduced by 10% during sleep²⁴) an ABPM device that provides 50 to 60 readings over 24 hours can be useful when evaluating children and adolescents for white-coat hypertension (elevated clinic BP with normal ambulatory BP), masked hypertension (normal clinic BP with elevated ambulatory BP), prehypertension and secondary hypertension (BP generally does not follow circadian patterns).²⁵ ABPM is more accurate than BP self-measurement, but usually is limited to children older than age 5

Steps to take for clinical evaluation

Start by conducting a thorough history and physical examination, looking for information that can help you select the most appropriate tests for the next phase of evaluation.^8,12 Calculate the patient’s BMI to screen for obesity, ask about a family history of hypertension or CVD, and determine if the patient is taking any medications that might cause hypertension, such as amphetamines, corticosteroids, or cyclosporine.⁸ Assess for signs and symptoms that suggest an underlying disease, such as renal disease (hematuria, edema, fatigue) or heart disease (chest pain, exertional dyspnea, palpitations).¹²

All children diagnosed with hypertension should be screened for secondary causes (TABLE 2). The recommended evaluation is to obtain a renal function panel, electrolytes, urinalysis, urine culture, complete blood count, renovascular imaging, and echocardiogram.¹² The most common etiologies for secondary hypertension are renal parenchymal disease (68%), renovascular abnormalities (10%), and endocrinopathies (10%).²⁶ Other causes, such as aortic coarctation, obstructive sleep apnea, iatrogenic factors (eg, toxins, medications, drugs of abuse), and genitourinary abnormalities, account for only a small percentage of cases and should be investigated as clinically indicated.²⁶

The most common etiology for secondary hypertension in children and adolescents is renal parenchymal disease.Renovascular assessment depends on facility expertise. Imaging options include renal ultrasound (with or without Doppler), computed tomography angiography, renal flow scan, and magnetic resonance angiography. These studies have similar sensitivities and specificities.²⁷ For patients in whom you strongly suspect renovascular disease, renal arteriography (digital subtraction angiography) provides the best images, although it is the most invasive study.²⁷

Refer children and adolescents who are found to have significant abnormalities during the initial evaluation to the appropriate specialist. BP measurements often improve when secondary causes are treated.

Which drugs for which patients?

Pharmacologic management is indicated for pediatric patients with stage 1 or stage 2 hypertension, secondary hypertension, and those with evidence of target-organ damage.¹² The goal of therapy is to reduce BP to <95th percentile. In patients with target organ damage, renal disease, or diabetes mellitus, the goal is <90th percentile.^12,15,28 Intensive management of BP (≤50th percentile) in children with chronic kidney disease has been shown to delay progression to renal failure,²⁹ but it is uncertain if lower BP goals can slow or prevent additional subclinical target organ damage. In patients with target-organ damage, renal disease, or diabetes, the goal of therapy is to reduce BP to <90th percentile.

Pharmacotherapy for hypertensive children or adolescents can be challenging because recommendations of which medication to use are based upon expert opinion and extrapolation from randomized trials of adults. The length of therapy (often lifelong), potential adverse effects, and unproven direct mortality benefit complicate this decision. Medication choice usually is based on physician preference or experience.¹² The most common antihypertensive drugs prescribed are angiotensin-converting enzyme (ACE) inhibitors (26%), followed by diuretics (20%), and beta-blockers (17%).^30,31 The starting doses and other details of medications commonly used to treat pediatric hypertension are listed in TABLE 3.^28,32-34

ARBs may be a more effective option than ACE inhibitors for African American children and adolescents.One approach to choosing an antihypertensive drug for children is to measure the patient’s ambulatory plasma renin activity (PRA) level before initiating therapy. Those with high PRA levels (>0.65 ng/mL/h), presumably due to peripheral vasoconstriction, may benefit more from ACE inhibitors, angiotensin receptor blockers (ARBs), or beta-adrenergic antagonists.³⁵ Individuals with low PRA levels (<0.65 ng/mL/h) maintain higher volume/sodium excess and may benefit more from diuretics or calcium channel blockers.³⁵

Ethnicity also may guide medication selection. African American adults do not respond well to ACE inhibitor monotherapy due to decreased PRA and increased salt hypersensitivity.³⁶ One meta-analysis found that African American children and adolescents had inadequate BP response to 6 individual ACE inhibitors, even at higher doses compared with white children and those of other ethnicities, who showed significant improvement in BP.³⁷ ARBs may be a more effective alternative for this population.

Most experts recommend initiating a single agent at a low dose.¹² A systematic review found that except for African American children, pediatric patients experienced comparable reductions in BP with ACE inhibitors (10.7/8.1 mm Hg), ARBs (10.5/6.9 mm Hg), and calcium channel blockers (9.3/7.2 mm Hg).³⁸ In addition, ACE inhibitors and ARBs significantly reduced proteinuria by 49% and 59%, respectively.³⁸

Schedule follow-up visits for 2 to 4 weeks (or sooner for patients with stage 2 Patients with prehypertension and stage 1 hypertension without target-organ damage generally can participate in competitive sports.hypertension) after initiating pharmacotherapy. If BP response is suboptimal, consider increasing the dose before adding a second agent. If the patient experiences significant adverse effects or has an inadequate BP response, changing to a drug from a different class is recommended.³⁹ Patients who do not adequately respond to these approaches may require combination therapy; in such cases, strongly consider consultation with pediatric nephrologist or cardiologist.³⁹ Medication compliance should be verified (eg, by pill counting, parental supervision) in patients who do not respond to therapy. Once BP control has been achieved, visits every 3 to 4 months are appropriate, with periodic laboratory monitoring, especially for children taking diuretics, ACE inhibitors, or ARBs or who have underlying renal disease.

Recommend exercise, but carefully monitor athlete's BP

Though the benefits of reducing sodium intake are small, doing so can be one of several lifestyles modifications to reduce BP in young patients.Encourage obese and overweight children and adolescents to lose weight to maintain a BMI <95th percentile. Current guidelines based on expert opinion recommend that children and adolescents should engage in 60 minutes of daily physical activity.¹² A meta-analysis found physical activity led to a 1% and 3% reduction in systolic and diastolic BP, respectively, although these results were not statistically significant.⁴⁰

Be aware, however, that children and adolescents with hypertension who engage in certain competitive sports can significantly increase their BP and may be at risk for complications.⁴¹ According to the AAP guidelines, patients with stage 2 hypertension should not engage in high-static sports (eg, gymnastics, weightlifting, wrestling, boxing, cycling, decathlon, triathlon) until BP is well controlled.⁴¹ Patients with target-organ damage, uncontrolled hypertension, or symptomatic hypertension should not participate until BP is well controlled. Patients with prehypertension and stage 1 hypertension without target-organ damage are eligible to participate in competitive athletics. Reassess BP every 6 months in patients who are prehypertensive and every one to 2 weeks for those with stage 1 hypertension. When the patient’s BP remains <90th percentile, routine surveillance every 3 to 6 months is recommended.

What about sodium? Encourage parents of pediatric patients with hypertension to limit their child’s salt intake to 1.2 g/d for those age 4 to 8 and 1.5 g/d for older children.⁴² A meta-analysis found salt reduction decreased systolic BP by 1.2 mm Hg and diastolic BP by 1.3 mm Hg.⁴³ Though these benefits are small, reducing sodium intake can be one of several lifestyle modifications, such as increased activity and quitting smoking, that can reduce young patients’ risk of hypertension and related cardiovascular sequelae.

CORRESPONDENCE
Robert Gauer, MD, Womack Army Medical Center, 2817 Reilly Road, Fort Bragg NC 28310; [email protected]